TY - BOOK T1 - Stem Cell Repair and Regeneration A1 - Habib NA A1 - Levicar N A1 - Gordon M A1 - Jiao LR A1 - Fisk N ED - Habib NA Levicar N Gordon MY Jiao LR Fisk N Y1 - 2007/// PB - Imperial College CY - London N2 - - ER - TY - BOOK T1 - Patient safety A1 - Vincent, C Y1 - 2006/// VL - 1st PB - Elsevier N2 - - ER - TY - BOOK T1 - Phosphoinositide 3-Kinase Signalling Pathway: The Key to Cell Proliferation and Death A1 - Eric W-F Lam ED - Eric W-F Lam Y1 - 2006/// VL - 1 PB - World Scientific Press CY - Singapore N2 - - ER - TY - BOOK T1 - 4. Stem Cell Repair and Regeneration A1 - Habib NA ED - Habib N; Gordon M; Levicar N; Jiao L; Thomas-Black G Y1 - 2005/// PB - Imperial College Press N2 - - ER - TY - BOOK T1 - Haemopoietic Stem Cell Transplantation A1 - Apperley JF ED - Apperley JF; Carreras E; Gluckman E; Gratwohl A; Masszi T Y1 - 2004/05// PB - European School of Hematology N2 - - ER - TY - BOOK T1 - Prostate Cancer. Clinical and Scientific Aspects - Bridging the Gap. A1 - Abel PD ED - Abel PD; Lalani E-N Y1 - 2003/// PB - Imperial College Press CY - 57 Shelton Street, LONDON, WC2H 9HE SN - 1-86094-327-6 SP - 1 EP - 1237 N2 - - ER - TY - BOOK T1 - Treatment Options in Urological Cancer A1 - Waxman J Y1 - 2002/// SN - 0-6320-5589-8 N2 - - ER - TY - BOOK T1 - Genetics of Apoptosis A1 - Grimm SW ED - Grimm S Y1 - 2002/// PB - BIOS Scientific Publishers CY - Oxford UK N2 - - ER - TY - BOOK T1 - Evaluation of certain veterinary drug residues in food: 58th Report of the Joint FAO/WHO Expert Committee on Food A1 - Anadon A A1 - Arnold D A1 - Boisseau J A1 - Boobis AR A1 - Ellis R A1 - Greenlees K A1 - McLean JG A1 - MacNeil J A1 - Rojas Martinez JL A1 - Miterna ES A1 - Palerm-Neta J A1 - Soback S A1 - Stephany RW Y1 - 2002/// SN - 9-2412-0911-9 N2 - - ER - TY - BOOK T1 - The Prostate Cancer Book A1 - Waxman J Y1 - 2002/// SN - 0-0918-5712-0 N2 - - ER - TY - BOOK T1 - Toxicological evaluation of certain veterinary drug residues in food A1 - Anadon A A1 - Arnold D A1 - Boisseau J A1 - Boobis AR A1 - Ellis R A1 - Greenlees K A1 - McLean JG A1 - MacNeil J A1 - Rojas Martinez JL A1 - Miterna ES A1 - Palerm-Neta J A1 - Soback S A1 - Stephany RW Y1 - 2002/// SN - 9-2416-6049-x N2 - - ER - TY - BOOK T1 - Pesticide Residues in Food:2001: toxicological evaluations A1 - Boobis AR A1 - Chen BH A1 - Moretto A A1 - Priestly BG A1 - Banasiak U A1 - Dutra Caldas E A1 - Funk S A1 - Hamilton DJ A1 - Ossendorp BC Y1 - 2002/// SN - 9-2416-6517-3 N2 - - ER - TY - BOOK T1 - Multi-treatment Modalities of Liver Tumours A1 - Habib NA ED - Habib NA Y1 - 2002/// PB - Kluwer Academic / Plenum Publishers CY - New York, USA SN - 0-3064-6746-1 N2 - - ER - TY - BOOK T1 - Evaluation of certain veterinary drug residues in food: fifty-fourth report of the Joint FAO/WHO expert Committee on Food Additives A1 - Anadon A A1 - Appelgren L A1 - Arnold D A1 - Boisseau J A1 - Boobis AR A1 - Kinabo LDB A1 - McLean JG A1 - MacNeil JD A1 - Miller MA A1 - Palermo-Neto J A1 - Rojas Martinez JL A1 - Soback S A1 - Stephany RW Y1 - 2001/// SN - 9-2412-0900-3 N2 - - ER - TY - BOOK T1 - Pesticides Residues in Food - 2000: toxicological evaluations A1 - Banasiak U A1 - Calumpang SMF A1 - Boobis AR A1 - Borzelleca JF A1 - Caldas ED A1 - Fenner-Crisp P A1 - Funk S A1 - Hajslova J A1 - Hakansson H A1 - Hamilton DJ A1 - Moretto A A1 - Ogura A A1 - Ossendorp BC A1 - Priestly BG A1 - Soliman SA Y1 - 2001/// SN - 9-2416-6516-5 N2 - - ER - TY - BOOK T1 - Pesticides Residues in Food - 2000 A1 - Banasiak U A1 - Boobis AR A1 - Borzelleca JF A1 - Caldas ED A1 - Calumpang SMF A1 - Fenner-Crisp P A1 - Funk S A1 - Hakansson H A1 - Hajslova J A1 - Hamilton DJ A1 - Moretto A A1 - Ogura A A1 - Ossendorp BC A1 - Priestly BG A1 - Soliman SA Y1 - 2001/// SN - 9-2510-4547-X N2 - - ER - TY - BOOK T1 - Pesticide Residues in Food - 2001 A1 - Banasiak U A1 - Boobis AR A1 - Caldas ED A1 - Chen B A1 - Funk S A1 - Hamilton DJ A1 - Moretto A A1 - Ossendorp BC A1 - Priestly BG Y1 - 2001/// SN - 9-2510-4662-X N2 - - ER - TY - BOOK T1 - Safety in Medicine A1 - Vincent CA ED - Vincent CA; de Mol B Y1 - 2000/// PB - Elsevier N2 - - ER - TY - CHAP T1 - Indications for liver resection A1 - Jiao LR A1 - Habib NA A1 - Tracey J A1 - Healey A ED - Karaliotas, Broelsch, Habib T2 - Liver and Biliary surgery Y1 - 2007/// PB - Springer Wien NY SP - 357 EP - 362 N2 - - ER - TY - CHAP T1 - Portal Vein Embolisation A1 - Habib NA A1 - Jiao LR A1 - Canelo R A1 - Damrah O ED - Karaliotas, Broelsch, Habib T2 - Liver and Biliary Tract Surgery Y1 - 2007/// PB - Springer Wien NY SP - 381 EP - 393 N2 - - ER - TY - CHAP T1 - Patient safety and iatrogenesis A1 - Woloshynowych, M A1 - Vincent, C ED - S. Ayers, A. Baum, C. McManus, S. Newman, K. Wallston, J. Weinman & R. West T2 - Cambridge Handbook of Psychology, Health and Medicine Y1 - 2007/// VL - 2nd PB - Cambridge University Press CY - Cambridge UK SP - 472 EP - 477 N2 - - ER - TY - CHAP T1 - Three demensional computed tomography images reconstruction in liver surgery A1 - Jiao, LR A1 - Habib, NA A1 - Tait, P A1 - Zacharoulis A1 - Canelo R A1 - Damrah o ED - Karaliotas, Broelsch and Habib T2 - Liver and Biliary Tract Surgery Y1 - 2007/// PB - Spronger Wien New York SP - 333 EP - 338 N2 - - ER - TY - CHAP T1 - Small Bowel A1 - Jiao, LR A1 - Williamson, RCN ED - Kirk RM T2 - General Surgery Operation Y1 - 2007/// VL - 5th PB - Churchill Lingstone SP - 209 EP - 227 N2 - - ER - TY - CHAP T1 - Small Bowel & Open Biliary Surgery A1 - L R Jiao A1 - RCN Williamson ED - RM Kirk; MC Winslet T2 - Essential General Surgical Operations Y1 - 2007/// VL - 2nd PB - Churchhill Livingstone CY - London N2 - - ER - TY - CHAP T1 - Radiofrequency Assisted Liver Resection A1 - Jiao RL A1 - Habib NA ED - Fan J T2 - Liver Surgery Y1 - 2007/// CY - HK N2 - - ER - TY - CHAP T1 - The Use of SIRTEX in Inoperable Liver Tumours: A Surgeon's View A1 - Jiao LR A1 - Habib NA A1 - Zacharoulis D ED - Karaliotas, Broelsch, Habib T2 - Liver and Biliary Track Surgery Y1 - 2007/// PB - SpringeWien NY SP - 419 EP - 420 N2 - - ER - TY - CHAP T1 - Liver Resection and Stapling Devices A1 - Jiao LR A1 - Habib NA A1 - Tracey J A1 - Healey A ED - Karaliotas, Broelsch, Habib T2 - Liver and Biliary Tract Surgery Y1 - 2007/// PB - Springer Wien NY SP - 363 EP - 366 N2 - - ER - TY - CHAP T1 - Liver Resection Assisted with the Radiofrequency Technique A1 - Jiao LR A1 - Habib NA A1 - Tracey J A1 - Healey A ED - Karaliotas, Broelsch, Habib T2 - Liver and Biliary Tract Surgery Y1 - 2007/// SP - 367 EP - 372 N2 - - ER - TY - CHAP T1 - Open Biliary Operations A1 - Jiao, LR A1 - Williamson, RCN ED - Kirk RM T2 - General Surgical Operations Y1 - 2006/// VL - 5th PB - Churchill Lingstone SP - 285 EP - 303 N2 - - ER - TY - CHAP T1 - The ceramide/sphingosine 1-phosphate biostat in cancer and the role of sphingosine kinase-1 as a therapeutic target A1 - Cuvillier O A1 - Bonhoure E A1 - Dayon A A1 - Martin C A1 - Malavaud B A1 - Pchejetski D A1 - Rischmann P ED - Albi E T2 - Sphingolipids and cell function Y1 - 2006/// PB - Transworld Research Network, Trivandrum N2 - - ER - TY - CHAP T1 - Cell Proliferation and Cell Death A1 - Andrew Sunters A1 - Eric W-F Lam ED - Eric W-F Lam T2 - Phosphoinositide 3-Kinase Signalling Pathway: The Key to Cell Proliferation and Death Y1 - 2006/// VL - 1 PB - World Scientific Press N2 - - ER - TY - CHAP T1 - Phosphoinositide 3-Kinase Signalling Pathway A1 - Eric W-F Lam ED - Eric W-F Lam T2 - Phosphoinositide 3-Kinase Signalling Pathway: The Key to Cell Proliferation and Death Y1 - 2006/// PB - World Scientic Press N2 - - ER - TY - CHAP T1 - FOXO transcription factors A1 - Silvia Fernandez de Mattos, Jan J. Brosens and Eric W.-F. Lam ED - Eric W-F Lam T2 - Phosphoinositide 3-Kinase Signalling Pathway: The Key to Cell Proleration and Death Y1 - 2006/// PB - World Scientific Press CY - Singapore N2 - - ER - TY - CHAP T1 - Hypoxia Inducible Factor-1 and oxygen sensing. A1 - P. Maxwell. T2 - In Actualities Nephrologiques Jean Hamburger Hospital Necker 2006 Y1 - 2006/// SN - 2257108213 N2 - - ER - TY - CHAP T1 - Handbook “Disorders of iron homeostasis, erythrocytes, erythropoiesis A1 - Maxwell PH A1 - Pugh CW ED - Beaumont C. Beuzard Y. Beris P. & Brugnara C. T2 - Regulation of oxygen sensing and erythropoietin production. Y1 - 2006/// VL - First PB - European School of Haematology CY - Paris, France SP - 13 EP - 36 N2 - - ER - TY - CHAP T1 - Techniques used in the investigation and analysis of critical incidents in healthcare. A1 - Rogers S A1 - Taylor-Adams S A1 - Woloshynowych M ED - K. Walshe and R. Boaden T2 - Patient Safety: Research Into Practice Y1 - 2006/// PB - Open University Press SN - 0-335-21853-9 SP - 130 EP - 143 N2 - - ER - TY - CHAP T1 - Liver and biliary tree A1 - Habib N A1 - Canelo R ED - Henry MM; Thompson JN T2 - Clinical Surgery 2nd Edition Y1 - 2005/// PB - Elsevier Saunders CY - London, UK N2 - - ER - TY - CHAP T1 - Nuclear magnetic resonance spectroscopy of in the study of human liver. A1 - Lim AK A1 - Khan SA A1 - Cox IJ A1 - Taylor-Robinson SD ED - Tosi R, Tugnoli V T2 - Nuclear Magnetic Resonance Spectroscopy in the Study of Neoplastic Tissue. Y1 - 2005/// VL - 1 PB - Nova Science CY - Hauppauge, New York SN - 1-59454-258-9 SP - 295 EP - 311 N2 - - ER - TY - CHAP T1 - Hormones and Cancer A1 - Bevan CL ED - M. Knowles and P. Selby T2 - Introduction to the Molecular and Cellular Biology of Cancer (4th Edition) Y1 - 2005/// PB - Oxford University Press CY - Oxford N2 - - ER - TY - CHAP T1 - Hematopoietic culture systems A1 - Laleh Safinia A1 - Nicki Panoskaltsis A1 - Athanasios Mantalaris ED - Al-Rubeai M and Chaudhuri J T2 - Bioreactors for Tissue Engineering: Principles, Design and Operation Y1 - 2005/// PB - Kluwer Academic Publishers N2 - - ER - TY - CHAP T1 - Stem Cell Sources and Assays A1 - Mantalaris A A1 - Panoskaltsis N A1 - Wu JHD ED - Wnek, G. and Bowlin G. T2 - Encyclopaedia of Biomaterials and Bioengineering Y1 - 2004/// PB - Marcel Dekker Inc. CY - New York, U.S.A. N2 - - ER - TY - CHAP T1 - The von Hippel-Lindau Protein: a key player in oxygen homeostasis and matrix assembly. A1 - Esteban M A1 - Mandriota S A1 - Maxwell P ED - Matsuzawa Y, Kita T, Nagai R & Teramoto T. T2 - Atherosclerosis XIII. Y1 - 2004/// VL - First Edition SN - 0444514481 SP - 450 EP - 453 N2 - - ER - TY - CHAP T1 - Tissue Engineering of Bone Marrow A1 - Mantalaris A A1 - Panoskaltsis N A1 - Wu JHD ED - Wnek, G. and Bowlin, G. T2 - Encyclopaedia of Biomaterials and Bioengineering Y1 - 2004/// PB - Marcel Dekker Inc. CY - New York, U.S.A. N2 - - ER - TY - CHAP T1 - Tissue Engineering of Bone Marrow, Culture Systems A1 - Mantalaris A A1 - Panoskaltsis N A1 - Wu JHD ED - Wnek, G. and Bowlin, G. T2 - Encyclopaedia of Biomaterials and Bioengineering Y1 - 2004/// PB - Marcell Dekker Inc. CY - New York, U.S.A. N2 - - ER - TY - CHAP T1 - Psychological factors in measurement of pain A1 - Koutantji A1 - Pearce S ED - C. Bountra, R. Munglani T2 - Current understanding, emerging therapies, and novel approaches to drug discovery Y1 - 2003/05// PB - Marcel Dekker CY - NY USA N2 - - ER - TY - CHAP T1 - JAK/STAT signalling: a tale of jeeps and trains A1 - Costa-Pereira A.P. A1 - Strobl B. A1 - Lillemeier B.F. A1 - Is'harc H. A1 - Kerr I.M. ED - Sehgal P.B., Levy D.E. and Hirano T. T2 - Signalt transducers and activators of transcription (STATs): activation and biology Y1 - 2003/// VL - 1 PB - Kluwer Academic Publishers CY - London, UK. SN - 1-4020-1619-0 SP - 355 EP - 365 N2 - - ER - TY - CHAP T1 - The Endocrinology of Malignancy A1 - Agarwal R A1 - Waxman J T2 - Treatment of Cancer Y1 - 2002/// SN - 0-3407-5964-X SP - 143 EP - 151 N2 - - ER - TY - CHAP T1 - Hepatic arterial chemotherapy for colorectal liver metatases A1 - Mathur P A1 - Tsavellas G A1 - Allen-Mersh TG T2 - Multi-treatment modalities for liver tumours Y1 - 2002/// M2 - 2002 (20) SN - 0-3064-6746-1 SP - 247 EP - 258 N2 - - ER - TY - CHAP T1 - Chapter 19: “Cell Junctions, Cell Adhesion, and the Extracellular Matrix” in , 2002). Eds. . Garland Science ISBN: 0815340729. A1 - Robert Kypta (based on text in 3rd Edition) ED - Alberts, Johnson, Lewis, Raff, Roberts and Walter T2 - Molecular Biology of the Cell ( Y1 - 2002/// VL - Fourth Edition PB - Garland Science SN - 0815340729 SP - 1063 EP - 1125 N2 - - ER - TY - CHAP T1 - Hormone therapy of prostate cancer A1 - Agarwal R A1 - Waxman J T2 - Treatment options in urological cancer Y1 - 2002/// SN - 0-6320-5589-8 SP - 220 EP - 236 N2 - - ER - TY - CHAP T1 - Prostate A1 - Agarwal R A1 - Waxman J T2 - Treatment of Cancer 4th Edition Y1 - 2002/// SN - 0-3407-5964-X SP - 633 EP - 645 N2 - - ER - TY - CHAP T1 - Intra-operative radiofrequency heat ablation for hepatic tumours A1 - Havlik R A1 - Usatoff V A1 - Serracino-Inglott F A1 - Athanassiou M A1 - Serracino-Inglott K A1 - Abo-El-Nazar E A1 - Nicholls JP A1 - Habib NA ED - Nagy A Habib T2 - Multi-treatment Modalities of Liver Tumours Y1 - 2002/// PB - Kluwer Academic / Plenum Publishers CY - New York, USA SN - 0-3064-6746-1 SP - 167 EP - 177 N2 - - ER - TY - CHAP T1 - Gene therapy approaches for cancer A1 - McNeish I A1 - Seckl MJ T2 - Gene therapy Y1 - 2002/// SN - 0-8536-9455-9 SP - 87 EP - 134 N2 - - ER - TY - CHAP T1 - Gestational trophoblastic tumours A1 - Seckl MJ A1 - Paradinas FJ A1 - Newlands ES T2 - The Oxford book of oncology 2nd edition Y1 - 2002/// SN - 0-1926-2926-3 SP - 1896 EP - 1897 N2 - - ER - TY - CHAP T1 - Ovarian germ-cell tumours and other rare ovarian tumours A1 - Newlands ES A1 - Paradinas FJ A1 - Seckl MJ T2 - The Oxford textbook of oncology Y1 - 2002/// SN - 0-1926-2926-3 SP - 1809 EP - 1829 N2 - - ER - TY - CHAP T1 - Tumours of the prostate A1 - Horwich A A1 - Waxman J A1 - Abel P A1 - Laniado M A1 - Dearnaley P T2 - Oxford textbook of oncology 2nd edition Y1 - 2002/// SN - 0-1926-2926-3 SP - 1939 EP - 1972 N2 - - ER - TY - CHAP T1 - Update of laser induced thermotherapy for liver tumours A1 - Usatoff V A1 - Habib NA ED - Nagy A Habib T2 - Multi-treatment Modalities of Liver Tumours Y1 - 2002/// PB - Kluwer Academic / Plenum Publishers CY - New York, USA SN - 0-3064-6746-1 SP - 189 EP - 195 N2 - - ER - TY - CHAP T1 - Liver resection in advanced hepatocellular carcinoma A1 - Usatoff V A1 - Isla AM A1 - Habib NA ED - Nagy A Habib T2 - Multi-treatment Modalities of Liver Tumours Y1 - 2002/// PB - Kluwer Academic / Plenum Publishers CY - New York, USA SN - 0-3064-6746-1 SP - 11 EP - 19 N2 - - ER - TY - CHAP T1 - Tumor imaging applications in the testing of new drugs A1 - Aboagye EO A1 - Saleem A A1 - Price PM T2 - Anticancer drug development Y1 - 2002/// SN - 0-1207-2651-3 SP - 353 EP - 369 N2 - - ER - TY - CHAP T1 - Cell culture systems in apoptosis A1 - Grimm S ED - Grimm, S T2 - Genetics of Apoptosis Y1 - 2002/// PB - BIOS Scientific Publishers CY - Oxford, UK N2 - - ER - TY - CHAP T1 - The molecular biology of prostate cancer A1 - Wang J A1 - Waxman J T2 - Treatment Options in Urological Cancer Y1 - 2002/// SN - 0-6320-5589-8 SP - 141 EP - 159 N2 - - ER - TY - CHAP T1 - Liver resection for colorectal liver metastases: Results and prognostic factors A1 - Usatoff V A1 - Hansen P A1 - Al Musawi D A1 - Havlik R A1 - Dore C A1 - Wright A A1 - Habib NA ED - Nagy A Habib T2 - Multi-treatment Modalities of Liver Tumours Y1 - 2002/// PB - Kluwer Academic / Plenum Publishers CY - New York, USA SN - 0-3064-6746-1 SP - 33 EP - 41 N2 - - ER - TY - CHAP T1 - Caring for Patients Harmed by Treatment A1 - Vincent CA ED - Vincent, C.A. T2 - Clinical Risk Management (2nd Edition) Y1 - 2001/// PB - BMJ Publications N2 - - ER - TY - CHAP T1 - Interindividual variation of P450 enzymes in vitro and its causes A1 - Pelkonen O A1 - Boobis AR A1 - Kremers P Y1 - 2001/// M2 - 10 SN - 0-7484-0864-9 SP - 269 EP - 332 N2 - - ER - TY - CHAP T1 - The Investigation and Analysis of Serious Incidents A1 - Vincent CA A1 - Taylor-Adams S ED - Vincent, C.A. T2 - Clinical Risk Management (2nd Edition) Y1 - 2001/// PB - BMJ Publications N2 - - ER - TY - CHAP T1 - Polyoma virus middle T-antigen: growth factor receptor mimic A1 - Nicholson PR A1 - Dilworth SM Y1 - 2001/// SN - 0-4445-0496-6 SP - 85 EP - 128 N2 - - ER - TY - CHAP T1 - Liver and biliary tree A1 - Habib N A1 - Scott-Coombes D ED - MM Henry and JN Thompson T2 - Clinical Surgery Y1 - 2001/// PB - WB Saunders SN - 0-7020-1588-1 SP - 273 EP - 292 N2 - - ER - TY - CHAP T1 - Clinical Risk Management and the Analysis of Incidents A1 - Vincent CA A1 - Walshe K ED - Clements, R.V. T2 - Risk Management and Litigation in Obstetrics and Gynaecology Y1 - 2001/// PB - Royal Society of Medicine Press N2 - - ER - TY - CHAP T1 - Recruitment of p160 coactivators to androgen receptors A1 - Parker M A1 - Bevan C ED - B. Jegou, C. Pinau and J. Saez T2 - Testis, Epididymis and Technologies in the Year 2000 Y1 - 2000/// PB - Springer-Verlag CY - Berlin SP - 165 EP - 172 N2 - - ER - TY - CHAP T1 - Human Factors Approaches to the Analysis of Serious Incidents A1 - Taylor-Adams S A1 - Vincent CA ED - Vincent, C.A. and de Mol, B. T2 - Safety in Medicine Y1 - 2000/// PB - Elsevier N2 - - ER - TY - CHAP T1 - Metabolic alterations associated with apoptosis A1 - Costa-Pereira A.P. A1 - Cotter T.G. ED - Studinzski G. T2 - Apoptosis - a practical approach Y1 - 1999/// PB - Oxford University Press CY - Oxford, UK. N2 - - ER - TY - CHAP T1 - Fallibility, Uncertainty and the Impact of Mistakes and Litigation A1 - Vincent CA ED - fFirth-Cozens, J. and Payne, R. T2 - Stress in Health Professionals (3rd Edition) Y1 - 1999/// PB - Wiley N2 - - ER - TY - CHAP T1 - Human Factors Approaches to Medicine A1 - Vincent CA A1 - Reason JT ED - Rosenthal, M. and Mulcahy, L. T2 - Medical Mishaps: Pieces of the Puzzle Y1 - 1999/// PB - Open University Press N2 - - ER - TY - CHAP T1 - Detection of Molecular Events During Apoptosis By Flow Cytometry A1 - Carmody R.J. A1 - Costa-Pereira A.P. A1 - McKenna S.L. A1 - Cotter T.G. ED - Strehler B. T2 - Ageing: Methods and Protocols Y1 - 1999/// PB - The Humana Press Inc. CY - Totowa, USA N2 - - ER - TY - CHAP T1 - Medical Accidents and Risk Management A1 - Vincent CA ED - Thomas, L and McNeil, P. T2 - The Medical Accidents Handbook Y1 - 1998/// PB - Wiley N2 - - ER - TY - CONF T1 - HOX genes are a major target for epigenetic mis-regulation in adult and childhood leukaemia A1 - Strathdee, G A1 - Holyoake, TL A1 - Sim, A A1 - Parker, A A1 - Oscier, DG A1 - Melo, JV A1 - Meyer, S A1 - Eden, T A1 - Dickinson, AM A1 - Soutar, R A1 - Brown, R Y1 - 2007/04// Y2 - // VL - 137 SN - 0007-1048 SP - 81 EP - 81 N2 - - ER - TY - CONF T1 - Minimal residue disease (MRD) - art. no. P18 A1 - Zaidi, A A1 - Tripuraneni, G A1 - Weller, S A1 - Ward, B A1 - Sinnett, HD A1 - Coombes, RC A1 - Slade, MJ U1 - 7th Madrid Breat Cancer Conference Y1 - 2007/01// Y2 - // VL - 9 SP - P18 EP - P18 N2 - - ER - TY - CONF T1 - Tumor-specific correlation of tumor-type M2 pyruvate kinase (Tu M2-PK) in patients with cervical carcinoma. A1 - Kuemmel, S A1 - Jeschke, S A1 - Landt, S A1 - Korlach, S A1 - Schmid, P A1 - Sehouli, J A1 - Blohmer, J A1 - Ulm, K A1 - Lichtenegger, W A1 - Thomas, A U1 - 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Y1 - 2006/06/20/ Y2 - // VL - 24 SP - 266S EP - 266S N2 - - ER - TY - CONF T1 - Analysis of the VEGF family and their receptors in serum/plasma of patients with pre-invasive and invasive cervical cancer. A1 - Landt, S A1 - Thomas, A A1 - Fueger, A A1 - Jeschke, S A1 - Korlach, S A1 - Adam, H A1 - Ulm, K A1 - Schmid, P A1 - Blohmer, J A1 - Lichtenegger, W A1 - Kuemmel, S U1 - 42nd Annual Meeting of the American-Society-of-Clinical-Oncology Y1 - 2006/06/20/ Y2 - // VL - 24 SP - 259S EP - 259S N2 - - ER - TY - CONF T1 - Combined proteasome and histone deacetylase inhibition in breast cancer cell lines. A1 - Rosche, M A1 - Zavrski, I A1 - Schmid, P A1 - Kaiser, M A1 - Elsmer, E A1 - Possinger, K A1 - Sezer, O U1 - 29th Annual San Antonio Breast Cancer Symposium Y1 - 2006/01// Y2 - // VL - 100 SP - S71 EP - S71 N2 - - ER - TY - CONF T1 - Preliminary results from a phase 2 trial of AG-858, an autologous heat shock protein-peptide vaccine, in combination with imatinib in patients with chronic phase chronic myeloid leukemia (CML) resistant to prior imatinib monotherapy. A1 - Marin, D A1 - Mauro, M A1 - Goldman, J A1 - Druker, B A1 - Devine, S A1 - Clark, RE A1 - Paquette, R A1 - Bashey, A A1 - Tallman, MS A1 - Dovholuk, A A1 - Hoos, A A1 - Srivastava, P U1 - 47th Annual Meeting of the American-Society-of-Hematology Y1 - 2005/11/16/ Y2 - // VL - 106 SP - 318A EP - 319A N2 - - ER - TY - CONF T1 - Use of direct sequence PCR for ABI kinase mutations in patients with CML blast crisis, treated prior to the availability of imatinib therapy A1 - Ghorashian, S A1 - Babb, A A1 - Khorasan, J A1 - Kaeda, J A1 - Marin, D A1 - Apperley, L U1 - 47th Annual Meeting of the American-Society-of-Hematology Y1 - 2005/11/16/ Y2 - // VL - 106 SP - 567A EP - 567A N2 - - ER - TY - CONF T1 - Who profits most from a guideline based Treatment for advanced breast cancer? A1 - Dieing, A A1 - Possinger, K A1 - Schmid, P A1 - Regierer, AC A1 - Schulz, CO A1 - Wolters, R A1 - Wischnewsky, MB U1 - 28th Annual San Antonio Breast Cancer Symposium Y1 - 2005/01// Y2 - // VL - 94 SP - S281 EP - S282 N2 - - ER - TY - CONF T1 - Radiofrequency assisted hepatectomy A1 - Ayav, A A1 - Pellici, A A1 - Tierris, J A1 - Milicevic, M A1 - Nicholls, JP A1 - Harris, D A1 - Costa, I A1 - Jiao, LR A1 - Habib, NA U1 - 40th Congress of the European-Society-for-Surgical-Research Y1 - 2005/// Y2 - // SP - 25 EP - 26 N2 - - ER - TY - CONF T1 - Leuprorelinacetate 3 month-depot versus CMF as adjuvant treatment in receptor- and node-positive premenopausal patients with breast cancer: long term results of the TABLE-study A1 - Schmid, P A1 - Possinger, K A1 - Kassjanenko, I A1 - Vassiljev, L A1 - Meurer, J A1 - Tschaika, M A1 - Maubach, L A1 - Wallwiener, D A1 - Kahlert, S A1 - Untch, M U1 - 28th Annual San Antonio Breast Cancer Symposium Y1 - 2005/01// Y2 - // VL - 94 SP - S99 EP - S99 N2 - - ER - TY - CONF T1 - Using interleukin-6 and hypothalamus-pituitary-adrenal (HPA) axis function as potential diagnostic markers in the assessment of depression in patients with advanced breast cancer A1 - Jehn, CF A1 - Kuehnhardt, D A1 - Bartholomae, A A1 - Pfeiffer, S A1 - Schmid, P A1 - Possinger, K A1 - Flath, BC U1 - 28th Annual San Antonio Breast Cancer Symposium Y1 - 2005/01// Y2 - // VL - 94 SP - S276 EP - S277 N2 - - ER - TY - CONF T1 - Frequency of blast crisis after achieving complete cytogenetic remission in first chronic phase CML patients who recieved imatinib therapy within six months of diagnosis. A1 - Laurence, A A1 - Marin, D A1 - Clark, R A1 - Shepherd, P A1 - Mackinnon, S U1 - 46th Annual Meeting of the American-Society-of-Hematology Y1 - 2004/11/16/ Y2 - // VL - 104 SP - 292A EP - 292A N2 - - ER - TY - CONF T1 - 4D PET with the quad-HIDAC: Development of dynamic list-mode EM image reconstruction A1 - Walledge, RJ A1 - Reader, AJ A1 - Aboagye, EO A1 - Spinks, TJ A1 - Honer, M A1 - Missimer, J A1 - Jeavons, AP U1 - IEEE Nuclear Science Symposium/Medical Imaging Conference (NSS/MIC) Y1 - 2003/// Y2 - // SP - 1716 EP - 1720 N2 - - ER - TY - CONF T1 - Therapeutic strategies in primary AL amyloidosis A1 - Sezer, O A1 - Eucker, J A1 - Heider, U A1 - Schweigert, M A1 - Schmid, P A1 - Possinger, K U1 - 4th International Stem Cell Workshop on High-Dose Therapy and Transplantation of Haematopoietic Stem Cells Y1 - 2000/// Y2 - // SP - 21 EP - 26 N2 - - ER - TY - CONF T1 - Recruitment of p160 coactivators to androgen receptors A1 - Parker, M A1 - Bevan, C U1 - 11th European Workshop on Molecular and Cellular Endocrinology of the Testis Y1 - 2000/// Y2 - // SP - 165 EP - 172 N2 - - ER - TY - CONF T1 - High-dose chemotherapy in metastatic breast cancer A1 - Grosse, Y A1 - Schmid, P A1 - Possinger, K U1 - 4th International Stem Cell Workshop on High-Dose Therapy and Transplantation of Haematopoietic Stem Cells Y1 - 2000/// Y2 - // SP - 29 EP - 33 N2 - - ER - TY - CONF T1 - High-dose melphalan and stem cell rescue for AL amyloidosis A1 - Gillmore, JD A1 - Apperley, JF A1 - Craddock, C A1 - Madhoo, S A1 - Pepys, MB A1 - Hawkins, PN U1 - VIIIth International Symposium on Amyloidosis Y1 - 1999/// Y2 - // SP - 102 EP - 104 N2 - - ER - TY - CONF T1 - Immunoglobulin gene rearrangement in AL amyloidosis A1 - Abusedra, A A1 - Vulliamy, T A1 - Gilmore, JD A1 - Bybee, A A1 - Hawkins, PN A1 - Laffan, M A1 - Apperley, JF U1 - VIIIth International Symposium on Amyloidosis Y1 - 1999/// Y2 - // SP - 124 EP - 126 N2 - - ER - TY - CONF T1 - Neuropeptides, signal transduction and small cell lung cancer A1 - Seckl, MJ A1 - Rozengurt, E U1 - Workshop on Prevention and Early Detection of Lung Cancer Y1 - 1998/// Y2 - // SP - 129 EP - 142 N2 - - ER - TY - CONF T1 - Metabolism and genotoxicity of food-derived heterocyclic amines A1 - Gooderham, NJ A1 - Lynch, AM A1 - Yadollahi-Farsani, M A1 - Murray, S A1 - Boobis, AR A1 - Davies, DS U1 - Symposium on Drug Metabolism - Towards the Next Millennium Y1 - 1998/// Y2 - // VL - 25 SP - 127 EP - 136 N2 - - ER - TY - CONF T1 - Preliminary results of Intratumoral plasmid p53 injection in patients with localised hepatocellular carcinoma A1 - Habib, NA A1 - El-Masry, R A1 - Mitry, RR A1 - Michail, NE A1 - Abdel-Ghaffar, Y A1 - Moenis, A U1 - 8th World Congress of the International Gastro-Surgical Club Y1 - 1998/// Y2 - // SP - 375 EP - 387 N2 - - ER - TY - CONF T1 - Mammalian in vitro systems: predictive value in drug metabolism A1 - Boobis, AR U1 - 2nd World Congress on Alternatives and Animal Use in the Life Sciences Y1 - 1997/// Y2 - // VL - 27 SP - 825 EP - 833 N2 - - ER - TY - JFULL T1 - Repeat retroperitoneal lymph-node dissection after chemotherapy for metastatic testicular germ cell tumour. A1 - Willis, SF A1 - Winkler, M A1 - Savage, P A1 - Seckl, MJ A1 - Christmas, TJ J1 - BJU Int Y1 - 2007/10// VL - 100 SN - 1464-4096 SP - 809 EP - 812 N2 - OBJECTIVES To examine the operative findings, histopathology and clinical outcome of patients undergoing repeat retroperitoneal lymph node dissection (RPLND) after initial chemotherapy and RPLND (PC-RPLND) for metastatic testicular germ cell tumour (GCT), as a small proportion relapse or have residual disease after incomplete resection in the lung, retrocrural or pelvic nodes, and retroperitoneum. PATIENTS AND METHODS Between September 1992 and May 2006, 359 patients had PC-RPLND under the care of one surgeon, 54 of which were repeat procedures. We compared the long-term outcome between those having primary and those having repeat PC-RPLND. RESULTS The median (range) time from original to repeat surgery was 2.4 (0.25-26.5) years, and the median follow-up after the repeat procedure was 5.8 (0.08-12.9) years. There was no difference in survival between patients requiring only one PC-RPLND and those having a repeat procedure (P = 0.592). The most frequent sites of recurrent disease were: behind the great vessels/para-aortic areas (38, 46%), in the suprahilar region (18, 18%), in the retrocrural area (16, 19%), in the pelvic nodes (10, 12%) and in the lung (one, 1%). The most common pathological findings in the repeat PC-RPLNDs were differentiated teratoma (19, 35%), malignant teratoma undifferentiated (nine, 17%), adenocarcinoma (eight, 15%) and necrotic tissue (five, 9.2%). CONCLUSION Although a small proportion of patients with metastatic GCT might require repeat PC-RPLND, there is no difference in survival between this group and those having one PC-RPLND. However, to avoid cancer recurrence and reoperation, it is crucial that the first PC-RPLND is careful and complete, preferably done in a centre with expertise in this procedure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17711512&query_hl=1 ER - TY - JFULL T1 - Incidence of hyperthyroidism after unrelated donor allogeneic stem cell transplantation. A1 - Perz, JB A1 - Marin, D A1 - Szydlo, RM A1 - Giles, C A1 - Olavarria, E A1 - Williams, G A1 - Apperley, JF J1 - Leuk Res Y1 - 2007/10// VL - 31 SN - 0145-2126 SP - 1433 EP - 1436 N2 - We report on three patients who developed overt thyrotoxicosis after volunteer unrelated donor bone marrow transplantation for Philadelphia chromosome positive chronic myeloid leukemia shortly after the onset of chronic graft versus host disease. In all three cases, the etiology of hyperthyroidism is likely to be a combination of toxic factors and an immune process. Systematic evaluation of thyroid function tests in 97 unrelated allograft recipients from our center who survived at least 100 days from stem cell or bone marrow transplantation for hematological diseases gave a rate of overt thyrotoxicosis at 3.1% in this cohort. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17433437&query_hl=1 ER - TY - JFULL T1 - Imaging early changes in proliferation at 1 week post chemotherapy: a pilot study in breast cancer patients with 3'-deoxy-3'-[(18)F]fluorothymidine positron emission tomography. A1 - Kenny, L A1 - Coombes, RC A1 - Vigushin, DM A1 - Al-Nahhas, A A1 - Shousha, S A1 - Aboagye, EO J1 - Eur J Nucl Med Mol Imaging Y1 - 2007/09// VL - 34 SN - 1619-7070 SP - 1339 EP - 1347 N2 - PURPOSE: 3'-Deoxy-3'-[(18)F]fluorothymidine positron emission tomography ([(18)F]FLT-PET) has been developed for imaging cell proliferation and findings correlate strongly with the Ki-67 labelling index in breast cancer. The aims of this pilot study were to define objective criteria for [(18)F]FLT response and to examine whether [(18)F]FLT-PET can be used to quantify early response of breast cancer to chemotherapy. METHODS: Seventeen discrete lesions in 13 patients with stage II-IV breast cancer were scanned prior to and at 1 week after treatment with combination 5-fluorouracil, epirubicin and cyclophosphamide (FEC) chemotherapy. The uptake at 90 min (SUV(90)) and irreversible trapping (K (i)) of [(18)F]FLT were calculated for each tumour. The reproducibility of [(18)F]FLT-PET was determined in nine discrete lesions from eight patients who were scanned twice before chemotherapy. Clinical response was assessed at 60 days after commencing FEC. RESULTS: All tumours showed [(18)F]FLT uptake and this was reproducible in serial measurements (SD of mean % difference = 10.5% and 15.1%, for SUV(90) and K (i), respectively; test-retest correlation coefficient >/=0.97). Six patients had a significant clinical response (complete or partial) at day 60; these patients also had a significant reduction in [(18)F]FLT uptake at 1 week. Decreases in K (i) and SUV(90) at 1 week discriminated between clinical response and stable disease (p = 0.022 for both parameters). In three patients with multiple lesions there was a mixed [(18)F]FLT response in primary tumours and metastases. [(18)F]FLT response generally preceded tumour size changes. CONCLUSION: [(18)F]FLT-PET can detect changes in breast cancer proliferation at 1 week after FEC chemotherapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17333178&query_hl=1 ER - TY - JFULL T1 - Mannose receptor regulation of macrophage cell migration. A1 - Sturge, J A1 - Todd, SK A1 - Kogianni, G A1 - McCarthy, A A1 - Isacke, CM J1 - J Leukoc Biol Y1 - 2007/09// VL - 82 SN - 0741-5400 SP - 585 EP - 593 N2 - The migration of macrophages through peripheral tissues is an essential step in the host response to infection, inflammation, and ischemia as well as in tumor progression and tissue repair. The mannose receptor (MR; CD206, previously known as the macrophage MR) is a 175-kDa type I transmembrane glycoprotein and is a member of a family of four recycling endocytic receptors, which share a common extracellular domain structure but distinct ligand-binding properties and cell type expression patterns. MR has been shown to bind and internalize carbohydrate and collagen ligands and more recently, to have a role in myoblast motility and muscle growth. Given that the related Endo180 (CD280) receptor has also been shown to have a promigratory role, we hypothesized that MR may be involved in regulating macrophage migration and/or chemotaxis. Contrary to expectation, bone marrow-derived macrophages (BMM) from MR-deficient mice showed an increase in random cell migration and no impairment in chemotactic response to a gradient of CSF-1. To investigate whether the related promigratory Endo180 receptor might compensate for lack of MR, mice with homozygous deletions in MR and Endo180 were generated. These animals showed no obvious phenotypic abnormality, and their BMM, like those from MR-deficient mice, retained an enhanced migratory behavior. As MR is down-regulated during macrophage activation, these findings have implications for the regulation of macrophage migration during different stages of pathogenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17596337&query_hl=1 ER - TY - JFULL T1 - Correlation between preoperative biliary drainage, bile duct contamination, and postoperative outcomes for pancreatic surgery. A1 - Limongelli, P A1 - Pai, M A1 - Bansi, D A1 - Thiallinagram, A A1 - Tait, P A1 - Jackson, J A1 - Habib, NA A1 - Williamson, RC A1 - Jiao, LR J1 - Surgery Y1 - 2007/09// VL - 142 SN - 0039-6060 SP - 313 EP - 318 N2 - BACKGROUND: Although previously examined, the potential relationship between preoperative biliary drainage (PBD), intraoperative bile culture (IBC), and postoperative morbidity and mortality rate for pancreatic surgery remains unclear. METHODS: Two hundred twenty patients underwent operation for either benign pancreatic disease or malignant periampullary and pancreatic neoplasms, consisting of pylorus-preserving proximal pancreatoduodenectomy (n = 180), biliary bypass (n = 31), and total pancreatectomy (n = 9). An intraoperative bile specimen was prospectively collected immediately after division of the bile duct and sent for bacteriologic evaluation for both aerobic and anaerobic microorganisms. Morbidity and mortality rates were evaluated. RESULTS: Of 220 patients evaluated, 113 patients (51.4%) had a positive IBC. Factors associated with a positive IBC were age >70 years (odds ratio [OR], 5.9;95% confidence interval, [CI]: 1.6-22.1; P = .007), history of coronary artery disease (OR, 0.08; 95% CI, 0.01-0.5; P = .007), diagnosis of neoplasia (OR, 0.3; 95% CI, 0.1-0.9; P =. 03), and PBD (OR, 0.1; 95% CI, 0.06-0.2; P = .0001). Infectious complications (OR, 1.8; 95% CI, 1-3; P = .03), and wound infection (OR, 2.8; 95% CI,1.4-5.3; P = .002) were greater in patients with positive IBC. CONCLUSIONS: PBD predisposes to a positive IBC. Patients with a positive IBC have a clinically important increased risk of developing both infectious complications and wound infection after pancreatic surgery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17723881&query_hl=1 ER - TY - JFULL T1 - Patient involvement in patient safety: what factors influence patient participation and engagement? A1 - Davis, RE A1 - Jacklin, R A1 - Sevdalis, N A1 - Vincent, CA J1 - Health Expect Y1 - 2007/09// VL - 10 SN - 1369-6513 SP - 259 EP - 267 N2 - BACKGROUND: Patients can play an important role in improving patient safety by becoming actively involved in their health care. However, there is a paucity of empirical data on the extent to which patients take on such a role. In order to encourage patient participation in patient safety we first need to assess the full range of factors that may be implicated in such involvement. OBJECTIVE: To delineate factors that could affect the participation of the patient in quality and safety issues in their health care. METHOD: Literature review of patient involvement in health care, drawing from direct evidence (specifically from the safety context) and indirect evidence (extrapolated from treatment decision-making research and the wider patient involvement in health care literature); synthesis and conceptual framework developed, illustrating the known and putative factors that could affect the participation of the patient in safety issues in their health care. MAIN RESULTS: Five categories of factors emerged that could affect patient involvement in safety: patient-related (e.g. patients' demographic characteristics), illness-related (e.g. illness severity), health-care professional-related (e.g. health care professionals' knowledge and beliefs), health care setting-related (e.g. primary or secondary care), and task-related (e.g. whether the required patient safety behaviour challenges clinicians' clinical abilities). CONCLUSION: The potential for engaging patients in patient safety is considerable but further research is needed to examine the influences on patient involvement, the limits and the possible dangers. Patients can act as 'safety buffers' during their care but the responsibility for their safety must remain with the health care professionals. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17678514&query_hl=1 ER - TY - JFULL T1 - Gestational trophoblastic neoplasia management: an update. A1 - Ngan, S A1 - Seckl, MJ J1 - Curr Opin Oncol Y1 - 2007/09// VL - 19 SN - 1040-8746 SP - 486 EP - 491 N2 - PURPOSE OF REVIEW: Gestational trophoblastic neoplasia represents the malignant end of the gestational trophoblastic disease spectrum. This review updates readers on developments in the management of gestational trophoblastic neoplasia over the past few years. RECENT FINDINGS: Progress has been made in elucidating the genetic changes that give rise to gestational trophoblastic neoplasia. The importance of accurate human chorionic gonadotrophin monitoring and the types of human chorionic gonadotrophin produced in cancer are also topical. Fortunately, most patients are cured with chemotherapy, and the choice of treatment schedule according to low-risk and high-risk prognostic groups is relatively unchanged. Indeed, most patients with low-risk gestational trophoblastic neoplasia are treated with single agent chemotherapy, and those who have high-risk disease with combination chemotherapy using etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide and oncovine. For resistant disease, new paclitaxel-containing regimens appear better tolerated than etoposide and cisplatin alternating weekly with etoposide, methotrexate and actinomycin D. SUMMARY: Prognosis in gestational trophoblastic neoplasia is now excellent following treatment. Virtually all patients with low-risk disease are cured, and survival is now 86% in high-risk patients. Optimization of treatment strategies for those who develop drug resistance remains a key challenge. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17762576&query_hl=1 ER - TY - JFULL T1 - Multidisciplinary Crisis Simulations: The Way Forward for Training Surgical Teams. A1 - Undre, S A1 - Koutantji, M A1 - Sevdalis, N A1 - Gautama, S A1 - Selvapatt, N A1 - Williams, S A1 - Sains, P A1 - McCulloch, P A1 - Darzi, A A1 - Vincent, C J1 - World J Surg Y1 - 2007/09// VL - 31 SN - 0364-2313 SP - 1843 EP - 1853 N2 - BACKGROUND: High-reliability organizations have stressed the importance of nontechnical skills for safety and of regularly providing such training to their teams. Recently safety skills training has been applied in the practice of medicine. In this study, we developed and piloted a module using multidisciplinary crisis scenarios in a simulated operating theatre to train entire surgical teams. METHODS: Twenty teams participated (n = 80); each consisted of a trainee surgeon, anesthetist, operating department practitioner (ODP), and scrub nurse. Crisis scenarios such as difficult intubation, hemorrhage, or cardiac arrest were simulated. Technical and nontechnical skills (leadership, communication, team skills, decision making, and vigilance), were assessed by clinical experts and by two psychologists using relevant technical and human factors rating scales. Participants received technical and nontechnical feedback, and the whole team received feedback on teamwork. RESULTS: Trainees assessed the training favorably. For technical skills there were no differences between surgical trainees' assessment scores and the assessment scores of the trainers. However, nurses overrated their technical skill. Regarding nontechnical skills, leadership and decision making were scored lower than the other three nontechnical skills (communication, team skills, and vigilance). Surgeons scored lower than nurses on communication and teamwork skills. Surgeons and anesthetists scored lower than nurses on leadership. CONCLUSIONS: Multidisciplinary simulation-based team training is feasible and well received by surgical teams. Nontechnical skills can be assessed alongside technical skills, and differences in performance indicate where there is a need for further training. Future work should focus on developing team performance measures for training and on the development and evaluation of systematic training for technical and nontechnical skills to enhance team performance and safety in surgery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17610109&query_hl=1 ER - TY - JFULL T1 - A review of the management by hysterectomy of 25 cases of gestational trophoblastic tumours from March 1993 to January 2006. A1 - Doumplis, D A1 - Al-Khatib, K A1 - Sieunarine, K A1 - Lindsay, I A1 - Seckl, M A1 - Bridges, J A1 - Smith, JR J1 - BJOG Y1 - 2007/09// VL - 114 SN - 1471-0528 SP - 1168 EP - 1171 N2 - We reviewed 25 cases of gestational trophoblastic tumours referred for surgical management from Charing Cross Hospital (the London centre for gestational trophoblastic disease [GTD]) over a 13-year period. The operation performed was total abdominal hysterectomy, with lymph node sampling in 9/25 (36%) women and bilateral salpingo-oophorectomy in 11/25 (44%) women. Radical hysterectomy and unilateral parametrectomy was required in 3/25 (12%) women. Three of 25 (12%) women failed to survive, i.e. the overall rate of survival was 88%. Management by hysterectomy of primary drug-resistant and relapse cases of GTD is a useful and safe adjunct to chemotherapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17617194&query_hl=1 ER - TY - JFULL T1 - P-STAT1 mediates higher-order chromatin remodelling of the human MHC in response to IFN{gamma} A1 - Christova, R A1 - Jones, T A1 - Wu, PJ A1 - Bolzer, A A1 - Costa-Pereira, AP A1 - Watling, D A1 - Kerr, IM A1 - Sheer, D J1 - J Cell Sci Y1 - 2007/08/28/ SN - 0021-9533 N2 - Transcriptional activation of the major histocompatibility complex (MHC) by IFNgamma is a key step in cell-mediated immunity. At an early stage of IFNgamma induction, chromatin carrying the entire MHC locus loops out from the chromosome 6 territory. We show here that JAK/STAT signalling triggers this higher-order chromatin remodelling and the entire MHC locus becomes decondensed prior to transcriptional activation of the classical HLA class II genes. A single point mutation of STAT1 that prevents phosphorylation is sufficient to abolish chromatin remodelling, thus establishing a direct link between the JAK/STAT signalling pathway and human chromatin architecture. The onset of chromatin remodelling corresponds with the binding of activated STAT1 and the chromatin remodelling enzyme BRG1 at specific sites within the MHC, and is followed by RNA-polymerase recruitment and histone hyperacetylation. We propose that the higher-order chromatin remodelling of the MHC locus is an essential step to generate a transcriptionally permissive chromatin environment for subsequent activation of classical HLA genes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17726060&query_hl=1 ER - TY - JFULL T1 - Genomic profile of chronic myelogenous leukemia: Imbalances associated with disease progression. A1 - Brazma, D A1 - Grace, C A1 - Howard, J A1 - Melo, JV A1 - Holyoke, T A1 - Apperley, JF A1 - Nacheva, EP J1 - Genes Chromosomes Cancer Y1 - 2007/08/15/ VL - 46 SN - 1045-2257 SP - 1039 EP - 1050 N2 - The expression of the chimeric BCR/ABL1 fusion gene resulting from t(9;22)(q34;q11) in chronic myelogenous leukemia (CML) is necessary for malignant transformation, but not sufficient to maintain disease progression. The appearance of various chromosomal and molecular alterations in the accelerated and terminal phase of CML is well documented, but evidence for causal relationship is largely lacking. We carried out a genome wide screening at a resolution of 1 Mb of 54 samples at different stages of CML together with 12 CML cell lines and found that disease progression is accompanied by a spectrum of recurrent genome imbalances. Among the most frequent are losses at 1p36, 5q21, 9p21, and 9q34 and gains at 1q, 8q24, 9q34, 16p, and 22q11, all of which were located with higher precision within the genome than previously possible. These genome imbalances are unique to CML cases with clinically manifested or suspected accelerated/blast stage alike, but not seen in chronic phase samples. Previously unrecognized cryptic imbalances occurring within the Ph-chromosome were also detected, although further scrutiny is required to pin-point gene involvement and seek association with disease features. Importantly, some of these imbalances were seen in the CD34(+) cells but not in the whole BM samples of patients in accelerated phase. Taken together, these findings highlight the potential of screening CD34(+) cells for genome wide imbalances associated with disease progression. Finally, the numerous single copy number variations recorded, many unique to this cohort of patients, raise the possible association of genome polymorphism and CML. (c) 2007 Wiley-Liss, Inc. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17696194&query_hl=1 ER - TY - JFULL T1 - Abnormal Preantral Folliculogenesis in Polycystic Ovaries is Associated with Increased Granulosa Cell Division. A1 - Stubbs, SA A1 - Stark, J A1 - Dilworth, SM A1 - Franks, S A1 - Hardy, K J1 - J Clin Endocrinol Metab Y1 - 2007/08/14/ SN - 0021-972X N2 - Context: Polycystic ovary syndrome (PCOS) is the commonest endocrine disorder in women but its etiology remains obscure. Recent data suggest that an intrinsic abnormality of early follicle development in the ovary is key to the pathogenesis of PCOS. We have recently found that in PCOS the proportion of primordial follicles is decreased with a reciprocal increase in the proportion of primary follicles. Objective: To examine whether the accelerated transition of follicles from primordial to primary stages in polycystic ovaries is due to increased granulosa cell (GC) division. Design: Comparison of expression of minichromosome maintenance protein 2 (MCM2; present in the nuclei of cells which are licensed to divide) in archive tissue from normal and polycystic ovaries. Setting: Laboratory-based study. Patients: 16 women with regular cycles (6 with normal and 10 with polycystic ovaries) and 5 anovulatory women with polycystic ovaries (anovPCO), classified histologically, with reference to menstrual history and ultrasound. Main outcome measure: Presence of MCM2 expression in GCs of 1371 follicles. Results: GC proliferation was increased in anovPCO compared with both normal and ovPCO, with an increased proportion of preantral follicles with MCM2-positive GCs (P /=3 organs involved in 33%. In a retrospective analysis, the 3-day premedication of corticosteroids and antihistamines proved to be as effective as the established but more toxic 5-day regimen in delaying and preventing the occurrence of docetaxel derived toxicities especially the cumulative fluid retention. In conclusion, docetaxel represents one of the most active agents for second-line treatment of metastatic breast cancer, especially for anthracycline-resistant patients. Due to comparable effectiveness of the 5-day regimen which is widely used by others and the 3-day premedication tested in this trial the latter proved to be more favourable and was therefore recommended for future therapies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17636328&query_hl=1 ER - TY - JFULL T1 - Development of force measurement system for clinical use in minimal access surgery. A1 - Hanna, GB A1 - Drew, T A1 - Arnold, G A1 - Fakhry, M A1 - Cuschieri, A J1 - Surg Endosc Y1 - 2007/07/11/ SN - 1432-2218 N2 - BACKGROUND: Analysis of force in minimal access surgery (MAS) is important for instrument design, surgical simulators, and in the understanding of tissue trauma incurred during surgery. The aim of this study is to develop a force measuring system for use with different instruments in clinical practice. METHODS: Strain gauges were connected to both arms of a standard -5 mm interchangeable forceps handle. A rotational sensor was used to indicate the relative position of the handle arms, and consequently the jaws' position. A generic force-direction assembly was manufactured to determine the force direction at the port site. Interface electronics included signal conditioning and patient isolation circuits. Dedicated software was used for data acquisition, display, and analysis. To test their performance after sterilization, repeated force measures were obtained with the instruments after 10 cycles of autoclaving. Graduated weights were used to calibrate the strain gauges and a spring balance was employed to calibrate the force applied at the instrument tip. Calibration tests were also carried out to determine the effect of mounting the force direction assembly onto the access port. RESULTS: Gripping, dissecting, pushing, and pulling forces, along with the vector sum of forces acting at the port site, were synchronously displayed with the operative video record. Repeated autoclaving caused no deterioration in force sensing or signal transmission. The accuracy of the strain gauge readings was +/-0.05 V for the jaw force and +/-0.1 V for the force at the access port. The additional force created by the force direction assembly force was 7% of the port force alone. CONCLUSION: Force measurement system has been developed for clinical use. The system measures the gripping, dissecting, pulling and pushing forces as well as the force vector at port site. It also determines the position of instrument's jaws. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17623237&query_hl=1 ER - TY - JFULL T1 - Does systemic leukocyte filtration affect perioperative hemorrhage in cardiac surgery? A systematic review and meta-analysis. A1 - Warren, O A1 - Wallace, S A1 - Massey, R A1 - Tunnicliffe, C A1 - Alexiou, C A1 - Powell, J A1 - Meisuria, N A1 - Darzi, A A1 - Athanasiou, T J1 - ASAIO J Y1 - 2007/07// VL - 53 SN - 1538-943X SP - 514 EP - 521 N2 - Cardiopulmonary bypass causes a systemic inflammatory reaction. Activation of leukocytes is an important part of this process, and is known to directly contribute to the development of postoperative coagulopathy, and thus hemorrhage. The removal of leukocytes from the cardiopulmonary bypass circulation, using specialized filters, has been proposed as one method for attenuating this inflammatory response. However, there is no consensus on its effectiveness. We used meta-analytical techniques to systematically assess the literature reporting on the potential effect of systemic leukofiltration on perioperative hemorrhage. Random effects modeling was used to calculate overall estimate, and heterogeneity was assessed. Systemic leukofiltration made no significant impact on chest tube drainage in the first 24 hours (weighted mean difference [WMD], x23.9 ml; 95% confidence interval [CI], x95.48-47.61; p = 0.51) or on the total packed red cell transfusion requirements of each patient (WMD, 7.84 ml; 95% CI, x80.13-95.81; p = 0.86). The studies performed in this area thus far are highly heterogeneous, due in part to relatively poor-quality design and inadequate matching of their study groups. Although further high-quality trials on systemic leukofiltration may be appropriate, other strategies to reduce the coagulopathy associated with cardiopulmonary bypass should be sought and evaluated. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17667241&query_hl=1 ER - TY - JFULL T1 - Placental site trophoblastic tumor with an ovarian metastasis. A1 - Milingos, D A1 - Doumplis, D A1 - Savage, P A1 - Seckl, M A1 - Lindsay, I A1 - Smith, JR J1 - Int J Gynecol Cancer Y1 - 2007/07// VL - 17 SN - 1048-891X SP - 925 EP - 927 N2 - Placental site trophoblastic tumors (PSTT) are the rarest form of gestational trophoblastic disease (GTD). The clinical management of PSTT differs from the other forms of GTD as surgery plays a more important role. The most common metastatic sites are the lung, liver, and vagina while spread to the adnexa is relatively unusual. We describe a case of a 35-year-old woman presenting with PSTT and ovarian metastasis who was successfully treated with radical hysterectomy, bilateral oophorectomy, pelvic lymph node dissection, and postoperative chemotherapy. The case highlights the possibility of ovarian metastases despite normal preoperative imaging and confirms the value of multidisciplinary management of this rare illness. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17343608&query_hl=1 ER - TY - JFULL T1 - Observational teamwork assessment for surgery (OTAS): refinement and application in urological surgery. A1 - Undre, S A1 - Sevdalis, N A1 - Healey, AN A1 - Darzi, A A1 - Vincent, CA J1 - World J Surg Y1 - 2007/07// VL - 31 SN - 0364-2313 SP - 1373 EP - 1381 N2 - BACKGROUND: Teamwork in surgical teams is at the forefront of good practice guidelines and empirical research as an important aspect of safe surgery. We have developed a comprehensive assessment for teamwork in surgery-the Observational Teamwork Assessment for Surgery (OTAS)-and we have tested it for general surgical procedures. The aim of the research reported here was to extend the assessment to urology procedures. METHODS: After refining the original assessment, we used it to observe 50 urology procedures. The OTAS comprises a procedural task checklist that assesses patient, equipment/provisions, and communication tasks as well as ratings on five team behavior constructs (communication, cooperation, coordination, leadership, and monitoring). Teamwork was assessed separately in the surgical, anesthesia, and nursing subteams in the operating theater. We also assessed the reliability of the behavioral scoring. RESULTS: Regarding task completion, a number of communication and equipment/provisions tasks were not routinely performed during the operations we observed. Regarding teamwork-related behaviors, adequate reliability was obtained in the scoring of behaviors. Anesthetists and nurses obtained their lowest scores on communication. Surgeons' scores revealed a more complex pattern. In addition to low scores on communication, surgeons' teamwork behaviors appeared to deteriorate as the procedures were finishing. CONCLUSIONS: Our findings suggest that OTAS is applicable to various branches of surgery. Separate assessment of the subteams in the operating theater provides useful information that can be used to build targeted teamwork training aiming to improve surgical patients' safety and outcomes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17487527&query_hl=1 ER - TY - JFULL T1 - Apoptosis and chemo-resistance in colorectal cancer. A1 - Prabhudesai, SG A1 - Rekhraj, S A1 - Roberts, G A1 - Darzi, AW A1 - Ziprin, P J1 - J Surg Oncol Y1 - 2007/07/01/ VL - 96 SN - 0022-4790 SP - 77 EP - 88 N2 - Systemic chemotherapy plays an integral part in treating advanced colorectal cancer. However 50% of patients respond poorly or have disease progression due to resistance to chemotherapeutic agents. This article reviews the pathways that regulate apoptosis, apoptotic mechanisms through which chemotherapeutic agents mediate their effect and how deregulation of apoptotic proteins may contribute to chemo-resistance. Also discussed are potential therapeutic strategies designed to target these proteins and thereby improve response rates to chemotherapy in colorectal cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17443738&query_hl=1 ER - TY - JFULL T1 - Major abdominal surgery increases plasma levels of vascular endothelial growth factor: open more so than minimally invasive methods. A1 - Prabhudesai, SG A1 - Leong, J A1 - Ziprin, P J1 - Ann Surg Y1 - 2007/07// VL - 246 SN - 0003-4932 SP - 160 EP - 161 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17592305&query_hl=1 ER - TY - JFULL T1 - Multiple perspectives on diagnosis delay for tuberculosis from key stakeholders in poor rural China: case study in four provinces. A1 - Yan, F A1 - Thomson, R A1 - Tang, S A1 - Squire, SB A1 - Wang, W A1 - Liu, X A1 - Gong, Y A1 - Zhao, F A1 - Tolhurst, R J1 - Health Policy Y1 - 2007/07// VL - 82 SN - 0168-8510 SP - 186 EP - 199 N2 - This study aims to understand the contextual barriers to accessing timely TB diagnosis after first seeking care, especially among the poor and vulnerable in rural China. Both quantitative and qualitative methods were used to elicit the experiences and perspectives of TB patients and suspected TB patients, community residents, health providers and policy makers in poor, rural areas of four provinces. Between 30 and 60% of patients across the four provinces experienced a delay in receiving a diagnosis after first seeking care. Most patients had to visit health facilities more than once before diagnosis, with 17-30% patients making more than 6 visits. These delays and multiple visits mainly occurred because of the limited capacity of health providers to recognize TB, and financial disincentives to refer patients to TB dispensaries, due to the pressures of the cost recovery system. Poverty and socio-economic disadvantage amongst patients also influenced their capability to seek further care to obtain a reliable diagnosis. Qualitative data showed that women and the elderly patients were likely to experience more 'system' delay, and these findings were to some extent supported by the survey. The study concludes that 'system' delay is a serious problem, which is influenced by the financing mechanisms for both TB control and general health services as well as poverty and disadvantage amongst patients. This requires a comprehensive strategy to shorten 'system' delay in order to enable successful DOTS expansion, including developing appropriate financing mechanisms to improve general provider capacity and encourage referral, as well as measures to improve financial and social access to services for potential TB patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17055105&query_hl=1 ER - TY - JFULL T1 - Effect of arylamine acetyltransferase Nat3 gene knockout on N-acetylation in the mouse. A1 - Sugamori, KS A1 - Brenneman, D A1 - Wong, S A1 - Gaedigk, A A1 - Yu, V A1 - Abramovici, H A1 - Rozmahel, R A1 - Grant, DM J1 - Drug Metab Dispos Y1 - 2007/07// VL - 35 SN - 0090-9556 SP - 1064 EP - 1070 N2 - Arylamine N-acetyltransferases (NAT) catalyze the biotransformation of many important arylamine drugs and procarcinogens. NAT can either detoxify or activate procarcinogens, complicating the manner in which these enzymes may participate in enhancing or preventing toxic responses to particular agents. Mice possess three NAT isoenzymes: Nat1, Nat2, and Nat3. Whereas Nat1 and Nat2 can efficiently acetylate many arylamines, few substrates appear to be appreciably metabolized by Nat3. We generated a Nat3 knockout mouse strain and used it along with our double Nat1/2(-/-) knockout strain to further investigate the functional role of Nat3. Nat3(-/-) mice showed normal viability and reproductive capacity. Nat3 expression was very low in wild-type animals and completely undetectable in Nat3(-/-) mice. In contrast, greatly elevated expression of Nat3 transcript was observed in Nat1/2(-/-) mice. We used a transcribed marker polymorphism approach to establish that the increased expression of Nat3 in Nat1/2(-/-) mice is a positional artifact of insertion of the phosphoglycerate kinase-neomycin resistance cassette in place of the Nat1/Nat2 gene region and upstream of the intact Nat3 gene, rather than a biological compensatory mechanism. Despite the increase in Nat3 transcript, the N-acetylation of p-aminosalicylate, sulfamethazine, 2-aminofluorene, and 4-aminobiphenyl was undetectable either in vivo or in vitro in Nat1/2(-/-) animals. In parallel, no difference was observed in the in vivo clearance or in vitro metabolism of any of these substrates between wild-type and Nat3(-/-) mice. Thus, Nat3 is unlikely to play a significant role in the N-acetylation of arylamines either in wild-type mice or in mice lacking Nat1 and Nat2 activities. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17403913&query_hl=1 ER - TY - JFULL T1 - Intelligent bioprocessing for haemotopoietic cell cultures using monitoring and design of experiments. A1 - Lim, M A1 - Ye, H A1 - Panoskaltsis, N A1 - Drakakis, EM A1 - Yue, X A1 - Cass, AE A1 - Radomska, A A1 - Mantalaris, A J1 - Biotechnol Adv Y1 - 2007/07// VL - 25 SN - 0734-9750 SP - 353 EP - 368 N2 - The need for successful ex-vivo expansion and directed differentiation of haematopoietic stem cells (HSCs) for therapeutic applications has increased over the past decade. Haematopoietic cell cultures are complex and full characterisation of the process environment has yet to be achieved. The complexity and transient nature of HSC cultures make the identification, maintenance and control of optimal operating conditions challenging. Application of real-time, on-line monitoring techniques and process control strategies enhances the ability to operate bioprocesses of desired reproducibility and high product quality. In this review, we discussed the methods by which in vitro culture information necessary for bioprocess control may be obtained, including process considerations, monitoring and analytical tools, and design of experiments (DOE). The successful application of these tools may result in time- and cost-effective cultures for directed differentiation and expansion of haematopoietic components intended for clinical use. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428632&query_hl=1 ER - TY - JFULL T1 - Management and outcome of healthy women with a persistently elevated beta-hCG. A1 - Palmieri, C A1 - Dhillon, T A1 - Fisher, RA A1 - Young, AM A1 - Short, D A1 - Mitchell, H A1 - Aghajanian, C A1 - Savage, PM A1 - Newlands, ES A1 - Hancock, BW A1 - Seckl, MJ J1 - Gynecol Oncol Y1 - 2007/07// VL - 106 SN - 0090-8258 SP - 35 EP - 43 N2 - PURPOSE: Raised serum beta human chorionic gonadotrophin (beta-hCG) not due to pregnancy can occur as a consequence of (1) gestational trophoblastic neoplasia (GTN), (2) non-gestational trophoblastic tumours, (3) a false-positive beta-hCG, (4) the menopause or (5) a high normal level. Accurate differentiation between these causes is vital to avoid potentially inappropriate investigations and therapies, which may induce infertility or other serious adverse events. Here we report the United Kingdom experience of patients with an elevated beta-hCG of initial uncertain cause and provide a clinical algorithm for the management of such cases. METHOD: The Charing Cross and Weston Park Hospital GTN databases were screened to identify patients referred with an elevated beta-hCG who were not pregnant and had no previous diagnosis of GTN. RESULTS: Between 1981 and 2004 fourteen women presented with persistently raised serum beta-hCG resulting in diagnostic problems. False-positive beta-hCG was excluded in all. Three patients developed gestational choriocarcinoma after 9-29 months. However, in 11 women no cause for the persistently elevated beta-hCG was found. One of these achieved chemotherapy-induced normalisation of serum beta-hCG, but the remaining 10 underwent surgery and/or chemotherapy without benefit. Thus, 71% (10/14) of patients remain well with unexplained elevated beta-hCG levels. CONCLUSION: Elevated serum and urinary beta-hCG levels in healthy women should be investigated systematically to exclude an underlying malignant process and to avoid inappropriate surgical and medical intervention. Long-term follow-up is required as tumours may not become apparent for many months or years. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17482245&query_hl=1 ER - TY - JFULL T1 - The polycomb group BMI1 gene is a molecular marker for predicting prognosis of chronic myeloid leukemia. A1 - Mohty, M A1 - Yong, AS A1 - Szydlo, RM A1 - Apperley, JF A1 - Melo, JV J1 - Blood Y1 - 2007/07/01/ VL - 110 SN - 0006-4971 SP - 380 EP - 383 N2 - Because the polycomb group gene BMI1 regulates the proliferation of both normal and leukemic stem cells, we examined whether BMI1 expression was associated with disease progression in chronic myeloid leukemia (CML). Levels of BMI1 RNA were significantly higher in patients with advanced-phase than in patients with chronic-phase CML in both CD34(+) cells (P = .006) and total peripheral-blood mononuclear cells (P < .001). E2F1, a transcription factor regulating BMI1, was up-regulated in CML compared with controls (P = .001). In a cohort of 64 CML patients, the level of BMI1 at diagnosis correlated with time to transformation to blast crisis, and the combination of low BMI1 and high proteinase-3 expression was associated in multivariate analysis with an improved overall survival (P = .001). We conclude that BMI1 may be a biomarker for the intrinsic heterogeneity of CML, and its measurement at diagnosis can help predict overall survival and thus contribute to better therapeutic decisions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17360938&query_hl=1 ER - TY - JFULL T1 - Leuprorelin acetate every-3-months depot versus cyclophosphamide, methotrexate, and fluorouracil as adjuvant treatment in premenopausal patients with node-positive breast cancer: the TABLE study. A1 - Schmid, P A1 - Untch, M A1 - Kossé, V A1 - Bondar, G A1 - Vassiljev, L A1 - Tarutinov, V A1 - Lehmann, U A1 - Maubach, L A1 - Meurer, J A1 - Wallwiener, D A1 - Possinger, K J1 - J Clin Oncol Y1 - 2007/06/20/ VL - 25 SN - 1527-7755 SP - 2509 EP - 2515 N2 - PURPOSE: Ovarian suppression with luteinizing hormone-releasing hormone (LHRH) agonists is an effective adjuvant treatment for premenopausal women with estrogen receptor (ER) -positive breast cancer. Whereas monthly LHRH agonist therapy has been well established, the value of every-3-months (3-monthly) formulations is unclear. PATIENTS AND METHODS: This randomized phase III trial was performed to compare the 3-monthly depot LHRH agonist leuprorelin acetate (LAD-3M; n = 299) and chemotherapy with cyclophosphamide, methotrexate, and fluorouracil (CMF; n = 300) in pre- or perimenopausal patients with ER-positive, node-positive breast cancer. RESULTS: With a median follow-up of 5.8 years, recurrence-free survival was similar for patients treated with LAD-3M or CMF (hazard ratio [HR], 1.19; 95% CI, 0.94 to 1.51; P = .15). There was no substantial heterogeneity in the relative treatment effect among subgroups defined by age, progesterone receptor (PR) status, nodal status, hormone levels, or menstrual recovery after treatment. Exploratory overall survival analysis favored LAD-3M (HR, 1.50; 95% CI, 1.13 to 1.99; P = .005). Chemotherapy-related adverse effects such as nausea, vomiting, and alopecia were more common with CMF, whereas symptoms of estrogen suppression such as hot flushes and sweating were initially more pronounced with LAD-3M. CONCLUSION: The 3-monthly depot LHRH-agonist leuprorelin acetate is an effective adjuvant treatment in premenopausal patients with hormone receptor-positive, node-positive breast cancer that is not inferior to CMF. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17577027&query_hl=1 ER - TY - JFULL T1 - Antiestrogen therapy is active in selected ovarian cancer cases: the use of letrozole in estrogen receptor-positive patients. A1 - Smyth, JF A1 - Gourley, C A1 - Walker, G A1 - MacKean, MJ A1 - Stevenson, A A1 - Williams, AR A1 - Nafussi, AA A1 - Rye, T A1 - Rye, R A1 - Stewart, M A1 - McCurdy, J A1 - Mano, M A1 - Reed, N A1 - McMahon, T A1 - Vasey, P A1 - Gabra, H A1 - Langdon, SP J1 - Clin Cancer Res Y1 - 2007/06/15/ VL - 13 SN - 1078-0432 SP - 3617 EP - 3622 N2 - PURPOSE: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)-positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. EXPERIMENTAL DESIGN: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. RESULTS: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, chi(2) for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. CONCLUSIONS: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17575226&query_hl=1 ER - TY - JFULL T1 - Mutagenesis of the herpesvirus saimiri terminal repeat region reveals important elements for virus production. A1 - White, RE A1 - Carline, L A1 - Allday, MJ J1 - J Virol Y1 - 2007/06// VL - 81 SN - 0022-538X SP - 6765 EP - 6770 N2 - Deletion of the terminal repeats (TR) from herpesvirus saimiri (HVS) renders it unable to produce infectious virus or generate plaques. However, a TR-deleted HVS bacterial artificial chromosome can form replication compartments. Complementation of this mutant shows that one copy of the TR, plus the right junction of the genome with the TR, is sufficient for efficient plaque formation and generation of infectious virus. Within the TR unit, the region around the cleavage site of the genome appears both necessary and sufficient for virus production. Analysis of episomes from productive cells indicates a propensity to amplify TR numbers during the lytic cycle. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428860&query_hl=1 ER - TY - JFULL T1 - The fibroblast growth factor receptor inhibitor PD0173074 as a potential novel anti-prostate cancer therapy A1 - Goldstraw, MA A1 - Christmas, T A1 - Seckl, MJ J1 - BJU INT Y1 - 2007/06// VL - 99 SN - 1464-4096 SP - 29 EP - 29 ER - TY - JFULL T1 - Perioperative synbiotic treatment to prevent postoperative infectious complications in biliary cancer surgery: a randomized control trial. A1 - Kinross, J A1 - Warren, O A1 - Silk, D A1 - Darzi, A J1 - Ann Surg Y1 - 2007/06// VL - 245 SN - 0003-4932 SP - 1000 EP - 1000 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522529&query_hl=1 ER - TY - JFULL T1 - The price for survival are all patients equal? A1 - Gabriel, I A1 - Schenk, M A1 - Foster, J A1 - Chaidos, A A1 - Kanfer, F A1 - Marin, D A1 - Milojkovic, D A1 - Rahemtulla, A A1 - Olavarria, E A1 - Apperley, J J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 223 EP - 223 ER - TY - JFULL T1 - Dual inhibition of ras and bcr-abl signalling pathways in chronic myeloid leukaemia: a phase I/II study in patients in complete haematological remission. A1 - Pavlu, J A1 - Andreasson, C A1 - Chuah, C A1 - Kaeda, J A1 - Goldman, JM A1 - Apperley, JF A1 - Marin, D J1 - Br J Haematol Y1 - 2007/06// VL - 137 SN - 0007-1048 SP - 423 EP - 428 N2 - Zoledronic acid inhibits the prenylation of ras-related proteins downstream of bcr-abl and preclinical studies have shown augmentation of the inhibitory effects of imatinib in BCR-ABL expressing cells. A Phase I/II study was designed to assess the safety and efficacy of the addition of zoledronic acid to imatinib in patients with chronic myeloid leukaemia (CML) with a suboptimal response to imatinib alone. Ten patients with CML who had been treated with imatinib for at least 2 years and had achieved and maintained a complete haematological response were included. Zoledronic acid was administered intravenously on one occasion every 28 d. The initial dose of 4 mg was given for three consecutive months; in the absence of significant toxicity and/or response the dose was escalated to 8 mg for an additional 3 months. Efficacy was assessed by serial monitoring of blood levels of BCR-ABL transcripts and bone marrow cytogenetics. Addition of zoledronic acid to imatinib caused no haematological toxicity. There were no grade III or IV non-haematological adverse effects. Grade I fatigue, hypocalcaemia and fever were common side effects. No responses were demonstrated after 6 months on the combination. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17428238&query_hl=1 ER - TY - JFULL T1 - BCR-ABL kinase mutations in response to dasatinib A1 - Khorashad, JS A1 - Mehta, P A1 - Milojkovic, D A1 - Marin, DC A1 - Kaeda, JS A1 - Swale, B A1 - Stevens, D A1 - Goldman, JM A1 - Apperley, JF J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 202 EP - 202 ER - TY - JFULL T1 - Mental training in surgical education: a randomized controlled trial. A1 - Aggarwal, R A1 - Warren, O A1 - Darzi, A J1 - Ann Surg Y1 - 2007/06// VL - 245 SN - 0003-4932 SP - 1002 EP - 1002 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522530&query_hl=1 ER - TY - JFULL T1 - An evaluation of the feasibility, validity, and reliability of laparoscopic skills assessment in the operating room. A1 - Aggarwal, R A1 - Grantcharov, T A1 - Moorthy, K A1 - Milland, T A1 - Papasavas, P A1 - Dosis, A A1 - Bello, F A1 - Darzi, A J1 - Ann Surg Y1 - 2007/06// VL - 245 SN - 0003-4932 SP - 992 EP - 999 N2 - OBJECTIVE: To assess the use of a synchronized video-based motion tracking device for objective, instant, and automated assessment of laparoscopic skill in the operating room. SUMMARY BACKGROUND DATA: The assessment of technical skills is fundamental to recognition of proficient surgical practice. It is necessary to demonstrate the validity, reliability, and feasibility of any tool to be applied for objective measurement of performance. METHODS: Nineteen subjects, divided into 13 experienced (performed >100 laparoscopic cholecystectomies) and 6 inexperienced (performed <10 LCs) surgeons completed LCs on 53 patients who all had a diagnosis of biliary colic. Each procedure was recorded with the ROVIMAS video-based motion tracking device to provide an objective measure of the surgeon's dexterity. Each video was also rated by 2 experienced observers on a previously validated operative assessment scale. RESULTS: There were significant differences for motion tracking parameters between the 2 groups of surgeons for the Calot triangle dissection part of procedure for time taken (P = 0.002), total path length (P = 0.026), and number of movements (P = 0.005). Both motion tracking and video-based assessment displayed intertest reliability, and there were good correlations between the 2 modes of assessment (r = 0.4 to 0.7, P < 0.01). CONCLUSIONS: An instant, objective, valid, and reliable mode of assessment of laparoscopic performance in the operating room has been defined. This may serve to reduce the time taken for technical skills assessment, and subsequently lead to accurate and efficient audit and credentialing of surgeons for independent practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522527&query_hl=1 ER - TY - JFULL T1 - Second autologous stem cell transplantation for multiple myeloma in first relapse A1 - Chaidos, A A1 - Giles, C A1 - Gabriel, I A1 - Apperley, JF A1 - Kanfer, E A1 - Olavarria, E A1 - Bua, M A1 - Samson, D A1 - Rahemtulla, A J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 256 EP - 256 ER - TY - JFULL T1 - Curriculum-based solo virtual reality training for laparoscopic intracorporeal knot tying: objective assessment of the transfer of skill from virtual reality to reality A1 - Munz, Y A1 - Almoudaris, AM A1 - Moorthy, K A1 - Dosis, A A1 - Liddle, AD A1 - Darzi, AW J1 - AM J SURG Y1 - 2007/06// VL - 193 SN - 0002-9610 SP - 774 EP - 783 N2 - Background: Very few studies have addressed the transferability of skills from virtual reality (VR) to real life. The aim of this study was to assess the feasibility and effectiveness of teaching intracorporeal knot tying (ICKT) by VR simulation only.Methods: Twenty novices underwent structured training of basic skills training on the Minimally Invasive Surgical Trainer simulator (Mentice AB, Gothenburg, Sweden) followed by knot tying training on the LapSim simulator (Surgical Science, Gothenburg, Sweden). They were assessed pre- and post-training on a video trainer. Assessment of performance included motion tracking and video-based checklist. Nonparametric statistical analysis was used, and P <.05 was deemed significant.Results: All participants completed a correct knot as compared with only 25% before VR training. Time to completion was 66% faster and knot quality 45% better after VR training. Significant reduction in number of movements (P = .006) and distance trave led (P < .000) by both hands after VR training.Conclusions: Teaching ICKT by VR simulators only is feasible and effective. Furthermore, this study highlights the complementary use of different VR simulators within a structured curriculum. (C) 2007 Published by Excerpta Medica Inc. ER - TY - JFULL T1 - The polycomb group BMI-1 gene is a molecular marker for predicting prognosis of chronic myeloid leukaemia A1 - Mohty, M A1 - Yong, ASM A1 - Szydlo, RM A1 - Apperley, JF A1 - Melo, JV J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 196 EP - 197 ER - TY - JFULL T1 - Chronic myeloid leukaemia as a model of disease evolution in human cancer. A1 - Melo, JV A1 - Barnes, DJ J1 - Nat Rev Cancer Y1 - 2007/06// VL - 7 SN - 1474-175X SP - 441 EP - 453 N2 - Chronic myeloid leukaemia (CML) can be considered as a paradigm for neoplasias that evolve through a multi-step process. CML is also one of the best examples of a disease that can be targeted by molecular therapy; however, the success of new 'designer drugs' is largely restricted to the chronic phase of the disease. If not cured at this stage, CML invariably progresses and transforms into an acute-type leukaemia undergoing a 'blast crisis'. The causes of this transformation are still poorly understood. What mechanisms underlie this progression, and are they shared by other common cancers? L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17522713&query_hl=1 ER - TY - JFULL T1 - Recent advances and current challenges in tumor immunology and immunotherapy A1 - Guinn, BA A1 - Kasahara, N A1 - Farzaneh, F A1 - Habib, NA A1 - Norris, JS A1 - Deisseroth, AB J1 - MOL THER Y1 - 2007/06// VL - 15 SN - 1525-0016 SP - 1065 EP - 1071 N2 - Despite advances in animal studies, where the cure of the majority of mice with pre-established (albeit early-stage) tumors has become almost standard, human clinical trials have been much less successful. Here we describe some of the most recent advances in the specialist field of tumor immunology and immunotherapy, highlighting salient work to identify key problem areas and potential solutions. We make particular note of recent developments in adoptive therapy; whole-cell, DNA, and peptide vaccines; and antibody therapy. We also describe the revival of interest in regulatory T cells and conclude by detailing the need for clinical trial read-out autonomy and methods to predict which patients will respond to a particular treatment. ER - TY - JFULL T1 - Diagnostic precision of magnetic resonance imaging for preoperative prediction of the circumferential margin involvement in patients with rectal cancer. A1 - Purkayastha, S A1 - Tekkis, PP A1 - Athanasiou, T A1 - Tilney, HS A1 - Darzi, AW A1 - Heriot, AG J1 - Colorectal Dis Y1 - 2007/06// VL - 9 SN - 1462-8910 SP - 402 EP - 411 N2 - OBJECTIVE: Circumferential margin involvement (CMI) is an important prognostic indicator for patients with rectal cancer. This meta-analysis aims at evaluating the diagnostic precision of magnetic resonance imaging (MRI) for the preoperative evaluation of CMI in patients with rectal cancer. METHOD: Quantitative meta-analysis was performed comparing MRI against histology after total mesorectal excision. Sensitivity, specificity and diagnostic odds ratio (DOR) were calculated for each study. Summary receiver operating characteristic (SROC) curves and subgroup analysis were undertaken. Study quality and heterogeneity were evaluated. Meta-regression meta-analysis was used to evaluate the significance of the difference in relative DORs. RESULTS: Nine studies evaluating 529 patients were included. Pooled results showed an overall sensitivity and specificity for MRI detecting CMI preoperatively of 94% and 85% respectively. The SROC analysis demonstrated an overall weighted area under the curve (AUC) of 0.92 (DOR 57.21, 95% CI 18.21-179.77), without significant heterogeneity between the studies (Q-value 14.66, P = 0.06). Good study quality further increased the sensitivity and specificity of MRI. The use of a 1.5 Tesla coil, a phased array coil and the inclusion of two interpreters also resulted in high preoperative diagnostic precision. Meta-regression meta-analysis showed a significant difference in the DOR for studies published in or since 2003 (P = 0.019). CONCLUSION: Magnetic resonance imaging can accurately predict CMI preoperatively for rectal cancer in single units and this is reproducible across different centres. This strategy has important implications for selection of patients for adjuvant therapy prior to surgery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17504336&query_hl=1 ER - TY - JFULL T1 - Nondestructive mechanical release of ordered polymer microfiber arrays from porous templates. A1 - Grimm, S A1 - Schwirn, K A1 - Göring, P A1 - Knoll, H A1 - Miclea, PT A1 - Greiner, A A1 - Wendorff, JH A1 - Wehrspohn, RB A1 - Gösele, U A1 - Steinhart, M J1 - Small Y1 - 2007/06// VL - 3 SN - 1613-6829 SP - 993 EP - 1000 N2 - The fabrication of one-dimensional (1D) nanostructures and microstructures inside the pores of porous templates is intensively investigated. The release of these structures is commonly accomplished by etching and destroying the templates. The 1D nanostructures and microstructures tend to condense because of the occurrence of capillary forces during drying of the specimens. It is shown that highly ordered arrays of polymer microfibers can be easily detached from silanized porous templates by mechanical lift-off. This procedure leaves the templates intact, thus allowing their recycling, and does not involve the use of solutions or solvents, thus circumventing condensation. Therefore, mechanical lift-off may enable the up-scaling of template-based approaches to the fabrication of highly ordered assemblies of 1D nanostructures and microstructures. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17352430&query_hl=1 ER - TY - JFULL T1 - When is a double Philadelphia not a double Philadelphia A1 - Brazma, D A1 - Grace, C A1 - Virgili, A A1 - Howard, J A1 - Chanalaris, A A1 - Melo, JV A1 - Apperley, JF A1 - Nacheva, EP J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 202 EP - 202 ER - TY - JFULL T1 - Lack of endothelial cell survivin causes embryonic defects in angiogenesis, cardiogenesis, and neural tube closure A1 - Zwerts, F A1 - Lupu, F A1 - De Vriese, A A1 - Pollefeyt, S A1 - Moons, L A1 - Altura, RA A1 - Jiang, YY A1 - Maxwell, PH A1 - Hill, P A1 - Oh, H A1 - Rieker, C A1 - Collen, D A1 - Conway, SJ A1 - Conway, EM J1 - BLOOD Y1 - 2007/06/01/ VL - 109 SN - 0006-4971 SP - 4742 EP - 4752 N2 - We explored the physiologic role of endothelial cell apoptosis during development by generating mouse embryos lacking the inhibitor of apoptosis protein (IAP) survivin in endothellum. This was accomplished by intercrossing survivin(lox/lox) mice with mice expressing cre recombinase under the control of the endothelial cell specific tiel promoter (tiel-cre mice). Lack of endothelial cell survivin resulted in embryonic lethality. Mutant embryos had prominent and diffuse hemorrhages from embryonic day 9.5 (E9.5) and died before E13.5. Heart development was strikingly abnormal. Survivin-null endocardial lineage cells could not support normal epithelial-mesenchymal transformation (EMT), resulting in hypoplastic endocardial cushions and in utero heart failure. In addition, 30% of mutant embryos had neural tube closure defects (NTDs) that were not caused by bleeding or growth retardation, but were likely due to alterations in the release of soluble factors from endothelial cells that otherwise support neural stem cell proliferation and neurulation. Thus, regulation of endothelial cell survival, and maintenance of vascular integrity by survivin are crucial for normal embryonic angiogenesis, cardiogenesis, and neurogenesis. ER - TY - JFULL T1 - Heparin-bonded circuits versus nonheparin-bonded circuits: an evaluation of their effect on clinical outcomes. A1 - Mangoush, O A1 - Purkayastha, S A1 - Haj-Yahia, S A1 - Kinross, J A1 - Hayward, M A1 - Bartolozzi, F A1 - Darzi, A A1 - Athanasiou, T J1 - Eur J Cardiothorac Surg Y1 - 2007/06// VL - 31 SN - 1010-7940 SP - 1058 EP - 1069 N2 - Heparinization of the blood contact surface in cardiopulmonary bypass circuits has been promoted as an important step in the development of open heart surgery. As it decreases the inflammatory response resulting from the extracorporeal circulation, it may have a positive effect on clinical outcomes. This meta-analysis was carried out to examine if heparin-bonded circuits (HBCs) reduce the need for blood products and improve overall clinical outcome. A systematic literature search was performed to identify randomized controlled trials reporting outcomes of HBCs compared with non-HBCs. Primary outcomes assessed were postoperative blood/blood-product transfusion and blood loss. Secondary outcomes included all-cause mortality, acute postoperative myocardial infarction, stroke, re-sternotomy for postoperative bleeding, wound infection, atrial fibrillation, duration of ventilation, intensive care unit (ICU) and hospital-length of stay (LOS). Random effects meta-analytical techniques were applied to identify differences in outcomes between the two groups. Quality of the included studies and heterogeneity were assessed. From an initial review of 762-published studies, 41-randomized trials fulfilled the inclusion criteria, leaving 3434-patients' data for analysis. HBCs significantly decreased the incidence of blood transfusion required (OR=0.8; 95% CI=0.6:0.9, P=0.004). It also significantly decreased re-sternotomy (OR=0.6; 95% CI=0.4:0.8, P=0.002), duration of ventilation (WMD= -1.3h; 95% CI= -1.9:-0.6, P<0.001), ICU-LOS (WMD= -9.3h; 95% CI=-14.7:-3.9, P<0.001) and hospital-LOS (WMD= -0.5 day; 95% CI= -0.9:-0.1, P=0.02). HBCs had no effect on other adverse events evaluated. Although HBCs showed a positive effect on some of the clinical outcomes, we identified only marginal differences for other outcomes. Further evaluation of the cost-effectiveness of this technology is required. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17306555&query_hl=1 ER - TY - JFULL T1 - The use of isobaric tag peptide labeling (iTRAQ) and mass spectrometry to examine rare, primitive hematopoietic cells from patients with chronic myeloid leukemia A1 - Griffiths, SD A1 - Burthem, J A1 - Unwin, RD A1 - Holyoake, TL A1 - Melo, JV A1 - Lucas, GS A1 - Whetton, AD J1 - MOL BIOTECHNOL Y1 - 2007/06// VL - 36 SN - 1073-6085 SP - 81 EP - 89 N2 - Chronic Myeloid Leukemia (CML) is a hematopoietic stem cell disease, associated with a t(9, 22) chromosomal translocation leading to formation of the BCR/ABL chimeric protein, which has an intrinsic tyrosine kinase activity. Recently, the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (imatinib) has been successfully used clinically, although, disease relapse can still occur. The precise detail of the mechanism by which CML cells respond to imatinib is still unclear. We therefore systematically examined the effects of imatinib on the primitive CML cell proteome, having first established that the drug inhibits proliferation and induces increased apoptosis and differentiation. To define imatinib-induced effects on the CML proteome, we employed isobaric tag peptide labeling (iTRAQ) coupled to two-dimensional liquid chromatography/tandem mass spectrometry. Given the limited clinical material available, the isobaric tag approach identified a large population of proteins and provided relative quantification on four samples at once. Novel consequences of the action of imatinib were identified using this mass spectrometric approach. DEAD-box protein 3, heat shock protein 105 kDa, and peroxiredoxin-3 were identified as potential protein markers for response to imatinib. ER - TY - JFULL T1 - The role of high dose chemotherapy and peripheral blood stem cell support in refractory trophoblastic disease and non-gestational choriocarcinoma: A review of eight patients A1 - Gabriel, I A1 - Chaidos, A A1 - Giles, C A1 - Apperley, J A1 - Seckl, M A1 - Bower, M A1 - Kanfer, E J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 185 EP - 185 ER - TY - JFULL T1 - The risk of cancer in patients with Crohn's disease. A1 - von Roon, AC A1 - Reese, G A1 - Teare, J A1 - Constantinides, V A1 - Darzi, AW A1 - Tekkis, PP J1 - Dis Colon Rectum Y1 - 2007/06// VL - 50 SN - 0012-3706 SP - 839 EP - 855 N2 - PURPOSE: The risk of cancer in patients with Crohn's disease is not well defined. Using meta-analytical techniques, the present study was designed to quantify the risk of intestinal, extraintestinal, and hemopoietic malignancies in such patients. METHODS: A literature search identified 34 studies of 60,122 patients with Crohn's disease. The incidence and relative risk of cancer were calculated for patients with Crohn's disease and compared with the baseline population of patients without Crohn's disease. Overall pooled estimates, with 95 percent confidence intervals, were obtained, using a random-effects model. RESULTS: The relative risk of small bowel, colorectal, extraintestinal cancer, and lymphoma compared with the baseline population was 28.4 (95 percent confidence interval, 14.46-55.66), 2.4 (95 percent confidence interval, 1.56-4.36), 1.27 (95 percent confidence interval, 1.1-1.47), and 1.42 (95 percent confidence interval, 1.16-1.73), respectively. On subgroup analysis, patients with Crohn's disease had an increased risk of colon cancer (relative risk, 2.59; 95 percent confidence interval, 1.54-4.36) but not of rectal cancer (relative risk, 1.46; 95 percent confidence interval, 0.8-2.55). There was significant association between the anatomic location of the diseased bowel and the risk of cancer in that segment. The risk of small bowel cancer and colorectal cancer was found to be higher in North America and the United Kingdom than in Scandinavian countries with no evidence of temporal changes in the cancer incidence. CONCLUSIONS: The present meta-analysis demonstrated an increased risk of small bowel, colon, extraintestinal cancers, and lymphoma in patients with Crohn's disease. Patients with extensive colonic disease that has been present from a young age should be candidates for endoscopic surveillance; however, further data are required to evaluate the risk of neoplasia over time. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17308939&query_hl=1 ER - TY - JFULL T1 - Novel pathway in BCR-ABL signal transduction involves Akt-independent activation of PLC-gamma/mTOR/P70-S6 kinase A1 - Markova, B A1 - Breitenbuecher, F A1 - Melo, JV A1 - Duyster, J A1 - Huber, C A1 - Fischer, T J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 338 EP - 338 ER - TY - JFULL T1 - Multiple molecular mechanism may account for resistanceto imatinib in resistant cell lines A1 - Pane, F A1 - Esposito, N A1 - Izzo, B A1 - Quarantelli, F A1 - Colavita, I A1 - Buonomo, T A1 - Roberti, V A1 - Soverini, S A1 - Melo, JV A1 - Martinelli, G A1 - Martinelli, R A1 - Ruoppolo, M A1 - Pane, F J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 418 EP - 418 ER - TY - JFULL T1 - Clinical and imaging experience with yttrium-90 microspheres in the management of unresectable liver tumours. A1 - Jiao, LR A1 - Szyszko, T A1 - Al-Nahhas, A A1 - Tait, P A1 - Canelo, R A1 - Stamp, G A1 - Wasan, H A1 - Lowdell, C A1 - Philips, R A1 - Thillainayagam, A A1 - Bansi, D A1 - Rubello, D A1 - Limongelli, P A1 - Woo, K A1 - Habib, NA J1 - Eur J Surg Oncol Y1 - 2007/06// VL - 33 SN - 0748-7983 SP - 597 EP - 602 N2 - INTRODUCTION: Selective internal radiation therapy (SIRT) is emerging as a new therapeutic modality in recent years for management of non-resectable hepatic malignancies. Our experience in clinical application of this treatment is reported here. MATERIAL AND METHODS: From June 2004, patients whose liver tumours were no longer amenable for any conventional treatment with either chemotherapy or surgery were considered for yttrium-90 microspheres treatment after discussion at our multidisciplinary meeting. A pre-treatment planning was carried out with visceral angiography and technetium-99m macroaggregated albumin (MAA) for assessment of both tumour volume and extrahepatic shunting in addition to a baseline PET and CT scans, respectively. Two weeks later, a second visceral angiogram was performed to deliver the calculated dosage of microspheres into the arterial system supplying the tumour. Patients were then followed up with tumour markers, repeat PET and CT scans of abdomen at 6 weeks and 3 monthly thereafter. RESULT: Twenty-one patients (F=11, M=10; age range 40-75 years, mean=58 years) received yttrium-90 microspheres consisting of liver metastases from colorectal primary (n=10) and non-colorectal primaries (n=8), and primary liver tumours (n=3). One patient received 2 treatments. The mean administered activity of microspheres delivered was 1.9 GBq (range 1.2-2.5 GBq). Injection of microspheres had no immediate effect on either clinical haematology or liver function tests. At follow-up, 86% of patients showed decreased activity on PET scan at 6 weeks (p=0.01). The mean pre-treatment SUV was 12.2+/-3.7 and the mean post-treatment SUV was 9.3+/-3.7, indicating a significant improvement measured with PET activity. Only 13% showed a reduction in the size of tumour on CT scan. For patients with colorectal liver metastases, there was no significant reduction in CEA level (127+/-115 vs 75+/-72 micro/l, p=0.39). Complications were seen in 4 patients (19%) including radiation hepatitis (n=2), cholecystitis (n=1) and duodenal ulceration (n=1). All resolved without surgical intervention. Seven patients died at follow-up from progressive extrahepatic disease (33%). CONCLUSION: SIRT should be considered for patients with advanced liver cancer. It has a significant effect on liver disease in the absence of extrahepatic disease. PET imaging has an integral role in the assessment of patients treated with yttrium-90 SIR-Spheres. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17433608&query_hl=1 ER - TY - JFULL T1 - A pervasive body sensor network for measuring postoperative recovery at home. A1 - Aziz, O A1 - Atallah, L A1 - Lo, B A1 - Elhelw, M A1 - Wang, L A1 - Yang, GZ A1 - Darzi, A J1 - Surg Innov Y1 - 2007/06// VL - 14 SN - 1553-3506 SP - 83 EP - 90 N2 - Patients going home following major surgery are susceptible to complications such as wound infection, abscess formation, malnutrition, poor analgesia, and depression, all of which can develop after the fifth postoperative day and slow recovery. Although current hospital recovery monitoring systems are effective during perioperative and early postoperative periods, they cannot be used when the patient is at home. Measuring and quantifying home recovery is currently a subjective and labor-intensive process. This case report highlights the development and piloting of a wireless body sensor network to monitor postoperative recovery at home in patients undergoing abdominal surgery. The device consists of wearable sensors (vital signs, motion) combined with miniaturized computers wirelessly linked to each other, thus allowing continuous monitoring of patients in a pervasive (unobtrusive) manner in any environment. Initial pilot work with results in both the simulated (with volunteers) and the real home environment (with patients) is presented. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17558012&query_hl=1 ER - TY - JFULL T1 - Shortened duration of human chorionic gonadotrophin surveillance following complete or partial hydatidiform mole: evidence for revised protocol of a UK regional trophoblastic disease unit. A1 - Sebire, NJ A1 - Foskett, M A1 - Short, D A1 - Savage, P A1 - Stewart, W A1 - Thomson, M A1 - Seckl, MJ J1 - BJOG Y1 - 2007/06// VL - 114 SN - 1471-0528 SP - 760 EP - 762 N2 - Following hydatidiform mole, women are at increased risk of persistent gestational trophoblastic neoplasia (pGTN) and are therefore monitored using serum human chorionic gonadotrophin (hCG) concentration measurements. We retrospectively evaluated the policy of extended (2 year) follow up for women with hCG concentrations returning to normal >56 days after evacuation. Of 6701 women registered for hCG follow up, 422 (6%) developed pGTN, 412 (98%) of these women presented within 6 months after evacuation. Three developed pGTN at 402, 677 and 1267 days after evacuation following spontaneous normalisation of hCG levels. Only one woman was detected by routine extended follow up. Prolonged surveillance after molar pregnancy causes significant anxiety and is not cost-effective. Therefore, the current revised protocol comprises hCG follow up for 6 months after spontaneous return of hCG levels to normal for all women. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17516969&query_hl=1 ER - TY - JFULL T1 - Risk assessment in haemotopoietic stem cell transplantation: disease and disease stage. A1 - Chaidos, A A1 - Kanfer, E A1 - Apperley, JF J1 - Best Pract Res Clin Haematol Y1 - 2007/06// VL - 20 SN - 1521-6926 SP - 125 EP - 154 N2 - This chapter addresses the impact of the disease and disease status on the outcome of stem-cell transplantation. In consideration of the other topics addressed within this volume we have elected to focus on allogeneic rather than autologous transplantation. Furthermore we have not tried to be comprehensive and discuss the role of disease status in all conditions amenable to allografting, but rather to review the evidence that exists for selected haematological malignancies. Where possible we have made some clear recommendations, but where evidence is less clear we have indicated the ongoing controversies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17448953&query_hl=1 ER - TY - JFULL T1 - Distracting communications in the operating theatre. A1 - Sevdalis, N A1 - Healey, AN A1 - Vincent, CA J1 - J Eval Clin Pract Y1 - 2007/06// VL - 13 SN - 1356-1294 SP - 390 EP - 394 N2 - RATIONALE AND AIMS: Research suggests that there are problems of communication effectiveness in surgery. Here we describe the content, initiators and recipients of communications that intrude or interfere with individual surgical cases. We also consider the level at which the surgical team and its team members are distracted by these case-irrelevant communications (CICs). METHODS: Two psychologist observers sampled 48 general surgery procedures and they recorded the initiator and the recipient of CIC events, their content and the level of observable distraction that they caused. RESULTS: Irrelevant comments and queries (i.e. 'small-talk') accounted for half of the observed CICs. From the remaining CICs that we observed, most were related to the organization and administration of the case-list, to operating theatre provisions and to teaching junior staff. Surgeons initiated a third of the observed CICs, while receiving two thirds of them. External staff visiting the operating theatre initiated the most distracting communications. The CICs addressed to surgeons introduced significantly less distraction to the operating theatre than those addressed to anaesthetists and nurses. CONCLUSIONS: Some of the observed CICs contributed to the administration of the operating theatre case-list. Nonetheless, this communication can interfere with highly sensitive work. More effectively co-ordinated communication could reduce this interference. More research should assess the communication effectiveness and the impact of CICs on task performance in the operating theatre. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17518804&query_hl=1 ER - TY - JFULL T1 - Enhanced Bcr-Abl-specific antileukemic activity of arsenic trioxide through glutathione-depletion in imatinib-resistant cells A1 - Konig, H A1 - Hartel, N A1 - Schultheis, B A1 - Schatz, M A1 - Lorentz, C A1 - Melo, JV A1 - Hehlmann, R A1 - Hochhaus, A A1 - La Rosee, P J1 - HAEMATOL-HEMATOL J Y1 - 2007/06// VL - 92 SN - 0390-6078 SP - 838 EP - 841 N2 - The development of resistance to imatinib mesylate may partly depend on high Bc-Abl-expression levels. Arsenic trioxide (ATO) has Bcr-Abl suppressing activity in vitro. Here we investigated means to improve ATO activity in CML by modulating cellular glutathione (GSH), a key regulator of ATO-activity in malignant disease. Our studies demonstrate that depletion of cellular glutathione using dl-buthionine-[S,R]-sulfoximine (BSO) enhances ATO activity against CML cells. GSH-depletion promotes enhanced Bcr-Abl specific activity of ATO through avid repression of Bcr-Abl protein levels and total cellular Bcr-Abl activity. These data provide a rationale for the clinical development of optimized ATO-based regimens through incorporation of GSH-modulators in CML treatment. ER - TY - JFULL T1 - Searching for novel biomarkers of centrally and peripehrally-acting neurotoxicants, using surface-enhanced laser desorption/ionisation-time-of-flight mass spectrometry (SELDI-TOF MS). A1 - Fang, M A1 - Boobis, AR A1 - Edwards, RJ J1 - Food Chem Toxicol Y1 - 2007/05/24/ SN - 0278-6915 N2 - The neurotoxicity of chemicals to humans is difficult to monitor as there are no suitable methods of detecting early neuronal dysfunction. Here, a proof of principle study was designed to assess the potential of identifying protein biomarkers in accessible biofluids for this purpose. Groups of rats were treated with a range of doses of the model neurotoxicants, acrylamide (0, 2, 10, 50mg/kg) and methylmercury (0, 0.2, 1, 5mg/kg) for up to 3 weeks and samples of serum, urine, and cerebral spinal fluid analysed by surface-enhanced laser desorption/ionisation-time-of-flight mass spectrometry. There was no neuropathology up to the highest dose tested. Protein profiles were obtained from all samples and changes in the levels of many proteins were detected in both serum and urine, although not cerebral spinal fluid. In serum, the combination of three protein ion levels with m/z values of 4968, 9402 and 12,948 was able to correctly classify the treatment groups thus: 88% control, 100% acrylamide, 92% methylmercury. In urine, three protein ions with m/z values of 4944, 12,966 and 21,992 classified correctly the groups: 67% control, 94% acrylamide, 97% methylmercury. Similar classifications using other serum and urinary protein ions were also possible. This indicates the potential of serum and urine protein biomarkers for the assessment of sub-clinical neurotoxicity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17602814&query_hl=1 ER - TY - JFULL T1 - Influence of instrument size on endoscopic task performance in pediatric intracorporeal knot tying : Smaller instruments are better in infants. A1 - Lee, AC A1 - Haddad, MJ A1 - Hanna, GB J1 - Surg Endosc Y1 - 2007/05/22/ SN - 1432-2218 N2 - BACKGROUND: The widespread availability of adult minimal access surgical (MAS) equipment together with resource constraints have led pediatric surgeons to adopt the adult setup. This study examined the influence of instrument size on task outcome and physical impact on the surgeon in pediatric endoscopic intracorporeal knot tying. METHODS: Sixteen surgeons participated in this study in which they had to tie surgeon's knots inside a neonatal simulator box with an endoscopic field of 40 mm. All surgeons tied 20 knots using paired pediatric needle-holders and 20 knots using paired adult needle-holders in a randomized order. Knot quality score (KQS) and wrap length were used as indices of knot quality and wrap tightness. Electromyographic (EMG) recordings of the upper limb muscle groups were used to indicate muscular recruitment. A questionnaire on discomfort and instrument preference was also completed by the surgeons. RESULTS: A total of 640 knots were analyzed. Median time was shorter for pediatric needle-holders than for adult needle-holders (94 s vs. 103 s; p < 0.001); however, KQS (0.271 vs. 0.260; p = 0.509) and the tightness around the tube (86 mm vs. 86 mm; p = 0.255) were not significantly different. The proportion of knots that completely slipped was also similar for both needle-holders (19% vs. 22%; p = 0.322). The normalized EMG values when using adult needle-holders were significantly higher than when using pediatric needle-holders in all upper limb muscle groups with the exception of left forearm extensors (p = 0.460). The surgeons reported less discomfort with the pediatric needle-holders in the right forearm and hand, and 13 surgeons expressed overall preference for the smaller instruments. CONCLUSION: Endoscopic knot tying was performed faster in the neonatal simulator box using pediatric needle-holders while maintaining knot quality. Upper limb muscular recruitment was reduced resulting in less discomfort for the surgeon. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17516118&query_hl=1 ER - TY - JFULL T1 - Expression of eEF1A2 is associated with clear cell histology in ovarian carcinomas: overexpression of the gene is not dependent on modifications at the EEF1A2 locus. A1 - Tomlinson, VA A1 - Newbery, HJ A1 - Bergmann, JH A1 - Boyd, J A1 - Scott, D A1 - Wray, NR A1 - Sellar, GC A1 - Gabra, H A1 - Graham, A A1 - Williams, AR A1 - Abbott, CM J1 - Br J Cancer Y1 - 2007/05/21/ VL - 96 SN - 0007-0920 SP - 1613 EP - 1620 N2 - The tissue-specific translation elongation factor eEF1A2 is a potential oncogene that is overexpressed in human ovarian cancer. eEF1A2 is highly similar (98%) to the near-ubiquitously expressed eEF1A1 (formerly known as EF1-alpha) making analysis with commercial antibodies difficult. We wanted to establish the expression pattern of eEF1A2 in ovarian cancer of defined histological subtypes at both the RNA and protein level, and to establish the mechanism for the overexpression of eEF1A2 in tumours. We show that while overexpression of eEF1A2 is seen at both the RNA and protein level in up to 75% of clear cell carcinomas, it occurs at a lower frequency in other histological subtypes. The copy number at the EEF1A2 locus does not correlate with expression level of the gene, no functional mutations were found, and the gene is unmethylated in both normal and tumour DNA, showing that overexpression is not dependent on genetic or epigenetic modifications at the EEF1A2 locus. We suggest that the cause of overexpression of eEF1A2 may be the inappropriate expression of a trans-acting factor. The oncogenicity of eEF1A2 may be related either to its role in protein synthesis or to potential non-canonical functions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17437010&query_hl=1 ER - TY - JFULL T1 - Outcome of kidney transplantation from nonheart-beating versus heart-beating cadaveric donors. A1 - Kokkinos, C A1 - Antcliffe, D A1 - Nanidis, T A1 - Darzi, AW A1 - Tekkis, P A1 - Papalois, V J1 - Transplantation Y1 - 2007/05/15/ VL - 83 SN - 0041-1337 SP - 1193 EP - 1199 N2 - BACKGROUND: This study aimed to assess outcomes of kidney transplants from nonheart-beating (NHB) compared with heart-beating (HB) cadaveric donors with meta-analytical techniques. METHODS: A literature search was performed for studies comparing kidney transplants from NHB vs. HB cadaveric donors between 1992 and 2005. The following outcomes were evaluated: warm and cold ischemia times, primary nonfunction, delayed graft function, length of hospital stay, acute graft rejection, patient and graft survival, and post-transplant serum creatinine. RESULTS: Eighteen comparative studies of 114,081 patients matched the selection criteria; 1,858 received kidney from NHB and 112,223 from HB donor. Warm ischemia time was significantly longer for the NHB group by 24 min (P<0.001). Cold ischemia time was similar for the two groups (P=0.97). The incidence of primary nonfunction and delayed graft function was 2.4 times (P<0.001) and 3.6 times (P<0.001) greater, respectively, in the NHB group. Length of hospital stay was longer for the NHB group by 4.6 days (P<0.001). The 6-month, 2-year, and 5-year patient survival were similar between the two groups. The incidence of acute rejection was similar between the two groups whereas the initial graft survival advantage in favor of the HB group diminished gradually over the course of time. There was no statistically significant difference between the two groups for the recipient serum creatinine levels at 3 and 12 months after transplantation. CONCLUSION: NHB donors carry the potential of expanding the cadaveric kidney pool. Although, transplants from NHB donors are associated with a greater incidence of early adverse events, long-term outcomes appear comparable with those of transplants from HB donors. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17496535&query_hl=1 ER - TY - JFULL T1 - Exemestane tamoxifen? Reply A1 - Coombes, RC A1 - Kilburn, LS A1 - Snowdon, CF A1 - Bliss, JM A1 - Intergroup Excemestane Study J1 - LANCET Y1 - 2007/05/12/ VL - 369 SN - 0140-6736 SP - 1600 EP - 1601 ER - TY - JFULL T1 - Resistance to imatinib mesylate in chronic myeloid leukaemia. A1 - Melo, JV A1 - Chuah, C J1 - Cancer Lett Y1 - 2007/05/08/ VL - 249 SN - 0304-3835 SP - 121 EP - 132 N2 - Despite the remarkable results achieved with imatinib for the treatment of chronic myeloid leukaemia, the emergence of resistance to this tyrosine kinase inhibitor has become a significant problem. Much progress has been recently made in elucidating the mechanisms which underlie imatinib resistance. The most common cause of such drug resistance is the selection of leukaemic clones with point mutations in the Abl kinase domain leading to amino acid substitutions which prevent the appropriate binding of the drug. Other mechanisms include genomic amplification of BCR-ABL and modulation of drug efflux or influx transporters. There is a pressing need, therefore, to develop and test novel drugs and strategies. Two such compounds are now being explored in clinical trials. This review will describe the molecular basis of imatinib-resistance and strategies to overcome resistance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16949736&query_hl=1 ER - TY - JFULL T1 - p53 therapy in a patient with Li-Fraumeni syndrome. A1 - Senzer, N A1 - Nemunaitis, J A1 - Nemunaitis, M A1 - Lamont, J A1 - Gore, M A1 - Gabra, H A1 - Eeles, R A1 - Sodha, N A1 - Lynch, FJ A1 - Zumstein, LA A1 - Menander, KB A1 - Sobol, RE A1 - Chada, S J1 - Mol Cancer Ther Y1 - 2007/05// VL - 6 SN - 1535-7163 SP - 1478 EP - 1482 N2 - Li-Fraumeni syndrome is an autosomal dominant disorder that greatly increases the risk of developing multiple types of cancer. The majority of Li-Fraumeni syndrome families contain germ-line mutations in the p53 tumor suppressor gene. We describe treatment of a refractory, progressive Li-Fraumeni syndrome embryonal carcinoma with a p53 therapy (Advexin) targeted to the underlying molecular defect of this syndrome. p53 treatment resulted in complete and durable remission of the injected lesion by fluorodeoxyglucose-positron emission tomography scans with improvement of tumor-related symptoms. With respect to molecular markers, the patient's tumor had abnormal p53 and expressed coxsackie adenovirus receptors with a low HDM2 and bcl-2 profile conducive for adenoviral p53 activity. p53 treatment resulted in the induction of cell cycle arrest and apoptosis documented by p21 and cleaved caspase-3 detection. Increased adenoviral antibody titers after repeated therapy did not inhibit adenoviral p53 activity or result in pathologic sequelae. Relationships between these clinical, radiographic, and molecular markers may prove useful in guiding future application of p53 tumor suppressor therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17483435&query_hl=1 ER - TY - JFULL T1 - Adenovirus 5 vector genetically re-targeted by an affibody molecule with specificity for tumor antigen HER2/neu A1 - Magnusson, MK A1 - Henning, P A1 - Myhre, S A1 - Wikman, M A1 - Uil, TG A1 - Friedman, M A1 - Andersson, KME A1 - Hong, SS A1 - Hoeben, RC A1 - Habib, NA A1 - Stahl, S A1 - Boulanger, P A1 - Lindholm, L J1 - CANCER GENE THER Y1 - 2007/05// VL - 14 SN - 0929-1903 SP - 468 EP - 479 N2 - In order to use adenovirus (Ad) type 5 (Ad5) for cancer gene therapy, Ad needs to be de-targeted from its native receptors and re-targeted to a tumor antigen. A limiting factor for this has been to find a ligand that (i) binds a relevant target, (ii) is able to fold correctly in the reducing environment of the cytoplasm and (iii) when incorporated at an optimal position on the virion results in a virus with a low physical particle to plaque-forming units ratio to diminish the viral load to be administered to a future patient. Here, we present a solution to these problems by producing a genetically re-targeted Ad with a tandem repeat of the HER2/neu reactive Affibody molecule (ZH) in the HI-loop of a Coxsackie B virus and Ad receptor (CAR) binding ablated fiber genetically modified to contain sequences for flexible linkers between the ZH and the knob sequences. ZH is an Affibody molecule specific for the extracellular domain of human epidermal growth factor receptor 2 (HER2/neu) that is overexpressed in inter alia breast and ovarian carcinomas. The virus presented here exhibits near wild-type growth characteristics, infects cells via HER2/neu instead of CAR and represents an important step toward the development of genetically re-targeted adenoviruses with clinical relevance. ER - TY - JFULL T1 - Total CD34+ cells per 10 HPF in bone marrow trephines of patients with chronic myeloid leukaemia correlates with probability of complete cytogenetic response following imatinib treatment. A1 - Elliot, V A1 - Marin, D A1 - Horncastle, D A1 - Elderfield, K A1 - Howard, J A1 - Apperley, JF A1 - Lampert, IA A1 - Naresh, KN J1 - Histopathology Y1 - 2007/05// VL - 50 SN - 0309-0167 SP - 810 EP - 812 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17376172&query_hl=1 ER - TY - JFULL T1 - Response to donor lymphocyte infusions for chronic myeloid leukemia is dose-dependent: the importance of escalating the cell dose to maximize therapeutic efficacy. A1 - Simula, MP A1 - Marktel, S A1 - Fozza, C A1 - Kaeda, J A1 - Szydlo, RM A1 - Nadal, E A1 - Bua, M A1 - Rahemtulla, A A1 - Kanfer, E A1 - Marin, D A1 - Olavarria, E A1 - Goldman, JM A1 - Apperley, JF A1 - Dazzi, F J1 - Leukemia Y1 - 2007/05// VL - 21 SN - 0887-6924 SP - 943 EP - 948 N2 - Donor lymphocyte infusions (DLI) are an effective treatment for patients with chronic myeloid leukemia (CML) in relapse after allografting but the optimal cell dose has yet to be identified. To address this question, we investigated the factors affecting the dose required to achieve remission (effective cell dose, (ECD)) in 81 patients treated with an escalating dose regimen. The overall proportion of patients who achieved a molecular remission was 88%. The cumulative proportion of remitters increased significantly at each dose level. With a CD3(+) cell dose < or =10(7)/kg, 56% of patients in molecular/cytogenetic relapse obtained molecular remission, whereas only 20% of those in hematologic relapse did so. At the same cell dose, 58% of patients who received lymphocytes from volunteer unrelated donors achieved remission, as compared to 29% of those who received DLI from sibling donors. We conclude that the response to DLI is dose-dependent and that the ECD is influenced by the quantity and phase of CML at relapse and degree of donor/recipient histocompatibility. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17361226&query_hl=1 ER - TY - JFULL T1 - Meta-analysis of short-term and long-term outcomes of J, W and S ileal reservoirs for restorative proctocolectomy. A1 - Lovegrove, RE A1 - Heriot, AG A1 - Constantinides, V A1 - Tilney, HS A1 - Darzi, AW A1 - Fazio, VW A1 - Nicholls, RJ A1 - Tekkis, PP J1 - Colorectal Dis Y1 - 2007/05// VL - 9 SN - 1462-8910 SP - 310 EP - 320 N2 - OBJECTIVE: The choice of ileal pouch reservoir has been a contentious subject with no consensus as to which technique provides better function. This study aimed to compare short- and long-term outcomes of three ileal reservoir designs. METHOD: Comparative studies published between 1985 and 2000 of J, W and S ileal pouch reservoirs were included. Meta-analytical techniques were employed to compare postoperative complications, pouch failure, and functional and physiological outcomes. Quality of life following surgery was also assessed. RESULTS: Eighteen studies, comprising 1519 patients (689 J pouch, 306 W pouch and 524 S pouch) were included. There was no significant difference in the incidence of early postoperative complications between the three groups. The frequency of defecation over 24 h favoured the use of either a W or S pouch [J vs S: weighted mean difference (WMD) 1.48, P < 0.001; J vs W: WMD 0.97, P = 0.01]. The S pouch was associated with an increased need for pouch intubation (S vs J: OR 6.19, P = 0.04). The use of a J pouch was associated with a significantly higher prevalence of use of anti-diarrhoeal medication (J vs S: OR 2.80, P = 0.01; J vs W: OR 3.55, P < 0.001). CONCLUSION: All three reservoirs had similar perioperative complication rates. The S pouch was associated with the need for anal intubation. There was less frequency and less need for antidiarrhoeal agents with the W rather than the J pouch. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17432982&query_hl=1 ER - TY - JFULL T1 - Proteomic analysis of proteins regulated by TRPS1 transcription factor in DU145 prostate cancer cells. A1 - Chang, GT A1 - Gamble, SC A1 - Jhamai, M A1 - Wait, R A1 - Bevan, CL A1 - Brinkmann, AO J1 - Biochim Biophys Acta Y1 - 2007/05// VL - 1774 SN - 0006-3002 SP - 575 EP - 582 N2 - The aim of the present study was to identify proteins differentially regulated by TRPS1 in human prostate cancer cells in order to better understand the role of TRPS1 in prostate cancer development. The proteomes of androgen-independent DU145 prostate cancer cells, that do not express TRPS1 and of genetically engineered DU145 cells that stable and inducible express recombinant TRPS1 protein, were compared. Using two-dimensional electrophoresis followed by mass spectrometric analysis, 13 proteins that were differentially expressed between these two cell lines were identified. These proteins represent a dominant reduction of expression of antioxidant proteins, including superoxide dismutase, protein disulfide isomerase A3 precursor, endoplasmin precursor and annexin A2. Furthermore, regulation was observed for mitochondrion-associated proteins, glycolytic enzymes, a cytoskeleton-associated protein, a nuclear protein and proteins involved in apoptosis. Our data indicate that overexpression of TRPS1 protein is correlated with reduced protein expression of certain antioxidants. This suggests a possible involvement of TRPS1 in oxidative stress, and possibly in apoptosis in androgen-independent DU145 prostate cancer cells. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17467349&query_hl=1 ER - TY - JFULL T1 - Authors' reply: Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma (Br J Surg; 2007; 94; 96-105). A1 - Allen-Mersh, TG J1 - Br J Surg Y1 - 2007/05// VL - 94 SN - 0007-1323 SP - 644 EP - 645 N2 - L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17443878&query_hl=1 ER - TY - JFULL T1 - C-terminal antibodies (CTAbs): a simple and broadly applicable approach for the rapid generation of protein-specific antibodies with predefined specificity. A1 - Edwards, RJ A1 - Wrigley, A A1 - Bai, Z A1 - Bateman, M A1 - Russell, H A1 - Murray, S A1 - Lu, H A1 - Taylor, GW A1 - Boobis, AR A1 - Sriskandan, S J1 - Proteomics Y1 - 2007/05// VL - 7 SN - 1615-9853 SP - 1364 EP - 1372 N2 - Recent advances in proteomic techniques have resulted in an ever-increasing need to produce antibodies. Here, to address this problem, a technically simple approach of targeting the extreme C-termini of proteins with antibodies (CTAbs) was investigated in proteins secreted by the human pathogen Streptococcus pyogenes. Target proteins were identified by a conventional proteomic approach and CTAbs produced against synthetic five amino acid peptides representing the C-terminus of each target protein. In every case where protein secretion was demonstrated (n = 20), CTAbs were successfully produced and bound specifically to the target protein (100% success rate). The apparent specificity was consistent with the structural heterogeneity of the C-termini of S. pyogenes proteins. The global specificity of CTAb binding was defined using a combinatorial library of synthetic peptides representing structural variants of the original synthetic immunogen. This is a systematic and comprehensive approach for the development of antibodies with defined specificity that can be used in a range of applications. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17407178&query_hl=1 ER - TY - JFULL T1 - Intraperitoneal chemotherapy as first-line treatment in the management of epithelial ovarian cancer. A1 - Rekhraj, S A1 - Kinross, J A1 - Prabhudesai, S A1 - Darzi, A A1 - Ziprin, P J1 - Mini Rev Med Chem Y1 - 2007/05// VL - 7 SN - 1389-5575 SP - 509 EP - 517 N2 - Recent evidence has suggested improved outcomes following incorporation of intraperitoneal chemotherapy administration with intravenous systemic chemotherapy as first-line treatment of small volume residual epithelial ovarian cancer. This review focuses on the mechanism of actions of the chemotherapeutic drugs and reviews the possible reasons for the superior outcomes of intraperitoneal chemotherapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17504186&query_hl=1 ER - TY - JFULL T1 - Identification of skills common to renal and iliac endovascular procedures performed on a virtual reality simulator. A1 - Neequaye, SK A1 - Aggarwal, R A1 - Brightwell, R A1 - Van Herzeele, I A1 - Darzi, A A1 - Cheshire, NJ J1 - Eur J Vasc Endovasc Surg Y1 - 2007/05// VL - 33 SN - 1078-5884 SP - 525 EP - 532 N2 - INTRODUCTION: There is a learning curve in the acquisition of endovascular skills for the treatment of vascular disease. Integration of Virtual reality (VR) simulator based training into the educational training curriculum offers a potential solution to overcome this learning curve. However evidence-based training curricula that define which tasks, how often and in which order they should be performed have yet to be developed. The aim of this study was to determine the nature of skills acquisition on the renal and iliac modules of a commercially-available VR simulator. METHOD: 20 surgical trainees without endovascular experience were randomised to complete eight sessions on a VR iliac (group A) or renal (group B) training module. To determine skills transferability across the two procedures, all subjects performed two further VR cases of the other procedure. Performance was recorded by the simulator for parameters such as time taken, contrast fluid usage and stent placement accuracy. RESULTS: During training, both groups demonstrated statistically significant VR learning curves: group A for procedure time (p<0.001) and stent placement accuracy (p=0.013) group B for procedure time (p<0.001), fluoroscopy time (p=0.003) and volume of contrast fluid used (p<0.001). At crossover, subjects in group B (renal trained) performed to the same level of skill on the simulated iliac task as group A. However, those in group A (iliac trained) had a significantly higher fluoroscopy time (median 118 vs 72 secs, p=0.020) when performing their first simulated renal task than for group B. CONCLUSION: Novice endovascular surgeons can significantly improve their performance of simulated procedures through repeated practice on VR simulators. Skills transfer between tasks was demonstrated but complex task training, such as selective arterial cannulation in simulators and possibly in the real world appears to involve a separate skill. It is thus suggested that a stepwise and hierarchical training curriculum is developed for acquisition of endovascular skill using VR simulation to supplement training on patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17291792&query_hl=1 ER - TY - JFULL T1 - The permeability transition pore in cell death. A1 - Grimm, S A1 - Brdiczka, D J1 - Apoptosis Y1 - 2007/05// VL - 12 SN - 1360-8185 SP - 841 EP - 855 N2 - The permeability transition pore (PT-pore) is a multi-component protein aggregate in mitochondria that comprises factors in the inner as well as in the outer mitochondrial membrane. This complex has two functions: firstly, it regulates the integration of oxidative phosphorylation into the cellular energy household and secondly, it induces cell death when converted into an unspecific channel. The latter causes a collapse of the mitochondrial membrane potential and activates a chain of events that culminate in the demise of the cell. It has been controversial for some time whether the PT-pore is causative for or only amplifies a signal of cell death but novel results confirm a central role of this protein complex for cell death induction. While a considerable body of data exist on its subunit composition, recent genetic knock-out experiments suggest that the identity of the core factors of the PT-pore is still unresolved. Moreover, accumulating evidence point to a much more complex composition of this protein complex than anticipated. Here, we review the current knowledge of its subunit composition, the evidence of a role in cell death, and we propose a model for the activation of the PT-pore for cell death. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17453156&query_hl=1 ER - TY - JFULL T1 - Critical role for lipid raft-associated Src kinases in activation of PI3K-Akt signalling. A1 - Arcaro, A A1 - Aubert, M A1 - Espinosa del Hierro, ME A1 - Khanzada, UK A1 - Angelidou, S A1 - Tetley, TD A1 - Bittermann, AG A1 - Frame, MC A1 - Seckl, MJ J1 - Cell Signal Y1 - 2007/05// VL - 19 SN - 0898-6568 SP - 1081 EP - 1092 N2 - Lipid rafts are membrane microdomains distinct from caveolae, whose functions in polypeptide growth factor signalling remain unclear. Here we show that in small cell lung cancer (SCLC) cells, specific growth factor receptors such as c-Kit associate with lipid rafts and that these domains play a critical role in the activation of phosphoinositide 3-kinase (PI3K) signalling. The class IA p85/p110alpha associated with Src in lipid rafts and was activated by Src in vitro. Lipid raft integrity was essential for Src activation in response to stem cell factor (SCF) and raft disruption selectively inhibited activation of protein kinase B (PKB)/Akt in response to SCF stimulation. Moreover, inhibition of Src kinases blocked PKB/Akt activation and SCLC cell growth. The use of fibroblasts with targeted deletion of the Src family kinase genes confirmed the role of Src kinases in PKB/Akt activation by growth factor receptors. Moreover a constitutively activated mutant of Src also stimulated PI3K/Akt in lipid rafts, indicating that these microdomains play a role in oncogenic signalling. Together our data demonstrate that lipid rafts play a key role in the activation of PI3K signalling by facilitating the interaction of Src with specific PI3K isoforms. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17275257&query_hl=1 ER - TY - JFULL T1 - Diffuse optical imaging of the healthy and diseased breast: A systematic review. A1 - Leff, DR A1 - Warren, OJ A1 - Enfield, LC A1 - Gibson, A A1 - Athanasiou, T A1 - Patten, DK A1 - Hebden, J A1 - Yang, GZ A1 - Darzi, A J1 - Breast Cancer Res Treat Y1 - 2007/04/28/ SN - 0167-6806 N2 - Screening X-ray mammography is limited by false positives and negatives leading to unnecessary physical and psychological morbidity. Diffuse Optical Imaging using harmless near infra red light, provides lesion detection based on functional abnormalities and represents a novel diagnostic arm that could complement traditional mammography. Reviews of optical breast imaging have not been systematic, are focused mainly on technological developments, and have become superseded by rapid technological advancement. The aim of this study is to review clinically orientated studies involving approximately 2,000 women in whom optical mammography has been used to evaluate the healthy or diseased breast. The results suggest that approximately 85% of breast lesions are detectable on optical mammography. Spectroscopic resolution of tissue haemoglobin composition and oxygen saturation may improve the detectability of breast diseases. Results suggest that breast lesions contain approximately twice the haemoglobin concentration of background tissue. Current evidence suggests that it is not possible to distinguish benign from malignant disease using optical imaging techniques in isolation. Methods to improve the performance of Diffuse Optical Imaging, such as better spectral coverage with additional wavelengths, improved modelling of light transport in tissues and the use of extrinsic dyes may augment lesion detection and characterisation. Future research should involve large clinical trials to determine the overall sensitivity and specificity of optical imaging techniques as well as to establish patient satisfaction and economic viability. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17468951&query_hl=1 ER - TY - JFULL T1 - Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. A1 - Crawley, C A1 - Iacobelli, S A1 - Björkstrand, B A1 - Apperley, JF A1 - Niederwieser, D A1 - Gahrton, G J1 - Blood Y1 - 2007/04/15/ VL - 109 SN - 0006-4971 SP - 3588 EP - 3594 N2 - Despite the widespread adoption of reduced-intensity conditioning (RIC) for myeloma, there are few data comparing outcomes with RIC with myeloablative conditioning (MAC). We report the outcomes of patients undergoing allogeneic transplantations for myeloma and reported to the EBMT. A minimum data set was available on 320 RIC and 196 MAC allografts performed between 1998 and 2002. The RIC patients were older (51 vs 45 years) with more progressive disease (28% vs 21%) and more had received a prior transplant (76% vs 11%). In addition, there was a longer time to transplantation and an increased use of peripheral blood and T-cell depletion. For RIC and MAC, respectively, the nonrelapse mortality (NRM) at 2 years was 24% and 37% (P = .002); overall survival, 38.1% and 50.8% (not significant [ns]); and progression-free survival (PFS), 18.9% and 34.5% (P = .001). On multivariate analysis, RIC was associated with a reduction in NRM (HR, 0.5), but this was offset by an increase in relapse risk (HR, 2.0), and the conditioning intensity did not impact on overall survival or retain significance for PFS. These data suggest that there is a continuing need to investigate dose intensity in the conditioning for myeloma allografts. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158231&query_hl=1 ER - TY - JFULL T1 - Upregulation of the TGF beta signalling pathway by Bcr-Abl: Implications for haemopoietic cell growth and chronic myeloid leukaemia A1 - Moller, GMO A1 - Frost, V A1 - Melo, JV A1 - Chantry, A J1 - FEBS LETT Y1 - 2007/04/03/ VL - 581 SN - 0014-5793 SP - 1329 EP - 1334 N2 - Chronic myeloid leukaemia (CML) is a myeloproliferative disorder characterized by uncontrolled growth of progenitor cells expressing the tyrosine kinase fusion gene product, Bcr-Abl. At present, little is known regarding how TGF beta, and downstream Smad transcription factors, influence CML cell proliferation in the context of Bcr-Abl expression. Here we show that ectopic Bcr-Abl expression dramatically increases TGF beta/Smad-dependent transcriptional activity in Cosl cells, and that this may be due to enhancement of Smad promoter activity. Bcr-Abl expressing TF-1 myeloid cells are more potently growth arrested by TGF beta compared to the parental TF-1 cell line. Additionally, growth of Bcr-Abl-expressing CD34+ cells from chronic phase CML patients is inhibited by TGF beta and, interestingly, treatment of a non-proliferating CD34+ CML cell subpopulation with the TGF beta kinase inhibitor SB431542 enhanced cell death mediated by the Bcr-Abl inhibitor imatinib. Our data suggest that the expression of Bcr-Abl leads to hyper-responsiveness of myeloid cells to TGF beta, and we hypothesise that this novel cross-regulatory mechanism might play an important role in maintaining the transformed progenitor cell population in CML. (c) 2007 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved. ER - TY - JFULL T1 - Expression of cytochromes P450 3A and P-glycoprotein in human large intestine in paired tumour and normal samples. A1 - Canaparo, R A1 - Nordmark, A A1 - Finnström, N A1 - Lundgren, S A1 - Seidegård, J A1 - Jeppsson, B A1 - Edwards, RJ A1 - Boobis, AR A1 - Rane, A J1 - Basic Clin Pharmacol Toxicol Y1 - 2007/04// VL - 100 SN - 1742-7835 SP - 240 EP - 248 N2 - Our objective was to investigate the expression of different cytochromes P450 3A (CYP3A4, CYP3A5, and CYP3A7) and P-glycoprotein (ABCB1) genes along the human large intestine in paired tumour and normal samples. Real-time reverse transcriptase-polymerase chain reaction was used to measure CYP3A4-, CYP3A5-, CYP3A7- and ABCB1-specific mRNA expression, and Western blot analysis was used to measure membrane protein levels of CYP3A4/7, CYP3A5 and P-glycoprotein. Levels of mRNA and membrane protein fractions in the large intestine were compared with those of normal human liver. The mRNA expressions of CYP3A4, CYP3A5, CYP3A7 and ABCB1 in the large intestine were found to be highly variable, but overall the levels were significantly lower than those measured in liver (P < 0.0001, P < 0.001, P < 0.0001 and P < 0.01, respectively). At the membrane protein level, CYP3A4/7 was detected in all large intestine samples examined and the levels were substantially higher than those of the liver (P < 0.01). Although expression of CYP3A5 was detected in all large intestine samples, in most the levels were too low to allow quantification. P-glycoprotein was readily detected at levels slightly higher than those of liver (P < 0.05). Comparison between paired samples of normal and tumour in large intestine showed no significant differences in either the mRNA or membrane protein levels of these genes. In conclusion, this work suggests a potential role of the large intestine in the absorption and metabolism of xenobiotics and nutrients and no difference in the CYP3A and P-glycoprotein membrane protein fractions and mRNA expression between normal and tumour tissues. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17371528&query_hl=1 ER - TY - JFULL T1 - Results of major hepatectomy without vascular clamping using radiofrequency-assisted technique compared with total vascular exclusion. A1 - Ayav, A A1 - Navarra, G A1 - Basaglia, E A1 - Tierris, J A1 - Healey, A A1 - Spalding, D A1 - Canelo, R A1 - Habib, NA A1 - Jiao, LR J1 - Hepatogastroenterology Y1 - 2007/04// VL - 54 SN - 0172-6390 SP - 806 EP - 809 N2 - BACKGROUND/AIMS: To improve major hepatectomy results, various techniques with or without vascular clamping have been developed. We report the results of major hepatectomies performed with radiofrequency-assisted technique (RF) without vascular clamping and compare these results to total vascular exclusion (TVE). METHODOLOGY: All patients who underwent a major hepatectomy between 1994 and 2004 were identified. Outcome of liver resection with these two techniques was compared. Data including blood transfusion requirement, intensive care admission, postoperative liver function, morbidity and mortality were collected. RESULTS: Seventy-eight patients underwent a major hepatectomy including resection using TVE (n = 51) and RF (n = 27). Blood transfusion rate was lower in RF group (26% vs. 53%, P = 0.04). Postoperative morbidity rate was similar in both groups, but there was a reduction in postoperative liver failure in RF group (0 vs. 9, p = 0.05). One patient developed biliary leak postoperatively in the RF group. No patients developed postoperative hemorrhage. In RF group, there was a reduction in both ICU admission (6% vs. 92%, P < 0.0001) and postoperative stay (10 vs. 17 days, P < 0.004). A substantial saving of pound 5185 per-patient could be achieved in RF patients. CONCLUSIONS: Major hepatectomy using RF decreases the rates of blood transfusion, postoperative liver failure, ICU admission, postoperative stay and the price, when compared to TVE. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17591068&query_hl=1 ER - TY - JFULL T1 - Laparoscopic liver resection assisted with radiofrequency. A1 - Bachellier, P A1 - Ayav, A A1 - Pai, M A1 - Weber, JC A1 - Rosso, E A1 - Jaeck, D A1 - Habib, NA A1 - Jiao, LR J1 - Am J Surg Y1 - 2007/04// VL - 193 SN - 0002-9610 SP - 427 EP - 430 N2 - BACKGROUND: Radiofrequency-assisted laparoscopic liver resection is reported. METHODS: Patients suitable for liver resection were carefully assessed for laparoscopic resection. Patient and intraoperative and postoperative data were prospectively collected and analyzed. RESULTS: Eighteen patients underwent laparoscopic liver resection. All operations were performed without vascular clamping and consisting of tumorectomy (n = 9), multiple tumoretcomies (n = 2), segmentectomy (n = 2), and bisegmentectomies (n = 2). Mean blood loss was 121 +/- 68 mL, and mean resection was time 167 +/- 45 minutes. There was no need for perioperative or postoperative transfusion of blood or blood products. One patient developed pneumothorax during surgery as a result of direct puncture of pleura with the radiofrequency probe, and 1 patient had transient liver failure and required supportive care after surgery. The mean length of hospital stay was 6.0 +/-1.5 days. At follow-up, those with liver cancer had no recurrence. CONCLUSIONS: Radiofrequency-assist laparoscopic liver resection can decrease the risk of intraoperative bleeding and blood transfusion. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17368282&query_hl=1 ER - TY - JFULL T1 - Echocardiographic findings in long term survivors of allogeneic stem cell transplantation for chronic myeloid leukemia A1 - Ayto, R A1 - Garfield, B A1 - Todd, J A1 - Kanfer, E A1 - Olavaria, E A1 - Rahemtulla, A A1 - Marin, D A1 - Apperley, J A1 - Salooja, N J1 - BRIT J HAEMATOL Y1 - 2007/04// VL - 137 SN - 0007-1048 SP - 77 EP - 78 ER - TY - JFULL T1 - Quantifying distraction and interruption in urological surgery. A1 - Healey, AN A1 - Primus, CP A1 - Koutantji, M J1 - Qual Saf Health Care Y1 - 2007/04// VL - 16 SN - 1475-3901 SP - 135 EP - 139 N2 - BACKGROUND: To enhance safety in surgery, it is necessary to develop a variety of tools for measuring and evaluating the system of work. One important consideration for safety in any high-risk work is the frequency and effect of distraction and interruption. AIM: To quantify distraction and interruption to the sterile surgical team in urology. METHODS: Observation of the behaviour of the surgical team and their task activity determined distraction and interruption recorded. Using an ordinal scale, an observer rated each salient distraction or interruption observed in relation to the team's involvement. RESULTS: The frequency of events and their attached ratings were high, deriving from varying degrees of equipment, procedure and environment problems, telephones, bleepers and conversations. DISCUSSION: With further refinement and testing, this method may be useful for distinguishing ordinal levels of work interference in surgery and helpful in raising awareness of its origin for postoperative surgical team debriefing. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17403761&query_hl=1 ER - TY - JFULL T1 - Intraperitoneal aerosolization of bupivacaine reduces postoperative pain in laparoscopic surgery: a randomized prospective controlled double-blinded clinical trial. A1 - Alkhamesi, NA A1 - Peck, DH A1 - Lomax, D A1 - Darzi, AW J1 - Surg Endosc Y1 - 2007/04// VL - 21 SN - 1432-2218 SP - 602 EP - 606 N2 - BACKGROUND: Laparoscopic strategies for managing intraabdominal pathologies offer significant benefits compared with conventional approaches. Of interest are reports of decreased postoperative pain, resulting in shorter hospitalization and earlier return to normal activity. However, many patients still require strong analgesia postoperatively. This study analyzed the use of intraoperatively delivered aerosolized intraperitoneal bupivacaine and its ability to reduce postoperative pain. METHODS: For this study, 80 patients undergoing laparoscopic cholecystectomy were recruited and divided randomly into four groups: control (n = 20), aerosolized bupivacaine (n = 20), aerosolized normal saline (n = 20), and local bupivacaine in the bladder bed (n = 20). All the patients had standard preoperative, intraoperative, and postoperative care. Pain scores were recorded by the nursing staff in recovery, then 6, 12, and 24 h postoperatively using a standard 0 to 10 pain scoring scale. In addition, opiate consumption and oral analgesia were recorded. RESULTS: Aerosolized bupivacaine significantly reduced postoperative pain in comparison with all other treatments (p < 0.05). Injection of bupivacaine into the gallbladder bed did not result in a significant difference from the control condition. CONCLUSION: Aerosolized intraperitoneal local anesthetic is an effective method for controlling postoperative pain. It significantly helped to reduce opiate use and contributed to rapid mobilization, leading to short hospitalization and possible reduction in treatment cost. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17180268&query_hl=1 ER - TY - JFULL T1 - The effects of various leukocyte filtration strategies in cardiac surgery. A1 - Warren, O A1 - Alexiou, C A1 - Massey, R A1 - Leff, D A1 - Purkayastha, S A1 - Kinross, J A1 - Darzi, A A1 - Athanasiou, T J1 - Eur J Cardiothorac Surg Y1 - 2007/04// VL - 31 SN - 1010-7940 SP - 665 EP - 676 N2 - It is known that cardiopulmonary bypass causes an inflammatory reaction with an associated morbidity and mortality. Several anti-inflammatory strategies have been implemented to reduce this response, including leukocyte removal from the circulation using specialised filters. The aim of this study is to systematically review the available evidence on leukocyte filtration in cardiac surgery, focusing on its effect on systemic inflammation and whether this has influenced clinical outcomes. Five electronic databases were systematically searched for studies reporting the effect of leukocyte filtration at any point within the cardiopulmonary bypass circuit in humans. Reference lists of all identified studies were checked for any missing publications. Two authors independently extracted the data from the included studies. Whilst systemic leukodepleting filters do not appear to consistently lower leukocyte counts, they may preferentially remove activated leukocytes. Small improvements in early post-operative lung function in patients receiving systemic leukodepletion have been reported, but this does not lead to reduced hospital stay or decreased mortality. There is substantial evidence that cardioplegic leukocyte filtration attenuates the reperfusion injury at a cellular level, but this has not been translated into clinical improvements. Finally, whilst various strategies involving multiple leukocyte filters, or the incorporation of pharmacological agents into leukocyte-depleting protocols have been evaluated, the current available results are not conclusive. Our study suggests that there is not enough high quality or consistent evidence to draw guidelines regarding the use of leukocyte-depleting filters within routine cardiac surgical practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17240156&query_hl=1 ER - TY - JFULL T1 - Does re-operation have an effect on outcome following heart transplantation? A1 - Kokkinos, C A1 - Athanasiou, T A1 - Rao, C A1 - Constantinidis, V A1 - Poullis, C A1 - Smith, A A1 - Ridgway, M A1 - Tekkis, PP A1 - Darzi, A J1 - Heart Lung Circ Y1 - 2007/04// VL - 16 SN - 1443-9506 SP - 93 EP - 102 N2 - OBJECTIVE: Previous cardiac operation has traditionally been considered as a potential risk factor for patients undergoing heart transplantation. This study aimed to evaluate the outcome of patients undergoing heart transplantation as a second cardiac procedure and compare it with primary heart transplantation, using meta-analytical methodology. METHODS: A literature search was undertaken to identify relevant comparative studies. Outcomes of interest were classified into four categories: (a) intra-operative times; (b) post-operative outcomes; (c) resources; (d) actuarial outcomes. RESULTS: Seven studies matched the selection criteria, reporting on 1004 patients. Six hundred and twenty-three had transplantation as primary operation and 381 as re-operation. The 1-year, 2-year, and 5-year mortality were similar for the two groups (HR=0.85, p=0.54; HR=0.97, p=0.88; and HR=1.04, p=0.92, respectively). Total operative, cold-ischaemic, by-pass, and cross-clamp times were significantly longer for the re-operation group by 59.44 (p<0.001), 14.62 (p=0.05), 25.24 (p<0.001), and 7.93 (p<0.001)min, respectively. Both ICU and hospital stay were longer for the re-operation group but only the former was statistically significant (WMD=1.37; p=0.02). Post-operative complications were similar, except re-exploration rate and blood transfusion requirement, which were higher in the re-operation group (OR=3.51; p<0.001 and WMD=2.21; p<0.001, respectively). CONCLUSIONS: Heart transplantation following previous cardiac operation is technically demanding requiring longer operative times compared to primary heart transplantation. It does not, however, add a significant risk to the survival of the patient, and associated morbidity is not significantly compromised. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17314069&query_hl=1 ER - TY - JFULL T1 - Vascular endothelial growth factor and calprotectin in blood and bile for diagnosis of pancreatobiliary carcinoma: A pilot study A1 - East, JE A1 - Troup, S A1 - Mawdsley, J A1 - Jiao, L A1 - Habib, N A1 - Westaby, D A1 - Bansi, D A1 - Muller, B A1 - Thillainayagam, AV J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A75 EP - A75 ER - TY - JFULL T1 - Targeted inactivation of fh1 causes proliferative renal cyst development and activation of the hypoxia pathway. A1 - Pollard, PJ A1 - Spencer-Dene, B A1 - Shukla, D A1 - Howarth, K A1 - Nye, E A1 - El-Bahrawy, M A1 - Deheragoda, M A1 - Joannou, M A1 - McDonald, S A1 - Martin, A A1 - Igarashi, P A1 - Varsani-Brown, S A1 - Rosewell, I A1 - Poulsom, R A1 - Maxwell, P A1 - Stamp, GW A1 - Tomlinson, IP J1 - Cancer Cell Y1 - 2007/04// VL - 11 SN - 1535-6108 SP - 311 EP - 319 N2 - Germline mutations in the fumarate hydratase (FH) tumor suppressor gene predispose to leiomyomatosis, renal cysts, and renal cell cancer (HLRCC). HLRCC tumors overexpress HIF1alpha and hypoxia pathway genes. We conditionally inactivated mouse Fh1 in the kidney. Fh1 mutants developed multiple clonal renal cysts that overexpressed Hif1alpha and Hif2alpha. Hif targets, such as Glut1 and Vegf, were upregulated. We found that Fh1-deficient murine embryonic stem cells and renal carcinomas from HLRCC showed similar overexpression of HIF and hypoxia pathway components to the mouse cysts. Our data have shown in vivo that pseudohypoxic drive, resulting from HIF1alpha (and HIF2alpha) overexpression, is a direct consequence of Fh1 inactivation. Our mouse may be useful for testing therapeutic interventions that target angiogenesis and HIF-prolyl hydroxylation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17418408&query_hl=1 ER - TY - JFULL T1 - Management of benign biliary strictures: Endoscopy versus surgery, institutional experience A1 - Damrah, OM A1 - Lauretta, A A1 - Thillinianagram, A A1 - Bansi, D A1 - Jiao, L A1 - Canelo, R A1 - Habib, N J1 - GUT Y1 - 2007/04// VL - 56 SN - 0017-5749 SP - A88 EP - A88 ER - TY - JFULL T1 - Framework for systematic training and assessment of technical skills. A1 - Aggarwal, R A1 - Grantcharov, TP A1 - Darzi, A J1 - J Am Coll Surg Y1 - 2007/04// VL - 204 SN - 1072-7515 SP - 697 EP - 705 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17382230&query_hl=1 ER - TY - JFULL T1 - Liver dysfunction in long-term survivors of stem cell transplantation A1 - Nathwani, R A1 - Olavarria, E A1 - Kanfer, E A1 - Rahemtulla, A A1 - Marin, D A1 - Todd, J A1 - Apperley, J A1 - Salooja, N J1 - BONE MARROW TRANSPL Y1 - 2007/04// VL - 39 SN - 0268-3369 SP - S205 EP - S206 ER - TY - JFULL T1 - Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. A1 - von Roon, AC A1 - Karamountzos, L A1 - Purkayastha, S A1 - Reese, GE A1 - Darzi, AW A1 - Teare, JP A1 - Paraskeva, P A1 - Tekkis, PP J1 - Am J Gastroenterol Y1 - 2007/04// VL - 102 SN - 0002-9270 SP - 803 EP - 813 N2 - OBJECTIVES: Fecal calprotectin (FC) is a relatively new marker of intraluminal intestinal inflammation. Using meta-analytical techniques, the study aimed to evaluate the diagnostic precision of FC for inflammatory bowel disease (IBD) and colorectal cancer (CRC) in adults and children. METHODS: Quantitative meta-analysis was performed on prospective studies, comparing FC levels against the histological diagnosis. Sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated for each study. Summary receiver-operating characteristic (sROC) curves and subgroup analysis were undertaken. Study quality and heterogeneity were evaluated. RESULTS: Thirty studies of 5,983 patients were included. FC levels in patients with IBD were higher by 219.2 micrograms per gram (microg/g) compared with normal patients (P < 0.001). sROC curve analysis showed a sensitivity of 0.95 (95% CI 0.93-0.97), specificity of 0.91 (95% CI 0.86-0.91), and an area under the curve (AUC) of 0.95 for the diagnosis of IBD. Patients with colorectal neoplasia had nonsignificantly higher FC levels by 132.2 microg/g compared with noncancer controls (P= 0.18). Sensitivity and specificity of FC for the diagnosis of CRC were 0.36 and 0.71, respectively, with an AUC of 0.66. The diagnostic precision of FC for IBD was higher in children than adults with better accuracy at a cutoff level of 100 microg/g versus 50 microg/g. Sensitivity analysis and metaregression analysis did not significantly alter the results. CONCLUSIONS: FC cannot be recommended as a screening test for CRC in the general population. FC appeared to offer a good diagnostic precision in distinguishing IBD from non-IBD diagnoses, with higher precision at a cutoff of 100 microg/g. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17324124&query_hl=1 ER - TY - JFULL T1 - Intraperitoneal local anesthesia during laparoscopic cholecystectomy: the role of meta-analytical subgroups and delivery of the local anesthetic. A1 - Purkayastha, S A1 - Alkhamesi, NA A1 - Darzi, AW J1 - Anesth Analg Y1 - 2007/04// VL - 104 SN - 1526-7598 SP - 994 EP - 994 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17377127&query_hl=1 ER - TY - JFULL T1 - Cost effectiveness analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. A1 - Rao, C A1 - Aziz, O A1 - Panesar, SS A1 - Jones, C A1 - Morris, S A1 - Darzi, A A1 - Athanasiou, T J1 - BMJ Y1 - 2007/03/24/ VL - 334 SN - 1468-5833 SP - 621 EP - 621 N2 - OBJECTIVE: To compare the cost effectiveness of percutaneous transluminal coronary artery stenting with minimally invasive internal thoracic artery bypass for isolated lesions of the left anterior descending artery. DESIGN: Cost effectiveness analysis. DATA SOURCES: Embase, Medline, Cochrane, Google Scholar, and Health Technology Assessment databases (1966-2005), and reference sources for utility values and economical variables. METHODS: Decision analytical modelling and Markov simulation were used to model medium and long term costs, quality of life, and cost effectiveness after either intervention using data from referenced sources. Probabilistic sensitivity and alternative analyses were used to investigate the effect of uncertainty about the value of model variables and model structure. RESULTS: Stenting was the dominant strategy in the first two years, being both more effective and less costly than bypass surgery. In the third year bypass surgery still remained more expensive but became marginally more effective. As the incremental cost effectiveness was 1,108,130.40 pounds sterling (1 682,146.00 euros; $2,179,194) per quality adjusted life year (QALY), the additional effectiveness could not be said to justify the additional cost at this stage. By five years, however, the incremental cost effectiveness ratio of 28,042.95 pounds sterling per QALY began to compare favourably with other interventions. At 10 years the additional effectiveness of 0.132 QALYs (range -0.166 to 0.430) probably justified the additional cost of 829.02 pounds sterling (range 205.56 pounds sterling to 1452.48 pounds sterling), with an incremental cost effectiveness of 6274.02 pounds sterling per QALY. Sensitivity and alternative analysis showed the results were sensitive to the time horizon and stent type. CONCLUSIONS: Minimally invasive left internal thoracic artery bypass may be a more cost effective medium and long term alternative to percutaneous transluminal coronary artery stenting. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17337457&query_hl=1 ER - TY - JFULL T1 - Meta-analysis of minimally invasive internal thoracic artery bypass versus percutaneous revascularisation for isolated lesions of the left anterior descending artery. A1 - Aziz, O A1 - Rao, C A1 - Panesar, SS A1 - Jones, C A1 - Morris, S A1 - Darzi, A A1 - Athanasiou, T J1 - BMJ Y1 - 2007/03/24/ VL - 334 SN - 1468-5833 SP - 617 EP - 617 N2 - OBJECTIVE: To compare outcomes between minimally invasive left internal thoracic artery bypass and percutaneous coronary artery stenting as primary interventions for isolated lesions of the left anterior descending artery. DESIGN: Meta-analysis of randomised and non-randomised comparative peer reviewed publications. DATA SOURCES: Embase, Medline, Cochrane, Google Scholar, and Health Technology Assessment databases (1966-2005). REVIEW METHODS: Studies comparing the two procedures as the primary intervention for isolated left anterior descending artery stenosis were identified and the following extracted: study design, population characteristics, severity of coronary artery disease, cardiovascular risk factors, and outcomes of interest. RESULTS: 12 studies (1952 patients) reporting results from eight groups were included: one was a retrospective design, one prospective non-randomised, and six prospective randomised. Meta-analysis of randomised trials showed a higher rate of recurrence of angina (odds ratio 2.62, 95% confidence interval 1.32 to 5.21), incidence of major adverse coronary and cerebral events (2.86, 1.62 to 5.08), and need for repeat revascularisation (4.63, 2.52 to 8.51) with percutaneous stenting. No significant difference was found in myocardial infarction, stroke, or mortality at maximum follow-up between interventions. CONCLUSIONS: Minimally invasive left internal thoracic artery bypass for isolated lesions of the left anterior descending artery resulted in fewer complications in the mid-term compared with percutaneous transluminal coronary artery stenting. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17337458&query_hl=1 ER - TY - JFULL T1 - Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. (vol 369, pg 559, 2007) A1 - Coombes, RC A1 - Kilburn, LS A1 - Snowdon, CF J1 - LANCET Y1 - 2007/03/17/ VL - 369 SN - 0140-6736 SP - 906 EP - 906 ER - TY - JFULL T1 - Prohibitin, a protein downregulated by androgens, represses androgen receptor activity. A1 - Gamble, SC A1 - Chotai, D A1 - Odontiadis, M A1 - Dart, DA A1 - Brooke, GN A1 - Powell, SM A1 - Reebye, V A1 - Varela-Carver, A A1 - Kawano, Y A1 - Waxman, J A1 - Bevan, CL J1 - Oncogene Y1 - 2007/03/15/ VL - 26 SN - 0950-9232 SP - 1757 EP - 1768 N2 - Prohibitin (PHB) is a cell cycle regulatory protein, known to repress E2F1-mediated gene activation via recruitment of transcriptional regulatory factors such as retinoblastoma and histone deacetylase 1 (HDAC1). We previously identified PHB as a target protein of androgen signaling in prostate cancer cells and showed that downregulation of PHB is required for androgen-induced cell cycle entry in these cells. We now present evidence that PHB, which has 54% homology at the protein level to the oestrogen receptor corepressor REA (repressor of oestrogen receptor activity), can repress androgen receptor (AR)-mediated transcription and androgen-dependent cell growth. Depletion of endogenous PHB resulted in an increase in expression of the androgen-regulated prostate-specific antigen gene. The repression appears to be specific to androgen and closely related receptors, as it is also evident for the glucocorticoid and progesterone, but not oestrogen, receptors. In spite of interaction of PHB with HDAC1, HDAC activity is not required for this repression. Although AR and PHB could be co-immunoprecipitated, no direct interaction was detectable, suggesting that PHB forms part of a repressive complex with the AR. Competition with the co-activator SRC1 further suggests that formation of a complex with AR, PHB and other cofactors is the mechanism by which repression is achieved. It appears then that repression of AR activity is one mechanism by which PHB inhibits androgen-dependent growth of prostate cells. Further, this study implies that the AR itself could, by mediating downregulation of a corepressor, be involved in the progression of prostate tumours to the hormone refractory stage. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16964284&query_hl=1 ER - TY - JFULL T1 - Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. A1 - Hochhaus, A A1 - Kantarjian, HM A1 - Baccarani, M A1 - Lipton, JH A1 - Apperley, JF A1 - Druker, BJ A1 - Facon, T A1 - Goldberg, SL A1 - Cervantes, F A1 - Niederwieser, D A1 - Silver, RT A1 - Stone, RM A1 - Hughes, TP A1 - Muller, MC A1 - Ezzeddine, R A1 - Countouriotis, AM A1 - Shah, NP J1 - Blood Y1 - 2007/03/15/ VL - 109 SN - 0006-4971 SP - 2303 EP - 2309 N2 - Although imatinib induces marked responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic, and treatment options for imatinib-resistant or -intolerant CML are limited. Dasatinib, a novel, highly potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, induced cytogenetic responses in a phase 1 study in imatinib-resistant or -intolerant CML and was well tolerated. Initial results are presented from a phase 2 study of 186 patients with imatinib-resistant or -intolerant chronic-phase CML (CML-CP) designed to further establish the efficacy and safety of dasatinib (70 mg twice daily). At 8-months' follow-up, dasatinib induced notable responses, with 90% and 52% of patients achieving complete hematologic and major cytogenetic responses (MCyR), respectively. Responses were long lasting: only 2% of patients achieving MCyR progressed or died. Importantly, comparable responses were achieved by patients carrying BCR-ABL mutations conferring imatinib resistance. Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months. Nonhematologic adverse events were generally mild to moderate, and most cytopenias were effectively managed with dose modifications. Cross-intolerance with imatinib was not evident. To conclude, dasatinib induces notable responses in imatinib-resistant or -intolerant CML-CP, is well tolerated, and represents a promising therapeutic option for these patients. This trial was registered at www.clinicaltrials.gov as CA180013. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17138817&query_hl=1 ER - TY - JFULL T1 - Reactivation of Snail genes in renal fibrosis and carcinomas - A process of reversed embryogenesis? A1 - Boutet, A A1 - Esteban, MA A1 - Maxwell, PH A1 - Nieto, MA J1 - CELL CYCLE Y1 - 2007/03/15/ VL - 6 SP - 638 EP - 642 N2 - While the activity of Snail genes is required during embryonic development for the formation of different tissues and organs, they must be repressed in the adult in order to maintain epithelial integrity and homeostasis. Indeed, pathological activation of Snail in epithelial tumors induces malignancy and the recurrence of tumors. Here we show that in dedifferentiated areas of human renal carcinomas, Snail undergoes a process of reactivation. In addition to tumor progression, renal fibrosis is also linked to the activity of Snail genes and indeed, reactivation of Snail in the adult kidney is sufficient to induce fibrosis. Thus, Snail genes illustrate a paradigm whereby reactivation of crucial embryonic genes in adult tissues provokes the onset of devastating diseases. ER - TY - JFULL T1 - A comparison of patients with relapsed and chemo-refractory gestational trophoblastic neoplasia. A1 - Powles, T A1 - Savage, PM A1 - Stebbing, J A1 - Short, D A1 - Young, A A1 - Bower, M A1 - Pappin, C A1 - Schmid, P A1 - Seckl, MJ J1 - Br J Cancer Y1 - 2007/03/12/ VL - 96 SN - 0007-0920 SP - 732 EP - 737 N2 - The majority of women requiring chemotherapy for gestational trophoblastic disease (GTN) are cured with their initial chemotherapy treatment. However, a small percentage either become refractory to treatment, or relapse after the completion of treatment. This study investigates the characteristics and outcome of these patients. Patients were identified from the Charing Cross Hospital GTD database. The outcome of these patients with relapsed disease was compared to those with refractory disease. Between 1980 and 2004, 1708 patients were treated with chemotherapy for GTN. Sixty (3.5%) patents relapsed following completion of initial therapy. The overall 5-year survival for patients with relapsed GTN was 93% (95% CI 86-100%). The overall survival for patients with low-risk and high-risk disease at presentation, who subsequently relapsed was 100% (n=35), and 84% (n=25) (95% CI: 66-96%: P<0.05), respectively. Eleven patients were identified who failed to enter remission and had refractory disease. These patients had a worse outcome compared to patients with relapsed disease (5-year survival 43% (95% CI:12-73% P<0.01)). The outcome of patients with relapsed GTN is good. However, patients with primary chemo-refractory disease do poorly and novel therapies are required for this group of patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17299394&query_hl=1 ER - TY - JFULL T1 - Re: Impact of classification of hilar cholangiocarcinomas (Klatskin tumors) on incidence of intra- and extrahepatic cholangiocarcinorna in the United States A1 - Matull, WR A1 - Khan, SA A1 - Pereira, SP J1 - J NATL CANCER I Y1 - 2007/03/07/ VL - 99 SN - 0027-8874 SP - 407 EP - 407 ER - TY - JFULL T1 - Factors for graft-versus-host disease after donor lymphocyte infusions with an escalating dose regimen: lack of association with cell dose. A1 - Fozza, C A1 - Szydlo, RM A1 - Abdel-Rehim, MM A1 - Nadal, E A1 - Goldman, JM A1 - Apperley, JF A1 - Dazzi, F J1 - Br J Haematol Y1 - 2007/03// VL - 136 SN - 0007-1048 SP - 833 EP - 836 N2 - We investigated the risk factors for graft-versus-host disease (GVHD) in 82 patients treated with donor lymphocyte infusions (DLI) using an escalating dose regimen for chronic myeloid leukaemia in relapse following conventional allografting. Two factors emerged as predictors of both acute and chronic GVHD: the infusion of male recipients with lymphocytes from a female donor and the interval between transplant and last DLI, but only the first remained significant at multivariate analysis. Surprisingly, lymphocyte dose did not influence the incidence of GVHD. Our results suggest that DLI can be given in large cell doses without increasing the risk of GVHD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17341269&query_hl=1 ER - TY - JFULL T1 - Triple-negative breast cancer: therapeutic options. A1 - Cleator, S A1 - Heller, W A1 - Coombes, RC J1 - Lancet Oncol Y1 - 2007/03// VL - 8 SN - 1470-2045 SP - 235 EP - 244 N2 - Triple-negative breast cancers are defined by a lack of expression of oestrogen, progesterone, and ERBB2 receptors. This subgroup accounts for 15% of all types of breast cancer and for a higher percentage of breast cancer arising in African and African-American women who are premenopausal. Because of the absence of specific treatment guidelines for this subgroup, triple-negative breast cancers are managed with standard treatment; however, such treatment leaves them associated with a high rate of local and systemic relapse. Histologically, such cancers are poorly differentiated, and most fall into the basal subgroup of breast cancers, characterised by staining for basal markers (ie, cytokeratin 5/6). Analyses of microarray gene-expression profiling data show that they form a homogeneous group (or so-called cluster) in transcriptional terms and, increasingly, research studies are identifying basal cancers on the basis of exhibiting this distinctive transcriptional profile. Histologically and transcriptionally, triple-negative breast cancers have many similarities to BRCA1-associated breast cancers, which suggests that dysfunction in BRCA1 or related pathways occurs in this subset of sporadic cancers. In this review, we discuss the molecular features of triple-negative breast cancers and consider how the use of existing cytotoxic agents can be optimised for this patient group. We discuss the implications of a possible underlying BRCA1-pathway dysfunction in this subgroup in terms of treatment and we also investigate the predominant proliferative signals and the on-going research addressing the suitability of these signals as therapeutic targets. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17329194&query_hl=1 ER - TY - JFULL T1 - Design and development of a prototype endocavitary probe for high-intensity focused ultrasound delivery with integrated magnetic resonance imaging A1 - Wharton, IP A1 - Rivens, IH A1 - ter Haar, GR A1 - Gilderdale, DJ A1 - Collins, DJ A1 - Hand, JW A1 - Abel, PD A1 - Desouza, NM J1 - J MAGN RESON IMAGING Y1 - 2007/03// VL - 25 SN - 1053-1807 SP - 548 EP - 556 N2 - Purpose: To integrate a high intensity focused ultrasound (HIFU) transducer with an MR receiver coil for endocavitary MR-guided thermal ablation of localized pelvic lesions.Materials and Methods: A hollow semicylindrical probe (diameter 3.2 ern) with a rectangular upper surface (7.2 cm X 3.2 cm) was designed to house a HIFU transducer and enable acoustic contact with an intraluminal wall. The probe was distally rounded to ease endocavitary insertion and was proximally tapered to a 1.5-cm diameter cylindrical handle through which the irrigation tubes (for transducer cooling) and electrical connections were passed. MR compatibility of piezoeeramic and piezocomposite transducers was assessed using gradient-echo (GRE) sequences. The radiofrequency (RF) tuning of identical 6.5 cm X 2.5 cm rectangular receiver coils on the upper surface of the probe was adjusted to compensate for the presence of the conductive components of the HIFU transducers. A T1-weighted (T1-W) sliding window dual-echo GRE sequence monitored phase changes in the focal zone of each transducer. High-intensity (2400 W/cm(-2)), short duration (< 1.5 seconds) exposures produced subtherapeutic temperature rises.Results: For T1-W images, signal-to-noise ratio (SNR) improved by 40% as a result of quartering the conductive surface of the piezoceramic transducer. A piezocomposite transducer showed a further 28% improvement. SNRs for an endocavitary coil in the focal plane of the HIFU transducer (4 cm from its face) were three times greater than from a phased body array coil. Local shimming improved uniformity of phase images. Phase changes were detected at subtherapeutic exposures.Conclusion: We combined a HIFU transducer with an MR receiver coil in an endocavitary probe. SNRs were improved by quartering the conductive surface of the piezoceramic. Further improvement was achieved with a piezoeomposite transducer. A phase change was seen on MR images during both subtherapeutic and therapeutic HIFU exposures. ER - TY - JFULL T1 - Redefining quality of care. A1 - Mayer, EK A1 - Purkayastha, S A1 - Athanasiou, T A1 - Darzi, AW J1 - J R Soc Med Y1 - 2007/03// VL - 100 SN - 0141-0768 SP - 122 EP - 124 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17339306&query_hl=1 ER - TY - JFULL T1 - Is the proposed EORTC prognostic algorithm for pTa/pT1 bladder transitional cell cancer (TCC) valid in a routine clinical setting? A1 - Pillai, R A1 - Wang, D A1 - Abel, P J1 - EUR UROL SUPPL Y1 - 2007/03// VL - 6 SN - 1569-9056 SP - 172 EP - 172 ER - TY - JFULL T1 - Objective assessment comparing hand-assisted and conventional laparoscopic surgery. A1 - Datta, V A1 - Bann, S A1 - Hernandez, J A1 - Darzi, A J1 - Surg Endosc Y1 - 2007/03// VL - 21 SN - 1432-2218 SP - 414 EP - 417 N2 - BACKGROUND: Although several reports have subjectively highlighted the benefits of hand-assisted as compared with conventional laparoscopic surgery, there has been little objective analysis comparing these two techniques. METHODS: For this study, 12 trained laparoscopic surgeons completed standardized knot-tying and dissection tasks in a laparoscopic trainer using both hand-assisted (HandPort) and traditional laparoscopic techniques. Motion analysis with the Imperial College Surgical Assessment Device was used to assess performance, measuring the number of movements made, the path length of hand travel, and the time taken. Mann-Whitney U tests were used to compare hand-assisted (HA) and conventional laparoscopic (L) performance. A p value less than 0.05 was deemed significant. Means and standard deviations are shown in the results. RESULTS: In knot tying, for both the dominant and nondominant hands, hand-assisted rather than conventional laparoscopic techniques resulted in reduced movements (dominant: HA [114 +/- 50] vs L [321 +/- 118, p < 0.001], nondominant: HA [89 +/- 36] vs L [296 +/- 96, p < 0.001]); path length (dominant: HA [1,083 +/- 680 mm] vs L [3,637 +/- 1,852 mm, p < 0.001], nondominant: HA [549 +/- 339 mm] vs L [2,556 +/- 1,042 mm, p < 0.001]); and time taken (HA [162 +/- 50 s] vs L [460 +/- 179 s, p < 0.001]). However, there was no statistical difference for any measured variable with respect to the dissection task. CONCLUSION: Hand-assisted surgery significantly improves the knot-tying ability among trained laparoscopic surgeons. However, there appears to be no improvement in performance for this specific dissection task. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17103283&query_hl=1 ER - TY - JFULL T1 - Laparoscopy simulators. A1 - Undre, S A1 - Darzi, A J1 - J Endourol Y1 - 2007/03// VL - 21 SN - 0892-7790 SP - 274 EP - 279 N2 - To reduce the complication rate associated with laparoscopic surgery and to improve training, several simulators have been incorporated into training curricula and skills courses. We discuss the advantages and disadvantages and compare the different types of simulators available. We also reviewed the literature to assess the acquisition of skills using these simulators and their transfer to real operations. It is important to realize that currently, any form of simulation is merely an adjunct to, and not a replacement for, traditional methods of training and that supervision and feedback are essential. More collaboration is needed between urologists and simulator companies to produce operation-specific simulated modules for urologic procedures. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17444771&query_hl=1 ER - TY - JFULL T1 - Different target range and cytotoxic specificity of adaphostin and 17-allylamino-17-demethoxygeldanamycin in imatinib-resistant and sensitive cell lines. A1 - Barnes, DJ A1 - De, S A1 - van Hensbergen, P A1 - Moravcsik, E A1 - Melo, JV J1 - Leukemia Y1 - 2007/03// VL - 21 SN - 0887-6924 SP - 421 EP - 426 N2 - Imatinib mesylate is a selective inhibitor of the oncogenic tyrosine kinase, Bcr-Abl, and is widely used as a first-line treatment for chronic myeloid leukaemia (CML). Prolonged monotherapy is frequently associated with patients becoming refractory to imatinib. Therefore, there is considerable interest in small molecule inhibitors which may be used either as replacements or as adjuncts to existing imatinib therapy. For this purpose, it is most likely that drugs which do not share imatinib's mechanism of action will be most valuable. We compared two such compounds with different modes of action, adaphostin and 17-allylamino-17-demethoxygeldanamycin (17-AAG), for their cytotoxic effect and ability to induce the downregulation of cellular proteins in a murine haemopoietic cell line transformed with human p210(Bcr-Abl), and two subclones resistant to imatinib owing to an Abl-kinase domain mutation (E255K) or amplification of the BCR-ABL gene, respectively. We found that, whereas 17-AAG selectively killed Bcr-Abl-positive cells and inhibited proteins dependent on heat-shock protein 90 for their stability (p210(Bcr-Abl) and Akt), adaphostin induced the downregulation of multiple cell-signalling proteins (p210(Bcr-Abl), Akt, Bcr, Abl and STAT5a) and was cytotoxic to both Bcr-Abl-positive and -negative cells. We suggest that both compounds may prove useful in the treatment of CML but caution that undesirable side-effects may result from the inhibition of multiple cell signalling proteins. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17252018&query_hl=1 ER - TY - JFULL T1 - The problem of engaging hospital doctors in promoting safety and quality in clinical care. A1 - Neale, G A1 - Vincent, C A1 - Darzi, SA J1 - J R Soc Health Y1 - 2007/03// VL - 127 SN - 0264-0325 SP - 87 EP - 94 N2 - There is widespread agreement that the medical profession has much to learn about addressing adverse events in clinical practice and participating in clinical governance. In England and Wales centrally driven initiatives such as medical audit, clinical governance and the National Reporting and Learning System have failed to transform the management of iatrogenic adverse events. In this article we explore the historical and cultural background of these issues with respect to hospital medicine and suggest means of tackling the challenges ahead. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17402315&query_hl=1 ER - TY - JFULL T1 - Induction of tumor-specific T-cell responses by vaccination with tumor lysate-loaded dendritic cells in colorectal cancer patients with carcinoembryonic-antigen positive tumors. A1 - Tamir, A A1 - Basagila, E A1 - Kagahzian, A A1 - Jiao, L A1 - Jensen, S A1 - Nicholls, J A1 - Tate, P A1 - Stamp, G A1 - Farzaneh, F A1 - Harrison, P A1 - Stauss, H A1 - George, AJ A1 - Habib, N A1 - Lechler, RI A1 - Lombardi, G J1 - Cancer Immunol Immunother Y1 - 2007/02/23/ SN - 0340-7004 N2 - BACKGROUND: Dendritic cells (DCs) are the most effective antigen-presenting cells. In the last decade, the use of DCs for immunotherapy of cancer patients has been vastly increased. High endocytic capacity together with a unique capability of initiating primary T-cell responses have made DCs the most potent candidates for this purpose. Although DC vaccination occasionally leads to tumor regression, clinical efficacy, and immunogenicity of DCs in clinical trials has not been yet clarified. The present study evaluated the safety and effectiveness of tumor-lysate loaded DC vaccines in advanced colorectal cancer (CRC) patients with carcinoembryonic antigen (CEA) positive tumors. RESULTS: Six patients HLA-A*0201-positive were vaccinated with autologous DCs loaded with tumor lysates (TL) together with tetanus toxoid antigen, hepatitis B, and influenza matrix peptides. Two additional patients were injected with DCs that were generated from their sibling or parent with one haplotype mismatch. All patients received the vaccines every 2 weeks, with a total of three intra-nodal injections per patient. The results indicated that DC vaccination was safe and well tolerated by the patients. Specific immune responses were detected and in some patients, transient stabilization or even reduction of CEA levels were observed. The injection of haplotype mismatched HLA-A*0201-positive DCs resulted in some enhancement of the anti-tumor response in vitro and led to stabilization/reduction of CEA levels in the serum, compared to the use of autologous DCs. CONCLUSION: Altogether, these results suggest that TL-pulsed DCs may be an effective vaccine method in CRC patients. Elimination of regulatory mechanisms as well as adjustment of the vaccination protocol may improve the efficacy of DC vaccination. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17333181&query_hl=1 ER - TY - JFULL T1 - Survival and safety of exemestane versus tamoxifen after 2-3 years' tamoxifen treatment (Intergroup Exemestane Study): a randomised controlled trial. A1 - Coombes, RC A1 - Kilburn, LS A1 - Snowdon, CF A1 - Paridaens, R A1 - Coleman, RE A1 - Jones, SE A1 - Jassem, J A1 - Van de Velde, CJ A1 - Delozier, T A1 - Alvarez, I A1 - Del Mastro, L A1 - Ortmann, O A1 - Diedrich, K A1 - Coates, AS A1 - Bajetta, E A1 - Holmberg, SB A1 - Dodwell, D A1 - Mickiewicz, E A1 - Andersen, J A1 - Lønning, PE A1 - Cocconi, G A1 - Forbes, J A1 - Castiglione, M A1 - Stuart, N A1 - Stewart, A A1 - Fallowfield, LJ A1 - Bertelli, G A1 - Hall, E A1 - Bogle, RG A1 - Carpentieri, M A1 - Colajori, E A1 - Subar, M A1 - Ireland, E A1 - Bliss, JM A1 - Intergroup Exemestane Study J1 - Lancet Y1 - 2007/02/17/ VL - 369 SN - 1474-547X SP - 559 EP - 570 N2 - BACKGROUND: Early improvements in disease-free survival have been noted when an aromatase inhibitor is given either instead of or sequentially after tamoxifen in postmenopausal women with oestrogen-receptor-positive early breast cancer. However, little information exists on the long-term effects of aromatase inhibitors after treatment, and whether these early improvements lead to real gains in survival. METHODS: 4724 postmenopausal patients with unilateral invasive, oestrogen-receptor-positive or oestrogen-receptor-unknown breast cancer who were disease-free on 2-3 years of tamoxifen, were randomly assigned to switch to exemestane (n=2352) or to continue tamoxifen (n=2372) for the remainder of a 5-year endocrine treatment period. The primary endpoint was disease-free survival; overall survival was a secondary endpoint. Efficacy analyses were intention-to-treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN11883920. RESULTS: After a median follow-up of 55.7 months (range 0-89.7), 809 events contributing to the analysis of disease-free survival had been reported (354 exemestane, 455 tamoxifen); unadjusted hazard ratio 0.76 (95% CI 0.66-0.88, p=0.0001) in favour of exemestane, absolute benefit 3.3% (95% CI 1.6-4.9) by end of treatment (ie, 2.5 years after randomisation). 222 deaths occurred in the exemestane group compared with 261 deaths in the tamoxifen group; unadjusted hazard ratio 0.85 (95% CI 0.71-1.02, p=0.08), 0.83 (0.69-1.00, p=0.05) when 122 patients with oestrogen-receptor-negative disease were excluded. CONCLUSIONS: Our results suggest that early improvements in disease-free survival noted in patients who switch to exemestane after 2-3 years on tamoxifen persist after treatment, and translate into a modest improvement in overall survival. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17307102&query_hl=1 ER - TY - JFULL T1 - The systems of surgery A1 - Healey AN A1 - Vincent CA J1 - Theoretical Issues in Ergonomic Science Y1 - 2007/02/14/ IS - 1 VL - 9 PB - Taylor & Francis SN - 1464-536X SP - 1 EP - 15 N2 - This paper raises the vital question of how the systems approach to safety should be implemented in the surgical domain. It argues that teams are the natural vehicles of change in a complex distributed system of work and so the ideal units of analysis. Generalized models of team performance frame the research needed to implement the approach. However, models of teamwork must be developed that account for the technical aspects of different procedures in order to improve team performance across systems. For that purpose, an account of the information that comprises teams and teamwork and the infrastructure and technology that supports it is essential. There could be an improvement in safety across healthcare if the design of surgical teams co-evolves systematically with technology, and if the technical relevance of teamwork is realized. L1 - http://www.informaworld.com/smpp/content~content=a770946718~db=all~order=pubdate ER - TY - JFULL T1 - Motion tracking systems for assessment of surgical skill. A1 - Aggarwal, R A1 - Dosis, A A1 - Bello, F A1 - Darzi, A J1 - Surg Endosc Y1 - 2007/02// VL - 21 SN - 1432-2218 SP - 339 EP - 339 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17146598&query_hl=1 ER - TY - JFULL T1 - Second consensus on medical treatment of metastatic breast cancer. A1 - Beslija, S A1 - Bonneterre, J A1 - Burstein, H A1 - Cocquyt, V A1 - Gnant, M A1 - Goodwin, P A1 - Heinemann, V A1 - Jassem, J A1 - Köstler, WJ A1 - Krainer, M A1 - Menard, S A1 - Petit, T A1 - Petruzelka, L A1 - Possinger, K A1 - Schmid, P A1 - Stadtmauer, E A1 - Stockler, M A1 - Van Belle, S A1 - Vogel, C A1 - Wilcken, N A1 - Wiltschke, C A1 - Zielinski, CC A1 - Zwierzina, H J1 - Ann Oncol Y1 - 2007/02// VL - 18 SN - 0923-7534 SP - 215 EP - 225 N2 - The present consensus manuscript defines evidence-based recommendations for state-of-the-art treatment of metastatic breast cancer depending on disease-associated and biologic variables. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16831851&query_hl=1 ER - TY - JFULL T1 - Impact of radiofrequency assisted hepatectomy for reduction of transfusion requirements. A1 - Ayav, A A1 - Bachellier, P A1 - Habib, NA A1 - Pellicci, R A1 - Tierris, J A1 - Milicevic, M A1 - Jiao, LR J1 - Am J Surg Y1 - 2007/02// VL - 193 SN - 0002-9610 SP - 143 EP - 148 N2 - BACKGROUND: Liver parenchyma transection technique using heat coagulative necrosis induced by radiofrequency (RF) energy is evaluated in this series. METHODS: Between January 2000 and October 2004, 156 consecutive patients underwent liver resection with the RF-assisted technique. Data were collected prospectively to assess the outcome, including intraoperative blood loss, blood transfusion requirement, and morbidity and mortality rates. RESULTS: There were 30 major hepatectomies and 126 minor resections. While total operative time was 241 +/- 89 minutes, the actual resection time was 75 +/- 51 minutes. Intraoperative blood loss was 139 +/- 222 mL. Nine patients (5%) received blood transfusion, predominantly those receiving major hepatectomy (P = .006). Thirty-six patients (23%) developed postoperative complications, and the mortality rate was 3.2%. Mean hospital stay was 12 +/- 12 days. CONCLUSION: The RF-assisted technique is associated with minimal blood loss, a low blood transfusion requirement, and reduced mortality and morbidity rates and can be used for both minor and major liver resections. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17236838&query_hl=1 ER - TY - JFULL T1 - Mesenchymal stem cells inhibit proliferation and apoptosis of tumor cells: impact on in vivo tumor growth. A1 - Ramasamy, R A1 - Lam, EW A1 - Soeiro, I A1 - Tisato, V A1 - Bonnet, D A1 - Dazzi, F J1 - Leukemia Y1 - 2007/02// VL - 21 SN - 0887-6924 SP - 304 EP - 310 N2 - Mesenchymal stem cells (MSC) have received much attention in the field of hematopoietic stem cell transplantation because not only do they support hematopoiesis but also exhibit a profound immunosuppressive activity that can be exploited to prevent undesired alloreactivity. We have previously shown that their immunosuppressive activity is mainly exerted at the level of T-cell proliferation. Here, we show that MSC exhibit a similar antiproliferative activity on tumor cells of hematopoietic and non hematopoietic origin. In vitro, MSC produced the transient arrest of tumor cells in the G(1) phase of cell cycle; this was accompanied by a reduction in the apoptotic rate even when survival factors were limiting. However, when tumor cells were injected into non-obese diabetic-severe combined immunodeficient mice in conjunction with MSC, their growth was much faster as compared to the group receiving only tumor cells. To explain the discrepancy between the in vitro and in vivo behavior, we suggest that MSC have the ability to form a cancer stem cell niche in which tumor cells can preserve the potential to proliferate and sustain the malignant process. We conclude that the clinical use of MSC in conditions in which a malignant disease is involved should be handled with extreme caution. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17170725&query_hl=1 ER - TY - JFULL T1 - Recombinant activated factor VII in cardiac surgery: a systematic review. A1 - Warren, O A1 - Mandal, K A1 - Hadjianastassiou, V A1 - Knowlton, L A1 - Panesar, S A1 - John, K A1 - Darzi, A A1 - Athanasiou, T J1 - Ann Thorac Surg Y1 - 2007/02// VL - 83 SN - 1552-6259 SP - 707 EP - 714 N2 - Postoperative hemorrhage is a common complication in cardiac surgery, and it is associated with a considerable increase in morbidity, mortality, and cost. Recombinant activated factor VII (rFVIIa) is an emerging hemostatic agent, increasingly used in cardiac surgery. This article systematically reviews the evidence regarding the efficacy, safety, and cost of rFVIIa in this setting. Although definitive evidence from randomized controlled trials is lacking, the use of rFVIIa in patients experiencing refractory postoperative hemorrhage seems promising and relatively safe. However further research is required to definitively establish its clinical utility in the postoperative cardiac patient. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17258029&query_hl=1 ER - TY - JFULL T1 - Recording of drug allergies: are we doing enough? A1 - Radford, A A1 - Undre, S A1 - Alkhamesi, NA A1 - Darzi, SA J1 - J Eval Clin Pract Y1 - 2007/02// VL - 13 SN - 1356-1294 SP - 130 EP - 137 N2 - OBJECTIVE: To assess the implementation of local and national guidelines concerning documentation of drug/clinical hypersensitivities. DESIGN: Audit with retrospective and prospective components used to assess the process of drug hypersensitivity documentation. PATIENTS: Fifty surgical inpatients' notes were retrospectively analysed followed by 63 patients prospectively. SETTING: West London teaching hospital. MAIN OUTCOME MEASURES: Drug hypersensitivity status correctly indicated on clinical notes, drug 'Kardex' charts, and anaesthetic records; these three documents were to concur. Hypersensitivities qualified according to symptoms experienced. RECOMMENDATIONS: Standardization of preoperative clinical notes and multidisciplinary responsibility for records between doctor, nurse and pharmacist. RESULTS: Hypersensitivity documentation in clinical notes improved by 7% after the introduction of a formalized history sheet for preoperative clinics. These were based upon the anaesthetic charts, which had demonstrated 100% documentation previously. Considerable improvements (70.8%) in the clarification of adverse reaction symptoms post recommendation were shown; this was also attributed to the new history sheet. Concurrence improved by 2%. CONCLUSIONS: The original study revealed areas for improvement and provided part of the solution--a more standardized preoperative assessment tool. Multidisciplinary cooperation in addition to formalizing the assessment process has led to a more efficient and safer service for patient and medicolegally for health care professionals. KEY MESSAGES: (1) Standardized forms, for the recording of clinical information preoperatively, ensure relevant guidelines are implemented in practice. (2) Multidisciplinary teams provide a vital safety net for their patients and colleagues. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17286735&query_hl=1 ER - TY - JFULL T1 - Latent protein LANA2 from Kaposi's sarcoma-associated herpesvirus interacts with 14-3-3 proteins and inhibits FOXO3a transcription factor. A1 - Muñoz-Fontela, C A1 - Marcos-Villar, L A1 - Gallego, P A1 - Arroyo, J A1 - Da Costa, M A1 - Pomeranz, KM A1 - Lam, EW A1 - Rivas, C J1 - J Virol Y1 - 2007/02// VL - 81 SN - 0022-538X SP - 1511 EP - 1516 N2 - The Kaposi's sarcoma-associated herpesvirus latent protein LANA2 has been suggested to have an important role in the transforming activity of the virus based on its capacity to inhibit p53 and PKR-dependent apoptosis as well as the interferon-dependent response. Here, we describe a novel interaction between LANA2 and both the phosphoserine/phosphothreonine-binding 14-3-3 proteins and the transcription factor FOXO3a. In addition, our results indicate that LANA2 inhibits the transcriptional activity of FOXO3a and blocks the G2/M arrest induced by 14-3-3 protein overexpression. These results suggest a novel mechanism by which LANA2 may promote tumorigenesis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17108038&query_hl=1 ER - TY - JFULL T1 - Magnetic resonance colonography vs computed tomography colonography for the diagnosis of colorectal cancer: an indirect comparison. A1 - Purkayastha, S A1 - Athanasiou, T A1 - Tekkis, PP A1 - Constantinides, V A1 - Teare, J A1 - Darzi, AW J1 - Colorectal Dis Y1 - 2007/02// VL - 9 SN - 1462-8910 SP - 100 EP - 111 N2 - OBJECTIVE: The primary aim of this study was to use meta-regression techniques to compare the diagnostic accuracy of computed tomography colonography (CTC) and magnetic resonance colonography (MRC), compared with conventional colonoscopy for patients presenting with colorectal cancer (CRC). METHOD: Quantitative meta-analysis was performed using prospective studies reporting comparative data between CTC and MRC individually to conventional colonoscopy. Study quality was assessed and sensitivities, specificities, diagnostic odds ratios (DOR) were calculated. Summary receiver operating characteristic (SROC) curves and sensitivity analysis were utilized. Meta-regression was used to indirectly compare the two modalities following adjustment for patient and study characteristics. RESULTS: Overall sensitivity and specificity for CTC (0.96, 95% CI 0.92-0.99; 1.00, 95% CI 0.99-1.00 respectively) and MRC (0.91, 95% CI 0.79-0.97; 0.98, 95% CI 0.96-0.99 respectively) for the detection of CRC was similar. Meta-regression analysis showed no significant difference in the diagnostic accuracy of both modalities (beta=-0.64, P=0.37 and 95% CI of 0.12-2.39). Both tests showed high area under the SROC curve (CTC=0.99; MRC=0.98), with high DORs (CTC=1461.90, 95% CI 544.89-3922.30; MRC=576.41, 95% CI 135.00-2448.56). Factors that enhanced the overall accuracy of MRC were the use intravenous contrast, faecal tagging and exclusion of low-quality studies. No factors improved diagnostic accuracy from CTC except studies with more than 100 patients (AUC=1.00, DOR=2938.35, 95%CI 701.84-12 302.91). CONCLUSION: This meta-analysis suggested that CTC and MRC have similar diagnostic accuracy for detecting CRC. Study quality, size and intravenous/intra-luminal contrast agents affect diagnostic accuracies. For an exact comparison to be made, studies evaluating CTC, MRC and colonoscopy in the same patient cohort would be necessary. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17223933&query_hl=1 ER - TY - JFULL T1 - Dose-dense chemotherapy for primary breast cancer. A1 - Kümmel, S A1 - Rezai, M A1 - Kimmig, R A1 - Schmid, P J1 - Curr Opin Obstet Gynecol Y1 - 2007/02// VL - 19 SN - 1040-872X SP - 75 EP - 81 N2 - PURPOSE OF REVIEW: Dose density is a relative term referring to the administration frequency of chemotherapy drugs and regimens compared with standard regimens. The concept of dose-dense chemotherapy is based on the hypothesis that maximal chemotherapy effectiveness can be achieved by scheduling the interval of chemotherapy to correspond to the period of most rapid tumor growth. The present paper aims to outline the theoretical framework for dose-dense chemotherapy and to review recent clinical trials addressing this concept within adjuvant breast cancer treatment. RECENT FINDINGS: Several randomized trials have been conducted to test the feasibility and effectiveness of anthracycline and/or taxanes-based dose-dense strategies. They demonstrate that using hematopoietic growth factor support has made dose-dense therapy safe and feasible. Dose-dense strategies have been associated with a modest impact on disease recurrence and overall survival of patients with early-stage breast cancer. Subset analyses suggest increased benefits for specific tumor subtypes such as hormone receptor-negative, highly proliferative or HER2 overexpressing tumors. SUMMARY: Trials in unselected patients with early-stage breast cancer have demonstrated promising results for dose-dense chemotherapy. Further studies are needed to define the optimal regimen and the patient population that will receive the greatest benefit from this therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17218856&query_hl=1 ER - TY - JFULL T1 - Skeletal effects of exemestane on bone-mineral density, bone biomarkers, and fracture incidence in postmenopausal women with early breast cancer participating in the Intergroup Exemestane Study (IES): a randomised controlled study. A1 - Coleman, RE A1 - Banks, LM A1 - Girgis, SI A1 - Kilburn, LS A1 - Vrdoljak, E A1 - Fox, J A1 - Cawthorn, SJ A1 - Patel, A A1 - Snowdon, CF A1 - Hall, E A1 - Bliss, JM A1 - Coombes, RC A1 - Intergroup Exemestane Study group J1 - Lancet Oncol Y1 - 2007/02// VL - 8 SN - 1470-2045 SP - 119 EP - 127 N2 - BACKGROUND: Tamoxifen preserves bone in postmenopausal women, but non-steroidal aromatase inhibitors accelerate bone loss and increase fracture risk. We aimed to study the effect on bone health in a subgroup of women included in the Intergroup Exemestane Study (IES), a large randomised trial that compared the switch to the steroidal aromatase inhibitor exemestane with continuation of tamoxifen in the adjuvant treatment of postmenopausal breast cancer. METHODS: Results were analysed from 206 evaluable patients from the IES, in which postmenopausal women with histologically confirmed and completely resected unilateral breast cancer (that was oestrogen-receptor positive or of unknown status), who were disease-free after 2-3 years of treatment with tamoxifen were randomised to continue oral tamoxifen 20 mg/day or switch to oral exemestane 25 mg/day to complete a total of 5 years of adjuvant endocrine therapy. The primary endpoint was change in bone-mineral density (BMD) assessed by dual energy X-ray absorptiometry. Changes in biochemical markers of bone turnover were also analysed in this substudy, and the incidence of fractures in the entire study reported. The IES is registered on the Current Controlled Trials website . FINDINGS: Within 6 months of switching to exemestane, BMD was lowered by 0.051 g/cm(3) (2.7%; 95% CI 2.0-3.4; p<0.0001) at the lumbar spine and 0.025 g/cm(3) (1.4%; 0.8-1.9; p<0.0001) at the hip compared with baseline. BMD decreases were only 1.0% (0.4-1.7; p=0.002) and 0.8% (0.3-1.4; p=0.003) in year 2 at the lumbar spine and hip, respectively. No patient with BMD in the normal range at trial entry developed osteoporosis. Bone resorption and formation markers increased at all time points in women receiving exemestane (p<0.001). With a median follow-up in all IES participants (n=4274) of 58 months, 162 (7%) and 115 (5%) patients in the exemestane and tamoxifen groups, respectively, had fractures (odds ratio 1.45 [1.13-1.87]; p=0.003). INTERPRETATION: These results indicate that the increase in survival shown previously with the IES switch strategy is achieved at the expense of some detriment to skeletal health, so the risk-benefit ratio to women needs to be individually assessed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17267326&query_hl=1 ER - TY - JFULL T1 - Novel compounds with antiproliferative activity against imatinib-resistant cell lines. A1 - Lerma, EI A1 - Nguyen, VA A1 - Wang, T A1 - Tipping, A A1 - Melo, JV A1 - Kufe, D A1 - Austin, DJ A1 - Deisseroth, A J1 - Mol Cancer Ther Y1 - 2007/02// VL - 6 SN - 1535-7163 SP - 655 EP - 666 N2 - Chronic myelogenous leukemia is caused by the Bcr-Abl hybrid gene that encodes the p210Bcr-Abl chimeric oncoprotein. Although it reduces the total body burden of leukemia cells, the use of imatinib mesylate as a single agent may be accompanied by the evolution of resistance due mainly to the acquisition of point mutations. Imatinib has been combined with drugs that inhibit both the active and the inactive states of the p210Bcr-Abl kinase. These combinations have reduced but not completely eliminated the rate at which point mutations are acquired in the p210Bcr-Abl kinase. Thus, it is important to identify additional new inhibitors of the p210Bcr-Abl kinase. One possible method to prevent evolution of resistance is to simultaneously use multiple kinase inhibitors each with a different mechanism of action. To identify such a new class of inhibitors that could suppress the growth of chronic myelogenous leukemia cells and prevent the evolution of cells that are resistant to imatinib, we screened two low-complexity libraries of compounds based on planar and linear scaffolds. These libraries were screened using a cell-based assay for molecules that suppress p210Bcr-Abl-dependent cell growth. The application of this method resulted in the isolation of two new classes of drugs, both of which inhibited imatinib-resistant cells in the low micromolar range. Some of these drugs were potent inhibitors not only of Abl tyrosine kinase but also of the Src, Lyn, and Fyn tyrosine kinases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17267662&query_hl=1 ER - TY - JFULL T1 - Laparoscopic versus open hepatic resections for benign and malignant neoplasms--a meta-analysis. A1 - Simillis, C A1 - Constantinides, VA A1 - Tekkis, PP A1 - Darzi, A A1 - Lovegrove, R A1 - Jiao, L A1 - Antoniou, A J1 - Surgery Y1 - 2007/02// VL - 141 SN - 0039-6060 SP - 203 EP - 211 N2 - BACKGROUND: Laparoscopic surgery for hepatic neoplasms aims to provide curative resection while minimizing complications. The present study compared laparoscopic versus open surgery for patients with hepatic neoplasms with regard to short-term outcomes. METHODS: Comparative studies published between 1998 and 2005 were included. Evaluated endpoints were operative, functional, and adverse events. A random-effects model was used and sensitivity analysis performed to account for bias in patient selection. RESULTS: Eight nonrandomized studies were included, reporting on 409 resections of hepatic neoplasms, of which 165 (40.3%) were laparoscopic and 244 (59.7%) were open. Operative blood loss (weighted mean difference = -123 mL; confidence interval = -179, -67 mL) and duration of hospital stay (weighted mean difference = -2.6 days; confidence interval = -3.8, -1.4 days) were significantly reduced after laparoscopic surgery. These findings remained consistent when considering studies matched for the presence of malignancy and segment resection. There was no difference in postoperative adverse events and extent of oncologic clearance. CONCLUSIONS: Laparoscopic resection results in reduced operative blood loss and earlier recovery with oncologic clearance comparable with open surgery. When performed by experienced surgeons in selected patients it may be a safe and feasible option. Because of the potential of significant bias arising from the included studies, further randomized controlled trials should be undertaken to confirm this bias and to assess long-term survival rates. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17263977&query_hl=1 ER - TY - JFULL T1 - Comparison of colonic stenting and open surgery for malignant large bowel obstruction. A1 - Tilney, HS A1 - Lovegrove, RE A1 - Purkayastha, S A1 - Sains, PS A1 - Weston-Petrides, GK A1 - Darzi, AW A1 - Tekkis, PP A1 - Heriot, AG J1 - Surg Endosc Y1 - 2007/02// VL - 21 SN - 1432-2218 SP - 225 EP - 233 N2 - BACKGROUND: Colonic stents potentially offer effective palliation for those with bowel obstruction attributable to incurable malignancy, and a "bridge to surgery" for those in whom emergency surgery would necessitate a stoma. The current study compared the outcomes of stents and open surgery in the management of malignant large bowel obstruction. METHODS: A literature search of the Medline, Ovid, Embase and Cochrane databases was performed to identify comparative studies reporting outcomes on colonic stenting and surgery for large bowel obstruction. Random effects meta-analytical techniques were applied to identify differences in outcomes between the two groups. Sensitivity analysis of high quality studies, those reporting on more than 35 patients, those solely concerning colorectal cancer and studies performing intention to treat analysis was undertaken to evaluate the study heterogeneity. RESULTS: A total of 10 studies satisfied the criteria for inclusion, with outcomes reported for 451 patients. Stent insertion was attempted for 244 patients (54.1%), and proved successful for 226 (92.6%). The length of hospital stay was shorter by 7.72 days in the stent group (p < 0.001), which also had lower mortality (p = 0.03) and fewer medical complications (p < 0.001). Stoma formation at any point during management was significantly lower than in the stent group (odds ratio, 0.02; p < 0.001), and "bridging to surgery" did not adversely influence survival. CONCLUSIONS: Colonic stenting offers effective palliation for malignant bowel obstruction, with short lengths of hospital stay and a low rate for stoma formation, but data on quality of life and economic evaluation are limited. There is no evidence of differences in long-term survival between those who have stents followed by subsequent resection and those undergoing emergency bowel resection. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17160651&query_hl=1 ER - TY - JFULL T1 - Bcr-Abl signaling through the PI-3/S6 kinase pathway inhibits nuclear translocation of the transcription factor Bach2, which represses the antiapoptotic factor heme oxygenase-1. A1 - Yoshida, C A1 - Yoshida, F A1 - Sears, DE A1 - Hart, SM A1 - Ikebe, D A1 - Muto, A A1 - Basu, S A1 - Igarashi, K A1 - Melo, JV J1 - Blood Y1 - 2007/02/01/ VL - 109 SN - 0006-4971 SP - 1211 EP - 1219 N2 - The malignant phenotype of chronic myeloid leukemia (CML) is due to the abnormal tyrosine kinase activity of the Bcr-Abl oncoprotein. We have previously reported that expression of the Bach2 transcription factor, which induces apoptosis in response to oxidative stress, is greatly reduced in CML cells. Because these cells are resistant to apoptosis, we tested whether Bach2 could also be regulated through posttranslational mechanisms that promote inhibition of the apoptotic response to mutagenic stimuli in CML. We found that Bach2 is phosphorylated on S521 via the phosphatidylinositol-3/S6 kinase pathway, and substitution of this site to alanine leads to nuclear accumulation of the protein, indicating that this phosphorylation is important for its subcellular localization. Ectopic expression of the S521 mutant imparts greater impairment to CML cell growth than the wild-type factor. Furthermore, we showed that Bach2 transcriptionally represses heme oxygenase-1, an antiapoptotic factor up-regulated in CML. Because CML cells are known to produce high levels of intracellular reactive oxygen species, overexpression of heme oxygenase-1 resulting from inhibition of Bach2 activity may contribute to their genomic instability and leukemic phenotype. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17018862&query_hl=1 ER - TY - JFULL T1 - Increased CD4+CD25high+regulatory T-cell are associated with disease relapse after allogeneic stem cell transplantation (SCT) for chronic myeloid leukaemia (CML) A1 - Nadal, E A1 - Kaeda, J A1 - Apperley, JF A1 - Lechler, R A1 - Dazzi, F J1 - BIOL BLOOD MARROW TR Y1 - 2007/02// VL - 13 SN - 1083-8791 SP - 15 EP - 15 ER - TY - JFULL T1 - Make surgeons more active in teaching anatomy at all levels. A1 - Purkayastha, S A1 - Paraskevas, P A1 - Darzi, A J1 - BMJ Y1 - 2007/01/20/ VL - 334 SN - 1468-5833 SP - 110 EP - 110 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17235064&query_hl=1 ER - TY - JFULL T1 - Comparison of laparoscopic versus hand-assisted live donor nephrectomy. A1 - Kokkinos, C A1 - Nanidis, T A1 - Antcliffe, D A1 - Darzi, AW A1 - Tekkis, P A1 - Papalois, V J1 - Transplantation Y1 - 2007/01/15/ VL - 83 SN - 0041-1337 SP - 41 EP - 47 N2 - BACKGROUND: The aim of the present study was to compare hand-assisted laparoscopic live donor nephrectomy with the classic laparoscopic method, using meta-analytical techniques. METHODS: A literature search was performed for studies comparing hand-assisted laparoscopic nephrectomy with classic laparoscopic nephrectomy for live kidney donation between 1999 and 2005. The following end points were evaluated: operative time, warm ischemia time, intraoperative adverse events, donor and recipient postoperative complications, and length of hospital stay. RESULTS: Nine comparative studies matched the selection criteria, reporting on 376 patients, of whom 202 (53.7%) had hand-assisted laparoscopic nephrectomy and 174 (46.3%) had the classic laparoscopic technique. Conversion to open surgery was 2.97% in the hand-assisted group and 4.60% in the laparoscopic group (P=0.35). Total operative and warm ischemia times were significantly shorter for hand-assisted laparoscopy by 30.03 minutes (P=0.02) and 1.14 minutes (P<0.001), respectively. The intraoperative blood loss was less for the hand-assisted laparoscopy group by 34.16 mL (P=0.008), although intraoperative (3.46% vs. 7.47%; P=0.24) and postoperative (5.94% vs. 10.34%; P=0.30) donor complications and recipient complications (including delayed graft function and primary nonfunction, 8.41% vs. 7.42%; P=0.32) were similar between the hand-assisted and laparoscopic groups. CONCLUSION: Hand-assisted laparoscopic nephrectomy appeared to have the same donor and recipient complication rate with standard laparoscopy but offered substantial advantages in terms of shortened operative and warm ischemia time as well as decreased intraoperative bleeding. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17220789&query_hl=1 ER - TY - JFULL T1 - Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. A1 - Ramasamy, R A1 - Fazekasova, H A1 - Lam, EW A1 - Soeiro, I A1 - Lombardi, G A1 - Dazzi, F J1 - Transplantation Y1 - 2007/01/15/ VL - 83 SN - 0041-1337 SP - 71 EP - 76 N2 - BACKGROUND: Mesenchymal stem cells (MSCs) play a crucial role in hematopoietic development and have been shown to exert a powerful immunosuppressive effect. In this study, we investigated the effect of bone marrow MSC on the differentiation and function of peripheral blood monocytes into dendritic cells (DCs). METHODS: Human MSCs, generated from normal bone marrow, were added to peripheral blood monocytes stimulated in vitro with granulocyte-macrophage colony stimulating factor and interleukin-4 to become DCs. Monocytes were then examined for the expression of markers characteristic of DCs and their ability to stimulate allogeneic T cells. In addition, the effect of MSCs on the cell cycle of monocyte-derived DCs and the expression of various cell cycle proteins were analyzed by cytometric analysis and Western blotting with specific antibodies. RESULTS: MSCs blocked the differentiation of monocytes into DCs and impaired their antigen-presenting ability. This resulted from a block of monocytes from entering the G1 phase of the cell cycle with a progressive number of cells accumulating in the G0 phase. Cyclin D2 was downregulated. However, differently from what was observed in T-cells stimulated in the presence of MSCs, the expression of p27 was found decreased, suggesting the involvement of similar but not identical pathways. CONCLUSIONS: We conclude that MSCs impair monocyte differentiation and function by interfering with the cell cycle. These findings imply that MSC-induced immunosuppression might be a side product of a more general antiproliferative effect. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17220794&query_hl=1 ER - TY - JFULL T1 - Oxidative stress-dependent sphingosine kinase-1 inhibition mediates monoamine oxidase A-associated cardiac cell apoptosis. A1 - Pchejetski, D A1 - Kunduzova, O A1 - Dayon, A A1 - Calise, D A1 - Seguelas, MH A1 - Leducq, N A1 - Seif, I A1 - Parini, A A1 - Cuvillier, O J1 - Circ Res Y1 - 2007/01/05/ VL - 100 SN - 1524-4571 SP - 41 EP - 49 N2 - The mitochondrial enzyme monoamine oxidase (MAO), its isoform MAO-A, plays a major role in reactive oxygen species-dependent cardiomyocyte apoptosis and postischemic cardiac damage. In the current study, we investigated whether sphingolipid metabolism can account for mediating MAO-A- and reactive oxygen species-dependent cardiomyocyte apoptosis. In H9c2 cardiomyoblasts, MAO-A-dependent reactive oxygen species generation led to mitochondria-mediated apoptosis, along with sphingosine kinase-1 (SphK1) inhibition. These phenomena were associated with generation of proapoptotic ceramide and decrease in prosurvival sphingosine 1-phosphate. These events were mimicked by inhibition of SphK1 with either pharmacological inhibitor or small interfering RNA, as well as by extracellular addition of C(2)-ceramide or H(2)O(2). In contrast, enforced expression of SphK1 protected H9c2 cells from serotonin- or H(2)O(2)-induced apoptosis. Analysis of cardiac tissues from wild-type mice subjected to ischemia/reperfusion revealed significant upregulation of ceramide and inhibition of SphK1. It is noteworthy that SphK1 inhibition, ceramide accumulation, and concomitantly infarct size and cardiomyocyte apoptosis were significantly decreased in MAO-A-deficient animals. In conclusion, we show for the first time that the upregulation of ceramide/sphingosine 1-phosphate ratio is a critical event in MAO-A-mediated cardiac cell apoptosis. In addition, we provide the first evidence linking generation of reactive oxygen species with SphK1 inhibition. Finally, we propose sphingolipid metabolites as key mediators of postischemic/reperfusion cardiac injury. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17158340&query_hl=1 ER - TY - JFULL T1 - Discrepancies between commercially available immunoassays in the detection of tumour-derived hCG. A1 - Mitchell, H A1 - Seckl, MJ J1 - Mol Cell Endocrinol Y1 - 2007/01/02/ VL - 260-262 SN - 0303-7207 SP - 310 EP - 313 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17069967&query_hl=1 ER - TY - JFULL T1 - Nuclear positioning of the BACH2 gene in BCR-ABL positive leukemic cells A1 - Ono, A A1 - Kono, K A1 - Ikebe, D A1 - Muto, A A1 - Sun, JY A1 - Kobayashi, M A1 - Ueda, K A1 - Melo, JV A1 - Igarashi, K A1 - Tashiro, S J1 - GENE CHROMOSOME CANC Y1 - 2007/01// VL - 46 SN - 1045-2257 SP - 67 EP - 74 N2 - BACH2 is a B-cell-specific transcription repressor and is also know as a tumor suppressor in B cell malignancy. Expression of BACH2 is induced in BCR-ABL positive lymphoid cell lines including BV173 by imatinib, a molecular targeting agent for the treatment of chronic myeloid leukemia (CML). Here we show that the activity of the BACH2 gene is related to the nuclear positioning of the gene loci. We examined the spatial association of the BACH2 gene with the centromeric heterochromatin, a transcriptionally repressive subnuclear compartment, by comparing cells with low (BV173 and K562) and high (NAMALWA) levels of BACH2 mRNA. The BACH2 gene was located closer to the centromeric heterochromatin in BV173 and K562 cells as compared to NAMALWA cells. In BV173 cells, the BACH2-centromere distance increased after imatinib treatment to levels similar to those in NAMALWA cells. We also found that diethylmaleate, an oxidative stressor, enhanced the antiproliferative effect of imatinib in only BV173 cells. Since BACH2 induces apoptosis by oxidative stress, these observations suggest that down-regulation of the BACH2 gene through the interaction with centromeric heterochromatin would take part in leukomogenesis of BCR-ABL positive lymphoid leukemia. 2006 Wiley-Liss, Inc. ER - TY - JFULL T1 - Overexpression of the heat-shock protein 70 is associated to imatinib resistance in chronic myeloid leukemia A1 - Pocaly, M A1 - Lagarde, V A1 - Etienne, G A1 - Ribeil, JA A1 - Claverol, S A1 - Bonneu, M A1 - Moreau-Gaudry, F A1 - Guyonnet-Duperat, V A1 - Hermine, O A1 - Melo, JV A1 - Dupouy, M A1 - Turcq, B A1 - Mahon, FX A1 - Pasquet, JM J1 - LEUKEMIA Y1 - 2007/01// VL - 21 SN - 0887-6924 SP - 93 EP - 101 N2 - Imatinib is an effective therapy for chronic myeloid leukemia ( CML), a myeloproliferative disorder characterized by the expression of the recombinant oncoprotein Bcr-AbI. In this investigation, we studied an imatinib-resistant cell line ( K562-r) generated from the K562 cell line in which none of the previously described mechanisms of resistance had been detected. A threefold increase in the expression of the heat-shock protein 70 ( Hsp70) was detected in these cells. This increase was not associated to heat-shock transcription factor-1 ( HSF-1) overexpression or activation. RNA silencing of Hsp70 decreased dramatically its expression ( 90%), and was accompanied by a 34% reduction in cell viability. Overexpression of Hsp70 in the imatinib-sensitive K562 line induced resistance to imatinib as detected by a large reduction in cell death in the presence of 1 mu M of imatinib. Hsp70 level was also increased in blast cells of CML patients resistant to imatinib, whereas the level remained low in responding patients. Taken together, the results demonstrate that overexpression of Hsp70 can lead to both in vitro and in vivo resistance to imatinib in CML cells. Moreover, the overexpression of Hsp70 detected in imatinib-resistant CML patients supports this mechanism and identifies potentially a marker and a therapeutic target of CML evolution. ER - TY - JFULL T1 - Genetic insights into the hypoxia-inducible factor (HIF) pathway. A1 - Kiriakidis, S A1 - Esteban, MA A1 - Maxwell, PH J1 - Adv Enzyme Regul Y1 - 2007/// VL - 47 SN - 0065-2571 SP - 288 EP - 306 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17335877&query_hl=1 ER - TY - JFULL T1 - Laparoscopic versus open colposuspension for urodynamic stress incontinence. A1 - Tan, E A1 - Tekkis, PP A1 - Cornish, J A1 - Teoh, TG A1 - Darzi, AW A1 - Khullar, V J1 - Neurourol Urodyn Y1 - 2007/// VL - 26 SN - 0733-2467 SP - 158 EP - 169 N2 - AIMS: Laparoscopic colposuspension aims to alleviate urodynamic stress incontinence whilst minimizing operative morbidity and mortality.The present study compared laparoscopic to open surgery with regards to short-term outcomes. METHODS: Meta-analysis of comparative studies published between 1995 and 2006 of laparoscopic versus open colposuspension was performed. End points evaluated were operative outcomes and subjective/objective cure. A random-effect model was used and sensitivity analysis performed to account for bias in patient selection. RESULTS: Sixteen studies matched the selection criteria, reporting on 1,807 patients, of whom 861 (47.6%) underwent laparoscopic and 946 (52.4%) underwent open colposuspension length of hospital stay (WMD = -1.52 days, CI = -2.08, -0.96 days) and return to normal life (WMD = -1.51 weeks, CI = -3.02, 0.01 weeks) were significantly reduced following laparoscopic surgery. These findings remained consistent on sensitivity analysis. Bladder injuries occurred more often in the laparoscopic group (OR = 2.23, CI = 1.11, 4.50), but only with marginal statistical significance. Comparable bladder injury rates were found when studies were matched for quality, year, and randomized trials. Cure rates were similar between the two procedures at 2 years follow-up. CONCLUSION: Laparoscopic colposuspension results in a significant reduction in hospital stay and earlier return to work, with a possible increased risk of bladder injury. When performed by appropriately experienced surgeons it may be a safe option with advantages for the patient, but further randomized controlled trials should be undertaken to evaluate continence in the longer term at 5 years. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17252603&query_hl=1 ER - TY - JFULL T1 - Multi-detector computed tomography in coronary artery bypass graft assessment: a meta-analysis. A1 - Jones, CM A1 - Athanasiou, T A1 - Dunne, N A1 - Kirby, J A1 - Aziz, O A1 - Haq, A A1 - Rao, C A1 - Constantinides, V A1 - Purkayastha, S A1 - Darzi, A J1 - Ann Thorac Surg Y1 - 2007/01// VL - 83 SN - 1552-6259 SP - 341 EP - 348 N2 - Multi-detector computed tomography (MDCT) has become an alternative to coronary angiography in diagnosis of graft occlusion and stenosis after coronary artery bypass. A literature search was performed for studies comparing angiography to 8-slice, 16-slice, and 64-slice MDCT in the assessment of coronary grafts. In assessing occlusion, 14 studies produced pooled sensitivity of 97.6%, specificity of 98.5%, diagnostic odds ratio of 934.2, area under the curve of 0.996, and Q* of 0.977. Ninety-six percent of all grafts were visualized for occlusion assessment. Beta blockers, symptomatic status, and postoperative period did not significantly affect diagnostic performance. Stenosis assessment produced sensitivity of 88.7% and specificity of 97.4%. Eighty-eight percent of patent grafts could be assessed for stenosis. The diagnostic accuracy of MDCT approaches angiography for diagnosing graft occlusion and stenosis in patients with venous and arterial coronary bypass grafts. Our findings show that cardiac surgeons will need to interpret MDCT images of both native and grafted vessels soon in preparation for primary or re-do coronary bypass grafting procedures. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17184705&query_hl=1 ER - TY - JFULL T1 - The clinical significance of disseminated tumor cells in breast cancer. A1 - Slade, MJ A1 - Coombes, RC J1 - Nat Clin Pract Oncol Y1 - 2007/01// VL - 4 SN - 1743-4262 SP - 30 EP - 41 N2 - The presence of tumor cells in the bone marrow of primary breast cancer patients at surgery has been shown to be an independent prognostic indicator of relapse. Tumor cells have been detected either directly, using immunocytochemical staining, or indirectly, using reverse transcription-polymerase chain reaction (RT-PCR). Studies have been initiated to determine whether the presence of disseminated cells can be monitored during the therapy of patients with primary breast cancer, and thus potentially be used to predict relapse before overt metastases are detectable. Studies are also ongoing to improve methods of detection, such as immunobead enrichment followed by staining and real-time RT-PCR, and to find alternative markers for the disseminated cells. Studies of patients with overt metastases have shown that there is a large tumor load in the peripheral blood and that this predicts overall survival. This article reviews the published literature on studies carried out in both primary and metastatic breast cancer patients, the methodologies and markers used, and improvements in detection methodologies that are being investigated including real-time RT-PCR, novel markers, enrichment and automated image analysis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17183354&query_hl=1 ER - TY - JFULL T1 - LACE-conditioned autologous stem cell transplantation for relapsed or refractory Hodgkin's lymphoma: treatment outcome and risk factor analysis in 67 patients from a single centre. A1 - Perz, JB A1 - Giles, C A1 - Szydlo, R A1 - O'Shea, D A1 - Sanz, J A1 - Chaidos, A A1 - Wagner, S A1 - Davis, J A1 - Loaiza, S A1 - Marin, D A1 - Apperley, J A1 - Olavarria, E A1 - Rahemtulla, A A1 - Lampert, I A1 - Naresh, K A1 - Samson, D A1 - MacDonald, D A1 - Kanfer, EJ J1 - Bone Marrow Transplant Y1 - 2007/01// VL - 39 SN - 0268-3369 SP - 41 EP - 47 N2 - High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a recognized treatment option for patients with relapsed Hodgkin's lymphoma. We have analysed 67 patients who underwent ASCT after LACE (lomustine (CCNU), cytarabine (Ara-C), cyclophosphamide, etoposide) conditioning for relapsed (n=61) or primary refractory (n=6) Hodgkin's lymphoma. The 100-day treatment-related mortality was 3%. With a median follow-up of 67 months (range 3.3-161.0) the probabilities of overall survival (OS) and progression-free survival (PFS) at 5 years were 68 and 64%, respectively. Probabilities for OS and PFS at 5 years for patients with chemosensitive relapse (n=40) were 81 and 78% versus 50 and 35%, respectively, for patients (n=27) with chemoresistant relapse (P=0.012 for OS, P=0.002 for PFS). In multivariate analysis mixed cellularity classical or lymphocyte-depleted classical histology subtype and haemoglobin level of 10 g/dl or less at the time of ASCT were identified as risk factors for worse OS, whereas stage III or IV disease at diagnosis and disease status at ASCT other than complete or partial remission predicted inferior PFS. LACE followed by ASCT is an effective treatment for the majority of patients with chemosensitive relapsed Hodgkin's lymphoma and a proportion of chemorefractory patients also benefit. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17115062&query_hl=1 ER - TY - JFULL T1 - Skills acquisition for laparoscopic gastric bypass in the training laboratory: an innovative approach. A1 - Aggarwal, R A1 - Boza, C A1 - Hance, J A1 - Leong, J A1 - Lacy, A A1 - Darzi, A J1 - Obes Surg Y1 - 2007/01// VL - 17 SN - 0960-8923 SP - 19 EP - 27 N2 - BACKGROUND: Laparoscopic Roux-en-Y gastric bypass (LRYGBP) is a technically demanding procedure, with a long learning curve. The aim of this study was three-fold: to develop a task-based approach to training in LRYGBP, define a tool for objective technical skills assessments, and objectively determine the efficacy of this approach. METHODS: Videos of expert and novice surgeons performing LRYGBP on patients and anesthetised porcine models were analyzed to define an appropriate task for skills assessment. Subsequently, a jejuno-jejunostomy model was developed using cadaveric porcine small bowel, placed into a video-box trainer. 27 surgeons of varying experience levels in advanced laparoscopic procedures performed the task. Assessments of technical skill were by hand motion analysis and video-based scoring. A further 16 surgeons inexperienced in LRYGBP attended a task-based hands-on training course and performed the jejuno-jejunostomy task at start and end of the course. RESULTS: The jejuno-jejunostomy model differentiated between surgeons of varying experience levels for time taken (P<0.001), economy of movement (P=0.001) and video scores (P<0.001). Surgeons attending the training course made significant improvements in time taken (P=0.002) and economy of movement (P=0.006), although not for generic video scores (P=0.243) by the end of course. CONCLUSIONS: The structured, task-based approach for commencement of training in LRYGBP leads to objective improvements in the technical skills of inexperienced surgeons at the end of a short course. The next stage of the curriculum should be to achieve proficiency in the complete procedure on an anesthetised porcine model, prior to preceptorship on human cases. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17355764&query_hl=1 ER - TY - JFULL T1 - Skeletonization of radial and gastroepiploic conduits in coronary artery bypass surgery. A1 - Massey, RM A1 - Warren, OJ A1 - Szczeklik, M A1 - Wallace, S A1 - Leff, DR A1 - Kokotsakis, J A1 - Darzi, A A1 - Athanasiou, T J1 - J Cardiothorac Surg Y1 - 2007/// VL - 2 SN - 1749-8090 SP - 26 EP - 26 N2 - The use of a skeletonized internal thoracic artery in coronary artery bypass graft surgery has been shown to confer certain advantages over a traditional pedicled technique, particularly in certain patient groups. Recent reports indicate that radial and gastroepiploic arteries can also be harvested using a skeletonized technique. The aim of this study is to systematically review the available evidence regarding the use of skeletonized radial and gastroepiploic arteries within coronary artery bypass surgery, focusing specifically on it's effect on conduit length and flow, levels of endothelial damage, graft patency and clinical outcome. Four electronic databases were systematically searched for studies reporting the utilisation of the skeletonization technique within coronary revascularisation surgery in humans. Reference lists of all identified studies were checked for any missing publications. There appears to be some evidence that skeletonization may improve angiographic patency, when compared with pedicled vessels in the short to mid-term. We have found no suggestion of increased complication rates or increased operating time. Skeletonization may increase the length of the conduit, and the number of sequential graft sites, but no clear clinical benefits are apparent. Our study suggests that there is not enough high quality or consistent evidence to currently advocate the application of this technique to radial or gastroepiploic conduits ahead of a traditional pedicled technique. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17550580&query_hl=1 ER - TY - JFULL T1 - Scaling factors for the extrapolation of in vivo metabolic drug clearance from in vitro data: reaching a consensus on values of human microsomal protein and hepatocellularity per gram of liver. A1 - Barter, ZE A1 - Bayliss, MK A1 - Beaune, PH A1 - Boobis, AR A1 - Carlile, DJ A1 - Edwards, RJ A1 - Houston, JB A1 - Lake, BG A1 - Lipscomb, JC A1 - Pelkonen, OR A1 - Tucker, GT A1 - Rostami-Hodjegan, A J1 - Curr Drug Metab Y1 - 2007/01// VL - 8 SN - 1389-2002 SP - 33 EP - 45 N2 - Reported predictions of human in vivo hepatic clearance from in vitro data have used a variety of values for the scaling factors human microsomal protein (MPPGL) and hepatocellularity (HPGL) per gram of liver, generally with no consideration of the extent of their inter-individual variability. We have collated and analysed data from a number of sources, to provide weighted meangeo values of human MPPGL and HPGL of 32 mg g-1 (95% Confidence Interval (CI); 29-34 mg.g-1) and 99x10(6) cells.g-1 (95% CI; 74-131 mg.g-1), respectively. Although inter-individual variability in values of MPPGL and HPGL was statistically significant, gender, smoking or alcohol consumption could not be detected as significant covariates by multiple linear regression. However, there was a weak but statistically significant inverse relationship between age and both MPPGL and HPGL. These findings indicate the importance of considering differences between study populations when forecasting in vivo pharmacokinetic behaviour. Typical clinical pharmacology studies, particularly in early drug development, use young, fit, healthy male subjects of around 30 years of age. In contrast, the average age of patients for many diseases is about 60 years of age. The relationship between age and MPPGL observed in this study estimates values of 40 mg.g-1 for a 30 year old individual and 31 mg.g-1 for a 60 year old individual. Investigators may wish to consider the reported covariates in the selection of scaling factors appropriate for the population in which estimates of clearance are being predicted. Further studies are required to clarify the influence of age (especially in paediatric subjects), donor source and ethnicity on values of MPPGL and HPGL. In the meantime, we recommend that the estimates (and their variances) from the current meta-analysis be used when predicting in vivo kinetic parameters from in vitro data. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17266522&query_hl=1 ER - TY - JFULL T1 - Ring-closing metathesis in the synthesis of biologically active peptidomimetics of apicidin A A1 - Deshmukh, PH A1 - Schulz-Fademrecht, C A1 - Procopiou, PA A1 - Vigushin, DA A1 - Coombes, RC A1 - Barrett, AGM J1 - ADV SYNTH CATAL Y1 - 2007/01// VL - 349 SN - 1615-4150 SP - 175 EP - 183 N2 - Syntheses of novel 16-membered macrocyclic peptidomimetics are reported, which employ iterative peptide coupling followed by high yielding ring-closing metathesis (RCM) as the key cyclization step. The target macrocyclic compounds include examples containing a (2S)-amino-8-oxodecanoic acid (Aoda) residue as analogues of apicidin A, a known potent histone deacetylase (HDAC) inhibitor. These showed modest levels of biological activity as HDAC inhibitors. ER - TY - JFULL T1 - Training and assessment of procedural skills in context using an Integrated Procedural Performance Instrument (IPPI). A1 - Kneebone, R A1 - Bello, F A1 - Nestel, D A1 - Yadollahi, F A1 - Darzi, A J1 - Stud Health Technol Inform Y1 - 2007/// VL - 125 SN - 0926-9630 SP - 229 EP - 231 N2 - The use of simulation in the training and assessment of procedural skills is widely acknowledged as a powerful and necessary alternative to the traditional apprenticeship model. However advanced, simulation on its own cannot provide the necessary conditions for holistic practice. The Integrated Procedural Performance Instrument presented in this paper combines simulated patients (SPs) with inanimate models, items of medical equipment or computer generated virtual models to recreate a panel of realistic scenarios, each addressing a combination of technical and non-technical clinical challenges. The result is a safe yet authentic clinical context which can be used for training and assessment. This novel use of simulation provides a patient-centred, learner-focused approach that builds up a composite picture of technical skills, communication skills and professional behaviours across a range of challenging clinical situations. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17377272&query_hl=1 ER - TY - JFULL T1 - Surgical trauma, minimal residual disease and locoregional cancer recurrence. A1 - Ceelen, WP A1 - Morris, S A1 - Paraskeva, P A1 - Pattyn, P J1 - Cancer Treat Res Y1 - 2007/// VL - 134 SN - 0927-3042 SP - 51 EP - 69 N2 - The persistence of residual tumour is associated with the histology and stage of the primary cancer, the completeness and quality of surgery, and postoperative events such as anastomotic leakage or entrapment of cells in exudating wound surfaces. At present, there is no clinical evidence that the use of laparoscopic techniques adversely influences the risk of residual disease. The inflammatory process associated with surgery shares a number of central mediators and pathways with tumour growth and invasiveness. Both cellular components (mainly macrophages and fibroblasts) and humoral factors associated with inflammation have been shown to enhance tumour growth in numerous preclinical studies. Tumour foci at a distance from the main cancer are kept in a dormant state by a range of anti-angiogenic mediators produced by the main cancer. Preclinical studies have shown that removal of the primary cancer reactivates proliferative and metastatic pathways in the residual tumour. Clinically, this phenomenon has been proposed as underlying the observed rapid systemic relapse after surgery in young node positive breast cancer patients. Strategies proposed to prevent residual disease encompass avoidance of tumour spill and minimization of surgical trauma and related inflammation. Efforts to remove or kill free intraperitoneal cells by local antiseptic or cytotoxic regimens have met only limited clinical success. Specific targeted therapy aimed at inhibiting the inflammatory response, tumour cell adhesion, or the metastatic phenotype of dormant cells appears promising in preclinical models and needs to be addressed in future clinical trials. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17633047&query_hl=1 ER - TY - JFULL T1 - Meta-analysis: Alvimopan vs. placebo in the treatment of post-operative ileus. A1 - Tan, EK A1 - Cornish, J A1 - Darzi, AW A1 - Tekkis, PP J1 - Aliment Pharmacol Ther Y1 - 2007/01/01/ VL - 25 SN - 0269-2813 SP - 47 EP - 57 N2 - BACKGROUND: Alvimopan is a selective, competitive mu-opioid receptor antagonist with limited oral bioavailability which may be used to reduce length of post-operative ileus. AIM: The study compared alvimopan with placebo following bowel resection or total abdominal hysterectomy. METHODS: A meta-analysis of randomized-controlled trials published between 2001 and 2006 of alvimopan vs. placebo was performed. The primary efficacy end-points were composite measures of passage of flatus, stool, and tolerance of solid food (GI-3) and passage of stool and tolerance of solid food (GI-2). The incidence of treatment emergent adverse events was assessed. RESULTS: Five trials matched the selection criteria, reporting on 2195 patients. A total of 1521 (69.3%) had alvimopan and 674 (30.7%) placebo. GI-3 significantly improved (hazard ratio 1.30; 95% confidence intervals 1.16, 1.45, P < 0.001), as did GI-2 (hazard ratio 1.61; 95% confidence intervals 1.26, 2.05, P < 0.001) on alvimopan 12 mg. Time to discharge (hazard ratio 1.26; 95% confidence intervals 1.13, 1.40, P < 0.001), time to bowel motion (hazard ratio 1.74; 95% confidence intervals 1.29, 2.35, P < 0.001), and time to solid food (hazard ratio 1.14; 95% confidence intervals 1.01, 1.30, P < 0.04) also improved significantly. No difference was noted in the incidence of treatment emergent adverse events. CONCLUSIONS: Alvimopan showed significant advantages over placebo in restoring gastro-intestinal function, and reduced time to discharge following major abdominal surgery, with acceptable side effects. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17042776&query_hl=1 ER - TY - JFULL T1 - Assessment of response to treatment of unresectable liver tumours with 90Y microspheres: value of FDG PET versus computed tomography. A1 - Szyszko, T A1 - Al-Nahhas, A A1 - Canelo, R A1 - Habib, N A1 - Jiao, L A1 - Wasan, H A1 - Pagou, M A1 - Tait, P J1 - Nucl Med Commun Y1 - 2007/01// VL - 28 SN - 0143-3636 SP - 15 EP - 20 N2 - INTRODUCTION: Selective internal radiation therapy (SIRT) with SIR spheres (90Y microspheres) is a treatment option for liver tumours in patients in whom other therapies are inappropriate or have failed. This study aims to assess the value of FDG PET in assessing the response to SIRT as compared to computed tomography (CT). MATERIAL AND METHODS: Twenty-one patients (11 F, 10 M; age range 40-75 years, mean, 58 years) received SIR spheres at the Hammersmith Hospital. One patient received two treatments. Most patients had colorectal metastases (n=10), while the others (n=11) had liver metastasis from different primaries. The mean administered dose was 1.9 GBq (range, 1.2-2.5 GBq). Follow-up was done with FDG PET and CT at 6 weeks, and 6-monthly thereafter. Pre-therapy and post-therapy CT and PET scans were assessed visually (RECIST criteria for CT) and semi-quantitative for PET using the standardized uptake value (SUV). RESULT: Eighty-six percent of patients showed decreased PET activity at 6 weeks while only 13% showed a partial response in the size of tumour on CT scan. The mean pre-treatment SUV was 12.2+/-3.7 and the mean post-treatment SUV was 9.3+/-3.7 (P=0.01). CT imaging showed progressive disease in 27% patients and stable liver disease in 60% patients. Based on FDG PET results one patient had surgery for down-staged tumour. CONCLUSION: FDG PET imaging is more sensitive than CT in the assessment of early response to SIR spheres, allowing clinicians to proceed with further therapeutic options. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17159544&query_hl=1 ER - TY - JFULL T1 - Metastatic ductal eccrine adenocarcinoma masquerading as an invasive ductal carcinoma of the male breast. A1 - Mclean, SR A1 - Shousha, S A1 - Francis, N A1 - Lim, A A1 - Eccles, S A1 - Brock, CS A1 - Palmieri, C J1 - J INVEST MED Y1 - 2007/01// VL - 55 SN - 1081-5589 SP - S93 EP - S93 ER - TY - JFULL T1 - Structure-activity relationships of aryloxyalkanoic acid hydroxyamides as potent inhibitors of histone deacetylase A1 - Marson, CM A1 - Mahadevan, T A1 - Dines, J A1 - Sengmany, S A1 - Morrell, JM A1 - Alao, JP A1 - Joel, SP A1 - Vigushin, DM A1 - Coombes, RC J1 - BIOORG MED CHEM LETT Y1 - 2007/01/01/ VL - 17 SN - 0960-894X SP - 136 EP - 141 N2 - Syntheses of aryloxyalkanoic acid hydroxyamides are described, all of which are potent inhibitors of histone deacetylase, some being more potent in vitro than trichostatin A (IC50 = 3 nM). Variation of the substituents on the benzene ring as well as fusion of a second ring have marked effects on potency, in vitro IC50 values down to I nM being obtained. (c) 2006 Elsevier Ltd. All rights reserved. ER - TY - JFULL T1 - Bloodless liver resection using radiofrequency energy. A1 - Ayav, A A1 - Jiao, LR A1 - Habib, NA J1 - Dig Surg Y1 - 2007/// VL - 24 SN - 0253-4886 SP - 314 EP - 317 N2 - BACKGROUND: Liver surgery carries the risk of intraoperative bleeding. In order to avoid bleeding, transection of the liver can be performed after coagulating the parenchyma by using monoplolar or bipolar radiofrequency energy. METHODS: 236 consecutive patients underwent liver resection with the radiofrequency-assisted technique using either a monopolar or a bipolar device. Data were collected prospectively to assess the outcome including, intraoperative blood loss, blood transfusion requirement, morbidity and mortality rates. RESULTS: There were 41 major hepatectomies and 195 minor resections. Overall mean intraoperative blood loss was 157 +/- 240 ml, while mean blood loss during liver transection was 90 +/- 105 ml. 10 patients (4%) received blood transfusion. 50 patients (21%) developed postoperative complications including 5 bile leaks (2%). The mortality rate was 2.1%. No patient was reoperated for postoperative haemorrhage or bile leak. The mean postoperative stay was 11 +/- 10 days. CONCLUSION: The radiofrequency-assisted liver resection technique offers hepatobiliary surgeons an additional method for performing liver resections with minimal blood loss, low transfusion requirement, and low morbidity and mortality rates. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17657158&query_hl=1 ER - TY - JFULL T1 - Case report: PET/CT, a cautionary tale. A1 - Wang, J A1 - Cook, G A1 - Frank, J A1 - Dina, R A1 - Livni, N A1 - Lynn, J A1 - Fleming, W A1 - Seckl, MJ J1 - BMC Cancer Y1 - 2007/// VL - 7 SN - 1471-2407 SP - 147 EP - 147 N2 - BACKGROUND: The use of combined positron emission tomography/computerised tomography (PET/CT) scanners in oncology has been shown to improve the staging of tumours and the detection of relapses. However, mis-registration errors are increasingly recognised to be a common pitfall of PET/CT studies. CASE PRESENTATION: We report a patient with a germ cell tumour of the testis, who underwent a PET/CT scan to detect the site of relapse with a view to surgical removal. However, the PET/CT scan mislocalised the tumour site to be within the T2 vertebral body. A subsequent endoscopic ultrasound scan however showed the tumour to be anterior to the vertebral body, which was confirmed at surgery. CONCLUSION: In this report, we highlight the artefactual mislocalisation errors which may occur with PET/CT imaging, and the need to review and verify these scans. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17683560&query_hl=1 ER - TY - JFULL T1 - Minimal residue disease (MRD) A1 - Zaidi, A A1 - Tripuraneni, G A1 - Weller, S A1 - Ward, B A1 - Sinnett, HD A1 - Coombes, RC A1 - Slade, MJ J1 - BREAST CANCER RES Y1 - 2007/01// VL - 9 SN - 1465-5411 ER - TY - JFULL T1 - Chemokine expression is associated with the accumulation of tumour associated macrophages (TAMs) and progression in human colorectal cancer. A1 - Bailey, C A1 - Negus, R A1 - Morris, A A1 - Ziprin, P A1 - Goldin, R A1 - Allavena, P A1 - Peck, D A1 - Darzi, A J1 - Clin Exp Metastasis Y1 - 2007/// VL - 24 SN - 0262-0898 SP - 121 EP - 130 N2 - Chemokines promote tumour progression by enhancing proliferation and modifying the immune response. The purpose of this study was to test the hypothesis that CCL2 monocyte chemotactic protein-1 (MCP-1) contributes to the progression of colorectal cancer by influencing the number and distribution of tumour associated macrophages (TAMs). Chemokine expression was assessed in human colorectal adenocarcinomas by ribonuclease protection assay (RPA). Colonic adenocarcinoma cell lines were used to assess chemokine production by enzyme linked immunosorbant assay (ELISA), and Boyden microchemotaxis assays were performed to determine cell line supernatant monocyte chemotactic activity. CCL2 production was assessed in paraffin embedded tumour samples by immunohistochemistry. Finally, the number of macrophages and their distribution was determined in the same colorectal adenocarcinomas and compared with CCL2 expression and tumour stage. Results showed that CCL2 produced by cell lines induced monocyte chemoattraction, the expression of this chemokine in solid cancers increased with tumour stage (P < 0.05) and immunohistochemistry localized production to tumour cells. Analysis of the macrophage infiltrate showed that the accumulation was significantly greater in tumours than controls (P < 0.005) and within tumours it was greatest in necrotic regions (median 44,600 per mm(3)). Macrophage accumulation increased with tumour stage and correlated with CCL2 expression (r(s) = 0.8). CXCL8 interleukin 8 (IL-8), a potent angiogenic factor and growth factor, was expressed in all tumours and cell lines. It is concluded that CCL2 induces the accumulation of tumour promoting TAMs in human colorectal cancer and represents a therapeutic target to modify the macrophage response and direct immune mediated therapy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17390111&query_hl=1 ER - TY - JFULL T1 - Stem cells as a treatment for chronic liver disease and diabetes. A1 - Levicar, N A1 - Dimarakis, I A1 - Flores, C A1 - Tracey, J A1 - Gordon, MY A1 - Habib, NA J1 - Handb Exp Pharmacol Y1 - 2007/// SN - 0171-2004 SP - 243 EP - 262 N2 - Advances in stem cell biology and the discovery of pluripotent stem cells have made the prospect of cell therapy and tissue regeneration a clinical reality. Cell therapies hold great promise to repair, restore, replace or regenerate affected organs and may perform better than any pharmacological or mechanical device. There is an accumulating body of evidence supporting the contribution of adult stem cells, in particular those of bone marrow origin, to liver and pancreatic islet cell regeneration. In this review, we will focus on the cell therapy for the diseased liver and pancreas by adult haematopoietic stem cells, as well as their possible contribution and application to tissue regeneration. Furthermore, recent progress in the generation, culture and targeted differentiation of human haematopoietic stem cells to hepatic and pancreatic lineages will be discussed. We will also explore the possibility that stem cell technology may lead to the development of clinical modalities for human liver disease and diabetes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17554512&query_hl=1 ER - TY - JFULL T1 - Neoadjuvant 5-fluorouracil, epirubicin and cyclophosphamide chemotherapy followed by docetaxel in refractory patients with locally advanced breast cancer. A1 - Heller, W A1 - Mazhar, D A1 - Ward, R A1 - Sinnett, HD A1 - Lowdell, C A1 - Phillips, R A1 - Shousha, S A1 - Fayaz, A A1 - Palmieri, C A1 - Coombes, RC J1 - Oncol Rep Y1 - 2007/01// VL - 17 SN - 1021-335X SP - 253 EP - 259 N2 - The objective of this study was to evaluate the clinical response of locally advanced breast cancer (LABC) to neoadjuvant (NA) chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) and to study the role of docetaxel in patients who fail to respond to first-line chemotherapy. Patients were enrolled who had primary tumours without distant metastasis that were too extensive for conservative surgery. All underwent NA chemotherapy for breast cancer and thereafter surgery and/or radical radiotherapy. NA chemotherapy with FEC was administered to 88 patients between February 1998 and June 2005. A median of 6 cycles of FEC (range 1-8) was given, followed in 21 cases by a median of 4 cycles (range 2-6) of docetaxel. Where clinically established, with FEC the clinical complete response (cCR) was 22/81 (27%), clinical partial response (cPR) 41/81 (51%), clinical stable disease (cSD) 18/81 (22%). In patients where the response to FEC was regarded as insufficient, docetaxel was given. Response rates were cCR 3/21 (14%); cPR 10/21 (48%), cSD 8/21 (38%). There were 11 cases of pathological complete response (pCR), 9 in the FEC-only group and 2 in the docetaxel group. Following chemotherapy 49 (56%) patients underwent mastectomy, 32 (36%) breast conserving surgery and 5 (6%) radical radiotherapy, giving a breast conservation rate of 42%. Two patients died before receiving surgery or radical radiotherapy. The results show that neoadjuvant FEC is a reasonable NA therapy in breast cancer and that docetaxel is effective in FEC refractory cases. Only 8 of 81 (10%) assessable patients did not respond to any chemotherapy, giving an overall clinical response rate of 90%, which is comparable to studies in which taxanes were given irrespective of response to preceding therapy with antracycline including regimes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17143506&query_hl=1 ER - TY - JFULL T1 - Durable responses to imatinib in patients with PDGFRB fusion gene-positive and BCR-ABL-negative chronic myeloproliferative disorders. A1 - David, M A1 - Cross, NC A1 - Burgstaller, S A1 - Chase, A A1 - Curtis, C A1 - Dang, R A1 - Gardembas, M A1 - Goldman, JM A1 - Grand, F A1 - Hughes, G A1 - Huguet, F A1 - Lavender, L A1 - McArthur, GA A1 - Mahon, FX A1 - Massimini, G A1 - Melo, J A1 - Rousselot, P A1 - Russell-Jones, RJ A1 - Seymour, JF A1 - Smith, G A1 - Stark, A A1 - Waghorn, K A1 - Nikolova, Z A1 - Apperley, JF J1 - Blood Y1 - 2007/01/01/ VL - 109 SN - 0006-4971 SP - 61 EP - 64 N2 - Fusion genes derived from the platelet-derived growth factor receptor beta (PDGFRB) or alpha (PDGFRA) play an important role in the pathogenesis of BCR-ABL-negative chronic myeloproliferative disorders (CMPDs). These fusion genes encode constitutively activated receptor tyrosine kinases that can be inhibited by imatinib. Twelve patients with BCR-ABL-negative CMPDs and reciprocal translocations involving PDGFRB received imatinib for a median of 47 months (range, 0.1-60 months). Eleven had prompt responses with normalization of peripheral-blood cell counts and disappearance of eosinophilia; 10 had complete resolution of cytogenetic abnormalities and decrease or disappearance of fusion transcripts as measured by reverse transcriptase-polymerase chain reaction (RT-PCR). Updates were sought from 8 further patients previously described in the literature; prompt responses were described in 7 and persist in 6. Our data show that durable hematologic and cytogenetic responses are achieved with imatinib in patients with PDGFRB fusion-positive, BCR-ABL-negative CMPDs. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16960151&query_hl=1 ER - TY - JFULL T1 - Communication skills for mobile remote presence technology in clinical interactions. A1 - Nestel, D A1 - Sains, P A1 - Wetzel, CM A1 - Nolan, C A1 - Tay, A A1 - Kneebone, RL A1 - Darzi, AW J1 - J Telemed Telecare Y1 - 2007/// VL - 13 SN - 1357-633X SP - 100 EP - 104 N2 - The use of mobile robotic units for teleconsultation means that the clinician's cognitive and attention skills are divided between tele-operation of the robotic unit and the consultation with the patient. We developed a communication guide based on evidence-based patient-centred interviewing and telephone conferencing skills. The communication guide was tested by five trainee surgeons in a pre- and post-test design. Each surgeon completed three simulated patient consultations. After reading the communication guide, trainees completed three further consultations. The trainees rated authenticity, degree of difficulty, familiarity of clinical presentation and confidence in using telepresence to manage the consultations. Their mean scores were 3.0-4.6, 2.2-4.0, 4.4-4.8 and 3.2-4.2 respectively (maximum possible score 5). The simulated patients rated their satisfaction with communication. Their ratings suggested that there were areas for communication skills development with mean scores ranging from 8.2 to 11.4 (maximum possible score = 15). Although we do not yet know enough about communicating with real patients using mobile robotic units, the communication guide appeared to be useful in our simulated interactions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17359575&query_hl=1 ER - TY - JFULL T1 - Tumour associated macrophages increase with advancing stage in human colorectal cancer in response to CCL2 (MCP-1) production. A1 - Bailey, C A1 - Negus, R A1 - Morris, A A1 - Ziprin, P A1 - Goldin, R A1 - Allavena, P A1 - Peck, D A1 - Darzi, A J1 - Clin Exp Metastasis Y1 - 2007/// VL - In press ER - TY - JFULL T1 - Novel Applications of Dermabondtrade mark (2-Octyl -Cyanoacrylate) in Cardiothoracic Surgery. A1 - Aziz, O A1 - Rahman, MS A1 - Hadjianastassiou, VG A1 - Kokotsakis, J A1 - Vitali, M A1 - Cherian, A A1 - Darzi, A A1 - Athanasiou, T J1 - Surg Technol Int Y1 - 2007/// VL - 16 SN - 1090-3941 SP - 46 EP - 51 N2 - Dermabondtrade mark (Ethicon Inc., Somerville, NJ, USA) is a cyanoacrylate adhesive normally indicated for skin wound closure. This study describes the emergency use of this adhesive to control bleeding close to coronary anastomoses in exceptional cases. Dermabondtrade mark was used in 17 patients who underwent cardiac surgery during an eight-month period, where other haemostatic interventions were unsuitable. It was applied for haemorrhage in 15 patients and control air leaks in two of the patients. Haemostasis was successful with Dermabondtrade mark alone in 11 patients; the remaining four required additional interventions. It effectively controlled haemorrhage from ventricular pacing wires, vascular sling holes, peri-anastomotic bleeding, and epicardial tears. The adhesive was not placed directly on any graft because of embolic risk. In the two patients with visible air leaks, it was successfully used. No patient events were recorded as a result of haemorrhage and no reported toxicity. Dermabondtrade mark may be indicated in circumstances in which haemostasis with traditional methods has failed or is inappropriate. A need for further high-quality objective research exists on the effectiveness and long-term safety of 2-octyl cyanoacrylate in cardiac surgery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17429768&query_hl=1 ER - TY - JFULL T1 - Promiscuous and lineage-specific roles of cell cycle regulators in haematopoiesis. A1 - Myatt, SS A1 - Lam, EW J1 - Cell Div Y1 - 2007/// VL - 2 SN - 1747-1028 SP - 6 EP - 6 N2 - Haematopoietic cell number is maintained by a delicate balance between cell proliferation, differentiation and death. Gene knockout studies in mice have revealed the complex roles of cyclins, CDKs, and CDK inhibitors in regulating cell proliferation and differentiation in the haematopoietic system. These studies point to families of cell cycle regulators which display both redundant and unique roles within a lineage and developmental-stage specific manner. Moreover, the promiscuity of these cell cycle regulators is critical for haematopoietic cell proliferation and differentiation. In this review, we discuss the current evidence from mouse models that the complexity and multifarious nature of the haematopoietic system is critical for its form and function. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17295909&query_hl=1 ER - TY - JFULL T1 - Role of circulating tumour cells in predicting recurrence after excision of primary colorectal carcinoma. A1 - Allen-Mersh, TG A1 - McCullough, TK A1 - Patel, H A1 - Wharton, RQ A1 - Glover, C A1 - Jonas, SK J1 - Br J Surg Y1 - 2007/01// VL - 94 SN - 0007-1323 SP - 96 EP - 105 N2 - BACKGROUND: This study assessed the potential for reverse transcriptase-polymerase chain reaction (RT-PCR)-based circulating tumour cell identification to predict colorectal cancer recurrence. METHODS: mRNA for carcinoembryonic antigen and cytokeratin 20 was identified by RT-PCR in blood from patients with colorectal cancer, before and after primary tumour resection. Cancer recurrence was assessed at follow-up, and the accuracy of RT-PCR and primary tumour lymph node positivity in predicting recurrence was estimated. RESULTS: One hundred and ninety-six patients with colorectal cancer were studied over a median follow-up of 1393 days from surgery. Regression analysis selected 24-h post-resection RT-PCR positivity (hazard ratio for a positive test in predicting recurrence 8.66 (95 per cent confidence interval (c.i.) 3.08 to 24.33)) before lymph node involvement (hazard ratio 7.92 (95 per cent c.i. 3.26 to 19.20)). When 24-h post-resection RT-PCR was combined with lymph node positivity, the hazard ratio increased to 18.54 (95 per cent c.i. 4.01 to 85.11), attributing a 3 per cent recurrence risk to 52 per cent, and a 50 per cent recurrence risk to 48 per cent, of patients with colorectal cancer resected with curative intent. CONCLUSION: RT-PCR positivity within 24 h of primary colorectal cancer resection is a strong predictor of colorectal cancer recurrence, and may be useful clinically. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17058316&query_hl=1 ER - TY - JFULL T1 - Selection of protein phosphatase 2A regulatory subunits is mediated by the C-terminus of the catalytic subunit. A1 - Longin, S A1 - Zwaenepoel , K A1 - Louis, JV A1 - Dilworth, S A1 - Goris, J J1 - J. Biol. Chem. Y1 - 2007/// ER - TY - JFULL T1 - Histomorphometric features of hydatidiform moles in early pregnancy: relationship to detectability by ultrasound examination. A1 - Fowler, DJ A1 - Lindsay, I A1 - Seckl, MJ A1 - Sebire, NJ J1 - Ultrasound Obstet Gynecol Y1 - 2007/01// VL - 29 SN - 0960-7692 SP - 76 EP - 80 N2 - OBJECTIVE: The majority of partial (PHM) and complete (CHM) hydatidiform moles are diagnosed in early pregnancy. About half are identified as molar on ultrasonographic examination prior to evacuation. It is uncertain whether unsuspected cases represent an intrinsically different molar phenotype or are simply dependant on sonographer expertise. We measured a microscopic parameter, average villus diameter, of evacuated PHMs and CHMs to ascertain the cause of non-detection on ultrasound. METHODS: Fifty-four molar pregnancies were examined from the files of the Trophoblastic Disease Unit, in which results of an ultrasound examination prior to evacuation were known. In each, the average cross-sectional diameter of the largest 10 villi was recorded. Maximum villus diameters were compared between gestational age groups (<14 weeks and >or=14 weeks), and ultrasound detection groups (detected (d) and not detected (nd)). RESULTS: The average maximum villus diameter of the largest hydropic villi was significantly less in the first trimester for both PHMs and CHMs that were undetected by ultrasound examination compared to those identified as molar sonographically (P<0.001 and P<0.001, respectively). There was no significant difference in the maximum villus diameter between PHMs and CHMs that were not detected sonographically in the first trimester (P=0.44). Beyond 14 weeks of gestation, there was no significant difference between PHMs detected and undetected sonographically (P=0.88). CONCLUSION: The average diameter of the largest, most hydropic villi, is significantly greater in cases of PHMs and CHMs detected by ultrasound examination in the first trimester compared to that of those not detected sonographically, but beyond 14 weeks such differences are minimal. These findings suggest that, although sonographer expertise could potentially increase ultrasound detection rates somewhat for PHMs and CHMs, a significant proportion of cases demonstrate minimal hydropic change in the first trimester and are therefore likely to remain unidentifiable by ultrasound examination prior to evacuation, even with improved sonographer expertise. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17171630&query_hl=1 ER - TY - JFULL T1 - Management and prevention of adverse effects related to treatment of liver tumours with 90Y microspheres. A1 - Szyszko, T A1 - Al-Nahhas, A A1 - Tait, P A1 - Rubello, D A1 - Canelo, R A1 - Habib, N A1 - Jiao, L A1 - Wasan, H A1 - Bansi, D A1 - Thillainayagam, A A1 - Nijran, K A1 - Stamp, G A1 - O'Rourke, E J1 - Nucl Med Commun Y1 - 2007/01// VL - 28 SN - 0143-3636 SP - 21 EP - 24 N2 - BACKGROUND AND AIM: Selective internal radiation therapy with 90Y microspheres (SIR spheres) is increasingly used in the treatment of extensive liver tumours. Careful selection and preparation of patients are necessary to avoid possible adverse effects. We aimed to evaluate the incidence and severity of adverse effects resulting from the administration of SIR spheres during therapy. MATERIALS AND METHODS: Between June 2004 and August 2006, 21 patients (11 women and 10 men; age range 40-75 years; mean, 58 years) with a wide range of extensive liver tumours were treated with SIR spheres. The mean administered dose was 1.87 GBq (range 1.2-2.5 GBq). During the follow-up period of 26 months, all adverse effects were monitored and classified according to the National Cancer Institute criteria. RESULTS: Four patients had adverse effects: one case of cholecystitis followed by fibrosis and portal hypertension, one case of peptic ulceration and two cases of radiation hepatitis. All cases responded to appropriate therapy. CONCLUSION: Proper selection of patients and accurate interpretation of pre-treatment investigations are vital for minimizing adverse effects following therapy with SIR spheres. In our experience, all adverse effects were moderate with no life-threatening consequences. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17159545&query_hl=1 ER - TY - JFULL T1 - The surgical care practitioner: a feasible alternative. Results of a prospective 4-year audit at St Mary's Hospital Trust, London. A1 - Martin, S A1 - Purkayastha, S A1 - Massey, R A1 - Paraskeva, P A1 - Tekkis, P A1 - Kneebone, R A1 - Darzi, A J1 - Ann R Coll Surg Engl Y1 - 2007/01// VL - 89 SN - 1478-7083 SP - 30 EP - 35 N2 - INTRODUCTION: Surgical care practitioners (SCPs) are an expanding group of professionals, drawn from nursing and the allied health professions. Amongst other functions, SCPs can provide a range of surgical procedures including a 'minor surgical' service. The aim of this study was to audit the volume and outcomes related to the SCP service at St Mary's since its inception. PATIENTS AND METHODS: All prospectively collected data regarding SCP-managed patients between 2001 and 2005 were retrospectively audited. Volume, case mix, waiting times, complications and patient satisfaction were recorded and evaluated. RESULTS: In this 4-year period, the SCP performed 381 minor operative cases (year 1 to year 4: 32, 74, 114 and 161 cases, respectively). These included excision of lipomas, sebaceous cysts and suspicious naevi under local anaesthesia and 7 similar cases under general anaesthetic. There were 11 minor postoperative complications which included 7 wound infections which were all resolved with a short course of oral antibiotics, 2 seromas of which one needed aspiration under local anaesthetic and one minor wound dehiscence which was re-sutured the same day. Overall, 71% were seen within 1 month of referral, 16% within 1-2 months, 3% within 3 months and 10% within 6 months. In addition, 59% were seen and treated within 20 min of their appointed time, 15% within 30-60 min and 24% within 1-2 h. The 3-month patient perspective audit carried out between May and July 2004 included 59 completed patient questionnaires following surgery; 100% were totally satisfied with the care that they received; 98% were happy to see the SCP and 98% documented that they would recommend the SCP to others. CONCLUSIONS: The 4-year period of using an SCP at St Mary's shows that it is feasible and safe for minor operative procedures, that it contributes positively to waiting times and is acceptable to patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17316517&query_hl=1 ER - TY - JFULL T1 - Operative strategies for diverticular peritonitis: a decision analysis between primary resection and anastomosis versus Hartmann's procedures. A1 - Constantinides, VA A1 - Heriot, A A1 - Remzi, F A1 - Darzi, A A1 - Senapati, A A1 - Fazio, VW A1 - Tekkis, PP J1 - Ann Surg Y1 - 2007/01// VL - 245 SN - 0003-4932 SP - 94 EP - 103 N2 - OBJECTIVE: To compare primary resection and anastomosis (PRA) with and without defunctioning stoma to Hartmann's procedure (HP) as the optimal operative strategy for patients presenting with Hinchey stage III-IV, perforated diverticulitis. SUMMARY BACKGROUND DATA: The choice of operation for perforated diverticulitis lies between HP and PRA. Postoperative mortality and morbidity can be high, and the long-term consequences life-altering, with no established criteria guiding clinicians towards selecting a particular procedure. METHODS: Probability estimates for 6879 patients with Hinchey III-IV perforated diverticulitis were obtained from two databases (n = 204), supplemented by expert opinion and summary data from 12 studies (n = 6675) published between 1980 and 2005. The primary outcome was quality-adjusted life-years (QALYs) gained from each strategy. Factors considered were the risk of permanent stoma, morbidity, and mortality from the primary or reversal operations. Decision analysis from the patient's perspective was used to calculate the optimal operative strategy and sensitivity analysis performed. RESULTS: A total of 135 PRA, 126 primary anastomoses with defunctioning stoma (PADS), and 6619 Hartmann's procedures (HP) were considered. The probability of morbidity and mortality was 55% and 30% for PRA, 40% and 25% for PADS, and 35% and 20% for HP, respectively. Stomas remained permanent in 27% of HP and in 8% of PADS. Analysis revealed the optimal strategy to be PADS with 9.98 QALYs, compared with 9.44 QALYs after HP and 9.02 QALYs after PRA. Complications after PRA reduced patients QALYs to a baseline of 2.713. Patients with postoperative complications during both primary and reversal operations for PADS and HP had QALYs of 0.366 and 0.325, respectively. HP became the optimal strategy only when risk of complications after PRA and PADS reached 50% and 44%, respectively. CONCLUSION: Primary anastomosis with defunctioning stoma may be the optimal strategy for selected patients with diverticular peritonitis as may represent a good compromise between postoperative adverse events, long-term quality of life and risk of permanent stoma. HP may be reserved for patients with risk of complications >40% to 50% after consideration of long-term implications. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17197971&query_hl=1 ER - TY - JFULL T1 - Technical-skills training in the 21st century A1 - Aggarwal, R A1 - Darzi, A J1 - NEW ENGL J MED Y1 - 2006/12/21/ VL - 355 SN - 0028-4793 SP - 2695 EP - 2696 ER - TY - JFULL T1 - A small molecule inhibitor for phosphatase and tensin homologue deleted on chromosome 10 (PTEN). A1 - Rosivatz, E A1 - Matthews, JG A1 - McDonald, NQ A1 - Mulet, X A1 - Ho, KK A1 - Lossi, N A1 - Schmid, AC A1 - Mirabelli, M A1 - Pomeranz, KM A1 - Erneux, C A1 - Lam, EW A1 - Vilar, R A1 - Woscholski, R J1 - ACS Chem Biol Y1 - 2006/12/15/ VL - 1 SN - 1554-8937 SP - 780 EP - 790 N2 - Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a phosphoinositide 3-phosphatase, is an important regulator of insulin-dependent signaling. The loss or impairment of PTEN results in an antidiabetic impact, which led to the suggestion that PTEN could be an important target for drugs against type II diabetes. Here we report the design and validation of a small- molecule inhibitor of PTEN. Compared with other cysteine-based phosphatases, PTEN has a much wider active site cleft enabling it to bind the PtdIns(3,4,5)P3 substrate. We have exploited this feature in the design of vanadate scaffolds complexed to a range of different organic ligands, some of which show potent inhibitory activity. A vanadyl complexed to hydroxypicolinic acid was found to be a highly potent and specific inhibitor of PTEN that increases cellular PtdIns(3,4,5)P3 levels, phosphorylation of Akt, and glucose uptake in adipocytes at nanomolar concentrations. The findings presented here demonstrate the applicability of a novel and specific chemical inhibitor against PTEN in research and drug development. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17240976&query_hl=1 ER - TY - JFULL T1 - Cytokine storm and an anti-CD28 monoclonal antibody - Reply A1 - Castello-Cortes, A A1 - Suntharalingam, G A1 - Panoskaltsis, N J1 - NEW ENGL J MED Y1 - 2006/12/14/ VL - 355 SN - 0028-4793 SP - 2593 EP - 2594 ER - TY - JFULL T1 - ATLS versus ETC: time for a decision? A1 - Kinross, J A1 - Warren, O A1 - Darzi, A J1 - Ann Emerg Med Y1 - 2006/12// VL - 48 SN - 1097-6760 SP - 761 EP - 762 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17112943&query_hl=1 ER - TY - JFULL T1 - Mechanisms of androgen receptor repression in prostate cancer. A1 - Powell, SM A1 - Brooke, GN A1 - Whitaker, HC A1 - Reebye, V A1 - Gamble, SC A1 - Chotai, D A1 - Dart, DA A1 - Belandia, B A1 - Bevan, CL J1 - Biochem Soc Trans Y1 - 2006/12// VL - 34 SN - 0300-5127 SP - 1124 EP - 1127 N2 - Anti-androgens used in prostate cancer therapy inhibit AR (androgen receptor) activity via largely unknown mechanisms. Although initially successful in most cases, they eventually fail and the disease progresses. We need to elucidate how anti-androgens work to understand why they fail, and prolong their effects or design further therapies. Using a cellular model, we found different anti-androgens have diverse effects on subcellular localization of AR, revealing that they work via different mechanisms and suggesting that an informed sequential treatment regime may benefit patients. In the presence of the anti-androgens bicalutamide and hydroxyflutamide, a significant proportion of the AR is translocated to the nucleus but remains inactive. Receptor inhibition under these conditions is likely to involve recruitment of co-repressor proteins, which interact with antagonist-occupied receptor but inhibit receptor-dependent transcription. Which co-repressors are required in vivo for AR repression by anti-androgens is not clear, but one candidate is the Notch effector Hey1. This inhibits ligand-dependent activity of the AR but not other steroid receptors. Further, it is excluded from the nucleus in most human prostate cancers, suggesting that abnormal subcellular distribution of co-repressors may contribute to the aberrant hormonal responses observed in prostate cancer. A decrease in co-repressor function is one possible explanation for the development of anti-androgen-resistant prostate cancer, and this suggests that it may not occur at the gross level of protein expression. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17073766&query_hl=1 ER - TY - JFULL T1 - Serum 25-hydroxyvitamin D levels in early and advanced breast cancer. A1 - Palmieri, C A1 - MacGregor, T A1 - Girgis, S A1 - Vigushin, D J1 - J Clin Pathol Y1 - 2006/12// VL - 59 SN - 0021-9746 SP - 1334 EP - 1336 N2 - BACKGROUND: Laboratory and epidemiological studies have implicated vitamin D deficiency in the pathogenesis of breast cancer. 1,25-Dihydroxyvitamin D (1,25(OH)(2)D) promotes differentiation and apoptosis, and potently inhibits proliferation of malignant breast epithelial cells in culture. Serum levels of 1,25(OH)(2)D are higher in normal women than in patients with primary breast cancer. AIM: To clarify the role of vitamin D in breast cancer progression by comparing the levels of serum vitamin D in patients with early and in those with advanced breast cancer. METHODS: Circulating levels of 25-hydroxyvitamin D (25(OH)D), parathyroid hormone (PTH) and calcium were measured prospectively in 279 Caucasian women with invasive breast cancer, 204 women with early-stage disease and 75 women with locally advanced or metastatic disease. RESULTS: Patients with early-stage breast cancer had significantly higher circulating levels of 25(OH)D (p<0.005) and significantly lower PTH (p<0.001) levels than those with advanced disease. Calcium levels did not differ significantly (p = 0.74). CONCLUSION: Serum levels of 25(OH)D are significantly higher in patients with early-stage breast cancer than in those with locally advanced or metastatic disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17046848&query_hl=1 ER - TY - JFULL T1 - Primitive, quiescent and difficult to kill: the role of non-proliferating stem cells in chronic myeloid leukemia. A1 - Barnes, DJ A1 - Melo, JV J1 - Cell Cycle Y1 - 2006/12// VL - 5 SN - 1551-4005 SP - 2862 EP - 2866 N2 - Recent studies have identified primitive, malignant stem cells which have entered the G0-phase of the cell cycle to become 'quiescent' and which are present, in small numbers, in all chronic myeloid leukaemia (CML) patients. These cells have attracted intense scrutiny because they are proving exceptionally refractory to attempts to kill them, in vitro, using imatinib mesylate, the current first-line therapy for CML, or conventional chemotherapeutic agents, such as cytosine arabinoside. This insensitivity, or resistance, to drug treatment is ominous and has important implications for the clinical management of CML, particularly with regard to relapse following an imatinib-induced remission. In this review, we consider the known properties of this cell population, including recent evidence which suggests that transcription of BCR-ABL occurs at an exceptionally high level in these cells despite them having only a single copy of the oncogene. We also discuss possible alternative, Bcr-Abl-independent, mechanisms for the insensitivity of these cells to agents which promote apoptosis, including the putative role of transporter proteins in causing abnormal drug influx or efflux. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17172863&query_hl=1 ER - TY - JFULL T1 - Biomarkers of depression in cancer patients. A1 - Jehn, CF A1 - Kuehnhardt, D A1 - Bartholomae, A A1 - Pfeiffer, S A1 - Krebs, M A1 - Regierer, AC A1 - Schmid, P A1 - Possinger, K A1 - Flath, BC J1 - Cancer Y1 - 2006/12/01/ VL - 107 SN - 0008-543X SP - 2723 EP - 2729 N2 - BACKGROUND: Inflammation and perturbation of the hypothalamic-pituitary-adrenal (HPA) axis function appears to play a putative role in the etiology of depression. Patients with metastatic cancer demonstrate elevated prevalence rates for depression. The objective of the current study was to illustrate the efficacy of interleukin-6 (IL-6) and HPA axis function as adjuncts to support the diagnosis of depression in cancer patients. METHODS: Plasma concentrations of IL-6 and cortisol were measured in 114 cancer patients with and without depression. The relative diurnal variation of cortisol (cortisol VAR), expressed as a percentage, was calculated. Receiver operating characteristics analysis was performed. RESULTS: Depression was associated with increased plasma concentrations of IL-6 (18.7 pg/mL vs. 2.7 pg/mL; P < .001) and higher cortisol concentrations at 8 AM and 8 PM. The relative cortisol VAR (11.7% vs. 60.6%, respectively; P < .001) was found to be decreased in cancer patients with depression, indicating a disturbed circadian function of the HPA axis. As a biomarker of depression, IL-6 yielded at a cutoff value of 10.6 pg/mL, a sensitivity of 79%, and a specificity of 87% (area under the curve [AUC] = 0.86; 95% confidence interval [95% CI], 0.78-0.94), whereas cortisol VAR demonstrated a sensitivity of 81% and a specificity of 88% (AUC = 0.85; 95% CI, 0.74-0.97) at a cutoff value of 33.5%. CONCLUSIONS: Depression is associated with increased plasma IL-6 concentrations in patients with cancer. These patients demonstrate a dysfunction of the HPA-axis, characterized by a decreased diurnal variation of cortisol. The high sensitivity and specificity of these parameters biomarkers of depression make IL-6 and cortisol VAR helpful tools in the diagnosis of depression in patients with cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17036362&query_hl=1 ER - TY - JFULL T1 - A modified radiofrequency-assisted approach to right hemihepatectomy A1 - Ferko, A A1 - Lesko, M A1 - Subrt, Z A1 - Melichar, B A1 - Hoffman, P A1 - Dvorak, P A1 - Vacek, Z A1 - Liao, LR A1 - Habib, NA A1 - Koci, J A1 - Motycka, P J1 - EJSO-EUR J SURG ONC Y1 - 2006/12// VL - 32 SP - 1209 EP - 1211 N2 - Aims: To evaluate a modified radiofrequency-assisted approach to right hemihepatectomy.Methods: Following a bilateral subcostal incision and intraoperative ultrasonography, the liver was mobilized in the standard manner, and a cholecystectomy was performed. The portal vein was isolated, encircled, and ligated. After demarcating the liver parenchyma, coagulation necrosis was achieved using a radiofrequency-assisted device along the line demarcated for transecting the liver parenchyma. The actual transection of the liver parenchyma and the right portal vein was done using a surgical scalpel along the radiofrequency-coagulated line. The right hepatic vein was coagulated using the radiofrequency sealer or by stitching in the resection plane. The hepatic artery was not dissected and was sealed together with the bile ducts in the resection plane using the radiofrequency instrument. The hepatic vein was not divided.Results: Between July 2005 and July 2006, a total of 49 liver resections were performed in our unit. Of these, the radiofrequency-assisted technique was used in 33 cases with metastatic disease; 14 of these cases had right hemihepatectomies, including 2 repeat resections. The mean operation time was 180 min (range, 120-240 min), and the average blood transfusion was 0.14 U (range, 0-2 U). Postoperatively, there was no morbidity, such as bleeding, infection, or biliary fistula, related to the liver resection technique, and no patients died as a result of surgery. In 8 out of the 14 right hemihepatectomies, a right-sided pleural effusion was observed; 3 of them required evacuation.Conclusion: This paper describes a modified radiofrequency-assisted hemihepatectomy, which allows one to obtain control of the portal blood flow going into the resected part of liver. The modified approach appears to be simple and safe. (c) 2006 Elsevier Ltd. All rights reserved. ER - TY - JFULL T1 - Human homologs of the putative G protein-coupled membrane progestin receptors (mPRalpha, beta, and gamma) localize to the endoplasmic reticulum and are not activated by progesterone. A1 - Krietsch, T A1 - Fernandes, MS A1 - Kero, J A1 - Lösel, R A1 - Heyens, M A1 - Lam, EW A1 - Huhtaniemi, I A1 - Brosens, JJ A1 - Gellersen, B J1 - Mol Endocrinol Y1 - 2006/12// VL - 20 SN - 0888-8809 SP - 3146 EP - 3164 N2 - The steroid hormone progesterone exerts pleiotrophic functions in many cell types. Although progesterone controls transcriptional activation through binding to its nuclear receptors, it also initiates rapid nongenomic signaling events. Recently, three putative membrane progestin receptors (mPRalpha, beta, and gamma) with structural similarity to G protein-coupled receptors have been identified. These mPR isoforms are expressed in a tissue-specific manner and belong to the larger, highly conserved family of progestin and adiponectin receptors found in plants, eubacteria, and eukaryotes. The fish mPRalpha has been reported to mediate progesterone-dependent MAPK activation and inhibition of cAMP production through coupling to an inhibitory G protein. To functionally characterize the human homologs, we established human embryonic kidney 293 and MDA-MB-231 cell lines that stably express human mPRalpha, beta, or gamma. For comparison, we also established cell lines expressing the mPRalpha cloned from the spotted seatrout (Cynoscion nebulosus) and Japanese pufferfish (Takifugu rubripes). Surprisingly, we found no evidence that human or fish mPRs regulate cAMP production or MAPK (ERK1/2 or p38) activation upon progesterone stimulation. Furthermore, the mPRs did not couple to a highly promiscuous G protein subunit, Galpha(q5i), in transfection studies or provoke Ca(2+) mobilization in response to progesterone. Finally, we demonstrate that transfected mPRs, as well as endogenous human mPRalpha, localize to the endoplasmic reticulum, and that their expression does not lead to increased progestin binding either in membrane preparations or in intact cells. Our results therefore do not support the concept that mPRs are plasma membrane receptors involved in transducing nongenomic progesterone actions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16959873&query_hl=1 ER - TY - JFULL T1 - Virtual reality simulation training can improve technical skills during laparoscopic salpingectomy for ectopic pregnancy. A1 - Aggarwal, R A1 - Tully, A A1 - Grantcharov, T A1 - Larsen, CR A1 - Miskry, T A1 - Farthing, A A1 - Darzi, A J1 - BJOG Y1 - 2006/12// VL - 113 SN - 1470-0328 SP - 1382 EP - 1387 N2 - OBJECTIVES: To assess the first commercially available virtual reality (VR) simulator to incorporate procedural modules for training of inexperienced gynaecological surgeons to perform laparoscopic salpingectomy for ectopic pregnancy. DESIGN: Prospective cohort study. SETTING: Departments of surgery and gynaecology in central London teaching hospitals. SAMPLE: Thirty gynaecological surgeons were recruited to the study, and were divided into novice (<10 laparoscopic procedures), intermediate (20-50) and experienced (>100) groups. METHODS: All subjects were orientated to the VR simulator with a basic skills task, followed by performing ten repetitions of the virtual ectopic pregnancy module, in a distributed manner. MAIN OUTCOME MEASURES: Operative performance was assessed by the time taken to perform surgery, blood loss and total instrument path length. RESULTS: There were significant differences between the groups at the second repetition of the ectopic module for time taken (median 551.1 versus 401.2 versus 249.2 seconds, P = 0.001), total blood loss (median 304.2 versus 187.4 versus 123.3 ml, P = 0.031) and total instrument path length (median 17.8 versus 8.3 versus 6.8 m, P = 0.023). The learning curves of the experienced operators plateaued at the second session, although greater numbers of sessions were necessary for intermediate (seven) and novice (nine) surgeons to achieve similar levels of skill. CONCLUSIONS: Gynaecological surgeons with minimal laparoscopic experience can improve their skills during short-phase training on a VR procedural module. In contrast, experienced operators showed nonsignificant improvements. Thus, VR simulation may be useful for the early part of the learning curve for surgeons who wish to learn to perform laparoscopic salpingectomy for ectopic pregnancy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17081183&query_hl=1 ER - TY - JFULL T1 - Robotic prostatectomy: the first UK experience. A1 - Mayer, EK A1 - Winkler, MH A1 - Aggarwal, R A1 - Karim, O A1 - Ogden, C A1 - Hrouda, D A1 - Darzi, AW A1 - Vale, JA J1 - Int J Med Robot Y1 - 2006/12// VL - 2 SN - 1478-596X SP - 321 EP - 328 N2 - BACKGROUND: We describe a teamwork approach to setting up the UK's first clinical programme for robotically assisted laparoscopic radical prostatectomy. METHODS: On 22 November 2004 the Imperial Robotic Urological Surgery Group performed their first robotically assisted prostatectomy. Robotically assisted prostatectomy lends itself to division into eight definable stages. A team of four consultant urological surgeons utilized a structured rotating system, using these stages, for time at the console and tableside assisting. Fluidity of surgery was maintained by a surgeon acting as the tableside assistant for the stage prior to moving to the console. Data was collected prospectively for the first 50 cases and parameters associated with the learning curve compared to other reported series. RESULTS: Median operative time of 369.5 mins, median blood loss of 700 ml, with 12% of patients requiring a blood transfusion. Four patients required conversion to an open procedure; one resulting from equipment failure and three due to failure of progression. Four patients had an anastomotic leak with resulting ileus and two patients sustained rectal injuries, which were repaired intraoperatively using the robot. Median hospital stay was 4 days with a 22% positive surgical margin rate. CONCLUSION: Parameters indicative of the learning curve are comparable to existing published initial series of other robotic centres. The use of teamwork has enabled us to provide safe and time-efficient training for four surgeons simultaneously. The structured approach used in this setting demonstrates that urological surgeons of varying laparoscopic experience can acquire the skills necessary to competently perform laparoscopic radical prostatectomy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17520650&query_hl=1 ER - TY - JFULL T1 - Stress-induced activation of the AMP-activated protein kinase in the freeze-tolerant frog Rana sylvatica A1 - Rider, MH A1 - Hussain, N A1 - Horman, S A1 - Dilworth, SM A1 - Storey, KB J1 - CRYOBIOLOGY Y1 - 2006/12// VL - 53 SN - 0011-2240 SP - 297 EP - 309 N2 - Survival in the frozen state depends on biochemical adaptations that deal with multiple stresses on cells including longterm ischaemia and tissue dehydration. We investigated whether the AMP-activated protein kinase (AMPK) could play a regulatory role in the metabolic re-sculpting that occurs during freezing. AMPK activity and the phosphorylation state of translation factors were measured in liver and skeletal muscle of wood frogs (Rana sylvatica) subjected to anoxia, debydration, freezing, and thawing after freezing. AMPK activity was increased 2-fold in livers of frozen frogs compared with the controls whereas in skeletal muscle, AMPK activity increased 2.5-, 4.5- and 3-fold in dehydrated, frozen and frozen/thawed animals, respectively. Immunoblotting with phospho-specific antibodies revealed an increase in the phosphorylation state of eukaryotic elongation factor-2 at the inactivating Thr56 site in livers from frozen frogs and in skeletal muscles of anoxic frogs. No change in phosphorylation state of eukaryotic initiation factor-2 alpha at the inactivating Ser51 site was seen in the tissues under any of the stress conditions. Surprisingly, ribosomal protein S6 phosphorylation was increased 2-fold in livers from frozen frogs and 10-fold in skeletal muscle from frozen/thawed animals. However, no change in translation capacity was detected in cell-free translation assays with skeletal muscle extracts under any of the experimental conditions. The changes in phosphorylation state of translation factors are discussed in relation to the control of protein synthesis and stress-induced AMPK activation. (c) 2006 Elsevier Inc. All rights reserved. ER - TY - JFULL T1 - Early outcomes in the elderly: a meta-analysis of 4921 patients undergoing coronary artery bypass grafting--comparison between off-pump and on-pump techniques. A1 - Panesar, SS A1 - Athanasiou, T A1 - Nair, S A1 - Rao, C A1 - Jones, C A1 - Nicolaou, M A1 - Darzi, A J1 - Heart Y1 - 2006/12// VL - 92 SN - 1468-201X SP - 1808 EP - 1816 N2 - OBJECTIVE: To assess early outcomes in the elderly population undergoing coronary revascularisation with and without cardiopulmonary bypass (CPB). METHODS: Meta-analysis of all retrospective, non-randomised studies comparing off-pump coronary artery bypass (OPCAB) versus CPB techniques in the elderly (> 70 years) between 1999 and 2005. Age-related early outcomes of interest were death, stroke, atrial fibrillation (AF), renal failure and length of stay in hospital. The random effects model was used. Sensitivity and heterogeneity were analysed. RESULTS: Analysis of 14 non-randomised studies comprising 4921 patients (OPCAB, 1533 (31.1%) and CPB, 3388 (68.9%)) showed a significantly lower incidence of death in the OPCAB group (odds ratio (OR) 0.48, 95% CI 0.28 to 0.84). This effect was greater in OPCAB octogenarians (OR 0.26, 95% CI 0.12 to 0.57). The pattern of incidence of stroke among the OPCAB octogenarians (OR 0.19, 95% CI 0.07 to 0.56) was similar. The incidence of AF was lower in the OPCAB group (OR 0.77, 95% CI 0.61 to 0.97). The incidence of renal failure did not differ. Length of hospital stay was shorter in the OPCAB group, although with significant heterogeneity. CONCLUSIONS: OPCAB may be associated with lower incidence of death, stroke and AF in the elderly, which may result in shorter length of hospital stay. A large randomised trial would confirm whether the elderly would benefit more from OPCAB surgery. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16775087&query_hl=1 ER - TY - JFULL T1 - [Chemotherapy for metastatic breast cancer] A1 - Schmid, P A1 - Possinger, K J1 - Zentralbl Gynakol Y1 - 2006/12// VL - 128 SN - 0044-4197 SP - 318 EP - 326 N2 - Primary goals of treatment in metastatic breast cancer include prevention and palliation of symptoms, maintenance or improvement of quality of life and prolongation of survival. In order to account for the variability of clinical courses, treatment decisions have to be made on an individual basis. Low risk patients without evidence of rapid disease progression or symptomatic disease are mainly considered for endocrine treatment or single agent chemotherapy, whereas patients at higher risk with rapidly progressive or symptomatic disease are candidates for poly-chemotherapies. Anthracyclines are one of the most active group of agents and remain active after adjuvant pre-treatment. The use of liposomal derivatives or weekly or prolonged application can decrease the risk of cardiotoxicity. There is only incomplete cross-resistance between anthracyclines and taxanes. Taxane-based weekly or 3 weekly regimens are therefore generally used in anthracycline-pretreated patients. Capecitabine, gemcitabine, or vinorelbine constitute candidate agents after failure of anthracyclines and/or taxanes and may result in objective responses or disease stabilisation. Data on the continuation beyond third-line chemotherapy are insufficient. Decisions have therefore to be made on an individual basis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17213969&query_hl=1 ER - TY - JFULL T1 - Imaging in drug development. A1 - Aboagye, EO J1 - Clin Adv Hematol Oncol Y1 - 2006/12// VL - 4 SN - 1543-0790 SP - 902 EP - 904 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17235274&query_hl=1 ER - TY - JFULL T1 - Drug-induced exacerbation of glomus tumour pain. A1 - Daghir, A A1 - Anand, P A1 - Gabra, H A1 - Elliot, D J1 - J Hand Surg [Br] Y1 - 2006/12// VL - 31 SN - 0266-7681 SP - 692 EP - 692 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16766103&query_hl=1 ER - TY - JFULL T1 - Long-term survival in a patient with AL amyloidosis after cardiac transplantation followed by autologous stem cell transplantation. A1 - Perz, JB A1 - Kristen, AV A1 - Rahemtulla, A A1 - Parameshwar, J A1 - Sack, FU A1 - Apperley, JF A1 - Goldschmidt, H A1 - Katus, HA A1 - Dengler, TJ J1 - Clin Res Cardiol Y1 - 2006/12// VL - 95 SN - 1861-0684 SP - 671 EP - 674 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16967191&query_hl=1 ER - TY - JFULL T1 - Fast-track failure after cardiac surgery: development of a prediction model. A1 - Constantinides, VA A1 - Tekkis, PP A1 - Fazil, A A1 - Kaur, K A1 - Leonard, R A1 - Platt, M A1 - Casula, R A1 - Stanbridge, R A1 - Darzi, A A1 - Athanasiou, T J1 - Crit Care Med Y1 - 2006/12// VL - 34 SN - 0090-3493 SP - 2875 EP - 2882 N2 - OBJECTIVE: Risk factors for unsuccessful fast-tracking of cardiac surgery patients have not been collectively defined in the literature. The aim of this study was to determine risk factors for fast-track failure and incorporate them into a predictive fast-track failure score. DESIGN: Prospective observational study. SETTING: Cardiothoracic Department of St Mary's Hospital, London. PATIENTS: Data were collected from April 2003 to April 2005 including 1,084 patients undergoing heart surgery who were admitted into the fast-track unit. INTERVENTIONS: Multifactorial logistic regression was used to develop a propensity score for estimating the likelihood of fast-track failure. MEASUREMENTS AND MAIN RESULTS: One hundred and sixty-nine patients failed fast-track management (15.6%). Independent predictors for fast-track failure were impaired left ventricular function with or without recent acute coronary syndrome (odds ratios 2.89 and 1.65 respectively), re-do operation (one, two, or more vs. none, odds ratio 1.75, 7.98), extracardiac arteriopathy (odds ratio 2.63), preoperative intra-aortic balloon pump (odds ratio 3.09), raised serum creatinine in micromol/L (120-150, >150 vs. <120, odds ratio 1.57, 11.24), and nonelective (odds ratio 3.43) and complex surgery (odds ratio 2.70). Model validation showed very good discrimination (area under the curve = 0.815) and calibration (ĉ statistic = 8.527, p = .129). CONCLUSIONS: The fast-track failure score incorporates several preoperative factors and has been successfully internally validated; after undergoing external validation and possible recalibration it may be used as a tool to facilitate planning and flow of cardiac surgery patients, based on the predicted probability of failure. Application of this score may limit fast-track failure rates and help to reduce morbidity and cost. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17075376&query_hl=1 ER - TY - JFULL T1 - Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney A1 - Boutet, A A1 - De Frutos, CA A1 - Maxwell, PH A1 - Mayol, MJ A1 - Romero, J A1 - Nieto, MA J1 - EMBO J Y1 - 2006/11/29/ VL - 25 SN - 0261-4189 SP - 5603 EP - 5613 N2 - During embryonic development, the kidney epithelium originates from cells that undergo a mesenchymal to epithelial transition (MET). The reverse process, epithelium to mesenchyme transition (EMT), has been implicated in epithelial tumor progression and in the fibrosis that leads to end-stage kidney failure. Snail transcription factors induce both natural and pathological EMT, but their implication in renal development and disease is still unclear. We show that Snail genes are downregulated during the MET that occurs during renal development and that this is correlated with Cadherin-16 expression. Snail suppresses Cadherin-16 via the direct repression of the kidney differentiation factor HNF-1 beta, a novel route by which Snail disrupts epithelial homeostasis. Indeed, Snail activation is sufficient to induce EMT and kidney fibrosis in adult transgenic mice. Significantly, Snail is also activated in patients with renal fibrosis. Thus, Snail expression is suppressed during renal development and it must remain silent in the mature kidney where its aberrant activation leads to fibrosis. ER - TY - JFULL T1 - Personal views - Shark cartilage in the water A1 - Waxman, J J1 - BRIT MED J Y1 - 2006/11/25/ VL - 333 SN - 0959-8146 SP - 1129 EP - 1129 ER - TY - JFULL T1 - Efficacy of dasatinib (SPRYCEL (R)) in patients (pts) with chronic phase chronic myelogenous leukemia (CP-CML) resistant to or intolerant of imatinib: Updated results of the CA180013 'START C' phase II study. A1 - Baccarani, M A1 - Kantarjian, HM A1 - Apperley, JF A1 - Lipton, JH A1 - Druker, B A1 - Countouriotis, A A1 - Ezzeddine, R A1 - Hochhaus, A J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 53A EP - 53A ER - TY - JFULL T1 - BMS-214662 eliminates CML stem cells and is active against blast crisis CML and cells expressing BCR-ABL kinase mutations. A1 - Copland, M A1 - Richmond, L A1 - Hamilton, A A1 - Allan, EK A1 - Melo, JV A1 - Holyoake, TL J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 222A EP - 222A ER - TY - JFULL T1 - Abnormalities in glucose uptake and metabolism in imatinib-resistant Bcr-Abl positive cells. A1 - Serkova, NJ A1 - Kominsky, DJ A1 - Brown, JL A1 - Miljus, J A1 - Boros, LG A1 - Eckhardt, GS A1 - Melo, JV J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 662A EP - 662A ER - TY - JFULL T1 - Dasatinib (SPRYCEL (R)) efficacy and safety in patients (pts) with chronic myelogenous leukemia in lymphoid (CML-LB) or myeloid blast (CML-MB) phase who are imatinib-resistant (Im-r) or -intolerant (Im-i). A1 - Martinelli, G A1 - Hochhaus, A A1 - Coutre, S A1 - Apperley, JF A1 - Shah, N A1 - Gollerkeri, A A1 - Agarwal, P A1 - Ottmann, OG J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 224A EP - 224A ER - TY - JFULL T1 - Abnormally small BCR-ABL transcripts in CML patients before and during imatinib treatment. A1 - Khorashad, JS A1 - Lipton, JH A1 - Marin, D A1 - Milojkovic, D A1 - Cross, NCP A1 - Dibb, N A1 - Melo, JV A1 - Kamel-Reid, S A1 - Goldman, JM A1 - Apperley, JF A1 - Kaeda, JS J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 611A EP - 611A ER - TY - JFULL T1 - Dasatinib (SPRYCEL (R)) in patients (pts) with chronic myelogenous leukemia in accelerated phase (AP-CML) that is imatinib-resistant (im-r) or -intolerant (im-i): Updated results of the CA180-005 'START-A' phase II study. A1 - Cortes, J A1 - Kim, DW A1 - Guilhot, F A1 - Rosti, G A1 - Silver, RT A1 - Gollerkeri, A A1 - Agarwal, P A1 - Branford, S A1 - Apperley, JF J1 - BLOOD Y1 - 2006/11/16/ VL - 108 SN - 0006-4971 SP - 613A EP - 613A ER - TY - JFULL T1 - Chronic protein kinase B (PKB/c-akt) activation leads to apoptosis induced by oxidative stress-mediated Foxo3a transcriptional up-regulation. A1 - van Gorp, AG A1 - Pomeranz, KM A1 - Birkenkamp, KU A1 - Hui, RC A1 - Lam, EW A1 - Coffer, PJ J1 - Cancer Res Y1 - 2006/11/15/ VL - 66 SN - 0008-5472 SP - 10760 EP - 10769 N2 - Increased protein kinase B (PKB; c-Akt) activation is a hallmark of diverse neoplasias providing both proliferative and antiapoptotic survival signals. In this study, we investigated the effect of chronic PKB activation on cellular survival and proliferation using cytokine-dependent bone marrow-derived Ba/F3 cells, in which PKBalpha activation can be directly, and specifically, induced by addition of 4-hydroxytamoxifen (4-OHT). Direct activation of PKB rescued Ba/F3 cells from cytokine withdrawal-induced apoptosis; however, surprisingly, these antiapoptotic effects were short lived, cells only being protected for up to 48 hours. We observed that activation of PKB in survival factor-deprived cells led to a dramatic increase of Foxo3a on both the transcriptional and protein level leading to expression of its transcriptional targets Bim and p27(kip1). High levels of PKB activity result in increased aerobic glycolysis and mitochondrial activity resulting in overproduction of reactive oxygen species. To determine whether oxidative stress might itself be responsible for Foxo3a up-regulation, we utilized hydrogen peroxide (H(2)O(2)) as an artificial inducer of oxidative stress and N-acetylcysteine (NAC), a thiol-containing radical oxygen scavenger. Addition of NAC to the culture medium prolonged the life span of cells treated with 4-OHT and prevented the up-regulation of Foxo3a protein levels caused by PKB activation. Conversely, treatment of Ba/F3 cells with H(2)O(2) caused an increase of Foxo3a on both transcriptional and protein levels, suggesting that deregulated PKB activation leads to oxidative stress resulting in Foxo3a up-regulation and subsequently cell death. Taken together, our data provide novel insights into the molecular consequences of uncontrolled PKB activation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17108112&query_hl=1 ER - TY - JFULL T1 - A novel HSV-1 virus, JS1/34.5-/47-, purges contaminating breast cancer cells from bone marrow. A1 - Hu, JC A1 - Booth, MJ A1 - Tripuraneni, G A1 - Davies, D A1 - Zaidi, SA A1 - Tamburo de Bella, M A1 - Slade, MJ A1 - Marley, SB A1 - Gordon, MY A1 - Coffin, RS A1 - Coombes, RC A1 - Kamalati, T J1 - Clin Cancer Res Y1 - 2006/11/15/ VL - 12 SN - 1078-0432 SP - 6853 EP - 6862 N2 - PURPOSE: Oncolytic herpes simplex virus type 1 (HSV-1) vectors show considerable promise as agents for cancer therapy. We have developed a novel recombinant HSV-1 virus (JS1/34.5-/47-) for purging of occult breast cancer cells from bone marrow of patients. Here, we evaluate the therapeutic efficacy of this oncolytic virus. EXPERIMENTAL DESIGN: Electron microscopy was used to determine whether human breast cancer and bone marrow cells are permissive for JS1/34.5-/47- infection. Subsequently, the biological effects of JS1/34.5-/47- infection on human breast cancer cells and bone marrow were established using cell proliferation and colony formation assays, and the efficiency of cell kill was evaluated. Finally, the efficiency of JS1/34.5-/47- purging of breast cancer cells was examined in cocultures of breast cancer cells with bone marrow as well as bone marrow samples from high-risk breast cancer patients. RESULTS: We show effective killing of human breast cancer cell lines with the JS1/34.5-/47- virus. Furthermore, we show that treatment with JS1/34.5-/47- can significantly inhibit the growth of breast cancer cell lines without affecting cocultured mononuclear hematopoietic cells. Finally, we have found that the virus is effective in destroying disseminated tumors cells in bone marrow taken from breast cancer patients, without affecting the hematopoietic contents in these samples. CONCLUSION: Collectively, our data show that the JS1/34.5-/47- virus can selectively target breast cancer cells while sparing hematopoietic cells, suggesting that JS1/34.5-/47- can be used to purge contaminating breast cancer cells from human bone marrow in the setting of autologous hematopoietic cell transplantation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17121907&query_hl=1 ER - TY - JFULL T1 - A phase I study of OncoVEXGM-CSF, a second-generation oncolytic herpes simplex virus expressing granulocyte macrophage colony-stimulating factor. A1 - Hu, JC A1 - Coffin, RS A1 - Davis, CJ A1 - Graham, NJ A1 - Groves, N A1 - Guest, PJ A1 - Harrington, KJ A1 - James, ND A1 - Love, CA A1 - McNeish, I A1 - Medley, LC A1 - Michael, A A1 - Nutting, CM A1 - Pandha, HS A1 - Shorrock, CA A1 - Simpson, J A1 - Steiner, J A1 - Steven, NM A1 - Wright, D A1 - Coombes, RC J1 - Clin Cancer Res Y1 - 2006/11/15/ VL - 12 SN - 1078-0432 SP - 6737 EP - 6747 N2 - PURPOSE: To conduct a phase I clinical trial with a second-generation oncolytic herpes simplex virus (HSV) expressing granulocyte macrophage colony-stimulating factor (Onco VEXGM-CSF) to determine the safety profile of the virus, look for evidence of biological activity, and identify a dosing schedule for later studies. EXPERIMENTAL DESIGN: The virus was administered by intratumoral injection in patients with cutaneous or s.c. deposits of breast, head and neck and gastrointestinal cancers, and malignant melanoma who had failed prior therapy. Thirteen patients were in a single-dose group, where doses of 10(6), 10(7), and 10(8) plaque-forming units (pfu)/mL were tested, and 17 patients were in a multidose group testing a number of dose regimens. RESULTS: The virus was generally well tolerated with local inflammation, erythema, and febrile responses being the main side effects. The local reaction to injection was dose limiting in HSV-seronegative patients at 10(7) pfu/mL. The multidosing phase thus tested seroconverting HSV-seronegative patients with 10(6) pfu/mL followed by multiple higher doses (up to 10(8) pfu/mL), which was well tolerated by all patients. Biological activity (virus replication, local reactions, granulocyte macrophage colony-stimulating factor expression, and HSV antigen-associated tumor necrosis), was observed. The duration of local reactions and virus replication suggested that dosing every 2 to 3 weeks was appropriate. Nineteen of 26 patient posttreatment biopsies contained residual tumor of which 14 showed tumor necrosis, which in some cases was extensive, or apoptosis. In all cases, areas of necrosis also strongly stained for HSV. The overall responses to treatment were that three patients had stable disease, six patients had tumors flattened (injected and/or uninjected lesions), and four patients showed inflammation of uninjected as well as the injected tumor, which, in nearly all cases, became inflamed. CONCLUSIONS: Onco VEXGM-CSF is well tolerated and can be safely administered using the multidosing protocol described. Evidence of an antitumor effect was seen. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17121894&query_hl=1 ER - TY - JFULL T1 - The significance of the time interval between antecedent pregnancy and diagnosis of high-risk gestational trophoblastic tumours. A1 - Powles, T A1 - Young, A A1 - Sanitt, A A1 - Sammit, A A1 - Stebbing, J A1 - Short, D A1 - Bower, M A1 - Savage, PM A1 - Seckl, MJ A1 - Schmid, P J1 - Br J Cancer Y1 - 2006/11/06/ VL - 95 SN - 0007-0920 SP - 1145 EP - 1147 N2 - It is thought that the time interval between the antecedent pregnancy and diagnosis of gestational trophoblastic tumours (GTTs) may influence the outcome of these patients. In this study, we investigate the significance of this time interval. Multivariate analysis was used to investigate if the time interval was of prognostic significance from our cohort of 241 high-risk patients with GTT. Subsequent cutpoint analysis was used to determine an optimal cutpoint for the interval covariate. The outcome of these patients was plotted according to the Kaplan-Meier method. The time interval was of prognostic significance on multivariate analysis. A period of greater than 2.8 years after pregnancy was found to be of most significance. The 5-year overall survival was 62.0% (95% CI: 47-76%) for greater than 2.8 years vs 94% (95% CI: 91-97%) for less than 2.8 years (P<0.001). Multivariate analysis showed the presence of liver metastasis and the number of metastasis was also of prognostic importance. The interval between antecedent pregnancy and diagnosis in high-risk GTT is of prognostic significance. This gives some insight into the pathogenesis of the disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17031399&query_hl=1 ER - TY - JFULL T1 - FOXO transcription factors: key regulators of cell fate. A1 - Lam, EW A1 - Francis, RE A1 - Petkovic, M J1 - Biochem Soc Trans Y1 - 2006/11// VL - 34 SN - 0300-5127 SP - 722 EP - 726 N2 - FOXO (forkhead box O) transcription factors are crucial regulators of cell fate. This function of FOXO proteins relies on their ability to control diverse and at times, opposing cellular functions, such as proliferation, differentiation, DNA repair, defence against oxidative stress damage and apoptosis, in response to hormones, growth factors and other environmental cues. This review discusses our current understanding of the regulation and role of FOXO transcription factors in determining cell fate and highlights their relevance to tumorigenesis and drug resistance. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17052182&query_hl=1 ER - TY - JFULL T1 - Outcomes following laparoscopic versus open repair of incisional hernia. A1 - Sains, PS A1 - Tilney, HS A1 - Purkayastha, S A1 - Darzi, AW A1 - Athanasiou, T A1 - Tekkis, PP A1 - Heriot, AG J1 - World J Surg Y1 - 2006/11// VL - 30 SN - 0364-2313 SP - 2056 EP - 2064 N2 - AIM: The purpose of this study was to compare short- and long-term outcomes for patients undergoing laparoscopic or open surgery for incisional hernia repair using meta-analytical techniques. METHODS: A literature search was performed to identify comparative studies reporting outcomes on laparoscopic versus open surgery for incisional hernia repair. A random-effect meta-analytical model was used and subgroup analysis performed on high-quality studies, those reporting on more than 30 patients, and those published since 2000. RESULTS: Five studies, with a total of 351 patients, satisfied the inclusion criteria. Laparoscopic surgery was attempted in 148 (42.2%) patients. Overall, in the laparoscopic group, operative time was significantly longer--by 12.0 minutes (P = 0.03) and length of stay reduced by 3.3 days (P < 0.003) although this finding was associated with significant heterogeneity between studies (P < 0.001). There was no difference in the short-term adverse events between the groups, but there were fewer wound infections for laparoscopic patients in high-quality studies [odds ratio (OR) = 0.22, 95% confidence interval (CI): 0.05, 0.85, P = 0.03] and those reporting on more than 30 patients (OR = 0.19, 95% CI: 0.04, 0.84, P = 0.03). No difference in hernia recurrence was shown in the overall or subgroup analysis. CONCLUSIONS: Laparoscopic incisional hernia repair was associated with a reduced length of stay and lower wound infection rate. The impact on post-operative quality of life and financial implications needs further prospective, validated evaluation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17058029&query_hl=1 ER - TY - JFULL T1 - Assessing procedural skills in context: Exploring the feasibility of an Integrated Procedural Performance Instrument (IPPI). A1 - Kneebone, R A1 - Nestel, D A1 - Yadollahi, F A1 - Brown, R A1 - Nolan, C A1 - Durack, J A1 - Brenton, H A1 - Moulton, C A1 - Archer, J A1 - Darzi, A J1 - Med Educ Y1 - 2006/11// VL - 40 SN - 0308-0110 SP - 1105 EP - 1114 N2 - BACKGROUND: The assessment of clinical procedural skills has traditionally focused on technical elements alone. However, in real practice, clinicians are expected to be able to integrate technical with communication and other professional skills. We describe an integrated procedural performance instrument (IPPI), where clinicians are assessed on 12 clinical procedures in a simulated clinical setting which combines simulated patients (SPs) with inanimate models or items of medical equipment. Candidates are observed remotely by assessors whose data are fed back to the clinician within 24 hours of the assessment. This paper describes the feasibility of IPPI. RESULTS: A full-scale IPPI and 2 pilot studies with trainee and qualified health care professionals has yielded an extensive data set including 585 scenario evaluations from candidates, 60 from clinical assessors and 31 from simulated patients (SPs). Interview and questionnaire data showed that for the majority of candidates IPPI provided a powerful and valuable learning experience. Realism was rated highly. Remote and real-time assessment worked effectively, although for some procedures limited camera resolution affected observation of fine details. DISCUSSION: IPPI offers an innovative approach to assessing clinical procedural skills. Although resource-intensive, it has the potential to provide insight into individual's performance over a spectrum of clinical scenarios and at no risk to the safety of patients. Additional benefits of IPPI include assessment in real time from experts (allowing remote rating by external examiners) as well as provision of feedback from simulated patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17054620&query_hl=1 ER - TY - JFULL T1 - TAPP repair for inguinal hernias--a new composite mesh technique. A1 - Watson, A A1 - Ziprin, P A1 - Chadwick, S J1 - Ann R Coll Surg Engl Y1 - 2006/11// VL - 88 SN - 1478-7083 SP - 678 EP - 678 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17396358&query_hl=1 ER - TY - JFULL T1 - GM1-gangliosidosis type I. A1 - Pavlu, J A1 - Jackson, M A1 - Panoskaltsis, N J1 - Br J Haematol Y1 - 2006/11// VL - 135 SN - 0007-1048 SP - 422 EP - 422 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16942584&query_hl=1 ER - TY - JFULL T1 - IPCS framework for analyzing the relevance of a cancer mode of action for humans. A1 - Boobis, AR A1 - Cohen, SM A1 - Dellarco, V A1 - McGregor, D A1 - Meek, ME A1 - Vickers, C A1 - Willcocks, D A1 - Farland, W J1 - Crit Rev Toxicol Y1 - 2006/11// VL - 36 SN - 1040-8444 SP - 781 EP - 792 N2 - The use of structured frameworks can be invaluable in promoting harmonization in the assessment of chemical risk. IPCS has therefore updated and extended its mode of action (MOA) framework for cancer to address the issue of human relevance of a carcinogenic response observed in an experimental study. The first stage is to determine whether it is possible to establish an MOA. This comprises a series of key events along the causal pathway to cancer, identified using a weight-of-evidence approach based on the Bradford Hill criteria. The key events are then compared first qualitatively and then quantitatively between the experimental animals and humans. Finally, a clear statement of confidence, analysis, and implications is produced. The IPCS human relevance framework for cancer provides an analytical tool to enable the transparent evaluation of the data, identification of key data gaps, and structured presentation of information that would be of value in the further risk assessment of the compound, even if relevancy cannot be excluded. This might include data on the shape of the dose-response curve, identification of any thresholds and recognition of potentially susceptible subgroups, for example, the basis of genetic or life-stage differences. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17118728&query_hl=1 ER - TY - JFULL T1 - Epstein-Barr virus represses the FoxO1 transcription factor through latent membrane protein 1 and latent membrane protein 2A. A1 - Shore, AM A1 - White, PC A1 - Hui, RC A1 - Essafi, A A1 - Lam, EW A1 - Rowe, M A1 - Brennan, P J1 - J Virol Y1 - 2006/11// VL - 80 SN - 0022-538X SP - 11191 EP - 11199 N2 - Epstein-Barr virus (EBV) infection is associated with the development of many B-cell lymphomas, including Burkitt's lymphoma, Hodgkin's lymphoma, and posttransplant lymphoproliferative disease. The virus alters a diverse range of cellular molecules, which leads to B-cell growth and immortalization. This study was initiated to investigate the interplay between EBV and a proapoptotic transcription factor target, FoxO1. In this report, we show that EBV infection of B cells leads to the downregulation of FoxO1 expression by phosphatidylinositol 3-kinase-mediated nuclear export, by inhibition of FoxO1 mRNA expression, and by alteration of posttranslational modifications. This repression directly correlates with the expression of the FoxO1 target gene Bcl-6 and inversely correlates with the FoxO1-regulated gene Cyclin D2. Expression of the EBV genes for latent membrane protein 1 and latent membrane protein 2A decreases FoxO1 expression. Thus, our data elucidate distinct mechanisms for the regulation of the proapoptotic transcription factor FoxO1 by EBV. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16943287&query_hl=1 ER - TY - JFULL T1 - Evolution of VHL tumourigenesis in nerve root tissue. A1 - Vortmeyer, AO A1 - Tran, MG A1 - Zeng, W A1 - Gläsker, S A1 - Riley, C A1 - Tsokos, M A1 - Ikejiri, B A1 - Merrill, MJ A1 - Raffeld, M A1 - Zhuang, Z A1 - Lonser, RR A1 - Maxwell, PH A1 - Oldfield, EH J1 - J Pathol Y1 - 2006/11// VL - 210 SN - 0022-3417 SP - 374 EP - 382 N2 - Haemangioblastomas are the key central nervous system manifestation of von Hippel-Lindau (VHL) disease, which is caused by germline mutation of the VHL gene. We have recently shown that 'tumour-free' spinal cord from patients with VHL disease contains microscopic, poorly differentiated cellular aggregates in nerve root tissue, which we descriptively designated 'mesenchymal tumourlets'. Here we have investigated spinal cord tissue affected by multiple tumours. We show that a small subset of mesenchymal tumourlets extends beyond the nerve root to form proliferative VHL-deficient mesenchyme and frank haemangioblastoma. We thus demonstrate that tumourlets present potential, but true precursor material for haemangioblastoma. We further show that intraradicular tumourlets consist of scattered VHL-deficient cells with activation of HIF-2alpha and HIF-dependent target proteins including CAIX and VEGF, and are associated with an extensive angiogenic response. In contrast, activation of HIF-1alpha was only observed in the later stages of tumour progression. In addition, ultrastructural examination reveals gradual transition from poorly differentiated VHL-deficient cells into vacuolated cells with a 'stromal' cell phenotype. The evolution of frank haemangioblastoma seems to involve multiple steps from a large pool of precursor lesions. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16981244&query_hl=1 ER - TY - JFULL T1 - 4-Aminobiphenyl and DNA reactivity: case study within the context of the 2006 IPCS Human Relevance Framework for Analysis of a cancer mode of action for humans. A1 - Cohen, SM A1 - Boobis, AR A1 - Meek, ME A1 - Preston, RJ A1 - McGregor, DB J1 - Crit Rev Toxicol Y1 - 2006/11// VL - 36 SN - 1040-8444 SP - 803 EP - 819 N2 - The IPCS Human Relevance Framework was evaluated for a DNA-reactive (genotoxic) carcinogen, 4-aminobiphenyl, based on a wealth of data in animals and humans. The mode of action involves metabolic activation by N-hydroxylation, followed by N-esterification leading to the formation of a reactive electrophile, which binds covalently to DNA, principally to deoxyguanosine, leading to an increased rate of DNA mutations and ultimately to the development of cancer. In humans and dogs, the urinary bladder urothelium is the target organ, whereas in mice it is the bladder and liver; in other species, other tissues can be involved. Differences in organ specificity are thought to be due to differences in metabolic activation versus inactivation. Based on qualitative and quantitative considerations, the mode of action is possible in humans. Other biological processes, such as toxicity and regenerative proliferation, can significantly influence the dose response of 4-aminobiphenyl-induced tumors. Based on the IPCS Human Relevance Framework, 4-aminobiphenyl would be predicted to be a carcinogen in humans, and this is corroborated by extensive epidemiologic evidence. The IPCA Human Relevance Framework is useful in evaluating DNA-reactive carcinogens. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17118730&query_hl=1 ER - TY - JFULL T1 - A national study on lymph node retrieval in resectional surgery for colorectal cancer. A1 - Tekkis, PP A1 - Smith, JJ A1 - Heriot, AG A1 - Darzi, AW A1 - Thompson, MR A1 - Stamatakis, JD A1 - Association of Coloproctology of Great Britain and Ireland J1 - Dis Colon Rectum Y1 - 2006/11// VL - 49 SN - 0012-3706 SP - 1673 EP - 1683 N2 - PURPOSE: This study was designed to develop a mathematical model for predicting the number of lymph nodes harvested in bowel cancer resection specimens based on the current clinical practice in the United Kingdom. METHODS: Prospective clinical data were collected from 8,409 newly diagnosed bowel cancer patients presenting to 79 hospitals in Great Britain and Ireland during a variable 12-month period from 2000 to 2002. A two-level hierarchical regression model was used to identify predictors for lymph node harvest. The model was internally validated by comparing observed and model predicted lymph node harvest for patient subgroups. RESULTS: Inclusion criteria were satisfied by 5,164 patients. The average lymph node harvest was 11.7 nodes with significant between-center variability in lymph node harvest (range, 5.5-21.3 nodes). Increasing age, American Society of Anesthesiology grade, and preoperative radiotherapy were associated with a reduction of lymph node harvest (P < 0.001). Abdominoperineal resection of the rectum and transverse colectomy were the lowest yield procedures for lymph node harvest. Independent predictors of lymph node harvest were age, American Society of Anesthesiology grade, Dukes stage, operative urgency, type of resection, and preoperative radiotherapy. When tested, the model was found to accurately predict lymph node harvest for group statistics (comparison of observed and model predicted lymph node harvest F(1,5154) = 0.63; P = 0.427). CONCLUSIONS: The results of the study suggest that the minimum number of lymph nodes harvested in colorectal cancer surgery cannot be set at a fixed value. The lymph node harvest model provides a simple tool to the frontline clinician for comparing standards between multidisciplinary bowel cancer teams. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17019656&query_hl=1 ER - TY - JFULL T1 - Plasma kisspeptin is raised in patients with gestational trophoblastic neoplasia and falls during treatment. A1 - Dhillo, WS A1 - Savage, P A1 - Murphy, KG A1 - Chaudhri, OB A1 - Patterson, M A1 - Nijher, GM A1 - Foggo, VM A1 - Dancey, GS A1 - Mitchell, H A1 - Seckl, MJ A1 - Ghatei, MA A1 - Bloom, SR J1 - Am J Physiol Endocrinol Metab Y1 - 2006/11// VL - 291 SN - 0193-1849 SP - E878 EP - E884 N2 - Kisspeptin is a 54-amino acid peptide, encoded by the anti-metastasis gene KiSS-1, that activates G protein-coupled receptor 54 (GPR54). The kisspeptin-GPR54 system is critical to normal reproductive development. KiSS-1 gene expression is increased in the human placenta in normal and molar pregnancies. Circulating kisspeptin is dramatically increased in normal pregnancy, but levels in GTN have not previously been reported. The present study was designed to determine whether plasma kisspeptin levels are altered in patients with malignant GTN. Thirty-nine blood samples were taken from 11 patients with malignant GTN at presentation during and after chemotherapy. Blood was also sampled from nonpregnant and pregnant volunteers. Plasma kisspeptin IR and hCG concentrations were measured. Plasma kisspeptin IR concentration in nonpregnant (n = 16) females was <2 pmol/l. Plasma kisspeptin IR in females was 803 +/- 125 pmol/l in the first trimester of pregnancy (n = 13), 2,483 +/- 302 pmol/l in the third trimester of pregnancy (n = 7), and <2 pmol/l on day 15 postpartum (n = 7). Plasma kisspeptin IR and hCG concentrations in patients with malignant GTN were elevated at presentation and fell during and after treatment with chemotherapy in each patient (mean plasma kisspeptin IR: prechemotherapy 1,363 +/- 1,076 pmol/l vs. post-chemotherapy <2 pmol/l, P < 0.0001; mean plasma hCG: prechemotherapy 227,191 +/- 152,354 U/l vs. postchemotherapy 2 U/l, P < 0.0001). Plasma kisspeptin IR strongly positively correlated with plasma hCG levels (r(2) = 0.99, P < 0.0001). Our results suggest that measurement of plasma kisspeptin IR may be a novel tumor marker in patients with malignant GTN. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16757546&query_hl=1 ER - TY - JFULL T1 - Importance of accurate human chorionic gonadotropin measurement in the treatment of gestational trophoblast disease and testicular cancer. A1 - Mitchell, H A1 - Bagshawe, KD A1 - Newlands, ES A1 - Savage, P A1 - Seckl, MJ J1 - J Reprod Med Y1 - 2006/11// VL - 51 SN - 0024-7758 SP - 868 EP - 870 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17165431&query_hl=1 ER - TY - JFULL T1 - Surgery for local recurrence of rectal cancer. A1 - Heriot, AG A1 - Tekkis, PP A1 - Darzi, A A1 - Mackay, J J1 - Colorectal Dis Y1 - 2006/11// VL - 8 SN - 1462-8910 SP - 733 EP - 747 N2 - OBJECTIVE: Despite improvement in management of primary rectal cancer, 2.6-32% of patients develop local recurrence. A proportion of these patients can be amenable to salvage surgery. The present article reviews the evidence for and against the surgical management for local recurrence of rectal cancer, the role of adjuvant and intraoperative radiotherapy (IORT), and evaluates short and long-term outcomes. METHOD: A literature search was performed using Medline, Embase, Ovid and Cochrane database for studies between 1980 and 2005 assessing surgical management of local recurrence of rectal cancer and the evidence was critically evaluated. RESULTS: Nearly 50% of rectal cancer recurrences are local and are therefore potentially amenable to curative resection. Preoperative imaging is important for appropriate selection of patients for surgery and preoperative adjuvant therapy is essential. Five-year survival following resection ranges from 18% to 58% with 5-year survival following complete resection of over 35% though morbidity ranges from 21% to 82%. Neoadjuvant radiotherapy is beneficial and IORT may have a contributory role in treatment. Aggressive surgical treatment favourably affects quality of life and is cost effective. Surgery for local recurrence can result in significant long-term survival with acceptable morbidity and improved quality of life in appropriately selected patients. Assessment in a specialist centre familiar with these techniques is essential. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17032318&query_hl=1 ER - TY - JFULL T1 - Evaluation of deletions in 7q11.2 and 8p12-p21 as prognostic indicators of tumour development following molar pregnancy. A1 - Burke, B A1 - Sebire, NJ A1 - Moss, J A1 - Hodges, MD A1 - Seckl, MJ A1 - Newlands, ES A1 - Fisher, RA J1 - Gynecol Oncol Y1 - 2006/11// VL - 103 SN - 0090-8258 SP - 642 EP - 648 N2 - OBJECTIVES: Previous studies have identified loss of chromosomal regions 7p12-q11.2 and 8p12-p21 in choriocarcinoma suggesting that suppressor genes involved in tumour development may be located within these regions. Our objectives were to refine the regions of loss and evaluate these deletions as prognostic indicators of trophoblastic tumour development following molar pregnancy. METHODS: Fluorescent microsatellite genotyping was used to perform deletion mapping in a series of thirty-nine gestational trophoblastic tumours (GTT) including both choriocarcinoma and placental site trophoblastic tumours. RESULTS: Significant loss of heterozygosity (LOH) was found for both regions in GTT that originated in non-molar pregnancies. Although no common interval of loss was found in those GTT with LOH for the 7q11.2 region, for the 8p12-p21 locus, markers D8S1731 and NEFL defined a minimal region of loss in all tumours showing LOH. However, complete LOH of either region occurred in only a minority of tumours (20%; chromosome 7: 24%; chromosome 8) suggesting that loss of neither region is likely to be a primary event in the development of GTT. This was further supported by the observation that no deletions were found in either region for the fourteen GTT that followed complete molar pregnancies. CONCLUSIONS: While we have defined a minimal interval in 8p12-p21 in which tumour suppressor genes involved in GTT are likely to be located, the data suggest that deletions in 7q11.2 or 8p12-p21 are unlikely to be useful prognostic indicators in the management of patients with molar pregnancies. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16806440&query_hl=1 ER - TY - JFULL T1 - Value of whole body 18FDG-PET to identify the active site of gestational trophoblastic neoplasia. A1 - Dhillon, T A1 - Palmieri, C A1 - Sebire, NJ A1 - Lindsay, I A1 - Newlands, ES A1 - Schmid, P A1 - Savage, PM A1 - Frank, J A1 - Seckl, MJ J1 - J Reprod Med Y1 - 2006/11// VL - 51 SN - 0024-7758 SP - 879 EP - 887 N2 - OBJECTIVE: To evaluate the usefulness of positron emission tomography with 18-fluorodeoxyglucose (18FDG-PET) in locating residual or relapsed gestational trophoblastic neoplasia (GTN). STUDY DESIGN: The Charing Cross GTN database was screened, and 11 patients who had undergone 18FDG-PET were identified. A retrospective analysis was conducted to determine the value of this investigation as compared with other imaging modalities in clinical care. RESULTS: All patients had elevated beta-human chorionic gonadotropin (beta-hCG) at the time of the investigation; none were false positive. In 7 patients the 18FDG-PET scans correctly confirmed the presence (4 of 7 cases) or absence (3 of 7 cases) of disease sites defined by other imaging investigations. In 2 patients positive PET-guided appropriate surgical resection of lung lesions that appeared of equivocal significance on computed tomography (CT) resulted in -hCG normalization. One patient had a pulmonary metastasis on CT not considered positive on 18FDG-PET (false negative). One patient with enlarged mediastinal lymph nodes on CT that were 18FDG-PET positive also had a vascular uterus on magnetic resonance imaging/Dopper ultrasound that was negative on PET (false negative). Hysterectomy led to hCG normalization and cure. The mediastinal lymph nodes were positive on CT and PET due to sarcoidosis (false positive). Patients with serum hCG levels <10 IU/L could have positive PET scans; that can contribute to patient care. CONCLUSION: 18FDG-PET can aid in identifying residual disease sites in women relapsing from previously treated GTN. However, careful evaluation in combination with other imaging modalities is required to reduce the risk of false positive and negative results. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17165434&query_hl=1 ER - TY - JFULL T1 - Thiazopyr and thyroid disruption: case study within the context of the 2006 IPCS Human Relevance Framework for analysis of a cancer mode of action. A1 - Dellarco, VL A1 - McGregor, D A1 - Berry, SC A1 - Cohen, SM A1 - Boobis, AR J1 - Crit Rev Toxicol Y1 - 2006/11// VL - 36 SN - 1040-8444 SP - 793 EP - 801 N2 - Thiazopyr increases the incidence of male rat thyroid follicular-cell tumors; however, it is not carcinogenic in mice. Thiazopyr is not genotoxic. Thiazopyr exerts its carcinogenic effect on the rat thyroid gland secondary to enhanced metabolism of thyroxin leading to hormone imbalance. The relevance of these rat tumors to human health was assessed by using the 2006 IPCS Human Relevance Framework. The postulated rodent tumor mode of action was tested against the Bradford Hill criteria and was found to satisfy the conditions of dose and temporal concordance, biological plausibility, coherence, strength, consistency, and specificity that fits with a well-established mode of action for thyroid follicular-cell tumors. Although the postulated mode of action could theoretically operate in humans, marked quantitative differences in the inherent susceptibility for neoplasia to thyroid hormone imbalance in rats allows for the conclusion that thiazopyr does not pose a carcinogenic hazard to humans. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17118729&query_hl=1 ER - TY - JFULL T1 - Antileukemic activity of lysophosphatidic acid acyltransferase-beta inhibitor CT32228 in chronic myelogenous leukemia sensitive and resistant to imatinib A1 - La Rosee, P A1 - Jia, TP A1 - Demehri, S A1 - Hartel, N A1 - de Vries, P A1 - Bonham, L A1 - Hollenback, D A1 - Singer, JW A1 - Melo, JV A1 - Druker, BJ A1 - Deininger, MW J1 - CLIN CANCER RES Y1 - 2006/11/01/ VL - 12 SN - 1078-0432 SP - 6540 EP - 6546 N2 - Purpose: Lysophosphatidic acid acyltransferase (LPAAT)-beta catalyzes the conversion of lysophosphatidic acid to phosphatidic acid, an essential component of several signaling pathways, including the Ras/mitogen-activated protein kinase pathway. Inhibition of LPAAT-beta induces growth arrest and apoptosis in cancer cell lines, implicating LPAAT-beta as a potential drug target in neoplasia.Experimental Design: In this study, we investigated the effects of CT32228, a specific LPAAT-inhibitor, on BCR-ABL-transformed cell lines and primary cells from patients with chronic myelogenous leukemia.Results: CT32228 had antiproliferative activity against BCR-ABL-positive cell lines in the nanomolar dose range, evidenced by cell cycle arrest in G(2)-M and induction of apoptosis. Treatment of K562 cells with CT32228 led to inhibition of extracellular signal-regulated kinase 1/2 phosphorylation, consistent with inhibition of mitogen-activated protein kinase signaling. Importantly, CT32228 was highly active in cell lines resistant to the Bcr-Abl kinase inhibitor imatinib. Combination of CT32228 with imatinib produced additive inhibition of proliferation in cell lines with residual sensitivity toward imatinib. In short-term cultures in the absence of growth factors, CT32228 preferentially inhibited the growth of granulocyte-macrophage colony-forming units from chronic myelogenous leukemia patients compared with healthy controls.Conclusion: These data establish LPAAT-beta as a potential drug target for the treatment of BCR-ABL-positive leukemias. ER - TY - JFULL T1 - Pouch-anal anastomosis vs straight ileoanal anastomosis in pediatric patients: a meta-analysis. A1 - Tilney, HS A1 - Constantinides, V A1 - Ioannides, AS A1 - Tekkis, PP A1 - Darzi, AW A1 - Haddad, MJ J1 - J Pediatr Surg Y1 - 2006/11// VL - 41 SN - 1531-5037 SP - 1799 EP - 1808 N2 - BACKGROUND: Restorative proctocolectomy is the treatment of choice for pediatric patients with refractory colitis, inherited polyposis syndromes, and some with colonic aganglionosis. Evidence concerning the optimal method of reconstruction is, however, sparse. METHODS: Studies comparing outcomes from ileal pouch-anal anastomosis (IPAA) and straight ileoanal anastomosis (SIAA) were identified by searching Medline, Ovid, and Embase. Suitable studies were selected and data extracted for meta-analysis. RESULTS: Of 13 studies identified by literature search, 5 satisfied the inclusion criteria, comprising a total of 306 patients, 86 of whom (28.1%) underwent SIAA, and the remainder, IPAA. Pouch failure was more common in the SIAA group (odds ratio, 3.21; confidence interval, 1.24-8.34), as were abdominal salvage procedures (odds ratio, 9.5; confidence interval, 3.14-28.77). Short-term adverse events were similar between the 2 groups, with the exception of perianal sepsis, the higher frequency of which, in SIAA, just reached statistical significance. Bowel frequency was lower in the IPAA patients, although few studies presented functional data in a comparable form. CONCLUSIONS: There are few good-quality studies that compare the outcomes from SIAA and IPAA, meaning that caution should be exercised in the generalization of the results of this meta-analysis, which suggests pouch procedures to be favorable in terms of reconstruction survival and functional outcome. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17101347&query_hl=1 ER - TY - JFULL T1 - Neutrophils from patients with heterozygous germline mutations in the von Hippel Lindau protein (pVHL) display delayed apoptosis and enhanced bacterial phagocytosis. A1 - Walmsley, SR A1 - Cowburn, AS A1 - Clatworthy, MR A1 - Morrell, NW A1 - Roper, EC A1 - Singleton, V A1 - Maxwell, P A1 - Whyte, MK A1 - Chilvers, ER J1 - Blood Y1 - 2006/11/01/ VL - 108 SN - 0006-4971 SP - 3176 EP - 3178 N2 - Neutrophils are key mediators of the innate immune response and are required to function at sites of low oxygenation. We have shown that in hypoxia neutrophils are protected from apoptosis via a mechanism dependent on prolyl hydroxylase domain/hypoxia-inducible factor 1alpha (PHD/HIF-1alpha). This response would be predicted to involve the von Hippel Lindau protein (pVHL)-dependent ubiquitination and degradation of HIF-1alpha. Patients with VHL disease inherit a mutation in one VHL allele, which allows us to study the effects of heterozygous VHL expression in human neutrophils. Neutrophils exhibited a striking "partial hypoxic" pheno-type, with delayed rates of apoptosis and enhanced bacterial phagocytosis under normoxic conditions and preserved responses to low levels of oxygen. This provides direct evidence that the HIF-1alpha/VHL pathway regulates the innate immune response in humans. It also establishes that heterozygous VHL defects are sufficient to perturb normal responses and illustrates the potential to use this to address the role of HIF and VHL in human biology. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16809612&query_hl=1 ER - TY - JFULL T1 - Regulation of the SUMO pathway sensitizes differentiating human endometrial stromal cells to progesterone. A1 - Jones, MC A1 - Fusi, L A1 - Higham, JH A1 - Abdel-Hafiz, H A1 - Horwitz, KB A1 - Lam, EW A1 - Brosens, JJ J1 - Proc Natl Acad Sci U S A Y1 - 2006/10/31/ VL - 103 SN - 0027-8424 SP - 16272 EP - 16277 N2 - cAMP is required for differentiation of human endometrial stromal cells (HESCs) into decidual cells in response to progesterone, although the underlying mechanism is not well understood. We now demonstrate that cAMP signaling attenuates ligand-dependent sumoylation of the progesterone receptor (PR) in HESCs. In fact, decidualization is associated with global hyposumoylation and redistribution of small ubiquitin-like modifier (SUMO)-1 conjugates into distinct nuclear foci. This altered pattern of global sumoylation was not attributable to impaired maturation of SUMO-1 precursor or altered expression of E1 (SAE1/SEA2) or E2 (Ubc9) enzymes but coincided with profound changes in the expression of E3 ligases and SUMO-specific proteases. Down-regulation of several members of the protein inhibitors of activated STAT (PIAS) family upon decidualization pointed toward a role of these E3 ligases in PR sumoylation. We demonstrate that PIAS1 interacts with the PR and serves as its E3 SUMO ligase upon activation of the receptor. Furthermore, we show that silencing of PIAS1 not only enhances PR-dependent transcription but also induces expression of prolactin, a decidual marker gene, in progestin-treated HESCs without the need of simultaneous activation of the cAMP pathway. Our findings demonstrate how dynamic changes in the SUMO pathway mediated by cAMP signaling determine the endometrial response to progesterone. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17053081&query_hl=1 ER - TY - JFULL T1 - The expression and functional characterization of sigma (sigma) 1 receptors in breast cancer cell lines. A1 - Aydar, E A1 - Onganer, P A1 - Perrett, R A1 - Djamgoz, MB A1 - Palmer, CP J1 - Cancer Lett Y1 - 2006/10/28/ VL - 242 SN - 0304-3835 SP - 245 EP - 257 N2 - Sigma (sigma) receptors have been implicated in cancer. However, to date there is little molecular data demonstrating the role of sigma1 receptors in cancer. Expression of sigma1 receptors in various human cancer cell lines in comparison to non-cancerous cell lines was investigated, using real time RT-PCR and by western blotting with a sigma1 receptor specific antibody. Our results indicate that cancer cells express higher levels of sigma1 receptors than corresponding non-cancerous cells. Localization of the sigma1 receptor was investigated in MDA-MB-231 cells by immunocytochemistry and confocal microscopy, expression was visualized predominantly at the cell periphery. We have tested the effect of sigma1 and sigma2 drugs and a sigma1 receptor silencing construct on various aspects of the metastatic process on two breast cell lines of different metastatic potential and a normal breast cell line. Both sigma1 and sigma2 drugs and the sigma1 receptor silencing construct had effects on proliferation and adhesion for breast cancer cell lines, compared to a non-cancerous breast cell line. This data suggests sigma1 receptor plays a role in proliferation and adhesion of breast cancer cells. Therefore, it is likely to be a potential target for the diagnosis and therapy of breast cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16388898&query_hl=1 ER - TY - JFULL T1 - Endosomes generate localized Rho-ROCK-MLC2-based contractile signals via Endo180 to promote adhesion disassembly. A1 - Sturge, J A1 - Wienke, D A1 - Isacke, CM J1 - J Cell Biol Y1 - 2006/10/23/ VL - 175 SN - 0021-9525 SP - 337 EP - 347 N2 - The regulated assembly and disassembly of focal adhesions and adherens junctions contributes to cell motility and tumor invasion. Pivotal in this process is phosphorylation of myosin light chain-2 (MLC2) by Rho kinase (ROCK) downstream of Rho activation, which generates the contractile force necessary to drive disassembly of epithelial cell-cell junctions and cell-matrix adhesions at the rear of migrating cells. How Rho-ROCK-MLC2 activation occurs at these distinct cellular locations is not known, but the emerging concept that endocytic dynamics can coordinate key intracellular signaling events provides vital clues. We report that endosomes containing the promigratory receptor Endo180 (CD280) can generate Rho-ROCK-MLC2-based contractile signals. Moreover, we provide evidence for a cellular mechanism in which Endo180-containing endosomes are spatially localized to facilitate their contractile signals directly at sites of adhesion turnover. We propose migration driven by Endo180 as a model for the spatial regulation of contractility and adhesion dynamics by endosomes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17043135&query_hl=1 ER - TY - JFULL T1 - Carotid artery stenting performed on a virtual reality simulator differentiates level of procedural experience and technical skill A1 - Van Herzeele, I A1 - Aggarwal, R A1 - Choong, A A1 - Neequaye, S A1 - Brightwell, R A1 - Darzi, A A1 - Cheshire, N J1 - AM J CARDIOL Y1 - 2006/10/22/ VL - 98 SN - 0002-9149 SP - 242M EP - 242M ER - TY - JFULL T1 - Malignant ovarian germ cell tumors: identification of novel prognostic markers and long-term outcome after multimodality treatment. A1 - Murugaesu, N A1 - Schmid, P A1 - Dancey, G A1 - Agarwal, R A1 - Holden, L A1 - McNeish, I A1 - Savage, PM A1 - Newlands, ES A1 - Rustin, GJ A1 - Seckl, MJ J1 - J Clin Oncol Y1 - 2006/10/20/ VL - 24 SN - 1527-7755 SP - 4862 EP - 4866 N2 - PURPOSE: Malignant ovarian germ cell tumors are rare and knowledge about prognostic parameters currently is limited. This study was undertaken to evaluate long-term outcome of patients with malignant ovarian germ cell tumors (MOGCTs) after chemotherapy and to assess prognostic parameters. PATIENTS AND METHODS: A total of 113 patients with stage IC to IV MOGCTs were included into this retrospective study. Patients were treated at two large regional cancer centers between 1977 and 2003. RESULTS: Ten-year recurrence-free and overall survival rates were 82% and 81%, respectively. A total of 20 patients experienced relapse, all within the first 8 years. Outcome after relapse was poor, with only 10% of patients achieving long-term survival. Univariate and multivariate analyses demonstrated that initial stage of disease (relative risk [RR], 5.96; 95% CI, 3.47 to 10.22; P = .03) and elevation of serum markers beta-human chorionic gonadotropin and alpha-fetoprotein (RR, 3.90; 95% CI, 1.40 to 10.9; P = .009) were significant predictors of overall survival, whereas age at diagnosis was of no prognostic value. CONCLUSION: This is the first study to identify stage and tumor markers as prognostic parameters for patients with MOGCTs. This might help to select patients for risk-adapted treatment. There is need for improvement of therapeutic strategies after relapse. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17050871&query_hl=1 ER - TY - JFULL T1 - A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer (vol 350, pg 1081, 2004) A1 - Coombes, RC J1 - NEW ENGL J MED Y1 - 2006/10/19/ VL - 355 SN - 0028-4793 SP - 1746 EP - 1746 ER - TY - JFULL T1 - Regulation of prostate cell growth and morphogenesis by Dickkopf-3. A1 - Kawano, Y A1 - Kitaoka, M A1 - Hamada, Y A1 - Walker, MM A1 - Waxman, J A1 - Kypta, RM J1 - Oncogene Y1 - 2006/10/19/ VL - 25 SN - 0950-9232 SP - 6528 EP - 6537 N2 - Wnt signalling plays a critical role in the development of cancer. Recent studies indicate that Wnt signalling is negatively regulated by secreted Wnt antagonists such as secreted frizzled related proteins (sFRPs) and Dickkopfs (Dkks). We compared Dkk family expression levels in normal prostate and prostate cancer cells and found a reduction in Dkk-3 expression in cancer cells. Ectopic expression of Dkk-3 inhibited colony formation in LNCaP and PC3 prostate cancer cell lines and inducible expression of Dkk-3 reduced LNCaP cell proliferation. Moreover, small interfering RNA-mediated downregulation of Dkk-3 enhanced cell cycle progression in untransformed RWPE-1 prostate epithelial cells. Immunohistochemical analysis revealed that Dkk-3 is expressed in a subset of normal prostate gland acini and that Dkk-3 expression is reduced in prostate tumours, particularly those with a high Gleason grade, suggesting a role for Dkk-3 in postmitotic differentiation. Consistent with this, depletion of Dkk-3 disrupted acinar morphogenesis of RWPE-1 cells in a three-dimensional cell culture model. Our results are consistent with the loss of Dkk-3 expression resulting in impairment of glandular structure and uncontrolled prostate epithelial cell (PrEC) proliferation, both of which are crucial for prostate cancer progression. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16751809&query_hl=1 ER - TY - JFULL T1 - Varying response to escalating the dose of imatinib in patients with CML who "acquire" a BCR-ABL M244V mutant allele. A1 - Anand, M A1 - Khorashad, J A1 - Marin, D A1 - Apperley, JF A1 - Goldman, JM A1 - Kaeda, JS J1 - Blood Y1 - 2006/10/15/ VL - 108 SN - 0006-4971 SP - 2881 EP - 2882 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17021308&query_hl=1 ER - TY - JFULL T1 - MRI in predicting curative resection of rectal cancer - New dilemma in multidisciplinary team management A1 - Heald, RJ A1 - O'Neill, BDP A1 - Moran, B A1 - Brown, G A1 - Darzi, AW A1 - Wotherspoon, AC A1 - Cunningham, D A1 - Tait, DM J1 - BRIT MED J Y1 - 2006/10/14/ VL - 333 SN - 0959-8146 SP - 808 EP - 808 ER - TY - JFULL T1 - Therapy Insight: parenteral estrogen treatment for prostate cancer--a new dawn for an old therapy. A1 - Ockrim, J A1 - Lalani, el-N A1 - Abel, P J1 - Nat Clin Pract Oncol Y1 - 2006/10// VL - 3 SN - 1743-4262 SP - 552 EP - 563 N2 - Oral estrogens were the treatment of choice for carcinoma of the prostate for over four decades, but were abandoned because of an excess of cardiovascular and thromboembolic toxicity. It is now recognized that most of this toxicity is related to the first pass portal circulation, which upregulates the hepatic metabolism of hormones, lipids and coagulation proteins. Most of this toxicity can be avoided by parenteral (intramuscular or transdermal) estrogen administration, which avoids hepatic enzyme induction. It also seems that a short-term but modest increase in cardiovascular morbidity (but not mortality) is compensated for by a long-term cardioprotective benefit, which accrues progressively as vascular remodeling develops over time. Parenteral estrogen therapy has the advantage of giving protection against the effects of andropause (similar to the female menopause), which are induced by conventional androgen suppression and include osteoporotic fracture, hot flashes, asthenia and cognitive dysfunction. In addition, parenteral estrogen therapy is significantly cheaper than contemporary endocrine therapy, with substantive economic implications for health providers. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17019433&query_hl=1 ER - TY - JFULL T1 - The human face of simulation: patient-focused simulation training. A1 - Kneebone, R A1 - Nestel, D A1 - Wetzel, C A1 - Black, S A1 - Jacklin, R A1 - Aggarwal, R A1 - Yadollahi, F A1 - Wolfe, J A1 - Vincent, C A1 - Darzi, A J1 - Acad Med Y1 - 2006/10// VL - 81 SN - 1040-2446 SP - 919 EP - 924 N2 - Simulation is firmly established within health care training but often focuses on training for technical tasks and can overlook crucial skills such as professionalism and physician-patient communication. The authors locate this paper within current developments in health care and relate it to the literature on simulation. They make the case for placing real human "patients" (played by actors) within simulation environments, thereby ensuring that the training experience remains rooted in actual practice. By practicing repeatedly within a safe environment, technical skills, communication with patients and team members, decision making, and clinical judgment may all be practiced and mastered while preserving patient safety. In elaborating this concept of patient-focused simulation (PFS), the authors draw on work already published by their group and several recent studies that are in review. These explore PFS in low, medium, and high complexity settings. Important or rare situations can be recreated and practiced, as well as key procedures required across a range of experience levels and clinical specialties. Finally, the case is made for curriculum redesign to ensure that simulator-based technical skills training and assessment take place within an authentic context that reflects the wider elements of clinical practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16985358&query_hl=1 ER - TY - JFULL T1 - Innovative training for new surgical roles--the place of evaluation. A1 - Kneebone, RL A1 - Nestel, D A1 - Chrzanowska, J A1 - Barnet, AE A1 - Darzi, A J1 - Med Educ Y1 - 2006/10// VL - 40 SN - 0308-0110 SP - 987 EP - 994 N2 - BACKGROUND: This paper describes the central role of 'external' evaluation, provided by an independent researcher, in developing an innovative curriculum for new professional roles with surgery. Workforce changes affecting the National Health Service provided an opportunity to develop 2 new roles and design training programmes to support them. The perioperative specialist practitioner (PSP) role was designed from scratch, while surgical care practitioner (SCP) training built on existing practice. Training programmes combined formal modules at Imperial College London (approximately 48 days over 10 months) with supervised clinical practice in each participant's base hospital. Programmes balanced factual knowledge, clinical and communication skills, professional issues and personal development and used a range of innovative techniques. EVALUATION METHODS: A qualitative approach based on a utilisation-focused model monitored the development and implementation of 4 pilot PSP and SCP training programmes. A total of 124 individual and 48 group interviews were conducted at intervals over 3 years, sampling course participants, the project team clinical supervisors and administrators. An independent researcher collected, analysed and presented data at key stages, feeding back findings to the project team as the programmes evolved. DISCUSSION: Effective training programmes for new roles can be developed, but the process is time-consuming and requires sensitivity. An independent evaluator offers great benefits, modulating the collaborative partnership between participants and project team. Positive responses (relating to content and teaching methods) from our study enabled us to refine a learner-centred programme. Negative responses often demanded immediate action to address important concerns, and evaluation provided early warning. External evaluation provides a vital perspective in the development of curricula supporting new roles. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16987189&query_hl=1 ER - TY - JFULL T1 - A comparison of segmental vs subtotal/total colectomy for colonic Crohn's disease: a meta-analysis. A1 - Purkayastha, S A1 - Tekkis, PP A1 - Lanitis, S A1 - Athanasiou, T A1 - Heriot, AG A1 - Darzi, AW A1 - Orchard, TR A1 - Nicholls, RJ J1 - Colorectal Dis Y1 - 2006/10// VL - 8 SN - 1462-8910 SP - 723 EP - 724 N2 - Purpose: To evaluate differences in short- and long-term outcomes of patients with colonic Crohn's disease (CD) undergoing either subtotal/total colectomy with ileorectal anastomosis (IRA) or segmental colectomy(SC). Method: Comparative studies from 1988 to 2002, of subtotal/total colectomy and IRA vs SC, were used. The study end points included surgical and overall recurrence, time to recurrence, postoperative morbidity and incidence of permanent stoma. Meta-analytical tools were used to evaluate the study outcomes. Results: Six studies, consisting of a total of 488 patients (223-IRA and 265-SC) were included. Meta-analysis suggested no significant difference between IRA and SC in recurrence of CD. Time to recurrence was longer in the IRA group by 4.4 years (95%CI, 3.1-5.8), P < 0.001. There was no difference in postoperative complications (OR = 1.4, 95%CI, 0.16-12.74) or the need for a permanent stoma between the two groups (OR = 2.75, 95%CI, 0.78-9.71). Patients with two or more colonic segments involved were associated with lower re-operation rate in the IRA group, a difference which did not reach statistical significance (P = 0.177). Conclusions: Both procedures were equally effective as treatment options for colonic CD, however, patients in the SC group exhibited recurrence earlier than those in the IRA group. The choice of operation is dependent on the extent of colonic disease, with a trend towards better outcomes with IRA for two or more colonic segments involved. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16970591&query_hl=1 ER - TY - JFULL T1 - Endo180 A1 - Wienke, D A1 - Sturge, J A1 - Pirinen, N.J. A1 - Henry, L.A. A1 - Davies, G.C. A1 - Isacke, C.M. J1 - AfCS-Nature Molecule Pages Y1 - 2006/10// VL - Online publication: doi:10.103 UR - http://www.signaling-gateway.org/molecule/query?afcsid=A003687 ER - TY - JFULL T1 - Improving outcomes in early prostate cancer: Part I--adjuvant treatment. A1 - Mazhar, D A1 - Ngan, S A1 - Waxman, J J1 - BJU Int Y1 - 2006/10// VL - 98 SN - 1464-4096 SP - 725 EP - 730 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16978266&query_hl=1 ER - TY - JFULL T1 - Differential expression of FOXO1 and FOXO3a confers resistance to oxidative cell death upon endometrial decidualization. A1 - Kajihara, T A1 - Jones, M A1 - Fusi, L A1 - Takano, M A1 - Feroze-Zaidi, F A1 - Pirianov, G A1 - Mehmet, H A1 - Ishihara, O A1 - Higham, JM A1 - Lam, EW A1 - Brosens, JJ J1 - Mol Endocrinol Y1 - 2006/10// VL - 20 SN - 0888-8809 SP - 2444 EP - 2455 N2 - The integrity of the feto-maternal interface is critical for survival of the conceptus. This interface, consisting of the maternal decidua and the invading placental trophoblast, is exposed to profound changes in oxygen tension during pregnancy. We demonstrate that human endometrial stromal cells become extraordinarily resistant to oxidative stress-induced apoptosis upon decidualization in response to cAMP and progesterone signaling. This differentiation process is associated with the induction of the forkhead transcription factor FOXO1, which in turn increases the expression of the mitochondrial antioxidant manganese superoxide dismutase. However, silencing of FOXO1 did not increase the susceptibility of decidualized cells to oxidative cell death. Comparative analysis demonstrated that hydrogen peroxide, a source of free radicals, strongly induces FOXO3a mRNA and protein expression in undifferentiated human endometrial stromal cells but not in decidualized cells. Expression of a constitutively active FOXO3a mutant elicited apoptosis in decidualized cells. Furthermore, silencing of endogenous FOXO3a in undifferentiated cells abrogated apoptosis induced by hydrogen peroxide. These results suggest that the induction of FOXO1 may enhance the ability of decidualized cells to prevent oxidative damage while the simultaneous repression of FOXO3a expression disables the signaling pathway responsible for oxidative cell death. The differential regulation of FOXO expression provides the decidua with a robust system capable of coping with prolonged episodes of oxidative stress during pregnancy. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16709600&query_hl=1 ER - TY - JFULL T1 - Approaches to postmastectomy radiotherapy (PMRT) in the intergroup exemestane study (IES) A1 - Jassem, J A1 - Coombes, RC A1 - Ireland, B A1 - Hall, E A1 - Snowdon, CF A1 - Bliss, JM J1 - RADIOTHER ONCOL Y1 - 2006/10// VL - 81 SN - 0167-8140 SP - S278 EP - S278 ER - TY - JFULL T1 - Improving outcomes in early prostate cancer: Part II--neoadjuvant treatment. A1 - Mazhar, D A1 - Ngan, S A1 - Waxman, J J1 - BJU Int Y1 - 2006/10// VL - 98 SN - 1464-4096 SP - 731 EP - 734 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16978267&query_hl=1 ER - TY - JFULL T1 - Diagnostic precision of anti-Saccharomyces cerevisiae antibodies and perinuclear antineutrophil cytoplasmic antibodies in inflammatory bowel disease. A1 - Reese, GE A1 - Constantinides, VA A1 - Simillis, C A1 - Darzi, AW A1 - Orchard, TR A1 - Fazio, VW A1 - Tekkis, PP J1 - Am J Gastroenterol Y1 - 2006/10// VL - 101 SN - 0002-9270 SP - 2410 EP - 2422 N2 - AIMS: The aim of this study was to assess the diagnostic precision of antiSaccharomyces cerevisiae (ASCA) and perinuclear antineutrophil cytoplasmic antibodies (pANCA) in inflammatory bowel disease (IBD) and evaluate their discriminative ability between ulcerative colitis (UC) and Crohn's disease (CD). METHODS: Meta-analysis of studies reporting on ASCA and pANCA in IBD was performed. Sensitivity, specificity, and likelihood ratios (LR+, LR-) were calculated for different test combinations for CD, UC, and for IBD compared with controls. Meta-regression was used to analyze the effect of age, DNAse, colonic CD, and assay type. RESULTS: Sixty studies comprising 3,841 UC and 4,019 CD patients were included. The ASCA+ with pANCA- test offered the best sensitivity for CD (54.6%) with 92.8% specificity and an area under the ROC (receiver operating characteristic) curve (AUC) of 0.85 (LR+ = 6.5, LR- = 0.5). Sensitivity and specificity of pANCA+ tests for UC were 55.3% and 88.5%, respectively (AUC of 0.82; LR+ = 4.5, LR- = 0.5). Sensitivity and specificity were improved to 70.3% and 93.4% in a pediatric subgroup when combined with an ASCA- test. Meta-regression analysis showed decreased diagnostic precision of ASCA for isolated colonic CD (RDOR = 0.3). CONCLUSIONS: ASCA and pANCA testing are specific but not sensitive for CD and UC. It may be particularly useful for differentiating between CD and UC in the pediatric population. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16952282&query_hl=1 ER - TY - JFULL T1 - The perioperative specialist practitioner: developing and evaluating a new surgical role. A1 - Kneebone, R A1 - Nestel, D A1 - Chrzanowska, J A1 - Barnet, AE A1 - Younger, J A1 - Burgess, A A1 - Darzi, A J1 - Qual Saf Health Care Y1 - 2006/10// VL - 15 SN - 1475-3901 SP - 354 EP - 358 N2 - INTRODUCTION: This paper describes the design, implementation and evaluation of a new professional role in surgery. The role of the perioperative specialist practitioner (PSP), conceived as a response to the Working Time Directive, provides integrated preoperative and postoperative care to patients undergoing surgery in hospital. METHODS: A 1-year training programme was designed, dealing with a wide range of knowledge, skills and attitudes. Effective communication was a key component. Nine intensive 5-day modules at Imperial College London (London, UK) alternated with supervised experience of the surgical team at each participant's home trust. Detailed evaluation of the role and the training programme was provided by an independent research team, using an interview-based qualitative approach. Observational data were provided by the project team. Data were analysed using standard qualitative methods. RESULTS: 27 PSPs across 12 National Health Service trusts took part in two PSP training programmes. A total of 124 interviews (94 individual and 30 group) were carried out with PSPs and their colleagues. Overall, the role was seen as successful and positive, with great potential for dealing with reductions in junior medical cover. Each site encountered different opportunities and problems. Lack of mentorship was a key issue, and the role provoked considerable opposition in trusts. The training programme was viewed as highly successful. DISCUSSION: PSPs can provide high levels of expertise, but within clear limits. Our training programme has been effective and is perceived to be of high quality. However, introducing a new role requires time and sensitivity if opposition is to be minimised. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17074873&query_hl=1 ER - TY - JFULL T1 - Observational assessment of surgical teamwork: a feasibility study. A1 - Undre, S A1 - Healey, AN A1 - Darzi, A A1 - Vincent, CA J1 - World J Surg Y1 - 2006/10// VL - 30 SN - 0364-2313 SP - 1774 EP - 1783 N2 - BACKGROUND: Teamwork is fundamental to effective surgery, yet there are currently no measures of teamwork to guide training, evaluate team interventions or assess the impact of teamwork on outcomes. We report the first steps in the development of an observational assessment of teamwork and preliminary findings. METHOD: We observed 50 operations in general surgery from a single operating theater using a measure of teamwork specifically developed for use in the operating theater. The OTAS (Observational Teamwork Assessment for Surgery) comprises a procedural task checklist centered on the patient, equipment and communications tasks and ratings on team behavior constructs, namely: communication, co-operation, co-ordination, shared-leadership and monitoring. RESULTS: Ratings of overall team performance were reasonably high, though variable, but there was evidence that clinically significant steps were being missed which at the very least eroded safety margins. There was, for instance, a frequent failure to check both surgical and anesthetic equipment and a failure to confirm the procedure verbally, patient notes were missing in about one-eighth of the cases and delays or changes occurred in over two-thirds of the cases. CONCLUSIONS: This study takes an initial step towards developing measures of team performance in surgery that are defined in relation to tasks and behaviors of the team. The observational method of assessment is feasible and can provide a wealth of potentially valuable research data. However, for these measures to be used for formal assessment, more research is needed to make them robust and standardized. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16983480&query_hl=1 ER - TY - JFULL T1 - The complexity of measuring interprofessional teamwork in the operating theatre. A1 - Healey, AN A1 - Undre, S A1 - Sevdalis, N A1 - Koutantji, M A1 - Vincent, CA J1 - J Interprof Care Y1 - 2006/10// VL - 20 SN - 1356-1820 SP - 485 EP - 495 N2 - Surgery depends on interprofessional teamwork, which is becoming increasingly specialized. If surgery is to become a highly reliable system, it must adapt and professionals must learn from, and share, tested models of interprofessional teamwork. Trainers also need valid measures of teamwork to assess individual and team performance. However, measurement and assessment of interprofessional teamwork is lacking and interprofessional team training is scarce in the surgical domain. This paper addresses the complexity of measuring interprofessional teamwork in the operating theatre. It focuses mainly on the design and properties of observational assessment tools. The report and analysis serves to inform the researcher or clinician of the issues to consider when designing or choosing from alternative measures of team performance for training or assessment. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17000474&query_hl=1 ER - TY - JFULL T1 - [Genetic heterogeneity for familial recurrent hydatidiform mole] A1 - Zhao, J A1 - Xiang, Y A1 - Huang, SZ A1 - Wan, XR A1 - Cui, QC A1 - Seckl, MJ A1 - Fisher, RA J1 - Zhonghua Yi Xue Yi Chuan Xue Za Zhi Y1 - 2006/10// VL - 23 SN - 1003-9406 SP - 511 EP - 514 N2 - OBJECTIVE: To determine the parental origin of the genome in the molar pregnancies of two familes with familial recurrent hydatidiform mole (FRHM) and to investigate whether the gene responsible for FRHM is likely to be located within the 19q13.4 region in these familes. METHODS: The features of complete hydatidiform mole (CHM) were confirmed by pathological examination. DNA of CHM was prepared from sections of formalin-fixed paraffin-embedded blocks of molar tissue following laser capture microdissection. The polymerace chain reaction was used to amplify microsatellite polymorphisms in DNA from the patients, their husbands and the captured molar tissue. Parental contributions to the molar tissue were determined using ABI 310 GeneScan software. Genotyping and haplotype analysis of the candidate region on 19q13.4 was performed for members of both families using 25 microsatellite markers. RESULTS: One CHM from each family was identified as a biparental complete hydatidiform mole. All patients were heterozygous for most of the markers in the chromosome region of interest. In addition the two affected sisters in one of the families had different genotypes for the 19q13.4 region, suggesting that mutations in a different locus might be responsible for the disorder in this family. CONCLUSION: The location of the gene responsible for FRHM is unlikely to be located in the 19q13.4 chromosomal region in these two families suggesting that FRHM shows genetic heterogeneity. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17029197&query_hl=1 ER - TY - JFULL T1 - Acute appendicitis: weighing up risks and benefits of investigations and treatments. A1 - Purkayastha, S A1 - Purkayastha, S A1 - Paraskevas, P J1 - BMJ Y1 - 2006/09/23/ VL - 333 SN - 1468-5833 SP - 652 EP - 653 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16990328&query_hl=1 ER - TY - JFULL T1 - Use of protein profiles to characterise concentration-effect curves of mixtures of estrogenic compounds in human breast cell lines A1 - Zhu, ZY A1 - Boobis, AR A1 - Edwards, RJ J1 - TOXICOL LETT Y1 - 2006/09/20/ VL - 164 SN - 0378-4274 SP - S165 EP - S166 ER - TY - JFULL T1 - OMICS research adds substantially to the safety assessment of chemicals: The case against A1 - Boobis, AR J1 - TOXICOL LETT Y1 - 2006/09/20/ VL - 164 SN - 0378-4274 SP - S28 EP - S28 ER - TY - JFULL T1 - Dose-dependent transitions in mechanisms of toxicity: Concluding remarks A1 - Boobis, AR J1 - TOXICOL LETT Y1 - 2006/09/20/ VL - 164 SN - 0378-4274 SP - S37 EP - S38 ER - TY - JFULL T1 - IPCS framework for analysing the relevance of a cancer mode of action for humans A1 - Boobis, AR A1 - Cohen, SM A1 - Dellarco, V A1 - McGregor, D A1 - Vickers, C A1 - Willcocks, D A1 - Farland, W J1 - TOXICOL LETT Y1 - 2006/09/20/ VL - 164 SN - 0378-4274 SP - S254 EP - S255 ER - TY - JFULL T1 - Quantifying the activity of adenoviral E1A CR2 deletion mutants using renilla luciferase bioluminescence and 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography imaging. A1 - Leyton, J A1 - Lockley, M A1 - Aerts, JL A1 - Baird, SK A1 - Aboagye, EO A1 - Lemoine, NR A1 - McNeish, IA J1 - Cancer Res Y1 - 2006/09/15/ VL - 66 SN - 0008-5472 SP - 9178 EP - 9185 N2 - The adenoviral E1A CR2 mutant dl922-947 has potent activity in ovarian cancer. We have used Renilla luciferase bioluminescence imaging to monitor viral E1A expression and replication and [18F]fluorothymidine positron emission tomography ([18F]FLT-PET) to quantify the activity of dl922-947 in vivo. We created dlCR2 Ren, with the same E1A CR2 deletion as dl922-947 and the luciferase gene from Renilla reniformis downstream of E1. Light emitted from s.c. and i.p. IGROV1 ovarian carcinoma xenografts was measured following treatment with dlCR2 Ren. Mice bearing s.c. IGROV1 xenografts were injected with 2.96 to 3.7 MBq of [18F]FLT 48 and 168 hours following i.t. injection of dl922-947 or control virus Ad LM-X. The presence of Renilla luciferase in dlCR2 Ren did not reduce in vitro nor in vivo potency compared with dl922-947. Light emission correlated closely with E1A expression in vitro and peaked 48 hours after dlCR2 Ren injection in both s.c. and i.p. IGROV1 xenografts. It diminished by 168 hours in s.c. tumors but persisted for at least 2 weeks in i.p. models. Normalized tumor [18F]FLT uptake at 60 minutes (NUV60), fractional retention, and area under radioactivity curve all decreased marginally 48 hours after dl922-947 treatment and significantly at 168 hours compared with controls. There was a close linear correlation between NUV60 and both tumor proliferation (Ki67 labeling index) and thymidine kinase 1 expression. Renilla luciferase bioluminescence and [18F]FLT-PET imaging are capable of quantifying the activity and effectiveness of E1A CR2-deleted adenoviral mutants in ovarian cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16982761&query_hl=1 ER - TY - JFULL T1 - Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. A1 - Suntharalingam, G A1 - Perry, MR A1 - Ward, S A1 - Brett, SJ A1 - Castello-Cortes, A A1 - Brunner, MD A1 - Panoskaltsis, N J1 - N Engl J Med Y1 - 2006/09/07/ VL - 355 SN - 1533-4406 SP - 1018 EP - 1028 N2 - Six healthy young male volunteers at a contract research organization were enrolled in the first phase 1 clinical trial of TGN1412, a novel superagonist anti-CD28 monoclonal antibody that directly stimulates T cells. Within 90 minutes after receiving a single intravenous dose of the drug, all six volunteers had a systemic inflammatory response characterized by a rapid induction of proinflammatory cytokines and accompanied by headache, myalgias, nausea, diarrhea, erythema, vasodilatation, and hypotension. Within 12 to 16 hours after infusion, they became critically ill, with pulmonary infiltrates and lung injury, renal failure, and disseminated intravascular coagulation. Severe and unexpected depletion of lymphocytes and monocytes occurred within 24 hours after infusion. All six patients were transferred to the care of the authors at an intensive care unit at a public hospital, where they received intensive cardiopulmonary support (including dialysis), high-dose methylprednisolone, and an anti-interleukin-2 receptor antagonist antibody. Prolonged cardiovascular shock and acute respiratory distress syndrome developed in two patients, who required intensive organ support for 8 and 16 days. Despite evidence of the multiple cytokine-release syndrome, all six patients survived. Documentation of the clinical course occurring over the 30 days after infusion offers insight into the systemic inflammatory response syndrome in the absence of contaminating pathogens, endotoxin, or underlying disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16908486&query_hl=1 ER - TY - JFULL T1 - Epididymal cystadenomas and epithelial tumourlets: effects of VHL deficiency on the human epididymis. A1 - Gläsker, S A1 - Tran, MG A1 - Shively, SB A1 - Ikejiri, B A1 - Lonser, RR A1 - Maxwell, PH A1 - Zhuang, Z A1 - Oldfield, EH A1 - Vortmeyer, AO J1 - J Pathol Y1 - 2006/09// VL - 210 SN - 0022-3417 SP - 32 EP - 41 N2 - Although epididymal cystadenomas (ECAs) are among the most frequent VHL disease-associated tumours, fundamental questions about their pathogenesis have remained unanswered. Classification of ECAs is controversial, and the cell of origin is unknown. It is also unknown whether ECAs-like other VHL disease-associated tumours-arise as a result of VHL gene inactivation, and whether ECAs exhibit subsequent activation of hypoxia-inducible factor HIF. Moreover, the morphological spectrum of earliest ECA formation is unknown. In a detailed molecular pathological analysis of a series of epididymides collected from VHL patients at autopsy, we found that ECAs are true neoplasms that arise secondary to inactivation of the wild-type copy of the VHL gene, followed by early and simultaneous activation of HIF1 and HIF2 associated with up-regulation of downstream targets, including CAIX and GLUT-1. The observations also indicate that ECA formation evolves from a variety of microscopic epithelial tumourlets, and that these tumourlets are confined to the efferent ductular system. Although genetic and immunohistochemical analysis of precursor structures consistently revealed VHL gene inactivation and activation of HIF in the precursor lesions, only a small subset appears to progress into frank cystadenoma. Thus, ECA tumorigenesis in VHL disease shares fundamental principles with tumorigenesis in other affected organ systems. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16841375&query_hl=1 ER - TY - JFULL T1 - The importance of careful blood processing in isolation of cell-free DNA. A1 - Page, K A1 - Powles, T A1 - Slade, MJ A1 - DE Bella, MT A1 - Walker, RA A1 - Coombes, RC A1 - Shaw, JA J1 - Ann N Y Acad Sci Y1 - 2006/09// VL - 1075 SN - 0077-8923 SP - 313 EP - 317 N2 - In healthy individuals, the source of cell-free plasma DNA is predominantly apoptotic, whereas, increased plasma DNA integrity is seen in cancer patients. Therefore, it is important to carefully isolate absolutely "cell-free" plasma DNA. Plasma DNA from 30 healthy females was analyzed using 4 PCR amplicons of increasing size, comparing standard blood processing with additional centrifugation steps prior to DNA extraction. Cellular DNA contamination, indicated by positive amplicons >300 bp was eliminated only after the extra centrifugation step. This highlights the importance of careful processing in preparation of cell-free plasma DNA as a tool for cancer detection and we recommend the use of a microcentrifuge spin, prior to DNA extraction. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17108226&query_hl=1 ER - TY - JFULL T1 - The VHL tumor suppressor gene and oxygen sensing A1 - Maxwell, PH J1 - J MED GENET Y1 - 2006/09// VL - 43 SN - 0022-2593 SP - S21 EP - S21 ER - TY - JFULL T1 - Patient safety alerts: a balance between evidence and action. A1 - Vincent, CA A1 - Lee, AC A1 - Hanna, GB J1 - Arch Dis Child Fetal Neonatal Ed Y1 - 2006/09// VL - 91 SN - 1359-2998 SP - F314 EP - F315 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16923929&query_hl=1 ER - TY - JFULL T1 - The developing market for medical robotics A1 - Wang, YL A1 - Butner, SE A1 - Darzi, A J1 - P IEEE Y1 - 2006/09// VL - 94 SN - 0018-9219 SP - 1763 EP - 1771 N2 - This paper discusses the developing market for medical robotics. It first describes some of the dynamics and market drivers in health care, and then provides an outline of the areas of consideration when developing a commercial medical robot. The paper also offers three case studies of robotic systems that have been commercialized. Finally, it summarizes some of the key ingredients to be considered for the commercialization process. ER - TY - JFULL T1 - A "field change" of inhibited apoptosis occurs in colorectal mucosa adjacent to colorectal adenocarcinoma. A1 - Badvie, S A1 - Hanna-Morris, A A1 - Andreyev, HJ A1 - Cohen, P A1 - Saini, S A1 - Allen-Mersh, TG J1 - J Clin Pathol Y1 - 2006/09// VL - 59 SN - 0021-9746 SP - 942 EP - 946 N2 - BACKGROUND: Colorectal cancer is associated with a "field change" of increased proliferation throughout the colonic and rectal mucosa. Both proliferation and apoptosis are disrupted during carcinogenesis. Whether altered apoptosis contributes to this field change of microscopic abnormality is, however, unclear. Bcl-xL is an anti-apoptotic protein that inhibits apoptosis by preventing release of cytochrome c, a recognised pathway to cell death. AIM: To determine whether Bcl-xL inhibition of apoptosis is increased in colorectal mucosa adjacent to colorectal adenocarcinoma over that in normal non-neoplastic colorectal mucosa. Patients: Patients undergoing surgical resection for neoplastic (adenocarcinoma) or non-neoplastic disease of the colorectum (rectal prolapse, diverticular disease or volvulus). METHODS: Formalin-fixed, paraffin-wax-embedded surgical colorectal resection specimens were immunostained for Bcl-xL protein. Labelling indices were determined by counting the proportion of positively stained cells in mucosal crypts. RESULTS: 85 patients were studied. Bcl-xL immunostaining was most marked in the upper third of mucosal crypts. It occurred in a minority of samples from non-neoplastic colorectal mucosa, but was seen in most mucosal samples adjacent to colorectal adenocarcinoma. Significant increases (p<0.001) were observed in Bcl-xL labelling indices in the mucosa at 1 cm (n = 46, median labelling index 31.8%, interquartile range 8.3-43.9%) and at 10 cm (n = 52, median labelling index 22.0%, interquartile range 0.0-36.3%) from colorectal carcinoma, compared with normal, non-neoplastic colorectal mucosa (n = 22, median labelling index 0.0%, interquartile range 0.0-0.0%). CONCLUSIONS: The findings are consistent with a field change of inhibited apoptosis in mucosa adjacent to colorectal carcinoma. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16679352&query_hl=1 ER - TY - JFULL T1 - Technical skills examination for general surgical trainees. A1 - Datta, V A1 - Bann, S A1 - Aggarwal, R A1 - Mandalia, M A1 - Hance, J A1 - Darzi, A J1 - Br J Surg Y1 - 2006/09// VL - 93 SN - 0007-1323 SP - 1139 EP - 1146 N2 - BACKGROUND: The technical skills of surgical trainees are difficult to assess and compare objectively. This study involved a structured, multistation, technical skills examination that enables the stratification of surgical trainees. METHODS: Twenty-two surgeons (five basic surgical trainees, eight junior specialist trainees, four senior specialist trainees and five consultants) participated in the study. All undertook a five-station technical skills examination consisting of three synthetic simulations (bowel anastomosis, vascular anastomosis, saphenofemoral dissection) and two virtual reality-based (flexible sigmoidoscopy and laparoscopy) assessment stations. Video-based analyses and in-built computer scoring were used to measure each surgeon's performance. The mean rank was determined for each variable, and the sum of the mean ranks produced a total score. RESULTS: There was a significant improvement in overall performance with increasing seniority (P<0.001). Significant differences were observed between basic surgical trainees and junior specialist trainees (P=0.019), and between junior and senior specialist trainees (P=0.048), but not between senior trainees and consultants. CONCLUSION: This examination successfully differentiated surgical skill, both between surgeons with different grades of experience and within the target study group of specialist trainees. The examination is feasible in terms of the timeframe needed to complete tasks, cost, and efficiency in performing video-based assessments. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16838394&query_hl=1 ER - TY - JFULL T1 - The Forkhead box M1 protein regulates the transcription of the estrogen receptor alpha in breast cancer cells. A1 - Madureira, PA A1 - Varshochi, R A1 - Constantinidou, D A1 - Francis, RE A1 - Coombes, RC A1 - Yao, KM A1 - Lam, EW J1 - J Biol Chem Y1 - 2006/09/01/ VL - 281 SN - 0021-9258 SP - 25167 EP - 25176 N2 - In this study, we have identified the Forkhead transcription factor FoxM1 as a physiological regulator of estrogen receptor alpha (ERalpha) expression in breast carcinoma cells. Our survey of a panel of 16 different breast cell lines showed a good correlation (13/16) between FoxM1 expression and expression of ERalpha at both protein and mRNA levels. We have also demonstrated that ectopic expression of FoxM1 in two different estrogen receptor-positive breast cancer cell lines, MCF-7 and ZR-75-30, led to up-regulation of ERalpha expression at protein and transcript levels. Furthermore, treatment of MCF-7 cells with the MEK inhibitor U0126, which blocks ERK1/2-dependent activation of FoxM1, also repressed ERalpha expression. Consistent with this, silencing of FoxM1 expression in MCF-7 cells using small interfering RNA resulted in the almost complete abrogation of ERalpha expression. We also went on to show that FoxM1 can activate the transcriptional activity of human ERalpha promoter primarily through two closely located Forkhead response elements located at the proximal region of the ERalpha promoter. Chromatin immunoprecipitation and biotinylated oligonucleotide pulldown assays have allowed us to confirm these Forkhead response elements as important for FoxM1 binding. Further co-immunoprecipitation experiments showed that FoxO3a and FoxM1 interact in vivo. Together with the chromatin immunoprecipitation and biotinylated oligonucleotide pulldown data, the co-immunoprecipitation results also suggest the possibility that FoxM1 and FoxO3a cooperate to regulate ERalpha gene transcription. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16809346&query_hl=1 ER - TY - JFULL T1 - Gaze-down three-dimensional 'open-box' training shortens the laparoscopic learning curve A1 - Aggarwal, R A1 - Boshier, P A1 - Hanna, G A1 - Darzi, A J1 - J AM COLL SURGEONS Y1 - 2006/09// VL - 203 SN - 1072-7515 SP - S77 EP - S77 ER - TY - JFULL T1 - Phosphorylation of ERalpha at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ERalpha phosphorylation in breast cancer progression. A1 - Sarwar, N A1 - Kim, JS A1 - Jiang, J A1 - Peston, D A1 - Sinnett, HD A1 - Madden, P A1 - Gee, JM A1 - Nicholson, RI A1 - Lykkesfeldt, AE A1 - Shousha, S A1 - Coombes, RC A1 - Ali, S J1 - Endocr Relat Cancer Y1 - 2006/09// VL - 13 SN - 1351-0088 SP - 851 EP - 861 N2 - Oestrogen receptor-alpha (ERalpha) is an important prognostic marker in breast cancer and endocrine therapies are designed to inhibit or prevent ERalpha activity. In vitro studies have indicated that phosphorylation of ERalpha, in particular on serine 118 (S118), can result in activation in a ligand-independent manner, thereby potentially contributing to resistance to endocrine agents, such as tamoxifen and aromatase inhibitors. Here we report the immunohistochemistry (IHC) of S118 phosphorylation in 301 primary breast tumour biopsies. Surprisingly, this analysis shows that S118 phosphorylation is higher in more differentiated tumours, suggesting that phosphorylation at this site is associated with a good prognosis in patients not previously treated with endocrine agents. However, we also report that S118 phosphorylation was elevated in tumour biopsies taken from patients who had relapsed following tamoxifen treatment, when compared to pre-treatment biopsies. Taken together, these data are consistent with the view that S118 phosphorylation is a feature of normal ERalpha function and that increases in levels of phosphorylation at this site may play a key role in the emergence of endocrine resistance in breast cancer. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16954434&query_hl=1 ER - TY - JFULL T1 - Gaze-contingent control for minimally invasive robotic surgery. A1 - Mylonas, GP A1 - Darzi, A A1 - Yang, GZ J1 - Comput Aided Surg Y1 - 2006/09// VL - 11 SN - 1092-9088 SP - 256 EP - 266 N2 - OBJECTIVE: Recovering tissue depth and deformation during robotically assisted minimally invasive procedures is an important step towards motion compensation, stabilization and co-registration with preoperative data. This work demonstrates that eye gaze derived from binocular eye tracking can be effectively used to recover 3D motion and deformation of the soft tissue. METHODS: A binocular eye-tracking device was integrated into the stereoscopic surgical console. After calibration, the 3D fixation point of the participating subjects could be accurately resolved in real time. A CT-scanned phantom heart model was used to demonstrate the accuracy of gaze-contingent depth extraction and motion stabilization of the soft tissue. The dynamic response of the oculomotor system was assessed with the proposed framework by using autoregressive modeling techniques. In vivo data were also used to perform gaze-contingent decoupling of cardiac and respiratory motion. RESULTS: Depth reconstruction, deformation tracking, and motion stabilization of the soft tissue were possible with binocular eye tracking. The dynamic response of the oculomotor system was able to cope with frequencies likely to occur under most routine minimally invasive surgical operations. CONCLUSION: The proposed framework presents a novel approach towards the tight integration of a human and a surgical robot where interaction in response to sensing is required to be under the control of the operating surgeon. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=17127651&query_hl=1 ER - TY - JFULL T1 - Redistribution of nucleoside transporters to the cell membrane provides a novel approach for imaging thymidylate synthase inhibition by positron emission tomography. A1 - Perumal, M A1 - Pillai, RG A1 - Barthel, H A1 - Leyton, J A1 - Latigo, JR A1 - Forster, M A1 - Mitchell, F A1 - Jackman, AL A1 - Aboagye, EO J1 - Cancer Res Y1 - 2006/09/01/ VL - 66 SN - 0008-5472 SP - 8558 EP - 8564 N2 - Thymidylate synthase (EC 2.1.1.45) is a key enzyme for the de novo synthesis of DNA and as such a target for anticancer drug development. There is a need to develop noninvasive methods for assessing thymidylate synthase inhibition in tumors. The aim of this study was to assess the potential of 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT) positron emission tomography (PET) for early measurement of thymidylate synthase inhibition and to elucidate the cellular mechanisms involved. Radiation-induced fibrosarcoma-1 tumor-bearing mice were injected with a single i.p. dose of the thymidylate synthase inhibitor 5-fluorouracil (5-FU; 165 mg/kg) and imaged by [(18)F]FLT-PET at 1 to 2 hours after treatment. Deoxyuridine, thymidine kinase 1 (cytoplasmic thymidine kinase; EC2.7.1.21), and ATP levels in excised tumors were measured. Cellular assays for membrane transport were also done. There was a 1.8-fold increase in the 60-minute [(18)F]FLT tumor/heart radioactivity ratio in drug-treated mice compared with vehicle controls (P = 0.0016). Plasma and tumor deoxyuridine levels increased significantly but thymidine kinase and ATP levels were unchanged. Whole-cell assays implicated a (low level) functional role for the type-1 equilibrative nucleoside transporter (ENT). There was an increase in type-1 ENT-binding sites per cell from 49,110 in untreated cells to 73,142 (P = 0.03) in cells treated with 10 mug/mL 5-FU for 2 hours, without a change in transporter affinity (P = 0.41). We conclude that [(18)F]FLT-PET can be used to measure thymidylate synthase inhibition as early as 1 to 2 hours after treatment with 5-FU by a mechanism involving redistribution of nucleoside transporters to the plasma membrane. (Cancer Res 2006; 66(17): 8558-64). L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16951168&query_hl=1 ER - TY - JFULL T1 - Evaluating surgical dexterity during corneal suturing A1 - Saleh, GM A1 - Voyazis, Y A1 - Hance, J A1 - Ratnasothy, J A1 - Darzi, A J1 - ARCH OPHTHALMOL-CHIC Y1 - 2006/09// VL - 124 SN - 0003-9950 SP - 1263 EP - 1266 N2 - Objective: To evaluate motion tracking as an aid to a more objective assessment of ophthalmic microsurgical skill.Methods: In a cohort study, 3 groups of differing levels of surgical experience were assessed. The groups included novice surgeons ( n= 10) with fewer than 5 previously performed corneal sutures, trainee surgeons ( n= 10) with 5 to 100 previously performed corneal sutures, and expert surgeons ( n= 10) with more than 100 previously performed corneal sutures. The Imperial College Surgical Assessment Device was used for the objective assessment of surgical dexterity during corneal suturing. Each of the subjects used a 10-0 nylon suture in a 3-1-1 pattern on an artificial eye ( Royal College of Ophthalmologists, London, England). The Imperial College Surgical Assessment Device measures 3-dimensional spatial vectors via electromagnetic sensors attached to the surgeon's fingers. The number of movements, path length for the respective movements, and time taken to complete the given task were recorded.Results: Highly statistically significant differences were found between the 3 grades of surgeon experience for time taken ( P < .001), number of hand movements ( P <. 001), and path length of the hand movements ( P=. 002) to complete the given task.Conclusions: Motion analysis measured by this technology may be useful in the formal surgical training of residents and as an objective quantitative measure of dexterity. ER - TY - JFULL T1 - Does serum procalcitonin have a role in evaluating the severity of acute pancreatitis? A question revisited. A1 - Purkayastha, S A1 - Chow, A A1 - Athanasiou, T A1 - Cambaroudis, A A1 - Panesar, S A1 - Kinross, J A1 - Tekkis, P A1 - Darzi, A J1 - World J Surg Y1 - 2006/09// VL - 30 SN - 0364-2313 SP - 1713 EP - 1721 N2 - PURPOSE: This study was designed to evaluate the diagnostic accuracy of serum procalcitonin (PCT) for the diagnosis of severity in acute pancreatitis (AP), compared with routine clinical, biochemical, radiological, and combination severity scoring systems. METHODS: Quantitative meta-analysis was performed on prospective studies, comparing serum PCT, against validated scoring systems for diagnosing severe AP. The sensitivity, specificity, and diagnostic odds ratio were calculated for each study. Summary receiver operating characteristic (SROC) curves and subgroup analysis were undertaken. Study quality and heterogeneity were evaluated. Meta-regression meta-analysis was used to evaluate the effect of using serum PCT in the diagnostic accuracy severity scoring in AP. RESULTS: Summary receiver operating characteristic analysis of nine studies showed an overall sensitivity and specificity of 74% (range: 66%-81%) and 83% (range: 79%-87%), respectively. Overall unweighted area under the curve (AUC) was 0.91 (DOR = 16.26 95% CI: 5.68-46.60), demonstrating significant heterogeneity (Q-value = 25.32; P = 0.001). When high-quality studies alone were evaluated, there was an increase in the overall sensitivity (89%); however, specificity was similar (82%), with an overall unweighted AUC of 0.94 (DOR 41.46, 95% CI: 17.95-95.80), with no significant heterogeneity. Meta-regression analysis confirmed the significant effect of study quality on the diagnostic accuracy of severity scoring using serum PCT (P = 0.025). CONCLUSIONS: The use of PCT for severity scoring in AP has a moderate sensitivity but higher specificity. However, the overall accuracy for predicting severity in AP is high. The prognosis of severity, especially early on (<48 hours from onset of symptoms), and the evaluation of potential infectious complications of AP may be the most useful factors to assess in subsequent clinical trials to identify its exact application in clinical practice in the management of AP. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16927057&query_hl=1 ER - TY - JFULL T1 - A new technique for spleen preservation with radiofrequency. A1 - Jiao, LR A1 - Tierris, I A1 - Ayav, A A1 - Milicevic, M A1 - Pellicci, R A1 - Navarra, G A1 - Habib, NA J1 - Surgery Y1 - 2006/09// VL - 140 SN - 0039-6060 SP - 464 EP - 466 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16934610&query_hl=1 ER - TY - JFULL T1 - Social deprivation and outcomes in colorectal cancer. A1 - Smith, JJ A1 - Tilney, HS A1 - Heriot, AG A1 - Darzi, AW A1 - Forbes, H A1 - Thompson, MR A1 - Stamatakis, JD A1 - Tekkis, PP A1 - Association of Coloproctology of Great Britain and Ireland J1 - Br J Surg Y1 - 2006/09// VL - 93 SN - 0007-1323 SP - 1123 EP - 1131 N2 - BACKGROUND: The aim of this study was to examine the influence of social deprivation on postoperative mortality and length of stay in patients having surgery for colorectal cancer. METHODS: Data were extracted from the Association of Coloproctology of Great Britain and Ireland database of patients presenting between April 2001 and March 2002. The effect of social deprivation, measured by the Townsend score, on 30-day postoperative mortality and length of stay was evaluated by two-level hierarchical regression analysis. RESULTS: A total of 7290 (86.8 percent) patients underwent surgery. Operative mortality was 6.7 percent and median length of stay 11 days. Deprivation indices were significantly higher in patients with Dukes' 'D' cancers, undergoing emergency surgery and with higher American Society of Anesthesiologists (ASA) grades (P<0.005). Worsening deprivation was associated with higher operative mortality and longer stay (P=0.014). For each unit increase in deprivation, there was 2.9 (95 percent confidence interval 0.5 to 5.2) percent increase in 30-day mortality. On multifactorial analysis, social deprivation was an independent predictor of length of stay, but its effect on operative mortality was explained by differences in ASA grade, operative urgency and Dukes' classification. CONCLUSION: Social deprivation was an independent risk factor of postoperative length of stay and associated with higher postoperative mortality. These results have important implications for risk modelling of postoperative outcomes. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16779877&query_hl=1 ER - TY - JFULL T1 - Multi-slice computed tomography in coronary artery disease. A1 - Jones, CM A1 - Athanasiou, T A1 - Dunne, N A1 - Kirby, J A1 - Attaran, S A1 - Chow, A A1 - Purkayastha, S A1 - Darzi, A J1 - Eur J Cardiothorac Surg Y1 - 2006/09// VL - 30 SN - 1010-7940 SP - 443 EP - 450 N2 - Multi-slice computed tomography technology is emerging as a realistic investigation in patients with suspected disease in native, stented or grafted coronary arteries. A non-invasive diagnostic tool is desirable as these patients are at high risk for complications of invasive angiography. A 64-slice CT may achieve the desired diagnostic accuracy, and overcome the limitations of spatial resolution, respiratory motion, artifacts from calcification and stents, and radiation dose considerations to produce reliable image quality. These advances, as well as the capacity for integrated functional cardiac assessment, may change the referral patterns in patients who have had previous bypass surgery or percutaneous intervention. This review outlines the debated issues about 64-slice cardiac CT in patients before and after coronary artery bypass surgery, as well as coronary stenting and functional assessment. A review of the recent literature on native coronary artery and bypass graft assessment by multi-slice CT is also performed. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16857366&query_hl=1 ER - TY - JFULL T1 - Human macrophages constitute targets for immunotoxic inorganic arsenic. A1 - Lemarie, A A1 - Morzadec, C A1 - Bourdonnay, E A1 - Fardel, O A1 - Vernhet, L J1 - J Immunol Y1 - 2006/09/01/ VL - 177 SN - 0022-1767 SP - 3019 EP - 3027 N2 - Chronic exposure to inorganic arsenic, a widely distributed environmental contaminant, can lead to toxic effects, including immunosuppression. Owing to the established roles of human macrophages in immune defense, we determined, in the present study, whether inorganic arsenic can affect these major immune cells. Our results demonstrate that noncytotoxic concentrations of arsenic trioxide (As2O3), an inorganic trivalent form, markedly impair differentiated features of human blood monocyte-derived macrophages. First, treatment of macrophages with 1 microM As2O3 induced a rapid cell rounding and a subsequent loss of adhesion. These morphologic alterations were associated with a marked reorganization of actin cytoskeleton, which includes retraction of peripheral actin extensions and formation of a cortical actin ring. In addition, As2O3 reduced expression of various macrophagic surface markers, enhanced that of the monocytic marker CD14, and altered both endocytosis and phagocytosis; unexpectedly, exposure of macrophages to the metalloid also strongly potentiated expression of TNFalpha and IL-8 induced by LPS. Finally, like monocytes, As2O3-treated macrophages can be differentiated into dendritic-like cells. Impairment of macrophage function by As2O3 mainly resulted from activation of a RhoA/Rho-associated kinase pathway; indeed, pretreatment of macrophages with the Rho-associated kinase inhibitor Y-27632 prevented metalloid effects on cytoskeleton and phagocytosis. Moreover, As2O3 was found to increase level of the active GTP-bound form of RhoA and that of phosphorylated-Moesin, a major cytoskeleton adaptor protein involved in RhoA regulation. Taken together, our results demonstrated that human macrophages constitute sensitive targets of inorganic arsenic, which may contribute to immunotoxicity of this environmental contaminant. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16920938&query_hl=1 ER - TY - JFULL T1 - The surgical efficiency score: a feasible, reliable, and valid method of skills assessment. A1 - Datta, V A1 - Bann, S A1 - Mandalia, M A1 - Darzi, A J1 - Am J Surg Y1 - 2006/09// VL - 192 SN - 0002-9610 SP - 372 EP - 378 N2 - BACKGROUND: Technical skills assessments are being increasingly used in surgical residency programs, with the objectivity and validity of several techniques well established. However, many of these methods are labor and time intensive, limiting their feasibility. This study aims to compare more efficient techniques of skills appraisals with an established gold standard. METHODS: Thirty surgeons completed 2 previously validated laboratory-based surgical models: small bowel anastomosis and vein patch insertion. Gold standard evaluation was the Objective Structured Assessment of Technical Skills (OSATS) method. "Efficient" techniques used were (1) quality of final product (FP); (2) snapshot assessment (SS), in which task performance was edited to a 2-minute sound bite and scored with OSATS; and (3) the surgical efficiency score (SES), a combination of final product quality and hand-motion analysis. All human observer evaluations used retrospective video analysis with 3 trained observers. Nonparametric tests were used to analyze the results. RESULTS: With respect to small bowel anastomosis, correlations with OSATS were as follows: FP 0.341 (P=.07), SS 0.577 (P<.001), and SES 0.842 (P<.001). For vein patch insertion, the correlations were as follows: FP 0.545 (P=.001), SS 0.609 (P<.001), and SES 0.700 (P<.001). Interobserver concordance was high for both models with respect to FP (Cronbach's alpha 0.80 for small bowel anastomosis and 0.84 for vein patch insertion). With respect to SS, interobserver reliability was high for vein patch insertion (Cronbach's alpha 0.80) but only moderate for small bowel anastomosis (0.59). CONCLUSIONS: The surgical efficiency score and snap shot assessments both show significant correlations with the traditional OSATS appraisals and suggest that skills assessment can be made more feasible. Correlations were closer with the former and interobserver concordance more variable with the latter, suggesting the surgical efficiency score as the most reliable of the methods evaluated. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16920433&query_hl=1 ER - TY - JFULL T1 - Fibroblast growth factor 2 (FGF-2), a growth factor known to cause chemoresistance in prostate cancer, cannot prevent death induced by a novel Src kinase inhibitor in-vltro A1 - Willis, S A1 - Goldstraw, M A1 - Christmas, T A1 - Hrouda, D A1 - Seckl, M J1 - EUR UROL SUPPL Y1 - 2006/09// VL - 5 SN - 1569-9056 SP - 796 EP - 796 ER - TY - JFULL T1 - Imatinib and ABCG2: who controls whom? A1 - Melo, JV J1 - BLOOD Y1 - 2006/08/15/ VL - 108 SN - 0006-4971 SP - 1116 EP - 1117 ER - TY - JFULL T1 - Randomized clinical trial of the effects of abdominal drainage after elective hepatectomy using the crushing clamp method (Br J Surg 2006; 93: 422-426). A1 - Jiao, LR A1 - Habib, NA J1 - Br J Surg Y1 - 2006/08// VL - 93 SN - 0007-1323 SP - 1024 EP - 1025 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16845700&query_hl=1 ER - TY - JFULL T1 - Genetic and structural analyses suggest that a novel SPG3A mutation causes severe phenotypes of hereditary spastic paraplegia A1 - Chen, SQ A1 - Zhou, Y A1 - Li, XH A1 - Labu A1 - Huang, S A1 - Huang, WJ A1 - Zhou, CL A1 - Maxwell, PH A1 - Wang, YM J1 - CHINESE SCI BULL Y1 - 2006/08// VL - 51 SN - 1001-6538 SP - 2038 EP - 2040 N2 - Hereditary spastic paraplegia (HSP) is a group of neurodegenerative diseases. The genotypes and phenotypes of HSP are extremely heterogenous. SPG3A is one of the identified genes underlying HSP, and codes for a GTPase, atlastin. Mutations in SPG3A are currently believed to be associated with early onset and mild phenotypes. And most structural predictions could not detect gross changes in the mutant protein. However, in a severely affected HSP family we have identified a novel SPG3A mutation, c.1228G > A (p.G410R), in a Tibetan kindred. The mutation occurred at the highly conserved nucleotide and co-segregated with the disease, and was absent in the control subjects. Structural predictions showed that the Tibetan mutation occurred at the linking part between the guanylate-binding protein domain (GB, the ball region) and the transmembrane helices (TM, the rod region) at the start point of an a-helix, which may disrupt the helix, and cause changes in the overall structure of the transmembrane region of the molecule. Our results indicate that severe phenotypes can also arise from SPG3A mutations and the linking part of the guanylate-binding protein domain and the transmembrane helices might be crucial in determining the severity of the disease. This paper not only presents the first SPG3A mutational report from the Chinese population, but also provides potential evidence for a possible correlation between the severity of the phenotypes of HSP with the extension of the changes in the protein structures of atlastin. ER - TY - JFULL T1 - Meta-analysis of studies of alcohol and breast cancer with consideration of the methodological issues. A1 - Key, J A1 - Hodgson, S A1 - Omar, RZ A1 - Jensen, TK A1 - Thompson, SG A1 - Boobis, AR A1 - Davies, DS A1 - Elliott, P J1 - Cancer Causes Control Y1 - 2006/08// VL - 17 SN - 0957-5243 SP - 759 EP - 770 N2 - OBJECTIVE: To give an up-to-date assessment of the association of alcohol with female breast cancer, addressing methodological issues and shortfalls in previous overviews. METHODS: Meta-analysis of studies (any language) providing original data on incidence of first primary breast cancer and alcohol. Two reviewers independently extracted data. Study quality assessed by objective criteria including degree of control for confounding; funnel plots examined for publication bias; meta-regression techniques to explore heterogeneity. Risks associated with drinking versus not drinking and dose-response not constrained through the origin estimated using random effects methods. RESULTS: Ninety-eight unique studies were included, involving 75,728 and 60,653 cases in drinker versus non-drinker and dose-response analyses, respectively. Findings were robust to study design and analytic approaches in the meta-analyses. For studies judged high quality, controlled for appropriate confounders, excess risk associated with alcohol drinking was 22% (95% CI: 9-37%); each additional 10 g ethanol/day was associated with risk higher by 10% (95% CI: 5-15%). There was no evidence of publication bias. Risk did not differ significantly by beverage type or menopausal status. Estimated population attributable risks were 1.6 and 6.0% in USA and UK, respectively. CONCLUSIONS: Taking account of shortcomings in the study base and methodological concerns, we confirm the alcohol-breast cancer association. We compared our results to those of an individual patient data analysis, with similar findings. We conclude that the association between alcohol and breast cancer may be causal. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16783604&query_hl=1 ER - TY - JFULL T1 - Defining the technical skills of teamwork in surgery. A1 - Healey, AN A1 - Undre, S A1 - Vincent, CA J1 - Qual Saf Health Care Y1 - 2006/08// VL - 15 SN - 1475-3901 SP - 231 EP - 234 N2 - Developments in surgical technology and procedure have accelerated and altered the work carried out in the operating theatre/room, but team modelling and training have not co-evolved. Evidence suggests that team structure and role allocation are sometimes unclear and contentious, and coordination and communication are not fully effective. To improve teamwork, clinicians need models that specify team resources, structure, process and tasks. They also need measures to assess performance and methods to train teamwork strategically. An effective training strategy might be to incorporate teamwork with other technical skills training in simulation. However, the measures employed for enhancing teamwork in training and practice will need to vary in their object of analysis, level of technical specificity, and system scope. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16885245&query_hl=1 ER - TY - JFULL T1 - Never say never again! A1 - Apperley, JF J1 - BLOOD Y1 - 2006/08/01/ VL - 108 SN - 0006-4971 SP - 786 EP - 787 ER - TY - JFULL T1 - Imatinib preceding allogeneic stem cell transplantation in chronic myeloid leukemia. A1 - Perz, JB A1 - Khorashad, JS A1 - Marin, D A1 - Apperley, JF A1 - Olavarria, E J1 - Haematologica Y1 - 2006/08// VL - 91 SN - 1592-8721 SP - 1145 EP - 1146 N2 - In 37 adults with chronic myeloid leukemia undergoing allogeneic stem cell transplantation imatinib prior to transplant had no discernible negative impact on 100-day mortality (13%) and severe acute (22%) or extensive chronic graft-versus- host disease (31%). After a median of 203 days (range: 18-1419) overall and progression-free survival rates are 62% and 54%, respectively. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16870551&query_hl=1 ER - TY - JFULL T1 - An evidence-based virtual reality training program for novice laparoscopic surgeons. A1 - Aggarwal, R A1 - Grantcharov, TP A1 - Eriksen, JR A1 - Blirup, D A1 - Kristiansen, VB A1 - Funch-Jensen, P A1 - Darzi, A J1 - Ann Surg Y1 - 2006/08// VL - 244 SN - 0003-4932 SP - 310 EP - 314 N2 - OBJECTIVE: To develop an evidence-based virtual reality laparoscopic training curriculum for novice laparoscopic surgeons to achieve a proficient level of skill prior to participating in live cases. SUMMARY BACKGROUND DATA: Technical skills for laparoscopic surgery must be acquired within a competency-based curriculum that begins in the surgical skills laboratory. Implementation of this program necessitates the definition of the validity, learning curves and proficiency criteria on the training tool. METHODS: The study recruited 40 surgeons, classified into experienced (performed >100 laparoscopic cholecystectomies) or novice groups (<10 laparoscopic cholecystectomies). Ten novices and 10 experienced surgeons were tested on basic tasks, and 11 novices and 9 experienced surgeons on a procedural module for dissection of Calot triangle. Performance of the 2 groups was assessed using time, error, and economy of movement parameters. RESULTS: All basic tasks demonstrated construct validity (Mann-Whitney U test, P < 0.05), and learning curves for novices plateaued at a median of 7 repetitions (Friedman's test, P < 0.05). Expert surgeons demonstrated a learning rate at a median of 2 repetitions (P < 0.05). Performance on the dissection module demonstrated significant differences between experts and novices (P < 0.002); learning curves for novice subjects plateaued at the fourth repetition (P < 0.05). Expert benchmark criteria were defined for validated parameters on each task. CONCLUSION: A competency-based training curriculum for novice laparoscopic surgeons has been defined. This can serve to ensure that junior trainees have acquired prerequisite levels of skill prior to entering the operating room, and put them directly into practice. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16858196&query_hl=1 ER - TY - JFULL T1 - The clinical outcome and toxicity of high-dose chemotherapy and autologous stem cell transplantation in patients with myeloma or amyloid and severe renal impairment: a British Society of Blood and Marrow Transplantation study. A1 - Bird, JM A1 - Fuge, R A1 - Sirohi, B A1 - Apperley, JF A1 - Hunter, A A1 - Snowden, J A1 - Mahendra, P A1 - Milligan, D A1 - Byrne, J A1 - Littlewood, T A1 - Fegan, C A1 - McQuaker, G A1 - Pagliuca, A A1 - Johnson, P A1 - Rahemtulla, A A1 - Morris, C A1 - Marks, DI A1 - British Society of Blood and Marrow Transplantation J1 - Br J Haematol Y1 - 2006/08// VL - 134 SN - 0007-1048 SP - 385 EP - 390 N2 - The outcome of high-dose chemotherapy (HDT) was evaluated retrospectively in 27 patients with myeloma and four patients with AL amyloidosis with severe renal impairment. Twenty-three patients were receiving dialysis and the rest had a creatinine clearance of <20 ml/min. The median melphalan dose was 140 mg/m2 (range: 60-200 mg/m2), but 10 patients (37%) received 200 mg/m2. Myeloid and platelet engraftment were similar to that seen in patients without renal failure. Five of 27 patients died of transplant-related toxicity before the day 100. Twenty of 27 patients had a response (70%). The median time to disease progression was 32 months (range: 6-54 months) and the median time to best response was 6.5 months. Four of 17 evaluable patients (24%) became dialysis-independent at a median of 5 months post-HDT/stem cell transplantation. At a median follow-up of 70 months, 7/23 patients with myeloma were alive but three of these seven patients had progressive disease. Two of the four patients with amyloidosis have survived. HDT is feasible in these patients and results in 5-year survival in about one-third of patients. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16822294&query_hl=1 ER - TY - JFULL T1 - Gestational trophoblastic diseases: 2. Hyperglycosylated hCG as a reliable marker of active neoplasia A1 - Cole, LA A1 - Butler, SA A1 - Khanlian, SA A1 - Giddings, A A1 - Muller, CY A1 - Seckl, MJ A1 - Kohorn, EI J1 - GYNECOL ONCOL Y1 - 2006/08// VL - 102 SN - 0090-8258 SP - 151 EP - 159 N2 - Objectives. To determine whether circulating hyperglycosylated human chorionic gonadotropin (KG-H), a promoter of choriocarcinoma growth and turnorigenesis, is a reliable marker of active gestational trophoblastic neoplasia (GTN) or choriocarcinoma, and whether hCG-H can consistently discriminate quiescent gestational trophoblastic disease (GTD) from neoplasia.Methods. Patients were those referred to the USA hCG Reference Service for consultation. These included a total of 82 women with GTN, including 30 with histologic choriocarcinoma. They were compared with 26 patients with resolving hydatidiform mole and 69 with quiescent GTD (persistent positive low value of real hCG but no clinical evidence of disease). All were tested for total hCG and hCG-H. hCG-H was calculated as the percentage of total hCG (hCG-H(%)).Results. We compared the utility of total hCG and hCG-H(%) in detecting active GTN and quiescent GTD. There was no significant difference when measuring total hCG (includes regular and hyperglycosylated hCG), between women with quiescent GTD and self-resolving hydatidiform mole compared to choriocarcinonna/GTN cases (P > 0.05 and P > 0.05). In contrast, hCG-H(%) was significantly higher in choriocarcinoma/GTN cases (P < 0.000001, and P < 0.000001). The usefulness of hCG and hCG-H(%) testing was assessed for discriminating between the 69 quiescent GTD cases, which required no therapy, and choriocarcinoma/GTN which need treatment. While hUG would detect 62% and 24% of malignancies at a 5% false positive rate, hCG-H(%) would detect 100% and 84% of malignancies at this same false positive rate. Follow-up data were received and repeat consultations were performed in 23 cases in which active disease was subsequently demonstrated. In 12 of 23 cases, hCG-H(%) results were able to first identify active disease 0.5 to 11 months prior to rapidly rising hCG or detection of clinically active neoplasia. In the remaining 11 cases, hCG-H(%) active disease appeared at the same time as rising hCG or demonstrable clinical tumor.Discussion and conclusion. hCG-H(%) appears to reliably identify active trophoblastic malignancy. It is a 100% sensitive marker for discriminating quiescent GTD from active GTN/choriocarcinoma. It is also a marker for the early detection of new or recurrent GTN/ choriocarcinoma. The data presented appear sufficient to encourage the adoption of hCG-H as a tumor marker in trophoblastic disease. Further studies are now urgently required to confirm and extend our findings. (c) 2006 Elsevier Inc. All rights reserved. ER - TY - JFULL T1 - Assessing the potential role of photopheresis in hematopoietic stem cell transplant. A1 - Greinix, HT A1 - Socié, G A1 - Bacigalupo, A A1 - Holler, E A1 - Edinger, MG A1 - Apperley, JF A1 - Schwarz, T A1 - Ullrich, SE A1 - Albert, ML A1 - Knobler, RM A1 - Peritt, D A1 - Ferrara, JL J1 - Bone Marrow Transplant Y1 - 2006/08// VL - 38 SN - 0268-3369 SP - 265 EP - 273 N2 - The First International Symposium on Photopheresis in Hematopoietic Stem Cell Transplantation was held in Vienna, Austria with an educational grant from Therakos Inc. from 25 May to 27 May 2005. Three general issues were addressed: (1) pathophysiology of graft-versus-host disease (GvHD), (2) induction of immune tolerance and the immunology of phototherapy and (3) current standard treatment and prevention strategies of acute and chronic GvHD and the use of extracorporeal photopheresis (ECP). The objectives of the meeting were to open a dialogue among leading researchers in photobiology, immunology, and hematopoietic stem cell transplantation; foster discussions and suggestions for future studies of the mechanism of action of ECP in acute and chronic GvHD; and promote collaboration between basic scientists and clinicians. As can be seen from the summaries of the individual presentations, important advances have been made in our understanding of GvHD, including the use of photoimmunology interventions and the development of robust model systems. It is our expectation that data from photoimmunology studies can be used to generate hypotheses in animal models that can further define the mechanism of action of ECP and help translate the findings to clinical trials of ECP for the prophylaxis and treatment of both chronic and acute GvHD. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16883310&query_hl=1 ER - TY - JFULL T1 - In vivo biological activity of the histone deacetylase inhibitor LAQ824 is detectable with 3'-deoxy-3'-[18F]fluorothymidine positron emission tomography. A1 - Leyton, J A1 - Alao, JP A1 - Da Costa, M A1 - Stavropoulou, AV A1 - Latigo, JR A1 - Perumal, M A1 - Pillai, R A1 - He, Q A1 - Atadja, P A1 - Lam, EW A1 - Workman, P A1 - Vigushin, DM A1 - Aboagye, EO J1 - Cancer Res Y1 - 2006/08/01/ VL - 66 SN - 0008-5472 SP - 7621 EP - 7629 N2 - Histone deacetylase inhibitors (HDACI) are emerging as growth inhibitory compounds that modulate gene expression and inhibit tumor cell proliferation. We assessed whether 3'-deoxy-3'-[(18)F]fluorothymidine-positron emission tomography ([18F]FLT-PET) could be used to noninvasively measure the biological activity of a novel HDACI LAQ824 in vivo. We initially showed that thymidine kinase 1 (TK1; EC2.7.1.21), the enzyme responsible for [18F]FLT retention in cells, was regulated by LAQ824 in a drug concentration-dependent manner in vitro. In HCT116 colon carcinoma xenograft-bearing mice, LAQ824 significantly decreased tumor [18F]FLT uptake in a dose-dependent manner. At day 4 of treatment, [18F]FLT tumor-to-heart ratios at 60 minutes (NUV60) were 2.16 +/- 0.15, 1.86 +/- 0.13, and 1.45 +/- 0.20 in vehicle, and 5 and 25 mg/kg LAQ824 treatment groups, respectively (P < or = 0.05). LAQ825 at 5 mg/kg also significantly reduced both TK1 levels and [18F]FLT uptake at day 10 but not at day 2 (P < or = 0.05). [18F]FLT NUV60 correlated significantly with cellular proliferation (r = 0.68; P = 0.0019) and was associated with drug-induced histone H4 hyperacetylation. Of interest to [18F]FLT-PET imaging, both TK1 mRNA copy numbers and protein levels decreased in the order vehicle >5 mg/kg LAQ824 > 25 mg/kg LAQ824, providing a rationale for the use of [18F]FLT-PET in this setting. We also observed increases in Rb hypophosphorylation and p21 levels, factors that could have contributed to the alteration in TK1 transcription in vivo. In conclusion, we have shown the utility of [18F]FLT-PET for monitoring the biological activity of the HDACI, LAQ824. Drug-induced changes in tumor [18F]FLT uptake were due, at least in part, to reductions in TK1 transcription and translation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16885362&query_hl=1 ER - TY - JFULL T1 - The permeability transition pore complex in cancer cell death A1 - Brenner, C A1 - Grimm, S J1 - ONCOGENE Y1 - 2006/08// VL - 25 SN - 0950-9232 SP - 4744 EP - 4756 N2 - The permeability transition pore (PTP) is a multi-protein complex at contact sites of the inner with the outer mitochondrial membrane. Research over the past years has led to the concept that the PTP occupies a central role in cell death induction. Numerous apoptosis signals convert this protein aggregate into an unspecific pore, thus activating mitochondria for the cellular self-destruction process. Here, we describe the evidence for this and the various approaches being undertaken to elucidate its subunit composition and mode of regulation. In particular, we review data that indicate a role of specific PTP subunits for apoptosis inhibition during tumorigenesis. ER - TY - JFULL T1 - p27Kip1 and p130 cooperate to regulate hematopoietic cell proliferation in vivo. A1 - Soeiro, I A1 - Mohamedali, A A1 - Romanska, HM A1 - Lea, NC A1 - Child, ES A1 - Glassford, J A1 - Orr, SJ A1 - Roberts, C A1 - Naresh, KN A1 - Lalani, el-N A1 - Mann, DJ A1 - Watson, RJ A1 - Thomas, NS A1 - Lam, EW J1 - Mol Cell Biol Y1 - 2006/08// VL - 26 SN - 0270-7306 SP - 6170 EP - 6184 N2 - To investigate the potential functional cooperation between p27Kip1 and p130 in vivo, we generated mice deficient for both p27Kip1 and p130. In p27Kip1-/-; p130-/- mice, the cellularity of the spleens but not the thymi is significantly increased compared with that of their p27Kip1-/- counterparts, affecting the lymphoid, erythroid, and myeloid compartments. In vivo cell proliferation is significantly augmented in the B and T cells, monocytes, macrophages, and erythroid progenitors in the spleens of p27Kip1-/-; p130-/- animals. Immunoprecipitation and immunodepletion studies indicate that p130 can compensate for the absence of p27Kip1 in binding to and repressing CDK2 and is the predominant CDK-inhibitor associated with the inactive CDK2 in the p27Kip1-/- splenocytes. The finding that the p27Kip1-/-; p130-/- splenic B cells are hypersensitive to mitogenic stimulations in vitro lends support to the concept that the hyperproliferation of splenocytes is not a result of the influence of their microenvironment. In summary, our findings provide genetic and molecular evidence to show that p130 is a bona fide cyclin-dependent kinase inhibitor and cooperates with p27Kip1 to regulate hematopoietic cell proliferation in vivo. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16880527&query_hl=1 ER - TY - JFULL T1 - Colorectal cancer and rectal bleeding in primary care: urban or rural myth? A1 - Purkayastha, S A1 - Darzi, A J1 - BMJ Y1 - 2006/07/22/ VL - 333 SN - 1468-5833 SP - 201 EP - 202 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16858062&query_hl=1 ER - TY - JFULL T1 - FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2. A1 - Pardo, OE A1 - Wellbrock, C A1 - Khanzada, UK A1 - Aubert, M A1 - Arozarena, I A1 - Davidson, S A1 - Bowen, F A1 - Parker, PJ A1 - Filonenko, VV A1 - Gout, IT A1 - Sebire, N A1 - Marais, R A1 - Downward, J A1 - Seckl, MJ J1 - EMBO J Y1 - 2006/07/12/ VL - 25 SN - 0261-4189 SP - 3078 EP - 3088 N2 - Patients with small cell lung cancer (SCLC) die because of chemoresistance. Fibroblast growth factor-2 (FGF-2) increases the expression of antiapoptotic proteins, XIAP and Bcl-X(L), and triggers chemoresistance in SCLC cells. Here we show that these effects are mediated through the formation of a specific multiprotein complex comprising B-Raf, PKCepsilon and S6K2. S6K1, Raf-1 and other PKC isoforms do not form similar complexes. RNAi-mediated downregulation of B-Raf, PKCepsilon or S6K2 abolishes FGF-2-mediated survival. In contrast, overexpression of PKCepsilon increases XIAP and Bcl-X(L) levels and chemoresistance in SCLC cells. In a tetracycline-inducible system, increased S6K2 kinase activity triggers upregulation of XIAP, Bcl-X(L) and prosurvival effects. However, increased S6K1 kinase activity has no such effect. Thus, S6K2 but not S6K1 mediates prosurvival/chemoresistance signalling. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16810323&query_hl=1 ER - TY - JFULL T1 - Formation of primary cilia in the renal epithelium is regulated by the von Hippel-Lindau tumor suppressor protein. A1 - Esteban, MA A1 - Harten, SK A1 - Tran, MG A1 - Maxwell, PH J1 - J Am Soc Nephrol Y1 - 2006/07// VL - 17 SN - 1046-6673 SP - 1801 EP - 1806 N2 - Growing evidence points to defects in the primary cilium as a critical mechanism underlying renal cyst development. Inactivation of the VHL gene is responsible for the autosomal dominant condition von Hippel-Lindau (VHL) disease and is implicated in most sporadic clear cell renal carcinomas. Manifestations of VHL disease include cysts in several organs, particularly in the kidney. Here it is shown that VHL inactivation is associated with abrogation of the primary cilium in renal cysts of patients with VHL disease and in VHL-defective cell lines. Complementation of VHL-defective clear cell renal carcinoma cell lines with wild-type VHL restored primary cilia. Moreover, it is shown that the effects of VHL on the primary cilium are mediated substantially via hypoxia-inducible factor. The effect of VHL status on the primary cilium provides a potential mechanism for renal cyst development in VHL disease and may help in the understanding of how VHL acts as a tumor suppressor. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16775032&query_hl=1 ER - TY - JFULL T1 - Dietary fat and breast cancer. A1 - Mazhar, D A1 - Waxman, J J1 - QJM Y1 - 2006/07// VL - 99 SN - 1460-2725 SP - 469 EP - 473 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16522716&query_hl=1 ER - TY - JFULL T1 - Self-assessment of performance among surgical trainees during simulated procedures in a simulated operating theater. A1 - Moorthy, K A1 - Munz, Y A1 - Adams, S A1 - Pandey, V A1 - Darzi, A A1 - Imperial College--St. Mary's Hospital Simulation Group J1 - Am J Surg Y1 - 2006/07// VL - 192 SN - 0002-9610 SP - 114 EP - 118 N2 - BACKGROUND: The ability of surgeons to assess their own performance is essential for training and self-regulation. The latter is based on the premise that they recognize their weaknesses and seek remedial action accordingly. METHODS: Twenty-seven surgical trainees performed a simulated saphenofemoral high-tie on a synthetic model in a simulated operating theater. The performance assessment consisted of blinded rating of technical skills and a global rating of team skills by a human factors expert and a trained surgical research fellow. Subjects also were asked to assess their own performance using the same methods. Spearman's rho was used for data analysis. RESULTS: There was a strong correlation between the experts rating of technical skills and self-assessment (rho = .64). However, the correlation improved with increasing experience. It was .24 for junior trainees, .43 for those with intermediate experience, and .52 for senior trainees. There was a low correlation between the self-assessment and the expert scores for human factors skills (rho = .31). The correlation was higher for the 2 junior groups compared with the senior trainees. CONCLUSIONS: Unlike other studies on self-assessment, this study found that senior surgical trainees are accurate in their self-assessment of technical skills. However, this was not true in the case of human factors skills. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16769287&query_hl=1 ER - TY - JFULL T1 - Low oxygen stimulates the intellect - Symposium on hypoxia and development, physiology and disease A1 - Koumenis, C A1 - Maxwell, PH J1 - EMBO REP Y1 - 2006/07// VL - 7 SN - 1469-221X SP - 679 EP - 684 ER - TY - JFULL T1 - Characterization and clinical application of human CD34+ stem/progenitor cell populations mobilized into the blood by granulocyte colony-stimulating factor. A1 - Gordon, MY A1 - Levicar, N A1 - Pai, M A1 - Bachellier, P A1 - Dimarakis, I A1 - Al-Allaf, F A1 - M'Hamdi, H A1 - Thalji, T A1 - Welsh, JP A1 - Marley, SB A1 - Davies, J A1 - Dazzi, F A1 - Marelli-Berg, F A1 - Tait, P A1 - Playford, R A1 - Jiao, L A1 - Jensen, S A1 - Nicholls, JP A1 - Ayav, A A1 - Nohandani, M A1 - Farzaneh, F A1 - Gaken, J A1 - Dodge, R A1 - Alison, M A1 - Apperley, JF A1 - Lechler, R A1 - Habib, NA J1 - Stem Cells Y1 - 2006/07// VL - 24 SN - 1066-5099 SP - 1822 EP - 1830 N2 - A phase I study was performed to determine the safety and tolerability of injecting autologous CD34(+) cells into five patients with liver insufficiency. The study was based on the hypothesis that the CD34(+) cell population in granulocyte colony-stimulating factor (G-CSF)-mobilized blood contains a subpopulation of cells with the potential for regenerating damaged tissue. We separated a candidate CD34(+) stem cell population from the majority of the CD34(+) cells (99%) by adherence to tissue culture plastic. The adherent and nonadherent CD34(+) cells were distinct in morphology, immunophenotype, and gene expression profile. Reverse transcription-polymerase chain reaction-based gene expression analysis indicated that the adherent CD34(+) cells had the potential to express determinants consistent with liver, pancreas, heart, muscle, and nerve cell differentiation as well as hematopoiesis. Overall, the characteristics of the adherent CD34(+) cells identify them as a separate putative stem/progenitor cell population. In culture, they produced a population of cells exhibiting diverse morphologies and expressing genes corresponding to multiple tissue types. Encouraged by this evidence that the CD34(+) cell population contains cells with the potential to form hepatocyte-like cells, we gave G-CSF to five patients with liver insufficiency to mobilize their stem cells for collection by leukapheresis. Between 1 x 10(6) and 2 x 10(8) CD34(+) cells were injected into the portal vein (three patients) or hepatic artery (two patients). No complications or specific side effects related to the procedure were observed. Three of the five patients showed improvement in serum bilirubin and four of five in serum albumin. These observations warrant further clinical trials. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16556705&query_hl=1 ER - TY - JFULL T1 - Outcome of kidney transplantation from non-heart-beating versus heart-beating cadaveric donors A1 - Kokkinos, C A1 - Antcliffe, D A1 - Nanidis, T A1 - Tekkis, P A1 - Athanasiou, T A1 - Darzi, A A1 - Papalois, V J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 522 EP - 523 ER - TY - JFULL T1 - Primary resection with anastomosis vs. Hartmann's procedure in nonelective surgery for acute colonic diverticulitis: a systematic review. A1 - Constantinides, VA A1 - Tekkis, PP A1 - Athanasiou, T A1 - Aziz, O A1 - Purkayastha, S A1 - Remzi, FH A1 - Fazio, VW A1 - Aydin, N A1 - Darzi, A A1 - Senapati, A J1 - Dis Colon Rectum Y1 - 2006/07// VL - 49 SN - 0012-3706 SP - 966 EP - 981 N2 - PURPOSE: This study compares primary resection with anastomosis and Hartmann's procedure in an adult population with acute colonic diverticulitis. METHODS: Comparative studies published between 1984 and 2004 of primary resection with anastomosis vs. Hartmann's procedure were included. The primary end point was postoperative mortality. Secondary end points included surgical and medical morbidity, operative time, and length of postoperative hospitalization. Random effects model was used and sensitivity analysis was performed. RESULTS: Fifteen studies, including 963 patients (57 percent primary resection with anastomoses, 43 percent Hartmann's procedures), were analyzed. Overall mortality was significantly reduced with primary resection and anastomosis (4.9 vs. 15.1 percent; odds ratio = 0.41). Subgroup analysis of trials matched for emergency operations showed significantly decreased mortality with primary resection and anastomosis (7.4 vs. 15.6 percent; odds ratio = 0.44). No significant difference in mortality was observed in trials matched for severity of peritonitis Hinchey > 2 (14.1 vs. 14.4 percent; odds ratio = 0.85). Sensitivity analysis did not reveal significant heterogeneity between the studies for the primary outcome. CONCLUSIONS: Patients selected for primary resection and anastomosis have a lower mortality than those treated by Hartmann's procedure in the emergency setting and comparable mortality under conditions of generalized peritonitis (Hinchey > 2). The retrospective nature of the included studies allows for a considerable degree of selection bias that limits robust and clinically sound conclusions. This analysis highlights the need for high-quality randomized trials comparing the two techniques. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16752192&query_hl=1 ER - TY - JFULL T1 - Expression and distribution of hypoxia inducible transcription factors in mouse liver, heart and kidney A1 - Bernhardt, WM A1 - Cramer, T A1 - Rohwer, N A1 - Klanke, B A1 - Wiesener, MS A1 - Maxwell, PH A1 - Eckardt, KU J1 - NEPHROL DIAL TRANSPL Y1 - 2006/07// VL - 21 SN - 0931-0509 SP - 17 EP - 17 ER - TY - JFULL T1 - Surgical crisis management skills training and assessment: a simulation[corrected]-based approach to enhancing operating room performance. A1 - Moorthy, K A1 - Munz, Y A1 - Forrest, D A1 - Pandey, V A1 - Undre, S A1 - Vincent, C A1 - Darzi, A J1 - Ann Surg Y1 - 2006/07// VL - 244 SN - 0003-4932 SP - 139 EP - 147 N2 - BACKGROUND: Intraoperative surgical crisis management is learned in an unstructured manner. In aviation, simulation training allows aircrews to coordinate and standardize recovery strategies. Our aim was to develop a surgical crisis simulation and evaluate its feasibility, realism, and validity of the measures used to assess performance. METHODS: Surgical trainees were exposed to a bleeding crisis in a simulated operating theater. Assessment of performance consisted of a trainee's technical ability to control the bleeding and of their team/human factors skills. This assessment was performed in a blinded manner by 2 surgeons and one human factors expert. Other measures consisted of time measures such as time to diagnose the bleeding (TD), inform team members (TT), achieve control (TC), and close the laceration (TL). Blood loss was used as a surrogate outcome measures. RESULTS: There were considerable variations within both senior (n = 10) and junior (n = 10) trainees for technical and team skills. However, while the senior trainees scored higher than the juniors for technical skills (P = 0.001), there were no differences in human factors skills. There were also significant differences between the 2 groups for TD (P = 0.01), TC (P = 0.001), and TL (0.001). The blood loss was higher in the junior group. CONCLUSIONS: We have described the development of a novel simulated setting for the training of crisis management skills and the variability in performance both in between and within the 2 groups. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16794399&query_hl=1 ER - TY - JFULL T1 - Comparison of laparoscopic and open ileocecal resection for Crohn's disease: a metaanalysis. A1 - Tilney, HS A1 - Constantinides, VA A1 - Heriot, AG A1 - Nicolaou, M A1 - Athanasiou, T A1 - Ziprin, P A1 - Darzi, AW A1 - Tekkis, PP J1 - Surg Endosc Y1 - 2006/07// VL - 20 SN - 1432-2218 SP - 1036 EP - 1044 N2 - BACKGROUND: The role of laparoscopic surgery for patients with ileocecal Crohn's disease is a contentious issue. This metaanalysis aimed to compare open resection with laparoscopically assisted resection for ileocecal Crohn's disease. METHODS: A literature search of the Medline, Ovid, Embase, and Cochrane databases was performed to identify comparative studies reporting outcomes for both laparoscopic and open ileocecal resection. Metaanalytical techniques were applied to identify differences in outcomes between the two groups. Sensitivity analysis was undertaken to evaluate the heterogeneity of the study. RESULTS: Of 20 studies identified by literature review, 15 satisfied the criteria for inclusion in the study. These included outcomes for 783 patients, 338 (43.2%) of whom had undergone laparoscopic resection, with an overall conversion rate to open surgery of 6.8%. The operative time was significantly longer in the laparoscopic group, by 29.6 min (p = 0.002), although the blood loss and complications in the two groups were similar. In terms of postoperative recovery, the laparoscopic patients had a significantly shorter time for recovery of their enteric function and a shorter hospital stay, by 2.7 days (p < 0.001). CONCLUSIONS: For selected patients with noncomplicated ileocecal Crohn's disease, laparoscopic resection offered substantial advantages in terms of more rapid resolution of postoperative ileus and shortened hospital stay. There was no increase in complications, as compared with open surgery. The contraindications to laparoscopic approaches for Crohn's disease remain undefined. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16715212&query_hl=1 ER - TY - JFULL T1 - Epigenetics: an emerging technology in the diagnosis and treatment of cancer. A1 - Stebbing, J A1 - Bower, M A1 - Syed, N A1 - Smith, P A1 - Yu, V A1 - Crook, T J1 - Pharmacogenomics Y1 - 2006/07// VL - 7 SN - 1462-2416 SP - 747 EP - 757 N2 - Transcriptional silencing resulting from changes in epigenetic regulation of gene expression is the most frequent mechanism by which tumor suppressor genes are inactivated in human cancer. Genes participating in numerous functional groups and pathways leading to malignancy are subject to aberrant CpG methylation, with associated downregulation of expression, in human carcinogenesis. Methylation profiling can identify distinct subtypes of common human cancers and may have utility in predicting clinical phenotypes in individual patients, including sensitivity to chemotherapeutic agents. Hypomethylating agents have clinical activity in some hematological malignancies, and there is accumulating evidence correlating clinical response with demethylation and concomitant reactivation of expression of specific target genes. Epigenetic analysis is likely to have an increasingly important part to play in the diagnosis, prognostic assessment and treatment of malignant disease. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16886899&query_hl=1 ER - TY - JFULL T1 - Pulmonary Kaposi sarcoma in the era of highly active antiretroviral therapy. A1 - Palmieri, C A1 - Dhillon, T A1 - Thirlwell, C A1 - Newsom-Davis, T A1 - Young, AM A1 - Nelson, M A1 - Gazzard, BG A1 - Bower, M J1 - HIV Med Y1 - 2006/07// VL - 7 SN - 1464-2662 SP - 291 EP - 293 N2 - OBJECTIVE: Since the introduction of highly active antiretroviral therapy (HAART) there has been a dramatic reduction in the incidence of Kaposi sarcoma (KS) and an improvement in survival. We wished to examine whether the outcome in pulmonary KS (pKS) has also altered. METHODS: In a single-institution cohort of 1140 HIV-positive patients with KS, 305 patients were diagnosed in the HAART era (1996-2004). We examined the clinicopathological features and outcomes of these patients, of whom 25 had pKS and 280 did not. RESULTS: Patients with pKS had lower CD4 cell counts at the time of KS diagnosis (Mann-Whitney U-test P=0.005). The incidence of pKS was higher in African patients than in non-African patients in this sample (Fisher's test, P=0.001). There were no significant differences in age, gender, plasma HIV-1 viral load or prior HAART treatment at the time of KS diagnosis. Five-year overall survival in the pKS group was 49% [95% confidence interval (CI) 26-73%] as compared with 82% (95% CI 76-87%) for the non-pKS group (log rank, P<0.0001). CONCLUSION: PKS remains an ominous diagnosis in the era of HAART, with a median survival of just 1.6 years. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16945073&query_hl=1 ER - TY - JFULL T1 - Mutation of von Hippel-Lindau tumour suppressor and human cardiopulmonary physiology. A1 - Smith, TG A1 - Brooks, JT A1 - Balanos, GM A1 - Lappin, TR A1 - Layton, DM A1 - Leedham, DL A1 - Liu, C A1 - Maxwell, PH A1 - McMullin, MF A1 - McNamara, CJ A1 - Percy, MJ A1 - Pugh, CW A1 - Ratcliffe, PJ A1 - Talbot, NP A1 - Treacy, M A1 - Robbins, PA J1 - PLoS Med Y1 - 2006/07// VL - 3 SN - 1549-1676 SP - e290 EP - e290 N2 - BACKGROUND: The von Hippel-Lindau tumour suppressor protein-hypoxia-inducible factor (VHL-HIF) pathway has attracted widespread medical interest as a transcriptional system controlling cellular responses to hypoxia, yet insights into its role in systemic human physiology remain limited. Chuvash polycythaemia has recently been defined as a new form of VHL-associated disease, distinct from the classical VHL-associated inherited cancer syndrome, in which germline homozygosity for a hypomorphic VHL allele causes a generalised abnormality in VHL-HIF signalling. Affected individuals thus provide a unique opportunity to explore the integrative physiology of this signalling pathway. This study investigated patients with Chuvash polycythaemia in order to analyse the role of the VHL-HIF pathway in systemic human cardiopulmonary physiology. METHODS AND FINDINGS: Twelve participants, three with Chuvash polycythaemia and nine controls, were studied at baseline and during hypoxia. Participants breathed through a mouthpiece, and pulmonary ventilation was measured while pulmonary vascular tone was assessed echocardiographically. Individuals with Chuvash polycythaemia were found to have striking abnormalities in respiratory and pulmonary vascular regulation. Basal ventilation and pulmonary vascular tone were elevated, and ventilatory, pulmonary vasoconstrictive, and heart rate responses to acute hypoxia were greatly increased. CONCLUSIONS: The features observed in this small group of patients with Chuvash polycythaemia are highly characteristic of those associated with acclimatisation to the hypoxia of high altitude. More generally, the phenotype associated with Chuvash polycythaemia demonstrates that VHL plays a major role in the underlying calibration and homeostasis of the respiratory and cardiovascular systems, most likely through its central role in the regulation of HIF. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16768548&query_hl=1 ER - TY - JFULL T1 - Impact of analytical bias in metabonomic studies of human blood serum and plasma. A1 - Teahan, O A1 - Gamble, S A1 - Holmes, E A1 - Waxman, J A1 - Nicholson, JK A1 - Bevan, C A1 - Keun, HC J1 - Anal Chem Y1 - 2006/07/01/ VL - 78 SN - 0003-2700 SP - 4307 EP - 4318 N2 - Concurrent with the explosion in the number of publications reporting biomarker discovery by profiling technologies, such as proteomics and pattern recognition, has been the increase in evidence highlighting the susceptibility of these approaches to analytical and experimental bias. The work presented here addresses these timely issues by delivering a detailed characterization of the effect of common sources of bias in clinical studies on serum and plasma profiles generated by a key technology in metabonomics, NMR spectroscopy. Specifically, differences in composition when blood samples were collected onto and in the absence of ice, over a series of serum-clot contact times, the stability of NMR-prepared samples over time and the effect on the metabolic profile of freeze-thawing were examined. While differences between individuals were far greater than variation from any other experimental factor, each of the conditions examined did cause slight alterations to the NMR profile that could produce a systematic bias. Variation due to clotting time caused changes in energy metabolites, which were delayed by ice with no other spectral effects. Room-temperature stability and hence NMR spectral repeatability were high (<1% intrasample variation). Higher molecular weight species such as lipoproteins were more susceptible to the variations present in the examined factors. These observations have implications for profiling study design, and hence, our results form a new and valuable resource for those attempting clinical metabolic profiling, for regulatory agencies involved in the licensing of clinical tests and in the generation of international reporting standards for metabonomics. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16808437&query_hl=1 ER - TY - JFULL T1 - P-450 and carcinogenesis A1 - Boobis, AR J1 - ACTA PHARMACOL SIN Y1 - 2006/07// VL - 27 SN - 1671-4083 SP - 24 EP - 24 ER - TY - JFULL T1 - A comparison of hand-sewn versus stapled ileal pouch anal anastomosis (IPAA) following proctocolectomy: a meta-analysis of 4183 patients. A1 - Lovegrove, RE A1 - Constantinides, VA A1 - Heriot, AG A1 - Athanasiou, T A1 - Darzi, A A1 - Remzi, FH A1 - Nicholls, RJ A1 - Fazio, VW A1 - Tekkis, PP J1 - Ann Surg Y1 - 2006/07// VL - 244 SN - 0003-4932 SP - 18 EP - 26 N2 - OBJECTIVE: Using meta-analytical techniques, the study compared postoperative adverse events and functional outcomes of stapled versus hand-sewn ileal pouch-anal anastomosis (IPAA) following restorative proctocolectomy. BACKGROUND: The choice of mucosectomy and hand-sewn versus stapled pouch-anal anastomosis has been a subject of debate with no clear consensus as to which method provides better functional results and long-term outcomes. METHODS: Comparative studies published between 1988 and 2003, of hand-sewn versus stapled IPAA were included. Endpoints were classified into postoperative complications and functional and physiologic outcomes measured at least 3 months following closure of ileostomy or surgery if no proximal diversion was used, quality of life following surgery, and neoplastic transformation within the anal transition zone. RESULTS: Twenty-one studies, consisting of 4183 patients (2699 hand-sewn and 1484 stapled IPAA) were included. There was no significant difference in the incidence of postoperative complications between the 2 groups. The incidence of nocturnal seepage and pad usage favored the stapled IPAA (odds ratio [OR] = 2.78, P < 0.001 and OR = 4.12, P = 0.007, respectively). The frequency of defecation was not significantly different between the 2 groups (P = 0.562), nor was the use of antidiarrheal medication (OR = 1.27, P = 0.422). Anorectal physiologic measurements demonstrated a significant reduction in the resting and squeeze pressure in the hand-sewn IPAA group by 13.4 and 14.4 mm Hg, respectively (P < 0.018). The stapled IPAA group showed a higher incidence of dysplasia in the anal transition zone that did not reach statistical significance (OR = 0.42, P = 0.080). CONCLUSIONS: Both techniques had similar early postoperative outcomes; however, stapled IPAA offered improved nocturnal continence, which was reflected in higher anorectal physiologic measurements. A risk of increased incidence of dysplasia in the ATZ may exist in the stapled group that cannot be quantified by this study. We describe a decision algorithm for the choice of IPAA, based on the relative risk of long-term neoplastic transformation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16794385&query_hl=1 ER - TY - JFULL T1 - First mature analysis of the Intergroup Exemestane Study A1 - Coombes, RC A1 - Paridaens, R A1 - Jassem, J A1 - Van de Velde, CJ A1 - Delozier, T A1 - Jones, SE A1 - Hall, E A1 - Kilburn, LS A1 - Snowdon, CF A1 - Bliss, JM A1 - IES J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 933S EP - 933S ER - TY - JFULL T1 - The outcome of patients with relapsed gestational trophoblastic neoplasm (GTN) after the completion of chemotherapy. A1 - Powles, T A1 - Young, A A1 - Short, D A1 - Savage, P A1 - Pappin, C A1 - Schmid, P A1 - Seckl, M J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 263S EP - 263S ER - TY - JFULL T1 - First mature survival analysis of the Intergroup Exemestane Study: A randomised trial in disease-free, postmenopausal patients with early breast cancer randomized to continue tamoxifen or switch to exemestane following an initial 2-3 years of adjuvant tamoxifen. A1 - Coombes, RC A1 - Paridaens, R A1 - Jassem, J A1 - Van de Velde, CJ A1 - Delozier, T A1 - Jones, SE A1 - Hall, E A1 - Kilburn, LS A1 - Snowdon, CF A1 - Bliss, JM A1 - Intergroup Exemestane Study J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 9S EP - 9S ER - TY - JFULL T1 - A feasibility study of [C-11]choline for the molecular imaging of human breast cancer in vivo using positron emission tomography (PET). A1 - Kenny, LM A1 - Coombes, RC A1 - Al-Nahhas, A A1 - Osman, S A1 - Lowdell, C A1 - Aboagye, E J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 31S EP - 31S ER - TY - JFULL T1 - Dasatinib (D) in patients with accelerated phase chronic myeloid leukemia (AP-CML) who are resistant or intolerant to imatinib: Results of the CA180005 'START-A' study. A1 - Talpaz, M A1 - Apperley, JF A1 - Kim, DW A1 - Silver, RT A1 - Bullorsky, EO A1 - Cheng, S A1 - Iyer, M A1 - Guilhot, F J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 343S EP - 343S ER - TY - JFULL T1 - Endocrine and clinical responses to steroid sulfatase inhibition: Results from the first phase I trial in women with breast cancer. A1 - Stanway, S A1 - Purohit, A A1 - Woo, LW A1 - Wilson, RH A1 - Stanczyk, FZ A1 - Dobbs, N A1 - Delavault, P A1 - Potter, BV A1 - Reed, MJ A1 - Coombes, RC J1 - J CLIN ONCOL Y1 - 2006/06/20/ VL - 24 SN - 0732-183X SP - 22S EP - 22S ER - TY - JFULL T1 - Venular basement membranes contain specific matrix protein low expression regions that act as exit points for emigrating neutrophils. A1 - Wang, S A1 - Voisin, MB A1 - Larbi, KY A1 - Dangerfield, J A1 - Scheiermann, C A1 - Tran, M A1 - Maxwell, PH A1 - Sorokin, L A1 - Nourshargh, S J1 - J Exp Med Y1 - 2006/06/12/ VL - 203 SN - 0022-1007 SP - 1519 EP - 1532 N2 - The mechanism of leukocyte migration through venular walls in vivo is largely unknown. By using immunofluorescence staining and confocal microscopy, the present study demonstrates the existence of regions within the walls of unstimulated murine cremasteric venules where expression of key vascular basement membrane (BM) constituents, laminin 10, collagen IV, and nidogen-2 (but not perlecan) are considerably lower (<60%) than the average expression detected in the same vessel. These sites were closely associated with gaps between pericytes and were preferentially used by migrating neutrophils during their passage through cytokine-stimulated venules. Although neutrophil transmigration did not alter the number/unit area of extracellular matrix protein low expression sites, the size of these regions was enlarged and their protein content was reduced in interleukin-1beta-stimulated venules. These effects were entirely dependent on the presence of neutrophils and appeared to involve neutrophil-derived serine proteases. Furthermore, evidence was obtained indicating that transmigrating neutrophils carry laminins on their cell surface in vivo. Collectively, through identification of regions of low extracellular matrix protein localization that define the preferred route for transmigrating neutrophils, we have identified a plausible mechanism by which neutrophils penetrate the vascular BM without causing a gross disruption to its intricate structure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16754715&query_hl=1 ER - TY - JFULL T1 - Association of MEGSIN 2093C-2180T haplotype at the 3 ' untranslated region with disease severity and progression of IgA nephropathy A1 - Xia, YF A1 - Li, YJ A1 - Du, Y A1 - Yang, NS A1 - Li, CX A1 - Leung, JCK A1 - Lam, MF A1 - Huang, WJ A1 - Chen, SQ A1 - Maxwell, PH A1 - Lai, KN A1 - Wang, YM J1 - NEPHROL DIAL TRANSPL Y1 - 2006/06// VL - 21 SN - 0931-0509 SP - 1570 EP - 1574 N2 - Background. MEGSIN is a gene predominantly expressed in the renal mesangium, and is upregulated in IgA nephropathy (IgAN). Our previous study has shown that the 2093C and 2180T alleles at the 3' untranslated region (3'UTR) of the gene are associated with susceptibility to IgAN, but the relationships of these genetic variants with the clinical manifestations and renal histological lesions of IgAN have not been examined previously.Methods. 302 IgAN patients followed up for 52.8 +/- 22.5 months were investigated. Haplotypes at the 3'UTR were constructed using the 2093C/T and 2180C/T alleles. The genotype-phenotype relationship was studied by correlations of haplotypes and the clinical data and renal histopathological changes.Results. The 2093C-2180T haplotype was present more often in patients with disease that progressed more rapidly (chi 2((C-T/others)) = 8.429, P = 0.004), and was also correlated with hypertension (chi 2((C-T/others)) = 6.459, P = 0.012), severe proteinuria (>= 2 g/d) (chi 2((C-T/others)) = 6.332, P = 0.013), and Lee's class IV and V histological changes (chi 2((C-T/others)) = 9.640, P = 0.008).Conclusion. In this Chinese population, the 2093C-2180T haplotype at the 3'UTR of MEGSIN gene is associated with more severe forms of IgAN, and more rapid disease progression. This provides further evidence for the involvement of genetic variations of MEGSIN in the pathogenesis of IgAN. ER - TY - JFULL T1 - Training junior operative residents in laparoscopic suturing skills is feasible and efficacious. A1 - Aggarwal, R A1 - Hance, J A1 - Undre, S A1 - Ratnasothy, J A1 - Moorthy, K A1 - Chang, A A1 - Darzi, A J1 - Surgery Y1 - 2006/06// VL - 139 SN - 0039-6060 SP - 729 EP - 734 N2 - BACKGROUND: Laparoscopic suturing has been regarded as an advanced operative task, and courses to develop this skill are aimed at senior trainees and consultants. This study evaluates the role of laparoscopic suturing courses in the modern operative training curriculum. METHODS: The performance of 9 senior operative trainees (course A) was compared to that of 14 junior operative trainees (course B) at identical, 2-day laparoscopic suturing courses. Pre- and post-course assessments measured time taken, dexterity, and quality for the placement of 1 intracorporeal suture on synthetic bowel. Post-course data was compared to the performance of a group of 6 experts. RESULTS: The median number of laparoscopic procedures carried out unassisted was 130 for surgeons on course A, and 0 for those on course B. At the pre-course assessment, senior trainees (course A) were significantly faster, more dexterous, and had higher checklist scores then those on course B. Both groups had improved significantly by the end of each the course. Post-course comparison between the 2 groups showed equivalent path length and checklist scores, although group A remained faster (P = .003) and made fewer movements (P = .033). Senior trainees had similar performance data to the group of expert surgeons, although this was not the case for junior trainees. CONCLUSIONS: Endoscopic suturing is a task that can be learned by operative trainees during short skills courses, regardless of baseline laparoscopic experience. Skills training in laparoscopic suturing should thus not be reserved only for those contemplating advanced laparoscopic operation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16782426&query_hl=1 ER - TY - JFULL T1 - BCR-ABL activity and its response to drugs can be determined in CD34(+) CML stem cells by CrkL phosphorylation status using flow cytometry A1 - Hamilton, A A1 - Elrick, L A1 - Myssina, S A1 - Copland, M A1 - Jorgensen, H A1 - Melo, JV A1 - Holyoake, T J1 - LEUKEMIA Y1 - 2006/06// VL - 20 SN - 0887-6924 SP - 1035 EP - 1039 N2 - In chronic myeloid leukaemia, CD34(+) stem/progenitor cells appear resistant to imatinib mesylate (IM) in vitro and in vivo. To investigate the underlying mechanism(s) of IM resistance, it is essential to quantify Bcr-AbI kinase status at the stem cell level. We developed a flow cytometry method to measure CrkL phosphorylation(P-CrkL) in samples with < 10(4) cells. The method was first validated in wild-type (K562) and mutant (BAF3) BCR-ABL(+) as well as BCR-ABL(-) (HL60) cell lines. In response to increasing IM concentration, there was a linear reduction in P-CrkL, which was Bcr-AbI specific and correlated with known resistance. The results were comparable to those from Western blotting. The method also proved to be reproducible with small samples of normal and Ph+ CD34(+) cells and was able to discriminate between Ph-, sensitive and resistant Ph+ cells. This assay should now enable investigators to unravel the mechanism(s) of IM resistance in stem cells. ER - TY - JFULL T1 - Laparoscopic vs open subtotal colectomy for benign and malignant disease. A1 - Tilney, HS A1 - Lovegrove, RE A1 - Purkayastha, S A1 - Heriot, AG A1 - Darzi, AW A1 - Tekkis, PP J1 - Colorectal Dis Y1 - 2006/06// VL - 8 SN - 1462-8910 SP - 441 EP - 450 N2 - AIM: The present meta-analysis aims to compare short-term and long-term outcomes in patients undergoing laparoscopic or open subtotal colectomy for benign and malignant disease. METHODS: A literature search of Medline, Ovid, Embase and Cochrane databases was performed to identify studies published between 1992 and 2005, comparing laparoscopic (LSC) and open (OSC) subtotal colectomy. A random effect meta-analytical technique was used and sensitivity analysis performed on studies published since the beginning of 2000, higher quality papers, those reporting on more than 40 patients, and those studies reporting on adult cases or acute colitis. RESULTS: A total of eight studies satisfied the criteria for inclusion. These included outcomes on 336 patients, 143 (42.6%) of whom had undergone laparoscopic resection, with an overall conversion rate to open surgery of 5% (range 0-11.8%). Operative time was significantly longer in the laparoscopic group by 86.2 min (P < 0.001) and throughout subgroup analysis, although it was only in patients with acute colitis that this finding was without significant heterogeneity. Operative blood loss was less in the laparoscopic group by 57.5 millilitres in high quality and studies published since 2000, and 65.3 millilitres in those reporting on more than 40 patients. There was no significant difference in early or long-term complications between the groups. A statistically significant reduction in length of postoperative stay was observed in the laparoscopic groups by 2.9 days (P < 0.001). CONCLUSION: Laparoscopic subtotal colectomy was associated with longer operating times but a reduced length of stay compared to open surgery. Although short-term outcomes were equivalent in both groups, the suggested benefits in terms of reduced long-term obstructive complications were not supported by this meta-analysis. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16684090&query_hl=1 ER - TY - JFULL T1 - Pregnancy after assisted conception following stem cell transplant in women with leukaemia A1 - Reddy, N A1 - Salooja, N A1 - Duffy, S A1 - Turner, C A1 - Apperley, JF A1 - Margara, R J1 - HUM REPROD Y1 - 2006/06// VL - 21 SN - 0268-1161 SP - I131 EP - I131 ER - TY - JFULL T1 - SRC kinase and voltage-gated sodium channel signalling: effects on human breast cancer cell migration A1 - Onganer, PU A1 - Djamgoz, M J1 - FEBS J Y1 - 2006/06// VL - 273 SN - 1742-464X SP - 106 EP - 106 ER - TY - JFULL T1 - Mechanical properties of the human abdominal wall measured in vivo during insufflation for laparoscopic surgery. A1 - Song, C A1 - Alijani, A A1 - Frank, T A1 - Hanna, GB A1 - Cuschieri, A J1 - Surg Endosc Y1 - 2006/06// VL - 20 SN - 1432-2218 SP - 987 EP - 990 N2 - BACKGROUND: Carbon dioxide insufflation of the peritoneal cavity for laparoscopic surgery offers a unique opportunity to measure some mechanical properties of the human abdominal wall that hitherto have been difficult to obtain. METHODS: The movement and change of the abdominal wall during insufflation to a pressure of 12 mmHg was studied in 18 patients undergoing laparoscopic surgery using a remote motion analysis system that does not compromise the sterility of the operative filed. These data together with the known abdominal wall thickness of each patient (measured by preoperative ultrasound scanning) enabled estimates of mechanical stiffness. RESULTS: The findings showed that the abdominal wall changes from a cylinder to a dome during inflation, and that its area is increased by 15%. A volume, averaging 1.27 x 10(-3)m(3), results from expansion, reshaping of the abdominal wall, and displacement of the diaphragm. The abdominal wall is stiffer in the transverse plane than in the sagittal plane (Young's modulus, 42.5 +/- 9.0 kPa vs 22.5 +/- 2.6 kPa; p = 0.03; paired t-test). CONCLUSIONS: Measurements of mechanical properties of the abdominal wall in patients undergoing laparoscopic surgery were obtained using a remote motion analysis system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16738998&query_hl=1 ER - TY - JFULL T1 - Carbogen and nicotinamide increase blood flow and 5-fluorouracil delivery but not 5-fluorouracil retention in colorectal cancer metastases in patients. A1 - Gupta, N A1 - Saleem, A A1 - Kötz, B A1 - Osman, S A1 - Aboagye, EO A1 - Phillips, R A1 - Vernon, C A1 - Wasan, H A1 - Jones, T A1 - Hoskin, PJ A1 - Price, PM J1 - Clin Cancer Res Y1 - 2006/05/15/ VL - 12 SN - 1078-0432 SP - 3115 EP - 3123 N2 - PURPOSE: To examine whether carbogen and nicotinamide increases 5-fluorouracil (5-FU) delivery to colorectal cancer metastases. EXPERIMENTAL DESIGN: Six patients were scanned using positron emission tomography. Two scans were done to coincide with the start of separate chemotherapy cycles. At the second positron emission tomography session, 60 mg/kg nicotinamide was given orally 2 to 3 hours before 10-minute carbogen inhalation. In the middle of carbogen treatment, [15O]H2O (to measure regional tissue perfusion) and then [18F]5-FU (to measure 5-FU tissue pharmacokinetics) were administered. RESULTS: Regions of interest were drawn in 12 liver metastases, 6 spleens, 6 livers, and 12 kidneys. Nicotinamide and carbogen administration increased mean blood pO2 from 93 mm Hg (95% confidence interval, 79-198) to 278 mm Hg (95% confidence interval, 241-316; P = 0.031). Regional perfusion (mL(blood)/min/mL(tissue)) increased in metastases (mean change = 52%, range -32% to +261%, P = 0.024), but decreased in kidney (mean change = -42%, range -82% to -11%, P = 0.0005) and liver (mean change = -34%, range -43% to -26%, P = 0.031). 5-FU uptake at 3.75 minutes (m(2)/mL) increased in tumor (mean change = 40%, range -39% to +196%, P = 0.06) and decreased in kidney (mean change = -25%, range -71% to 12%, P = 0.043). 5-FU delivery measured as K1 increased in tumor (mean change = 74%, range -23% to +293%, P = 0.0039). No differences were seen in [18F]5-FU tumor exposure (net area under curve) and retention. CONCLUSION: Nicotinamide and carbogen administration can increase 5-FU delivery to colorectal cancer liver metastases. Despite an increase in perfusion and 5-FU delivery, the effects were not directly related and did not increase 5-FU retention or tissue exposure. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16707610&query_hl=1 ER - TY - JFULL T1 - Serial measurement of BCR-ABL transcripts in the peripheral blood after allogeneic stem cell transplantation for chronic myeloid leukemia: an attempt to define patients who may not require further therapy. A1 - Kaeda, J A1 - O'Shea, D A1 - Szydlo, RM A1 - Olavarria, E A1 - Dazzi, F A1 - Marin, D A1 - Saunders, S A1 - Khorashad, JS A1 - Cross, NC A1 - Goldman, JM A1 - Apperley, JF J1 - Blood Y1 - 2006/05/15/ VL - 107 SN - 0006-4971 SP - 4171 EP - 4176 N2 - We identified 243 patients with Philadelphia (Ph) chromosome-positive chronic myeloid leukemia (CML) who had BCR-ABL transcripts monitored by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) after allogeneic stem cell transplantation for a median of 84.3 months. Individual patients were regarded as having achieved molecular relapse (MR) if the BCR-ABL/ABL ratio exceeded 0.02% on 3 occasions or reached 0.05% on 2 occasions. Patients were allocated to 1 of 4 categories: (1) 36 patients were "persistently negative" or had a single low-level positive result; (2) 51 patients, "fluctuating positive, low level," had more than 1 positive result but never more than 2 consecutive positive results; (3) 27 patients, "persistently positive, low level," had persisting low levels of BCR-ABL transcripts but never more than 3 consecutive positive results; and (4) 129 patients relapsed. In 107 of these, relapse was based initially only on molecular criteria; in 72 (67.3%) patients the leukemia progressed to cytogenetic or hematologic relapse either prior to or during treatment with donor lymphocyte infusions. We conclude that the pattern of BCR-ABL transcript levels after allograft is variable; only a minority of patients with fluctuating or persistent low levels of BCR-ABL transcripts satisfied our definitions of MR, whereas the majority of patients who did so were likely to progress further. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16449534&query_hl=1 ER - TY - JFULL T1 - Mechanical properties of the human abdominal wall measured in vivo during insufflation for laparoscopic surgery. A1 - Song, C A1 - Alijani, A A1 - Frank, T A1 - Hanna, GB A1 - Cuschieri, A J1 - Surg Endosc Y1 - 2006/05/12/ SN - 1432-2218 N2 - BACKGROUND: Carbon dioxide insufflation of the peritoneal cavity for laparoscopic surgery offers a unique opportunity to measure some mechanical properties of the human abdominal wall that hitherto have been difficult to obtain. METHODS: The movement and change of the abdominal wall during insufflation to a pressure of 12 mmHg was studied in 18 patients undergoing laparoscopic surgery using a remote motion analysis system that does not compromise the sterility of the operative filed. These data together with the known abdominal wall thickness of each patient (measured by preoperative ultrasound scanning) enabled estimates of mechanical stiffness. RESULTS: The findings showed that the abdominal wall changes from a cylinder to a dome during inflation, and that its area is increased by 15%. A volume, averaging 1.27 x 10(-3)m(3), results from expansion, reshaping of the abdominal wall, and displacement of the diaphragm. The abdominal wall is stiffer in the transverse plane than in the sagittal plane (Young's modulus, 42.5 +/- 9.0 kPa vs 22.5 +/- 2.6 kPa; p = 0.03; paired t-test). CONCLUSIONS: Measurements of mechanical properties of the abdominal wall in patients undergoing laparoscopic surgery were obtained using a remote motion analysis system. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16699888&query_hl=1 ER - TY - JFULL T1 - On a new vision for academia. A1 - Darzi, A J1 - Health Serv J Y1 - 2006/05/11/ VL - 116 SN - 0952-2271 SP - 33 EP - 33 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16749404&query_hl=1 ER - TY - JFULL T1 - Minimally invasive pharmacokinetic and pharmacodynamic technologies in hypothesis-testing clinical trials of innovative therapies. A1 - Workman, P A1 - Aboagye, EO A1 - Chung, YL A1 - Griffiths, JR A1 - Hart, R A1 - Leach, MO A1 - Maxwell, RJ A1 - McSheehy, PM A1 - Price, PM A1 - Zweit, J A1 - Cancer Research UK Pharmacodynamic/Pharmacokinetic Technologies Advisory Committee J1 - J Natl Cancer Inst Y1 - 2006/05/03/ VL - 98 SN - 1460-2105 SP - 580 EP - 598 N2 - Clinical trials of new cancer drugs should ideally include measurements of parameters such as molecular target expression, pharmacokinetic (PK) behavior, and pharmacodynamic (PD) endpoints that can be linked to measures of clinical effect. Appropriate PK/PD biomarkers facilitate proof-of-concept demonstrations for target modulation; enhance the rational selection of an optimal drug dose and schedule; aid decision-making, such as whether to continue or close a drug development project; and may explain or predict clinical outcomes. In addition, measurement of PK/PD biomarkers can minimize uncertainty associated with predicting drug safety and efficacy, reduce the high levels of drug attrition during development, accelerate drug approval, and decrease the overall costs of drug development. However, there are many challenges in the development and implementation of biomarkers that probably explain their disappointingly low implementation in phase I trials. The Pharmacodynamic/Pharmacokinetic Technologies Advisory committee of Cancer Research UK has found that submissions for phase I trials of new cancer drugs in the United Kingdom often lack detailed information about PK and/or PD endpoints, which leads to suboptimal information being obtained in those trials or to delays in starting the trials while PK/PD methods are developed and validated. Minimally invasive PK/PD technologies have logistic and ethical advantages over more invasive technologies. Here we review these technologies, emphasizing magnetic resonance spectroscopy and positron emission tomography, which provide detailed functional and metabolic information. Assays that measure effects of drugs on important biologic pathways and processes are likely to be more cost-effective than those that measure specific molecular targets. Development, validation, and implementation of minimally invasive PK/PD methods are encouraged. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16670384&query_hl=1 ER - TY - JFULL T1 - Gastrointestinal: gastric wall hematoma. A1 - Ng, SC A1 - Shariff, M A1 - Datta, D A1 - Hanna, G A1 - Holdstock, G J1 - J Gastroenterol Hepatol Y1 - 2006/05// VL - 21 SN - 0815-9319 SP - 915 EP - 915 L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16704546&query_hl=1 ER - TY - JFULL T1 - Topical issues in unrelated donor haematopoietic stem cell transplants: a report from a workshop convened by the Anthony Nolan Trust in London - 2005. A1 - Duarte, RF A1 - Pamphilon, D A1 - Cornish, J A1 - Shaw, BE A1 - Samson, D A1 - Craddock, C A1 - Marks, D A1 - Mufti, GJ A1 - Powles, RL A1 - Apperley, JF A1 - Madrigal, JA A1 - Goldman, JM J1 - Bone Marrow Transplant Y1 - 2006/05// VL - 37 SN - 0268-3369 SP - 901 EP - 908 N2 - Over more than three decades, The Anthony Nolan Trust (ANT) has provided an unrelated donor (UD) for over 4000 children and adults lacking a suitable family member donor, and has remained at the forefront of developments in haematopoietic stem cell transplantation (HSCT) and bone marrow register management. These three decades have seen major changes in clinical practice of UD-HSCT, including new indications, increased use of alternative haematopoietic cell sources, significant improvement of the outcome as a result of better support care, less-toxic conditioning regimens, and better donor selection, and expansion to older patients with higher comorbidities. In order to foster our goal of improving UD-HSCT availability and outcome in a progressively more complex clinical scenario, a new initiative from ANT was launched in 2005 to convene an experts workshop to address the topical issues in this field. Four consecutive panels addressed factors influencing donor selection and transplant outcome, the use of cord blood, regulatory and accreditation issues, and future developments in this field. This report summarizes the discussions held in this workshop, which will likely develop into a periodic event where transplant clinicians, scientists and registry members will meet to share their experience and vision in the field of UD-HSCT. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16670700&query_hl=1 ER - TY - JFULL T1 - Epstein-Barr virus origin of lytic replication mediates association of replicating episomes with promyelocytic leukaemia protein nuclear bodies and replication compartments. A1 - Amon, W A1 - White, RE A1 - Farrell, PJ J1 - J Gen Virol Y1 - 2006/05// VL - 87 SN - 0022-1317 SP - 1133 EP - 1137 N2 - Epstein-Barr virus (EBV) establishes a latent persistence from which it can be reactivated to undergo lytic replication. Late lytic-cycle gene expression is linked to lytic DNA replication, as it is sensitive to the same inhibitors that block lytic replication, and it has recently been shown that the viral origin of lytic replication (ori lyt) is required in cis for late-gene expression. During the lytic cycle, the viral genome forms replication compartments, which are usually adjacent to promyelocytic leukaemia protein (PML) nuclear bodies. A tetracycline repressor DNA-binding domain-enhanced green fluorescent protein fusion was used to visualize replicating plasmids carrying a tetracycline operator sequence array. ori lyt mediated the production of plasmid replication compartments that were associated with PML nuclear bodies. Plasmids carrying ori lyt and EBV itself were visualized in the same cells and replicated in similar regions of the nucleus, further supporting the validity of the plasmids for studying late-gene regulation. L1 - http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=16603513&query_hl=1 ER - TY - JFULL T1 - Functional categories of TP53 mutation in colorectal cancer: results of an International Collaborative Study. A1 - Iacopetta, B A1 - Russo, A A1 - Bazan, V A1 - Dardanoni, G A1 - Gebbia, N A1 - Soussi, T A1 - Kerr, D A1 - Elsaleh, H A1 - Soong, R A1 - Kandioler, D A1 - Janschek, E A1 - Kappel, S A1 - Lung, M A1 - Leung, CS A1 - Ko, JM A1 - Yuen, S A1 - Ho, J A1 - Leung, SY A1 - Crapez, E A1 - Duffour, J A1 - Ychou, M A1 - Leahy, DT A1 - O'Donoghue, DP A1 - Agnese, V A1 - Cascio, S A1 - Di Fede, G A1 - Chieco-Bianchi, L A1 - Bertorelle, R A1 - Belluco, C A1 - Giaretti, W A1 - Castagnola, P A1 - Ricevuto, E A1 - Ficorella, C A1 - Bosari, S A1 - Arizzi, CD A1 - Miyaki, M A1 - Onda, M A1 - Kampman, E A1 - Diergaarde, B A1 - Royds, J A1 - Lothe, RA A1 - Diep, CB A1 - Meling, GI A1 - Ostrowski, J A1 - Trzeciak, L A1 - Guzinska-Ustymowicz, K A1 - Zalewski, B A1 - Capellá, GM A1 - Moreno, V A1 - Peinado, MA A1 - Lönnroth, C A1 - Lundholm, K A1 - Sun, XF A1 - Jansson, A A1 - Bouzourene, H A1 - Hsieh, LL A1 - Tang, R A1 - Smith, DR A1 - Allen-Mersh, TG A1 - Khan, ZA A1 - Shorthouse, AJ A1 - Silverman, ML A1 - Kato, S A1 - Ishioka, C A1 - TP53-CRC Collaborative Group J1 - Ann Oncol Y1 - 2006/05// VL - 17 SN - 0923-7534 SP - 842 EP - 847 N2 - BACKGROUND: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found consid