Table Of Content

Contributors Numbers in parentheses indicate the pages on which the authors’ Sonia Y. Archer (557) contributions begin. Department of Surgery,Beth Israel Deaconess Medical William M. Abbott (1011) Center,Boston,Massachusetts 02215 Division of Vascular Surgery,Massachusetts General Arlene S. Ash (81) Hospital,Boston,Massachusetts 02114 Boston University School of Medicine and School of Steve F. Abcouwer (217) Public Health,Boston,Massachusetts 02218 Department of Biochemistry and Molecular Biology, Stanley W. Ashley (3) University of New Mexico,School of Medicine, Department of Surgery,Brigham and Women’s Hospital, Albuquerque,New Mexico 87131 Boston,Massachusetts 02115 N. Scott Adzick (1065) Anthony Atala (1107) Division of Pediatric General,Thoracic and Fetal Surgery, Laboratory for Tissue Engineering and Cellular The Children’s Hospital of Philadelphia,Philadelphia, Therapeutics,Department of Urology,Children’s Pennsylvania 19104 Hospital and Harvard Medical School,Boston, Samuel S. Ahn (1001) Massachusetts 02115 Division of Vascular Surgery,UCLA School of Medicine, Alfred Ayala (317) Los Angeles,California 90095 Center for Surgical Research and Department of Surgery, David C. Allison (193) Brown University School of Medicine and Rhode Island Departments of Surgery,Medicine,and Physiology and Hospital,Providence,Rhode Island 02903 Molecular Medicine,Medical College of Ohio,Toledo, Matthew D. Bacchetta (137) Ohio 43614 Department of Surgery,Anne and Max A. Cohen Surgical J. B. Ames (757) Intensive Care Unit,New York-Presbyterian Hospital–New Surgical Research Laboratory,Harvard Medical School and York Weill Cornell Center,Weill Medical College of Department of Surgery,Brigham and Women’s Hospital, Cornell University,New York,New York 10021 Boston,Massachusetts 02115 Charles M. Balch (1237) Keith D. Amos (497) Departments of Surgery and Oncology,Johns Hopkins Department of Surgery,Washington University School of Medical Center,Baltimore,Maryland 21231 Medicine,St. Louis,Missouri 63110 Anirban Banerjee (285) Robert W. Anderson (1279) Department of Surgery,University of Colorado Health Department of Surgery,Duke University Medical Center, Sciences Center,Denver,Colorado 80262 Durham,North Carolina 27710 Adrian Barbul (1249) Jeffrey M. Arbeit (175) Departments of Surgery,Sinai Hospital of Baltimore,and Department of Surgery,UCSF/MT Zion Cancer Center, the Johns Hopkins Medical Institutions,Baltimore, University of California,San Francisco,California 94115 Maryland 21215 xix xx Contributors Philip S. Barie (137) Cynthia S. Chin (415) Department of Surgery,Anne and Max A. Cohen Surgical Division of Surgical Oncology,Department of Surgery, Intensive Care Unit,New York-Presbyterian Hospital–New Medical College of Virginia at Virginia Commonwealth York Weill Cornell Center,Weill Medical College of University,Richmond,Virginia 23298 Cornell University,New York,New York 10021 Gyu S. Chin (1081) Clyde F. Barker (1261) Department of Surgery,New York University Medical Department of Surgery,University of Pennsylvania, Center,New York,New York 10016 Philadelphia,Pennsylvania 19104 Alexander W. Clowes (971) Jeffrey S. Barkun (155) Department of Surgery,University of Washington,Seattle, McGill University Health Centre,Montreal,Quebec, Washington 98195 Canada H3A 1A1 Lisa Colletti (1349) Robert E. Barrow (367) Department of Surgery,University of Michigan Medical The University of Texas Medical Branch and Shriners’ School,Ann Arbor,Michigan 48109 Burns Hospital,Galveston,Texas 77555 Joy L. Collins (949) Harry D. Bear (415) Department of Surgery,University of Pittsburgh, Division of Surgical Oncology,Department of Surgery, Pittsburgh,Pennsylvania 15261 Medical College of Virginia at Virginia Commonwealth Suzy Conway (1319) University,Richmond,Virginia 23298 Francis A. Countway Library of Medicine,Harvard Russell S. Berman (435) Medical School,Boston,Massachusetts 02115 Departments of Surgical Oncology and Cancer Biology, Clay Cothren (1343) The University of Texas M. D. Anderson Cancer Center, Department of Surgery,University of Colorado,Denver, Houston,Texas 77030 Colorado 80262 Walter L. Biffl(331) Christopher A. Crisera (613) Department of Surgery,Denver Health Medical Center, Department of Surgery,Children’s Mercy Hospital,Kansas University of Colorado Health Sciences Center,Denver, City,Missouri 64108 Colorado 80204 Joseph J. Cullen (507) Timothy R. Billiar (949) University of Iowa Hospitals and Clinics,Iowa City,Iowa Department of Surgery,University of Pittsburgh, 52242 Pittsburgh,Pennsylvania 15261 P. William Curreri (1241) John D. Birkmeyer (101, 127) Stratagem,Inc.,Daphne,Alabama 36526 VA Outcomes Group,VA Medical Center,White River Junction,Vermont 05009 James C. Cusack, Jr. (457) Timothy G. Buchman (307, 1309) Division of Surgical Oncology,Massachusetts General Department of Surgery,Washington University School of Hospital,Boston,Massachusetts 02114 Medicine,St. Louis,Missouri 63110 Roger E. De Filippo (1107) Eileen M. Bulger (893) Laboratory for Tissue Engineering and Cellular Department of Surgery,Harborview Medical Center and the Therapeutics,Department of Urology,Children’s University of Washington,Seattle,Washington 98104 Hospital and Harvard Medical School,Boston, Massachusetts 02115 Charles B. Cairns (285) Department of Surgery,University of Colorado Health Edwin A. Deitch (599) Sciences Center,Denver,Colorado 80262 Department of Surgery,UMD–New Jersey Medical School, Newark,New Jersey 07003 Casey Calkins (1343) Department of Surgery,University of Colorado,Denver, E. Patchen Dellinger (909) Colorado 80262 Department of Surgery,University of Washington Medical William G. Cance (253) Center,University of Washington School of Medicine, Department of Surgery and UNC Lineberger Seattle,Washington 98195 Comprehensive Cancer Center,University of North Achilles A. Demetriou (623, 709) Carolina at Chapel Hill,Chapel Hill,North Carolina 27599 Department of Surgery,Cedars-Sinai Medical Center,Los Irshad H. Chaudry (317, 357) Angeles,California 90048 Center for Surgical Research,Department of Surgery, Jeffrey A. Drebin (445) Brown University School of Medicine and Rhode Island Department of Surgery,Washington University School of Hospital,Providence,Rhode Island 02903 Medicine,St. Louis,Missouri 63110 Contributors xxi Soumitra R. Eachempati (137) Raquel M. Forsythe (599) Department of Surgery,Anne and Max A. Cohen Department of Surgery,UMD—New Jersey Medical Surgical Intensive Care Unit,New York-Presbyterian School,Newark,New Jersey 07003 Hospital–New York Weill Cornell Center,Weill Bradley D. Freeman (307) Medical College of Cornell University,New York,New Department of Surgery,Washington University School of York 10021 Medicine,St. Louis,Missouri 63110 Timothy J. Eberlein (497) Fabia Gamboni-Robertson (285) Department of Surgery,Washington University School of Department of Surgery,University of Colorado Health Medicine,St. Louis,Missouri 63110 Sciences Center,Denver,Colorado 80262 R. Neal Garrison (1027) David T. Efron (1249) Department of Surgery,University of Louisville,and Departments of Surgery,Sinai Hospital of Baltimore,and Veterans Affairs Medical Center,Louisville,Kentucky the Johns Hopkins Medical Institutions,Baltimore, 40292 Maryland 21215 James Garvey (1405) Nancy R. Ehrlich (1217) Schroder Ventures International Life Science Fund,Boston, The Recanati/Miller Transplantation Institute,New York, Massachusetts 02114 New York 10029 M. Gasser (757) Theresa L. Eisenbraun (271) Surgical Research Laboratory,Harvard Medical School and University of Wisconsin Comprehensive Cancer Center, Department of Surgery,Brigham and Women’s Hospital, Madison,Wisconsin 53792 Boston,Massachusetts 02115; and Department of Surgery, Lee M. Ellis (401, 435) University of Wuerzburg,97080 Wuerzburg,Germany Departments of Surgical Oncology and Cancer Biology, Jonathan Gertler (1405) The University of Texas M. D. Anderson Cancer Center, Division of Vascular Surgery,Massachusetts General Houston,Texas 77030 Hospital; Harvard Medical School; and Schroder Ventures Darwin Eton (1001) International Life Science Fund,Boston,Massachusetts Division of Vascular Surgery,University of Miami School 02114 of Medicine,Miami,Florida 33136 Anna Getselman (1319) B. Mark Evers (23) Francis A. Countway Library of Medicine,Harvard Department of Surgery,The University of Texas Medical Medical School,Boston,Massachusetts 02115 Branch,Galveston,Texas 77555 George K. Gittes (613) Liane Feldman (155) Department of Surgery,Children’s Mercy Hospital,Kansas McGill University Health Centre,Montreal,Quebec, City,Missouri 64108 Canada H3A 1A1 Matthew I. Goldblatt (721) Department of Surgery,Medical College of Wisconsin, Mitchell P. Fink (875) Milwaukee,Wisconsin 53226 Departments of Anesthesiology,Critical Care Medicine, Paul J. Gorman (1299) and Surgery,University of Pittsburgh Medical School, Department of Surgery,Stanford University,Stanford, Pittsburgh,Pennsylvania 15261 California 94043 Joseph J. Fins (137) Douglas W. Green (445) Department of Medicine,Anne and Max A. Cohen Surgical Department of Surgery,Washington University School of Intensive Care Unit,New York-Presbyterian Hospital–New Medicine,St. Louis,Missouri 63110 York Weill Cornell Center,Weill Medical College of David G. Greenhalgh (379) Cornell University,New York,New York 10021 Department of Surgery,Shriners Hospitals for Children, David R. Fischer (825) Northern California,and University of California,Davis, Department of Surgery,University of Cincinnati College of Sacramento,California 95817 Medicine,Cincinnati,Ohio 45267 Jurgen Hannig (297) Josef E. Fischer (63) Pritzker School of Medicine,The University of Chicago, Department of Surgery,University of Cincinnati, Chicago,Illinois 60637 Cincinnati,Ohio 45267 Alden H. Harken (1343) Alan W. Flake (207) Department of Surgery,University of Colorado,Denver, Department of Surgery and the Center for Fetal Diagnosis Colorado 80262 and Therapy,Children’s Hospital of Philadelphia, Per-Olof Hasselgren (825) University of Pennsylvania,Philadelphia,Pennsylvania Department of Surgery,University of Cincinnati College of 19104 Medicine,Cincinnati,Ohio 45267 xxii Contributors Julie Heimbach (1343) Jerald J. Killion (435) Department of Surgery,University of Colorado,Denver, Department of Cancer Biology,The University of Texas Colorado 80262 M. D. Anderson Cancer Center,Houston,Texas 77030 Peter K. Henke (989) Denise E. Kirschner (1309) Jobst Vascular Research Laboratory,Section of Vascular Departments of Microbiology and Immunology,The Surgery,Department of Surgery,University of Michigan University of Michigan,Ann Arbor,Michigan 48109 Medical Center,Ann Arbor,Michigan 48109 Thomas M. Krummel (1299) David N. Herndon (367) Department of Surgery,Stanford University,Stanford, The University of Texas Medical Branch and Shriners’ California 94043 Burns Hospital,Galveston,Texas 77555 Alexander Sasha Krupnick (1065) Graham L. Hill (797) Division of Pediatric General,Thoracic and Fetal Surgery, University Department of Surgery,Auckland Hospital, The Children’s Hospital of Philadelphia,Philadelphia, Auckland 1001,New Zealand Pennsylvania 19104 I. L. Laskowski (757) Richard A. Hodin (557) Surgical Research Laboratory,Harvard Medical School and Department of Surgery,Beth Israel Deaconess Medical Department of Surgery,Brigham and Women’s Hospital, Center,Boston,Massachusetts 02215 Boston,Massachusetts 02115; and Department of General Susan D. Horn (1393) and Transplant Surgery,Warsaw Medical University, Institute for Clinical Outcomes Research,Salt Lake City, 02-006 Warsaw,Poland Utah 84109 Robert D. Lasley (1119) Lisa I. Iezzoni (81) Department of Surgery,University of Kentucky College of Harvard Medical School and Division of General Medicine Medicine,Lexington,Kentucky 40536 and Primary Care,Department of Medicine,Beth Israel Stephen R. Lauterbach (1011) Deaconess Medical Center,Boston,Massachusetts 02215 Division of Vascular Surgery,Massachusetts General Daniel Inderbitzen (709) Hospital,Boston,Massachusetts 02114 Department of Surgery,Cedars-Sinai Medical Center,Los Jeffrey H. Lawson (1279) Angeles,California 90048 Department of Surgery,Duke University Medical Center, Svetlana Ivanova (1095) Durham,North Carolina 27710 Laboratory of Biomedical Science,North Shore University Raphael C. Lee (297) Hospital,Manhasset,New York 11030 Pritzker School of Medicine,The University of Chicago, Danny O. Jacobs (813) Chicago,Illinois 60637; and Burn Center,St. Mary’s Laboratories of Surgical Metabolism,Department of Medical Center,Hobart,Indiana 46342 Surgery and Nutrition,Brigham and Women’s Hospital, David Lee-Parritz (47) Harvard Medical School,Boston,Massachusetts 02115; Center for Animal Resources and Comparative Medicine, and Creighton University Surgical Laboratories for Harvard Medical School,Boston,Massachusetts 02115 Biomedical Investigation,Omaha,Nebraska 68131 David C. Linehan (497) Daniel B. Jones (573) Department of Surgery,Washington University School of Southwestern Center for Minimally Invasive Surgery and Medicine,St. Louis,Missouri 63110 Department of Surgery,The University of Texas Jean Y. Liu (101) Southwestern Medical Center,Dallas,Texas 75235 VA Outcomes Group,VA Medical Center,White River Mary Jane Kagarise (29) Junction,Vermont 05009 Department of Surgery,The University of North Carolina Michael T. Longaker (1081) School of Medicine,The University of North Carolina at Department of Surgery,Stanford University School of Chapel Hill,Chapel Hill,North Carolina 27599 Medicine,Stanford,California 94305 Gordon L. Kauffman, Jr. (71, 1201) Charles Lucey (1383) Department of Surgery,The Milton S. Hershey Medical 21stCentury Health Concepts,Houston,Texas 77061; and Center,Penn State College of Medicine,Hershey, Dartmouth College,Hanover,New Hampshire 03755 Pennsylvania 17033 Nancy R. Macdonald (1011) Richard D. Kenagy (971) Division of Vascular Surgery,Massachusetts General Department of Surgery,University of Washington,Seattle, Hospital,Boston,Massachusetts 02114 Washington 98195 Ronald V. Maier (893) Gregory D. Kennedy (271) Department of Surgery,Harborview Medical Center University of Wisconsin Comprehensive Cancer Center, and the University of Washington,Seattle,Washington Madison,Wisconsin 53792 98104 Contributors xxiii Thomas S. Maldonado (613) Michael W. Mulholland (9) Department of Surgery,Children’s Mercy Hospital,Kansas University of Michigan Medical Center,Ann Arbor, City,Missouri 64108 Michigan 48109 John C. Marshall (921) Joseph Murphy (583) Department of Surgery,University of Toronto,and Department of Surgery,University of Texas Southwestern University Health Network,Toronto,Ontario,Canada Medical Center and the Veterans Affairs North Texas M5G 2C4 Health Care System,Dallas,Texas 75216 Takeaki Matsuda (813) Rene J. P. Musters (285) Laboratories of Surgical Metabolism,Department of Department of Surgery,University of Colorado Health Surgery and Nutrition,Brigham and Women’s Hospital, Sciences Center,Denver,Colorado 80262 Harvard Medical School,Boston,Massachusetts 02115; Thomas A. Mustoe (857) and Creighton University Surgical Laboratories for Division of Plastic and Reconstructive Surgery, Biomedical Investigation,Omaha,Nebraska 68131 Northwestern University Medical School,Chicago,Illinois Jeffrey B. Matthews (533) 60611 Department of Surgery,Beth Israel Deaconess Medical Daniel D. Myers, Jr. (989) Center,Harvard Medical School,Boston,Massachusetts Jobst Vascular Research Laboratory,Section of Vascular 02215 Surgery,Unit for Laboratory Animal Medicine,University David T. Mauger (71, 1201) of Michigan Medical Center,Ann Arbor,Michigan 48109 Department of Health Evaluation Sciences,The Milton S. Attila Nakeeb (721) Hershey Medical Center,Penn State College of Medicine, Department of Surgery,Medical College of Wisconsin, Hershey,Pennsylvania 17033 Milwaukee,Wisconsin 53226 Lucretia W. McClure (1319) Avery B. Nathens (893) Francis A. Countway Library of Medicine,Harvard Department of Surgery,Harborview Medical Center and the Medical School,Boston,Massachusetts 02115 University of Washington,Seattle,Washington 98104 Jonathan L. Meakins (155) Andrea L. Nestor (193) McGill University Health Centre,Montreal,Quebec, Departments of Surgery,Medicine,and Physiology and Canada H3A 1A1 Molecular Medicine,Medical College of Ohio,Toledo, Andreas H. Meier (1299) Ohio 43614 Department of Surgery,Stanford University,Stanford, John E. Niederhuber (271) California 94043 University of Wisconsin Comprehensive Cancer Center, Robert M. Mentzer, Jr. (1119) Madison,Wisconsin 53792 Department of Surgery,University of Kentucky College of Keith O’Rourke (167) Medicine,Lexington,Kentucky 40536 Department of Surgery and Clinical Epidemiology Unit, Tanya K. Meyer (253) University of Ottawa,Ottawa Hospital,Ottawa,Ontario, Department of Surgery and UNC Lineberger Canada K1Y OK6 Comprehensive Cancer Center,University of North Marshall J. Orloff (637) Carolina at Chapel Hill,Chapel Hill,North Carolina 27599 Department of Surgery,School of Medicine,University of Rebecca M. Minter (933) California,San Diego,La Jolla,California 92093 Department of Surgery,University of Florida College of Mary F. Otterson (507) Medicine,Gainesville,Florida 32610 Medical College of Wisconsin,Milwaukee,Wisconsin Lyle L. Moldawer (933) 53226 Department of Surgery,University of Florida College of Medicine,Gainesville,Florida 32610 Wayne R. Patterson (13) Ernest E. Moore (331) The University of Texas Medical Branch,Galveston,Texas Department of Surgery,Denver Health Medical Center, 77555 University of Colorado Health Sciences Center,Denver, Timothy M. Pawlik (1349) Colorado 80204 Department of Surgery,University of Michigan Medical Daniel Most (1249) School,Ann Arbor,Michigan 48109 Departments of Surgery,Sinai Hospital of Baltimore,and Henry A. Pitt (721) the Johns Hopkins Medical Institutions,Baltimore, Department of Surgery,Medical College of Wisconsin, Maryland 21215 Milwaukee,Wisconsin 53226 Caren M. Mulford (1119) Lindsay D. Plank (797) Department of Surgery,University of Kentucky College of University Department of Surgery,Auckland Hospital, Medicine,Lexington,Kentucky 40536 Auckland 1001,New Zealand xxiv Contributors Timothy A. Pritts (825) Martin G. Schwacha (357) Department of Surgery,University of Cincinnati College of Center for Surgical Research,Department of Surgery, Medicine,Cincinnati,Ohio 45267 Brown University School of Medicine and Rhode Island R. Lawrence Reed II (347) Hospital,Providence,Rhode Island 02903 Department of Surgery,Loyola University Medical Center, Patrica M. Scott (271) Maywood,Illinois 60153 University of Wisconsin Comprehensive Cancer Center, Robert V. Rege (573) Madison,Wisconsin 53792 Southwestern Center for Minimally Invasive Surgery and Patricia A. Sheiner (1217) Department of Surgery,The University of Texas The Recanati/Miller Transplantation Institute,and the Southwestern Medical Center,Dallas,Texas 75235 Mount Sinai School of Medicine,New York,New York Robert S. Rhodes (1393) 10029 University of Pennsylvania School of Medicine, George F. Sheldon (29) Philadelphia,Pennsylvania 19103 Department of Surgery,The University of North Carolina Henry E. Rice (207) School of Medicine,The University of North Carolina at Division of Pediatric Surgery,Department of Surgery, Chapel Hill,Chapel Hill,North Carolina 27599 Duke University Medical Center,Durham,North Carolina Michael Shwartz (81) 27710 School of Management,Boston University,Boston, Martin Riegler (533) Massachusetts 02215 University Clinic of Surgery,Vienna General Hospital, H. Hank Simms (393) A-1090 Vienna,Austria Division of Surgical Critical Care,Rhode Island Hospital, Kyung M. Ro (1001) Providence,Rhode Island 02903 Division of Vascular Surgery,UCLA School of Medicine, Marcus K. Simpson (1383) Los Angeles,California 90095 Dartmouth College,Hanover,New Hampshire 03755 Thomas N. Robinson (285, 1343) Clay Smith (207) Department of Surgery,University of Colorado Health Center for Genetic and Cellular Therapy,Duke University Sciences Center,Denver,Colorado 80262 Medical Center,Durham,North Carolina 27710 John L. Rombeau (547) Scott D. Somers (1361) Harrison Department of Surgical Research,University of Division of Pharmacology,Physiology,and Biological Pennsylvania,Philadelphia,Pennsylvania 19104 Chemistry,The National Institute of General Medical Joseph M. Rosen (1383) Sciences,Bethesda,Maryland 20892 Plastic and Reconstructive Surgery,Dartmouth-Hitchcock Medical Center,Lebanon,New Hampshire 03756; and Wiley W. Souba (773, 1375) Department of Surgery,The Milton S. Hershey Medical Thayer School of Engineering,Dartmouth College, Center,Penn State College of Medicine,Hershey, Hanover,New Hampshire 03755 Pennsylvania 17033 Ori D. Rotstein (1337) Departments of Surgery,University Health Network,and David A. Spain (1027) University of Toronto,Toronto,Ontario,Canada M56 24C Department of Surgery,University of Louisville,and Veterans Affairs Medical Center,Louisville,Kentucky Jacek Rozga (623, 703, 709) 40292 Department of Surgery,Cedars-Sinai Medical Center,Los Angeles,California 90048 Jason A. Spector (1081) Justin T. Sambol (599) Department of Surgery,New York University Medical Department of Surgery,UMD–New Jersey Medical School, Center,New York,New York 10016 Newark,New Jersey 07003 Michael L. Steer (733) Michael G. Sarr (507) Department of Surgery,Beth Israel Deaconess Medical Division of Gastroenterologic and General Surgery,Mayo Center,Harvard Medical School,Boston,Massachusetts Clinic,Mayo Medical School,Rochester,Minnesota 55902 02215 Alexandrina Saulis (857) Bruce R. Stevens (845) Division of Plastic and Reconstructive Surgery, Department of Physiology,College of Medicine,University Northwestern University Medical School,Chicago,Illinois of Florida,Gainesville,Florida 32610 60611 Robert W. Storms (207) Mary C. Schuerman (1241) Center for Genetic and Cellular Therapy,Duke University Stratagem,Inc.,Daphne,Alabama 36526 Medical Center,Durham,North Carolina 27710 Contributors xxv Kenneth K. Tanabe (115, 457) Brad W. Warner (1047) Division of Surgical Oncology,Massachusetts General Division of Pediatric Surgery,Children’s Hospital Medical Hospital,Boston,Massachusetts 02114 Center,Cincinnati,Ohio 45229 James C. Thompson (1) Stephen M. Warren (1081) Department of Surgery,The University of Texas Medical Department of Surgery,Oregon Health Science University, Branch,Galveston,Texas 77555 Portland,Oregon 97201 James M. Watters (167) N. L. Tilney (757) Department of Surgery,Loeb Health Research Institute, Surgical Research Laboratory,Harvard Medical School and University of Ottawa,Ottawa Hospital,Ottawa,Ontario, Department of Surgery,Brigham and Women’s Hospital, Canada K1Y OK6 Boston,Massachusetts 02115 Ronald J. Weigel (233) Daniel L. Traber (367) Stanford University,School of Medicine,Stanford, The University of Texas Medical Branch and Shriners’ California 94305 Burns Hospital,Galveston,Texas 77555 Frank J. Wessels (933) Kevin J. Tracey (1095) Department of Surgery,University of Florida College of Laboratory for Tissue Engineering and Cellular Medicine,Gainesville,Florida 32610 Therapeutics,Department of Urology,Children’s Edward E. Whang (3) Hospital and Harvard Medical School,Boston, Department of Surgery,Brigham and Women’s Hospital, Massachusetts 02115 Boston,Massachusetts 02115 Richard H. Turnage (583) D. Whitley (757) Department of Surgery,University of Texas Southwestern University of Alabama,Birmingham,Alabama 35294 Medical Center and the Veterans Affairs North Texas James Willey (193) Health Care System,Dallas,Texas 75216 Departments of Surgery,Medicine,and Physiology and A. Simon Turner (1137) Molecular Medicine,Medical College of Ohio,Toledo, Department of Clinical Sciences,Colorado State Ohio 43614 University,Fort Collins,Colorado 80523 Douglas W. Wilmore (773, 1375) Thomas C. Vary (747) Department of Surgery,Brigham and Women’s Hospital, Department of Cellular and Molecular Physiology,Penn Boston,Massachusetts 02115 State University College of Medicine,Hershey, Robert R. Wolfe (789) Pennsylvania 17033 The University of Texas Medical Branch,Galveston,and Shriners Burns Hospital,Metabolism Unit,Galveston, Gus J. Vlahakes (1037) Texas 77550 Massachusetts General Hospital and Harvard Medical Shirley K. Wrobleski (989) School,Boston,Massachusetts 02114 Jobst Vascular Research Laboratory,Section of Vascular Yoram Vodovotz (949) Surgery,Department of Surgery,University of Michigan Department of Surgery,University of Pittsburgh, Medical Center,Ann Arbor,Michigan 48109 Pittsburgh,Pennsylvania 15261 George P. Yang (233) Thomas W. Wakefield (989) Stanford University,School of Medicine,Stanford, Jobst Vascular Research Laboratory,Section of Vascular California 94305 Surgery,Department of Surgery,University of Michigan Heidi Yeh (547) Medical Center; and Ann Arbor Veterans Administration Harrison Department of Surgical Research,University of Medical Center,Ann Arbor,Michigan 48109 Pennsylvania,Philadelphia,Pennsylvania 19104 Ping Wang (317, 357) Barbara A. Zehnbauer (307) Center for Surgical Research,Department of Surgery, Departments of Pediatrics and Pathology,Washington Brown University School of Medicine and Rhode Island University School of Medicine and St. Louis Childrens’ Hospital,Providence,Rhode Island 02903 Hospital,St. Louis,Missouri 63110 Glenn D. Warden (379) Moritz M. Ziegler (1287) Shriners Hospitals for Children—Cincinnati Burns Hospital, Department of Surgery,Children’s Hospital Medical and University of Cincinnati,Cincinnati,Ohio 45229 Center,Boston,Massachusetts 02115 Foreword Surgical research probably offers better opportunities to the identification and enumeration of cancer cells in bone for success than it ever has before because of the advances marrow or blood during the development of a clinical can- in other sciences and in technology. Unfortunately, there cer. seem to be forces in American medicine that discourage Clearly, the value of such a book must depend on the active participation in surgical research. Foremost among insight and experience of its editors, Dr. Wiley Souba and these factors are economic disincentives. First, medical Dr. Douglas Wilmore. Dr. Douglas Wilmore has long been schools have raised their tuitions to levels that leave the known to me,first as a medical student and later as a teacher new M.D. buried under a burden of debt. Second,when he who brought me new information from his research and col- or she finally gets into practice, managed care can be a lective experience. Dr. Wilmore took his surgical residency driving force to see more and more patients at lower and at the Hospital of the University of Pennsylvania during the lower rates of remuneration. Not only does this affect the years I was chairman of that department. As a surgical resi- practitioner, but it affects the hospital where more and dent he was superb in his approach to patients, his knowl- more patients and procedures are required to balance its edge of surgery,his research endeavors during his residency, budget. Most medical schools and hospitals with research and, most importantly, his ability to teach. Even in those departments look to those who do research not only to give days,his thoroughness in research was evident in a lengthy their time and effort but to raise money through grants that study of the adaptability of duodenal mucosa to the loss of provide heavy overhead funds in order to have the space much of the jejuno-ileum in dogs. His interest in the short and facilities to pursue their work. These pressures, some bowel syndrome stemmed at least in part out of the brilliant of which will be commented on later in this foreword, case that he and Dr. Stanley Dudrick managed at the Chil- make a volume such as this most timely and important in dren’s Hospital of Philadelphia of a female infant born with the new millennium. atresia of most of the jejuno-ileum and also the sigmoid. Upon learning of the plan to create a single-volume book This patient and the subsequent report in the Journal of the for surgical research and receiving an invitation to write a American Medical Association probably did more to bring foreword,I will admit that I cringed a bit,as the subject is so the attention of surgeons to the possibility of total parenteral vast and potentially draws on a large number of scientific nutrition than any other single article. It demonstrated so disciplines,each of which has its own distinctive and exten- clearly that not only could life be maintained, but if suffi- sive set of contributions relating to research in the field of cient nutrients were given,normal growth would occur even surgery. On second thought,however,I realized that with the in an individual who could take nothing by mouth but water. capacity of the electronic media to make a vast array of ref- It was typical of Dr. Wilmore’s subsequent career that he erence material available, such a book would be an enor- took this problem to the laboratory to see how much mous help in particular to younger students entering areas jejunum and ileum could be sacrificed if TPN were given that are relatively new to them. Thus,this volume can serve long enough for the duodenum to compensate maximally. as a screen to show people whether or not their fresh ideas He measured the weight of the duodenum per linear cen- have already been explored and to what extent, and it can timeter and the thickness of the mucosa and observed the point the way to much relevant material in disciplines far architecture of the mucosa at various stages of its compensa- removed from surgery, ranging from electrical engineering tory transformation. Thus,in dogs he established most of the xxvii xxviii Foreword criteria we now use in deciding whether a patient with a lim- work’this can be a terrifying experience for the basic scien- ited length of jejuno-ileum can compensate for the loss of tist. However,for a surgeon it may be a source of pride and much of the intestine. He went on to spend many valuable is called the ‘Stradivarius problem’”[1]. years with Dr. Basil Pruitt at the Surgical Research Center at In writing the beginning chapter of a textbook published Brooke Army Hospital in San Antonio. From there he was by the J. B. Lippincott Company in 1957,edited by J. Gar- appointed to the faculty at Harvard,where he was entrusted rott Allen, Henry N. Harkins, Carl Moyer, and myself [2], with the very productive laboratory previously headed by we emphasized the responsibility of those going into sur- Dr. Francis Moore and devoted to the study of the metabo- gery not only to learn the science and art of surgery and to lism of surgical patients. Here he has continued to make practice it as perfectly as possible, but also to enhance important contributions showing that at least one of the knowledge in the field of surgery,thus making an addition to nonessential amino acids,arginine,is really essential in the surgical science, whether this be clinical or laboratory nourishment of the surgically stressed patient. based. It is therefore most appropriate that this volume on Dr. Wiley Souba has worked in several venues,a portion surgical research draws together a large body of experience of the time with Dr. Dudrick and a portion of the time with to help new surgical students find available resources and Dr. Wilmore,and currently has assumed the chairmanship of avoid some of the pitfalls that beset those of us who attempt the Department of Surgery at Pennsylvania State University surgical research. in Hershey, formerly headed by Dr. John Waldhausen. His It was my privilege to meet on several occasions the contributions to surgical research also have been highly sig- chairman of the Department of Physiological Chemistry at nificant. Dr. Souba has devoted himself to the study of par- Harvard Medical School, Otto Folin, whose daughter later enteral nutrition and particularly to the metabolism of gluta- became my wife. He said that he thought that half of one’s mine and the effects of inflammation and tumors on success in medical research was in the selection of the glutamine metabolism. He has gone on to study the means problem. He had worked seven years at a mental institution by which amino acids gain entrance to cells and he has also in an effort to see whether new biochemical techniques studied independent amino acid transport in endotoxemic might throw light on the cause of mental illness. He rats, gaining evidence of selective stimulation of arginine employed these years to develop improved methods of uri- transport. His papers constitute many pages in the Journal of nalysis, many of which were used widely by other bio- Parenteral and Enteral Nutritionand a good number of con- chemists and clinical pathologists. However, he became tributions to the Annals of Surgery,The Surgical Forum,and convinced that the biochemistry then available was not like- many other prestigious journals. His bibliography shows ly to solve the problems of mental illness. He had the beyond a doubt that he is familiar with many laboratory opportunity of changing his work to the Department of techniques and the various aspects of clinical investigation. Physiological Chemistry at Harvard, where he worked on The senior editors of this volume speak from a background methods for most of his career. In short, he felt that one of personal success in surgical research and they have select- should select a problem that was likely to have an attainable ed a remarkable group of section editors and authors. Nearly solution. every field of surgical research is discussed in detail in this Somewhat in contrast to this, my surgical mentor, I. S. volume by individuals who have been and are successfully Ravdin, often remarked that he had a particular respect for engaged in investigative work. The volume is valuable for its the individual who had worked on a difficult problem long overview of the whole field and equally valuable to the indi- and hard and had finally solved the problem. It seems to be a vidual who has selected his field and wants to be updated on matter of judgment as to what to choose and how long to recent progress and the directions in which it seems to be pursue the search. Undoubtedly,there are many people who going. stick with one problem and never achieve a solution. I have Drs. Souba and Wilmore not only have a rich background the temerity to suggest that the younger surgical scientists in surgical research themselves,but also have a remarkably probably do well to undertake more straightforward prob- broad knowledge of the leaders in various aspects of surgi- lems at the beginning of their careers,as suggested by Folin. cal research. They have been very fortunate to recruit such a After this experience, which usually brings some recogni- fine group of editors and authors. tion,they are in a better position to venture into more diffi- We speak of surgical research instead of surgical search. cult fields and may have better judgment on the basis of their The purpose is to learn new things that will help the surgical early experience as to whether the methods are available to patient. The term research implies that the results of the solve the more difficult problems. search must be repeatable. As remarked by Judah Folkman, Surgeons have an unusual opportunity to see parts of the “After a paper is published that contains new methods it may body that are hidden from the view of most specialists,even take some time before other researchers can learn the meth- with the aid of modern radiologic techniques. Thus, obser- ods and reproduce the work. If a basic scientist receives a vations in the operating room may often be the starting point call from a colleague, who says, ‘I cannot reproduce your for studies involving several disciplines. Foreword xxix Surgical research is often considered applied research, a necessary evil in many types of biological research. While meaning that the underlying principles have been discovered it quantitates the chances of error,it may lead the unwary to in other areas and are simply being applied to surgical prob- conclude that because a difference is not statistically signifi- lems. For me this does not detract from its importance, as cant there is no difference. The accepted borderline between the increase in basic science knowledge would not benefit statistical significance and the lack thereof is 5%. Thus, if the surgical patient unless the means of applying it for the the chances due to random sampling between experimental benefit of the patient is found. Furthermore, surgical tech- and control results have a probability of occurring by chance niques have in their turn contributed to the work of the pre- differences of less than 5%,one considers it statistically sig- clinical scientist. An obvious example is the heart–lung nificant,whereas if it is over 5%,it is statistically insignifi- apparatus developed by the late John Gibbon,Jr.,which has cant. The author was pleased to learn some years ago that made possible many studies of the heart that could not have this figure was selected as the borderline because the great been successful without this methodology. Surgical research statistician Dr. C. Fisher said so. Perhaps no better border- is an umbrella term covering a great many approaches to the line could be agreed upon,but it follows that if you reach 20 problems of surgical patients and their many diseases. The conclusions each at the 5% confidence level, the odds are major categories are studies on the chemical environment of that one of your conclusions will be false. cells and organs, the immune system, and genetics; patho- In the area of clinical trials one is confronted with the fol- physiology and pharmacology of organs affected by surgical lowing ethical problem. If therapy A is shown to be better diseases and surgical procedures; animal experimentation; for patients than therapy B to the 5% confidence level (or to statistical applications in clinical trials; and reevaluation of the 1% confidence level),how long is one justified in with- psychosocial problems. Surgeons are often in a unique posi- holding therapy A from the control group of patients not tion to explore and understand some of the latter. In the fol- receiving the apparently better therapy? Also, if one shows lowing pages you will see this categorization broken down that therapy A is better than therapy B with a 10% confi- more explicitly and indexed in a way that will permit readers dence limit, does one declare that there is no difference to focus on the special aspects of the things in which they between the two because there is no statistically significant are interested. difference,or does one persist in adding cases to the series in When such studies suggest, they may bring the results the hope of reaching statistical significance? back to the bedside and the operating room for evaluation. One additional pitfall in surgical and indeed medical Patients are safeguarded in the United States and in many research is the measurement of the value of a project by peer other countries. Regulations are imposed by both hospitals review for a grant such as an RO1 grant from the National and government. These prescribe a stepwise approach to the Institutes of Health. The fact that one has submitted a grant introduction of new drugs, new methods, and new equip- request and that it has received sufficiently high priority ment, when the latter is to be introduced into the human from a carefully chosen group of people in the same field body. usually means that it is not very original, because it is in What are some of the major pitfalls in surgical research? keeping with the thinking of the members of the study sec- One has already been alluded to:the attack on problems that tion group. Tremendous emphasis is attached to receiving a are not likely to be solved by available methods. Another, peer-reviewed grant from the NIH and this review process undoubtedly,is the temptation as surgeons become busier in surely eliminates many ill-considered projects. However,the practice to relegate their research to assistants, employees, true measurement of success in research is not the extent of and collaborators,so they are not personally in a position to funding that supports it, but the actual discoveries that are recognize the significance of findings that may turn up unex- made or the truths substantiated. There are many problems pectedly and so miss an important observation that could that cannot be successfully attacked solo or even with a lead them to find an unexpected truth. Another pitfall is to small group of investigators and require major funding. focus too much on priority. This tendency often leads inves- However,if one achieves such funding and employs numer- tigators to jump from one problem to another in the hope of ous people to participate, what becomes of these people if adding something obvious that they can claim as a first. The the problem is solved or the results are clearly negative? tendency to start a new problem before one has finished the Rightly or wrongly,the leader of such a project feels under last was identified in the field of electricity by Faraday, strong pressures to extend the study and maintain the jobs of whose motto is said to have been “work,finish,publish.”We the people that he has recruited. Although this is certainly have all known people who are perfectionists and keep put- fair from the standpoint of the persons recruited,it may not ting off publication until the original important findings are be in the best interest of science. In this day and age, the stale. Possibly the biggest sin of all is to claim more in one’s National Institutes of Health and many other funding agen- conclusions than is the logical result of one’s findings. One cies provide for the overhead expense of the institution; can go back to Aristotle and his list of ways in which false thus, in the case of large grants, this overhead becomes a conclusions may be drawn. The use of statistical methods is significant part of the income on which the institution’s

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1428 Pages·2001·26.049 MB·English
by  Wiley W. Souba and Douglas W. Wilmore (Eds.)
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Contributors Numbers in parentheses indicate the pages on which the authors’ Sonia Y. Archer (557) contributions begin. Department of Surgery,Beth Israel Deaconess Medical William M. Abbott (1011) Center,Boston,Massachusetts 02215 Division of Vascular Surgery,Massachusetts General Arlene S. Ash (81) Hospital,Boston,Massachusetts 02114 Boston University School of Medicine and School of Steve F. Abcouwer (217) Public Health,Boston,Massachusetts 02218 Department of Biochemistry and Molecular Biology, Stanley W. Ashley (3) University of New Mexico,School of Medicine, Department of Surgery,Brigham and Women’s Hospital, Albuquerque,New Mexico 87131 Boston,Massachusetts 02115 N. Scott Adzick (1065) Anthony Atala (1107) Division of Pediatric General,Thoracic and Fetal Surgery, Laboratory for Tissue Engineering and Cellular The Children’s Hospital of Philadelphia,Philadelphia, Therapeutics,Department of Urology,Children’s Pennsylvania 19104 Hospital and Harvard Medical School,Boston, Samuel S. Ahn (1001) Massachusetts 02115 Division of Vascular Surgery,UCLA School of Medicine, Alfred Ayala (317) Los Angeles,California 90095 Center for Surgical Research and Department of Surgery, David C. Allison (193) Brown University School of Medicine and Rhode Island Departments of Surgery,Medicine,and Physiology and Hospital,Providence,Rhode Island 02903 Molecular Medicine,Medical College of Ohio,Toledo, Matthew D. Bacchetta (137) Ohio 43614 Department of Surgery,Anne and Max A. Cohen Surgical J. B. Ames (757) Intensive Care Unit,New York-Presbyterian Hospital–New Surgical Research Laboratory,Harvard Medical School and York Weill Cornell Center,Weill Medical College of Department of Surgery,Brigham and Women’s Hospital, Cornell University,New York,New York 10021 Boston,Massachusetts 02115 Charles M. Balch (1237) Keith D. Amos (497) Departments of Surgery and Oncology,Johns Hopkins Department of Surgery,Washington University School of Medical Center,Baltimore,Maryland 21231 Medicine,St. Louis,Missouri 63110 Anirban Banerjee (285) Robert W. Anderson (1279) Department of Surgery,University of Colorado Health Department of Surgery,Duke University Medical Center, Sciences Center,Denver,Colorado 80262 Durham,North Carolina 27710 Adrian Barbul (1249) Jeffrey M. Arbeit (175) Departments of Surgery,Sinai Hospital of Baltimore,and Department of Surgery,UCSF/MT Zion Cancer Center, the Johns Hopkins Medical Institutions,Baltimore, University of California,San Francisco,California 94115 Maryland 21215 xix xx Contributors Philip S. Barie (137) Cynthia S. Chin (415) Department of Surgery,Anne and Max A. Cohen Surgical Division of Surgical Oncology,Department of Surgery, Intensive Care Unit,New York-Presbyterian Hospital–New Medical College of Virginia at Virginia Commonwealth York Weill Cornell Center,Weill Medical College of University,Richmond,Virginia 23298 Cornell University,New York,New York 10021 Gyu S. Chin (1081) Clyde F. Barker (1261) Department of Surgery,New York University Medical Department of Surgery,University of Pennsylvania, Center,New York,New York 10016 Philadelphia,Pennsylvania 19104 Alexander W. Clowes (971) Jeffrey S. Barkun (155) Department of Surgery,University of Washington,Seattle, McGill University Health Centre,Montreal,Quebec, Washington 98195 Canada H3A 1A1 Lisa Colletti (1349) Robert E. Barrow (367) Department of Surgery,University of Michigan Medical The University of Texas Medical Branch and Shriners’ School,Ann Arbor,Michigan 48109 Burns Hospital,Galveston,Texas 77555 Joy L. Collins (949) Harry D. Bear (415) Department of Surgery,University of Pittsburgh, Division of Surgical Oncology,Department of Surgery, Pittsburgh,Pennsylvania 15261 Medical College of Virginia at Virginia Commonwealth Suzy Conway (1319) University,Richmond,Virginia 23298 Francis A. Countway Library of Medicine,Harvard Russell S. Berman (435) Medical School,Boston,Massachusetts 02115 Departments of Surgical Oncology and Cancer Biology, Clay Cothren (1343) The University of Texas M. D. Anderson Cancer Center, Department of Surgery,University of Colorado,Denver, Houston,Texas 77030 Colorado 80262 Walter L. Biffl(331) Christopher A. Crisera (613) Department of Surgery,Denver Health Medical Center, Department of Surgery,Children’s Mercy Hospital,Kansas University of Colorado Health Sciences Center,Denver, City,Missouri 64108 Colorado 80204 Joseph J. Cullen (507) Timothy R. Billiar (949) University of Iowa Hospitals and Clinics,Iowa City,Iowa Department of Surgery,University of Pittsburgh, 52242 Pittsburgh,Pennsylvania 15261 P. William Curreri (1241) John D. Birkmeyer (101, 127) Stratagem,Inc.,Daphne,Alabama 36526 VA Outcomes Group,VA Medical Center,White River Junction,Vermont 05009 James C. Cusack, Jr. (457) Timothy G. Buchman (307, 1309) Division of Surgical Oncology,Massachusetts General Department of Surgery,Washington University School of Hospital,Boston,Massachusetts 02114 Medicine,St. Louis,Missouri 63110 Roger E. De Filippo (1107) Eileen M. Bulger (893) Laboratory for Tissue Engineering and Cellular Department of Surgery,Harborview Medical Center and the Therapeutics,Department of Urology,Children’s University of Washington,Seattle,Washington 98104 Hospital and Harvard Medical School,Boston, Massachusetts 02115 Charles B. Cairns (285) Department of Surgery,University of Colorado Health Edwin A. Deitch (599) Sciences Center,Denver,Colorado 80262 Department of Surgery,UMD–New Jersey Medical School, Newark,New Jersey 07003 Casey Calkins (1343) Department of Surgery,University of Colorado,Denver, E. Patchen Dellinger (909) Colorado 80262 Department of Surgery,University of Washington Medical William G. Cance (253) Center,University of Washington School of Medicine, Department of Surgery and UNC Lineberger Seattle,Washington 98195 Comprehensive Cancer Center,University of North Achilles A. Demetriou (623, 709) Carolina at Chapel Hill,Chapel Hill,North Carolina 27599 Department of Surgery,Cedars-Sinai Medical Center,Los Irshad H. Chaudry (317, 357) Angeles,California 90048 Center for Surgical Research,Department of Surgery, Jeffrey A. Drebin (445) Brown University School of Medicine and Rhode Island Department of Surgery,Washington University School of Hospital,Providence,Rhode Island 02903 Medicine,St. Louis,Missouri 63110 Contributors xxi Soumitra R. Eachempati (137) Raquel M. Forsythe (599) Department of Surgery,Anne and Max A. Cohen Department of Surgery,UMD—New Jersey Medical Surgical Intensive Care Unit,New York-Presbyterian School,Newark,New Jersey 07003 Hospital–New York Weill Cornell Center,Weill Bradley D. Freeman (307) Medical College of Cornell University,New York,New Department of Surgery,Washington University School of York 10021 Medicine,St. Louis,Missouri 63110 Timothy J. Eberlein (497) Fabia Gamboni-Robertson (285) Department of Surgery,Washington University School of Department of Surgery,University of Colorado Health Medicine,St. Louis,Missouri 63110 Sciences Center,Denver,Colorado 80262 R. Neal Garrison (1027) David T. Efron (1249) Department of Surgery,University of Louisville,and Departments of Surgery,Sinai Hospital of Baltimore,and Veterans Affairs Medical Center,Louisville,Kentucky the Johns Hopkins Medical Institutions,Baltimore, 40292 Maryland 21215 James Garvey (1405) Nancy R. Ehrlich (1217) Schroder Ventures International Life Science Fund,Boston, The Recanati/Miller Transplantation Institute,New York, Massachusetts 02114 New York 10029 M. Gasser (757) Theresa L. Eisenbraun (271) Surgical Research Laboratory,Harvard Medical School and University of Wisconsin Comprehensive Cancer Center, Department of Surgery,Brigham and Women’s Hospital, Madison,Wisconsin 53792 Boston,Massachusetts 02115; and Department of Surgery, Lee M. Ellis (401, 435) University of Wuerzburg,97080 Wuerzburg,Germany Departments of Surgical Oncology and Cancer Biology, Jonathan Gertler (1405) The University of Texas M. D. Anderson Cancer Center, Division of Vascular Surgery,Massachusetts General Houston,Texas 77030 Hospital; Harvard Medical School; and Schroder Ventures Darwin Eton (1001) International Life Science Fund,Boston,Massachusetts Division of Vascular Surgery,University of Miami School 02114 of Medicine,Miami,Florida 33136 Anna Getselman (1319) B. Mark Evers (23) Francis A. Countway Library of Medicine,Harvard Department of Surgery,The University of Texas Medical Medical School,Boston,Massachusetts 02115 Branch,Galveston,Texas 77555 George K. Gittes (613) Liane Feldman (155) Department of Surgery,Children’s Mercy Hospital,Kansas McGill University Health Centre,Montreal,Quebec, City,Missouri 64108 Canada H3A 1A1 Matthew I. Goldblatt (721) Department of Surgery,Medical College of Wisconsin, Mitchell P. Fink (875) Milwaukee,Wisconsin 53226 Departments of Anesthesiology,Critical Care Medicine, Paul J. Gorman (1299) and Surgery,University of Pittsburgh Medical School, Department of Surgery,Stanford University,Stanford, Pittsburgh,Pennsylvania 15261 California 94043 Joseph J. Fins (137) Douglas W. Green (445) Department of Medicine,Anne and Max A. Cohen Surgical Department of Surgery,Washington University School of Intensive Care Unit,New York-Presbyterian Hospital–New Medicine,St. Louis,Missouri 63110 York Weill Cornell Center,Weill Medical College of David G. Greenhalgh (379) Cornell University,New York,New York 10021 Department of Surgery,Shriners Hospitals for Children, David R. Fischer (825) Northern California,and University of California,Davis, Department of Surgery,University of Cincinnati College of Sacramento,California 95817 Medicine,Cincinnati,Ohio 45267 Jurgen Hannig (297) Josef E. Fischer (63) Pritzker School of Medicine,The University of Chicago, Department of Surgery,University of Cincinnati, Chicago,Illinois 60637 Cincinnati,Ohio 45267 Alden H. Harken (1343) Alan W. Flake (207) Department of Surgery,University of Colorado,Denver, Department of Surgery and the Center for Fetal Diagnosis Colorado 80262 and Therapy,Children’s Hospital of Philadelphia, Per-Olof Hasselgren (825) University of Pennsylvania,Philadelphia,Pennsylvania Department of Surgery,University of Cincinnati College of 19104 Medicine,Cincinnati,Ohio 45267 xxii Contributors Julie Heimbach (1343) Jerald J. Killion (435) Department of Surgery,University of Colorado,Denver, Department of Cancer Biology,The University of Texas Colorado 80262 M. D. Anderson Cancer Center,Houston,Texas 77030 Peter K. Henke (989) Denise E. Kirschner (1309) Jobst Vascular Research Laboratory,Section of Vascular Departments of Microbiology and Immunology,The Surgery,Department of Surgery,University of Michigan University of Michigan,Ann Arbor,Michigan 48109 Medical Center,Ann Arbor,Michigan 48109 Thomas M. Krummel (1299) David N. Herndon (367) Department of Surgery,Stanford University,Stanford, The University of Texas Medical Branch and Shriners’ California 94043 Burns Hospital,Galveston,Texas 77555 Alexander Sasha Krupnick (1065) Graham L. Hill (797) Division of Pediatric General,Thoracic and Fetal Surgery, University Department of Surgery,Auckland Hospital, The Children’s Hospital of Philadelphia,Philadelphia, Auckland 1001,New Zealand Pennsylvania 19104 I. L. Laskowski (757) Richard A. Hodin (557) Surgical Research Laboratory,Harvard Medical School and Department of Surgery,Beth Israel Deaconess Medical Department of Surgery,Brigham and Women’s Hospital, Center,Boston,Massachusetts 02215 Boston,Massachusetts 02115; and Department of General Susan D. Horn (1393) and Transplant Surgery,Warsaw Medical University, Institute for Clinical Outcomes Research,Salt Lake City, 02-006 Warsaw,Poland Utah 84109 Robert D. Lasley (1119) Lisa I. Iezzoni (81) Department of Surgery,University of Kentucky College of Harvard Medical School and Division of General Medicine Medicine,Lexington,Kentucky 40536 and Primary Care,Department of Medicine,Beth Israel Stephen R. Lauterbach (1011) Deaconess Medical Center,Boston,Massachusetts 02215 Division of Vascular Surgery,Massachusetts General Daniel Inderbitzen (709) Hospital,Boston,Massachusetts 02114 Department of Surgery,Cedars-Sinai Medical Center,Los Jeffrey H. Lawson (1279) Angeles,California 90048 Department of Surgery,Duke University Medical Center, Svetlana Ivanova (1095) Durham,North Carolina 27710 Laboratory of Biomedical Science,North Shore University Raphael C. Lee (297) Hospital,Manhasset,New York 11030 Pritzker School of Medicine,The University of Chicago, Danny O. Jacobs (813) Chicago,Illinois 60637; and Burn Center,St. Mary’s Laboratories of Surgical Metabolism,Department of Medical Center,Hobart,Indiana 46342 Surgery and Nutrition,Brigham and Women’s Hospital, David Lee-Parritz (47) Harvard Medical School,Boston,Massachusetts 02115; Center for Animal Resources and Comparative Medicine, and Creighton University Surgical Laboratories for Harvard Medical School,Boston,Massachusetts 02115 Biomedical Investigation,Omaha,Nebraska 68131 David C. Linehan (497) Daniel B. Jones (573) Department of Surgery,Washington University School of Southwestern Center for Minimally Invasive Surgery and Medicine,St. Louis,Missouri 63110 Department of Surgery,The University of Texas Jean Y. Liu (101) Southwestern Medical Center,Dallas,Texas 75235 VA Outcomes Group,VA Medical Center,White River Mary Jane Kagarise (29) Junction,Vermont 05009 Department of Surgery,The University of North Carolina Michael T. Longaker (1081) School of Medicine,The University of North Carolina at Department of Surgery,Stanford University School of Chapel Hill,Chapel Hill,North Carolina 27599 Medicine,Stanford,California 94305 Gordon L. Kauffman, Jr. (71, 1201) Charles Lucey (1383) Department of Surgery,The Milton S. Hershey Medical 21stCentury Health Concepts,Houston,Texas 77061; and Center,Penn State College of Medicine,Hershey, Dartmouth College,Hanover,New Hampshire 03755 Pennsylvania 17033 Nancy R. Macdonald (1011) Richard D. Kenagy (971) Division of Vascular Surgery,Massachusetts General Department of Surgery,University of Washington,Seattle, Hospital,Boston,Massachusetts 02114 Washington 98195 Ronald V. Maier (893) Gregory D. Kennedy (271) Department of Surgery,Harborview Medical Center University of Wisconsin Comprehensive Cancer Center, and the University of Washington,Seattle,Washington Madison,Wisconsin 53792 98104 Contributors xxiii Thomas S. Maldonado (613) Michael W. Mulholland (9) Department of Surgery,Children’s Mercy Hospital,Kansas University of Michigan Medical Center,Ann Arbor, City,Missouri 64108 Michigan 48109 John C. Marshall (921) Joseph Murphy (583) Department of Surgery,University of Toronto,and Department of Surgery,University of Texas Southwestern University Health Network,Toronto,Ontario,Canada Medical Center and the Veterans Affairs North Texas M5G 2C4 Health Care System,Dallas,Texas 75216 Takeaki Matsuda (813) Rene J. P. Musters (285) Laboratories of Surgical Metabolism,Department of Department of Surgery,University of Colorado Health Surgery and Nutrition,Brigham and Women’s Hospital, Sciences Center,Denver,Colorado 80262 Harvard Medical School,Boston,Massachusetts 02115; Thomas A. Mustoe (857) and Creighton University Surgical Laboratories for Division of Plastic and Reconstructive Surgery, Biomedical Investigation,Omaha,Nebraska 68131 Northwestern University Medical School,Chicago,Illinois Jeffrey B. Matthews (533) 60611 Department of Surgery,Beth Israel Deaconess Medical Daniel D. Myers, Jr. (989) Center,Harvard Medical School,Boston,Massachusetts Jobst Vascular Research Laboratory,Section of Vascular 02215 Surgery,Unit for Laboratory Animal Medicine,University David T. Mauger (71, 1201) of Michigan Medical Center,Ann Arbor,Michigan 48109 Department of Health Evaluation Sciences,The Milton S. Attila Nakeeb (721) Hershey Medical Center,Penn State College of Medicine, Department of Surgery,Medical College of Wisconsin, Hershey,Pennsylvania 17033 Milwaukee,Wisconsin 53226 Lucretia W. McClure (1319) Avery B. Nathens (893) Francis A. Countway Library of Medicine,Harvard Department of Surgery,Harborview Medical Center and the Medical School,Boston,Massachusetts 02115 University of Washington,Seattle,Washington 98104 Jonathan L. Meakins (155) Andrea L. Nestor (193) McGill University Health Centre,Montreal,Quebec, Departments of Surgery,Medicine,and Physiology and Canada H3A 1A1 Molecular Medicine,Medical College of Ohio,Toledo, Andreas H. Meier (1299) Ohio 43614 Department of Surgery,Stanford University,Stanford, John E. Niederhuber (271) California 94043 University of Wisconsin Comprehensive Cancer Center, Robert M. Mentzer, Jr. (1119) Madison,Wisconsin 53792 Department of Surgery,University of Kentucky College of Keith O’Rourke (167) Medicine,Lexington,Kentucky 40536 Department of Surgery and Clinical Epidemiology Unit, Tanya K. Meyer (253) University of Ottawa,Ottawa Hospital,Ottawa,Ontario, Department of Surgery and UNC Lineberger Canada K1Y OK6 Comprehensive Cancer Center,University of North Marshall J. Orloff (637) Carolina at Chapel Hill,Chapel Hill,North Carolina 27599 Department of Surgery,School of Medicine,University of Rebecca M. Minter (933) California,San Diego,La Jolla,California 92093 Department of Surgery,University of Florida College of Mary F. Otterson (507) Medicine,Gainesville,Florida 32610 Medical College of Wisconsin,Milwaukee,Wisconsin Lyle L. Moldawer (933) 53226 Department of Surgery,University of Florida College of Medicine,Gainesville,Florida 32610 Wayne R. Patterson (13) Ernest E. Moore (331) The University of Texas Medical Branch,Galveston,Texas Department of Surgery,Denver Health Medical Center, 77555 University of Colorado Health Sciences Center,Denver, Timothy M. Pawlik (1349) Colorado 80204 Department of Surgery,University of Michigan Medical Daniel Most (1249) School,Ann Arbor,Michigan 48109 Departments of Surgery,Sinai Hospital of Baltimore,and Henry A. Pitt (721) the Johns Hopkins Medical Institutions,Baltimore, Department of Surgery,Medical College of Wisconsin, Maryland 21215 Milwaukee,Wisconsin 53226 Caren M. Mulford (1119) Lindsay D. Plank (797) Department of Surgery,University of Kentucky College of University Department of Surgery,Auckland Hospital, Medicine,Lexington,Kentucky 40536 Auckland 1001,New Zealand xxiv Contributors Timothy A. Pritts (825) Martin G. Schwacha (357) Department of Surgery,University of Cincinnati College of Center for Surgical Research,Department of Surgery, Medicine,Cincinnati,Ohio 45267 Brown University School of Medicine and Rhode Island R. Lawrence Reed II (347) Hospital,Providence,Rhode Island 02903 Department of Surgery,Loyola University Medical Center, Patrica M. Scott (271) Maywood,Illinois 60153 University of Wisconsin Comprehensive Cancer Center, Robert V. Rege (573) Madison,Wisconsin 53792 Southwestern Center for Minimally Invasive Surgery and Patricia A. Sheiner (1217) Department of Surgery,The University of Texas The Recanati/Miller Transplantation Institute,and the Southwestern Medical Center,Dallas,Texas 75235 Mount Sinai School of Medicine,New York,New York Robert S. Rhodes (1393) 10029 University of Pennsylvania School of Medicine, George F. Sheldon (29) Philadelphia,Pennsylvania 19103 Department of Surgery,The University of North Carolina Henry E. Rice (207) School of Medicine,The University of North Carolina at Division of Pediatric Surgery,Department of Surgery, Chapel Hill,Chapel Hill,North Carolina 27599 Duke University Medical Center,Durham,North Carolina Michael Shwartz (81) 27710 School of Management,Boston University,Boston, Martin Riegler (533) Massachusetts 02215 University Clinic of Surgery,Vienna General Hospital, H. Hank Simms (393) A-1090 Vienna,Austria Division of Surgical Critical Care,Rhode Island Hospital, Kyung M. Ro (1001) Providence,Rhode Island 02903 Division of Vascular Surgery,UCLA School of Medicine, Marcus K. Simpson (1383) Los Angeles,California 90095 Dartmouth College,Hanover,New Hampshire 03755 Thomas N. Robinson (285, 1343) Clay Smith (207) Department of Surgery,University of Colorado Health Center for Genetic and Cellular Therapy,Duke University Sciences Center,Denver,Colorado 80262 Medical Center,Durham,North Carolina 27710 John L. Rombeau (547) Scott D. Somers (1361) Harrison Department of Surgical Research,University of Division of Pharmacology,Physiology,and Biological Pennsylvania,Philadelphia,Pennsylvania 19104 Chemistry,The National Institute of General Medical Joseph M. Rosen (1383) Sciences,Bethesda,Maryland 20892 Plastic and Reconstructive Surgery,Dartmouth-Hitchcock Medical Center,Lebanon,New Hampshire 03756; and Wiley W. Souba (773, 1375) Department of Surgery,The Milton S. Hershey Medical Thayer School of Engineering,Dartmouth College, Center,Penn State College of Medicine,Hershey, Hanover,New Hampshire 03755 Pennsylvania 17033 Ori D. Rotstein (1337) Departments of Surgery,University Health Network,and David A. Spain (1027) University of Toronto,Toronto,Ontario,Canada M56 24C Department of Surgery,University of Louisville,and Veterans Affairs Medical Center,Louisville,Kentucky Jacek Rozga (623, 703, 709) 40292 Department of Surgery,Cedars-Sinai Medical Center,Los Angeles,California 90048 Jason A. Spector (1081) Justin T. Sambol (599) Department of Surgery,New York University Medical Department of Surgery,UMD–New Jersey Medical School, Center,New York,New York 10016 Newark,New Jersey 07003 Michael L. Steer (733) Michael G. Sarr (507) Department of Surgery,Beth Israel Deaconess Medical Division of Gastroenterologic and General Surgery,Mayo Center,Harvard Medical School,Boston,Massachusetts Clinic,Mayo Medical School,Rochester,Minnesota 55902 02215 Alexandrina Saulis (857) Bruce R. Stevens (845) Division of Plastic and Reconstructive Surgery, Department of Physiology,College of Medicine,University Northwestern University Medical School,Chicago,Illinois of Florida,Gainesville,Florida 32610 60611 Robert W. Storms (207) Mary C. Schuerman (1241) Center for Genetic and Cellular Therapy,Duke University Stratagem,Inc.,Daphne,Alabama 36526 Medical Center,Durham,North Carolina 27710 Contributors xxv Kenneth K. Tanabe (115, 457) Brad W. Warner (1047) Division of Surgical Oncology,Massachusetts General Division of Pediatric Surgery,Children’s Hospital Medical Hospital,Boston,Massachusetts 02114 Center,Cincinnati,Ohio 45229 James C. Thompson (1) Stephen M. Warren (1081) Department of Surgery,The University of Texas Medical Department of Surgery,Oregon Health Science University, Branch,Galveston,Texas 77555 Portland,Oregon 97201 James M. Watters (167) N. L. Tilney (757) Department of Surgery,Loeb Health Research Institute, Surgical Research Laboratory,Harvard Medical School and University of Ottawa,Ottawa Hospital,Ottawa,Ontario, Department of Surgery,Brigham and Women’s Hospital, Canada K1Y OK6 Boston,Massachusetts 02115 Ronald J. Weigel (233) Daniel L. Traber (367) Stanford University,School of Medicine,Stanford, The University of Texas Medical Branch and Shriners’ California 94305 Burns Hospital,Galveston,Texas 77555 Frank J. Wessels (933) Kevin J. Tracey (1095) Department of Surgery,University of Florida College of Laboratory for Tissue Engineering and Cellular Medicine,Gainesville,Florida 32610 Therapeutics,Department of Urology,Children’s Edward E. Whang (3) Hospital and Harvard Medical School,Boston, Department of Surgery,Brigham and Women’s Hospital, Massachusetts 02115 Boston,Massachusetts 02115 Richard H. Turnage (583) D. Whitley (757) Department of Surgery,University of Texas Southwestern University of Alabama,Birmingham,Alabama 35294 Medical Center and the Veterans Affairs North Texas James Willey (193) Health Care System,Dallas,Texas 75216 Departments of Surgery,Medicine,and Physiology and A. Simon Turner (1137) Molecular Medicine,Medical College of Ohio,Toledo, Department of Clinical Sciences,Colorado State Ohio 43614 University,Fort Collins,Colorado 80523 Douglas W. Wilmore (773, 1375) Thomas C. Vary (747) Department of Surgery,Brigham and Women’s Hospital, Department of Cellular and Molecular Physiology,Penn Boston,Massachusetts 02115 State University College of Medicine,Hershey, Robert R. Wolfe (789) Pennsylvania 17033 The University of Texas Medical Branch,Galveston,and Shriners Burns Hospital,Metabolism Unit,Galveston, Gus J. Vlahakes (1037) Texas 77550 Massachusetts General Hospital and Harvard Medical Shirley K. Wrobleski (989) School,Boston,Massachusetts 02114 Jobst Vascular Research Laboratory,Section of Vascular Yoram Vodovotz (949) Surgery,Department of Surgery,University of Michigan Department of Surgery,University of Pittsburgh, Medical Center,Ann Arbor,Michigan 48109 Pittsburgh,Pennsylvania 15261 George P. Yang (233) Thomas W. Wakefield (989) Stanford University,School of Medicine,Stanford, Jobst Vascular Research Laboratory,Section of Vascular California 94305 Surgery,Department of Surgery,University of Michigan Heidi Yeh (547) Medical Center; and Ann Arbor Veterans Administration Harrison Department of Surgical Research,University of Medical Center,Ann Arbor,Michigan 48109 Pennsylvania,Philadelphia,Pennsylvania 19104 Ping Wang (317, 357) Barbara A. Zehnbauer (307) Center for Surgical Research,Department of Surgery, Departments of Pediatrics and Pathology,Washington Brown University School of Medicine and Rhode Island University School of Medicine and St. Louis Childrens’ Hospital,Providence,Rhode Island 02903 Hospital,St. Louis,Missouri 63110 Glenn D. Warden (379) Moritz M. Ziegler (1287) Shriners Hospitals for Children—Cincinnati Burns Hospital, Department of Surgery,Children’s Hospital Medical and University of Cincinnati,Cincinnati,Ohio 45229 Center,Boston,Massachusetts 02115 Foreword Surgical research probably offers better opportunities to the identification and enumeration of cancer cells in bone for success than it ever has before because of the advances marrow or blood during the development of a clinical can- in other sciences and in technology. Unfortunately, there cer. seem to be forces in American medicine that discourage Clearly, the value of such a book must depend on the active participation in surgical research. Foremost among insight and experience of its editors, Dr. Wiley Souba and these factors are economic disincentives. First, medical Dr. Douglas Wilmore. Dr. Douglas Wilmore has long been schools have raised their tuitions to levels that leave the known to me,first as a medical student and later as a teacher new M.D. buried under a burden of debt. Second,when he who brought me new information from his research and col- or she finally gets into practice, managed care can be a lective experience. Dr. Wilmore took his surgical residency driving force to see more and more patients at lower and at the Hospital of the University of Pennsylvania during the lower rates of remuneration. Not only does this affect the years I was chairman of that department. As a surgical resi- practitioner, but it affects the hospital where more and dent he was superb in his approach to patients, his knowl- more patients and procedures are required to balance its edge of surgery,his research endeavors during his residency, budget. Most medical schools and hospitals with research and, most importantly, his ability to teach. Even in those departments look to those who do research not only to give days,his thoroughness in research was evident in a lengthy their time and effort but to raise money through grants that study of the adaptability of duodenal mucosa to the loss of provide heavy overhead funds in order to have the space much of the jejuno-ileum in dogs. His interest in the short and facilities to pursue their work. These pressures, some bowel syndrome stemmed at least in part out of the brilliant of which will be commented on later in this foreword, case that he and Dr. Stanley Dudrick managed at the Chil- make a volume such as this most timely and important in dren’s Hospital of Philadelphia of a female infant born with the new millennium. atresia of most of the jejuno-ileum and also the sigmoid. Upon learning of the plan to create a single-volume book This patient and the subsequent report in the Journal of the for surgical research and receiving an invitation to write a American Medical Association probably did more to bring foreword,I will admit that I cringed a bit,as the subject is so the attention of surgeons to the possibility of total parenteral vast and potentially draws on a large number of scientific nutrition than any other single article. It demonstrated so disciplines,each of which has its own distinctive and exten- clearly that not only could life be maintained, but if suffi- sive set of contributions relating to research in the field of cient nutrients were given,normal growth would occur even surgery. On second thought,however,I realized that with the in an individual who could take nothing by mouth but water. capacity of the electronic media to make a vast array of ref- It was typical of Dr. Wilmore’s subsequent career that he erence material available, such a book would be an enor- took this problem to the laboratory to see how much mous help in particular to younger students entering areas jejunum and ileum could be sacrificed if TPN were given that are relatively new to them. Thus,this volume can serve long enough for the duodenum to compensate maximally. as a screen to show people whether or not their fresh ideas He measured the weight of the duodenum per linear cen- have already been explored and to what extent, and it can timeter and the thickness of the mucosa and observed the point the way to much relevant material in disciplines far architecture of the mucosa at various stages of its compensa- removed from surgery, ranging from electrical engineering tory transformation. Thus,in dogs he established most of the xxvii xxviii Foreword criteria we now use in deciding whether a patient with a lim- work’this can be a terrifying experience for the basic scien- ited length of jejuno-ileum can compensate for the loss of tist. However,for a surgeon it may be a source of pride and much of the intestine. He went on to spend many valuable is called the ‘Stradivarius problem’”[1]. years with Dr. Basil Pruitt at the Surgical Research Center at In writing the beginning chapter of a textbook published Brooke Army Hospital in San Antonio. From there he was by the J. B. Lippincott Company in 1957,edited by J. Gar- appointed to the faculty at Harvard,where he was entrusted rott Allen, Henry N. Harkins, Carl Moyer, and myself [2], with the very productive laboratory previously headed by we emphasized the responsibility of those going into sur- Dr. Francis Moore and devoted to the study of the metabo- gery not only to learn the science and art of surgery and to lism of surgical patients. Here he has continued to make practice it as perfectly as possible, but also to enhance important contributions showing that at least one of the knowledge in the field of surgery,thus making an addition to nonessential amino acids,arginine,is really essential in the surgical science, whether this be clinical or laboratory nourishment of the surgically stressed patient. based. It is therefore most appropriate that this volume on Dr. Wiley Souba has worked in several venues,a portion surgical research draws together a large body of experience of the time with Dr. Dudrick and a portion of the time with to help new surgical students find available resources and Dr. Wilmore,and currently has assumed the chairmanship of avoid some of the pitfalls that beset those of us who attempt the Department of Surgery at Pennsylvania State University surgical research. in Hershey, formerly headed by Dr. John Waldhausen. His It was my privilege to meet on several occasions the contributions to surgical research also have been highly sig- chairman of the Department of Physiological Chemistry at nificant. Dr. Souba has devoted himself to the study of par- Harvard Medical School, Otto Folin, whose daughter later enteral nutrition and particularly to the metabolism of gluta- became my wife. He said that he thought that half of one’s mine and the effects of inflammation and tumors on success in medical research was in the selection of the glutamine metabolism. He has gone on to study the means problem. He had worked seven years at a mental institution by which amino acids gain entrance to cells and he has also in an effort to see whether new biochemical techniques studied independent amino acid transport in endotoxemic might throw light on the cause of mental illness. He rats, gaining evidence of selective stimulation of arginine employed these years to develop improved methods of uri- transport. His papers constitute many pages in the Journal of nalysis, many of which were used widely by other bio- Parenteral and Enteral Nutritionand a good number of con- chemists and clinical pathologists. However, he became tributions to the Annals of Surgery,The Surgical Forum,and convinced that the biochemistry then available was not like- many other prestigious journals. His bibliography shows ly to solve the problems of mental illness. He had the beyond a doubt that he is familiar with many laboratory opportunity of changing his work to the Department of techniques and the various aspects of clinical investigation. Physiological Chemistry at Harvard, where he worked on The senior editors of this volume speak from a background methods for most of his career. In short, he felt that one of personal success in surgical research and they have select- should select a problem that was likely to have an attainable ed a remarkable group of section editors and authors. Nearly solution. every field of surgical research is discussed in detail in this Somewhat in contrast to this, my surgical mentor, I. S. volume by individuals who have been and are successfully Ravdin, often remarked that he had a particular respect for engaged in investigative work. The volume is valuable for its the individual who had worked on a difficult problem long overview of the whole field and equally valuable to the indi- and hard and had finally solved the problem. It seems to be a vidual who has selected his field and wants to be updated on matter of judgment as to what to choose and how long to recent progress and the directions in which it seems to be pursue the search. Undoubtedly,there are many people who going. stick with one problem and never achieve a solution. I have Drs. Souba and Wilmore not only have a rich background the temerity to suggest that the younger surgical scientists in surgical research themselves,but also have a remarkably probably do well to undertake more straightforward prob- broad knowledge of the leaders in various aspects of surgi- lems at the beginning of their careers,as suggested by Folin. cal research. They have been very fortunate to recruit such a After this experience, which usually brings some recogni- fine group of editors and authors. tion,they are in a better position to venture into more diffi- We speak of surgical research instead of surgical search. cult fields and may have better judgment on the basis of their The purpose is to learn new things that will help the surgical early experience as to whether the methods are available to patient. The term research implies that the results of the solve the more difficult problems. search must be repeatable. As remarked by Judah Folkman, Surgeons have an unusual opportunity to see parts of the “After a paper is published that contains new methods it may body that are hidden from the view of most specialists,even take some time before other researchers can learn the meth- with the aid of modern radiologic techniques. Thus, obser- ods and reproduce the work. If a basic scientist receives a vations in the operating room may often be the starting point call from a colleague, who says, ‘I cannot reproduce your for studies involving several disciplines. Foreword xxix Surgical research is often considered applied research, a necessary evil in many types of biological research. While meaning that the underlying principles have been discovered it quantitates the chances of error,it may lead the unwary to in other areas and are simply being applied to surgical prob- conclude that because a difference is not statistically signifi- lems. For me this does not detract from its importance, as cant there is no difference. The accepted borderline between the increase in basic science knowledge would not benefit statistical significance and the lack thereof is 5%. Thus, if the surgical patient unless the means of applying it for the the chances due to random sampling between experimental benefit of the patient is found. Furthermore, surgical tech- and control results have a probability of occurring by chance niques have in their turn contributed to the work of the pre- differences of less than 5%,one considers it statistically sig- clinical scientist. An obvious example is the heart–lung nificant,whereas if it is over 5%,it is statistically insignifi- apparatus developed by the late John Gibbon,Jr.,which has cant. The author was pleased to learn some years ago that made possible many studies of the heart that could not have this figure was selected as the borderline because the great been successful without this methodology. Surgical research statistician Dr. C. Fisher said so. Perhaps no better border- is an umbrella term covering a great many approaches to the line could be agreed upon,but it follows that if you reach 20 problems of surgical patients and their many diseases. The conclusions each at the 5% confidence level, the odds are major categories are studies on the chemical environment of that one of your conclusions will be false. cells and organs, the immune system, and genetics; patho- In the area of clinical trials one is confronted with the fol- physiology and pharmacology of organs affected by surgical lowing ethical problem. If therapy A is shown to be better diseases and surgical procedures; animal experimentation; for patients than therapy B to the 5% confidence level (or to statistical applications in clinical trials; and reevaluation of the 1% confidence level),how long is one justified in with- psychosocial problems. Surgeons are often in a unique posi- holding therapy A from the control group of patients not tion to explore and understand some of the latter. In the fol- receiving the apparently better therapy? Also, if one shows lowing pages you will see this categorization broken down that therapy A is better than therapy B with a 10% confi- more explicitly and indexed in a way that will permit readers dence limit, does one declare that there is no difference to focus on the special aspects of the things in which they between the two because there is no statistically significant are interested. difference,or does one persist in adding cases to the series in When such studies suggest, they may bring the results the hope of reaching statistical significance? back to the bedside and the operating room for evaluation. One additional pitfall in surgical and indeed medical Patients are safeguarded in the United States and in many research is the measurement of the value of a project by peer other countries. Regulations are imposed by both hospitals review for a grant such as an RO1 grant from the National and government. These prescribe a stepwise approach to the Institutes of Health. The fact that one has submitted a grant introduction of new drugs, new methods, and new equip- request and that it has received sufficiently high priority ment, when the latter is to be introduced into the human from a carefully chosen group of people in the same field body. usually means that it is not very original, because it is in What are some of the major pitfalls in surgical research? keeping with the thinking of the members of the study sec- One has already been alluded to:the attack on problems that tion group. Tremendous emphasis is attached to receiving a are not likely to be solved by available methods. Another, peer-reviewed grant from the NIH and this review process undoubtedly,is the temptation as surgeons become busier in surely eliminates many ill-considered projects. However,the practice to relegate their research to assistants, employees, true measurement of success in research is not the extent of and collaborators,so they are not personally in a position to funding that supports it, but the actual discoveries that are recognize the significance of findings that may turn up unex- made or the truths substantiated. There are many problems pectedly and so miss an important observation that could that cannot be successfully attacked solo or even with a lead them to find an unexpected truth. Another pitfall is to small group of investigators and require major funding. focus too much on priority. This tendency often leads inves- However,if one achieves such funding and employs numer- tigators to jump from one problem to another in the hope of ous people to participate, what becomes of these people if adding something obvious that they can claim as a first. The the problem is solved or the results are clearly negative? tendency to start a new problem before one has finished the Rightly or wrongly,the leader of such a project feels under last was identified in the field of electricity by Faraday, strong pressures to extend the study and maintain the jobs of whose motto is said to have been “work,finish,publish.”We the people that he has recruited. Although this is certainly have all known people who are perfectionists and keep put- fair from the standpoint of the persons recruited,it may not ting off publication until the original important findings are be in the best interest of science. In this day and age, the stale. Possibly the biggest sin of all is to claim more in one’s National Institutes of Health and many other funding agen- conclusions than is the logical result of one’s findings. One cies provide for the overhead expense of the institution; can go back to Aristotle and his list of ways in which false thus, in the case of large grants, this overhead becomes a conclusions may be drawn. The use of statistical methods is significant part of the income on which the institution’s

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