Schwartz's Manual of Surgery 8th Edition PDF

Schwartz’s MANUAL OF SURGERY i Editor-in-Chief F. Charles Brunicardi, MD, FACS DeBakey/Bard Professor and Chairman Michael E. DeBakey Department of Surgery Baylor College of Medicine Houston, Texas Associate Editors Dana K. Andersen, MD, FACS Professor and Vice-Chair Department of Surgery Johns Hopkins School of Medicine Surgeon-in-Chief Johns Hopkins Bayview Medical Center Baltimore, Maryland Timothy R. Billiar, MD, FACS George Vance Foster Professor and Chairman of Surgery Department of Surgery University of Pittsburgh School of Medicine Pittsburgh, Pennsylvania David L. Dunn, MD, PhD, FACS Vice President for Health Sciences University at Buffalo/SUNY Buffalo, New York John G. Hunter, MD, FACS Mackenzie Professor and Chairman of Surgery Department of Surgery Oregon Health and Science University Portland, Oregon Raphael E. Pollock, MD, PhD, FACS Head, Division of Surgery Professor and Chairman Department of Surgical Oncology Senator A.M. Aiken, Jr., Distinguished Chair The University of Texas M. D. Anderson Cancer Center Houston, Texas ii Schwartz’s MANUAL OF SURGERY EIGHTH EDITION Editor-in-Chief F. Charles Brunicardi, MD, FACS Associate Editors Dana K. Andersen, MD, FACS Timothy R. Billiar, MD, FACS David L. Dunn, MD, PhD, FACS John G. Hunter, MD, FACS Raphael E. Pollock, MD, PhD, FACS McGRAW-HILL Medical Publishing Division New York Chicago San Francisco Lisbon London Madrid Mexico City Milan New Delhi San Juan Seoul Singapore Sydney Toronto iii Copyright © 2006 by The McGraw-Hill Companies, Inc. All rights reserved. Manufactured in the United States of America. 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However, in view of the possibility of human error or changes in medical sciences, neither the authors nor the publisher nor any other party who has been involved in the preparation or publication of this work warrants that the information contained herein is in every respect accurate or complete, and they disclaim all responsibility for any errors or omis- sions or for the results obtained from use of the information contained in this work. Readers are encouraged to conﬁrm the information con- tained herein with other sources. For example and in particular, read- ers are advised to check the product information sheet included in the package of each drug they plan to administer to be certain that the information contained in this work is accurate and that changes have not been made in the recommended dose or in the contraindications for administration. This recommendation is of particular importance in connection with new or infrequently used drugs. v To my wife, Melissa, my children, Isaac and Jackson, my mother, Rose, and my late father, Edward Brunicardi, for their love and support FCB To my wife, Cindy, and my children, Ashley, Lauren, Kathryn, Thomas, and Olivia DKA To Edith, Isabel and Alex TRB To my wife, Kelli, for all of her support of my career and academic endeavors, and my children, Michael, Evelyn, Julia, and Edward DLD To my wife, Laura, my children, Sarah, Sam, and Jillian, and the residents, fellows, and surgical faculty at OSHU who have created a community of health, collegiality, and open–minded intellectual rigor JGH To my wife, Dina, and my children, Jessica, Sam, Eden, Noam, and Omer REP vi For more information about this title, click here Contents Contributors xi Preface xxiii PART I BASIC CONSIDERATIONS 1 Systemic Response to Injury and Metabolic Support 3 J. Martin Perez, Edward Lim, Steven E. Calvano, and Stephen F. Lowry 2 Fluid and Electrolyte Management of the Surgical Patient 32 Rosemary A. Kozar and Frederick A. Moore 3 Hemostasis, Surgical Bleeding, and Transfusion 46 Seymour I. Schwartz 4 Shock 56 Andrew B. Peitzman, Brian G. Harbrecht, and Timothy R. Billiar 5 Surgical Infections 78 Gregory J. Beilman and David L. Dunn 6 Trauma 97 John M. Burch, Reginald J. Franciose, and Ernest E. Moore 7 Burns 138 James H. Holmes and David M. Heimbach 8 Wound Healing 165 Adrian Barbul 9 Oncology 183 Funda Meric-Bernstam and Raphael E. Pollock 10 Transplantation 216 Abhinav Humar and David L. Dunn 11 Patient Safety, Errors, and Complications in Surgery 245 Mark L. Shapiro and Peter B. Angood 12 Physiologic Monitoring of the Surgical Patient 275 Louis H. Alarcon and Mitchell P. Fink vii viii CONTENTS 13 Minimally Invasive Surgery 293 Blair A. Jobe and John G. Hunter 14 Cell, Genomics, and Molecular Surgery 309 Xin-Hua Feng, Jeffrey B. Matthews, Xia Lin, and F. Charles Brunicardi PART II SPECIFIC CONSIDERATIONS 15 Skin and Subcutaneous Tissue 329 Scott L. Hansen, Stephen J. Mathes, and David M. Young 16 The Breast 344 Kirby I. Bland, Samuel W. Beenken, and Edward E. Copeland, III 17 Disorders of the Head and Neck 369 Richard O. Wein, Rakesh K. Chandra, and Randal S. Weber 18 Chest Wall, Lung, Mediastinum, and Pleura 396 Michael A. Maddaus and James D. Luketich 19 Congenital Heart Disease 436 Tara B. Karamlou, Irving Shen, and Ross M. Ungerleider 20 Acquired Heart Disease 458 Charles F. Schwartz, Aubrey C. Galloway, Ram Sharony, Paul C. Saunders, Eugene A. Grossi, and Stephen B. Colvin 21 Thoracic Aortic Aneurysms and Aortic Dissection 496 Joseph S. Coselli and Scott A. LeMaire 22 Arterial Disease 515 Alan B. Lumsden, Peter H. Lin, Ruth L. Bush, and Changyi Chen 23 Venous and Lymphatic Disease 556 Gregory L. Moneta 24 Esophagus and Diaphragmatic Hernia 573 Jeffrey H. Peters and Tom R. DeMeester 25 Stomach 650 Daniel T. Dempsey 26 The Surgical Management of Obesity 685 Philip R. Schauer and Bruce David Schirmer CONTENTS ix 27 Small Intestine 702 Edward E. Whang, Stanley W. Ashley, and Michael J. Zinner 28 Colon, Rectum, and Anus 732 Kelli M. Bullard and David A. Rothenberger 29 The Appendix 784 David H. Berger and Bernard M. Jaffe 30 Liver 800 Steven A. Curley and Timothy D. Sielaff 31 Gallbladder and Extrahepatic Biliary System 821 Margrét Oddsdóttir and John G. Hunter 32 Pancreas 845 William E. Fisher, Dana K. Anderson, Richard H. Bell, Jr., Ashok K. Saluja, and F. Charles Brunicardi 33 Spleen 879 Adrian E. Park and Rodrick McKinlay 34 Abdominal Wall, Omentum, Mesentery, and Retroperitoneum 897 Robert L. Bell and Neal E. Seymour 35 Soft Tissue Sarcomas 906 Janice N. Cormier and Raphael E. Pollock 36 Inguinal Hernias 920 Robert J. Fitzgibbons, Jr. and Hardeep S. Ahluwalia 37 Thyroid, Parathyroid, and Adrenal 943 Geeta Lal and Orlo H. Clark 38 Pediatric Surgery 989 David J. Hackam, Kurt Newman, and Henri R. Ford 39 Urology 1036 Hyung L. Kim and Arie Belldegrun 40 Gynecology 1061 Gregory P. Sutton, Robert E. Rogers, William W. Hurd, and Martina F. Mutone 41 Neurosurgery 1102 Michael L. Smith and M. Sean Grady 42 Orthopaedics 1130 Dempsey Springﬁeld 43 Plastic and Reconstructive Surgery 1169 Saleh M. Shenaq, John Y.S. Kim, Alan Bienstock, Forrest S. Roth, and Eser Yuksel 44 Surgical Considerations in Older Adults 1188 Rosemarie E. Hardin and Michael E. Zenilman x CONTENTS 45 Anesthesia of the Surgical Patient 1201 Robert S. Dorian 46 ACGME Core Competencies 1223 Liz Nguyen, Mary L. Brandt, Samir S. Awad, Ruth Bush, David H. Berger, and F. Charles Brunicardi Index 1231 Contributors Hardeep S. Ahluwalia, MD Department of Surgery Medical Dean, Housestaff Brigham and Women’s Department of Surgery Hospital/Harvard Medical School Creighton University Medical Boston, Massachusetts Center Chapter 27: Small Intestine Omaha, Nebraska Chapter 36: Inguinal Hernias Samir S. Awad, MD Associate Professor of Surgery Louis H. Alarcon, MD Chief, Section of Critical Care Assistant Professor Michael E. DeBakey Department Departments of Surgery and Critical of Surgery Care Medicine Baylor College of Medicine University of Pittsburgh School of Medical Director SICU Medicine Michael E. DeBakey Veterans Pittsburgh, Pennsylvania Affairs Medical Center Chapter 12: Physiologic Monitoring Houston, Texas of the Surgical Patient Chapter 46: ACGME Core Competencies Dana K. Andersen, MS, FACS Professor and Vice-Chair Adrian Barbul, MD, FACS Department of Surgery Surgeon-in-Chief, Sinai Hospital Johns Hopkins School of Medicine of Baltimore and Surgeon-in-Chief Professor and Vice-Chairman, Johns Hopkins Bayview Medical Department of Surgery Center Johns Hopkins Medical Institutions Baltimore, Maryland Baltimore, Maryland Chapter 32: Pancreas Chapter 8: Wound Healing Peter B. Angood, MD, FACS, FCCM Samuel W. Beenken, MD, Professor of Surgery Anesthesia and FRCS(C), FACS Emergency Medicine Professor of Surgery Chief, Division of Trauma and The University of Alabama at Critical Care Birmingham University of Massachusetts Birmingham, Alabama Medical School and Chapter 16: The Breast University of Massachusetts— Memorial Health Care System Gregory J. Beilman, MD, FACS Worcester, Massachusetts Associate Professor of Surgery and Chapter 11: Patient Safety, Errors, Anesthesia and Complications in Surgery University of Minnesota Medical School Stanley W. Ashley, MD Minneapolis, Minnesota Professor and Vice Chairman Chapter 5: Surgical Infections xi Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of use. xii CONTRIBUTORS Richard H. Bell, Jr., MD, FACS Timothy R. Billiar, MD Loyal and Edith Davis Professor and George Vance Foster Chair Professor and Chairman Department of Surgery Department of Surgery Feinberg School of Medicine University of Pittsburgh School of Northwestern University Medicine Chicago, Illinois Pittsburgh, Pennsylvania Chapter 32: Pancreas Chapter 4: Shock Robert L. Bell, MD, MA Kirby I. Bland, MD, FACS Assistant Professor Fay Fletcher Kerner Professor and Department of Surgery Chairman Yale University School of Medicine Deputy Director, UAB New Haven, Connecticut Comprehensive Cancer Center Chapter 34: Abdominal Wall, Department of Surgery Omentum, Mesentery, and University of Alabama at Retroperitoneum Birmingham Birmingham, Alabama Arie Belldegrun, MD, FACS Chapter 16: The Breast Roy and Carol Doumani Chair in Urologic Oncology Mary L. Brandt, MD Professor of Urology Chief, Colorectal Clinic and Chief, Chief, Division of Urologic Oncology Pediatric Surgery Clinic David Geffen School of Medicine at Texas Children’s Hospital, Houston, University of California, Los Texas Angeles Professor of Surgery, Michael E. Los Angeles, California DeBakey Department of Chapter 39: Urology Surgery Professor of Pediatrics, Baylor David H. Berger, MD, FACS College of Medicine Associate Professor and Vice Chair Houston, Texas Michael E. DeBakey Department of Chapter 46: ACGME Core Surgery Competencies Baylor College of Medicine Operative Care Line Executive F. Charles Brunicardi, MD, FACS Chief, Surgical Services DeBakey/Bard Professor and Michael E. DeBakey Veterans Chairman Affairs Medical Center Michael E. DeBakey Department of Houston, Texas Surgery Chapter 29: The Appendix Baylor College of Medicine Chapter 46: ACGME Core Houston, Texas Competencies Chapter 14: Cell, Genomics, and Molecular Surgery Alan Bienstock, MD, BS Chapter 32: Pancreas Resident Chapter 46: ACGME Core Division of Plastic Surgery Competencies Michael E. DeBakey Department of Surgery Kelli M. Bullard, MD, FACS Baylor College of Medicine Assistant Professor of Surgery and Houston, Texas Laboratory Medicine and Chapter 43: Plastic and Pathology Reconstructive Surgery University of Minnesota CONTRIBUTORS xiii Minneapolis, Minnesota Division of Vascular Surgery and Chapter 28: Colon, Rectum, Endovascular Therapy and Anus Michael E. DeBakey Department of Surgery John M. Burch, MD Baylor College of Medicine Professor of Surgery Houston, Texas University of Colorado Health Chapter 22: Arterial Disease Sciences Center Chief of General and Vascular Orlo H. Clark, MD Surgery Professor of Surgery Denver Health Medical Center University of California, San Denver, Colorado Francisco/Mt. Zion Medical Chapter 6: Trauma Center Department of Surgery Ruth L. Bush, MD San Francisco, California Assistant Professor of Surgery Chapter 37: Thyroid, Parathyroid, Division of Vascular Surgery and and Adrenal Endovascular Therapy Michael E. DeBakey Department of Stephen B. Colvin, MD Surgery Chief, Cardiothoracic Surgery Baylor College of Medicine New York University School of Houston, Texas Medicine Chapter 22: Arterial Disease New York, New York Chapter 46: ACGME Core Chapter 20: Acquired Heart Competencies Disease Steven E. Calvano, PhD Edward E. Copeland, III, MD Associate Professor Distinguished Professor of Division of Surgical Sciences Surgery Department of Surgery University of Florida College of University of Medicine and Medicine Dentistry of New Jersey—Robert Gainesville, Florida Wood Johnson Medical School Chapter 16: The Breast New Brunswick, New Jersey Chapter 1: Systemic Response to Janice N. Cormier, MD, MPH Injury and Metabolic Support Assistant Professor of Surgery Department of Surgical Oncology Rakesh K. Chandra, MD The University of Texas M. D. Assistant Professor Anderson Cancer Center Director, Division of Nasal and Houston, Texas Sinus Disorders Chapter 35: Soft Tissue Sarcomas Residency Program Director Department of Otolaryngology— Joseph C. Coselli, MD Head and Neck Surgery Professor and Chief University of Tennessee Health Division of Cardiothoracic Science Center Surgery Memphis, Tennessee Michael E. DeBakey Department of Chapter 17: Disorders of the Head Surgery and Neck Baylor College of Medicine Houston, Texas Changyi Chen, MD, PhD Chapter 21: Thoracic Aortic Professor of Surgery Aneurysms and Aortic Dissection xiv CONTRIBUTORS Steven A. Curley, MD, FACS Mitchell P. Fink, MD Professor, Department of Surgical Professor and Chairman Oncology Department of Critical Care Chief, Gastrointestinal Tumor Medicine Surgery Watson Chair in Surgery The University of Texas M.D. University of Pittsburgh Anderson Cancer Center Pittsburgh, Pennsylvania Houston, Texas Chapter 12: Physiologic Monitoring Chapter 30: Liver of the Surgical Patient Tom R. DeMeester, MD William E. Fisher, MD, FACS The Jeffrey P. Smith Professor of Associate Professor of Surgery General and Thoracic Surgery Michael E. DeBakey Department of Chairman, Department of Surgery Surgery Keck School of Medicine, Baylor College of Medicine University of Southern California Houston, Texas Los Angeles, California Chapter 32: Pancreas Chapter 24: Esophagus and Diaphragmatic Hernia Robert J. Fitzgibbons, Jr., MD Harry E. Stuckenhoff Professor of Daniel T. Dempsey, MD, FACS Surgery Professor and Chairman of Department of Surgery Surgery Creighton University School of Temple University School of Medicine Medicine Omaha, Nebraska Philadelphia, Pennsylvania Chapter 36: Inguinal Hernias Chapter 25: Stomach Henri R. Ford, MD Robert S. Dorian, MD Benjamin R. Fisher Chair Chairman and Program Director Professor and Chief Department of Anesthesiology Division of Pediatric Surgery Saint Barnabas Medical Center Children’s Hospital of Livingston, New Jersey Pittsburgh Chapter 45: Anesthesia of the University of Pittsburgh School of Surgical Patient Medicine Pittsburgh, Pennsylvania David L. Dunn, MD, PhD Chapter 38: Pediatric Surgery Vice President for Health Sciences University at Buffalo/SUNY Reginald J. Franciose, MD Buffalo, New York Assistant Professor of Surgery Chapter 5: Surgical Infections University of Colorado Health Chapter 10: Transplantation Sciences Center Attending Surgeon Xin-Hua Feng, PhD Denver Health Medical Center Associate Professor of Surgery Denver, Colorado Division of General Surgery Chapter 6; Trauma Michael E. DeBakey Department of Surgery Aubrey C. Galloway, MD Baylor College of Medicine Professor of Surgery, Cardiothoracic Houston, Texas Surgery Chapter 14: Cell, Genomics, and Director, Cardiac Surgical Molecular Surgery Research CONTRIBUTORS xv New York University School of Rosemarie E. Hardin, MD Medicine Resident New York, New York Department of Surgery Chapter 20: Acquired Heart State University of New York Health Disease Science Medical Center Brooklyn, New York M. Sean Grady, MD, FACS Chapter 44: Surgical Charles Harrison Frazier Professor Considerations in the and Chairman Elderly Department of Neurosurgery University of Pennsylvania School David M. Heimbach, MD, FACS of Medicine Professor of Surgery Philadelphia, Pennsylvania University of Washington Burn Chapter 41: Neurosurgery Center Harborview Medical Center Eugene A. Grossi, MD Seattle, Washington Professor of Surgery, Cardiothoracic Chapter 7: Burns Surgery New York University School of James H. Holmes, MD Medicine Burn Fellow & Acting Instructor in New York, New York Surgery Chapter 20: Acquired Heart Harborview Medical Center— Disease University of Washington Seattle, Washington David J. Hackam, MD, PhD Chapter 7: Burns Assistant Professor of Surgery, Cell Biology and Physiology Abhinav Humar, MD, FRCS (Can) University of Pittsburgh School of Associate Professor Medicine Department of Surgery Attending Pediatric Surgeon University of Minnesota Co-Director, Fetal Diagnosis and Minneapolis, Minnesota Treatment Center Chapter 10: Transplantation Children’s Hospital of Pittsburgh Pittsburgh, Pennsylvania John G. Hunter, MD, FACS Chapter 38: Pediatric Surgery Mackenzie Professor and Chairman of Surgery Scott L. Hansen, MD Department of Surgery Resident, Plastic and Reconstructive Oregon Health and Science Surgery University University of California, San Portland, Oregon Francisco Chapter 13: Minimally-Invasive San Francisco, California Surgery Chapter 15; Skin and Subcutaneous Chapter 31: Gallbladder and Tissue Extrahepatic Biliary System Brain G. Harbrecht, MD, FACS Associate Professor of William W. Hurd, MD, FACOG, Surgery FACS Department of Surgery Nicholas J. Thompson Professor and University of Pittsburgh Chair Pittsburgh, Pennsylvania Department of Obstetrics and Chapter 4: Shock Gynecology xvi CONTRIBUTORS Wright State University School of Houston, Texas Medicine Chapter 2: Fluid and Electrolyte Dayton, Ohio Management of the Surgical Chapter 40: Gynecology Patient Bernard M. Jaffe, MD Greeta Lal, MD Professor of Surgery Assistant Professor of Surgery Tulane University School of Surgical Oncology and Endocrine Medicine Surgery New Orleans, Louisiana University of Iowa Hospital and Chapter 29: The Appendix Clinics Iowa City, Iowa Blair A. Jobe, MD Chapter 37: Thyroid, Parathyroid, Assistant Professor and Adrenal Department of Surgery Oregon Health and Science Scott A. LeMaire, MD University Assistant Professor Portland, Oregon Division of Cardiothoracic Surgery Chapter 13: Minimally-Invasive Baylor College of Medicine Surgery The Methodist DeBakey Heart Center Tara B. Karamlou, MD Houston, Texas Senior Research Fellow Chapter 21: Thoracic Aortic Division of Cardiothoracic Surgery Aneurysms and Aortic Oregon Health and Science Dissection University Portland, Oregon Edward Lin, DO, CNSP Chapter 19: Congenital heart Assistant Professor of Surgery Disease Division of Gastrointestinal and General Surgery Hyung L. Kim, MD Surgical Metabolism Laboratory Assistant Professor Emory University School of Department of Urology Medicine Department of Cellular Stress Atlanta, Georgia Biology Chapter 1: Systemic Response to Roswell Park Cancer Institute Injury and Metabolic Support Buffalo, New York Chapter 39: Urology Peter H. Lin, MD Associate Professor of Surgery John Y. S. Kim, MD Division of Vascular Surgery and Assistant Professor, Division of Endovascular Therapy Plastic Surgery Michael E. DeBakey Department of Department of Surgery Surgery Northwestern University School of Baylor College of Medicine Medicine Houston, Texas Chicago, Illinois Chapter 22: Arterial Disease Chapter 43: Plastic and Reconstructive Surgery Xia Lin, PhD Assistant Professor of Surgery Rosemary A. Kozar, MD, PhD Division of General Surgery Associate Professor of Surgery Michael E. DeBakey Department of University of Texas-Houston Surgery CONTRIBUTORS xvii Baylor College of Medicine University of California, San Houston, Texas Francisco Chapter 14: Cell, Genomics, and San Francisco, California Molecular Surgery Chapter 15: Skin and Subcutaneous Tissue Steven F. Lowry, MD, FACS Professor and Chairman Jeffrey B. Matthews, MD, FACS Department of Surgery Christian R. Holmes Professor and UMDNJ - Robert Wood Johnson Chairman Medical School Department of Surgery New Brunswick, New Jersey University of Cincinnati Chapter 1: Systemic Response to Cincinnati, Ohio Injury and Metabolic Chapter 14: Cell, Genomics, Support and Molecular Surgery James D. Luketich, MD Rodrick McKinlay, MD Professor and Chief, Division of Gastrointestinal and Minimally Thoracic and Foregut Invasive Surgery Surgery Rocky Mountain Associated University of Pittsburgh Medical Physicians Center Salt Lake City, Utah Pittsburgh, Pennsylvania Chapter 33: Spleen Chapter 18: Chest Wall, Lung, Mediastinum, and Pleura Funda Meric-Bernstam, MD, FACS Alan B. Lumsden, MD Assistant Professor Professor of Surgery Department of Surgical Oncology Division of Vascular Surgery and University of Texas M. D. Anderson Endovascular Therapy Cancer Center Michael E. DeBakey Department of Houston, Texas Surgery Chapter 9: Oncology Baylor College of Medicine Houston, Texas Gregory L. Moneta, MD Chapter 22: Arterial Disease Professor and Chief Vascular Surgery Michael A. Maddaus, MD, FACS Oregon Health and Science Professor and Head, Section of University General Thoracic Surgery Portland, Oregon Garamella-Lynch-Jensen Chair in Chapter 23: Venous and Lymphatic Thoracic and Cardiovascular Disease Surgery Co-Director, Minimally Invasive Ernest E. Moore, MD, FACS Surgery Center Professor and Vice Chairman, University of Minnesota Department of Surgery Minneapolis, Minnesota University of Colorado Health Chapter 18: Chest Wall, Lung, Sciences Center Mediastinum, and Pleura Chief of Surgery and Trauma Services Stephen J. Mathes, MD Denver Health Medical Professor of Surgery Center Chief, Division of Plastic and Denver, Colorado Reconstructive Surgery Chapter 6: Trauma xviii CONTRIBUTORS Frederick A. Moore, MD Adrian E. Park, MD, FRCS(C), James H. “Red” Duke, Jr. Professor FACS & Vice Chairman Campbell and Jeanette Plugge Department of Surgery Professor of Surgery The University of Texas Houston Chief, Division of General Surgery, Medical School Department of Surgery, University Houston, Texas of Maryland Medical Center Chapter 2: Fluid and Electrolyte Baltimore, Maryland Management of the Surgical Chapter 33: Spleen Patient Andre B. Peitzman, MD, FACS Martina F. Mutone, MD Professor and Vice-Chairman, Clinical Assistant Professor Department of Surgery Indiana University/Methodist University of Pittsburgh Medical Hospital Center St. Vincent Hospitals and Health Pittsburgh, Pennsylvania Services Chapter 4: Shock Indianapolis, Indiana Chapter 40: Gynecology J. Martin Perez MD Assistant Professor of Surgery Trauma and Surgical Critical Kurt Newman, MD, FACS Care Executive Director and Surgeon in University of Medicine and Chief Dentistry of New Jersey Joseph E. Robert, Jr. Center for New Brunswick, New Jersey Surgical Care Chapter 1: Systemic Response to Children’s National Medical Injury and Metabolic Support Center Professor of Surgery and Jeffrey H. Peters, MD, FACS Pediatrics Seymour I. Schwartz Professor and George Washington University Chairman School of Medicine University of Rochester School of Washington, D.C. Medicine and Dentistry Chapter 38: Pediatric Surgery Surgeon-in-Chief Strong Memorial Hospital Liz Nguyen, MD Department of Surgery Surgery Resident Rochester, New York Baylor College of Medicine Chapter 24; Esophagus and Houston, Texas Diaphragmatic Hernia Chapter 46: ACGME Core Competencies Raphael E. Pollock, MD, PhD, FACS Margrét Oddsdóttir, MD Head, Division of Surgery Professor of Surgery Professor and Chairman Chief of General Surgery Department of Surgical Oncology Landspitali–University Senator A.M. Aiken, Jr., Hospital Distinguished Chair Hringbraut The University of Texas M. D. Reykjavik, Iceland Anderson Cancer Center Chapter 31: Gallbladder and the Houston, Texas Extrahepatic Biliary Chapter 9: Oncology System Chapter 35: Soft Tissue Sarcomas CONTRIBUTORS xix Robert E. Rogers, MD The University of Pittsburgh Emeritus Professor, Obstetrics and Pittsburgh, Pennsylvania Gynecology Chapter 26: The Surgical Indiana University School of Management of Obesity Medicine Indianapolis, Indiana Bruce D. Schirmer, MD, FACS Chapter 40: Gynecology Stephen H. Watts Professor of Surgery Forrest S. Roth, MD University of Virginia Health Fellow in Plastic Reconstructive and System Microsurgery Charlottesville, Virginia Division of Plastic and Chapter 26: The Surgical Reconstructive Surgery Management of Obesity Michael E. DeBakey Department of Surgery Charles F. Schwartz, MD Baylor College of Medicine Assistant Professor of Surgery Houston, Texas Division of Cardiothoracic Surgery Chapter 43: Plastic and New York University School of Reconstructive Surgery Medicine New York, New York David A. Rothenberger, MD Chapter 20: Acquired Heart Disease Professor of Surgery Chief, Divisions of Colon and Rectal Surgery and Surgical Oncology Seymour I. Schwartz, MD, FACS Department of Surgery Distinguished Alumni Professor of University of Minnesota Surgery Minneapolis, Minnesota University of Rochester School of Chapter 28: Colon, Rectum, and Medicine and Dentistry Anus Rochester, New York Chapter 3: Hemostasis, Surgical Ashok K. Saluja, PhD Bleeding, and Transfusion Professor of Surgery, Medicine, and Cell Biology Neal E. Seymour, MD, FACS University of Massachusetts Associate Professor Tufts University Medical School School of Medicine Worcester, Massachusetts Vice Chairman Department of Chapter 32: Pancreas Surgery Baystate Medical Center Paul C. Saunders, MD Springﬁeld, Massachusetts Fellow Chapter 34: Abdominal Wall, Division of Cardiothoracic Surgery Omentum, Mesentery, and New York University School of Retroperitoneum Medicine New York, New York Mark L. Shapiro, MD Chapter 20: Acquired Heart Assistant Professor of Surgery Disease Department of Surgery Division of Trauma and Critical Care Philip R. Schauer, MD University of Massachusetts Associate Professor of Surgery Medical School Director of Bariatric Surgery Worcester, Massachusetts Chief, Minimally Invasive General Chapter 11: Patient Safety, Errors, Surgery and Complications in Surgery xx CONTRIBUTORS Ram Sharony, MD Gregory P. Sutton, MD Minimally Invasive Cardiac Surgery Director, Gynecologic Fellow Oncology Division of Cardiothoracic Surgery St. Vincent Oncology Center New York University Medical St. Vincent Hospitals and Health Center Services New York, New York Indianapolis, Indiana Chapter 20: Acquired Heart Disease Chapter 40: Gynecology Ross M. Ungerleider, MD Irving Shen, MD Professor of Surgery Assistant Professor of Surgery Chief, Division of Cardiothoracic Division of Cardiothoracic Surgery Surgery Oregon Health and Science Oregon Health and Science University University Portland, Oregon Portland, Oregon Chapter 19: Congenital Heart Chapter 19: Congenital Heart Disease Disease Randal S. Weber, MD, FACS Saleh M. Shenaq, MD Hubert L. and Olive Stringer, Chief, Division of Plastic Surgery Distinguished Professor and Professor of Surgery Chairman Michael E. DeBakey Department of Department of Head and Neck Surgery Surgery Baylor College of Medicine University of Texas M.D. Anderson Houston, Texas Cancer Center Chapter 43: Plastic and Houston, Texas Reconstructive Surgery Chapter 17: Disorders of the Head and Neck Timothy D. Sielaff, MD, PhD, FACS Richard O. Wein, MD Associate Professor Assistant Professor Department of Surgery Department of Otolaryngology and University of Minnesota Communicative Sciences Minneapolis, Minnesota University of Mississippi Medical Chapter 30: Liver Center Jackson, Mississippi Michael L. Smith, MD Chapter 17: Disorders of the Head Resident and Neck Department of Neurosurgery University of Pennsylvania School Edward E. Whang, MD of Medicine Assistant Professor of Surgery Philadelphia, Pennsylvania Brigham and Women’s Hospital Chapter 41: Neurosurgery Harvard Medical School Boston, Massachusetts Dempsey Springﬁeld, MD Chapter 27: Small Intestine Professor and Chairman Department of Orthopaedics David M. Young, MD, FACS The Mount Sinai School of Medicine Associate Professor of Plastic New York, New York Surgery Chapter 42: Orthopedics Department of Surgery CONTRIBUTORS xxi University of California, San Michael E. Zenilman, MD Francisco Clarence and Mary Dennis Professor San Francisco, California and Chairman Chapter 15: Skin and Subcutaneous Department of Surgery Tissue State University of New York Downstate Medical Center Eser Yuksel, MD Brooklyn, New York Assistant Professor Plastic Chapter 44: Surgical Surgery Considerations in the Elderly Division of Plastic Surgery Baylor College of Medicine Michael J. Zinner, MD Adjunct Assistant Professor Moseley Professor of Surgery Department of Bioengineering Harvard Medical School Rice University Surgeon-in-Chief and Chairman ONEP Plastic Surgery Institute, Department of Surgery Istanbul Brigham and Women’s Hospital Chapter 43: Plastic and Boston, Massachusetts Reconstructive Surgery Chapter 27: Small Intestine This page intentionally left blank Preface This manual, crafted for easy portability and convenient reference by surgical students and house ofﬁcers, is intended as a supplement to the eighth edition of Schwartz’s Principles of Surgery. These condensed chapters, edited by their original authors, provide a concise synopsis of each chapter and are meant as a companion to the main text. I am grateful for the efforts of all whom contributed and their willingness and dedication to further the education of students of surgery. I also express my deep appreciation to Katie Elsbury, who worked with the contributors, the publisher, and with me in every step of the production of this book. F. Charles Brunicardi, MD, FACS Editor-in-Chief xxiii Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of use. This page intentionally left blank PART I BASIC CONSIDERATIONS Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of use. 1 This page intentionally left blank 1 Systemic Response to Injury and Metabolic Support J. Martin Perez, Edward Lim, Steven E. Calvano, and Stephen F. Lowry The inﬂammatory response to injury is designed to restore tissue function and eradicate invading microorganisms. Injuries of limited duration are usually fol- lowed by functional restoration with minimal intervention. By contrast, major insults to the host are associated with an overwhelming inﬂammatory response that, without appropriate and timely intervention, can lead to multiple-organ failure and adversely impact patient survival. Therefore, understanding how the inﬂammatory response is mobilized and controlled provides a functional framework on which interventions and therapeutics are formulated for the surgical patient. This chapter addresses the hormonal, immunologic, and cellular responses to injury. Alterations of metabolism and nutrition in injury states are discussed in continuum because the utilization of fuel substrates during injury also is subject to the inﬂuences of hormonal and inﬂammatory mediators. THE SYSTEMIC INFLAMMATORY RESPONSE SYNDROME The systemic response to injury can be broadly compartmentalized into two phases: (1) a proinﬂammatory phase characterized by activation of cellular pro- cesses designed to restore tissue function and eradicate invading microorgan- isms, and (2) an antiinﬂammatory (counterregulatory phase) that is important for preventing excessive proinﬂammatory activities and restoring homeostasis in the individual (Table 1-1). CENTRAL NERVOUS SYSTEM REGULATION OF INFLAMMATION Reﬂex Inhibition of Inﬂammation The central nervous system (CNS), via autonomic signaling, has an integral role in regulating the inﬂammatory response that is primarily involuntary. The autonomic system regulates heart rate, blood pressure, respiratory rate, gastrointestinal (GI) motility, and body temperature. The autonomic nervous system also regulates inﬂammation in a reﬂex manner, much like the patellar tendon reﬂex. The site of inﬂammation sends afferent signals to the hypothal- amus, which in turn rapidly relays opposing antiinﬂammatory messages to reduce inﬂammatory mediator release by immunocytes. Afferent Signals to the Brain The CNS receives immunologic input from both the circulation and neural pathways. Areas of the CNS devoid of blood–brain barrier admit the passage of inﬂammatory mediators such as tumor necrosis factor (TNF)-α. Fevers, anorexia, and depression in illness are attributed to the humoral (circulatory) route of inﬂammatory signaling. Although the mechanism for vagal sensory input is not fully understood, it has been demonstrated that afferent stimuli 3 Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of use. 4 PART I BASIC CONSIDERATIONS TABLE 1-1 Clinical Spectrum of Infection and Systemic Inflammatory Response Syndrome (SIRS) Term Deﬁnition Infection Identiﬁable source of microbial insult SIRS Two or more of following criteria Temperature ≥38◦ C or ≤36◦ C Heart rate ≥90 beats/min Respiratory rate ≥20 breaths/min or Paco2 ≤32 mm Hg or mechanical ventilation White blood cell count ≥12,000/µL or ≤4000/µL or ≥10% band forms Sepsis Identiﬁable source of infection + SIRS Severe sepsis Sepsis + organ dysfunction Septic shock Sepsis + cardiovascular collapse (requiring vasopressor support) to the vagus nerve include cytokines (e.g., TNF-α and interleukin [IL]-1), baroreceptors, chemoreceptors, and thermoreceptors originating from the site of injury. Cholinergic Antiinﬂammatory Pathways Acetylcholine, the primary neurotransmitter of the parasympathetic system, reduces tissue macrophage activation. Furthermore, cholinergic stimulation directly reduces tissue macrophage release of the proinﬂammatory mediators TNF-α, IL-1, IL-18, and high mobility group protein (HMG-1), but not the antiinﬂammatory cytokine IL-10. The attenuated inﬂammatory response in- duced by cholinergic stimuli was further validated by the identiﬁcation of acetylcholine (nicotinic) receptors on tissue macrophages. In summary, vagal stimulation reduces heart rate, increases gut motility, dilates arterioles, and causes pupil constriction, and regulates inﬂammation. Unlike the humoral antiinﬂammatory mediators, signals discharged from the vagus nerve are targeted at the site of injury or infection. Moreover, this cholin- ergic signaling occurs rapidly in real time. HORMONAL RESPONSE TO INJURY Hormone Signaling Pathways Hormones are chemically classiﬁed as polypeptides (e.g., cytokines, glucagon, and insulin), amino acids (e.g., epinephrine, serotonin, and histamine), or fatty acids (e.g., glucocorticoids, prostaglandins, and leukotrienes [LT]). Most hor- mone receptors generate signals by one of three major overlapping pathways: (1) receptor kinases such as insulin and insulin-like growth factor receptors, (2) guanine nucleotide-binding or G-protein receptors such as neurotransmit- ter and prostaglandin receptors, (3) ligand-gated ion channels, which permit ion transport when activated. Membrane receptor activation leads to ampliﬁca- tion via secondary signaling pathways. Hormone signals are further mediated by intracellular receptors with binding afﬁnities for both the hormone itself, and for the targeted gene sequence on the deoxyribonucleic acid (DNA). The classic example of a cytosolic hormonal receptor is the glucocorticoid (GC) receptor. CHAPTER 1 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT 5 TABLE 1-2 Hormones Regulated by the Hypothalamus, Pituitary, and Autonomic System Hypothalamic Regulation Corticotropin-releasing hormone Thyrotropin-releasing hormone Growth hormone-releasing hormone Luteinizing hormone-releasing hormone Anterior Pituitary Regulation Adrenocorticotropic hormone Cortisol Thyroid-stimulating hormone Thyroxine Triiodothyronine Growth hormone Gonadotrophins Sex hormones Insulin-like growth factor Somatostatin Prolactin Endorphins Posterior Pituitary Regulation Vasopressin Oxytocin Autonomic System Norepinephrine Epinephrine Aldosterone Renin-angiotensin system Insulin Glucagon Enkephalins Hormones of the hypothalamic-pituitary-adrenal (HPA) axis inﬂuences the physiologic response to injury and stress (Table 1-2), but some with direct inﬂuence on the inﬂammatory response or immediate clinical impact will be highlighted. Adrenocorticotropic Hormone Adrenocorticotropic hormone (ACTH) is synthesized and released by the an- terior pituitary. In healthy humans, ACTH release is regulated by circadian signals with high levels of ACTH occurring late at night until the hours im- mediately before sunrise. During injury, this pattern is dramatically altered. Elevations in corticotropin-releasing hormone and ACTH are typically pro- portional to the severity of injury. Pain, anxiety, vasopressin, angiotensin II, cholecystokinin, vasoactive intestinal polypeptide (VIP), catecholamines, and proinﬂammatory cytokines are all prominent mediators of ACTH release in the injured patient. Cortisol and Glucocorticoids Cortisol is the major glucocorticoid in humans and is essential for survival during signiﬁcant physiologic stress. Following injury, the degree of cortisol elevation is dependent on the degree of systemic stress. For example, burn 6 PART I BASIC CONSIDERATIONS patients have elevated circulating cortisol levels for up to 4 weeks, whereas lesser injuries may exhibit shorter periods of cortisol elevation. Cortisol potentiates the actions of glucagon and epinephrine that manifest as hyperglycemia. Cortisol stimulates gluconeogenesis, but induces insulin resis- tance in muscles and adipose tissue. In skeletal muscle, cortisol induces protein degradation and the release of lactate that serve as substrates for hepatic glu- coneogenesis. During injury, cortisol potentiates the release of free fatty acids, triglycerides, and glycerol from adipose tissue providing additional energy sources. Acute adrenal insufﬁciency (AAI) secondary to exogenous glucocorti- coid administration can be a life-threatening complication most commonly seen in acutely ill patients. These patients present with weakness, nausea, vomiting, fever, and hypotension. Objective ﬁndings include hypoglycemia from decreased gluconeogenesis, hyponatremia, and hyperkalemia. Insufﬁ- cient mineralocorticoid (aldosterone) activity also contributes to hyponatremia and hyperkalemia. Glucocorticoids have long been employed as immunosuppressive agents. Immunologic changes associated with glucocorticoid administration include thymic involution, depressed cell-mediated immune responses reﬂected by decreases in T-killer and natural killer cell functions, T-lymphocyte blasto- genesis, mixed lymphocyte responsiveness, graft-versus-host reactions, and delayed hypersensitivity responses. With glucocorticoid administration, mono- cytes lose the capacity for intracellular killing but appear to maintain nor- mal chemotactic and phagocytic properties. For neutrophils, glucocorticoids inhibit intracellular superoxide reactivity, suppress chemotaxis, and normal- ize apoptosis signaling mechanisms. However, neutrophil phagocytosis func- tion remains unchanged. Clinically, glucocorticoids has been associated with modest reductions in proinﬂammatory response in septic shock, surgical trauma, and coronary artery bypass surgery. However, the appropriate dos- ing, timing, and duration of glucocorticoid administration have not been validated. Macrophage Inhibitory Factor Macrophage inhibitory factor (MIF) is a glucocorticoid antagonist produced by the anterior pituitary that potentially reverses the immunosuppressive ef- fects of glucocorticoids. MIF can be secreted systemically from the anterior pituitary and by T lymphocytes situated at the sites of inﬂammation. MIF is a proinﬂammatory mediator that potentiates gram-negative and gram-positive septic shock. Growth Hormones and Insulin-Like Growth Factors During periods of stress, growth hormone (GH), mediated in part by the secondary release of insulin-like growth factor-1 (IGF-1), promotes protein synthesis and enhances the mobilization of fat stores. IGF, formerly called somatomedin C, circulates predominantly in bound form and promotes amino acid incorporation, cellular proliferation, skeletal growth, and attenuates pro- teolysis. In the liver, IGFs are mediators of protein synthesis and glycogenesis. In adipose tissue, IGF increases glucose uptake and fat utilization. In skeletal muscles, IGF increases glucose uptake and protein synthesis. The decrease in protein synthesis and observed negative nitrogen balance following injury is at- tributed in part to a reduction in IGF-1 levels. GH administration has improved CHAPTER 1 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT 7 the clinical course of pediatric burn patients. Its use in injured adult patients remains unproven. Catecholamines The hypermetabolic state observed following severe injury is attributed to activation of the adrenergic system. Norepinephrine (NE) and epinephrine (EPI) are increased 3- to 4-fold in plasma immediately following injury, with elevations lasting 24–48 hours before returning toward baseline levels. In the liver, EPI promotes glycogenolysis, gluconeogenesis, lipolysis, and ketogenesis. It also causes decreased insulin release, but increases glucagon secretion. Peripherally, EPI increases lipolysis in adipose tissues and in- duces insulin resistance in skeletal muscle. These collectively manifest as stress-induced hyperglycemia, not unlike the effects of cortisol on blood sugar. Like cortisol, EPI enhances leukocyte demargination with resultant neu- trophilia and lymphocytosis. However, EPI occupation of β receptors present on leukocytes ultimately decreases lymphocyte responsiveness to mitogens. In noncardiac surgical patients with heart disease, perioperative β-receptor blockade also reduced sympathetic activation and cardiac oxygen demand with signiﬁcant reductions in cardiac-related deaths. Aldosterone The mineralocorticoid aldosterone is synthesized, stored, and released, via ACTH stimulation, in the adrenal zona glomerulosa. The major function of aldosterone is to maintain intravascular volume by conserving sodium and eliminating potassium and hydrogen ions in the early distal convoluted tubules of the nephrons. Patients with aldosterone deﬁciency develop hypotension and hyperkalemia, whereas patients with aldosterone excess develop edema, hypertension, hy- pokalemia, and metabolic alkalosis. Insulin Hormones and inﬂammatory mediators associated with stress response inhibit insulin release. In conjunction with peripheral insulin resistance following injury, this results in stress-induced hyperglycemia and is in keeping with the general catabolic state immediately following major injury. In the healthy individual, insulin exerts a global anabolic effect by promot- ing hepatic glycogenesis and glycolysis, glucose transport into cells, adipose tissue lipogenesis, and protein synthesis. During injury, insulin release is ini- tially suppressed followed by normal or excessive insulin production despite hyperglycemia. Activated lymphocytes express insulin receptors, and activation enhances T-cell proliferation and cytotoxicity. Tight control of glucose levels in the critically ill has been associated with signiﬁcant reductions in morbidity and mortality. Acute Phase Proteins The acute phase proteins are nonspeciﬁc biochemical markers produced by hepatocytes in response to tissue injury, infection, or inﬂammation. IL-6 is a potent inducer of acute phase proteins that can include proteinase inhibitors, coagulation and complement proteins, and transport proteins. Only C-reactive 8 PART I BASIC CONSIDERATIONS protein (CRP) has been consistently used as a marker of injury response because of its dynamic reﬂection of inﬂammation. The accuracy of CRP ap- pears to surpass that of the erythrocyte sedimentation rate. MEDIATORS OF INFLAMMATION Cytokines Cytokines are the most potent mediators of the inﬂammatory response. When functioning locally at the site of injury or infection, cytokines eradicate invad- ing microorganisms and promote wound healing. Overwhelming production of proinﬂammatory cytokines in response to injury can cause hemodynamic instability (e.g., septic shock) or metabolic derangements (e.g., muscle wast- ing). If uncontrolled, the outcome of these exaggerated responses is end-organ failure and death. The production of antiinﬂammatory cytokines serves to op- pose the actions of proinﬂammatory cytokines. To view cytokines merely as proinﬂammatory or antiinﬂammatory oversimpliﬁes their functions, and over- lapping bioactivity is the rule (Table 1-3). Heat Shock Proteins Hypoxia, trauma, heavy metals, local trauma, and hemorrhage all induce the production of intracellular heat shock proteins (HSPs). HSPs are intracellular protein modiﬁers and transporters that are presumed to protect cells from the deleterious effects of traumatic stress. The formation of HSPs requires gene induction by the heat shock transcription factor. Reactive Oxygen Metabolites Reactive oxygen metabolites are short-lived, highly reactive molecular oxygen species with an unpaired outer orbit. Tissue injury is caused by oxidation of unsaturated fatty acids within cell membranes. Activated leukocytes are potent generators of reactive oxygen metabolites. Furthermore, ischemia with reperfusion also generates reactive oxygen metabolites. Oxygen radicals are produced by complex processes that involve anaerobic glucose oxidation coupled with the reduction of oxygen to superoxide anion. Superoxide anion is an oxygen metabolite that is further metabolized to other reactive species such as hydrogen peroxide and hydroxyl radicals. Cells are generally protected by oxygen scavengers that include glutathione and cata- lases. Eicosanoids The eicosanoid class of mediators, which encompasses prostaglandins (PGs), thromboxanes (TXs), LTs, hydroxy-icosatetraenoic acids (HETEs), and lipox- ins (LXs), are oxidation derivatives of the membrane phospholipid arachidonic acid (eicosatetraenoic acid). Eicosanoids are secreted by virtually all nucleated cells except lymphocytes. Products of the cyclooxygenase pathway include all of the prostaglandins and thromboxanes. The lipoxygenase pathway generates the LT and HETE. Eicosanoids are synthesized rapidly on stimulation by hypoxic injury, direct tissue injury, endotoxin, NE, vasopressin, angiotensin II, bradykinin, serotonin, acetylcholine, cytokines, and histamine. COX-2, a second cyclooxygenase enzyme, converts arachidonate to prostaglandin E2 (PGE2 ). PGE2 increases CHAPTER 1 SYSTEMIC RESPONSE TO INJURY AND METABOLIC SUPPORT 9 TABLE 1-3 Cytokines and Their Sources Cytokine Source Comment TNF-α Macrophages/monocytes Among earliest responders following Kupffer cells injury; half-life 40% Pulse rate 100 >120 >140 Blood pressure Normal Normal Decreased Decreased Pulse pressure Normal or Decreased Decreased Decreased (mm Hg) increased Respiratory rate 14–20 20–30 30–40 >35 Urine output (mL/h) >30 20–30 5–15 Negligible CNS/mental status Slightly Mildly anxious Anxious and Confused anxious confused and lethargic BV = blood volume; CNS = central nervous system. may not be able to increase their heart rate in response to stress. In children relative bradycardia can occur with severe blood loss and is an ominous sign. On the other hand, hypoxia, pain, apprehension, and stimulant drugs (co- caine, amphetamines) will produce a tachycardia. In healthy patients blood volume must decrease by 30–40 percent before hypotension occurs (Table 6-1). Younger patients with good sympathetic tone can maintain systemic blood pressure with severe intravascular deﬁcits. Acute changes in mental status can be caused by hypoxia, hypercarbia, hypovolemia or may be an early sign of increasing intracranial pressure (ICP). A deterioration in mental status may be subtle and may not progress in a predictable fashion. Previously cooperative patients may become anxious and combative as they become hypoxic; whereas, a patient agitated from drugs or alcohol may become somnolent if hypovolemic shock develops. Urine output is a sensitive indicator of organ perfusion. Adequate urine output is.5 mL/kg/h in an adult, 1 mL/kg/h in a child, and 2 mL/kg/h in an infant younger than 1 year of age. Based on the initial response to ﬂuid resuscitation, hypovolemic injured patients will separate themselves into three broad categories: responders, tran- sient responders, and nonresponders. Persistent Hypotension (Nonresponders) The spectrum of disease in this category ranges from nonsurvivable multisys- tem injury to problems as simple as a tension pneumothorax. An evaluation of the patient’s neck veins and central venous pressure (CVP) is an important early maneuver. CVP determines right ventricular preload; and in otherwise healthy trauma patients, its measurement yields objective information regard- ing the patient’s overall volume status. A hypotensive patient with a CVP less than 5 cm H2 O is hypovolemic and is likely to have ongoing hemorrhage. A hypotensive patient with a CVP greater than 15 cm H2 O is likely to be in cardiogenic shock. In trauma patients the differential diagnosis of cardiogenic shock is a short list: 1) tension pneumothorax, 2) pericardial tamponade, 3) myocardial contusion or infarction, and 4) air embolism. Tension pneumothorax is the most frequent cause of cardiac failure. Traumatic pericardial tamponade most 100 PART I BASIC CONSIDERATIONS often is associated with penetrating injury to the heart. As blood leaks out of the injured heart, it accumulates in the pericardial sac. When the pressure ex- ceeds that of the right atrium, right ventricular preload is reduced. With acute tamponade as little as 100 mL of blood within the pericardial sac can pro- duce life-threatening hemodynamic compromise. The usual presentation is a patient with a penetrating injury in proximity to the heart who is hypotensive and has distended neck veins or an elevated CVP. Ultrasonography (US) in the emergency department using a subxiphoid or parasternal view is extremely helpful. Once the diagnosis of cardiac tamponade is established, pericardio- centesis should be performed. Evacuation of as little as 15–25 mL of blood may dramatically improve the patient’s hemodynamic proﬁle. While pericardiocen- tesis is being performed, preparation should be made for emergent transport to the OR. If pericardiocentesis is unsuccessful and the patient remains severely hypotensive (SBP 5 mL/day) re- quire a similar dressing as moderately draining wounds, but with the addition of a highly absorbent secondary layer. Mechanical Devices The VAC (vacuum-assisted closure) system assists in wound closure by ap- plying localized negative pressure to the surface and margins of the wound. This negative pressure therapy is applied to a special foam dressing cut to the dimensions of the wound and positioned in the wound cavity or over a ﬂap or graft. The continuous negative pressure is very effective in removing exu- dates from the wound. This form of therapy has been found to be effective for chronic open wounds (diabetic ulcers and stages 3 and 4 pressure ulcers), acute and traumatic wounds, ﬂaps and grafts, and subacute wounds (i.e., dehisced incisions). CHAPTER 8 WOUND HEALING 181 Skin Replacements All wounds require coverage to prevent evaporative losses and infection and to provide an environment that promotes healing. Both acute and chronic wounds may demand use of skin replacement, and several options are available. Conventional Skin Grafts Split- or partial-thickness grafts consist of the epidermis plus part of the dermis, although full-thickness grafts retain the entire dermis. Autologous grafts are transplants from one site on the body to another; allogeneic grafts (allografts, homografts) are transplants from a living nonidentical donor or cadaver to the host; and xenogeneic grafts (heterografts) are taken from another species (e.g., porcine). Split-thickness grafts require less blood supply to restore skin function. The dermal component of full-thickness grafts lends mechanical strength and resists wound contraction better, resulting in improved cosmesis. Allogeneic and xenogeneic grafts are subject to rejection, and may contain pathogens. The use of skin grafts or bioengineered skin substitutes and other inno- vative treatments cannot be effective unless the wound bed is adequately prepared. Skin Substitutes Skin substitutes promote healing, either by stimulating host cytokine genera- tion or by providing cells that may also produce growth factors locally. Their disadvantages include limited survival, high cost, and the need for multiple applications. Composite substitutes provide both the dermal and epidermal components essential for permanent skin replacement. The acellular (e.g., native collagen or synthetic material) component acts as a scaffold, promotes cell migration and growth, and activates tissue regeneration and remodeling. The cellular elements re-establish lost tissue and associated function, synthesize extracellular matrix components, produce essential mediators such as cytokines and growth factors, and promote proliferation and migration. Cultured epithelial autografts (CEAs) represent expanded autologous or homologous keratinocytes. CEAs are expanded from a biopsy of the patient’s own skin, will not be rejected, and can stimulate re-epithelialization and the growth of underlying connective tissue. Keratinocytes harvested from a biopsy roughly the size of a postage stamp are cultured with ﬁbroblasts and growth factors and grown into sheets that can cover large areas and give the appear- ance of normal skin. Until the epithelial sheets are sufﬁciently expanded, the wound must be covered with an occlusive dressing or a temporary allograft or xenograft. Viable ﬁbroblasts can be grown on bioabsorbable or nonbioabsorbable meshes to yield living dermal tissue that can act as a scaffold for epider- mal growth. Fibroblasts stimulated by growth factors can produce type I collagen and glycosaminoglycans which adhere to the wound surface to permit epithelial cell migration, and adhesive ligands (e.g., the matrix pro- tein ﬁbronectin), which promote cell adhesion. This approach has the virtue of being less time-consuming and expensive than culturing keratinocyte sheets. 182 PART I BASIC CONSIDERATIONS Growth Factor Therapy It is believed that nonhealing wounds result from insufﬁcient or inadequate growth factors in the wound environment. Although there is a large body of work demonstrating the effects of growth factors in animals, translation of these data into clinical practice has met with limited success. At present, only platelet-derived growth factor BB (PDGF-BB) is currently approved by the Food and Drug Administration (FDA) for treatment of diabetic foot ulcers. Application of recombinant human PDGF-BB in a gel suspension to these wounds increases the incidence of total healing and decreases healing time. Suggested Readings Witte MB, Barbul A: General principles of wound healing. Surg Clin NA 77:509–528, 1997. Singer AJ, Clark RAF: Cutaneous wound repair. N Engl J Med 341:738–746, 1999. Williams JZ, Barbul A: Nutrition and Wound Healing. Surgical Clinics of North America 83:571–596, 2003. Cross KJ, Mustoe TA: Growth factors in wound healing. Surgical Clinics of North America 83:531–545, 2003. Rahban SR, Garner WL: Fibroproliferative scars. Clin Plastic Surg 30:77–89, 2003. Werner S, Grose R: regulation of wound healing by growth factors and cytokines. Physiol Rev 83:835–870, 2002. 9 Oncology Funda Meric-Bernstam and Raphael E. Pollock As the population ages, oncology is becoming a larger portion of surgical practice. Modern cancer therapy is multidisciplinary, involving the coordinated care of surgeons, medical oncologists, radiation oncologists, reconstructive surgeons, pathologists, radiologists, and primary care physicians. Primary (or deﬁnitive) therapy refers to en bloc resection of tumor with adequate margins of normal tissues and in some cases regional lymph nodes. Adjuvant therapy refers to radiation therapy and systemic therapies, including chemotherapy, immunotherapy, hormonal therapy, and increasingly, biologic therapy. The primary goal of surgical and radiation therapy is local and regional control. On the other hand, the primary goal of systemic therapies is systemic control by treating distant foci of subclinical disease to prevent recurrence. Surgeons must be familiar with adjuvant therapies to coordinate multidisciplinary care. Knowledge of cancer epidemiology, etiology, staging and natural history is also required to determine the optimal surgical therapy. EPIDEMIOLOGY Basic Principles of Cancer Epidemiology The term incidence refers to the number of new cases occurring; incidence usually is expressed as the number of new cases per 100,000 persons per year. Mortality refers to the number of deaths occurring and is expressed as the number of deaths per 100,000 persons per year. Incidence and mortality data are usually available through cancer registries. The incidence of cancer is variable by geography. This is due in part to genetic differences and in part to differences in environmental and dietary exposures. Epidemiologic studies that monitor trends in cancer incidence and mortality have tremendously enhanced our understanding of the etiology of cancer. The two types of epidemiologic studies that are conducted most often to investigate the etiology of cancer and the effect of prevention modalities are cohort studies and case-control studies. Cohort studies follow a group of peo- ple who initially do not have a disease over time and measure the rate of development of a disease. In cohort studies, a group that is exposed to a certain environmental factor or intervention usually is compared to a group that has not been exposed (e.g., smokers vs. nonsmokers). Case-control studies compare a group of patients affected with a disease to a group of individuals without the disease for a given exposure. The results are expressed in terms of an odds ratio, or relative risk. A relative risk less than 1 indicates a protective effect, although a relative risk greater than 1 indicates an increased risk of developing the disease with exposure. Cancer Incidence and Mortality in the United States In the year 2003, an estimated 1,334,100 new cases of invasive cancer will be diagnosed in the United States. Furthermore, an estimated 556,500 people will die from cancer in the United States in the same year. The most common 183 Copyright © 2006 by The McGraw-Hill Companies, Inc. Click here for terms of use. 184 PART I BASIC CONSIDERATIONS causes of cancer death in men are cancers of the lung and bronchus, prostate, and colon and rectum; in women, the most common cancers are of the lung and bronchus, breast, and colon and rectum. Trends in Cancer Incidence and Mortality Cancer deaths accounted for 23 percent of all deaths in the United States in 2000, second only to deaths from heart disease, which accounted for 29.6 percent of total deaths. As the life expectancy of the human population in- creases because of reductions in other causes of death such as infections and cardiovascular disease, cancer is becoming the leading cause of death. Cancer is already the leading cause of death among women aged 40–79 and among men aged 60–79. Cancer incidence increased by 0.3 percent per year in females during the period from 1987 to 1999, but it stabilized in males between 1995 and 1999. Interestingly, prostate cancer rates increased dramatically between 1988 and 1992, and declined between 1992 and 1995. These trends are thought to reﬂect the extensive use of prostate-speciﬁc antigen (PSA) screening, leading to the earlier diagnosis of prostate cancers. From 1992 to 1999, for all cancer types combined, cancer death rates de- creased by 1.5 percent per year in males and by 0.6 percent per year in females. In fact, the 5-year survival rates from 1974 to 1998 reveal improvement in rel- ative survival rates for cancers in almost all sites. How much of this improve- ment reﬂects actual improvement of cancer therapy and how much simply reﬂects earlier diagnosis of tumors with stage-for-stage outcome remaining unchanged, is not yet known. Global Statistics on Cancer Incidence and Mortality It has been estimated that there were a total of 10.1 million new cancer cases around the world in 2000, a number 22 percent higher than estimates for 1990. The most common cancers in terms of new cases were lung cancer (1.2 million), breast cancer (1.05 million), colon-rectum (945,000), stomach (876,000), and liver (564,000) in 2000. The most common causes of death because of cancer in 2000 were cancers of the lung (1.1 million), stomach (647,000), and liver cancer (549,000). Stomach Cancer The incidence of stomach cancer varies signiﬁcantly among different regions of the world. The age-adjusted incidence is highest in Japan. The difference in risk by country is presumed to be because of differences in dietary factors and in the incidence of infection with Helicobacter pylori, which is known to play a major role in gastric cancer development. Fortunately, a steady decline is being observed in the incidence and mortality rates of gastric cancer. This may be related to improvements in preservation and storage of foods. Breast Cancer The incidence of breast cancer is high in all of the most highly developed regions except Japan, including the United States and Canada, Australia, and Northern and Western Europe. The highest breast cancer incidence is in the United States and the lowest is in China. Although breast cancer has been linked to cancer susceptibility genes, mutations in these genes account for only 5–10 percent of breast tumors, suggesting that the wide geographic variations CHAPTER 9 ONCOLOGY 185 in breast cancer incidence are not because of geographic variations in the prevalence of these genes. Most of the differences, therefore, are attributed to differences in reproductive factors, diet, and other environmental differences. Indeed, breast cancer risk increases signiﬁcantly in females who have migrated from Asia to America. Overall, the incidence of breast cancer is rising in most countries. Colon and rectal cancer. The incidence of colon and rectal cancer is higher in developed countries than developing countries. The incidence rates are highest in Australia/New Zealand, North America, and Northern and Western Europe. These geographic differences are thought to reﬂect environmental exposures and are presumed to be mainly dietary differences. Liver cancer. Eighty percent of liver cancers occur in developing countries. The incidence of liver cancer is especially high in China and other countries in Eastern Asia. Worldwide, the major risk factors for liver cancer are infection with hepatitis viruses and consumption of foods contaminated with aﬂatoxin. Hepatitis B immunization in children has recently been shown to reduce the incidence of hepatitis infection in China, Korea, and West Africa. Whether this will translate into a reduction in the incidence in liver cancer in these regions will soon be determined. Prostate cancer. The incidence of prostate cancer is dramatically higher in North America than in China, Japan, and the rest of Asia, and even in Northern and Western Europe. A considerable part of the international dif- ferences in prostate cancer incidence is thought to reﬂect differences in diag- nostic practices. As previously mentioned, the introduction of PSA screening has led to a signiﬁcant increase in the diagnosis of prostate cancer in the United States. Esophageal cancer. Geographic variations in the incidence of esophageal cancer are also striking. The highest incidence of this cancer is in South- ern Africa and China. These geographic differences are attributed to nu- tritional deﬁciencies and exposures to exogenous carcinogens. Esophageal cancer in North America and Europe is attributed to tobacco and alcohol use. The mortality rates of different cancers also vary signiﬁcantly among coun- tries. This is attributable not only to variations in incidence but also to variations in survival after a cancer diagnosis. Survival rates are inﬂuenced not only by treatment patterns but also by variations in cancer screening practices, which affect the stage of cancer at diagnosis. For example, the 5-year survival rate of stomach cancer is much higher in Japan, where the cancer incidence is high enough to warrant mass screening and is presumed to lead to earlier diagnosis. In the case of prostate cancer, the mortality rates diverge much less than the incidence rates among countries. Survival rates for prostate cancer are much higher in North America than in developing countries (88 vs. 41 percent). It is possible that the extensive screening practices in the United States allow discovery of cancers at an earlier, more curable stage; however, it is also pos- sible that this screening leads to discovery of more latent, less biologically aggressive cancers, which may not have caused death even if they had not been identiﬁed. 186 PART I BASIC CONSIDERATIONS CANCER BIOLOGY Cell Proliferation and Transformation In normal cells, cell growth and proliferation are under strict control. In cancer cells, cells become unresponsive to normal growth controls, leading to uncon- trolled growth and proliferation. Abnormally proliferating, transformed cells outgrow normal cells in the culture dish (i.e., in vitro) and commonly dis- play several abnormal characteristics. These include loss of contact inhibition (i.e., cells continue to proliferate after a conﬂuent monolayer is formed); an altered appearance and poor adherence to other cells or the substratum; loss of anchorage-dependence for growth; immortalization; and gain of tumorigenic- ity (i.e., the ability to give rise to tumors when injected into an appropriate host). Cancer Initiation Tumorigenesis is proposed to have three steps: initiation, promotion, and pro- gression. Initiating events may lead a single cell to acquire a distinct growth advantage, such as gain of function of genes known as oncogenes, or loss of function of genes known as tumor suppressor genes. Subsequent events can lead to accumulations of additional deleterious mutations in the clone. Cancer is a disease of clonal progression as tumors arise from a single cell and accumulate mutations that confer on the tumor an increasingly aggressive behavior. Most tumors are thought to go through a progression from benign lesions to in situ tumors to invasive cancers (e.g., atypical ductal hyperplasia to ductal carcinoma in situ to invasive ductal carcinoma of the breast). Fearon and Vogelstein proposed the model for colorectal tumorigenesis. Colorectal tumors arise from the mutational activation of oncogenes coupled with mutational in- activation of tumor suppressor genes, the latter being the predominant change. Mutations in at least four or ﬁve genes are required for formation of a malignant tumor, although fewer changes sufﬁce for a benign tumor. Although genetic mutations often occur in a preferred sequence, a tumor’s biologic properties are determined by the total accumulation of its genetic changes. Gene expression is a multistep process that starts from transcription of a gene into messenger ribonucleic acid (mRNA) and then translation of this sequence into the functional protein. There are several controls at each level. In addition to alterations at the genome level, alterations at the transcription level (e.g., methylation of the DNA leading to transcriptional silencing), or at the mRNA processing, mRNA stability, mRNA translation, or protein stability levels, can alter critical proteins and thus contribute to tumorigenesis. Cell-Cycle Dysregulation in Cancer The proliferative advantage of tumor cells is a direct result of their ability to bypass quiescence. Mutations or alterations in the expression of cell-cycle pro- teins, growth factors, growth factor receptors, intracellular signal transduction proteins, and nuclear transcription factors all can lead to disturbance of the basic regulatory mechanisms that control the cell cycle, allowing unregulated cell growth and proliferation. The cell cycle is divided into four phases. During the synthetic or S phase, the cell generates a single copy of its genetic material, although in the mitotic or M phase, the cellular components are partitioned between the two identical daughter cells. The G1 and G2 phases represent gap phases during which the cells prepare themselves for completion of the S and M phases, respectively. CHAPTER 9 ONCOLOGY 187 When cells cease proliferation, they exit the cell cycle and enter the quiescent state referred to as G0. Cell-cycle progression is regulated by a series of checkpoints that pre- vent cells from entering a new phase without completing the previous phase. The central regulators are serine-threonine kinases referred to as the cyclin- dependent kinases (CDKs). CDK4 and CDK6 are thought to be involved in the early G1 phase, whereas CDK2 is required to complete G1 and initiate S phase. CDK4 and CDK6 form active complexes with the D-type cyclins, cyclins D1, D2, and D3. CDK2 is activated by the cyclins E1 and E2, during the G1/S transition and by cyclins A1 and A2, during the S phase. The principal downstream target of the activated complex of cyclin D and CDK4 or CDK6 is the retinoblastoma protein (Rb). In its hypophosphorylated form, Rb suppresses cellular growth by binding the E2F family of transcrip- tion factors. Furthermore, Rb binding to the promoter as a complex with E2F can actively repress transcription through chromatin remodeling, by recruit- ing proteins such as histone diacetylases and SWI/SNF complexes. Following cyclin/CDK-mediated phosphorylation, Rb releases E2F transcription factors that then activate downstream transcriptional targets involved in S phase, such as DNA polymerase alpha, cyclin A, cyclin E, and CDK1. Regulators of CDKs can affect cell-cycle progression. CDKs are phosphory- lated and activated by CDK-activating kinase. CDK inhibitors (CKIs) comprise two classes, the INK4 family and the WAF/Kip family. The INK4 family has four members: INK4A (p16), INK4B (p15), INK4C (p18), and INK4D (p19). The INK4 proteins bind CDK4 and CDK6 and prevent their association with D-type cyclins and cyclin D activation. The WAF/Kip family members include WAF1 (p21), KIP1 (p27), and KIP2 (p57). These CKIs bind and inactivate cy- clin/CDK2 complexes. Molecular alterations of human tumors have demonstrated that cell-cycle regulators are frequently mutated. Other alterations include overexpression of cyclins D1 and E, and CDK4 and CDK6, and loss of CKIs INK4A, INK4B, and KIP1. Oncogenes Normal cellular genes that contribute to cancer when abnormal are called onco- genes. The normal counterpart of such a gene is referred to as a protooncogene. Oncogenes are usually designated by three-letter abbreviations, such as myc or ras. Oncogenes are further designated by the preﬁx of “v-” for virus or “c-” for cell or chromosome, corresponding to the origin of the oncogene when it was ﬁrst detected. Protooncogenes can be activated (have increased activity) or overexpressed (expressed at increased protein levels) by translocation (e.g., abl), promoter insertion (e.g., c-myc), mutations (e.g., ras), or ampliﬁcation (e.g., HER2/ neu). More than 100 oncogenes have been identiﬁed. Oncogenes may be growth factors (e.g., platelet-derived growth factor), growth factor receptors (e.g., HER2/neu), intracellular signal transduction molecules (e.g., ras), nuclear transcription factors (e.g., c-myc), or other molecules involved in the regulation of cell growth and proliferation. Growth factors are proteins that are produced and secreted by cells locally and that stimulate cell proliferation by binding speciﬁc cell-surface receptors on the same cells (autocrine stimulation) or on neighboring cells (paracrine stimu- lation). Persistent overexpression of growth factors can lead to uncontrolled autostimulation and neoplastic transformation. Alternatively, growth factor 188 PART I BASIC CONSIDERATIONS receptors can be aberrantly activated (turned on) through mutations, or over- expressed (continually presenting cells with growth-stimulatory signals, even in the absence of growth factors), leading cells to respond as if growth factor levels are altered. The growth-stimulating effect of growth factors and other mi- togens is mediated through postreceptor signal transduction molecules. These molecules mediate the passage of growth signals from the outside to the inside of the cell and then to the cell nucleus, initiating the cell cycle and deoxyri- bonucleic acid (DNA) transcription. Aberrant activation or expression of cell- signaling molecules, cell-cycle molecules, or transcription factors may play an important role in neoplastic transformation. Alterations in Apoptosis in Cancer Cells Apoptosis (programmed cell death) is a genetically regulated program to dis- pose of cells. Cancer cells must avoid apoptosis if tumors are to arise. The growth of a tumor mass is dependent not only on an increase of prolifera- tion of tumor cells but also on a decrease in their apoptotic rate. Apopto- sis is distinguished from necrosis because it leads to several characteristic changes. In early apoptosis, the changes in membrane composition lead to extracellular exposure of phosphatidylserine residues, which avidly bind an- nexin, a characteristic used to discriminate apoptotic cells in laboratory stud- ies. Late in apoptosis there are characteristic changes in nuclear morphology, such as chromatin condensation, nuclear fragmentation, and DNA laddering, and membrane blebbing. Apoptotic cells are then engulfed and degraded by phagocytic cells. The effectors of apoptosis are a family of proteases called caspases (cysteine-dependent and aspartate-directed proteases). The initiator caspases (e.g., 8, 9, and 10), which are upstream, cleave the downstream exe- cutioner caspases (e.g., 3, 6, and 7) that carry out the destructive functions of apoptosis. Two principal molecular pathways signal apoptosis by cleaving the initiator caspases with the potential for cross-talk: the mitochondrial pathway and the death receptor pathway. In the mitochondrial pathway, sometimes referred to as the intrinsic pathway, death results from the release of cytochrome c from the mitochondria. Cytochrome c, procaspase-9, and apoptotic protease-activating factor-1 (Apaf-1) form an enzyme complex, referred to as the apoptosome, which activates the effector caspases. In addition to these proteins, the mito- chondria contain other proapoptotic proteins such as SMAC/DIABLO. The mitochondrial pathway can be stimulated by many factors, including DNA damage, reactive oxygen species, or withdrawal of survival factors. The mito- chondrial membrane permeability determines whether the apoptotic pathway will proceed. The Bcl-2 family of regulatory proteins includes proapoptotic proteins (e.g., Bax, Bad, and Bak) and antiapoptotic proteins (e.g., Bcl-2 and Bcl-xL); the activity of the Bcl-2 proteins is centered on the mitochondria, in which they regulate membrane permeability. The second principal apoptotic pathway is the death receptor pathway, some- times referred to as the extrinsic pathway. Cell-surface death receptors in- clude Fas/APO1/CD95, tumor necrosis factor receptor 1 (TNFR1), and KILL- ER/DR5, which bind their ligands FasL, TNF, and TRAIL, respectively. When the receptors are bound by their ligands, they form a death-inducing signaling complex (DISC). At the DISC, procaspase-8 and procaspase-10 are cleaved, yielding active initiator caspases. The death receptor pathway may be regulated at the cell surface by the expression of “decoy” receptors for Fas and TRAIL. CHAPTER 9 ONCOLOGY 189 The decoy receptors are closely related to the death receptors but lack a functional death domain, therefore they bind death ligands, but do not trans- mit a death signal. Another regulatory group is the FADD-like interleukin-1 protease-inhibitory proteins (FLIPs). FLIPs have homology to caspase-8; they bind to the DISC and inhibit the activation of caspase-8. Finally, inhibitors of apoptosis proteins (IAPs) block caspase-3 activation and have the ability to regulate both the death receptor and the mitochondrial pathway. The IAP family includes XIAP, cIAP1, cIAP2, NAIP, ML-IAP, ILP2, livin, apollon, and survivin. NF-κB also induces cellular resistance to apoptosis by transcrip- tionally activating cIAP1 and cIAP2, and other speciﬁc antiapoptotic proteins such as A20 and Mn-SOD. In human cancers, aberrations in the apoptotic program include increased expression of Fas and TRAIL decoy receptors; increased expression of an- tiapoptotic Bcl-2; increased expression of IAP-related protein survivin; in- creased expression of c-FLIP; mutations or downregulation of proapoptotic Bax, caspase-8, APAF1, XAF1, and death receptors CD95, TRAIL-R1, and TRAIL-R2; alterations of the p53 pathway; overexpression of growth factors and growth factor receptors; and activation of the PI3-K/Akt survival pathway. Cancer Invasion A feature of malignant cells is their ability to invade the surrounding normal tissue. Tumors in which the malignant cells appear to lie exclusively above the basement membrane are referred to as in situ cancer, although tumors in which the malignant cells are demonstrated to breach the basement membrane, penetrating into surrounding stroma, are termed invasive cancer. The ability to invade involves changes in adhesion, initiation of motility, and proteolysis of the extracellular matrix (ECM). Cell-to-cell adhesion in normal cells involves interactions between cell- surface proteins. Calcium adhesion molecules of the cadherin family (E- cadherin, P-cadherin, and N-cadherin) are thought to enhance the cells’ ability to bind to one another and suppress invasion. Migration occurs when cancer cells penetrate and attach to the basal matrix of the tissue being invaded; this allows the cancer cell to pull itself forward within the tissue. Attachment to gly- coproteins of the ECM such as ﬁbronectin, laminin, and collagen is mediated by tumor cell integrin receptors. Integrins are a family of glycoproteins that form heterodimeric receptors for ECM molecules. In addition to regulating cell adhesion to the ECM, integrins relay molecular signals regarding the cellular environment that inﬂuence shape, survival, proliferation, gene transcription, and migration. Serine, cysteine, and aspartic proteinases and matrix metalloproteinases (MMPs) have all been implicated in cancer invasion. Urokinase plasminogen activators (uPA) and tissue plasminogen activators (tPA) are serine proteases that convert plasminogen into plasmin. Plasmin, in return, can degrade several ECM components. Plasmin also may activate several MMPs. Plasminogen activator inhibitors (PAI-1 and PAI-2) are produced in tissues and counteract the activity of plasminogen activators. MMPs are upregulated in almost every type of cancer. Some of the MMPs are expressed by cancer cells, although others are expressed by the tumor stromal cells. Experimental models have demonstrated that MMPs promote cancer pro- gression by increasing cancer cell growth, migration, invasion, angiogenesis, and metastasis. The activity of MMPs is regulated by their endogenous 190 PART I BASIC CONSIDERATIONS inhibitors, including α2 -macroglobulin, membrane-bound inhibitors RECK (reversion-inducing cysteine-rich protein with kazal domains), and tissue in- hibitors of MMPs (TIMP-1, -2, -3, and -4). Thus regulation of MMPs occurs at three levels: alterations of gene expression, activation of latent zymogens, and inhibition by endogenous inhibitors. Alterations of all three levels of control have been associated with tumor progression. Angiogenesis Angiogenesis is the establishment of new blood vessels from a preexisting vas- cular bed. This neovascularization is essential for tumor growth and metastasis. Tumors develop an angiogenic phenotype as a result of accumulated genetic alterations and in response to local selection pressures such as hypoxia. Many of the common oncogenes and tumor suppressor genes have been shown to play a role in inducing angiogenesis, including ras, myc, HER2/ neu, and mutations in p53. Angiogenesis is mediated by factors produced by various cells including tumor cells, endothelial cells, stromal cells, and inﬂammatory cells. Several factors have been shown to be proangiogenic or antiangiogenic. Of the angio- genic stimulators, the best studied are the vascular endothelial growth factors (VEGF). The VEGF family consists of six growth factors (VEGF-A, VEGF-B, VEGF-C, VEGF-D, VEGF-E, and placental growth factor) and three receptors (VEGFR1 or Flt-1, VEGFR2 or KDR/FLK-1, and VEGFR3 or FLT4). Neu- ropilin 1 and 2 also may act as receptors for VEGF. VEGF is induced by hypoxia and by different growth factors and cytokines, including EGF, PDGF, TNF-α, TGF-β, and interleukin 1β (IL-1β). VEGF has various functions including in- creasing vascular permeability, inducing endothelial cell proliferation and tube formation, and inducing endothelial cell synthesis of proteolytic enzymes such as uPA, PAI-1, UPAR, and MMP-1. Furthermore, VEGF may mediate blood ﬂow by its effects on the vasodilator nitric oxide and act as an endothelial sur- vival factor, thus protecting the integrity of the vasculature. The proliferation of new lymphatic vessels, lymphangiogenesis, is also thought to be controlled by the VEGF family. Signaling in lymphatic cells is thought to be modulated by VEGFR3. Experimental studies with VEGF-C and VEGF-D have shown that they can induce tumor lymphangiogenesis and direct metastasis via the lymphatic vessels and lymph nodes. PDGFs A, B, C, and D also play important roles in angiogenesis. PDGFs can not only enhance endothelial cell proliferation directly but also upregulate VEGF expression in vascular smooth muscle cells, promoting endothelial cell survival via a paracrine effect. The angiopoietins, angiopoietin 1 (Ang-1) and angiopoietin 2 (Ang-2), in return, are thought to regulate blood vessel matu- ration. Ang-1 and Ang-2 both bind endothelial cel

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