general methods and overviews, lung carcinoma and prostate carcinoma

1. General Methods and Overviews, Lung Carcinoma and Prostate Carcinoma

2. Methods of Cancer Diagnosis, Therapy, and Prognosis Volume 2 For other titles published in this series, go to www.springer.com/series/8172

3. Methods of Cancer Diagnosis, Therapy, and Prognosis Volume 2 General Methods and Overviews, Lung Carcinoma and Prostate Carcinoma Edited by M.A. Hayat Department of Biological Sciences, Kean University, Union, NJ, USA

4. ISBN 978-1-4020-8441-6 e-ISBN 978-1-4020-8442-3 Library of Congress Control Number: 2008930172 2008 Springer Science + Business Media B.V. No part of this work may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, electronic, mechanical, photocopying, microlming, recording or otherwise, without written permission from the Publisher, with the exception of any material supplied specically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Printed on acid-free paper 9 8 7 6 5 4 3 2 1 springer.com Editor M.A. Hayat Department of Biological Sciences Kean University Union, NJ USA

5. New technology, for better or for worse, will be used, as that is our nature. Lewis Thomas You have been given the key that opens the gates of heaven; the same key opens the gates of hell. Writing at the entrance to a Buddhist temple

6. Authors and Co-Authors of Volume 2 Naglaa F. Abbas Medical Division, National Research Center, Al-Tahrir Street, Dokki Giza, Egypt Imran Ahmad Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 E-mail: [email protected] Shahid Ahmed Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 Annette Altmann Clinical Cooperation Unit Nuclear Medicine, German Cancer Research Center, Im Neuenheimer Feld 280, FRG-69120 Heidelberg, Germany E-mail: [email protected] Samuel G. Armato III Department of Radiology- MC 2026, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637 E-mail: [email protected] Florence Arnold Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 Armando Bartolazzi Department of Oncology-Pathology, Cellular and Molecular Pathology, Cancer Center Karolinska, CCK R8:04 Karolinska Hospital, 17176 Stockholm, Sweden E-mail: [email protected] Susana Benlloch Research Unit, Alicante University General Hospital, Avda Pintor Baeza 12, Alicante 03010, Spain E-mail: [email protected] Heinrich Bulzebruck IT-Abteilung der Thoraxklinik am Universitatsklinikum, Heidelburg, Amalienstrasse 5, D-69126 Heidelberg, Germany Loren E. Clarke Penn State Milton S. Hershey Medical Center-M.C. H179, P. O. Box 850, 500 University Drive, Hershey, PA 17033 vii

7. Philip Clewer Medical Physics and Bioengineering, Southampton General Hospital, Tremona Road Southampton, SO16 6YD, United Kingdom E-mail: [email protected] Gaetano Compagnone Department of Medical Physics, S. Orsola-Malpighi Hospital, Azienda Ospedaliero-Universitaria di Bologna, Via Massarenti, 9 40138 Bologna, Italy E-mail: [email protected]. unibo.it Leslie C. Costello Department of Biomedical Sciences, Dental School and the Greenbaum Cancer Center, University of Maryland, 650 West Baltimore, MD 21201 E-mail: [email protected] Juanita Crook University of Toronto/Princess Margaret Hospital, 610 University Avenue, Toronto M5G 2M9 E-mail: [email protected] Gabriel D. Dakubo Genesis Genomics, Inc., 290 Munro Street, Ste. 1000, Thunder Bay, ON P7A 7T1, Canada E-mail: Gabriel.dakubo @genesisgenomics.com Marco Das Hochschule Aachen University, Rheinisch-Westfalische Technische, Department of Diagnostic Radiology, Pauwelsstrasse 30, Aachen 52074, Germany E-mail: [email protected] Henndrik Dienemann Chirurgische Abteilung der Thoraxklinik am Universitatsklinikum, Heidelburg, Amalienstrasse 5, D-69126 Heidelberg, Germany David Dingli Harvard University, Program for Evolutionary Dynamics, One Brattle Sq. Suite 6, Cambridge, MA 02138 E-mail: [email protected] Vikram S. Dogra University of Rochester, School of Medicine, Department of Imaging Sciences, 601 Elmwood Avenue, Box 648, Rochester, NY 14642 E-mail: vikram_dogra@urmc. rochester.edu Nadia G. EL-Hefnawy Pathology Department, Faculty of Medicine, Ain-Shams University, Cairo, Egypt Sonia L. El-Sharkawy Medical Division, National Research Center, Al-Tahrir Street, Dokki Giza, Egypt E-mail: [email protected] Renty B. Franklin Department of Biomedical Sciences, Dental School and the Greenbaum Cancer Center, University of Maryland, 650 West Baltimore, MD 21201 Jos Marcelo Galbis-Caravajal Medical Oncology, Alicante University General Hospital, Avda Pintor Baeza 12, Alicante 03010, Spain viii Authors and Co-Authors of Volume 2

8. Christian Grg Department of Internal Medicine, Philipps-University Marburg, Baldingerstrae, D-35033 Marburg, Germany E-mail: Christian.Goerg@med. uni-marburg.de Peter Grandics A-D Research Foundation, 5922 Farnsworth Ct., Carlsbad, CA 92008 E-mail: [email protected] Cesare Gridelli Division of Medical Oncology, S.G. Moscati Hospital, Contreds Amorette, 83100 Avellino, Italy E-mail: [email protected] Olli H.J. Grohn Department of Biochemistry, University of Cambridge, Old Addenbrookes Site, 80 Tennis Court Road, CB2 1GA Cambridge, United Kingdom S.J. Gwyther East Surrey Healthcare NHS Trust, Redhill, Canda Avenue, Surrey, United Kingdom E-mail: [email protected] Uwe Haberkorn Clinical Cooperation Unit Nuclear Medicine,German Cancer Research Center, Im Neuenheimer Feld 280, FRG-69120 Heidelberg, Germany Kamal Haider Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 Kristie Harding Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 M.A. Hayat Kean University, 1000 Morris Avenue, Union, NJ 07083 E-mail: [email protected] Rui Henrique Department of Pathology, Portugese Oncology Institute Porto, Rua Dr. Antonio, Bernardino de Almeida, 4200-072 Porto, Portugal Kenzo Hiroshima Kenzo Hiroshima, Department of Diagnostic Pathology, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba 260-8670, Japan E-mail: [email protected] Angelique Holland Department of Internal Medicine, Philipps-University Marburg, Baldingerstrae, D-35033 Marburg, Germany John P. Jakupciak National Institute of Standards and Technology, Biochemical Science Division, Gaithersburg, MD 20899 Samer Kalakish Comprehensive Cancer Center, Wake Forest University, School of Medicine, Winston Salem, NC 27157 E-mail: [email protected] Authors and Co-Authors of Volume 2 ix

9. Mikko I. Kettunen Department of Biochemistry, University of Cambridge, Old Addenbrookes Site, 80 Tennis Court Road, CB2 1GA Cambridge, United Kingdom E-mail: [email protected] Katsuyuki Kiura Department of Respiratory Medicine, Okayama University Hospital, Graduate School of Medicine, Okayama 700-8558, Japan Shan Lu Department of Pathology, University of Cincinnati, College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267 E-mail: [email protected] Charles M. Ludgate Radiation Oncology Program, BC Cancer Agency - Vancouver Island Centre, 2410 Lee Ave., Victoria, BC, Canada, V8R 6V5 Edmond S.K. Ma Division of Molecular Pathology, Department of Pathology and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, 2 Village Road, Happy Valley, Hong Kong E-mail: [email protected] Paolo Maione Division of Medical Oncology, S.G. Moscati Hospital, Contreds Amorette, 83100 Avellino, Italy Stephen Man Department of Medical Biochemistry and Immunology, Health Park, Cardiff, CF14 4XN, School of Medicine, Cardiff University, U.K Bartomeu Massut Thoracic Surgery, Hospital de La Ribera, Alzira, Valencia, Spain Luca Moscetti Medical Oncology Department, Centreal Hospital of Outcome, Research Network for Evaluation of Treatment, Results in Oncology, Belcolle-ASL di Viterbo, Strada Sammartinese snc, 01100 Viterbo, Italy E-mail: [email protected] Fabrizio Nelli Medical Oncology Department, Centreal Hospital of Outcome, Research Network for Evaluation of Treatment, Results in Oncology, Belcolle-ASL di Viterbo, Strada Sammartinese snc, 01100 Viterbo, Italy Brad H. Nelson Trev and Joyce Deeley Research Centre, BC Cancer Agency Vancouver Island Centre, 2410 Lee Ave., Victoria, BC, Canada, V8R 6V5 E-mail: [email protected] Nancy J. Nesslinger Trev and Joyce Deeley Research Centre, BC Cancer Agency Vancouver Island Centre, 2410 Lee Ave., Victoria, BC, Canada, V8R 6V5 Hiroaki Nomori Department of Thoracic Surgery, Graduate School of Medicine, Kumamoto University, 1-1-1 Honjo, Kumamoto 860-8556, Japan E-mail: [email protected] x Authors and Co-Authors of Volume 2

10. Jorge M. Pacheco Harvard University, Program for Evolutionary Dynamics, One Brattle Sq., Suite 6, Cambridge, MA 02138 Howard H. Pai Radiation Oncology Program, BC Cancer Agency - Vancouver Island Centre, 2410 Lee Ave., Victoria, BC, Canada, V8R 6V5 Klaus Pantel Institute of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany E-mail: [email protected] Ryan L. Parr Genesis Genomics, Inc., 290 Munro Street, Ste. 1000, Thunder Bay, ON P7A 7T1, Canada Joachim Pfannschmidt Chirurgische Abteilung der Thoraxklinik am Universitatsklinikum, Heidelburg, Amalienstrasse 5, D-69126 Heidelberg, Germany E-mail: joachim.pfannschmidt @thoraxklinik-heidelberg.de David Popkin Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 Garth Powis Department of Experimental Therapeutics, University of Texas, M.D. Anderson Cancer Center, 1400 Holcombe Blvd., FC6. 3044, Unit 422, Houston, TX 77030 E-mail: [email protected] Franclim R. Ribeiro Department of Genetics, Portuguese Oncology Institute - Porto, Portugal Rua Dr. Antonio Bernardino de Almeida, Porto, 4200-072, Portugal E-mail: [email protected] Amer Sami Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 Heidi Schwarzenbach Institute of Tumor Biology, University Medical Center, Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany Yoshihiko Segawa Department of Medicine and Thoracic Oncology, National Hospital Organization, Shikoku Cancer Center, 160 Kou-Minami-Umemoto-cho, Matsuyama, Ehime 791-0288, Japan E-mail: [email protected] William F. Sensakovic Department of Radiology- MC 2026, The University of Chicago, 5841 S. Maryland Ave., Chicago, IL 60637 Rabia K. Shahid Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada S7N 4H4 Rolf I. Skotheim Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Center, NO-0310 Oslo, Norway Authors and Co-Authors of Volume 2 xi

11. Zsuzsanna Tabi Department of Oncology and Palliative Medicine, Velindre Hospital, Whitchurch, CF14 2TL Cardiff, United Kingdom E-mail: [email protected]. nhs.uk Nagio Takigawa Department of Respiratory Medicine, Okayama University Hospital, Graduate School of Medicine, Okayama 700-8558, Japan E-mail: [email protected] Manuel R. Teixeira Department of Genetics, Portuguese Oncology Institute - Porto, Portugal Rua Dr. Antonio Bernardino de Almeida, Porto, 4200-072, Portugal Franck Toledo Institut Curie, Centre de Recherche, UMR CNRS 7147, 26 rue dUlm 75248, Cedex 05 Paris, France E-mail: [email protected] Frank M. Torti Comprehensive Cancer Center, Wake Forest University, School of Medicine, Winston-Salem, NC 27157 Ahmet T. Turgut Department of Radiology, Ankara Training and Research Hospital, 25. Cadde 362. Sokak Hner Sitesi No: 18/30 Karakusunlar, Ankara, TR-06530 Turkey Sarah J. Welsh University of Oxford, Harris Manchester College, Manchester Road, Oxford, OX1 3 TD, UK Chris L.P. Wong Division of Molecular Pathology, Department of Pathology and Cancer Genetics Center, Hong Kong Sanatorium and Hospital, 2 Village Road, Happy Valley, Hong Kong Sunil Yadav Saskatoon Cancer Center, University of Saskatchewan, 20 Campus Drive, University of Saskatchewan, Saskatoon, SK, Canada, S7N 4H4 Dani S. Zander Penn State Milton S. Hershey Medical Center-M.C. H179, P. O. Box 850, 500 University Drive, Hershey, PA 17033 E-mail: [email protected] Pat Zanzonico Room Z 2002 (Zuckerman Research Center), Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10021 E-mail: [email protected] xii Authors and Co-Authors of Volume 2

12. Preface Cancer is the leading cause of death, after cardiovascular diseases, in the United States. A total of 1,399,790 new cancer cases and 564,830 deaths were reported in the year 2006 in the country. Approximately, one in every two men and one in every three women in the country will have some type of cancer during their lifetime. Healthcare costs exceed 1.7 trillion dollars per year in the United States, which is 15% of the countrys gross domestic product. Tobacco use is the most serious prevent- able cause of cancer. Tobacco use causes cancer of the lung, throat, mouth, pancreas, urinary bladder, stomach, liver, kidney, and other types. Passive smoking causes lung cancer. In 2007, 168,000 cancer deaths were expected to be caused by tobacco use (Am. Cancer Society, 2007). The most important risk factor for the development of cancer is increasing age. This factor and epidemiologic shifts have resulted in a marked increase in the number of older patients with cancer. This fact will result in marked increased burden of cancer to the world, including the United States. The fastest-growing segment of the United States population comprises persons of 65 years and older, and an increase in the number of older cancer patients is expected. Approximately, 77% of all types of cancers are diagnosed in persons of 55 years and older. It was estimated that one- third of the 559,650 cancer deaths in 2007 in the United States were related to over- weight or obesity, physical inactivity, and nutrition, and thus could also be prevented (Am. Cancer Society, 2007). However, in developed countries, including United States, the average person of 65 years can expect to live another 15 years in a fairly good health. Persons of 75 or 85 years old have an average expectancy of 10 and 6 years, respectively. During the last three decades, intensive clinical research has resulted in reduced cancer incidence, side effects of treatments, and death rates and increased sur- vival rates. As a result, there are ten million cancer survivors in the United States; some of them are cancer-free, while others may still have cancer and may be undergoing treatment. It is recognized that scientific journals facilitate exchange of information, result- ing in rapid progress. In this endeavor, the main role of scientific books is to present information in more detail after careful, additional evaluation of the investigational xiii

13. results, especially those of new or rela- tively new methods, and their potential side-effects. Although subjects of diagnosis, therapy assessment, and prognosis of various types of cancers, cancer recurrence, and resistance to chemotherapy are scattered in a vast number of journals and books, there is need of combining these subjects in single volumes. An attempt has been made to accomplish this goal in these volumes. A constructive evaluation of commonly used methods for elucidating primary and secondary cancer initiation, progression, relapse, and metastasis is presented. In the era of cost-effectiveness, my opin- ion may be a minority prospective, but it needs to be recognized that the potential for false-positive or false-negative interpretation on the basis of a single laboratory test in clinical pathology does exist. Interobservor or intraobservor variability in the interpretation of results in pathology is not uncommon. Interpretive differences often are related to the relative importance of criteria being used. Generally, no test always performs per- fectly. Although there is no perfect remedy to this problem, standardized classifica- tions with written definitions and guide- lines will help. Standardization of methods to achieve objectivity is imperative in this effort. The validity of a test should be based on the objective interpretation of the photomicrographs or tomographic images. The interpretation of the results should be explicit rather than implicit. To achieve accurate diagnosis, and correct prognosis, the use of molecular criteria is important. Indeed, molecular medicine has arrived. This volume discusses in detail all aspects of lung cancer and prostate cancer, including diagnosis using molecular genetics, various imaging modalities, and tumor markers. Treatments such as chemotherapy, radiation, chemoradiation, hormonal therapy, immunotherapy, and surgery; and prognosis. The side effects of the treatments are also pointed out. Both primary and secondary cancers, and risk of cancer survivors developing other cancers are explained. An attempt is also made to translate molecular genetics into clinical practice. Evidence-based therapy is included. Role of metabolism in malignancy and cancer stem cells are discussed in detail. Methods of cancer diagnosis discussed include various modalities of imaging (e.g., MRI, PET, Whole-Body PET, Multidetector-Row Computed Tomography, Transcutaneous Contrast- Enhanced Sonography, and Transrectal Sonography), and Histology and Immuno- histochemistry. Other methodologies, such as Array-Based Comparative Genomic Hybridization and Polymerase Chain Reaction Analysis, are also included. Prognostic biological markers such as mitochondrial mutations and circulating DNA in blood for prostate cancer are described. Treatment of NSCLC with docetaxel, platinum-based chemotherapy, and gefitinib is discussed. Chemotherapy with vinorelbine, doxorubicin, and prednisone, and radiotherapy for prostate cancer are discussed. Overexposure of patients to radiology is included. Each chapter is written by distinguished, practicing clinicians/surgeons/oncologists. Their practical experience highlights their writings, which should build and further the endeavors of the readers. This volume was written by 75 scientists representing 14 countries. It is my hope that these handbooks would assist in more complete xiv Preface

14. understanding of at least some of the globally-encountered cancer problems. Successful cancer treatment, cure, and prevention are areas of immediate concern of and demand by the public. I am grateful to the contributors for their promptness in accepting my suggestions, and appreciate their dedication and hard work in sharing their invaluable knowledge with the readers. Each chapter provides unique individual, practical knowledge based on the expertise and practical experience of the authors. The chapters contain the most up-to-date practical as well as theoretical information. It is my hope that the book will be published expeditiously. I am thankful to the Board of Trustees, Dr. Dawood Farahi, and Dr. Kristie Reilly for recognizing the importance of schol- arship in an institution of higher edu- cation and providing the resources for completing this important project. I am thankful to Ayesha Muzaffar and Lina Builes for their expert help in preparing this volume. M.A. Hayat February 2008 Preface xv

15. Authors and Co-Authors of Volume 2.................................................................. vii Preface..................................................................................................................... xiii Contents of Volume 1............................................................................................. xxxiii Part I General Methods and Overviews 1. Metabolic Transformations of Malignant Cells: An Overview................... 3 Leslie C. Costello and Renty B. Franklin Introduction.................................................................................................... 3 Axioms of Relationships of Cellular Activity, Cellular Metabolism, and Malignancy.......................................................................................... 3 Dening a Malignant Cell: A Parasitic Existence ......................................... 4 The In Situ Environment of the Malignant Cell Dictates its Metabolism...... 5 Tumor Cell Proliferation and Involved Metabolic Pathways for its Achievement.................................................................................... 6 The Coupling of Glycolysis via Citrate to De Novo Lipogenesis/Cholesterogenesis.................................................................. 7 The Operation of the Krebs Cycle in Tumor Cells ........................................ 9 Glutaminolysis as an Alternative or Additional Pathway in Tumor Cells..... 9 The Application of Molecular Genetics and Proteomics to Tumor Cell Intermediary Metabolism........................................................................... 10 References...................................................................................................... 15 2. Detection of Recurrent Cancer by Radiological Imaging ........................... 17 S.J. Gwyther Introduction.................................................................................................... 17 Lung Cancer............................................................................................... 22 Breast Cancer............................................................................................. 24 Contents xvii

16. Colorectal Cancer....................................................................................... 25 Lymphomas................................................................................................ 27 Pancreatic Cancer....................................................................................... 27 Prostate Cancer .......................................................................................... 28 Esophageal Cancer..................................................................................... 29 Melanoma .................................................................................................. 29 Gynecological Cancers .............................................................................. 29 Ovarian Cancer....................................................................................... 29 Endometrial Cancer................................................................................ 31 Cervical Cancer...................................................................................... 31 Head and Neck Cancers............................................................................. 32 Thyroid Cancer .......................................................................................... 33 Renal and Bladder Tumors ........................................................................ 33 Primary Intracranial Tumors...................................................................... 34 Conclusions................................................................................................ 34 References...................................................................................................... 35 3. Tumor Gene Therapy: Magnetic Resonance Imaging and Magnetic Resonance Spectroscopy .................................................... 39 Mikko I. Kettunen and Olli H.J. Grhn Introduction.................................................................................................... 39 Tumor Gene Therapy..................................................................................... 39 Magnetic Resonance Imaging........................................................................ 40 Endogenous Magnetic Resonance Imaging Contrast ................................ 41 Exogenous Contrast Agents....................................................................... 42 Magnetic Resonance Spectroscopy................................................................ 43 Detection of Transgene Delivery and Expression Using Magnetic Resonance Imaging and Spectroscopy....................................................... 44 Detection of Gene Therapy Response Using Magnetic Resonance Imaging and Spectroscopy....................................................... 46 Volumetric Imaging ................................................................................... 46 Endogenous Contrasts................................................................................ 46 Sodium Magnetic Resonance Imaging ...................................................... 48 Molecular Imaging..................................................................................... 48 Magnetic Resonance Spectroscopy of Metabolic Alterations ................... 49 Summary........................................................................................................ 51 References...................................................................................................... 52 4. Assessment of Gene Transfer: Magnetic Resonance Imaging and Nuclear Medicine Techniques............................................................. 55 Annette Altmann and Uwe Haberkorn Introduction.................................................................................................... 55 Molecular Imaging Modalities for Gene Expression................................. 57 Molecular Imaging of Suicide Gene Transfer and Therapeutic Effects .... 58 xviii Contents

17. Molecular Imaging of Suicide Gene Therapy by the Uptake of Specic Substrates............................................................................. 63 Noninvasive Imaging of Reporter Gene Transfer ...................................... 65 References...................................................................................................... 69 5. Role of TP53 Mutations in Cancer (An Overview)...................................... 75 Franck Toledo Introduction.................................................................................................... 75 Impact of TP53 Mutations on P53 Transactivation Capacity ........................ 75 Other Effects of TP53 Mutations................................................................... 79 TP53 Mutations and the Etiology of Human Cancers ................................... 81 Prognostic and Predictive Value of TP53 Mutations ..................................... 83 Correction of P53 Pathway in Tumors........................................................... 84 Future Perspectives ........................................................................................ 87 References...................................................................................................... 90 6. Personalized Medicine for Cancer................................................................. 93 Sarah J. Welsh and Garth Powis Introduction.................................................................................................... 93 Why Is Personalized Medicine Important in Cancer? ............................... 94 To What Extent Is Cancer Medicine Already Personalized?..................... 94 The Future of Personalized Medicine in Cancer........................................ 99 The Challenges for Achieving Personalized Medicine.............................. 102 References...................................................................................................... 105 7. Radiation Doses to Patients Using Computed Radiography, Direct Digital Radiography, and Screen-Film Radiography................... 109 Gaetano Compagnone Introduction.................................................................................................... 109 Radiation Quantities Used in Patient Dosimetry ........................................... 109 Conventional Screen-Film Systems............................................................... 112 Patient Dose and Image Quality with Conventional Screen-Film Systems... 115 Computed Radiography ................................................................................. 117 Patient Dose and Image Quality with Computed Radiography..................... 119 Direct Digital Radiography............................................................................ 122 Patient Dose and Image Quality with Direct Digital Radiography................ 124 Conclusions.................................................................................................... 126 References...................................................................................................... 127 8. Cancer Vaccines and Immune Monitoring (An Overview)......................... 129 Zsuzsanna Tabi and Stephen Man Introduction.................................................................................................... 129 Prophylactic Cancer Vaccines........................................................................ 130 Contents xix

18. Vaccines to Prevent HPV Infection and Cervical Cancer.............................. 130 Vaccines to Prevent Hepatitis B Infection and Liver Cancer......................... 133 Prophylactic Vaccines Against HBV ......................................................... 133 Vaccines to Prevent Hepatitis C Infection and Liver Cancer......................... 133 Other Viruses Associated with Cancer .......................................................... 134 Therapeutic Cancer Vaccines......................................................................... 134 Dendritic Cell Vaccines.................................................................................. 134 Exogenously Loaded Antigen.................................................................... 136 Endogenously Synthesized Antigens......................................................... 137 Adoptive T Cell Transfer ............................................................................... 138 Peptide- and Protein-Based Vaccines, Adjuvants........................................... 140 Recombinant Viral Vector-Vaccines .............................................................. 141 Nonspecic Immune Stimulants Immune Response Modiers.................. 141 Adjuvants ................................................................................................... 141 Cytokines, Chemokines ............................................................................. 142 Ligands/Antibodies.................................................................................... 142 Combination of Cancer Vaccines with Chemo- and Radiotherapy ............... 143 Combined Chemoimmunotherapy............................................................. 143 Combined Radio-Immunotherapy ............................................................. 145 Monitoring Immune Responses..................................................................... 146 Proliferation Assays....................................................................................... 146 Cytotoxicity Assays ....................................................................................... 147 Cytokine Secretion Assays ............................................................................ 149 Tetramers.................................................................................................... 152 Standardization .............................................................................................. 153 Summary........................................................................................................ 154 Conclusion and Outlook ................................................................................ 155 References...................................................................................................... 156 9. New Insights into the Role of Infection, Immunity and Apoptosis in the Genesis of the Cancer Stem Cell..................................................... 161 Peter Grandics Introduction.................................................................................................... 161 The Exterior Cell Surface Layer (Cell Coat) ............................................. 162 Activation of Coagulation.......................................................................... 163 Infection and Inammation........................................................................ 165 Infection, Autoimmunity, and Cancer........................................................ 167 Defective Apoptosis................................................................................... 168 Discussion and Therapeutic Implications.................................................. 170 Summary........................................................................................................ 175 References...................................................................................................... 175 xx Contents

19. 10. Successful Cancer Treatment: Eradication of Cancer Stem Cells ............ 179 David Dingli and Jorge M. Pacheco Introduction.................................................................................................. 179 Tissue Organization and Stem Cells ............................................................ 179 Evidence for Cancer Stem Cells .................................................................. 180 Origin of Cancer Stem Cells........................................................................ 181 Stochastic Dynamics of Cancer Stem Cells................................................. 182 Markers of Cancer Stem Cells ..................................................................... 184 Treating Cancer Stem Cells ......................................................................... 185 Problems with Targeting Cancer Stem Cells ........................................... 186 Overcoming Drug Resistance .................................................................. 186 Evidence for Effective Anti-Cancer Stem Cell Therapy.......................... 187 The Future................................................................................................ 188 References.................................................................................................... 188 11. Overexposure of Patients to Ionizing Radiation: An Overview................. 193 Philip Clewer Introduction.................................................................................................. 193 Justication and Optimization ..................................................................... 193 Unintended Exposures ................................................................................. 194 Overexposure in Radiology ......................................................................... 195 Overexposure in Nuclear Medicine ............................................................. 196 Overexposure in Radiotherapy..................................................................... 196 At What Level Should We Be Concerned About Overexposures?.............. 197 References.................................................................................................... 200 Part II Lung Cancer 12. Lung Carcinoma ............................................................................................ 203 M.A. Hayat Introduction.................................................................................................. 203 References.................................................................................................... 206 13. Extra-Pulmonary Small Cell Cancer: Diagnosis, Treatment, and Prognosis ............................................................................................. 207 Rabia K. Shahid, Kamal Haider, Amer Sami, Imran Ahmad, Florence Arnold, Sunil Yadav, Kristie Harding, David Popkin, and Shahid Ahmed Introduction.................................................................................................. 207 Epidemiology............................................................................................... 208 Pathology ..................................................................................................... 208 Histogenesis............................................................................................. 208 Contents xxi

20. Light Microscopic Features ..................................................................... 208 Immunophenohistochemistry................................................................... 209 Electron Microscopy................................................................................ 209 Cytogenetics............................................................................................. 209 Clinical Features .......................................................................................... 209 Differential Diagnosis.................................................................................. 209 Staging ......................................................................................................... 210 Management................................................................................................. 210 Limited Stage Disease.............................................................................. 211 Extensive Stage Disease........................................................................... 211 Prognosis...................................................................................................... 211 Genitourinary Tract...................................................................................... 212 Urinary Bladder ....................................................................................... 212 Prostate..................................................................................................... 212 Gynaecological Sites.................................................................................... 213 Cervix....................................................................................................... 213 Endometrium............................................................................................ 213 Gastrointestinal Tract................................................................................... 213 Esophagus ................................................................................................ 213 Colon and Rectum.................................................................................... 214 Head and Neck Region ................................................................................ 214 Larynx...................................................................................................... 214 Salivary Glands........................................................................................ 215 Breast ........................................................................................................... 215 Unknown Primary Sites ............................................................................... 215 Summary...................................................................................................... 215 References.................................................................................................... 216 14. Magnetic Resonance Imaging of the Lung: Automated Segmentation Methods .............................................................................. 219 William F. Sensakovic and Samuel G. Armato III Introduction.................................................................................................. 219 Thoracic Magnetic Resonance Imaging and Acquisition Artifacts ............. 220 Automated Segmentation Methods.............................................................. 221 Thresholding, Shape Descriptors, and Morphological Operators................ 221 Model-Based Segmentation......................................................................... 226 Parametric Active Contours......................................................................... 228 Neural Network/Active Contour Combination............................................ 231 References.................................................................................................... 234 15. Peripheral Lung Lesions: Diagnosis Using Transcutaneous Contrast-Enhanced Sonography .............................................................. 235 Christian Grg and Angelique Holland Introduction.................................................................................................. 235 Pathophysiologic Basics of Pulmonary Vascularity..................................... 236 xxii Contents

21. General Considerations of Contrast-Enhanced Sonography........................ 236 Clinical Data of Contrast-Enhanced Sonography........................................ 237 Pleurisy .................................................................................................... 237 Pulmonary Embolism............................................................................... 237 Pleural Based Pulmonary Nodules........................................................... 239 Pneumonia................................................................................................ 240 Atelectasis................................................................................................ 242 Primary Lung Tumors.............................................................................. 242 References.................................................................................................... 244 16. Small Pulmonary Nodules: Detection Using Multidetector-Row Computed Tomography............................................................................. 247 Marco Das Pulmonary.................................................................................................... 247 The Pulmonary Nodule................................................................................ 247 Differential Diagnosis of Pulmonary Nodules............................................. 247 Granuloma, Harmatomas......................................................................... 247 Lung Cancer............................................................................................. 248 Metastasis................................................................................................. 249 Rare Differential Diagnosis ..................................................................... 249 Multidetector-Row Computed Tomography for Pulmonary Nodules.......... 249 Technique................................................................................................. 249 Low-Dose Computed Tomography.......................................................... 250 Contrast-Enhanced Computed Tomography............................................ 250 Dynamic Computed Tomography............................................................ 251 Diagnostic Workup ...................................................................................... 251 Detection of Pulmonary Nodules............................................................. 251 Nodule Density ........................................................................................ 252 Nodule Size.............................................................................................. 252 Nodule Growth......................................................................................... 253 Recommended Workup Algorithms......................................................... 253 Lung Cancer Screening................................................................................ 254 Advanced Diagnosis of Pulmonary Nodules ............................................... 255 Computer Aided Detection ...................................................................... 256 Computer Aided Volumetry..................................................................... 257 References.................................................................................................... 258 17. Secondary Primary Cancer Following Chemoradiation for Non-Small-Cell Lung Cancer.............................................................. 261 Nagio Takigawa, Yoshihiko Segawa, and Katsuyuki Kiura Introduction.................................................................................................. 261 Methods........................................................................................................ 261 Results.......................................................................................................... 262 Contents xxiii

22. Discussion.................................................................................................... 264 References.................................................................................................... 265 18. Advanced Non-Small Cell Lung Cancer: Second-Line Treatment with Docetaxel ............................................................................................ 269 Cesare Gridelli and Paolo Maione Introduction.................................................................................................. 269 Second-Line Treatment................................................................................ 269 Docetaxel Versus Best Supportive Care in the Second-Line Treatment...... 270 Docetaxel Versus Other Chemotherapeutic Agents in the Second-Line Treatment............................................................................ 271 Docetaxel Given Every 3 Weeks Compared with Weekly Schedule ........... 273 Docetaxel Versus Targeted Therapies in the Second-Line Treatment ......... 275 Ongoing Studies on Docetaxel..................................................................... 277 References.................................................................................................... 277 19. Non-Small Cell Lung Cancer with Brain Metastases: Platinum-Based Chemotherapy................................................................ 281 Fabrizio Nelli and Luca Moscetti Epidemiology............................................................................................... 281 Prognosis and Treatment Options................................................................ 281 Shifting the Paradigm of the Blood-Brain Barrier....................................... 282 Role of Chemotherapy................................................................................. 283 Platinum-Based Chemotherapy: Phase II Trials .......................................... 284 Platinum-Based Chemotherapy: Phase III Trials......................................... 285 References.................................................................................................... 287 20. Non-Small Cell Lung Carcinoma: EGFR Gene Mutations and Response to Getinib.......................................................................... 291 Armando Bartolazzi Introduction.................................................................................................. 291 Epidermal Growth Factor Receptor and Downstream Signaling................. 292 Epidermal Growth Factor Receptor Molecular Targeted Therapy for Non-Small Cell Lung Carcinomas..................................................... 294 Epidermal Growth Factor Receptor Mutations and Their Clinical Relevance................................................................................................. 296 Oncogene Addiction and Getinib Response.............................................. 298 Non-Small Cell Lung Carcinoma Sensitivity to Epidermal Growth Factor Receptor Targeted Therapy, and Mechanisms of Resistance............................................................................................ 299 Irreversible Epidermal Growth Factor Inhibitors and Combinatorial Approaches with Other Targeted Therapies............................................. 301 Future Advances .......................................................................................... 302 References.................................................................................................... 303 xxiv Contents

23. 21. Advanced Non-Small Cell Lung Carcinoma: Acquired Resistance to Getinib............................................................................... 307 Katsuyuki Kiura, Nagio Takigawa, and Yoshihiko Segawa Introduction.................................................................................................. 307 Discovery of Somatic EGFR-TK Mutations............................................ 307 Resistance to Getinib............................................................................. 308 Primary Resistance................................................................................... 309 RAS...................................................................................................... 309 Other Mechanisms ............................................................................... 309 Acquired Resistance................................................................................. 309 Mutation of Threonine 790 to Methionine in EGFR ........................... 309 MET Amplication.............................................................................. 311 Clinical Factors Affecting Acquired Resistance to Getinib............... 312 Overcoming Acquired Resistance to Getinib ........................................ 312 References.................................................................................................... 313 22. Prognostic Signicance of [18 F]-Fluorodeoxyglucose Uptake on Positron Emission Tomography in Patients with Pathological Stage I Lung Adenocarcinoma ................................................................. 317 Hiroaki Nomori Introduction.................................................................................................. 317 Patients and Methods ................................................................................... 317 PET Data Analysis................................................................................... 318 Follow-up and Assessment of Tumor Recurrence................................... 318 Statistical Analysis................................................................................... 318 Results.......................................................................................................... 319 Univariate Analysis.................................................................................. 319 Multivariate Analysis............................................................................... 320 Discussion.................................................................................................... 320 References.................................................................................................... 322 23. Non-Small Cell Lung Cancer: Prognosis Using the TNM Staging System ........................................................................................... 323 Joachim Pfannschmidt, Heinrich Bulzebruck, and Hendrik Dienemann Introduction.................................................................................................. 323 History of TNM ........................................................................................... 323 TNM Descriptors ......................................................................................... 324 Staging Procedures....................................................................................... 326 Stage Grouping in NSCLC .......................................................................... 328 Prognostic Implications of TNM Classication and Stage in NSCLC........ 329 Stage IA and IB............................................................................................ 329 Stage IIA and IIB......................................................................................... 330 Stage IIIA and IIIB ...................................................................................... 331 Contents xxv

24. xxvi Contents Stage IV ....................................................................................................... 332 Stage Reporting: Future Perspective............................................................ 333 References.................................................................................................... 334 24. Differentiation Between Malignant and Benign Pleural Effusions: Methylation Specic Polymerase Chain Reaction Analysis................... 337 Susana Benlloch, Jos Marcelo Galbis-Caravajal, and Bartomeu Massut Introduction.................................................................................................. 337 Materials and Methods................................................................................. 339 Patients..................................................................................................... 339 Collection and Processing of Pleural Fluid Samples and DNA Extraction............................................................................................. 339 Methylation-Specic Polymerase Chain Reaction (MSP)....................... 340 Statistical Analysis............................................................................... 340 Results.......................................................................................................... 341 Discussion.................................................................................................... 342 References.................................................................................................... 345 25. Pathological Distinction of Pulmonary Large Cell Neuroendocrine Carcinoma from Small-Cell Lung Carcinoma Using Immunohistochemistry.............................................................................. 349 Kenzo Hiroshima Introduction.................................................................................................. 349 Small-Cell Lung Carcinoma ........................................................................ 350 Clinical Presentation................................................................................ 350 Pathologic Features.................................................................................. 350 Large Cell Neuroendocrine Carcinoma ....................................................... 352 Clinical Presentation................................................................................ 352 Pathologic Features.................................................................................. 352 Morphometry ............................................................................................... 353 Molecular Biology ....................................................................................... 354 Immunohistochemistry ................................................................................ 354 CD56........................................................................................................ 355 hASH1...................................................................................................... 355 TTF-1....................................................................................................... 356 Cytokeratins............................................................................................. 356 p53, Rb, Bcl-2.......................................................................................... 357 CD117...................................................................................................... 357 Differential Diagnosis.................................................................................. 357 References.................................................................................................... 359

25. Contents xxvii 26. Differentiation Between Pleuropulmonary Desmoid Tumors and Solitary Fibrous Tumors: Role of Histology and Immunohistochemistry.............................................................................. 363 Dani S. Zander and Loren E. Clarke Introduction.................................................................................................. 363 Gross and Microscopic Pathology ............................................................... 363 Gross Features.......................................................................................... 363 Microscopic Features............................................................................... 364 Immunohistochemistry ................................................................................ 366 Conventional Antibodies.......................................................................... 366 -Catenin and Cyclin D1 ......................................................................... 368 References.................................................................................................... 369 27. Non-Small Cell Lung Cancer with Brain Metastasis: Role of Epidermal Growth Factor Receptor Gene Mutation......................... 371 Edmond S.K. Ma and Chris L.P. Wong Introduction.................................................................................................. 371 Histopathological Correlation.................................................................. 371 Epidermal Growth Factor Receptor Gene Mutation................................ 372 Epidermal Growth Factor Receptor Gene Amplication ........................ 373 Materials ...................................................................................................... 373 Methods........................................................................................................ 375 Tissue Preparation.................................................................................... 375 EGFR Gene PCR Amplication and Sequencing Analysis..................... 376 Fluorescence In-Situ Hybridization Detection of EGFR Gene Amplication and Loss of Heterozygosity .......................................... 377 MLPA Detection of EGFR Gene Copy Number Changes....................... 379 Results and Discussion ................................................................................ 380 Spectrum of EGFR Mutations in Hong Kong Chinese Patients with NSCLC......................................................................................... 380 Role of EGFR Gene Mutation in Brain Metastases from NSCLC.......... 380 Molecular Genetic Study of NSCLC with Brain Metastasis ................... 382 Getinib Response of Brain Metastases from NSCLC............................ 383 References.................................................................................................... 385 Part III Prostate Cancer 28. Prostate Carcinoma ....................................................................................... 391 M.A. Hayat Introduction.................................................................................................. 391 Prostate Specic Antigen......................................................................... 392 References.................................................................................................... 395

26. 29. The Role of Intermediary Metabolism and Molecular Genetics in Prostate Cancer...................................................................................... 397 Renty B. Franklin and Leslie C. Costello Introduction.................................................................................................. 397 Citrate Production and the Human Prostate Gland...................................... 398 Citrate Metabolism in Normal Prostate Epithelial Cells.............................. 399 M-Aconitase and Zinc in Citrate Production............................................... 399 Glucose Utilization for Net Citrate Production ........................................... 400 Aspartate as the Source of Oxalacetate for Citrate Production.................... 402 The Bioenergetics of Net Citrate Production............................................... 402 The Citrate Relationship in Prostate Cancer................................................ 403 The Genetic/Metabolic Transformation in Malignant Cells........................ 404 Is Zinc a Tumor Suppressor in Prostate Cancer?......................................... 405 Is Zip1 a Tumor Suppressor Gene in Prostate Cancer?................................ 406 Citrate Metabolism and De Novo Lipogenesis ............................................ 406 The Concept of Metabolic Genes............................................................. 408 The Clinical Application of Prostate Cancer Metabolism........................... 409 References.................................................................................................... 411 30. Array-Based Comparative Genomic Hybridization in Prostate Cancer: Research and Clinical Applications............................ 415 Franclim R. Ribeiro, Rolf I. Skotheim, Rui Henrique, and Manuel R. Teixeira Introduction.................................................................................................. 415 The Methodology......................................................................................... 415 Platforms and Methodologies .................................................................. 416 Scoring Approaches and Common Pitfalls.............................................. 418 Technical Limitations of Prostate Cancer Sampling.................................... 419 Genomic Data on Prostate Cancer............................................................... 420 Genomic Hotspots in Prostate Cancer ................................................. 423 Recurrent Copy Number Gains and Candidate Oncogenes......................... 423 Recurrent Copy Number Losses and Putative Tumor Suppressor Genes..................................................................................... 423 Fusion Genes Newly Discovered Players ................................................. 424 Complementary Technologies ................................................................. 425 Conclusions and Future Perspectives........................................................... 426 References.................................................................................................... 426 31. Prostate Cancer: Role of Vav3 Overexpression in Development and Progression.......................................................................................... 431 Shan Lu Introduction.................................................................................................. 431 Multiple Functions of Vav Family Proteins ................................................. 431 Vav3 is Overexpressed in Human Prostate Cancer and Stimulates Growth of Prostate Cancer Cells...................................................................... 432 xxviii Contents

27. Vav3 Overexpression Enhances AR Transactivation Activity...................... 433 The Potential Impact of Vav3 on Nongenomic Androgen Receptor Activity..................................................................................... 433 Vav3 Signaling in Prostate Cancer............................................................... 435 The Role of Vav3 in Prostate Cancer Biology ............................................. 436 References.................................................................................................... 438 32. Prostate Cancer: Detection and Monitoring Using Mitochondrial Mutations as a Biomarker......................................................................... 441 Gabriel D. Dakubo, Ryan L. Parr, and John P. Jakupciak Introduction.................................................................................................. 441 Mitochondrial Genetics................................................................................ 442 Mitochondrial Bioenergetics........................................................................ 444 Mitochondrial Oncology.............................................................................. 446 Unique Prostate Epithelial Cell Metabolism................................................ 447 Mitochondrial DNA Mutations in Prostate Cancer...................................... 448 Sample Preparation for Mitochondrial DNA Mutation Analysis in Prostate Cancer ........................................................................................ 451 Analysis of Mitochondrial DNA Point Mutations in Prostate Cancer......... 452 Microarray Resequencing of Mitochondrial DNA .................................. 453 Denaturing High-Performance Liquid Chromatography......................... 455 Pyrosequencing........................................................................................ 456 Other Emerging Sequencing Technologies.............................................. 458 Real Time PCR Analysis of Mitochondrial DNA in Prostate Cancer ......... 458 Quality Assurance Issues to Be Considered in Mitochondrial DNA Analysis.................................................................................................... 461 References.................................................................................................... 463 33. Prognostic Markers in Prostatic Carcinoma............................................... 465 Sonia L. El-Sharkawy, Naglaa F. Abbas, and Nadia G. EL-Hefnawy Introduction.................................................................................................. 465 Materials and Methods................................................................................. 467 Results and Discussion ................................................................................ 470 References.................................................................................................... 477 34. Prostate Cancer: Detection of Free Tumor-Specic DNA in Blood and Bone Marrow ...................................................................................... 481 Heidi Schwarzenbach and Klaus Pantel Introduction.................................................................................................. 481 Genetics and Epigenetics of Prostate Tumors.............................................. 482 Limitations of Using Tumor Tissues for Genetic and Epigenetic Analyses................................................................................. 482 History of Detection Circulating DNA in Blood ......................................... 483 Elevated Levels of Cell-Free Nucleic Acids in Prostate Cancer Patients.... 484 Contents xxix

28. xxx Contents Plasma-Based Microsatellite Analysis......................................................... 486 Plasma-Based Single Nucleotide Polymorphism Analysis.......................... 489 PCR-Based Fluorescence Microsatellite and SNP Technique Using Blood and Bone Marrow DNA ................................................................ 490 Limitations of the Blood-Based LOH Analysis........................................... 490 Technical Considerations of the Plasma-Based Analyses ........................... 492 Plasma-Based Epigenetic Analysis.............................................................. 493 DNA Methylation Analysis by the Sodium Bisulte Technique................. 494 References.................................................................................................... 495 35. Prostate Carcinoma: Evaluation Using Transrectal Sonography ............. 499 Ahmet T. Turgut and Vikram S. Dogra Introduction.................................................................................................. 495 Prostate Carcinoma Diagnosis..................................................................... 500 Transrectal Ultrasonography Using Assessment of Prostate Cancer........... 501 Anatomy....................................................................................................... 501 Physics ......................................................................................................... 501 Sonographic Anatomy ................................................................................. 501 Techniques ................................................................................................... 502 Gray Scale Ultrasound................................................................................. 503 Color Doppler Ultrasound............................................................................ 507 Power Doppler Ultrasound........................................................................... 509 Contrast-Enhanced Ultrasound Imaging...................................................... 510 Elastography ................................................................................................ 512 Transrectal Ultrasound-Guided Prostate Biopsy.......................................... 513 Repeat Biopsies............................................................................................ 514 Complications .............................................................................................. 515 Pain or Discomfort....................................................................................... 515 Anesthesia.................................................................................................... 516 Therapeutic Applications of Transrectal Ultrasound for Prostate Cancer ... 517 Transrectal Ultrasound in the Evaluation of Local Recurrence After Radical Prostatectomy.................................................................... 517 References.................................................................................................... 518 36. Prostate Cancer: 16b-[18 F]Fluoro-5-Dihydrotesterone(FDHT) Whole-Body Positron Emission Tomography.......................................... 521 Pat Zanzonico Introduction.................................................................................................. 521 The Potential Role of Androgen-Receptor Imaging in Prostate Cancer...... 521 Positron Emission Tomography................................................................... 522 Pre-Clinical Studies of Androgen Receptor Radioligands........................... 523 Clinical Studies of 16-[18 F]Fluoro-5-Dihydrotesterone.......................... 525 Radiation Dosimetry of 16-[18 F]Fluoro-5-Dihydrotesterone .................. 528 References.................................................................................................... 528

29. Contents xxxi 37. Effects of Standard Treatments on the Immune Response to Prostate Cancer...................................................................................... 531 Nancy J. Nesslinger, Howard H. Pai, Charles M. Ludgate, and Brad H. Nelson Introduction.................................................................................................. 531 Methodology................................................................................................ 536 Western Blotting Assay............................................................................ 536 Materials for Cell Culture.................................................................... 536 Materials for Protein Lysate Preparation and Quantication............... 536 Materials for Western Blotting Assay.................................................. 536 Protocol for Cell Culture, Protein Lysate Preparation and Quantication............................................................................ 537 Protocol for Western Blotting .............................................................. 538 SEREX Screening.................................................................................... 538 Materials for cDNA Library Construction........................................... 539 Materials for SEREX Screening.......................................................... 539 Protocol for cDNA Library Construction ............................................ 540 Protocol for Pre-Clearing Serum Samples........................................... 541 Protocol for SEREX Screening............................................................ 542 Protocol for Analyzing SEREX Antigen Arrays ................................. 543 Protocol for Purifying Phage Clones ................................................... 544 Results and Discussion ................................................................................ 545 References.................................................................................................... 551 38. Vinorelbine, Doxorubicin, and Prednisone in Hormone Refractory Prostate Cancer................................................. 557 Samer Kalakish and Frank M. Torti Introduction.................................................................................................. 557 Eligibility ..................................................................................................... 558 Treatment Plan............................................................................................. 559 Evaluation .................................................................................................... 559 Statistical Analysis....................................................................................... 560 Results.......................................................................................................... 560 Discussion.................................................................................................... 561 References.................................................................................................... 562 39. Locally Advanced Prostate Cancer Biochemical Recurrence after Radiotherapy: Use of Cyclic Androgen Withdrawal Therapy ........ 565 Juanita Crook Introduction.................................................................................................. 565 Laboratory Basis for Human Studies........................................................... 566 Mechanisms of Progression to Androgen Independence............................. 567 Clonal Selection....................................................................................... 567 Molecular Adaptation .............................................................................. 567

30. xxxii Contents Rationale for Intermittent Administration of Androgen Suppression in Clinical Practice................................................................................... 567 Phase II Clinical Studies.............................................................................. 568 The Canadian Prospective Trial............................................................... 569 The Ottawa Phase II Intermittent Androgen Suppression Experience .... 570 Side Effects of Treatment......................................................................... 571 Bone Density............................................................................................ 572 Phase III Clinical Studies............................................................................. 572 Is There an Accepted Standard Regimen of Intermittent Androgen Suppression? ............................................................................................ 573 Summary and Conclusions .......................................................................... 574 References.................................................................................................... 575 Index ...................................................................................................................... 579

31. xxxiii Contents of Volume 1 1. Breast Cancer: An Introduction 2. Breast Cancer: Computer-Aided Detection 3. Sebaceous Carcinoma of the Breast: Clinicopathologic Features 4. Breast Cancer: Detection by In-Vivo Imaging of Angiogenesis 5. Breast and Prostate Biopsies: Use of Optimized High-Throughput MicroRNA Expression for Diagnosis (Methodology) 6. Familial Breast Cancer: Detection of Prevalent High-Risk Epithelial Lesions 7. Differentiation Between Benign and Malignant Papillary Lesions of Breast: Excisional Biopsy or Stereotactic Vacuum-Assisted Biopsy (Methodology) 8. Multicentric Breast Cancer: Sentinel Node Biopsy as a Diagnostic Tool 9. Breast Cancer Recurrence: Role of Serum Tumor Markers CEA and CA 15-3 10. Breast Cancer Patients Before, During or After Treatment: Circulating Tumor Cells in Peripheral Blood Detected by Multigene Real-Time Reverse Transcriptase-Polymerase Chain Reaction 11. Breast Cancer Patients: Diagnostic Epigenetic Markers in Blood

32. 12. Breast Cancer Patients: Detection of Circulating Cancer Cell-Related mRNA Markers with Membrane Array Method 13. Prediction of Metastasis and Recurrence of Breast Carcinoma: Detection of Survivin-Expressing Circulating Cancer Cells 14. Node-Negative Breast Cancer: Predictive and Prognostic Value of Peripheral Blood Cytokeratin-19 mRNA-Positive Cells 15. Breast and Colon Carcinomas: Detection with Plasma CRIPTO-1 16. Breast Cancer Risk in Women with Abnormal Cytology in Nipple Aspirate Fluid 17. Tissue Microarrays: Construction and Utilization for Biomarker Studies 18. Systematic Validation of Breast Cancer Biomarkers Using Tissue Microarrays: From Construction to Image Analysis 19. Phyllodes Tumors of the Breast: The Role of Immunohistochemistry in Diagnosis 20. Phyllodes Tumor of the Breast: Prognostic Assessment Using Immunohistochemistry 21. Metaplastic Breast Carcinoma: Detection Using Histology and Immunohistochemistry 22. Invasive Breast Cancer: Overexpression of HER-2 Determined by Immunohistochemistry and Multiplex Ligation-Dependent Probe Amplication 23. Operable Breast Cancer: Neoadjuvant Treatment (Methodology) 24. Chemotherapy for Breast Cancer 25. Locally Advanced Breast Cancer: Role of Chemotherapy in Improving Prognosis 26. Relevance of Dose-Intensity for Adjuvant Treatment of Breast Cancer xxxiv Contents of Volume 1

33. 27. Advanced Breast Cancer: Treatment with Docetaxel/Epirubicin 28. Systemic Therapy for Breast Cancer: Using Toxicity Data to Inform Decisions 29. Chemotherapy for Metastatic Breast Cancer Patients Who Received Adjuvant Anthracyclines (An Overview) 30. Estrogen Receptor-Negative and HER-2/neu-Positive Locally Advanced Breast Carcinoma: Therapy with Paclitaxel and Granulocyte-Colony Stimulating Factor 31. Breast Cancer: Side Effects of Tamoxifen and Anastrozole 32. Breast Cancer: Expression of HER-2 and Epidermal Growth Factor Receptor as Clinical Markers for Response to Targeted Therapy 33. Young Breast Cancer Patients Undergoing Breast-Conserving Therapy: Role of BRCA1 and BRCA2 34. Radiation Therapy for Older Women with Early Breast Cancer 35. Acute Side Effects of Radiotherapy in Breast Cancer Patients: Role of DNA-Repair and Cell Cycle Control Genes 36. 18 F-Fluorodeoxyglucose/Positron Emission Tomography in Primary Breast Cancer: Factors Responsible for False-Negative Results 37. Sentinel Lymph Node Surgery During Prophylactic Mastectomy (Methodology) 38. Breast Conservation Surgery: Methods 39. Lymph Node-Negative Breast Carcinoma: Assessment of HER-2/neu Gene Status as Prognostic Value 40. Multifocal or Multicentric Breast Cancer: Understanding Its Impact on Management and Treatment Outcomes 41. Are Breast Cancer Survivors at Risk for Developing Other Cancers? Contents of Volume 1 xxxv

34. 42. Distant Metastasis in Elderly Patients with Breast Cancer: Prognosis with Nodal Status 43. Concomitant Use of Tamoxifen with Radiotherapy Enhances Subcutaneous Breast Fibrosis in Hypersensitive Patients 44. Malignant Phyllodes Tumor of the Breast: Is Adjuvant Radiotherapy Necessary? 45. Locally Advanced Breast Cancer: Multidrug Resistance 46. Breast Cancer: Diagnosis of Recurrence Using 18 F-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography 47. Role of Sentinel Lymph Node Biopsy in Ductal Carcinoma In Situ: Diagnosis and Methodology 48. Breast Conservation Treatment of Early Stage Breast Carcinoma: Risk of Cardiac Mortality Index xxxvi Contents of Volume 1

35. 1 Metabolic Transformations of Malignant Cells: An Overview Leslie C. Costello and Renty B. Franklin INTRODUCTION It is generally considered that the hallmark studies of Otto Warburg and colleagues reported in 1926 (Warburg et al., 1926) sparked the era of tumor cell metabolism. From that time until around 1980, and especially from 19401970, studies of intermediary metabolism of normal and malignant cells were dominant areas of research and graduate and post-graduate training in biomedical sciences. Pursuant to ~ 1980, the advent, development, and subsequent dom- inance of molecular genetics, proteomics, and molecular technology in clinical and experimental biomedical application was accompanied by the nearly complete sub- mersion of interest and training in areas of intermediary metabolism and tumor cell metabolism. (The contemporary con- sequences of this transition are discussed in a following section.) Now a resurging interest in intermediary metabolism along with the development of metabolomics in relation to cancer and other diseases has emerged. This provides a timely reason to revisit some of the important issues of tumor cell metabolism with a perspective of the contemporary associations of genomics/proteomics/metabolomics, cou- pled with molecular technology; none of which existed during the days of the out- standing biochemists and mitochondriacs of earlier times. The following overview will present some important considerations that relate to the intermediary energy metabolic requirements of tumor cells. However, one must also recognize that differing metabolic pathways exist for different malignant cells in situ; therefore, gener- alizations of metabolic transformations are not likely to be uniformly applicable to all malignant cells. Also, as authors, we take license to present some concepts of malignancy that might be challenged by others. Nevertheless, this presentation will serve as food for thought that might stimulate interest and further studies in the exciting field of metabolism of malignancy. AXIOMS OF RELATIONSHIPS OF CELLULAR ACTIVITY, CELLULAR METABOLISM, AND MALIGNANCY The following are important generaliza- tions that we consider to be axiomatic and applicable to all cells. 3

36. 4 L.C. Costello and R.B. Franklin 1. The existing cellular intermediary metabolism of a cell provides the bioenergetic/synthetic/catabolic requirements that are essential for the manifestation of the cells current activities (function, growth, and proliferation). 2. When the activity of a cell changes, its metabolism must also be adjusted consistent with any newly estab- lished bioenergetic/synthetic/catabolic requirements. 3. Malignant cells exhibit a parasitic existence. They have no specialized function other than the activities essential for their generational propagation (growth and proliferation), which occur at the expense of their host. 4. Malignant cells are derived from normal cells that have undergone a genetic transformation to a neoplastic cell phenotype that is endowed with malignant potential. 5. Manifestation of the malignant potential of the neoplastic cell necessitates alterations in its metabolism (i.e., a metabolic transformation) to provide the bioenergetic/synthetic requirements of malignancy. 6. In the absence of the metabolic transformation, the neoplastic cell will not progress to complete malignancy. Con- versely, the metabolic transformation, in the absence of the genetic transformation to a neoplastic malignant cell, will not cause malignancy. 7. Common to all malignant cells is the metabolic requirement for de novo lipogenesis/cholesterogenesis for mem- braneogenesis that is essential for their proliferative existence. These axioms define a relationship (rep- resented in Figure 1.1) that we propose is applicable to all malignancies. DEFINING A MALIGNANT CELL: A PARASITIC EXISTENCE An understanding of the purpose of the existence of a cell at any point in time in its life provides information of the requirement Figure 1.1. The role of altered intermediary metabolism in the process of the development of malignancy. Malignancy begins with the genetic transformation of a normal cell to a neoplastic malignant phenotype. The neoplastic cell undergoes genetic expression changes involved in the metabolic transformation from the normal cell metabolism of ABC to the malignant cell metabolism of XYZ to fulfill the energetic and synthetic metabolic requirements of malignancy. The neoplastic cell can then fulfill its malignant potential

37. 1. Metabolic Transformations of Malignant Cells: An Overview 5 for and role of its intermediary metabolism. Malignant cells are parasitic cells. They exist for one purpose, that is, to grow and to proliferate to ensure their generational propagation. They do so at the expense and destruction of the host. These are the criteria that define a parasitic life-style. Except for the relevance to clinical identification, it is an error (in our view) to consider or to describe tumor cells as dedifferentiated or undifferentiated cells. To do so places tumor cells in the same category as normal undifferentiated cells (e.g., stem cells, basal cells, mesenchyme cells and others that we will refer to collectively as stem cells). Stem cells, like tumor cells, also exist to grow and proliferate, but they do so for the purpose of differentiating into specialized cells that perform specific functions. Stem cells proliferate to maintain a con- tinual population of cells for further differentiation. However, unlike the parasitic tumor cells, these cells grow/proliferate in harmony with the host tissue, i.e., they exhibit a symbiotic life-style. In this sense these are sane cells, while tumor cells are insane cells. The malignant cells exhibit two essential activities for their progression and propagation: (1) growth and proliferation; (2) invasion and motility. The latter are life-cycle activities in support of the former. The intermediary metabolism of the malignant cells must provide the bioenergetic and synthetic requirements for these activities. THE IN SITU ENVIRONMENT OF THE MALIGNANT CELL DICTATES ITS METABOLISM Especially for solid tumors, the malignant cells are subjected to a changing environment as they grow and progress. Most notable is the influence of the availability of oxygen and micronutrients derived from circulation. The former is of paramount importance in relation to the intermediary metabolism of the malignant cell. The initiation of the malignant cell activity is followed by growth and proliferation that results in an increasing mass of malignant cells. This subjects the population of malignant cells to different gradients of oxygen ranging from normoxia through hypoxia toward anoxia. One can visualize a solid ball of cells in which the outside layer of cells is in apposition to the air, and each inner layer of cells progressively is more distant from the air. Thus, the intermediary metabolism of the malignant cells comprising the tumor mass cannot be expected to be uni- form at any one time, and the intermediary metabolism of the malignant cells can be expected to change as the availability of oxygen changes. As the environment becomes more hypoxic leading to anoxia, the continued malignant proliferation and other activities will become compromised and ultimately arrested. This is due to the inability of the major population of malignant cells to derive their metabolic bioenergetic and biosynthetic requirements. The lack of available oxygen and nutrients, such as glucose, from circulation prevents the malignancy from progressing. This is best illustrated by the requirements for lipogenesis/cholesterogenesis and even the accelerated glycolysis, neither of which can be sustained under such conditions. One must not forget that the waste prod- ucts of the metabolism of the malignant cells also need to be eliminated, which also requires the availability of circulation. In other words, a refurbished perfusate is an essential environmental condition for tumor progression. Indeed, the successful

38. 6 L.C. Costello and R.B. Franklin evolution of malignant cells has resulted from adaptive capabilities to confront and to overcome this adversity. For example, they upregulate hypoxia inducible factor and stimulate angiogenesis to create the circulation and environment that allows their further progression. Therefore, the cycle of malignancy involves periods of growth and proliferation and periods of arrest to refuel the environment; all of which accommodate the metabolic requirements of the mali

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