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
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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
per- sons 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 treat- ments,
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 resist- ance 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 inter- pretation on
the basis of a single labora- tory 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, includ- ing diagnosis using molecular genetics, various
imaging modalities, and tumor markers. Treatments such as
chemother- apy, radiation, chemoradiation, hormonal therapy,
immunotherapy, and surgery; and prognosis. The side effects of the
treat- ments 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 clini- cal practice. Evidence-based therapy is included. Role
of metabolism in malignancy and cancer stem cells are discussed in
detail. Methods of cancer diagnosis dis- cussed 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 circulat- ing 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 pred- nisone, 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 expe- rience 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
espe- cially from 19401970, studies of interme- diary metabolism of
normal and malignant cells were dominant areas of research and
graduate and post-graduate training in bio- medical 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 perspec- tive 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 malig- nancy 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 bioen-
ergetic/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 exist- ence. 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 nor- mal cells
that have undergone a genetic transformation to a neoplastic cell
phe- notype that is endowed with malignant potential. 5.
Manifestation of the malignant poten- tial 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 trans- formation,
the neoplastic cell will not progress to complete malignancy. Con-
versely, the metabolic transformation, in the absence of the
genetic transforma- tion 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 crite- ria 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 special- ized cells that perform specific
functions. Stem cells proliferate to maintain a con- tinual
population of cells for further dif- ferentiation. 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 progres- sion and propagation: (1) growth and pro-
liferation; (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 malig- nant 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 malig- nant 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 dif- ferent 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
metabo- lism of the malignant cells comprising the tumor mass
cannot be expected to be uni- form at any one time, and the
intermedi- ary 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 malig- nant cells to derive their metabolic bioen-
ergetic 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
prolifera- tion and periods of arrest to refuel the environment;
all of which accommodate the metabolic requirements of the
mali