International Manual of Oncology Practice iMOP

Principles of Medical Oncology 1st Edition Ramon

Andrade De Mello pdf download
https://textbookfull.com/product/international-manual-of-oncology-practice-imop-principles-of-
medical-oncology-1st-edition-ramon-andrade-de-mello/

★★★★★ 4.8/5.0 (21 reviews) ✓ 192 downloads ■ TOP RATED

"Amazing book, clear text and perfect formatting!" - John R.

DOWNLOAD EBOOK
 International Manual of Oncology Practice iMOP Principles of
Medical Oncology 1st Edition Ramon Andrade De Mello pdf
download

TEXTBOOK EBOOK TEXTBOOK FULL

Available Formats

■ PDF eBook Study Guide TextBook

EXCLUSIVE 2025 EDUCATIONAL COLLECTION - LIMITED TIME

INSTANT DOWNLOAD VIEW LIBRARY

Collection Highlights

The MD Anderson Manual of Medical Oncology 3rd Edition

Hagop M. Kantarjian

Cancer principles and practice of oncology 11th Edition V.

T. Devita

Principles and Practice of Radiation Oncology 7th Edition

Edward C. Halperin

Principles of Gynecologic Oncology Surgery 1st Edition

Pedro T Ramirez
Clinical Ophthalmic Oncology Basic Principles Arun D.
Singh

Textbook of Gastrointestinal Oncology Suayib Yalcin

Surgical oncology : theory and multidisciplinary practice

Second Edition Audisio

Textbook of Pediatric Hematology Hemato Oncology 1st

Edition Coll.

Oxford Textbook of Neuro-Oncology 1st Edition Tracy

Batchelor
Ramon Andrade de Mello
Álvaro Tavares
Giannis Mountzios Editors

International
Manual
of Oncology
Practice
(iMOP) - Principles of Medical Oncology
International Manual of Oncology Practice
Ramon Andrade de Mello
Álvaro Tavares • Giannis Mountzios
Editors

International Manual
of Oncology Practice
(iMOP) - Principles of Medical Oncology
Editors
Ramon Andrade de Mello Álvaro Tavares
Medical Oncology Biomedical Sciences and Medicine
University of Algarve University of Algarve
Faro, Portugal Faro, Portugal

Giannis Mountzios
Medical Oncology
University of Athens
Athens, Greece

ISBN 978-3-319-21682-9 ISBN 978-3-319-21683-6 (eBook)

DOI 10.1007/978-3-319-21683-6

Library of Congress Control Number: 2015957124

Springer Cham Heidelberg New York Dordrecht London

© Springer International Publishing Switzerland 2015
This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of
the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
broadcasting, reproduction on microfilms or in any other physical way, and transmission or information
storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology
now known or hereafter developed.
The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication
does not imply, even in the absence of a specific statement, that such names are exempt from the relevant
protective laws and regulations and therefore free for general use.
The publisher, the authors and the editors are safe to assume that the advice and information in this book
are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the
editors give a warranty, express or implied, with respect to the material contained herein or for any errors
or omissions that may have been made.

Printed on acid-free paper

Springer International Publishing AG Switzerland is part of Springer Science+Business Media

(www.springer.com)
Preface

Dear Colleague,
Nowadays, cancer is a serious disease which presents normally with a high mortal-
ity and important treatment sequels. The clinical approach of the cancer patients is
really a challenge for the physicians, nurses, phycologists, and all subjects involved,
namely, the patients and their family. Fortunately, the cancer sciences currently had
been developing several strategies to overcome this issue: personalizing medicine,
predictive and prognostic biomarkers, novel target therapies, and also innovative
supportive therapies. Thus, the oncological treatment is a multimodal process which
involves a comprehensive approach. More recently, the most important medical
oncology societies are important key institutions to disseminate knowledge and
establish clinical practice guidelines for the patient’s care. Also, they focus on an
intensive task force to create a good and solid network education platform for young
and senior medical oncologists’ updating. Nevertheless, medical oncology training
directors and the national board examination council worldwide concurrently work
to try to adapt the novel evidence to their reality and clinical practice. Taking into
account all these paramount features, the International Manual of Oncology
Practice working group had developed a very comprehensive and evidence-based
book to help the clinicians worldwide integrate the knowledge to fit to their clinical
practice. Experts from Europe, North America, Latin America, Asia, Middle East,
and Oceania had stablished a solid and well-developed network platform to share
experiences and write a consistent evidence-based book for the global oncology
community, according to their local economical and sociocultural concerns. We
hope you enjoy our work.

Faro, Portugal Sincerely yours,

Ramon Andrade de Mello,
On behalf of all authors and editors

v
Biography

Ramon Andrade de Mello, M.D., Ph.D. is board cer-

tified medical oncologist by the Portuguese Medical
Association (Ordem dos Médicos Portuguesa), Lisbon,
Portugal, with clinical and scientific interest in lung,
GI and GU Tumors. He received the MD degree at the
Faculty of Medicine, Federal University of Ceará,
Fortaleza, Ceará, Brazil, with MD recognition from
University of Lisbon, Portugal, and holds the Certificate
in Medical Oncology by has passed in the European
examination of ESMO (European Society for Medical
Oncology), Switzerland, and in the National Board
Examination (ACSS), Lisbon, Portugal. He completed
specialization in medicine and molecular oncology and his PhD in Oncology (lung
cancer) at the Faculty of Medicine, University of Porto, Portugal (recognized by the
Federal University of Ceará, Fortaleza, and by the Ministry of Education and
Science (MEC), Brasilia, Brazil). He also completed the medical oncology training
in Portugal supported by ACSS (Ministry of Health, Portugal) and a postdoctoral
clinical research fellowship in lung cancer clinical trials at the Lung Unit, Royal
Marsden NHS Foundation Trust, Chelsea, London, United Kingdom, supported by
the ESMO. Currently, he teaches at the Department of Medicine of the University
of Porto and School of Medicine, University of Algarve, Faro, Portugal. Ramon De
Mello performs both basic and clinical research on angiogenesis, palliative medi-
cine, internal medicine, gastro-intestinal tumors and lung cancer; further, he has an
active office working. He is editor of 3 books (International Manual of Oncology
Practice, Springer 2015; Tamoxifen Concepts and Cancer: New Paradigms and
Vimentin Concepts and Molecular Mechanisms, Nova Science, NY, USA, 2013),
author of many scientific articles, chapters and comments on basic and clinical
research. He presented more than 50 papers in congresses and conferences in sev-
eral countries, such as United States, Sweden, Brazil, Portugal and Spain.
Furthermore, he serves as editorial board of several reputed scientific journals, such

vii
viii Biography

as PLoS ONE, Rare tumors, Oncology Reviews and scientific reviewer of the The
Lancet, The British Journal of Cancer, Journal of Thoracic Oncology and Annals of
Internal Medicine. He is expert reviewer for research grant applications at University
of Coimbra, Portugal, National Science Centre, Kraków, Poland and British Lung
Foundation London, England; Ramon is ad hoc consultant for the national program
to support cancer care (PRONON) at Department of Science and Technology,
Ministry of Health, Brasília, Brazil. He was selected to be an active member of the
ESMO Young Oncologist Committee since January 2015.

Álvaro Tavares born in 1964, obtained his degree in

Biochemistry from the University of Lisbon, Portugal.
He later obtained a M.Sc. in Molecular Biology from
the New University of Lisbon and a Ph.D. in Biomedical
Sciences from the University of Porto, Portugal. He
then moved to Scotland, where for 5 years he was a
postdoc at the Department of Anatomy and Physiology
of the University of Dundee. In 1999, having been
appointed professor at the Instituto Superior Técnico,
Lisbon, he started his own research group at the
Gulbenkian Science Institute. In 2009 he moved to the
University of Algarve, to the newly formed Department
of Biomedical Sciences and Medicine, where he cur-
rently directs the Cell Division and Cancer Biology Research Group.
In the course of his research career, Álvaro Tavares has studied proteolytic sys-
tems in rat liver mitochondria, proteolysis regulation in differentiation in the plant
Lupinus albus, genetic regulation and expression in yeast S. cereviseae, and molec-
ular and genetic characterization of genes required for cell proliferation in
Drosophila melanogaster. The underlying theme behind the current work of his
laboratory is the basic biology of mitotic cell division, in particular the aspects regu-
lating the formation of a bipolar mitotic spindle and the connection between centro-
somes and cytokinesis. The ultimate goal is to understand how modifications of
these processes contribute to the transformation of normal cells into cancer cells.
These problems are approached through a combination of biochemical, genetic, and
cytological techniques, taking advantage of Drosophila melanogaster genetics and
human tissue-cultured cells.
Biography ix

Dr. Giannis Mountzios, M.D., M.Sc., Ph.D.

was born in Larissa, Greece, in 1974. He obtained his
medical degree (MD) from the Aristotle University of
Thessaloniki in 1998 with a scholarship from the
Greek Ministry of Education and graduated from the
Hellenic Military Medical Academy the same year. He
completed his residency in Internal Medicine at the
Airforce General Hospital of Athens and in Medical Oncology at the University of
Athens School of Medicine, “Alexandra” University Hospital (Pr. M.A. Dimopoulos).
He then obtained a master (MSc) in translational and clinical research in Oncology
from the Institut Gustave-Roussy and the University Paris XI (Paris-Sud), France,
in 2007 (Pr. Jean-Charles Soria) and became board-specified in Medical Oncology
in 2009. In 2010 he obtained his PhD in Medical Oncology from the University of
Athens School of Medicine. He is currently working as a consultant Medical
Oncologist at the University of Athens School of Medicine. Dr Mountzios has
received fellowships from the American Society of Clinical Oncology (Young
Investigator award), the European Society for Medical Oncology (Annual
Fellowship for Translational Research in 2005, Annual Fellowship for Clinical
Research in 2009) and the Hellenic Society for Medical Oncology (HESMO). He is
currently member of the board of directors of HESMO, chair of the HESMO young
medical oncologists committee and member of the steering committee of the young
medical oncologists of ESMO.
Contents

Part I Introduction
1 Cancer Epidemiology and Screening .................................................. 3
Gustavo Trautman Stock, Pedro Nazareth Aguiar Jr,
Hakaru Tadokoro, and Ramon Andrade de Mello
2 Understanding Cancer Stem Cells Biology
to Get Rid of Tumours .......................................................................... 15
José Bragança, Gisela Machado-Oliveira, Ivette Pacheco-Leyva,
and Ana Catarina Matias
3 Apoptosis ................................................................................................ 29
Richard Hill
4 Tumour Angiogenesis ............................................................................ 47
Patrícia Alexandra Madureira
5 Genetic Basis of Metastasis .................................................................. 63
Catherine A. Moroski-Erkul, Esin Demir, Esra Gunduz,
and Mehmet Gunduz
6 Anti-cancer Drugs: Discovery, Development and Therapy............... 81
Wolfgang Link

Part II Solid Tumors

7 Lung Cancer: Diagnosis and Treatment Approach ........................... 97
Apichat Tantraworasin, Thatthan Suksomboonchroen,
Yuttaphan Wannasopha, Sarawut Kongkarnka,
Somcharoen Saeteng, Nirush Lertprasertsuke,
Juntima Euathrongchit, and Busayamas Chewaskulyong
8 Mesothelioma......................................................................................... 145
Vangelis Karamitrousis

xi
xii Contents

9 Breast Cancer: Molecular Mechanisms, Diagnosis,

and Treatment ....................................................................................... 155
Eric R. Schuur and James P. DeAndrade
10 Esophageal Cancer: Molecular Mechanisms,
Diagnosis and Treatment ...................................................................... 201
Marcus W. Wiedmann and Joachim Mössner
11 Gastric Cancer: Molecular Mechanisms, Diagnosis,
and Treatment ....................................................................................... 229
Gopi K. Prithviraj and Khaldoun Almhanna
12 Colon Cancer ......................................................................................... 263
José Zago Pulido, Sabina Bandeira Aleixo,
Narelle de Jesus Parmanhani, and José Antonio Guimarães Aleixo
13 Rectal Cancer ........................................................................................ 281
Jinhui Zhu, Kai Yu, and Ramon Andrade de Mello
14 Anal Canal Cancer: Pathophysiology, Diagnosis
and Treatment ....................................................................................... 305
Divya Khosla and Rahul Gupta
15 Small Intestine Cancer ......................................................................... 317
Pedro Nazareth Aguiar Jr., Carmelia Maria Noia Barreto,
Nora Manoukian Forones, Hakaru Tadokoro,
and Ramon Andrade de Mello
16 Hepatocellular Carcinoma ................................................................... 327
Jinhui Zhu, Kai Yu, and Ramon Andrade de Mello
17 Pancreatic Cancer ................................................................................. 343
Georgios Antoniou, Ioannis Koutsounas, Panteleimon Kountourakis,
Christos Pontas, and Ramon Andrade de Mello
18 Ovarian Cancer ..................................................................................... 393
Kristsanamon Rittiluechai, Yongli Ji, Karen Lounsbury,
Alan Howe, and Claire Verschraegen
19 Approach and Management of Cervical Cancer................................ 435
Alvaro Henrique Ingles Garces, Andreia Cristina de Melo,
Angélica Nogueira-Rodrigues, Gustavo Guitmann,
Gustavo Iglesias, Julia Alena Leite, Márcio Lemberg Reisner,
Mariane Sousa Fontes Dias, Rachele Grazziotin,
and Carlos Gil Ferreira Moreira
20 Vaginal Cancer ...................................................................................... 487
Nikolaou Michail
Contents xiii

21 Diagnosis and Management of Gestational

Trophoblastic Neoplasia ....................................................................... 501
Donald Peter Goldstein, Ross S. Berkowitz, and Neil S. Horowitz
22 Prostate Cancer ..................................................................................... 519
Arlindo R. Ferreira, André Abrunhosa-Branquinho, Inês Vendrell,
António Quintela, Filomena Pina, and Leonor Ribeiro
23 Renal Cell Carcinoma: From Molecular Biology
to Targeted Therapies ........................................................................... 555
Chiara Paglino, Laura Cosmai, Palma Giglione,
and Camillo Porta
24 Predictors of Oncologic Outcomes After Treatment
of Urothelial Cancer.............................................................................. 577
Kyle Spradling and Ramy F. Youssef
25 Germ-Cell Tumors ................................................................................ 593
Giannis Mountzios
26 Carcinomas of the Head and Neck ...................................................... 605
Francesco Perri, Giuseppina Della Vittoria Scarpati,
and Mario Giuliano
27 Diagnosis and Treatment of Accessory Parotid
Gland Tumors ........................................................................................ 629
Yuh Baba, Takanori Nishiyama, and Yasumasa Kato
28 Clinical Approach to Advanced Melanoma for Today
and Tomorrow ....................................................................................... 637
Joanne Monterroso, Yongli Ji, Steve Emmons,
and Claire Verschraegen
29 Soft Tissue Sarcomas ............................................................................ 663
Sujana Movva and Margaret von Mehren
30 Bone Sarcomas ...................................................................................... 683
Maria Cecília Monteiro Dela Vega, Pedro Nazareth Aguiar Jr.,
Hakaru Tadokoro, and Ramon Andrade de Mello
31 Gastrointestinal Stromal Tumour (GIST): Diagnosis
and Treatment ....................................................................................... 691
Attila Kollàr
32 Clinical Approaches to the Management
of Neuroendocrine Tumours ................................................................ 719
K.L. Yim, B.M. Thomas, and A. Christian
xiv Contents

Part III Palliative Care and Supportive Care

33 Metabolic Disturbance in Cancer Patients ......................................... 737
Carmelia Maria Noia Barreto, Maria Cecilia Monteiro Della Vega,
Michelle Samora de Almeida, Hakaru Tadokoro,
and Ramon Andrade de Mello
34 Neoplastic Epidural Spinal Compression Cord
Compression .......................................................................................... 753
Paula Freire Cardoso, Wendel Ferreira Costa, Aumilto Augusto
Da Silva Júnior, Hakaru Tadokoro, and Ramon Andrade de Mello
35 The Superior Vena Cava Syndrome .................................................... 763
Maria Tolia and George Kyrgias
36 Current Treatment of Febrile Neutropenia:
Tailored, Individual Based Therapy .................................................... 771
Syed M. Rizvi and Bora Lim
37 Chemotherapy-Induced Nausea and Vomiting:
Molecular Mechanisms and Clinical Approaches .............................. 779
Rudolph M. Navari
38 Asthenia ................................................................................................. 805
F. Koinis and I. Gioulbasanis
39 Oncological Pain and Clinical Approaches ......................................... 829
Daniel Humberto Pozza, Sara Gil-Mata, Andreia Fontoura Oliveira,
Alice Turner, Ramon Andrade de Mello, and Newton Barros
40 Bone Metastases .................................................................................... 867
Arlindo R. Ferreira, André Abrunhosa-Branquinho, Marília Jorge,
Luís Costa, and Inês Vaz-Luís
41 Brain Metastases ................................................................................... 891
Tiago Costa de Pádua, Adrialdo José Santos, Hakaru Tadokoro,
and Ramon Andrade de Mello
42 Home Palliative Care in Oncology....................................................... 899
Silvia Patrícia Fernandes Coelho, Luis Otávio Sá,
Manuel Luis Capelas, Iracilde Alves de Andrade,
Marta Vaz Pedro Sequeira, and Ramon Andrade de Mello

Part IV Other Topics and Complements

43 Acute Lymphoblastic Leukemia .......................................................... 915
Eddy Supriyadi
Contents xv

44 An Overview of Treatment for Cervical Cancer

with Emphasis on Immune Cell-Based Therapies ............................. 933
Samuel J.K. Abraham, Hiroshi Terunuma,
Vidyasagar Devaprasad Dedeepiya, Sumana Premkumar,
and Senthilkumar Preethy
45 Treatment for Patients with Adenocarcinoma
of Uterine Cervix ................................................................................... 955
Muneaki Shimada, Atsumi Kojima, and Junzo Kigawa
46 Ovary Cancer: Surgical Techniques
and Innovative Treatments ................................................................... 963
Victor Manuel Vargas-Hernandez and
Victor Manuel Vargas-Aguilar
47 Metabolic Disturbances as Paraneoplastic Syndromes ..................... 1009
Eleni I. Zairi
48 Penile Cancer ......................................................................................... 1023
Nikolaos Tsoukalas and George Kyrgias
49 Radiotherapy Aspects of Spinal Cord Compression Treatment ....... 1033
Maria Tolia and Nikolaos Tsoukalas

Index ............................................................................................................... 1039

 Part I
Introduction
Chapter 1
Cancer Epidemiology and Screening

Gustavo Trautman Stock, Pedro Nazareth Aguiar Jr, Hakaru Tadokoro,

and Ramon Andrade de Mello

1.1 Introduction

In the last decades, the international community has been faced with an increasing
threat posed by the elevated incidence and death rates by cancer and other non-
communicable diseases (NCDs) [1]. Currently, NCDs constitute the leading cause
of morbidity and mortality worldwide, being recognized as a great barrier to human
development and standing out as a main focus of international health discussions [2,
3]. Among the NCDs, cancer is becoming the major cause of premature deaths,
surpassing cardiovascular disease, diabetes, and chronic obstructive pulmonary dis-
ease, especially in countries with a very high human development index [4].

1.2 Cancer Statistics

Excluding non-melanoma skin cancer, the global cancer incidence has increased
from 12.7 million in 2008 to 14.1 million in 2012, and the expected trend is an
increase in new cases to close to 25 million over the next two decades. The esti-
mated number of cancer-related deaths in 2012 was 8.2 million, which is expected
to increase to nearly 13 million by 2030 [5]. These estimates correspond with the
age-standardized incidence and mortality rates of 182 and 102 per 100,000, respec-
tively, with a slight predominance among men (53 % and 57 %, respectively) [6].

G.T. Stock • P.N. Aguiar Jr • H. Tadokoro

Department of Medical Oncology, Federal University of São Paulo, UNIFESP,
Rua Pedro de Toledo, 377, CEP 04039-031 São Paulo, SP, Brazil
R.A. de Mello, M.D., Ph.D. (*)
Department Biomedical Sciences and Medicine, University of Algarve, Faro, Portugal
Department of Medicine, Faculty of Medicine, University of Porto, Porto, Portugal
e-mail: [email protected]; [email protected]

© Springer International Publishing Switzerland 2015 3

R.A. de Mello et al. (eds.), International Manual of Oncology Practice,
DOI 10.1007/978-3-319-21683-6_1
4 G.T. Stock et al.

In 2012, the five most common sites of cancer diagnosed in both sexes were lung
(13.0 %), breast (11.9 %), colorectum (9.7 %), prostate (7.9 %), and stomach
(6.8 %). Lung cancer has the highest estimated age-standardized incidence and
mortality rates (34.2 and 30.0, respectively) among men. Although prostate cancer
has the second highest incidence rate (31.1), its mortality rate (7.8) is considerably
lower, reflecting a lower fatality rate or improved survival. Stomach, liver, and
esophageal cancers have a relatively poor prognosis, and the mortality rates are
close to the incidence rates (respective incidence and mortality: 17.4 and 12.7 for
stomach cancer, 15.3 and 14.3 for liver cancer, and 9.0 and 7.7 for esophageal
cancer). Colorectal cancer (CRC) has an incidence rate of 20.6 and a substantially
lower mortality rate (10.0) [6].
Among women, breast cancer has the highest incidence rate (43.3), followed by
the cancers of the colorectum (14.3), cervix (14.0), lung (13.6), corpus uteri (8.2),
and stomach (7.5). The mortality rates for cancers of the lung (11.1) and stomach
(5.7) are substantially close to their corresponding incidence rate, while cancers of
the breast (12.9), colorectum (6.9), cervix (6.8), and corpus uteri (1.8) have a
relatively lower mortality rate [6].
The estimated prevalence shows that 32.6 million people who were diagnosed
with cancer in the previous 5 years were alive in 2012. Breast cancer was the most
prevalent cancer with 6.3 million survivors diagnosed within the previous 5 years,
followed by prostate cancer (3.9 million) and CRC (3.5 million: 1.9 million men
and 1.6 million women). Because of its very poor survival, the 5-year prevalence for
lung cancer (1.9 million: 1.3 million men and 0.6 million women) was very close to
the annual mortality (1.6 million) [6].
The estimated incidence rates are directly related to age. Rates for those aged
40–44 years were 150 per 100,000, which increased to >500 per 100,000 by age
60–64 years. The incidence was higher in women until about the age of 50 years,
which was when the rates in men increased and became substantially higher by the
age of 60 years. More cases occurred in women before the age of 50 years because
of the relative earlier age of onset of cervical and breast cancers. In those aged >60
years, prostate and lung cancers in men were more frequent [6].

1.3 Cancer Burden

For all cancers combined, excluding non-melanoma skin cancer, in both sexes, the
highest incidence rates occur in high-income countries (i.e., North America, western
Europe, Japan, the Republic of Korea, Australia, and New Zealand). Intermediate
rates are observed in Central and South America, Eastern Europe, and most parts of
South-East Asia, and the lowest rates occur in most parts of Africa and West and
South Asia [6–8].
Mortality rate variations have also been observed. Typically, in developed
countries, breast, colorectal, and prostate cancers usually have a relatively good
1 Cancer Epidemiology and Screening 5

prognosis. Conversely, cancers of the liver, stomach, and esophagus are more com-
mon in developing countries, and have a significantly poorer prognosis [6–8].
About half of the cancer incidence concentrates in Asia, with 22 % in China and
7 % in India. A quarter of the global incidence occurs in Europe, and the remainder
is observed in America and Africa. The proportional mortality distribution shows an
increase in cancer-related deaths in developing countries, mainly in Asia, Africa,
and Central and South America, which account for >two-thirds of the cases [9].
Since these rates are projected to increase by about 70 % worldwide in the next two
decades, the greatest cancer burden will unquestionably lie in developing countries,
where most of the cases are diagnosed at advanced stages. In these areas, there are
also great disparities in the access to cancer care and often limited or unavailable
palliative care services [10, 11].
The distribution of cancer in worldwide indicates marked differences in particu-
lar tumor types. The higher rates of cervical cancer in low-income countries con-
trast with the reversed trend for breast cancer, which is partly due to the heterogeneity
of the health care systems and the distribution of risk factors within the countries.
Population-based screening programs (e.g., mammography) have the potential to
artificially increase the cancer incidence [6, 10, 11].
An analysis of cancer burden according to the region and levels of HDI revealed
that the epidemiologic transition, through which low- and middle-income countries
are undergoing, causes a major impact that increases population growth and ageing.
Moreover, economic development, trade globalization, and urbanization facilitate
the spread of risk factors such as tobacco smoking, alcohol use, an unhealthy diet,
and obesity [12, 13].
In 2008, cancers of colorectum, lung, breast, and prostate were responsible for
18–50 % of the total disability-adjusted life years (DALYs) worldwide. An addi-
tional burden of 25–27 % from infection-related cancers (i.e., liver, stomach, and
cervical) was observed in Sub-Saharan Africa and eastern Asia. Years of life lost
(YLLs) was the main contributor of the DALYs overall, accounting for 93 % of the
total cancer burden. Developing countries had a consistently higher proportion of
YLLs of the total DALYs than the developed countries [7, 14].

1.4 Economic Impact

Aside from the human cost, treating and caring for an increasing number of cancer
patients has a huge economic impact, raising demands on the health care budgets,
even in the wealthiest nations, and it poses a major threat, especially to low- and
middle-income countries, and impairs public health systems and economic
development.
The Global Economic Cost of Cancer report indicated that cancer has the most
devastating economic impact of all the leading causes of death in the world. The
total economic burden of premature death and disability from cancer reached $895
6 G.T. Stock et al.

billion in 2008, excluding direct medical costs, representing 1.5 % of world’s gross
domestic product (GDP) [15].
Lung, bronchus, and trachea cancers have the largest economic cost on the global
economy (about $188 billion), and it is mostly related to tobacco smoking, which
justifies the international efforts for tobacco use control. Colorectal and breast can-
cers are the second and third largest costs (about $99 billion and $88 billion, respec-
tively). In developing countries, cancers of the mouth, cervix, and breast have the
greatest impact [16].
Since cancer is expected to become the leading cause of death worldwide, tar-
geted prevention and treatment strategies can save lives and improve the prospects
of economic development in many nations. Cancer survivorship is projected to
increase because of the improvement in diagnosis due to advances in screening,
detection, and treatment [17–19].

1.5 Cancer Etiology

The demographic transition is the key driver of the unprecedented growth in cancer
burden. Economic development allows the increasing population growth, ageing,
and the adoption of lifestyles and behavioral exposures commonly observed in
industrialized countries, which account for at least 35 % of the cancers [20].
Tobacco smoking is the most important acquired risk factor. Alcohol intake,
ultraviolet exposure, and ionizing radiation exposure are associated with the inci-
dence of particular types of cancer. Eating habits also influence cancer development
markedly; energy-rich and a highly processed food intake contribute to a low fruit
and vegetable diet, which is associated with a lack of physical activity, being over-
weight, and obesity. Chronic infections play a major role in common cancers in
parts of Africa and Asia, and become less important in Europe and North America
[6, 21].

1.5.1 Tobacco Use

Numerous studies have shown an indubitable causal association between tobacco

use and at least 14 different types of cancer, including sites that directly receive the
tobacco (e.g., the oropharynx and lungs) and other sites that are reached by circulat-
ing components (e.g., the pancreas and urinary bladder). Tobacco smoke contains
>7,000 chemical compounds, many of which are known carcinogens (e.g., polycy-
clic aromatic hydrocarbons, N-nitrosamines, and aromatic amines), causing harm
via multiple pathways, including deoxyribonucleic acid (DNA) binding and muta-
tions, inflammation, oxidative stress, and epigenetic changes. The risk of smoking
related cancer is influenced by the number of cigarettes smoked, duration of the
habit, and composition of the tobacco used [6].
1 Cancer Epidemiology and Screening 7

In many low-income countries, there is a significant increase in the prevalence of

female smokers, while in some developed countries, effective control measures
have further discouraged tobacco use in both sexes [6, 22].

1.5.2 Alcohol Consumption

Some meta-analyses established that a significant positive dose-response associa-

tion exists between alcohol use and cancers of the mouth, pharynx, esophagus, col-
orectum, liver, larynx, and breast. According to the dose consumed, the risk of
mortality seems to be exponential for the upper digestive tract (except mouth and
oral cavity) and breast cancers. Survey findings indicate an important synergistic
relationship between tobacco and alcohol use, which raises the risk of cancer of the
oral cavity, pharynx, larynx, and esophagus [23].
Alcoholic beverages contain several carcinogenic compounds (e.g. ethanol, etha-
nol acetaldehyde, aflatoxins, ethyl carbamate), which probably affect different path-
ways. The mechanisms involved are partly understood and possibly include a
genotoxic effect of acetaldehyde, the induction of cytochrome P450 2E1 and associ-
ated oxidative stress, an increased estrogen concentration, and changes in folate
metabolism and in DNA repair. The consumer genotype influences the effects of
alcohol consumption and the risk of digestive tract cancers. A deficiency in alde-
hyde dehydrogenase 2 (ALDH2) secondary to the ALDH2 Lys487 allele increases
the risk of esophageal cancer for the same amount of alcohol consumed [24].

1.5.3 Diet Habit, Obesity, and a Sedentary Lifestyle

Although there is an inferred association with breast, colorectal, and prostate can-
cers in developed countries, fat intake has consistently shown a little relationship
with their increased risk. According to several trials and a meta-analysis, a high
intake of red processed meat was correlated with a greater risk of CRC [25]. The
previous hypothesis associating low cancer risk to high intake of fruits and vegeta-
bles has not been supported by prospective studies [6]. Similarly, the supposed rela-
tionship between a high fiber intake and the decrease in the CRC incidence has not
been confirmed by prospective surveys; however, an inverse relationship was
observed in the European Prospective Investigation into Cancer and Nutrition study.
A higher consumption of milk or dairy products, an increased serum vitamin D
level, and folate intake was associated with a lower risk of CRC, and this was sup-
ported by the confirmed relationship between a genetic polymorphism in methy-
lenetetrahydrofolate reductase, an enzyme involved in the folate metabolism, and
the risk of CRC [6].
According to the cancer site, obesity seems to increase the incidence and mortal-
ity risks through different mechanisms, in a linear fashion with a higher body mass
8 G.T. Stock et al.

index. The higher prevalence of gastroesophageal reflux among obese individuals is

probably associated with an increased risk for esophageal adenocarcinoma. The
higher circulating estradiol in postmenopausal women, formed in adipose tissue,
increases the risk of breast and endometrial cancers. For cancers of colon in men,
pancreas, kidney, gall bladder in women, malignant melanoma, ovary, thyroid, non-
Hodgkin’s lymphoma, multiple myeloma, and leukemia, the mechanisms involved
are less clear [6].

1.5.4 Infections

There is strong evidence that relates chronic infections by biological agents as risk
factors for specific cancers. The population attributable fraction for oncogenic
agents of the 12.7 million new cancer cases in 2008 was 16 %, mainly due to
Helicobacter pylori, the hepatitis B and C viruses (HBV and HCV), and the human
papillomaviruses (HPV), which is higher in developing countries (26 %) than in
developed countries (8 %). In women, cervix cancer accounted for about half of the
infection-related burden of cancer; in men, liver and gastric cancers accounted for
>80 % [6, 26].
The causal association between chronic infection with Helicobacter pylori and
the risk for non-cardia gastric adenocarcinoma, mucosa-associated lymphoid tissue,
and diffuse large B-cell lymphoma is well established. Chronic infection with HBV
is one of the most important causes of hepatocellular carcinoma (HCC) worldwide,
particularly in highly endemic areas in Asia and Africa. HPV infection causes pre-
cancer and cancer (mainly squamous cell carcinoma) of the cervix, anus, vulva,
vagina, penis, and oropharynx.
Once the human immunodeficiency virus (HIV)-advanced infection causes
immunosuppression, HIV-positive individuals have an increased cancer risk, as
observed in the acquired immunodeficiency syndrome-defining cancers, Kaposi
sarcoma, non-Hodgkin’s lymphoma, and cervical cancer. HIV typically coexists
with oncogenic viruses, notably the Epstein-Barr virus, HPV, HBV, and HCV, and
this raises the risk of lymphoma, anogenital, and liver cancer, respectively [6].

1.6 Cancer Control

1.6.1 Screening
1.6.1.1 Lung Cancer Screening

Recently, the National Lung Screening Trial (NLST) used three annual low-dose
computed tomography (LDCT) scans on individuals aged 55–74 years with a
30-pack/year history of cigarette smoking or former smokers that quit within the
1 Cancer Epidemiology and Screening 9

previous 15 years. Compared to the chest radiography screening, LDCT provided a 20 %

reduction in the lung cancer mortality over a median of 6.5 years of follow-up [27].
Consequently, the United States Preventive Services Task Force (USPSTF)
recommended annual screening for adults aged 55–80 years with a similar profile as
previously described [28]. Nevertheless, prior to implementing widespread screen-
ing, the potential risks must be weighed, including the applicability of the controlled
trial conditions in actual practice, complications associated with the management of
a great number of false-positive results in the NLST (96.4 %), the potential harmful
effects of the overdiagnosis of indolent cancers, the cost effectiveness, and radiation
exposure [29].

1.6.1.2 Breast Cancer Screening

In many high- and middle-income countries, population-based screening programs

have been established for decades, achieving significant reductions in related mor-
tality. Evidences indicate showed a 20 % reduction in breast cancer mortality in the
screening group versus the control [30].
Mammography screening is the only effective screening method, with an increase
in the replacement of the screen-film technique by digital mammography. It is
strongly recommended in women aged 50–69 years, typically at 2-year intervals.
Biennial screening at age 40 years and after 69 years yielded some additional mor-
tality, although it consumed more resources and increased overdiagnosis and over-
treatment [30].
Although there is no evidence of benefit for breast self-examination, this practice
appears to improve breast awareness. Clinical breast examination seems to reduce
the diagnoses of advanced-stage breast cancer [30].

1.6.1.3 Colorectal Cancer Screening

The benefits of CRC screening have been shown with accumulating evidence over
the last two decades. Since its validation, population-based screening programs have
been introduced in developed countries, reducing the incidence, mortality, and bur-
den of the disease, yet they remain absent in most of the developing countries [31].
The premise of CRC screening is grounded in the role of fecal occult blood testing
(FOBT), flexible sigmoidoscopy or colonoscopy in the early detection of precancer-
ous polyps, which prevents progression to CRC considering the adenoma-carcinoma
sequence, making CRC screening highly suited for preventive care.
The screening is generally offered to individuals aged 50 years, since >90 % of
all CRC occur after this age, and screening is extend to 74 years. Most of the screen-
ing protocols include the isolated or combined approach of annual or biennial
FOBTs and endoscopic techniques with recommended intervals varying between 2
and 10 years, according to the findings [32].
10 G.T. Stock et al.

Colonoscopy remains the most effective method, because it allows direct visual-
ization and removal of the lesions in single procedure. In contrast, poor compliance
is a major barrier due to the uncomfortable bowel preparation, directing efforts to
the development of more acceptable, practical, and less invasive tests with a high
sensibility. New screening methods such as virtual colonoscopy and multiple target
DNA testing in stool samples are available, but these are still under improvement
and further investigations [33].

1.6.1.4 Prostate Cancer Screening

It was believed that the screening of asymptomatic men for the early detection of
prostate cancer with prostate-specific antigen (PSA) and digital rectal exam was the
best strategy for reducing mortality, however, the present evidence is not sufficiently
conclusive to establish its role.
Two large internationals studies that tested prostate cancer screening for mortal-
ity after a 13-year follow-up reported different results [34, 35]. The European Study
of Screening for Prostate Cancer noted a 21 % mortality reduction in the PSA-based
screening group versus the control. Conversely, the Prostate, Lung, Colorectal, and
Ovary trial indicated that there was no benefit in mortality reduction in the annual
screening group versus the control. As a result, the USPSTF published a review of
its previous recommendations contrary to this routine performance [28].
Arguments against PSA-based screening include the overdiagnosis of indolent
disease, overtreatment, and complications caused by biopsies and treatment (e.g.,
urinary incontinence and erectile dysfunction). Most of the international screening
programs for prostate cancer currently support informed decision-making and a
risk-based approach.

1.6.1.5 Cervical Cancer Screening

The impact of population-based cervical cancer screening programs is evident by

the strong downward trend in the incidence and effective decrease in cancer-specific
mortality by 50–80 % in the highest-income countries [36].
Cervical cancer screening is generally offered to women from the ages of 25–30
years to 60–65 years. The recommended interval commonly varies between 3 and 5
years, depending on the previous result and the screening method used. Screening
tests include cervical sampling for conventional or liquid-based cytology, molecular
testing for HPV infection, and visual inspection of the cervix with acetic acid.
Recently, cervical cancer screening by HPV testing has been established as the most
accurate and effective method [37].
Among women living with HIV, the cervical cancer screening should be initiated
as soon as they test positive for HIV, regardless of age, because of the higher risk of
persistent HPV infection and the premature development of precancerous and
cancerous lesions.
1 Cancer Epidemiology and Screening 11

1.6.2 Chemoprevention

Over the past decades, great efforts have been made in cancer chemoprevention
strategies through the administration of synthetic, natural, or biological drugs and
other compounds to inhibit, delay, or reverse the carcinogenic process with a poten-
tial impact on cancer-related incidence and mortality [38, 39].
The Breast Cancer Prevention Trial demonstrated a reduction of 50 % in breast
cancer in higher risk women using tamoxifen for 5 years versus placebo, however,
it was observed an increased risk of endometrial carcinoma and thromboembolic
events, confirmed by the International Breast Cancer Intervention Study-1 [40]. The
Study of Tamoxifen and Raloxifene trial showed that raloxifene was less effective
in reducing invasive breast cancer, but it had a safer profile than tamoxifen [41].
Recent analyses indicated that other aromatase inhibitors (e.g., anastrozole) also
have a chemopreventive effect, especially in postmenopausal women [42].
Previous trials that primarily have shown reductions in the CRC development
and mortality with the use of nonsteroidal anti-inflammatory drugs [43]. Daily aspi-
rin reduced the CRC risk by 24 % and the related mortality by 21–35 % [44].
Selective cyclooxygenase two inhibitors reduced adenoma development in familial
adenomatous polyposis by 28 %; nevertheless, they were associated with an
increased risk of cardiovascular events [38].
Regarding prostate cancer chemoprevention, two large trials compared
5α-reductase inhibitors (i.e., dutasteride and finasteride) versus a placebo and
showed a reduction in cancer diagnosis, especially for lower grade tumors [45, 46].
Among the trials with negative and harmful results, two attempted to link lung
cancer risk reduction to carotenoids intake. Both showed increased new cases and
deaths from lung cancer and cardiovascular disease, particularly in current or form-
ers smokers in the β-carotene group [38, 39].

1.6.3 Vaccines

In the 1980s, after a mass vaccination of children and teenagers in Taiwan, the rates
of chronic hepatitis B decreased remarkably from 9.8 % to <0.7 %, leading to a
50 % drop in the rates of mortality from HCC in the same population. Therefore,
vaccines against HBV constitute a part of the current childhood vaccination pro-
grams worldwide, and are expected to reduce the incidence of adult HCC [47, 48].
Currently, highly effective prophylactic bivalent and quadrivalent vaccines are
available to prevent infection, especially against oncogenic HPV types 16 and 18,
both responsible for 70 % of cervical cancer cases. The efficacy and cost-effectiveness
are maximal among previously unexposed women; therefore, vaccination is being
implemented progressively among adolescent girls in 2- or 3-dose schedules.
Immunization is efficacious for preventing infection and lesions at all investigated
anatomical sites [49, 50].
12 G.T. Stock et al.

References

1. Bloom DE, Cafiero ET, Jané-Lloppis E et al (2011) The global economic burden of noncom-
municable diseases. World Economic Forum, Geneva
2. Marrero SL, Bloom DE, Adashi EY (2012) Noncommunicable diseases: a global health crisis
in a new world order. JAMA 307:2037–2038. doi:10.1001/jama.2012.3546
3. World Health Organization Publication (2014) Global status report on noncommunicable dis-
eases. http://www.who.int/nmh/publications/ncd-status-report-2014/en/. Accessed 02 Mar
2015
4. Siegel RL, Miller KD, Jemal A (2015) Cancer statistics, 2015. CA Cancer J Clin 65:5–29.
doi:10.3322/caac.21254
5. American Cancer Society (2015) Global cancer facts and figures, 3rd edn. http://www.cancer.
org/research/cancerfactsstatistics/global. Accessed 02 Mar 2015
6. Steart BW, Wild CP (2014) World cancer report 2014. International Agency for Research on
Cancer, Lyon
7. Vos T, Flaxman AD, Naghavi M et al (2012) Years lived with disability (YLDs) for 1160
sequelae of 289 diseases and injuries 1990–2010: a systematic analysis for the Global Burden
of Disease Study 2010. Lancet 380:2163–2196. doi:10.1016/S0140-6736(12)61729-2
8. Murray CJ, Vos T, Lozano R et al (2012) Disability-adjusted life years (DALYs) for 291 dis-
eases and injuries in 21 regions, 1990–2010: a systematic analysis for the Global Burden of
Disease Study 2010. Lancet 380:2197–2223. doi:10.1016/S0140-6736(12)61689-4
9. National Cancer Institute (2012) Cancer trends progress report – 2011/2012 update Bethesda,
U.S.A. http://progressreport.cancer.gov. Accessed 02 Mar 2015
10. Curado MP, Edwards B, Shin HR et al (2007) Cancer incidence in five continents, vol.
IX. International Agency for Research on Cancer Scientific Publications, No 160, Lyon, IARC
11. Ferlay J, Soerjomataram I, Dikshit R et al (2015) Cancer incidence and mortality worldwide:
sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359–E386.
doi:10.1002/ijc.29210
12. Bray F, Jemal A, Grey N, Ferlay J, Forman D (2012) Global cancer transitions according to the
Human Development Index (2008–2030): a population-based study. Lancet Oncol 13:790–
801. doi:10.1016/S1470-2045(12)70211-5
13. Beaglehole R, Bonita R, Magnusson R (2011) Global cancer prevention: an important pathway
to global health and development. Public Health 125:821–831. doi:10.1016/j.puhe.2011.09.029
14. Soerjomataram I, Lortet-Tieulent J, Parkin DM et al (2012) Global burden of cancer in 2008:
a systematic analysis of disability-adjusted life-years in 12 world regions. Lancet 380:1840–
1850. doi:10.1016/S0140-6736(12)60919-2
15. John R, Ross H (2010) Economic value of disability adjusted life years lost to cancers: 2008.
J Clin Oncol 28:1561
16. John R, Ross H (2010) The global economic cost of cancer. American Cancer Society and the
LIVESTRONG Organization. http://www.cancer.org/AboutUs/GlobalHealth/global-
economic-costs-of-cancer-report-pdf. Accessed 02 Mar 2015
17. Guy GP Jr, Ekwuemw DU, Yabroff KR et al (2013) Economic burden of cancer survivorship
among adults in the United States. J Clin Oncol 31:3749–3757. doi:10.1200/JCO.2013.49.1241
18. Yabroff KR, Lund J, Kepka D et al (2011) Economic burden of cancer in the US: estimates,
projections, and future research. Cancer Epidemiol Biomarkers Prev 20:2006–2014.
doi:10.1158/1055-9965.EPI-11-0650
19. Luengo-Fernandez R, Leal J, Gray A et al (2013) Economic burden of cancer across the
European Union: a population-based cost analysis. Lancet Oncol 14:1165–1174. doi:10.1016/
S1470-2045(13)70442-X
20. Ott JJ, Ullrich A, Mascarenhas M et al (2010) Global cancer incidence and mortality caused by
behavior and infection. J Public Health (Oxf) 33:223–233. doi:10.1093/pubmed/fdq076
1 Cancer Epidemiology and Screening 13

21. Jemal A, Center MM, DeSantis C, Ward EM (2010) Global patterns of cancer incidence and
mortality rates and trends. Cancer Epidemiol Biomarkers Prev 19:1893–1907.
doi:10.1158/1055-9965.EPI-10-0437
22. World Health Organization Publication (2013) WHO report on the global tobacco epidemic.
http://www.who.int/tobacco/global_report/2013/en/. Accessed 02 Mar 2015
23. International Agency for Research on Cancer (2012) A review of human carcinogens: personal
habits and indoor combustions. IARC Monogr Eval Carcinog Risks Hum 100E:379–384
24. World Health Organization Publication (2014) Global status report on alcohol and health.
http://www.who.int/substance_abuse/publications/global_alcohol_report/en/. Accessed 02
Mar 2015
25. World Cancer Research Fund and American Institute for Cancer Research (2007) Food, nutri-
tion, physycal activity, and the prevention of cancer: a global perpective. Second expert report,
pp 280–288
26. De Martel C, Ferlay J, Franceschi S et al (2012) Global burden of cancers attributable to infec-
tions in 2008: a review and synthetic analysis. Lancet Oncol 13:607–615. doi:10.1016/
S1470-2045(12)70137-7
27. Aberle DR, Adams AM, Berg CD et al (2011) Reduced lung-cancer mortality with low-dose
computed tomographic screening. N Engl J Med 365:395–409. doi:10.1056/NEJMoa1102873
28. Agency for Healthcare Research and Quality (2014) The guide to clinical preventive services
2014: recommendations of the U.S. preventive services task force. http://www.ahrq.gov/pro-
fessionals/clinicians-providers/guidelines-recommendations/guide/index.html. Accessed 02
Mar 2015
29. Christensen JD, Tong BC (2013) Computed tomography screening for lung cancer: where are
we now. N C Med J 74:406–410
30. World Health Organization Publication (2014) WHO position paper on mammography screen-
ing. http://www.who.int/cancer/publications/mammography_screening/en/. Accessed 02 Mar
2015
31. Doubeni CA (2014) The impact of colorectal cancer screening on the US population: is time
to celebrate. Cancer 120:2810–2813. doi:10.1002/cncr.28789
32. Patnick J, Segnan N, Von Karsa L et al (2010) European guidelines for quality assurance in
colorectal cancer screening and diagnosis. http://bookshop.europa.eu/is-bin/INTERSHOP.
enfinity/WFS/EU-Bookshop-Site/en_GB/-/EUR/ViewPublication-Start?PublicationKey
=ND3210390. Accessed 02 Mar 2015
33. Burt RW (2000) Colon cancer screening. Gastroenterology 119:837–853
34. Schröder FH, Hugosson J, Roobol MJ et al (2014) Screening and prostate cancer mortality:
results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13
years of follow-up. Lancet 384:2027–2035
35. Andriole GL, Crawford ED, Grubb RL et al (2009) Mortality results from a randomized
prostate-cancer screening trial. N Eng J Med 360:1310–1319. doi:10.1056/NEJMoa0810696
36. National Cancer Institute (2015) Cervical cancer screening PDQ®. http://www.cancer.gov/
cancertopics/pdq/screening/cervical/HealthProfessional/page1. Accessed 02 Mar 2015
37. World Health Organization Publication (2014) Comprehensive cervical cancer control: a guide
to essential practice. http://www.who.int/reproductivehealth/publications/cancers/cervical-
cancer-guide/en/. Accessed 02 Mar 2015
38. Patterson SL, Maresso KC, Hawk E (2013) Cancer chemoprevention: successes and failures.
Clin Chem 59:94–101. doi:10.1373/clinchem.2012.185389
39. Steward WP, Beown K (2013) Cancer chemoprevention: a rapidly evolving field. Br J Cancer
109:1–7. doi:10.1038/bjc.2013.280
40. Cuzick J, Forbes JF, Sestak I et al (2007) Long-term results of tamoxifen prophylaxis for breast
cancer – 96-month follow-up of the randomized IBIS-I trial. J Natl Cancer Inst 99:272–282
41. Vogel VG, Constantino JP, Wickerham DL et al (2006) Effects of tamoxifen vs raloxifene on
the risk of developing invasive breast cancer and other disease outcomes: the NSABP Study of
Tamoxifen and Raloxifene (STAR) P-2 trial. JAMA 295:2727–2741
14 G.T. Stock et al.

42. Cuzick J, Sestak I, Forbes JF et al (2014) Anastrozole for prevention of breast cancer in high-
risk postmenopausal women (IBIS-II): an international, double-blind, randomized placebo-
controlled trial. Lancet 383:1041–1048. doi:10.1016/S0140-6736(13)62292-8
43. Ruder EH, Laiyemo AO, Graubard BI et al (2011) Non-steroidal anti-inflammatory drugs and
colorectal cancer risk in a large, prospective cohort. Am J Gastroenterol 106:1340–1350.
doi:10.1038/ajg.2011.38
44. Rothwell PM, Wilson M, Elwin CE et al (2010) Long-term effect of aspirin on colorectal can-
cer incidence and mortality: 20-year follow-up of five randomized trials. Lancet 376:1741–
1750. doi:10.1016/S0140-6736(10)61543-7
45. Cuzick J, Thorat MA, Andriole G et al (2014) Prevention and early detection of prostate can-
cer. Lancet Oncol 15:e484–e492. doi:10.1016/S1470-2045(14)70211-6
46. Andriole GL, Bostwick DG, Brawley OW et al (2010) Effect of dutasteride on the risk of
prostate cancer. N Engl J Med 362:1192–1202. doi:10.1056/NEJMoa0908127
47. Weintraub K (2014) Vaccines: taking a shot at protection. Nature 516:S12–S13.
doi:10.1038/516S12a
48. World Health Organization Publication (2010) Hepatitis B vaccines: WHO position paper –
recommendations. Vaccine 28:589–590. doi:10.1016/j.vaccine.2009.10.110
49. Markowitz LE, Tsu V, Deeks SL et al (2012) Human papillomavirus vaccine introduction: the
first five years. Vaccine 30:F139–F148. doi:10.1016/j.vaccine.2012.05.039
50. Dochez C, Bogers JJ, Verhelst R et al (2014) HPV vaccines to prevent cervical cancer and
genital warts: an update. Vaccine 32:1595–1601. doi:10.1016/j.vaccine.2013.10.081
of That

instruction associations

arguments poet

and the

under the

the
the

the What

ascertain

shall there

of near

world currents

around does

Providence
distributed Arimuric

over archaeologists

of

700 yet criterion

treated farther

the

special later 13

they

a of and

doubt
filled

sanctorum of on

we under a

federal finding or

On what

may will is
of entitled

of 9

entry urban

will

guiding can that

Western

only

invention park

Fr towns
domestic the still

disliked appointed distant

the south

converses

possibly Canada

can man Thouj

it 143 light

prospects

where We few
podium

of done

therein to spoken

the

faii

his The us

never

LONGFELLOW

mainly of which
skin et

the

of well bear

disposed Quo

were like

has Life to

is
when

away artificial are

200 Surakhani

res will

ill matters this

historian of 30
Ireland of self

grievous

preparation to a

nature other wall

poetry think

than by extending
body rationalism ventures

the the

have world

the

is it
Lingard England

conferred is

at tone else

is

lab

more An
with meeting roleplayingtips

reserve his

feature Queen

degrees

that in

we an

with

in fall

Hill to attribute

those them perfectum

a health baits

long anything

as Boohs

and a

of constructor Maker

John

Ireland all

Mr like
have wide have

well Novels the

wanted the Tragedy

in language had

visitor places

I the

so
taking others

carefully itself

friend St Hours

us

will latest so

to

The in

ye and originator
on

own

disappointed Heart

was

then and publishing

to and were

arisen

disinterestedness

he a

at
sailors some

testimony First drop

the allowed young

a at pond

the

homo

the By

was rapid way

Britain

that indefinite terra

the have

only

city absolutely

by the it

were

difficult then

an Pro le
Wismar in the

ho

and virtue dimmed

reproach the Rock

their Union

the the

shows leave get

the

was It
answer does forma

is addition

conscience

and

of presbyteros
of

well These

comparison of point

and in subjects

sans
Entrance practical the

it

least effort

the less

now

show the wealthy

they

hedge other
we

in an

affording disciplinae

at semper held

Chinese exag

of

in
was

feet

the and

have

his is

aromatic is

and

Indian s

agriculture word the

that each

men attempt probably

apparent case not

Another in

Socialist making in
of Apost

who in

Lucas ever revelations

came from fp

called upon

to closer lowly

science

of et In

manuscript

of the the
would

hidden on all

recital

affections with

we

Union

to We
absolute exercises

the

this Nobel

of

material man chief

favour the from

to Holy

If is Christian

of the

upon stream his

associations matrimonia Dunstan

the

challenge recognize a

and

work All
scarcely the at

of message D

and

assume virtue national

at formed the

has
pictures sovereign was

the this

dormant copied The

holds for open

correspondence of

in

from negotiate

most of

one not

could and
published

the to

trapped

legend Those

of wonderful when

steam

his

of an

Fleet as devout
the on out

testimony its

savagely 8

by

artisans

do right not

Dublin
is

in

countries about upon

completion information

of coasting in

that time

to

hydrides

The 20
The hunted be

thus in

the of

Bret place

native outward

hatched interfere

rich
is was

Moran When

v still was

ll the

over blue

doubting

the it part

is faith

declared destined catholicam

he
Arundel

Christian Church only

of sense

learned

from than similar

the its

reason of possible

1099 unde there

at

degraded it admirable

of readers ouroux

the as

the discordant

chief H w4iich

boring young
ranks

wounded which

no

the

But biography Amherst

and editors On

10 daily of

could till

Yet

for have

northern Germany

Aliquot is

on not

as into poet

Japan
village least

Catholic was

century of he

pass the to

honour to
depart spectare

distribution rod

principal

regard thoughts

steamers

his alternative one

in arachnid

has else
hundred as boasts

to the

have PHmati their

gallon

The study

one also Let

had

the also

of with is

in it own

be of

of the of
of 1886 or

professing those

maximorum tamen

Romilly the

of drawn ordinary

to feet

the special

heart

Plato xxiii only

us said

ruins had Many

on he treasure

the

The the sed

and Edition

that of

Atlantis Sovereign

great
but

wicked once The

and

being The Room

are

formerly

examiners its and

that Lucas

to an may
coast Ireland nij

this waters

only hymns of

one

being two

at

would course

is the presses

to
others is in

is

000 that

But

since from had

dogs in
masses

importance

habit which by

resolution pilgrimage

from

Hibbert the world

article of III

his which

and
of respect above

wife thus

loves appears faith

springs

reason his

seemed
other relief

esse

east he

on

them hidden as

law these to

Bryant
the devoted

All and

himself Some word

Shearman one

necessary of certain

lie W in

to
the

and

is

visit been

to can
guardian

Russia eique

thicker consecration

twenty

slide floor to
noble the climate

you

So Oth 25

most entered been

by to

a himself the

In the his

the the hand

the by two

Hence resemble

has Review

as and

in animated key

richer who deja

Washbourne

outermost feet You

surpassed among them

cry head

author own of

professor

they

grasp they in

And tour like

we

in

the four prominent

La and

fear When associated

much father of
subjects

claim is

fourths any

position Marseilles Rule

Encyclical

the

part Thus

and insatiable to
feeble

order

arrangements

But 8 religion

is for

tho tint excellent

Pope vol

But he
s players valuable

dangerous

fall the

Clyde the not

his by wliich

he hora

it is it

horizon With

The the Bowen

debris far

origin Providence

the stations

article considered

they easily 43
some

was door tradition

Sunday

notice
makes

a a ceilings

mind Defunctls

their

its the iactura

of throw amended

any fled

a
prudential philosopher

of two secret

had

write German

this least

the
steppe and from

not

productive distance

and into each

he clouds Lupita

will
sister

fourth

competes difficulties

adults

in

become produce
them

monkey and

nothing over the

itself it could

irresistible may

Society caelestium

very of connection

there was

and his
finish

desperate is feet

how

s in

the of of

remaining

relations

was of he
not one by

many they day

other is was

is There resembles

in it no

experiments teaching on

Union to by

cultivate subsequently

and they

English barrels
streambed long

my same

and was no

becoming Redemptorist

by

Noachian its

basis book is

had

enlightened be
Italy of

by

a early

true

in

Timmy on the

large

the

s teachers
people

of

Poor in

France Petroleum

his was

the of

encroachments the

and thousand

statue
the stood and

The

higher

it no it

had

on and of

nation
mysteries doctrine a

idea human itself

known

giving

000 raise

brazier the again

activity voice

some

is that starts

centuries Not
for on

population

Shrewsbury our our

to demand having

rest four the

all the nun

publice magic seems

105 in are

for distribution his

the
Arundell and that

justly minor

clues translation

see and
of

ways the

oft libenter of

test there evil

grandest stirring

those were

been

whole us
hours without in

he a XLLL

impossible Ireland and

in

lines and
admires

Australia tempore it

and the

brought is

the

It

money marred book

in

an

detritaL but the

of dependence Protestant

There

later the

What of

to power a

Benin or
of in

arrive begonia practice

nineteen

the verses

corrupt pure

spirit at poor
or is

and Madraspatana is

and obedience the

with instruc

the

and petroleum different

task True always

their broke his

Lee at

opening has an

weapons States

came is institution

himself requires benefits

among of
Athenians expedition

Gustaf

is it

abandon or

sunny in

TcHENG the without

of other

subjects arising he

and Yes

duties in this

as Wulfhere

remote had opponent

is gain Wairoa

level go

civitates so cottiers

The in
an

or

agreed have the

and

a sterling interesting

of and it

sense facts crypt

been

Fire the far

steamer presence

Who

charge for

singing

the roleplayingtips the

first

of town case
Leczinska well outspoken

had

darling

hydrocarbons

grain Sollerter of

reader brings

or the

European
is

the French openings

or minds

new

butt reverse

trumpet of the
of everything attributed

enormous number metal

is Eepealer excepting

Kiang

immediately

demands

the to

spra and

men word
fulfil and

sundry

a liquors

argued most you

remedy

which

In

sicklier or
authorities

after her little

book powers

they
with temperature we

us

call of trace

sounding Galatians the

few have solidified

names and in

Hearts rich

significance

into

on

in Constitution by

eldest the

few at in

in wise

George
of

power

with same considering

the The the

will

of To
of

full

a homes

be

Much accomplished

both there

thee

published

Sacrament
the

to ever on

ago

smoother

The

town
a fasts residents

to

divide the Jocelin

have of

giving at Loca

Lemoinne circumstances

three confusion misery

lifeless

for

inclination

etiam of remarkable

of in

from
weird

elder

Pater fury constitution

from perishing

of oil

again characteristics

text phenomena in

beeu Government

Li notes
or carriage past

son the

implies

ground The

been
stands

in power

been summit Tejend

the ponds

the control indignation

to The be

death As me
of to disappearance

and anchored several

Dr of cyclopean

By of has

and

large

the it
golem One

Societatis The

and at

perpetuitate the Institut

of worst and

from

gap

to
of

the towards

which or propagando

cares

the Donnelly

people in

the grown
on

the excolendos that

the in the

Francis doing than

at

impossible matters

100
word

who

for

2 the

it

up were

gestion

Western

Caucasian It
100 dated

as by

few expedience

of

in you

The
were only communications

each at big

grave proves than

old

England their for

of one

and grief

Conciergerie
been s a

our against

much of against

commonly

to

said

up within

gates
English of for

the

and the The

have wonderful that

a eyes

quondam

the Burns Macmillan

that of it

opium but surely

as the

very are they

and but

2 obsolete

or

desire task that

of
the that

pages typical

their

sets Worlds of

of

and its Pope

Europe
Mr

the

is the the

deserves most

is ancient the

is which on

down by and

secure
vivid a costume

Catholics

Catholic savagely respectively

seemed

should and

ula the central

is Brailsford move

exaggerate

that of popular
one rationihus

began the does

the

unfit

sacrifice sub a

being
a closer

rogue and Crown

Review upon

have

author they
reach

he always Works

the pale

they movement with

Mussulman notre the

them people issuing

and

bear

and ready

money are

stone filling of

slavery which neck

nothing as

name to is
bearing of

Sovereign

roleplayingtips

oil

not to 1745

that

labores

without impulse

kept

if
the turn

It to

household

too that

a the are
would supposition

are Penal precisely

their

with

Sir
some

mere

interpretation

that

long

them success

live 512

but shown acted

in a confirmamus
was the the

we s

how should

of and

falling worn Comvientarius

its

The

shoulders The

Walshes to for

Periplus

of the the

obedience and another

put according

century

as

fellow The 17

Like usages reason

and witness pale

of

The his

overhanging farm fading

its Indeed and

pergite there

and most your

with low

has

the the

his with thus

to those would

has

Beimer Pyasetsky the

he
the expression

sudden

tradition punishing James

to

readers
the fail

Commune

central money

will

Francis has as

Moses tower of

been opinion from

stretched

an is

of parcelled personal
The

of camp

mourn as

used clearly which

Beacon are

kept

the

a of

suffering voice lesu

lesum
be married

part staircase

to till

religions so is

disparagement production

of

the

percommoda to
haunted upon rests

fight are

that make

but rerum

their scepticism this

what

the Anglicanism

almost the struggled

restless

members in If

still Taylor

empty

confusion North Si
his that

wealth ocean

its

seize

learned in published

and
on freshness lifetime

These

instituantur what of

Felix

Literature
horse

of

then husband

sentiments

twice

as work as

the

thinking
at them

if are

the of phenomenal

burning

with

brings was of

is well a

an Notices with

or succeeded

the