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Jeffrey Huang
Jiapeng Huang
Henry Liu
Editors
Anesthesia
for Oncological
Surgery
123
Anesthesia for Oncological Surgery
Jeffrey Huang • Jiapeng Huang • Henry Liu
Editors
Anesthesia for Oncological

Surgery
Editors
Jeffrey Huang Jiapeng Huang
Department of Anesthesiology Department of Anesthesiology
Moffitt Cancer Center University of Louisville Hospital
Tampa, FL, USA Louisville, KY, USA
Henry Liu
Anesthesiology and Critical Care
University of Pennsylvania
Philadelphia, PA, USA
ISBN 978-3-031-50976-6 ISBN 978-3-031-50977-3 (eBook)

https://doi.org/10.1007/978-3-031-50977-3
© The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
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Paper in this product is recyclable

Foreword
The global burden of new cancer cases reached an alarming 19.3 million in 2020, resulting in
nearly 10 million cancer-related deaths. However, amidst this concerning trend, there is a glim-
mer of progress. The 5-year survival rates for all cancers from 2012 to 2018 have nearly dou-
bled compared to the 1970s, primarily attributed to advancements in early detection and cancer
management.
A pivotal player in this progress is personalized medicine, a groundbreaking approach tai-
loring treatment plans to each patient’s unique genetic makeup, medical conditions, and spe-
cific cancer characteristics.
An often overlooked but crucial aspect of cancer care is anesthesia. Whether during diag-
nostic, therapeutic, or palliative procedures, personalized anesthesia care is vital, considering
factors such as comorbidities, medications, and treatment history. The success of oncological
surgeries hinges on well-managed anesthesia, contributing to improved recovery, fewer com-
plications, and better patient outcomes.
Given the dynamic evolution of cancer treatment approaches, surgical techniques, and med-
ical therapies, dedicated textbooks in this area become imperative. “Anesthesia for Oncological
Surgery,” edited by Professors Jeffrey Huang, Jiapeng Huang, and Henry Liu, emerges as a
standout resource. This concise yet comprehensive guide addresses the unique challenges of
anesthesia in cancer surgery, often overlooked by general anesthesia textbooks.
This textbook transcends the role of a mere manual for perioperative cancer patient care. It
delves into crucial aspects such as disease epidemiology, survival rates, pathology, risk factors,
screening, diagnosis, and latest treatment approaches for various cancer types across all
systems.
Central to the book is its exploration of how diseases and cancer treatments impact anes-
thetic planning. It provides detailed insights into preoperative evaluation, intraoperative man-
agement, and postoperative care, empowering anesthesia providers to make informed decisions
throughout the oncological surgical journey.
“Anesthesia for Oncological Surgery” serves a dual purpose, functioning as both a compre-
hensive textbook and a quick reference guide. Its versatility makes it an indispensable compan-
ion for anesthesia professionals, not just in the operating room but also in their ongoing
practice.
This book caters to anesthesia professionals of all experiences, offering an opportunity to
deepen their knowledge, enhance patient outcomes, and elevate the overall quality of practice
in the realm of oncological surgery.
Department of Anesthesiology and Perioperative Medicine Carin A. Hagberg

The University of Texas MD Anderson Cancer Center
Houston, TX, USA
Department of Anesthesiology
The University of Texas UTHealth McGovern Medical School
Houston, TX, USA
v
Preface
The steadily increasing prevalence of cancer patients in recent decades has subsequently led to
ever-increasing demands for more oncological surgical interventions, and more and more dedi-
cated oncological surgeons practice not only in major university/tertiary medical centers but
also in community hospitals. With the significant rise in the volume and the ever-expanding
range of oncological procedures, anesthesia care for these oncological procedures can be very
challenging; all these call for a reference book which addresses these challenges faced by
anesthesia providers for these oncological surgeries.
The book should cover all organ systems and all oncological procedures, especially those
newer and unique oncological procedures unfamiliar to anesthesia providers. The need for an
oncological anesthesia-focused reference book and the scarcity of such books led us to the
decision to edit this book entitled Anesthesia for Oncological Surgery. Recognizing that mod-
ern anesthesia care, especially for those newer oncological procedures, demands thorough,
updated medical and anesthetic knowledge to ascertain the quality of care for cancer patients
undergoing surgical interventions, because oncological surgical procedures are usually com-
plex and often involve diverse patient needs, which sometimes go beyond anesthesia practices
per se. Furthermore, cancer management can be very dynamic, medical interventions as che-
motherapy, radiation therapy, and immunotherapy can be integrated and interposed. Thus, it is
crucial for anesthesia providers to have a thorough understanding of dynamic oncological
management and its impact on anesthesia care. Adequate preoperative assessment, physical
and mental preparations, effective and appropriate intraoperative monitoring, timely manage-
ment of all potential adverse events, and satisfactory postoperative analgesia are all issues that
anesthesia providers will have to deal with. This book will focus on all these important issues.
Anesthesia for Oncological Surgery will serve as a comprehensive reference book and also
as a handy practice guide. The book intends to offer insights into anesthesia care specifically
for cancer patients, covering preoperative assessment, intraoperative management, and postop-
erative care. Each chapter provides pertinent oncological information, latest literature updates,
and evidence-based recommendations to enhance anesthesia providers’ understanding of the
unique challenges posed by oncological surgery.
We believe this book Anesthesia for Oncological Surgery will significantly contribute to the
knowledge in anesthesia care for oncological patients, enhance the expertise of anesthesia
providers, and ultimately improve the care delivery and clinical outcomes of perioperative
oncological patients.
Tampa, FL, USA Jeffrey Huang

Louisville, KY, USA Jiapeng Huang
Philadelphia, PA, USA Henry Liu
vii
Acknowledgments
I would like to express my gratitude to my wife, Frances Wu and my children Evan Huang and
Alexis Huang. Their unwavering support and belief, in me have been the foundation of my
accomplishments. I am also incredibly grateful for the colleagues I have had the privilege of
working with at Moffitt Cancer Center. The collaborative spirit within our hospital has fostered
an environment of innovation, research and exceptional care in the field of anesthesia and sur-
gery. It is my hope that this book will contribute to advancements, in onco-anesthesiology
through collaboration and the collective efforts of all the colleagues who have contributed to
its book.
Jeffrey Huang, MD, FASA
ix
Contents
Part I Basic Science of Oncology
Oncogenesis, What Is New?�� 3

Humberto Trejo Bittar
Epidemiology of Cancer�� 11
Hui-Yi Lin and Jong Y. Park
Immunemodulation and Cancer�� 17
Jinhong Liu and Jeffrey Huang
Cancer Targeted Molecular Therapy �� 27
Jinhong Liu
CAR T-Cell Therapy�� 35
Vivian M. Irizarry Gatell, Jeffrey Huang, and Omar A. Castaneda Puglianini
Part II Perioperative Oncology

The Surgeon: Anesthesia Professional Relationship�� 47
Alexander S. Rosemurgy, Sharona B. Ross, and Iswanto Sucandy

Anesthetic Technique and Cancer Recurrence �� 51
William M. Fowler, Kevin Thai, Thomas M. Kane, and John A. Hodgson
Prehabilitation�� 57
Relin Yang, Troy Rush, and Charles Huang

Preoperative Evaluation and Preparations for Oncological Surgery�� 65
Julia K. Labovsky

Perioperative Surgical Home, Enhanced Recovery After Surgery,
and High-Risk Committee�� 71
Kathleen J. Lee, Timothy D. Quinn, and Raymond Sroka

Blood Management for Oncological Surgery�� 79
Juan P. Cata

Acute Pain Service for Oncological Surgery �� 87
Stephania Paredes Padilla, Chelsea Skinner, Sydney L. Keller, Surendrasingh
Chhabada, Ryu Komatsu, and Jijun Xu

Chronic Pain Clinic in Cancer Center and Oncological Services �� 101
Jessica Ibañez

Non pharmaceutics Therapy for Oncological Patients�� 111
Sahana Rajasekhara, Kristine A. Donovan, and Lora M. A. Thompson
xi
xii Contents
Part III Oncological Neurosurgery
Craniotomy for Meningioma�� 121

Mian Shen
Craniotomy for Glioma �� 125
Jerrad R. Businger and Brian J. Williams
Craniotomy for Brainstem Tumors�� 129
Raja Jani, Aneeta Bhatia, Ajmal Zemmar, Akshitkumar Mistry, and Brian J.
Williams
Awake Craniotomy�� 137
Maria Birzescu

Resection of Pituitary Gland Tumor�� 143
Raja Jani, Brian J. Williams, Marina Varbanova, and Alexander Bautista
Posterior Fossa Tumor Resection �� 149
Matthew Protas, Satish Krishnamurthy, Fenghua Li, and Reza Gorji

Cervical Spine Cancer Surgery�� 157
Brianna Johnson, Nazar Dubchak, and Callum Dewar

Thoracic Spine Malignancy Surgery�� 161
Daniel Haines and Bryant M. England

Lumbar Spine Surgery (Tumors in The Lumbar Skeletal Systems and Muscles)�� 165
Shawn W. Adams, Brian J. Williams, Carlos Perez Ruiz, and Alexander Bautista

Surgery for Spinal Cord Tumors�� 169
Jeremy Crane and Justin Zeien
Part IV Head and Neck Oncological Surgery

Oral Cavity, Larynx, and Tonsil Cancer Surgery �� 177
Melanie Townsend, Ramesh Mariyappa, and Emma C. Huang

Parotid Gland Cancer Surgery�� 183
Diana Hamann
Laryngeal Cancer Surgery�� 187
James Miranda, S. Nini Malayaman, Joshua H. Atkins, and Henry Liu

Tracheostomy in Cancer Patients�� 193
Kate Williams and Madeleine Strohl

Thyroid and Parathyroid Cancer Surgery�� 199
Lin Tang and Samira M. Sadowski

Neck Dissection and Reconstruction�� 207
Joshua Read and Brielle Klein
Part V Thoracic Oncological Surgery

Lobectomy for Lung Cancer�� 215
William E. Rallya, Christopher Russo, and John Hodgson

Surgery for Pleural Malignancies�� 221
Sandra M. Orfgen
Contents xiii

Surgery for Cardiac Malignancies �� 225
Tianyu Jiang and Jeffrey Huang

Surgery for Mediastinal Cancer �� 229
Muhammad F. Sarwar, Jason M. Wallen, and Henry Liu
Surgery for Tracheal Cancer�� 233
Melissa A. Burger

Surgery for Mainstem Bronchial Cancer�� 241
Melissa A. Burger
Part VI Gastrointestinal Cancer Surgery
Esophageal Cancer Surgery�� 251

Rana K. Latif, Prejesh Philips, Zachary J. Senders, and Sean P. Clifford
Gastric Cancer Surgery�� 257
Amber F. Gallanis, Andrew J. Mannes, and Jeremy L. Davis
Liver Cancer Surgery�� 263
Michael Leclerc, Sean Stokes, Daniel Saenz Anaya, and Jeffrey Huang
Pancreatic Cancer�� 269
Jeffrey Huang
Colon/Rectal Cancer Surgery �� 273
Brendan L. Hagerty, Anthony Dakwar, and Kathleen J. Lee
HIPEC�� 279
Shadin Ghabra, Andrew M. Blakely, Andrew Mannes, and Ning Miao

Biliary System Cancer Surgery�� 287
Jeffrey Huang, Benjamin Powers, and Renee Mapes
Appendiceal Cancer Surgery�� 293
Vicente Ramos-Santillan, Gary Mann, and Timothy Quinn
Retroperitoneal Tumor Surgery �� 297
Korina E. Sandoval and Richard L. Burgan
Part VII Urological Oncology
Renal Cancer Surgery �� 303

Ryan Grell and Mohammed Said
Bladder Cancer Surgery�� 307
Daisy Sangroula, Kellen B. Choi, and Sean P. Clifford
Prostate Cancer Surgery �� 313
Daniel Nethala and Andrew J. Mannes
Urothelial Cancer Surgery�� 317
Mark M. Hanna, Taylor Peak, Herney Andrés García-Perdomo, Gagan Prakash,
Andrea Necchi, and Philippe E. Spiess
Testicular/Penile Cancer Surgery�� 323
Tianyu Jiang, Taylor Peak, Philippe Spiess, and Jeffrey Huang
xiv Contents
Part VIII Endocrine and Metabolic Oncological Surgery
Surgery for Adrenal Tumors �� 331

Shadin Ghabra, Kenneth Luberice, Naris Nilubol, Andrew Mannes, and Xiaowei Lu

Surgery for Carcinoid Syndrome �� 341
Shadin Ghabra, Tracey Pu, Naris Nilubol, Andrew Mannes, and Ning Miao
Neuroendocrine/CREST Cancer Surgery �� 349
Andrew C. Baek, Kenny Wise, and Emanuela C. Peshel
Part IX Gynecological Cancer Surgery
Ovarian Cancer Surgery �� 357

Brittany Maggard, Sarah Todd, Faizan Ahmed, Sean Clifford, Jiapeng Huang,
and Rana Latif
Uterine Cancer Surgery�� 363
Monica Avila and Rohini Kotha
Cervical Cancer Surgery �� 369
Allyn O. Toles, Briana Rice, Jordyn Tumas, and Henry Liu
Perineal Cancer Surgery �� 373
Andrewston Ting, Monica Avila, and Jeffrey Huang
Part X Surgery for Skeletal and Muscular Malignancies

Surgery for Bone Sarcoma�� 381
Raymond Evans, Andrew Serdiuk, Douglas Letson, and Jeffrey Huang
Surgery for Rhabdomyosarcoma�� 387
Jamie Hoffman, Rachel Voss, and Jeffrey Huang
Part XI Surgery for Breast Cancer and Cutaneous Cancer

Surgery for Breast Cancer�� 395
Cindy B. Yeoh, Kelly Elleson, Todd Schultz, Brielle Weinstein, Nicholas Panetta,
and Marie Catherine Lee
Cutaneous Cancer Surgery �� 403
Matthew Benesch, Julia Faller, and Joseph Skitzki
Part XII Pediatric Cancer Surgery

Anesthesia for Pediatric Procedures Outside of the Operating Room�� 411
Ashley Bocanegra and Christopher Setiawan
Wilms Tumor and Hepatoblastoma�� 417
Alex Y. Chung
Pheochromocytoma�� 423
Neethu Chandran
Medulloblastoma�� 427
John Zhong
Pilocytic Astrocytoma�� 431
John Zhong
Contents xv
Part XIII Other Oncological Surgical Procedures

Intra-arterial Therapy for Primary and Secondary Liver Cancer �� 437
Hakob Kocharyan, Altan Ahmed, and Nainesh Parikh

Percutaneous Ablative Techniques for Liver and Kidney Cancer�� 441
Altan F. Ahmed, Hakob Kocharyan, Andrei Lojec, Kenny Le, and Nainesh Parikh

Interventional Diagnostic and Therapeutic Procedures in Surgical Oncology�� 447
Kara M. Barnett, Victoria Brennan, Suken H. Shah, Elizabeth F. Rieth,
and Marisa A. Kollmeier

Intensive Care of Cancer Patients�� 457
Aditi Balakrishna, Daniel Nahrwold, and Christopher Hughes

Palliative Care Surgery of Cancer Patients �� 471
Zhaosheng Jin, Vincent Bargnes, Alexandra Tsivitis, Jonathan B. Oster, and Jun Lin

Hospice Care and Palliative Care in Cancer Patients�� 477
Hui Liu, Lin Chen, Lauren Hollifield, James E. Miranda, Brian Entler,
Nini Malayaman, and Henry Liu
Index�� 483
Part I
Basic Science of Oncology
Huang Jeffrey
Oncogenesis, What Is New?
Humberto Trejo Bittar
Nothing has revolutionized the field of cancer treatment in growth factor receptor), HER2, among many others), tumor
recent years more than the establishment of personalized suppressor genes, those that inhibit cell growth and their
medicine. Personalized cancer treatment uses therapies/ loss of function allows uncontrolled cell growth (p53 the
treatments targeted to the patient’s tumor profile, intending most commonly mutated gene in cancers and RB, etc.),
to provide a more precise and targeted therapy than conven- apoptotic genes, those regulate apoptosis promoting cancer
tional chemotherapy, particularly in advanced/metastatic cells survival (the BCL2 family of genes), and lastly genes
cancers. Pathologic assessment is an essential component of that affect the interactions between cancer cells and host
personalized cancer treatment by providing accurate cancer cells (checkpoint inhibitors genes would be in this category).
diagnoses and proper testing of tumors for those specific All the gene alterations act together to allow the cancer cells
molecular and immunohistochemical biomarkers used to to proliferate without the need for growth signals and avoid
guide targeted treatment strategies. To design targeted thera- inhibitory/apoptotic signals, to have altered cell metabolism
pies, one needs to understand the pathophysiology behind that supports continued cell growth, to guarantee blood sup-
oncogenesis. While a detailed review of oncogenesis ply, to evade the host immune system and to allow for inva-
deserves its book, in this book chapter, I focus on the impor- sion and metastasis, essentially becoming immortal [1].
tant issues of oncogenesis and personalized cancer treat- Some significant genetic changes/mutations in cancer
ment, using lung cancer as an example as I am a thoracic include point mutations, a change in a single nucleotide in
pathologist with minor references to the generalities of a gene sequence, for example, in the KRAS gene in lung
oncogenesis. adenocarcinomas. Gene rearrangements change the struc-
ture of a chromosome(s) by inversion or translocation, as it
occurs in ALK translocated lung adenocarcinomas. Gene
1 Oncogenesis and Personalized Cancer deletions, in which a portion of the chromosome is lost,
Treatment often affect tumor suppressor genes. Gene amplifications,
meaning producing multiple copies of the same gene with
Oncogenesis is a very complex and multifactorial process overexpression and activation, can be seen with HER2
related to not only the more well-known oncogenes and amplification in breast cancer. Aneuploidy is when a cancer
tumor suppressor genes but also the effect that the environ- cell has more than the standard number of chromosomes
ment has on them and the overall physiology of the normal and thus copies numbers of oncogenes. microRNAs are
cells and heritable conditions (not discussed in this chapter). small single-stranded RNA fragments that can bind to mes-
Genes are the center of oncogenesis, and simply said, the senger RNA after transcription and facilitate its degrada-
origin of cancer is related to genetic and epigenetic changes tion. This process specifically targets tumor suppressor
and mutations that alter the function of genes. There are genes, leading to downregulation of the corresponding pro-
oncogenes, those that promote cancer cells growth (RAS is teins and potentially enabling uncontrolled cell prolifera-
the most commonly mutated oncogene, EGFR (Epidermal tion, as observed in lung cancer cases [2].
Notably, a single mutation/genetic change cannot cause
the transformation of normal cells to cancer cells. Instead, in
H. T. Bittar (*) almost all cancers, multiple mutations accumulate (double/
Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA
multiple hit hypothesis) in a single cell to transform it. It is
Department of Oncologic Sciences, University of South Florida, also essential to recognize that while theoretically tumors are
Tampa, FL, USA
made of proliferation from a single mutated cell
e-mail: [email protected]
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 3

J. Huang et al. (eds.), Anesthesia for Oncological Surgery, https://doi.org/10.1007/978-3-031-50977-3_1
4 H. T. Bittar
( monoclonality), in reality, tumors are heterogenous in their genes). There is currently no role for biomarkers testing in
cell composition. This is because, within the life of a tumor, small cell carcinoma.
new mutations can occur (because of the genetic instability
present in tumors), leading to new subclones of tumor cells,
which are often selected to proliferate better and become 2 The Increasing Role
resistant to treatments. This is the origin of tumor progres- of Immunotherapy
sion and the development of treatment resistance.
Changes in the integrity of the end of chromosomes, so- Immunotherapy in cancer treatment refers to using medica-
called telomeres that protect chromosomes from degrada- tions to improve the person’s immune system’s capacity to
tion, are a standard component of aging and have also been attack neoplastic cells.
implicated in the development of many conditions, including Immune checkpoint is a normal physiologic phenomenon
cancers. The length of telomeres is maintained by the tran- aimed to prevent the building of immune responses against
scription enzyme complex telomerase (some of its vital com- healthy/non-neoplastic cells. Generally speaking, it prevents
ponents are TERT (telomerase reverse transcriptase) and T-cells from activating and promoting cell death. In the cen-
TERC (telomerase RNA component)). Shortening of telo- ter of these complicated pathways are the proteins program
meres is a normal phenomenon that occurs with each cell death-1 (PD-1) and the program death-1 ligand (PD-L1).
cycle (prevented by the telomerase) or an abnormal one due PD-L1 is a transmembrane protein that downregulates
to excess reactive oxygen species (or lack of antioxidants). immune responses by binding to its two inhibitory PD-1 and
When telomeres shorten beyond a critical point, the cell B7–1 (CD80). PD-1 is an inhibitory receptor expressed on
becomes senescent and undergoes apoptosis/cell death with T-cells following their activation, which is sustained in states
the associated loss of tissue function (as it occurs in normal of chronic stimulation such as in chronic infection or cancer.
aging). To become immortal, an important step in tumori- The binding of PD-L1 with PD-1 inhibits T-cell prolifera-
genesis, cancer cells must irreversibly prevent the shortening tion, cytokine production, and cytolytic activity, leading to
of telomeres, most often by constitutively activating telomer- the functional inactivation or exhaustion of T cells. PD-L1
ase (frequently by amplification and mutations in the pro- expression has been observed in immune cells and tumor
moter regions of the TERT and TERC genes), thus avoiding cells. Aberrant expression of PD-L1 on tumor cells has been
the DNA damage cell death pathways [3]. reported to impede anti-tumor immunity, resulting in immune
The recent advances in lung cancer treatment are a perfect evasion. Therefore, interruption of the PD-L1/PD-1 pathway
example of successful personalized cancer treatment, par- represents a novel strategy to reactivate the tumor-specific
ticularly in lung adenocarcinomas, for which potentially tar- T-cell mediated immunity suppressed by the expression of
getable oncogenic mutations are present in over 75% of PD-L1 in the tumor microenvironment.
cases. In the United States, KRAS is the most frequently PD-L1/PD-1 inhibitors (collectively called immune
mutated oncogene in lung adenocarcinoma, followed by checkpoint inhibitors) are nowadays the cornerstone of the
EGFR [4, 5]. EGFR (upstream tyrosine kinase receptor) and treatment of many cancer types. PD-L1 is expressed in a
KRAS (downstream signaling molecule) are part of the broad range of cancer cells, including lung, melanoma, uro-
MAP-kinase pathway that regulates cell growth, prolifera- thelial, kidney, ovarian, breast, and colorectal cancer [8]. For
tion, and survival. Not surprisingly, most of the targeted many of the FDA-approved indications, immune checkpoint
therapies available for lung adenocarcinomas affect this inhibitors have proven to be a superior therapy with or with-
pathway. There are multiple guidelines [6] aligning with the out concurrent chemoradiation (depending on the cancer
current state of drugs approved by the U.S. Food and Drug stage and history of prior therapies) compared to chemora-
Administration (FDA), helping clinicians in their choice of diation alone [9].
biomarkers testing (see below) and targeted treatment strate- It is impossible to discuss immunotherapy without incor-
gies. Some recommendations include molecular testing of porating T-cell transfer therapies. The main principle is
nonsquamous lung non-small cell carcinomas for KRAS, removing the patient’s T-cells and, in the laboratory, select-
EGFR, HER2, and BRAF mutations; ALK, ROS1, RET, ing and conditioning them to better attack the patient’s can-
NTRK translocations, MET exon 14 alterations, and of cer cells [10]. There are two main types of T-cells transfer
course, PD-L1 status. In squamous cell carcinomas, the most therapies.
common genetic changes include those in p53, PI3KCA,
SOX2, and FGFR1. There is currently no FDA-approved tar- • Tumor-infiltrating lymphocytes (TIL) therapy uses the
geted therapy (or need for biomarkers testing) in these lymphocytes that are enriched on the patient’s tumor
tumors [7] unless the patient is young and has never been a (requires resection of the tumor to obtain the TILs) but
smoker. Lastly, for small cell carcinomas, the most common that is not sufficient or activated enough to destroy the
(essentially all cases) genetic alterations involve downregu- tumor, and in the laboratory, select and expand those
lating of p53 and Rb proteins (by the genetic loss of their T-lymphocytes that best recognize the tumor cells (refer
Oncogenesis, What Is New? 5
to as TIL products). The TIL product is then infused back immunostain is finally evaluated under the microscope for
into the patient with the improved capacity to attack the the presence or absence and the semiquantitative estimation
tumor cells. TIL therapy has been used to treat melanoma of the targeted protein.
[11] and is currently being studied and used experimen- Important examples of the use of immunohistochemistry
tally to treat other solid tumors like cervical squamous include the assessment of PD-L1 expression in many cancer
cell carcinoma, cholangiocarcinoma, and lung carcino- types. For instance, hormone receptors status in breast can-
mas [12]. cer, mismatch repair enzymes expression status in colon and
• The other technique is CAR-T cell therapy, which uses endometrial cancer, and ALK expression in ALK translo-
the patient’s T-lymphocytes after being genetically modi- cated lung adenocarcinomas, among many others. It is
fied in the lab to express a chimeric antigen receptor important to know that there are certain preanalytical require-
(CAR) that is a modified receptor specifically designed to ments that must be met for the immunostains to be properly
attach to the patient’s tumor cells. CAR-T cell therapy is interpreted. Many of these requirements are regulated by the
FDA-approved to treat many advanced forms of leuke- Food and Drug Administration (FDA) and many pathology
mias and lymphomas [13]. While very promising, CAR-T and oncology professional organizations. Some examples of
cell therapy is not free of secondary effects and is notori- these requirements include:
ously very costly.
• For PD-L1 expression in lung non-small cell carcinoma,
at least 100 viable tumor cells must be present on the
slide, and tissue should not be over 3 years old. This can
3 The Importance of Tissue Adequacy be easily obtained by small biopsies and cytology speci-
in Biomarker/Ancillary Studies mens [6, 14–16]. Following testing guidelines is
Testing extremely important to avoid misclassifying patients
who could have potentially benefited from
Biomarkers/prognostics testing in the personalized treatment immunotherapies.
of cancer can be done by multiple techniques (see Table 1) • For hormone receptors (estrogen, progesterone, and
with different degrees of complexity. The easiest and quick- HER2) expression status in breast cancer, we have
est way of testing is by immunohistochemistry. In this tech- some of the strictest guidelines (by the College of
nique, biopsy tissue or cells collected by cytology techniques, American Pathologists (CAP) and the American
like fine needle aspiration, are exposed to antibodies that rec- Association of Clinical Oncology (ASCO)) and stan-
ognize the targeted protein (so-called primary antibody). The dard operating procedures, and their mandatory appli-
expression of the target protein is then demonstrated by cation is tightly regulated. Some of the
using a secondary antibody against the immunoglobulin recommendations include short ischemic time (the
used as the primary antibody. A distinct color (usually time between removal of the tissue/stopping of the
brown) is produced because the secondary antibody is bound blood supply and the beginning of 10% formalin fixa-
to a reagent that produces color after a specific chemical tion), the fixation time should be at least 6 h, and no
reaction (so-called detection agent). The final product is a more than 72 h, and slides should not be older than
section of tumor stained (because of the presence of color) 6 weeks, mandatory participation in external profi-
with the targeted protein, which we call immunostain. The ciency testing, among many others [17].
Table 1 Tissue sampling for personalized cancer treatment

Sample procedure Samples and tests Important factors
• Surgical resection • Fresh tissue • Preoperative evaluation and need for anesthesia
• Surgical biopsy • Formalin-fixed, paraffin-embedded (FFPE) • Choice of sampling method (invasive vs.
• Cytology specimen • Smears non-invasive)
(aspirate or fluid) • Liquid biopsies • Need for intraoperative or intraprocedural sample
• Non-invasive procedures: • Diagnostic evaluation (histology or cytology) adequacy assessment
– Blood • Protein expression: • Limitations of the length of the ischemic time
– Urine – Immunohistochemistry • Assessment of adequacy before sequencing
• Genetic tests: procedures (is there enough material after
– Conventional PCR diagnosis and further processing)
– FISH • Is there a good proportion of tumors within the
– Next-generation sequencing (NGS) sample
– RT-qPCR/gene expression panels/ • Avoid using old samples
RNA-sequencing • Need for biostatistics and data analysis of NGS
data
6 H. T. Bittar
The use of immunohistochemistry for the assessment of dye to the complementary and highly specific DNA sequence
prognostic biomarkers has many benefits, including shorter of the target gene. Using fluorescent microscopy, the loca-
turn-around time with results being available as early as tion of the probes on chromosomes can be visualized in the
within 24 h, their more cost-effective and less of a financial individual cancer cell using formalin fixed tissue sections.
burden for patients and the health system (compared to the By consensus, at least 50 well-visualized tumor calls must be
more expensive sequencing studies), and their easier to per- present on the slide [6, 22] to be an adequate sample.
form, more widely available and, in many cases, more Immunohistochemistry, a more cost-effective, faster, and
straightforward to interpret [18]. less technically demanding technique, is gradually replacing
the use of FISH in evaluating ALK rearrangement in lung
carcinomas. Confirmation by FISH studies is still necessary
3.1 Sequencing in unequivocal cases [23].
Sequencing of DNA (determining the exact sequence of

nucleotides/bases) and fluorescent in-situ hybridization stud- 3.3 RNA Gene Expression
ies (FISH) are extensively used to select patients for targeted
therapy and biomarker testing. As mentioned, these tech- The most recent molecular technique being used is the RNA
niques are used to find those specific genetic changes in the gene expression panels. Simply said, this technique uses
cancer cell’s genome. RNA instead of DNA as the input to identify gene altera-
tions. The benefit of this is that RNA detection is more sensi-
• The most effective technique for sequencing the tumor tive than DNA by detecting known and novel fusions/
genome is next-generation sequencing (NGS). While the alterations. It measures expressed genes rather than predicted
specifics of this technique are out of the scope of this gene expression, which aligns better with the true pathologic
chapter, the concept is that the whole genome or targeted drivers of the disease. When done correctly, they have better
parts of it are sequenced in parallel by millions of indi- sample yield and are more cost-effective [24, 25].
vidual smaller fragments of genetic material multiple
times (something referred to as depth of the sequencing).
Using bioinformatics tools, the fragments are pieced 3.4 Liquid Biopsies
together, mapping each fragment to the expected normal
genome, allowing by comparison to find those single Clinicians must also be aware of the usefulness of the so-
nucleotide mutations or much more significant changes in called “liquid biopsies.” Essentially, the principle behind this
individual genes or whole chromosomes. Tumor sequenc- technique is that tumor cells can shed their genetic material
ing is one of the necessary steps for most personalized into the bloodstream. Thus, we can measure the presence of
cancer treatments and often an indication for biopsy pro- that material (providing diagnosis) and its genetic sequence
cedures, particularly in the recurrence setting. (providing personalized treatment options information)
using a simple blood sample. Essentially, replacing the need
It is important to adequately obtain these tissue samples. for tissue, which might be important in patients with poor
Recent recommendations have suggested at least 1 mm2 of performance status for whom undergoing anesthesia would
formalin—fixed-paraffin-embedded tissue, needing as little be contraindicated. Other benefits of liquid biopsy include
as just five sections that must contain at least 20% of viable early cancer detention (when tumors are too small to be seen
tumor [6, 19]. It is imperative to test the adequacy, which is by imaging studies or to obtain a tissue sample), assessment
done by rapid on-site evaluation by cytologists in procedures of treatment response, and easy monitoring of recurrence
like fine needle aspirates or by frozen section examination and development of treatment resistance. Despite this, tissue
[20, 21]. The overall goal is to ensure enough and proper sampling continues to be the preferred method for diagnosis
material has been collected to avoid unnecessary repeated and molecular testing, and is considered the gold standard to
procedures, which will necessitate further anesthesia. this day [26, 27].
3.2 Fluorescent In-Situ Hybridization (FISH) 4 The Environment, Chemicals,

and Cancer
Another molecular technique used in personalized cancer
treatment is fluorescent in-situ hybridization (FISH). In this It is widely accepted that gene expression is affected by the
technique, large gene/chromosome changes are identified by environment and that different environmental conditions par-
hybridizing (binding of complementary DNA sequences) ticipate as risk factors for many cancers. This is supported by
small fragments of DNA that are tagged with a fluorescent the fact that there are regional differences in cancer types and
incidences. For example, liver cancer is more prominent in 5 Microbial Oncogenesis

East Asia, which is related to the presence of liver flukes; or
the higher incidence of certain types of cancers associated There are a few oncogenic microorganisms, including
with obesity, alcohol consumption, the Western diet, and Helicobacter pylori, and DNA and RNA viruses. Altogether
developed nations. Some of these exposures include chemi- they are believed to be responsible for approximately 15% of
cal carcinogens, ultraviolet light, tobacco smoke, and micro- cancers worldwide. Some effects on oncogenesis include
organisms (see below), among many others, all of which stimulation of cell proliferation, enhancement of cell sur-
share a common potential DNA damaging effect. It has been vival, and interference with cell cycle regulation. Some nota-
proposed that up to 85% of cancers could be prevented by ble examples include:
modifying these genes-environment interactions [28].
Cigarette smoke contains over 60 chemical carcinogens, • HPV in oropharyngeal and cervical cancer via oncogenic
including nicotine, ammonia, carbon monoxide and diox- proteins that inactivate RB and p53. The recent wide-
ide, tar, formaldehyde, acetone, and cadmium) is associated spread use of HPV vaccines is an extraordinary example
with an increased risk of many types of cancers. While lung of cancer prevention via vaccination [30, 31].
cancer is the most known association, smoking is also • Merkel cell polyomavirus, via viral integration and
linked to cancers of the head and neck, esophagus, pan- expression of the viral LT and ST proteins and thus RB
creas, bladder, and liver, among others. The effect of ciga- inhibition. More recently, immunotherapy has been
rette smoking is mainly at the level of the DNA, where it proven to be an evolving option for the treatment of this
induces distinct signature mutations (e.g., C>A transver- malignant neoplasm [32].
sions), indirect activation of DNA editing, and DNA meth- • Hepatitis B and C virus infection are one of the main etio-
ylation, helping in increasing the risk of acquiring cancer logic factors in hepatocellular carcinoma [33, 34]. There
driver mutations. Moreover, the direct effect of smoking are many ways these viruses can be oncogenic, including
inducing epithelial damage (e.g., precursor lesions of can- the promotion of chronic inflammation, dysregulation of
cer like squamous metaplasia), chronic inflammation, and cytotoxic CD8 T-cells, stimulation of hepatocytes prolif-
inhibiting apoptosis support the survival of cancer cells. eration, and increased reactive oxygen species, all leading
Outside of carcinogenesis, cigarette smoke also induces to DNA damage. There are also direct effects of viral pro-
immunosuppression, disbalances in proteases and antipro- teins (e.g., HBx and HVC core protein) on p53 function
teases, and decreases phagocytic activity, leading to many by activating transcription factors.
other diseases, including chronic obstructive pulmonary • Epstein-Barr Virus (EBV) is a human oncogenic virus
disease (COPD) [29]. that can be lifelong asymptomatic but also associated
Certain occupations and their associated exposures are with many diseases. Some of these are non-neoplastic,
known to have links with cancer. These include asbestos and including Burkitt lymphoma, some Hodgkin lymphomas,
mesothelioma, benzene and acute myeloid leukemia, beryl- nasopharyngeal carcinomas, some gastric carcinomas,
lium and lung cancer, cadmium and prostate cancer, vinyl and rare sarcomas. The exact mechanisms of oncogenesis
chloride and angiosarcoma, radon and lung cancer, among linked to EBV remain a research challenge; at least in
others. part, they are related to dysregulated normal B-cells pro-
There are many chemical carcinogens. Some act directly liferation [35].
and do not need to be metabolized. A typical example is • Helicobacter pylori, best known for its role in the patho-
alkylating chemicals, as they are used in some chemotherapy genesis of gastric peptic ulcers, is also the first bacteria to
regimens that can lead to secondary malignancies. Others be recognized as having a role in oncogenesis. Like the
need to be metabolized. Not surprisingly, some include hepatitis viruses, the bacteria, by creating a chronic
chemicals formed after the combustion of tobacco and fossil inflammatory state in the gastric mucosa, leading to atro-
fuels, those found in aromatic amines (used in the dye and phy and intestinal metaplasia, increases the risk of gastric
rubber industry), and in natural sources like aflatoxins in adenocarcinoma and lymphoma. Also, direct effects of
plants). These agents are mutagenic and directly bind to helicobacter pylori genes have been implicated (e.g.,
DNA leading to oncogenic mutations. A last mention should CagA and VacA genes), which can upregulate growth fac-
be given to the role of ionizing and ultraviolet radiations, tors [36, 37].
which are also mutagenic, including their effect on chromo-
some morphology by breaking the DNA, the excessive for- The overall organ microbiome could also participate in
mation of pyrimidine dimers overwhelming the DNA repair tumorigenesis. It has been recently described that gut and
mechanisms, and point mutations. lung microbiomes can predict response to immune therapies
8 H. T. Bittar
(e.g., anti PD-L1) by inducing immune dysregulation and small cell lung cancer and their prognostic significance according
to clinicopathological factors and diagnostic markers. Int J Mol Sci.
tolerance and directly increasing the risk of malignancy due
2019;20(4):824.
to chronic inflammation [38]. 9. Onoi K, Chihara Y, Uchino J, Shimamoto T, Morimoto Y, Iwasaku
Additional attention is now paid to the tumor ecosystem M, et al. Immune checkpoint inhibitors for lung cancer treatment: a
and microenvironment, a field that was until recently over- review. J Clin Med. 2020;9(5):1362.
10. Diaz-Cano I, Paz-Ares L, Otano I. Adoptive tumor infiltrating lym-
looked. The tumor microenvironment includes endothelial
phocyte transfer as personalized immunotherapy. Int Rev Cell Mol
cells, multiple immune cells, fibroblasts, pericytes, the extra- Biol. 2022;370:163–92.
cellular matrix, and many other organ-specific cells. While 11. Rohaan MW, van den Berg JH, Kvistborg P, Haanen J. Adoptive
this field is quickly evolving, some recent discoveries include transfer of tumor-infiltrating lymphocytes in melanoma: a viable
treatment option. J Immunother Cancer. 2018;6(1):102.
regulating immunotherapy efficiency in different tumor
12. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, et al.
microenvironments by excluding cytotoxic T-cells or induc- Lung cancer immunotherapy: progress, pitfalls, and promises. Mol
ing immunosuppression [39, 40]. Cancer. 2023;22(1):40.
In summary, tissue sampling and acquisition for per- 13. Hoffmann MS, Hunter BD, Cobb PW, Varela JC, Munoz
J. Overcoming barriers to referral for chimeric antigen receptor
forming molecular and immunohistochemical studies in
T-cell therapy in patients with relapsed/refractory diffuse large
cancer specimens have become a standard of care. B-cell lymphoma. Transplant Cell Ther. 2023;29:440–8.
Surgeons, anesthesiologists, radiologists, and of course, 14. Naito T, Udagawa H, Sato J, Horinouchi H, Murakami S, Goto
pathologists must be familiar with the most current Y, et al. A minimum of 100 tumor cells in a single biopsy sam-
ple is required to assess programmed cell death ligand 1 expres-
requirements of tissue sampling. Particularly, tissue ade-
sion in predicting patient response to Nivolumab treatment in
quacy is an important consideration that can dramatically nonsquamous non-small cell lung carcinoma. J Thorac Oncol.
affect the need for further surgical procedures, which is 2019;14(10):1818–27.
undesirable. Nowadays, anatomic and molecular patholo- 15. Faber E, Grosu H, Sabir S, San Lucas FA, Barkoh BA, Bassett RL,
et al. Adequacy of small biopsy and cytology specimens for com-
gists can perform many tests with very little tissue.
prehensive genomic profiling of patients with non-small-cell lung
Moreover, liquid biopsies are becoming more frequent, cancer to determine eligibility for immune checkpoint inhibitor and
reducing the need for procedures with additional morbid- targeted therapy. J Clin Pathol. 2022;75(9):612–9.
ity and mortality, many of which might be done in poor 16. Kalemkerian GP, Narula N, Kennedy EB, Biermann WA, Donington
J, Leighl NB, et al. Molecular testing guideline for the selection of
surgical candidates.
patients with lung cancer for treatment with targeted tyrosine kinase
inhibitors: American Society of Clinical Oncology endorsement of
the College of American Pathologists/International Association for
References the Study of Lung Cancer/Association for Molecular Pathology
clinical practice guideline update. J Clin Oncol. 2018;36(9):911–9.
17. Mahlow J, Goold EA, Jedrzkiewicz J, Gulbahce HE. What to
1. Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A,
expect from the new ASCO/CAP guideline recommendations for
Garmpis N, et al. Role of oncogenes and tumor-suppressor genes
hormone receptor testing in breast cancer: a national reference
in carcinogenesis: a review. Anticancer Res. 2020;40(11):6009–15.
laboratory experience. Appl Immunohistochem Mol Morphol.
2. Du X, Zhang J, Wang J, Lin X, Ding F. Role of miRNA in lung
2021;29(4):245–50.
cancer-potential biomarkers and therapies. Curr Pharm Des.
18. Mino-Kenudson M. Immunohistochemistry for predictive bio-
2018;23(39):5997–6010.
markers in non-small cell lung cancer. Transl Lung Cancer Res.
3. Holesova Z, Krasnicanova L, Saade R, Pos O, Budis J, Gazdarica J,
2017;6(5):570–87.
et al. Telomere length changes in cancer: insights on carcinogenesis
19. Cho M, Ahn S, Hong M, Bang H, Van Vrancken M, Kim S, et al.
and potential for non-invasive diagnostic strategies. Genes (Basel).
Tissue recommendations for precision cancer therapy using next
2023;14(3):715.
generation sequencing: a comprehensive single cancer center’s
4. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and
experiences. Oncotarget. 2017;8(26):42478–86.
coincidence in non small-cell lung cancer: meta-analyses by ethnic-
20. De Las Casas LE, Hicks DG. Pathologists at the leading edge of
ity and histology (mutMap). Ann Oncol. 2013;24(9):2371–6.
optimizing the tumor tissue journey for diagnostic accuracy and
5. Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K,
molecular testing. Am J Clin Pathol. 2021;155(6):781–92.
et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung
21. Rafael OC, Aziz M, Raftopoulos H, Vele OE, Xu W, Sugrue
cancer. Transl Lung Cancer Res. 2015;4(2):156–64.
C. Molecular testing in lung cancer: fine-needle aspiration speci-
6. Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB,
men adequacy and test prioritization prior to the CAP/IASLC/
Bernicker EH, et al. Updated molecular testing guideline for the
AMP molecular testing guideline publication. Cancer Cytopathol.
selection of lung cancer patients for treatment with targeted tyro-
2014;122(6):454–8.
sine kinase inhibitors: guideline from the College of American
22. Trejo Bittar HE, Luvison A, Miller C, Dacic S. A comparison
Pathologists, the International Association for the Study of Lung
of ALK gene rearrangement and ALK protein expression in
Cancer, and the Association for Molecular Pathology. Arch Pathol
primary lung carcinoma and matched metastasis. Histopathology.
Lab Med. 2018;142(3):321–46.
2017;71(2):269–77.
7. Perez-Moreno P, Brambilla E, Thomas R, Soria JC. Squamous cell
23. Lin C, Shi X, Yang S, Zhao J, He Q, Jin Y, et al. Comparison of
carcinoma of the lung: molecular subtypes and therapeutic oppor-
ALK detection by FISH, IHC and NGS to predict benefit from
tunities. Clin Cancer Res. 2012;18(9):2443–51.
crizotinib in advanced non-small-cell lung cancer. Lung Cancer.
8. Pawelczyk K, Piotrowska A, Ciesielska U, Jablonska K, Gletzel-
2019;131:62–8.
Plucinska N, Grzegrzolka J, et al. Role of PD-L1 expression in non-
24. Jennings LJ, Arcila ME, Corless C, Kamel-Reid S, Lubin IM, 33. Peneau C, Imbeaud S, La Bella T, Hirsch TZ, Caruso S, Calderaro
Pfeifer J, et al. Guidelines for validation of next-generation J, et al. Hepatitis B virus integrations promote local and distant
sequencing-based oncology panels: a joint consensus recommen- oncogenic driver alterations in hepatocellular carcinoma. Gut.
dation of the Association for Molecular Pathology and College of 2022;71(3):616–26.
American pathologists. J Mol Diagn. 2017;19(3):341–65. 34. Khatun M, Ray R, Ray RB. Hepatitis C virus associated hepatocel-
25. Barua S, Wang G, Mansukhani M, Hsiao S, Fernandes H. Key con- lular carcinoma. Adv Cancer Res. 2021;149:103–42.
siderations for comprehensive validation of an RNA fusion NGS 35. Yu H, Robertson ES. Epstein-Barr virus history and pathogenesis.
panel. Pract Lab Med. 2020;21:e00173. Viruses. 2023;15(3):714.
26. Rodriguez J, Avila J, Rolfo C, Ruiz-Patino A, Russo A, Ricaurte L, 36. Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, et al.
et al. When tissue is an issue the liquid biopsy is nonissue: a review. Association between helicobacter pylori eradication and gas-
Oncol Ther. 2021;9(1):89–110. tric cancer incidence: a systematic review and meta-analysis.
27. Wu X, Li J, Gassa A, Buchner D, Alakus H, Dong Q, et al. Gastroenterology. 2016;150(5):1113–24.e5.
Circulating tumor DNA as an emerging liquid biopsy biomarker for 37. Sukri A, Hanafiah A, Mohamad Zin N, Kosai NR. Epidemiology
early diagnosis and therapeutic monitoring in hepatocellular carci- and role of Helicobacter pylori virulence factors in gastric cancer
noma. Int J Biol Sci. 2020;16(9):1551–62. carcinogenesis. APMIS. 2020;128(2):150–61.
28. Wray AJD, Minaker LM. Is cancer prevention influenced by the 38. Kennedy K, Khaddour K, Ramnath N, Weinberg F. The lung micro-
built environment? A multidisciplinary scoping review. Cancer. biome in carcinogenesis and immunotherapy treatment. Cancer J.
2019;125(19):3299–311. 2023;29(2):61–9.
29. Yamaguchi NH. Smoking, immunity, and DNA damage. Transl 39. de Visser KE, Joyce JA. The evolving tumor microenvironment:
Lung Cancer Res. 2019;8(Suppl 1):S3–6. from cancer initiation to metastatic outgrowth. Cancer Cell.
30. Shigeishi H. Association between human papillomavirus and oral 2023;41(3):374–403.
cancer: a literature review. Int J Clin Oncol. 2023;28:982–9. 40. Kirchhammer N, Trefny MP, Auf der Maur P, Laubli H, Zippelius
31. Kjaer SK, Dehlendorff C, Belmonte F, Baandrup L. Real-world A. Combination cancer immunotherapies: emerging treatment
effectiveness of human papillomavirus vaccination against cervical strategies adapted to the tumor microenvironment. Sci Transl Med.
cancer. J Natl Cancer Inst. 2021;113(10):1329–35. 2022;14(670):eabo3605.
32. DeCoste RC, Carter MD, Ly TY, Gruchy JR, Nicolela AP, Pasternak
S. Merkel cell carcinoma: an update. Hum Pathol. 2023;140:39–52.
Epidemiology of Cancer
Hui-Yi Lin and Jong Y. Park
1 Introduction a 28% increase, three-fold higher than the trend of total mor-
tality during the same period (9%) [2, 3]. Cancer mortality
Over 19 million new cancer cases [1–4] lead to almost ten rates are varied in different parts of the world due to genetic
million deaths globally in 2020 [1, 2]. The most common and environmental factors, such as quality of patient care,
cancers worldwide are breast and lung cancers, while pros- availability of medical facilities, and socioeconomic status.
tate cancer is the most common in the male population These factors affect the application of screening, prevention
(Table 1) [2]. The responsible risk factors for cancer inci- strategies, and appropriate treatments for cancers. Recent
dence vary by cancer type, geographical region, and popula- advances in medical technologies can provide better screen-
tion [5]. In addition, recent environmental changes by climate ing tools and, more importantly, better patient care and treat-
changes, industrialization, and lifestyle, such as diet patterns, ments. These advances improved the prognosis and survival
are suggested as potential contributing factors for increasing of most cancers. However, patient care and public health sys-
cancer incidence [6]. Increased incidences in different tems are considerably different among countries, and these
regions or populations (such as race or gender) have been differences exist within countries [2]. These systems, socio-
reported for specific cancer types. The incidence rates in men economic, genetic, and environmental factors can be
are higher than those in women in all cancers except thyroid explained different survival rates. Among environmental fac-
cancer. For example, the bladder (2.87), liver (2.35), and tors, diet patterns and physical activity are often associated
esophageal (2.36) cancers showed the highest men/women with a risk for several cancers [7]. Typically, a healthy diet
ratios [2, 3]. and being physically active can lower the risk and improve
In terms of cancer mortality, cancer is the second leading a survival for women with breast cancer. Several factors,
cause of death, accounting for 9.9 million deaths worldwide such as the type of cancer, clinical stage at diagnosis, and
[2]. The trend of cancer mortality in the last decade showed medical care, are the main factors for cancer survival. In
most cases, early diagnosis is a main key for better outcomes
Table 1 Number of new cancer cases in worldwide and survival. The incidence rank of cancer type does not nec-
Cancer sites Cases Percentage essarily overlap with the mortality rank due to different can-
Breast 2,261,419 12.5% cer survival rates. The numbers of deaths from lung, liver,
Lung 2,206,771 12.2% pancreas, and stomach cancers are much higher than others.
Colorectal 1,931,590 10.7% In men, lung, liver, stomach, esophageal, and prostate can-
Prostate 1,414,259 7.8%
cers are the deadliest. In women, breast, lung, and stomach
Stomach 1,089,103 6.0%
cancers are the lethal ones. Colorectal cancer is the second
Liver 905,677 5.0%
leading cause of cancer mortality in both populations [8].
Data from GLOBOCAN 2020 [2–4]
H.-Y. Lin
Biostatistics Program, School of Public Health, Louisiana State
University Health Sciences Center, New Orleans, LA, USA
J. Y. Park (*)
Department of Cancer Epidemiology, Moffitt Cancer Center,
Tampa, FL, USA

12 H.-Y. Lin and J. Y. Park
2 Cancer Incidence and Trend with MRI for prostate cancer provides better sensitivity for
detection, reduces the over-diagnosis, and over-treatment
The World Health Organization (WHO) data from WHO [16]. However, the main obstacles, such as const-
shows cancers cause the largest economic burden worldwide effectiveness, to apply MRI as a prostate cancer screening
among all human diseases [2, 3]. The most considerable tool need to be cleared.
cancer-related burden is in the population aged 60 years or Lung cancer is the second most common cancer and the
older. According to the WHO Global Cancer Observatory leading cause of cancer mortality in 2020 [4]. The incidence
data, breast (2.3 million cases), lung (2.21 million cases), rate has decreased since the mid-1980s as the prevalence of
colorectal (1.93 million patients), and prostate (1.41 million smoking declined [17]. However, the incidence of lung can-
patients) cancers are the most common cancers [2, 3]. The cer among women is still rising in many countries. In these
most common cancers in men are lung, prostate, stomach, countries, smoking prevalence in women has either peaked
and liver, while breast, lung, cervical, and colon cancers are recently or continues to rise. Therefore, lung cancer inci-
most frequent among women. In terms of incidence rates, dence in women will most likely increase for at least a few
breast cancer has the highest incidence rate (46.3 per 100,000), decades more [18].
then prostate (29.3 per 100,000), lung (22.5 per 100,000), and Breast cancer incidence has increased since the 1980s due
colorectal (19.2 per 100,000) cancers are followed [4]. to the early detection of asymptomatic cases by mammogra-
Based on the American Cancer Society (ACS) report [8], phy screening. In addition, body mass index (BMI) changes,
the trend of cancer incidence was mainly influenced by envi- rising age for the first births, and declining fertility rate also
ronmental factors and patient care, especially cancer screen- contribute to the increasing trend of breast cancer incidence
ing. The discussion of incidence trends for these common [19].
cancer types is listed below. As for colorectal cancer, its incidence rates are rising in
Prostate cancer cases surged in the 1990s due to the intro- low-income countries, while incidences have declined in
duction of prostate-specific antigen (PSA) screening tests. developed countries since the mid-1990. The introduction of
Most cases identified through this screening test are asymp- screening tests, such as a colonoscopy and fecal occult blood
tomatic and early-stage prostate cancer cases. Therefore, ris- test, in old age groups drives decreased an incidence rate of
ing prostate cancer incidence may lead to the over-diagnosis colorectal cancer. However, incidence rates in the younger
and over-treatment due to these new PSA screening tests. generation are rising, most likely due to environmental fac-
Because of these concerns, there were uncertainty and dis- tors, such as lifestyle, rapid dietary transition, and obesity
agreement on the value of the PSA test [9]. The United States [20].
Preventive Services Task Force (USPSTF) recommended In addition to these four most common cancer types, cer-
new guidelines on PSA tests in 2008 and 2012 [10, 11]. They vical cancer incidence rates have decreased since the 1970s
advised against PSA screening among men older than due to PAP smear screening, which evaluates for cancerous
75 years in 2008. In 2012, the USPSTF recommended or precancerous cells on the cervix. The trend of cervical
against PSA screening for all men, regardless of age [11]. As cancer incidence rates varies by race and age group. Hispanic
a result, prostate cancer incidence was increased from 2013 women in the United States showed the highest incidence of
until now. In 2018, the USPSTF recommended that men cervical cancer compared with other racial groups. Especially
aged 55–69 should discuss the possible benefits and harms of the incidence rates are increased in young Hispanic women
PSA screening with their healthcare provider and make an [21, 22]. Low cervical cancer screening rates and high human
individualized decision about whether to get screened [12, papillomavirus (HPV) infection among Hispanic women can
13]. partially explain rising cervical cancer incidence rates [22].
For the impact of the PSA test on prostate cancer mortal- Perhaps, the most significant impact on reducing cervical
ity, Fenton et al. (2018) reported that PSA screening might cancer incidence is the introduction of vaccines against car-
provide benefits in reducing prostate cancer-specific mortal- cinogenic HPVs, type 16 and 18. These vaccines were
ity. However, this PSA test is notoriously linked to high approved in 2006 by the US Food and Drug Administration
false-positive results, often leading to an unnecessary biopsy [23]. Therefore, incidence rates of cervical cancer in the gen-
and overtreatment. In addition, long-term survival benefits eration who received the HPV vaccine were declined signifi-
among screen-detected prostate cancer were unclear [13]. cantly [24].
Recent studies evaluated magnetic resonance imaging (MRI)
as a new screening tool for prostate cancer [14]. MRI of the
prostate has become an important part of the initial radio- 3 Lifetime Risk for Cancers
graphic evaluation for the diagnosis of prostate cancer.
Recent European Association of Urology (EAU) guidelines The lifetime probability of developing cancer is 41% in men
recommend performing MRI before prostate biopsy in men and 40% in women [21]. The lifetime risk varies significantly
with high risk for prostate cancer [15]. A risk assessment by different cancer types. According to the ACS data, the high-
Epidemiology of Cancer 13
Table 2 Lifetime risk for cancers by gender in the United States Table 3 Five-year relative cancer survival rates of the top 10 common
Cancer sites Gender Percentage cancersa
All sites Male 41% Cancer sites Percentage
Female 40% All sites 68%
Breast Female 13% Prostate 97%
Prostate Male 13% Breast 91%
Lung Male 6.2% Bladder 77%
Female 5.8% Non-Hodgkin lymphoma 74%
Colorectal Male 4.3% Cervix 67%
Female 3.9% Leukemia 66%
a
Modified from ACS data [8] Colorectal 65%
Ovary 50%
Lung 23%
Pancreas 12%
est risks for cancer were found for prostate (13%), lung (6.2%), a
Modified from ACS data 2012–2018 [8]
and colorectal cancer (4.3%) in men, and breast (13%), lung
(5.8%), and colorectal (3.9%) in women (Table 2) [3, 8].
The lifetime risk for overall cancer mortality is 10.6%. leukemia has provided many new innovative treatments,
The highest risks of cancer mortality are from lung (3.19%), such as monoclonal antibodies and immune CAR-T cells.
liver (1.46%), and stomach (1.36%) in men and breast These new treatments significantly improved the prognosis
(1.41%), lung (1.32%), and cervix (0.77%) in women [8]. of chronic myeloid leukemia [27]. For melanoma metastasis,
Generally, the mortality rate of each cancer in men is higher several new immune therapies, and BRAF and MEK inhibi-
than in women, except for thyroid cancer. Especially mortal- tors were introduced [29]. Immune checkpoint inhibitors
ity rate ratios of the bladder (2.87), esophagus (2.36), and induce cancer-cell killing by activated CD8-positive T cells.
liver (2.35) cancers between men and women are among the Immune checkpoint inhibitors, such as anti-CTLA4 and anti-
highest cancers [8]. PD-1, changed the methods of patient care in several cancer
types, including melanoma and kidney cancer. Due to these
new therapies, the survival rate of melanoma dramatically
4 Survival Rates for Cancers increased [29]. These immunotherapies also demonstrated
their potential benefits for lung cancer. Due to these treat-
Based on the ACS report for the US population in 2012– ments, 3-year survival for all lung cancer cases increased
2018 [8], the 5-year survival rates of the top 10 common from 22 to 33% over time, corresponding to the timing of
types of cancers are listed in Table 3. The 5-year relative sur- approval of targeted therapy [30]. On the other hand, uterine
vival rate for all cancers was 68% in 2012–2018, while the cancer has not improved its survival rate long time, possibly
5-year survival rate was 49% in the 1970s. Prostate cancer due to the lack of new treatments [31].
showed the best overall prognosis with a 5-year survival rate Survival rates for cancers are also different in different
of 97%. However, lung and pancreas cancers have the worst racial groups. Survival rates in non-Hispanic black group are
5-year survival rates, 23%, and 12%, respectively [8]. usually lower than in non-Hispanic white group for most
Globally, the 5-year survival rates are 70–100% for prostate cancers. Even after adjusting for clinical stage, gender, and
cancer, 80–85% for breast cancer, 50–70% for colorectal age at diagnosis, the survival rates are 33% lower in non-
cancer, and 10–20% for lung cancer [3]. Hispanic blacks as compared with non-Hispanic whites [32].
Improvement of cancer patients’ survival is affected by For example, survival rates for uterine cancer are different in
multiple factors, including early detection and better treat- different racial groups. African American women are more
ments [25]. For example, the 5-year survival rate for chronic likely to be diagnosed with higher clinical stages and
myeloid leukemia has significantly increased from 17% in this higher clinical stage in diagnosis often leads to lower
1975 to 73% in 2012 [26, 27], although the incidence of survival rates [33]. Therefore, African American women
chronic myeloid leukemia has been growing in the last few have the highest mortality rate in all races for uterine corpus
decades. The potential explanation for the increasing inci- cancer [33]. The recent reclassification of subtypes based on
dence rate can be the reclassification of other leukemia sub- molecular biomarkers from next-generation sequencing was
types, raising awareness, improved diagnostic sensitivity, introduced for targeted therapies. Recent whole-exome
better-reporting systems for new cases, and other risk fac- sequencing studies have identified a role of the HER2/NEU
tors, such as obesity [27]. Further, the 5-year survival rate and driver mutations in the PIK3CA/AKT/mTOR oncogenic
increase of chronic myeloid leukemia was also due to new pathways [34]. These results emphasize the relevance of
innovative treatments, such as stem cell transplantation these novel therapeutic targets for targeted therapy. These
through national health policies and cancer control programs therapies provided a large impact because almost one-half of
[28]. The progress in pre-clinical and clinical research on uterine cancers are candidates for targeted therapies [35].
Table 4 Number of deaths by top 5 deadliest cancers based cancer risk stratification [38–40]. Although accuracy
Cancer sites Incidence Percentage of these PRS are different in different cancers, a high poly-
Lung 1,796,144 18.2% genic risk score is correlated with a higher risk of cancer. In
Colorectal 935,173 9.5% prostate cancer, the detection rate of polygenic risk score
Liver 830,180 8.4 ranged from 0.56 to 0.67 [40]. Recent large studies observed
Stomach 768,793 7.8
that the top 10% polygenic risk score group increased risk
Breast 684,996 6.9%
2.7-fold [41, 42].
Data from GLOBOCAN 2020 [2–4]
Smoking is the most well-established risk factor for many
cancers, including lung, laryngeal, oral, esophageal, pan-
5 Cancer Mortality and Trend creas, bladder, kidney, liver, stomach, pancreas, colorectal,
and cervical cancers. Especially cigarette smoking is respon-
Currently, heart disease is the leading cause of death in the sible for approximately 80–90% of lung cancer mortality
world, based on WHO data [4]. The second leading cause of [43]. Heavy smokers showed a 20 times higher risk for lung
death is cancer. In Table 4, a list of cancer deaths was pre- cancer-specific death than never-smokers. Alcohol drinking
sented based on GLOBOCAN 2020 [2, 4]. As expected, the also increases the risk for several cancers, such as oral, laryn-
rank in cancer mortality does not necessarily match with one geal, colorectal, esophageal, liver, and breast cancers. Almost
in cancer incidence because the survival rates are different in 4% of new cancers diagnosed in 2020 worldwide can be
different cancer types. Overall, lung, colorectal, liver, stom- explained by alcohol drinking based on WHO data [4]. Diets,
ach, and breast cancers are the deadliest cancers (Table 4). especially high-fat diets, are associated with an increased
Cancer mortality rates have increased consistently from the risk of colorectal, lung, and prostate cancers. The previous
1930s until the 2000s. One of the main attributable factors is pre-clinical study reported that certain compounds induced
a rapid increase in lung cancer mortality due to the smoking cancers [44]. However, these findings are not consistent with
epidemic. However, smoking reduction has significantly results from human studies. Recent epidemiological studies
declined cancer deaths since 1991 [8]. In addition, lung suggested that high-fat diets have been linked with an
screening with low-dose computed tomography (CT) for increased risk of these cancers [45].
high-risk populations, such as heavy smokers, leads to detect Infections are another risk factor for several cancers.
early-stage lung cancers successfully and lower cancer mor- Approximately 15–20% of cancer incidences in the world
tality [36]. are related to infections, especially carcinogenic viruses
[46], such as Human Papillomavirus, Hepatitis B virus,
Hepatitis C virus, Helicobacter pylori, Human
6 Risk Factors for Cancers Immunodeficiency virus, and Epstein-Barr virus. Human
papillomavirus infection, especially types 16 and 18,
The development of cancers is the result of the combination increases the risk of cervical cancer [47], while Hepatitis B
of genetic and environmental factors. The leading risk factor and C viruses increase the risk of liver cancer [48, 49].
is age, probably due to the accumulation of various risks Helicobacter pylori infection is associated with a high risk of
with age. In addition, DNA repair processes are less efficient stomach cancer [50]. Human immunodeficiency virus
in the elderly. There are other well-established risk factors increases the risk of developing some cancers such as Kaposi
for cancers, such as genetics, smoking, alcohol drinking, sarcoma [51]. Epstein-Barr virus is linked to Hodgkin lym-
high-fat diet, and infections, particularly carcinogenic infec- phoma, Burkitt lymphoma, and nasopharyngeal cancers
tions. Genetic factors contribute to almost one-third of all [46].
cancer cases [37]. However, an individual genetic variant
was not demonstrated as a major factor for cancer risk.
However, the polygenic risk scores provided more reliable 7 Summary
predictions. The polygenic risk scores are usually built based
on the sum of multiple germline genetic variants identified Based on the current trend of cancer epidemiological data,
from genome-wide association studies and can be used to these malignant diseases will be a significant public health
classify people’s risk of diseases based on their genetic pro- issue. This disease will impact clinical and social standards
files. These scores may help to predict lifetime risk, plan for and impose an enormous economic burden. However, recent
better screening, predict prognosis and, more importantly, advances in medical technology provide promising tools for
support personalized medicine [38–40]. Although the pre- better cancer care, screening, and early detection. For exam-
diction of individual cancer risk based on only polygenic risk ple, liquid biopsy, a blood test that detects cancer cells or
scores is not ready for the clinical use, an increasing number tumor DNA that are circulating in the blood, can be used for
of studies support using polygenic risk scores for population- more efficient screening, early detection, and monitoring
Epidemiology of Cancer 15
treatment responses. Second, MRI can be used for diagnosis 12. Fenton JJ, Weyrich MS, Durbin S, Liu Y, Bang H, Melnikow
J. Prostate-specific antigen-based screening for prostate cancer:
and monitoring progression. Third, genetic profile contrib-
evidence report and systematic review for the US preventive ser-
utes to a risk classification for utilization in personalized vices task force. JAMA. 2018;319(18):1914–31.
medicine. Fourth, a new generation of treatments, especially 13. U.S. Preventive Services Task Force, Grossman DC, Curry SJ,
immunotherapy, opened a promising path for cancer treat- Owens DK, Bibbins-Domingo K, Caughey AB, et al. Screening for
prostate cancer: US preventive services task force recommendation
ment by enhancing immune function against cancer cells.
statement. JAMA. 2018;319(18):1901–13.
Finally, statistical learning and artificial intelligence 14. Nordstrom T, Discacciati A, Bergman M, Clements M, Aly M,
improved accuracy and efficiency in pathology and imaging Annerstedt M, et al. Prostate cancer screening using a combination
analysis for tumor tissues. of risk-prediction, MRI, and targeted prostate biopsies (STHLM3-
MRI): a prospective, population-based, randomised, open-label,
Despite recent advances in cancer treatment and screen-
non-inferiority trial. Lancet Oncol. 2021;22(9):1240–9.
ing, there are still several challenges to be overcome for bet- 15. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T,
ter survival and early detection. For example, disparity Cumberbatch MG, De Santis M, et al. EAU-EANM-ESTRO-
among people with a low socioeconomic status and different ESUR-SIOG guidelines on prostate cancer-2020 update. Part 1:
screening, diagnosis, and local treatment with curative intent. Eur
racial groups is one of the main obstacles. These people are
Urol. 2021;79(2):243–62.
less likely screened and receive less quality cancer cares. In 16. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V,
summary, the recent trends in cancer incidence and mortality Mynderse LA, Vaarala MH, et al. MRI-targeted or standard biopsy
rates have increased. These trends may be continued due to for prostate-cancer diagnosis. N Engl J Med. 2018;378(19):1767–77.
17. Jemal A, Ma J, Rosenberg PS, Siegel R, Anderson WF. Increasing
various factors, such as industrialization, air pollution, diet
lung cancer death rates among young women in southern and mid-
change, and longer life span. western states. J Clin Oncol. 2012;30(22):2739–44.
18. Jha P. Avoidable global cancer deaths and total deaths from smok-
ing. Nat Rev Cancer. 2009;9(9):655–64.
19. Giaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA,
References Minihan A, et al. Breast cancer statistics, 2022. CA Cancer J Clin.
2022;72(6):524–41.
1. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Pineros M, 20. Siegel RL, Torre LA, Soerjomataram I, Hayes RB, Bray F, Weber
Znaor A, et al. Cancer statistics for the year 2020: an overview. Int TK, et al. Global patterns and trends in colorectal cancer incidence
J Cancer. 2021;149:778–89. in young adults. Gut. 2019;68(12):2179–85.
2. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne 21. Miller KD, Ortiz AP, Pinheiro PS, Bandi P, Minihan A, Fuchs HE,
M, et al. Global burden of colorectal cancer in 2020 and 2040: et al. Cancer statistics for the US Hispanic/Latino population, 2021.
incidence and mortality estimates from GLOBOCAN. Gut. CA Cancer J Clin. 2021;71(6):466–87.
2023;72(2):338–44. 22. Ortiz AP, Ortiz-Ortiz KJ, Colon-Lopez V, Tortolero-Luna G,
3. Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang Torres-Cintron CR, Wu CF, et al. Incidence of cervical cancer in
XS, et al. Global surveillance of cancer survival 1995-2009: analy- Puerto Rico, 2001-2017. JAMA Oncol. 2021;7(3):456–8.
sis of individual data for 25,676,887 patients from 279 population- 23. de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide bur-
based registries in 67 countries (CONCORD-2). Lancet. den of cancer attributable to HPV by site, country and HPV type.
2015;385(9972):977–1010. Int J Cancer. 2017;141(4):664–70.
4. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, 24. Mix JM, Van Dyne EA, Saraiya M, Hallowell BD, Thomas
Jemal A, et al. Global cancer statistics 2020: GLOBOCAN esti- CC. Assessing impact of HPV vaccination on cervical cancer
mates of incidence and mortality worldwide for 36 cancers in 185 incidence among women aged 15-29 years in the United States,
countries. CA Cancer J Clin. 2021;71(3):209–49. 1999-2017: an ecologic study. Cancer Epidemiol Biomark Prev.
5. Feola S, Chiaro J, Martins B, Russo S, Fusciello M, Ylosmaki E, 2021;30(1):30–7.
et al. A novel immunopeptidomic-based pipeline for the generation 25. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer
of personalized oncolytic cancer vaccines. Elife. 2022;11:e71156. screening: lessons from history and study design issues. Semin
6. Eala MAB, Robredo JPG, Dee EC, Lin V, Lagmay A. Climate cri- Oncol. 2010;37(3):202–15.
sis and cancer: perspectives from the hardest hit. Lancet Oncol. 26. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva
2022;23(3):e92. M, et al. Relative survival in patients with chronic-phase chronic
7. Byrne S, Boyle T, Ahmed M, Lee SH, Benyamin B, Hypponen myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of
E. Lifestyle, genetic risk and incidence of cancer: a prospective patient data from six prospective clinical trials. Lancet Haematol.
cohort study of 13 cancer types. Int J Epidemiol. 2023;52:817–26. 2015;2(5):e186–93.
8. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. 27. Yang X, Chen H, Man J, Zhang T, Yin X, He Q, et al. Secular trends
CA Cancer J Clin. 2023;73(1):17–48. in the incidence and survival of all leukemia types in the United
9. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of States from 1975 to 2017. J Cancer. 2021;12(8):2326–35.
increasing detection in the rising incidence of prostate cancer. 28. Bailey C, Richardson LC, Allemani C, Bonaventure A, Harewood R,
JAMA. 1995;273(7):548–52. Moore AR, et al. Adult leukemia survival trends in the United States
10. Jemal A, Fedewa SA, Ma J, Siegel R, Lin CC, Brawley O, by subtype: a population-based registry study of 370,994 patients
et al. Prostate cancer incidence and PSA testing patterns in diagnosed during 1995-2009. Cancer. 2018;124(19):3856–67.
relation to USPSTF screening recommendations. JAMA. 29. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in
2015;314(19):2054–61. melanoma. Lancet. 2021;398(10304):1002–14.
11. Moyer VA, U.S. Preventive Services Task Force. Screening for 30. Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin
prostate cancer: U.S. preventive services task force recommenda- KA, et al. The effect of advances in lung-cancer treatment on popu-
tion statement. Ann Intern Med. 2012;157(2):120–34. lation mortality. N Engl J Med. 2020;383(7):640–9.
31. McConechy MK, Talhouk A, Leung S, Chiu D, Yang W, Senz 42. Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed
J, et al. Endometrial carcinomas with POLE exonuclease M, Saunders EJ, et al. Association analyses of more than 140,000
domain mutations have a favorable prognosis. Clin Cancer Res. men identify 63 new prostate cancer susceptibility loci. Nat Genet.
2016;22(12):2865–73. 2018;50(7):928–36.
32. Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, 43. Morabia A, Wynder EL. Cigarette smoking and lung cancer cell
et al. Annual report to the nation on the status of cancer, 1975-2014, types. Cancer. 1991;68(9):2074–8.
featuring survival. J Natl Cancer Inst. 2017;109(9):djx030. 44. Yang J, Wei H, Zhou Y, Szeto CH, Li C, Lin Y, et al. High-fat diet
33. Clarke MA, Devesa SS, Hammer A, Wentzensen N. Racial and promotes colorectal tumorigenesis through modulating gut micro-
ethnic differences in hysterectomy-corrected uterine corpus can- biota and metabolites. Gastroenterology. 2022;162(1):135–49 e2.
cer mortality by stage and histologic subtype. JAMA Oncol. 45. Dunneram Y, Greenwood DC, Cade JE. Diet, menopause and the
2022;8(6):895–903. risk of ovarian, endometrial and breast cancer. Proc Nutr Soc.
34. Ding J, Bashashati A, Roth A, Oloumi A, Tse K, Zeng T, et al. 2019;78(3):438–48.
Feature-based classifiers for somatic mutation detection in tumour- 46. Gomez K, Schiavoni G, Nam Y, Reynier JB, Khamnei C, Aitken
normal paired sequencing data. Bioinformatics. 2012;28(2):167–75. M, et al. Genomic landscape of virus-associated cancers. medRxiv.
35. Black JD, English DP, Roque DM, Santin AD. Targeted therapy 2023.
in uterine serous carcinoma: an aggressive variant of endometrial 47. Eun BW, Bahar E, Xavier S, Kim H, Borys D. Post-marketing sur-
cancer. Womens Health (Lond). 2014;10(1):45–57. veillance study of the safety of the HPV-16/18 vaccine in Korea
36. de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, (2017-2021). Hum Vaccin Immunother. 2023;19(1):2184756.
Nackaerts K, Heuvelmans MA, et al. Reduced lung-cancer mortal- 48. Min Y, Wei X, Xia X, Wei Z, Li R, Jin J, et al. Hepatitis B virus
ity with volume CT screening in a randomized trial. N Engl J Med. infection: an insight into the clinical connection and molecular
2020;382(6):503–13. interaction between hepatitis B virus and host extrahepatic cancer
37. Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, risk. Front Immunol. 2023;14:1141956.
Scheike T, et al. Familial risk and heritability of cancer among 49. Fraile-Lopez M, Alvarez-Navascues C, Gonzalez-Dieguez ML,
twins in Nordic countries. JAMA. 2016;315(1):68–76. Cadahia V, Chiminazzo V, Castano A, et al. Predictive models
38. Dai J, Lv J, Zhu M, Wang Y, Qin N, Ma H, et al. Identification of for hepatocellular carcinoma development after sustained viro-
risk loci and a polygenic risk score for lung cancer: a large-scale logical response in advanced hepatitis C. Gastroenterol Hepatol.
prospective cohort study in Chinese populations. Lancet Respir 2023;46:754–63.
Med. 2019;7(10):881–91. 50. Liao O, Ye G, Du Q, Ye J. Gastric microbiota in gastric cancer and
39. Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, precancerous stages: mechanisms of carcinogenesis and clinical
van Duijnhoven FJB, et al. Genome-wide modeling of poly- value. Helicobacter. 2023;28:e12964.
genic risk score in colorectal cancer risk. Am J Hum Genet. 51. Mendoza Mori LM, Valenzuela Medina JB, Gotuzzo Herencia JE,
2020;107(3):432–44. Bravo Puccio FG, Mejia Cordero FA, Mohanna Barrenechea S,
40. Oh JJ, Hong SK. Polygenic risk score in prostate cancer. Curr Opin et al. Kaposi’s sarcoma in people living with HIV/aids in a pub-
Urol. 2022;32(5):466–71. lic referral hospital in Peru. Rev Peru Med Exp Salud Publica.
41. Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth 2022;39(3):352–6.
SK, et al. Multiple newly identified loci associated with prostate
cancer susceptibility. Nat Genet. 2008;40(3):316–21.
Immunemodulation and Cancer
Jinhong Liu and Jeffrey Huang
1 Introduction In vivo, tumor antigens are generated endogenously as cyto-

solic or nuclear proteins that are coupled with class I major
The immune system serves as the fundamental defense histocompatibility complex (MHC)-associated peptides.
mechanism of the human body, playing a crucial role in pre- These peptides can then be recognized by CD8+ CTLs that
venting tumorigenesis and managing the pathological pro- are restricted by class I MHC and possess the ability to kill
gression of cancer. Despite constant pressure from the antigen-specific target cells. The process of CTL activation is
immune system and the tumor microenvironment, cancer highly regulated and modulated at both the molecular and
cells can transform into aggressive, abnormal malignant cellular levels, involving multiple stimulatory and inhibitory
cells and develop immunity-suppressing capabilities, even- steps. Failure to properly regulate these positive and negative
tually leading to mutant progression or immune evasion. The balances can result in tumor immune evasion.
immune system is a highly organized and intricate network
of cells that is both dynamic and complex. Immune cells are
motile and migrate to specific organs in a context-specific 2.2 T Cell Activation Require Antigen
manner, where they must come into close proximity with Presenting Cell
other cells to exchange information and function appropri-
ately. These interactions give rise to diverse immune For CD8+ cells to differentiate into CTLs, a healthy individ-
responses in different situations. In cancer, the intra-organ ual requires an antigen-presenting cell (APC) that can present
movement or infiltration of active immune cells into the tumor antigen (a protein peptide associated with class I MHC)
tumor tissue is a decisive factor that determines immune out- to T cells. Tumor antigens or tumor-associated antigens
come [1, 2]. Over the past decade, significant progress has (TAAs) resulting from mutations and epigenetic changes in
been made in cancer immunotherapy, which has successfully APCs induce the expansion of specific CTLs, differentiation
cured certain types of cancer in some patients across several into effector cells, and the generation of memory cells. The
different cancer types. A key factor in this success is under- interaction between the T cell receptor (TCR) and MHC-
standing the mechanisms of immune modulation and effec- associated peptides on APCs (signal 1) determines the quality
tively directing cytotoxic T cell responses against tumors. of T cell activation, which is further influenced by the pres-
ence, type, and strength of signaling through costimulatory
receptors on T cells and APCs (signal 2). The degree and type
2 Tumor Immunity of activation of CD8+ T lymphocytes are strongly influenced
by these factors. As a consequence of interactions and recog-
2.1 Tumor Immunity Require CD8+ T Cell nition of tumor antigen presented by APCs through T cell
Activation antigen receptor, it initiates and activates a series of sequen-
tial process that lead to the generation of both antigen specific
The key immune mechanism that combats cancer is the acti- effector and memory CTLs. These cytotoxic CD8+ T lym-
vation of cytotoxic T lymphocytes (CTLs), which specifi- phocytes provide long-term protection against pathogens and
cally target tumor cells through tumor-specific antigens [3]. carry out immune surveillance to eliminate cancer cells,
therefore, APCs are the most efficient stimulators of naïve T
J. Liu (*) · J. Huang cells into CD8+ CTLs. Many types of cells originating from
Anesthesiology Department, Moffitt Cancer Center, myeloid linage can serve as APCs, including dendritic cells,
Tampa, FL, USA
monocytes/macrophages, and granulocytes [4, 5].

18 J. Liu and J. Huang
3 Antigen Presenting Cells and Cancer tumors through various mechanisms and can impede the effi-
cacy of immunotherapy, chemotherapy, and irradiation. In
3.1 Basic Biology of Dendritic Cells contrast, DCs thus have a unique feature and potential to pro-
cess and transfer tumor antigens to the draining lymph nodes
Dendritic cells (DCs) are vital in activating naïve CD4+ T leading to the activation of T-cell, a crucial step that is abso-
cells and are classified as professional antigen-presenting lutely required for T cell-dependent tumor immunity and
cells (APCs), alongside macrophages, granulocytes, and B response to immunotherapy. Tumor-resident DCs have an
cells. DCs are the essential APCs of the immune system, increasingly important function in regulating the T cell
playing a crucial role in connecting innate and adaptive response within tumors during therapy [5, 6, 9–11]. These
immunity, particularly in stimulating anti-tumor T cells [5– functions establish DCs as a critical component of the antitu-
7]. DCs arise from bone marrow progenitors known as com- mor T cell response and indicate that modulating the biologi-
mon myeloid progenitors (CMPs). CMPs have the ability to cal activity of these cells is a valuable therapeutic strategy
differentiate into monocytes or the common dendritic cell for indirectly promoting a T cell response during therapy.
progenitor, which gives rise to various subpopulations of Among DC suptype, studies in both mice and humans
dendritic cells (DCs), including plasmacytoid DCs (pDCs), have demonstrated that the cDC subset of DCs is primarily
conventional DCs (cDCs), and monocytic-derived DCs. responsible for eliciting an effective immune response
These immature DCs require maturation signals, such as against cancer. The regulation and function of cDCs are gov-
damage or pathogen-associated molecular patterns (DAMPs) erned by CCR7, a leukocyte chemotactic receptor that directs
and inflammatory cytokines, to effectively fulfill their role in the migration of DCs to the lymph node and facilitates the
the immune response. Upon maturation and activation, DCs generation of a systemic CTL-mediated anti-tumor immune
reduce their phagocytic activity, increase expression of MHC response. In mouse tumor models, cDCs that lack CCR7
class II and costimulatory molecules, produce more cyto- expression are unable to attract CD8+ T cells to the tumor
kines, and demonstrate enhanced migration to lymph nodes site and also fail to stimulate T cells within the tumor to dif-
through increased expression of chemokine receptors [5, 8]. ferentiate into effector CTLs capable of eliminating the
DCs exist as resident lymphoid tissue, such as spleen and tumor. Defective expression of CCR7 in cDCs in multiple
lymph nodes were critical for sampling blood and lymph mouse tumor models leads to an inability to attract CD8+ T
born antigens, respectively. This event is relatively important cells to the tumor site, as well as a failure to stimulate T cells
because distributing and presenting antigens is highly within the tumor tissue to differentiate into effector CTLs
context-specific, depending on the type of antigen and route capable of eliminating the tumors [6]. Notably, it has been
of exposure. In the case of cancer, it is not fully understood shown that the failure of tumors to attract the cDCs inhibits
how endogenous tumor antigen is processed and delivered activation of CD8+ CTLs response to malignant cells [12].
into lymphoid tissue, although naïve T cell activation has However, this defect can be reversed by immunotherapy that
long been known to be mediated by DCs within the draining increases the number of cDCs within the tumor [12], under-
lymph node. Nonetheless, two recent investigations have scoring the critical role of cDCs in regulating CD8+ T cell
revealed that tumor-associated fluorescent proteins are function within tumors. Modulating cDC levels within local
actively conveyed by CD103+ conventional dendritic cells tumors may therefore be a promising therapeutic strategy.
(cDCs) that travel from the tumor to the lymph nodes in a
CCR7-dependent fashion [6, 9]. Notably, this phenomenon
occurs in both implantable and spontaneous tumor models, 3.3 Cross Talk of DC with
circumventing any experimental anomalies that may arise T Cells and NK Cells
when injecting significant amounts of dead or dying cells.
Another level of upregulation of anti-tumor immunity is to
modulate cDC and CD8+ CTL interaction/engagement. The
3.2 DC Plays Pivotal Roles in migration of cDCs to the location of T cells has been shown to
Tumor Immunity be critical to the induction of effective CTL mediated adaptive
immune response [13]. This essential step is dependent on the
Regulation of the function of dendritic cells (DCs) is crucial production of stimulatory cytokines and chemokines by cDCs
in establishing adaptive immunity against cancer, as evi- within the tumor microenvironment. Studies have shown that
denced by both animal models and human cancer patients. In chemokine production by cDCs, such as CXCL9 and
solid tumors, antigen uptake and presentation are mainly car- CXCL10, is essential for enhancing the efficacy of immuno-
ried out by monocytes and DCs. Although monocytes are the therapy. Along with chemokines, immune-related cytokines,
principal phagocytic cells in tumors, they are unable to acti- including IL-12 and IFNγ, are critical for promoting crosstalk
vate T cells in some cases and do not migrate to lymph nodes between CD8+ T cells and cDCs within the tumor microenvi-
[5]. Instead, monocytes often hinder T-cell responses against ronment. Interestingly, cDCs have also been shown to interact
Immunemodulation and Cancer 19
with Natural Killer (NK) cells, which play a crucial role in are critical in bridging innate and adaptive immune responses;
immune surveillance against cancer. Activated NK cells can specifically, TLRs play a critical role in stimulating DC mat-
recruit cDCs to infiltrate the tumor tissue. Analysis of gene uration, antigen uptake and presentation and the differentia-
signatures in human tumors has indicated that the presence of tion of T helper cells such as Th1, Th2 and Th17 and
NK cells is associated with the recruitment and appearance of controlling the suppressive function of regulatory T (Treg)
cDCs within the tumor microenvironment, suggesting that cells. In addition, signals via TLRs represent a potent means
modulation of NK cell presence within the tumor could sig- of modulating immune responses to cancer vaccines, a novel
nificantly enhance CTL-mediated immune responses [12, 14]. strategy now being evaluated in clinical trials. Vaccination
The requirement for interaction and cross-talk between cDC against cancer antigens largely relies on the use of DCs [16].
and other types of immune cells, particularly of CD8+ CTLs, As mentioned previously, DCs act as sentinels of the immune
demonstrates that the complexity of the antitumor immune system and play a crucial role in initiating and directing
response within the tumor and indicates that the migration/ immune responses. This is due to their ability to capture, pro-
localization of DCs and lymphocytes within the tumor is a key cess, and present self-tumor antigens to T cells and other
regulator of their function and activities. immune cells, ultimately leading to a potent and cancer-
specific immune response capable of killing tumors.
However, it is widely acknowledged within the field that
4 Regulation DC by TLR Receptors tumor antigens alone are not strong enough to stimulate
APCs to induce clinically significant anti-tumor immune
4.1 Basic Biology of Toll-like Receptors responses, unless there is the involvement of professional
(TLRs) DCs to some extent [18]. As professional APCs, DCs express
a significant number of TLRs and possess powerful effects
Since activation of DC is central and induction of their on lymphocytes. TLRs can promote DC and immune
in vivo function is critical, therefore targeting DCs may pro- response, because DCs are at the interface of innate and
vide clinical approaches to improve immune responses in adaptive immune responses. However, in most cases, there is
cases where targeting T cells alone is not effective. Over the often lacking activation of DC, as a result of inhibitory sig-
past two decades, a significant advancement in DC activation nals from tumor cells—which may also induce immune tol-
has been the use of exogenous activation signals through erance through T cell deletion or through suppressive Tregs
Toll-like receptors (TLRs). TLRs function as pathogen pat- [19], thus helping tumors escape from immune surveillance.
tern recognition molecules that detect and initiate innate and Over the past decade, numerous efforts have been made to
adaptive immune responses against pathogens and malignant promote DC activation using agonists of the innate immune
cells, acting as a first line of defense against infectious dis- system. For instance, intratumoral injection of TLR agonists,
eases and cancer. Recognition of ligands by TLRs triggers alarmins, defensin peptides, DAMPs, or cytolytic peptides
the secretion of proinflammatory cytokines and promotes can be utilized to improve the in situ antitumor response. As
DC maturation programs for the induction of adaptive a result, many TLR agonists have been investigated in the
immune responses. To date, more than 12 TLRs have been context of cancer treatment and could serve as useful thera-
identified in both humans and animals. TLRs belong to peutic strategies aimed at enhancing DC function to bolster
type-1 integral membrane glycoproteins and are character- the antitumor response [16, 20].
ized by extracellular domains containing a variable number
of leucine-rich repeat motifs and cytoplasmic Toll/interleu-
kin (IL-1R homology domain). TLRs can recognize a highly 4.3 Antitumor Effect of TLR3
conserved sets of molecular structures, so-called pathogen-
associated molecular patterns (PAMP), and/or damage asso- Among all the TLRs, TLR3 has been broadly studied for
ciated molecular patterns (DAMPs) such as RAGE and more than three decades. TLR3 is mainly expressed in neu-
HMGB, which leads to pathogen antigen uptake, processing, roectodermal and myeloid cells (including DCs). TLR3 of
and presentation to naive T cells in peripheral blood, lymph myeloid cells favorably acts as a receptor for the surface rec-
node, and tissues [15–17]. ognition of viral double-stranded RNA (dsRNA) [21]. The
effect of dsRNA as a TLR3 agonist in oncology has been
accessed by randomized clinical trials since the 1990s. Since
4.2 TLRs Play a Pivotal Role in Bringing then, many TLR3 agonists have been designed to mimic the
Innate and Adaptive Immunity dsRNA and have been studied, indicating that numerous
mechanisms subsidize the efficacy of TLR3 agonists. The
The recognition of PAMPs or DAMPs by TLRs leads to pro- TLR3 agonists, including RGC100, ARNAX, and polyino-
ducing proinflammatory cytokines, chemokines, type I inter- sinic: polycytidylic acid (poly-IC), are currently being exten-
ferons, and antimicrobial peptides 254,281. Therefore, TLRs sively studied. These agonists are used as adjuvants for
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CHAPTER VIII.
DANIEL POLLITT, ESQ., AND FAMILY.
The grand dinner-party at 500, Princes Gate, was over, the last
silken train had swept down the steps, the last brougham had
bowled away, and a somewhat bored-looking young man indulged in
a stretch and a prodigious yawn, and strolled slowly back to the
library, where the master of the house, a spruce little person of sixty,
with a rosy cheek and active eye, stood before the empty fireplace
(the month was June) with his coat-tails under his arms, engaged in
chewing a tooth-pick. Wealthy he may be, judging from his
surroundings, but he is certainly not distinguished in appearance; his
scanty locks are brushed out into two sharp horns over his large
ears. In spite of his blazing solitaire stud and faultless claw-hammer
coat, he is plebeian; yes, from the points of his patent leather shoes
to the crown of his bald head. It is difficult to believe that he is the
uncle of the aristocratic young fellow who has just entered and cast
himself into a deep armchair. What the French call “the look of race,”
is the principal thing that strikes one about Mark Jervis. It is
afterwards—possibly some time afterwards—that you realize the fact
that he is remarkably handsome, and considerably older than you
took him to be at the first glance. His smooth face and sunny hazel
eyes are misleading: young Jervis is more than nineteen, he is five
and twenty.
“Well, Mark, that’s over, thank God,” exclaimed Mr. Pollitt. “I hate
these big dinners; but your aunt will have them. She says we owe
them; women are never backward in paying those sort of debts. It
was well done, hey? That new chef is a success. Did you taste the
Perdreaux aux Chartreuse—or the Bouchée à la financière, or that
cold entrée?”
“No, Uncle Dan,” strangling another great yawn.
“Ah, you sly dog! You were too much taken up with Lady
Boadicea! She is considered a beauty—at least her picture made
rather a stir. What do you think? How does she strike you?”
“To me—she looks like a wax doll that has been held too close to
the fire—and she is about as animated.”
“Well, you can’t say that of the American girl, Miss Clapper—
there’s a complexion!—there’s animation!—there’s a stunner for
you!”
“A stunner, indeed! She thrust her money down my throat in such
enormous quantities that I could scarcely swallow anything else!”
“Then why the deuce did you not stuff some of mine down hers,
hey?” chuckling. “I saw you at Hurlingham this afternoon.”
“Did you, sir? I had no idea you were there.”
“It was a frightful squash—hardly a chair to be had; the Royalties,
a fine day and a popular match, brought ’em. I suppose that was the
new pony you were trying, brown with white legs. How do you like
him?”
“He is not handy, and he is a bit slow. He is not in the same class
with Pipe-clay, or the chestnut Arab; I don’t think we will buy him, sir.”
“Lord Greenleg was very anxious to hear what I thought of him. He
only wants a hundred and thirty—asked me to give him an answer
there and then, as he had another customer, but I thought I had
better wait till I heard your opinion. Is the pony worth one hundred
and thirty guineas? What do you say?”
“I say, cut off the first figure, and that is about his value,” rejoined
his nephew shortly.
Mr. Pollitt looked blank. He rather liked buying ponies from lords,
even at a high figure, but a hundred guineas too much was a stiff
sum. He knew that he could rely on the young fellow’s opinion, for
lazy as he seemed, lounging there in an easy chair, he could both
buy a horse and ride a horse—which does not always follow. The
languid-looking youth was a hard rider to hounds, and a finished polo
player.
“Then I suppose we shan’t mind the brown, eh, Mark?” said his
uncle rather dolefully. “After all, it is getting late in the season, and
his lordship has another offer.”
“Has he!” expressively. “Oh, then, that is all right.”
“Your side played up well to-day, my boy!”
“And were well beaten—two goals to four. Johnny Brind is no good
as a back. He sits doubled up in his saddle, like an angry cat, and
lets the ball roll out between his pony’s fore legs—and his language!”
“That did not come as far as my ears. I saw you speaking to Lord
Robert Tedcastle. You were at Eton with him—you might bring him
home to lunch some Sunday; and that Italian prince, did you come
across him?” anxiously.
“No; I did not see him.”
“I noticed you having a long talk with that young Torrens; what was
he yarning about? He was nodding his head and waving his hands
like a cheap toy.”
“He was telling me of his plans. He and his brother are off to
America next week, they are going on to Japan, Australia, and India.
I say, Uncle Dan,” suddenly sitting erect, “I wish you would let me
travel for a couple of years and see the world.”
A silence of nearly a minute, and then Mr. Pollitt burst out—
“Now, this is some stuff that young ass Torrens has been putting
into your head. To see the world! What world? You see it at home.
England is the world. You have the best of everything here—the
handsomest women, finest horses, best food and drink, best——” he
paused, and his nephew, who was nursing his leg, blandly
suggested “climate.”
“Climate be hanged! best society,” bawled Mr. Pollitt. “The fact of
the matter is, you young chaps don’t know when you are well off.
Travel—see the world—skittles!”
“I know that I am exceedingly well off, thanks to you, Uncle Dan,”
rejoined his nephew, quietly. “I have capital polo ponies, a first-rate
stud of hunters, a splendid allowance—but a fellow can’t play polo,
and hunt, and go to balls and theatres all his life; at least, that’s not
my idea of life. I have nothing to do, no profession, you know; you
would not hear of my going into the service.”
“No—I hate the army—what prospect does it offer the young idiots
who are slaving to get into it—to live vagabonds, and die beggars!”
“There was the diplomatic corps; but I’ve not brains enough for
that.”
“Bosh! You don’t want a profession, taking bread out of other
people’s mouths. You are my heir—that’s your profession. As to
intellect, there is a great deal too much intellect in these days; the
world would be far easier to govern if there was less! You have
brains enough, my boy, you did very well at Oxford.”
“I know that I am very fortunate,” repeated the young man, “and
that thousands of fellows would give anything to stand in my shoes.”
“Clarence for one,” interrupted his uncle, with a loud chuckle.
“But I’m sick of the eternal treadmill round of the London season—
Ascot, Goodwood, Cowes, Scotland. Then back to London, and we
begin the whole business over again. We see the same people, and
do the same things.”
“How old are you, Mark?” broke in Mr. Pollitt, excitedly.
“Five and twenty.”
“One would think you were eighty-five! But it is all the rage to be
bored and blasé, and to give out that life is not worth living. You are
in the height of the fashion, my boy! The fact of the matter is—that
you are too prosperous. A blow of real trouble, cutting to the very
bone, would do you no harm.”
“Perhaps so. Properly speaking, I believe I ought to have been a
poor man’s son, and had to work my way. I feel that I could do it. I
would not have minded being a soldier, a sailor, an explorer, or even
a stock-rider.”
“In fact, to put the matter in a nutshell, anything but what you are.”
“Well, Uncle Dan, you have fought your way up to the front, step
by step, and won your spurs, and enjoyed the battle. I should like to
take some weapon, and strike into the fray.” Here he suddenly got
up, and came over to his uncle, and, putting his hand affectionately
on his shoulder said, “I would like to do something to make you”—
with a nervous laugh—“proud of me;” and as he looked into his
uncle’s shrewd little face, his eyes shone with repressed excitement.
“I’m proud enough. You are my own flesh and blood—a good-
looking chap, a capital rider, and a gentleman; a bit too fond of
dabbling with your nasty, dirty oil paints, a bit dreamy and Quixotic,
but——”
At this juncture the door was gently pushed open, and a long,
hooked nose came slowly into the room, followed by a tall, thin,
elderly lady, attired in a clinging mist-coloured robe, and blazing with
diamonds. A sallow, discontented-looking person, with a high-bred
air, despite her touzled fringe.
“So you are both here!” she murmured sweetly.
“Yes,” assented Mr. Pollitt; “and here is Mark,” waving a short
square hand towards him. “What do you think is his last craze,
Selina? He wants to travel for a couple of years, in order to see the
world. Just like the hero of a fairy tale.”
Mark hastened to place a chair for his aunt, into which she gently
sank, keeping her eyes steadily fixed on his as she did so, and
gradually narrowing her gaze to a cat-like glint.
“Do you know that I rather like the idea!” she remarked, after a
momentary silence. “I think it is a shocking thing for a young man to
waste his life, lounging in clubs gossipping and gambling, or playing
a game on the back of a pony. Travelling improves the mind and
enlarges the ideas.” Here, catching sight of Mr. Pollitt’s face of angry
scorn, she lost no time in adding, “You know, it is all the fashion to
travel, it’s only the second-rate people and nobodies who stay at
home. Lady Grace and Lord Kenneth are going out to India this cold
weather, so is the Duke of Saltminster, the Marquis and Marchioness
of Tordale, and crowds of other smart people.”
Smart people were to Mr. Pollitt, as his crafty wife knew, the very
salt of the earth; and his expression changed from that of repressed
fury to grave attention.
“India! Perhaps I would not mind so much,” he admitted, after a
pause. “The boy was born there, and he could look up his father.
Yes, and he might have some shooting, and pick up a few tigers, and
nice acquaintances and companions.”
“Oh, but, of course, Mark could not travel alone, dear. He must
have a pleasant and experienced——”
“Bear-leader or keeper; or what would you say to a chaperon?”
broke in her husband.
“My dearest!” she gravely expostulated. “You know perfectly well
that it would be frightfully dull for the poor boy roaming about the
country with no one to keep him company, not knowing where to go,
or what to say. Now Clarence,” and she hesitated.
“Yes—now Clarence. What now?” sharply.
“Clarence,” speaking very distinctly, “was stationed in India for
eight years. He is an experienced Anglo-Indian, has hundreds of
friends, talks Hindostani fluently, and could get no end of shooting
and introductions to native princes” (great emphasis on princes). “He
would be a capital guide for Mark.”
“Umph!” with a short laugh. “I’m not so sure of that, Mrs. Pollitt.”
“Oh, my dear Dan, he is perfectly steady now. Why, he is thirty-
five, and has sown his wild oats. I never quite believe in these
wonderfully good young men,” and she shot a swift glance at Mark.
“Except Mark, of course, and he ought to have been a parson, and,”
with a little sneer, “he may yet become a missionary.”
“But India is no novelty to Clarence,” protested Mr. Pollitt; “and, by
all accounts, he made it too hot to hold him. Mark can easily tack
himself on to some party of friends, and do the tour with them. You
say that the Rothmores——”
“Oh yes,” impatiently; “and they have made their arrangements
months ago. Mark cannot tack himself on to people, as you express
it; it would not do at all. On the contrary, he must have some one
tacked on to him. The trip will be a boon to my brother, as well as to
your nephew. Poor Clarence loves India. He is frightfully hard up; he
would be an ideal companion for Mark,” turning to him. “What do you
say, Mark? Answer us quite frankly.”
And under these circumstances what could Mark say but, “Yes; oh,
certainly. Clarence is a good sort.”
“And at any rate, he can well be spared from home,” added Mr.
Pollitt, dryly.
“Then you will consent to Mark’s request, darling?” said his wife,
rising and tapping him playfully with her big feather fan. “Think of all
he will have to tell you, and of all the pretty things he will bring us.”
“As long as he does not bring a wife!” growled the old gentleman.
“Well, well, well, it is not often that you and Mark are on the same
side in a debate, or that you second the resolution. When you
combine, you are too strong for me. I’ll think it over.”
Mrs. Pollitt gave her nephew by marriage a quick significant
glance, for this speech distinctly showed that the bill before the
(head of the) house had passed, and that it now only remained to go
into a committee of ways and means.
CHAPTER IX.
PERMISSION TO TRAVEL.
Mark Jervis had been agreeably surprised by his aunt’s

enthusiastic co-operation; thanks to her powerful alliance, he had
carried his point, and was to spend twelve months travelling in India,
accompanied by Mrs. Pollitt’s brother, Captain Clarence Waring. The
latter was about to revisit his former haunts in an entirely new
character—that of mentor and companion to a young man—and,
moreover, a wealthy young man. All the world has heard of “Pollitt’s
Pearl Barley,” and “Pollitt’s Patent Fowls’ Food.” Are not its merits
blazoned in flaming letters in railway stations, in fields bordering the
rocking expresses that thunder through the land? Does not the name
of “Pollitt” greet the miserable eyes of sea-sick travellers, as they
stagger down the companion ladders of ocean greyhounds? In short,
the enterprise of Daniel Pollitt, and the fame of Pollitt’s pearl barley,
is of universal renown.
Although he has never boasted of the fact, or assured his
intimates that “he began life with the traditional sixpence,” Mr. Pollitt
is a self-made man. He talks freely enough of his wife’s relations, of
his nephew’s famous pedigree, but he has not once alluded in the
most distant fashion to his own little family tree. Yet he has nothing to
be ashamed of. His father was a gentleman by birth, a poor curate,
who had left two almost penniless orphans, Dan and a sister, several
years younger than himself. The former, while yet in his early teens,
had clambered on to a stool in an office in the city, from thence
(unusual flight) he had soared to success and wealth. Thanks to
indomitable industry, shrewdness, and pluck, he was now a
merchant of credit and renown. The latter, who was a remarkably
pretty and well-educated girl, accompanied a lady to India, in the
capacity of governess, and, in a startlingly short time, married
Captain Jervis of the Bengal Cavalry, a good-looking popular officer,
with a long pedigree and a somewhat slender purse. By all accounts,
the marriage was a happy one. At the end of six years Mrs. Jervis
died, and their only child, a boy of five, was sent to school in
England. Five years later, he was followed by his father, who rushed
home on three months’ leave, in order to see little Mark as well as
his tailor and his dentist. Major Jervis, a bronzed, handsome,
distinguished soldier, made an excellent impression on the plodding
city man—his brother-in-law, who cordially invited him to stay with
him at Norwood, where he had a luxurious bachelor establishment.
And here, over unimpeachable claret and cigars, the Indian officer
unfolded his plans.
Little Mark was about to have a stepmother, the lady was a Miss
Cardozo, of Portuguese extraction, dark, handsome, not very young,
but enormously wealthy, and quite infatuated about little Mark’s
papa. Her grandfather had been a military adventurer, whose sword
and swagger had gained him the heart and treasures of a Begum.
Miss Cardozo’s father was an indigo planter, in those good old times
when indigo crops brought in lacs of rupees, and she was his sole
heiress and an orphan. Besides the Begum’s wealth and jewels, she
owned property in the Doon, property in the hills, property in Tirhoot,
shares in banks and railways, and large investments in the funds.
Mr. Pollitt’s shrewd little eyes glistened approvingly as he
absorbed these particulars.
“Cut the service, bring her to England, and take a fine country
place,” was his prompt suggestion.
“No, no, she hates England; she was at school over here. She
dreads our winters, and rain and fog,” replied Major Jervis. “And she
likes my being in the service. I can tell you that our men and horses
are something to see! Mércèdes—that is her name—delights in
pomp and show and glitter, and is much attached to India; and to tell
you the honest truth, Pollitt, I’m partial to the country too. I have been
out there twenty-two years, ever since I was eighteen, with only two
short furloughs, and it’s a country that suits me down to the ground.
My near relations in England are every one dead, I have no ties
here, all my friends and interests are out there, and I don’t mind if I
end my days in the East.”
“And what about Mark?” demanded his listener.
“Yes, that is the question,” said his father. “It’s hard lines on the
boy, to have no home with me—but later on he shall go into the
service, and come out to us. You have been wonderfully kind to him I
know, having him here in his holidays, and he is very fond of you, as
he ought to be. I feel rather guilty about him, poor chap; he is ten
years old and I have seen nothing of him for half that time, and now,
goodness knows how or where we may meet again. Of course no
money shall be spared on his education, and all that—but——” he
paused.
“But I’ll tell you what you will do,” continued Mr. Pollitt. “I’ll put the
whole matter in a nutshell. You are making a fresh start, you and the
boy are almost strangers, so you won’t feel the wrench. Give him to
me, I am fond of him, I have no family—he is a handsome, plucky
little fellow, with poor Lucy’s eyes—I will ensure him a first-class
education, bring him up as my son, and make him my heir, and leave
him all I am worth; come now?”
“It is a splendid offer, Pollitt, but I am fond of him too. I cannot
provide for him as you would, I can only set him out in the world with
a profession, and make him a small allowance, for of course
Mércèdes’ money will be settled on herself. If I resigned him to you,
in years to come I might repent, I might want him back.”
“In years to come you will probably have half a dozen other sons,
and be thankful to have one of them off your hands.”
After considerable discussion—Jervis, the father, a little reluctant;
Pollitt, the uncle, exceedingly eager and pressing—the matter was
concluded. Mark was to correspond with his parent as regularly as
he pleased, but he was to be, to all intents and purposes, his uncle
Daniel’s son.
Major Jervis made the most of his five weeks in England. He
invested in a new and gorgeous uniform, a new battery of guns,
saddlery, presents for Indian friends and his fiancée, and saw as
much as possible of Mark. The more the pair were acquainted the
better they liked each other. They went to the Tower, Madame
Tussaud’s, the Zoo, the theatres. Mark invariably accompanied his
parent to tailors, boot-makers and gun-smiths, and became
subsequently quite the authority on these matters at school. His
soldierly, open-handed sire, who loaded him with gifts, who told him
tales of the stirring deeds of his ancestors, of his own swarthy
sowars, of tiger-hunting and elephant drives, speedily became his
hero and his idol.
On being sounded as to his own choice of a profession, Mark,
after taking thought for a considerable time, gravely announced to
his father and uncle, “that he would prefer to be a bachelor.”
“And by no means a bad choice,” roared Mr. Pollitt, in great glee.
“Stick to that, my boy, stick to that, copy your old uncle.”
“I don’t think he will,” remarked Major Jervis, with decision; “he will
take after me. We are a susceptible race, we Jervises, and I’ll give
him till he is two and twenty.”
The day of parting was a dismal one for father and son. The child
struggled desperately to be a man, to shed no tears, and bore
himself wonderfully, at any rate in public, but after the cab had driven
off, he rushed away and shut himself up in his own little bedroom,
and flung himself upon the floor, and abandoned himself to the
bitterest grief he had ever experienced, and he was ten years old.
Some years after this scene, Mr. Pollitt, to every one’s surprise,
married a faded, elegant-looking woman, of good family, but
portionless. He bought a house in Princes Gate, rented a grouse
moor, deer forest, and hunting box, and invested in some celebrated
diamonds. He had now amassed a great fortune, and at the age of
fifty-five, retired from business, in order to spend it. But here arose
an unexpected difficulty, he did not know how to enjoy the result of
his labours, save by proxy. He looked up to his handsome well-born
nephew to manipulate his thousands, much as a child appeals to an
experienced friend to work a new mechanical toy. All his own youth
had been spent among great city warehouses, on wharves, and in
offices. He had never ridden, save on the top of an omnibus, he
could not drive, shoot, row, or even fish, and, alas! it was now too
late to learn. He, however, took to field sports in the character of a
spectator, with surprising enthusiasm. He walked with the guns on
his moors, and was much excited respecting the bag. He gave fancy
prices for his nephew’s hunters, and attended every meet (on
wheels), where there was a prospect of seeing their performance,
following the line, and keeping the hounds in sight as far as possible,
by means of short cuts and glasses.
He was a truly proud man when he saw his nephew’s name in the
Field as foremost rider in a sensational run. The worst of it was, that
Mark hated notoriety of any kind, hung back where he should come
forward, came forward when he should have hung back; had actually
no desire to lease a theatre, keep race-horses, or even gamble; in
short, he had not a single extravagant taste. (Here, indeed, was a
most singular case. How many fathers are there in these latter days
who feel hurt and disappointed because their sons will not spend
thousands?) On the other hand, Mrs. Pollitt was only too ready to
assist her partner in laying out large sums. She had many needy
connections, and hoped to do great things for them; but she found,
to her deep chagrin, that the personal spending of her husband’s
wealth was denied her. She had a liberal dress allowance, diamonds
of the first water, equipages, a fine establishment, a French maid;
but she might not thrust her hand into her lord and master’s purse
and scatter largesse to her poor relations, and—what was a truly
hard case—she might not even attempt to arrange an alliance
between Mark and one of her nieces. No, Mr. Pollitt was resolved
that his heir should marry rank. It must be “Mr. and Lady Somebody
Jervis,” and with Mark’s good looks, money, and birth, there would
be no difficulty in this little matter. Then Mark must go into
Parliament, settle down as a great landed proprietor, and ruffle it with
the best. Thus was his future sketched out by his uncle, who wisely
kept the sketch to himself.
Mrs. Pollitt was surprised to find her dear Daniel so obstinate and
impracticable on several trifling matters. For instance, she had made
up her mind to change the spelling of his name, and had even gone
so far as to have her own cards printed, “Mrs. D. Murray-Paulet, 500,
Princes Gate.”
“How lucky that Daniel has a second name!” she said to herself as
she complacently examined her new title a few days after her
marriage. She tripped across the room and held a card playfully
before the bridegroom’s spectacles, and the tiresome man had
exclaimed—
“Who is she? I can’t stand visitors. Here, let me clear out first, if
she is coming up——”
“The new card trick,” as he subsequently called it, had been their
first trial of strength, and the bride had succumbed with tears.
“Change his name!” he had roared— “his name, that he had
made! Never! He was proud of it. It was the wife who changed her
name on marriage, not the husband. Was she aware of that?”
Another subject on which she had had to yield was the
housekeeping bills; they all passed through Mr. Pollitt’s hands, who
settled them by cheque, consequently there were no pickings.
Mrs. Pollitt had her own particular schemes; she could not offer
her kinsfolk much solid assistance, but did what she could. To her
sister and nieces she distributed dresses and mantles scarcely worn;
she gave them drives, boxes at the theatre, tickets, and perpetual
invitations to dinner, lunch, and all her parties; to her brother
Clarence such sums as she could spare from her pin-money.
Clarence was ten years her junior, gay, débonnaire, and good-
looking. He had a pair of handsome, insolent blue eyes, a well-
cultivated moustache, an admirable figure, and a rather overbearing
manner. He was a complete man of the world, who had many
pecuniary troubles, no fixed principles, and but few scruples. He
was, nevertheless, pleasant, and by no means unpopular.
Captain Waring had spent every penny that he possessed (and a
good many pennies belonging to other people); and when his
regiment came home from India, he had been compelled to retire
from the service, and had been living ever since on his friends and
his wits. This Indian trip would be a capital thing for him, all
expenses paid; and if he and Mark remained away a year, some of
the other connections might get a footing at Princes Gate. The
aphorism, “Absence makes the heart grow fonder,” does not apply to
uncles and nephews.
If Mark were never to return, it would not break his aunt’s heart. If
he had not been her husband’s favourite, she might have been fond
of him. He was exceedingly presentable; she liked to exhibit him in
her carriage or opera-box (a gratification she seldom enjoyed). He
was always polite, always thoughtful of her comfort, always
respectful, though he had shown himself ready with a forcible reply
on one or two critical occasions; but he did not understand the art of
administering flattery, and she consumed it in large doses. Now here
Clarence was supreme; it was he who had solemnly assured her that
she bore a striking resemblance to Sara Bernhardt. Yes, golden
voice and all; and the poor deluded lady believed him, and attired
herself in clinging draperies, and combed her fringe well over her
brows in order to emphasize her undeniable resemblance to the
great actress. Once, when she questioned Mr. Pollitt on the subject,
he had laughed so uproariously—so like a husband—that an
apoplectic seizure seemed imminent.
Captain Waring was most enthusiastic respecting this Indian
scheme, and naturally gave the project his warmest support. Tête-à-
tête, he said, “It’s a first-class notion of Mark’s. The uncle keeps him
far too tight in hand. No wonder he wants to break away and see the
world and live his own life, poor devil!”
“What nonsense!” protested Mrs. Pollitt, irritably. “He has plenty of
liberty and a latch-key.”
“And does not know how to use one or other. Besides, the uncle’s
proud eye is always on him; he follows him about like a dog—worse,
for dogs are not admitted into clubs! However, this twelve months’
holiday in a far country will be a most blessed relief to the boy and
A1 business for me. I’m on my last legs; and if this had not turned
up, I’d have had to make strong running with Miss Clodde. She is
common and repulsive looking, but has thirty thousand pounds. I
hope I may never be so desperate as to marry her—at any rate, I
have a year’s respite.”
“How do you know she would have you, Clar?”
Clar’s laugh was an interesting study in manly assurance.
“I really wish you were married,” continued his sister rather
peevishly.
“Yes; to a rich elderly widow who has had her fling—that is my
style.”
“What a horrible way of talking! You are really too dreadful. I
suppose this trip will be rather costly?”
“Ra—ther!” emphatically.
“And you will be the treasurer?” opening her pale eyes to their
widest extent.
“I’m not so sure of that,” shaking his head. “Of course, as I am the
manager, and am personally conducting this tour, all payments ought
to come from me. ‘The uncle,’ however, is rather shy of having
monetary dealings with his brother-in-law, as you know by sad
experience. However, I may be able to work it, once we are in India,
and you may depend upon me for making the most of my time and—
opportunities. I was so hard up, I was thinking of taking a leaf out of
Charlie Wilde’s book. He writes hymns and tracts——”
“How absurd you are! What preposterous nonsense! Charlie
Wilde, who has never entered a place of worship for years, write
tracts!”
“I tell you that he does!” persisted Clarence. “He has a wonderful
knack, and does the pathetic and emotional style A1. Gets about ten
pounds apiece, and invests the money in a flutter on the turf.”
“Well, Clar,” said his deeply shocked sister, “I cannot compliment
you on your companions; and, whatever you may come to, I hope
you will never arrive at such a pitch of wickedness as that.”
On one point Captain Waring and Mr. Pollitt were most warmly
agreed, viz. that “the trip must be done in good style if done at all.”
Mark was inclined to travel “on the cheap,” his uncle had
complained, and had protested against a large quantity of baggage,
a battery of guns, and a valet.
“Thirty pair of boots!” he cried. “What rubbish! I am not going to
walk round India!”
“But Clarence says you can’t do with less, and he must know
better than you do,” argued Mr. Pollitt. “I wish you to travel like a
gentleman, not like a bag-man. There is where you disappoint me,
my boy—you make no show, no dash; your tastes are all for quiet—
your favourite character is the violet, and you prefer a back seat. You
are going out in the same steamer with a lot of nobs—I’ve seen to
that—and it is as likely as not that you will join forces when you land.
These swells take to you. As for me, they only take to my dinners,
and my deer forest. However, as long as you are in the best set, I
don’t care—I’m satisfied.”
“I think Clarence and I will stick to ourselves, and not join any
party, sir; we will be more independent. He has sketched out our
beat—Bombay, Poonah, Secunderabad, Travancore, Madras,
Ceylon, Calcutta, the hills; and that puts me in mind to ask if you
have any idea of my father’s whereabouts?”
“Bostock and Bell, Bombay, are his agents,” evading the question
and his nephew’s eyes.
“I know that; I have written to their care steadily for the last six
years.”
“And never had an answer?” with ill-concealed satisfaction.
“No, except a ‘Pioneer’ at long, long intervals.”
“Just to show that he is alive? Let me see, it is eight years since
he left the service and went to live at a place called the Doon. He
wrote pretty regularly up to then; and when Mrs. Jervis was killed in
that carriage accident, he never sent a line, only a paper. Poor
woman! I believe she led him a devil of a life. She was insanely
jealous.”
“I suppose I can get his address in Bombay—his real address, I
mean?”
“Yes, I should think so.”
“And then I shall look him up—at once.”
“If he will be looked up. The Jervises are an eccentric family. I
heard some queer stories of them not long ago.”
“But my father never struck you as eccentric, did he?”
“No. And, of course, you must try and see him; but don’t let him lay
hands on you and keep you, my boy. He was a handsome,
persuasive sort of fellow, and had wonderful personal charm—when
he chose to exert it. India has cast a spell upon him, and kept him
with her for the best part of his life. Don’t let India do the same by
you.”
“No fear of that,” with emphasis.
“Well, I’m sorry now you are going out there, for several reasons. I
would have preferred China or Australia, but Waring has his say and
his way.”
“And I had my say and my way too, Uncle Dan. India is my native
land; I remember it distinctly—the servants with their dark faces and
big white turbans, my little chestnut pony, which was called the ‘Lal
Tatoo,’ and I want to see my father. You know we have not met for
fifteen years.”
“I know,” assented Mr. Pollitt, gloomily, and added, after a pause, “I
wonder now, if it would be possible for you to throw me over—and
stop out there with him!”
“There is not the smallest probability of that. Besides, my father
does not want me.”
“And supposing that he did!” exclaimed Mr. Pollitt, suddenly
jumping up and beginning to walk about the room. “Bear this in view,
that you must make up your mind between us! You cannot be son
and heir to two men! You can pay him a visit of a week, or at most a
month; but if you postpone coming home at his request—I warn you,
that you may stay in India till I fetch you! To put the matter in a
nutshell, I wash my hands of you for ever! Not one farthing of my
money will you see,” he continued, speaking in great excitement. “I
shall leave every shilling to hospitals, you understand that, eh?” he
gasped, breathless.
“Yes, and it would be but just. I cannot live with my father in India
and be your adopted son at home, but you are needlessly alarmed. I
shall turn up again within a year without fail. I’ll take a return ticket if
you like.”
“Well, that’s a bargain, my boy. I’m a bit jealous of your father, and
it’s a nasty, low, ungentlemanly feeling. I must confess that I have
been glad that he, so to speak, dropped you. But he handed you
over to me when he married the Begum, and you are my son—not
his.”
The day of departure arrived; the valet (a somewhat garrulous
person, with superb references), in charge of three cabs loaded with
baggage, preceded the travellers to Victoria, whilst Mr. and Mrs.
Pollitt drove the young men in the family landau, in order to see the
last of them.
As Mark and his uncle slowly paced the platform, the latter, who
had been incessantly fussy all the morning, said—
“Now, I hope nothing has been forgotten, and that you have
everything you want?”
“I’m sure we have—and ten times over.”
“You will write often—once a week—if only a line, eh? Mind you
don’t forget us.”
“No fear of that, Uncle Dan.”
“And remember our bargain. Though I have not taken return
tickets, after all. Don’t stay longer than the year. I don’t know how I’m
to get on without you. I can never use the mail-phaeton now, for I
hate sitting beside the coachman—and—you know, I tried to drive
once—and the result. There will be no one to take me on the river on
a hot afternoon—other people but you think an old fogey has no
business there. Oh, I shall miss you! I’ve lodged money for you in
Bombay with Bostock & Bell’s” (naming a magnificent sum), “and
when it’s done, you must come home, for I won’t send you another
stiver. It’s in your name, of course—you will be paymaster.”
“All right, uncle.”
“Keep your cheque-book locked up. Don’t let a tiger get hold of
you, or one of those scheming, husband-hunting women that
Clarence talks about.”
“You may make your mind quite easy on that score,” with a rather
derisive smile.
“Well, time is up, my dear boy. I am sorry you are going; take care
of yourself. God bless you!” wringing his hand as he spoke.
Meanwhile Mrs. Pollitt and her brother had also been having a few
parting words.
“Now, Clar,” she said impressively, “I have done a good thing for
you. This is a splendid chance. Be sure you make the most of it; if
you please the ‘uncle,’ as you call him, he will help you to something
better by-and-by.”
Clarence nodded sagaciously. He was in the highest spirits.
“You are not really limited to time, you know,” she continued, in a
whisper.
“I know,” and there was a significant look in his right eye, almost
approaching to a wink.
“And you will be manager—and paymaster.”
“Guide, councillor, and friend, you bet.”
“And now, dear boy, do be prudent; don’t get into any more
entanglements with grass widows; don’t get into any more betting or
gambling scrapes—promise me.”
“I shall be as steady as old Time or young Mark himself, and I
can’t say more. Well, good-bye—and thanks awfully, Lina. I must say
you do stick to your own people”—adding, with a hasty kiss—“I see
we are off.”
As the carriage moved slowly past the Pollitts, who were standing
side by side, Clarence flung himself back with a boisterous laugh, as
he exclaimed—
“I declare, the uncle seems quite cut up—ha, ha, ha! Upon my
soul, I believe the old chap is crying!”

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