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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
This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or
part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation,
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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
recent years more than the establishment of personalized
medicine. Personalized cancer treatment uses therapies/
treatments targeted to the patient’s tumor profile, intending
to provide a more precise and targeted therapy than conven-
tional chemotherapy, particularly in advanced/metastatic
cancers. Pathologic assessment is an essential component of
personalized cancer treatment by providing accurate cancer
diagnoses and proper testing of tumors for those specific
molecular and immunohistochemical biomarkers used to
guide targeted treatment strategies. To design targeted thera-
pies, one needs to understand the pathophysiology behind
oncogenesis. While a detailed review of oncogenesis
deserves its book, in this book chapter, I focus on the impor-
tant issues of oncogenesis and personalized cancer treat-
ment, using lung cancer as an example as I am a thoracic
pathologist with minor references to the generalities of
oncogenesis.
1 Oncogenesis and Personalized Cancer
Treatment
Oncogenesis is a very complex and multifactorial process
related to not only the more well-known oncogenes and
tumor suppressor genes but also the effect that the environ-
ment has on them and the overall physiology of the normal
cells and heritable conditions (not discussed in this chapter).
Genes are the center of oncogenesis, and simply said, the
origin of cancer is related to genetic and epigenetic changes
and mutations that alter the function of genes. There are
oncogenes, those that promote cancer cells growth (RAS is
the most commonly mutated oncogene, EGFR (Epidermal
H. T. Bittar (*)
Department of Pathology, Moffitt Cancer Center, Tampa, FL, USA
Department of Oncologic Sciences, University of South Florida,
Tampa, FL, USA
e-mail: Humberto.TrejoBittar@moffitt.org
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
J. Huang et al. (eds.), Anesthesia for Oncological Surgery, https://doi.org/10.1007/978-3-031-50977-3_1
growth factor receptor), HER2, among many others), tumor
suppressor genes, those that inhibit cell growth and their
loss of function allows uncontrolled cell growth (p53 the
most commonly mutated gene in cancers and RB, etc.),
apoptotic genes, those regulate apoptosis promoting cancer
cells survival (the BCL2 family of genes), and lastly genes
that affect the interactions between cancer cells and host
cells (checkpoint inhibitors genes would be in this category).
All the gene alterations act together to allow the cancer cells
to proliferate without the need for growth signals and avoid
inhibitory/apoptotic signals, to have altered cell metabolism
that supports continued cell growth, to guarantee blood sup-
ply, to evade the host immune system and to allow for inva-
sion and metastasis, essentially becoming immortal [1].
Some significant genetic changes/mutations in cancer
include point mutations, a change in a single nucleotide in
a gene sequence, for example, in the KRAS gene in lung
adenocarcinomas. Gene rearrangements change the struc-
ture of a chromosome(s) by inversion or translocation, as it
occurs in ALK translocated lung adenocarcinomas. Gene
deletions, in which a portion of the chromosome is lost,
often affect tumor suppressor genes. Gene amplifications,
meaning producing multiple copies of the same gene with
overexpression and activation, can be seen with HER2
amplification in breast cancer. Aneuploidy is when a cancer
cell has more than the standard number of chromosomes
and thus copies numbers of oncogenes. microRNAs are
small single-stranded RNA fragments that can bind to mes-
senger RNA after transcription and facilitate its degrada-
tion. This process specifically targets tumor suppressor
genes, leading to downregulation of the corresponding pro-
teins and potentially enabling uncontrolled cell prolifera-
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
almost all cancers, multiple mutations accumulate (double/
multiple hit hypothesis) in a single cell to transform it. It is
also essential to recognize that while theoretically tumors are
made of proliferation from a single mutated cell
3
4 H. T. Bittar
(­ monoclonality), in reality, tumors are heterogenous in their
cell composition. This is because, within the life of a tumor,
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
resistant to treatments. This is the origin of tumor progres-
sion and the development of treatment resistance.
Changes in the integrity of the end of chromosomes, so-­
called telomeres that protect chromosomes from degrada-
tion, are a standard component of aging and have also been
implicated in the development of many conditions, including
cancers. The length of telomeres is maintained by the tran-
scription enzyme complex telomerase (some of its vital com-
ponents are TERT (telomerase reverse transcriptase) and
TERC (telomerase RNA component)). Shortening of telo-
meres is a normal phenomenon that occurs with each cell
cycle (prevented by the telomerase) or an abnormal one due
to excess reactive oxygen species (or lack of antioxidants).
When telomeres shorten beyond a critical point, the cell
becomes senescent and undergoes apoptosis/cell death with
the associated loss of tissue function (as it occurs in normal
aging). To become immortal, an important step in tumori-
genesis, cancer cells must irreversibly prevent the shortening
of telomeres, most often by constitutively activating telomer-
ase (frequently by amplification and mutations in the pro-
moter regions of the TERT and TERC genes), thus avoiding
the DNA damage cell death pathways [3].
The recent advances in lung cancer treatment are a perfect
example of successful personalized cancer treatment, par-
ticularly in lung adenocarcinomas, for which potentially tar-
getable oncogenic mutations are present in over 75% of
cases. In the United States, KRAS is the most frequently
mutated oncogene in lung adenocarcinoma, followed by
EGFR [4, 5]. EGFR (upstream tyrosine kinase receptor) and
KRAS (downstream signaling molecule) are part of the
MAP-kinase pathway that regulates cell growth, prolifera-
tion, and survival. Not surprisingly, most of the targeted
therapies available for lung adenocarcinomas affect this
pathway. There are multiple guidelines [6] aligning with the
current state of drugs approved by the U.S. Food and Drug
Administration (FDA), helping clinicians in their choice of
biomarkers testing (see below) and targeted treatment strate-
gies. Some recommendations include molecular testing of
nonsquamous lung non-small cell carcinomas for KRAS,
EGFR, HER2, and BRAF mutations; ALK, ROS1, RET,
NTRK translocations, MET exon 14 alterations, and of
course, PD-L1 status. In squamous cell carcinomas, the most
common genetic changes include those in p53, PI3KCA,
SOX2, and FGFR1. There is currently no FDA-approved tar-
geted therapy (or need for biomarkers testing) in these
tumors [7] unless the patient is young and has never been a
smoker. Lastly, for small cell carcinomas, the most common
(essentially all cases) genetic alterations involve downregu-
lating of p53 and Rb proteins (by the genetic loss of their
genes). There is currently no role for biomarkers testing in
small cell carcinoma.
2 The Increasing Role
of Immunotherapy
Immunotherapy in cancer treatment refers to using medica-
tions to improve the person’s immune system’s capacity to
attack neoplastic cells.
Immune checkpoint is a normal physiologic phenomenon
aimed to prevent the building of immune responses against
healthy/non-neoplastic cells. Generally speaking, it prevents
T-cells from activating and promoting cell death. In the cen-
ter of these complicated pathways are the proteins program
death-1 (PD-1) and the program death-1 ligand (PD-L1).
PD-L1 is a transmembrane protein that downregulates
immune responses by binding to its two inhibitory PD-1 and
B7–1 (CD80). PD-1 is an inhibitory receptor expressed on
T-cells following their activation, which is sustained in states
of chronic stimulation such as in chronic infection or cancer.
The binding of PD-L1 with PD-1 inhibits T-cell prolifera-
tion, cytokine production, and cytolytic activity, leading to
the functional inactivation or exhaustion of T cells. PD-L1
expression has been observed in immune cells and tumor
cells. Aberrant expression of PD-L1 on tumor cells has been
reported to impede anti-tumor immunity, resulting in immune
evasion. Therefore, interruption of the PD-L1/PD-1 pathway
represents a novel strategy to reactivate the tumor-specific
T-cell mediated immunity suppressed by the expression of
PD-L1 in the tumor microenvironment.
PD-L1/PD-1 inhibitors (collectively called immune
checkpoint inhibitors) are nowadays the cornerstone of the
treatment of many cancer types. PD-L1 is expressed in a
broad range of cancer cells, including lung, melanoma, uro-
thelial, kidney, ovarian, breast, and colorectal cancer [8]. For
many of the FDA-approved indications, immune checkpoint
inhibitors have proven to be a superior therapy with or with-
out concurrent chemoradiation (depending on the cancer
stage and history of prior therapies) compared to chemora-
diation alone [9].
It is impossible to discuss immunotherapy without incor-
porating T-cell transfer therapies. The main principle is
removing the patient’s T-cells and, in the laboratory, select-
ing and conditioning them to better attack the patient’s can-
cer cells [10]. There are two main types of T-cells transfer
therapies.
• Tumor-infiltrating lymphocytes (TIL) therapy uses the
lymphocytes that are enriched on the patient’s tumor
(requires resection of the tumor to obtain the TILs) but
that is not sufficient or activated enough to destroy the
tumor, and in the laboratory, select and expand those
T-lymphocytes that best recognize the tumor cells (refer
Oncogenesis, What Is New?
to as TIL products). The TIL product is then infused back
into the patient with the improved capacity to attack the
tumor cells. TIL therapy has been used to treat melanoma
[11] and is currently being studied and used experimen-
tally to treat other solid tumors like cervical squamous
cell carcinoma, cholangiocarcinoma, and lung carcino-
mas [12].
• The other technique is CAR-T cell therapy, which uses
the patient’s T-lymphocytes after being genetically modi-
fied in the lab to express a chimeric antigen receptor
(CAR) that is a modified receptor specifically designed to
attach to the patient’s tumor cells. CAR-T cell therapy is
FDA-approved to treat many advanced forms of leuke-
mias and lymphomas [13]. While very promising, CAR-T
cell therapy is not free of secondary effects and is notori-
ously very costly.
3 The Importance of Tissue Adequacy
in Biomarker/Ancillary Studies
Testing
Biomarkers/prognostics testing in the personalized treatment
of cancer can be done by multiple techniques (see Table 1)
with different degrees of complexity. The easiest and quick-
est way of testing is by immunohistochemistry. In this tech-
nique, biopsy tissue or cells collected by cytology techniques,
like fine needle aspiration, are exposed to antibodies that rec-
ognize the targeted protein (so-called primary antibody). The
expression of the target protein is then demonstrated by
using a secondary antibody against the immunoglobulin
used as the primary antibody. A distinct color (usually
brown) is produced because the secondary antibody is bound
to a reagent that produces color after a specific chemical
reaction (so-called detection agent). The final product is a
section of tumor stained (because of the presence of color)
with the targeted protein, which we call immunostain. The
Table 1 Tissue sampling for personalized cancer treatment
Sample procedure Samples and tests
• Surgical resection • Fresh tissue
• Surgical biopsy • Formalin-fixed, paraffin-­embedded (FFPE)
• Cytology specimen • Smears
(aspirate or fluid) • Liquid biopsies
• Non-­invasive procedures: • Diagnostic evaluation (histology or cytology)
  – Blood • Protein expression:
  – Urine   – Immunohistochemistry
• Genetic tests:
   – Conventional PCR
  – FISH
   – Next-generation sequencing (NGS)
   – RT-qPCR/gene expression panels/
RNA-sequencing
5
immunostain is finally evaluated under the microscope for
the presence or absence and the semiquantitative estimation
of the targeted protein.
Important examples of the use of immunohistochemistry
include the assessment of PD-L1 expression in many cancer
types. For instance, hormone receptors status in breast can-
cer, mismatch repair enzymes expression status in colon and
endometrial cancer, and ALK expression in ALK translo-
cated lung adenocarcinomas, among many others. It is
important to know that there are certain preanalytical require-
ments that must be met for the immunostains to be properly
interpreted. Many of these requirements are regulated by the
Food and Drug Administration (FDA) and many pathology
and oncology professional organizations. Some examples of
these requirements include:
• 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
be easily obtained by small biopsies and cytology speci-
mens [6, 14–16]. Following testing guidelines is
extremely important to avoid misclassifying patients
who could have potentially benefited from
immunotherapies.
• For hormone receptors (estrogen, progesterone, and
HER2) expression status in breast cancer, we have
some of the strictest guidelines (by the College of
American Pathologists (CAP) and the American
Association of Clinical Oncology (ASCO)) and stan-
dard operating procedures, and their mandatory appli-
cation is tightly regulated. Some of the
recommendations include short ischemic time (the
time between removal of the tissue/stopping of the
blood supply and the beginning of 10% formalin fixa-
tion), the fixation time should be at least 6 h, and no
more than 72 h, and slides should not be older than
6 weeks, mandatory participation in external profi-
ciency testing, among many others [17].
Important factors
• Preoperative evaluation and need for anesthesia
• Choice of sampling method (invasive vs.
non-invasive)
• Need for intraoperative or intraprocedural sample
adequacy assessment
• Limitations of the length of the ischemic time
• Assessment of adequacy before sequencing
procedures (is there enough material after
diagnosis and further processing)
• Is there a good proportion of tumors within the
sample
• Avoid using old samples
• Need for biostatistics and data analysis of NGS
data
6 H. T. Bittar
The use of immunohistochemistry for the assessment of
prognostic biomarkers has many benefits, including shorter
turn-around time with results being available as early as
within 24 h, their more cost-effective and less of a financial
burden for patients and the health system (compared to the
more expensive sequencing studies), and their easier to per-
form, more widely available and, in many cases, more
straightforward to interpret [18].
3.1 Sequencing
Sequencing of DNA (determining the exact sequence of
nucleotides/bases) and fluorescent in-situ hybridization stud-
ies (FISH) are extensively used to select patients for targeted
therapy and biomarker testing. As mentioned, these tech-
niques are used to find those specific genetic changes in the
cancer cell’s genome.
• The most effective technique for sequencing the tumor
genome is next-generation sequencing (NGS). While the
specifics of this technique are out of the scope of this
chapter, the concept is that the whole genome or targeted
parts of it are sequenced in parallel by millions of indi-
vidual smaller fragments of genetic material multiple
times (something referred to as depth of the sequencing).
Using bioinformatics tools, the fragments are pieced
together, mapping each fragment to the expected normal
genome, allowing by comparison to find those single
nucleotide mutations or much more significant changes in
individual genes or whole chromosomes. Tumor sequenc-
ing is one of the necessary steps for most personalized
cancer treatments and often an indication for biopsy pro-
cedures, particularly in the recurrence setting.
It is important to adequately obtain these tissue samples.
Recent recommendations have suggested at least 1 mm2 of
formalin—fixed-paraffin-embedded tissue, needing as little
as just five sections that must contain at least 20% of viable
tumor [6, 19]. It is imperative to test the adequacy, which is
done by rapid on-site evaluation by cytologists in procedures
like fine needle aspirates or by frozen section examination
[20, 21]. The overall goal is to ensure enough and proper
material has been collected to avoid unnecessary repeated
procedures, which will necessitate further anesthesia.
3.2 Fluorescent In-Situ Hybridization (FISH)
Another molecular technique used in personalized cancer
treatment is fluorescent in-situ hybridization (FISH). In this
technique, large gene/chromosome changes are identified by
hybridizing (binding of complementary DNA sequences)
small fragments of DNA that are tagged with a fluorescent
dye to the complementary and highly specific DNA sequence
of the target gene. Using fluorescent microscopy, the loca-
tion of the probes on chromosomes can be visualized in the
individual cancer cell using formalin fixed tissue sections.
By consensus, at least 50 well-visualized tumor calls must be
present on the slide [6, 22] to be an adequate sample.
Immunohistochemistry, a more cost-effective, faster, and
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
in unequivocal cases [23].
3.3 RNA Gene Expression
The most recent molecular technique being used is the RNA
gene expression panels. Simply said, this technique uses
RNA instead of DNA as the input to identify gene altera-
tions. The benefit of this is that RNA detection is more sensi-
tive than DNA by detecting known and novel fusions/
alterations. It measures expressed genes rather than predicted
gene expression, which aligns better with the true pathologic
drivers of the disease. When done correctly, they have better
sample yield and are more cost-effective [24, 25].
3.4 Liquid Biopsies
Clinicians must also be aware of the usefulness of the so-­
called “liquid biopsies.” Essentially, the principle behind this
technique is that tumor cells can shed their genetic material
into the bloodstream. Thus, we can measure the presence of
that material (providing diagnosis) and its genetic sequence
(providing personalized treatment options information)
using a simple blood sample. Essentially, replacing the need
for tissue, which might be important in patients with poor
performance status for whom undergoing anesthesia would
be contraindicated. Other benefits of liquid biopsy include
early cancer detention (when tumors are too small to be seen
by imaging studies or to obtain a tissue sample), assessment
of treatment response, and easy monitoring of recurrence
and development of treatment resistance. Despite this, tissue
sampling continues to be the preferred method for diagnosis
and molecular testing, and is considered the gold standard to
this day [26, 27].
4 The Environment, Chemicals,
and Cancer
It is widely accepted that gene expression is affected by the
environment and that different environmental conditions par-
ticipate as risk factors for many cancers. This is supported by
the fact that there are regional differences in cancer types and
Oncogenesis, What Is New?
incidences. For example, liver cancer is more prominent in
East Asia, which is related to the presence of liver flukes; or
the higher incidence of certain types of cancers associated
with obesity, alcohol consumption, the Western diet, and
developed nations. Some of these exposures include chemi-
cal carcinogens, ultraviolet light, tobacco smoke, and micro-
organisms (see below), among many others, all of which
share a common potential DNA damaging effect. It has been
proposed that up to 85% of cancers could be prevented by
modifying these genes-environment interactions [28].
Cigarette smoke contains over 60 chemical carcinogens,
including nicotine, ammonia, carbon monoxide and diox-
ide, tar, formaldehyde, acetone, and cadmium) is associated
with an increased risk of many types of cancers. While lung
cancer is the most known association, smoking is also
linked to cancers of the head and neck, esophagus, pan-
creas, bladder, and liver, among others. The effect of ciga-
rette smoking is mainly at the level of the DNA, where it
induces distinct signature mutations (e.g., C>A transver-
sions), indirect activation of DNA editing, and DNA meth-
ylation, helping in increasing the risk of acquiring cancer
driver mutations. Moreover, the direct effect of smoking
inducing epithelial damage (e.g., precursor lesions of can-
cer like squamous metaplasia), chronic inflammation, and
inhibiting apoptosis support the survival of cancer cells.
Outside of carcinogenesis, cigarette smoke also induces
immunosuppression, disbalances in proteases and antipro-
teases, and decreases phagocytic activity, leading to many
other diseases, including chronic obstructive pulmonary
disease (COPD) [29].
Certain occupations and their associated exposures are
known to have links with cancer. These include asbestos and
mesothelioma, benzene and acute myeloid leukemia, beryl-
lium and lung cancer, cadmium and prostate cancer, vinyl
chloride and angiosarcoma, radon and lung cancer, among
others.
There are many chemical carcinogens. Some act directly
and do not need to be metabolized. A typical example is
alkylating chemicals, as they are used in some chemotherapy
regimens that can lead to secondary malignancies. Others
need to be metabolized. Not surprisingly, some include
chemicals formed after the combustion of tobacco and fossil
fuels, those found in aromatic amines (used in the dye and
rubber industry), and in natural sources like aflatoxins in
plants). These agents are mutagenic and directly bind to
DNA leading to oncogenic mutations. A last mention should
be given to the role of ionizing and ultraviolet radiations,
which are also mutagenic, including their effect on chromo-
some morphology by breaking the DNA, the excessive for-
mation of pyrimidine dimers overwhelming the DNA repair
mechanisms, and point mutations.
7
5 Microbial Oncogenesis
There are a few oncogenic microorganisms, including
Helicobacter pylori, and DNA and RNA viruses. Altogether
they are believed to be responsible for approximately 15% of
cancers worldwide. Some effects on oncogenesis include
stimulation of cell proliferation, enhancement of cell sur-
vival, and interference with cell cycle regulation. Some nota-
ble examples include:
• HPV in oropharyngeal and cervical cancer via oncogenic
proteins that inactivate RB and p53. The recent wide-
spread use of HPV vaccines is an extraordinary example
of cancer prevention via vaccination [30, 31].
• Merkel cell polyomavirus, via viral integration and
expression of the viral LT and ST proteins and thus RB
inhibition. More recently, immunotherapy has been
proven to be an evolving option for the treatment of this
malignant neoplasm [32].
• Hepatitis B and C virus infection are one of the main etio-
logic factors in hepatocellular carcinoma [33, 34]. There
are many ways these viruses can be oncogenic, including
the promotion of chronic inflammation, dysregulation of
cytotoxic CD8 T-cells, stimulation of hepatocytes prolif-
eration, and increased reactive oxygen species, all leading
to DNA damage. There are also direct effects of viral pro-
teins (e.g., HBx and HVC core protein) on p53 function
by activating transcription factors.
• Epstein-Barr Virus (EBV) is a human oncogenic virus
that can be lifelong asymptomatic but also associated
with many diseases. Some of these are non-neoplastic,
including Burkitt lymphoma, some Hodgkin lymphomas,
nasopharyngeal carcinomas, some gastric carcinomas,
and rare sarcomas. The exact mechanisms of oncogenesis
linked to EBV remain a research challenge; at least in
part, they are related to dysregulated normal B-cells pro-
liferation [35].
• Helicobacter pylori, best known for its role in the patho-
genesis of gastric peptic ulcers, is also the first bacteria to
be recognized as having a role in oncogenesis. Like the
hepatitis viruses, the bacteria, by creating a chronic
inflammatory state in the gastric mucosa, leading to atro-
phy and intestinal metaplasia, increases the risk of gastric
adenocarcinoma and lymphoma. Also, direct effects of
helicobacter pylori genes have been implicated (e.g.,
CagA and VacA genes), which can upregulate growth fac-
tors [36, 37].
The overall organ microbiome could also participate in
tumorigenesis. It has been recently described that gut and
lung microbiomes can predict response to immune therapies
8 H. T. Bittar
(e.g., anti PD-L1) by inducing immune dysregulation and
tolerance and directly increasing the risk of malignancy due
to chronic inflammation [38].
Additional attention is now paid to the tumor ecosystem
and microenvironment, a field that was until recently over-
looked. The tumor microenvironment includes endothelial
cells, multiple immune cells, fibroblasts, pericytes, the extra-
cellular matrix, and many other organ-specific cells. While
this field is quickly evolving, some recent discoveries include
regulating immunotherapy efficiency in different tumor
microenvironments by excluding cytotoxic T-cells or induc-
ing immunosuppression [39, 40].
In summary, tissue sampling and acquisition for per-
forming molecular and immunohistochemical studies in
cancer specimens have become a standard of care.
Surgeons, anesthesiologists, radiologists, and of course,
pathologists must be familiar with the most current
requirements of tissue sampling. Particularly, tissue ade-
quacy is an important consideration that can dramatically
affect the need for further surgical procedures, which is
undesirable. Nowadays, anatomic and molecular patholo-
gists can perform many tests with very little tissue.
Moreover, liquid biopsies are becoming more frequent,
reducing the need for procedures with additional morbid-
ity and mortality, many of which might be done in poor
surgical candidates.
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 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
e-mail: hlin1@lsuhsc.edu
J. Y. Park (*)
Department of Cancer Epidemiology, Moffitt Cancer Center,
Tampa, FL, USA
e-mail: Jong.park@moffitt.org

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 11

J. Huang et al. (eds.), Anesthesia for Oncological Surgery, https://doi.org/10.1007/978-3-031-50977-3_2
12
2 Cancer Incidence and Trend
The World Health Organization (WHO) data from WHO
shows cancers cause the largest economic burden worldwide
among all human diseases [2, 3]. The most considerable
cancer-­related burden is in the population aged 60 years or
older. According to the WHO Global Cancer Observatory
data, breast (2.3 million cases), lung (2.21 million cases),
colorectal (1.93 million patients), and prostate (1.41 million
patients) cancers are the most common cancers [2, 3]. The
most common cancers in men are lung, prostate, stomach,
and liver, while breast, lung, cervical, and colon cancers are
most frequent among women. In terms of incidence rates,
breast cancer has the highest incidence rate (46.3 per 100,000),
then prostate (29.3 per 100,000), lung (22.5 per 100,000), and
colorectal (19.2 per 100,000) cancers are followed [4].
Based on the American Cancer Society (ACS) report [8],
the trend of cancer incidence was mainly influenced by envi-
ronmental factors and patient care, especially cancer screen-
ing. The discussion of incidence trends for these common
cancer types is listed below.
Prostate cancer cases surged in the 1990s due to the intro-
duction of prostate-specific antigen (PSA) screening tests.
Most cases identified through this screening test are asymp-
tomatic and early-stage prostate cancer cases. Therefore, ris-
ing prostate cancer incidence may lead to the over-diagnosis
and over-treatment due to these new PSA screening tests.
Because of these concerns, there were uncertainty and dis-
agreement on the value of the PSA test [9]. The United States
Preventive Services Task Force (USPSTF) recommended
new guidelines on PSA tests in 2008 and 2012 [10, 11]. They
advised against PSA screening among men older than
75 years in 2008. In 2012, the USPSTF recommended
against PSA screening for all men, regardless of age [11]. As
a result, prostate cancer incidence was increased from 2013
until now. In 2018, the USPSTF recommended that men
aged 55–69 should discuss the possible benefits and harms of
PSA screening with their healthcare provider and make an
individualized decision about whether to get screened [12,
13].
For the impact of the PSA test on prostate cancer mortal-
ity, Fenton et al. (2018) reported that PSA screening might
provide benefits in reducing prostate cancer-specific mortal-
ity. However, this PSA test is notoriously linked to high
false-positive results, often leading to an unnecessary biopsy
and overtreatment. In addition, long-term survival benefits
among screen-detected prostate cancer were unclear [13].
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-
graphic evaluation for the diagnosis of prostate cancer.
Recent European Association of Urology (EAU) guidelines
recommend performing MRI before prostate biopsy in men
with high risk for prostate cancer [15]. A risk assessment
H.-Y. Lin and J. Y. Park
with MRI for prostate cancer provides better sensitivity for
detection, reduces the over-diagnosis, and over-treatment
[16]. However, the main obstacles, such as const-­
effectiveness, to apply MRI as a prostate cancer screening
tool need to be cleared.
Lung cancer is the second most common cancer and the
leading cause of cancer mortality in 2020 [4]. The incidence
rate has decreased since the mid-1980s as the prevalence of
smoking declined [17]. However, the incidence of lung can-
cer among women is still rising in many countries. In these
countries, smoking prevalence in women has either peaked
recently or continues to rise. Therefore, lung cancer inci-
dence in women will most likely increase for at least a few
decades more [18].
Breast cancer incidence has increased since the 1980s due
to the early detection of asymptomatic cases by mammogra-
phy screening. In addition, body mass index (BMI) changes,
rising age for the first births, and declining fertility rate also
contribute to the increasing trend of breast cancer incidence
[19].
As for colorectal cancer, its incidence rates are rising in
low-income countries, while incidences have declined in
developed countries since the mid-1990. The introduction of
screening tests, such as a colonoscopy and fecal occult blood
test, in old age groups drives decreased an incidence rate of
colorectal cancer. However, incidence rates in the younger
generation are rising, most likely due to environmental fac-
tors, such as lifestyle, rapid dietary transition, and obesity
[20].
In addition to these four most common cancer types, cer-
vical cancer incidence rates have decreased since the 1970s
due to PAP smear screening, which evaluates for cancerous
or precancerous cells on the cervix. The trend of cervical
cancer incidence rates varies by race and age group. Hispanic
women in the United States showed the highest incidence of
cervical cancer compared with other racial groups. Especially
the incidence rates are increased in young Hispanic women
[21, 22]. Low cervical cancer screening rates and high human
papillomavirus (HPV) infection among Hispanic women can
partially explain rising cervical cancer incidence rates [22].
Perhaps, the most significant impact on reducing cervical
cancer incidence is the introduction of vaccines against car-
cinogenic HPVs, type 16 and 18. These vaccines were
approved in 2006 by the US Food and Drug Administration
[23]. Therefore, incidence rates of cervical cancer in the gen-
eration who received the HPV vaccine were declined signifi-
cantly [24].
3 Lifetime Risk for Cancers
The lifetime probability of developing cancer is 41% in men
and 40% in women [21]. The lifetime risk varies significantly
by different cancer types. According to the ACS data, the high-
Epidemiology of Cancer
Table 2 Lifetime risk for cancers by gender in the United States
Cancer sites Gender Percentage
All sites Male 41%
Female 40%
Breast Female 13%
Prostate Male 13%
Lung Male 6.2%
Female 5.8%
Colorectal Male 4.3%
Female 3.9%
a
Modified from ACS data [8]
est risks for cancer were found for prostate (13%), lung (6.2%),
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%.
The highest risks of cancer mortality are from lung (3.19%),
liver (1.46%), and stomach (1.36%) in men and breast
(1.41%), lung (1.32%), and cervix (0.77%) in women [8].
Generally, the mortality rate of each cancer in men is higher
than in women, except for thyroid cancer. Especially mortal-
ity rate ratios of the bladder (2.87), esophagus (2.36), and
liver (2.35) cancers between men and women are among the
highest cancers [8].
4 Survival Rates for Cancers
Based on the ACS report for the US population in 2012–
2018 [8], the 5-year survival rates of the top 10 common
types of cancers are listed in Table 3. The 5-year relative sur-
vival rate for all cancers was 68% in 2012–2018, while the
5-year survival rate was 49% in the 1970s. Prostate cancer
showed the best overall prognosis with a 5-year survival rate
of 97%. However, lung and pancreas cancers have the worst
5-year survival rates, 23%, and 12%, respectively [8].
Globally, the 5-year survival rates are 70–100% for prostate
cancer, 80–85% for breast cancer, 50–70% for colorectal
cancer, and 10–20% for lung cancer [3].
Improvement of cancer patients’ survival is affected by
multiple factors, including early detection and better treat-
ments [25]. For example, the 5-year survival rate for chronic
myeloid leukemia has significantly increased from 17% in
1975 to 73% in 2012 [26, 27], although the incidence of
chronic myeloid leukemia has been growing in the last few
decades. The potential explanation for the increasing inci-
dence rate can be the reclassification of other leukemia sub-
types, raising awareness, improved diagnostic sensitivity,
better-reporting systems for new cases, and other risk fac-
tors, such as obesity [27]. Further, the 5-year survival rate
increase of chronic myeloid leukemia was also due to new
innovative treatments, such as stem cell transplantation
through national health policies and cancer control programs
[28]. The progress in pre-clinical and clinical research on
13
Table 3 Five-year relative cancer survival rates of the top 10 common
cancersa
Cancer sites Percentage
All sites 68%
Prostate 97%
Breast 91%
Bladder 77%
Non-Hodgkin lymphoma 74%
Cervix 67%
Leukemia 66%
Colorectal 65%
Ovary 50%
Lung 23%
Pancreas 12%
a
Modified from ACS data 2012–2018 [8]
leukemia has provided many new innovative treatments,
such as monoclonal antibodies and immune CAR-T cells.
These new treatments significantly improved the prognosis
of chronic myeloid leukemia [27]. For melanoma metastasis,
several new immune therapies, and BRAF and MEK inhibi-
tors were introduced [29]. Immune checkpoint inhibitors
induce cancer-cell killing by activated CD8-positive T cells.
Immune checkpoint inhibitors, such as anti-CTLA4 and anti-­
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
increased [29]. These immunotherapies also demonstrated
their potential benefits for lung cancer. Due to these treat-
ments, 3-year survival for all lung cancer cases increased
from 22 to 33% over time, corresponding to the timing of
approval of targeted therapy [30]. On the other hand, uterine
cancer has not improved its survival rate long time, possibly
due to the lack of new treatments [31].
Survival rates for cancers are also different in different
racial groups. Survival rates in non-Hispanic black group are
usually lower than in non-Hispanic white group for most
cancers. Even after adjusting for clinical stage, gender, and
age at diagnosis, the survival rates are 33% lower in non-­
Hispanic blacks as compared with non-Hispanic whites [32].
For example, survival rates for uterine cancer are different in
different racial groups. African American women are more
likely to be diagnosed with higher clinical stages and
this higher clinical stage in diagnosis often leads to lower
survival rates [33]. Therefore, African American women
have the highest mortality rate in all races for uterine corpus
cancer [33]. The recent reclassification of subtypes based on
molecular biomarkers from next-generation sequencing was
introduced for targeted therapies. Recent whole-exome
sequencing studies have identified a role of the HER2/NEU
and driver mutations in the PIK3CA/AKT/mTOR oncogenic
pathways [34]. These results emphasize the relevance of
these novel therapeutic targets for targeted therapy. These
therapies provided a large impact because almost one-half of
uterine cancers are candidates for targeted therapies [35].
14
Table 4 Number of deaths by top 5 deadliest cancers
Cancer sites Incidence Percentage
Lung 1,796,144 18.2%
Colorectal 935,173 9.5%
Liver 830,180 8.4
Stomach 768,793 7.8
Breast 684,996 6.9%
Data from GLOBOCAN 2020 [2–4]
5 Cancer Mortality and Trend
Currently, heart disease is the leading cause of death in the
world, based on WHO data [4]. The second leading cause of
death is cancer. In Table 4, a list of cancer deaths was pre-
sented based on GLOBOCAN 2020 [2, 4]. As expected, the
rank in cancer mortality does not necessarily match with one
in cancer incidence because the survival rates are different in
different cancer types. Overall, lung, colorectal, liver, stom-
ach, and breast cancers are the deadliest cancers (Table 4).
Cancer mortality rates have increased consistently from the
1930s until the 2000s. One of the main attributable factors is
a rapid increase in lung cancer mortality due to the smoking
epidemic. However, smoking reduction has significantly
declined cancer deaths since 1991 [8]. In addition, lung
screening with low-dose computed tomography (CT) for
high-risk populations, such as heavy smokers, leads to detect
early-stage lung cancers successfully and lower cancer mor-
tality [36].
6 Risk Factors for Cancers
The development of cancers is the result of the combination
of genetic and environmental factors. The leading risk factor
is age, probably due to the accumulation of various risks
with age. In addition, DNA repair processes are less efficient
in the elderly. There are other well-established risk factors
for cancers, such as genetics, smoking, alcohol drinking,
high-fat diet, and infections, particularly carcinogenic infec-
tions. Genetic factors contribute to almost one-third of all
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
predictions. The polygenic risk scores are usually built based
on the sum of multiple germline genetic variants identified
from genome-wide association studies and can be used to
classify people’s risk of diseases based on their genetic pro-
files. These scores may help to predict lifetime risk, plan for
better screening, predict prognosis and, more importantly,
support personalized medicine [38–40]. Although the pre-
diction of individual cancer risk based on only polygenic risk
scores is not ready for the clinical use, an increasing number
of studies support using polygenic risk scores for population-­
H.-Y. Lin and J. Y. Park
based cancer risk stratification [38–40]. Although accuracy
of these PRS are different in different cancers, a high poly-
genic risk score is correlated with a higher risk of cancer. In
prostate cancer, the detection rate of polygenic risk score
ranged from 0.56 to 0.67 [40]. Recent large studies observed
that the top 10% polygenic risk score group increased risk
2.7-fold [41, 42].
Smoking is the most well-established risk factor for many
cancers, including lung, laryngeal, oral, esophageal, pan-
creas, bladder, kidney, liver, stomach, pancreas, colorectal,
and cervical cancers. Especially cigarette smoking is respon-
sible for approximately 80–90% of lung cancer mortality
[43]. Heavy smokers showed a 20 times higher risk for lung
cancer-specific death than never-smokers. Alcohol drinking
also increases the risk for several cancers, such as oral, laryn-
geal, colorectal, esophageal, liver, and breast cancers. Almost
4% of new cancers diagnosed in 2020 worldwide can be
explained by alcohol drinking based on WHO data [4]. Diets,
especially high-fat diets, are associated with an increased
risk of colorectal, lung, and prostate cancers. The previous
pre-clinical study reported that certain compounds induced
cancers [44]. However, these findings are not consistent with
results from human studies. Recent epidemiological studies
suggested that high-fat diets have been linked with an
increased risk of these cancers [45].
Infections are another risk factor for several cancers.
Approximately 15–20% of cancer incidences in the world
are related to infections, especially carcinogenic viruses
[46], such as Human Papillomavirus, Hepatitis B virus,
Hepatitis C virus, Helicobacter pylori, Human
Immunodeficiency virus, and Epstein-Barr virus. Human
papillomavirus infection, especially types 16 and 18,
increases the risk of cervical cancer [47], while Hepatitis B
and C viruses increase the risk of liver cancer [48, 49].
Helicobacter pylori infection is associated with a high risk of
stomach cancer [50]. Human immunodeficiency virus
increases the risk of developing some cancers such as Kaposi
sarcoma [51]. Epstein-Barr virus is linked to Hodgkin lym-
phoma, Burkitt lymphoma, and nasopharyngeal cancers
[46].
7 Summary
Based on the current trend of cancer epidemiological data,
these malignant diseases will be a significant public health
issue. This disease will impact clinical and social standards
and impose an enormous economic burden. However, recent
advances in medical technology provide promising tools for
better cancer care, screening, and early detection. For exam-
ple, liquid biopsy, a blood test that detects cancer cells or
tumor DNA that are circulating in the blood, can be used for
more efficient screening, early detection, and monitoring
Epidemiology of Cancer
treatment responses. Second, MRI can be used for diagnosis
and monitoring progression. Third, genetic profile contrib-
utes to a risk classification for utilization in personalized
medicine. Fourth, a new generation of treatments, especially
immunotherapy, opened a promising path for cancer treat-
ment by enhancing immune function against cancer cells.
Finally, statistical learning and artificial intelligence
improved accuracy and efficiency in pathology and imaging
analysis for tumor tissues.
Despite recent advances in cancer treatment and screen-
ing, there are still several challenges to be overcome for bet-
ter survival and early detection. For example, disparity
among people with a low socioeconomic status and different
racial groups is one of the main obstacles. These people are
less likely screened and receive less quality cancer cares. In
summary, the recent trends in cancer incidence and mortality
rates have increased. These trends may be continued due to
various factors, such as industrialization, air pollution, diet
change, and longer life span.
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 Immunemodulation and Cancer
Jinhong Liu and Jeffrey Huang
1 Introduction
The immune system serves as the fundamental defense
mechanism of the human body, playing a crucial role in pre-
venting tumorigenesis and managing the pathological pro-
gression of cancer. Despite constant pressure from the
immune system and the tumor microenvironment, cancer
cells can transform into aggressive, abnormal malignant
cells and develop immunity-suppressing capabilities, even-
tually leading to mutant progression or immune evasion. The
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
manner, where they must come into close proximity with
other cells to exchange information and function appropri-
ately. These interactions give rise to diverse immune
responses in different situations. In cancer, the intra-organ
movement or infiltration of active immune cells into the
tumor tissue is a decisive factor that determines immune out-
come [1, 2]. Over the past decade, significant progress has
been made in cancer immunotherapy, which has successfully
cured certain types of cancer in some patients across several
different cancer types. A key factor in this success is under-
standing the mechanisms of immune modulation and effec-
tively directing cytotoxic T cell responses against tumors.
2 Tumor Immunity
2.1 Tumor Immunity Require CD8+ T Cell
Activation
The key immune mechanism that combats cancer is the acti-
vation of cytotoxic T lymphocytes (CTLs), which specifi-
cally target tumor cells through tumor-specific antigens [3].
J. Liu (*) · J. Huang
Anesthesiology Department, Moffitt Cancer Center,
Tampa, FL, USA
e-mail: Jinhong.Liu@Moffitt.org
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
J. Huang et al. (eds.), Anesthesia for Oncological Surgery, https://doi.org/10.1007/978-3-031-50977-3_3
In vivo, tumor antigens are generated endogenously as cyto-
solic or nuclear proteins that are coupled with class I major
histocompatibility complex (MHC)-associated peptides.
These peptides can then be recognized by CD8+ CTLs that
are restricted by class I MHC and possess the ability to kill
antigen-specific target cells. The process of CTL activation is
highly regulated and modulated at both the molecular and
cellular levels, involving multiple stimulatory and inhibitory
steps. Failure to properly regulate these positive and negative
balances can result in tumor immune evasion.
2.2 T Cell Activation Require Antigen
Presenting Cell
For CD8+ cells to differentiate into CTLs, a healthy individ-
ual requires an antigen-presenting cell (APC) that can present
tumor antigen (a protein peptide associated with class I MHC)
to T cells. Tumor antigens or tumor-associated antigens
(TAAs) resulting from mutations and epigenetic changes in
APCs induce the expansion of specific CTLs, differentiation
into effector cells, and the generation of memory cells. The
interaction between the T cell receptor (TCR) and MHC-
associated peptides on APCs (signal 1) determines the quality
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
of activation of CD8+ T lymphocytes are strongly influenced
by these factors. As a consequence of interactions and recog-
nition of tumor antigen presented by APCs through T cell
antigen receptor, it initiates and activates a series of sequen-
tial process that lead to the generation of both antigen specific
effector and memory CTLs. These cytotoxic CD8+ T lym-
phocytes provide long-term protection against pathogens and
carry out immune surveillance to eliminate cancer cells,
therefore, APCs are the most efficient stimulators of naïve T
cells into CD8+ CTLs. Many types of cells originating from
myeloid linage can serve as APCs, including dendritic cells,
monocytes/macrophages, and granulocytes [4, 5].
17
18
3 Antigen Presenting Cells and Cancer
3.1 Basic Biology of Dendritic Cells
Dendritic cells (DCs) are vital in activating naïve CD4+ T
cells and are classified as professional antigen-presenting
cells (APCs), alongside macrophages, granulocytes, and B
cells. DCs are the essential APCs of the immune system,
playing a crucial role in connecting innate and adaptive
immunity, particularly in stimulating anti-tumor T cells [5–
7]. DCs arise from bone marrow progenitors known as com-
mon myeloid progenitors (CMPs). CMPs have the ability to
differentiate into monocytes or the common dendritic cell
progenitor, which gives rise to various subpopulations of
dendritic cells (DCs), including plasmacytoid DCs (pDCs),
conventional DCs (cDCs), and monocytic-derived DCs.
These immature DCs require maturation signals, such as
damage or pathogen-associated molecular patterns (DAMPs)
and inflammatory cytokines, to effectively fulfill their role in
the immune response. Upon maturation and activation, DCs
reduce their phagocytic activity, increase expression of MHC
class II and costimulatory molecules, produce more cyto-
kines, and demonstrate enhanced migration to lymph nodes
through increased expression of chemokine receptors [5, 8].
DCs exist as resident lymphoid tissue, such as spleen and
lymph nodes were critical for sampling blood and lymph
born antigens, respectively. This event is relatively important
because distributing and presenting antigens is highly
context-­specific, depending on the type of antigen and route
of exposure. In the case of cancer, it is not fully understood
how endogenous tumor antigen is processed and delivered
into lymphoid tissue, although naïve T cell activation has
long been known to be mediated by DCs within the draining
lymph node. Nonetheless, two recent investigations have
revealed that tumor-associated fluorescent proteins are
actively conveyed by CD103+ conventional dendritic cells
(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,
circumventing any experimental anomalies that may arise
when injecting significant amounts of dead or dying cells.
3.2 DC Plays Pivotal Roles in
Tumor Immunity
Regulation of the function of dendritic cells (DCs) is crucial
in establishing adaptive immunity against cancer, as evi-
denced by both animal models and human cancer patients. In
solid tumors, antigen uptake and presentation are mainly car-
ried out by monocytes and DCs. Although monocytes are the
principal phagocytic cells in tumors, they are unable to acti-
vate T cells in some cases and do not migrate to lymph nodes
[5]. Instead, monocytes often hinder T-cell responses against
J. Liu and J. Huang
tumors through various mechanisms and can impede the effi-
cacy of immunotherapy, chemotherapy, and irradiation. In
contrast, DCs thus have a unique feature and potential to pro-
cess and transfer tumor antigens to the draining lymph nodes
leading to the activation of T-cell, a crucial step that is abso-
lutely required for T cell-dependent tumor immunity and
response to immunotherapy. Tumor-resident DCs have an
increasingly important function in regulating the T cell
response within tumors during therapy [5, 6, 9–11]. These
functions establish DCs as a critical component of the antitu-
mor T cell response and indicate that modulating the biologi-
cal activity of these cells is a valuable therapeutic strategy
for indirectly promoting a T cell response during therapy.
Among DC suptype, studies in both mice and humans
have demonstrated that the cDC subset of DCs is primarily
responsible for eliciting an effective immune response
against cancer. The regulation and function of cDCs are gov-
erned by CCR7, a leukocyte chemotactic receptor that directs
the migration of DCs to the lymph node and facilitates the
generation of a systemic CTL-mediated anti-tumor immune
response. In mouse tumor models, cDCs that lack CCR7
expression are unable to attract CD8+ T cells to the tumor
site and also fail to stimulate T cells within the tumor to dif-
ferentiate into effector CTLs capable of eliminating the
tumor. Defective expression of CCR7 in cDCs in multiple
mouse tumor models leads to an inability to attract CD8+ T
cells to the tumor site, as well as a failure to stimulate T cells
within the tumor tissue to differentiate into effector CTLs
capable of eliminating the tumors [6]. Notably, it has been
shown that the failure of tumors to attract the cDCs inhibits
activation of CD8+ CTLs response to malignant cells [12].
However, this defect can be reversed by immunotherapy that
increases the number of cDCs within the tumor [12], under-
scoring the critical role of cDCs in regulating CD8+ T cell
function within tumors. Modulating cDC levels within local
tumors may therefore be a promising therapeutic strategy.
3.3 Cross Talk of DC with
T Cells and NK Cells
Another level of upregulation of anti-tumor immunity is to
modulate cDC and CD8+ CTL interaction/engagement. The
migration of cDCs to the location of T cells has been shown to
be critical to the induction of effective CTL mediated adaptive
immune response [13]. This essential step is dependent on the
production of stimulatory cytokines and chemokines by cDCs
within the tumor microenvironment. Studies have shown that
chemokine production by cDCs, such as CXCL9 and
CXCL10, is essential for enhancing the efficacy of immuno-
therapy. Along with chemokines, immune-related cytokines,
including IL-12 and IFNγ, are critical for promoting crosstalk
between CD8+ T cells and cDCs within the tumor microenvi-
ronment. Interestingly, cDCs have also been shown to interact
Immunemodulation and Cancer
with Natural Killer (NK) cells, which play a crucial role in
immune surveillance against cancer. Activated NK cells can
recruit cDCs to infiltrate the tumor tissue. Analysis of gene
signatures in human tumors has indicated that the presence of
NK cells is associated with the recruitment and appearance of
cDCs within the tumor microenvironment, suggesting that
modulation of NK cell ­presence within the tumor could sig-
nificantly enhance CTL-mediated immune responses [12, 14].
The requirement for interaction and cross-talk between cDC
and other types of immune cells, particularly of CD8+ CTLs,
demonstrates that the complexity of the antitumor immune
response within the tumor and indicates that the migration/
localization of DCs and lymphocytes within the tumor is a key
regulator of their function and activities.
4 Regulation DC by TLR Receptors
4.1 Basic Biology of Toll-like Receptors
(TLRs)
Since activation of DC is central and induction of their
in vivo function is critical, therefore targeting DCs may pro-
vide clinical approaches to improve immune responses in
cases where targeting T cells alone is not effective. Over the
past two decades, a significant advancement in DC activation
has been the use of exogenous activation signals through
Toll-like receptors (TLRs). TLRs function as pathogen pat-
tern recognition molecules that detect and initiate innate and
adaptive immune responses against pathogens and malignant
cells, acting as a first line of defense against infectious dis-
eases and cancer. Recognition of ligands by TLRs triggers
the secretion of proinflammatory cytokines and promotes
DC maturation programs for the induction of adaptive
immune responses. To date, more than 12 TLRs have been
identified in both humans and animals. TLRs belong to
type-1 integral membrane glycoproteins and are character-
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
conserved sets of molecular structures, so-called pathogen-­
associated molecular patterns (PAMP), and/or damage asso-
ciated molecular patterns (DAMPs) such as RAGE and
HMGB, which leads to pathogen antigen uptake, processing,
and presentation to naive T cells in peripheral blood, lymph
node, and tissues [15–17].
4.2 TLRs Play a Pivotal Role in Bringing
Innate and Adaptive Immunity
The recognition of PAMPs or DAMPs by TLRs leads to pro-
ducing proinflammatory cytokines, chemokines, type I inter-
ferons, and antimicrobial peptides 254,281. Therefore, TLRs
19
are critical in bridging innate and adaptive immune responses;
specifically, TLRs play a critical role in stimulating DC mat-
uration, antigen uptake and presentation and the differentia-
tion of T helper cells such as Th1, Th2 and Th17 and
controlling the suppressive function of regulatory T (Treg)
cells. In addition, signals via TLRs represent a potent means
of modulating immune responses to cancer vaccines, a novel
strategy now being evaluated in clinical trials. Vaccination
against cancer antigens largely relies on the use of DCs [16].
As mentioned previously, DCs act as sentinels of the immune
system and play a crucial role in initiating and directing
immune responses. This is due to their ability to capture, pro-
cess, and present self-tumor antigens to T cells and other
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
tumor antigens alone are not strong enough to stimulate
APCs to induce clinically significant anti-tumor immune
responses, unless there is the involvement of professional
DCs to some extent [18]. As professional APCs, DCs express
a significant number of TLRs and possess powerful effects
on lymphocytes. TLRs can promote DC and immune
response, because DCs are at the interface of innate and
adaptive immune responses. However, in most cases, there is
often lacking activation of DC, as a result of inhibitory sig-
nals from tumor cells—which may also induce immune tol-
erance through T cell deletion or through suppressive Tregs
[19], thus helping tumors escape from immune surveillance.
Over the past decade, numerous efforts have been made to
promote DC activation using agonists of the innate immune
system. For instance, intratumoral injection of TLR agonists,
alarmins, defensin peptides, DAMPs, or cytolytic peptides
can be utilized to improve the in situ antitumor response. As
a result, many TLR agonists have been investigated in the
context of cancer treatment and could serve as useful thera-
peutic strategies aimed at enhancing DC function to bolster
the antitumor response [16, 20].
4.3 Antitumor Effect of TLR3
Among all the TLRs, TLR3 has been broadly studied for
more than three decades. TLR3 is mainly expressed in neu-
roectodermal and myeloid cells (including DCs). TLR3 of
myeloid cells favorably acts as a receptor for the surface rec-
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
then, many TLR3 agonists have been designed to mimic the
dsRNA and have been studied, indicating that numerous
mechanisms subsidize the efficacy of TLR3 agonists. The
TLR3 agonists, including RGC100, ARNAX, and polyino-
sinic: polycytidylic acid (poly-IC), are currently being exten-
sively studied. These agonists are used as adjuvants for
Another random document with
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 9. The connection of this verse also does not appear. According
to Targum (on verse 13) Jabez = Othniel, the nephew or brother of
Caleb.

And Jabez, etc.] Render, And Jabez came to be honoured

above his brethren, but his mother had called his name Jabez,
saying, Because I bare him with pain. Jabez suggests a
somewhat similar word spelt with the same consonants but in a
different order, and meaning “he giveth pain.” The stylistic similarity
between this verse and many passages in Genesis (e.g. Genesis
xxx.) cannot fail to be noticed, and it is important to observe that a
tradition of this popular character was current in the style of the
patriarchal narratives of Genesis in the Chronicler’s time. Compare
also vii. 23. The man with the ill-omened name staved off ill-fortune
by his prayer which is given in the following verse.

¹⁰And Jabez called on the God of Israel,

saying, Oh that thou wouldest bless me
indeed, and enlarge my border, and that thine
hand might be with me, and that thou
wouldest keep me from evil, that it be not to
my sorrow! And God granted him that which
he requested.
10. that thou wouldest keep me from evil] Literally that thou
wouldest make ... from evil. The Hebrew is therefore strange, though
not indefensible. Perhaps some words have fallen out, and it may
originally have read somewhat as follows, that thou wouldest make
[room (merḥābh) for me, and wouldest redeem (phādīthā) me] from
evil.

that it be not to my sorrow] or so that no pain befell me.

11‒15 for Chelub (verse 11) = Caleb (see on ii. 9, 42).

Sons of Caleb.
 ¹¹And Chelub the brother of Shuhah begat
Mehir, which was the father of Eshton. ¹²And
Eshton begat Beth-rapha, and Paseah, and
Tehinnah the father of Ir-nahash ¹. These are
the men of Recah.
¹ Or, the city of Nahash.

12. These are the men of Recah] Recah is unknown. Perhaps the
true reading is that of the LXX. (B), the men of Rechab, i.e.
Rechabite families; compare ii. 55, note.

¹³And the sons of Kenaz; Othniel, and

Seraiah: and the sons of Othniel; Hathath.
13. Othniel] Eponym of a Kenizzite clan, closely connected with
the Calebites. Compare note on i. 36, and Judges i. 13 and iii. 9‒11.

¹⁴And Meonothai begat Ophrah: and Seraiah

begat Joab the father of Ge-harashim ¹; for
they were craftsmen.
¹ Or, the valley of craftsmen.

14. Meonothai] perhaps a son of Othniel.

Ge-harashim] or, as margin, the valley of craftsmen. It is

mentioned Nehemiah xi. 35 along with Lod (the Lydda of Acts ix. 32)
and therefore was probably near Lydda.

¹⁵And the sons of Caleb the son of

Jephunneh; Iru, Elah, and Naam: and the
 sons of Elah; and Kenaz.
15. Caleb the son of Jephunneh] Compare ii. 42, note.

the sons of Elah; and Kenaz] The sons of Elah and Kenaz seem
to be co-ordinated, as each represented a family descended from
Caleb; but perhaps the text is faulty.

¹⁶And the sons of Jehallelel; Ziph, and

Ziphah, Tiria, and Asarel.
16‒20. The connection of these names with Judah does not
appear. In accordance with the structure of this section (see note on
Carmi, verse 1) we might expect here to find “the sons of Hezron or
Perez”; and, since the relationship between Jehallelel (16) and Ezrah
(17) is not indicated, it has been suggested that we should insert in
verse 16 “And the sons of Perez and Jehallelel and Ezrah.” No
certainty can be felt in the matter.

Ziph] in south Judah, 1 Samuel xxiii. 15. Ziphah, a feminine form

of the same name.

¹⁷And the sons of Ezrah; Jether, and Mered,

and Epher, and Jalon: and she bare Miriam,
and Shammai, and Ishbah the father of
Eshtemoa.
17. and Jalon: and she bare Miriam] As the text stands she has
no antecedent. It has therefore been proposed to transfer from verse
18 the words And these are the sons of Bithiah the daughter of
Pharaoh, which Mered took, and put them after Jalon. Bithiah then
appears as the mother of Miriam, Shammai, and Ishbah, and the
difficulty of the absence of her sons’ names from verse 18
disappears. For father of Eshtemoa see ii. 24 note, and for
Eshtemoa see Joshua xxi. 14.
 ¹⁸And his wife the Jewess ¹ bare Jered the
father of Gedor, and Heber the father of Soco,
and Jekuthiel the father of Zanoah. And these
are the sons of Bithiah the daughter of
Pharaoh, which Mered took.
¹ Or, Hajehudijah.

18. his wife] the wife of Mered, if the transposition mentioned in

the last note be accepted.

his wife the Jewess] so called in contrast to his Egyptian wife.

Gedor] compare verse 4, where a different person is perhaps by

a different tradition called father of Gedor. Gedor is to be identified
with the ruins of Jedur on the road between Jerusalem and Hebron,
compare verse 39.

Soco ... Zanoah] The Soco (Joshua xv. 48) and Zanoah (Joshua
xv. 56) here mentioned were situated to the south-west of Hebron.
They are to be distinguished from a Soco near the valley of Elah
(Joshua xv. 35, 2 Chronicles xi. 7, xxviii. 18) and Zanoah near Beth-
shemesh (Joshua xv. 34).

these are the sons of Bithiah] See note on verse 17. A “daughter
of Pharaoh” is somewhat strange in such surroundings. For an
interesting emendation and interpretation, see Macalister, Palestine
Exploration Fund, Quarterly Statement, 1905, p. 252.

¹⁹And the sons of the wife of Hodiah, the sister

of Naham, were the father of Keilah the
Garmite, and Eshtemoa the Maacathite. ²⁰And
the sons of Shimon; Amnon, and Rinnah, Ben-
 hanan, and Tilon. And the sons of Ishi;
Zoheth, and Ben-zoheth.
19. Keilah] a town of the Shephelah (Joshua xv. 44), the scene of
one of David’s exploits (1 Samuel xxiii. 1‒5).

Eshtemoa the Maacathite] The epithet distinguishes this

Eshtemoa from that of verse 17. The Maacathite may mean the
descendant of Maacah (ii. 48), the concubine of Caleb the brother of
Jerahmeel.

21‒23. These verses purport to give some fragmentary

information of the descendants of Shelah. It must be owned that they
are most obscure, and much more difficult than they appear at first.
In the Palestine Exploration Fund Statement, 1905, pp. 243 ff., 328
ff., R. A. S. Macalister gives a highly ingenious reinterpretation of this
passage in the light of certain jar handles inscribed with names
similar to those mentioned here and in certain other passages of the
Chronicler’s genealogies; and conjectures that throughout the
chapter we have a (mutilated) genealogy of a family of craftsmen,
tracing descent from two individuals, a Jerahmeel and a Caleb. In a
text so obscure it is no objection that the theory involves several
textual emendations, and is too intricate for further treatment here. It
is rejected by Driver, Modern Research, p. 77.

²¹The sons of Shelah the son of Judah; Er

the father of Lecah, and Laadah the father of
Mareshah, and the families of the house of
them that wrought fine linen, of the house of
Ashbea;
21. Shelah] mentioned in ii. 3 as a son of Judah. As there is no
reference to him in iv. 1, perhaps these difficult verses are an
addition. For other references to his descendants, see ix. 5,
Nehemiah xi. 5.
 Mareshah] ii. 42; 2 Chronicles xi. 8; Joshua xv. 44 (mentioned
with Keilah). A town in the south of Judah.

the house of Ashbea] Nothing is known of such a family. Render

perhaps Beth-Ashbea, but the place is otherwise unknown.

²²and Jokim, and the men of Cozeba, and

Joash, and Saraph, who had dominion in
Moab, and Jashubi-lehem. And the records ¹
are ancient.
¹ Hebrew words.

22. and Joash, and Saraph, who, etc.] We find no other trace of
these two as rulers of Moab. The Targum fancifully identified them
with Mahlon and Chilion of Ruth i. 2, 4. For a conjecture as to the
cause of their presence in Moab, see Macalister, Palestine
Exploration Fund, Quarterly Statement, 1905, p. 340.

and Jashubi-lehem] render, with Vulgate, who returned to

Bethlehem, a translation which requires only an easy emendation of
the present Hebrew text.

²³These were the potters, and the inhabitants ¹

of Netaim and Gederah: there they dwelt with
the king for his work.
¹ Or, those that dwelt among plantations and hedges.

23. there they dwelt with the king for his work] In the days of the
kingdom the families were clients of the king and did his work;
compare 1 Kings vii. 46. The simplicity of this statement seems to
have been a stumbling-block to the early translators who
paraphrase; LXX., They were strong in his kingdom and dwelt there;
Targum, They made their dwelling there with the Shekinah of the
King of the World for the practice of the Law.

24‒27.
The Genealogy of Simeon.

²⁴The sons of Simeon; Nemuel ¹, and Jamin,

Jarib ², Zerah ³, Shaul: ²⁵Shallum his son,
Mibsam his son, Mishma his son. ²⁶And the
sons of Mishma; Hammuel his son, Zaccur his
son, Shimei his son. ²⁷And Shimei had sixteen
sons and six daughters; but his brethren had
not many children, neither did all their family
multiply, like to the children of Judah.
¹ In Genesis xlvi. 10, Exodus vi. 15, Jemuel.

² In Genesis xlvi. 10, Jachin. ³ Genesis xlvi. 10, Zohar.

24‒27. The sons of Simeon] With unimportant variations in the

names, the five sons of Simeon are mentioned also in Genesis xlvi.
10, Exodus vi. 15, and Numbers xxvi. 12, 13. A sixth son, Ohad, is
given by the list in Genesis. As the mother of one, Shaul, was a
Canaanitess (Genesis xlvi. 10) and Mibsam and Mishma are also
reckoned Ishmaelites (i. 29, 30), the tribe of Simeon contained
marked non-Israelite elements. This is the more natural by reason of
its location in the extreme south of Palestine.

27. six daughters] LXX. three daughters.

28‒33 (= Joshua xix. 2‒8).

The Territory of Simeon.
 ²⁸And they dwelt at Beer-sheba, and Moladah,
and Hazar-shual;
28. Beer-sheba] at the southern extremity of Palestine, as Dan
was at the northern (1 Samuel iii. 20).

²⁹and at Bilhah, and at Ezem, and at Tolad;

29. Tolad] In Joshua xix. 4 Eltolad.

³⁰and at Bethuel, and at Hormah, and at

Ziklag;
30. Bethuel] compare Genesis xxii. 22. In Joshua xix. 4 Bethul. In
1 Samuel xxx. 27 Bethel (not the famous Bethel near Jerusalem).

Hormah] Numbers xiv. 45, xxi. 3; Judges i. 17.

Ziklag] 1 Samuel xxvii. 6. The site is not certainly identified.

³¹and at Beth-marcaboth, and Hazar-susim,

and at Beth-biri, and at Shaaraim. These were
their cities unto the reign of David.
31. Beth-marcaboth ... Hazar-susim] perhaps royal chariot-cities,
1 Kings ix. 19. The names mean House of chariots and Court of
horses.

Shaaraim] 1 Samuel xvii. 52.

These were their cities unto the reign of David] either a reference
to David’s census; or else it is implied that these cities ceased to
belong to Simeon after David’s day. The clause breaks the
connection of verses 31, 32; and is perhaps a late gloss.
 ³²And their villages were Etam, and Ain,
Rimmon, and Tochen, and Ashan, five cities:
32. And their villages were Etam] more probably and their
villages (end of verse 31). Etam, etc. (continuing the list of cities as
in verse 31). By villages (Ḥăṣērīm) are meant small hamlets
dependent on larger towns and generally unwalled (Leviticus xxv.
31).

Ain, Rimmon] so also in the parallel passage, Joshua xix. 7; but

certainly only one place is meant, Ain-Rimmon (see the
commentaries on Joshua xv. 42 and xix. 7). The number of the cities
here ought therefore to be reckoned four, not five.

³³and all their villages that were round about

the same cities, unto Baal. These were their
habitations, and they have their genealogy.
33. unto Baal] Baal (“lord”) standing by itself is an unlikely name
for a town. Read Baalath-beer, Ramah of the South (“the mistress of
the well, the high place of the South”), as in Joshua xix. 8.

34‒43.
The Heroes of Simeon and their Exploits.

It seems probable that the exploits mentioned in these verses are

derived from some old, though obscure, tradition, and are therefore
of historical value for the movements of the tribe of Simeon.
Apparently we are to understand that in the time of Hezekiah a band
of the wild semi-nomadic tribe of Simeon made a successful raid
upon a fertile valley near Gerar (a correction for Gedor, see verse
39), a township on the Philistine border, taking by surprise its
peaceful population who were partly Canaanites, partly settlers who
had come originally from a place Maon (see verse 41). Gedor, the
reading of the Hebrew text, was a town just north of Hebron. A raid
by Simeonites on such a town is a startling, but not incredible,
episode in Hezekiah’s time; but see also note on verse 40. Finally
verses 42, 43 record a further assault by Simeonites, this time
against Edomite territory. For full discussion see Hogg in
Encyclopedia Biblia iv. 4527 ff.; also Macalister, Palestine
Exploration Fund Statement, 1905, 335 ff.

³⁴And Meshobab, and Jamlech, and Joshah

the son of Amaziah; ³⁵and Joel, and Jehu the
son of Joshibiah, the son of Seraiah, the son
of Asiel; ³⁶and Elioenai, and Jaakobah, and
Jeshohaiah, and Asaiah, and Adiel, and
Jesimiel, and Benaiah; ³⁷and Ziza the son of
Shiphi, the son of Allon, the son of Jedaiah,
the son of Shimri, the son of Shemaiah;
³⁸these mentioned by name were princes in
their families: and their fathers’ houses
increased greatly.
38. their fathers’ houses] See note on chapter v. 13.

³⁹And they went to the entering in of Gedor,

even unto the east side of the valley, to seek
pasture for their flocks.
39. the entering in of Gedor] Compare verse 18. The Gedor of
Joshua xv. 58 is identified with Jedur, Ijdur (north of Hebron,
Bädeker, Palestine⁵, p. 112). See Macalister, Palestine Exploration
Fund, Quarterly Statement, 1905, 335. LXX. has Gerar (compare
Genesis xx. 1; xxvi. 1), on the Philistine border.

⁴⁰And they found fat pasture and good, and

the land was wide, and quiet, and peaceable;
 for they that dwelt there aforetime were of
Ham.
40. they ... of Ham] i.e. Canaanites, who had long been settled in
the district (compare the security felt by the people of Laish, Judges
xviii. 27). Their presence would seem natural in Gerar on the
Philistine border but strange in Gedor near Hebron. If therefore the
reading Gedor be preferred above, there is something to be said for
the suggestion of Macalister (p. 335) that we should here read “of
Menahem” (a change of one letter in Hebrew), some unwarlike
Hebrew family, perhaps potters.

⁴¹And these written by name came in the days

of Hezekiah king of Judah, and smote their
tents, and the Meunim that were found there,
and destroyed ¹ them utterly, unto this day, and
dwelt in their stead: because there was
pasture there for their flocks. ⁴²And some of
them, even of the sons of Simeon, five
hundred men, went to mount Seir, having for
their captains Pelatiah, and Neariah, and
Rephaiah, and Uzziel, the sons of Ishi.
¹ Hebrew devoted them.

41. written by name] Apparently those mentioned in verses 34‒

37; but the names there are of a late character, and have perhaps
been artificially connected with the old tradition of the raiders in
verses 41 ff.

in the days of Hezekiah] The Hebrew is ambiguous, but the

clause should probably be connected with the verb “came,” not with
“written”: the raid, not the record, was made in the days of Hezekiah.
 and the Meunim] Here, and in 2 Chronicles xx. 1 (see note), xxvi.
7, the LXX. has Minaeans, an Arabian people who from the 8th or
9th century b.c. or perhaps much earlier exercised great authority in
South Arabia (see Encyclopedia Britannica¹¹ II. 264). The Meunim of
the present passage are to be connected with an Edomitic city or
tribe not far from Petra, south of the Dead Sea; or (so Macalister, p.
336) are simply the people of Maon, a township near Hebron in
Judah. 2 Chronicles xx. 1 (note) and xxvi. 7, Revised Version.

destroyed them utterly] or, as margin, devoted them (compare

Joshua vi. 18, 21, Revised Version). See note 2 Chronicles xx. 23.

⁴³And they smote the remnant of the

Amalekites that escaped, and dwelt there,
unto this day.
43. the remnant of the Amalekites] i.e. the descendants of those
who had escaped the attacks of Saul and David (1 Samuel xiv. 48,
xv. 3 ff.). They had apparently found refuge in some part of the
Edomite territory, for mount Seir is a synonym for the land of Edom.
 Chapter V.
1‒10.
The Genealogy of Reuben.

¹And the sons of Reuben the firstborn of

Israel, (for he was the firstborn; but,
forasmuch as he defiled his father’s couch, his
birthright was given unto the sons of Joseph
the son of Israel; and the genealogy is not to
be reckoned after the birthright.
1. he defiled] Genesis xxxv. 22, xlix. 4.

his birthright was given unto the sons of Joseph] Compare

Genesis xlviii. 5, “Ephraim and Manasseh, even as Reuben and
Simeon, shall be mine,” words of Jacob which might be interpreted
to mean that the rights of the firstborn were to pass from Reuben
and Simeon to Ephraim and Manasseh, the sons of Joseph.

the genealogy is not to be reckoned after the birthright] i.e.

though the birthright of Reuben has been given to Joseph, yet the
genealogy of Joseph is not to be given before that of Reuben. Verse
2 intimates that, though Joseph possessed the birthright, Judah had
a primacy as supplying the royal family. In this confusion of claims
the natural order is followed and the genealogy of Reuben is given
first.

²For Judah prevailed above his brethren, and

of him came the prince ¹; but the birthright was
 Joseph’s:)
¹ Or, leader.

2. Judah prevailed above his brethren] Compare Genesis xlix. 8

(Jacob to Judah) “Thy father’s children shall bow down before thee.”

the prince] The Hebrew word is nāgīd. The immediate reference

is to David (Saul being virtually ignored by the Chronicler).

³the sons of Reuben the firstborn of Israel;

Hanoch, and Pallu, Hezron, and Carmi.
3. the sons of Reuben] The same four names (with one
unimportant variation in spelling in Authorized Version) appear
Genesis xlvi. 9; Exodus vi. 14.

Hanoch] the correct spelling of the familiar name Enoch; compare

i. 3.

Hezron, and Carmi] also given as sons of Judah: for Hezron,

compare ii. 5 (note); for Carmi ii. 7, iv. 1.

⁴The sons of Joel; Shemaiah his son, Gog his

son, Shimei his son; ⁵Micah his son, Reaiah
his son, Baal his son;
4. sons of Joel] the connection, if any, with the preceding verse is
not known.

⁶Beerah his son, whom Tilgath-pilneser ² king

of Assyria carried away captive: he was prince
of the Reubenites. ⁷And his brethren by their
families, when the genealogy of their
 generations was reckoned; the chief, Jeiel,
and Zechariah,
² In 2 Kings xv. 29, xvi. 7, Tiglath-pileser.

6. Beerah ... captive] The deportation of Beerah is recorded only

here, but there is no reason why the tradition should not be
historical. The information is of very slight importance in itself, but
since there is absolutely no motive to make the Chronicler invent the
statement, this is precisely the kind of notice which implies that he
had some sources oral or traditional at his command outside the
canonical material (see Introduction. § 5).

Tilgath-pilneser] called Tiglath-pileser (2 Kings xv. 29), and no

doubt identical with Pul (see below, verse 26).

⁸and Bela the son of Azaz, the son of Shema,

the son of Joel, who dwelt in Aroer, even unto
Nebo and Baal-meon: ⁹and eastward he dwelt
even unto the entering in of the wilderness
from the river Euphrates: because their cattle
were multiplied in the land of Gilead.
8. Aroer] now ‘Ar‘āir, a heap of ruins near the wādy Mojib, i.e. the
Arnon (Joshua xii. 2). According to Joshua xiii. 9‒16 it passed from
Sihon king of the Amorites into the hands of the Reubenites. See
Bädeker, Palestine⁵, p. 153.

Nebo and Baal-meon] A line drawn due north from Aroer (see
last note) passes close first to Ma‘in (which may be Baal-meon) and
then to Jebel Nebā, which evidently preserves the name of Mount
Nebo.

Baal-meon] called more correctly Beth-baal-meon Joshua xiii. 17.

 ¹⁰And in the days of Saul they made war with
the Hagrites, who fell by their hand: and they
dwelt in their tents throughout all the land east
of Gilead.
10. in the days of Saul] Saul’s victory over the Ammonites (1
Samuel xi.) may have paved the way for the expansion of Israel east
of Jordan, but see also the note on verse 19.

the Hagrites] compare Psalms lxxxiii. 6 (Revised Version margin).

They were an Arab people. See further the note on verse 19.

the land east of Gilead] i.e. the land between Gilead and the
Euphrates (compare verse 9). On Gilead, see note, ii. 22.

11‒17.
The Genealogy and Settlements of Gad.

¹¹And the sons of Gad dwelt over against

them, in the land of Bashan unto Salecah:
11. Bashan] the wide district extending from the Jabbok on the
south to Hermon in the north and from the Sea of Galilee on the west
to the mountains of Hauran on the east (compare verse 23). Remark
that in Numbers xxxii. 33; Deuteronomy iii. 12; Joshua xiii. 25, Gad is
located in Gilead (south of Bashan) where the Chronicler has placed
Reuben.

Salecah] is probably represented at the present day by the ruins

of Salkhad due south of the Jebel Hauran and almost due east of
Boṣra.

¹²Joel the chief, and Shapham the second,

and Janai, and Shaphat in Bashan: ¹³and their
brethren of their fathers’ houses; Michael, and
 Meshullam, and Sheba, and Jorai, and Jacan,
and Zia, and Eber, seven. ¹⁴These were the
sons of Abihail the son of Huri, the son of
Jaroah, the son of Gilead, the son of Michael,
the son of Jeshishai, the son of Jahdo, the son
of Buz; ¹⁵Ahi the son of Abdiel, the son of
Guni, chief of their fathers’ houses.
12. and Janai, and Shaphat] LXX. “Janin the scribe”; Targum,
“Janai the judge.”

of their fathers’ houses] This rather awkward phrase means clans

or patriarchal families (πατριαί). Sometimes it is used to denote the
whole tribe, compare Numbers xvii. 17.

¹⁶And they dwelt in Gilead in Bashan, and in

her towns ¹, and in all the suburbs ² of Sharon,
as far as their borders ³.
¹ Hebrew daughters. ² Or, pasture lands

³ Hebrew goings forth.

16. in Gilead in Bashan] a contradictory phrase, since Gilead

means the southern and Bashan the northern part of Israel’s trans-
Jordanic territory. Perhaps in Bashan is here an addition made by
the Chronicler or a later hand to harmonise in Gilead (the territory
usually assigned to Gad—see note on verse 11 above) with verses
11 and 23. The emendation “in Gilead in Jabesh” has been
suggested.

Sharon] some place, unidentified, to the east of Jordan. LXX. (B)

has Sirion. (The well-known Sharon lay in the maritime plain
between Joppa and Caesarea.)
 ¹⁷All these were reckoned by genealogies in
the days of Jotham king of Judah, and in the
days of Jeroboam king of Israel.
17. reckoned by genealogies ... and in the days of Jeroboam]
“Reckoning by genealogy” is a phrase used only in the writings of the
Chronicler (Chronicles, Ezra, Nehemiah), but the practice probably
resembled what is called in other books “numbering the people”: see
the example in Nehemiah vii. 5‒65. The object however was
different and corresponded with the circumstances of the returned
exiles, who found themselves in the midst of a Gentile population in
Judea. The people were “reckoned by genealogy” not so much to
take a census of them, as to inquire into the purity of their Israelite
descent. The ancient term “numbering” would be a more suitable
description of a transaction belonging to the days of Jotham. For
Jotham see 2 Chronicles xxvii. and for Jeroboam 2 Kings xiv. 23‒29.
The last years of the reign of Jeroboam II probably synchronized
with part of the reign of Jotham.

18‒22.
The War of the Trans-Jordanic Tribes against Arabian
Tribes.

¹⁸The sons of Reuben, and the Gadites,

and the half tribe of Manasseh, of valiant men,
men able to bear buckler and sword, and to
shoot with bow, and skilful in war, were forty
and four thousand seven hundred and
threescore, that were able to go forth to war.
18. skilful in war] compare xii. 8, 21.

forty and four thousand] According to Joshua iv. 13 “about forty

thousand” from these tribes crossed the Jordan with Joshua.
 ¹⁹And they made war with the Hagrites, with
Jetur, and Naphish, and Nodab.
19. made war with the Hagrites...] Possibly this war described in
verses 18‒22 is only a midrashic variation of the war briefly noted in
verse 10; possibly we have traditions of separate conflicts. That
fighting against Arabian tribes took place in the time of Saul (verse
10) is quite probable, and perhaps there is here a definite
recollection of the fact. Yet conflicts on the eastern borders were no
doubt frequent, and the ancient fights may have been overlaid with
the memories and details of more recent struggles, and especially
the names assigned may be those of later foes. Though the Hagrites
are mentioned in inscriptions of Sennacherib, they seem to have
grown more prominent and powerful in later days (compare Psalms
lxxxiii. 7), and their name in the Chronicler’s time may have been
somewhat loosely and generally applied to the Arabian tribes near
Palestine.

Jetur, and Naphish, and Nodab] Other Bedouin tribes, Jetur,

Naphish, Kedemah are given as sons of Ishmael in i. 31.

²⁰And they were helped against them, and the

Hagrites were delivered into their hand, and all
that were with them: for they cried to God in
the battle, and he was intreated of them;
because they put their trust in him. ²¹And they
took away their cattle; of their camels fifty
thousand, and of sheep two hundred and fifty
thousand, and of asses two thousand, and of
men ¹ an hundred thousand.
¹ Hebrew souls of men.
 20. they were helped] with Divine assistance; compare xv. 26.

²²For there fell many slain, because the war

was of God. And they dwelt in their stead until
the captivity.
22. was of God] i.e. was prompted by God; compare 1 Samuel
xv. 2, 3.

23, 24.
The Half Tribe of Manasseh.

²³And the children of the half tribe of

Manasseh dwelt in the land: they increased
from Bashan unto Baal-hermon and Senir and
mount Hermon. ²⁴And these were the heads of
their fathers’ houses; even Epher, and Ishi,
and Eliel, and Azriel, and Jeremiah, and
Hodaviah, and Jahdiel, mighty men of valour,
famous men, heads of their fathers’ houses.
23. For the genealogy of Manasseh, see vii. 14 ff.

Baal-hermon] In Judges iii. 3 a mount Baal-hermon is mentioned.

Here probably a city is meant, possibly Banias, on the eastern slope
of Hermon.

Senir] an Amorite name for Mt Hermon or a peak of the range

(Deuteronomy iii. 9).

25, 26.
The Captivity of the Trans-Jordanic Tribes.