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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 glimmer of progress. The 5-year survival rates for all cancers from 2012 to 2018 have nearly doubled 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 tailoring treatment plans to each patient’s unique genetic makeup, medical conditions, and specifc cancer characteristics.
An often overlooked but crucial aspect of cancer care is anesthesia. Whether during diagnostic, 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 complications, and better patient outcomes.
Given the dynamic evolution of cancer treatment approaches, surgical techniques, and medical 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 anesthetic planning. It provides detailed insights into preoperative evaluation, intraoperative management, 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 comprehensive textbook and a quick reference guide. Its versatility makes it an indispensable companion 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
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
Carin A. Hagberg
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 dedicated oncological surgeons practice not only in major university/tertiary medical centers but also in community hospitals. With the signifcant 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 modern 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 complex and often involve diverse patient needs, which sometimes go beyond anesthesia practices per se. Furthermore, cancer management can be very dynamic, medical interventions as chemotherapy, 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 management 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 specifcally for cancer patients, covering preoperative assessment, intraoperative management, and postoperative 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 signifcantly 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
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 Mofftt Cancer Center. The collaborative spirit within our hospital has fostered an environment of innovation, research and exceptional care in the feld of anesthesia and surgery. 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
Stephania Paredes Padilla, Chelsea Skinner, Sydney L. Keller, Surendrasingh
Chhabada, Ryu Komatsu, and Jijun Xu
Sahana Rajasekhara, Kristine A. Donovan, and Lora M. A. Thompson
Part III Oncological Neurosurgery
Craniotomy for Meningioma
Mian Shen
Craniotomy for Glioma
Jerrad R. Businger and Brian J. Williams
125
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
Brianna Johnson, Nazar Dubchak, and Callum Dewar
Thoracic Spine Malignancy Surgery
Daniel Haines and Bryant M. England
157
161
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 .
James Miranda, S. Nini Malayaman, Joshua H. Atkins, and Henry Liu
Tracheostomy in Cancer Patients
Kate Williams and Madeleine Strohl
187
193
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
Tianyu Jiang and Jeffrey Huang
Muhammad F. Sarwar, Jason M. Wallen, and Henry Liu
for Tracheal Cancer
Melissa A. Burger Surgery for Mainstem Bronchial Cancer
Melissa A. Burger
Part VI Gastrointestinal Cancer
Rana K. Latif, Prejesh Philips, Zachary J. Senders, and Sean P. Clifford
Gastric Cancer Surgery
Amber F. Gallanis, Andrew J. Mannes, and Jeremy L. Davis
Michael Leclerc, Sean Stokes, Daniel Saenz Anaya, and Jeffrey Huang
Brendan L. Hagerty, Anthony Dakwar, and Kathleen J. Lee
Shadin Ghabra, Andrew M. Blakely, Andrew Mannes, and Ning Miao
System Cancer
Vicente Ramos-Santillan,
Sangroula, Kellen B. Choi, and Sean P. Clifford
Daniel Nethala and Andrew J. Mannes
Urothelial Cancer Surgery
Mark M. Hanna, Taylor Peak, Herney Andrés García-Perdomo, Gagan Prakash, Andrea Necchi, and Philippe E. Spiess
Testicular/Penile Cancer Surgery
Tianyu Jiang, Taylor Peak, Philippe Spiess, and Jeffrey Huang
Part VIII Endocrine and Metabolic Oncological Surgery
Surgery for Adrenal Tumors
Shadin Ghabra, Kenneth Luberice, Naris Nilubol, Andrew Mannes, and Xiaowei Lu
Surgery for Carcinoid Syndrome
Shadin Ghabra, Tracey Pu, Naris Nilubol, Andrew Mannes, and Ning Miao
Neuroendocrine/CREST Cancer Surgery
Andrew C. Baek, Kenny Wise, and Emanuela C. Peshel
Part IX Gynecological Cancer Surgery
349
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
Allyn O. Toles, Briana Rice, Jordyn Tumas, and Henry Liu
369
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
Jamie Hoffman, Rachel Voss, and Jeffrey Huang
Part XI Surgery for Breast Cancer and Cutaneous Cancer
Surgery for Breast Cancer
Cindy B. Yeoh, Kelly Elleson, Todd Schultz, Brielle Weinstein, Nicholas Panetta, and Marie Catherine Lee
Cutaneous Cancer Surgery
Matthew Benesch, Julia Faller, and Joseph Skitzki
Part XII Pediatric Cancer Surgery
Anesthesia for Pediatric Procedures Outside of the Operating Room
Ashley Bocanegra and Christopher Setiawan
Wilms Tumor and Hepatoblastoma
Alex Y. Chung
Pheochromocytoma
Neethu Chandran
Medulloblastoma
John Zhong
Pilocytic Astrocytoma
John Zhong
Part XIII Other Oncological Surgical Procedures
Intra-arterial Therapy for Primary and Secondary Liver Cancer . .
Hakob Kocharyan, Altan Ahmed, and Nainesh Parikh
Percutaneous Ablative Techniques for Liver and Kidney Cancer .
Altan F. Ahmed, Hakob Kocharyan, Andrei Lojec, Kenny Le, and Nainesh Parikh
Interventional Diagnostic and Therapeutic Procedures in Surgical Oncology
Kara M. Barnett, Victoria Brennan, Suken H. Shah, Elizabeth F. Rieth, and Marisa A. Kollmeier
Intensive Care of Cancer Patients
Aditi Balakrishna, Daniel Nahrwold, and Christopher Hughes
Palliative Care Surgery of Cancer Patients
Zhaosheng Jin, Vincent Bargnes, Alexandra Tsivitis, Jonathan B. Oster, and Jun Lin
Hospice Care and Palliative Care in Cancer Patients
Hui Liu, Lin Chen, Lauren Hollifeld, James E. Miranda, Brian Entler,
Nini Malayaman, and Henry Liu
Part I
Basic Science of Oncology
Huang Jefrey
Oncogenesis, What Is New?
Humberto Trejo Bittar
Nothing has revolutionized the feld 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 profle, intending to provide a more precise and targeted therapy than conventional 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 specifc molecular and immunohistochemical biomarkers used to guide targeted treatment strategies. To design targeted therapies, 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 important issues of oncogenesis and personalized cancer treatment, 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 environment 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, Mofftt Cancer Center, Tampa, FL, USA
Department of Oncologic Sciences, University of South Florida, Tampa, FL, USA
e-mail: Humberto.TrejoBittar@mofftt.org
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 supply, to evade the host immune system and to allow for invasion and metastasis, essentially becoming immortal [1].
Some signifcant 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 structure 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 amplifcations, meaning producing multiple copies of the same gene with overexpression and activation, can be seen with HER2 amplifcation 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 messenger RNA after transcription and facilitate its degradation. This process specifcally targets tumor suppressor genes, leading to downregulation of the corresponding proteins and potentially enabling uncontrolled cell proliferation, 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
(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 progression and the development of treatment resistance.
Changes in the integrity of the end of chromosomes, socalled telomeres that protect chromosomes from degradation, 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 transcription enzyme complex telomerase (some of its vital components are TERT (telomerase reverse transcriptase) and TERC (telomerase RNA component)). Shortening of telomeres 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 tumorigenesis, cancer cells must irreversibly prevent the shortening of telomeres, most often by constitutively activating telomerase (frequently by amplifcation and mutations in the promoter 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, particularly in lung adenocarcinomas, for which potentially targetable 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, proliferation, 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 strategies. 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 targeted 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 downregulating 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 medications 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 center 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 proliferation, 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-specifc 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, urothelial, 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 without concurrent chemoradiation (depending on the cancer stage and history of prior therapies) compared to chemoradiation alone [9].
It is impossible to discuss immunotherapy without incorporating T-cell transfer therapies. The main principle is removing the patient’s T-cells and, in the laboratory, selecting and conditioning them to better attack the patient’s cancer cells [10]. There are two main types of T-cells transfer therapies.
• Tumor-infltrating 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 suffcient or activated enough to destroy the tumor, and in the laboratory, select and expand those T-lymphocytes that best recognize the tumor cells (refer
H. T. Bittar
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 experimentally to treat other solid tumors like cervical squamous cell carcinoma, cholangiocarcinoma, and lung carcinomas [12].
• The other technique is CAR-T cell therapy, which uses the patient’s T-lymphocytes after being genetically modifed in the lab to express a chimeric antigen receptor (CAR) that is a modifed receptor specifcally designed to attach to the patient’s tumor cells. CAR-T cell therapy is FDA-approved to treat many advanced forms of leukemias and lymphomas [13]. While very promising, CAR-T cell therapy is not free of secondary effects and is notoriously 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 quickest way of testing is by immunohistochemistry. In this technique, biopsy tissue or cells collected by cytology techniques, like fne needle aspiration, are exposed to antibodies that recognize 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 specifc chemical reaction (so-called detection agent). The fnal product is a section of tumor stained (because of the presence of color) with the targeted protein, which we call immunostain. The
Sample procedure
• Surgical resection
• Surgical biopsy
• Cytology specimen (aspirate or fuid)
• Non-invasive procedures:
– Blood – Urine
immunostain is fnally 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 cancer, mismatch repair enzymes expression status in colon and endometrial cancer, and ALK expression in ALK translocated lung adenocarcinomas, among many others. It is important to know that there are certain preanalytical requirements 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 specimens [6, 14–16]. Following testing guidelines is extremely important to avoid misclassifying patients who could have potentially benefted 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 standard operating procedures, and their mandatory application 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 fixation), 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 proficiency testing, among many others [ 17 ].
Samples and tests
• Fresh tissue
• Formalin-fxed, paraffn-embedded (FFPE)
• Smears
• Liquid biopsies
• Diagnostic evaluation (histology or cytology)
• Protein expression:
– Immunohistochemistry
• Genetic tests:
– Conventional PCR – FISH
– Next-generation sequencing (NGS)
– RT-qPCR/gene expression panels/ RNA-sequencing
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
Table 1 Tissue sampling for personalized cancer treatment
The use of immunohistochemistry for the assessment of prognostic biomarkers has many benefts, including shorter turn-around time with results being available as early as within 24 h, their more cost-effective and less of a fnancial burden for patients and the health system (compared to the more expensive sequencing studies), and their easier to perform, 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 fuorescent in-situ hybridization studies (FISH) are extensively used to select patients for targeted therapy and biomarker testing. As mentioned, these techniques are used to fnd those specifc genetic changes in the cancer cell’s genome.
• The most effective technique for sequencing the tumor genome is next-generation sequencing (NGS). While the specifcs 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 individual 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 fnd those single nucleotide mutations or much more signifcant changes in individual genes or whole chromosomes. Tumor sequencing is one of the necessary steps for most personalized cancer treatments and often an indication for biopsy procedures, particularly in the recurrence setting.
It is important to adequately obtain these tissue samples. Recent recommendations have suggested at least 1 mm2 of formalin—fxed-paraffn-embedded tissue, needing as little as just fve 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 fne 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 fuorescent in-situ hybridization (FISH). In this technique, large gene/chromosome changes are identifed by hybridizing (binding of complementary DNA sequences) small fragments of DNA that are tagged with a fuorescent
T. Bittar
dye to the complementary and highly specifc DNA sequence of the target gene. Using fuorescent microscopy, the location of the probes on chromosomes can be visualized in the individual cancer cell using formalin fxed 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. Confrmation 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 alterations. The beneft of this is that RNA detection is more sensitive 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 socalled “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 benefts 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 participate as risk factors for many cancers. This is supported by the fact that there are regional differences in cancer types and
H.
incidences. For example, liver cancer is more prominent in East Asia, which is related to the presence of liver fukes; 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 chemical carcinogens, ultraviolet light, tobacco smoke, and microorganisms (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 dioxide, 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, pancreas, bladder, and liver, among others. The effect of cigarette smoking is mainly at the level of the DNA, where it induces distinct signature mutations (e.g., C>A transversions), indirect activation of DNA editing, and DNA methylation, helping in increasing the risk of acquiring cancer driver mutations. Moreover, the direct effect of smoking inducing epithelial damage (e.g., precursor lesions of cancer like squamous metaplasia), chronic infammation, and inhibiting apoptosis support the survival of cancer cells. Outside of carcinogenesis, cigarette smoke also induces immunosuppression, disbalances in proteases and antiproteases, 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, beryllium 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 afatoxins 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 chromosome morphology by breaking the DNA, the excessive formation of pyrimidine dimers overwhelming the DNA repair mechanisms, and point mutations.
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 survival, and interference with cell cycle regulation. Some notable examples include:
• HPV in oropharyngeal and cervical cancer via oncogenic proteins that inactivate RB and p53. The recent widespread 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 etiologic factors in hepatocellular carcinoma [33, 34]. There are many ways these viruses can be oncogenic, including the promotion of chronic infammation, dysregulation of cytotoxic CD8 T-cells, stimulation of hepatocytes proliferation, and increased reactive oxygen species, all leading to DNA damage. There are also direct effects of viral proteins (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 proliferation [35].
• Helicobacter pylori, best known for its role in the pathogenesis of gastric peptic ulcers, is also the frst bacteria to be recognized as having a role in oncogenesis. Like the hepatitis viruses, the bacteria, by creating a chronic infammatory state in the gastric mucosa, leading to atrophy 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 factors [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
(e.g., anti PD-L1) by inducing immune dysregulation and tolerance and directly increasing the risk of malignancy due to chronic infammation [38].
Additional attention is now paid to the tumor ecosystem and microenvironment, a feld that was until recently overlooked. The tumor microenvironment includes endothelial cells, multiple immune cells, fbroblasts, pericytes, the extracellular matrix, and many other organ-specifc cells. While this feld is quickly evolving, some recent discoveries include regulating immunotherapy effciency in different tumor microenvironments by excluding cytotoxic T-cells or inducing immunosuppression [39, 40].
In summary, tissue sampling and acquisition for performing 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 adequacy is an important consideration that can dramatically affect the need for further surgical procedures, which is undesirable. Nowadays, anatomic and molecular pathologists can perform many tests with very little tissue. Moreover, liquid biopsies are becoming more frequent, reducing the need for procedures with additional morbidity and mortality, many of which might be done in poor surgical candidates.
References
1. Kontomanolis EN, Koutras A, Syllaios A, Schizas D, Mastoraki A, Garmpis N, et al. Role of oncogenes and tumor-suppressor genes in carcinogenesis: a review. Anticancer Res. 2020;40(11):6009–15.
2. Du X, Zhang J, Wang J, Lin X, Ding F. Role of miRNA in lung cancer-potential biomarkers and therapies. Curr Pharm Des. 2018;23(39):5997–6010.
3. Holesova Z, Krasnicanova L, Saade R, Pos O, Budis J, Gazdarica J, et al. Telomere length changes in cancer: insights on carcinogenesis and potential for non-invasive diagnostic strategies. Genes (Basel). 2023;14(3):715.
4. Dearden S, Stevens J, Wu YL, Blowers D. Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013;24(9):2371–6.
5. Kohno T, Nakaoku T, Tsuta K, Tsuchihara K, Matsumoto S, Yoh K, et al. Beyond ALK-RET, ROS1 and other oncogene fusions in lung cancer. Transl Lung Cancer Res. 2015;4(2):156–64.
6. Lindeman NI, Cagle PT, Aisner DL, Arcila ME, Beasley MB, Bernicker EH, et al. Updated molecular testing guideline for the selection of lung cancer patients for treatment with targeted tyrosine kinase inhibitors: guideline from the College of American Pathologists, the International Association for the Study of Lung Cancer, and the Association for Molecular Pathology. Arch Pathol Lab Med. 2018;142(3):321–46.
7. Perez-Moreno P, Brambilla E, Thomas R, Soria JC. Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res. 2012;18(9):2443–51.
8. Pawelczyk K, Piotrowska A, Ciesielska U, Jablonska K, GletzelPlucinska N, Grzegrzolka J, et al. Role of PD-L1 expression in non-
small cell lung cancer and their prognostic signifcance according to clinicopathological factors and diagnostic markers. Int J Mol Sci. 2019;20(4):824.
9. Onoi K, Chihara Y, Uchino J, Shimamoto T, Morimoto Y, Iwasaku M, et al. Immune checkpoint inhibitors for lung cancer treatment: a review. J Clin Med. 2020;9(5):1362.
10. Diaz-Cano I, Paz-Ares L, Otano I. Adoptive tumor infltrating lymphocyte transfer as personalized immunotherapy. Int Rev Cell Mol Biol. 2022;370:163–92.
11. Rohaan MW, van den Berg JH, Kvistborg P, Haanen J. Adoptive transfer of tumor-infltrating lymphocytes in melanoma: a viable treatment option. J Immunother Cancer. 2018;6(1):102.
12. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, et al. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer. 2023;22(1):40.
13. Hoffmann MS, Hunter BD, Cobb PW, Varela JC, Munoz J. Overcoming barriers to referral for chimeric antigen receptor T-cell therapy in patients with relapsed/refractory diffuse large B-cell lymphoma. Transplant Cell Ther. 2023;29:440–8.
14. Naito T, Udagawa H, Sato J, Horinouchi H, Murakami S, Goto Y, et al. A minimum of 100 tumor cells in a single biopsy sample is required to assess programmed cell death ligand 1 expression in predicting patient response to Nivolumab treatment in nonsquamous non-small cell lung carcinoma. J Thorac Oncol. 2019;14(10):1818–27.
15. Faber E, Grosu H, Sabir S, San Lucas FA, Barkoh BA, Bassett RL, et al. Adequacy of small biopsy and cytology specimens for comprehensive genomic profling of patients with non-small-cell lung cancer to determine eligibility for immune checkpoint inhibitor and targeted therapy. J Clin Pathol. 2022;75(9):612–9.
16. Kalemkerian GP, Narula N, Kennedy EB, Biermann WA, Donington J, Leighl NB, et al. Molecular testing guideline for the selection of patients with lung cancer for treatment with targeted tyrosine kinase inhibitors: American Society of Clinical Oncology endorsement of the College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology clinical practice guideline update. J Clin Oncol. 2018;36(9):911–9.
17. Mahlow J, Goold EA, Jedrzkiewicz J, Gulbahce HE. What to expect from the new ASCO/CAP guideline recommendations for hormone receptor testing in breast cancer: a national reference laboratory experience. Appl Immunohistochem Mol Morphol. 2021;29(4):245–50.
18. Mino-Kenudson M. Immunohistochemistry for predictive biomarkers in non-small cell lung cancer. Transl Lung Cancer Res. 2017;6(5):570–87.
19. Cho M, Ahn S, Hong M, Bang H, Van Vrancken M, Kim S, et al. Tissue recommendations for precision cancer therapy using next generation sequencing: a comprehensive single cancer center’s experiences. Oncotarget. 2017;8(26):42478–86.
20. De Las Casas LE, Hicks DG. Pathologists at the leading edge of optimizing the tumor tissue journey for diagnostic accuracy and molecular testing. Am J Clin Pathol. 2021;155(6):781–92.
21. Rafael OC, Aziz M, Raftopoulos H, Vele OE, Xu W, Sugrue C. Molecular testing in lung cancer: fne-needle aspiration specimen adequacy and test prioritization prior to the CAP/IASLC/ AMP molecular testing guideline publication. Cancer Cytopathol. 2014;122(6):454–8.
22. Trejo Bittar HE, Luvison A, Miller C, Dacic S. A comparison of ALK gene rearrangement and ALK protein expression in primary lung carcinoma and matched metastasis. Histopathology. 2017;71(2):269–77.
23. Lin C, Shi X, Yang S, Zhao J, He Q, Jin Y, et al. Comparison of ALK detection by FISH, IHC and NGS to predict beneft from crizotinib in advanced non-small-cell lung cancer. Lung Cancer. 2019;131:62–8.
H. T. Bittar
24. Jennings LJ, Arcila ME, Corless C, Kamel-Reid S, Lubin IM, Pfeifer J, et al. Guidelines for validation of next-generation sequencing-based oncology panels: a joint consensus recommendation of the Association for Molecular Pathology and College of American pathologists. J Mol Diagn. 2017;19(3):341–65.
25. Barua S, Wang G, Mansukhani M, Hsiao S, Fernandes H. Key considerations for comprehensive validation of an RNA fusion NGS panel. Pract Lab Med. 2020;21:e00173.
26. Rodriguez J, Avila J, Rolfo C, Ruiz-Patino A, Russo A, Ricaurte L, et al. When tissue is an issue the liquid biopsy is nonissue: a review. Oncol Ther. 2021;9(1):89–110.
27. Wu X, Li J, Gassa A, Buchner D, Alakus H, Dong Q, et al. Circulating tumor DNA as an emerging liquid biopsy biomarker for early diagnosis and therapeutic monitoring in hepatocellular carcinoma. Int J Biol Sci. 2020;16(9):1551–62.
28. Wray AJD, Minaker LM. Is cancer prevention infuenced by the built environment? A multidisciplinary scoping review. Cancer. 2019;125(19):3299–311.
29. Yamaguchi NH. Smoking, immunity, and DNA damage. Transl Lung Cancer Res. 2019;8(Suppl 1):S3–6.
30. Shigeishi H. Association between human papillomavirus and oral cancer: a literature review. Int J Clin Oncol. 2023;28:982–9.
31. Kjaer SK, Dehlendorff C, Belmonte F, Baandrup L. Real-world effectiveness of human papillomavirus vaccination against cervical cancer. J Natl Cancer Inst. 2021;113(10):1329–35.
32. DeCoste RC, Carter MD, Ly TY, Gruchy JR, Nicolela AP, Pasternak S. Merkel cell carcinoma: an update. Hum Pathol. 2023;140:39–52.
33. Peneau C, Imbeaud S, La Bella T, Hirsch TZ, Caruso S, Calderaro J, et al. Hepatitis B virus integrations promote local and distant oncogenic driver alterations in hepatocellular carcinoma. Gut. 2022;71(3):616–26.
34. Khatun M, Ray R, Ray RB. Hepatitis C virus associated hepatocellular carcinoma. Adv Cancer Res. 2021;149:103–42.
35. Yu H, Robertson ES. Epstein-Barr virus history and pathogenesis. Viruses. 2023;15(3):714.
36. Lee YC, Chiang TH, Chou CK, Tu YK, Liao WC, Wu MS, et al. Association between helicobacter pylori eradication and gastric cancer incidence: a systematic review and meta-analysis. Gastroenterology. 2016;150(5):1113–24.e5.
37. Sukri A, Hanafah A, Mohamad Zin N, Kosai NR. Epidemiology and role of Helicobacter pylori virulence factors in gastric cancer carcinogenesis. APMIS. 2020;128(2):150–61.
38. Kennedy K, Khaddour K, Ramnath N, Weinberg F. The lung microbiome in carcinogenesis and immunotherapy treatment. Cancer J. 2023;29(2):61–9.
39. de Visser KE, Joyce JA. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell. 2023;41(3):374–403.
40. Kirchhammer N, Trefny MP, Auf der Maur P, Laubli H, Zippelius A. Combination cancer immunotherapies: emerging treatment strategies adapted to the tumor microenvironment. Sci Transl Med. 2022;14(670):eabo3605.
Epidemiology of Cancer
Hui-Yi Lin and Jong Y. Park
1 Introduction
Over 19 million new cancer cases [1–4] lead to almost ten million deaths globally in 2020 [1, 2]. The most common cancers worldwide are breast and lung cancers, while prostate cancer is the most common in the male population (Table 1) [2]. The responsible risk factors for cancer incidence vary by cancer type, geographical region, and population [5]. In addition, recent environmental changes by climate changes, industrialization, and lifestyle, such as diet patterns, are suggested as potential contributing factors for increasing cancer incidence [6]. Increased incidences in different regions or populations (such as race or gender) have been reported for specifc cancer types. The incidence rates in men are higher than those in women in all cancers except thyroid cancer. For example, the bladder (2.87), liver (2.35), and esophageal (2.36) cancers showed the highest men/women ratios [2, 3].
In terms of cancer mortality, cancer is the second leading cause of death, accounting for 9.9 million deaths worldwide [2]. The trend of cancer mortality in the last decade showed
Table 1 Number of new cancer cases in worldwide
2,261,419 12.5%
2,206,771 12.2%
1,931,590 10.7%
Prostate 1,414,259 7.8%
Stomach 1,089,103 6.0%
Liver 905,677 5.0%
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, Mofftt Cancer Center, Tampa, FL, USA
e-mail: Jong.park@mofftt.org
a 28% increase, three-fold higher than the trend of total mortality during the same period (9%) [2, 3]. Cancer mortality rates are varied in different parts of the world due to genetic and environmental factors, such as quality of patient care, availability of medical facilities, and socioeconomic status. These factors affect the application of screening, prevention strategies, and appropriate treatments for cancers. Recent advances in medical technologies can provide better screening tools and, more importantly, better patient care and treatments. These advances improved the prognosis and survival of most cancers. However, patient care and public health systems are considerably different among countries, and these differences exist within countries [2]. These systems, socioeconomic, genetic, and environmental factors can be explained different survival rates. Among environmental factors, diet patterns and physical activity are often associated with a risk for several cancers [7]. Typically, a healthy diet and being physically active can lower the risk and improve a survival for women with breast cancer. Several factors, such as the type of cancer, clinical stage at diagnosis, and medical care, are the main factors for cancer survival. In most cases, early diagnosis is a main key for better outcomes and survival. The incidence rank of cancer type does not necessarily overlap with the mortality rank due to different cancer survival rates. The numbers of deaths from lung, liver, pancreas, and stomach cancers are much higher than others. In men, lung, liver, stomach, esophageal, and prostate cancers are the deadliest. In women, breast, lung, and stomach cancers are the lethal ones. Colorectal cancer is the second leading cause of cancer mortality in both populations [8].
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 infuenced by environmental factors and patient care, especially cancer screening. The discussion of incidence trends for these common cancer types is listed below.
Prostate cancer cases surged in the 1990s due to the introduction of prostate-specifc antigen (PSA) screening tests. Most cases identifed through this screening test are asymptomatic and early-stage prostate cancer cases. Therefore, rising 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 disagreement 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 benefts 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 mortality, Fenton et al. (2018) reported that PSA screening might provide benefts in reducing prostate cancer-specifc mortality. 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 benefts 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 radiographic 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
with MRI for prostate cancer provides better sensitivity for detection, reduces the over-diagnosis, and over-treatment [16]. However, the main obstacles, such as consteffectiveness, 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 cancer 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 incidence 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 mammography screening. In addition, body mass index (BMI) changes, rising age for the frst 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 factors, such as lifestyle, rapid dietary transition, and obesity [20].
In addition to these four most common cancer types, cervical 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 signifcant impact on reducing cervical cancer incidence is the introduction of vaccines against carcinogenic 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 generation who received the HPV vaccine were declined signifcantly [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 signifcantly by different cancer types. According to the ACS data, the high-
Table 2 Lifetime risk for cancers by gender in the United States
a Modifed 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 mortality 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 survival 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 treatments [25]. For example, the 5-year survival rate for chronic myeloid leukemia has signifcantly 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 incidence rate can be the reclassifcation of other leukemia subtypes, raising awareness, improved diagnostic sensitivity, better-reporting systems for new cases, and other risk factors, 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
Table 3 Five-year relative cancer survival rates of the top 10 common cancersa
a Modifed 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 signifcantly improved the prognosis of chronic myeloid leukemia [27]. For melanoma metastasis, several new immune therapies, and BRAF and MEK inhibitors were introduced [29]. Immune checkpoint inhibitors induce cancer-cell killing by activated CD8-positive T cells. Immune checkpoint inhibitors, such as anti-CTLA4 and antiPD-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 benefts for lung cancer. Due to these treatments, 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 nonHispanic 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 reclassifcation of subtypes based on molecular biomarkers from next-generation sequencing was introduced for targeted therapies. Recent whole-exome sequencing studies have identifed 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].
Table 4 Number of deaths by top 5 deadliest cancers
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 presented 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, stomach, 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 signifcantly 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 mortality [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 effcient 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 infections. 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 identifed from genome-wide association studies and can be used to classify people’s risk of diseases based on their genetic profles. These scores may help to predict lifetime risk, plan for better screening, predict prognosis and, more importantly, support personalized medicine [38–40]. Although the prediction 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-
based cancer risk stratifcation [38–40]. Although accuracy of these PRS are different in different cancers, a high polygenic 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, pancreas, bladder, kidney, liver, stomach, pancreas, colorectal, and cervical cancers. Especially cigarette smoking is responsible for approximately 80–90% of lung cancer mortality [43]. Heavy smokers showed a 20 times higher risk for lung cancer-specifc death than never-smokers. Alcohol drinking also increases the risk for several cancers, such as oral, laryngeal, 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 fndings 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 Immunodefciency 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 immunodefciency virus increases the risk of developing some cancers such as Kaposi sarcoma [51]. Epstein-Barr virus is linked to Hodgkin lymphoma, Burkitt lymphoma, and nasopharyngeal cancers [46].
7 Summary
Based on the current trend of cancer epidemiological data, these malignant diseases will be a signifcant 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 example, liquid biopsy, a blood test that detects cancer cells or tumor DNA that are circulating in the blood, can be used for more effcient screening, early detection, and monitoring
treatment responses. Second, MRI can be used for diagnosis and monitoring progression. Third, genetic profle contributes to a risk classifcation for utilization in personalized medicine. Fourth, a new generation of treatments, especially immunotherapy, opened a promising path for cancer treatment by enhancing immune function against cancer cells. Finally, statistical learning and artifcial intelligence improved accuracy and effciency in pathology and imaging analysis for tumor tissues.
Despite recent advances in cancer treatment and screening, there are still several challenges to be overcome for better 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.
References
1. Ferlay J, Colombet M, Soerjomataram I, Parkin DM, Pineros M, Znaor A, et al. Cancer statistics for the year 2020: an overview. Int J Cancer. 2021;149:778–89.
2. Morgan E, Arnold M, Gini A, Lorenzoni V, Cabasag CJ, Laversanne M, et al. Global burden of colorectal cancer in 2020 and 2040: incidence and mortality estimates from GLOBOCAN. Gut. 2023;72(2):338–44.
3. Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, et al. Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 populationbased registries in 67 countries (CONCORD-2). Lancet. 2015;385(9972):977–1010.
4. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–49.
5. Feola S, Chiaro J, Martins B, Russo S, Fusciello M, Ylosmaki E, et al. A novel immunopeptidomic-based pipeline for the generation of personalized oncolytic cancer vaccines. Elife. 2022;11:e71156.
6. Eala MAB, Robredo JPG, Dee EC, Lin V, Lagmay A. Climate crisis and cancer: perspectives from the hardest hit. Lancet Oncol. 2022;23(3):e92.
7. Byrne S, Boyle T, Ahmed M, Lee SH, Benyamin B, Hypponen E. Lifestyle, genetic risk and incidence of cancer: a prospective cohort study of 13 cancer types. Int J Epidemiol. 2023;52:817–26.
8. Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73(1):17–48.
9. Potosky AL, Miller BA, Albertsen PC, Kramer BS. The role of increasing detection in the rising incidence of prostate cancer. JAMA. 1995;273(7):548–52.
10. Jemal A, Fedewa SA, Ma J, Siegel R, Lin CC, Brawley O, et al. Prostate cancer incidence and PSA testing patterns in relation to USPSTF screening recommendations. JAMA. 2015;314(19):2054–61.
11. Moyer VA, U.S. Preventive Services Task Force. Screening for prostate cancer: U.S. preventive services task force recommendation statement. Ann Intern Med. 2012;157(2):120–34.
12. Fenton JJ, Weyrich MS, Durbin S, Liu Y, Bang H, Melnikow J. Prostate-specifc antigen-based screening for prostate cancer: evidence report and systematic review for the US preventive services task force. JAMA. 2018;319(18):1914–31.
13. U.S. Preventive Services Task Force, Grossman DC, Curry SJ, Owens DK, Bibbins-Domingo K, Caughey AB, et al. Screening for prostate cancer: US preventive services task force recommendation statement. JAMA. 2018;319(18):1901–13.
14. Nordstrom T, Discacciati A, Bergman M, Clements M, Aly M, Annerstedt M, et al. Prostate cancer screening using a combination of risk-prediction, MRI, and targeted prostate biopsies (STHLM3MRI): a prospective, population-based, randomised, open-label, non-inferiority trial. Lancet Oncol. 2021;22(9):1240–9.
15. Mottet N, van den Bergh RCN, Briers E, Van den Broeck T, Cumberbatch MG, De Santis M, et al. EAU-EANM-ESTROESUR-SIOG guidelines on prostate cancer-2020 update. Part 1: screening, diagnosis, and local treatment with curative intent. Eur Urol. 2021;79(2):243–62.
16. Kasivisvanathan V, Rannikko AS, Borghi M, Panebianco V, Mynderse LA, Vaarala MH, et al. MRI-targeted or standard biopsy for prostate-cancer diagnosis. N Engl J Med. 2018;378(19):1767–77.
17. Jemal A, Ma J, Rosenberg PS, Siegel R, Anderson WF. Increasing lung cancer death rates among young women in southern and midwestern states. J Clin Oncol. 2012;30(22):2739–44.
18. Jha P. Avoidable global cancer deaths and total deaths from smoking. Nat Rev Cancer. 2009;9(9):655–64.
19. Giaquinto AN, Sung H, Miller KD, Kramer JL, Newman LA, Minihan A, et al. Breast cancer statistics, 2022. CA Cancer J Clin. 2022;72(6):524–41.
20. Siegel RL, Torre LA, Soerjomataram I, Hayes RB, Bray F, Weber TK, et al. Global patterns and trends in colorectal cancer incidence in young adults. Gut. 2019;68(12):2179–85.
21. Miller KD, Ortiz AP, Pinheiro PS, Bandi P, Minihan A, Fuchs HE, et al. Cancer statistics for the US Hispanic/Latino population, 2021. CA Cancer J Clin. 2021;71(6):466–87.
22. Ortiz AP, Ortiz-Ortiz KJ, Colon-Lopez V, Tortolero-Luna G, Torres-Cintron CR, Wu CF, et al. Incidence of cervical cancer in Puerto Rico, 2001-2017. JAMA Oncol. 2021;7(3):456–8.
23. de Martel C, Plummer M, Vignat J, Franceschi S. Worldwide burden of cancer attributable to HPV by site, country and HPV type. Int J Cancer. 2017;141(4):664–70.
24. Mix JM, Van Dyne EA, Saraiya M, Hallowell BD, Thomas CC. Assessing impact of HPV vaccination on cervical cancer incidence among women aged 15-29 years in the United States, 1999-2017: an ecologic study. Cancer Epidemiol Biomark Prev. 2021;30(1):30–7.
25. Croswell JM, Ransohoff DF, Kramer BS. Principles of cancer screening: lessons from history and study design issues. Semin Oncol. 2010;37(3):202–15.
26. Sasaki K, Strom SS, O’Brien S, Jabbour E, Ravandi F, Konopleva M, et al. Relative survival in patients with chronic-phase chronic myeloid leukaemia in the tyrosine-kinase inhibitor era: analysis of patient data from six prospective clinical trials. Lancet Haematol. 2015;2(5):e186–93.
27. Yang X, Chen H, Man J, Zhang T, Yin X, He Q, et al. Secular trends in the incidence and survival of all leukemia types in the United States from 1975 to 2017. J Cancer. 2021;12(8):2326–35.
28. Bailey C, Richardson LC, Allemani C, Bonaventure A, Harewood R, Moore AR, et al. Adult leukemia survival trends in the United States by subtype: a population-based registry study of 370,994 patients diagnosed during 1995-2009. Cancer. 2018;124(19):3856–67.
29. Carlino MS, Larkin J, Long GV. Immune checkpoint inhibitors in melanoma. Lancet. 2021;398(10304):1002–14.
30. Howlader N, Forjaz G, Mooradian MJ, Meza R, Kong CY, Cronin KA, et al. The effect of advances in lung-cancer treatment on population mortality. N Engl J Med. 2020;383(7):640–9.
31. McConechy MK, Talhouk A, Leung S, Chiu D, Yang W, Senz J, et al. Endometrial carcinomas with POLE exonuclease domain mutations have a favorable prognosis. Clin Cancer Res. 2016;22(12):2865–73.
32. Jemal A, Ward EM, Johnson CJ, Cronin KA, Ma J, Ryerson B, et al. Annual report to the nation on the status of cancer, 1975-2014, featuring survival. J Natl Cancer Inst. 2017;109(9):djx030.
33. Clarke MA, Devesa SS, Hammer A, Wentzensen N. Racial and ethnic differences in hysterectomy-corrected uterine corpus cancer mortality by stage and histologic subtype. JAMA Oncol. 2022;8(6):895–903.
34. Ding J, Bashashati A, Roth A, Oloumi A, Tse K, Zeng T, et al. Feature-based classifers for somatic mutation detection in tumournormal paired sequencing data. Bioinformatics. 2012;28(2):167–75.
35. Black JD, English DP, Roque DM, Santin AD. Targeted therapy in uterine serous carcinoma: an aggressive variant of endometrial cancer. Womens Health (Lond). 2014;10(1):45–57.
36. de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, Nackaerts K, Heuvelmans MA, et al. Reduced lung-cancer mortality with volume CT screening in a randomized trial. N Engl J Med. 2020;382(6):503–13.
37. Mucci LA, Hjelmborg JB, Harris JR, Czene K, Havelick DJ, Scheike T, et al. Familial risk and heritability of cancer among twins in Nordic countries. JAMA. 2016;315(1):68–76.
38. Dai J, Lv J, Zhu M, Wang Y, Qin N, Ma H, et al. Identifcation of risk loci and a polygenic risk score for lung cancer: a large-scale prospective cohort study in Chinese populations. Lancet Respir Med. 2019;7(10):881–91.
39. Thomas M, Sakoda LC, Hoffmeister M, Rosenthal EA, Lee JK, van Duijnhoven FJB, et al. Genome-wide modeling of polygenic risk score in colorectal cancer risk. Am J Hum Genet. 2020;107(3):432–44.
40. Oh JJ, Hong SK. Polygenic risk score in prostate cancer. Curr Opin Urol. 2022;32(5):466–71.
41. Eeles RA, Kote-Jarai Z, Giles GG, Olama AA, Guy M, Jugurnauth SK, et al. Multiple newly identifed loci associated with prostate cancer susceptibility. Nat Genet. 2008;40(3):316–21.
42. Schumacher FR, Al Olama AA, Berndt SI, Benlloch S, Ahmed M, Saunders EJ, et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat Genet. 2018;50(7):928–36.
43. Morabia A, Wynder EL. Cigarette smoking and lung cancer cell types. Cancer. 1991;68(9):2074–8.
44. Yang J, Wei H, Zhou Y, Szeto CH, Li C, Lin Y, et al. High-fat diet promotes colorectal tumorigenesis through modulating gut microbiota and metabolites. Gastroenterology. 2022;162(1):135–49 e2.
45. Dunneram Y, Greenwood DC, Cade JE. Diet, menopause and the risk of ovarian, endometrial and breast cancer. Proc Nutr Soc. 2019;78(3):438–48.
46. Gomez K, Schiavoni G, Nam Y, Reynier JB, Khamnei C, Aitken M, et al. Genomic landscape of virus-associated cancers. medRxiv. 2023.
47. Eun BW, Bahar E, Xavier S, Kim H, Borys D. Post-marketing surveillance study of the safety of the HPV-16/18 vaccine in Korea (2017-2021). Hum Vaccin Immunother. 2023;19(1):2184756.
48. Min Y, Wei X, Xia X, Wei Z, Li R, Jin J, et al. Hepatitis B virus infection: an insight into the clinical connection and molecular interaction between hepatitis B virus and host extrahepatic cancer risk. Front Immunol. 2023;14:1141956.
49. Fraile-Lopez M, Alvarez-Navascues C, Gonzalez-Dieguez ML, Cadahia V, Chiminazzo V, Castano A, et al. Predictive models for hepatocellular carcinoma development after sustained virological response in advanced hepatitis C. Gastroenterol Hepatol. 2023;46:754–63.
50. Liao O, Ye G, Du Q, Ye J. Gastric microbiota in gastric cancer and precancerous stages: mechanisms of carcinogenesis and clinical value. Helicobacter. 2023;28:e12964.
51. Mendoza Mori LM, Valenzuela Medina JB, Gotuzzo Herencia JE, Bravo Puccio FG, Mejia Cordero FA, Mohanna Barrenechea S, et al. Kaposi’s sarcoma in people living with HIV/aids in a public referral hospital in Peru. Rev Peru Med Exp Salud Publica. 2022;39(3):352–6.
H.-Y.
Immunemodulation and Cancer
Jinhong Liu
and Jefrey Huang
1 Introduction
The immune system serves as the fundamental defense mechanism of the human body, playing a crucial role in preventing tumorigenesis and managing the pathological progression 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, eventually 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 specifc organs in a context-specifc manner, where they must come into close proximity with other cells to exchange information and function appropriately. These interactions give rise to diverse immune responses in different situations. In cancer, the intra-organ movement or infltration of active immune cells into the tumor tissue is a decisive factor that determines immune outcome [1, 2]. Over the past decade, signifcant 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 understanding the mechanisms of immune modulation and effectively 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 activation of cytotoxic T lymphocytes (CTLs), which specifcally target tumor cells through tumor-specifc antigens [3].
J. Liu (*) · J. Huang
Anesthesiology
Tampa, FL, USA
Department, Mofftt Cancer Center,
e-mail: Jinhong.Liu@Mofftt.org
In vivo, tumor antigens are generated endogenously as cytosolic 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-specifc 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 individual 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 specifc CTLs, differentiation into effector cells, and the generation of memory cells. The interaction between the T cell receptor (TCR) and MHCassociated peptides on APCs (signal 1) determines the quality of T cell activation, which is further infuenced by the presence, 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 infuenced by these factors. As a consequence of interactions and recognition of tumor antigen presented by APCs through T cell antigen receptor, it initiates and activates a series of sequential process that lead to the generation of both antigen specifc effector and memory CTLs. These cytotoxic CD8+ T lymphocytes provide long-term protection against pathogens and carry out immune surveillance to eliminate cancer cells, therefore, APCs are the most effcient 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].
Dendritic cells (DCs) are vital in activating naïve CD4+ T cells and are classifed 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 common 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 infammatory cytokines, to effectively fulfll 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 cytokines, 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-specifc, 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 fuorescent 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 signifcant 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 evidenced by both animal models and human cancer patients. In solid tumors, antigen uptake and presentation are mainly carried out by monocytes and DCs. Although monocytes are the principal phagocytic cells in tumors, they are unable to activate T cells in some cases and do not migrate to lymph nodes [5]. Instead, monocytes often hinder T-cell responses against
tumors through various mechanisms and can impede the effcacy of immunotherapy, chemotherapy, and irradiation. In contrast, DCs thus have a unique feature and potential to process and transfer tumor antigens to the draining lymph nodes leading to the activation of T-cell, a crucial step that is absolutely 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 antitumor T cell response and indicate that modulating the biological 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 governed 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 differentiate 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], underscoring 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 effcacy of immunotherapy. 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 microenvironment. Interestingly, cDCs have also been shown to interact
with Natural Killer (NK) cells, which play a crucial role in immune surveillance against cancer. Activated NK cells can recruit cDCs to infltrate 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 signifcantly 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 provide clinical approaches to improve immune responses in cases where targeting T cells alone is not effective. Over the past two decades, a signifcant advancement in DC activation has been the use of exogenous activation signals through Toll-like receptors (TLRs). TLRs function as pathogen pattern recognition molecules that detect and initiate innate and adaptive immune responses against pathogens and malignant cells, acting as a frst line of defense against infectious diseases and cancer. Recognition of ligands by TLRs triggers the secretion of proinfammatory cytokines and promotes DC maturation programs for the induction of adaptive immune responses. To date, more than 12 TLRs have been identifed in both humans and animals. TLRs belong to type-1 integral membrane glycoproteins and are characterized by extracellular domains containing a variable number of leucine-rich repeat motifs and cytoplasmic Toll/interleukin (IL-1R homology domain). TLRs can recognize a highly conserved sets of molecular structures, so-called pathogenassociated molecular patterns (PAMP), and/or damage associated 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 producing proinfammatory cytokines, chemokines, type I interferons, and antimicrobial peptides 254,281. Therefore, TLRs
are critical in bridging innate and adaptive immune responses; specifcally, TLRs play a critical role in stimulating DC maturation, antigen uptake and presentation and the differentiation 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, process, and present self-tumor antigens to T cells and other immune cells, ultimately leading to a potent and cancerspecifc immune response capable of killing tumors. However, it is widely acknowledged within the feld that tumor antigens alone are not strong enough to stimulate APCs to induce clinically signifcant anti-tumor immune responses, unless there is the involvement of professional DCs to some extent [18]. As professional APCs, DCs express a signifcant 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 signals from tumor cells—which may also induce immune tolerance 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 therapeutic strategies aimed at enhancing DC function to bolster the antitumor response [16, 20].
4.3 Antitumor Efect of TLR3
Among all the TLRs, TLR3 has been broadly studied for more than three decades. TLR3 is mainly expressed in neuroectodermal and myeloid cells (including DCs). TLR3 of myeloid cells favorably acts as a receptor for the surface recognition 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 effcacy of TLR3 agonists. The TLR3 agonists, including RGC100, ARNAX, and polyinosinic: polycytidylic acid (poly-IC), are currently being extensively studied. These agonists are used as adjuvants for
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have been previously done, the shorter length is no disadvantage. For fine work the cap-iron of this plane may be set as close as one thirty-second of an inch to the cutting edge of the plane-iron. The plane-iron should be set correspondingly shallow.
F . 51.
23. The Jointer.
—This plane is used for straightening long and uneven stock. It is most commonly used for preparing the parts for glue joints. Fig. 52.
Its advantage lies in its length, often two feet or more, which prevents the blade from cutting in the hollow places until all of the high places have been leveled. A short plane would simply follow the irregularities, smoothing but not straightening. The plane-iron of the jointer should be ground straight across.
Fore-planes are short jointers, next in size to the jack-planes, and are used for such work as straightening the edges of doors, windows, etc., when fitting them.
24. The Block-Plane.
—The block-plane is about six inches long.
Fig. 53. It is made especially for cutting across the end of the wood. In addition to the adjusting nut, which is in a different position but serves the same purpose as in the jackplane, and the lateral adjusting lever, there is a lever for adjusting the size of the opening at the mouth of this plane.
53.
The block-plane differs from the planes just described in that it has no cap-iron, none being needed in end-planing. The plane iron is put in place with the bevel side up instead of down as in the other planes.
The block-plane is not a necessity where a vise can be used for holding the piece to be planed. A smooth-plane or jack-plane may, if the plane-iron be set very shallow, do the work just as well. The block-plane is used mostly by carpenters in fitting together pieces which cannot be taken to the vise. Here the smallness of the plane and the fact that but one hand is needed to operate it are of very great advantage.
25. The Wooden Plane.
—The old-fashioned wooden planes are still preferred by some woodworkers. The iron bodied planes have displaced them because of the ease with which they can be adjusted rather than because they produce any better results. Wooden planes are subject to warpage and as the bottoms become uneven thru wear, it is necessary to straighten and level them occasionally. The plane-iron and cap-iron of the wooden plane are fastened in the throat of the plane by means of a wooden wedge. This wedge is driven in place with the hammer. Fig. 54 shows the manner of holding the plane while setting the irons and wedge. If the plane-iron does not project enough, the iron is lightly tapped as indicated. If too much projects, the stock is tapped as in Fig. 55. This figure also illustrates the manner of removing the
wedge, two or three blows being sufficient to release it so that it can be withdrawn with the hand. In setting the plane-iron, should either corner project more than the other, tap the side of the iron.
F . 54.
F . 55.
F . 56.
Fig. 56 shows the manner of holding the smooth plane in releasing the wedge, as well as when the cutting edge projects too much. —A true surface is one which is straight as to its length and width and which has its surface at the four corners in the same plane. Select for this first surface, which we shall call the face side, the better of the two broad surfaces. Knots, sap, wind, shakes, etc., should there be any, must be taken into account when passing judgment. Often the two sides are so nearly alike that there is little reason for choice.
26. Planing First Surface True.
Where several parts are to be fitted together, the faces are turned in; in this case, the best surfaces should not be selected for faces. Chapter VII, section 75.
Before beginning to plane hold the piece toward the light, close one eye and sight as in Fig. 57. If the surface is not warped or in wind, the back arris ab will appear directly behind the front arris cd. Also sight the arrises for straightness, Fig. 58, being careful to hold so as to get the full benefit of the light. Again, test from arris to arris, Fig. 59. The try-square may be used either side up, but the beam must not be held against either edge. It is not for squareness but for straightness that this test is made.
Notice the direction of the grain and place the piece so as not to plane against it. In Fig. 60 plane from A toward B or the surface will
F . 57.
F . 58.
F . 59.
be roughened instead of smoothed. When the stock is rough, the direction of the grain cannot be told readily. A few strokes of the plane will give the desired information. As most stock is to be planed to size, it is well to test with the rule before beginning to plane, so as to know just how much margin has been allowed. If you find you cannot true this first surface without getting the piece within onesixteenth of an inch of the thickness required, ask your instructor to show you where the trouble lies.
F 60
These tests ought to give the worker a pretty fair idea of what and how much he dare plane, so that when he begins he may work intelligently. As few shavings as possible, and those thin ones, with the proper result attained, show forethought and care. Nowhere can good, common sense be used to better advantage than in learning to plane.
When planes are not in use they should be laid on their sides, or otherwise placed so that the cutting edge shall not touch anything. For roughing off and straightening broad surfaces, the jack-plane should be used, and this followed by the smooth-plane. When using the plane, stand with the right side to the bench; avoid a stooping position. Fig. 61. The plane should rest flat upon the wood from start to finish. Press heavily upon the knob in starting and upon the handle in finishing the stroke. Unless care is taken to hold the plane level in starting and stopping, the result will be as indicated in Fig. 62 A.
F . 61.
F . 62.
Take as long a shaving as the nature of the work will permit. In planing long boards or where it is desired to lower one particular place only, it becomes necessary to stop the stroke before the end of the board is reached. That no mark shall show at the place where the plane-iron is lifted, it is necessary to feather the shaving. This is done by holding the toe of the plane upon the board and raising the heel as the stroke proceeds, beginning just before the stopping point is reached. If the cut is to commence other than at the end of the piece, lower the heel after having started the forward stroke with the toe upon the board.
It is customary to raise the heel of the plane slightly on the backward stroke that the edge may not be dulled.
When the surface has been planed so that it fulfills the tests by sighting described above, an additional test may be given it. Should the board be of any considerable width—three or more inches—the following test will prove sufficient: Place a straight-edge lengthwise, then crosswise the surface planed and along each of its two diagonals. If no light can be seen between the piece and the straight-
edge in any of these four tests, the surface may be considered level or true. Fig. 63.
F . 63.
F . 64.
A second test, one which will answer for narrow as well as broad surfaces, differs from the above only in the manner of determining whether the surface is in wind or not. Two sticks, called winding sticks, are prepared by planing their two opposite edges straight and parallel to each other. These sticks are placed across the surface to be tested, close to the ends, and a sight taken over their top edges. If the surface is in wind the edges cannot be made to sight so that one edge will appear directly back of the other, Fig. 64; one end of the back stick will appear high, at the same time the other one will appear low with reference to the edge of the fore stick. The back corner is high only as compared with the fore corner. The wind may be taken out of the surface just as well by planing the fore corner which is diagonally opposite. Usually, equal amounts should be planed from the surface at each of these corners. If, however, the board is thicker at one corner than the other, it is best to take the whole amount at the thicker corner.
27. Face Side, Face Edge.
—The first surface and the first edge planed serve a special purpose and are given special names. The first surface is called the face side, and the first edge, the face edge; both may be referred to as the faces. These faces are sometimes known by other names such as working face and joint edge, marked face and marked edge, etc., but their meaning is the same.
That these faces may be known, they are marked with pencil with what are called face marks. There are various ways of making face marks. Unless otherwise instructed, the marks may be made as in Fig. 65; for the face side, a light slanting line about one inch long extending to the edge which is to become the face edge; for the face edge, two light lines across the edge. The marks on both face side and face edge should be placed about the middle of the piece and close together.
These two surfaces are the only ones marked. From one or the other of these, measurements and tests are made. In squaring up stock, for illustration (which means to reduce a piece of rough lumber to definite length, width and thickness so that it shall have smooth, flat sides at right angles to each other) the gage block is held against one or the other of these faces only, and the beam of the try-square when testing for squareness is placed against one or the other of these faces only.
28. Planing First Edge Square with Face Side.
—Make a preliminary test with the eye before beginning to plane. Sight the arrises of the edge to see where it needs straightening. Examine the end to see which arris is high. Also look to see which way the grain runs. Avoid imperfections in the wood as far as possible in choosing this edge.
It is the part of wisdom to examine the plane-iron to see that the surface planing has not caused the cutting edge to project unevenly. A plane, set out of true, is likely to cause hours of extra work; it defeats every effort that may be made to hold the plane properly.
Strive to get shavings the full length of the piece, especially on the last few strokes.
The smooth-plane is little if ever used for edge planing on account of its short length. In using the jack-plane in which the edge is slightly rounded, thus making a shaving thicker in the middle than at the edges, avoid tilting the plane to make it cut on one side rather than the other. Move the whole plane over to the high side so that the middle of the cutting edge shall be directly over the high place. Keep the sides of the plane parallel with the edge so as to get the full benefit of the length of the plane.
The two tests which this first edge must fulfill are: First, that it shall be straight; second, that it shall be square with the face side. Fig. 6, Chapter I, shows the method of testing for squareness. As in planing the face side, try to accomplish the desired result with as few shavings as possible.
The caution about planing the first surface, where a definite size is to be attained, applies equally to planing the first edge. When the edge has been properly trued, put on the face marks suitable for the face edge.
29. Finishing the Second Edge.
—A line gaged from the face edge indicates the proper stopping place in planing the second edge. This line, if lightly made, should be half planed off.
As the line is parallel with the face edge, no straight edge test is necessary. The try-square test for squareness, the beam being held against the face side, must be frequently applied when approaching the gage line.
Where the amount of waste stock to be planed is about an eighth of an inch, the plane-iron may be set a little deeper than average. When near the line, however, it must be set quite shallow. If the waste stock measures more than three sixteenths of an inch, the ripsaw should be used, sawing parallel to the gage line and about oneeighth of an inch away from it.
30. Finishing the Second Side.
—Lines gaged from the face side on the two edges show the amount to be planed.
The test for this side is made by placing the straight-edge across the piece from arris to arris as the planing proceeds, to see that the middle shall be neither high nor low when the gage lines have been reached. No other test is necessary; a little thought will show the reason.
Never attempt to work without lines. If by mistake you plane out your line, take the piece to your instructor at once, unless you have been otherwise directed, that he may tell you what to do.
31. Planing the First End Square.
—See that the cutting edge is very sharp and that the planeiron is set perfectly true and very shallow. Examine one of the ends of the piece by placing the beam of the try-square against the face side then against face edge to locate the high places. Fig. 6.
F . 66.
In free end planing, the cutting edge must not be allowed to reach the farther corner or the corner will be broken off. Plane only part way across the end, stopping the cutting edge half an inch or more from the far edge. Fig. 66. After a few strokes in this direction, reverse the position and plane in the opposite direction, stopping the cutting edge half an inch or more of the first edge.
Keep testing the end as the planing proceeds that you may know what you are doing. Remove no more material than is necessary to square the end, and lay on the rule occasionally that you may not endanger the correct length in your efforts to square this end. —Knife lines squared entirely around the piece, at a given
32. Finishing the Second End.
distance from the end first squared, limit the amount of the planing that can be done on this end. If the waste stock is over one-eighth of an inch the saw should be used to remove all but a thirty-second of an inch before beginning to plane. Watch the lines. If you are uncertain as to their accuracy, test this end as you did the first one.
33. End Planing with the Shooting Board.
Fig. 67 illustrates a way in which the ends of narrow pieces may be easily squared. The plane is pressed to the shooting board with the right hand. The left hand holds the piece against the stop and to the plane.
The face edge of the piece should be held against the stop; the wood must not be allowed to project beyond the stop. If it does, the corners, being unsupported, will be broken away as in free planing when the cutting edge is accidentally shoved entirely across the piece.
F . 68.
The bench hook makes an admirable shooting board. Fig. 68.
34. Rules for Planing to Dimensions.
1. True and smooth a broad surface; put on a face mark. This becomes the face side.
2. Joint (straighten and square) one edge from the face side; put on a face mark. This becomes the face edge.
3. Gage to required width from the face edge, and joint to the gage line.
4. Gage to required thickness on both edges from the face side; plane to the gage lines.
5. Square one end from the face side and face edge.
6. Lay off with knife and square the required length from the squared end; saw to the knife line.
F . 69.
F . 70.
35. Planing a Chamfer.
—Fig. 69 illustrates a good way to lay out a chamfer. A notch in the back end of the gage-stick holds the pencil in position. Holding pencil in this way draw lines on face and edge indicating width of the chamfer. Fig. 70 illustrates the manner of block planing a chamfer, the piece being held on the benchhook. Where the piece can be placed in the vise, Fig. 71 illustrates the method of planing a chamfer with one of the larger planes. First, plane the chamfers which are parallel to the grain; then the ends. If the plane-iron is sharp and set shallow, it can be run entirely across without danger of splitting the corners.
Hold the plane parallel to the edge in planing with the grain. Swing it to an angle of about forty-five degrees in end chamfering, but move it parallel with the edge, and not with the length of the plane.
The eye will detect inaccuracies in planing. If further test is desired, Fig. 72 illustrates one.
CHAPTER IV.
B T —B .
36. Brace or Bitstock.
Fig. 73 illustrates a common form of brace. This tool is used for holding the various kinds of bits which are used in boring, reaming, etc.
The ratchet brace consists of essentially the same parts but in addition has an attachment which permits of the crank’s acting in one direction or the other only. It is a necessity where the crank cannot make an entire revolution, and is very convenient for boring in hard wood, or for turning large screws.
To insert a bit, hold the brace firmly with the left hand, revolve the crank until the jaws are opened far enough to allow the bit tang to pass entirely within so that the ends of the jaws shall grip the round part—the shank of the bit. Still firmly holding the brace, revolve the crank in the opposite direction until the bit is firmly held. Fig. 74.
37. Center Bit.
—The old fashioned center bit, Fig. 75, is still used by carpenters for certain kinds of work. It has, for the most part, given way to the more modern auger bit.
F 75
38. The Auger Bit.
—The auger bit, Fig. 76, is used for all ordinary boring in wood. The action of an auger bit is readily understood by referring to Fig. 76. The spur draws the bit into the wood. The two nibs cut the fibers, after which the lips remove the waste, later to be passed along the twist to the surface.
Auger bits are usually supplied in sets of thirteen, in sizes varying from one-fourth of an inch to one inch, by sixteenths. The size of hole that an auger bit will bore can be told by looking at the number on the tang or shank. If a single number, it is the numerator of a fraction whose denominator is sixteen, the fraction referring to the diameter of the hole which the bit will bore.
