Principles of Tumors: A Translational Approach to Foundations

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Principles of Tumors: A Translational Approach to Foundations
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Preface to the second edition
1. Introduction
	1.1 General
		1.1.1 Features distinguishing tumors from other swellings
		1.1.2 Basic classifications and terminology of the tumor types
	1.2 “Translational” aspects and issues in the study of tumors
		1.2.1 Range of sciences contributing to the understanding and treatment of tumors
		1.2.2 Definitions of “translational medicine” and “translational issues”
	References
2. Theories and definitions of tumors
	2.1 Historical influences in concepts of tumors
		2.1.1 Humors, lymph, degenerations, diatheses, and temperaments
		2.1.2 “Pathology is only abnormal physiology”
		2.1.3 “Unity of nature”—“unity of cancer”
		2.1.4 “Plasias”
	2.2 Deviations in normal biological or nontumorous pathological processes
		2.2.1 Embryonic reversion
		2.2.2 Altered “development”/“maturation”/“differentiation” of local specialization
		2.2.3 Abnormal directions of specialization
		2.2.4 Abnormalities deriving from inflammatory responses
		2.2.5 Early infection theories
	2.3 Definitions offered by 19th and early 20th century authors
		2.3.1 1850–1920
		2.3.2 R.A. Willis' definition
	2.4 Early genomic theories, viral carcinogenesis, and definitions
		2.4.1 Hansemann's theory of abnormalities in chromosomes as the basis of tumor formation
		2.4.2 Work of Theodor Boveri
		2.4.3 K.H. Bauer on somatic mutation as the basis of tumors
		2.4.4 J.P. Lockhart-Mummery suggests somatic genomic instability in tumors
		2.4.5 R.A. Willis' morphological arguments against the somatic mutation theory
		2.4.6 Transformation of cells in vitro; viral causation; monoclonality of tumors
			(a) Discovery of transformation in vitro
			(b) Studies with viruses lead to discovery of “oncogenes”
			(c) Persisting uncertainty concerning the genomic basis of spontaneous transformation
		2.4.7 Uni- or oligo-nucleotide error genomic models analogous to sickle cell anemia assume monoclonality
		2.4.8 Later 20th century definitions
	2.5 Theories of limited polyclonalities in tumor cell populations
		2.5.1 Discovery of polyclonality/“heterogeneity” in tumors
		2.5.2 Theories of the origins of polyclonality
			(a) Multiple clones arising from different applications of carcinogen
			(b) Multiple clones result from possibly semiregular sequences of genomic events
			(c) Polyclonality arising from simultaneous genomic events in multiple adjacent originally normal cells with one application of ...
			(d) Illicit activation of normal gene rearrangement mechanisms
		2.5.3 Additional points concerning clones in tumor cell populations
			(a) Many cases of tumor produce no colonies when cultured in vitro or grafted into experimental animals
			(b) The cell lines which have been grown ex-corpore from cases of human tumor are individually unique
		2.5.4 The theory of heterogeneously heterogenizing tumor cell populations, including “mutator phenotype” (see also Appendix A4)
	2. 6 Other theories and concepts of tumors
		2.6.1 “Blasts” in tumor terminology
		2.6.2 “Histogenesis” applied to tumors
		2.6.3 Stem cells and transit-amplifying cells in the origins of tumors
			(a) Gametogenic cells as stem cells (see Fig. 2.4B and C)
			(b) Embryonic stem cells
			(c) Local tissue stem cells in adults (see Fig. 2.4D)
			(d) Any dividing cell in adults, including transit-amplifying cells
		2.6.4 Theories involving telomeres and the immortality of tumor cell populations
		2.6.5 Theories involving plasma membrane and cytoskeleton
		2.6.6 Epigenetic DNA modification and tumor formation; similarity to adduct models of carcinogenesis
		2.6.7 Theories involving immunity
		2.6.8 Field theory
		2.6.9 Biochemical theories
		2.6.10 Later chromosomal observations
		2.6.11 Excessive angiogenesis
		2.6.12 Discussion of the “one process fits all” theories
	2.7 Current definitions
		2.7.1 Definitions in textbooks
		2.7.2 Hanahan and Weinberg's “hallmarks” of cancer
		2.7.3 Definitions currently provided by major health agencies
		2.7.4 Author's definition
	References
3. Etiopathogenesis of tumors
	3.1 General aspects of tumor formation by known etiological agents
		3.1.1 Tumor formation is not “spontaneous”
		3.1.2 The five necessary steps in the etiopathogenesis of tumors by external agents
		3.1.3 Diverse physicochemical natures of etiological factors
		3.1.4 Many carcinogens have multiple other noxious effects
		3.1.5 Time factors
			(a) Repeated or continuous exposures
			(b) Delays and “latencies”
		3.1.6 Dose, dose rates, and “threshold” doses
		3.1.7 Multifactorial causation of tumors
	3.2 Specific aspects of radiations
		3.3.1 Background
		3.2.2 Radio waves, microwaves, infrared, and visible light
		3.2.3 Ultraviolet light
			(a) Physics
			(b) Damage to DNA from ultraviolet light
			(c) Damage to proteins from ultraviolet light
			(d) Protein–DNA cross-linking
		3.2.4 Ionizing radiations
			(a) Physics
			(b) Damage to DNA from ionizing radiations
			(c) Damage to proteins from ionizing radiations
			(d) Protein–DNA cross-links
		3.2.5 Biological bases of cumulative ionizing and nonionizing radiation damage over long periods of time
		3.2.6 Species differences in susceptibility to radiation-induced tumors are unexplained
	3.3 Specific aspects of chemical carcinogens
		3.3.1 Many carcinogens must be activated in the body to have their effect and can then act remotely
		3.3.2 Chemical carcinogens have different chemical reactivities
			(a) Carcinogens which react covalently only with or are incorporated into DNA
			(b) Carcinogens which react covalently with both DNA and proteins
			(c) Carcinogens which react covalently only with proteins
			(d) Carcinogens which react with neither DNA nor proteins
		3.3.3 Chemical structure does not perfectly correlate with carcinogenic potency
		3.3.4 Species differences in susceptibilities to chemical carcinogens
		3.3.5 Metabolic explanations of species differences are insufficient
		3.3.6 Differences between the kinds of parent cells in susceptibilities to carcinogens
			(a) Human chronic arsenic toxicity
			(b) Human and experimental skin tumors induced by coal tar and shale oil
			(c) Human mesothelioma caused by asbestos
			(d) Human vinyl chloride exposure
			(e) Human thorium exposure
			(f) Experimental nitrosamine carcinogenesis
			(g) Perspective on these differences
		3.3.7 The two-stage skin model of carcinogenesis, including inhibitors and enhancers
			(a) General
			(b) Exposures to carcinogens in specific sequences
		3.3.8 Routes of administration, solvents used, and other factors in experimental chemical carcinogenesis
		3.3.9 Not all chemicals which cause hyperplasias cause tumors
	3.4 Viruses
		3.4.1 Background
		3.4.2 General aspects of viral infections
			(a) Classifications of viruses
			(b) Tropisms
			(c) Morphologically detectable pathogenetic effects
			(d) Different effects in different species
		3.4.3 Human tumor types associated with viral infections
			(a) Epstein–Barr virus
			(b) Hepatitis B viruses
			(c) Hepatitis C viruses
			(d) Human herpesvirus-8 and Kaposi's sarcoma
			(e) Human immunodeficiency virus 1
			(f) Human papilloma viruses
			(g) Human T-cell lymphotropic virus type-1
			(h) The Merkel cell polyoma virus
		3.4.4 Potential bases for associations between viral infections and tumor formation
			(a) The viral infection is the essential sole causative agent of the tumor formation, but
			(b) The viral infection is the essential causative agent, but tumor formation requires a second agent
			(c) Another factor is the essential causative agent, and the virus is a second agent
			(d) The infection is not an etiological factor for the tumor, but a coincidental infection which is more likely in the individu ...
			(e) The virus has been a passenger in the genome of the individual
			(f) The virus is an intercurrent infection of the tumor cell population
			(g) The virus induced the tumorigenic change in the original cell, but its presence is not required for the descendant cells to ...
		3.4.5 Genomic lesions potentially inducible by viruses and other agents
			(a) Insertion of viral genes into the genome
			(b) Possible actions of viral DNA through position effects in host DNA
			(c) Viral infections producing genomic transfection events between genomes of adjacent host cells
			(d) Permanent effects of transiently expressed viral proteins as the mechanism of genomic
	3.5 Other microorganisms as carcinogens
		3.5.1 Bacteria
		3.5.2 Fungi
		3.5.3 Parasites
	3.6 Hormones as carcinogens
	3.7 “Solid” carcinogens in vivo
		3.7.1 Asbestos fibers
		3.7.2 Other fibers and dusts
		3.7.3 Plastic film and miscellaneous experimental “solid” carcinogen–induced tumors
			(a) In vivo
			(b) In vitro
		3.7.4 Breast implant–associated anaplastic large cell lymphoma
	3.8 Summary of translational issues
		3.8.1 The translational issue of histology and susceptibility to spontaneous tumors
	References
4. Growth of cells, growth factors, and oncogenes
	4.1 General
		4.1.1 Terminology
		4.1.2 Physical factors affecting cell growth in vitro
			(a) Anchorage dependency
			(b) Contact inhibition
		4.1.3 Extrinsic chemicals affecting cell growth
			(a) Serum and plasma factors
			(b) Factors released by other cells
		4.1.4 Cytokines and cytokine networks
	4.2 Intracellular (intracrine) mechanisms of growth control: cell signaling pathways
		4.2.1 Oncogenes: discovery, definitions, activations, and mechanisms of action
			(a) Current definitions of oncogenes
			(b) Activations
			(c) Mechanisms of action
		4.2.2 Principles of cell signaling
		4.2.3 Pathways involving tyrosine kinase activations
			(a) The ErbB family and pathways
			(b) The insulin and insulin-like growth factor receptors
			(c) c-Met
			(d) VEGF receptors
			(e) WNT-beta-catenin pathway
		4.2.4 Pathways involving serine-threonine kinase activity
			(a) TGF-beta
			(b) Other serine-threonine kinases
		4.2.5 Guanine-phosphate-dependent activity
		4.2.6 Other pathways
			(a) Pathways involving other enzymatic activities in membrane receptors
			(b) Hedgehog-patched pathway
			(c) Notch protein
	4.3 Other aspects of cell signaling, growth factors, and oncogenes
		4.3.1 Pleiotropies and redundancies in intracellular signaling events
			(a) Pleiotropy(ism)
			(b) Redundancy
		4.3.2 Networks in intracellular signaling events
		4.3.3 The diffusion-feasibility aspect of the pathway concept
		4.3.4 Oncogene “cooperation” may be necessary for tumor formation
		4.3.5 Oncogene “addiction”
	4.4 Summary of the translational issues
		4.4.1 Recent trends in translating genomic research to clinical practice
	References
5. Hereditary predispositions to tumors, tumor suppressor genes, and their clinico-genomic complexities
	5.1 General features of high-penetrance hereditary predispositions to tumors in humans
		5.1.1 Definitions and characteristics of inherited and familial predispositions versus sporadic cases
		5.1.2 Specificity of each hereditary predisposition to particular kinds of parent cells
		5.1.3 Variabilities in penetrances, expressivities, and timing of inheritable predispositions
			(a) In penetrance and expressivity case-to-case
			(b) Different penetrances of the different tumor types in various syndromes
			(c) Different penetrances of the nontumorous lesions occurring in some human hereditary predisposition syndromes
			(d) Earlier appearance of tumors in comparison with sporadic cases
	5.2 General aspects of tumor suppressor genes
		5.2.1 Discovery: Knudson's work and options for loci of the germline and somatic events for each predisposition
			(i) On the same allele as the germline genomic event
		5.2.2 Subsequent studies
		5.2.3 Widened definition
		5.2.4 Possible roles of tumor suppressor genes in nonhereditary tumors
		5.2.5 Mechanisms of action of tumor suppressor genes
		5.2.6 Relevant principles of gene structure
	5.3 Phenotype–genotype relationship I: A single tumor type deriving from one parent cell type with one or more genes involved
		5.3.1 Familial melanoma (CDK4 and CDKN2A)
		5.3.2 MUTYH polyposis coli
	5.4 Phenotype–genotype relationship II: several tumor types deriving from one (or closely related) parent cell type with one ge ...
		5.4.1 Neurofibromatosis 2
	5.5 Phenotype–genotype relationship III: multiple tumor types and even nontumor lesions arising in different kinds of parent ce ...
		5.5.1 Retinoblastoma
		5.5.2 Familial adenomatous polyposis
			(i) Turcot's syndrome
			(ii) Gardner's syndrome
		5.5.3 Neurofibromatosis 1
		5.5.4 Von Hippel–Lindau disease
		5.5.5 BCC syndrome (syn. Gorlin syndrome, basal cell nevus syndrome) (PTCH1 gene)
		5.5.6 Ataxia-telangiectasia
		5.5.7 Bloom's syndrome
		5.5.8 Peutz–Jeghers syndrome
	5.6 Phenotype–genotype relationship IV: multiple tumor types and even nontumor lesions arising in different kinds of parent cel ...
		5.6.1 Hereditary nonpolyposis coli (Lynch Syndrome)
		5.6.2 BRCA1 and BRCA2
		5.6.3 Wilm's tumor
			(a) WT1 gene
			(b) WT-2 gene
			(c) WT-3 gene
		5.6.4 Tuberous sclerosis complex
		5.6.5 Carney Complex
		5.6.6 Li–Fraumeni Syndrome
		5.6.7 Xeroderma pigmentosum
	5.7 Phenotype–genotype relationship V: predispositions to different syndromes according to position of the germline event in th ...
		5.7.1 RET gene: different germline mutations cause MEN Type 2 versus Hirschsprung's disease
		5.7.2 PTEN gene: Cowden's and related syndromes
	5.8 Genomic models for the inherited predispositions
		5.8.1 Mutations in different genes causing the same syndrome
		5.8.2 Different mutations in the same gene having different clinical features
		5.8.3 Different penetrances of different tumors associated with the same germline event
			(a) Modifier genes
			(b) Somatic mutations occur less commonly in one somatic cell compared with another
			(c) The second somatic event occurs during embryonic development, when the parent cells of the tumors are, for some reason, sim ...
		5.8.4 Models for the parent cell–type specificities of dominant inherited predispositions
			(a) A parent cell–specific gene product is a necessary enhancer modifier of the tumorigenic effect of the loss of the tumor sup ...
			(b) Comutation of proximate (contiguous) genomic elements
		5.8.5 Models for autosomal recessive inheritance of predisposition to a specific tumor type
			(a) The autosomal state allows greater ingress of carcinogen
			(b) Possible requirement of a “third hit” for which there are the three of Knudson's options (see Fig. 6.6)
			(c) Other possible model
	5.9 Low-penetrance inherited susceptibility syndromes in humans
		5.9.1 Background; GWAS data
		5.9.2 Polygenism in low-penetrance tumor predispositions
		5.9.3 In relation to carcinoma of the breast
		5.9.4 In relation to other tumors
	5.10 Hereditary predispositions to tumors in experimental animals
		5.10.1 Incrementally increasing susceptibility with inbreeding
		5.10.2 Sporadic “large impact” genomic events predisposing to tumors in animals
		5.10.3 Genetically engineered large impact inherited predispositions to tumors in animals
	5.11 Summary of translational issues in inherited predispositions to tumors
	References
6. The tumor types: the complexities in the combinations and variabilities of their traits
	6.1 The traits of tumor cells and the complexities of the tumor types
		6.1.1 The kinds of traits in tumor cells
			(a) Uncontrolled accumulation of cells
			(b) Alterations in specific traits of the parent kind of cell
			(c) Miscellaneous cytoplasmic abnormalities
			(d) Alterations in the nonspecific cytomorphology and metabolism of the parent cells
			(e) Alterations in relationships to each other and with surrounding tissues
			(f) Adjacent cytostructural irregularity in continuity
			(g) Adjacent cytostructural irregularity in discontinuous foci
			(h) Induction of abnormalities in adjacent other kinds of cells
				(i) Desmoplasia
				(ii) Benign proliferation
				(iii) Lymphoid associations
				(iv) Vessels
			(i) Remaining within boundaries
			(j) Capacity to grow in other tissues
			(k) Derepressions of traits, especially traits of embryonic cells or other mature kinds of cells
			(l) Abnormalities in nuclei
				(i) Size of nuclei
				(ii) Shapes of nuclei
				(iii) Mitotic figures
				(iv) “Chromatism” and chromatin “patterns”
				(v) Miscellaneous abnormalities of nuclei in tumor cells
		6.1.2 There are different numbers of traits in the combinations of different tumor types
		6.1.3 There is no universal association of nongrowth features in the different tumor types
		6.1.4 Different numbers and ratios of tumor types arise from different kinds of parent cells
			(a) Numbers of tumor types according to parent kind of cell
			(b) Ratios of benign: malignant tumor types according to parent kind of cell
		6.1.5 Some potential tumor types (i.e., combinations of traits) do not occur in many kinds of normal cells
		6.1.6 Tumor types which exhibit continuous spectra from benign to malignant
		6.1.7 Benign tumors which appear malignant, “IDLE” lesions
		6.1.8 Malignant tumors which appear benign
		6.1.9 Mixed tumors
		6.1.10 Tumor types with unusual behavioral features
			(a) Melanocytic tumors
			(b) Keratoacanthoma
		6.1.10 In situ tumors
	6.2 Further variabilities in tumor traits and types
		6.2.1 Ambiguity in the term “differentiation”
		6.2.2 Classification of variabilities in tumors: between the types, between cases of the same type, and between foci in the same case
			(a) Intertype variability
			(b) Intercase variability in the same type
			(c) Focus-to-focus variability within the same case
		6.2.3 In growth rates: relationship to characteristics of parent cells
		6.2.4 In biomarker expressions (as used in diagnosis and therapy)
		6.2.5 For malignant tumors, in degrees of malignancy
		6.2.6 In relative proportions of tumor cells and supporting cells in microenvironments
		6.2.7 Use of “heterogeneity” in reference to tumor cell populations
	6.3 “Progression” in tumor cell populations
		6.3.1 Foulds' general principles (Ref. [78], vol. 1, pp. 69ff)
		6.3.2 Progression occurs variably in different types of tumors
		6.3.4 Metastases are usually more “undifferentiated”/“progressed” compared with their respective primary tumors
	6.4 Hematopoietic tumors similar in principle to solid tumors
		6.4.1 Background to the special nomenclatures of hematolymphoid tumors
		6.4.2 Specialization morphology in hematopoietic tumors
		6.4.3 Lack of particular specialization morphology in lymphomas
		6.4.4 Aspects of other kinds of hematolymphoid tumors
	6.5 Invasion: pathological observations, cell biology, and possible genomic pathogenesis
		6.5.1 Terminological issue: the tumor “microenvironment”
		6.5.2 Diversity in invasions by tumor cell populations
			(a) Epithelium invading supportive tissues
			(b) Epithelial and melanocytic tumors invading other epithelia
			(c) Behavior of lymphoma cells
			(d) Invasion without metastasis
		6.5.3 Possible mechanism of movements of tumor cells
	6.6 Metastasis: pathological observations, cell biology, and possible genomic pathogenesis
		6.6.1 Tumor type–characteristic patterns of metastases
		6.6.2 Excessive transplantability of tumor cells compared with the cells from which they arise: tissue-specific antigens
		6.6.3 General cell biological factors affecting the likelihood of metastasis of a case of tumor
			(a) The inherent invasiveness of the tumor
			(b) The quantity of adjacent structures which can serve as avenues for the tumor to spread
			(c) The degree of degradation of the walls of the vessels into which the tumor cells may grow
			(d) The period of time during which the tumor cells have been near the relevant structures
		6.6.4 Survival in lymph and/or blood stream
		6.6.5 Thrombosis and the impaction site
		6.6.6 Factors in growth at the metastatic site
		6.6.7 Possible genomic bases of invasion and metastasis
	6.7 Summary of translational issues in the morphology of tumors
		6.7.1 Features explicable by Mendelian principles
		6.7.2 Features dependent on genomic instability
	References
7. Epidemiology of tumors
	7.1 Data and measures used in epidemiological studies of tumors
		7.1.1 Sources of raw data
		7.1.2 Standardizations
		7.1.3 Incidence
		7.1.4 Mortality
		7.1.5 Difficulties of incidence and mortality data collection
		7.1.6 Survival
		7.1.7 Prevalence, life-years lost, and disability-adjusted life years
			(a) Prevalence
			(b) “Life-years lost”
			(c) “Disability-adjusted life years”
		7.1.8 Difficulties of prevalence and related data collection
	7.2 Medical practice factors affecting the reported incidence and mortality data
		7.2.1 Changes in histopathological criteria for diagnosis of malignancy
			(a) Reclassification of previously considered benign lesions as malignancies
			(b) Reclassification of “tumor-like” lesions including “atypias” as “neoplasias” or malignancies (see Section 6.1.7)
			(c) Reclassification of accepted malignancies
		7.2.2 Changes in clinical, imaging, and biochemical criteria for diagnosis
			(a) Clinical
			(b) Imaging
			(c) Changes in biochemical test criteria
		7.2.3 Effects of screening programs on incidence rates
		7.2.4 Effects of better therapies on mortality and survival rates
		7.2.5 Role of autopsies
	7.3 Comparative international data on incidences and mortalities of cancers by type
		7.3.1 Incidences and mortalities of tumors by geographical region: totals and by types
			(a) Total cancers by geographical region
			(b) World incidence and mortality rates of common types of malignant tumors in 2012 according to geographical region
			(c) Trends in cancer incidences by type, world 1990–2016
		7.3.2 Trends in mortalities of various types of cancer: world, United States 1930–2010 and United Kingdom
		7.3.3 World trends in incidence and mortality of colorectal cancer 1975–2010 males and females (Fig. 7.6)
		7.3.4 World trends in incidence and mortality of breast cancer 1975–2010 (Fig. 7.7)
		7.3.5 World trends in incidence and mortality of prostate cancer 1975–2010 (Fig. 7.8)
		7.3.6 Discussion of international comparisons
			(a) Incidence data
			(b) Death certificate data
	7.4 Significance of overdiagnosis
		7.4.1 Sources
			(a) Prostate
			(b) Breast
			(c) Thyroid
			(d) Other
		7.4.2 Effects on patients
		7.4.3 Effects on credibility of statements about cancer overall
	7.5 Suggested subcategories of “incidence” to accommodate factors in medical practice
		7.5.1 The diagnosed incidence rate
			(a) The incidence rate of tumors diagnosed through medical investigation of clinical manifestations
			(b) The incidence rate of tumors found by medical investigation of an unrelated condition
			(c) The incidence rate of tumors found by screening methods for prevention
		7.5.2 The undiagnosed incidence rate
		7.5.3 The total incidence [Fig. 7.10]
	7.6 Summary of translational issues in cancer epidemiology
		7.6.1 How to diagnose overdiagnosis
		7.6.2 Diagnostic drift
	References
8. Prevention of tumors
	8.1 Confirmed human carcinogens: preventative measures
		8.1.1 Deriving from early work on occupational cancers
			(a) Arsenic
			(b) Polyaromatic hydrocarbons especially in tars and mineral oils
			(c) Chemical dyes
			(d) Ionizing radiations: uranium miners
			(e) Mixed radiations: radium poisoning
			(f) Ionizing radiations: thorium dioxide (Thorotrast)
		8.1.2 The beginnings of “environmental carcinogenesis”: leaked and dumped industrial and nonindustrial chemicals: the work of W.  ...
		8.1.3 Reduced exposure to amphibole (mainly “blue” and “brown”) kinds of asbestos
		8.1.4 Reduction in tobacco usage
		8.1.5 Sunscreen lotions for the reduction skin cancers
		8.1.6 Vinyl chloride
		8.1.7 Immunization against human papilloma viruses in the prevention of cervical cancer
		8.1.8 Attempts to reduce transmission of the human immunodeficiency virus in the prevention of Kaposi's sarcoma and other HIV-rel ...
	8.2 Identifying and investigating further carcinogens: epidemiological data and methods
		8.2.1 Data specifications
			(a) General
			(b) Self-reported data
			(c) Biodata
			(d) Concurrent anticarcinogens have rarely been studied
		8.2.2 Complexities of geographical/cultural/ethnic factors
		8.2.3 Cross-sectional studies
		8.2.4 Cohort studies: finding changing incidences of disease
		8.2.5 Case-controlled studies
		8.2.6 Interventional studies
	8.3 Association does not prove causation
		8.3.1 General
		8.3.2 Bradford Hill's guidelines
	8.4 Other aspects of interpreting cancer-causation epidemiological data
		8.4.1 Importance of finding factors least associated with others
		8.4.2 Use of “risk” for associations
		8.4.3 Classification of “risk”/association: absolute risk, difference in absolute risk, relative risk, and odds ratio
			(a) Absolute risk
			(b) Difference in absolute risk
			(c) Relative risk
			(d) Odds ratio
		8.4.4 Attribution of fractions of “risk”
	8.5 Problematic issues with low-level or disputed carcinogens and carcinogenic factors
		8.5.1 Aging and background radiation enhancing “normal” rates of mutation
		8.5.2 Air pollution
		8.5.3 Lung cancer in never-smokers
		8.5.4 Water pollution, chlorination
		8.5.5 Low dose exposure to chrysotile and bronchogenic lung cancer
			(a) Pulmonary and mesothelial tumors
			(b) Other cancers
			(c) Particular properties of chrysotile asbestos
		8.5.6 Affected family members
		8.5.7 Alcohol consumption
		8.5.8 Caffeine, especially in coffee
		8.5.9 Pharmaceuticals, other health-related products, talc
		8.5.10 Glyphosate
		8.5.11 Red meat
		8.5.12 “Poor diet” and “fiber”
			(a) Definition of “poor diet”
			(b) Diets with a low component of vegetable fiber (cellulose) and prevention of carcinomas of the colon and rectum
		8.5.13 The World Cancer Research Fund/American Institute for Cancer Research studies
			(a) Diet
			(b) Lack of physical exercise
			(c) Obesity
		8.5.14 Gut flora
		8.5.15 Acrylonitrile
		8.5.16 Wood dust
	8.6 Laboratory methods in the identification of environmental carcinogens
		8.6.1 Background
		8.6.2 Tumors in animals
		8.6.3 Enhanced rates of malignant transformation in cells cultured in vitro
			(a) Methodological issues
			(b) Advantages
		8.6.4 Other genopathic phenomena used for testing potential carcinogenicity
			(a) In living animals
			(b) In cultured cells
				(i) In vitro mammalian cell micronucleus test
				(ii) In vitro mammalian chromosome aberration test
				(iii) In vitro mammalian cell gene mutation assay
			(c) Tests in bacteria
			(d) Other tests
		8.6.5 Multiplicity of tests and methods for their use
		8.6.6 Co-carcinogens and other multifactorial circumstances
		8.6.7 Noncorrelation of relative potencies for carcinogenesis in relation to other effects
		8.6.8 Possible future experimental methods
	8.7 Human lesion and genetic screening programs and their efficacies in preventing deaths from tumors
		8.7.1 Overview
		8.7.2 For carcinoma of the bronchi
		8.7.3 For colorectal carcinoma
		8.7.4 For carcinoma of the breast
		8.7.5 For carcinoma of the prostate
		8.7.6 For carcinoma of the cervix
		8.7.7 Other biomarker or lesional screening
		8.7.8 Screening for germline genetic predispositions/personalized disease prevention through genomic studies
			(a) Selective gene sequencing
		8.7.9 Assessing benefits of screening
		8.7.10 Harms of screening
	8.8 Cancer-preventative drugs: benefits and potential dangers
		8.8.1 General
		8.8.2 Difficulties in assessing complex mixtures
		8.8.3 Classification of cancer-preventative drugs
			(a) Preventing carcinogens reaching susceptible cells
			(b) Preventing “maturation” of susceptible cells
			(c) “Suppressive agents”
		8.8.4 Laboratory assessments of these agents
		8.8.5 Difficulties of clinical trials of these agents
		8.8.6 Currently recommended cancer-preventative drugs for particular tumor types
			(a) Lung carcinoma
			(b) Breast carcinoma
			(c) Colorectal carcinoma
			(d) Prostatic carcinoma
	8.9 Barriers to prevention
		8.9.1 Lack of information
		8.9.2 Failure to access or act on information
	8.10 Summary of translational issues in cancer prevention
		8.10.1 Lack of data on mutation accumulation over lifetimes of individuals
		8.10.2 Lack of data on bioaccumulations
			(a) Maximum permissible exposures/“levels”
		8.10.3 Vagueness in the biology and mutagenic implications of “lifestyle” factors
		8.10.4 Data currently unavailable
	References
9. Clinical features of tumors
	9.1 General
		9.1.1 Terminology
		9.1.2 Malignant tumors have clinical features in addition to those of benign tumors
		9.1.3 Features of tumor masses
			(a) Qualities
			(b) Ulceration
			(c) Bleeding
			(d) Pain and tenderness
			(e) Tethering to adjacent tissues
			(f) Obstruction of a hollow organ
		9.1.4 “Systemic” (nonlocal) symptoms and signs of tumors
			(a) Loss of appetite (“anorexia”), loss of weight, and cachexia
			(b) Anemia
			(c) Fever
	9.2 Symptoms and signs of the most common malignant tumors
		9.2.1 Carcinoma of the lung
			Local involvement
			Regional involvement
		9.2.2 Carcinoma of the colon
		9.2.3 Carcinoma of the female breast
		9.2.4 Carcinoma of the prostate
	9.3 Symptoms and signs of less common malignant tumors
		9.3.1 Melanomas of the skin
		9.3.2 Upper gastrointestinal tract, liver, and pancreas
		9.3.3 Hematopoietic and lymphoid systems
			(a) Leukemias
				Acute lymphoblastic leukemia/lymphoblastic lymphoma
			(b) Lymphomas
				Hodgkin's lymphoma
				Non-Hodgkin's lymphoma
		9.3.4 Female genital
			(a) Vulva and vagina
			(b) Carcinoma of cervix
			(c) Ovaries
		9.3.5 Urinary system
		9.3.6 Testis
		9.3.7 Nervous system
		9.3.8 Skeletal system
		9.3.9 Soft tissues
		9.3.10 Other systems including endocrine and special senses
	References
10. Typing, grading, and staging of cases of tumor
	10.1 Morphological bases for the typing of tumors
		10.1.1 Pre-1940s—mid 20th century
		10.1.2 Armed Forces Institute of Pathology's “Atlas of Tumor Pathology”
		10.1.3 World Health Organization: International classification of diseases and international histological classification of tumors
		10.1.4 General aspects of identification of new types and subtypes of tumors
		10.1.5 Other classifications
	10.2 “Molecular” and other contributions to the typing of tumors
		10.2.1 Terminology of “molecular pathology” in medicine and genetics
		10.2.2 Immunohistochemistry-based molecular studies
			(a) Molecules specific to the lineage of a parent cell for the tumor
			(b) Molecules which are specific to other lineages than the lineage of cells from which the tumor arose
			(c) Molecules normally expressed only embryos, expressed in tumor cells in the adult
			(d) Molecules of cell growth and signaling
			(e) Neomolecules in tumors
		10.2.3 Chromosomal (“cytogenetic”) abnormalities in hematological and solid tumors
			(a) In hematolymphoid tumors
			(b) In solid tumors
		10.2.4 Further aspects of translocations in tumor types
		10.2.5 “Liquid biopsies”: “circulating” solid tumor cells DNA and RNA
			(a) Circulating solid tumor cells
			(b) Circulating exosomes
			(c) Circulating free DNA and RNAs
			(d) Circulating free RNA
	10.3 Grading of solid tumors for planning therapy
		10.3.1 General aspects of grading
		10.3.2 Immunohistochemistry-based studies for grading
			(a) Particular growth-related molecules
			(b) Molecules associated with the cell division process
			(c) Molecules related to invasion or metastasis
		10.3.3 Specific DNA lesions according to tumor type
			(a) Lung carcinoma
			(b) Colorectal carcinoma
			(c) Breast carcinoma
			(d) Prostate carcinoma
			(e) Other
		10.3.4 Identifying resistance mutations
		10.3.5 Prognostic significance of lymphocytes infiltrating solid tumors
		10.3.6 Other molecular factors in prognostication of tumors including epigenetic data
		10.3.7 Current grading of common malignancies
			(a) Carcinomas of the lung
			(b) Carcinomas of the large bowel (colon and rectum)
			(c) Carcinomas of the breast
			(d) Carcinomas of the prostate
			(e) Other
		10.3.8 Grading of metastases more relevant than of primary tumors
	10.4 Staging of cases of solid tumor by examination of the resected specimen
		10.4.1 Early staging systems
		10.4.2 The TNM system and the impacts of imaging technologies and comorbidities
		10.4.3 American Joint Committee on Cancer staging of carcinoma of the lung
		10.4.4 AJCC staging of carcinoma of the large bowel (colon and rectum)
		10.4.5 AJCC staging of carcinoma of the breast
		10.4.6 AJCC staging of carcinoma of the prostate
		10.4.7 Reasons for discrepancies between pathologist staging and imaging specialist staging
		10.4.8 Issue of micrometastases
		10.4.9 Lack of hierarchy of importance of features in the specimen
	10.5 “Prognostic indices” using multiple factors
		10.5.1 Lung Cancer Prognostic Index
		10.5.2 Glasgow prognostic score for colorectal carcinoma
		10.5.3 The Nottingham Prognostic Index for breast carcinoma
		10.5.4 Prognostic indices for prostate carcinoma
	10.6 Sampling artifact in pathological assessments of cases of tumor
		10.6.1 “Artifact” rather than error
		10.6.2 Needle aspirate samples and needle core biopsies are small; histological sections are thin
			(a) Biopsy samples
			(b) Histological sections
			(c) Problems arising
		10.6.3 Tumor types particularly susceptible to sampling variations
	10.7 Other difficulties in grading and staging
		10.7.1 How to type lesions with multiple pattern variants and grade levels
			(a) Carcinoma of the breast
			(b) Adenocarcinomas of the large bowel (colon and rectum)
			(c) Malignant lymphoma
				(i) Hodgkin's lymphoma
				(ii) Non-Hodgkin's lymphoma
			(d) Testis
			(e) Thyroid
		10.7.2 Classifying tumors showing continuous spectra of morphological or genomic features
		10.7.3 Sources of biologically erroneous information from immunohistochemical and genome tests
	10.8 Summary notes of translational issues in typing grading, staging, and prognosis
		10.8.1 Typing
		10.8.2 Grading
		10.8.3 Staging
		10.8.4 Correlation of these and prognosis
		10.8.5 Dealing with interpathologist differences in diagnoses
	References
11. Endoscopic visualization and imaging assessments of cases of tumor
	11.1 Endoscopic and other internal visualizations
		11.1.1 Background
		11.1.2 Visualizations with biopsy
			(a) Visualization of organs having natural openings to the surface, with biopsy
			(b) Endoscopic avenues for biopsies of internal organs
			(c) Inspection of body cavities with potential for biopsies or surgical resection
		11.1.3 Hazards of endoscopic procedures
	11.2 Imaging techniques: physical principles
		11.2.1 Plain X-rays; fluoroscopy
		11.2.2 Ultrasonography
		11.2.3 Computerized axial tomography
		11.2.4 (Nuclear) magnetic resonance imaging
		11.2.5 Radiation-emitting isotopic scans
			(a) Bone scintigraphy
			(b) Nuclide tomography
		11.2.6 Combined technologies
			(a) Fluoroscopy-ultrasound techniques
			(b) MR-ultrasound combination
			(c) Positron emission tomography/computed tomography
			(d) Positron emission tomography/magnetic resonance imaging
	11.3 Imaging in diagnosis, staging, biopsies, and therapies of particular tumors
		11.3.1 Carcinoma of lung
		11.3.2 Carcinoma of large bowel (colorectum)
		11.3.3 Carcinoma of breast
		11.3.4 Carcinoma of prostate
		11.3.5 Imaging-guided percutaneous biopsies and therapies
			(a) For biopsy
			(b) For therapy
	11.4 Hazards of imaging
		11.4.1 Of diagnostic ultrasound
		11.4.2 Of radiations
		11.4.3 Of MRI machines
	11.5 Other difficulties in imaging
		11.5.1 Sampling artifacts of MRIs
		11.5.2 Discrepant interpretations
	References
12. Principles of surgery for tumors
	12.1 Preoperative considerations
		12.1.1 Review of clinical features, imaging, and comorbidities
		12.1.2 Informed consent
		12.1.3 Facilities
	12.2 Classification of operations
		12.2.1 Biopsies for diagnosis
		12.2.2 Biopsies for staging: sentinel node biopsy
			(a) General
			(b) Sentinel node biopsies in the treatment of carcinoma of the breast
			(c) Sentinel node biopsies in the treatment of malignant melanoma
		12.2.3 Removal of the primary tumor
		12.2.4 After neoadjuvant chemotherapy and radiotherapy
		12.2.5 Palliative procedures: “debulking,” removal of local recurrences, and removal of metastases
			(a) “Debulking”/“cytoreductive” operations
			(b) Removal of local recurrences
		12.2.6 Other
			(a) For relief of specific complications
			(b) Reconstruction
			(c) Prophylactic
	12.3 Aspects of particular cancer operations and their complications
		12.3.1 Lung
			(a) Biopsies
			(b) Resections
				(i) Wedge resection
				(ii) Segmentectomy
				(iii) Lobectomy
				(iv) Pneumonectomy
		12.3.2 Colon and rectum
			(a) Biopsies
			(b) Resections
		12.3.3 Breast
			(a) Biopsies
			(b) Resection
		12.3.4 Prostate
			(a) Biopsies
			(b) Resections
		12.3.5 Other
	12.4 “Robotic” surgery
		12.4.1 Background
		12.4.2 Advantages and disadvantages
	12.5 Translational notes on surgery in cases of cancer
	References
13. Principles of nonsurgical therapies
	13.1 General
		13.1.1 Biochemical and genomic bases of the sensitivity of tumor cells to cytotoxic agents; “therapeutic window”; “therapeutic index”
			(a) Metabolic deficiencies
			(b) Deficiencies in specific defense mechanisms and capacities to recover after injury
			(c) Increased accumulation of the active drug into the tumor cells
			(d) Therapeutic window
			(e) Therapeutic index
		13.1.2 Sensitivities of tumor types often reflect the sensitivities of their parent cells; mitotic rate
		13.1.3 “First-line,” “second line,” etc., therapies and regimens
		13.1.4 Greater efficacies in split doses: resistance factors combined with recovery factors
			(a) Radiotherapy
			(b) Anticancer chemotherapy
			(c) Principle of effect
			(d) Factors in increased efficacies of split doses
		13.1.5 “Rescue” from therapy
		13.1.6 Combination therapies
		13.1.7 Adjuvant regimens
		13.1.8 Neoadjuvant regimens
		13.1.9 Common side effects of nonsurgical anticancer therapies
			(a) Bone marrow suppression: anemia and infections
			(b) Arising from damage to other organs
			(c) Systemic
		13.1.10 Side effects limit immediate and total lifetime doses for the patient
		13.1.11 Effects on agents on genomic stability; second malignancies
	13.2 Reasons for partial responses and relapses
		13.2.1 The original tumor cell population had a component which was not reached by the agent
			(a) Hypo vascularization and hypoxia
			(b) Desmoplasia
		13.2.2 A proportion of the cells are resistant ab initio
			(a) The resistant cells are unaltered descendants of local tissue stem cells
			(b) The resistant cells are descendants of resistant cells formed by the initiating genomic event
		13.2.3 “Acquired” increased proliferation and resistance
			(a) In radiotherapy
			(b) In anticancer chemotherapy
		13.2.4 Role of genomic instability in resistance
	13.3 Monitoring responses and relapses in the patient
		13.3.1 Clinical measures
		13.3.2 Imaging
		13.3.3 Biomarker levels
	13.4 Summary of translational issues in nonsurgical therapies
	References
14. Aspects of radiation therapy
	14.1 General
		14.1.1 Units of therapeutic radiation and absorption
		14.1.2 Aspects of kinds of damage; differences according to species and kinds of cells
			(a) Species
			(b) Cells
		14.1.3 Oxygen effect
		14.1.4 Hyperthermia as a possible adjunct in radiation and chemotherapy distinct from thermal ablation
		14.1.5 Radiation therapy enhancing metastasis
		14.1.6 Specific issues in radiations acting on genomic stability in cells
	14.2 Aspects of particular forms of radiation therapy
		14.2.1 Electron beam radiation therapies
		14.2.2 Nuclear particle beams
			(a) Protons in comparison with high energy radiations
			(b) Neutrons
			(c) Helium nuclei (α-rays)
			(d) “Heavy” ions: carbon nuclei
		14.2.3 Radio-sensitizers and protectors
		14.2.4 Aspects of applications in the clinic
			(a) Anatomical precision
			(b) Treatment of regular side effects
			(c) Limitations to total doses of radiation therapy
			(d) Protection of radiation therapy staff
	14.3 Recommended regimens for common malignancies
		14.3.1 Carcinoma of lung
		14.3.2 Carcinoma of the colon and rectum
		14.3.3 Carcinoma of breast
		14.3.4 Carcinoma of prostate
		14.3.5 Hematological malignancies
		14.3.6 Gamma knife radiosurgery for tumor deposits in the brain
	References
15. Specific aspects of cytotoxic and hormonal drug therapies
	15.1 General
		15.1.1 Differences in chemical structures and mechanisms of effects of cytotoxic drugs
			(a) Arsenic trioxide
			(b) Nitrogen mustards
			(c) Antimetabolites
				(i) Methotrexate
				(ii) 5-Fluorouracil
				(iii) Hydroxyurea and nitrosoureas
			(d) Cis-platin
			(e) Poly (ADP-ribose) polymerase inhibitors
			(f) Antimicrotubule agents
				(i) Vinca alkaloids
				(ii) Taxanes
				(iii) Other
			(g) Antitumor drugs related to antibiotics
		15.1.2 Activation of prodrugs to active compounds
		15.1.3 Differences in the potencies for a variety of biological effects among different analogues in the same chemical class
		15.1.4 Multiplicity of molecules affected: “polypharmacology”
		15.1.5 Techniques for increasing diffusion and active transport of drugs into tumor cells
		15.1.6 Endocytosis-dependent drug uptake into cells
	15.2 “Target-selective” drugs
		15.2.1 General
		15.2.2 Antibodies against specific cell surface receptors
		15.2.3 Drugs against intracellular signaling enzymes
		15.2.4 Antiangiogenesis drugs
		15.2.5 Aptamers and aptamer targeting
		15.2.6 Difficulties in drugging certain targets
		15.2.7 “On-target” and “off-target” effects of targeted drugs
	15.3 Aspects of personalized medicine
		15.3.1 Terminology
		15.3.2 Studies of the patient's tumor cells in cultures or as xenografts
			(a) Cell biological and pharmacological assessments of cultured cells from the patient's tumor
		15.3.3 Patients' normal genomes and therapy (pharmacogenomics)
	15.4 Chemotherapies for particular malignant tumors
		15.4.1 Small-celled carcinoma of lung
		15.4.2 Nonsmall-celled carcinoma of lung
		15.4.3 Colorectal carcinoma
		15.4.4 Carcinoma of the breast
		15.4.5 Prostate
		15.4.6 Other
			(a) Melanoma
			(b) Renal cell carcinoma
			(c) Gastric and pancreatic cancer
	15.5 Antihormone therapies
		15.5.1 Breast carcinoma
			(a) Estrogen production suppressors
				(i) Chemical ovariectomy
				(ii) Aromatase inhibitors
			(b) Estrogen receptor blockers
			(c) Antiestrogen: estrogen receptor degrader
		15.5.2 Prostate carcinoma
			(a) Androgen production suppressants
			(b) Androgen receptor blockers/antagonists (antiandrogens)
	15.6 Summary of translational issues
		15.6.1 Pharmacokinetics and -dynamics in relation to tumor cells
	References
16. Immunotherapies
	16.1 Tumor antigens
		16.1.1 Antigens in general
		16.1.2 Tumor-associated antigens: substances in human tumors which provoke immune responses in at least one nonhuman species
		16.1.3 Mechanisms of responses of naïve B and T cells to antigens
			(a) Naïve B cells
			(b) Naïve T cells
		16.1.4 Antigen-presenting cells
			(a) Role of macrophages
			(b) Role of dendritic cells
			(c) Other antigen-presenting cells
	16.2 Cytotoxic responses of immune cells
		16.2.1 Cell killing by antibodies and macrophages
		16.2.2 Cell killing by T lymphocytes
		16.2.3 Cell killing by NK cells
	16.3 Possible explanations of tumor growth in the presence of normal immune responses generally
		16.3.1 Background
		16.3.2 The tumors' antigens are too weak to provoke a response
		16.3.3 The tumor is suppressing, or at least locally defending itself against, antitumor immune reactions
		16.3.4 The patient's immune system has become “tolerant” of the tumor antigens
			(a) “Tolerance” as in the phenomenon of unrejected grafts
			(b) Immune paralysis
	16.4 Therapies specifically or nonspecifically increasing patient's cellular immune responses
		16.4.1 Autologous vaccines: stimulation of the patient's immune reactions to particular antigens
		16.4.2 General stimulation of patient's immune system with cytokines
		16.4.3 General stimulation of production of cytotoxic T cells: “checkpoint inhibitors”
		16.4.4 Other
	16.5 Therapies supplying additional unmodified specific effector cells
		16.5.1 Ex vivo expanded peripheral blood cytotoxic lymphocytes
		16.5.2 Ex-vivo expanded tumor-infiltrating lymphocytes
		16.5.3 Allogenic expanded natural killer cells
		16.5.4 Ex vivo manipulation of dendritic cells
	16.6 Therapies supplying genetically modified effector cytotoxic cells
		16.6.1 CRISPR for editing genes in cells
		16.6.2 CAR-T cells
		16.6.3 “Universal” CAR-T cells
		16.6.4 Other drawbacks of genetically engineered lymphocytes
			(a) Costs
			(b) CRISPR errors
			(c) Of allogenic T-cell transfusions
	16.7 Managing the treatment
		16.7.1 Preconditioning
		16.7.2 Clinical follow-up
		16.7.3 Assessment of effects: lack of monitoring of immunological responses
		16.7.4 Identifying resistance
	16.8 Potentially fatal side effects
		16.8.1 Constitutional and gradual-onset inflammatory effects
		16.8.2 Infections
		16.8.3 “Cytokine release syndrome”/“cytokine storm”
		16.8.4 CNS leukoencephalopathies
	16.9 Summary of translational issues in immunotherapies of tumors
		Pharmacokinetic considerations
		Regulation/economic/social considerations
	References
17. Gene therapies not related to immunological therapies
	17.1 Techniques and strategies
		17.1.1 Background—treatment of hereditary metabolic diseases
		17.1.2 Vectors
			(a) Viral vectors
			(b) Nonviral methods for gene delivery
		17.1.3 Editing genes with CRISPR in the patient
		17.1.4 Rationales and genes inserted; personalizing the therapy
			Identification of therapeutic genes
			(a) Knock-out of oncogene or related signaling mechanism
			(b) Wild-type tumor suppressor gene to compensate for its loss/deregulation, e.g., P53
			(c) Prodifferentiation genes
			(d) Antiangiogenesis or related microenvironment-relevant gene
			(e) Transcription factors
			(f) MicroRNAs
			(g) Genes for conversion of prodrugs to active counterparts
			(h) Genes to induce apoptosis or enhance tumor sensitivity to conventional drug/radiation therapy, e.g., TRAIL
				(i) Inserting an antigen to which the patient's immune system can mount cytotoxic reactions
	17.2 Management of treatment in the individual patient
		17.2.1 Clinical follow-up for cancer patients
		17.2.2 Assessing transferred gene expression in the patient's tumor
		17.2.3 Side effects
			(a) General
			(b) Of the viral vector if used
			(c) Second malignancies
	17.3 Summary of translational issues
		Prevention of tumors
		Technological developments and clinical trials
	References
18. Less common and controversial therapies
	18.1 Therapies using microbiological agents
		18.1.1 Bacterial toxins
		18.1.2 Live bacterial infection: BCG therapy for tumors of the bladder
		18.1.3 Oncolytic viruses
	18.2 Stem cell therapies
		18.2.1 Hematologic stem cells in the treatment of hematological and some other disseminated malignancies
		18.2.2 “Embryonic” and “mesenchymal” stem cells as treatment for solid tumors
		18.2.3 Advice from the food and drug administration
	18.3 Epigenetic therapies
		18.3.1 Rationales
		18.3.2 Current therapies offered
	18.4 “Complementary” and “alternative” regimens
		18.4.1 General
		18.4.2 Terminology
		18.4.3 Complementary therapies as those being essentially additional psychological assistance
		18.4.4 Alternative therapies as those having no biological or psychological basis—other than placebo—for benefit
	References
19. Care after primary therapy
	19.1 Definitions
		19.1.1 “Palliative” and “supportive”
		19.1.2 Aspects of the use of the term “survivorship”
	19.2 Needs of the patient and care after primary therapy
		19.2.1 Symptom relief and rehabilitation from effects of primary care and recurrences/relapses (if applicable)
		19.2.2 Symptom relief and assistance with daily living when active disease is progressive and untreatable
		19.2.3 Psychological support
		19.2.4 Social, financial, informational, and spiritual needs
		19.2.5 Support for families
		19.2.6 Sources and standards
		19.2.7 Statements of “unmet needs”
	19.3 Problems of particular cancers
		19.3.1 Carcinoma of the lung
		19.3.2 Carcinoma of the large bowel
		19.3.3 Carcinoma of the breast
		19.3.4 Carcinoma of the prostate
		19.3.5 Other cancers
			(a) Leukemia
			(b) Lymphomas
			(c) Gliomas
			(d) Malignant melanoma
			(e) Gastric cancer
			(f) Liver cancer
			(g) Renal cell carcinoma
	19.4 Advance Care Planning
		19.4.1 History and current situation
		19.4.2 Practicalities
	References
20. Costs, ethics, and malpractice litigation
	20.1 General
		20.1.1 Rising costs of cancer
		20.1.2 Classification of costs by activity
		20.1.3 Classification of costs by phase of illness
		20.1.4 Costs arising from side effects and complications of therapies
		20.1.5 Cost-effectiveness versus cost– benefit analyses
		20.1.6 Attempts at cost containment
		20.1.7 The hospice movement, the Liverpool Care Pathway, current hospice care
		20.1.8 Statement of principles on cost containment by the American Cancer Society
		20.1.9 The global perspective
	20.2 Paying for the costs
		20.2.1 Government-funded health care and private medical insurance
		20.2.2 Sources of “financial toxicity”
	20.3 Ethical issues in medical treatment
		20.3.1 At diagnosis of cancer: who should be told?
		20.3.2 Deciding no treatment–any treatment and nature of primary treatment
			(a) No treatment versus any treatment
			(b) Suitable for primary treatment: which?
		20.3.3 Ethical issues in the monitoring and terminal phases: hope and abuse of hope
		20.3.4 Ethical issues in withdrawal of supportive care: physician-assisted suicide—euthanasia
		20.3.5 Role and rights of relatives
		20.3.6 Ethics of reducing the patient's estate
	20.4 Ethical issues in oncological research
		20.4.1 Research “participation”
		20.4.2 Likelihood that the research will produce an outcome
		20.4.3 Risk that the research will produce harm to the participants
	20.5 Ethical issues in resource allocations at national and international levels
		20.5.1 Allocation of resources nationally
		20.5.2 Allocation of resources internationally
		20.5.3 Ethical considerations in relation to health care availability according to international standards
		20.5.4 Ethics and research
	20.6 Litigation, malpractice, and avoidance of errors
		20.6.1 Scope and natures of complaints
		20.6.2 Avoidance of errors: second opinions
		20.6.3 Arising from advance care directives
		20.6.4 Importance of multidisciplinary meetings
	References
APPENDIX
1 - Principles of normal embryology, histology, and related cell biology
	A1.1 Aspects of normal development and organs and tissues of the adult
		A1.1.1 Meiosis and the origins of individuality
		A1.1.2 Aspects of early embryonic development
		A1.1.3 The organ systems of the adult body
		A1.1.4 The tissues and categories of cells in the adult body
			(a) Tissues
			(b) Categories of cells
			(c) The “reticuloendothelial system”
		A1.1.5 Cells mixed with some epithelia
		A1.1.6 The interstitium as the “microenvironment” of cells
		A1.1.7 Physiological and nontumorous variabilities in tissues
	A1.2 Aspects of normal cells
		A1.2.1 Cytostructural regularity of each kind of normal cell
		A1.2.2 Cells having the same general function may have different structural details in different organs
		A1.2.3 The cell/plasma membrane
		A1.2.4 Cell membrane–cytoskeletal interactions
		A1.2.5 The cytoplasmic and functional variabilities in each kind of cell
		A1.2.6 The nucleus in general and as the compartment for the genome and genomic activity
			(a) Size
			(b) The nuclear membrane and perinuclear cytoplasm
			(c) Nucleolus
			(d) Nonstaining nuclear substance, including “matrix”/“scaffold”
			(e) Chromatin
			(f) Chromosomes
		A1.2.7 Variability in activation status of cells of the same kind: “cytes” and “blasts”
		A1.2.8 Other physiological variabilities within the one population of the same kind of normal cell
			(a) Stage of specialization
			(b) Periods and phases in the cell cycle
	A1.3 Aspects of growth in normal tissues and cells
		A1.3.1 General
			(a) In embryonic development
			(b) In adult life
			(c) In normal and regenerative production of labile cells
			(d) In compensatory and pathological proliferative lesions
			(e) The phasic aspect of cell production in embryonic and normal cells
			(f) Changes with age of the individual
		A1.3.2 The different concepts of “stem cells” in embryology and adult histology
			(a) In embryology
			(b) In histology, including hematology in adults
			(c) In studies of tumor cell populations
		A1.3.3 The different life cycles of different kinds of cells in adults
			(a) Labile” cells: those in which local tissue stem cells continuously produce functional cells
			(b) Stable” cells: those comprising uniformly long-lived cells which can reproduce their own kind under certain pathological ci ...
			(c) Permanent” cells: those comprising uniformly long-lived cells which cannot reproduce under any circumstances
		A1.3.4 Division period,” “interdivision period,” and the cell cycle
		A1.3.5 Nuclear division: mitosis
			(a) Pro(sub)phase
			(b) Meta(sub)phase
			(c) Ana(sub)phase
			(d) Telo(sub)phase
			(e) Cytokinesis
		A1.3.6 Biochemical aspects of cell division
			(a) Initiation through cyclins
			(b) Check points” in cell division
	A1.4 Different susceptibilities and responses of normal cells to injuries
		A1.4.1 Metabolic susceptibilities and particular defenses in cells of different kinds
		A1.4.2 Increased cell production after tissue loss: reconstitution, regeneration, and repair
		A1.4.3 Increased production of individual kinds of cells after chemical damage
			(a) Ethanol poisoning of liver cells
			(b) Cytotoxic damage to bone marrow cells
			(c) Ischemic damage to renal tubular epithelial cells
			(d) Other
		A1.4.4 Metaplastic responses
	A1.5 Invasions and metastases by normal individual cells and populations of cells
		A1.5.1 Physiological invasions and metastases
		A1.5.2 The relocalizing of normal cell populations by differential localized growth
		A1.5.3 Passive movements of cells
		A1.5.4 The kinds of active movements of individual normal cells
			(a) Sliding movement”
			(b) Ameboid movement
			(c) The crawling movements of other cells in culture (such as fibroblasts)
	References
APPENDIX
2 - Aspects of the normal genome
	A2.1 General
		A2.1.1 Terminology
		A2.1.2 Functional aspects of genes
			(a) “Dominance,” “recessivity,” and the functional “morphisms” of genes
			(b) Haploinsufficiency and -sufficiency
			(c) Activity repertoires
				(i) The constant expressions of “structural” genes
				(ii) “One-off” physiological phasic expression of genes
				(iii) Regularly recurrent phasic expressions of genes
				(iv) “On demand” expression of genes
		A2.1.3 Polygenic traits
		A2.1.4 Descriptions by role
			(a) “Executive” and “realizator” genes in “cascades”
			(b) “Gate-keeper” and “caretaker” genes
			(c) “Landscaper” genes
			(d) “Executioner” genes
		A2.1.5 Differences between genomes of different kinds of cells in the same individual
		A2.1.6 Mitochondrial DNA
	A2.2 Composition
		A2.2.1 Background
		A2.2.2 DNA coding for proteins
		A2.2.3 Nongenic RNAs
			(a) Relating to protein synthesis
			(b) Others (some may have more than one function)
		A2.2.4 RNA genes (“regulatory RNAs”)
		A2.2.5 Never transcribed genomic elements
			(a) “Pseudogenes”
			(b) Repetitive sequences including “satellite” DNA
			(c) Insulators
			(d) “Scaffold/matrix-attachment regions” (“matrix-binding domains”)
			(e) Centromeric DNA
			(f) Telomeres
			(g) The inactive X chromosome (the Barr body) in human females
	A2.3 General aspects of synthesis of nucleic acids
		A2.3.1 Structural biology of the sites of molecular interactions
		A2.3.2 Some genomic processes involve enzyme-induced breaking of DNA strands
			(a) Untwisting and unraveling not related to synthesis
			(b) Presynthesis nucleotide excision repairs
		A2.3.3 The support functions involved in genome-related processes; implications for mutagenesis and clastogenesis
			(a) “Tether” function during the particular process
			(b) “Motor functions” for polymerase complexes
			(c) Protein structures for integrity of the complexes
			(d) Significance of the complexities of genome process–associated proteins to mutagenesis and clastogenesis
	A2.4 Synthesis of DNA
		A2.4.1 Steps in synthesis
		A2.4.2 The problem of the “lagging” strand
		A2.4.3 Postsynthesis corrections
	A2.5 Synthesis of RNA (“transcription”)
		A2.5.1 Turnover of the different types of RNAs in cells
		A2.5.2 Steps in RNA synthesis
		A2.5.3 Regulation of synthesis of mRNAs
			(a) External agents
			(b) Regulatory proteins (transcription factors)
			(c) Other regulatory mechanisms
		A2.5.4 Pleiotropy of regulators
		A2.5.5 Alternative splicing and mRNA editing and their regulation
	A2.6 Protein synthesis and posttranslational modifications
		A2.6.1 Protein synthesis and factors modifying
			(a) Synthesis (“translation”)
			(b) Regulation
		A2.6.2 Posttranslational modification and its regulation
		A2.6.3 Pleiotropy of proteins
	A2.7 Concepts of epigenesis in the genome
		A2.7.1 Terminology
		A2.7.2 DNA methylation
			(a) General
			(b) Patterns of methylation
		A2.7.3 Inheritability: germline (identical twins) and in development of tissues of individuals
			(a) Between identical twins
			(b) Development and tissues of individuals
				(i) Development
				(ii) Tissues in the adult
		A2.7.4 Overlap with RNA genetics
		A2.7.5 Tentative summary
	References
APPENDIX
3 - Fixed genomic events and possible mechanisms of their causation by etiological agents
	A3.1 Terminology and basic concepts of fixed genomic events
		A3.1.1 “Mutation” and “genomic event”
		A3.1.2 “Nongenopathic” and “genopathic” in relation to agents which damage the genome
		A3.1.3 Ambiguity of “genotoxic” in the same regard
		A3.1.4 Clastogens
	A3.2 Nucleotide errors and their mechanisms
		A3.2.1 The kinds of fixed uni- or oligonucleotide errors and origins in DNA synthesis
			(a) Classification of these errors
			(b) Errors in synthesis
		A3.2.2 Damage to DNA, repairs, and errors arising
			(a) Damage
			(b) Repairs
				(i) Removal of adducts by scavenging enzymes, such as methyltransferases [31]
				(ii) Base-excision repair and nucleotide excision repair
				(iii) These errors may be commoner in metabolically active or dividing cells
		A3.2.3 Other non-DNA damage theories of nucleotide errors
			(a) “One-off” episodes of impaired replicative fidelity
			(b) Transcriptional errors as source of multiple genomic lesions
	A3.3 Nucleotide errors produced by known carcinogens
		A3.3.1 Radiations
		A3.3.2 Specific chemical carcinogens and specific nucleotide errors genome wide
		A3.3.3 Specific chemical carcinogens and specific genomic sites of errors: “mutational spectra”
	A3.4 Nucleotide errors according to tumor type
		A3.4.1 General complexities of findings in tumor genomes
		A3.4.2 Mutational spectra according to tumor types
	A3.5 Further perspectives on nucleotide error formation in the pathogenesis of tumors
		A3.5.1 Species differences in radio-sensitivities to genomic damage
		A3.5.2 Genomic damage caused by noncarcinogens
		A3.5.3 Similar genomic damage in nontumorous pathological processes
		A3.5.4 Lack of correlation between potencies in carcinogenicity and other genopathic effects of many agents
		A3.5.5 Adducts on DNA are not always associated with tumors in the relevant cells
		A3.5.6 Most damage to the genomes of somatic cells is probably inconsequential
			(a) The genome overall is dilute in respect to genes
			(b) In embryonic and adult life, cells presumably use only a small part of their genomes
			(c) Many proteins can sustain alterations of amino acid sequence without altered function
			(d) Tissue and cell factors in the protection of the normal cell population
		A3.5.7 No particular error of this type has been found so far in all tumors, but nevertheless could exist
	A3.6 Chromosomal aberrations
		A3.6.1 Aberrations in chromosomal numbers
		A3.6.2 Aberrations in chromosomal compositional structure (see also Section 10.2.3)
			(a) General
			(b) Terminology
		A3.6.3 Kinds of chromosomal aberrations according to size
		A3.6.4 Functional effects of chromosomal aberrations
		A3.6.5 No relationship between carcinogen and type of chromosomal aberration
	A3.7 Theories of mechanisms of chromosomal abnormalities
		A3.7.1 Early theories based on breaks in arms of assembled chromosomes
		A3.7.2 The “tether drop” theory of chromosomal aberrations involving primary DNA strand breaks
	A3.8 Genomic lesions potentially inducible by viruses and other agents
		A3.8.1 Insertion of viral genes into the genome
			(a) Expression of a viral protein with growth-promoting properties
			(b) Expression of viral protein which inhibits a tumor suppressor gene
			(c) Loss-of-function genomic event in a host gene: “common insertion sites”
			(d) Secondary “hot spots” of genomic events
		A3.8.2 Possible actions of viral DNA through position effects in host DNA
		A3.8.3 Viral infections producing genomic transfection events between genomes of adjacent host cells
		A3.8.4 Permanent effects of transiently expressed viral proteins as the mechanism of genomic
	A3.9 Translational issues in molecular mutagenesis, clastogenesis, and carcinogenesis
		A3.9.1 Imperfect correlations between chromosomal abnormalities and carcinogenesis
		A3.9.2 Mechanisms of solid-phase clastogenesis
	References
APPENDIX
4 - Genomic instabilities: kind, effects, and roles in the immortality of tumor cell populations
	A4.1 Continuously accumulating nucleotide errors (“mutator phenotype”)
		A4.1.1 DNA-related mechanisms of “mutator phenotype”
		A4.1.2 mRNA editing–based mechanisms
	A4.2 Continuously accumulating chromosomal/karyotypic instability
		A4.2.1 “Karyoinstablity” not “aneuploidy”: the distinction between fixed and unstable genomic abnormalities in cell populations
		A4.2.2 Near-universality of hyperploidy and karyoinstability in tumor cell populations
		A4.2.3 Mechanisms of karyoinstability
	A4.3 Other kinds of genomic instability in tumors
		A4.3.1 Microsatellite” instabilities
		A4.3.2 Irregular and possibly partial endoreduplication
		A4.3.3 Intertumor cell gene transfer/“horizontal gene transfer”
		A4.3.4 Other mechanisms and considerations
			(a) Inappropriate meiotic crossing over as a kind of genomic instability
			(b) Inappropriate gene rearrangements in lymphocytes as physiological, limited kind of somatic cell genomic instability
			(c) Abnormalities in the nuclear “matrix”
			(d) Tetraploidy and subtraction of chromosomes
	A4.4 Potential effects of the genomic instabilities in tumor cell populations
		A4.4.1 Unstable genomic abnormalities as a source of morphological, behavioral, and molecular variabilities and heterogeneities
		A4.4.2 Different cell lines being grown from different cases of the same tumor type
		A4.4.3 As a mechanism of delays in carcinogenesis
		A4.4.4 As the mechanisms of tumor progression
	A4.5 Immortality of tumor cell line arises because nucleotide error accumulation is countered by chromosomal maldistributions, l ...
	A4.6 Summary of translational issues in genomic instabilities
		Uncertainty about types of instabilities, and hence how they might be controlled
			Unexplained aspects of tandem nucleotide repeat variabilities in cancer
	References
APPENDIX
5 - Methods in histologic and molecular assessments of tumors
	A5.1 Basic histologic processing
		A5.1.1 Fixation; shrinkage
		A5.1.2 Preparing thin slices/“sections”; shrinkage
		A5.1.3 Standard chemical stains for cell and tissue components
		A5.1.4 Some special chemical stains
	A5.2 Staining using antibodies raised in nonhuman species
		A5.2.1 Fluorescein-labeled antibody techniques
		A5.2.2 Immunohistochemical staining
			(a) Single block staining for general histology and histopathology
			(b) Tissue microarrays
			(c) Scoring and interpretation
			(d) Deterioration of tissue stainability with time
	A5.3 Identification of specific DNA and RNA nucleotide sequences in tissues
		A5.3.1 Specific DNA
		A5.3.2 Specific RNA
	A5.4 Methods in chromosomal analyses of tumors
		A5.4.1 Microscopical studies of cells
			(a) Metaphase
				(i) Traditional staining
				(ii) Microscopy-based molecular biological method: comparative genomic hybridization
			(b) Interphase
		A5.4.2 Studies on extracted DNA
			Array-based CGH
	References
APPENDIX
6 - “Biomarkers” in molecular pathology and oncology
	A6.1 Terminology and applications
		A6.1.1 Definitions of “biomarkers”
		A6.1.2 Biomarkers for physiological and pathological processes
		A6.1.3 Biomarkers of exposure to noxious agents, as used in epidemiological studies
		A6.1.4 Biomarkers in screening, diagnosis, and monitoring of disease progression
	A6.2 Validation of biomarkers
		A6.2.1 General
		A6.2.2 Development of new biomarkers
		A6.2.3 “Theranostics”
	A6.3 Translational issues in biomarkers
		A6.3.1 Biomarkers as prognostic and predictive indicators
	References
APPENDIX
7 - Sublethal injuries and deaths of cells and tissues
	A7.1 Sublethal nongenopathic effects in cells: “degenerations,” “cell stress,” and “cell stress responses”
		A7.1.1 Terminology
		A7.1.2 Different effects with different doses of injurious agent
		A7.1.3 Morphological manifestations: “degenerations”
			(a) Swelling due to accumulation of water
			(b) “Fatty change” (accumulations of triglycerides in vacuoles) (Figs. 10.1C, D)
			(c) “Hyaline degeneration”
			(d) “Zeiosis,” “blebbing,” and “exosomes”
			(e) “Granularity” of cytoplasm
		A7.1.4 Lysosomes; autophagy; exocytosis
		A7.1.5 Ubiquitin–proteasome pathway
		A7.1.6 Caspase proteolysis
		A7.1.7 Cell stress
		A7.1.8 Cell stress responses
	A7.2 Sublethal genopathic injuries to cells
		A7.2.1 Transient reductions in DNA and RNA syntheses
		A7.2.2 Limited damage to genes
		A7.2.3 Limited chromosomal aberrations
		A7.2.4 Formation of “micronuclei”
		A7.2.5 Other
	A7.3 Cell deaths in normal cell populations in vivo
		A7.3.1 General
		A7.3.2 Autolysis
	A7.4 Necrosis
		A7.4.1 Macroscopic and microscopic features
		A7.4.2 “Necrosis”: electron microscopic appearances and biochemical changes
		A7.4.3 No specific term for slow death of cells in pathological conditions
	A7.5 Apoptosis
		A7.5.1 Original description
		A7.5.2 Various uses of the term
		A7.5.3 Biochemical “surrogates” for apoptosis
		A7.5.4 “Apoptosis” in nontumorous human pathological conditions
	A7.6 Other forms of cell death
		A7.6.1 “Area” coagulative necrosis
		A7.6.2 Inappropriate vegetative state (“reproductive death”) in tumor cell populations
		A7.6.3 Mitotic catastrophe
		A7.6.4 Senescence” of in vitro cultures
		A7.6.5 “Autophagic” cell death
	A7.7 Inflammation and other tissue effects
		A7.7.1 “Acute” and “chronic” inflammation
		A7.7.2 Morphological forms of inflammation
		A7.7.3 Healing by scarring
	References
APPENDIX
8 - “Pretarget,” “target,” and recovery capacity defenses of cells against carcinogens and cytotoxic agents
	A8.1 Pretarget defenses
		A8.1.1 Defensive barriers at the whole-body level
			(a) At the portal of entry of the agent
			(b) In the circulation and other organs
			(c) In the interstitial spaces/“microenvironment” surrounding the target cells
		A8.1.2 Defensive barriers of the cell and of the genome compartment
			(a) At the cell membrane or in the cytoplasm
			(b) (Potentially) at the nuclear membrane or in the nucleus (Fig. A8.1)
		A8.1.3 Cellular phenomena which might reduce pretarget resistance factors
			(a) The events of cell division
			(b) Degree of specialization
			(c) Concurrent pathological processes
		A8.1.4 Species differences in pretarget resistance factors
	A8.2 Defenses relating to the target
		A8.2.1 Relative quantity of target
		A8.2.2 Qualitative differences in targets
		A8.2.3 Rates of turnover of target
	A8.3 Recovery defenses
		A8.3.1 Capacities for return to normal function by damaged cells
		A8.3.2 Capacities for regenerations with new cells to replace lost cells
	A8.4 Potential roles of defensive factors in conflicting results of animal tests for carcinogens and anticancer drugs
	References
APPENDIX
9 - Developing and testing new therapies: clinical trials
	A9.1 Developing new regimens involving established agents without involving clinical trials
		A9.1.1 With reference to the literature, but without formal controls
			(a) Case reports
			(b) Series of cases
			(c) Analyses from databases
		A9.1.2 With some controls
			(a) Retrospective case series with matched controls
			(b) Case series with historical controls (often same institution)
	A9.2 Developing treatments involving new agents: animal experimental and preclinical trial studies
		A9.2.1 “Lead” compounds and analogues
		A9.2.2 Evaluation of efficacy, toxicity, and pharmacokinetic factors in in vitro and animal tests
	A9.3 Clinical trials: general
		A9.3.1 Types of clinical trials
		A9.3.2 Registering with and obligations to regulatory agencies
		A9.3.3 Reporting progress
		A9.3.4 The phases in clinical trials
			(a) General
			(b) Phase 0 and 1 trials
			(c) Phase 2 trials
			(d) Phase 3 trials
			(e) Phase 4 trials
	A9.4 Difficulties of clinical trials: measures of benefit
		A9.4.1 Recruitment and related issues
		A9.4.2 Quality of data for measuring benefit
			(a) Response rate of first regimen
			(b) Disease-free survival
			(c) Progression-free survival
			(d) Quality of life years
			(e) Specified period survival
			(f) Overall survival time
		A9.4.3 Biases
			(a) Patient selection biases
			(b) Diagnostic selection biases
			(c) Size of “sample / power” of study and other statistical issues
			(d) In relation to “double blinding” of trials
			(e) Compliance bias
			(f) Contamination
		A9.4.4 Costs
	A9.5 Metaanalyses of multiple trials
		A9.5.1 General
		A9.5.2 As applied to comparing institutions
	References
Index
	A
	B
	C
	D
	E
	F
	G
	H
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	K
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	M
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	P
	Q
	R
	S
	T
	U
	V
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	X
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