CRITERIA SUGGESTIVE OF HEREDITARY CANCER
- Tumor development at a much younger age than usual 2. Presence of bilateral disease 3. Presence of multiple primary malignancies 4. Presentation of a cancer in less than affected sex. 5. Clustering of the same cancer type in relatives 6. Cancer associated with other conditions such as mental retardation and pathognomic skin lesion
the gene mutated in multiple advanced cancers 1
PTEN
Metastases diagnosed at the initial cancer diagnosis
SYNCHRONOUS METASTASES
Activating mutations in BRAF causes:
Melanoma Sporadic colorectal cancer Papillary thyroid cancer
angiogenic oncogenes and tumor-suppressor genes
Ras Myc HER2/ neu p53
viral DNA can be integrated into the cellular chromosomal DNA, leading to transformation of cells to a neoplastic state
Non Permissive Host
Breast self-examination
Monthly, starting at age 20
Cells present in the blood that possess antigenic or genetic characteristics of a specific tumor type
CA – CIRCULATING TUMOR CELLS
PTEN ((phosphatase and tensin homologue)
Cowden Disease (multiple hamartoma syndrome)
Encodes for the human homologue of the yeast Cds1 and the RAD53 G2 checkpoint, whose activation by DNA damage prevents entry into mitosis
hCHK2 gene
Disappearance of disease and no evidence of new for a specified interval of 4 weeks
Complete response
Is a tumor related antigen that is elevated in colon and pancreatic ca; Measured at the start of therapy and every 1-3 mos while under treatment
CA 19-9
Step in Tumorigenesis that may lead a single cell to acquire a distinct growth advantage
Initiation
2 types of oncogenes
Growth Factors Growth Factor Receptors
other names for gene p16
INK4A, CDKN1, CDKN2A, and MTS1
3 groups of chemical carcinogens
- Genotoxins 2. Co-carcinogens 3. Tumor promoters
irradiated cells secrete cytokines and other factors that increase production of reactive oxygen species in bystander cells, may involve cell to cell communication via gap junction
“By stander effect”
Tumor cell-cycle regulators (in human) which are frequently mutated or altered in expression:
INK4a INK4b KIP1
Major cellular pathway for protein and organelle turnover
Autophagy
Progression step in tumorigenesis
Repeated promoter application to acquire spontaneous mutation
hereditary predisposition for colorectal cancer with early age of onset and an excess of synchronous and metachronous colonic cancers
Lynch 1
Tamoxifen
Endometrial CA
5q Mutation
FAP (Familial Adenomatous Polyposis)
A genetically regulated program to dispose of cells
Apoptosis
What are the types of Adjuvant Therapy?
Chemotherapy Hormonal therapy Immuno-therapy Biologic therapy Radiation Therapy
What is formed when ligands are bound to the receptors
DISC (Death Inducing Signal Complex)
50% or more decrease of the original size, determined by two observations (not less than 4 weeks apart); No appearance or progress of new lesion progression of any lesion demonstrated
Partial Response
Benzene, Chlorambucil
Leukemia
infection with an oncogenic DNA virus result in a productive lytic infection, leading to cell death and release of newly formed viruses
Permissive Host
Ubiquitous proteins that are produced and secreted by cells locally which stimulates cell proliferation
Growth factors
Steps in Tumorigenisis
Initiation Promotion Progression
Types of Alkylating Agents
- Classic alkylators 2. Nitrosoureas 3. Miscellaneous DNA-binding agents
Two types of epidemiological studies that are done most commonly
Cohort Study Case-control Study
Glycoprotein encoded by MUC1 gene that tumor cells shed into the blood stream and useful in diagnosis of advanced breast CA
CA15-3
Antitumor Antibiotic
Bleomycin
Tumor suppressor that acts by binding CDK4 and CDK6 and inhibiting the catalytic activity of the CDK4-CDK6/cyclin D complex
p16
CEA (Carcinoembryonic Antigen) is elevated specially in?
colon cancer
Anti-metabolites
Folate analogues Methotrexate Purine analogues Azathioprine Mercaptopurine Thioguanine Cladibrine (2-chlorodeoxyadenosine) Fludarabine Pentostatin Pyrimidine analogues Capecitabine Cytarabine Floxuridine Gemcitabine Ribonucleotide reductase inhibitors Hydroxyurea
25% or greater increase in size or appearance of new lesions
Progressive
Classifications of Biopsy
- Mucosal biopsy via endoscopic exam 2. Palpable external lesions a. Needle biopsy - Fine needle biopsy - Core needle biopsy 3. Open biopsy (When needle biopsy is questionable) - Incision biopsy - Excision biopsy
Breast Cancer Global Statistics
2ND LEADING CANCER IN THE WORLD 5th MOST COMMON CAUSE OF CANCER DEATH
Physical Carcinogens cause cancer either by:
a. Induction of inflammation and cell proliferation b. Exposure induces DNA damages and mutation
Administration before surgery of tumor considered initially inoperable
preoperative chemotherapy, neoadjuvant chemotherapy, or induction therapy
hMLH1; hMSH2; hMSH6;PMS1; hPMS2
Hereditary nonpolyposis colorectal cancer
What is the primary goal of PRIMARY / DEFINITIVE THERAPY?
Local and regional control of cancer
Block caspase 3 activation
Inhibitors of Apoptosis Proteins (IAPs)
rb
Retinoblastoma
Uses of Cancer Staging
- Selection of therapy – basis for selection of therapy 2. Estimation of prognosis 3. Evaluation of treatments 4. Exchange of information among tx centers 5. Continued investigation of human cancers
It is detected by staining bone marrow aspirates with monoclonal antibodies to cytokeratin.
Bone marrow Metastases
Surgical ablation of organs producing the hormones- oophorectomy for breast cancer
Hormonal Therapy
Not a single cell but rather a large number of cells in a target organ may have undergone the initiating genetic event
Field Theory
Indications for Chemotherapy
- Established / documented distant metastatic disease: 2. Therapy given for patient with high risk for distant metastasis known as adjuvant chemotherapy.
Treatment for breast cancer which work by targeting bcr-abl, c-kit, and HER2/ neu,
Trastuzumab (Herceptin)
Cells that have the ability to perpetuate themselves through self-renewal and to generate mature cells of a particular tissue through differentiation
Cancer stem cells
Benzidine
Bladder cancer
Plant Alkaloids
VInca alkaloids Vinblastine Vincristine Vindesine Vinorelbine Epipodophyllotoxins Etoposide Teniposide Taxanes Paclitaxel Docetaxel
stimulate hydrolysis of the bound GTP to return RAS to its inactive form
GTPase activating proteins (GAP’s)
Compare a group of patients affected with a disease to a group of individuals without the disease for a given exposure
Case-Conrol Study
Heat shock proteins
hsp27, hsp70
Promoters include:
Hormones Growth Factors Cytokines *Chronic Smoking
System describing the extent malignancy
Cancer Staging
Cells exhibit reduced sensitivity to drugs-by virtue of their cell cycle distribution
Kinetic Resistance
Spread from the primary site and formation of new tumor in distant sites
Metastasis
Bind to the DISC & inhibit activation of caspase 8
FADD-like interleukin-1 protease-inhibitory proteins (FLIPs)
hereditary predisposition for colorectal cancer with early age of onset and an excess of synchronous and metachronous colonic cancers and has a high risk for: carcinoma of the endometrium transitional cell carcinoma of the ureter and renal pelvis carcinomas of the stomach, small bowel, ovary, and pancreas
Lynch 2
Mechanisms of Viral Oncogenes
a. Interfere cell-cycle check points and DNA repair b. Expression of cytokines and other growth factors c. Alteration of immune system
Hepatocellular carcinoma
Hepatitis B Hepatitis C
Miscellaneous Agents
Asparaginase Estramustine Mitotane
3 stages of Adenomas:
Increase size Dysplasia Villous content
HPV type 16 and 18
Cervical cancer Anal cancer
Metastasis diagnosed after a disease-free interval
METACHRONOUS METASTASES
Nitrosoureas
Carmustine (BCNU) Lomustine (CCNU) Semustine (MeCCNU) Streptozocin
EBV (Epstein Barr Virus)
Burkitt’s lymphoma, Hodgkin’s disease Immunosuppression-related lymphoma Sinonasal angiocentric, T-cell lymphoma, Nasopharyngeal carcinoma
3rd most common cause of cancer death
Colorectal Cancer
if tumor is small, instead of removal of the whole breast, you only remove one quadrant
Conservative surgery
To induce or potentiate inherent anti-tumor immunity to destroy cancer cells
Immune therapy
Medullary thyroid carcinoma and pheochromocytoma (in 50%) or parathyroid adenoma (in 20%)
MEN2A
p53
Li-Fraumeni syndrome
Potentially best tumor marker available
PSA (Prostate Specific antigen)
Failure to kill cells is due to insufficient drug concentration occurs when tumor cells are located in sites where effective drug concentrations are difficult to achieve
Pharmacologic Resistance
The intent is not for cure because of the nature of the disease
Palliative surgery
Glycoprotein that is ideal for tumor marker
PSA (Prostate Specific antigen)
Adult T-cell leukemia or lymphoma
Human T-cell lymphotropic viruses
Follow a group of people who initially do not have a disease over time and measure the rate of development of a disease
Cohort Study
Metastatic process involves
- Access to circulation 2. Survival 3. Lodge in new organ 4. Initiate growth 5. Establish vascularization for survival
aberrations in the apoptotic program in human cancers:
- Increased expression of -Fas and TRAIL decoy receptors -anti-apoptotic Bcl-2 -IAP-related protein surviving -c-FLIP -growth factors and growth factor receptors activation of the PI3-K/Akt survival pathway 2. Mutations or downregulation of -proapoptotic Bax -caspase-8 -APAF1 -XAF1 -CD95, TRAIL-R1, and TRAIL-R2 (death receptors) 3. Alterations of the p53 pathway
Pathognomonic features of Cowden disease
Trichilemmomas, benign tumors of the hair follicle infundibulum, and mucocutaneous papillomatosis
Mammography
Annual, starting at age 40
Links Ras to activation of protein kinase C and calcium mobilization
Phospholipase C
Exploits the molecular difference between normal and cancer cells; Directed at the processes involved in tumor growth rather than directly targeting the tumor cells
Biological Therapy
Neither complete or partial response nor
Minimal or stable response
PSA (Prostate Specific antigen) sensitive for
prostate cancer benign prostate hypertrophy prostatis
Miscellaneous DNA-binding agents
Carboplatin Cisplatin Dacarbazinw (DTIC) Hexamethylmelamine Procarbazine
this cancer has the highest age-adjusted incidence in JAPAN
Stomach/Gastric Cancer
For large lesion done directly overlie the area to be removed than tunneling.
Incision Biopsy
five groups of human carcinogens
(1) Proven carcinogens (2A) Probable carcinogens (suggestive epidemiological evidence; no causality evidence and inadequate) basis (2B) Possible carcinogen (3) Not classifiable as to carcinogenicity in human but carcinogenic in animals (4) Probably not carcinogenic humans
Tumors that appear to lie exclusively above the basement membrane
In situ Cancer
Substances detected in higher levels produced either by cancer or body response to cancer can be both prognostic or predictive values
Tumor Markers
plays an important role in cell-cell interactions, cell adhesion, regulation of β-catenin, and maintenance of cytoskeletal microtubules
APC
Beryllium Cadmium
Lung cancer
identification of metastases that had formerly been silent and unidentified→stage migration→ perceived improvement in chances of survival
“Will Rogers effect”
TWO CRITERIA USED TO ASSESS THE EFFICACY OF A SENTINEL LYMPH NODE BIOPSY:
- Sentinel lymph node identification rate 2. False-negative rate
Performed using isosulfan blue dye, technetium-labeled sulfur colloid or albumin or a combination of both techniques to detect sentinel nodes which may improve the capability of detecting sentinel lymph nodes
LYMPHATIC MAPPING
Drive a quiescent cell from G0 into the cell cycle
Mitogenic Growth Factors
These are closely related to the death receptors but lack a functional death domain
Decoy receptors
What are the stimuli for the Mitochondrial Pathway of Apoptosis
o DNA damages o ROS o Withdrawal of survival factors
Eradication of micrometastatic disease with the intent of decreasing relapse rates and improving survival rates
Adjuvant Therapy (goal)
MEN1
Multiple endocrine neoplasia type 1
2 of the best studied oncogenes
- HER2/Neu (c-erb B-2) 2. RAS
PSA level of _____should be used as threshold for performing prostate biopsy
4ng/mL
Classic alkylators
Busulfan Chlorambucil Cyclophosphamide Ifosfamide Mechlorethamine (nitrogen mustard) Melphalan Mitomycin Triethylene thiophosphoramide (thiotepa)
Downstream pathways activated by RAS-GTP
Serine-Threonine Kinase RAF PI3K RAS-related RAL protein Phospholipase C
Performed for lesions for which either core biopsy is not possible or the results are nondiagnostic
Open Biopsy
Stimulate the formation of RAS-GTP (active form)
Guanine nucleotide exchange factors (GEFs)
Criteria for classic LFS in an individual (the proband):
a. A bone or soft tissue sarcoma when younger than 45 years b. A first-degree relative with cancer before age 45 years c. First- or second-degree relative with either a sarcoma diagnosed at any age or any cancer diagnosed before age 45 years
Attachment to glycoproteins of the ECM such as fibronectin, laminin, and collagen is mediated by
tumor cell integrin receptors
A family of proteases (Cysteine-dependent and aspartate-directed proteases) that effects the apoptosis
Caspases
Sometimes referred to as a second form of programmed cell death
Autophagy
Normal cellular gene that contributes to cancer when abnormal
Oncogene
defines the cancer in terms of the anatomic extent of disease and is based on assessment of three components; applies only to tumors that have been microscopically confirmed to be malignant
TNM staging
Surgeon in Oncology should:
- be responsible for the initial diagnosis and management of solid tumors 2. have knowledge of cancer epidemiology, etiology, staging and natural history since it is required for initial assessment and determination of optimal surgical therapy
ADJUVANT THERAPY primary goal
- Systemic control by treatment of distant foci of subclinical disease 2. Prevent distant recurrence
Types of Initiator Caspases:
Caspase 8 Caspase 9 Caspase 10
Procedure to remove a small area of diseased or problematic tissue with a margin of normal tissue
Excision Biopsy
States that lymphadenectomy is important for staging and survival; More extensive lymphadenectomy yielding of nodes reduces the risk of regional recurrence
Traditional Halsted View
First node to receive drainage from the tumor site
Sentinel Node
determines the tumor histology and grade and thus assists in definitive therapeutic planning
Biopsy
Process Involved in Invasion
- Changes in adhesion 2.Initiation of Motility 3. ECM proteolysis
Global Statistics of Lung Cancer
NO. 1 LEADING CANCER IN THE WORLD NO. 1 MOST COMMON CAUSE OF CANCER DEATH
What are the type of activation of the following genes? abl c-myc ras HER-2/neu
abl (Translocation) c-myc (Promoter insertion) ras (Mutation) HER-2/neu (Amplification)
Achieved with the help of MMP, proteinases, serine and cysteine and plasminogen activator
ECM proteolysis
Chemotherapy administered to a patient who is at high risk for distant recurrence but has no evidence of distant disease
Adjuvant Therapy
generally used to describe molecular markers that predict disease-free survival, disease-specific survival, and overall survival
Prognostic Markers
Types of Executioner Caspases:
Caspase 3 Caspase 6 Caspase 7
Usually is expressed as the number of new cases per 100,000 persons per year
Incidence
Another factor limiting optimal killing for drug-sensitive cancers; Dose reduction of 20% because of drug toxicity = decline in the cure rate by as much as 50%
IMPROPER DOSING
What are the 6 hallmarks of Cancer?
- self sufficiency of growth signals 2. Insensitivity to growth-inhibiting growth factors 3. Evasion of apoptosis 4. Potential for limitless replication 5. Angiogenesis 6. Invasion and Metastasis
Encodes small GTP-binding proteins that regulate several cellular processes
RAS
what are the 2 functions of Heat Shock Proteins in Apoptosis?
- Blocking formation of the apoptosome complex 2. Inhibiting release of cytochrome c from the mitochondria
Revised Criteria for Hereditary Nonpolyposis Colon Cancer (HNPCC) (Amsterdam Criteria II):
3-2-1-0 3 or more relatives with an HNPCC-associated cancer (colorectal cancer, endometrial cancer, cancer of the small bowel, ureter, or renal pelvis), one of whom is a first-degree relative of the other two At least 2 successive generations affected At least 1 case diagnosed before age 50 y Familial adenomatous polyposis excluded (0) Tumors verified by pathologic examination
BRCA1,BRCA2
Breast-ovarian syndrome
Response to Chemotherapy
Progressive Minimal or stable response Partial Response Complete response
Promoters enhance cell replication by:
- Interacting with self-surface receptors (to effect intracellular pathway) 2. Altering Gene expression
4 Phases of Cell cycle
S phase G1,G2 G0 M phase
Monitor trends in cancer incidence and mortality
Epidemiological Studies
infection of the cell is permanent (DNA or RNA virus)
RNA (Retro virus)
hCHK2
Li-Fraumeni syndrome and hereditary breast cancer
cell-cycle regulators which suppresses cell-cycle inhibitors like p27
cyclin D1
Characteristics of abnormally proliferating cells (5)
- Loss of contact inhibition 2. Altered Appearance and poor adherence to cells and substartum 3. Loss of Anchorage 4. Immortalization 5. Gain of Tumorigenicity
Proportion of patients in whom a sentinel lymph node was identified and removed among all patients undergoing an attempted sentinel lymph node biopsy
Sentinel lymph node identification rate
Normal gene that becomes an oncogene due to mutation or increased expression
Proto-Oncogenes
2nd most common cause of cancer death
Gastric cancer
Affect cell by binding to tubulin S phase Blocks microtubule polymerization impairing mitotic spindle formation M phase. Inhibits enzymes necessary to synthesize DNA.
Plant Alkaloids
cancer cells initially grow rapidly (exponential growth phase), then the growth slows down owing to hypoxia and decreased nutrient supply
GOMPERTZIAN MODEL
p53 gene is located in?
p arm of Chromosome 17 (17p)
Location of the following: HRAS KRAS NRAS
HRAS (Ch 11) KRAS (Ch 12) NRAS (Ch 1)
Establishment of new blood vessels from a preexisting vascular bed
Angiogenesis
Disadvantage of Fine Needle Biopsy
Cannot differentiate between invasive and noninvasive tumor.
this cancer is related mainly to dietary differences in consumption of animal fat, meat, and fiber.
Colorectal Cancer
Constitutive activation of RAF is common in some tumors such as:
Non–small cell lung cancer Renal cell carcinoma Hepatocellular cancer
Aflatoxins
Liver cancer
H. Pylori plays a major role in what cancer development?
Stomach/Gastric Cancer
the first breast cancer susceptibility gene identified
BRCA1
Primary modality of therapy for distant metastatic disease
Chemotherapy
What happens in Heterodimerization with HER2/neu?
Heterodimerization potentiates recycling of receptors rather than degradation
Proangiogenic factors
- VASCULAR ENDOTHELIAL GROWTH FACTORS (VEGF) 2. Platelet Derived Growth Factors (PDGF’s) A,B, C, D 3. ANGIOPOIETINS
TWO OPPOSING VIEWS REGARDING THE ROLE OF LYMPHADENECTOMY:
- The traditional Halsted view 2. The opposing view
factors responsible for initiating motility
autocrine motility factor autotaxin, scatter factor TGF-α EGF Insulin like GF
Components of Apoptosome
Cytochrome c Procaspase 9 Apoptotic protease activating factor 1 (Apaf-1)
Medullary thyroid carcinoma, marfanoid habitus, mucosal neuromas, and ganglioneuromatosis
MEN2B
Stages of Evaluation of Cancer Patient
- Cancer risk assessment 2. Cancer screening 3. Diagnosis 4. Cancer staging
APC
Familial adenomatous polyposis (FAP)
p16;CDK4
Familial melanoma
model uses risk factors such as an individual’s age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, number of previous breast biopsies, and whether the biopsy results revealed atypical ductal hyperplasia
GAIL MODEL
Treatment for chronic myelogenousleukemia and gastrointestinal stromal tumors
Imitanib Mesylate, Gleevec
Hallmark of HNPCC
microsatellite instability - unrepaired mismatches and small insertion or deletion loops
CDH1
Hereditary diffuse gastric cancer
tumor cells are genetically unstable and tend to mutate to form different cell clones
Goldie-Coldman hypothesis:
Best known agent of physical carcinogenesis
Radiation
HIV-1
Kaposi’s sarcoma Non-Hodgkin’s lymphoma
Tumors demonstrating ability to breach the basement membrane, penetrating into surrounding stroma
Invasive Cancer
En-bloc resection with adequate margins of normal tissues and regional nodes in some cases
PRIMARY / DEFINITIVE THERAPY
Autophagy is involved in:
o Starvation o Cellular differentiation o Cell death o Aging
cell that has a proliferative advantage by bypassing quiescence stage
Tumor Cell
Major groups of targeted therapy
Inhibition of growth factor receptors Intracellular signal transduction Cell cycle inhibitors Apoptosis based therapy Anti angiogenic compounds
RET
Multiple endocrine neoplasia type 2
SURGICAL GOLD STANDARD
negative surgical margins
Defined on the basis of observed clustering of malignancies, including early-onset breast cancer, soft tissue sarcomas, brain tumors, adrenocortical tumors, and leukemia
LI-FRAUMENI SYNDROME (LFS)
One of the best characterized tyrosine kinases because it is the preferred partner in heterodimer formation with all the other EGFR family
HER2/Neu (c-erb B-2)
Develop hundreds to thousands of polyps in the colon and rectum
FAMILIAL ADENOMATOUS POLYPOSIS (FAP)
Most common cancer in men
Prostate Cancer
Types of Cancer screening tests
- Physical examination 2. Laboratory 3. Imaging procedures 4. Genetic tests 5. BIRADS VI
Number of deaths occurring
Mortality
Colorectal CA Procedures for screening
Fecal occult blood test (FOBT) Flexible sigmoidoscopy Fecal occult blood test and flexible sigmoidoscopy Double-contrast barium enema (DCBE) Colonoscopy
Anti-angiogenesis Factors
thrombospondin-1 angiostatin
2 FOLD EFFECT OF APPROPRIATE STAGING ON SURVIVAL:
- Patients with nodal metastases may be offered adjuvant therapy, which improves their survival chances 2. improved staging can improve perceived survival rates through a “Will Rogers effect”
Combining cell cycle specific and cell cycle nonspecific agents
Combination Therapy
CEA (Carcinoembryonic Antigen)
Glycoprotein found in embryonic endodermal epithelium, that is associated with the plasma membrane of tumor cells, from which may be released in the blood
Uniform goal for all oncologic operations
achieving widely negative margins with no evidence of macroscopic or microscopic tumor at the surgical margins
often is used in the context of predicting response to certain therapies. The markers are markers that can prospectively identify patients who will benefit from certain therapy
Predictive Marker
The predominant change in Colorectal Cancer (Molecular)
Mutational Inactivation of Tumor Suppressor Genes
Compatibility between cancer biology and its new microenvironment
Seed and soil theory
HER2/Neu (c-erb B-2) is amplified in what common types of tumors?
(LOBOG) Lung Oral Breast Ovarian Gastric
Proportion of patients with regional lymph node metastases in whom the sentinel lymph node was found to be negative
False-negative rate
FACTORS CAUSING DISTURBANCE OF REGULATORY MECHANISMS
CKI&CKI-kinase inhibitors Cell cycle proteins Growth Factors GF receptors Intracellular signal transduction proteins Nuclear transcription Factors