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What are the 4 steps of carcinogenesis?
- 1. Initiation
- 2. Promotion
- 3. Conversion or transformation
- 4. Progression
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Normal cells are exposed to carcinogenc substances, leading to genetic damage, leading to irreversible cellular mutations.
Initiation
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Carcinogens of other factors create an environment that favors growth of mutated cells over normal cells. This process is reversible.
Promotion
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Cell become cancerous. Could be years before diagnosis occurs.
Conversion or transformation
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Tumor invasion into local and distal sites (metastasis).
Progression
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What are the risk factors for development of cancer?
- 1. chemical: aniline dye exposure, benzene, smoking, drugs
- 2. physcial agents: radiation, UV lights
- 3. biologic: Epstein-Barr virus, HPV
- 4. age: > 50-60
- 5. gender: hormonal patterns
- 6. diet
- 7. chronic irritation: persistent cell damage & repair
- 8. family history: genetics
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Which drugs are known to cause cancer?
- 1. alkylating agents
- 2. anabolic steroids
- 3. analgesics containing phenacetin
- 4. anthracyclines (doxorubicin)
- 5. antiestrogens (tamoxifen)
- 6. coal tar (topical)
- 7. estrogens
- 8. nonsteroidal (diethyl stilbestrol)
- 9. steroidal (estrogen replacement therapy, OC)
- 10. epipodophyllotoxins (etoposide, teniposide)
- 11. immunosuppressives (cyclosporine, azathioprine)
- 12. oxazaphosphorines (cyclophosphamide, ifosfamide)
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What is an oncogene?
- develop from normal genes called protooncogenes
- protooncogenes --> oncogenes
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What is a protooncogene?
- present in all cells
- regulate normal cell cycle & function
- alterations lead to oncogenes by means of point mutations, insertions, deletions & translocations
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What are some examples of oncogenes?
- EFGR
- HER-2/neu
- RET
- BCL-2
- BCR-ABL
- N-MYC
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What is the function of a tumor suppressor gene?
- regulate & inhibit inappropriate cell growth & cell proliferation
- mutation or loss of the gene leads to uncontrolled, unregulated, unchecked, unimpeded cell growth
- ex: p53, BRCA1, BRCA2, Rb1
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What are the steps of the normal cell cycle?
- 1. cyclins and cyclin-dependent kinases (CDKs)
- 2. apoptosis
- 3. cellular senescence
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What is the function of CDKs and how do they relate to cancer?
- Function: regulate checkpoints in the cell cycle
- dysfunctional or non-existent in cancer cells --> cells continue to proliferate unregulated
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What is the function of apoptosis and how does it relate to cancer?
- Function: backup defense mechanism
- dysfunctional or non-existent in cancer cells --> increases risk for malignancy
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What is the function of ellular senescence and how does it relate to cancer?
- Function: telomeres regulate the life-span of the cell (pre-set # of divisions); caps at the end of the chromosome
- protects DNA from damage
- shortened w/ each cell cycle
- telomerase is over-produced in cancer cells
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If a tissue is identified as ending in -oma, what can be said about the state of that tissue?
benign
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If a tissue is identified as a carcinoma or a sarcoma, what can be said about the state of that tissue?
malignant
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What are the mechanisms of tumorigenesis exhibited by most cancers?
- 1. self-sufficient in growth signals: activation of H-Ras oncogene
- 2. insensitive to anti-growth signals: loss of tumor suppressor genes
- 3. evades apoptosis: produces growth factor survival factors
- 4. limitless replicative potential: turns on telomerase
- 5. sustained angiogenesis: express vascular endothelial growth factor (VEGF) inducers
- 6. tissue invasion & metastasis: inactivation of E-cadherin
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Identify the components of tumr staging, TNM.
- T = tumor (size & invasion)
- N = lymph node involvement
- M = metastasis (0= no; 1= yes)
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Define the stages of cancer (1-4)
- Stage 1: localized cancer
- Stage 2-3: regional invasion (N > 1)
- Stage 4: metastatic cancer (M at least = 1)
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What are the 4 modalities of treatment?
- 1. surgery (local)
- 2. radiation (local)
- 3. chemotherapy (systemic)
- 4. biologic therapy (systemic)
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What is the treatment of choice for most solid tumors when possible?
surgery
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Which modality of treatment destroys cancer cells in the early & some more advanced stages, helps eradicate cancer cells left behind by surgery and aids in tumor size reduction prior to other therapies?
radiation
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Which modality of treatment is used for management & treatment of primary tumor & any metastatic disease?
chemotherapy
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What are the adverse effects of surgery for cancer treatment?
surgical complications, damage to surrounding tissue, possible metastasis
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What are the adverse effects of radiation for cancer treatment?
irritation of the skin & tissue underneath, fatigue, infertility & secondary cancers are a possibility
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What are the adverse effects of chemotherapy for cancer treatment?
N/V, alopecia, fatigue, myelosuppression (anemia, neutropenia, thrombocytopenia), mucositis, infertility, extravasation, cutaneous reactions, secondary malignancies
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Which form of biologic therapy is broad? More specific?
- immunotherapy = broad
- targeted therapy = more specific
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What is neoadjuvant therapy?
chemo administered before surgery or radiation (primary treatment)
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What is adunctive therapy?
used concomitantly with primary treatment
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What is adjuvant therapy?
given after the primary therapy to enhance possibility of a cure
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What is palliative therapy?
to palliate or decrease symptoms of the cancer or its therapy
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What is salvage therapy?
administered after primary therapy has failed (usually different regimen)
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What is induction therapy?
1st step of therapy (loading dose or 1st chemo treatment)
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What is consolidation therapy?
intensive chemo given after the inital induction therapy
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What is maintenance therapy?
use of low dose chemo to promote lifelong remission
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What year was Tamoxifen discovered?
1967
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What year did Tamoxifen prevential trials occur?
1989
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What year did proof of principle that chemoprevention works occur?
1990
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What year was BCG shown to prevent bladder cancer?
1991
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What year were antiestrogen drugs found to prevent DCIS?
1995
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What year was it discovered that Tamoxifen reduces breast cancer incidence?
1998
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What year was it discovered that finasteride reduces prostate cancer incidence?
2003
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What year was it found that aspirin prevents colon cancer?
2003
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What is the purpose of a performance scale (i.e., Karnofsky, ECOG)?
determines if a patient is healthy enough to tolerate chemotherapy
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What does a patient's Karnofsky perfomance scale need to be for them to be eligible for chemotherapy?
- usually > 60%
- < 40% = significantly disabled and needs a lot of care & attention
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What does a patient's ECOG score need to be in order to be considered elibile to receive chemotherapy?
- usually < 2
- 0= fully active
- 2= ambulatory & capable of self care but not able to carry out work activities
- 5= near death
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