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Cancer is what # cause of death in the united states?
#2
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What is the most common cancer in women?
breast Ca
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What is the most common cause of cancer related death in women?
lung cancer
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Most common cause of cancer in men?
prostate cancer
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most common cause of cancer related death in men?
lung cancer
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What scan can be used to identify metastases?
PET (positron emission tomography) scan- used to identify metastases--> detects fluorodeoxyglucose molecules
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What do T cells need in order to attack tumor?
T cells need MHC complex to attack tumor
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What do natural killer cells need in order to kill tumor cells?
Natural killer cells can independently attack tumor cells
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Tumor antigens:
tumor antigens are random unless viral induced tumor
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Hyperplasia:
increased number of cells
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Metaplasia:
replacement of one tissue with another (GERD squamous epithelium in esophagus changed to columnar gastric tissue)
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Dysplasia:
altered size, shape, and organization (Barrett's esophagus)
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Tumor markers (to follow):
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Pancreatic cancer:
CA 19-9
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Testicular cancer/choriocarcinoma:
Beta-HCG
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Prostate Cancer:
PSA (thought to be the tumor marker with the highest sensitivity).
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Small cell lung cancer, neuroblastoma
NSE
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What are the half lives of some of these markers?
- CEA: 18 days
- PSA: 18 days
- AFP: 5 days
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Oncogenesis:
- Cancer Transformation:
- 1) heritable alteration in genome
- 2) loss of growth regulation
- Latency period- time between exposure and formation of clinially detectable tumor
- Initiation- carcinogen acts with DNA
- Promotion of cancer cells
- Progression of cancer cells to clinically detectable tumor
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Neoplasms can arise from:
- 1) carcinogens (i.e. smoking)
- 2) viruses (i.e. EBV)
- 3) immunodeficiency (i.e. HIV)
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Retroviruses contain oncogenes:
Epstein-Barr virus- associated with Burkitt's lymphoma (8:14 translocation) and nasopharyngeal Ca (c-myc)
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Malignancies Associated with Infectious Agents:
Cervical Ca:
Gastric Ca:
Hepatocellular Ca:
Kaposi's sarcoma:
Primary effusion lymphoma:
Splenic lymphoma:
Nasopharyngeal Ca:
Burkitt's lymphoma:
Adult T-cell leukemia/lymphoma:
Various lymphomas:
- Cervical Ca: human papillomavirus
- Gastric Ca: Helicobacter pylori
- Hepatocellular Ca: hepatitis B and hepatitis C
- Kaposi's sarcoma: HHV-8
- Primary effusion lymphoma: HHV-8
- Splenic lymphoma: Hepatitis C
- Nasopharyngeal Ca: EBV
- Burkitt's lymphoma: EBV
- Adult T-cell leukemia/lymphoma: Human T-cell leukemia virus-1
- Various lymphomas: HIV
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What are proto-oncogenes?
proto-oncogenes are human genes with malignant potential
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Radiation therapy (XRT)- slides to follow
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What stage of the cell cycle is most vulnerable to XRT
M phase- most vulnerable stage of cell cycle for XRT
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How is the damage done in XRT?
most damage done by formation of oxygen radicals--> maximal effect with high oxygen levels
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what is the main cellular target of XRT?
Main target is DNA- oxygen radicals cause damage of DNA and other molecules
XRT itself can also cause some damage by causing small breaks in DNA
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What type of radiation has skin-preserving effect?
High-energy radiation has skin-preserving effect (maximal ionizing potential not reached until deeper structures)
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Fractionate doses:
- 1) allows repair of normal cells
- 2) allows reoxygenation of tumor
- 3) allows redistribution of tumor cells in cell cycle
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Very radiosensitive tumors:
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Very radioresistant tumors
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What structures have increased sensitivity to XRT?
- 1) kidneys
- 2) lungs
- 3) liver
- 4) lymphocytes
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Large tumors and XRT:
Large tumors- less responsive to XRT due to lack of oxygen in the tumor
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Brachytherapy
source of radiation in or next to tumor (Au-198. I-128); delivers high, concentrated doses of radiation
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Chemotherapy agents (following slides)
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Cell cycle-specific agents:
- 1) i.e. 5-FU, methotrexate
- 2) exhibit plateau in cell-killing ability
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Cell cycle-nonspecific agents
linear response to cell killing
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Tamoxifen
- 1) blocks estrogen receptor
- 2) decreases short-term (5 year) risk of breast Ca 45%
- 3) 1% risk of blood clots
- 4) 0.1% risk of endometrial cancer
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Taxol
1) promotes microtubule formation and stabilization that cannot be broken down; cells are ruptured
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Which two chemotherapy agents cause pulmonary fibrosis?
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Cisplatin
- 1) platinum alkylating agent
- 2) Side effects:
- 1- nephrotoxic
- 2- neurotoxic
- 3- ototoxic
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Carboplatin
- 1) platinum alkylating agent
- 2) bone (myelo) suppression
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Vincristine
- 1) microtubule inhibitor
- 2) peripheral neuropathy
- 3) neurotoxic
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Vinblastin
- 1) microtubule inhibitor
- 2) bone (myelo) suppression
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Alkylating agents
1) transfer alkyl groups; form covalent bonds
- Cyclophosphamide
- 1- acrolein is the active metabolite
- 2) Side effects:
- 1- gonadal dysfunction
- 2- hemorrhagic cystitis
- 3- SIADH
3)- Mesna can help with hemorrhagic cystitis
Isofosfamide
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Levamisole
antihelminthic drug thought to stimulate immune system against cancer
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Methotrexate
- 1) inhibits dihydrofolate reductase (DHFR), which inhibits purine and DNA synthesis
- 2) Side effects: 1) renal toxicity 2) radiation recall
- 3) Leucovorin rescue- decrease folate (tetrahydrofolic acid); reverses effects of methotrexate
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5-Fluorouracil (5FU)
- 1) inhibits thymidylate synthesis, which inhibits purine and DNA synthesis
- 2) Leucovorin- increases toxicity of 5FU
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Doxorubicin:
- 1) DNA intercalator
- 2) O2 radical formation
- 3) heart toxicity secondary to O2 radicals at >500mg/m2
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Etoposide (VP-16)
inhibits topoisomerase (which normally unwinds DNA)
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Which chemotherapy agents have least myelosuppression:
- 1) bleomycin
- 2) busulfan
- 3) vincristine
- 4) cisplatin
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GCSF (granulocyte colony-stimulating factor):
- 1) used for neutrophil recovery after chemo
- 2) Side effects: Sweet's syndrome (acute febrile neutropenic dermatitis)
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In which conditions would you resect a normal organ to prevent cancer?
Colon- FAP
Breast- BRCA I or II with strong family history
Thyroid- RET proto-oncogene or MENIN gene with family history of MEN or thyroid cancer
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Tumor suppressor genes (on slides to follow):
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Retinoblastoma:
- Retinoblastoma (Rb1)-
- 1- chromosome 13
- 2- involved in cell cycle
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p53:
- 1) chromosome 17
- 2) involved in cell cycle (normal gene induces cell cycle arrest and apoptosis; abnormal gene allows unrestrained cell growth.
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APC:
- 1) chromosome 5
- 2) involved with cell adhesion and cytoskeleton function
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DCC:
- 1) chromosome 18
- 2) involved in cell adhesion
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bcl
involved in apoptosis (programmed cell death)
BRCA is also a tumor suppressor gene
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Proto-oncogenes (on following slides):
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ras proto-oncogene
G-protein defect
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src proto-oncogene
tyrosine kinase defect
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sis proto-oncogene
platelet-derived growth factor (PDGF) receptor defect
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erb B proto-oncogene
epidermal growth factor receptor defect
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myc (c-myc, n-myc, l-myc) proto-oncogenes-
transcription factors
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Li-Fraumeni Syndrome:
- 1) defect in p53 gene
- 2) Patients get:
- 1- childhood sarcomas
- 2- brain tumors
- 3- leukemia
- 4- adrenal cancer
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Medullary Ca of the thyroid:
- 1) associated with Ret proto-oncogene (chromosome 10)
- 2) patients with Ret gene defect plus family history--> 90% get medullary Ca of thyroid; need prophylactic thyroidectomy
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Genes involved in development of Colon Ca:
Comment on metastatic trend of Colon Ca.
- 1) Genes involved in development include:
- 1-APC
- 2- p53
- 3- DCC
- 4- K-ras
APC involved in cell adhesion and cytoskeleton function- thought to be the initial mutation in the development of colon Ca
Colon Ca usually does not go to bone
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Carcinogens:
- Coal tar:
- 1) skin
- 2) larynx
- 3) bronchial Ca
- Beta-Naphthylamine:
- 1) urinary tract Ca/bladder Ca
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Cancer spread (following cards):
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Suspicious supraclavicular nodes:
- 1) neck
- 2) breast
- 3) lung
- 4) stomach (virchow's node)
- 5) pancreas
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Suspicious axillary node:
- 1) lymphoma (#1)
- 2) breast
- 3) melanoma
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Suspicious periumbilical node-
pancreas (Sister Mary Joseph's node)
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Ovarian metastases
- 1) stomach (Krukenberg tumor)
- 2) colon
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Bone mets:
- 1) breast (#1)
- 2) prostate
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small bowel metastases
melanoma (#1)
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Clinical trials:
- Phase I- is it safe and at what dose?
- Phase II- is it effective?
- Phase III- is it better than existing therapy?
- Phave IV- implementation and marketing
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Types of therapy (cards to follow):
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Induction:
- 1) sole treatment
- 2) often used for advanced disease or when no other treatment exists
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Primary (neoadjuvant)
- 1) chemotherapy given 1st
- 2) followed by another (secondary) therapy
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Adjuvant:
- 1) combined with another modality
- 2) given after other therapy is used
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Salvage:
for tumors that fail to respond to initial chemotherapy
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What is the barrier function of lymph nodes?
Lymph nodes have poor barrier function--> better to view them as signs of probable metastasis
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En bloc multiorgan resection:
- 1) can be attempted for some tumors (colon into uterus, adrenal into liver, gastric into diaphram)
- 2) aggressive local invasiveness is different from metastatic disease
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Palliative surgery:
- 1) tumors of hollow viscus causing obstruction or bleeding (colon Ca)
- 2) pancreatic Ca with biliary obstruction
- 3) breast Ca with skin or chest wall involvement
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Sentinel lymph node biopsy:
no role in patients with clinically palpable nodes; you need to go after and sample these nodes
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Colon metastases to the liver:
25% 5 year survival rate if successfully resected
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Most successfully cured metastases with surgery:
- 1) colon Ca in liver
- 2) sarcoma to the lung
- but survival still low overall for these
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See charts on pg.53:
1) Predictors of Mortality and Survival Following Resection of Hepatic Colorectal Metastases
2)Survival Based on # of factors
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Ovarian cancer and surgical debulking:
Ovarian Ca- one of the few tumors for which surgical debulking improves chemotherapy (not seen in other tumors)
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Curable solid tumors with chemotherapy only
- 1) hodgkin's disease
- 2) non-hodgkin's lymphoma
- 3) most lymphomas are B-cell
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T-cell lymphomas
- 1) HTLV-1 (skin lesions)
- 2) mycosis fungoides (sezary cells)
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HIV-related malignancies
- 1) kaposi's sarcoma
- 2) non-hodgkins lymphoma
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