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199 Cards in this Set
- Front
- Back
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What translocation is involved in Burkitt’s lymphoma?
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Chrosomes 8 and 14 (c-myc gene)
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How do you treat acute promyelocytic leukemia?
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ATRA
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What are cytokeratin 7 and 20 used for?
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Cytokeratin 7 and 20 are important to diagnose epithelial tumors (e.g., adenocarcinomas)
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What example did Petrich give of a molecule that was diagnostic, prognostic, and predictive for cancer?
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ALK (Anaplastic Lymphoma Kinase), detected in about 50% of anaplastic large cell lymphomas. It’s prognostic in ALCL, because patients with ALK+ in ALCL have a better prognosis than those that don’t.
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What’s the difference between prognostic and predictive?
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• Prognostic tells how you will do generally
• Predictive tells how you’ll do in response to a specific therapy |
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Which tumor markers are prognostic in testicular cancer?
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AFP and B-HCG are prognostic in testicular cancer
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What’s an example given by Petrich in lecture of an illness whose prognosis was determined primarily by stage?
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Mycosis fungoides (cutaneous T-cell lymphoma)
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What are clinical presentational signs and symptoms for lung cancer?
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• SOB
• Dyspnea on exertion • Cough • Hemoptysis • Unilateral pleural effusion |
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What are clinical presentational signs and symptoms for liver cancer?
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• RUQ pain
• Hiccups (diaphragmatic irritation) • Abdominal distension • Jaundice/scleral icterus • Early satiety |
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What are clinical presentational signs and symptoms for brain cancer?
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• Seizures
• Confusion • Morning headaches (high intra-cerebral venous volume) • Refractory nausea • Personality changes |
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For the following cytokeratin combinations, what is the likely diagnosis:
CK 7+ CK20- CK 7- CK 20+ ? |
CK 7+ CK20- : more likely lung carcinoma
CK 7- CK 20+ : more likely colorectal carcinoma |
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What are the following markers indicative of: CA125, CA19-9?
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• CA125: ovarian cancer
• CA19-9: hepatobiliary, pancreatic cancer (may be elevated in pancreatitis, cholangitis) |
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What is “adjuvant therapy?”
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Adjuvant therapy is additional therapy after surgical resection to decrease risk of recurrence, refers to treatment of presumed microscopic disease (may include chemotherapy, radiation and/or biologic therapy).
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What is “neoadjuvant therapy?”
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Neoadjuvant therapy is therapy administered prior to surgical resection to allow for surgical resection and/or assess tumor responsiveness to therapy.
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What is the defining count of myeloid blasts for Acute Myeloid Leukemia (AML)?
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AML is defined by >20 % myeloid blasts in the bone marrow or blood or the presence of particular cytogenetic abnormalities regardless of blast count.
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What mutation do polycythemia vera (PV) patients commonly have?
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PV patients commonly have a JAK2 mutation (gain of function), as JAK2 is important for the signaling in erythropoiesis.
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What Myeloproliferative Neoplasms (MPNs)—overproliferation of mature blood cells—have JAK2 mutations?
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• Polycythemia Vera (PV)
• Essential Thrombocytosis (ET) (5% MPL) • Primary myelofibrosis (PMF) (5% MPL) |
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What are the B symptoms?
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B symptoms are symptoms classically associated with lymphomas:
• Chronic ongoing fever without infectious source • Night sweats • Increasing fatigue • Decreased appetite/Weight loss |
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How does bone marrow cellularity change as we age?
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As we age, bone marrow cellularity should decrease, and a good rule of thumb is 100%-age for percent cellularity.
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What are the most common group of hematologic malignancies?
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Nonhodgkin’s Lymphoma (NHL)
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What is the most common NHL?
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Diffuse large B cell lymphoma
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What is the most common childhood leukemia?
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Acute Lymphoblastic Leukemia (ALL)
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What is the most common adult leukemia?
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Chronic lymphocytic leukemia (CLL)
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What cells are CD30+, CD15+ and of B cell origin?
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Reed-Sternberg cells
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Monoclonal Antibodies for cancer therapy:
1. Always target antigens restricted to cancer. 2. Are usually IgM subtype. 3. Recognize a distinct antigen epitope. 4. Must be given intravenously. 5. None of the above 6. All of the above |
3. Recognize a distinct antigen epitope.
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Recombinant Toxins:
1. Are FDA approved against multiple targets. 2. Require internalization to be effective. 3. Do not elicit an immune response. 4. Deliver potent toxins in a selective manner. 5. All of the above 6. Answers 2 and 4 |
6. Answers 2 and 4
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Tumor vaccines:
1. Are highly effective in animal models 2. Work solely through the production of antibodies 3. Show significant clinical activity in several tumor types. 4. Are always derived from tumor specimens. 5. All of the above 6. None of the above |
1. Are highly effective in animal models
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Adoptive Immunotherapy:
1. Has been a significant advance in the treatment of solid tumors. 2. Is most effective against indolent hematologic malignancies. 3. Is non-toxic 4. Requires HLA typing of donor and recipient 5. All of the above 6. Answers 2 and 4 |
Answers 2 and 4
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Interferons:
1. Are a family of glycoproteins. 2. Stimulate multiple signaling pathways. 3. May cause significant malaise and fatigue. 4. Have activity against lymphomas, renal cell cancers, and melanoma. 5. All of the above 6. None of the above |
5. All of the above
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Hormonal Therapy:
1. Is usually administered intravenously. 2. Requires expression of its target receptor. 3. Is non-toxic 4. Is effective in the treatment of breast cancer, prostate cancer and hematologic malignancies. 5. All of the above 6. Answers 2 and 4 |
6. Answers 2 and 4
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Signal Transduction Modifiers:
1. Have had a profound effect on the treatment of hematologic malignancies and solid tumors. 2. Often target kinases. 3. The paradigm is bcr-abl inhibition in Chronic Myelogenous Leukemia. 4. Are often oral agents. 5. All of the above 6. None of the above |
5. All of the above
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Transcriptional Regulators:
1. Effect RNA expression. 2. Influence the epigenetics of the cell. 3. Can alter Histone Acetylation. 4. Can alter DNA Methylation. 5. All of the above 6. None of the above |
5. All of the above
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Anti-Sense Compounds:
1. Are FDA approved for cancer therapy 2. Theoretically target one RNA message decreasing the expression of one protein. 3. Are typically comprised of amino acids. 4. Are most effective when ingested. 5. All of the above 6. None of the above |
2. Theoretically target one RNA message decreasing the expression of one protein.
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Anti-angiogenesis Agents:
1. Work effectively in animal models 2. May enhance chemotherapy effects. 3. Are believed to effect tumor neo-vascularization 4. Has the potential to cause vascular related toxicity. 5. All of the above 6. None of the above |
5. All of the above
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Proteasome Inhibitors:
1. Targeted a cellular organelle. 2. Effect protein degradation. 3. Have a role in the treatment of Multiple Myeloma 4. Neurotoxicity is a known side effect of bortezomib 5. All of the above 6. None of the above |
5. All of the above
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DNA Repair Inhibitors:
1. Effect key cellular processes (i.e. base excision repair or homologous recombination repair). 2. Are currently in clinical trials 3. May be more effective against cancers with underlying pathway defects 4. Maybe oral agents 5. All of the above 6. None of the above |
5. All of the above
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What cell marker is associated with B cells, and what drug is targeted to this area?
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B cells have the CD20 marker, and this is targeted by Rituximab.
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Do follicular lymphomas tend to occur in adults or children?
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Follicular lymphomas tend to occur in adults; they’re very rare in children.
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Which diffuse large B cell lymphoma types have a better prognosis, Germinal Center phenotype or Non-GC phenotype?
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GC phenotype tend to have a better prognosis.
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Which type of B cell NHLs is more curable, Follicular or Diffuse Large B Cell?
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DLBCL is much easier to cure whereas Follicular is very difficult to treat and often relapses.
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What is the classic phenotype for Reed-Sternberg cells?
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45(-)
30(+), 15(+), pax5(+), usually CD20(-) |
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What are the important immunophenotypic markers for T cells?
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CD3 (all T cells)
CD5 (All T cells; some B cells) CD4 (Ths) CD8 (T cytotoxic cells) |
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What are the important immunophenotypic markers for B cells?
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Ig (B cells)
CD20 (most B cells) CD10 (Progenitors; Germinal center B cells) CD5 (some B cells) |
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What is an important immunophenotypic marker for all leukocytes?
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CD45
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What are the important immunophenotypic markers for Germinal center cells?
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BCL6
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What characteristic translocation do follicular lymphomas contain?
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Follicular lymphomas contain the characteristic t(14;18) translocation (IgH/BCL2 translocation) resulting in over-expression of the anti-apoptotic BCL2 protein.
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What type of cancer are Reed-Sternberg cells associated with?
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Reed-Sternberg cells are diagnostic for Hodgkin Lymphoma and have multiple nuclei and prominent eosinophilic nucleoli. R-S cells are B cells.
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The following classification is associated with what stage of lymphoma, according to the Ann arbor clinical staging system: Involvement of 2 or more lymph node regions on the same side of the diaphragm or localized involvement of an extralymphatic organ or site and one or more lymph node regions on the same side of the diaphragm?
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Stage II
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The following classification is associated with what stage of lymphoma, according to the Ann arbor clinical staging system: Involvement of lymph node regions on both sides of the diaphragm which may also be accomplished by localized involvement of an extralymphatic organ or site or by involvement of the spleen or both?
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Stage III
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What translocation is Mantle Cell lymphoma associated with?
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Mantle cell lymphoma is associated with the characteristic translocation t(11;14), which leads to the over-expression of cyclin D1/BCL1 protein, a cell cycle associated protein, not normally expressed in lymphocytes.
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What cell markers are associated with Burkitt lymphoma?
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Burkitt lymphomas are of B cell type and express CD10 and BCL6 as well as Ki67 >95%. However, most Burkitt lymphomas are BCL2 negative. A proportion of cases are positive for EBV and classically contain a rearrangement involving the MYC gene with one of the Ig genes, usually Ig heavy chain gene on chromosome 14, resulting in t(8;14) translocation (t(8;22) and t(2;8) involving the light chain genes are also seen).
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What are the most common translocations detected in MALT lymphoma, and what markers are associated with them?
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t(11;18) is associated with MALT lymphoma, and the cells are negative for CD5, CD10, and BCL-6.
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In T-Lymphoblastic Leukemia/lymphoma, what is the expression pattern of the cells?
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• The cells characteristically express TdT (terminal deoxynucleotide transferase, a nuclear enzyme that catalyzes the random addition of nucleotides to DNA)
• CD1, CD4, CD8 |
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These neoplastic cells are usually large with abundant cytoplasm and pleomorphic, often horsehoe-shaped nuclei. What is the name of the type of cancer, and what gene translocation is associated with it?
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Anaplastic large cell lymphoma (ALCL) is the cancer, and the cells contain a translocation involving the ALK gene (t(2;5) involving the ALK gene on chromosome 2 and the nucleophosmin [NPM] gene on chromosome 5).
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Which leukemia/lymphoma is associated with HTLV-1 infection?
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Adult T cell leukemia/lymphoma is associated with HTLV1 infection. Patients present with elevated white blood cell count, lymphadenopathy, skin rash, hypercalcemia, and lytic bone lesions. Patients usually have high LDH and may have eosinophilia.
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What Ig is associated with Waldenstrom’s macroglobulinemia? What Ig is associated with multiple myeloma?
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IgM is associated with Waldenstrom’s macroglobulinemia.
IgG or IgA (less common) is associated with multiple myeloma. |
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What’s the difference between cryoglobulinemia and cold agglutinin hemolytic anemia?
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Cryoglobulinemia are proteins precipitating while the cold agglutinins are Abs that attach to RBCs and proceed to clump.
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What is the pathogenesis of hyperviscosity syndrome in Waldenstrom’s Macroglobulinemia, and what is the clinical presentation?
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An excessive amount of IgM is produced, and since IgM is a large molecule, it causes hyperviscosity, particularly in small vessels like capillaries. This can present with blurry vision, headache, dizziness, hearing loss, confusion, stroke.
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What is a rapid way to reduce the levels of IgM in Waldenstrom’s Macroglobulinemia? What else would be used to treat WM?
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• Plasmapharesis can rapidly reduce IgM in WM.
• Long term treatment would include chemotherapy (e.g., Rituximab and Alemtuzumab). You could also use immunomodulatory agents (e.g., thalidomide) or proteasome inhibitors (Bortezomib). • The only hope of cure is hematopoietic stem cell transplant. |
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What is a one line statement describing what plasma cell myeloma is? What disease can progress to plasma cell myeloma/multiple myeloma?
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• Plasma cell myeloma is a malignant proliferation of plasma cells producing monoclonal immunoglobulin.
• MGUS can progress to plasma cell myeloma. |
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How does multiple myeloma result in lytic bone lesions and cause hypercalcemia?
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Myeloma cells home to bone marrow and attach to stromal cells and induce the production of IL-6 and cytokines which stimulate the production of osteoclasts which break down bone, which increases calcium (hypercalcemia).
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How can multiple myeloma result in renal failure?
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Excessive production of misfolded monoclonal protein (Ig light chains) can deposit in the tissue, like the kidney and cause renal failure/nephrotic syndrome. You can also have low EPO production due to renal insufficiency.
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What medical emergency can result secondary from plasma cell myeloma?
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Spinal cord compression. Cord compression can occur because myeloma involving vertebral disk can cause the bone to be weak and then compress and tumor cells can be propelled backward OR the disk can rupture and fragments of bone can be propelled backward and damage the spinal cord. If it’s the tumor, then you can use medical therapy or radiation therapy.
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Why do cells stack upon one another in multiple myeloma?
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Rouleaux formation: Normally RBCs have negative charge, but when serum protein coats them, negative charge is coated, and they can stack upon one another. It’s a sign of increased serum protein and can be a sign of multiple myeloma
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What cytogenetic abnormalities are associated with good prognosis or poor prognosis in plasma cell/multiple myeloma?
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• Odd number chromosomes associated with better prognosis (e.g., 3, 5, 6, 9, etc.)
• t(4;14) and t(14;16) are associated with a poor prognosis • Deletion of 13q14 or -13: shorter survival • Deletion of TP53/17p13: poor prognosis |
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What mneumonic is used to remember symptoms/end organ damage that occurs in multiple myeloma?
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• Calcium in the blood
• Renal insufficiency • Anemia • Bone (lytic bone lesions or osteoporosis) |
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When do you call a liquid tumor a lymphoma versus leukemia?
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If it primarily presents as a mass (lymphadenopathy) without bone marrow involvement, that it’s called lymphoma. If bone marrow involvement <20-25%, then it’s called lymphoblastic lymphoma. If >25% involvement, then it’s called leukemia/lymphoma, but it’s the same disease.
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What are typical clinical features for T-ALL?
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Young male, high white count, large rapid growing anterior mediastinal mass.
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How does bone marrow differ from normal in acute lymphoblastic leukemia?
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In ALL, there’s a loss of the normal heterogeneity of the bone marrow, and there’s a predominance of blasts. The bone marrow is also hypercellular (less fat content) in ALL as compared to normal.
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What marker signifies that a lymphocytic cell is immature?
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TdT is in the early stage of T/B cell development.
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What markers are important for ALL?
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see image
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What cytogenetic markers are important in ALL?
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• 12;21 translocation more common in children, less common in adults whereas the 9;22 translocation is more common in adults and less common in children
• 12;21 is a good player, but 9;22 is a bad player. That’s why children have better prognosis • 12;21 has to be detected by FISH and not normal cytogenetics. • t(v;11q23) has a poor prognosis in both children and adults. |
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Are hyperdiploidy/hypodiploidy good or bad in ALL?
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Hyperdiploidy – good (the more the merrier)
Hypodiploidy – bad |
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What is the most common cytogenetic abnormality for ALL seen in an infant?
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t(4;11)
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What are key differences between the acute leukemias and the chronic lymphoid leukemias?
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• The chronic leukemias have a mature phenotype (i.e., not blasts)
• Patients with chronic lymphoid leukemia can survive months or years without therapy • Chronic leukemias are usually incurable. |
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What is the most common leukemia in Western countries?
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Chronic Lymphocytic Leukemia (CLL) is the most common leukemia in Western countries.
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What immunophenotypic markers are important for diagnosing CLL?
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CD19, CD5, CD23, and CD20
Also, you would expect to see clonal lymphocytosis on the CBC (>5000/uL) small lymphocytes with condensed chromatin. |
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What cytogenetics are important for CLL?
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see image
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What factors are good prognostic indicators versus bad prognostic indicators for CLL?
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• Good prognosis
o Low clinical stage o Mutated (not available clinically) o 13q as sole abnormality • Poorer prognosis o High clinical stage o Unmutated o 11q, 17p abnormalities |
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What’s the treatment for CLL?
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• For many, the treatment is no treatment (especially in the elderly).
• Traditionally “watch and wait” for early stage CLL o Chlorambucil standard therapy o CLL incurable • Now more effective therapies o Purine analogues, MoAb, transplantation o Molecular remission can be achieved |
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What leukemia has monocytopenia (decreased monocytes)?
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Hairy Cell Leukemia
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What are clinical features of hairy cell leukemia?
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• Pancytopenia (50%) or cytopenias (100%)
o Leukocyte count usually low (neutropenia, monocytopenia); hairy cells usually present but may be rare o Anemia and/or thrombocytopenia frequent • Splenomegaly (80%) – very common • Peripheral lymphadenopathy usually absent |
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What immunophenotype is specific for hairy cell leukemia?
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• Express B-cell surface antigens (CD19,CD20)
• Monoclonal surface immunoglobulin o Kappa or lambda • Negative for CD5 • Positive for CD11c, CD25, CD103 |
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What mutated serine/threonine kinase is present in virtually all hairy cell leukemias?
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BRAF
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What immunophenotype is characteristics for Large Granular Lymphocyte Leukemia?
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In most cases lymphocytes exhibit mature T cytotoxic phenotype (CD3+, CD8+, CD4-, CD56-/+, CD57+, CD16+, )
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What virus causes Adult T-cell Leukemia/lymphoma?
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HTLV-1 retrivirus causes Adult T-cell Leukemia/lymphoma, and it can be acquired via parenteral means (e.g., sexual transmission, placental transmission, needle exchange, etc.).
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Which disease has a morphological appearance akin to a flower-like arrangement?
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Adult T-Cell Leukemia/Lymphoma
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What is the immunophenotype for Adult T-Cell Leukemia/Lymphoma?
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Lymphocytes are CD3+, CD7-, CD4+, CD8-, CD25-,
(It’s a T-helper cell type phenotype) |
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What is the immunophenotype for Sezary syndrome?
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Mature T- helper phenotype (CD3+, CD4+, CD8-)
Usually CD7-, CD25- What disease is a leukemic form of cutaneous T-cell lymphoma, characterized by generalized erythroderma and lymphadenopathy? Sezary syndrome |
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Which disease is commonly associated with “smudge” cells?
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CLL
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Are the majority of lymphomas B or T cell?
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B cell (85-90%)
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What are characteristics of Ann Arbor staging for lymphoma?
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Stage I Involvement of a single lymph node region
Stage II Involvement of 2 lymph node regions on the same side of the diaphragm Stage III Involvement of lymph node regions on both sides of the diaphragm Stage IV Multifocal involvement of 1 extralymphatic sites ± associated lymph nodes or isolated extralymphatic organ involvement with distant nodal involvement |
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What therapy is the standard treatment for diffuse large B cell lymphoma?
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• R-CHOP is the standard for DLBCL
Rituxan, Cyclophosphamide, doxorubicin (H), vincristine (O), Prednisone |
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Which disease has a cytomorphological “starry sky” appearance?
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Burkitt’s lymphoma
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What translocation is characteristics of follicular lymphoma (FL)?
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t(14;18); present in 90% of cases
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What are the two expression profile subgroups of DLBCL, and which has the better prognosis?
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GC B cells<--better prognosis
Activated B-cell like type cell |
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What are the cytogenetics and the immunophenotypic markers for Mantel Cell Lymphoma (MCL)?
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Immunophenotype: CD5+, CD10-, Bcl6-
Cytogenetics: t(11;14) |
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Which NHL is the most common indolent NHL subtype?
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Follicular Lymphoma
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What are the different types of HL and their relative prevalences?
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• Nodular Lymphocyte Predominant Hodgkin Lymphoma (LP) 3%
• Classical Hodgkin Lymphoma (>95%) – Nodular Sclerosis (NS) 65% – Mixed Cellularity (MC) 25% – Lymphocyte Rich (LR) 2% – Lymphocyte Depletion (LD) 0.8% |
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What is the immunophenotype for Nodular Sclerosis (NS) HL?
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CD30+, CD15+, CD45-
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What is the immunophenotype for Nodular Lymphocyte Predominant Hodgkin Lymphoma (LP)?
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CD 45 +, CD 20+, CDw75+, CD15-, CD30+/-
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Would you use fine needle aspiration to biopsy the lymph node for a clinical suspicion of HL? Why or Why not?
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No, you would not use FNA, because the characteristic Reed-Sternberg cells compose a small percentage of the lymph node. Thus, you would use excisional biopsy mandatorily.
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What is the standard treatment for early stage HL?
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Stage I and II “favorable”
– Combined modality therapy with chemotherapy (ABVD) and RT from 2500-3600 cGy – Number of cycles question: 2 or 4 or 6? – ABVD chemotherapy is the standard – Adriamycin (doxorubicin), Bleomycin, Vinblastine, Dacarbazine 90-95% of patients can be cured |
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How does treatment for the more advanced Stage III/IV HL patient differ from the early stage I/II patient?
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For advance staged patients, they don’t use radiation, but they use more chemotherapy
80-85% of patients cured |
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What treatment is useful for relapsed patients and is the first FDA-approved drug specifically targeted for HL?
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– CD30 antibody: SGN-35 (Brentuximab-vedotin)
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What are short term and long term effects of treatment for HL?
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• Short Term
• Long Term – Radiation • Lhermitte’s syndrome • Pneumonitis • Cardiac damage • Secondary tumors (brca in women 10 yrs later) – Chemotherapy • Sterility • Acute leukemia (from 2 to 10 years after treatment) • Second malignancies • Cardiomyopathy (adriamycin) • Pulmonary injury (bleomycin) |
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What virus is associated with HL?
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EBV appears in 50% of HL cases
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What is the JAK2 pathway pathogenesis of Polycythemia Vera?
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A JAK2 mutation causes the excessive proliferation and differentiation of a hematopoietic progenitor cell to overproduce mature blood elements.
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For the following diseases: Essential Thrombocytosis (ET), Proliferative Myelofibrosis (PMF), and Polycythemia Vera (PV), in what percentage of each is there a JAK2 V617F mutation?
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• ~50% of ET and PMF cases
• 95% of PV cases |
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In which MPN do you have a somatic, gain of function mutation in exon 12?
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Polycythemia Vera
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What cells on the bone marrow stain would be indicative of Essential Thrombocythemia (ET)?
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Enlarged megakaryocytes
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Why would you get bleeding in Essential Thrombocythemia (ET)?
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Bleeding is more rare than blood clotting, but it becomes more likely than clotting if the platelet number is very high. The bleeding is due to the patient acquiring von Willebrand syndrome where there’s an accumulation of vWF by the platelets, so they would test for vWF before giving aspirin, otherwise the bleeding would be consequential.
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What is the treatment for Essential Thrombocythemia (ET)?
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Treatment includes an aspirin to lower vascular risk of clotting, and potentially, agents to lower the platelet count
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In which myeloproliferative neoplasm would you expect to see trilineage proliferation?
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Polycythemia Vera
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In which myeloproliferative neoplasm would you expect to see aquagenic pruritus (itching after showers)?
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Polycythemia Vera (due to increased histamine levels)
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How would you treat a patient with polycythemia vera?
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You would manage similarly with ET (aspirin to reduce risk of clotting) except you would also phlebotomize the patient to reduce the Hb. They may also be treated with pegylated interferon.
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In which myeloproliferative disorder would you see nucleated RBCs in the peripheral blood smear as well as teardrop RBCs and circulating immature WBC precursors?
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This syndrome describes (among other things) Leukoerythroblastosis and occurs in Myelofibrosis (i.e., the bone marrow is being replaced by scar formation).
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How would you diagnose myelofibrosis?
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You have to do a bone marrow biopsy and see abnormal megakaryocyte s with increased proliferation and fibrosis. The peripheral blood smear will often have leukoerythroblastosis, and the patients can become anemic and have elevated LDH. Furthermore, patients will often have an enlarged spleen. Also look for JAK2 mutation (occurs in 50%).
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How would you treat myelofibrosis?
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• Palliation of splenomegaly, constitutional symptoms, and anemia becomes a major goal
• Thalidomide and prednisone for leukocytosis (can reduce spleen size) • Hydroxyurea • Splenic radiation • JAK2 inhibitors (Ruxolitinib) may not alter the natural history of the disease, but are welcomed additions |
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What chromosomal translocation occurs in CML?
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t(9;22) Philadelphia chromosome – BCR(22)-ABL(9) fusion gene which produces a constitutively active tyrosine kinase.
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In what disease do you see basophils in the peripheral blood?
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CML
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What disease is characterized by uncontrolled proliferation of maturing granulocytes, predominantly neutrophils but also eosinophils and basophils?
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CML
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What is a common clinical presentation of a patient with CML?
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Most CML patients present in their chronic phase with B symptoms (fatigue, weight loss, night sweats) and early satiety (due to splenomegaly).
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What’s the role of IFN-alpha in the treatment of CML?
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IFN-alpha helps improve the blood count in patients with CML (complete hematologic remission in 22-81%), but it doesn’t get rid of the disease burden (complete cytogenic remission in 0-26%). It also makes them feel like crap.
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What is the mechanism of action of imatinib?
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Imatinib is a competitive inhibitor of the BCR-ABL tyrosine kinase. It binds in the spot that ATP usually binds.
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What are some mechanisms of resistance to imatinib?
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• Primary resistance to imatinib (rare)
o Intrinsic heterogeneity of leukemia o Individual variations in pharmacokinetics - IM cellular uptake by hOCT1 varies - IM is a substrate for P-glycoprotein, the product of the MDR-1 gene • Secondary resistance to imatinib o Mutations in binding pocket prevent imatinib from binding (most common is P-loop mutation) o T315I mutation - 20% of BCR-ABL mutations are T315I |
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Which of the following can be decreased in MDS?
A) White blood cells B) Red blood cells C) Platelets D) All of the above |
All of the above
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What criteria are used in the International Prognostic Scoring System in Myelodysplastic syndrome (MDS)?
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Karyotype
Cytopenia (lineages affected) Bone marrow blasts (%) |
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What are the 4 main morphological features of blood cells seen in Myelodysplastic syndrome?
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• Howell-Jolly bodies (precipitation of Hb in RBCs)
• Pelger-Huet anomaly (abnormal chromatin condensation) • Micro-megakaryocytes in the bone marrow • Dohle bodies in RBCs • Ringed sideroblasts |
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What phenotypically similar disease must be ruled out in order to make a diagnosis of myelodysplastic syndrome (MDS)?
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Vitamin B12 deficiency can look like MDS.
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What severe illness can myelodysplastic syndrome progress to?
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MDS can progress to AML
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What cytogenetic abnormalities have a favorable prognosis according to the International Prognostic Scoring System in Myelodysplastic syndrome (MDS)? What cytogenetic abnormalities have a poor prognosis associated with it?
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Good – 5q deletion, 20q deletion, normal
Bad - Chromosome 7 abnormalities (particularly monosomy 7) |
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What clinical abnormalities would appear in the peripheral blood smear of a patient with myelodysplastic syndrome (MDS)?
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Ringed sideroblasts would appear due to iron accumulation in the mitochondria due to an inability to incorporate iron into Hb
Increased HbF and decreased HbA (probably due to defect in gene switching) |
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Why do patients with myelodysplastic syndrome (MDS) get frequent infections?
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Patients with MDS have defective neutrophils, which predisposes them to infections. Up to 21% of patients with MDS die of infection.
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What illness is a smiley face neutrophil associated with?
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Myelodysplastic syndrome (MDS); it’s a Dohle body
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In which types of myelodysplastic syndrome (MDS) could you prescribe Lenalidomide?
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Lenalidomide is only effective in 5q- MDS.
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What are treatments available for myelodysplastic syndrome (MDS) besides Lenalidomide for 5q- MDS?
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Stem cell transplant is an option (the only curative option)
You could also use low dose chemotherapy (e.g., 5-Azacytidine) |
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What exposures are known to be associated with MDS?
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Toxic chemicals (benzee, toluene)
Radiation (therapeutic, occupational, other environmental) Chemotherapy (alkylating agents, topoisomerase II inhibitors) |
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What is the most common chromosomal abnormality in MDS, and what’s the associated prognosis?
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Monosomy 7 is the most common chromosomal abnormality in MDS, and it’s associated with a poor prognosis.
5q- is the second most common abnormality, and it’s associated with a good prognosis |
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What cytopenias can occur in MDS?
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Anemia – almost 100%
Neutropenia – 60% Thrombocytopenia – 60%s |
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In what illness do you see Auer rods?
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AML. If you see the Auer Rod (lysosomes fused together and sit in cytoplasm), you know it’s AML, but not all AMLs have Auer Rods. Auer rods are needle-like azurophilic granules.
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What percentage of blasts present is necessary for a diagnosis of AML?
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At least 20% myeloid blasts must be present in the bone marrow. Blasts may be completely absent from the peripheral blood. There are several types of myeloid blasts: myeloblasts, monoblasts, megakaryoblasts,erythroblasts.
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What are the most important prognostic characteristics for AML (in terms of predicting the rate of remission, relapse, and overall survival)?
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• Age
• Cytogenetic changes in leukemia cells at diagnosis • Molecular genetic changes in leukemia cells at diagnosis |
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What translocation is associated with APL?
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t(15;17)
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Which FAB subtype is associated with APL?
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M3
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Which FAB subtypes love to infiltrate the tissue?
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M4/M5
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What are the most important prognostic factors for AML?
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• Age
• Cytogenetics o Favorable o Intermediate o Unfavorable • Performance status • Intensity of post-remission therapy (younger adults only) |
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What cytogenetic groups are considered to have a favorable prognosis in AML?
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Inv(16) (without KIT mutation)
t(15;17) (PML/RARalpha) t(8;21) (without KIT mutation) |
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What cytogenetic risk groups in AML are considered to have an unfavorable prognosis?
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First three are: -5/del(5q), -7/del(7q), inv(3q)
Complex: more than 3 chromosomal abnormalities |
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What thrombotic syndrome is always associated with APL?
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DIC
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There are 2 classes of mutations that give rise to AML. What are they and what are specific examples for each class?
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• Class I mutations – activating mutations. For example:
o Activating mutations in RTKs FLT3 and KIT o Activating mutations in RAS family members o Loss of function mutations in NF-1 • Class II mutations – termination of differentiation. For example: o Interference with transcription factors o Interference with transcriptional co-activators |
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What is FLT3 in the context of AML?
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FLT3 is a trans-membrane TKR that stimulates cell proliferation; it’s associated with increased relapse rate, leukocytosis and high percentage of bone marrow blasts as well as de-novo AML. There are FLT3 inhibitors in development.
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WHAT IS NPM1?
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NPM1 (good—confers an improved outcome) mutations result in the generation of a nuclear export signal that relocalizes the NPM1 protein from the nucleus to the cytoplasm. This aberrant localization inhibits its normal shuttle function btwn nucleus and cytoplasm, which is needed for it participation with certain P53 tumor suppressor pathways. RNA binding nucleolar phosphoprotein involved in preribosomal assembly; transport ribonucleoproteins between cellular compartments
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What is KIT’s relationship with other cytogenetic abnormalities?
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KIT mutation in inv(16) or t(8;21) has bad prognosisconsider stem cell transplant
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What coagulopathy is APL associated with, and what ethinicity more commonly gets APL?
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DIC; Hispanics get APL.
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What treatment is given for APL?
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Some combination of chemo and ATRA
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Hematopoeitic stem cell transplantation is the intravenous infusion of:
A) Totipotent hematopoietic stem cells B) Pluripotent hematopoietic stem cells C) Multipotent hematopoietic stem cells D) Unipotent hematopoietic stem cells |
B) Pluripotent hematopoietic stem cells
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What is the positive benefit of graft-versus-tumor reactions?
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The graft-versus tumor reactions result in the elimination of residual tumor cells and consequently reduce the relapse incidence after syngeneic or autologous transplants.
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For autotransplantation, a source other than the bone marrow is currently more commonly used. What is that source?
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Blood has essentially replaced marrow as the source of stem cells for autotransplantation, and it’s increasingly used for allogeneic transplantation. Stem cells circulating in the blood can be harvested by leukapheresis on a cell separator. The number of hematopoietic progenitor cells can also be increased using growth factors like granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF).
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Which organs of the body bear the brunt of the GVHD attack?
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• Skin
• Liver • Gut |
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What are the basic requirements for GVHD, as postulated by Dr. Billingham?
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• The graft must contain immunocompetent cells (now recognized as T cells).
• The host must be incapable of mounting an effective response to eliminate the transplanted cells. • The host must express tissue antigens not expressed in the donor. |
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What are the 3 steps in the development and evolution of acute GVHD in HSCT?
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• Activation of APCs
• Expansion – donor T cells activation, proliferation, differentiation, and migration • Effector – target tissue destruction |
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What factor characterizes hematopoietic stem cell transplant graft rejection?
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Rejection is characterized by persistent neutropenia or a decline in the neutrophil count after the initial adequate recovery, hypocellular bone marrow, often with host-type lymphocytosis.
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Which of the following have the highest risk for relapse:
A) Patient with Acute GVHD + Chronic GVHD B) Patient with Acute GVHD C) Patient with no GVHD D) Twins |
D) Twins
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What is the definition of ionizing radiation?
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Ionization—if radiation has sufficient energy to eject one or more orbital e-, it is called ionizing
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What is the most important cellular target for radiation therapy?
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Most important target for radiation damage in the cell is the DNA (nuclear DNA and not mitochondrial DNA)
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What is the difference between the direct and indirect action radiation?
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Direct action: ionizing event happens directly on DNA
Indirect action: radiation works on water molecule, you get a hydroxyl radical (unpaired electron in outer shel); it can then attack the DNA and cause damage |
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What are the 3 DNA-repair mechanisms that are relevant for ionizing radiation?
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• Base excision repair
• Non-homologous end joining repair • Homologous recombination repair |
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What do we need to know about the alpha/beta ratio and D0 in the survival-dose curves?
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• Alpha/beta ratio tells something about the shape of the survival curve; it varies from one tissue to another, which helps radiation oncologists determine what fractionation regiment they will use in a patient
• D0 dose is the amount to reduce the survival; the amount to cause 37% killing on the survival curve. If you have a high D0 dose-->better survival; lower D0 dose-->lower survival (i.e., how well the cell responds to radiation) |
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At what point during the cell cycle are cells most susceptible to death via radiation?
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Cells are more radiosensitive when they are actively dividing i.e. M phase:
M>G2>G1>early S phase> late S phase Hypoxia makes cells more radioresistant |
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What are the most radiosensitive cells in the body?
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Lymphocytes are the most radiosensitive cells in the body.
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What lethal aberrations are most common causes of death in cells due to radiation?
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Chromosomal aberrations:
• Dicentric chromosomes • Rings |
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What are the 4 Rs of radiobiology?
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• Repair (Recovery)—tumor and normal cells, benefits normal cells
o You give 2 doses instead of 1 so the normal cells can repair - good • Reassortment of cells within the cell cycle—tumor and normal cells, benefits killing of tumor cells o reassortment: G2/M cells get killed off first; the day after treatment, you get more cells reassorted into G2/M phase, so you get more killing than if you were to try to kill them all in 1 crack - good • Repopulation of the cells—affects mostly tumor cells, negative consequence of fractionation o The tumor is growing/repopulating as you give more fractions - bad • Reoxygenation—affects tumor cells, enhances therapy o new hypoxic cells become oxic; better chance to kill the cells - good |
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What are the 3 radiation syndromes that result from excessive exposure to radiation?
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• Cerebrovascular Syndrome—50Gy total body (or equivalent in neutrons)—death in 30-49h, cause of death is likely to be changes in permeability of small blood vessels in brain
• GI syndrome—Total body exposures of 10-50Gy—death occurs in 9d from depopulation of epithelial lining of the GI tract • Hematopoietic syndrome—2.5-10Gy total body exposure—destruction of mitotically active blood precursor cells, BM transplant is often useful (8-10Gy) |
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What is the difference between deterministic and stochastic events in radiobiology?
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• Stochastic—having no threshold, mostly events with DNA as the target, mostly affects single cells—carcinogenesis, mutation, e.g.
• Deterministic—having a threshold, but increasing severity with dose, mostly events with loss of function as the end-point, usually affects tissues—early/late effects, most acute effects, cataracts, etc. |
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What is External Beam Radiation Therapy?
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• Aiming ionizing radiation at a tumor using beams that come from the outside
• Current method – Megavoltage x-ray radiation using a linear accelerator |
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What energy range is used for radiation therapy?
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– Energy range:
• 4 MV – 20 MV (4,000,000 – 20,000,000 V) |
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What is Intensity Modulated Radiation Therapy?
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Radiotherapy using computer-aided planning with multiple (~100) overlapping fields
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Can you describe attributes of each phase of the cell cycle?
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G0: Quiescent state
G1: Interphase, period of growth determines readiness for division Checkpoint: Permit DNA repair or induce cellular suicide mechanisms S: DNA synthesis: topoisomerase I and II G2: Determine fidelity of DNA and correct errors Checkpoint: DNA mismatch repair enzymes recruited M: Mitosis Checkpoint: Ensure integrity of mitotic spindle |
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What phase of the cell cycle are chemotherapeutic drugs most effective? Least effective?
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Most effective: S phase
Least effective: G0 phase |
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Which of the following would least likely be affected by chemotherapeutics?
• Bone marrow • Gametes • Growth in children • Neurons • Wound healing • Fetus |
Neurons
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How do alkylating agents enact their cytotoxic effects?
|
Alkylating agents cross link DNA and decrease transcription and replication.
They break the DNA strands and enact inappropriate base pairing. |
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Which chemotherapeutic agents are considered radiosensitizing?
|
• Alkylating agents, like temozolomide (indication: GBM) are considered radiosensitizing.
• 5FU is also radiosensitizing. • Paclitaxel inhibits microtubule depolymerization, which blocks cell cycle progression, accumulating tumor cells in the G2/M phase. • Gemcitabine has exhibited radiosensitizing properties in vitro, even at non-cytotoxic doses. |
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What are two chemotherapeutic drugs that can penetrate “sanctuary sites,” such as the blood-brain-barrier or the blood-testis barrier and can also be safely administered intrathecally?
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• High dose methotrexate
• High dose cytarabine |
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What is the therapeutic use for cytosine arabinoside (aka. Cytarabine)?
|
Cytarabine is limited to use against hematologic malignancies, e.g. AML, NHL, ALL
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What are examples of purine analog chemotherapeutics?
|
• 6-Mercaptopurine, 6-Thioguanine
o Converted to “fraudulent nucleotides” o Inhibit enz’s nec for purine synth • Fludarabine o Converted to triphosphate o Mech action sim to ara-C o Strong effects on bone marrow; can cause MDS o Used in NHL • Pentostatin o Inhibits adenosine deaminase o Interferes w/ purine metabolism, cell prolif’n |
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What are the indications for the Vinca Alkyloids?
|
Vincristine: ALL, NHL
Vinblastine: HL |
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What is the mechanism of action and indication for sorafenib?
|
Sorafenib targets intracellular Raf kinases (CRAF, BRAF, and mutant BRAF)
Used to treat renal cell carcinoma and HCC |
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What is the mechanism of action and indication for Sunitinib and axitinib?
|
Sunitinib and axitinib inhibit platelet-derived growth factors (PDFGFR-alpha and PDGFR-Beta) and vascular endothelial growth factors (VEGFR1, VEGFR2, and VEGFR3)
Used to treat RCC |
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|
What is the mechanism of action and indication for Vemurafenib?
|
Vemurafenib inhibits mutated forms of BRAF, including BRAF with V600E mutation
Used to treat metastatic melanoma |
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|
What are the “sanctuary sites?”
|
CNS
Testis |
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What is Temozolamide, and what is it’s use/mechanism of action?
|
Temozolamide is a nitrosurea, and it methylates DNA for the treatment of cancer. Other drugs of its type are procarbazine and busulfan.
Notable side effects: cerebellar toxicity (ataxia, dizziness), pulmonary fibrosis |
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What is 5-fluorouracil (5FU), and what is its mechanism of action?
|
5FU is an antimetabolite, and is mechanism of action: deoxyUMP is converted to deoxyTMP via thymidylate synthase (TS) but when 5FU is incorporated in place of uracil, F-dUMP covalently binds to TS causing inhibition of DNA synthesis (lack of thymine). Note: since leucovorin (a folate analog) is a cofactor, adding this to 5FU increases efficacy of 5FU (as well as toxicity).
Notable side effects: hand-foot syndrome Resistance: increased degradation of 5FU (by dihydropyrimidine dehydrogenase or DPD), increased expression of TS |
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What is irinotecan, and what is its mechanism of action?
|
Irinotecan is a Camptothecin, and it inhibits topoisomerase I (single strand breaks) by stabilizing the DNA-topo I complex to prevent re-sealing of the DNA. DNA damage induces apoptosis. Not cell cycle dependent.
Activation: hepatic carboxylesterase. Notable side effect: secretory diarrhea, cholinergic syndrome Resistance: decreased carboxylesterase activity |
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What is etoposide, and what is its mechanism of action?
|
Etoposide is an Epipodophyllotoxin, and it inhibits topoisomerase II (double strand breaks) by stabilizing the DNA-topo II complex to prevent re-sealing of the DNA, arresting the cell in G2.
Notable side effect: AML with 11q23 mutation Resistance: decreased topo II activity, altered topo II binding site |
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What is the “AC” chemotherapeutic regimen and what is it used to treat?
|
AC treats Breast cancer:
Doxorubicin (Adriamycin) – DNA intercalacting agent Cyclophosphamide – cross-links DNA (nitrogen mustard) |
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What is the “BEP” chemotherapeutic regimen and what is it used to treat?
|
BEP treats Testicular cancer:
Bleomycin – DNA intercalacting agent Etoposide – inhibits topoisomerase II Cisplatin – crosslinks DNA |
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What is the “FOLFOX” chemotherapeutic regimen and what is it used to treat?
|
FOLFOX treats colon cancer:
Folinic acid (leucovorin) - folate analog 5FU – inhibits thymidylate synthetase; cell cycle S-phase specific Oxaliplatin – crosslinks DNA |
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What is the “FOLFIRI” chemotherapeutic regimen and what is it used to treat?
|
FOLFIRI treats colon cancer:
Folinic acid (leucovorin) – folate analog 5FU - inhibits thymidylate synthetase; cell cycle S-phase specific Irinotecan – inhibits topoisomerase I |
