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1/4 CML Case
CML Case
| Question | Answer |
|---|---|
| What is the cause of gouty attacks? | MONO-SODIUM URATE (1NaU) crystals deposit in a joint or kidney. |
| Why would someone with CML also have Gout? | Purines from ↑ cell turnover can’t be salvaged so they’re broken down into uric acid. |
| Define Dysplasia. | Abnormal growth of organs or cells |
| What is Myelodysplastic Syndrome? | PRE-LEUKEMIA: dysplasia of myelocytes & other elements in BM, which may take form of myelosuppression or of abnormal proliferation (which may precede myelogenous leukemia). |
| How do you treat hyperleukocytosis? | leukapheresis + hydroxyurea to bring down WBC count |
| How do you treat acute gout? | start Colchicine (or indomethacin) |
| Why does Colchicine cause diarrhea? | It's an ANTI-MITOTIC that has its greatest effect on rapidly dividing cells (GI epithelium). |
| Why is Colchicine used for gout? | Given for gout b/c lowers neutrophils so less purine metabolism. |
| What is CNS Leukemia? | This happens when the leukemia (WBC precursors) spread outside the blood. Indications that this has happened are splenomegaly, hepatomegaly, & SX of CNS leukemia; HA, weakness, seizures, vomiting, poor balance, blurry vision. |
| How do you treat CNS Leukemia? | Same as hyperleukocytosis - leukapheresis + hydroxyurea. Sx decrease as WBC ct returns to normal. |
| What do you do if Colchicine causes too much diarrhea? | Change to Allopurinol & treat dehydration w/ fluids & K+. |
| What is urate deposition in gout caused by? | ↑ [urate] d/t either: Overproduxn of urate, or under excretion of urate. |
| When do crystals form in gout? | When there is 1NaU SUPERSATURATION in the blood |
| What are TOPHI? | Nodular masses of 1NaU crystals in soft tissue. |
| How does gouty arthritis develop? | Crystals=> tissue damage=> inflamm response=> PMN (granulocyte) recruitment. PMNs phagocytize crystals=> damage phagosome membrane=> release lysosomal enzymes (O2 metabolites) in jt. Inflamm response to lysosomal enzymes damages jt surface=> arthritis. |
| What are the symptoms of Gout? | Usually monarticular (affect 1 jt) – MC 1st metatarsophalangeal jt. Acute onset, fever, typically nocturnal. Local postinflamm desquamation (skin peeling) & pruritis (itchy). |
| How do you diagnose Gout? | Definitive Dx = aspiration of negatively birefringent needles, but blood test (hyperuricemia) less painful. |
| What causes acute pain in gouty attacks? | Rapid Δ (either ↑↓) in [urate] of jt; loose crystals irritate synovium → inflamm response |
| What are the 3 stages of Gout? | ACUTE stage, INTERCRITICAL stage, CHRONIC stage. |
| Describe the acute stage of Gout. | Jt swelling & discomfort. Pain peaks w/in 1 day. Mostly affects MCP jt. |
| Describe the intercritical stage of Gout. | Time btn attacks. Pt is asymptomatic. |
| Describe the chronic stage of Gout. | Persistent sx of soreness & aching in the affected jts. |
| What is Imatinib Mesylate? | A protein tyrosine kinase inhibitor. (PTK inhibitor) that inhibits BCR-ABL TK. |
| How does Imatinib work? | Inhibits BCR/ABL TK by inducing apoptosis & preventing cell proliferation. |
| What does Imatinib work on? | Effective on BCR/ABL SC lines & “fresh leukemic cells” that are Ph+. Also inhibits TK receptor ptns of PDGF & SC factor (SCF).Little effect on normal hematopoietic cells b/c its designed for BCR/ABL. |
| What is the MOA of Imatinib? | ATP is the energy & phosphate source for the kinase enzyme. Imatinib blocks the kinase pocket where ATP binds. |
| When should Imatinib be used? | EARLY STAGES OF CML!!! In later stages, further mutations dampen the effectiveness. |
| How effective is Imatinib? | ~75% of pts on imatinib achieve complete cytogenic remission. |
| Describe the pathogenesis of CML. | The BCR-ABL translocation => constitutive TK activity. Net effect is unregulated cell division & inhibition of apoptosis. |
| What distinguishes CML from other Myeloproliferative Disorders (MPDs)? | 210kD BCR-ABL translocation. Chrom 22 gets a new 3’ end from Chrom 9. Chrom 22 is shortened into Philadelphia chromosome. The mutation is then passed on to cells in the line. |
| Describe the clinical course of CML. | TRIPHASIC: Chronic phase, Accelerated Phase, Blast Crisis |
| During what phase are most pts diagnosed with CML? | ~85% pts diagnosed in the CHRONIC PHASE |
| How long does the Chronic Phase typically last? | It can last from 2-10y depending on Tx. |
| What is considered the hallmark of the Chronic Phase? | Uncontrolled production of maturING granulocytes. |
| Describe the Chronic Phase. | Peripheral blood LEUKOCYTOSIS of myeloid precursors. >25,000 WBCs – mainly PMNs. Also THROMBOCYTOSIS (in 50% pts) of non-fxning plts. |
| What is a "Left Shift"? | Proliferation of maturing cells. Immature cells on L – mature cells on R (arbitrary). |
| What are some signs of Chronic Phase seen on physical exam? | SPLENOMEGALY d/t extramedullary hematopoiesis. Occasionally hepatomegaly or adenopathy. |
| What are some other lab findings seen during Chronic Phase? | Leukocyte Alkaline Phosphatase (LAP) score abnormally low. Marrow hypercellular; hematopoietic tissue dominates (esp. granulopoiesis). |
| What symptoms will a pt have during Chronic Phase? | Gradual onset of sx: fatigue, anorexia/early satiety, wt loss, LUQ discomfort, excessive sweating. |
| How is CML diagnosed? | ID Ph+ Chromosome. |
| What is Accelerated Phase? | Essentially a transition to blast crisis |
| Do all pts go thru Accelerated Phase? | No. At least 20% go straight to BC w/o evidence of AP. |
| Describe what happens during Accelerated Phase. | PMN diff progressively impaired. WBC cts more difficult to ctrl w/ myelosuppresive meds. Devo of ↑ing degrees of anemia unaccounted for by bleeding or chemo. Splenomegaly & anemia may not be controllable. |
| What is Blast Crisis? | Resembles acute leukemia; myeloid or lymphoid blasts fail to differentiate. Can be misdiagnosed if initial Dx occurs during this phase. |
| What do you see on lab analysis during Blast Crisis? | ↑↑↑ blast count (> 30%) in blood smear or BM. Extramedullary infiltration of lymph nodes, skin, subcutaneous tissue, & bone. |
| What are the physical findings of Blast Crisis? | Subcutaneous nodules, hemorrhagic skin lesions & lymphadenopathy more common. |
| What exacerbates Blast Crisis? | Smoking |
| How long is a patient estimated to survive once they enter Blast Crisis? | Survival is 3-6 months at this point |
| What is the DDx of CML? | Essentially any myeloproliferative disorder. Polycythemia Vera, Reactive Leukocytosis, Essential Thrombocytosis, Angiogenic Myeloid Metaplasia. |
| What findings are indicative of CML? | No leukocyte alkaline phosphatase. ↓ Hct. Normal RBC morph w/ 0-few nucleated RBCs. BCR/ABL gene = definitive Dx. |
| How do other MPDs differ from CML? | WBC ct usually <50,000/uL. Usually no splenomegaly. Elevated leukocyte alkaline phosphatase. Most important! No BCR/ABL gene! |
| Describe Polycythemia Vera. | Neoplasm from multipotent myeloid SC. ↑BM produxn of erythroid, granulocytic & megakaryocytic cells. RBCs produced in greatest excess – so ↑↑ H&H. ↑total blood volume, splenomegaly, leukocytosis, & thrombocytosis. |
| Describe Reactive Leukocytosis. | Assoc/w infection. Differs in all the general ways listed before: WBC ct usually <50,000/uL. Usually no splenomegaly. Elevated leukocyte alkaline phosphatase. Most important! No BCR/ABL gene! |
| Describe Essential Thrombocytosis. | Plts don’t fxn properly → excessive bleeding. Least common MPD; cause = mutation in JAK2 kinase. ↑↑plt ct w/ no alternative cause. Hb levels N, megakaryocytes often ↑↑, mild ↑PMNs. |
| Describe Angiogenic Myeloid Metaplasia. | (AKA. chronic idiopathic myelofibrosis) Hematopoietic SC disorder → chronic myeloproliferation & megakaryocytic hyperplasia. BM fibrosis d/t abnormal GF levels. Anemia, splenomegaly & severe RBC morphology changes. |
| How is CML diagnosed? | ++WBC & significant L-SHIFT of myeloid progenitor cells (w/ --promyelocyte & blasts). Presence of Ph+ chromosome or BCR/ABL gene. |
| How does Ph+ chromosome occur? | Reciprocal translocation btn long arms of chromosome 9 & 22. |
| In what kind of cell does the Ph+ translocation occur? | Pluripotent SC |
| What % of CML pts are Ph+? | 95% |
| What is ABL? | Proto-oncogene on chromosome 9q (q = long arm). ABL – Abelson, name of a leukemia virus with similar ptn. Encodes a non-receptor ptn tyrosine kinase (c-ABL). |
| What is BCR? | "Breakpoint Cluster Region". Located on 22q. Named for pt at which chromosome breaks in CML translocation. BCR protein is involved in oligomerization, serine kinase activity, guanine nucleotide exchange and GTPase activity |
| Describe the BCR/ABL fusion ptn. | 210kD fusion ptn is when both genes are translated into a single ptn w/ no stop codon. Found on cytoplasmic side of the cell membrane. Has a constitutively active tyrosine kinase region. |
| What does the BCR/ABL fusion ptn cause? | INCREASED PROLIFERATION, DECREASED APOPTOSIS, DISTURBED INTERACTION W/ CELL'S ECM. |
| Describe the increased proliferation caused by BCR/ABL. | ++cell cycle entry of hematopoietic cell lines & primary cells in the absence of GFs. Causes these cell lines to become independent of cytokines for survival & proliferation. |
| Describe the decreased apoptosis caused by BCR/ABL. | Tyrosine kinase activates downstream kinases that prevent apoptosis. |
| Describe the disturbed interaction w/ cell's ECM caused by BCR/ABL. | Activates several proteins associated w/ cytoskeletal structure & function. |
| What were the 1st line drugs for CML before imatinib? | Interferon α (INF) + cytosine arabinoside (cytarabine - CA) or hydroxyurea |
| What is the problem with treating CML using INF + CA? | INF + CA = very broad spectrum chemotherapy. Nonspecific w/ heavy SEs (<1% Imatinib vs. 25% for INF). |
| What is the advantage of imatinib over INF? | More pts achieved a COMPLETE CYTOGENIC RESPONSE (absence of Ph+) w/ Imatinib. 76% imatinib vs. 14% INF. |
| How does colchicine work? | Colchicine binds to tubulin, a microtubular protein, causing its depolymerization. This disrupts cellular fxns, such as the mobility of granulocytes, thus decreasing their migration to the affected area. |
| What is probenecid? | It’s a uricosuric agent: it is a weak organic acid that promotes renal clearance of uric acid by inhibiting the urate-anion exchanger in the proximal tubule that mediates urate reabsorption |
| Why is it helpful that Allopurinol blocks xanthine oxidase? | W/ inhibited xanthine oxidase, circulating purine derivatives (xanthine & hypoxanthine) are more soluble, & less likely to precipitate. Also causes feedback inhibition of purine synthesis. |
| What is oxypurinol? | A metablite of allopurinol that also inhibits xanthine oxidase. |
| What is RN reductase? | Ribonucleotide Reductase: the rate-limiting enzyme in DNA synthesis. |
| What does SNoW DRoP stand for? | Southern blot: DNA, Northern blot: RNA, Western blot: Protein |
| When was hydroxyurea used in CML in the past? | When pt was resistant to or did not respond to INF. |
| How does hydroxyurea help in CML? | Manages the disease, but does not cure. Holds cells in G1 – lethal to those in S phase. |
| Our pt has hyperleukotic syndrome. How is that treated? | Leukophoresis + hydroxyurea is the 1st step in Tx. Imatinib is then added while hydroxyurea is tapered as WBCs lower. |
| What is the Rational Drug Design? | finding drugs based on their BIOLOGICAL TARGET – usually a molecule in a signaling or metabolic pathway |
| How is Rational Drug Design developed? | Use X-RAY CRYSTALLOGRAPHY at atomic resolution to understand structures of receptor complexes so ligands can be designed & drug resistance minimized. |
| What is Dasatinib? | More effectively inhibits BCR-ABL KINASE than imatinib. |
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