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28 Cards in this Set
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Lecture 18 – disorders of WBC’s
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Beware the Angry Neutrophil!
Changes in neutrophil appearance reflective of a hypermetabolic state: -... – Prominence of azurophilic granules containing bacteriocidal enzymes -... – Aggregations of rough endoplasmic reticulum -Cytoplasmic vacuoles –Phagocytosis -“... shift” - Release of immature neutrophils from the marrow compartment |
Toxic granulation
Döhle bodies Left |
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look at slide 12, 14, and 16 in lecture 18
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Functional Classification of the Major Granulocyte Disorders:
Disorders of granulocyte function -Disorders of oxidative metabolism *Chronic ... disease (CGD) * ... deficiency -Disorders of ...– Chediak-Higashi syndrome -Disorders of ... – Leukocyte adhesion deficiency -Disorders of ... – Hyper IgE syndrome Disorders of granulocyte production/maturation -Congenital ... |
granulomatous
Myeloperoxidase degranulation adhesion chemotaxis neutropenias |
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...:
Defect: -Inability to produce superoxide radicals (respiratory burst) -Impaired defense against microbes producing catalase – (Staphylococcus aureus, E. coli, Klebsiella, Serratia, Salmonella, Pseudomonas) |
Chronic granulomatous disease (CGD)
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...:
Defect: -Abnormal ... (mutation of post-translational processing) -Bacterial killing delayed, but eventually normal -Impaired killing of fungal pathogens (Candida, Aspergillus) |
Myeloperoxidase deficiency
myeloperoxidase |
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...:
Defect: -Aberrant vesicle sorting/transport leads to abnormal granule formation (gene involved has been identified) -Granules progressively fuse to form oversized, dysmorphic granules which are functionally inefficient *Degranulation delayed in response to infection *Chemotaxis also impaired -Defect is systemic, affecting all granule-containing cells (including melanocytes, Schwann cells, platelets) |
Chediak Higashi syndrome
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...:
Defect: -Mutations in integrin function such that neutrophils cannot exit from the circulation or properly adhere to endothelium (“roll”) *LAD I – CD18 mutation --> lack of functional CD11/CD18 integrin dimers --> neutrophils can’t “adhere” *LAD II – Neutrophil metabolic defect --> loss of L-selectin --> neutrophils can’t “roll” |
Leukocyte adhesion deficiency
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Congenital Neutropenias:
Kostmann syndrome: Defect: -Neutrophil elastase gene mutation --> maturation arrest at ...-myelocyte stage Clinical presentation: -Early onset recurrent, life-threatening ... infections -ANC < ... -10% of patients progress to MDS/AML Diagnosis: -Marrow reveals characteristic ... arrest -Clinical presentation as above (not subtle) Treatment: -Most respond well to G-CSF (90%) *Prior to G-CSF most Kostmann’s patients died in early childhood -For severe cases, BMT may be an option -10% eventually develop MDS/AML |
promyelocyte
bacterial 200 maturation |
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Congenital Neutropenias:
Cyclic neutropenia: Defect: -Mutations in neutrophil elastase gene (different than Kostmann’s) – not a preleukemic state. Thought to affect maturation and chemotaxis Clinical presentation -... neutropenia with 21-day periodicity *Monocytes, platelets, reticulocytes and lymphocytes cycle at same frequency – Autosomal dominant in 50% of cases Diagnosis: -Demonstration of periodicity with regular (e.g. twice-weekly) ... -Confirmed by marrow findings of myeloid maturation arrest/... Treatment: -Increased risk of opportunistic infections at the neutrophil nadirs. - G-CSF helpful for symptomatic patients *Appears to both raise the nadir and decrease the periodicity of neutropenia -Careful attention to symptoms of infection |
Oscillatory
CBCs hypoplasia |
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lecture 19a – Oncogenesis
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The retinoblastoma protein is a tumor ... protein that is dysfunctional in many types of cancer. One highly studied function of pRb is to prevent excessive ... by inhibiting cell cycle progression until a cell is ready to divide.
It is a regulatory point within the cell cycle |
suppressor
cell growth |
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Oncogenesis:
Steps to malignant transformation: starts with a single cell (...) with genetic lesion All of the resulting cells have the same lesion Accumulation of further mutations leads to ... -Escape from growth inhibition -escape from apoptosis -escape from telomere loss -escape from local area (...) |
clonal
cancer metastasis |
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Basic types of gene mutations:
Point mutations -Premature termination --> ... function -Altered amino acids --> ... function -Regulatory sequences --> altered ... Large scale (chromosomal) aberrations -Deletions -Translocations -Amplification |
loss of
altered expression |
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Know the types of changes that convert a proto-oncogene to an oncogene:
(1) ... factors abnormally expressed or activated (2) ... factor receptors are inappropriately expressed (3) loss of growth-... via mutated tumor suppressor genes (4) “...” mutations which are called chimeras (5) Mutation in ... pathway (6) gene ... |
transcription
growth inhibition gain-of-function apoptosis amplification |
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Cancer in both children and adults is a ... process
Childhood cancers often arise from ... genetic lesions |
multistep
fewer |
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Cancer cells have inherent genetic ...
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instability
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lecture 23 – acute leukemia
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ALL – high risk groups:
Trisomy ... Disorders of DNA replication and repair -... syndrome -... anemia -Ataxia-... Other preleukemic conditions -Neurofibromatosis (NF1) -Shwachman-... syndrome |
21
Bloom’s Fanconi’s telangiectasia Diamond |
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ALL – other risk factors:
Environmental factors -Previous ... -Ionizing radiation -Electromagnetic fields ... a demonstrated risk factor Immunodeficiencies -... syndrome -Congenital ... ... infections |
chemotherapy
not Wiskott-Aldrich hypogammaglobulinemia Viral |
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ALL – prognostic factors:
Age ->2 years but < 10 years ... prognosis Initial WBC count at diagnosis -< ... best Day 7 and day 14 marrow exams -“Rapid early responder” best Immunophenotype -... best Cytogenetics -t(4;11), t(8;14), t(9;22) – poor outcome |
best
50,000 Early pre-B |
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ALL induction therapy:
Goal of induction therapy: ... ... = absence of detectable leukemia and the return of normal marrow elements -A 99% reduction in tumor burden for 10 leukemic blasts still leaves 10 ! Specific chemotherapy agents in ALL induction -Prednisone, vincristine, L-asparaginase (+/- daunomycin) 95% of ALL patients achieve remission |
Remission
Remission |
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ALL – consolidation therapy:
... disease is present in all patients Consolidation therapy -CNS prophylaxis with intrathecal chemotherapy -... irradiation only for high-risk patients ... -Improves relapse-free survival -Recent protocols have two rounds of DI |
Occult
Cranial Delayed intensification |
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ALL – maintenance therapy:
Uses different chemotherapy agents -Methotrexate -6-mercaptopurine Goal is to maintain the maximal tolerated dose Duration of maintenance -Girls - ... years -Boys - ... years |
2
3 |
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ALL – relapse:
Sites of relapse: ..., CNS, testes Systemic treatment always required -Repeat ..., some different drugs Prognosis related to timing of relapse: -Early (<12 months off therapy) – BMT if able -Late (>12 months off therapy) – chemotherapy with BMT in reserve |
Marrow
induction |
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Treatment for childhood leukemia is stratified based on ...
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risk
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AML – cytogenetics:
Poor prognosis -Monosomy 7 -11q23 gene rearrangements -FLT-3 amplification Improved prognosis -... translocation, inv(16) *Both involve fusion of CBP subunits (a transcription factor controlling expression of hematopoietic growth proteins) to other genes resulting in chimeras *Loss of normal CBP function -... translocation in acute promyelocytic leukemia *PML gene fused to retinoic acid receptor alpha gene (RARalpha) *Fusion protein binds to normal binding partners of both PML and RARalpha *Results in dysregulated differentiation -Trisomy ... |
(8;21)
(15;17) 21 |
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The few known environmental risk factors for leukemia include exposure to ... and ...
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chemical mutagens
ionizing radiation |
