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Interesting Case

69 year oldMaleKnown case of Type 2 Diabetes Mellitus since 25 yrsOn OHA . Case . Generalised weakness - 1 week Fatigue - 1 week H/O loss of appetite Vomiting - 2 days 2 episodes undigested food no hemetemesis no abdominal pain . History . No fever No histo

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Interesting Case

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    1. T.O.Jose Mrd : 766632 29/04/09 Dr.ChaitanyaVemuri Interesting Case

    2. 69 year old Male Known case of Type 2 Diabetes Mellitus since 25 yrs On OHA Case

    3. Generalised weakness - 1 week Fatigue - 1 week H/O loss of appetite Vomiting - 2 days 2 episodes undigested food no hemetemesis no abdominal pain History

    4. No fever No history suggestive of cardiac, respiratory and nervous system involvement. urine output - 2 days ( 500 – 700 ml / 24 hrs ) No documented weight loss Not a known hypertensive, dyslipidemic

    5. He was evaluated in a local hospital 1 ½ months ago for b/l pedal edema. At that time : wbc : 23,100 / cu.mm s.creatinine : 1.49 mg / dl blood urea : 36 mg / dl USG abdomen : chronic calculous cholecystitis prostatomegaly b/l renal parenchymal changes Past history

    6. No tuberculosis, asthma, malaria, typhoid, jaundice, blood transfusions PERSONAL HISTORY : Takes mixed diet Smoker – stopped 33 yrs back Does not take alcohol

    7. Pallor + Icterus + B/L Axillary lymphadenopathy + , 3 x 2 cm , firm, mobile, not matted, non tender No cyanosis, clubbing , pedal edema Icthyosis + Gum hypertrophy + No thyroid swelling On examination

    8. No varicose veins Dehydration + Pulse : 70 /min , regular BP : 110 / 70 mm Hg Temp : 98.6 F RR : 20 /min JVP : Not raised

    9. RS : B/L Normal vesicular breath sounds No Added sounds CVS : S1+, S2+ No murmurs P/ A : Soft Tenderness in Right Hypochondrium Hepatomegaly + ( 3 cm from Rt costal margin ) No Splenomegaly Bowel Sounds +

    10. NS : HMF – normal Cranial Nerves : normal Motor System : normal Sensory System : normal DTR B/L + + Plantar B/L Flexor No signs of Cerebellar Dysfunction No Neck Stiffness

    11. TC : 272 K /ul DC : N – 97.6 % L – 1.94% M- 0.25 % E – 0.03 % B – 0.14 % Hb : 8.88 g/dl MCV : 82.5fL MCH : 29.4 pg Plt : 79 K /ul Investigations

    12. ESR : 78 mm / hr INR : 2.10 s APTT : 41.6 /32.2 s S.LDH : 1383U/L ( 0- 240 ) Reticulocyte count : 1 .10% ( 0.87 – 2.63 ) Absolute reticulocyte count : 33 K.ul ( 26 – 126 ) S.Na + : 138.6 mmol/L S.K+ : 3.0 mmol /L S. Ca 2+ : 9.5 mg /L S.Mg 2 + : 2 mg / dl S.Phosphorus : 1.7 mg / dl Investigations

    13. RBS : 118.6 mg / dl HbA1 C : 10. 3 % Blood Urea : 64 mg / dl S.Creatinine : 3.64 mg / dl S.PSA : 1.212 ng / ml ( 0 – 4 ) Urine K + : 40. 4 mmol/L CXR : normal ECG : normal USG abdomen : Hepatosplenomegaly Investigations

    14. S.Bilirubin : 2.7 mg / dl S.Bilirubin Direct : 1.6 mg / dl S.Protein : 6.9 g/dl S.Albumin : 3.4 g/dl S.Globulin : 3.5 g/dl AST : 291 IU/L ALT : 193 IU/L ALP : 636 IU/L LFT

    15. Microscopy : 50 -70 RBCs numerous pus cells Leucocytes : 3 + Protein : 2 + Blood : 3 + HIV ELISA : Negative HBsAg IgM ELISA : Negative HCV ELISA : Negative Urine R/E

    16. Acute leukemia DM 2 Renal Failure Provisional diagnosis

    17. RBC : normocytic normochromic WBC : cytoplasm bluish contains plenty of granules possibly promyelocytes No Auer rods / Faggot cells Manual DC : Promyelocytes : 95 % Blasts : 4 % Lymphocyte : 1 % Platelets : , seen singly Peripheral Blood Smear

    18. Acute Leukemia To consider AML – M3 Impression

    19. Blasts : 51 % Promyelocytes : 40 % Bands : 4 % Lymphocytes : 2 % Normoblasts : 3 % Auer rods + Faggot cells + MPO : strongly positive Other hemopoetic elements suppressed Imp : AML – M3 Bone Marrow Study – Aspiration Cytology

    20. AML –M3

    21. Blast cells with numerous auer rods in the cytoplasm Accumulation of auer rods gives an appearance of bundle of sticks Often seen in hypergranular form of acute promyelocytic leukemia. Faggot Cell

    22. Faggot Cell

    23. Seen in blast cells of AML Clumps of azurophilic granular material that form elongated needles seen in cytoplasm of leukemic blasts They are composed of fused lysosomes, contain peroxidase, lysosomal enzymes and large crystalline inclusions. Auer Rods

    24. Cellular marrow showing sheets of immature myeloid cells – resembling promyelocytes AML –M3 Bone Marrow Biopsy

    25. AML – M3

    26. Acute Promyelocytic Leukemia ( AML – M3 ) Type 2 DM Renal Failure DIAGNOSIS

    27. The myeloid leukemias are a heterogeneous group of diseases characterized by infiltration of the blood, bone marrow, and other tissues by neoplastic cells of the hematopoietic system. Incidence : 3.7 per 1,00,000 people per year Male > female Increases with age 1.9 in individuals < 65 yrs 18.6 in individuals > 65 yrs Acute Myeloid Leukemia

    28. Most of the cases – no identifiable risk factor Antecedent hematological disorders : High risk MDS : refractory anemia with excess blasts Aplastic anemia Myelofibrosis Paroxysmal nocturnal hemoglobinuria Polycythemia vera Etiology

    29. Congenital disorders : Down syndrome Fanconi Anemia Bloom syndrome Kostmann syndrome ( cong.neutropenia ) Radiation Chemical exposure : Benzene Paint Petroleum products

    30. Drugs : Anti cancer drugs are leading cause of therapy associated AML Topoisomerase II Inhibitors – Etoposide Alkylating agents – Cyclophosphamide, Melphalan Chloramphenicol Phenylbutazone

    31. WHO Classification – categorized, non categorized FAB Classification Diagnosis of AML based on blast cut off - > 20 % WHO - > 30 % FAB Classification

    32. AML with recurrent genetic abnormalities AML with t( 8,21)(q22,q22) AML with abnormal bone marrow eosinophils inv (16)(p13q22) ; t(16,16)(p13q22) Acute promyelocytic leukemia AML with t (15,17)(q22q12) AML with 11q23 (MLL) abnormalities WHO Classification – AML categorized

    33. AML with multilineage dysplasia Following a myelodysplastic syndrome or myelodysplastic syndrome/myeloproliferative disorder Without antecedent myelodysplastic syndrome AML and myelodysplastic syndromes, therapy-related Alkylating agent–related Topoisomerase type II inhibitor–related Other types Contd…

    34. AML minimally differentiated AML without maturation AML with maturation Acute myelomonocytic leukemia Acute monoblastic and monocytic leukemia Acute erythroid leukemia Acute megakaryoblastic leukemia Acute basophilic leukemia Acute panmyelosis with myelofibrosis Myeloid sarcoma WHO Classification of AML not categorized

    35. MO : Minimally differentiated leukemia M1 : Myeloblastic leukemia without maturation M2 : Myeloblastic leukemia with maturation M3 : Hypergranular promyelocytic leukemia M4 : Myelomonocytic leukemia M4Eo : variant : abnormal marrow Eosinophils M5 : Monocytic leukemia M6 : Erythroleukemia ( Di Guglielmo’s disease ) M7 : Megakaryoblastic leukemia FAB Classification

    36. Acute Promyelocytic Leukemia

    37. Arrest of leukocyte differentiation at promyelocytic stage. t ( 15,17 ) Acute promyelocytic leukemia was first described as an entity in the late 1950s in Norway and France as a hyperacute fatal illness associated with a hemorrhagic syndrome. In 1959, Jean Bernard et al described the association of APL with a severe hemorrhagic diathesis that lead to disseminated intravascular coagulation (DIC) and hyperfibrinolysis. Acute Promyelocytic Leukemia

    38. Over 95% of cases are characterized by a balanced translocation between chromosome 17q21 and chromosome 15q22.  This leads to an abnormal fusion protein called alpha PML-RAR This translocation can be detected by karyotyping or FISH studies, and the transcript can be detected by PCR techniques. Cytogenetics

    39. Myeloperoxidase + CD 33 + HLA – DR : negative APML

    40. Males = Females Median age of onset - 40 years Incidence

    41. Fatigue, weakness, dyspnea – related to anemia Easy bruising, bleeding – related to thrombocytopenia coagulopathy Fever & infection – related to leukopenia APML vs Other subtypes – DIC .

    42. APML has been associated with low levels of plasminogen, alpha2-plasmin inhibitor, and plasminogen activator inhibitor 1 found in fibrinolytic states.   There is increased expression of annexin II, a receptor for plasminogen and plasminogen-activating factor, on the surface of leukemic promyelocytes. This leads to overproduction of plasmin and fibrinolysis.

    43. Hypergranular subtype (classic M3) : frequent Auer rods, clumps of granular material containing lysosomes, peroxidase, lysosomal enzymes, and large crystalline inclusions Microgranular variant : folded nucleus, cytoplasm has fine dusky granules , auer rods are rare. 25 % of cases Hyperbasophilic subtype : increased nucleocytoplasmic ratio, strongly basophilic cytoplasm with blebs. Few granules , No auer rods PLZF-RAR alpha variant : regular condensed chromatin in nucleus, fewer granules & auer rods Types of acute promyelocytic leukemia

    44. Induction therapy Consolidation therapy Maintainence therapy Relapsed / refractory disease Treatment

    45. Tretinoin Cytarabine Anthracycline : idarubicin , daunorubicin The combination of Tretinoin with chemotherapy improves long-term survival and has 85-90% complete remission rates.  Tretinoin should be started immediately to control DIC. Induction Therapy

    46. during treatment with ATRA.  occurs within the first 21 days of treatment Fever hypotension weight gain respiratory distress serositis with pleural or pericardial effusions Hypoxemia radiologic infiltrates acute renal failure hepatic dysfunction. associated with hyperleukocytosis Rx : IV Dexamethasone 10 mg q12h for at least 3 days. Retinoic acid syndrome

    47. 2-3 cycles of anthracycline-based chemotherapy The benefit of ATRA with consolidation therapy has not been proven in randomized studies 3 cycles of consolidation with idarubicin to mitoxantrone to idarubicin Consolidation Therapy

    48. 3-drug regimen : ATRA 45 mg/m2 daily given 15 days every 3 months, oral 6-MP 60 mg/m2 once daily, methotrexate 20 mg/m2 PO once weekly are administered for 2 years.  Patients should be monitored for abnormal liver function and myelosuppression during this time period Pateints of APML – should undergo RT-PCR assay for PML-RAR alpha fusion trnascript. Can help in diagnosing APML – when cytogenetics and FISH fail Help in diagnosing minimal residual disease. Maintainence Therapy

    49. Arsenic trioxide Gemtuzumab ozogamicin Bone Marrow Transplantation Refractory disease

    50. For induction or relapsed therapy - 0.15 mg/kg/day until bone marrow remission maximum of 60 doses.  For consolidation - same dose for 5 weeks, Maximum of 25 doses. sideeffects : prolongation of the QTc interval, hepatotoxicity rash fluid retention nausea & vomiting Arsenic trioxide

    51. Humanized anti CD33 antibody Studies show 9 / 11 acheieved molecular remission after 2 doses @ 6 mg / m2 After 3rd dose 13/13 patients achieved molecular remission . Side effects : myelosuppression thrombocytopenia hepatic toxicity veno-occlusive disease infusion related events like fever, rash Gemtuzumab Ozogamicin

    52. Thank You

    53. Autosomal recessive disorder Congenital Telangiectatic Erythema Features : Short stature Facial rash High pitched voice Long narrow face Micrognathia Prominent nose and ears Pigmentation Café – au – lait spots Bloom syndrome

    54. Telangiectasia Moderate immune deficiency Hypogonadism Diabetes Mental retardation in a few Increased suseptibility to cancer: leukemia,lymphoma Mutations in “BLM” GENE

    55. Infantile genetic agranulocytosis Inherited disorder of bone marrow Autosomal recessive Lack of neutrophils – suspectibility to infections Children – increased risk of developing AML / Myelodysplasia Kostmann Syndrome

    56. Absolute monocytosis Eosinophilia Thrombocytosis Defect in the gene on chr 1 that codes for G CSF receptor Treatment : recombinant G CSF Other hematological manifestations in Kostmann syndrome

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