Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0023467 (acute myeloid leukemia)
 35,200 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The eldest brother in a sibship of five children died of acute myelogenous leukemia at 10 years of age. The second and third eldest brothers died of hypoplastic anemia at ages five and nine years, respectively. A surviving 6 year old brother, the proband of the study, has abnormalities that suggest a preleukemic state: mild pancytopenia, platelet dysfunction, immunodeficiency, and bone marrow hypoplasia with approximately 18 per cent blast forms. His 17 year old sister has a mild normochromic normocytic anemia. Cytogenetic studies revealed C-group monosomy in the bone marrows of the proband and the third brother (45, XY, -C); band studies demonstrated that a No. 8 chromosome was missing in the proband (45, XY, -8). At least four of the siblings and their father had cerebellar ataxia, and evidence of a small cerebellum at autopsy examination or by computerized axial tomography. The disorder in this family has major features of two autosomal recessive preleukemic diseases, ataxia-telangiectasia and Fanconi's anemia. However, these and other inherited conditions were excluded by clinical or laboratory criteria, and no environmental causes of the familial disorder were found. The constellation of abnormalities in the family may constitute a new genetic syndrome.
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PMID:A family with acute leukemia, hypoplastic anemia and cerebellar ataxia: association with bone marrow C-monosomy. 28 89

In a family with ataxia and pancytopenia, the proband had cerebellar ataxia, developed hypoplastic anemia at age 3 years, and died of acute myelomonocytic leukemia at age 7. Serial cytogenetic studies of the proband's hypoplastic bone marrow over a 25-month period revealed progressive expansion of a clone of cells with C(6 - 12 + X) monosomy from 33% to 94% of metaphases. The missing chromosome by banding was deduced to be No.7. No increased sensitivity of the patient's cells was found in response to ultraviolet or ionizing radiation or to mitomycin C. Cerebellar atrophy was confirmed at autopsy. Family studies revealed cerebellar ataxia in the proband's father and all four siblings. Two brothers, including one with C-monosomy, died with hypoplastic anemia and another brother died with acute myelocytic leukemia. The only surviving sibling is a 19-year-old sister who has unexplained anemia, decreased mitotic activity in bone marrow, and slow progressive cerebellar ataxia. The name ataxia-pancytopenia syndrome is proposed to encourage study of additional patients with this disorder, which predisposes to pancytopenia and acute leukemia.
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PMID:Ataxia-pancytopenia: syndrome of cerebellar ataxia, hypoplastic anemia, monosomy 7, and acute myelogenous leukemia. 694 57

We report a case of cerebellar astrocytoma occurring 8 years after the second bone marrow transplantation (BMT) in 32-year-old man. The patient was admitted to our hospital in December 1997 because of dysarthria and gait disturbance. He had been treated earlier for acute myeloid leukemia (AML M2) with chemotherapy and cranial irradiation followed by allogeneic BMT from a sibling in december 1988. Three months after the first BMT, testicular relapse was observed and followed by systemic relapse. The patient received reinduction therapy and a second successful BMT. He had been well until about 1 month before admission to our hospital. Neurological examination revealed left cerebellar ataxia, and brain magnetic resonance imaging disclosed a left cerebellar tumor. The tumor was surgically resected and a histological diagnosis of cerebellar astrocytoma was made. The patient was further treated by irradiation for residual tumor and discharged without progression of the disease.
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PMID:[Development of cerebellar astrocytoma in a patient with acute myeloid leukemia 8 years after his second bone marrow transplant]. 1039 Aug 94

Valspodar (PSC-833) is a derivative of cyclosporin but devoid of the immunosuppressive and nephrotoxic properties seen in cyclosporin A. It exhibited high affinity binding to Mdr1 P-glycoprotein (P-gp) and demonstrated multidrug resistance-reversing activity superior to cyclosporin A and verapamil both in vitro and in vivo. Preclinical and phase I/II clinical data have indicated that plasma levels of PSC-833 with multidrug resistance-reversing activities are achievable. Potent inhibition of intestinal, hepatobiliary and blood-brain barrier P-gp function has been demonstrated. Since valspodar is also a substrate of cytochrome P450 3A (CYP3A), dual interactions of this compound with P-gp and CYP3A are the basis for the pharmacokinetic interactions seen in preclinical and clinical studies. A new formulation of the drug has recently been developed with better oral bioavailability (60%) and less interindividual variability. The toxicity profiles of valspodar are acceptable and dose-limited by transient and reversible cerebellar ataxia. It has shown multidrug resistance-modulating activities towards acute myeloid leukemia, multiple myeloma and ovarian cancer in phase I/II clinical trials. Phase III studies with respect to these three diseases are ongoing.
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PMID:Technology evaluation: Valspodar, Novartis AG. 1124 78

PSC 833 (Valspodar) can reverse multidrug resistance (MDR) in patients with hematologic malignancies, but alters the pharmacokinetics of concomitant anticancer agents. A phase I, dose-finding study was initiated to define a safe and effective regimen of mitoxantrone, etoposide, and cytarabine (MEC) when administered with PSC 833 to patients with early relapsed or refractory acute myeloid leukemia (AML). Poor-prognosis AML patients refractory to first-line induction therapy or relapsing within 9 months of attaining complete remission (CR) were treated with cytarabine (1.0 g/m2/day), etoposide (30 mg/m2/day), and mitoxantrone at a dose of either 3.0 mg/m2/day (cohort 1) or 4.5 mg/m2/day (cohorts 2 and 3) for 6 days plus continuous-infusion PSC 833 (10 mg/kg/24 h with a 2.0 mg/kg loading dose) for 6 or 7 days each 21-day cycle. Patients achieving CR were given a 4-day MEC plus PSC 833 consolidation cycle. Twenty-three patients were enrolled (eight with primary refractory AML and 15 in relapse). Dose-limiting toxicity occurred in one of six patients in cohort 2 (grade 4 mucositis) and one of seven patients in cohort 3 (grade 4 hyperbilirubinemia). The maximum tolerated dose of mitoxantrone was defined as 4.5 mg/m2/day. Clinically significant grade 4 hyperbilirubinemia, possibly related to PSC 833, occurred in four patients. Hematologic toxicities were as expected in this patient population, but were not dose limiting. Mild to moderate cerebellar ataxia and paresthesia occurred in six (26%) and five (22%) patients, respectively, but were not dose limiting. Overall, six of 23 (26%) patients achieved CR, including five patients with demonstrated P-glycoprotein expression and/or function. The median overall survival was 4 months. All six patients with a CR were alive and four (17%) patients were disease free at 12 months. Blood levels of PSC 833 were well above the target level of 1000 ng/ml, a concentration that is known to reverse MDR in vitro. PSC 833 reduced the clearance of etoposide by approximately two-fold. No correlation was observed between the mitoxantrone or etoposide area under the curve and response. In conclusion, the MEC plus PSC 833 tested regimen was well tolerated and the 26% CR rate warrants further testing of this regimen in a randomized, phase III trial.
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PMID:Combined action of PSC 833 (Valspodar), a novel MDR reversing agent, with mitoxantrone, etoposide and cytarabine in poor-prognosis acute myeloid leukemia. 1136 37

The human AF9/MLLT3 gene is a common fusion partner for the MLL gene in translocations t(9;11)(p22;q23) associated with acute myeloid leukemia and acute lymphocytic leukemia. The exact function of the gene is still unknown, although a mouse knock-out model points to a role as a controller of embryo patterning. We report the case of a constitutional translocation t(4;9)(q35;p22) disrupting the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia and epilepsy. Array-CGH analysis at 1 Mbase resolution did not reveal any additional deletions/duplications. We hypothesize a loss-of-function mutation of the AF9/MLLT3 gene, and a possible role for the FAT gene on chromosome 4, in the genesis of the proband's severe neurological phenotype.
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PMID:Loss-of-function mutation of the AF9/MLLT3 gene in a girl with neuromotor development delay, cerebellar ataxia, and epilepsy. 1600 Dec 62

Granulocytic sarcomas are rare tumors that occur primarily in patients with acute myelogenous leukemia or other myeloproliferative disorders, are seldom seen in patients with acute promyelocytic leukemia (APL), and have never been reported to occur in the cerebellum. The authors describe the case of a patient with APL who harbored a hemorrhagic granulocytic sarcoma in the cerebellum. This 39-year-old woman presented with cerebellar ataxia. Magnetic resonance images revealed an intraaxial tumor in the cerebellum. Bone marrow samples showing infiltration by leukemic blast cells and data from hematological tests led to a diagnosis of APL. The patient was treated with chemotherapy and surgery. She had no response to chemotherapy and died of progressive intratumoral hemorrhage. Results of histopathological studies and immunohistochemical staining of the cerebellar tumor confirmed a granulocytic sarcoma. Flow cytometry showed that the blast cells were positive for leukocyte common antigen, CD13, and CD33 markers. Bone marrow cytogenetics revealed that the patient had a 46,XX karyotype. Although no cytogenetic abnormality was present, fluorescence in situ hybridization detected a chimeric fusion of PML and RARA. This is the first report to document a granulocytic sarcoma in the cerebellum as the primary presentation in a patient with APL and abnormal coagulation. As predicted by the unusual clinical manifestations and radiological findings, the patient's survival was short. Although central nervous system complications in patients with APL are rare, the data in this case highlight the need for individualized treatment when such conditions occur.
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PMID:Granulocytic sarcoma: an unusual complication of acute promyelocytic leukemia causing cerebellar hemorrhage. Case report. 1740 65

The syndrome of ataxia-pancytopenia is an autosomal dominant disorder characterized by cerebellar ataxia, peripheral neuropathies, pancytopenia and a predilection to myelodysplastic syndrome and acute myeloid leukemia. The genetic basis of this condition is unknown. We describe a child who presented with ataxia and pancytopenia and was found to have a heterozygous mutation, c.845G>A (Arg282His) in TINF2, a gene recently reported to be mutated in a subset of patients with autosomal dominant dyskeratosis congenita. We propose that some cases of ataxia-pancytopenia may be affected by DC.
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PMID:Ataxia and pancytopenia caused by a mutation in TINF2. 1897 21