PubMed Health⌕ Search

Biomedical subjects

M Talpaz

Publications and source records attributed to M Talpaz.

At least 271 records · Page 15Linked to original sources
PubMed1989

Myeloproliferative disorders: usefulness of X-linked probes in diagnosis.

Myeloproliferative disorders are neoplasms of the pluripotent hematopoietic stem cell. Accurate diagnosis and distinction from reactive processes can be difficult therein with cytogenetic analysis only being useful in a minority of patients. Use of X-linked restriction fragment length polymorphism and methylation analysis has enabled clonal analysis to be performed in up to 50% of females, significantly increasing the proportion of analyzable patients over methods dependent on glucose-6-phosphate dehydrogenase heterozygosity. Using hypoxanthine phosphoribosyl transferase and phosphoglycerate kinase probes, we have demonstrated monoclonality of peripheral blood leukocytes in three females with myeloproliferative disorders who had uninformative chromosomal analysis. This technique greatly enhances the diagnosis of early myeloproliferative disorder.

Adult↗
PubMed1989

Ras oncogene mutations are rare late stage events in chronic myelogenous leukemia.

DNA from bone marrow and peripheral blood samples of 44 chronic myelogenous leukemia (CML) patients were analyzed for the presence of mutations of codons 12, 13 or 61 of the N-ras, H-ras, or K-ras genes. In seven patients, samples were available from both their chronic phase and blast crisis. A total of 29 samples examined were at chronic phase and 22 were at blast crisis (eight lymphoid, eight myeloid, and six undifferentiated). No mutations were identified in N-ras or H-ras. Two patients in myeloid blast crisis had K-ras mutations, one patient at codon 12, the other at codon 13. In the former patient the mutation was not present and the latter patient was not tested in chronic phase. Our findings indicate ras mutations are an infrequent late stage event in CML that occur in myeloid blast crisis.

Genes, ras↗
PubMed1989

Therapy of chronic myelogenous leukaemia with interferons.

Therapy of Philadelphia positive chronic myelogenous leukaemia (CML Ph1) with alpha interferon (IFN-alpha) resulted in a high frequency of haematological remissions. Effective suppression of the malignant Ph1 clone and concomitant partial or complete restoration of normal haemopoiesis is reproducibly noted in a proportion (30%-50%) of the patients. This and the low incidence of blast crisis underscore the profound effect this therapy has on the disease. Marked heterogeneity in the response to IFN-alpha was noted as well, and sensitivity or resistance to interferon was phenotypically indistinguishable. Studies of the IFN-resistant disease failed to disclose alteration in IFN receptors or in IFN-inducible genes and are suggestive, therefore, of a limited alteration in IFN-induced intracellular pathways.

Humans↗
PubMed1989

Detection of two alternative bcr/abl mRNA junctions and minimal residual disease in Philadelphia chromosome positive chronic myelogenous leukemia by polymerase chain reaction.

The Philadelphia (Ph') chromosome in chronic myelogenous leukemia (CML) results in fusion of the bcr gene and c-abl oncogene, which transcribes into two types of chimeric bcr/abl mRNAs: the L-6 junction and the K-28 junction. By means of a highly sensitive assay, combination of reverse transcription and polymerase chain reaction (RT/PCR), we analyzed 38 blood samples obtained from 31 patients with Ph'-positive CML and two patients with Ph'-negative bcr rearranged CML. Among the 21 samples obtained in chronic phase, eight patients had the L-6 mRNA, 11 had the K-28 mRNA, and two had both the L-6 and K-28 mRNAs. Among the nine samples obtained in blast crisis, four contained the L-6 mRNA, two contained the K-28 mRNA, and three contained both the K-28 and L-6 mRNAs. This finding supports the concept of alternative splicing of bcr/abl mRNAs transcribed in Ph'-positive CML. However, it appears to be a rare event. Of the eight samples obtained from eight patients who had achieved complete cytogenetic remission and negativity for bcr region rearrangement for 6 months to 3 years after recombinant alpha interferon (r alpha-IFN) therapy, all of them showed evidence of minimal residual Ph'-positive clones as detected by the RT/PCR assay. This finding suggests that interferon therapy suppresses the proliferation of the Ph'-positive clones, but it does not completely eradicate the Ph'-positive stem cells.

DNA-Directed DNA Polymerase↗
PubMed1989

Alternative 5' end of the bcr-abl transcript in chronic myelogenous leukemia.

Philadelphia chromosome positive acute lymphocytic leukemia and chronic myelogenous leukemia are strongly associated with two distinct forms of bcr-abl chimeric protein, known as P190 and P210, respectively. By studying cDNA clones obtained from the cell line KBM-5, we identified two new bcr-abl transcripts. These are formed by alternative splicing of at least two exons to the known bcr exon 2. One novel transcript can encode a protein kinase of approximately 190 kd, while the other can direct the synthesis of a larger protein whose amino terminus remains to be defined. The alternative exons can be spliced also to the two normal bcr transcripts, reflecting the activation of a cryptic promoter. These messages were present at low abundance in two cases of blastic crisis but were not detected in the chronic phase. It is conceivable that the proteins encoded by the new bcr-abl mRNAs are involved in the transformation to the acute phase in some cases of chronic myelogenous leukemia.

Amino Acid Sequence↗
PubMed1988

Treatment of the blastic phase of chronic myelogenous leukemia with mitoxantrone and high-dose cytosine arabinoside.

Twenty-seven patients in the blastic phase of chronic myelogenous leukemia received combination chemotherapy with mitoxantrone 5 mg/m2 intravenously daily for 5 days, and cytosine arabinoside 3 g/m2 intravenously over 2 hours every 12 hours for six doses. The patients' median age was 42 years (range, 19-61 years), and 26 of them had Philadelphia chromosome-positive disease. Overall, seven patients (26%) achieved complete remission, and one (4%) had a partial remission for an overall response rate of 30%. Eight patients died during remission induction, and 11 had resistant disease. The median survival was 14 weeks for the total population, and 24 weeks for patients achieving a complete remission. The nonmyelosuppressive toxicity of the combination was acceptable; serious neurologic and pulmonary toxicities were uncommon. Significant marrow hypoplasia was observed resulting in a high incidence of febrile episodes (85% of patients). The combination of mitoxantrone and high-dose cytosine arabinoside did not significantly improve overall prognosis. Since chemotherapy continues to produce disappointing results, other innovative approaches need to be explored.

Adult↗
PubMed1988

Characteristics of accelerated disease in chronic myelogenous leukemia.

Determination of the characteristics of accelerated disease in chronic myelogenous leukemia (CML) helps in individual prognostication, and in the introduction and analysis of investigative approaches based on risk-benefit ratios. The outcome of 357 patients with Philadelphia chromosome-positive CML was analysed from the time of development of suspected features of accelerated disease. Median survivals shorter than 18 months were associated with the appearance of any of the following: cytogenetic clonal evolution; extramedullary disease; peripheral blasts greater than or equal to 15%, peripheral blasts and promyelocytes greater than or equal to 30%, or peripheral basophils greater than or equal to 20%; platelet count less than 1.0 X 10(5)/microliters; marrow blasts greater than or equal to 15%, marrow blasts and promyelocytes greater than or equal to 30%, or marrow basophils greater than or equal to 20%. Relative hazard ratios, or risk of death per unit time, were calculated based on the relative survivals of patients who did or did not develop the particular feature of accelerated disease, after accounting for the time to development of the characteristic. Further analysis identified five features that have additive independent prognostic importance: cytogenetic clonal evolution; peripheral blasts greater than or equal to 15%; peripheral basophils greater than or equal to 20%; peripheral blasts and promyelocytes greater than or equal to 30%; and thrombocytopenia. By providing an objective estimate of prognosis in accelerated disease, the model identifies patients in need of different therapeutic interventions before the development of blastic crisis.

Follow-Up Studies↗
PubMed1988

Philadelphia-negative chronic myelogenous leukemia with breakpoint cluster region rearrangement: molecular analysis, clinical characteristics, and response to therapy.

We have detected rearrangement in the breakpoint cluster region (bcr) on chromosome 22 in cells derived from seven chronic myelogenous leukemia (CML) patients who had no cytogenetic evidence of a chromosome abnormality. These Philadelphia (Ph)-negative, bcr rearrangement-positive CML patients had clinical features and laboratory parameters that bore a strong resemblance to those of Ph-positive CML; all patients have shown a favorable response to hydroxyurea, busulphan, or alpha interferon (IFN-alpha) therapy. In one patient, because of the deletion of distal 3' sequences, detection of bcr rearrangement required a large probe that recognized proximal 5' sequences. Cells obtained from five patients were studied by Northern blotting and showed an aberrant 8 kilobase (kb) mRNA indistinguishable from the bcr-abl transcript that is felt to be a pathogenetic factor in Ph-positive CML. In three patients with a normal karyotype, bcr rearrangement was detected at the time of hematologic remission, and represented the only evidence for persistent malignancy. Our results suggest that: (1) the presence of bcr rearrangement in CML is associated with clinical features of Ph-positive disease, even in the absence of the Ph chromosome; (2) deletions occur within bcr and necessitate the use of probes covering both 5' and 3' DNA segments for accurate diagnosis; (3) molecular analysis may provide a useful approach to the follow-up of leukemia therapy in some patients; and (4) these patients respond to hydroxyurea, busulphan, and IFN-alpha therapy.

Adolescent↗
PubMed1988

Malignancy-associated Sweet's syndrome: review of the world literature.

Sweet's syndrome is an acute febrile neutrophilic dermatosis in which approximately 20% of the reported patients have an associated cancer. We review the 79 patients with malignancy-associated Sweet's syndrome documented in the world literature. The most common underlying neoplasm was acute myelogenous leukemia (AML). Lymphomas, chronic leukemias, myelomas, myelodysplastic syndromes, and a variety of solid tumors have also been observed. The onset of Sweet's syndrome either preceded or coincided with the discovery of a previously undiagnosed cancer in greater than 60% of malignancy-associated Sweet's syndrome patients. In contrast to patients with the idiopathic form of the disease, those with a malignancy often presented with more severe cutaneous lesions, cytopenias, and/or immature cells in the peripheral blood. Extracutaneous sites of involvement included the eyes, muscles and joints, kidneys, lungs, and liver. All the manifestations of Sweet's syndrome improved dramatically with corticosteroid therapy, regardless of the response of the associated neoplasm to tumor-directed therapy.

Adrenal Cortex Hormones↗
PubMed1988

A phase I trial of intravenously-administered recombinant tumor necrosis factor-alpha in cancer patients.

We report a phase I clinical investigation of 30-minute and four-hour intravenous (IV) infusions of recombinant tumor necrosis factor (rTNF)-alpha. Thirty-nine patients with disseminated cancer received escalating doses of rTNF-alpha for five consecutive days every 2 weeks for a total duration of 8 weeks. Dose escalations followed a modified Fibonacci scale with a minimum of four patients entered at each dose level: 5, 10, 25, 50, 75, 100, 150, 200, and 250 micrograms/m2/d. Toxicities consisted mainly of constitutional symptoms including fever, chills, headache, and fatigue, increasing in severity with dose escalation. No significant differences in dose-limiting toxicities were seen between the two rates of IV infusion. The maximum tolerated dose (MTD) was 200 micrograms/m2 with dose limiting toxicity being constitutional symptoms and hypotension. Hematologic changes included median decrease in both granulocyte and platelet counts of 38% and 41%, respectively (range, 16% to 85%), although clinically significant granulocytopenia and thrombocytopenia were not observed. Hematological parameters returned to baseline within 72 hours after rTNF-alpha was stopped. rTNF-alpha induced changes in lipid metabolism were manifested by median fasting triglyceride elevations above baseline (median, 103 micrograms/dL) of 157% (range, 16% to 389%) after five days of therapy with doses greater than 75 micrograms/m2, associated with a median increase in very-low-density lipoprotein (VLDL) of 80%. Serum rTNF peak levels exceeding 10 ng/mL were observed 30 minutes following rTNF-alpha infusions at MTD dose. Twelve of 34 patients had no change in their evaluable disease for a median duration of 18 weeks (range, 8 to 30 weeks), and 22 patients showed progressive disease. This study forms the framework for phase II trials of IV administered rTNF-alpha.

Adult↗
PubMed1988

Detection of minimal residual bcr/abl transcripts by a modified polymerase chain reaction.

The Philadelphia (Ph1) chromosome in chronic myelogenous leukemia (CML) involves reciprocal translocation of the bcr gene and the c-abl oncogene. The fused bcr/abl gene is transcribed into two types of chimeric mRNA. By means of a combined method of S1 nuclease protection and polymerase chain reaction, we amplified sequences representative of the chimeric bcr/abl transcripts. Only 5 micrograms of total cellular RNA is needed and the chimeric bcr/abl message can be detected at a dilution of 1:100,000. We also detected residual chimeric bcr/abl transcripts in the remission samples from two Ph1-positive CML patients. This technique has the potential to identify a subpopulation of Ph1-positive CML patients in remission who are at high risk of relapse.

Base Sequence↗
PubMed1988

Fludarabine therapy in chronic lymphocytic leukemia (CLL).

Fludarabine (9-beta-D-arabinofuranosyl 2-fluoro-adenine monophosphate) is a fluorinated analogue of adenine which is relatively resistant to deamination by adenosine deaminase. Phase I clinical trials disclosed significant antitumor activity in lymphoid malignancies. Fludarabine has been used in the treatment of CLL since March, 1985, at a dose of 25-30 mg/m2/day x 5 days each 3-4 weeks by short intravenous infusion. Sixty-eight previously treated patients with CLL are evaluable for response. The median age was 60 years, 50 were male the median number of prior chemotherapy regimens was 2, and the median time from initial chemotherapy to fludarabine was 45 months. Forty-three (63%) were Rai stages 3 and 4, 31 (46%) were Binet Stage C. Twenty patients (29%) obtained a complete remission (CR), defined as peripheral lymphocytes less than 4,000/microliters, no clinical evidence of disease, less than 30% of lymphocytes in the bone marrow (with no residual nodules), or a nodular partial remission, NPR (CR except for residual lymphoid nodules), and 19 (28%) a partial remission (less than 50% reduction in tumor in nodes, liver, spleen and bone marrow and greater than 1 log reduction in the lymphocyte count). The complete remission rate for the various involved sites were blood (69%), liver (52%), spleen (55%), and nodes (48%). The bone marrow was the least responsive site with 16% CR and 44% PR. The number of prior regimens did not have a significant response rate or survival. The serum albumin , alkaline phosphatase, platelet and hemoglobin level all were associated with survival from the start of fludarabine.(ABSTRACT TRUNCATED AT 250 WORDS)

Antimetabolites, Antineoplastic↗