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Stephen J Forman

Publications and source records attributed to Stephen J Forman.

60 records · Page 4Linked to original sources
PubMed2002

Imatinib mesylate (STI571) inhibits growth of primitive malignant progenitors in chronic myelogenous leukemia through reversal of abnormally increased proliferation.

Imatinib mesylate (STI571) is a promising new treatment for chronic myelogenous leukemia (CML). The effect of imatinib mesylate on primitive malignant progenitors in CML has not been evaluated, and it is not clear whether suppression of progenitor growth represents inhibition of increased proliferation, induction of apoptosis, or both. We demonstrated here that in vitro exposure to concentrations of imatinib mesylate usually achieved in patients (1-2 microM) for 96 hours inhibited BCR/ABL-positive primitive progenitors (6-week long-term culture-initiating cells [LTCICs]) as well as committed progenitors (colony-forming cells [CFCs]). No suppression of normal LTCICs and significantly less suppression of normal CFCs were observed. A higher concentration of imatinib mesylate (5 microM) did not significantly increase suppression of CML or normal LTCICs but did increase suppression of CML CFCs, and to a lesser extent, normal CFCs. Analysis of cell division using the fluorescent dye carboxyfluorescein diacetate succinimidyl ester indicated that imatinib mesylate (1-2 microM) inhibits cycling of CML primitive (CD34(+)CD38(-)) and committed (CD34(+)CD38(+)) progenitors to a much greater extent than normal cells. Conversely, treatment with 1 to 2 microM imatinib mesylate did not significantly increase the percentage of cells undergoing apoptosis. Although a higher concentration of imatinib mesylate (5 microM) led to an increase in apoptosis of CML cells, apoptosis also increased in normal samples. In summary, at clinically relevant concentrations, imatinib mesylate selectively suppresses CML primitive progenitors by reversing abnormally increased proliferation but does not significantly increase apoptosis. These results suggest that inhibition of Bcr-Abl tyrosine kinase by imatinib mesylate restores normal hematopoiesis by removing the proliferative advantage of CML progenitors but that elimination of all CML progenitors may not occur.

Adolescent↗
PubMed2002

Diagnostic utility of bilateral bone marrow examination: significance of morphologic and ancillary technique study in malignancy.

BACKGROUND: To retrospectively evaluate the significance of morphologic examination and ancillary studies performed on bilateral bone marrow biopsy specimens, 1864 bone marrow samples were studied. METHODS: Bilateral bone marrow biopsy specimens included 883 specimens that were evaluated for involvement by non-Hodgkin lymphoma (NHL); 381 specimens that were evaluated for involvement by carcinoma (CA); 362 specimens that were evaluated for involvement by Hodgkin disease (HD); 94 specimens that were evaluated for involvement by sarcoma (SA); 56 specimens that were evaluated for involvement by multiple myeloma (MM); 53 specimens that were evaluated for involvement by acute and chronic leukemia, myelodysplasia, and/or myeloproliferative disorders (LEUK); and 35 specimens that were evaluated for other reasons. RESULTS: Of all 1864 specimens, 410 samples (22.0%) were positive for disease, including 77% of MM samples, 58% of LEUK samples, 29.6% of NHL samples, 14% of SA samples, 9.9% of HD samples, and 6.8% of CA samples. A discrepancy between the left and right sides was identified in 48 specimens (11.7% of positive samples). The discrepancy rate was 39% for HD samples, 29% for SA samples, 23% for CA samples, and 9.2% for NHL samples. No morphologic discrepancies between bilateral samples were found in MM samples or LEUK samples. Bilateral flow cytometric studies (n = 113 samples) were positive in 11 samples (9.7%; all morphologically positive), with two discrepancies detected between bilateral samples. Bilateral cytogenetic studies (n = 74 samples) were positive in 5 samples (7%), and there were no discrepancies. Bilateral molecular studies (n = 16 samples) were positive in 7 samples (44%), and there were 3 discrepancies. CONCLUSIONS: Bilateral morphologic evaluation is useful in the evaluation of patients with NHL, HD, CA, and SA and is not indicated for patients with acute or chronic leukemia, myelodysplasia, MM, and other diseases. Bilateral flow cytometric or cytogenetic studies of bone marrow did not provide additional information in this population to justify bilateral samples. The role of bilateral molecular analysis needs to be defined further, but pooled samples for molecular studies may be adequate.

Biopsy↗
PubMed2002

The myelodysplastic syndromes: morphology, risk assessment, and clinical management (2002).

The Myelodysplastic Syndromes (MDS) represent a group of potentially acute myeloid leukemic disorders. There exists a delicate balance between increased apoptosis and proliferation of the leukemic hematopoietic stem cell that permits many patients to survive for years. When the balance shifts towards proliferation AML develops with a poor outcome for most but not all patients. I will review the latest proposals from the W.H.O. in classification, including pediatric MDS, prognostic factors and response criteria. Then I will present a strategy for the management of low risk patients with supportive care or low intensity treatment (cytokines, Immune modulation, anti-VEGF agents) and finally chemotherapy and intensive therapy with auto and allo BMT.

Cell Transformation, Neoplastic↗
PubMed2002

Conditioning therapy with intravenous busulfan and cyclophosphamide (IV BuCy2) for hematologic malignancies prior to allogeneic stem cell transplantation: a phase II study.

Busulfan (Bu) is commonly used as a component of conditioning regimens for hematopoietic stem cell transplantation. Precise delivery of the oral formulation is compromised by erratic gastrointestinal absorption. An IV Bu formulation was developed to provide dose assurance and complete bioavailability. In a phase I study, the plasma bioequivalence of IV Bu was established at approximately 80% of the oral dose. We now report the findings of the first phase II study, in which 61 adults with hematologic cancers were treated with a Bu-cyclophosphamide (BuCy) regimen consisting of IV Bu (0.8 mg/kg every 6 hours x 16) followed by Cy (60 mg/kg qd x 2) and transplantation of stem cells from an HLA-matched sibling donor. The median age of study participants was 37 years; 75% of patients had active disease; 48% were heavily pretreated, and 13% had undergone a prior transplantation. Median follow-up was 2.3 years; median time to engraftment (absolute neutrophil count, >0.5 x 10(9)/L) was 13 days; 100% of patients with cytogenetic and/or molecular markers had documented chimerism; and there were no engraftment failures. Two-year overall and disease-free survival were 67% and 42%, respectively. There were no unexpected toxic reactions. Fatal veno-occlusive disease occurred in 2 patients, 1 of whom had undergone a prior transplantation. Treatment-related mortality at 100 days was 9.8% (6/61). Bu pharmacokinetics after IV drug administration demonstrated high inter- and intrapatient consistency; 86% of patients maintained an area under the curve between 800 and 1500 microMol-min. In conclusion, the IV Bu in this regimen was very well tolerated and demonstrated excellent antitumor efficacy, most likely because of dose assurance with predictable pharmacokinetics.

Adult↗
PubMed2002

Hematopoietic potential of neural stem cells: plasticity versus heterogeneity.

Organ-specific stem cells have been identified in a variety of mammalian tissues. These cells hold great promise for cellular therapy if they can reliably produce functional progeny of specific lineages. A central dogma in development has been that organ-specific stem cells are restricted to making the differentiated cell types of the tissue from which they are isolated. However, a substantial body of evidence exists that stem-cell populations from neural and hematopoietic tissues can generate the other cell types, suggesting that adult organ-specific stem cells may have a broader differentiation potential than originally thought. It remains unclear whether this apparent stem cell plasticity is attributable to transdifferentiation of tissue specific stem cells, the co-existence of multiple stem cells with different potentials, or resident totipotent stem cells in these tissues. Recent evidence, in fact, indicates that there may be a fourth explanation for the "apparent" plasticity of stem cells: cell fusion. Here, the authors critically examine the existing data to assess the extent of phenotypic conversion of bone marrow-to-brain and brain-to-blood and discuss some of the contentious issues surrounding these studies. We conclude that there is strong evidence for a multipotent neurohematopoietic stem-cell population in human and mouse brain, although further characterization of these cells will be required if the goal of engineering tissues for therapeutic applications is to be realized.

Animals↗