Biomedical subjects

Michael J Borowitz

Publications and source records attributed to Michael J Borowitz.

12 recordsLinked to original sources

PubMed2006

Risk- and response-based classification of childhood B-precursor acute lymphoblastic leukemia: a combined analysis of prognostic markers from the Pediatric Oncology Group (POG) and Children's Cancer Group (CCG).

The Children's Cancer Group (CCG) and the Pediatric Oncology Group (POG) joined to form the Children's Oncology Group (COG) in 2000. This merger allowed analysis of clinical, biologic, and early response data predictive of event-free survival (EFS) in acute lymphoblastic leukemia (ALL) to develop a new classification system and treatment algorithm. From 11 779 children (age, 1 to 21.99 years) with newly diagnosed B-precursor ALL consecutively enrolled by the CCG (December 1988 to August 1995, n=4986) and POG (January 1986 to November 1999, n=6793), we retrospectively analyzed 6238 patients (CCG, 1182; POG, 5056) with informative cytogenetic data. Four risk groups were defined as very high risk (VHR; 5-year EFS, 45% or below), lower risk (5-year EFS, at least 85%), and standard and high risk (those remaining in the respective National Cancer Institute [NCI] risk groups). VHR criteria included extreme hypodiploidy (fewer than 44 chromosomes), t(9;22) and/or BCR/ABL, and induction failure. Lower-risk patients were NCI standard risk with either t(12;21) (TEL/AML1) or simultaneous trisomies of chromosomes 4, 10, and 17. Even with treatment differences, there was high concordance between the CCG and POG analyses. The COG risk classification scheme is being used for division of B-precursor ALL into lower- (27%), standard- (32%), high- (37%), and very-high- (4%) risk groups based on age, white blood cell (WBC) count, cytogenetics, day-14 marrow response, and end induction minimal residual disease (MRD) by flow cytometry in COG trials.

Adolescent↗

PubMed2006

Resolution of ambiguous low-level positive quantitative polymerase chain reaction results in TEL-AML1 positive ALL using a post-PCR fluorescent oligoligation method.

The interpretation of low-level or non-reproducible amplification results in clinical quantitative polymerase chain reaction (Q-PCR) assays can be difficult to definitively resolve. Concerning minimal residual disease detection in leukaemia, indeterminate low-level results might create prognostic or therapeutic dilemmas. We evaluated low-level, ambiguous Q-PCR results in a study of paired diagnostic and end-induction (day 29) TEL-AML1 positive acute lymphoblastic leukaemia samples utilising a novel fluorescent primer ligation detection assay. The data presented here indicate that a significant number of low-level apparent Q-PCR positive results may be spurious or non-specific in nature, requiring additional technical manoeuvres for confirmation of true positive cases.

Child↗

PubMed2006

Biologic pathways associated with relapse in childhood acute lymphoblastic leukemia: a Children's Oncology Group study.

Outcome for children with childhood acute lymphoblastic leukemia (ALL) who relapse is poor. To gain insight into the mechanisms of relapse, we analyzed gene-expression profiles in 35 matched diagnosis/relapse pairs as well as 60 uniformly treated children at relapse using the Affymetrix platform. Matched-pair analyses revealed significant differences in the expression of genes involved in cell-cycle regulation, DNA repair, and apoptosis between diagnostic and early-relapse samples. Many of these pathways have been implicated in tumorigenesis previously and are attractive targets for intervention strategies. In contrast, no common pattern of changes was observed among late-relapse pairs. Early-relapse samples were more likely to be similar to their respective diagnostic sample while we noted greater divergence in gene-expression patterns among late-relapse pairs. Comparison of expression profiles of early- versus late-relapse samples indicated that early-relapse clones were characterized by overexpression of biologic pathways associated with cell-cycle regulation. These results suggest that early-relapse results from the emergence of a related clone, characterized by the up-regulation of genes mediating cell proliferation. In contrast, late relapse appears to be mediated by diverse pathways.

Apoptosis↗

PubMed2006

A clinical evaluation of high fluorescent platelet fraction percentage in thrombocytopenia.

We evaluated an automated method (XE-2100 automated blood cell counter equipped with a laser and upgraded software, Sysmex, Kobe, Japan) to quantify the high fluorescent platelet fraction percentage (HFPF%) as an indicator of platelet production. The mean HFPF% value was 3.1 in 80 healthy subjects (95% confidence interval, 2.8%-3.5%). The coefficient of variation was less than 10% for elevated values and 10% to 20% for normal values. Sample stability was up to 48 hours. We tested the HFPF% in 171 patients with thrombocytopenia. The highest values were found in patients with autoimmune thrombocytopenia and disseminated intravascular coagulation, although HFPF% also was increased in patients with regenerating marrows. In other patient groups with decreased platelet production, the HFPF% was within the normal range. The HFPF% was predictive in the evaluation of thrombocytopenia. We found elevated HFPF% values in disorders associated with increased platelet production, particularly associated with platelet destruction, and normal values in disorders associated with decreased platelet production. The results are precise; testing can be performed as readily as a CBC count using an EDTA-anticoagulated blood sample.

Adult↗

PubMed2006

The usefulness of CD71 expression by flow cytometry for differentiating indolent from aggressive CD10+ B-cell lymphomas.

We studied 34 low- and 30 high-grade CD10+ B-cell lymphomas. Forward light scatter (FSC) and CD71 fluorescence intensity (CD71i) of tumor cells were measured and normalized by corresponding values for resting T cells. Significant differences in CD71i values between low- and high-grade lymphomas were observed by the Mann-Whitney U test (P < .001) and receiver operating characteristic (ROC) curve analysis (P < .001). FSC was not significantly different between low- and high-grade lymphomas; the area under the ROC curve was less than that for CD71i. Neither FSC nor CD71i significantly differentiated follicular lymphoma (FL) grades. A comparison of all FLs (grades 1-3) and non-FL high-grade lymphomas (Burkitt lymphoma [BL] and large B-cell lymphoma [LBCL]) showed significant differences in CD71i (P < .001) and FSC (P = .021). Differences were significant in CD71i and FSC between FL and LBCL (P < .001) but not between FL and BL. CD71i is more potent than FSC for distinguishing CD10+ low- from high-grade lymphomas and FL from non-FL high-grade lymphomas. Sensitivity and specificity are limited owing to inability to identify FL3. In ROC analysis, a high value for CD71i can identify BL and LBCL with a high degree of certainty.

Antigens, CD↗

PubMed2005

Comparison of diagnostic and relapse flow cytometry phenotypes in childhood acute lymphoblastic leukemia: implications for residual disease detection: a report from the children's oncology group.

BACKGROUND: Flow cytometric analysis of minimal residual disease (MRD) depends on detecting phenotypically abnormal populations. However, little is known about how phenotypic shifts between diagnosis and relapse affect MRD detection in childhood acute lymphoid leukemia (ALL). METHODS: We compared diagnostic and relapse bone marrow specimens in 42 children with precursor B-ALL studied with the two-tube panel CD19-APC/CD45-PerCP/CD10-PE/CD20-FITC and CD19-APC/CD45-PerCP/CD9-PE/CD34-FITC. RESULTS: At least 29 cases had phenotypic shifts of intensity or coefficient of variation of distribution of one or more markers. Shifts were complex and could not be explained by change in maturation stage. In the majority of cases MRD populations more closely resembled the diagnostic than the relapse specimen. In 6 of 7 MRD negative cases we did not identify an abnormal population that resembled diagnosis or relapse. In the remaining case, in which CD34 and CD10 were lost between diagnosis and relapse, it is possible that we could have missed an MRD population resembling relapse. CONCLUSIONS: Phenotypic shifts are common, but do not affect MRD recognition. At most 1 of 42 cases might have harbored an abnormal population undetected because of shift. However, MRD analysis with rigid gating (looking strictly for abnormal phenotypes at diagnosis) might have missed many positive cases, 8 of 22 (36%) in this series.

Child↗

PubMed2005

Outcomes of autologous and allogeneic blood or marrow transplantation for mantle cell lymphoma.

To evaluate high-dose therapy and autologous or allogeneic blood or marrow transplantation (BMT) for mantle cell lymphoma, patients receiving BMT for newly diagnosed or relapsed mantle cell lymphoma were identified through the registry at Johns Hopkins. The pathologic diagnostic criteria were reviewed, and details of the presentation, transplant procedure, and survival outcomes were determined. Fifty-eight patients were identified, of whom 64% underwent transplantation in first remission and 12% had primary induction failure. Nineteen patients (one third) received an allograft. Preparative regimens consisted of cyclophosphamide in combination with either busulfan or total body irradiation. On multiple regression analysis, transplantation after 1 or more relapses (hazard ratio, 2.98; P = .02), primary induction failure (hazard ratio, 5.39; P = .002), and allogeneic transplantation (hazard ratio, 3.03; P = .007) were associated with an inferior event-free survival (EFS). However, EFS curves were not statistically different for autologous and allogeneic BMT performed in first remission, with an estimated 3-year EFS approaching or equaling 70%. Primary induction failure and residual bone marrow involvement were the only statistically significant predictors of relapse on multiple regression analysis. At 3 years, the estimated EFS for the entire cohort after BMT was 51%, the probability of relapse was 31%, and the overall survival was 59%. The benefit of autologous or allogeneic BMT for mantle cell lymphoma is thus most apparent when transplantation is performed in first remission. Whether allogeneic BMT ultimately confers an advantage because of a graft-versus-lymphoma effect remains to be determined.

Adult↗

PubMed2005

High-dose therapy and blood or marrow transplantation for non-Hodgkin lymphoma with central nervous system involvement.

The role of autologous or allogeneic blood or marrow transplantation (BMT) remains undefined in patients with central nervous system (CNS) involvement by lymphoma. The records of all adult and pediatric non-Hodgkin lymphoma patients receiving BMT at Johns Hopkins from 1980 to 2003 were reviewed, and 37 patients were identified who had CNS involvement that was treated into remission by the time of BMT. The chief histologies were diffuse large B-cell lymphoma and T-cell lymphoblastic lymphoma/leukemia. Twenty-four percent received intrathecal chemotherapy alone, and 70% received intrathecal chemotherapy and CNS irradiation before BMT. The main preparative regimens were cyclophosphamide/total body irradiation and busulfan/cyclophosphamide. Forty-one percent received an allogeneic transplant. Lymphoma relapsed after BMT in 14 patients (38%), and at least 5 had documented or suspected CNS relapse. In multivariate models, age > or =18 years at diagnosis, resistant systemic disease, busulfan/cyclophosphamide conditioning, and lack of intrathecal consolidation after BMT were statistically significant predictors of inferior survival. The 5-year actuarial event-free survival was 36%, and overall survival was 39%. After BMT, long-term survival is thus achievable in a subset of patients with a history of treated CNS involvement by non-Hodgkin lymphoma. The survival rates are not dissimilar to those typically seen in other high-risk lymphoma patients undergoing BMT. These data suggest that patients with lymphomatous involvement of the CNS who achieve CNS remission should be offered BMT if it is otherwise indicated.

Adolescent↗

PubMed2004

Inter- and intra-observer reliability of Epstein-Barr virus detection in Hodgkin lymphoma using histochemical procedures.

EBER in situ hybridization (EBER) and LMP-1 immunohistochemistry (LMP-1) are widely used for identifying Epstein-Barr virus (EBV) within tumor cells of Hodgkin lymphoma (HL), but measurement error has never been formally evaluated. To determine assay reliability, 40 HL tumors with known EBV status were stained for both EBER and LMP-1 by two laboratories and reviewed twice by four hematopathologists. Inter- and intra-observer agreement were good to excellent, with kappas above 0.78 overall and above 0.60 for most subgroup analyses. However, reliability varied by histologic subtype, preparing laboratory, reviewer and EBV status determined on consensus review. For EBER, inter-observer agreement was high for nodular sclerosis HL but somewhat lower for EBV-negative mixed cellularity HL. For LMP-1, agreement was excellent for mixed cellularity HL but somewhat less reliable for EBV-positive nodular sclerosis HL. Agreement was good for EBER and LMP-1 applied to the same specimens but differed by consensus EBV status. The variability in assay interpretation justifies caution in comparing EBV association results across HL studies and underscores the need for interpretation guidelines.

Herpesvirus 4, Human↗

PubMed2004

FLT3 mutations in myeloid sarcoma.

Myeloid sarcoma is an extramedullary tumour that typically occurs in the setting of acute myeloid leukaemia (AML), or myeloproliferative disorders. In AML, two types of mutations in Fms-like tyrosine kinase 3 (FLT3) have been described; internal tandem duplications (ITD) and point mutations at aspartic acid residue 835 (D835). We analysed 24 myeloid sarcoma specimens from 20 patients for FLT3 ITD and D835 mutations. FLT3 ITD mutations were identified in three of 20 cases (15%); no D835 mutations were identified. The ITD inserts ranged in size from 33 to 198 base pairs (bp) and represented approximately 20-40% of the FLT3 alleles. Two cases showed discordance in FLT3 ITD mutational status. In one case, the leukaemia specimen was positive for a FLT3 ITD mutation and the myeloid sarcoma specimen was negative. In the second case, the myeloid sarcoma was positive for a FLT3 ITD mutation at diagnosis, but negative in subsequent relapse samples. Our findings suggest that small molecule inhibitors of FLT3 may be useful therapeutic agents for treatment of myeloid sarcomas-containing FLT3 mutations, however, the potential for discordance between the leukaemia and myeloid sarcoma, necessitates that the myeloid sarcoma tumour itself be analysed for FLT3 mutations.

Acute Disease↗

PubMed2003

Immature granulocyte measurement using the Sysmex XE-2100. Relationship to infection and sepsis.

We determined the usefulness of immature granulocyte measurement as a predictor of infection or positive blood culture and compared the results with total WBC count and absolute neutrophil count (ANC). Blood samples from 102 infected and 69 noninfected patients were analyzed using the Sysmex XE-2100 automated blood cell counter (Sysmex, Kobe, Japan). The percentage of immature granulocytes was significantly higher in infected than in noninfected patients and in patients with positive than patients with negative blood cultures. Receiver operating characteristic curves showed that the percentage of immature granulocytes was a better predictor of infection than the WBC count and comparable to the ANC. Automated immature granulocyte measurements reflect a biologically and clinically relevant phenomenon but are not sensitive enough to be used as screening assays for prediction of infection or bacteremia. However, although infrequently encountered, a percentage of immature granulocytes of more than 3 was a very specific predictor of sepsis and might help expedite microbiologic laboratory evaluation of a subset of patients.

Granulocytes↗

PubMed2002

Lack of surface immunoglobulin light chain expression by flow cytometric immunophenotyping can help diagnose peripheral B-cell lymphoma.

We determined the prevalence and significance of finding B cells without surface immunoglobulin (SIg) light chain expression. The flow cytometry database at Johns Hopkins Medical Institutions was searched for cases in which immunoglobulin light chain staining was performed to rule out a B-cell malignant neoplasm between January 1994 and February 2000. We excluded plasma cell dyscrasias, precursor B-cell acute lymphoblastic leukemia/lymphomas, and hematogones. Cases with more than 25% of B cells lacking SIg light chain expression were retrieved. Polymerase chain reaction assays for immunoglobulin heavy chain gene rearrangements were performed in SIg-negative cases with available tissue blocks. We identified 36 cases; all represented lymphoma. Their diagnoses included diffuse large B-cell lymphoma (20), HIV-related lymphoma (5), follicular lymphoma (5), Burkitt lymphoma (2), monomorphic posttransplant lymphoproliferative disorder (1), chronic lymphocytic leukemia/small lymphocytic lymphoma (1), marginal zone B-cell lymphoma (1), and low grade B-cell lymphoma (1). Of the 17 SIg-negative cases with amplifiable DNAs, 12 (71%) showed a clonal immunoglobulin heavy chain gene rearrangement. SIg-negative B-cell lymphomas are rare. Complete absence of SIg light chain expression in a mature B cell proliferation can be used as a surrogate marker to help diagnose peripheral B-cell lymphoma.

Adult↗