Biomedical subjects

M J Borowitz

Publications and source records attributed to M J Borowitz.

At least 73 records · Page 4Linked to original sources

PubMed1992

Trisomy of leukemic cell chromosomes 4 and 10 identifies children with B-progenitor cell acute lymphoblastic leukemia with a very low risk of treatment failure: a Pediatric Oncology Group study.

To account for the superior prognosis of hyperdiploid, B-progenitor acute lymphoblastic leukemia (ALL), we investigated the influence of trisomy in 1021 children greater than or equal to 1 year old by recursive partitioning analysis. The patients were treated according to a stratified, randomized study testing antimetabolite-based therapies. Trisomies of several individual chromosomes were associated with a better prognosis in a univariate statistical analysis. Of greater importance, trisomy of both chromosomes 4 and 10 identified a subgroup of patients (n = 180) with an extremely favorable 4-year event-free survival (EFS). Combined trisomy of chromosomes 4 and 10 retained its prognostic significance after stratification of patients by DNA index, age, and leukocyte count. Among patients with a DNA index greater than 1.16, patients with trisomies of both chromosomes 4 and 10 had a 4-year EFS of 96.6% (n = 161, SE = 3.8%), whereas patients with neither or only one of these trisomies had a 4-year EFS of 70.4% (n = 73, SE = 11.5%). All 19 patients with a DNA index less than or equal to 1.16 but with trisomies of chromosomes 4 and 10 remain in remission, suggesting that favorable chromosome trisomy dominates in a situation in which the cellular DNA content of less than or equal to 1.16 predicts a less favorable outcome. We conclude that combined trisomy of chromosomes 4 and 10 independently predicts EFS among children with B-progenitor ALL. Patients within the B-progenitor group who have this feature (about 20% of those with clonal abnormalities) are likely to be cured with antimetabolite-based chemotherapy--an approach that should produce few significant late effects.

Adolescent↗

PubMed1992

Isochromosomes in childhood acute lymphoblastic leukemia: a collaborative study of 83 cases.

Cytogenetic analysis of leukemic cells from 2,805 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified 83 cases (3%) that had a stemline with at least one isochromosome. The i(9q) was present in 28 (1%), the i(17q) in 23 (0.8%), and the i(7q) in 23 (0.8%). Other isochromosomes--i(21q), i(6p), i(1q), i(8q), or i(Xq)--were found in only 12 cases (0.4%). The isochromosome cases were more likely than were other ALL cases to have a pre-B immunophenotype (38% v 25%, P = .02) and leukemic cell hyperdiploidy greater than 50 (37% v 24%, P = .02); five cases had both features. The i(9q) was associated with age greater than 10 years (P less than .05) and the pre-B immunophenotype (P = .05); both the i(17q) and i(7q) had high frequencies of hyperdiploidy greater than 50 (P less than .0001 and P = .05, respectively). The t(1;19)(q23;p13) was a common feature (23%) in cases with the i(9q), i(7q), i(6p), or i(1q). These findings establish the i(9q), i(17q), and i(7q) as nonrandom chromosomal abnormalities in ALL. The prognostic significance of the presence of isochromosome(s) remains to be determined.

Adolescent↗

PubMed1992

t(2;14)(p13;q32): a recurring abnormality in lymphocytic leukemia. A Pediatric Oncology Group study.

Chromosome banding studies of 1,411 children with newly diagnosed acute lymphocytic leukemia (ALL) identified two patients with the t(2;14)(p13;q32) chromosome abnormality and a third patient with a complex three-way translocation involving the same breakpoints on chromosomes 2 and 14 but also involving chromosome 12 at band q11. The three cases demonstrated variability of immunophenotypes: one was a T-cell ALL, and two were early pre-B ALLs. All three patients achieved complete remissions and have remained in remission for 14-19 months.

B-Lymphocytes↗

PubMed1992

Human B-cell lymphoma in severe combined immunodeficient mice after active infection with Epstein-Barr virus.

BACKGROUND: B-cell lymphomas (BCL) occur with increased frequency in immunosuppressed patients. BCL develop in severe combined immunodeficient (SCID) mice after engraftment with human peripheral blood leukocytes (PBL; hu-PBL-SCID mice) and infection with Epstein-Barr virus (EBV). The contributions of latent and active EBV infection to BCL development, the potential enhancing effects of immunosuppressive therapy, and inhibitory effects of antiviral therapy on the development of BCL in this model were studied. METHODS: SCID mice were engrafted with PBL from EBV-seropositive donors (latent infection), PBL from EBV-seronegative donors followed by infection with EBV (active infection), PBL from EBV-seropositive donors followed by infection with EBV (latent plus active infection), or EBV-transformed B-lymphoblastoid cells and monitored for the development of BCL. Hu-PBL-SCID mice were treated with the immunosuppressive agents cyclosporine or methylprednisolone or the antiviral agents acyclovir or ganciclovir. RESULTS: Tumors developing in hu-PBL-SCID mice were high-grade lymphomas of human B-cell origin and contained EBV-DNA. BCL developed in 70% of mice 11 to 14 weeks after latent infection. BCL developed after 4 to 7 weeks in all hu-PBL-SCID mice after active infection. Treatment with cyclosporine or methylprednisolone had no effect on BCL development after active infection, but inhibited rather than enhanced the development of BCL in latently infected mice. Ganciclovir, but not acyclovir, inhibited BCL development after active infection. CONCLUSIONS: The hu-PBL-SCID mouse provides an in vivo model of BCL associated with immunosuppression. Active EBV infection results in the rapid development of BCL in this model even when latently infected B cells are present. Inhibition of BCL development in latently infected hu-PBL-SCID mice by immunosuppressive therapy may reflect inhibition of a T-cell/B-cell interaction necessary for B-cell activation. Inhibition of BCL development by granciclovir suggests a possible role for this agent in the management of BCL associated with immunosuppression.

Acute Disease↗

PubMed1992

Different patterns of relapse associated with three intensive treatment regimens for pediatric E-rosette positive T-cell leukemia: a Pediatric Oncology Group study.

One hundred and ninety-three children with T-cell acute lymphocytic leukemia (T-ALL) whose leukemia cells were E-rosette positive were treated on a Pediatric Oncology Group study (1979-1986) designed specifically for patients with T-ALL. The results of modified LSA2L2 therapy with or without intensified intrathecal chemotherapy and cranial irradiation (radiotherapy) were compared with those obtained using a simpler multi-agent protocol which included radiotherapy (T-cell 2). The complete remission (approximately 90%) and 3-year event-free survival rates (approximately 40%) were similar in the three treatment groups. However, the pattern of extramedullary relapse varied according to specific treatment regimen. Patients who received LSA2L2 therapy with less intensive intrathecal chemotherapy and no radiotherapy had a central nervous system (CNS) relapse rate (i.e. isolated CNS +/- other site) of over 20%, compared to only 10% for patients receiving the same systemic chemotherapy with intensified intrathecal therapy and radiotherapy, and less than 5% for those receiving T-cell 2 therapy. In contrast, males receiving T-cell 2 therapy had a testicular relapse rate of greater than 20% compared to less than 10% for patients receiving either regimen (i.e. +/- intensified intrathecal chemotherapy and radiotherapy) of modified LSA2L2 therapy. We conclude that, in the context of these therapies, central nervous system irradiation plus intensive triple (hydrocortisone, methotrexate, cytarabine) intrathecal chemotherapy is more effective than CNS preventative therapy comprised of intrathecal low-dose methotrexate only, and that the more complex multi-agent chemotherapy used in the modified LSA2L2 regimens appeared to be more effective in prevention of testicular leukemia, indicating that the effectiveness of sanctuary site treatment was therapy-specific.

Adolescent↗

PubMed1991

Laboratory correlates and prognostic significance of granular acute lymphoblastic leukemia in children. A Pediatric Oncology Group study.

As part of a comprehensive prospective clinicopathologic study by the Pediatric Oncology Group (POG), 2,092 children with acute lymphoblastic leukemia (ALL) were evaluated by uniform morphologic, cytochemical, and immunologic methods to assess the frequency and implications of granular lymphoblasts. All cases were Sudan black or myeloperoxidase negative and met French-American-British (FAB) morphologic criteria for ALL. Granular ALL, characterized by the presence of more than 5% marrow blasts with at least three clearly defined azurophilic cytoplasmic granules, was identified in 56 of the 1,252 fully studied cases (4.5%). The frequency of granular features did not differ among early pre-B (4.3%), pre-B (3.6%), and T (5.8%) ALL; no cases were identified among the 12 patients with B ALL. Within the early pre-B/pre-B group, granular ALL was equally distributed between good- and poor-risk clinical groups but was more frequent among FAB L2 than FAB L1 cases (12% vs. 2%; P less than or equal to 0.001). Patients were treated with standard POG protocols for early pre-B/pre-B and T ALL. Complete remission (CR) rates were significantly lower for those with granular lymphoblasts, regardless of risk group, immunophenotype, or FAB type. Analysis of event-free survival (EFS) showed a significantly poorer outcome for granular early pre-B/pre-B cases with FAB L2 morphologic characteristics (P less than 0.001) and for those classified as poor risk (P = 0.015). These findings suggest a relationship between granules and L2 morphologic characteristics in childhood ALL and indicate that the presence of granular lymphoblasts conveys a worse prognosis for certain subgroups of children with ALL.

Azure Stains↗

PubMed1991

DNA ploidy of malignant melanoma determined by image cytometry of fresh frozen and paraffin-embedded tissue.

Image analysis of DNA content was performed from single nuclei of melanoma monolayer imprints made from fresh frozen tissue of 14 patients with primary malignant melanoma and 16 patients with local recurrences at the incision site and local or distant metastases. This procedure requires fewer cells and is an advantage when the quantity of tumor available is limited, especially in thin low Breslow depth cutaneous melanomas. Image analysis allowed reproducible measurement of DNA ploidy from 100 cells. The frequency of aneuploidy was similar in primary and metastatic melanomas. Three of 3 patients with euploid primary melanomas showed no evidence of recurrences or metastases, though one died of unrelated disease with short follow-up. The 4 patients with primary melanoma who developed metastases had aneuploid primaries; two of these patients died of metastatic disease. Three of 4 patients with euploid metastatic tumors were free of disease at last follow-up, and 1 patient died with stable disease. Nine of 12 patients with aneuploid tumors died of metastatic disease. The frequency of DNA ploidy in the present image analysis study correlated with previous flow cytometry studies. In 9 patients with primary tumors with a Breslow depth greater than 0.75 mm, the DNA content was also determined in nuclei obtained from formalin-fixed paraffin-embedded tissue. The frequency of aneuploidy was higher in fresh tissue (7 of 9) as compared with paraffin-embedded tissue of the same cases (4 of 9).

Aneuploidy↗

PubMed1990

A novel ribonucleoprotein complex defined by monoclonal antibodies to NIH 3T3 cells transfected with human pancreatic adenocarcinoma DNA.

Three monoclonal antibodies elicited to NIH 3T3 cells transfected with DNA from a human pancreatic adenocarcinoma cell line recognized a novel ribonucleoprotein complex. Minimally, this ribonucleoprotein complex contained a Mr 240,000 protein (by sodium dodecyl sulfate-polyacrylamide gel electrophoresis) and two RNA species with apparent sizes of 1.5 and 3.0 kilobases (by formaldehyde agarose gel electrophoresis). In addition to a cytoplasmic and nuclear subcellular localization, the RNA antigen was secreted from human tumor cell lines and NIH 3T3 cells transfected with pancreatic tumor DNA (inhibitable by monensin) and was apparently not a viral or Mycoplasma contaminant. The ribonucleoprotein antigen was detected in some normal tissues by immunoperoxidase but was not found in or secreted from in vitro cultured normal human fibroblasts, nontransfected or spontaneously transformed NIH 3T3 cells, or normal peripheral blood leukocytes.

Adenocarcinoma↗

PubMed1990

Impact of the Medicare fee schedule on payments to physicians.

Beginning in 1992, the Medicare program will pay physicians by the Medicare Fee Schedule, a system of geographically adjusted standardized payment rates based in part on the Resource-Based Relative Value Scale developed by Hsaio et al and in part on current Medicare payments. In our simulations of the Medicare Fee Schedule, we find that (1) redistributions of Medicare-allowed charges across specialities will be substantial but approximately only half the size projected by Hsaio, (2) there will be large redistributions among geographic areas that tend to compound the specialty redistributions, and (3) there will be wide variation within specialties as to how individual providers are affected. The majority of the redistributive impact of the Medicare Fee Schedule is attributable to implementation of a geographically adjusted system of standardized payments rather than to the particular work values developed by Hsiao et al in the Resource-Based Relative Value Scale.

Costs and Cost Analysis↗

PubMed1990

Near-triploid and near-tetraploid acute lymphoblastic leukemia of childhood.

Cytogenetic and DNA flow cytometric analyses of leukemic cells from 1,971 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified stem lines with modal chromosome numbers greater than 65 in 26 patients (1.3%). Near-triploidy (66 to 73 chromosomes) was found in six cases and near-tetraploidy (82 to 94 chromosomes) in 20. A striking morphologic finding was the presence of clumped chromatin with grooved nuclei or Rieder cell formation in 20 cases. Other than a slight excess of the pre-B immunophenotype, the near-triploid cases did not appear to differ substantially from the general ALL population in clinical features. In contrast, near-tetraploid cases were more often associated with a T-cell immunophenotype (47% v 14%, P less than .001) and L2 morphology (30% v 22%, P less than .01), and were older at diagnosis (median age, 8.6 v 4.8 years, P = .01) than cases with other ploidies. Moreover, an unusually high proportion of near-tetraploid cases tested (6 of 15) expressed one or more of the myeloid-associated antigens CD13, CD15, and CD33. Despite the use of contemporary intensive chemotherapy and short follow-up for most patients, 6 of the 20 near-tetraploid cases have relapsed or died. This study suggests that the near-tetraploid subtype differs from other cases of hyperdiploid greater than 50 ALL, which have been associated with a favorable prognosis.

Adolescent↗

PubMed1990

Clinical presentation, karyotypic characterization, and treatment outcome of childhood acute lymphoblastic leukemia with a near-haploid or hypodiploid less than 45 line.

Cytogenetic and DNA flow cytometric analyses of leukemic cells from 2,184 children with newly diagnosed acute lymphoblastic leukemia (ALL) identified 27 cases (1.2%) that had a hypodiploid line with fewer than 45 chromosomes per cell. Had cytogenetic techniques been used alone, seven cases would have been missed, compared with five if only flow cytometry had been used. For comparative purposes, the 27 cases were divided into three groups: near-haploid (n = 10), hypodiploid 30-40 (n = 9), and hypodiploid 41-44 (n = 8). Blast cells from patients with near-haploid ALL lacked structural chromosomal abnormalities; showed nonrandom retention of two copies of chromosomes 8, 10, 14, 18, 21, and the sex chromosomes; and had a second leukemic line with exactly twice the number of chromosomes or DNA content. Karyotypic analysis of the hypodiploid 30-40 and hypodiploid 41-44 groups disclosed structural abnormalities in the stemline or sideline of most of the well-banded cases; those in the latter group were similar to findings in cases with 45 chromosomes. As in the near-haploid group, chromosome 21 and the sex chromosomes were preferentially retained in the hypodiploid 30-40 and 41-44 cases. Except for a slight excess of female patients in the near-haploid group and an older age at diagnosis in the hypodiploid 30-40 cases, there were no initial clinical features that distinguished these patients from the general ALL population. Despite intensive treatment and short follow-up, 17 of the 27 patients have relapsed. This study suggests that the poor treatment responsiveness of hypodiploid ALL is not limited to the more than 80% of the patients who have 45 chromosomes per leukemic cell and demonstrates that cytogenetic and flow cytometric analyses are complementary in the evaluation of children with ALL.

Aneuploidy↗

PubMed1990

Extranodal head and neck lymphoma. Prognosis and patterns of recurrence.

Stages I and II extranodal head and neck lymphomas treated between 1969 and 1986 were reviewed to determine prognosis and recurrence patterns. Forty-four patients had low-grade lymphoma, with 57% remaining disease free (median survival, 7.2 years). Radiotherapy provided long-term disease-free survival and palliation in the majority of patients. Relapse did not adversely affect survival. Eighty-eight patients had intermediate- or high-grade lymphoma, with 42% remaining disease free (median survival, 2.4 years). Treatment with radiotherapy alone was inadequate. Combined radiotherapy and anthracycline-containing chemotherapy appeared to be superior. Extranodal sites of first relapse were common. Central nervous system relapse was common with primary tumors located above the pterygopalatine line. Central nervous system staging and prophylactic therapy is warranted in patients with tumors above the pterygopalatine line.

Adult↗

PubMed1990

Prognostic significance of CD34 expression in childhood B-precursor acute lymphocytic leukemia: a Pediatric Oncology Group study.

We studied the blasts from 795 children greater than 1 year of age with newly diagnosed, untreated B-precursor acute lymphoblastic leukemia (ALL) for expression of the hematopoietic stem cell-associated antigen CD34. All cases were confirmed as B-lineage lymphoblastic leukemia by virtue of expression of CD19 and/or CD22, lack of T-cell antigens, and lack of surface-membrane immunoglobulin (Ig). The CD34 antigen was present in at least 10% of blast cells in 587 (73.8%) of the patients. There was no significant difference in presenting clinical characteristics between CD34+ and CD34- patients save for an increased incidence of CNS involvement at diagnosis in the latter. Patients with CD34+ leukemia were more likely to have blasts expressing CD22, CD9, and CD13 antigens but were less likely to coexpress CD20. Patients with pre-B (cytoplasmic mu) ALL were significantly more likely to lack CD34 on their blasts, while children with hyperdiploid ALL were more likely to be CD34+. Although remission induction rates were not significantly different between patients with CD34+ and CD34-ALL (P = .23), event-free survival was shorter for patients with CD34- leukemia (P = .0014). Even though CD34 expression was associated with certain other known prognostically favorable variables including hyperdiploidy and lack of cytoplasmic Ig, it had an independent favorable effect on treatment outcome, even after adjusting for competing prognostic factors.

Antigens, CD↗

PubMed1990

Immunologic markers in childhood acute lymphoblastic leukemia.

This article details the immunologic diversity of acute lymphoblastic leukemia in children. A historical review of developments in immunophenotyping is followed by a discussion of how major subgroups of leukemia are best defined today. The relationship of immunologic subtypes to stages of normal lymphoid development is explored, and the clinical impact of immunophenotyping is discussed.

Antibodies, Monoclonal↗

PubMed1990

Clinical and biological heterogeneity of childhood B cell acute lymphocytic leukemia: implications for clinical trials.

Thirty-two children or adolescents had B cell acute lymphocytic leukemia (ALL) diagnosed by demonstration of surface immunoglobulin expression on greater than 10% of their bone marrow blasts. All patients had greater than 25% bone marrow lymphoblasts. Only five of 32 patients (16%) presented with an abdominal mass; however, 24 cases (75%) had FAB L3 morphology. By comparison with findings in common ALL, these 32 children were older (median age, 8 years) and had a higher incidence of central nervous system disease at presentation (22%); all but one were white, and 24 were males. Blast cells from individual cases expressed mu kappa (n = 13), mu lambda (n = 9), gamma kappa (n = 1), alpha kappa (n = 1), or mu with an undetermined light chain (n = 8). The most frequently identified cytogenetic abnormality was the classic B cell-associated t(8;14)(q23;q24) (n = 4); the t(1;19)(q23;p13.3), t(9;22)(q23;q11), and t(1;22) were observed in single cases. Twenty patients were treated uniformly on a single protocol designed for children with advanced B cell malignancy; therapy for the other 12 children varied. Nine children (28%) are surviving event-free; all but one for 3 years or more. We conclude that approximately 25% of children with B cell ALL are curable with intensive multiagent chemotherapy and that classification by immunophenotyping is superior to use of clinical and/or lymphoblast morphologic features.

Adolescent↗

PubMed1989

Phase I study of an anti-breast cancer immunotoxin by continuous infusion: report of a targeted toxic effect not predicted by animal studies.

260F9 Monoclonal antibody-recombinant ricin A chain, an immunotoxin reactive with approximately 50% of breast carcinomas, was given by continuous iv infusion at a dose of 50 micrograms/kg per day or 100 micrograms/kg per day. Five patients with refractory breast cancer received treatment for from 6 to 8 days. Severe toxic effects, including marked fluid overload and debilitating sensorimotor neuropathies, occurred in most patients. Immunoperoxidase studies suggested that 260F9 monoclonal antibody targeting of the Schwann cells may have induced demyelination and subsequent neuropathy. This is the first report of a targeted toxic effect due to an immunoconjugate.

Adult↗

PubMed1989

An anti-CD5 immunotoxin for chronic lymphocytic leukemia: enhancement of cytotoxicity with human serum albumin-monensin.

Five patients with B-cell chronic lymphocytic leukemia (B-CLL) were treated with 6 courses of the anti-CD5 immunotoxin T101-ricin A chain (T101-RTA). Each course consisted of 8 bi-weekly infusions of T101-RTA (7 or 14 mg/m2). The immunotoxin was well tolerated in all cases with no major toxicities. Though saturation of circulating leukemic cell-associated target antigen was demonstrated by FACS analysis in all patients, no intact immunotoxin was detected in bone-marrow or lymph-node aspirates. Pharmacokinetic studies revealed rapid clearance of T101-RTA, with a half-life of 43 min. None of the patients developed detectable titers of antibody against either T101 murine antibody or ricin A chain. Clinical response was limited to a rapid and transient fall in WBC count lasting less than 24 hr, most likely secondary to the antibody portion of the conjugate. In vitro, fresh B-CLL cells were resistant to T101-RTA at concentrations up to 10(-8)M, while fresh malignant T-cells with a 10-fold increase in expression of CD5 antigen were sensitive. In the presence of the enhancing agent human serum albumin-monensin, fresh B-CLL cells were sensitive to T101-RTA, with an ID50 more than 2 logs below the maximal concentration of immunotoxin achieved in vivo. We conclude that T101-RTA is a potentially useful agent in the treatment of T-cell leukemias. In the presence of HSA-monensin, this spectrum of activity may be extended to B-CLL.

Aged↗

PubMed1989

Heterogeneity of antigen expression in benign and malignant breast and ovarian epithelial cells.

Expression of II distinct antigen families has been studied in normal and malignant epithelial cells from breast and ovary by avidin-biotin immunoperoxidase staining of frozen tissue sections. Each of the antigens was expressed in a fraction of the normal and malignant breast tissues from different individuals. Among breast and ovarian cancers, a similar fraction of tumors expressed each of the determinants. An epitope on a 42-kDa glycoprotein was expressed significantly more often by ovarian carcinomas than by benign ovarian epithelium. Several determinants on 66-, 240-kDa or high-molecular-weight proteins or glycoproteins were expressed significantly more often on benign breast epithelium than on normal ovarian epithelium. Substantial heterogeneity in antigen expression was observed among different tumor specimens. Each of 14 epithelial ovarian cancers expressed a distinctive combination of antigens. Among 18 breast cancers, 16 distinct antigenic phenotypes were observed. Interestingly, comparable heterogeneity was observed in the expression of epitopes on benign breast and ovarian epithelium, compatible with the possibility that the monoclonal reagents recognized polymorphic determinants. Substantial variations in antigen expression were also observed among cells within each neoplasm. However, when antibodies against 5 different determinants were used in combination, a majority of cells could be stained intensely in all 13 breast carcinomas tested and more than 95% of tumor cells could be stained in 10 of the 13.

Antigens, Neoplasm↗