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Biomedical subjects

M Borowitz

Publications and source records attributed to M Borowitz.

At least 37 records · Page 2Linked to original sources
PubMed1992

t(12;17)(p13;q21) in early pre-B acute lymphoid leukemia.

Structural rearrangements involving the short arm of chromosome 12 occur in 10% of cases of childhood acute lymphoid leukemia. The translocation t(12;17)(p13;q21), an uncommon 12p abnormality, was identified in five of 2620 cases (0.2%) successfully karyotyped by the Pediatric Oncology Group or St Jude Children's Research Hospital. All five cases were classified as early pre-B; however, CD10 (common acute lymphoblastic leukemia antigen) was expressed at lower levels than other markers of B-cell lineage. Two cases also expressed the myeloid-associated antigen CD33. Leukemic cells were pseudodiploid in four cases, with an extra chromosome 21 in the fifth case. All of these patients achieved complete remission. Two relapsed during subsequent therapy, and three remain in continuous remission for greater than or equal to 20 months.

Adolescent↗
PubMed1992

Morphologic, immunologic and cytogenetic studies in children with acute lymphoblastic leukemia at diagnosis and relapse: a Pediatric Oncology Group study.

The morphologic, immunologic and cytogenetic features of leukemic cells obtained at the time of first bone marrow relapse were compared with those obtained at initial diagnosis in 287 children with acute lymphoblastic leukemia (ALL) who were entered consecutively in a laboratory classification study of the Pediatric Oncology Group (POG). L1 to L2 shifts in French-American-British morphologic subtype were more common than the reverse (81/178 versus 15/61, p less than 0.001). A small but marginally significant number of cases acquired cytoplasmic granules at relapse, and 50 cases underwent a shift in periodic acid-Schiff reactivity that slightly favoured positive to negative. Shifts in immunophenotype were relatively rare, although shifts in cases with a pre-B phenotype to early pre-B ALL or vice versa occurred in about a third of pre-B cases. Loss of HLA-DR or the common ALL antigen occurred in 20 and 11% of cases, respectively. Of the 116 cases with analyzable karyotypes at diagnosis and relapse, 36 (31%) showed a change in karyotypes at relapse, usually from normal to pseudodiploid or hyperdiploid. Cytogenetic evidence for the emergence of a new clone after initial diagnosis was found in only one case. Analysis of the correlation of clinical and lymphoblast biologic features with event-free survival after an initial marrow relapse failed to demonstrate any prognostic significance for the changes identified in this study. T-cell immunophenotype proved to be the only factor significantly related to the outcome of retrieval therapy.

Antigens, Differentiation↗
PubMed1992

Current results of studies of immunophenotype-, age- and leukocyte-based therapy for children with acute lymphoblastic leukemia. The Pediatric Oncology Group.

From February 1986 to January 1991 the Pediatric Oncology Group (POG) treated 2404 children or adolescents with acute lymphoblastic leukemia (ALL) on immunophenotype (T-, B-, Pre-B, or Early pre-B-cell), age, and leukocyte count based treatment protocols (ALinC 14, T-cell 3, B-cell and infant leukemia studies). The immunophenotypic subgroups comprised 78.9% B-precursor cell, 15.1% T-cell, 2.0% B-cell, and 4% infant ALL. Patients with B-progenitor cell ALL were stratified by age and leukocyte count and randomized to receive induction therapy comprised of vincristine, prednisone, and asparaginase with triple intrathecal chemotherapy (methotrexate, hydrocortisone, cytarabine), followed by intensification with moderate-dose MTX (Regimen A), moderate-dose MTX plus asparaginase (Regimen B), moderate-dose MTX plus cytarabine given early (Regimen C), or moderate-dose MTX plus cytarabine given over the first 16 months of therapy (Regimen D). Continuation therapy comprised mercaptopurine and methotrexate with vincristine plus prednisone pulses. Central nervous system preventive treatment was continued for two years. Patients with T-cell or B-cell ALL or infants less than 1 yr old were treated on individual very intensive multiagent therapy protocols. The 4-year event-free survival for all patients was 66.4% +/- 2.4%; B-precursor ALL approximately 72%, T-ALL approximately 50%, B-ALL approximately 60%, and infants less than 1 yr old approximately 16.5%. We conclude that about two-thirds of newly diagnosed children with ALL can be cured with this approach which spares the majority of children exposure to alkylating agents, anthracyclines, epipodophylotoxins, and irradiation, diminishing the risks of serious acute and late effects.

Adolescent↗
PubMed1992

The non-random dic(9;12) translocation in acute lymphoblastic leukemia is associated with B-progenitor phenotype and an excellent prognosis.

A dicentric translocation involving the short arms (p) of chromosomes 9 and 12 was identified in 15 of 2303 successfully banded cases of acute lymphoblastic leukemia (ALL) in children, consecutively entered on protocols of the Pediatric Oncology Group (1986-1990) or St Jude Children's Research Hospital (1984 and 1990). The dic(9;12)(p1?1;p1?2) was seen only in patients with a B progenitor cell immunophenotype: the frequency was 0.8% among pre-B cases (4/508) and 0.9% (11/1177) among early pre-B cases. Laboratory and clinical characteristics were similar to those of the general population of children with ALL, with the exception of a marked male preponderance (12/15 cases). Flow cytometric studies revealed a leukemic cell DNA index of 1.0 in all cases. All fifteen patients are in continuous complete remission at a median follow-up duration of 57+ months (range 9-93+ months). These findings suggest that the dic(9;12) is a recurrent chromosomal translocation in pediatric ALL, occurs exclusively in B-progenitor ALL, and unlike other non-random translocations, is associated with an excellent prognosis.

Adolescent↗
PubMed1991

Philadelphia chromosome and monosomy 7 in childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study.

During an 8-year period, 3,638 children from institutions of the Pediatric Oncology Group (POG) were diagnosed with acute lymphoblastic leukemia (ALL). Fifty-seven patients had Philadelphia chromosome-positive (Ph1) ALL. Blast cells obtained at diagnosis from 13 of these 57 cases (23%) were also found to have partial or complete monosomy 7 (-7). This subgroup of children with Ph1/-7 ALL was comprised primarily of older males with early B-lineage ALL. Bone marrow specimens from six Ph1/-7 patients were studied further using the polymerase chain reaction and primers that flank the ALL, and chronic myelogenous leukemia breakpoints to determine the molecular characteristic of the 9;22 translocation. Rearrangements were detected in RNA from bone marrow and/or peripheral blood cells of six patients, although four were in hematologic remission at the time of the analysis. Five cases showed the ALL breakpoint, while one child with Ph1/-7 showed the chronic myelogenous leukemia breakpoint. The induction failure rate was much higher in this subgroup (31%) as compared with Ph1-negative cases, and the projected duration of event-free survival reflected the aggressive nature of this subgroup because no children are projected to remain in remission at 2 years. ALL with both the 9;22 translocation and -7 appears to represent a unique and previously undescribed subgroup of childhood ALL associated with a particularly adverse outcome. Leukemic transformation in such patients may involve the interaction of a dominant oncogene (Ph1) and a tumor suppressor gene (-7).

Adolescent↗
PubMed1991

Clinical characteristics and treatment outcome of children with acute lymphocytic leukemia and Down's syndrome. A Pediatric Oncology Group study.

Of 2947 children with acute lymphocytic leukemia (ALL), treated during three consecutive studies of the Pediatric Oncology Group (1974-1986), 52 (1.8%) had Down's Syndrome (DS). Comparison of clinical and laboratory characteristics showed no significant differences in leukocyte count, racial distribution, sex ratio, platelet count, incidence of mediastinal mass, lymphadenopathy or hepatosplenomegaly, or percentage of blood or bone marrow blasts for children with ALL with or without Down's Syndrome (DS-ALL or NDS-ALL, respectively). However, children with DS-ALL were slightly older at the time of presentation and had higher hemoglobin values. The relative frequency of each major immunophenotype (early pre-B, pre-B, T, or B) was also comparable for patients with or without DS. For this report, treatment regimens were categorized as either conventional (no consolidation therapy) or intensive. Cox regression analysis revealed that the presence of DS, a higher leukocyte count, black race, or age older than 10 years was independently associated with a poorer event-free survival (EFS) for children treated with conventional chemotherapy. However, for the cohort of children who received intensive chemotherapy, DS was no longer an independent risk factor. In fact, event-free survival (EFS) was markedly improved to a level comparable with that observed in the children diagnosed as having NDS-ALL. On the other hand, serious toxicity, requiring interruption of treatment, was significantly more frequent in the intensively treated children with DS compared with similarly treated patients with NDS-ALL, although deaths resulting from toxicity occurred infrequently.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

The erythrocytes in paroxysmal nocturnal haemoglobinuria of intermediate sensitivity to complement lysis.

The sensitivity to lysis by complement of the erythrocytes of 56 patients with paroxysmal nocturnal haemoglobinuria (PNH) was compared to the membrane expression of decay accelerating factor (DAF, CD55), membrane inhibitor of reactive lysis (MIRL, CD59) and acetylcholinesterase (AChE). Most patients (36/50 72% in whom the analysis could be made) appeared to have erythrocytes of intermediate sensitivity to complement in the blood. These cells appeared as a discrete population of cells (PNH II cells), as a 'tail' of cells slightly less sensitive than the predominant PNH III cells (previously called PNH IIIb cells), or as a continuous spectrum of cells sensitive to complement. The PNH III cells totally lacked all three proteins (DAF, MIRL, AChE) by flow cytometric analysis whereas PNH I cells appeared to have normal or nearly normal amounts of each. The cells of intermediate sensitivity (PNH II) had coordinately decreased expression of all three proteins; the level of expression of DAF and MIRL paralleled the sensitivity of the cells to the haemolytic action of complement.

Acetylcholinesterase↗
PubMed1990

Favorable prognosis associated with hyperdiploidy in children with acute lymphocytic leukemia correlates with extra chromosome 6. A Pediatric Oncology Group study.

Pretreatment bone marrow cytogenetic studies were included for 1664 patients with acute lymphoblastic leukemia (ALL) accrued to Pediatric Oncology Group (POG) 8035 laboratory classification study from May 1981 through January 1986. There was a significant difference (P = 0.0001) in distribution of stem-line karyotype (normal, hypodiploid, pseudodiploid, or hyperdiploid) among children with early pre-B, pre-B, or T-cell ALL, with early pre-B patients demonstrating a higher proportion of hyperdiploid karyotypes with modal chromosome numbers greater than 51. Cytogenetic classification of 1216 patients with early pre-B or pre-B ALL evaluable for duration of event-free survival (EFS), with median follow-up of 42 months, showed a significant prolongation of five-year EFS associated with hyperdiploidy greater than 51 (75%; standard error [SE] = 5%) compared with hyperdiploidy 47 to 51 (46%; SE = 7%), hypodiploidy (55%; SE = 11%), and pseudodiploidy (45%; SE = 7%) (P = 0.0001). Five-year EFS was intermediate for patients with normal (58%), constitutionally abnormal (66%), or unsuccessful analyses (66%). The breakpoint defining hyperdiploidy associated with better prognosis was best defined as greater than 51 (P = 0.0002). Of 239 children with hyperdiploid karyotypes, analysis of the contribution of each chromosome to EFS duration showed a significant association between improved EFS and additional chromosome(s) six (P = 0.02). Chromosome translocation was associated with shorter EFS (P = 0.0001).

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Philadelphia chromosome positive childhood acute lymphoblastic leukemia: clinical and cytogenetic characteristics and treatment outcome. A Pediatric Oncology Group study.

Among 3,638 children with acute lymphoblastic leukemia (ALL) entered on Pediatric Oncology Group (POG) protocols between June 1981 and April 1989, successful cytogenetic studies were available for 2,519, 58 (2.3%) of which had the Philadelphia (Ph) chromosome detected. Features associated with the presence of the Ph chromosome were high leukocyte count (median, 33 x 10(9)/L), older age median, 9.6 years), a higher proportion of French-American-British L2 morphology, and a lower frequency of mediastinal mass. Immunologic marker studies at diagnosis in 56 Ph+ cases identified early pre-B ALL in 42 cases (75%), pre-B-cell in 9 (16%), and T-cell in 5 (9%). This distribution is similar to that found in Ph+ ALL. Intensive multiagent chemotherapy induced complete remissions in only 78% of eligible Ph+ patients compared with 96% of those without an identified Ph chromosome (P less than .001). Of 44 eligible Ph+ patients treated on POG frontline protocols for children with non-T, non-B-cell ALL, 27 have failed therapy, compared with 520 of 1,892 without an identified Ph chromosome (logrank P less than .001). Ph+ ALL is an aggressive form of acute leukemia that frequently presents in older children with a high leukocyte count, FAB L2 morphology, and a pseudodiploid karyotype, and becomes multidrug-resistant early. Thus, Ph+ cases require early identification to permit treatment with intensive induction regimens and experimental approaches such as bone marrow transplantation.

Asparaginase↗
PubMed1990

Prognostic factors in childhood T-cell acute lymphoblastic leukemia: a Pediatric Oncology Group study.

Two hundred fifty-three children with newly diagnosed T-cell acute lymphoblastic leukemia (ALL), who were treated uniformly with modified LSA2L2 therapy, were evaluated using univariate and recursive partition analyses to define clinical or biologic features associated with risk of treatment failure. Overall event-free survival (EFS) at 4 years was 43% (SE = 4%). Factors examined included white blood cell (WBC) level, age, gender, race (black v other), presence of a mediastinal mass, hepatomegaly, splenomegaly, marked lymphadenopathy, hemoglobin level, platelet count, blast cell expression of antigens such as the common acute lymphoblastic leukemia antigen (CALLA, CD10), HLA-DR, and T-cell-associated antigens (CD3, CD4, CD8, CD7, CD5, and THY). Univariate analysis showed that age less than or equal to 5 or less than or equal to 7 years, WBC level less than 10, less than 25, less than 50 or less than 100 x 10(3)/microL, and blast cell expression of CD4, CD8, or CALLA were associated with significantly better EFS, while hepatomegaly and splenomegaly were associated with worse EFS. Recursive partitioning analysis showed that the most important single favorable prognostic factor was a WBC level less than 50 x 10(3)/microL and, for patients with WBC counts below this level, the most important predictor of EFS was blast cell expression of the pan-T antigen defined by the monoclonal antibody (MoAb), L17F12 (CD5). For patients with higher WBC levels, the most important predictor of EFS was blast cell expression of THY antigen. The recursive partitioning analysis defined three groups of patients with widely varied prognoses identified as follows: (1) those with a WBC count less than 50 x 10(3)/microL who lacked massive splenomegaly and had blasts expressing CD5 had the best prognosis (66%, SE = 7%, EFS 4 years, n = 84); (2) those with (b1) WBC counts less than 50 x 10(3)/microL with either massive splenomegaly or who had blasts lacking CD5 expression, or (b2) WBC counts greater than 50 x 10(3)/microL with expression of the THY antigen had an intermediate prognosis (39%, SE = 7% EFS at 4 years, n = 94); (3) those with WBC counts greater than 50 x 10(3)/microL and whose blasts lacked expression of THY antigen had the poorest outcome (EFS = 19% at 4 years, SE = 8%, n = 63). A three-way comparison of EFS according to these groupings showed significant differences among the three patient groups (P less than .001). The recursive partitioning was able to classify 241 (95%) of the patients.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, CD↗
PubMed1989

Phase II treatment of medulloblastoma and pineoblastoma with melphalan: clinical therapy based on experimental models of human medulloblastoma.

We conducted a phase II study of intravenous (IV) melphalan in the treatment of children with recurrent medulloblastoma and in the initial treatment of children with poor-prognosis medulloblastoma and pineoblastoma. There was one complete response (CR) and two partial responses (PRs) among the 12 children with recurrent medulloblastoma. There were three PRs in the four patients initially treated with melphalan for poor-prognosis medulloblastoma or pineoblastoma. Toxicity was limited to severe myelosuppression with marked neutropenia and thrombocytopenia. These results support our laboratory studies demonstrating melphalan activity in human medulloblastoma, suggest that similar activity may be demonstrated against pineoblastoma, and support further trials with this agent (administered prior to radiotherapy) in the treatment of patients with newly diagnosed poor-prognosis medulloblastoma.

Adolescent↗
PubMed1989

Prognostic importance of the pre-B-cell immunophenotype and other presenting features in B-lineage childhood acute lymphoblastic leukemia: a Pediatric Oncology Group study.

We report the prognostic significance of the pre-B-cell immunophenotype and other presenting features, including blast cell karyotype, in a randomized clinical trial conducted from 1981 to 1986 for children with early pre-B (n = 685) or pre-B (n = 222) acute lymphoblastic leukemia (ALL). Patients greater than or equal to 1 year and less than or equal to 21 years of age who attained complete remission were stratified by conventional risk criteria and immunophenotype and then randomized to receive continuation therapy with either of two regimens of intensive chemotherapy, designated S (standard) and SAM (standard plus intermediate-dose methotrexate, 1 g/m2 every 8 weeks). The proportions of subjects achieving complete remission in the two phenotypically defined subgroups were identical, 96%. At a median follow-up time of 42 months, the overall probability of 4-year event-free survival (+/- SE) was 63% +/- 2% (pre-B = 51% +/- 5% and early pre-B = 66% +/- 3%). Children with pre-B ALL had significantly shorter durations of continuous complete remission (P = .0004); this association included both bone marrow and CNS remissions (P = .0004 and P = .02, respectively). In a univariate Cox regression analysis of potentially important prognostic factors, the pre-B immunophenotype was significantly related to a poorer outcome, as were other recognized biologic and clinical features (eg, pseudodiploidy, older age, male sex, black race, and a higher WBC). It retained its prognostic strength in a multivariate model based on age, WBC, ploidy, and sex. The risk of failure at any point in the clinical course of a child with the pre-B immunophenotype was 1.8 times as great as that in a patient lacking this feature but otherwise having an equivalent risk status. It should be stressed that the predictive value of any of the significant characteristics identified in this study could diminish in the context of another, more effective treatment program. Nevertheless, our major conclusion, that children with pre-B ALL fare worse than those with early pre-B disease in a contemporary clinical trial has implications for stratified randomization of patients and the design of risk-specific treatment protocols.

Analysis of Variance↗
PubMed1988

Altered immunologic reconstitution after standard-dose chemotherapy or high-dose chemotherapy with autologous bone marrow support.

Altered immunologic reconstitution is observed in patients treated with high-dose chemotherapy consisting of cyclophosphamide, cisplatin, and carmustine, melphalan, or etoposide with autologous bone marrow support, and it is similar to that seen in patients treated with high-dose chemoradiotherapy and allogeneic bone marrow transplantation. A decrease in the absolute number and percentage of B cell and CD4 antigen-positive cells and an increase in the absolute number and percentage of CD8 and Ia antigen-positive cells occur along with a decrease in the CD4/CD8 ratio that persists for 6-12 months after high-dose chemotherapy and autologous bone marrow support. These changes have been associated with four serious infectious episodes usually seen only in immunocompromised patients. The above changes were not seen in patients treated with high-dose busulfan, a drug that has relatively specific effects on granulocytes. It is postulated that these alterations result from effects of chemotherapy on the residual lymphocytes or on the environment of repopulating lymphocytes. Functional studies of lymphocyte populations during immunologic reconstitution after standard-dose combination chemotherapy and high-dose chemotherapy with autologous bone marrow support are needed.

Antibodies, Viral↗
PubMed1988

Acute lymphoid leukemia in adolescents: clinical and biologic features predict a poor prognosis--a Pediatric Oncology Group Study.

Analysis of remission induction rates for 1,768 children (1.5 to 11 years) and 425 adolescents (greater than or equal to 11 years) with acute lymphoid leukemia (ALL), and of event-free survival times for 570 children and 147 adolescents, disclosed that adolescents fared significantly worse by both measures of treatment outcome (P = .0001). Adolescents with either T cell or non-T cell ALL entered remission significantly less often than did children (P = less than .02 and P = less than .001, respectively). Within each of the major immunophenotypes of ALL, adolescents had shorter duration of continuous complete remission: early pre-B (non-B, non pre-B, non-T) (P = .001), pre-B (P = .05), and T (P = .027). We compared the clinical characteristics of adolescents and children, and lymphoblast characteristics present at diagnosis to account for the inferior prognosis of adolescent patients. Adolescents had a higher incidence of T cell ALL (P = .0001) and thus a higher incidence of all T cell-associated characteristics. Adolescents with non-T, non-B ALL were more likely to be male (P = .044), and to have higher leukocyte counts (P = .002) and lower levels of IgG (P = .0003), IgA (P = .0001), and IgM (P = .002). Their leukemic cells had lower PAS scores (P = .0001), a higher incidence rate of L2 morphology by French-American-British (FAB) criteria (P = .001), common ALL antigen negativity (P = .0001), and hypodiploid or pseudodiploid karyotypes (P = .004). These findings clearly indicate an increased incidence of prognostically unfavorable clinical and biologic features in adolescents with ALL, providing a biologic explanation for their poor prognosis.

Adolescent↗
PubMed1987

tdic(9;12): a nonrandom chromosome abnormality in childhood B-cell precursor acute lymphoblastic leukemia: a Pediatric Oncology Group Study.

In a review of 432 children with newly diagnosed acute lymphoblastic leukemia (ALL), we identified a new nonrandom translocation, tdic(9;12)(p1?1;p1?2), in the leukemic marrow cells of eight patients. Seven had hypodiploid karyotypes that lacked chromosomes 9 and 12 and contained a der(12), tdic(9;12); the eighth had a pseudodiploid karyotype with two normal 9 chromosomes, one normal 12 and the der(12), tdic(9;12). Abnormalities involving chromosomes other than 9 and 12 were noted in four of the eight patients. All cells with the tdic(9;12) expressed both the common ALL antigen and HLA-DR. Cytoplasmic immunoglobulin, a marker of pre-B ALL, was detected in one case with the tdic(9;12) but was absent in the other seven. Our results suggest that the tdic(9;12)(p1?1;p1?2) rearrangement is specifically associated with leukemic B cell precursors.

B-Lymphocytes↗
PubMed1986

Acid phosphatase positivity in childhood acute lymphocytic leukemia.

The Pediatric Oncology Group analyzed 103 cases of childhood acute lymphocytic leukemia (ALL) with an acid phosphatase stain and with a series of immunologic markers. As reported by others, the authors demonstrated a high correlation of acid phosphatase (AP) positivity and T-ALL. However, a subset of T-ALL was acid phosphatase negative, and some non-T, non-B, non-pre-B-ALL cases were AP positive. The predictive value of the AP test was, therefore, poor as a marker of T-ALL. AP-negative T-ALL cases appeared to be a distinctive subset of T-ALL, and AP negativity an intrinsic characteristic of this subset, rather than a failure of the test system. AP-positive n-ALL cases demonstrated no difference from AP-negative cases and, in particular, no evidence of early T-ALL differentiation.

Acid Phosphatase↗
PubMed1986

Primary cutaneous lymphoma of the head and neck.

One hundred three patients with Stage I and II extranodal primary lymphomas of the head and neck were reviewed. Six patients (5%) presented with cutaneous lesions, five with single site and one with multiple sites of involvement. Histopathology was malignant lymphoma (ML) large cell (3), ML small cleaved cell (1), ML small lymphocytic (1), and ML mixed large and small cell (1). Five of six patients relapsed following initial treatment. Four patients were treated with primary radiation therapy, three of which had relapses outside the treatment area. One patient was treated with intralesional steroid injection and also recurred outside the treated area. One patient was treated with radiation and chemotherapy and recurred outside the treatment area. Three patients are alive without disease, two died of disseminated disease, and one died of unrelated causes. Isolated cutaneous presentation of head and neck lymphoma is uncommon. Radiation therapy appears to have been curative in one patient with localized disease. Four patients recurred outside the radiation portals despite careful staging, suggesting that systemic therapy may be necessary for disease control.

Aged↗