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Biomedical subjects

S B Murphy

Publications and source records attributed to S B Murphy.

At least 127 records · Page 7Linked to original sources
PubMed1986

Phase I-II study of recombinant alpha-2 interferon against advanced leukemia and lymphoma in children.

Alpha-2 interferon, produced in Escherichia coli using recombinant DNA techniques, was administered to 17 children with refractory acute lymphoblastic leukemia (ALL) in relapse, two children with TdT-positive, Philadelphia chromosome-positive chronic myelocytic leukemia (CML) in blast crisis, and one child with B cell (SIg+) non-Hodgkin's lymphoma (NHL) in a second extramedullary relapse. An initial 2-week intravenous (IV) phase of interferon was followed by a 3-month subcutaneous (SC) maintenance phase if patients had an objective response or disease stabilization without significant bleeding or infectious complications. When interferon dosages were escalated from 3 to 100 X 10(6) U/m2 in the first phase of therapy, there was rapid progression of disease in the first four patients treated, prompting a modification of the treatment plan. The last 16 patients enrolled received fixed dosages of interferon (ie, 10, 20, 30, and 50 X 10(6) U/m2 administered to four subjects each). One child with T cell ALL had an 11-month complete remission; the patient with lymphoma had a dramatic but brief response; three others (one CML and two ALL) showed disease stabilization for 3 to 6 months with a definite oncolytic effect in two of the three patients. The remaining 15 patients had progressive disease within 2 months and were removed from the study. Acute toxicity included a flu-like syndrome in all patients, increased serum transaminase levels in five, seizures in three (two cases temporally related to fever and one to a thrombocytopenic subarachnoid hemorrhage), and prolonged activated partial thromboplastin times in seven. This phase I-II trial of recombinant alpha-2 interferon demonstrated definite activity without dose-limiting toxicity.

Adolescent↗
PubMed1986

Biologic and prognostic significance of the presence of more than two mu heavy-chain genes in childhood acute lymphoblastic leukemia of B precursor cell origin.

We examined the arrangement of the mu heavy-chain immunoglobulin (Ig) genes in the leukemic blast cell DNA of 93 children with acute lymphoblastic leukemia (ALL). All cases met morphologic and cytochemical criteria for ALL, lacked detectable T cell surface antigens, and expressed HLA-DR (Ia) antigens. Eighty-three of the 93 patients (89%) were positive for the common acute lymphoblastic leukemia antigen (CALLA), and 20 of 91 (22%) tested had detectable cytoplasmic immunoglobulin. As expected, the heavy-chain lg gene was rearranged in all cases, and the pattern of rearrangements was variable; 23 had one allele rearranged and one in the germ line configuration; 15 had one rearranged and one deleted; and 37 had two rearranged. Unexpectedly, in 18 patients the presence of more than two mu gene-hybridizing bands was detected. Combinations of enzymes and heavy-chain gene probes were used to confirm that the extra bands were not the result of underdigestion of the DNA or DNA restriction site polymorphism. In eight of the 18 patients, we identified an extra chromosome 14 as a possible cause of the extra bands' hybridizing to the mu heavy-chain constant-region probe. In the remaining ten patients, the presence of three or four bands hybridizing with the mu probe suggests the presence of two populations of leukemic cells that may have arisen either by separate leukemic transformation events or by clonal evolution of one clone into two related lines. Although preliminary (2-year follow-up), our data suggest that childhood ALL of B lineage with more than two mu heavy-chain genes, but without extra copies of chromosome 14, may be more resistant to therapy.

Adolescent↗
PubMed1986

Cytogenetic features and serum lactic dehydrogenase level predict a poor treatment outcome for children with pre-B-cell leukemia.

Leukemic cells from 89 (24%) of 369 children with newly diagnosed acute lymphoblastic leukemia (ALL) were found to have a pre-B immunophenotype. By comparison with blasts having the common ALL phenotype, the pre-B cells were more likely to have a DNA index less than 1.16 (P = 0.02), a pseudodiploid karyotype (P less than 0.001), and a chromosomal translocation (P = 0.001). Increased serum lactic dehydrogenase levels (P = 0.001) were also characteristic of pre-B ALL; otherwise, the clinical and laboratory features of the two groups were similar. A nonrandom chromosomal translocation, t(1;19)(q23;p13.3), was identified in blast cells from 16 (23%) of the 70 patients with pre-B ALL and adequate chromosome banding studies; different translocations were found in 11 of the remaining patients. The presence of any chromosomal translocation in the pre-B group was significantly related to a higher leukocyte count, an increased level of serum lactic dehydrogenase, an increased percentage of S-phase cells, black race, and a blast cell DNA index less than 1.16. Four presenting features were found to confer an increased risk of treatment failure among pre-B patients: pseudodiploidy, chromosomal translocation, black race, and higher serum lactic dehydrogenase level. In a multivariate analysis, pseudodiploidy emerged as the strongest factor for predicting relapse in pre-B ALL. The frequent association of chromosomal abnormalities of known adverse prognostic significance and high serum lactic dehydrogenase levels with pre-B-cell ALL explains, at least in part, the poor treatment outcome reported for children with this subtype of leukemia.

Adolescent↗
PubMed1986

Phase I-II study of continuous-infusion high-dose human lymphoblastoid interferon and the in vitro sensitivity of leukemic progenitors in nonlymphocytic leukemia.

Twelve pediatric patients with nonlymphocytic leukemia were treated for 10 days with high-dose (15, 20, or 30 million U/m2/day) human lymphoblastoid interferon (Wellferon) administered by continuous iv infusion. Nine children had acute nonlymphocytic leukemia (ANLL) in relapse, two had Philadelphia chromosome-positive chronic myelocytic leukemia in myeloblastic crisis, and one had juvenile chronic myelocytic leukemia. Blast cell counts in the peripheral blood decreased in five patients with ANLL treated with the higher interferon doses; however, there was no evidence of an antileukemic effect in the marrow. Dose-limiting toxicity, which included malaise, hepatotoxicity, and coagulation abnormalities, was observed in patients given 20 or 30 million U/m2/day. Studies of the growth of leukemic progenitor cells in vitro in the presence of interferon disclosed a concentration-related inhibition of colony formation. Patients who had a decrease in peripheral blast cell counts demonstrated greater in vitro inhibition of clonogenic leukemic progenitors than patients whose blast cell counts did not decrease. However, the serum interferon concentrations in patients given clinically tolerable doses were lower than those concentrations which inhibited leukemic cell growth in vitro by a median of 42% (1000 U/ml). This study failed to demonstrate clinically significant antileukemic activity against nonlymphocytic leukemia in patients given high-dose constant-infusion interferon, and the toxicity of this approach was prohibitive.

Adolescent↗
PubMed1986

Chromosomal translocations play a unique role in influencing prognosis in childhood acute lymphoblastic leukemia.

Certain types of chromosomal abnormalities have been shown to exert strong independent influence on treatment outcome in acute lymphoblastic leukemia (ALL). To identify the changes most closely associated with prognosis, we analyzed the completely banded blast cell karyotypes of 161 children with this disease. One hundred twenty-five cases had one or more chromosomal abnormalities, with 45 showing translocations. The frequency of translocations was highest (58%) among patients with pseudodiploid karyotypes and lowest (0%) in the hyperdiploid group defined by 51 or more chromosomes. During the maximum 6-year follow-up period, 30 of the 45 patients with a translocation failed therapy, compared with only 27 of the 116 who lacked this feature. Life-table estimates of event-free survival indicate that only 14% of the translocation group will be in complete remission at 3 years. The percentages of failures associated with random and nonrandom translocations were virtually identical (68% v 65%). When entered in a Cox proportional hazards model with seven other types of chromosomal abnormalities, and then with 11 clinical and laboratory variables of known prognostic value in ALL, translocation emerged as the strongest single predictor of treatment outcome (P less than 0.0001). The model indicated that translocation increases the risk of treatment failure six times by comparison with the absence of this feature. These findings offer an explanation for the majority of early treatment failures in childhood ALL, including those previously attributed to ploidy classification.

Child↗
PubMed1986

Nonrandom involvement of the 12p12 breakpoint in chromosome abnormalities of childhood acute lymphoblastic leukemia.

We studied the presenting clinical and biologic features of 23 children with acute lymphoblastic leukemia (ALL) whose leukemic marrow karyotypes contained abnormalities involving the short arm of chromosome 12. Nineteen of the abnormalities were assigned to the 12p12 breakpoint. The median age of the children was 5 years (range 2 to 13 years) and their initial leukocyte counts ranged from 1,800 to 424,000/microL (median 30,000/microL). Twenty-one patients (91%) had common phenotype ALL (CALLA+, HLA-DR+), including three cases with a pre-B cell phenotype (CIg+). The remaining two cases were T cell in origin. The French-American-British (FAB) morphologic type of lymphoblastic leukemia was L1 in all cases but one. With a median follow-up of 11 months, four patients have relapsed and another failed induction therapy. The modal chromosome number in all cases was less than 50. Three distinct cytogenetic patterns, with apparently similar clinical manifestations, were noted: terminal deletions of chromosome 12 in 10 cases, apparently balanced reciprocal translocations in 6, and unbalanced translocations in 7. All translocations were between the 12p arm and different donor chromosomes except for chromosomes 7, 9, and 17, which participated twice. Only two patients had identical translocations: t(7;12)(q11;p12). This unusual variation in donor chromosomes and breakpoints suggests that translocations involving the 12p are specific with respect to only one member of the translocation pair, namely chromosome 12. The relatively high frequency of the 12p abnormalities in this study (10% of all completely banded cases seen over a 35-month period) warrants further investigation.

Adolescent↗
PubMed1986

Computer-aided simulation, analysis, and design in orthopedic surgery.

Three-dimensional computer reconstructions of bony anatomy based on computed tomographic images and radiographs may be used to analyze, simulate, and design certain orthopedic procedures. In osteotomy surgery, the computer-reconstructed models may be used to measure critical angles, surface area, and congruity of the joint surfaces. Computer reconstructions may be used in total joint replacement surgery to simulate the effect of surgical reamers and rasps, to select the geometrically optimum standard implant, or to design a custom implant. In allograft reconstructive surgery, computer reconstructions may be used to measure bony defects and to identify the appropriate allografts for the reconstruction. Plastic models may be sterilized and used as templates to sculpt the allografts immediately preoperatively. In all three applications in orthopedic surgery, three-dimensional, computer-aided reconstructions have the potential to improve results and reduce morbidity.

Bone Transplantation↗
PubMed1985

A novel treatment of childhood lymphoblastic non-Hodgkin's lymphoma: early and intermittent use of teniposide plus cytarabine.

We treated 24 children and adolescents with stage III or IV lymphoblastic non-Hodgkin's lymphoma, using a protocol designed for patients with poor-prognosis acute lymphoblastic leukemia (ALL). Early therapy consisted of teniposide plus cytarabine administered before and immediately after prednisone, vincristine, and asparaginase. The two-drug combination was also given intermittently with continuous 6-mercaptopurine and methotrexate during the first year of continuation chemotherapy. Periodic intrathecal methotrexate and delayed cranial irradiation were used to prevent central nervous system involvement. Anthracycline compounds, alkylating agents, high-dose methotrexate, and involved-field irradiation were not used in any phase of treatment. Twenty-two (96%) of the 23 evaluable patients achieved complete remission. With a median follow-up of 2 1/2 years, only four patients have relapsed; the remainder have been disease-free for eight months to more than five years. The projected four-year continuous complete remission rate is 73% for all patients and 79% for the 19 with mediastinal involvement at diagnosis. These results demonstrate that use of teniposide plus cytarabine with an otherwise conventional plan of ALL therapy is an effective approach to the treatment of childhood lymphoblastic lymphoma.

Adolescent↗
PubMed1985

Advanced stage (III-IV) Burkitt's lymphoma and B-cell acute lymphoblastic leukaemia in children: kinetic and pharmacologic rationale for treatment and recent results (1979-1983).

Since 1979, we have treated a total of 29 children with advanced-stage B-cell tumours (diffuse undifferentiated, small non-cleaved cells): 18 stage III and three stage IV, according to a clinical staging classification (Murphy, 1980), and eight with B-cell acute lymphoblastic leukaemia (B-ALL). Treatment has been based upon appreciation of rapid tumour growth kinetics and has consisted of high-dose fractionated cyclophosphamide courses, vincristine, adriamycin and infusions of cytosine arabinoside (Ara-C) with intrathecal chemotherapy. The first 12 patients (1979-1981) received, in addition, superfractionated radiotherapy (twice a day) to the involved field (22.5 Gy) and the craniospinal axis (18 Gy). Since January 1981, radiation therapy has been omitted, and subsequent patients have received the same agents as above plus high doses of methotrexate coordinated with the escalating doses of Ara-C infusions. Toxicity has consisted mainly of universal, severe but reversible haematopoietic suppression with attendant febrile episodes. Complete-remission rate for all 29 patients has been 86%, with three early failures due to progressive disease and one death from infection. Overall disease-free survival for children with stage III disease has been excellent (78%). Initial involvement of central nervous system (CNS) and/or marrow is grave: none of three patients with stage IV lymphoma and only one of eight with B-ALL is surviving off therapy without evidence of disease, suggesting a need for alternative therapies for these cases. Results are significantly better than our historical institutional experience.

Adolescent↗
PubMed1985

Rearrangement of immunoglobulin heavy chain genes in T cell acute lymphoblastic leukemia.

We studied the arrangement of the immunoglobulin heavy chain genes by Southern blot analysis of DNA freshly obtained from marrow blast cells of 14 children with T cell acute lymphoblastic leukemia (T-ALL) using probes to the C mu and JH gene segments: At least one of the C mu-gene alleles was rearranged in three cases. In two of these, one C mu gene had the germ-line configuration and one was rearranged, whereas both alleles were rearranged in the third case. In one case, a rearranged heavy chain gene hybridized to the C mu-region probe, but not to the JH probe, indicating that the entire JH region had been deleted. These results demonstrate that immunoglobulin heavy chain gene rearrangements are not restricted to B lineage lymphoproliferative diseases in humans.

Adolescent↗
PubMed1985

Acute megakaryoblastic leukemia. Blast cell aggregates simulating metastatic tumor.

Acute megakaryoblastic leukemia is a rare leukemia that can present diagnostic problems. We describe two children who have this disease and had clumps of blast cells in their bone marrow, a finding usually attributed to metastatic tumor. The megakaryocytic origin of the cells was supported by their cytochemical staining pattern (positive alpha-naphthyl acetate esterase resistant to sodium fluoride inhibition and negative alpha-naphthyl butyrate esterase) and by the presence of factor VIII-related antigen. Ultrastructural studies of blast cells from one patient demonstrated platelet peroxidase. The mechanism of blast cell clump formation in these cases is unknown; nevertheless, awareness that this feature can occur in acute megakaryoblastic leukemia may avoid a misdiagnosis of metastatic solid tumor.

Acute Disease↗
PubMed1985

Acute mixed lineage leukemia: clinicopathologic correlations and prognostic significance.

The frequency and clinical significance of acute leukemia displaying both lymphoid and myeloid characteristics was determined in 123 consecutive children using a panel of lineage-associated markers. The leukemic blasts from 18 of 95 children (19%) with the diagnosis of acute lymphoblastic leukemia (ALL) by standard diagnostic criteria expressed myeloid-associated cell surface antigens. Despite immunological evidence of lymphoid differentiation (17 CALLA + and one T cell-associated antigen +) and findings of immunoglobulin gene rearrangement, blasts from these patients reacted with one to five monoclonal antibodies identifying myeloid-associated cell surface antigens (My-1, MCS.2, Mo1, SJ-D1, or 5F1). Dual staining with microsphere-conjugated antibodies and analysis by flow cytometry confirmed that some blasts were simultaneously expressing lymphoid- and myeloid-associated antigens. Conversely, blasts from seven of 28 patients (25%) with acute nonlymphocytic leukemia (ANLL), diagnosed by otherwise standard morphological and cytochemical criteria, expressed lymphoid-associated surface antigens. Dual staining of individual blasts demonstrated simultaneous expression of myeloperoxidase (MPO) (including Auer rods) in association with either T-11, CALLA, or terminal deoxynucleotidyl transferase. Blasts from one patient with ANLL demonstrated T cell receptor gene rearrangement, while blasts from another patient demonstrated characteristics associated with T (T-11), B (CALLA and heavy-chain immunoglobulin gene rearrangement), and myeloid (MPO) lineage. There were no consistent cytogenetic abnormalities, and no patient demonstrated independent leukemic clones. Each patient with typical ALL, except for myeloid-associated antigens, achieved complete remission with conventional induction therapy for ALL. By contrast, three of the seven children with ANLL whose blasts expressed the T-11 surface antigen failed ANLL induction therapy. These three patients subsequently achieved remission with ALL therapy.

Acute Disease↗