Chromosomal translocations and timing of malignant transformation in Burkitt's lymphoma.
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B-Lymphocytes↗
Biomedical subjects
S B Murphy
Publications and source records attributed to S B Murphy.
The relationship of blast cell glucocorticoid receptor levels to response to single-agent steroid trial and remission response in children with acute lymphoblastic leukemia.
Of 263 children with glucocorticoid receptor (GR) levels measured at diagnosis of acute lymphoblastic leukemia (ALL), 27 received single-agent glucocorticoid before combination induction chemotherapy and were evaluable for in vivo clinical response to steroid. Twenty-one were glucocorticoid-responsive and 6 were resistant. There was no difference between the two groups in the distribution of age, sex, white blood cell count, immunophenotype of blasts, initial central nervous system disease or mediastinal mass. The median GR level, however, was appreciably lower in the group of patients with resistant disease (6250 vs 17,800 sites/cell, p = 0.06). Five of 12 patients with GR levels of less than 10,000 sites/cell compared to 1 of 15 with higher levels had glucocorticoid-resistant ALL (p = 0.03). All 21 patients with glucocorticoid-sensitive disease achieved a complete remission after combination induction chemotherapy, but only 3 of 5 evaluable patients in the other group did (p less than 0.04). Two patients were studied both at diagnosis and at relapse; both had decreased GR levels at relapse (below detection in one) and failed to respond to glucocorticoid. We conclude that a lower GR level is associated with glucocorticoid resistance and furthermore that a decrease in the level of GR is a mechanism of acquiring steroid resistance.
Adolescent↗
Acute leukaemia with mixed lymphoid and myeloid phenotype.
Three children with acute leukaemia had blasts that expressed both lymphoid and myeloid markers. The blasts met immunological criteria for acute lymphoblastic leukaemia (ALL)--common ALL antigen+, HLA-DR+, terminal deoxynucleotidyl transferase+--but their cytochemical features, including positive myeloperoxidase and Sudan black B, were those of acute nonlymphoblastic leukaemia (ANLL) as defined by the French-American-British Group. 30% of the blasts from one of two patients tested reacted with a monoclonal antibody specific for nonlymphoid cells (MCS-2). The wide overlap in the percentages of blasts expressing lymphoid or myeloid markers indicates that some leukaemic cells in each child had a mixed phenotype. There were no consistent cytogenetic findings, and the Philadelphia chromosome was not present. Complete remission was induced by treatment effective for either ALL (two patients) or ANLL. These three cases appear to represent a rare leukaemia subtype that we have designated acute leukaemia with mixed lymphoid and myeloid phenotype. Its recognition may be important in treatment, since two patients achieved remission with standard therapy for ALL. These cases demonstrate further the phenotypic heterogeneity that may be seen in leukaemic cell differentiation.
Acute Disease↗
Quantitative variation of the common acute lymphoblastic leukemia antigen (gp100) on leukemic marrow blasts.
Marrow blasts from children with B cell precursor acute lymphoblastic leukemia (ALL) were studied for differences in quantitative expression of the common ALL antigen (CALLA). Of 42 untreated patients, 35 had detectable amounts of CALLA by flow cytometric (FCM) analysis of J-5 monoclonal antibody binding. Using an FCM technique that provides correlated measurements of a given cell surface antigen, cell size, and DNA content, we detected increased CALLA expression as lymphoblasts moved from G0/G1 phase through S phase of the cell cycle. The density of the antigen (per unit of blast surface area) remained relatively constant over the same interval, indicating that the change was not due to S phase-specific enhancement of CALLA expression. Eight cases had hyperdiploid cellular DNA content and in seven of these, only cells with clonal abnormalities of DNA content expressed the CALLA marker. Mean amounts of CALLA for each patient ranged widely within the study group, from very high to marginally detectable. This variation had no discernible relation to cell size, stem-line DNA content, percentage of cells in S phase, or the presence or absence of cytoplasmic immunoglobulin. Results of a univariate proportional hazards analysis showed that both quantitative level of CALLA for S phase cells (P = 0.048) and white blood cell count (P = 0.012) had made significant contributions to treatment outcome. Patients with relative amounts of CALLA less than the median value for the entire CALLA+ group had a higher rate of failure, which was virtually identical to that for the seven HLA-DR+ patients whose blasts lacked detectable CALLA. The observed interpatient variation in quantitative expression of CALLA is consistent with recognized steps in B cell precursor differentiation and may be useful in distinguishing patients with a less favorable prognosis.
Antibodies, Monoclonal↗
Poland's syndrome associated with childhood non-Hodgkin's lymphoma.
Poland's syndrome is a congenital absence of the sternal portion of the pectoralis major muscle, often associated with ipsilateral upper-limb anomalies. We describe two children with non-Hodgkin's lymphoma associated with Poland's syndrome, ie, an association between childhood cancer and congenital anomalies previously unreported and unlikely to be due to chance. In addition, we report another case of acute leukemia in a child with Poland's syndrome. In view of the rarity of Poland's syndrome in the general pediatric population, we conclude that there is an increased association of the syndrome with both leukemia and non-Hodgkin's lymphoma, the biologic basis of which is unclear.
Adolescent↗
Lineage switch in acute leukemia.
Conversions of leukemic cell lineage (lymphoid or myeloid) have been reported only rarely. Our review of the cytochemical and immunophenotypic features of 89 cases of childhood leukemia in marrow relapse indicated lineage switch (lymphoid to myeloid or the reverse) in six patients (6.7%). Five patients with acute lymphoblastic leukemia (ALL) at diagnosis had converted to acute nonlymphoblastic leukemia (ANLL), and one had converted from ANLL to ALL. Each child received lineage-specific multiagent chemotherapy when initially diagnosed, and all achieved a complete remission. After conversion, four patients readily achieved second remissions with treatment for the phenotype evident at lineage switch. Two patients with ANLL at conversion failed ALL-directed reinduction, while one of the two responded to high-dose cytarabine but died during bone marrow hypoplasia, emphasizing the importance of prompt recognition of lineage switch and selection of an appropriate plan of retreatment. Cytogenetic studies disclosed evidence of clonal selection in one patient and clonal stability in two. These findings indicate an unexpectedly high frequency of lineage switch in patients who relapse in the bone marrow after intensive chemotherapy. Although specific causative factors could not be identified, our observations suggest at least two general mechanisms for lineage switch in acute leukemia. In one, chemotherapy appears to eradicate the dominant clone present at diagnosis, permitting expansion of a secondary clone with a different phenotype. In the second, drug-induced changes in the original clone may either amplify or suppress differentiation programs so that phenotypic shift is possible.
Acute Disease↗
Adaptive changes in the femur after implantation of an Austin Moore prosthesis.
We studied the bone adaptation in a retrieved femur six years after implantation of an Austin Moore prosthesis. Strains caused by loading of the femoral head and greater trochanter were measured in this femur as well as in the contralateral, normal femur before and immediately after postmortem implantation of a prosthesis. Immediately after implantation the strains were abnormally high, particularly in the calcar region. However, six years after implantation all strains were close to normal. This was found to be due to an increase in both the bone density and the bone area. Changes were also noted in the structure of the osteons, particularly adjacent to areas of endosteal compressive stress-transfer.
Adaptation, Physiological↗
Predicting activity and satisfaction following cataract surgery.
This was the second in a series of studies intended to develop a method for predicting the degree of recovery and satisfaction of elderly patients following cataract surgery. Sixty-six patients (mean age, 68 years; 27 men and 39 women) completed an activity questionnaire and a series of walking, reaching, and hand-eye coordination tasks 1 day prior to cataract surgery. An average of 6 months later, the patients completed the activity questionnaire and some of the motor tasks again and then made a four-point assessment of satisfaction with their recovery. Postoperative reaching, walking, activity, and satisfaction ere all positively correlated with scores on some of the preoperative tasks. Together with earlier published data, these data also show that patients report less postoperative activity after an eyeglass correction than after a lens-implant or contact-lens correction.
Activities of Daily Living↗
Response of recurrent acute lymphoblastic leukemia to glucocorticoids: serial studies of receptor content, in vivo cytokinetic changes and clinical responses.
The sensitivity of relapsed acute lymphoblastic leukemia (ALL) to treatment with steroids was assessed by measuring bone marrow blast, whole-cell glucocorticoid receptor (GR) levels and serial cytokinetic and clinical responses to steroids, both as single agents and in combination reinduction chemotherapy. GR levels ranged widely, from 1800 to 47,800 sites/cell (median 16,000), and did not differ significantly from levels measured in newly diagnosed patients (p = 0.50). Nineteen of the 48 children studied had GR levels measured both at diagnosis and relapse, and in 14 the values at relapse were either decreased or increased by more than 25%. For nine children, the sensitivity to a three-day oral course of dexamethasone alone (6 mg/m2 per day) was estimated from daily leukocyte counts and serial bone marrow cytokinetic studies. A clinical oncolytic effect of dexamethasone was associated with a reduction in the marrow cell proliferating compartment, as judged from labeling indices, mitotic indices and percent S + G2 + M in five patients. We found, however, that GR levels either alone or combined with clinical or cytokinetic responses to dexamethasone as a single agent did not reliably identify patients who were likely to respond favorably to reinduction with steroid-containing combination chemotherapy. The 35 children who successfully attained subsequent remissions had GR levels similar to those who failed (p = 0.35). While not statistically significant, two observations suggest an association between lower receptor content and drug resistance. Receptor levels from patients with ALL who relapsed while on chemotherapy were appreciably lower (median 15,700, n = 31) than GR levels from patients who relapsed off therapy (median 20,300, n = 17) (p = 0.08). Moreover, three of seven patients with serial studies, whose GR levels at relapse were lower than at diagnosis, failed reinduction--compared to only one of twelve whose levels were either increased or remained unchanged (p = 0.11). Although not having any obvious clinical utility, studies of GR at diagnosis and at relapse may aid in clarifying mechanisms of drug resistance in leukemic blasts.
Acute Disease↗
Phenotypic conversion of acute leukaemia from T-lymphoblastic to myeloblastic induced by therapy with 2'-deoxycoformycin.
A 6-year-old boy with T-cell acute lymphoblastic leukaemia (ALL) in relapse was treated with the adenosine deaminase inhibitor, 2'-deoxycoformycin (DCF). Remarkably, his residual leukaemia underwent an abrupt phenotypic shift, coincident with a massive anti-leukaemic effect of DCF. Both at diagnosis and prior to therapy with DCF, blast cells had typical lymphoblastic morphology and T-cell characteristics (terminal transferase +, T-antigen +, Ia -, cALLa -, myeloperoxidase -, and high in adenosine deaminase content). After four courses of DCF by constant infusion, the blast cells were myeloid in appearance and reactivity to a variety of tests (terminal transferase -, myeloperoxidase +, Sudan black B +, esterase +, My-1 +). We hypothesize that DCF therapy created a selection pressure, blocking pathways of T-cell differentiation and proliferation, permitting the emergence of a newly dominant myeloid subclone of a multipotential leukaemic cell progenitor with the innate capacity for both T-lymphocytic and myeloid differentiation.
Adenosine Deaminase Inhibitors↗
End results of treating children with localized non-Hodgkin's lymphomas with a combined modality approach of lessened intensity.
From 1978 to 1982, 28 children with localized non-Hodgkin's lymphomas, stages I and II, were treated with a combined modality protocol, reduced in intensity in comparison to our previous institutional protocol (1975-1978, reported in Cancer 45: 630-637, 1980), and modest by comparison to many current intensive regimens in widespread use. Induction consisted of vincristine (6 weekly doses, 1.5 mg/m2), cyclophosphamide (3 doses, on days 0, 21, and 42, 600 mg/m2 IV), and oral prednisone (40 mg/m2, daily for 1 mo) combined with low-dose, involved-field, supervoltage radiotherapy (2000 rads). Prophylactic treatment of the central nervous system was not given to all children, but only to those with primary tumors in the head and neck region, and consisted of intermittent intrathecal methotrexate only (12 mg/dose, three times in induction, and subsequently every 6 wk). Maintenance therapy, consisting of oral daily 6-mercaptopurine (75 mg/m2) and oral weekly methotrexate (30 mg/m2), was continued for a total duration of 15 mo from diagnosis. Overall, there were 15 children with stage I and 13 with stage II disease, and the majority of the cases (17 of 28) were localized to the head and neck. In addition, 7 children, all stage II, had completely resected gastrointestinal tumors; the other 4 cases presented in inguinal nodes. Histologically, 27 of the 28 tumors were high-grade diffuse (13 undifferentiated, i.e., small noncleaved cell type; 11 histiocytic, i.e., 5 large noncleaved cell type, and 6 immunoblastic type; and 3 lymphoblastic type); 1 case was mixed cell type, nodular and diffuse. All children were judged to be in complete remission at the end of induction, and 24 of 28 (85.7%) remain free of disease 4+ mo to nearly 4 yr from diagnosis (median 24+ mo); 19 have completed all planned therapy and are in unmaintained remission. The 4 cases failing therapy all were characterized by diffuse undifferentiated (small noncleaved cell) histology and exhibited regrowth of local tumor, resulting in a failure rate for this group (4 of 13, 30%) significantly different than for all remaining cases of other histologies (0 of 15), p less than 0.02 by log rank analysis. Patient tolerance to therapy was excellent, with negligible acute toxicity, and ambulatory outpatient management was the norm. Long-term follow-up will be necessary to judge whether adverse late consequences of treatment have been reduced by this approach. We conclude that a reduction in the intensity of therapy for children with stage I and II non-Hodgkin's lymphomas is feasible, apparently without significantly jeopardizing their excellent chance for cure.
Adolescent↗
Anaphylactoid reactions to Escherichia coli and Erwinia asparaginase in children with leukemia and lymphoma.
The incidence and clinical characteristics of anaphylactoid reactions to intravenous asparaginase were assessed in 196 patients given E. coli asparaginase and 49 patients given Erwinia asparaginase. All patients were given a 50 IU intravenous test dose followed in 30 min by the full dosage (10,000 IU/m2), if no reaction occurred to the test dose. Twenty-nine of 196 patients (14.8%) given E. coli asparaginase had an anaphylactoid reaction, occurring after their first through 12th doses. The probability of an anaphylactoid reaction was significantly greater in those patients not receiving concomitant prednisone-vincristine and patients with a hiatus between courses of asparaginase therapy. By logistic regression analysis, other variables such as age, sex, race, diagnosis, total number of doses and concurrent methotrexate or arabinosylcytosine did not contribute significantly to the probability of a reaction. Twenty-three of the patients who had reacted to E. coli asparaginase and 26 patients who had not reacted to E. coli asparaginase were subsequently given Erwinia asparaginase. Seven of these 49 patients (14%) had an anaphylactoid reaction. The probability of a reaction to Erwinia asparaginase was significantly related to a prior reaction to E. coli asparaginase, concomitant prednisone-vincristine therapy, total number of asparaginase doses, number of prior E. coli asparaginase doses, and diagnosis, when assessed by a logistic regression model. However, after adjusting for prior reaction to E. coli asparaginase and the total number of asparaginase doses given, the other variables did not contribute significantly to the probability of a reaction. Only 5/29 patients reacting to E. coli asparaginase and 1/7 reacting to Erwinia asparaginase had a reaction to the test dose. None of the reactions were fatal.
Adolescent↗
VM-26 with prednisone and vincristine for treatment of refractory acute lymphocytic leukemia.
Fifty-six children with refractory acute lymphocytic leukemia (ALL) were assessed for remission-induction responses to VM-26 (250 mg/m2 per week) in combination with prednisone (40 mg/m2 per day) and vincristine (1.5 mg/m2 per week). Each child had been treated intensively with steroids, vincristine, daunorubicin and L-asparaginase. In fact, all patients had failed to respond to previous reinduction therapy with prednisone-vincristine or had relapsed while receiving vincristine. Our intent in this study was to test whether or not addition of VM-26 to prednisone-vincristine would overcome clinical resistance to these established agents. Complete remissions were induced in 17 patients (0.30) over 4 to 6 weeks. Five of these children, all clinically unresponsive to prednisone-vincristine alone, had complete remissions that lasted longer than 1 year; two remain in remission for 2 1/2 years and both are now off therapy. Myelosuppression, the most serious treatment complication, was documented in 20 of 26 evaluable patients. The median time to recovery of normal marrow function was 15 days. These results demonstrate further the potential of VM-26 in combined-drug treatment of refractory ALL. Whether the effectiveness of this combination represents potentiation of prednisone and vincristine activity by VM-26 or some other, as yet unidentified interaction, remains to be determined.
Adolescent↗
Metastatic epidural tumors in children.
Spinal cord compression is a rare but serious complication of malignant diseases in children. Epidural cord compression was noted in 81 patients within the past 17 years at this center. The complication developed at different times during the course of the primary disease. For 29 of our patients, cord dysfunction was one of the initial signs of cancer--Ewing sarcoma, neuroblastoma, Hodgkin disease, and malignant lymphoma. By contrast, for most of the patients with osteosarcoma and rhabdomyosarcoma, it appeared later in their clinical course. The treatment outcome of patients who were paraplegia with complete loss of sensory function for greater than or equal to 48 hours was poor. Only four of 22 in this group became ambulatory. Ten patients with osteosarcoma did not undergo laminectomies because they all had multiple metastases and terminal disease. Paraplegia developed in all ten. There was no difference in ambulatory rates among other patients, with or without laminectomies.
Child↗
VM26 therapy in children with drug-refractory lymphocytic leukemia.
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Child↗
Determination of the significance of in vitro blast cell [3H]thymidine labelling indices obtained initially and serially during induction therapy of acute non-lymphocytic leukemia.
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Acute Disease↗
Non-T, non-B lymphomas are rare in childhood and associated with cutaneous tumor.
Tumor cells from a total of 116 children with non-Hodgkin's lymphoma were studied for their pattern of reactivity with a battery of cell markers, including their capacity for spontaneous formation of sheep erythrocyte rosettes (E-rosettes), demonstration of surface immunoglobulins (SIg), and positivity with antisera against T-cell antigens, the common acute-lymphoblastic-leukemia-associated antigen (cALLa), and Ia-like antigens. Fifty-eight children (50%) had T-cell lymphomas, including all those with mediastinal tumors. Fifty children (43%) had B-cell lymphomas, including 44 of the 45 with abdominal primaries. Eight children (7%) had non-T, non-B tumors, 4 of whom presented at a young age with cutaneous lymphoblastic tumors. These results demonstrate that the great majority of children with NHL, not leukemic at diagnosis, have tumors clearly committed to either T- or B-cell differentiation pathways and only rarely exhibit the common ALL phenotype (cALLa+, Ia+, E-, T-, SIg-), contrasting with the distribution of childhood lymphoblastic leukemias. The unusual association of these non-T, non-B cases with skin involvement has not previously been reported, raising speculation regarding patterns of lymphocyte traffic and origins of childhood lymphomas and leukemias.
Adolescent↗
Aneuploidy and percentage of S-phase cells determined by flow cytometry correlate with cell phenotype in childhood acute leukemia.
Cellular DNA content distributions of propidium-iodide-stained bone marrow blasts were determined by flow cytometry (FCM) for 225 untreated children with acute leukemia and were correlated with leukemia cell phenotype and karyotype. Aneuploidy of the primary malignant stem line was detected in 54 cases (24%): 51 hyperdiploid and 3 hypodiploid. A second stem line with approximately twice the DNA content of the primary stem line was recognized by FCM in 28 cases (23 ALL, 5 ANLL) and may be an important source of leukemia cell heterogeneity. The degree of DNA content abnormality detected by FCM was highly correlated (r = 0.98) with the number of whole chromosome gains or losses in the leukemia karyotype. Aneuploidy detectable by FCM was more frequent in acute lymphoblastic leukemia (ALL) (52 of 173, 30.1%) than in acute nonlymphoblastic leukemia (2 of 52, 3.8%) (p less than 0.001). In the ALL group, aneuploidy was significantly correlated with the cell surface expression of common ALL antigen: 46 of 127 antigen-positive cases were aneuploid compared to 6 of 46 antigen-negative cases (p less than 0.003). Only 2 of 21 cases of T-cell ALL without common ALL antigen had detectable aneuploidy, which was significantly less than in the common ALL group (p = 0.02). The median percentage of cells in S-phase was significantly greater for B-cell and erythrocyte rosette-positive T-cell ALL, than for the other phenotypic subgroups. We conclude that aneuploidy and S-phase cell percentage are correlated with the state of leukemia cell differentiation. The biologic basis for the correlation is not established, but may be linked to the process of malignant transformation.
Acute Disease↗