Biomedical subjects
J Shuster
Publications and source records attributed to J Shuster.
Invasion of selectively permeable sea urchin embryo basement membranes by metastatic tumor cells, but not by their normal counterparts.
The selectively permeable basement membranes and the associated extracellular matrix of sea urchin embryos can be obtained intact. Their exterior surfaces have been used as invasion substrates for metastatic melanoma, squamous cell carcinoma, and fibrosarcoma cells, for primary squamous cell carcinoma cells, and for neonatal melanocytes, fibroblasts, and keratinocytes. About 18% of all metastatic tumor cells placed in contact with sea urchin embryo basement membranes and their associated extracellular matrix invaded them. About 4% of the cells of a primary squamous cell carcinoma, which later metastasized, invaded these substrates. As expected, neonatal melanocytes, keratinocytes, and fibroblasts failed to invade; however, melanocytes treated with scatter factor (hepatocyte growth factor) invaded as efficiently as metastatic tumor cells. This suggests that the lack of invasion by epidermal melanocytes is not due to irreversible differentiation to a noninvasive phenotype. Invasion time courses showed that the metastatic cells tested reached their maximal invasion frequencies in 4 h; thus, invasion of these substrates is rapid and efficient. This suggests that molecules participating in basement membrane recognition and invasion have been functionally conserved during the time separating vertebrates from invertebrates and that their constitutive activity may allow metastatic cells to escape their tissues of origin.
Leukemic cell growth in SCID mice as a predictor of relapse in high-risk B-lineage acute lymphoblastic leukemia.
Mice with severe combined immunodeficiency (SCID) provide a model system to examine the in vivo homing, engraftment, and growth patterns of normal and malignant human hematopoietic cells. The relation between leukemic cell growth in this model and the treatment outcome in patients from whom cells were derived has not been established. Leukemic cells from 42 children with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia were inoculated intravenously into CB.17 SCID mice. Mice were killed at 12 weeks or when they became moribund as a result of disseminated leukemia. All mice were necropsied and subjected to a series of laboratory studies to assess their burden of human leukemic cells. Twenty-three patients whose leukemic cells caused histopathologically detectable leukemia in SCID mice had a significantly higher relapse rate than the 19 patients whose leukemic cells did not (estimated 5-year event-free survival: 29.5% v 94.7%; 95% confidence intervals, 11.2% to 50.7% v 68.1% to 99.2%; P < .0001 by log-rank test). The occurrence of overt leukemia in SCID mice was was a highly significant predictor of patient relapse. The estimated instantaneous risk of relapse for patients whose leukemic cells caused overt leukemia in SCID mice was 21.5-fold greater than that for the remaining patients. Thus, growth of human leukemic cells in SCID mice is a strong and independent predictor of relapse in patients with newly diagnosed high-risk B-lineage acute lymphoblastic leukemia.
Prognostic features of Ewing's sarcoma on radionuclide bone scan after initial treatment.
OBJECTIVE: To study short-term changes in the radiopharmaceutical bone scan (BS) appearance of Ewing's sarcoma for indicators of decreased survival or future disease progression. METHODS: One-hundred and four patients with non-metastatic Ewing's sarcoma were evaluated at three time points: time of diagnosis (pre-biopsy), after induction chemotherapy (13 weeks) and after radiation therapy (20 weeks). Radiographs, computed tomograms (CTs) and BSs were obtained at each interval. Primary lesion activity and size on BS were evaluated and compared to radiographic and CT findings. RESULTS: No significant relationship was found at any time point between absolute radiopharmaceutical activity within the primary lesion and either disease progression or patient survival. Relative changes in BS activity between time points were also not significantly related to disease progression or survival despite a significant decrease in activity among the three time points. The size of the BS abnormality compared to the CT abnormality at the primary lesion site was related to both survival and disease progression at the post-induction chemotherapy time point (P = 0.025 and P = 0.014, respectively) with larger BS abnormalities indicating worse prognosis and survival. This relationship lost its significance at the post-radiation time point. No other significant relationship between the relative size of the BS abnormality and the size of the plain radiographic or CT abnormality was detected. CONCLUSION: Our data suggest that BS imaging of the primary lesion of Ewing's sarcoma provides little information in terms of predicting long-term survival or disease progression in patients with non-metastatic Ewing's sarcoma.
Prognostic features of Ewing sarcoma on plain radiograph and computed tomography scan after initial treatment. A Pediatric Oncology Group study (8346)
BACKGROUND: The authors studied the short-term changes in the plain radiographic and computed tomography (CT) appearance of Ewing sarcoma for indicators of decreased survival or future disease progression. METHODS: The authors evaluated CT scans and plain radiographs of the primary tumor site from 105 patients with Ewing sarcoma at diagnosis (prebiopsy), after induction chemotherapy (13 weeks), and after radiation therapy (20 weeks). RESULTS: Data suggest an association between postinduction CT findings of medullary involvement, cortical destruction, lysis, permeation, and unhealed pathologic fracture and decreased survival. On the postradiation scans, only medullary involvement was associated with worsened survival. No plain radiographic features were significant at any time. Absolute greatest tumor dimension was not significantly related to survival or tumor progression. The Cox model suggested that fractional change in greatest tumor dimension on CT at the time points studied relative to the prebiopsy CT was correlated to survival. Log-rank testing did not corroborate this finding. All significant associations appeared to result from adverse outcomes in small subgroups. CONCLUSIONS: Our data suggest that CT obtained immediately after induction chemotherapy and radiation may have some limited use in predicting the long-term prognosis of patients with Ewing sarcoma.
Treatment of late bone marrow relapse in children with acute lymphoblastic leukemia: a Pediatric Oncology Group study.
Children with acute lymphoblastic leukemia (ALL) who have completed 2.5 to 3 years of initial chemotherapy have an off-therapy relapse rate of approximately 20%. In an attempt to improve the survival of children with a late bone marrow (BM) relapse (ie, occurring greater than 6 months after cessation of primary therapy), the Pediatric Oncology Group designed a randomized study to compare the efficacy of doxorubicin/prednisone and cytarabine/teniposide in a multidrug retreatment chemotherapy program. Treatment consisted of remission reinduction with vincristine, prednisone, and doxorubicin, central nervous system prophylaxis with triple intrathecal chemotherapy, and continuation therapy (for 132 weeks) with alternating cycles of oral 6-mercaptopurine/methotrexate and intravenous vincristine/cyclophosphamide. Patients received intermittent courses of either prednisone/doxorubicin (regimen 1) or teniposide/cytarabine (regimen 2) during continuation therapy and a late intensification phase with either vincristine, prednisone, and doxorubicin (regimen 1) or teniposide and cytarabine (regimen 2). One hundred two of 105 evaluable patients (97%) achieved a second complete remission. Twenty-eight of 50 patients on regimen 1 have failed compared with 28 or 52 patients on regimen 2 (log-rank analysis, P = .68), indicating that this trial was inconclusive as to which treatment regimen was superior. The overall 4-year event-free survival for children with a late BM relapse was 37% +/- 6%. Age less than 10 years at initial diagnosis (P < or = .001), white blood cell count less than 5,000/microL at relapse (P = .036) and duration of first remission greater than 54 months (P = .039) were independently associated with a more favorable outcome. While the randomized trial was inconclusive, prolonged second complete remissions were secured in more than one-third of children with a late BM relapse of ALL. The prognostic factors identified may help select children with a late BM relapse who can be successfully retreated with chemotherapy alone.
Correction regarding an adverse reaction to the recombinant hepatitis B vaccine.
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Ten years' experience with LSA2-L2 therapy for childhood advanced lymphoblastic lymphoma.
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Treatment of CNS relapse in children with acute lymphoblastic leukemia: A Pediatric Oncology Group study.
PURPOSE: To assess the efficacy and toxicity of chemotherapy and cranial radiation for the treatment of children with acute lymphoblastic leukemia (ALL) following first isolated CNS relapse. PATIENTS AND METHODS: One hundred twenty children were treated on Pediatric Oncology Group (POG) protocol 8304. All children had received prophylactic CNS therapy during their initial treatment. The treatment protocol included a four-drug reinduction and six weekly doses of triple intrathecal therapy (TIT). Cranial radiation, 24 Gy, was followed by monthly TIT. Systemic consolidation and maintenance therapy included 6-week cycles of mercaptopurine/methotrexate (6MP/MTX) and vincristine/cyclophosphamide (VCR/CTX), with randomization to intervening pulses of prednisone/doxorubicin (PDN/DOX) or teniposide (VM26)/cytarabine (Ara-C) for a total of 88 weeks. RESULTS: All 120 patients achieved a second complete remission. There have been 61 protocol failures. Thirty-five patients had a bone marrow relapse, four with simultaneous CNS involvement and one with concurrent testicular leukemia. Thirteen patients had a second isolated CNS relapse, 10 a testicular relapse, and two relapsed in other sites. One patient died in remission. Overall event-free survival (EFS) at 4 years was 46% +/- 7%. The toxicity associated with this protocol was minimal except for leukoencephalopathy, which occurred in 20 (17%) patients. The treatment comparison between VM26/Ara-C or PDN/DOX pulses showed a trend toward superior EFS (P = .12) in favor of VM-26/Ara-C. CONCLUSION: To date, this represents the largest series of patients with ALL treated uniformly for an isolated CNS relapse. Since marrow relapse remains the primary site of failure, future protocols must intensify systemic therapy.
Extended triple intrathecal chemotherapy trial for prevention of CNS relapse in good-risk and poor-risk patients with B-progenitor acute lymphoblastic leukemia: a Pediatric Oncology Group study.
PURPOSE: The Pediatric Oncology Group (POG) acute leukemia in childhood (ALinC) 13 study tested two treatment regimens that used different CNS chemoprophylaxis for children older than 12 months with non-T, non-B acute lymphoblastic leukemia (ALL) and with no demonstrable CNS disease at diagnosis. PATIENTS AND METHODS: With the first regimen, standard (S), six injections of triple intrathecal chemotherapy (TIC), consisting of methotrexate (MTX), hydrocortisone (HC), and cytarabine (ara-C), were administered during intensification treatment and at every-8-week intervals throughout the maintenance phase for 17 additional doses. The second regimen, standard and MTX pulses (SAM), also specified six TICs during intensification, but substituted every-8-week pulses of intermediate-dose parenteral methotrexate (IDM; 1 g/m2) for the 17 maintenance TIC injections, with a low-dose intrathecal (IT) MTX boost administered with the first four maintenance IDM pulses. Otherwise, systemic therapy on regimen SAM was identical to regimen S. There were 1,152 patients randomized to the S and SAM regimens after stratification by risk group (age/leukocyte count) and immunophenotype. RESULTS: The 5-year probabilities (+/- SE) of an isolated CNS relapse were regimen S: good risk (n = 381), 2.8% +/- 1.3%; poor risk (n = 196), 7.7% +/- 3.2%; good + poor risk (n = 577), 4.7% +/- 1.5%; regimen SAM: good risk (n = 388), 9.6% +/- 2.2%; poor risk (n = 187), 12.7% +/- 4.2%; good + poor risk (n = 575), 10.9% +/- 2.2%. In poor-risk patients, approximately one third of the isolated CNS relapses occurred before preventive CNS therapy was begun at week 9. Hence, regimen S has provided better CNS preventive therapy for both good- and poor-risk patients (P < .001 overall). The difference is statistically significant for good-risk patients (P < .001), but not for poor-risk patients (P = .20). Neither treatment has shown a significant advantage in terms of general outcome. CONCLUSION: TIC injections extended throughout the intensification and maintenance periods are superior to IDM pulses for prevention of CNS leukemia. Our results with TIC seem comparable with those achieved with other contemporary methods of CNS preventative therapy. Thus, extended TIC affords a reasonable alternative to CNS irradiation plus upfront IT MTX for patients with B-progenitor ALL.
Transitional pre-B-cell acute lymphoblastic leukemia of childhood is associated with favorable prognostic clinical features and an excellent outcome: a Pediatric Oncology Group study.
The presenting characteristics and survival of children with the newly recognized transitional cell pre-B immunophenotype of acute lymphoblastic leukemia (ALL) are compared with those of children with pre-B ALL to determine the clinical significance of the new phenotype. Patients with transitional pre-B ALL (n = 17), defined by lymphoblasts expressing cytoplasmic and surface mu heavy chains without kappa or lambda light chains, have lower initial leukocyte counts (p = 0.02) and a higher frequency of DNA indexes > 1.16 (p < 0.001) than patients with pre-B ALL (n = 501), whether or not cases with the unfavorable prognostic (1;19) translocation are included in the analysis. Patients with transitional pre-B ALL lack FAB L3 morphology, bulky extramedullary disease, surface kappa or lambda chains, and the (8;14), (8;22), and (2;8) translocations, features that characterize the syndrome of B-cell ALL. The 4-year relapse-free survival result for children with transitional pre-B ALL appears better than that for children with pre-B ALL (93.3 +/- 17% versus 72.9% +/- 4.6%), but this difference is not statistically significant. We conclude that patients with transitional pre-B ALL have a very favorable prognosis in the context of the therapy used in this study.
Soft drink consumption and urinary stone recurrence: a randomized prevention trial.
The object of this study was to determine if a strong association between soft drink (soda) consumption and recurrence of urinary stone disease, found in an earlier case-control study of adult males, had a causal component. The study sample consisted of 1009 male subjects, who completed an episode of urinary stone disease, who were aged 18-75 at that time, and who reported consuming at least 160 ml per day of soft drinks. Half of the subjects were randomized to refrain from consuming soft drinks, while the remaining subjects served as controls. The intervention group had an observed 6.4% advantage in actuarial 3 yr freedom from recurrence (p = 0.023 one-sided) over the control group. One important secondary finding was that for those who reported at the time of the index stone that their most consumed drink was acidified by phosphoric acid but not citric acid, the experimental group had a 15% higher 3 yr recurrence-free rate than the controls, p = 0.002, while for those who reported at the time of the index stone that their most consumed drink was acidified by citric acid with or without phosphoric acid, the experimental group had a similar 3 yr recurrence-free rate to the controls, p = 0.55. This interaction was significant, p = 0.019.
A population-based study of neuroblastoma incidence, survival, and mortality in North America.
PURPOSE: The purpose of this study was twofold: (1) to provide a population-based estimate of neuroblastoma incidence, disease stage and age distribution, and survival and mortality rates in North America; and (2) to compare these figures in the province of Quebec at a time shortly before the institution of province-wide screening with those in a population-based control group, the Greater Delaware Valley (GDV) Pediatric Tumor Registry. MATERIALS AND METHODS: In Quebec, the four major pediatric teaching hospital records were searched for children with a diagnosis of neuroblastoma. Tumor board registry data and information supplied to the Division of Vital Statistics were also reviewed. Birth statistics were obtained from the population registry. The GDV Pediatric Tumor Registry is a population-based registry of pediatric cancer covering all of Delaware and parts of New Jersey, Pennsylvania, and Maryland. Age, stage of disease, and follow-up data were obtained through December 31, 1989, with Evans neuroblastoma staging data used for all comparisons. RESULTS: One hundred thirty children with neuroblastoma were identified in Quebec and 165 in the GDV, in a combined population of 3,178,736 children. The annual incidence of neuroblastoma was 10.95/10(6) under the age of 15 years and 27.75/10(6) between the ages of 0 and 4 years. The annual mortality rate due to neuroblastoma was 4.89/10(6) and 9.10/10(6) for the age groups 0 to 14 and 0 to 4, respectively. The overall 10-year survival rate for the 295 cases of neuroblastoma was 55%. The 10-year survival rates for patients with Evans stage I-IV and IVS disease were 88%, 90%, 63%, 21%, and 81%. There was no significant difference observed in the incidence, mortality, or survival in the two populations. CONCLUSION: These data represent the first large, population-based description of the clinical presentation and outcome of patients with neuroblastoma in North America, with no significant differences noted between Quebec patients and the GDV patients.
Ploidy of lymphoblasts is the strongest predictor of treatment outcome in B-progenitor cell acute lymphoblastic leukemia of childhood: a Pediatric Oncology Group study.
PURPOSE: Using the technique of recursive partitioning and amalgamation analysis with verification, the Pediatric Oncology Group (POG) investigated the independent prognostic significance of previously published prognostic factors significantly associated with event-free survival (EFS) in B-progenitor cell acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Age, leukocyte count, sex, immunophenotype (expression of cytoplasmic immunoglobulin [Ig] and of surface antigens CD10 and CD34), and DNA index (ratio of the flow cytometry-determined DNA content of leukemia cells to that of normal diploid cells) were the variables used in the evaluation of four antimetabolite-based chemotherapy regimens in 1,535 children with the newly diagnosed B-progenitor cell ALL between February 1986 and May 1990. RESULTS: There were three subgroups at widely different risks of treatment failure. A DNA index greater than 1.16 was the most prognostic feature. The final prognostic subgrouping was as follows: (1) DNA index greater than 1.16; (2) DNA index less than or equal to 1.16, age less than 11.0 years, and leukocyte count less than 50 x 10(9)/L; and (3) DNA index less than or equal to 1.16, (age greater than 11.0 years, and/or leukocyte count greater than 50 x 10(9)/L). These groups made up 20%, 53%, and 27% of the patients and had 4-year EFS rates (SE) of 90.1% (6.3%), 80.5% (5.1%), and 50.4% (7.6%), respectively. CONCLUSIONS: Use of the DNA index, leukocyte count, and age--data that are relatively inexpensive and simple to obtain--may be sufficient to stratify patients with B-progenitor cell ALL for risk-directed therapy. Patients at an extremely low risk of failing therapy (approximately 20% of cases in this study) can thus be identified and spared the toxic short-term and late effects of more intensive therapies that may be needed for children with less favorable clinical and biologic features.
Interpretation of nonsignificant results.
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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.
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).