Safety profile of HIV vaccination: first 1000 volunteers of AIDS vaccine evaluation group. NIAID AIDS Vaccine Clinical Trials Network.
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AIDS Vaccines↗
Biomedical subjects
R Sposto
Publications and source records attributed to R Sposto.
Levels of parathyroid hormone and calcitonin in serum among atomic bomb survivors.
To examine the potential causes of increased levels of calcium in serum with increasing dose of atomic bomb radiation, which was obtained from the previous preliminary analysis, levels of parathyroid hormone (PTH) and calcitonin in serum were examined among 1459 subjects in Hiroshima and Nagasaki. A significant effect of radiation on levels of calcium, PTH and calcitonin in serum was found, even after patients with hyperparathyroidism were excluded. The level of calcium in serum increased with radiation dose; this can be explained partly by the increase in the level of PTH with radiation dose. However, the dose effect on calcium remained even after adjustment for PTH, calcitonin and confounding factors such as renal function, serum albumin level and medication. Parathyroid hormone increased initially by 6.8% per gray, but the dose response leveled off after about 1 Gy. The level of calcitonin increased with radiation dose, probably in part due to feedback mechanisms stimulated by the increase in calcium. However, after adjustment for the level of calcium, the increase in the level of calcitonin with dose was still found. Although the etiological mechanisms of the effect of radiation on serum levels of calcium, PTH and calcitonin are unclear, radiation exposure may affect secretion of PTH and calcitonin and regulation of calcium a long time after atomic bomb exposure.
Adult↗
Induction of HIV-1-neutralising and syncytium-inhibiting antibodies in uninfected recipients of HIV-1IIIB rgp120 subunit vaccine.
A recombinant human immunodeficiency virus 1 IIIB (HIV-1IIIB) gp120 subunit vaccine (IIIB-rgp120/HIV-1, Genentech) was tested for safety and immunogenicity in a randomised, double-blind, placebo-controlled phase-I trial. HIV-1-seronegative adult volunteers received three 100 micrograms or 300 micrograms doses of IIIB-rgp120/HIV-1 in alum adjuvant (10 vaccinees in each group), or alum adjuvant alone (8 vaccinees), at 0, 4, and 32 weeks by intramuscular injection. The three injections were well tolerated in both vaccine groups. Antibodies that neutralised homologous HIV-1IIIB were induced in 9 of 10 recipients after three 300 micrograms doses, and 6 of these 9 sera also neutralised heterologous HIV-1SF2. A dose response was evident, since three 100 micrograms injections induced lower titres of HIV-1IIIB neutralising antibodies and in fewer recipients (5 of 9) than the higher dose, with no neutralisation of HIV-1SF2. Similarly, syncytia-inhibiting, CD4-rgp120-blocking, and HIV-1IIIB V3-binding antibodies were induced in a dose dependent manner. Response to the 300 micrograms per dose vaccination occurred in a larger proportion of volunteers and at higher mean titres than seen in previous human trials with other recombinant envelope subunit vaccines or live vaccinia-env priming followed by envelope subunit boosting.
AIDS Vaccines↗
Long-term follow-up of patients treated with COMP or LSA2L2 therapy for childhood non-Hodgkin's lymphoma: a report of CCG-551 from the Childrens Cancer Group.
PURPOSE: We analyzed the long-term results of a Childrens Cancer Group (CCG) randomized study comparing cyclophosphamide, vincristine, methotrexate, and prednisone (COMP) versus LSA2L2 as treatment for childhood non-Hodgkin's lymphoma. The initial results were previously reported (N Engl J Med 308:559, 1983). PATIENTS AND METHODS: A total of 429 patients are reported here, 68 with localized disease and 361 with disseminated disease. The distribution of disseminated-disease patients by histologic type was 164 lymphoblastic, 60 large-cell, and 137 undifferentiated lymphomas. Median follow-up duration of surviving patients is 8 years. RESULTS: Event-free survival (EFS) of patients with localized disease was 84% at 5 years. No differences were seen between the two treatment regimens. Results for patients with disseminated disease was dependent on histologic subtype: patients with lymphoblastic lymphoma did better when treated with LSA2L2 (5-year EFS of 64% v 35% for COMP); COMP produced better results for patients with undifferentiated lymphoma (5-year EFS of 50% v 29% for LSA2L2). Results for large-cell lymphoma patients were similar (5-year EFS of 52% for COMP v 43% for LSA2L2). Five percent of patients died of treatment-related complications while on therapy (primarily infections). Only four deaths without progression have been observed off-therapy (two from restrictive lung disease, one from an acute asthma attack, one from colon cancer). Patient survival rates after recurrence were poor. CONCLUSION: Treatment success can be expected in 84% of pediatric patients with localized non-Hodgkin's lymphoma. For patients with disseminated disease, treatment success can be expected in 64% of those with lymphoblastic and 50% of those with undifferentiated or large-cell disease. To date, late adverse events are rare.
Adolescent↗
Stable chromosome aberrations among A-bomb survivors: an update.
Analysis of data on stable chromosome aberrations collected between 1968 and 1985 by the Radiation Effects Research Foundation (RERF) on 1703 individuals exposed to A-bomb radiation in Hiroshima and Nagasaki, Japan, reveals different dose-response relationships in the two cities, as well as significant effects of both time of assay and age at exposure. In Hiroshima, the proportion of cells with aberrations increased by 0.080 per sievert at low doses, assuming a constant neutron radiation RBE of 10 relative to gamma radiation, for assays performed during the latest period (1981-1985). In Nagasaki, the low-dose increase was 0.0126 per sievert. There was evidence that radiation exposure was more effective for producing stable aberrations at some younger ages at exposure, although the interpretation of this interaction is difficult. Modeling neutron and gamma-ray components of dose separately in a way which allows the neutron RBE to vary with dose yielded an estimated low-dose limiting value of RBE of 707 (95% confidence bound 200-infinity), with a low-dose response of approximately 0.008 aberrations per sievert. This RBE is much higher than the published RBEs for induction of aberrations in vitro. The high estimated RBE and the differences in dose response by city both are suggestive of systematic dose estimation errors in which either neutrons were underestimated in Hiroshima or gamma rays were overestimated in Nagasaki.
Adolescent↗
Dose survival of G0 lymphocytes irradiated in vitro: a test for a possible population bias in the cohort of atomic bomb survivors exposed to high doses.
This study was intended to test for a possible early selective loss of relatively radiosensitive individuals from those atomic bomb survivors exposed to high doses using an in vitro X-ray dose-survival assay of peripheral blood lymphocytes. The assay was reasonably reproducible since the coefficient of variation (CV) was 8.2% for the mean D10 (the dose required to kill 90% of cells) of 3.39 Gy after 15 repeat tests for one control donor during the study period. The CV for single tests for 201 survivors was essentially the same, i.e., 7.7% with a mean D10 of 3.37 Gy, indicating very little heterogeneity of lymphocyte radiosensitivity among individuals. Linear regression analysis of D10 on the DS86 dose showed no evidence for the consistent change in average D10 values among the survivors exposed to high doses. The results might imply that the G0 lymphocytes do not express full variations in radiosensitivity and may not be suitable for quantitative measurements of relative radiosensitivity. Alternatively, the very small variation in lymphocyte radiosensitivity may be real and detection of the rare individuals with altered radiosensitivity may require much larger-scale testing. Therefore, no conclusive answer to the question of population bias was provided for the survivors.
Adult↗
A comparison of tests of the difference in the proportion of patients who are cured.
We compared by simulation the likelihood ratio, Wald, and score tests based on a mixture model similar to that proposed by Farewell (1982, Biometrics 38, 1041-1046), and a simple nonparametric test based on the plateau value of the product-limit estimate, for testing the difference in cured proportions between two groups. The parametric tests obtained their asymptotic properties even in small samples provided that one could assume equal failure rates in the two groups. Otherwise, good agreement with predictions required that essentially all potential failures had been observed. The comparative properties of the parametric tests depended on whether the population survival functions crossed, with the power of the Wald test as good as or better than the others in the common situation when the survival functions do not cross. However, its size was sometimes less than nominal. The score test was often not defined and is therefore of limited value. The product-limit test often performed as well as the parametric tests, and despite being biased in some circumstances, may be a useful alternative to these, especially in small samples when some potential failures have not been observed.
Biometry↗
Hyperparathyroidism among atomic bomb survivors in Hiroshima.
To determine the effect of exposure to atomic bomb radiation on the occurrence of hyperparathyroidism, the prevalence was determined among a population of 3,948 atomic bomb survivors and their controls in Hiroshima. The diagnosis of hyperparathyroidism was based upon histopathological findings or the presence of consistent hypercalcemia and elevated levels of serum parathyroid hormone. Primary hyperparathyroidism was diagnosed in 19 persons (3 males, 16 females). Females had approximately a threefold higher overall prevalence of hyperparathyroidism than males (P less than 0.05). The prevalence rates of hyperparathyroidism increased with radiation dose (chi2(1) = 12, P less than 0.001) after adjusting for sex and age at the time of the bombing. The estimated relative risk was 4.1 at 1 Gy (95% confidence limits 1.7 to 14). There was some evidence that the effect of radiation was greater for individuals who were younger at the time of the bombing. In conclusion, exposure to atomic bomb radiation affected the occurrence of hyperparathyroidism, suggesting that doses of radiation lower than those used in radiotherapy may also induce this disorder.
Adolescent↗
The effect of diagnostic misclassification on non-cancer and cancer mortality dose response in A-bomb survivors.
We used the EM algorithm in the context of a joint Poisson regression analysis of cancer and non-cancer mortality in the Radiation Effects Research Foundation (RERF) Life Span Study (LSS) to assess whether the observed increased risk of non-cancer death due to radiation exposure (Shimizu et al., RERF Technical Report 02-91, 1991) can be attributed solely to misclassification of cancer as non-cancer on death certificates. We show that greater levels of dose-independent misclassification than are indicated by a series of autopsies conducted on a subset of LSS members would be required to explain the non-cancer dose response, but that a relatively small amount of dose-dependence in the misclassification of cancer would explain the result. The adjustment for misclassification also results in higher risk estimates for cancer mortality. We review applications of similar statistical methods in other contexts and discuss extensions of the methods to more than two causes of death.
Age Factors↗
Recent uses of biological data for the evaluation of A-bomb radiation dosimetry.
Random errors in the DS86 radiation dose estimates used in the analysis of A-bomb survivor data are recognized to have an important impact upon estimates of the risk of late effects such as cancer. Little however is known for certain concerning the distribution of such random errors. This paper gives an overview of recent work at the Radiation Effects Research Foundation (RERF) using multivariate analysis of biological data, including acute effects of radiation exposure, late effects (eg leukemia mortality) and stable chromosome aberrations, for the purpose of evaluating the extent of random error in the estimation of individual doses using DS86. The emphasis here is on analyses of apparent association between biological endpoints, in light of a dosimetry error model framework proposed recently by Pierce et al. Analyses performed to date appear to be consistent with the view that lognormal random dosimetry errors with a standard deviation of 40% or greater of true dose may exist in DS86. Association between radiogenic outcomes in A-bomb survivors, after adjustment for DS86 estimated dose level, has been detected for such widely varying pairs of outcomes as mutant T-cell frequencies and chromosome aberrations, epilation and leukemia mortality, and epilation and chromosome aberrations. The motivation for examining association between pairs of biological endpoints has usually been to determine the extent to which radiation sensitivity varies between individual survivors. Recognizing, however, that random error in dose estimates results in apparent association between biological outcomes is crucial to interpreting studies, such as these, which use data on multiple biological endpoints. To go one step further, in situations where there is a prior knowledge about the biological plausibility of such associations in outcome data the amount of association between radiogenic outcomes (remaining after adjustment for estimated dose), to the extent that they are greater than that assumed to be reasonable, is an important potential source of information concerning the magnitude of random errors in the DS86 dose estimates.
Chromosome Aberrations↗
An estimate of the magnitude of random errors in the DS86 dosimetry from data on chromosome aberrations and severe epilation.
An analysis of the proportion of cells with chromosome aberrations in cultured blood lymphocytes from A-bomb survivors in Hiroshima and Nagasaki reveals that the dose-response relationship using DS86 assigned dose is significantly steeper in the subsample of individuals who reported severe epilation after the bombings than in those who did not report severe epilation. This effect is due either to random errors in the DS86 dose assignments or to individual differences in sensitivity to radiation, or to both. In this paper, working within a class of dosimetry error models, we estimate the magnitude of random dosimetry errors which would be required to account for all of the difference in the observed dose response between people who did and did not report severe epilation under the assumption that random dosimetry error is the only cause of the effect. We conclude that random dosimetry errors in the range 45 to 50% of true dose are necessary to explain completely the difference in dose response between the two epilation groups. We discuss evidence that the contribution of individual differences in radiation sensitivity to the observed epilation effect is likely to be small, so that random dosimetry errors may be the major cause of this effect.
Adolescent↗
Is interindividual variation of cellular radiosensitivity real or artifactual?
A recently developed dose-survival assay using human G0 T lymphocytes from peripheral blood was employed to assess possible interindividual variation of cellular radiosensitivity by comparing variability between a single test for different individuals and repeated tests for a single donor. The surviving fraction at each X-ray dose level fluctuated similarly between the two groups, and the X-ray dose required to kill 90% of the cells (D10) was 3.59 +/- 0.18 Gy (mean +/- SD) for 31 different individuals and 3.66 +/- 0.21 Gy for 28 repeated tests of one individual. Analysis of variance to compare the two sets of data showed that variation in the D10 value was not significantly greater in the former group. Analysis of D50 and D90 showed similar results. These results support the hypothesis that interindividual variation in cellular radiosensitivity is quite small, if it exists at all, as far as can be determined by the loss of colony-forming ability of irradiated G0 lymphocytes.
Cell Survival↗
The treatment of medulloblastoma. Results of a prospective randomized trial of radiation therapy with and without CCNU, vincristine, and prednisone.
In a prospective randomized trial designed to study the effectiveness of adjuvant chemotherapy following standard surgical treatment and radiation therapy, 233 eligible patients with medulloblastoma were treated by members of the Children's Cancer Study Group and the Radiation Therapy Oncology Group. Eligible patients were randomly assigned to receive radiation therapy with or without adjuvant chemotherapy consisting of 1-(2-chloroethyl)-3-cyclohexyl-nitrosourea (CCNU), vincristine, and prednisone. The estimated 5-year event-free survival probability was 59% for patients treated with radiation therapy and chemotherapy and 50% for patients treated with radiation therapy alone, a difference which is not statistically significant. The 5-year survival probability was 65% for both groups. Although the treatment difference was not statistically significant when all patients were combined, in the small number of patients with more extensive tumors, event-free survival was better in the group receiving chemotherapy (48% vs. 0%, p = 0.006). In these latter patients the survival time is also significantly prolonged. Extent of disease (as measured by the M staging criteria described by Chang) and age at diagnosis were significantly associated with outcome; advanced disease and young age had a worse prognosis. The extent of tumor resection was not an independent prognostic factor. It is concluded that chemotherapy does not benefit patients with low-stage medulloblastoma, but may benefit those with more advanced stages of disease.
Adolescent↗
The effectiveness of chemotherapy for treatment of high grade astrocytoma in children: results of a randomized trial. A report from the Childrens Cancer Study Group.
Fifty-eight patients with high-grade astrocytoma were treated by members of the Childrens Cancer Study Group in a prospective randomized trial designed to study the effectiveness of chemotherapy as an adjuvant to standard surgical treatment and radiotherapy. Following surgical therapy, patients were assigned randomly to radiotherapy with or without chemotherapy consisting of chloroethyl-cyclohexyl nitrosourea, vincristine, and prednisone. Treatment with chemotherapy prolonged survival and event-free survival. Five-year event-free survival was 46% for patients in the radiotherapy and chemotherapy group, and 18% for patients in the radiotherapy-alone group. Five-year survival was similarly improved. The differences in outcome due to treatment were statistically significant after correcting for imbalances in important prognostic factors (event-free survival, p = 0.026; survival, p = 0.067). The presence of mitoses or necrosis in the tumor specimen was associated with poorer outcome. Patients whose initial surgery was limited to biopsy, and patients with basal ganglia lesions, also had significantly worse outcome. Chemotherapy administered at the time of recurrence in a small number of patients did not produce any long-term survivors. This study is to our knowledge the only randomized trial to investigate effectiveness of chemotherapy in the treatment of high-grade astrocytoma in children.
Adolescent↗
Similar efficacy of 6 and 18 months of therapy with four drugs (COMP) for localized non-Hodgkin's lymphoma of children: a report from the Childrens Cancer Study Group.
Successful treatment of localized non-Hodgkin's lymphoma (NHL) in childhood with 18 months of cyclophosphamide, vincristine, methotrexate (MTX), and prednisone (COMP) prompted a randomized clinical trial to determine whether a 6-month course of the same therapy was as effective as an 18-month course when combined with local irradiation. Two successive Childrens Cancer Study Group (CCSG) protocols (CCG 551 and CCG 501) entered 232 eligible patients from October 1979 until April 1986. Initially, all children with localized disease were considered eligible, but by a subsequent amendment, those with lymphoblastic (LB) histology were excluded. Hence, the study population consisted of 211 patients with nonlymphoblastic (NLB) and 21 with LB disease. Early relapses (before 6 months) occurred in 13 patients with NLB histology. Late relapses were seen in seven patients, three with LB histology. Among the 104 randomized patients who followed the prescribed therapy, there were four recurrences and no differences between 6-month and 18-month therapy. The overall survival for NLB disease was 91% on CCG 551 and 98% on CCG 501. We conclude that 6 months of COMP is excellent therapy for children with localized NLB NHL.
Adolescent↗
X-ray-induced mutations in cultured human thyroid cells.
Cultured human thyroid cells were X-irradiated in vitro and assayed for resistance to 6-thioguanine. The average mutant frequency was 1.69 +/- 1.34 X 10(-5) (mean +/- SD) in controls, 3.74 +/- 2.21 X 10(-5) in cells exposed to 1 Gy, and 7.19 +/- 5.37 X 10(-5) in cells exposed to 2 Gy. The positive association between mutant frequency and dose was statistically significant. The estimated mutation induction rate was 2.54 +/- 0.71 X 10(-5) per gray, which is in close agreement with published results for human skin fibroblasts and mammary epithelial cells. These results extend and confirm earlier reports that mutation induction rates for fibroblasts and epithelial cells after exposure to X rays are similar.
Adult↗
Use of unequal allocation in survival trials.
In some two-treatment clinical survival trials, a large imbalance in the allocation of patients to treatments will result in approximately the same power for the logrank test as equal allocation. This fact can be used in some trials to reduce significantly the number of patients allocated to a potentially inferior treatment.
Biometry↗
The pathology of non-Hodgkin's lymphoma of childhood: II. Reproducibility and relevance of the histologic classification of "undifferentiated" lymphomas (Burkitt's versus non-Burkitt's).
The Children's Cancer Study Group conducted prospective clinical trials of 608 children with non-Hodgkin's lymphoma from 1977 to 1983. In 1980, significant differences in survival of children with disseminated disease correlated with histologic diagnosis and the randomized treatment employed. A pathology reproducibility review showed the lymphoblastic lymphoma cases to be virtually 100 per cent distinguishable histologically from the nonlymphoblastic lymphomas (Burkitt's, non-Burkitt's, and "histiocytic"). However, diagnostic reproducibility of the pathologist-of-record was 59 per cent in the Burkitt's and non-Burkitt's lymphoma group. Therefore, 159 cases, agreed on by the pathologist-of-record and the "lymphoma panel" as Burkitt's (77 cases) or non-Burkitt's lymphoma (82 cases) and designated as the "reference diagnosis," were blindly reviewed twice each by two hematopathologists to yield the "review diagnoses." Consensus agreement was achieved in 67 per cent of cases overall, 82 per cent of Burkitt's and 54 per cent of non-Burkitt's lymphoma. Using the "reference diagnoses," we found that the relative frequency of Burkitt's and non-Burkitt's lymphoma was associated with the extent of disease at diagnosis (P = 0.06) but not with other prognostic factors. Despite the difficulties in histologic classification, analyses that used either "reference diagnoses" or "consensus review diagnoses" and that were adjusted for extent of disease consistently demonstrated significantly shorter event-free survival for patients having Burkitt's lymphoma; their failure rate was four times that for patient's with non-Burkitt's lymphoma. Newer cell biologic techniques hopefully will enhance histopathologic distinctions that remain the basis for diagnosis.
Burkitt Lymphoma↗