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Biomedical subjects

A I Goldman

Publications and source records attributed to A I Goldman.

At least 19 recordsLinked to original sources
PubMed1992

Exemplary data: sample size and power in the design of event-time clinical trials.

In planning a complex clinical trial with time to event as the outcome, it is difficult to derive the power of the test statistic analytically. In this paper we describe an algorithm for generating exemplary data from an alternative hypothesis that can be used to compute the expected value of a logrank test statistic and its power under that alternative. Exemplary data are nonrandomly computer-generated data that are constructed from a complex stochastic process and have desirable characteristics such as distributional moments similar to those of the process. An algorithm for generating exemplary timed events data is presented and its use in evaluating power for the planning of clinical trials demonstrated. These data represent "expectations" of outcome, data censoring, and censoring event times. A test statistic, z, such as the logrank can be computed from the data. It is distributed asymptotically, N(mu A, 1), under the alternative hypothesis and its value is used to estimate mu A and the power of the test for a given trial scenario. The results compare favorably to results from analytical methods and Monte Carlo simulations published in the literature. The advantages of the method lie in the degree of flexibility in study design, choice of models that describe the timing of events, and the range of testing methods that can be used. Although Monte Carlo methods may appear to have similar flexibility, the exemplary algorithm is more practical because only one data set need be analyzed and the modifications can be achieved without reprogramming.

Algorithms↗
PubMed1991

The cure model and time confounded risk in the analysis of survival and other timed events.

The use of the Kaplan-Meier estimator for the analysis and testing of cure model data is discussed and results are compared with the more commonly used logrank test. The Kaplan-Meier estimator is particularly appropriate for describing the shape of the underlying survival distribution of data from bone marrow transplantation but is also relevant for different types of timed events data from other chronic diseases. The estimate of the event-free fraction by the product limit, may have a bias depending on the extent of follow-up, the parameters of the model, and confounding by competing risk events. The test based on the product limit has appropriate size and is more powerful as long as follow-up is sufficient to minimize the bias. On the other hand, the logrank test, which is optimal for testing differences in time-to-event curves under proportional hazard assumptions, may be inappropriate and misleading for evaluating the difference in event-free fractions under the cure model.

Bias↗
PubMed1991

Matrix engineering.

Matrix engineering is a technology that utilizes hyaluronan (HA, hyaluronic acid) based matrices to control, direct or augment tissue regenerative processes. Hyaluronan and the concept of matrix engineering have become established tools in ophthalmic and orthopaedic medicine. The clinical indications for HA are limited by the physical properties and short residence time of the natural HA molecule. To expand and improve upon its current medical applications, a family of HA derivatives was prepared by chemical modification and cross-linking. Relative to the non-modified HA molecule, the hylan family of polymers provides more versatile physical forms, improved mechanical properties and an extended residence time. Hylan can also be used as a surface coating to improve blood compatibility. The chemical, physical and biological properties of hylans will be reviewed, focusing on the specific therapeutic indications they enable.

Animals↗
PubMed1989

Six-year follow-up of the clinical significance of karyotype in acute lymphoblastic leukemia.

To evaluate the importance of pretreatment karyotype in predicting long-term outcome in acute lymphoblastic leukemia (ALL), we performed a follow-up study of the 329 patients from the Third International Workshop on Chromosomes in Leukemia. Living patients have now been followed a minimum of 6 years. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, rearrangements involving 8q24, t(4;11), 14q+, 6q-] or, in the remaining cases, modal number (less than 46, 46, 47-50, greater than 50). As previously reported for achievement and duration of complete remission, and overall survival, disease-free survival differed significantly (p less than 0.001) among chromosome groups for both adults and children. Among children, karyotype was an independent prognostic factor for predicting disease-free survival. Because of the long follow-up, we now have been able to utilize statistical models to estimate the percentage of patients cured, according to karyotype alone and combined with other risk factors. Adults with the highest likelihood of cure (21-33%) were those patients with FAB-L1, a leukocyte count of 50,000/microliters or less, and one of the following chromosome groups: greater than 50, 47-50, 6q-, or normal. In children these same characteristics were associated with the highest percentage of cure (58-71% cured). In addition, we identified several groups of children with less than 15% chance of cure who clearly need to be treated as high-risk patients at diagnosis. Future studies of patients who have received risk-adapted therapy based on these chromosome data are needed to determine if more intensive treatment will improve the outlook of patients with cytogenetically unfavorable types of ALL.

Adult↗
PubMed1988

Four- and five-year follow-up results from four seventh-grade smoking prevention strategies.

Recent studies have suggested that a prevention program that addresses the social influences that encourage smoking can be effective in deterring cigarette use by adolescents. This study presents 4- and 5-year follow-up results from two studies which evaluated three variations of this social influences model and compared them to a health consequences program and an existing-curriculum condition. The results suggest that a seventh-grade program, built around the social influences model and taught jointly by same-age peer leaders and local classroom teachers, may reduce 4-year weekly- and daily-smoking cumulative incidence rates, providing the first evidence for any long-term effects for the social influences model. However, the results also suggest that any long-term effects from such interventions are probably limited and may depend heavily on the manner in which the social influences model is translated during the intervention. Additional follow-up studies are needed to clarify the long-term effects of these intervention programs.

Adolescent↗
PubMed1988

Smokeless tobacco use among ninth graders in a north-central metropolitan population: cross-sectional and prospective associations with age, gender, race, family structure, and other drug use.

Smokeless tobacco use was analyzed in relation to demographic factors and to past and current use of tobacco, alcohol, and marijuana in 4,249 ninth graders in the Twin Cities metropolitan area. Smokeless tobacco use was found to be more common among males, particularly whites; among whites relative to blacks; among adolescents from one-parent households; and among those who reported current or prior use of cigarettes, alcohol, or marijuana. Smokeless tobacco use was also very common among the Native Americans and Hispanics sampled. The results suggest that smokeless tobacco may be joining the list of common recreational drugs that have potential for both short and long-term danger to the adolescent user.

Adolescent↗
PubMed1988

Allogeneic bone marrow transplantation for acute leukaemia: comparative outcomes for adults and children.

Advances in both allogeneic marrow transplantation and conventional therapy for acute leukaemia have complicated the choice between bone marrow transplantation (BMT) and other remission treatment options. Because older patients may be more susceptible to BMT-related complications, this study analysed the effect of age on clinical outcome for 149 patients with acute leukaemia in remission receiving allogeneic BMT. Overall projected relapse-free survival at 3 years post-transplant is equivalent for 48 adults (18 years or older) and 101 children (less than 18) at 45.4% (31.1-59.6; 95% confidence interval) and 39.9% (30.1-49.7; 95% C.I.), respectively. Among 73 patients with acute lymphocytic leukaemia (ALL) 35.3% of adults and 30.1% of children survive relapse-free at 3 years. Cox multiple regression analysis demonstrated that higher diagnostic white count, but not pre-transplant extramedullary leukaemia, remission number, or age, was important as an independent adverse clinical prognostic factor for patients with ALL. Overall outcome was better for 76 patients with acute myeloid leukaemia (AML) with 51.6% of adults and 52.9% of children surviving relapse-free at 3 years post-transplant. Cox multivariate regression analysis identified first remission status and lower white cell count, but not patient age, as independent predictors of improved relapse-free survival for AML patients. Adults had greater transplant morbidity, predominantly related to a higher incidence of acute graft-versus-host disease (GVHD), resulting in longer hospital stay. Survival at 100 d, long-term survival and clinical performance status were similar in both age groups. These data suggest that results of allogeneic BMT for adults with acute leukaemia compare favourably with those found in children and are superior to most reports of conventional chemotherapy. Allogeneic BMT remains a reasonable option for remission acute leukaemia patients up to the age of 45.

Adolescent↗
PubMed1987

Comparison of autologous and allogeneic bone marrow transplantation for treatment of high-risk refractory acute lymphoblastic leukemia.

Chemoradiotherapy and transplantation of bone marrow from matched sibling donors have been useful for the treatment of acute lymphoblastic leukemia in patients with a poor prognosis but are not available to some two thirds of patients who do not have a matched allogeneic donor. We undertook this study to compare autologous and allogeneic marrow transplantation in the treatment of such cases. We treated 91 patients with high-dose chemoradiotherapy and followed them for 1.4 to 5 years. Forty-six patients with an HLA-matched donor received allogeneic marrow, and 45 patients without a matched donor received their own marrow taken during remission and purged of leukemic cells with use of monoclonal antibodies. Bone marrow engraftment occurred earlier in patients who received autologous marrow. Recipients of autologous marrow had shorter hospital courses, with significantly fewer peritransplantation deaths than recipients of allogeneic marrow. Post-transplantation relapse of leukemia was the most frequent cause of treatment failure; relapses occurred in an estimated 37 percent of patients with allogeneic grafts in whom graft-versus-host disease developed, 75 percent of patients with allogeneic grafts in whom graft-versus-host disease did not develop, and 79 percent of patients who received autologous grafts. The interval before relapse was significantly shorter in the autologous-marrow group than in the allogeneic-marrow group. Recipients of autologous and allogeneic marrow whose first pretransplantation remissions were short (less than 18 months) had eventual outcomes similar to those whose first remissions were longer than 18 months. Patients with a first remission lasting less than 18 months had an outcome better than that expected with chemotherapy alone. The fractions of "cured" patients were estimated to be 20 percent in the autologous-marrow group and 27 percent in the allogeneic-marrow group--not a significant difference, but because of the limited statistical power of the study, the question of long-term disease-free survival must still be considered open.

Adolescent↗
PubMed1987

Central nervous system involvement in acute nonlymphocytic leukemia. A prospective study of adults in remission.

To identify adults with acute nonlymphocytic leukemia at risk for the development of central nervous system involvement, we performed periodic cerebrospinal fluid examinations on patients in remission. Among 58 consecutive patients monitored during first remission, central nervous system leukemia developed in nine (16 percent). Four patients, including one who was symptomatic, had central nervous system leukemia detected simultaneously with marrow relapse. Five additional patients were asymptomatic and continue to have bone marrow remission. Following central nervous system and systemic treatment, two of these five patients have never had relapse, and three had relapse in the bone marrow five, 10, and 21 months later. Factors at diagnosis associated with the subsequent development of central nervous system leukemia were elevated leukocyte count, serum lysozyme and lactate dehydrogenase, extramedullary infiltration including splenomegaly, and monocytic (FAB M4 or M5a) morphology. In six of 17 patients (35 percent) with monocytic morphology, central nervous system leukemia developed compared with only three of 41 patients (7 percent) with other subtypes (p = 0.02). Discriminant analysis identified leukocyte count, splenomegaly, and M4 or M5a morphology as the most important risk factors and led to a mathematical formula that correctly identified 90 percent of the patients. Although the risk of central nervous system leukemia in adults with acute nonlymphocytic leukemia is too low to justify routine prophylaxis, those patients recognized to be at a greater risk should receive prophylaxis or be monitored closely with periodic lumbar punctures.

Acute Disease↗
PubMed1987

Issues in designing sequential stopping rules for monitoring side effects in clinical trials.

In a clinical trial of a new treatment, severe side effects may be a problem, and the trial may have to be stopped if the incidence is too high. We need to anticipate the need for such a decision to halt the trial early, and possibly design formal stopping rules for an excess of untoward events. The work presented here discusses the issues involved in such monitoring in comparison with more conventional analysis of the outcome variable. Stopping rules are derived by application of the sequential probability ratio test (SPRT), followed by computation of the exact size and power and adjustments of the consequent rules to achieve chosen operating characteristics appropriate to a monitoring situation. Rules are also derived from a Bayesian approach. These rules are applied to an illustrative trial and compared to the actual conditions that lead to the closing the trial.

Bone Marrow Transplantation↗
PubMed1987

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.

Actuarial Analysis↗
PubMed1987

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease.

Forty remission patients with high-risk acute lymphoblastic leukemia (ALL) underwent matched allogenic bone marrow transplantation (BMT) following preparation with cyclophosphamide and fractionated total body irradiation (TBI). As of March 1987, the median follow-up is more than 3 1/2 years. Thirteen patients are alive (11 relapse free) between 2 and 4 1/2 years post-BMT. Neither age, sex, remission number, prior extramedullary leukemia, nor WBC at diagnosis of ALL was statistically significant as a predictor of relapse-free survival. The development of acute graft-v-host disease (GVHD) in 17 patients was found, with time-dependent Cox regression analysis, to be associated with a significant reduction in post-BMT relapse risk (P = .04) and improved disease-free survival (P = .11). A prospective, randomized trial of maintenance chemotherapy with oral methotrexate and mercaptopurine did not demonstrate improvement in relapse risk or survival for those assigned maintenance chemotherapy (P = .7). These results suggest that allogeneic BMT can result in extended relapse-free survival for some patients with high-risk ALL. More effective preparative chemoradiotherapy and exploitation of the apparent graft-v-leukemia effect may be useful in future trials.

Acute Disease↗
PubMed1986

Chromosomal abnormalities identify high-risk and low-risk patients with acute lymphoblastic leukemia.

The importance of banded chromosome analyses in predicting long-term outcome in acute lymphoblastic leukemia (ALL) was evaluated in this follow-up study of 329 patients from the Third International Workshop on Chromosomes in Leukemia. Patients were divided into ten groups according to pretreatment karyotype: no abnormalities, one of the following structural abnormalities [the Philadelphia chromosome, translocations involving 8q24,t(4;11), 14q+, 6q-] or, in the remaining cases, modal number [less than 46, 46, 47 to 50, greater than 50]. Achievement and duration of complete remission (CR) and survival differed among chromosome groups (P less than .0001). Karyotype was an independent prognostic factor for duration of first CR and survival, even when age, initial leukocyte count (WBC), French-American-British (FAB) type, and immunologic phenotype were considered. Among adults, prolonged remission and survival were uncommon in all chromosome groups. Only in the normal karyotype group was median survival even two years. Among children, striking differences in long-term remission and survival were seen depending upon karyotype. Children in the greater than 50 group did best, with 70% remaining in first CR for a median duration in excess of five years. Children in the 47-50, 6q-, and normal karyotype groups also had prolonged survivals. In contrast, certain translocations [t(9;22)(q34;q11), t(4;11)(q21;q14-23), t(8;14)(q24;q32)] identified children who had short survivals, even in the presence of favorable prognostic factors including a low WBC, L1 morphology, and non-T, non-B immunologic phenotype. We conclude that chromosome analysis is required at diagnosis in patients with ALL, and that children with these specific translocations should be managed as having high-risk ALL.

Adult↗
PubMed1979

Clinical utility of lymphocyte surface markers combined with the Lukes-Collins histologic classification in adult lymphoma.

To determine whether analysis of lymphocyte surface markers adds clinically useful information to the Lukes-Collins classification of lymphomas, tumors from 107 adults were histologically classified and studied for surface markers. Ninety-six cases were histologically classified as Lukes-Collins B-cell lymphomas; 87 showed B and one showed T surface markers, whereas eight had neither marker. Eleven lymphomas were histologically T-cell tumors; four of the 11 showed T surface markers, and seven had neither marker. Both the Lukes-Collins classification and surface markers identified patient groups with different clinical characteristics, chemotherapeutic responsiveness and survival. However, by combining surface markers and histologic features, additional important therapeutic and prognostic information was obtained. In each histologic class, patients whose lymphomas failed to express immunologically the histologically predicted marker had fewer responses to chemotherapy and shorter survivals than patients whose lymphomas expressed the predicted marker. Our data suggest that the analysis of surface markers in combination with the Lukes-Collins classification identifies many patients who respond poorly to current therapy and who thus require new therapeutic approaches.

Aged↗
PubMed1978

Estrogen receptors and responses to chemotherapy and hormonal therapy in advanced breast cancer.

To determine the correlation between the estrogen-receptor status and responses to chemotherapy or hormonal therapy, we retrospectively analyzed the clinical data of 143 patients with advanced breast cancer. Receptor contents were determined by a sucrose-gradient method and designated arbitrarily as "rich" or "poor". The response rate to chemotherapy was significantly higher in receptor-rich tumors (86 per cent) than in receptor-poor tumors (36 per cent) (P less than 0.001). Patients with receptor-rich tumors also responded favorably to hormonal therapy. However, there was no correlation between the responses to hormonal therapy and to chemotherapy when they were used sequentially, a phenomenon that may be attributed to the changes in tumor receptor content during the clinical course. These data suggest that separate factors associated with the response to chemotherapy may coexist with estrogen receptors in breast cancer.

Adult↗
PubMed1978

Phagocytosis in the retinal pigment epithelium of the RCS rat.

The retinal pigment epithelium of RCS rats, previously thought not to phagocytize photoreceptor outer segments, exhibited a peak of phagocytosis in vivo when animals were kept under conditions of cyclic lighting (12 hours of darkness and 12 hours of light). The peak occurred at 1 hour after the onset of light, with maximum and minimum levels of phagocytosis averaging about 5 percent of that found in the pigment epithelium of Osborn-Mendel rats used as a control. Eyecups that were obtained from Osborn-Mendel rats and maintained for up to 3 hours in organ culture demonstrated levels of phagocytosis that were sevenfold greater than those of unincubated controls. Likewise a tenfold increase occurred in incubated as opposed to unicubated RCS eyes, raising the possibility that phagocytosis could be experimentally stimulated in vivo.

Animals↗