Biomedical subjects

Thomas M Braun

Publications and source records attributed to Thomas M Braun.

13 recordsLinked to original sources

PubMed2007

Comparing the small sample performance of several variance estimators under competing risks.

We examine several variance estimators for cumulative incidence estimators that have been proposed over time, some of which are derived from asymptotic martingale or counting process theory, and some of which are developed from the moments of the multinomial distribution. There is little published work comparing these variance estimators, largely because the variance estimators are algebraically complex and difficult to interpret and all but one have yet to be programmed for a standard statistical package. Through simulation and application to real data, we compare the performance of six variance estimators in relation to each other and the bootstrap in order to confirm earlier reports of their performance and to provide future direction toward their application. We find that the multinomial-moment-based estimators have performance close to that of the bootstrap, and are quite accurate for estimating the variance, even in samples of 20 subjects. All but one of the martingale theory-based estimators tend to perform poorly in small samples, tending to either overestimate or underestimate the empirical variance in samples of fewer than 100 subjects.

Analysis of Variance↗

PubMed2006

Generalizing the TITE-CRM to adapt for early- and late-onset toxicities.

Due to the staggered entry of subjects in phase I trials, some subjects will only be partially through the study when others are ready to be enrolled. Nonetheless, many phase I designs focus solely upon whether or not subjects experience toxicity, thereby determining the maximum tolerated dose (MTD) with a binomial likelihood using data from fully observed subjects. The time-to-event continual reassessment method (TITE-CRM) was the first attempt to incorporate information from partially observed subjects by using a weighted binomial likelihood in which the weights are based upon the actual toxicity time distribution. Unfortunately, it is difficult to accurately estimate the toxicity time distribution because only a small proportion of enrolled subjects will experience toxicity. Creators of the TITE-CRM propose the simple alternative of weighting subjects by the proportion of time observed, as well as two adaptive weights to adjust for late-onset toxicities. As a alternative to these approaches, we suggest assuming the toxicity times, as a proportion of the total time under observation, have a Beta distribution with parameters 1.0 and theta; we also allow theta to vary by dose. The value of theta allows us to reflect the occurrence of early- or late-onset toxicities without correctly specifying the actual distribution of toxicity times. Through this model, we do not necessarily expect to improve identification of the MTD, but rather hope to reduce the exposure of subjects to overly toxic doses. Through simulation, we examine how well our model identifies the MTD and allocates dose assignments in three scenarios investigated by previous publications.

Clinical Trials, Phase I as Topic↗

PubMed2006

Ex vivo culture with interleukin (IL)-12 improves CD8(+) T-cell adoptive immunotherapy for murine leukemia independent of IL-18 or IFN-gamma but requires perforin.

In animal models and clinical trials, adoptive transfer of activated, antigen-specific CD8(+) T cells mediates tumor regression in a cell dose-dependent manner. The cytokine interleukin (IL)-12 promotes CD8(+) T-cell cytotoxicity and, with IL-18, synergistically up-regulates IFN-gamma release. We have shown that culturing CD8(+) T cells ex vivo with IL-12 and IL-18 enhanced antitumor responses in vivo and in vitro using a model of C1498/ovalbumin, a murine acute myeloid leukemia cell line expressing the antigen ovalbumin. Activated ovalbumin-specific CD8(+) T cells cultured with IL-12, IL-18, both, or neither were assayed for antigen-specific cytokine production and cytolytic activity and adoptively transferred to C57BL/6 mice with established tumors. Maximal IFN-gamma release occurred after T-cell culture with IL-12 and IL-18. Tumor-specific in vitro cytotoxicity was enhanced by IL-12, unaffected by addition of IL-18, and abrogated in perforin-deficient T cells irrespective of cytokine exposure. T cells cultured with IL-12 more effectively eliminated tumors, and addition of IL-18 did not further augment responses. IFN-gamma-deficient CD8(+) T cells showed effective antitumor activity that was enhanced by IL-12 with or without IL-18. Perforin-deficient CD8(+) T cells were poor mediators of antitumor activity, though, and showed no improvement after culture with IL-12 and/or IL-18. Thus, ex vivo culture with IL-12 was sufficient to augment antigen-specific in vitro cytotoxicity and antitumor activity in vivo in an IFN-gamma-independent but perforin-dependent manner. Ex vivo culture with IL-12 may improve CD8(+) T-cell immunotherapy of cancer in the absence of donor cell-derived IFN-gamma via perforin-mediated cytolysis.

Acute Disease↗

PubMed2006

Comparing an experimental agent to a standard agent: relative merits of a one-arm or randomized two-arm Phase II design.

BACKGROUND: Phase II clinical trials in cancer are used to assess whether a new agent has sufficiently promising efficacy to proceed on to a larger definitive study comparing the new agent to a standard agent. PURPOSE: A crucial issue in determining the usefulness of a one-arm design is the uncertainty of the historical response rate of the standard therapy. Therefore, we contrast the usual one-arm design of a Phase II trial with a randomized two-arm design that uses the same number of patients. METHODS: We use simulations and analytical approximations to compare the two designs under a range of realistic values for the historical rate uncertainty and a range of treatment effects. We also extend the simulation model to compare the efficiency of the two designs in settings where multiple Phase II studies are used to make decisions about moving on to a Phase III study. RESULTS: For a one-arm design the probability of correctly identifying an effective experimental agent tends to be at least 0.7 in the cases considered, with the corresponding value for a randomized two-arm design within 0.05-0.10 above or below the one-arm design. An increase in total sample size from 30 patients to 80 patients tends to increase the probability of correctly identifying an effective experiment agent more in the two-arm design than the the one-arm design, particularly when the uncertainty in the historical response rate is large. LIMITATIONS: These results for binary response measures are derived from the specific scenarios and assumptions considered in the simulation study and may not apply to situations outside the range considered. CONCLUSIONS: We find that a one-arm design is preferred for small sample sizes, but a two-arm design may be preferred with larger sample sizes or if the uncertainty in the historical response rates is large.

Antineoplastic Agents↗

PubMed2005

Utility of cranial boost in addition to total body irradiation in the treatment of high risk acute lymphoblastic leukemia.

PURPOSE: Total body irradiation (TBI) as part of a conditioning regimen before hematopoietic stem cell transplant (HSCT) is an important component in the management of acute lymphoblastic leukemia (ALL) that has relapsed or has other certain high-risk features. Controversy exists, however, as to whether a cranial boost in addition to TBI is necessary to prevent central nervous system (CNS) recurrences in these high-risk cases. Previous national trials have included a cranial boost in the absence of data to justify its use. Therefore, the aim of this study was to assess risk of CNS recurrence in ALL patients treated with TBI, to identify subsets of these high-risk patients at an increased or decreased risk of CNS recurrence after TBI, and to investigate whether regimens with higher doses of cranial irradiation further reduce the risk of CNS recurrence. METHODS AND MATERIALS: Charts of 67 consecutively treated patients with ALL who received TBI before HSCT were reviewed. Data including patient demographics, clinical features at presentation, conditioning regimen, donor source, use of a cranial boost, remission stage at transplant, histologic subtype, cytogenetics, and extramedullary site of presentation were retrospectively collected and correlated with the risk of subsequent CNS recurrence. RESULTS: At the time of analysis, 30 (45%) patients were alive with no evidence of disease, 8 (12%) were alive with recurrence of leukemia, 7 (10.5%) had recurrent ALL but with successful salvage, 7 (11%) died subsequent to recurrence, 14 (21%) died from complications related to HCST, and 1 patient was lost to follow-up (1.5%). Of the patients who recurred after HSCT, the relapses were hematologic in 13 (57%), CNS with or without simultaneous marrow involvement in 3 (13%), and other sites in 7 (30%). Forty-one (61%) patients did not receive an extracranial boost of irradiation with TBI. Two of these patients (4.9%) suffered CNS failures compared with 1 of 26 (3.8%) who received a cranial boost (p = 0.84). None of the 40 patients who presented only with hematologic disease developed a CNS recurrence despite the fact that only 13 of 40 of these patients received a cranial boost after TBI. Cranial boost was therefore not associated with a reduction in CNS recurrence, especially in patients with only hematologic disease at presentation for which there were no failures regardless of the use of additional cranial radiotherapy. CONCLUSIONS: Patients who present with hematologic disease only at the time of HSCT have a low risk of CNS recurrence after TBI regardless of the use of a cranial boost, suggesting that a cranial boost may not be necessary in these patients.

Adolescent↗

PubMed2005

Determining a maximum-tolerated schedule of a cytotoxic agent.

Most phase I clinical trials are designed to determine a maximum-tolerated dose (MTD) for one initial administration or treatment course of a cytotoxic experimental agent. Toxicity usually is defined as the indicator of whether one or more particular adverse events occur within a short time period from the start of therapy. However, physicians often administer an agent to the patient repeatedly and monitor long-term toxicity due to cumulative effects. We propose a new method for such settings. It is based on the time to toxicity rather than a binary outcome, and the goal is to determine a maximum-tolerated schedule (MTS) rather than a conventional MTD. The model and method account for a patient's entire sequence of administrations, with the overall hazard of toxicity modeled as the sum of a sequence of hazards, each associated with one administration. Data monitoring and decision making are done continuously throughout the trial. We illustrate the method with an allogeneic bone marrow transplantation (BMT) trial to determine how long a recombinant human growth factor can be administered as prophylaxis for acute graft-versus-host disease (aGVHD), and we present a simulation study in the context of this trial.

Algorithms↗

PubMed2004

Small sample estimation of relative accuracy for binary screening tests.

Comparing the accuracy of two screening tests is ideally achieved by administering both tests as well as a gold standard test to all study subjects. In practice, a more ethical screen positive study design is often used, one that requires gold standard determination only for subjects that screen positive on either test under investigation. Although it is not possible to quantify the absolute accuracy of each test with such a design,the relative accuracy of the tests can be estimated. Since relative accuracy estimation has poor small sample properties, adjusted estimators based on adding constants to the observed data have been proposed. The adjusted estimators have the advantage that they yield point and variance estimates of relative accuracy in all settings. However, we show through both theory and numerical examples that adding constants to the data can be beneficial or detrimental to small sample performance. Furthermore, the performance of the adjusted estimator depends not only on the magnitude of the constant but also on parameters that cannot be estimated with data from a screen positive study, making selection of an optimal constant difficult in practice. We also examine the performance of the adjusted estimator using data from a study comparing the accuracy of two screening tests for cervical cancer.

Adult↗

PubMed2003

Phase II trial of autologous tumor vaccination, anti-CD3-activated vaccine-primed lymphocytes, and interleukin-2 in stage IV renal cell cancer.

PURPOSE: Previous preclinical and clinical studies have demonstrated that autologous tumor vaccines can induce relatively specific tumor-reactive T cells in draining lymph nodes. The adoptive transfer of these cells can result in tumor regression. PATIENTS AND METHODS: Patients with stage IV renal cell cancer (RCC) were vaccinated with irradiated autologous tumor cells admixed with Calmette-Guérin bacillus. Approximately 7 days later, vaccine-primed lymph nodes (VPLNs) were harvested and the lymphoid cells secondarily activated with anti-CD3 monoclonal antibody and expanded in interleukin 2 (IL-2). The activated cells were subsequently infused intravenously along with the concomitant administration of bolus IL-2 (360,000 U/kg intravenously x 15 doses). RESULTS: Thirty-nine patients were entered onto the study, of whom 34 completed an initial course of cell therapy consisting of a mean (SEM) number of 4.3 (2.2) x 10(10) VPLN cells. Among subjects who received cell therapy, there were nine responses (four complete responses [CRs] and five partial responses [PRs]), for an overall response rate of 27%. The durations of the CRs were > 48, 45, > 35, and 12 months, and the durations of the PRs were > 63, 48, 15, 12, and 4 months. Cultured tumor cells were available to assess in vitro cytokine release of VPLN cells in 24 subjects. The median cytokine release ratio of interferon gamma (IFNgamma) to IL-10 for responders and nonresponders was 992 and 5, respectively, which was significantly different (P =.047). CONCLUSION: The treatment protocol resulted in durable tumor responses in patients with advanced RCC. The ratio of IFNgamma and IL-10 cytokines released in response to tumor by the VPLN cells was a significant correlate with tumor response.

Adoptive Transfer↗

PubMed2003

Determining a maximum tolerated cumulative dose: dose reassignment within the TITE-CRM.

We present a phase I design that is a modification to the time-to-event continual reassessment method (TITE-CRM) by Cheung and Chappell that is useful when each dose actually denotes how long a drug is administered. Because of the lengthy duration required for subjects receiving the higher doses, we enroll each subject on the best estimate of the maximum tolerated cumulative dose (MTCD) as soon as each subject is eligible. Once each previously enrolled subject is fully evaluated, we update our estimate of the MTCD and modify currently enrolled subjects to receive the MTCD if they are currently receiving a nonoptimal dose. Thus, our method is adaptive both between subjects and within subjects. We show through simulation that our study design has excellent operating characteristics that are as good as the TITE-CRM while not exposing greater numbers of subjects to doses beyond the MTCD. Our simulations are based upon a study in bone marrow transplant patients that seeks to determine how many weeks of recombinant human keratinocyte growth factor can be administered while keeping toxicity rates below a desired threshold.

Bayes Theorem↗

PubMed2003

Impact of ECMO on neonatal mortality in Michigan (1980-1999).

PURPOSE: Although extracorporeal membrane oxygenation (ECMO) is a potentially lifesaving intervention, the effect of ECMO on neonatal mortality has never been evaluated. In this study, we examined the relationship between increased ECMO utilization and its effect on the neonatal mortality rate in the state of Michigan. METHODS: Neonatal mortality data were obtained from the Michigan State Department of Community Health. Data included total annual live births, total neonatal deaths, and deaths from respiratory causes in neonates > or =35 weeks' gestational age (ie, potential ECMO candidates). Pooled ECMO patient data from Michigan's 3 ECMO centers were obtained from the Extracorporeal Life Support Organization (ELSO) Registry. Associations between ECMO volume and neonatal mortality rates were assessed using simple linear regression. A scatterplot of ECMO volume and mortality rates was created, and the resulting fitted regression lines were superimposed on the plots. Statistical significance of the associations (ie, difference in slope of the regression line from zero) were based on a standard 2-sided Wald test for the regression slope parameter. RESULTS: From 1980 through 1999, 1,061 neonates were treated with ECMO in Michigan, and 875 (82.5%) survived. When annual neonatal mortality rate (from all causes) and the rate from respiratory causes versus ECMO volume (cases per year) are superimposed with fitted regression lines, both are significantly different from zero (P =.041 and P =.002, respectively). The model predicts that for every 100 neonates treated with ECMO in Michigan, 38 lives are saved. The model also can be used to predict the annual neonatal mortality rate in Michigan if ECMO had not been utilized. CONCLUSIONS: A strong association exists between ECMO volume and observed reductions in neonatal mortality seen in Michigan over the last 2 decades. This is the first study to show an association between ECMO and neonatal mortality rate at the population level.

Extracorporeal Membrane Oxygenation↗

PubMed2002

The bivariate continual reassessment method. extending the CRM to phase I trials of two competing outcomes.

Traditional phase I studies find the therapeutic dose of an investigational drug based solely on toxicity and without regard to the drug's efficacy. We propose extending the continual reassessment method (CRM) to a bivariate trial design in which the maximum tolerated dose is based jointly on both toxicity and disease progression. We call our study design bCRM, for bivariate CRM, which we apply to a study of bone marrow patients seeking to find the optimal time after bone marrow transplant at which to taper immune suppression and eventually begin donor leukocyte infusions. We demonstrate through simulation that bCRM has excellent operating characteristics and compare the performance of bCRM in a bone marrow transplantation study to designs proposed by previous investigators. We also attempt to provide some direction to future investigators with regard to plausible models and distributions to use with a bivariate study design.

Bayes Theorem↗

PubMed2002

Enhanced allostimulatory activity of host antigen-presenting cells in old mice intensifies acute graft-versus-host disease.

Older bone marrow transplantation (BMT) recipients are at heightened risk for acute graft-versus-host disease (GVHD) after allogeneic BMT, but the causes of this association are poorly understood. Using well-characterized murine BMT models we have explored the mechanisms of increased GVHD in older mice. GVHD mortality, morbidity, and pathologic and biochemical indices were all worse in old recipients. Donor T cell responses were significantly increased in old recipients both in vivo and in vitro when stimulated by antigen-presenting cells (APCs) from old mice, which also secreted more TNF-alpha and IL-12 after LPS stimulation. In a B6 --> B6D2F1 model, CD4(+) donor T cells but not CD8(+) T cells mediated more severe GVHD in old mice. We confirmed the role of aged APCs in GVHD using B6D2F1 BM chimeras created with either old or young BM. Four months after chimera creation, allogeneic BMT from B6 donors caused significantly worse GVHD in old BM chimeras. APCs from these mice also stimulated greater responses from allogeneic cells in vitro. These data demonstrate a hitherto unsuspected mechanism of amplified donor T cell responses by aged allogeneic host APCs that increases acute GVHD in aged recipients in this BMT model.

Aging↗

PubMed2002

A phase I trial of tumor lysate-pulsed dendritic cells in the treatment of advanced cancer.

PURPOSE: The objectives of this study were to assess the toxicity and immunological response induced by the intradermal (i.d) administration of tumor lysate-pulsed dendritic cells (DCs). EXPERIMENTAL DESIGN: Patients with stage IV solid malignancies were treated in cohorts that received 10(6), 10(7), and 10(8) DCs i.d. every 2 weeks for three vaccines. Each vaccine was composed of a mixture of half DCs pulsed with autologous tumor lysate and the other half with keyhole limpet hemocyanin (KLH). Peripheral blood mononuclear cells (PBMCs) harvested 1 month after the last immunization was compared with pretreatment PBMCs for immunological response. Delayed-type hypersensitivity reactivity to tumor antigen and KLH was also assessed. RESULTS: Fourteen patients received all three vaccines and were evaluable for toxicity and/or immunological monitoring. There were no grade 3 or 4 toxicities associated with the vaccines or major evidence of autoimmunity. Local accumulation of CD4(+) and CD8(+) T cells were found at the vaccination sites. There was a significant proliferative response of PBMCs to KLH induced by the vaccine. In 5 of 6 patients, the vaccine resulted in increased IFN-gamma production by PBMCs to KLH in an ELISPOT assay. Using the same assay, 3 of 7 patients' PBMCs displayed increased IFN-gamma production in response to autologous tumor lysate. One patient with melanoma also was observed to have an increased frequency of MART-1- and gp100-reactive CD8(+) T cells after vaccination. By delayed-type hypersensitivity testing, 8 of 9 and 4 of 10 patients demonstrated reactivity to KLH and autologous tumor, respectively. Two patients with melanoma experienced a partial and a minor response, respectively. CONCLUSION: The administration of tumor lysate-pulsed DCs is nontoxic and capable of inducing immunological response to tumor antigen. Additional studies are necessary to improve tumor rejection responses.

Adult↗