Erika Graf

BCNU for recurrent glioblastoma multiforme: efficacy, toxicity and prognostic factors

BackgroundThe prognosis for patients with recurrent glioblastoma is still poor with a median survival between 3 and 6 months. Reports about the application of carmustine (BCNU), one of the standard chemotherapeutic drugs in the treatment of newly diagnosed glioblastoma, in the recurrent situation are rare.MethodsWe performed a retrospective analysis of 35 patients with recurrent or progressive glioblastoma treated with 80 mg/m2 BCNU on days 1 on 3 intravenously at our department for efficacy, toxicity and prognostic factors. Progression free survival and overall survival were estimated by the Kaplan-Meier method. The influence of age, Karnofsky performance status (KPS), tumor burden, pretreatment with temozolomide (TMZ), type of surgery for initial diagnosis and number of previous relapses on outcome was analyzed in a proportional hazards regression model.ResultsThe median age of the group was 53 years, median KPS was 70. Median progression free survival was 11 weeks (95% confidence interval [CI]: 8-15), median overall survival 22 weeks (95% CI: 18-27). The rate of adverse events, especially hematological toxicity, is relatively high, and in 3 patients treatment had to be terminated due to adverse events (one pulmonary embolism, one pulmonary fibrosis, and one severe bone marrow suppression). No influence of age, KPS, tumor burden, pre-treatment with TMZ and number of previous relapses on outcome could be demonstrated, while gross total resection prior to recurrence showed a borderline statistically significant negative impact on PFS and OS. These data compare well with historical survival figures. However prospective randomized studies are needed to evaluate BCNU efficacy against newer drugs like bevacizumab or the intensified temozolomide regime (one week on/one week off).ConclusionIn summary, BCNU treatment appears to be a valuable therapeutic option for recurrent glioblastomas, where no other validated radio- and/or chemotherapy are available.

Design of a placebo-controlled, randomized study of the efficacy of repetitive transcranial magnetic stimulation for the treatment of chronic tinnitus

BackgroundChronic tinnitus is a frequent condition, which can have enormous impact on patients life and which is very difficult to treat. Accumulating data indicate that chronic tinnitus is related to dysfunctional neuronal activity in the central nervous system. Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive method which allows to focally modulate neuronal activity. An increasing amount of studies demonstrate reduction of tinnitus after repeated sessions of low-frequency rTMS and indicate that rTMS might represent a new promising approach for the treatment of tinnitus. However available studies have been mono-centric and are characterized by small sample sizes. Therefore, this multi-center trial will test the efficacy of rTMS treatment in a large sample of chronic tinnitus patients.Methods/DesignThis is a randomized, placebo-controlled, double-blind multi-center trial of two weeks 1 Hz rTMS-treatment in chronic tinnitus patients. Eligible patients will be randomized to either 2 weeks real or sham rTMS treatment. Main eligibility criteria: male or female individuals aged 18–70 years with chronic tinnitus (duration > 6 months), tinnitus-handicap-inventory-score ≥ 38, age-adjusted normal sensorineural hearing (i.e. not more than 5 dB below the 10% percentile of the appropriate age and gender group (DIN EN ISO 7029), conductive hearing loss ≤ 15dB. The primary endpoint is a change of tinnitus severity according to the tinnitus questionnaire of Goebel and Hiller (baseline vs. end of treatment period). A total of 138 patients are needed to detect a clinical relevant change of tinnitus severity (i.e. 5 points on the questionnaire of Goebel and Hiller; alpha = 0.05; 1-beta = 0.80). Assuming a drop-out rate of less than 5% until the primary endpoint, 150 patients have to be randomized to guarantee the target number of 138 evaluable patients. The study will be conducted by otorhinolaryngologists and psychiatrists of 7 university hospitals and 1 municipal hospital in Germany.DiscussionThis study will provide important information about the efficacy of rTMS in the treatment of chronic tinnitus.Trial registrationCurrent Controlled Trials ISRCTN89848288

German Validation of the Conners Adult ADHD Rating Scale–Self-Report: Confirmation of Factor Structure in a Large Sample of Participants with ADHD

Objective: The Conners Adult ADHD Rating Scales (CAARS) assess symptoms specific to adults that are frequently used and have been translated into German. The current study tests the factor structure of the CAARS in a large sample of German adults with ADHD and compares the means of the CAARS subscales with those of healthy German controls. Method: CAARS were completed by 466 participants with ADHD and 851 healthy control participants. Confirmatory factor analysis was used to establish model fit with the American original. Comparisons between participants with ADHD and healthy controls and influences of gender, age, and degree of education were analyzed. Results: Confirmatory factor analysis showed a very good fit with the model for the American original. Differences between ADHD participants and healthy controls on all Conners Adult ADHD Rating Scales–Self-Report (CAARS-S) subscales were substantial and significant. Conclusion: The factor structure of the original American model was successfully replicated in this sample of adult German ADHD participants.

Estimators and confidence intervals for the marginal odds ratio using logistic regression and propensity score stratification.

Propensity score methods are widely used to estimate treatment or exposure effects in observational studies. In studies with binary response the effect can be described as an odds ratio, and the Mantel-Haenszel estimator is traditionally used for stratified data. Although propensity score methods are designed for marginal treatment effects, it has been shown that the Mantel-Haenszel estimator stratified for propensity score is a questionable estimator for the marginal odds ratio, which describes the change in odds of response if everybody versus nobody were treated.We studied recently proposed alternative estimators for the marginal odds ratio, one stratified for propensity score, the other derived from logistic regression. Additionally, we adapted the methodology of the logistic regression based estimator for the derivation of a marginal odds ratio estimator to covariate adjustment by the propensity score. We also derived corresponding variance estimators using the Delta-method.The estimators were illustrated and compared to the inverse probability weighted estimator and the stratified Mantel-Haenszel estimator in a study dealing with respiratory tract infections in children in Germany. Furthermore, simulation studies that were carried out to investigate relative bias, variance and coverage probability showed reasonable performance of marginal odds ratio estimators if response rates or regression based approaches were used. Their variances were accurately estimated. In contrast, the stratified Mantel-Haenszel estimator was substantially biased in some situations due to problems of non-collapsibility and thus it is generally inappropriate for a reliable estimation of the marginal odds ratio.

Vector Selection of a Quadripolar Left Ventricular Pacing Lead Affects Acute Hemodynamic Response to Cardiac Resynchronization Therapy: A Randomized Cross-Over Trial

Background A suboptimal left ventricular (LV) pacing site may account for non-responsiveness of patients to cardiac resynchronization therapy (CRT). The vector selection of a novel quadripolar LV pacing lead, which was mainly developed to overcome technical issues with stimulation thresholds and phrenic nerve capture, may affect hemodynamic response, and was therefore assessed in this study. (German Clinical Trials Register DRKS00000573). Methods and Results Hemodynamic effects of a total of 145 LVPCs (9.1 per patient) of CRT devices with a quadripolar LV lead (Quartet™, St. Jude Medical) were assessed in 16/20 consecutive patients by invasive measurement of LV+dP/dtmax at an invasively optimized AV-interval in random order. Optimal (worst) LVPCs per patient were identified as those with maximal (minimal) %change in LV+dP/dtmax (%ΔLV+dP/dtmax) as compared to a preceding baseline. LV+dP/dtmax significantly increased in all 145 LVPCs (p<0.0001 compared to baseline) with significant intraindividual differences between LVPCs (p<0.0001). Overall, CRT acutely augmented %ΔLV+dP/dtmax by 31.3% (95% CI 24%–39%) in the optimal, by 21.3% (95% CI: 15%–27%) in the worst and by 28.2% (95% CI: 21%–36%) in a default distal LVPC. This resulted in an absolute additional acute increase in %ΔLV+dP/dtmax of 10.0% (95% CI: 7%–13%) of the optimal when compared to the worst (p<0.0001), and of 3.1% (95% CI: 1%–5%) of the optimal when compared to the default distal LVPC (p<0.001). Optimal LVPCs were not programmable with a standard bipolar lead in 44% (7/16) of patients. Conclusion The pacing configuration of a quadripolar LV lead determinates acute hemodynamic response. Pacing in the individually optimized configuration gives rise to an additional absolute 10% increase in %ΔLV+dP/dtmax when comparing optimal and worst vectors.

Measures of prediction error for survival data with longitudinal covariates

Prediction of future events using longitudinally collected patient measurements is increasingly popular as technical and methodological advances allow the construction of more and more complex prognostic models. We aim to give an overview of existing approaches to measure the prediction error of such dynamic predictions and link these to a measure proposed in a preceding paper (Schoop et al.), the conditional prediction error. We present theoretical results of the conditional prediction error, especially regarding the comparison of different prediction rules and its behavior in the presence of misspecification of the link between longitudinal covariates and survival time. A simulation study investigating the performance of its estimator in finite sample sizes rounds off this paper.

Correction of confounding bias in non-randomized studies by appropriate weighting.

In non-randomized studies, the assessment of a causal effect of treatment or exposure on outcome is hampered by possible confounding. Applying multiple regression models including the effects of treatment and covariates on outcome is the well-known classical approach to adjust for confounding. In recent years other approaches have been promoted. One of them is based on the propensity score and considers the effect of possible confounders on treatment as a relevant criterion for adjustment. Another proposal is based on using an instrumental variable. Here inference relies on a factor, the instrument, which affects treatment but is thought to be otherwise unrelated to outcome, so that it mimics randomization. Each of these approaches can basically be interpreted as a simple reweighting scheme, designed to address confounding. The procedures will be compared with respect to their fundamental properties, namely, which bias they aim to eliminate, which effect they aim to estimate, and which parameter is modelled. We will expand our overview of methods for analysis of non-randomized studies to methods for analysis of randomized controlled trials and show that analyses of both study types may target different effects and different parameters. The considerations will be illustrated using a breast cancer study with a so-called Comprehensive Cohort Study design, including a randomized controlled trial and a non-randomized study in the same patient population as sub-cohorts. This design offers ideal opportunities to discuss and illustrate the properties of the different approaches.

Normal Neurochemistry in the Prefrontal and Cerebellar Brain of Adults with Attention-Deficit Hyperactivity Disorder.

Attention-deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. In an attempt to extend earlier neurochemical findings, we organized a magnetic resonance spectroscopy (MRS) study as part of a large, government-funded, prospective, randomized, multicenter clinical trial comparing the effectiveness of specific psychotherapy with counseling and stimulant treatment with placebo treatment (Comparison of Methylphenidate and Psychotherapy Study). We report the baseline neurochemical data for the anterior cingulate cortex (ACC) and the cerebellum in a case–control setting. For the trial, 1,480 adult patients were contacted for participation, 518 were assessed for eligibility, 433 were randomized, and 187 were potentially eligible for neuroimaging. The control group included 119 healthy volunteers. Single-voxel proton MRS was performed. In the patient group, 113 ACC and 104 cerebellar spectra fulfilled all quality criteria for inclusion in statistical calculations, as did 82 ACC and 78 cerebellar spectra in the control group. We did not find any significant neurometabolic differences between the ADHD and control group in the ACC (Wilks’ lambda test: p = 0.97) or in the cerebellum (p = 0.62). Thus, we were unable to replicate earlier findings in this methodologically sophisticated study. We discuss our findings in the context of a comprehensive review of other MRS studies on ADHD and a somewhat skeptical neuropsychiatric research perspective. As in other neuropsychiatric disorders, the unclear nosological status of ADHD might be an explanation for false-negative findings.

Comments on ‘The performance of different propensity score methods for estimating marginal odds ratios’ by Peter C. Austin, Statistics in Medicine 2007; 26(16):3078–3094

In a recent Monte Carlo study, Austin investigated the performance of several odds ratio estimators derived by propensity score (PS) methods. He demonstrated that the popular PS-based approaches can yield substantially biased results. It has been known for some time that PS estimation can be biased when employed to estimate a conditional odds ratio. However, claims that popular approaches using PS stratification estimate the marginal odds ratio have now also been proven wrong by Austin. This note proposes two natural alternative estimators for the marginal odds ratio not included in his simulation study, one stratified for the PS and the other derived from traditional logistic regression.