Subgroup analyses in randomised controlled trials: cohort study on trial protocols and journal publications

OBJECTIVE: To investigate the planning of subgroup analyses in protocols of randomised controlled trials and the agreement with corresponding full journal publications. DESIGN: Cohort of protocols of randomised controlled trial and subsequent full journal publications. SETTING: Six research ethics committees in Switzerland, Germany, and Canada. DATA SOURCES: 894 protocols of randomised controlled trial involving patients approved by participating research ethics committees between 2000 and 2003 and 515 subsequent full journal publications. RESULTS: Of 894 protocols of randomised controlled trials, 252 (28.2%) included one or more planned subgroup analyses. Of those, 17 (6.7%) provided a clear hypothesis for at least one subgroup analysis, 10 (4.0%) anticipated the direction of a subgroup effect, and 87 (34.5%) planned a statistical test for interaction. Industry sponsored trials more often planned subgroup analyses compared with investigator sponsored trials (195/551 (35.4%) v 57/343 (16.6%), P<0.001). Of 515 identified journal publications, 246 (47.8%) reported at least one subgroup analysis. In 81 (32.9%) of the 246 publications reporting subgroup analyses, authors stated that subgroup analyses were prespecified, but this was not supported by 28 (34.6%) corresponding protocols. In 86 publications, authors claimed a subgroup effect, but only 36 (41.9%) corresponding protocols reported a planned subgroup analysis. CONCLUSIONS: Subgroup analyses are insufficiently described in the protocols of randomised controlled trials submitted to research ethics committees, and investigators rarely specify the anticipated direction of subgroup effects. More than one third of statements in publications of randomised controlled trials about subgroup prespecification had no documentation in the corresponding protocols. Definitive judgments regarding credibility of claimed subgroup effects are not possible without access to protocols and analysis plans of randomised controlled trials.

Severe traumatic brain injury in a high-income country: an epidemiological study.

This adult cohort determined the incidence and patients' short-term outcomes of severe traumatic brain injury (sTBI) in Switzerland and age-related differences. A prospective cohort study with a follow-up at 14 days was performed. Patients ≥16 years of age sustaining sTBI and admitted to 1 of 11 trauma centers were included. sTBI was defined by an Abbreviated Injury Scale of the head (HAIS) score >3. The centers participated from 6 months to 3 years. The results are presented as percentages, medians, and interquartile ranges (IQRs). Subgroup analyses were performed for patients ≤65 years (younger) and >65 (elderly). sTBI was observed in 921 patients (median age, 55 years; IQR, 33-71); 683 (74.2%) were male. Females were older (median age, 67 years; IQR, 42-80) than males (52; IQR, 31-67; p<0.00001). The estimated incidence was 10.58 per 100,000 inhabitants per year. Blunt trauma was observed in 879 patients (95.4%) and multiple trauma in 283 (30.7%). Median Glasgow Coma Score (GCS) on the scene was 9 (IQR 4-14; 8 in younger, 12 in elderly) and in emergency departments 5 (IQR, 3-14; 3 in younger, 8 in elderly). Trauma mechanisms included the following: 484 patients with falls (52.6%; younger, 242 patients [50.0%]; elderly, 242 [50.0%]), 291 with road traffic accidents (31.6%; younger, 237 patients [81.4%]; elderly, 54 [18.6%]), and 146 with others (15.8%). Mortality was 30.2% (24.5% in younger, 40.9% in elderly). Median GCS at 14 days was 15 (IQR, 14-15) without differences among subgroups. Estimated incidence of sTBI in Switzerland was low, age was high, and mortality considerable. The elderly had higher initial GCS and a higher death rate, but high GCS at 14 days.

A threefold dose intensity treatment with ifosfamide, carboplatin, and etoposide for patients with small cell lung cancer: a randomized trial.

BACKGROUND: The dose intensity of chemotherapy can be increased to the highest possible level by early administration of multiple and sequential high-dose cycles supported by transfusion with peripheral blood progenitor cells (PBPCs). A randomized trial was performed to test the impact of such dose intensification on the long-term survival of patients with small cell lung cancer (SCLC). METHODS: Patients who had limited or extensive SCLC with no more than two metastatic sites were randomly assigned to high-dose (High, n = 69) or standard-dose (Std, n = 71) chemotherapy with ifosfamide, carboplatin, and etoposide (ICE). High-ICE cycles were supported by transfusion with PBPCs that were collected after two cycles of treatment with epidoxorubicin at 150 mg/m(2), paclitaxel at 175 mg/m(2), and filgrastim. The primary outcome was 3-year survival. Comparisons between response rates and toxic effects within subgroups (limited or extensive disease, liver metastases or no liver metastases, Eastern Cooperative Oncology Group performance status of 0 or 1, normal or abnormal lactate dehydrogenase levels) were also performed. RESULTS: Median relative dose intensity in the High-ICE arm was 293% (range = 174%-392%) of that in the Std-ICE arm. The 3-year survival rates were 18% (95% confidence interval [CI] = 10% to 29%) and 19% (95% CI = 11% to 30%) in the High-ICE and Std-ICE arms, respectively. No differences were observed between the High-ICE and Std-ICE arms in overall response (n = 54 [78%, 95% CI = 67% to 87%] and n = 48 [68%, 95% CI = 55% to 78%], respectively) or complete response (n = 27 [39%, 95% CI = 28% to 52%] and n = 24 [34%, 95% CI = 23% to 46%], respectively). Subgroup analyses showed no benefit for any outcome from High-ICE treatment. Hematologic toxicity was substantial in the Std-ICE arm (grade > or = 3 neutropenia, n = 49 [70%]; anemia, n = 17 [25%]; thrombopenia, n = 17 [25%]), and three patients (4%) died from toxicity. High-ICE treatment was predictably associated with severe myelosuppression, and five patients (8%) died from toxicity. CONCLUSIONS: The long-term outcome of SCLC was not improved by raising the dose intensity of ICE chemotherapy by threefold.

Extent of resection in glioblastoma - variation between molecular risk groups in rtog-0525

Whether maximal surgical resection of glioblastoma improves patient survival has been controversial, as it is difficult to perform an unbiased assessment of extent of resection (EOR) independent of other patient-specific prognostic factors. Recently, glioblastoma has been sub-classified into 4 distinct molecular risk groups (RGs), which have been validated as prognostic biomarkers in the randomized clinical trial of temozolomide dosing in glioblastoma: the Radiation Therapy Oncology Group 0525 (RTOG-0525) trial. We sought to perform exploratory analyses examining gross total resection (GTR) versus sub-total resection (STR) within these RGs in RTOG-0525 patients. Across all randomized patients, n ¼ 354 had STR and n ¼ 450 had GTR as determined by neurosurgeon operative report. GTR was not significantly associated with survival across the overall study group. A total of 725 patients had sufficient tissue for determination of molecular RG. There were no significant differences in percentage of GTR between each of the 4 RGs (P ¼ 0.64). In exploratory subgroup analyses, GTR was associated with improved survival only for patients with tumors from RG4. Hazard ratios (95% confidence intervals) were 0.52 (0.08-2.07) for RG1 (n ¼ 28, 68% GTR), 1.74 (0.75-4.05) for RG2 (n ¼ 39, 56% GTR), 1.09 (0.84-1.42) for RG3 (n ¼ 284, 56% GTR), and 1.26 (1.01-1.56) for RG4 (n ¼ 374, 55% GTR). In univariate analysis within RG4, GTR was associated with a median survival of 14.6 months vs 12.7 months for STR (P ¼ 0.0352. In a Cox model adjusting for age, KPS, and neurologic function (NF), surgery remained an independent factor within RG4: GTR (P ¼ 0.0331), age (P ¼ 0.0014), KPS (P ¼ .3289), and NF (P ¼ 0.3804). There are important cautions in the interpretation of these data, including lack of MRI confirmation of EOR, and inclusion of a range of STR (from biopsy to near-total resection). However, these exploratory results raise the possibility that upfront characterization of tumor molecular profile may allow for personalized therapeutic strategies to improve outcomes for patients with glioblastoma.

Predictors of asthma control in everyday clinical practice in Switzerland.

OBJECTIVE: To identify predictors of improved asthma control under conditions of everyday practice in Switzerland. RESEARCH DESIGN AND METHODS: A subgroup of 1380 patients with initially inadequately controlled asthma was defined from a cohort of 1893 asthmatic patients (mean age 45.3 + or - 19.2 years) recruited by 281 office-based physicians who participated in a previously-conducted asthma control survey in Switzerland. Multiple regression techniques were used to identify predictors of improved asthma control, defined as an absolute decrease of 0.5 points or more in the Asthma Control Questionnaire between the baseline (V1) and follow-up visit (V2). RESULTS: Asthma control between V1 and V2 improved in 85.7%. Add-on treatment with montelukast was reported in 82.9% of the patients. Patients with worse asthma control at V1 and patients with good self-reported adherence to therapy had significantly higher chances of improved asthma control (OR = 1.24 and 1.73, 95% CI 1.18-1.29 and 1.20-2.50, respectively). Compared to adding montelukast and continuing the same inhaled corticosteroid/fixed combination (ICS/FC) dose, the addition of montelukast to an increased ICS/FC dose yielded a 4 times higher chance of improved asthma control (OR = 3.84, 95% CI 1.58-9.29). Significantly, withholding montelukast halved the probability of achieving improved asthma control (OR = 0.51, 95% CI = 0.33-078). The probability of improved asthma control was almost 5 times lower among patients in whom FEV(1) was measured compared to those in whom it was not (OR = 0.23, 95% CI = 0.09-0.55). Patients with severe persistent asthma also had a significantly lower probability of improved control (OR = 0.15, 95% CI = 0.07-0.32), as did older patients (OR = 0.98, 95% CI = 0.97-0.99). Subgroup analyses which excluded patients whose asthma may have been misdiagnosed and might in reality have been chronic obstructive pulmonary disease (COPD) showed comparable results. CONCLUSIONS: Under conditions of everyday clinical practice, the addition of montelukast to ICS/FC and good adherence to therapy increased the likelihood of achieving better asthma control at the follow-up visit, while older age and more severe asthma significantly decreased it.

A vaccine against nicotine for smoking cessation: a randomized controlled trial.

BACKGROUND: Tobacco dependence is the leading cause of preventable death and disabilities worldwide and nicotine is the main substance responsible for the addiction to tobacco. A vaccine against nicotine was tested in a 6-month randomized, double blind phase II smoking cessation study in 341 smokers with a subsequent 6-month follow-up period. METHODOLOGY/PRINCIPAL FINDINGS: 229 subjects were randomized to receive five intramuscular injections of the nicotine vaccine and 112 to receive placebo at monthly intervals. All subjects received individual behavioral smoking cessation counseling. The vaccine was safe, generally well tolerated and highly immunogenic, inducing a 100% antibody responder rate after the first injection. Point prevalence of abstinence at month 2 showed a statistically significant difference between subjects treated with Nicotine-Qbeta (47.2%) and placebo (35.1%) (P = 0.036), but continuous abstinence between months 2 and 6 was not significantly different. However, in subgroup analysis of the per-protocol population, the third of subjects with highest antibody levels showed higher continuous abstinence from month 2 until month 6 (56.6%) than placebo treated participants (31.3%) (OR 2.9; P = 0.004) while medium and low antibody levels did not increase abstinence rates. After 12 month, the difference in continuous abstinence rate between subjects on placebo and those with high antibody response was maintained (difference 20.2%, P = 0.012). CONCLUSIONS: Whereas Nicotine-Qbeta did not significantly increase continuous abstinence rates in the intention-to-treat population, subgroup analyses of the per-protocol population suggest that such a vaccination against nicotine can significantly increase continuous abstinence rates in smokers when sufficiently high antibody levels are achieved. Immunotherapy might open a new avenue to the treatment of nicotine addiction. TRIAL REGISTRATION: Swiss Medical Registry 2003DR2327; ClinicalTrials.gov NCT00369616.

Mortality of patients with COPD participating in chronic disease management programmes: a happy end?

BACKGROUND: Concerns about increased mortality could question the role of COPD chronic disease management (CDM) programmes. We aimed at extending a recent Cochrane review to assess the effects of CDM on mortality in patients with COPD. METHODS: Mortality data were available for 25 out of 29 trials identified in a COPD integrated care systematic review. Meta-analysis using random-effects models was performed, followed by subgroup analyses according to study length (3-12 months vs >12 months), main intervention component (exercise, self-management, structured follow-up) and use of an action plan. RESULTS: The meta-analysis showed no impact of CDM on mortality (pooled OR: 1.00, 95% CI 0.79 to 1.28). CONCLUSIONS: These results do not suggest that CDM programmes expose patients with COPD to excessive mortality risk.

Concurrent use of cisplatin or cetuximab with definitive radiotherapy for locally advanced head and neck squamous cell carcinomas. Strahlentherapie in Kombination mit platinbasierter Chemotherapie oder Cetuximab zur Behandlung von lokal fortgeschrittenen Plattenepithelkarzinomen im Kopf-Hals-Bereich.

AIM: The goal of the present work was to compare outcomes of definitive concurrent cisplatin-based chemoradiotherapy (CRT) with cetuximab-based bioradiotherapy (BRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Between 2006 and 2012, 265 patients with locally advanced HNSCC were treated at our institution with CRT (n = 194; 73 %) with three cycles of cisplatin (100 mg/m(2), every 3 weeks) or BRT (n = 71; 27 %) with weekly cetuximab. Patients receiving BRT had more pre-existing conditions (Charlson index ≥ 2) than the CRT group (p = 0.005). RESULTS: Median follow-up was 29 months. In all, 56 % of patients treated with CRT received the planned three cycles (92 % at least two cycles) and 79 % patients treated with BRT received six cycles or more. The 2-year actuarial overall survival (OS) and progression-free survival (PFS) were 72 % and 61 %, respectively. In the multivariate analysis (MVA), T4 stage, N2-3 stage, smoking status (current smoker as compared with never smoker), and non-oropharyngeal locations predicted for OS, whereas BRT association with OS was of borderline significance (p = 0.054). The 2-year actuarial locoregional control (LRC) and distant control (DC) rates were 73 and 79 %, respectively. CRT was independently associated with an improved LRC (2-year LRC: 76 % for CRT vs. 61 % for BRT) and DC (2-year LRC: 81 % for CRT vs. 68 % for BRT) in comparison with BRT (p < 0.001 and p = 0.01 in the MVA). Subgroup analyses showed that T4 patients benefited significantly from CRT (vs. BRT) in LRC, while T1-3 did not. BRT patients had more G3-4 skin complications (p < 0.001) and CRT patients had higher rates of feeding tube placement (p = 0.006) and G3-4 gastrointestinal toxicities (p < 0.001). CONCLUSION: This retrospective analysis showed a better LRC in locally advanced HNSCC treated by cisplatin-based CRT than cetuximab-based BRT, and a nonsignificant trend towards an improved OS.

A multicentre, retrospective case-control study assessing the role of trabecular bone score (TBS) in menopausal Caucasian women with low areal bone mineral density (BMDa): Analysing the odds of vertebral fracture.

INTRODUCTION: The trabecular bone score (TBS) is a new parameter that is determined from grey level analysis of DXA images. It relies on the mean thickness and volume fraction of trabecular bone microarchitecture. This was a preliminary case-control study to evaluate the potential diagnostic value of TBS, both alone and combined with bone mineral density (BMDa), in the assessment of vertebral fracture. METHODS: Out of a subject pool of 441 Caucasian, postmenopausal women between the ages of 50 and 80 years, we identified 42 women with osteoporosis-related vertebral fractures, and compared them with 126 age-matched women without any fractures (1 case: 3 controls). Primary outcomes were BMDa and TBS. Inter-group comparisons were undertaken using Student's t-tests and Wilcoxon signed ranks tests for parametric and non-parametric data, respectively. Odds ratios for vertebral fracture were calculated for each incremental one standard deviation decrease in BMDa and TBS, and areas under the receiver operating curve (AUC) calculated and sensitivity analysis were conducted to compare BMDa alone, TBS alone, and the combination of BMDa and TBS. Subgroup analyses were performed specifically for women with osteopenia, and for women with T-score-defined osteoporosis. RESULTS: Across all subjects (n=42, 126) weight and body mass index were greater and BMDa and TBS both less in women with fractures. The odds of vertebral fracture were 3.20 (95% CI, 2.01-5.08) for each incremental decrease in TBS, 1.95 (1.34-2.84) for BMDa, and 3.62 (2.32-5.65) for BMDa + TBS combined. The AUC was greater for TBS than for BMDa (0.746 vs. 0.662, p=0.011). At iso-specificity (61.9%) or iso-sensitivity (61.9%) for both BMDa and TBS, TBS + BMDa sensitivity or specificity was 19.1% or 16.7% greater than for either BMDa or TBS alone. Among subjects with osteoporosis (n=11, 40) both BMDa (p=0.0008) and TBS (p=0.0001) were lower in subjects with fractures, and both OR and AUC (p=0.013) for BMDa + TBS were greater than for BMDa alone (OR=4.04 [2.35-6.92] vs. 2.43 [1.49-3.95]; AUC=0.835 [0.755-0.897] vs. 0.718 [0.627-0.797], p=0.013). Among subjects with osteopenia, TBS was lower in women with fractures (p=0.0296), but BMDa was not (p=0.75). Similarly, the OR for TBS was statistically greater than 1.00 (2.82, 1.27-6.26), but not for BMDa (1.12, 0.56-2.22), as was the AUC (p=0.035), but there was no statistical difference in specificity (p=0.357) or sensitivity (p=0.678). CONCLUSIONS: The trabecular bone score warrants further study as to whether it has any clinical application in osteoporosis detection and the evaluation of fracture risk.

Subclinical hypothyroidism and the risk of coronary heart disease: a meta-analysis.

PURPOSE: Subclinical hypothyroidism has been associated with elevated cholesterol and increased risk for atherosclerosis, but data on the risk of coronary heart disease (CHD) are conflicting. We performed a systematic review to determine whether subclinical hypothyroidism is associated with CHD in adults. METHODS: We searched MEDLINE from 1966 to April 2005, and the bibliographies of key articles to identify studies that provided risk estimates for CHD or cardiovascular mortality associated with subclinical hypothyroidism. Two authors independently reviewed each potential study for eligibility, assessed methodologic quality, and extracted the data. RESULTS: We identified 14 observational studies that met eligibility criteria. Subclinical hypothyroidism increased the risk of CHD (summary odds ratio [OR]: 1.65, 95% confidence interval [CI], 1.28-2.12). The summary OR for CHD was 1.81 (CI, 1.38-2.39) in 9 studies adjusted or matched for demographic characteristics, and 2.38 (CI, 1.53-3.69) after pooling the studies that adjusted for most cardiovascular risk factors. Sensitivity analyses including only population-based studies and those with formal outcome adjudication procedures yielded similar results. Subgroup analyses by type of study design showed a similar trend, but lower risk, in the 5 prospective cohort studies (OR 1.42, CI, 0.91-2.21), compared with the case-control and cross-sectional studies (OR 1.72, CI, 1.25-2.38). CONCLUSION: Our systematic review indicates that subclinical hypothyroidism is associated with an increased risk of CHD. Clinical trials are needed to assess whether thyroxine replacement reduces the risk of CHD in subjects with subclinical hypothyroidism.

Educational achievement in Swiss childhood cancer survivors compared with the general population.

BACKGROUND: The objective of this study was to describe educational achievements of childhood cancer survivors in Switzerland compared with the general population. In particular, the authors investigated educational problems during childhood, final educational achievement in adulthood, and its predictors. METHODS: Childhood cancer survivors who were aged <16 years at diagnosis from 1976 to 2003 who had survived for ≥5 years and were currently ages 20 to 40 years received a postal questionnaire during 2007 to 2009. Controls were respondents of the Swiss Health Survey ages 20 to 40 years. Educational achievement included compulsory schooling, vocational training, upper secondary schooling, and university degree. The analysis was weighted to optimize comparability of the populations. The authors analyzed the association between demographic and clinical predictors and educational achievement using multivariable logistic regression. Subgroup analyses focused on survivors aged ≥27 years. RESULTS: One-third of survivors encountered educational problems during schooling (30% repeated 1 year, and 35% received supportive tutoring). In the total sample, more survivors than controls achieved compulsory schooling only (8.7% vs 5.2%) and fewer acquired a university degree (7.3% vs 11%), but more survivors than controls achieved an upper secondary education (36.1 vs 24.1%). In those aged ≥27 years, differences in compulsory schooling and university education largely disappeared. In survivors and controls, sex, nationality, language region, and migration background were strong predictors of achievement. Survivors of central nervous system tumors or those who had a relapse had poorer outcomes (P < .05). CONCLUSIONS: Childhood cancer survivors encountered problems during schooling and completed professional education with some delay. However, with the exception of patients who had central nervous system tumors and those who experienced a relapse, the final educational achievement in survivors of child cancer was comparable to that of the general population.

HMG CoA reductase inhibitors (statins) for preventing acute kidney injury after surgical procedures requiring cardiac bypass.

BACKGROUND: Acute kidney injury (AKI) is common in patients undergoing cardiac surgery among whom it is associated with poor outcomes, prolonged hospital stays and increased mortality. Statin drugs can produce more than one effect independent of their lipid lowering effect, and may improve kidney injury through inhibition of postoperative inflammatory responses. OBJECTIVES: This review aimed to look at the evidence supporting the benefits of perioperative statins for AKI prevention in hospitalised adults after surgery who require cardiac bypass. The main objectives were to 1) determine whether use of statins was associated with preventing AKI development; 2) determine whether use of statins was associated with reductions in in-hospital mortality; 3) determine whether use of statins was associated with reduced need for RRT; and 4) determine any adverse effects associated with the use of statins. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 13 January 2015 through contact with the Trials' Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: Randomised controlled trials (RCTs) that compared administration of statin therapy with placebo or standard clinical care in adult patients undergoing surgery requiring cardiopulmonary bypass and reporting AKI, serum creatinine (SCr) or need for renal replacement therapy (RRT) as an outcome were eligible for inclusion. All forms and dosages of statins in conjunction with any duration of pre-operative therapy were considered for inclusion in this review. DATA COLLECTION AND ANALYSIS: All authors extracted data independently and assessments were cross-checked by a second author. Likewise, assessment of study risk of bias was initially conducted by one author and then by a second author to ensure accuracy. Disagreements were arbitrated among authors until consensus was reached. Authors from two of the included studies provided additional data surrounding post-operative SCr as well as need for RRT. Meta-analyses were used to assess the outcomes of AKI, SCr and mortality rate. Data for the outcomes of RRT and adverse effects were not pooled. Adverse effects taken into account were those reported by the authors of included studies. MAIN RESULTS: We included seven studies (662 participants) in this review. All except one study was assessed as being at high risk of bias. Three studies assessed atorvastatin, three assessed simvastatin and one investigated rosuvastatin. All studies collected data during the immediate perioperative period only; data collection to hospital discharge and postoperative biochemical data collection ranged from 24 hours to 7 days. Overall, pre-operative statin treatment was not associated with a reduction in postoperative AKI, need for RRT, or mortality. Only two studies (195 participants) reported postoperative SCr level. In those studies, patients allocated to receive statins had lower postoperative SCr concentrations compared with those allocated to no drug treatment/placebo (MD 21.2 µmol/L, 95% CI -31.1 to -11.1). Adverse effects were adequately reported in only one study; no difference was found between the statin group compared to placebo. AUTHORS' CONCLUSIONS: Analysis of currently available data did not suggest that preoperative statin use is associated with decreased incidence of AKI in adults after surgery who required cardiac bypass. Although a significant reduction in SCr was seen postoperatively in people treated with statins, this result was driven by results from a single study, where SCr was considered as a secondary outcome. The results of the meta-analysis should be interpreted with caution; few studies were included in subgroup analyses, and significant differences in methodology exist among the included studies. Large high quality RCTs are required to establish the safety and efficacy of statins to prevent AKI after cardiac surgery.

Subgroup And Quality Of Life Analyses Of The Phase Iii Clinical Trial Of Novottf-100a Versus Best Standard Chemotherapy For Recurrent Glioblastoma

BACKGROUND: NovoTTF is a portable device delivering low-intensity, intermediate-frequency, electric fields using noninvasive, disposable scalp electrodes. These fields physically interfere with cell division. Preliminary studies in recurrent and newly diagnosed glioblastoma (GBM) have shown promising results. A phase III study in recurrent GBM has recently been concluded. METHODS: Adults (KPS ≥ 70%) with recurrent GBM (any recurrence) were randomized (stratified by surgery and center) to either NovoTTF administered continuously (20-24 hours/day, 7 days/week) or the best available chemotherapy (best physician choice [BPC]). Primary endpoint was overall survival (OS); 6-month progression-free survival (PFS6), 1-year survival, and QOL were secondary endpoints. RESULTS: Two hundred thirty-seven patients were randomized (28 centers in the United States and Europe) to either NovoTTF alone (120 patients) or BPC (117 patients). Patient characteristics were balanced, median age was 54 years (range, 23-80 years), median KPS was 80% (range, 50-100). One quarter had surgery for recurrence, and over half were at their second or more recurrence. A survival advantage for the device group was seen in patients treated according to protocol (median OS, 7.8 months vs. 6.1 months; n = 185; p = 0.01). Moreover, subgroup analysis in patients with better prognostic baseline characteristics (KPS ≥ 80%; age ≤ 60; 1st-3rd recurrence) demonstrated a robust survival benefit for NovoTTF patients compared to matched BPC patients (median OS, 8.8 months vs. 6.6 months; n = 110; p < 0.01). In this group, 1-year survival was 35% vs. 20% and PFS6 was 25.6% vs. 7.7%. Interestingly, in patients who failed bevacizumab prior to the trial, OS was also significantly extended by NovoTTF (4.4 months vs. 3.1 months; n = 23 vs. n = 21; p < 0.02). Quality of life was equivalent or superior in NovoTTF patients. CONCLUSIONS: NovoTTF, a noninvasive, novel cancer treatment modality shows significant therapeutic efficacy with improved quality of life. The impact of NovoTTF was more pronounced when patients with better baseline prognostic factors were treated. A large scale phase III clinical trial in newly diagnosed GBM is currently being conducted.

Low rates of X-Y recombination, not turnovers, account for homomorphic sex chromosomes in several diploid species of Palearctic green toads (Bufo viridis subgroup).

Contrasting with birds and mammals, most ectothermic vertebrates present homomorphic sex chromosomes, which might be due either to a high turnover rate or to occasional X-Y recombination. We tested these two hypotheses in a group of Palearctic green toads that diverged some 3.3 million years ago. Using sibship analyses of sex-linked markers, we show that all four species investigated share the same pair of sex chromosomes and a pattern of male heterogamety with drastically reduced X-Y recombination in males. Phylogenetic analyses of sex-linked sequences show that X and Y alleles cluster by species, not by gametolog. We conclude that X-Y homomorphy and fine-scale sequence similarity in these species do not stem from recent sex-chromosome turnovers, but from occasional X-Y recombination.

Comprehensive Expression Analyses of Neural Cell-Type-Specific miRNAs Identify New Determinants of the Specification and Maintenance of Neuronal Phenotypes.

MicroRNAs (miRNAs) have been shown to play important roles in both brain development and the regulation of adult neural cell functions. However, a systematic analysis of brain miRNA functions has been hindered by a lack of comprehensive information regarding the distribution of miRNAs in neuronal versus glial cells. To address this issue, we performed microarray analyses of miRNA expression in the four principal cell types of the CNS (neurons, astrocytes, oligodendrocytes, and microglia) using primary cultures from postnatal d 1 rat cortex. These analyses revealed that neural miRNA expression is highly cell-type specific, with 116 of the 351 miRNAs examined being differentially expressed fivefold or more across the four cell types. We also demonstrate that individual neuron-enriched or neuron-diminished RNAs had a significant impact on the specification of neuronal phenotype: overexpression of the neuron-enriched miRNAs miR-376a and miR-434 increased the differentiation of neural stem cells into neurons, whereas the opposite effect was observed for the glia-enriched miRNAs miR-223, miR-146a, miR-19, and miR-32. In addition, glia-enriched miRNAs were shown to inhibit aberrant glial expression of neuronal proteins and phenotypes, as exemplified by miR-146a, which inhibited neuroligin 1-dependent synaptogenesis. This study identifies new nervous system functions of specific miRNAs, reveals the global extent to which the brain may use differential miRNA expression to regulate neural cell-type-specific phenotypes, and provides an important data resource that defines the compartmentalization of brain miRNAs across different cell types.