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Objective We sought to understand the alteration in the anisotropic, or direction dependent, character of muscle as measured by electrical impedance myography (EIM) in subjects with Duchenne muscular dystrophy (DMD) and its potential to serve as a biomarker of disease status. Methods Thirty-six boys with DMD and 27 healthy controls were measured with EIM, with electrical current applied both parallel and perpendicular to the major muscle fiber direction. In addition, muscle extracted from 10 mdx and 10 wild-type mice were measured analogously. Results Normalized reactance anisotropy, a direction-dependent measure of membrane charge storage capability, was significantly lower in the four muscles of DMD subjects as compared to controls ( p < 0.01). Normalized reactance anisotropy also decreased with increasing age in DMD subjects ( r = −0.36, p = 0.031), but not in healthy boys. Analogous changes were observed in mdx mouse gastrocnemius as compared to wild type ( p = 0.019). Conclusion These results support that loss of electrical anisotropy is a previously unrecognized feature of dystrophic muscle. Significance Anisotropic alterations may offer novel indices to assist in neuromuscular disease diagnosis and to serve as easy-to-obtain biomarkers in clinical therapeutic trials. [ABSTRACT FROM AUTHOR]

Abstract: Background context: Effective strategies for preventing low back pain (LBP) have remained elusive, despite annual direct health care costs exceeding $85 billion dollars annually. In our recently completed Prevention of Low Back Pain in the Military (POLM) trial, a brief psychosocial education program (PSEP) that reduced fear and threat of LBP reduced the incidence of health care–seeking for LBP. Purpose: The purpose of this cost analysis was to determine if soldiers who received psychosocial education experienced lower health care costs compared with soldiers who did not receive psychosocial education. Study design/Setting: The POLM trial was a cluster randomized trial with four intervention arms and a 2-year follow-up. Consecutive subjects (n=4,295) entering a 16-week training program at Fort Sam Houston, TX, to become a combat medic in the U.S. Army were considered for participation. Methods: In addition to an assigned exercise program, soldiers were cluster randomized to receive or not receive a brief psychosocial education program delivered in a group setting. The Military Health System Management Analysis and Reporting Tool was used to extract total and LBP-related health care costs associated with LBP incidence over a 2-year follow-up period. Results: After adjusting for postrandomization differences between the groups, the median total LBP-related health care costs for soldiers who received PSEP and incurred LBP-related costs during the 2-year follow-up period were $26 per soldier lower than for those who did not receive PSEP ($60 vs. $86, respectively, p=.034). The adjusted median total health care costs for soldiers who received PSEP and incurred at least some health care costs during the 2-year follow-up period were estimated at $2 per soldier lower than for those who did not receive PSEP ($2,439 vs. $2,441, respectively, p=.242). The results from this analysis demonstrate that a brief psychosocial education program was only marginally effective in reducing LBP-related health care costs and was not effective in reducing total health care costs. Had the 1,995 soldiers in the PSEP group not received PSEP, we would estimate that 16.7% of them would incur an adjusted median LBP-related health care cost of $517 compared with the current 15.0% soldiers incurring an adjusted median cost of $399, which translates into an actual LBP-related health care cost savings of $52,846 during the POLM trial. However, it is likely that the unaccounted for direct and indirect costs might erase even these small cost savings. Conclusion: The results of this study will help to inform policy- and decision-making regarding the feasibility of implementing psychosocial education in military training environments across the services. It would be interesting to explore in future research whether cost savings from psychosocial education could be enhanced given a more individualized delivery method tailored to an individual's specific psychosocial risk factors. [Copyright &y& Elsevier]

Abstract: Context: The successful conduct of clinical trials in palliative care is challenged by low accrual rates, high attrition of study patients during trials, difficulties managing comorbidity, and other factors. But what has been learned about improving the feasibility of palliative care research studies? Objective: To develop standard terms to describe patient accrual, and using these terms, describe an approach to allow investigators to predict trial feasibility. Methods: We proposed a standard language and definitions for specific elements of feasibility within clinical trial design and conduct. We then developed an approach to apply data generated from the use of these terms to allow researchers to predict feasibility at the design stage of a clinical trial''s development. Results: We developed a taxonomy and then retrospectively applied the approach to four trials selected from our library of completed studies, to provide preliminary validity evidence. The approach includes a framework to help predict the number of patients needed to be assessed to achieve a study''s accrual targets, as part of ongoing operational oversight to monitor the conduct and feasibility of a clinical trial. Conclusion: Challenges to successful completion of palliative care trials are prevalent and serious. A taxonomy to characterize the eligible patient pool, and an approach by which feasibility is systematically investigated, hold the promise to enhance the effectiveness of scarce resources applied to palliative and end-of-life research. [Copyright &y& Elsevier]

Abstract: It is often necessary to conduct a pilot study to determine the sample size required for a clinical trial. Due to differences in sampling environments, the pilot data are usually discarded after sample size calculation. This paper tries to use the pilot information to modify the subsequent testing procedure when a two-sided -test or a regression model is used to compare two treatments. The new test maintains the required significance level regardless of the dissimilarity between the pilot and the target populations, but increases the power when the two are similar. The test is constructed based on the posterior distribution of the parameters given the pilot study information, but its properties are investigated from a frequentist''s viewpoint. Due to the small likelihood of an irrelevant pilot population, the new approach is a viable alternative to the current practice. [Copyright &y& Elsevier]

Objectives:To compare and contrast the definitions of primary treatment endpoints in randomized studies of dose-fractionation schedules for treating bone metastases and to identify basic characteristics of treatment endpoint that may require consensus among investigators. Methods:Randomized controlled trials (RCTs) of various dose-fractionation schedules for painful bone metastases, published between 1980 and 1999, and on-going trials whose protocols were available, were systematically reviewed based on the following features of the primary treatment endpoint: (i) degree of pain relief; (ii) timing of the pain response assessment; (iii) effect of co-interventions on pain relief; (iv) the reduction of analgesic as a treatment response; and (v) quantification of response duration. Results:Ten published RCTs (each sampled over 100 patients), plus two current trial protocols were reviewed. Five of the 12 studies defined any reduction in pain score as the primary endpoint. Three trials defined response at pre-determined time points, whereas eight studies attributed pain improvement at any time during follow-up to the effect of radiotherapy. No trial incorporated effect of systemic treatments on response. Only two trials incorporated analgesic scores into the primary endpoint criteria, although several trials reported results of combined pain and analgesic relief. Eight trials reported duration of response. Three provided some estimation of duration with respect to survival: two of them employing actuarial time to pain progression, and one calculated the ratio of pain response to median survival duration (percent net relief). Quality of life was measured in four of 12 studies, as secondary endpoint. Conclusion:Although available data suggest similarity in pain relief among various dose-fractionation scedules, accurate and consistent description of the degree of benefit from radiotherapy is lacking. While pain relief is a consistent primary treatment goal among randomized trials, a consensus on several important features of treatment endpoint is needed in order to establish common grounds for future trials in palliative radiotherapy. [Copyright &y& Elsevier]

Abstract: Adaptive design is widely used in clinical trials. In this paper, we consider the problem of estimating the mean of the selected normal population in two-stage adaptive designs. Under the LINEX and L 2 loss functions, admissibility and minimax results are derived for some location invariant estimators of the selected normal mean. The naive sample mean estimator is shown to be inadmissible under the LINEX loss function and to be not minimax under both loss functions. [Copyright &y& Elsevier]

Background: Pain flare occurs after palliative radiotherapy, and dexamethasone has shown potential for prevention of such flare. We aimed to compare the efficacy of dexamethasone with that of placebo in terms of reduction of incidence of pain flare.Methods: In this double-blind, randomised, placebo-controlled phase 3 trial, patients from 23 Canadian centres were randomly allocated (1:1) with a web-based system and minimisation algorithm to receive either two 4 mg dexamethasone tablets or two placebo tablets taken orally at least 1 h before the start of radiation treatment (a single 8 Gy dose to bone metastases; day 0) and then every day for 4 days after radiotherapy (days 1-4). Patients were eligible if they had a non-haematological malignancy and bone metastasis (or metastases) corresponding to the clinically painful area or areas. Patients reported their worst pain scores and opioid analgesic intake before treatment and daily for 10 days after radiation treatment. They completed the European Organisation for Research and Treatment of Cancer (EORTC) quality of life QLQ-C15-PAL, the bone metastases module (EORTC QLQ-BM22), and the Dexamethasone Symptom Questionnaire at baseline, and at days 10 and 42 after radiation treatment. Pain flare was defined as at least a two-point increase on a scale of 0-10 in the worst pain score with no decrease in analgesic intake, or a 25% or greater increase in analgesic intake with no decrease in the worst pain score from days 0-10, followed by a return to baseline levels or below. Primary analysis of incidence of pain flare was by intention-to-treat (patients with missing primary data were classified as having pain flare). This study is registered with ClinicalTrials.gov, number NCT01248585, and is completed.Findings: Between May 30, 2011, and Dec 11, 2014, 298 patients were enrolled. 39 (26%) of 148 patients randomly allocated to the dexamethasone group and 53 (35%) of 150 patients in the placebo group had a pain flare (difference 8·9%, lower 95% confidence bound 0·0, one-sided p=0·05). Two grade 3 and one grade 4 biochemical hyperglycaemic events occurred in the dexamethasone group (without known clinical effects) compared with none in the placebo group. The most common adverse events were bone pain (61 [41%] of 147 vs 68 [48%] of 143), fatigue (58 [39%] of 147 vs 49 [34%] of 143), constipation (47 [32%] of 147 vs 37 [26%] of 143), and nausea (34 [23%] of 147 vs 34 [24%] of 143), most of which were mild grade 1 or 2.Interpretation: Dexamethasone reduces radiation-induced pain flare in the treatment of painful bone metastases.Funding: The NCIC CTG's programmatic grant from the Canadian Cancer Society Research Institute. [ABSTRACT FROM AUTHOR]

Background context Choosing the best surgical treatment for patients with spinal metastases remains a significant challenge for spine surgeons. There is currently no gold standard for surgical treatments. The Aarhus Spinal Metastases Algorithm (ASMA) was established to help surgeons choose the most appropriate surgical intervention for patients with spinal metastases. Purpose The purpose of this study was to evaluate the clinical outcome of stratified surgical interventions based on the ASMA, which combines life expectancy and the anatomical classification of patients with spinal metastases to inform surgical decision making. Study design/Setting This is a retrospective study based on a prospective database. Patient sample A consecutive series of 515 spinal metastatic patients who underwent surgically treatment from December 1992 to June 2012 in Aarhus University Hospital were included prospectively and analyzed in detail retrospectively. Outcome measures Survival time after surgery was determined for all patients. Neurological function was assessed using the Frankel score preoperatively and postoperatively (at the time of discharge). Complete outcome data were retrieved in 97.5% of this cohort. Methods Patients with spinal metastases were identified from an institutional database that prospectively collected data since 1992. Survival status data were obtained from a national registry. Neurological function was determined from the same institutional database or local Electronic Patient Journal system. Surgeons evaluated and classified patients into five surgical groups preoperatively by using the revised Tokuhashi score (TS) and the Tomita anatomical classification (TC). Results The overall median survival time of the cohort was 6.8 (95% confidence interval: 6.1–7.9) months. The median survival times in the five surgical groups determined by the ASMA were 2.1 (TS 0–4, TC 1–7), 5.1 (TS 5–8, TC 1–7), 12.1 (TS 9–11, TC 1–7 or TS 12–15, TC 7), 26.0 (TS 12–15, TC 4–6), and 36.0 (TS 12–15, TC 1–3) months. The 30-day mortality rate was 7.5%. Postoperative neurological function was maintained or improved in 469 patients (92.3%). Overall reoperation rate was 13.5%, commonly because of postoperative hematoma and new limb weakness. Conclusions The ASMA recommends at least two surgical options for a particular patient by determining the preoperative life expectancy and anatomical classification of the spinal metastases. This algorithm could help spine surgeons to discriminate the risks of surgeries. The ASMA provides a tool to guild surgeons to evaluate the spinal metastases patients, select potential optimal surgery, and avoid life-threatening risks. [ABSTRACT FROM AUTHOR]

Background: KRAS mutations are detected in 25% of non-small-cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. We report a phase II trial comparing trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC. Patients and methods: Eligible patients with histologically confirmed KRAS-mutant NSCLC previously treated with one prior platinum-based chemotherapy were randomly assigned in a ratio of 2 : 1 to trametinib (2 mg orally once daily) or docetaxel (75 mg/m² i.v. every 3 weeks). Crossover to the other arm after disease progression was allowed. Primary end point was progression-free survival (PFS). The study was prematurely terminated after the interim analysis of 92 PFS events, which showed the comparison of trametinib versus docetaxel for PFS crossed the futility boundary. Results: One hundred and twenty-nine patients with KRAS-mutant NSCLC were randomized; of which, 86 patients received trametinib and 43 received docetaxel. Median PFS was 12 weeks in the trametinib arm and 11 weeks in the docetaxel arm (hazard ratio [HR] 1.14; 95% CI 0.75--1.75; P = 0.5197). Median overall survival, while the data are immature, was 8 months in the trametinib arm and was not reached in the docetaxel arm (HR 0.97; 95% CI 0.52--1.83; P = 0.934). There were 10 (12%) partial responses (PRs) in the trametinib arm and 5 (12%) PRs in the docetaxel arm (P=1.0000). The most frequent adverse events (AEs) in ≥20% of trametinib patients were rash, diarrhea, nausea, vomiting, and fatigue. The most frequent grade 3 treatment-related AEs in the trametinib arm were hypertension, rash, diarrhea, and asthenia. Conclusion: Trametinib showed similar PFS and a response rate as docetaxel in patients with previously treated KRASmutant- positive NSCLC. [ABSTRACT FROM AUTHOR]

Abstract: Background: Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown. Methods: We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2 to 14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual. Results: Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P < 0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = −0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = −0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = −0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = −0.40; P = 0.054 and rho = −0.32; P = 0.13, respectively). Conclusions: Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted. [Copyright &y& Elsevier]

Background Central nervous system (CNS) disease as the site of first relapse after exposure to adjuvant trastuzumab has been reported. We carried out comprehensive meta-analysis to determine the risk of CNS metastases as the first site of recurrence in patients with HER2-positive breast cancer who received adjuvant trastuzumab. Methods Eligible studies include randomized trials of adjuvant trastuzumab administered for 1 year to patients with HER2-positive breast cancer who reported CNS metastases as first site of disease recurrence. Statistical analyses were conducted to calculate the incidence, relative risk (RR), and 95% confidence intervals (CIs) using fixed-effects inverse variance and random-effects models. Results A total of 9020 patients were included. The incidence of CNS metastases as first site of disease recurrence in HER2-positive patients receiving adjuvant trastuzumab was 2.56% (95% CI 2.07% to 3.01%) compared with 1.94% (95% CI 1.54% to 2.38%) in HER2-positive patients who did not receive adjuvant trastuzumab. The RR of the CNS as first site of relapse in trastuzumab-treated patients was 1.35 (95% CI 1.02–1.78, P = 0.038) compared with control arms without trastuzumab therapy. The ratio of CNS metastases to total number of recurrence events was 16.94% (95% CI 10.85% to 24.07%) and 8.33% (95% CI 6.49% to 10.86%) for the trastuzumab-treated and control groups, respectively. No statistically significant differences were found based on trastuzumab schedule or median follow-up time. No evidence of publication bias was observed. Conclusions Adjuvant trastuzumab is associated with a significant increased risk of CNS metastases as the site of first recurrence in HER2-positive breast cancer patients. [ABSTRACT FROM PUBLISHER]