Citations

Objectives To survey experts in Headache Medicine on their opinions regarding appropriate non‐inferiority margins for outcomes commonly used in migraine research. Methods Members of the American Headache Society and the Canadian Headache Society were invited to participate in the Non‐Inferiority Margins in Migraine Research (NIMM) survey. Adult and child neurologists with expertise in Headache Medicine were eligible to participate. The survey had a multiple choice format and comprised questions on respondent characteristics, eligibility, as well as expert opinion on non‐inferiority margins for outcomes commonly used in trials of both prophylactic and acute interventions for migraine. Results Ninety‐nine eligible respondents completed the survey. Most respondents were adult neurologists (84.9%) and 74% reported practicing in the USA. The following were the most commonly selected non‐inferiority margins: (1) change in monthly migraine attacks comparing baseline to the treatment period: 1 attack (39.4% selecting), (2) change in monthly migraine days comparing baseline to the treatment period: 1 day (44.4%), (3) change in average migraine intensity on a 4‐point scale comparing baseline to the treatment period: 1.0 (31.3%), (4) percentage of participants who are pain‐free 2 hours after the intervention: 5% (41.4%), (5) percentage of participants who have a migraine recurrence within 48 hours of treatment: 5% (42.4%), and (6) percentage of participants with sustained pain freedom: 5% (42.4%). Conclusions The results of the NIMM survey describe the opinions of a group of experts on appropriate non‐inferiority margins for outcomes commonly used in migraine clinical trials. There was significant variability in responses and lack of consensus on the choice of non‐inferiority margins. The survey did not incorporate the patient perspective and was not validated prior to distribution. Further work in this area is required in order to explore how to incorporate clinical considerations into the selection of non‐inferiority margins for migraine research.

Abstract Purpose The aim of this study was to investigate whether progression-free survival (PFS) can be considered a surrogate endpoint for overall survival (OS) in malignant mesothelioma. Materials and Methods Individual data were collected from 15 Cancer and Leukemia Group B (615 patients) and 2 North Central Cancer Treatment Group (101 patients) phase II trials. The effects of 5 risk factors for OS and PFS, including age, histology, performance status (PS), white blood cell count, and European Organisation for Research and Treatment of Cancer (EORTC) risk score, were used in the analysis. Individual-level surrogacy was assessed by Kendall’s tau through a Clayton bivariate Copula survival (CBCS) model. Summary-level surrogacy was evaluated via the association between logarithms of the hazard ratio (log HR)—log HROS and log HRPFS—measured in R2 from a weighted least-square (WLS) regression model and the CBCS model. Results The median PFS for all patients was 3.0 months (95% confidence interval [CI], 2.8–3.5 months) and the median OS was 7.2 months (95% CI, 6.5–8.0 months). Moderate correlations between PFS and OS were observed across all risk factors at the individual level, with Kendall’s tau ranging from 0.46 to 0.47. The summary-level surrogacy varied among risk factors. The Copula R2 ranged from 0.51 for PS to 0.78 for histology. The WLS R2 ranged from 0.26 for EORTC and PS to 0.67 for age. Conclusions The analyses demonstrated low to moderate individual-level surrogacy between PFS and OS. At the summary level, the surrogacy between PFS and OS varied significantly across different risk factors. With a short postprogression survival and a moderate correlation between PFS and OS, there is no evidence that PFS is a valid surrogate endpoint for OS in malignant mesothelioma.

Nonselective beta‐blockers (NSBBs) have played an important role in the prevention of portal hypertensive bleeding in patients with cirrhosis. However, recent studies have suggested that NSBBs may be harmful in some patients with end‐stage liver disease. The purpose of this article is to evaluate the association between use of NSBB and the incidence of acute kidney injury (AKI). We conducted a nested case‐control study in a cohort of liver transplant wait‐list registrants. Each patient with AKI was matched to a control by the Model for End‐Stage Liver Disease–Na score, age, serum creatinine, and follow‐up duration. Out of a total of 2361 wait‐list registrants, 205 patients developed AKI after a median follow‐up duration of 18.2 months. When compared with matched controls, ascites (79.0% versus 51.7%) and non‐Caucasian race (16.6% versus 7.8%) were more common among the cases. The frequency of NSBB use was higher among the cases than controls, albeit insignificantly (45.9% versus 37.1%; P = 0.08). In multivariate analyses, the impact of nonselective beta blockade on the development of AKI was dependent on the presence of ascites: nonselective beta blockade in patients with ascites significantly increased the risk of AKI (hazard ratio [HR], 3.31; 95% confidence interval [CI], 1.57‐6.95), whereas in patients without ascites, NSBB use reduced it (HR, 0.19; 95% CI, 0.06‐0.60). Potential benefits and harms of a NSBB in terms of AKI depend on the presence of ascites in liver transplant candidates. NSBB therapy in patients with cirrhosis may need to be individualized. Liver Transplantation 23 733–740 2017 AASLD.

AbstractTo investigate the effect of sustained bone morphogenetic protein‐2 (BMP‐2) release kinetics on bone formation in poly(propylene fumarate) (PPF) scaffolds, different poly(lactic‐co‐glycolic acid) (PLGA) microspheres were used as delivery vehicles. All PPF scaffolds had the same 75% porous structure, while the degradation rate of the embedded PLGA microspheres was changed to tailor BMP‐2 release by varying the lactic‐to‐glycolic acid (L:G) ratio in the copolymer. Four PLGA microsphere formulations with 50/50, 65/35, 75/25, and 85/15 L:G ratios and varying in vivo degradation rates were fabricated. The in vitro and in vivo BMP‐2 release kinetics were determined by analyzing radiolabeled 125I‐BMP‐2. Biological activity of released BMP‐2 was tested using a W20‐17 cell culture model in vitro and a subcutaneous rat model in vivo. Corresponding outcome parameters were defined as capacity to increase the in vitro AP activity in weekly consecutive cell cultures over 14 weeks and the in vivo bone formation after 7 and 14 weeks. The PLGA/PPF composites showed similar biological activity and BMP‐2 release profiles in vitro. In vivo, PPF/PLGA 85:15 composite released significantly less BMP‐2 per time point in the first weeks. Micro‐CT and histological analysis after 7 and 14 weeks of implantation showed bone formation, which significantly increased over time for all composites. No significant differences were seen between the composites. Overall, the results of this study show that small differences in BMP‐2 sustained release had no significant effect on BMP‐2 osteogenic efficacy in PPF/PLGA composites. © 2017 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 477–487, 2018.

OBJECTIVESpinal epidural arteriovenous fistulas (SEDAVFs) constitute a rare but treatable cause of vascular myelopathy and are a different subtype from the more common Type I spinal dural AVFs. The purpose of this study was to review a consecutive series of SEDAVFs from a single institution and report on the clinical presentations, functional status, and treatment outcomes.METHODSThe authors identified all SEDAVFs treated at their institution from 2005 to 2015. SEDAVFs were defined as spinal AVFs in which the fistulous connection occurred in the epidural venous plexus. The clinical presentation, functional status, immediate treatment outcomes, and long-term neurological outcomes were analyzed.RESULTSTwenty-four patients with SEDAVFs were included in this study. The patients' mean age at presentation was 66.9 years. The most common presenting symptoms were pain and numbness (22 patients, 91.7%), followed by lower-extremity weakness (21 patients, 87.5%). The mean duration of symptoms prior to diagnosis was 11.8 months. Eighteen patients (75.0%) were treated with endovascular therapy alone, 4 (16.7) with surgery, and 2 (8.3%) with a combination of techniques. There was 1 major treatment-related complication (4.2%). Fifteen patients (62.5%) had improvement in disability, and 12 patients (54.5%) had improvement in sensory symptoms.CONCLUSIONSSEDAVFs often present with lower-extremity motor dysfunction and sensory symptoms. With the availability of newer liquid embolic agents, these lesions can be effectively treated with endovascular techniques. Surgery is also effective at treating these lesions, especially in situations where endovascular embolization fails or is not safe and in patients presenting with mass effect from compressive varices.

SummaryBackgroundGonadotropin‐inhibitory hormone (GnIH, human homologue of RFRP‐3) suppresses gonadotropin secretion in animal models, but its effects have not been studied in the human.ObjectiveWe tested the hypotheses that exogenous GnIH inhibits LH secretion (i) in postmenopausal women and (ii) in men concurrently administered exogenous kisspeptin.DesignFollowing in vitro and in vivo preclinical studies to functionally characterize the GnIH peptide, a dose‐finding study (human GnIH: 1·5–150 μg/kg/h, iv for 3 h) was undertaken, and 50 μg/kg/h selected for further evaluation. Five postmenopausal women were administered 50 μg/kg/h iv infusion for 3 h or vehicle on two separate days. Four men were administered kisspeptin‐10 (0·3 μg/kg iv bolus) with simultaneous infusion of GnIH (50 μg/kg/h, iv for 3 h) or vehicle.ParticipantsHealthy postmenopausal women (mean age 58 ± 2 years, LH: 30·8 ± 2·9 IU/l, FSH: 78·7 ± 6·4 IU/l, oestradiol: <50 pmol/l) and men (39·8 ± 2·1 years, mean total testosterone 12·1 ± 1·8 nmol/l, LH 2·2 ± 0·2 IU/l).Primary outcomeChange in area under curve (AUC) of LH during GnIHvs vehicle.ResultsDuring GnIH administration in postmenopausal women, LH secretion decreased (ΔAUC: −9·9 ± 1·8 IU/3 h) vs vehicle (ΔAUC: −0·5 ± 1·7 IU/3 h; P = 0·02). Kisspeptin‐10‐stimulated LH responses in men were not affected by GnIH co‐administration (60‐min AUC of LH 6·2 ± 0·8 IU/h with kisspeptin‐10 alone, 6·3 ± 1·0 IU/h, kisspeptin‐10 with GnIH, P = 0·72). Exogenous GnIH was well tolerated, with no adverse events reported.ConclusionsGonadotropin‐inhibitory hormone decreased LH secretion in postmenopausal women in this first‐in‐human study. Kisspeptin‐stimulated LH secretion in men was not inhibited during concomitant administration of GnIH.