Citations

Objective Global Trigger Tool (GTT) has been proposed as a low-cost method to detect adverse events (AEs). The validity of the methodology has been questioned because of moderate interrater agreement. Continuous training has been suggested as a means to improve consistency over time. We present the main findings of the implementation of the Italian version of the GTT and evaluate efforts to improve the interrater reliability over time. Methods The Italian version of the GTT was developed and implemented at the San Bonifacio Hospital, a 270-bed secondary care acute hospital in Verona, Italy. Ten clinical records randomly selected every 2 weeks were reviewed from 2009 to 2014. Two-stage interrater reliability assessment between team members was conducted on 2 subsamples of 50 clinical records before and after the implementation of specific review rules and staff training. Results Among 1320 medical records reviewed, a total of 366 AEs were found with at least 1 AE on 20.2% of all discharges, 27.7 AEs/100 admissions, and 30.6 AEs/1000 patient-days. Adverse events with harm score E and F were respectively 58.2% (n = 213) and 38.8% (n = 142). First round interrater reliability was comparable with other international studies. The interrater agreement improved significantly after intervention (κ interrater I = 0.52, κ interrater II = 0.80, P < 0.001). Conclusions Despite the improvements in the interrater consistency, overall results did not show any significant trend in AEs over time. Future studies may be directed to apply and adapt the GTT methodology to more specific settings to explore how to improve its sensitivity.

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.

Background Lapatinib (L) plus trastuzumab (T) improves outcomes for metastatic human epidermal growth factor 2–positive breast cancer and increases the pathologic complete response in the neoadjuvant setting, but their role as adjuvant therapy remains uncertain. Methods In the Adjuvant Lapatinib and/or Trastuzumab Treatment Optimization trial, patients with centrally confirmed human epidermal growth factor 2–positive early breast cancer were randomly assigned to 1 year of adjuvant therapy with T, L, their sequence (T→L), or their combination (L+T). The primary end point was disease-free survival (DFS), with 850 events required for 80% power to detect a hazard ratio (HR) of 0.8 for L+T versus T. Results Between June 2007 and July 2011, 8,381 patients were enrolled. In 2011, due to futility to demonstrate noninferiority of L versus T, the L arm was closed, and patients free of disease were offered adjuvant T. A protocol modification required P ≤ .025 for the two remaining pairwise comparisons. At a protocol-specified analysis with a median follow-up of 4.5 years, a 16% reduction in the DFS hazard rate was observed with L+T compared with T (555 DFS events; HR, 0.84; 97.5% CI, 0.70 to 1.02; P = .048), and a 4% reduction was observed with T→L compared with T (HR, 0.96; 97.5% CI, 0.80 to 1.15; P = .61). L-treated patients experienced more diarrhea, cutaneous rash, and hepatic toxicity compared with T-treated patients. The incidence of cardiac toxicity was low in all treatment arms. Conclusion Adjuvant treatment that includes L did not significantly improve DFS compared with T alone and added toxicity. One year of adjuvant T remains standard of care.

The ability to identify the clinical nature of the recurrent duplication of chromosome 17q12 has been limited by its rarity and the diverse range of phenotypes associated with this genomic change. In order to further define the clinical features of affected patients, detailed clinical information was collected in the largest series to date (30 patients and 2 of their siblings) through a multi‐institutional collaborative effort. The majority of patients presented with developmental delays varying from mild to severe. Though dysmorphic features were commonly reported, patients do not have consistent and recognizable features. Cardiac, ophthalmologic, growth, behavioral, and other abnormalities were each present in a subset of patients. The newly associated features potentially resulting from 17q12 duplication include height and weight above the 95th percentile, cataracts, microphthalmia, coloboma, astigmatism, tracheomalacia, cutaneous mosaicism, pectus excavatum, scoliosis, hypermobility, hypospadias, diverticulum of Kommerell, pyloric stenosis, and pseudohypoparathryoidism. The majority of duplications were inherited with some carrier parents reporting learning disabilities or microcephaly. We identified additional, potentially contributory copy number changes in a subset of patients, including one patient each with 16p11.2 deletion and 15q13.3 deletion. Our data further define and expand the clinical spectrum associated with duplications of 17q12 and provide support for the role of genomic modifiers contributing to phenotypic variability. © 2015 Wiley Periodicals, Inc.

Background: The aim of this retrospective study is to test the hypothesis that the use of spinal analgesia shortens the length of hospital stay after partial nephrectomy. Materials and Methods: We reviewed all patients undergoing partial nephrectomy for malignancy through flank incision between January 1, 2008, and June 30, 2011. We excluded patients who underwent tumor thrombectomy, used sustained-release opioids, or had general anesthesia supplemented by epidural analgesia. Patients were grouped into “spinal” (intrathecal opioid injection for postoperative analgesia) versus “general anesthetic” group, and “early” discharge group (within 3 postoperative days) versus “late” group. Association between demographics, patient physical status, anesthetic techniques, and surgical complexity and hospital stay were analyzed using multivariable logistic regression analysis. Results: Of 380 patients, 158 (41.6%) were discharged “early” and 151 (39.7%) were “spinal” cases. Both spinal and early discharge groups had better postoperative pain control and used less postoperative systemic opioids. Spinal analgesia was associated with early hospital discharge, odds ratio 1.52, (95% confidence interval 1.00-2.30), P = 0.05, but in adjusted analysis was no longer associated with early discharge, 1.16 (0.73-1.86), P = 0.52. Early discharge was associated with calendar year, with more recent years being associated with early discharge. Conclusion: Spinal analgesia combined with general anesthesia was associated with improved postoperative pain control during the 1 st postoperative day, but not with shorter hospital stay following partial nephrectomy. Therefore, unaccounted practice changes that occurred during more recent times affected hospital stay.

Background There is a considerable amount of practice variation in managing migraines in emergency settings, and evidence-based therapies are often not used first line. Methods A peer-reviewed search of databases (MEDLINE, Embase, CENTRAL) was carried out to identify randomized and quasi-randomized controlled trials of interventions for acute pain relief in adults presenting with migraine to emergency settings. Where possible, data were pooled into meta-analyses. Results Two independent reviewers screened 831 titles and abstracts for eligibility. Three independent reviewers subsequently evaluated 120 full text articles for inclusion, of which 44 were included. Individual studies were then assigned a US Preventive Services Task Force quality rating. The GRADE scheme was used to assign a level of evidence and recommendation strength for each intervention. Interpretation We strongly recommend the use of prochlorperazine based on a high level of evidence, lysine acetylsalicylic acid, metoclopramide and sumatriptan, based on a moderate level of evidence, and ketorolac, based on a low level of evidence. We weakly recommend the use of chlorpromazine based on a moderate level of evidence, and ergotamine, dihydroergotamine, lidocaine intranasal and meperidine, based on a low level of evidence. We found evidence to recommend strongly against the use of dexamethasone, based on a moderate level of evidence, and granisetron, haloperidol and trimethobenzamide based on a low level of evidence. Based on moderate-quality evidence, we recommend weakly against the use of acetaminophen and magnesium sulfate. Based on low-quality evidence, we recommend weakly against the use of diclofenac, droperidol, lidocaine intravenous, lysine clonixinate, morphine, propofol, sodium valproate and tramadol.

Abstract Purpose: A phase I, dose-finding study of vorinostat in combination with temozolomide (TMZ) was conducted to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics in patients with high-grade glioma (HGG). Experimental Design: This phase I, dose-finding, investigational study was conducted in two parts. Part 1 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days every 28 days. Part 2 was a dose-escalation study of vorinostat in combination with TMZ 150 mg/m2/day for 5 days of the first cycle and 200 mg/m2/day for 5 days of the subsequent 28-day cycles. Results: In part 1, the MTD of vorinostat administered on days 1 to 7 and 15 to 21 of every 28-day cycle, in combination with TMZ, was 500 mg daily. Dose-limiting toxicities (DLT) included grade 3 anorexia, grade 3 ALT, and grade 5 hemorrhage in the setting of grade 4 thrombocytopenia. In part 2, the MTD of vorinostat on days 1 to 7 and 15 to 21 of every 28-day cycle, combined with TMZ, was 400 mg daily. No DLTs were encountered, but vorinostat dosing could not be escalated further due to thrombocytopenia. The most common serious adverse events were fatigue, lymphopenia, thrombocytopenia, and thromboembolic events. There were no apparent pharmacokinetic interactions between vorinostat and TMZ. Vorinostat treatment resulted in hyperacetylation of histones H3 and H4 in peripheral mononuclear cells. Conclusion: Vorinostat in combination with temozolomide is well tolerated in patients with HGG. A phase I/II trial of vorinostat with radiotherapy and concomitant TMZ in newly diagnosed glioblastoma is underway. Clin Cancer Res; 18(21); 6032–9. ©2012 AACR.