Citations

SummaryThe randomized, double‐blind, double‐dummy, phase 3b RELIEF trial evaluated polycythaemia vera (PV)‐related symptoms in patients who were well controlled with a stable dose of hydroxycarbamide (also termed hydroxyurea) but reported PV‐related symptoms. Patients were randomized 1:1 to ruxolitinib 10 mg BID (n = 54) or hydroxycarbamide (prerandomization dose/schedule; n = 56); crossover to ruxolitinib was permitted after Week 16. The primary endpoint, ≥50% improvement from baseline in myeloproliferative neoplasm ‐symptom assessment form total symptom score cytokine symptom cluster (TSS‐C; sum of tiredness, itching, muscle aches, night sweats, and sweats while awake) at Week 16, was achieved by 43·4% vs. 29·6% of ruxolitinib‐ and hydroxycarbamide‐treated patients, respectively (odds ratio, 1·82; 95% confidence interval, 0·82–4·04; P = 0·139). The primary endpoint was achieved by 34% of a subgroup who maintained their hydroxycarbamide dose from baseline to Weeks 13–16. In a post hoc analysis, the primary endpoint was achieved by more patients with stable screening‐to‐baseline TSS‐C scores (ratio ≤ 2) receiving ruxolitinib than hydroxycarbamide (47·4% vs. 25·0%; P = 0·0346). Ruxolitinib treatment after unblinding was associated with continued symptom score improvements. Adverse events were primarily grades 1/2 with no unexpected safety signals. Ruxolitinib was associated with a nonsignificant trend towards improved PV‐related symptoms versus hydroxycarbamide, although an unexpectedly large proportion of patients who maintained their hydroxycarbamide dose reported symptom improvement.

BACKGROUNDStereotactic body radiotherapy (SBRT) is the standard of care for patients with nonoperative, early‐stage non–small cell lung cancer (NSCLC) measuring < 5 cm, but its use among patients with tumors measuring ≥5 cm is considerably less defined, with the existing literature limited to small, single‐institution reports. The current multi‐institutional study reported outcomes evaluating the largest such population reported to date.METHODSClinical/treatment characteristics, outcomes, toxicities, and patterns of failure were assessed in patients with primary NSCLC measuring ≥5 cm without evidence of distant/lymph node metastasis who underwent SBRT using ≤5 fractions. Statistics included Kaplan‐Meier survival analyses and univariate/multivariate Cox proportional hazards models.RESULTSA total of 92 patients treated from 2004 through 2016 were analyzed from 12 institutions. The median follow‐up was 12 months (15 months in survivors). The median age and tumor size among the patients were 73 years (range, 50‐95 years) and 5.4 cm (range, 5.0‐7.5 cm), respectively. The median dose/fractionation was 50 Gray/5 fractions. The actuarial local control rates at 1 year and 2 years were 95.7% and 73.2%, respectively. The disease‐free survival rate was 72.1% and 53.5%, respectively, at 1 year and 2 years. The 1‐year and 2‐year disease‐specific survival rates were 95.5% and 78.6%, respectively. The median, 1‐year, and 2‐year overall survival rates were 21.4 months, 76.2%, and 46.4%, respectively. On multivariate analysis, lung cancer history and pre‐SBRT positron emission tomography maximum standardized uptake value were found to be associated with overall survival. Posttreatment failures were most commonly distant (33% of all disease recurrences), followed by local (26%) and those occurring elsewhere in the lung (23%). Three patients had isolated local failures. Grade 3 to 4 toxicities included 1 case (1%) and 4 cases (4%) of grade 3 dermatitis and radiation pneumonitis, respectively (toxicities were graded according to the Common Terminology Criteria for Adverse Events [version 4.0]). Grades 2 to 5 radiation pneumonitis occurred in 11% of patients. One patient with a tumor measuring 7.5 cm and a smoking history of 150 pack‐years died of radiation pneumonitis.CONCLUSIONSThe results of the current study, which is the largest study of patients with NSCLC measuring ≥5 cm reported to date, indicate that SBRT is a safe and efficacious option. Cancer 2017;123:688–696. © 2016 American Cancer Society.

CONTEXT: Although practice guidelines suggest that primary care providers working with children and adolescents incorporate BMI surveillance and counseling into routine practice, the evidence base for this practice is unclear. OBJECTIVE: To determine the effect of brief, primary care interventions for pediatric weight management on BMI. DATA SOURCES: Medline, CENTRAL, Embase, PsycInfo, and CINAHL were searched for relevant publications from January 1976 to March 2016 and cross-referenced with published studies. STUDY SELECTION: Eligible studies were randomized controlled trials and quasi-experimental studies that compared the effect of office-based primary care weight management interventions to any control intervention on percent BMI or BMI z scores in children aged 2 to 18 years. DATA EXTRACTION: Two reviewers independently screened sources, extracted data on participant, intervention, and study characteristics, z-BMI/percent BMI, harms, and study quality using the Cochrane and Newcastle-Ottawa risk of bias tools. RESULTS: A random effects model was used to pool the effect size across eligible 10 randomized controlled trials and 2 quasi-experimental studies. Compared with usual care or control treatment, brief interventions feasible for primary care were associated with a significant but small reduction in BMI z score (–0.04, [95% confidence interval, –0.08 to –0.01]; P = .02) and a nonsignificant effect on body satisfaction (standardized mean difference 0.00, [95% confidence interval, –0.21 to 0.22]; P = .98). LIMITATIONS: Studies had methodological limitations, follow-up was brief, and adverse effects were not commonly measured. CONCLUSIONS: BMI surveillance and counseling has a marginal effect on BMI, highlighting the need for revised practice guidelines and the development of novel approaches for providers to address this problem.

Interplay between cell polarity module Scribble‐Lethal Giant Larvae‐Discs Large 1 (DLG1) and Yes‐associated protein (YAP) appears critical in tumor metastasis. We identified zinc finger protein 191 (ZNF191) as a metastasis suppressor acting through DLG‐YAP crosstalk in hepatocellular carcinoma (HCC). Overexpression of ZNF191 in HCC cells impaired cell motility, while ZNF191 depletion promoted cell migration in vitro and metastasis in vivo through triggering YAP signaling. Chromatin immunoprecipitation‐sequencing revealed that ZNF191 specifically bound to the promoter of DLG1, a cell polarity maintainer and a negative regulator of YAP. The binding sequence of ZNF191 at the DLG1 promoter is a seven‐repeat of TCAT motif. Double‐knockdown experiments inferred that DLG1 was not only the mediator of the function of ZNF191 to suppress migration but also a link between ZNF191 and YAP signaling. Decreased expression of ZNF191 in human metastatic HCC specimens correlated positively with DLG1 levels but inversely with YAP activation. Our findings illustrate a YAP‐targeting, antimetastasis function of ZNF191, thereby representing a possible prognostic marker and a potential target for metastasis therapy. Conclusion: ZNF191 directly binds to the DLG1 promoter at a typical TCAT repeating motif and activates the expression of DLG1; through up‐regulating DLG1, ZNF191 inhibits cell migration and YAP activation in HCC cells and eventually inhibits metastasis. (Hepatology 2016;64:1148‐1162)

Objective and design We conducted a systematic review and meta-analysis to evaluate the incidence of adverse events in the emergency department (ED) during procedural sedation in the paediatric population. Randomised controlled trials and observational studies from the past 10 years were included. We adhere to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Setting ED. Participants Children. Interventions Procedural sedation. Outcomes Adverse events like vomiting, agitation, hypoxia and apnoea. Meta-analysis was performed with random-effects model and reported as incidence rates with 95% CIs. Results A total of 1177 studies were retrieved for screening and 258 were selected for full-text review. 41 studies reporting on 13 883 procedural sedations in 13 876 children (≤18 years) were included. The most common adverse events (all reported per 1000 sedations) were: vomiting 55.5 (CI 45.2 to 65.8), agitation 17.9 (CI 12.2 to 23.7), hypoxia 14.8 (CI 10.2 to 19.3) and apnoea 7.1 (CI 3.2 to 11.0). The need to intervene with either bag valve mask, oral airway or positive pressure ventilation occurred in 5.0 per 1000 sedations (CI 2.3 to 7.6). The incidences of severe respiratory events were: 34 cases of laryngospasm among 8687 sedations (2.9 per 1000 sedations, CI 1.1 to 4.7; absolute rate 3.9 per 1000 sedations), 4 intubations among 9136 sedations and 0 cases of aspiration among 3326 sedations. 33 of the 34 cases of laryngospasm occurred in patients who received ketamine. Conclusions Serious adverse respiratory events are very rare in paediatric procedural sedation in the ED. Emesis and agitation are the most frequent adverse events. Hypoxia, a late indicator of respiratory depression, occurs in 1.5% of sedations. Laryngospasm, though rare, happens most frequently with ketamine. The results of this study provide quantitative risk estimates to facilitate shared decision-making, risk communication, informed consent and resource allocation in children undergoing procedural sedation in the ED.

Objective To compare efficacy of pharmacotherapies for chronic idiopathic constipation (CIC) based on comparisons to placebo using Bayesian network meta-analysis. Data sources We conducted searches (inception to May 2015) of MEDLINE, EMBASE, Scopus and Cochrane Central, as well as original data from authors or drug companies for the medications used for CIC. Study selection Phase IIB and phase III randomised, placebo-controlled trials (RCT) of ≥4 weeks' treatment for CIC in adults with Rome II or III criteria for functional constipation; trials included at least one of four end points. Data extraction and synthesis Two investigators independently evaluated all full-text articles that met inclusion criteria and extracted data for primary and secondary end points, risk of bias and quality of evidence. Outcomes Primary end points were ≥3 complete spontaneous bowel movements (CSBM)/week and increase over baseline by ≥1 CSBM/week. Secondary end points were change from baseline (Δ b ) in the number of SBM/week and Δ b CSBM/week. Results Twenty-one RCTs (9189 patients) met inclusion and end point criteria: 9 prucalopride, 3 lubiprostone, 3 linaclotide, 2 tegaserod, 1 each velusetrag, elobixibat, bisacodyl and sodium picosulphate (NaP). All prespecified end points were unavailable in four polyethylene glycol studies. Bisacodyl, NaP, prucalopride and velusetrag were superior to placebo for the ≥3 CSBM/week end point. No drug was superior at improving the primary end points on network meta-analysis. Bisacodyl appeared superior to the other drugs for the secondary end point, Δ b in number of SBM/week. Conclusions Current drugs for CIC show similar efficacy. Bisacodyl may be superior to prescription medications for Δ b in the number of SBM/week in CIC.

Both vitamin D deficiency and cognitive impairment are common in patients with chronic kidney disease (CKD). Vitamin D exerts neuroprotective and regulatory roles in the central nervous system. Hypovitaminosis D has been associated with muscle weakness and bone loss, cardiovascular diseases (hypertension, diabetes and hyperlipidemia), inflammation, oxidative stress, immune suppression and neurocognitive impairment. The combination of hypovitaminosis D and CKD can be even more debilitating, as cognitive impairment can develop and progress through vitamin D-associated and CKD-dependent/independent processes, leading to significant morbidity and mortality. Although an increasingly recognized comorbidity in CKD, cognitive impairment remains underdiagnosed and often undermanaged. Given the association of cognitive decline and hypovitaminosis D and their deleterious effects in CKD patients, determination of vitamin D status and when appropriate, supplementation, in conjunction with neuropsychological screening, should be considered integral to the clinical care of the CKD population.