Yuki Kataoka

Majority of systematic reviews published in high-impact journals neglected to register the protocols: a meta-epidemiological study

OBJECTIVES To describe the registration of systematic review (SR) protocols and examine whether or not registration reduced the outcome reporting bias in high-impact journals. STUDY DESIGN AND SETTING We searched MEDLINE via PubMed to identify SRs of randomized controlled trials of interventions. We included SRs published between August 2009 and June 2015 in the 10 general and internal medicinal journals with the highest impact factors in 2013. We examined the proportion of SR protocol registration and investigated the relationship between registration and outcome reporting bias using multivariable logistic regression. RESULTS Among the 284 included reviews, 60 (21%) protocols were registered. The proportion of registration increased from 5.6% in 2009 to 27% in 2015 (P for trend <0.001). Protocol registration was not associated with outcome reporting bias (adjusted odds ratio [OR] 0.85, 95% confidence interval [CI] 0.39-1.86). The association between Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) adherence and protocol registration was not statistically significant (OR 1.09, 95% CI 0.59-2.01). CONCLUSIONS Six years after the launch of the PRISMA statement, the proportion of protocol registration in high-impact journals has increased some but remains low. The present study found no evidence suggesting that protocol registration reduced outcome reporting bias.

A new prognostic index for overall survival in malignant pleural mesothelioma: the rPHS (regimen, PS, histology or stage) index.

OBJECTIVE Existing prognostic indices for malignant pleural mesothelioma do not incorporate the recent advances in oncology care. The purpose of this study was to provide a prognostic index for overall survival in malignant pleural mesothelioma patients treated with chemotherapy with pemetrexed or best supportive care in the recent clinical setting. METHODS A retrospective cohort study was performed in two hospitals in Japan (2007-13). The primary outcome was overall survival. The Cox proportional hazards model was used for multivariable analyses to identify prognostic factors. A final model was chosen based on both clinical and statistical significance. RESULTS A total of 283 patients (chemotherapy: n = 228, best supportive care: n = 55) were enrolled in the study. On multivariate analysis, regimen including platinum plus pemetrexed, a performance status >0, non-epithelial histological type and Stage IV disease predicted poor overall survival in chemotherapy patients. As hazard ratios of individual risk factors were approximately similar, a prognostic index for overall survival was constructed by counting the risk factors. Median overall survival in chemotherapy patients decreased by each one-point increase in this count: 1030 days for zero; 658 days for one; 373 days for two; 327 days for three; 125 days for four. Internal validation using the bootstrapping technique showed robustness of the model (c-index, 0.677; 95% confidence interval, 0.624-0.729). Further, the discrimination was consistent in best supportive care patients (c-index, 0.799; 95% confidence interval, 0.725-0.874). CONCLUSIONS This novel index can provide clinicians and malignant pleural mesothelioma patients with a better framework for discussing prognosis at the time of diagnosis.

External validation of prognostic indices for overall survival of malignant pleural mesothelioma

OBJECTIVE There are several prognostic indices (PIs) to predict overall survival (OS) in malignant pleural mesothelioma (MPM) patients. Before using a clinical prediction model in the actual clinical setting, empiric evaluation of its performance based on datasets that were not used to develop the model (i.e., external validation) is essential. The purpose of this study was to conduct an external validation of the PIs for MPM. MATERIALS AND METHODS A retrospective cohort study was performed on MPM patients treated at 2 tertiary hospitals in Japan between 2007 and 2015. The primary outcome was OS. Harrells c-index, and was calculated to examine the discrimination of three models. The bootstrapping technique was used to evaluate optimism. RESULTS The participants comprised 183 patients who underwent surgical treatment (n=61), chemotherapy (n=101), and best supportive care (BSC, n=21). The median OS rates were 1014days for surgery, 690days for chemotherapy, and 545days for best supportive care (BSC). The respective discriminations (95% confidence interval) of the Eastern Cooperative Oncology Group Performance Status, the European Organisation for Research and Treatment of Cancer index, regimen, PS, histology or stage (rPHS) index, and Tagawa index for the OS of MPM patients were 0.532 (0.444-0.620), 0.560 (0.472-0.648), 0.584 (0.452-0.716), and 0.525 (0.453-0.596) for surgery; 0.632 (0.539-0.724), 0.622 (0.548-0.696), 0.677 (0.587-0.766), and 0.545 (0.436-0.653) for chemotherapy; and 0.504 (0.365-0.644), 0.583 (0.456--0.710), 0.704 (0.508-0.899), and 0.583 (0.436-0.730) for BSC. CONCLUSIONS Each PI showed poor discrimination for MPM patients who underwent surgical treatment. The rPHS index showed moderate discrimination for patients given chemotherapy and BSC.

Meningococcemia in Adults: A Review of the Literature

We mainly refer to the acute setting of meningococcemia. Meningococcemia is an infection caused by Neisseria meningitidis, which has 13 clinically significant serogroups that are distinguishable by the structure of their capsular polysaccharides. N. meningitidis, also called meningococcus, is a Gram-negative, aerobic, diplococcus bacterium. The various consequences of severe meningococcal sepsis include hypotension, disseminated intravascular coagulation (DIC), multiple organ failure, and osteonecrosis due to DIC. The gold standard for the identification of meningococcal infection is the bacteriologic isolation of N. meningitidis from body fluids such as blood, cerebrospinal fluid (CSF), synovial fluid, and pleural fluid. Blood, CSF, and skin biopsy cultures are used for diagnosis. Meningococcal infection is a medical emergency that requires antibiotic therapy and intensive supportive care. Management of the systemic circulation, respiration, and intracranial pressure is vital for improving the prognosis, which has dramatically improved since the wide availability of antibiotics. This review of the literature provides an overview of current concepts on meningococcemia due to N. meningitidis infection.

Polymyxin B-immobilised haemoperfusion and mortality in critically ill patients with sepsis/septic shock: a protocol for a systematic review and meta-analysis

Introduction Polymyxin-B immobilised haemoperfusion (PMX-HP) is a promising adjuvant strategy for the treatment of sepsis and septic shock. PMX-HP therapy works by clearing circulating endotoxin through binding to polymyxin-immobilised fibres during haemoperfusion. Small clinical trials have shown that PMX-HP therapy is associated with improved haemodynamic profile, oxygenation and survival. However, clear inferences have been largely inconclusive due to limitations in study design (eg, small, unblinded) and generalisability. We therefore propose to perform an up-to-date systematic review and evidence synthesis to describe the efficacy, safety and effectiveness of PMX-HP for adult patients with sepsis or septic shock. Methods and analysis We will search the following databases from 1946 to 2016 MEDLINE (Ovid), EMBASE (Ovid), Cochrane Library, Health Technology Assessment Database (HTA), Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed and ‘Igaku Chuo Zasshi’ (ICHUSHI) for randomised controlled trials of PMX-HP in critically ill patients with sepsis or septic shock. There will be no language restrictions in the electronic search for studies. Two reviewers will extract data and appraise the quality of each study independently. The primary outcome will be the pooled risk ratio of 28-day all-cause mortality. Serious adverse events and changes in organ dysfunction scores will also be evaluated. The secondary outcomes will be 90-day all-cause mortality, changes in haemodynamic profile and endotoxin levels, and health services use. Ethics and dissemination Our systematic review will synthesise the evidence on use of the PMX-HP as an adjuvant therapy in sepsis/septic shock to improve patient-centred, physiological and health services outcomes. Research ethics is not required for this review. The study will be disseminated by peer-reviewed publication and conference presentation. Trial registration number CRD42016038356.

Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: A multicenter retrospective cohort study

INTRODUCTION Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. METHODS We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. RESULTS Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation - or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). CONCLUSIONS Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumabs efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Prior radiotherapy does not predict nivolumab response in non-small-cell lung cancer: a retrospective cohort study

Nivolumab is one of the standard therapy for previously treated advanced non-small-cell lung cancer (NSCLC) [1]. Durable responses are observed in NSCLC patients treated with nivolumab, but there are fewer than half of patients who will benefit [1]. Immunotherapy administration after radiotherapy may provide synergistic effects (i.e. abscopal effect) [2, 3]. However, it is unclear whether past radiotherapy especially to lung is predictive or not in NSCLC who receive immune checkpoint inhibitor. We conducted a multicenter retrospective cohort study. We included consecutive patients treated with nivolumab between January 2016 and October 2016 after the second line systemic chemotherapy outside of a clinical trial. Variables were retrieved from the medical records before the administration of nivolumab. All variables were dichotomized based on previous study or median [4, 5]. Primary endpoint was progression-free survival (PFS) defined by response evaluation criteria in solid tumors (RECIST) 1.1. Two researchers evaluated the endpoint independently. Any disagreements were resolved by discussion. Cox proportional hazards models were used to assess the impact of pretreatment markers on PFS. One hundred forty-six patients were included. Median observation period were 153 days. Patients characteristics were as follows: median age 69 years, female 36 (25%), never smoker 28 (19%), performance status<2 110 (75%), non-squamous histology 107 (73%). The main results are shown in Table 1. No difference of progression free survival between those without past radiotherapy and received in past 6 months was noted [adjusted hazard ratio (HR) 0.65; 95% confidence interval (CI) 0.37–1.14]. Ten patients (7%) suffered pneumonitis. Two patients received radiotherapy to the lung before one year. Eight patients did not received radiotherapy to the lung (risk ratio 1.34; 95% CI 0.30– 5.90). Past radiotherapy was not a predictive factor. Our study had limited sample size (146 patients with 112 events). Assuming a two-sided a of 0.05, the power to detect the HR of 0.65 was 0.63. So, the conclusion might change with the larger sample size. The results do not deny the additional effect of concurrent radiotherapy with immune checkpoint inhibitor in NSCLC. Further investigation of concurrent radiotherapy is warranted.

Are All ALK Inhibitors Really Necessary

In Response: We thank Dr. Kim for insightful comments and fully agree that the current practice in the United States, supported by the National Comprehensive Cancer Network guidelines, is not evidence based. Indeed, the European Organization for Research and Treatment of Cancer randomized trial that showed improvement in overall survival with the addition of prophylactic cranial irradiation (PCI) did not use brain magnetic resonance imaging (MRI) before treatment or during follow-up. From Dr. Kim’s letter, it is evident that on the basis of the results of the Japan Clinical Oncology Group (JCOG) randomized trial, our Japanese colleagues do not routinely use PCI in extensive stage SCLC but instead follow patients by close monitoring with brain MRI imaging at regular intervals and offer whole brain radiation therapy to patients who develop brain metastases. Our main concern with the JCOG trial is that was presented in 2014 but has not yet been published, either in Japan or elsewhere. A trial that has not been published within 2 years of initial presentation raises significant suspicions and should not dictate the standard of care. Until the JCOG trial is published, clinicians will not know the true benefit (or harm) of PCI in patients who are screened with brain MRI before starting the treatment, and a new clinical trial is greatly needed to answer this question. Our goal with this survey study was to highlight the disconnect between the clinical evidence and practice in the United States and, it is hoped, incite interest in conducting a new randomized trial for patients with extensive stage SCLC.

Exercise can improve sleep quality: a systematic review and meta-analysis

Background Insomnia is common. However, no systematic reviews have examined the effect of exercise on patients with primary and secondary insomnia, defined as both sleep disruption and daytime impairment. This systematic review and meta-analysis aimed to examine the effectiveness/efficacy of exercise in patients with insomnia. Methods We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, PsycINFO, World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov to identify all randomized controlled trials that examined the effects of exercise on various sleep parameters in patients with insomnia. All participants were diagnosed with insomnia, using standard diagnostic criteria or predetermined criteria and standard measures. Data on outcome measures were subjected to meta-analyses using random-effects models. The Cochrane Risk of Bias Tool and Grading of Recommendations, Assessment, Development, and Evaluation approach were used to assess the quality of the individual studies and the body of evidence, respectively. Results We included nine studies with a total of 557 participants. According to the Pittsburgh Sleep Quality Index (mean difference [MD], 2.87 points lower in the intervention group; 95% confidence interval [CI], 3.95 points lower to 1.79 points lower; low-quality evidence) and the Insomnia Severity Index (MD, 3.22 points lower in the intervention group; 95% CI, 5.36 points lower to 1.07 points lower; very low-quality evidence), exercise was beneficial. However, exercise interventions were not associated with improved sleep efficiency (MD, 0.56% lower in the intervention group; 95% CI, 3.42% lower to 2.31% higher; moderate-quality evidence). Only four studies noted adverse effects. Most studies had a high or unclear risk of selection bias. Discussion Our findings suggest that exercise can improve sleep quality without notable adverse effects. Most trials had a high risk of selection bias. Higher quality research is needed.

Rehabilitation for patients with sepsis: A systematic review and meta-analysis

The objective of this systematic review was to determine whether rehabilitation impacts clinically relevant outcomes among adult patients with sepsis. Randomized controlled trials from the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PEDro, and the World Health Organization International Clinical Trials Platform Search Portal, as well as conference proceedings and reference lists of relevant articles were collected. Two reviewers independently identified randomized controlled trials on the rehabilitation of patients with sepsis, and the two reviewers independently abstracted trial level data including population characteristics, interventions, comparisons, and clinical outcomes. Our primary outcomes were quality of life (QOL), activity of daily living (ADL), and mortality. Our secondary outcomes were length of stay, return to work, muscle strength, delirium, and all adverse events. The quality of evidence was determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. We included two trials enrolling 75 patients. The mean difference (95% confidence interval [CI]) of physical function and physical role in QOL measured by SF-36 were 21.10 (95% CI: 6.57–35.63) and 44.40 (95% CI: 22.55–66.05), respectively. Rehabilitation did not significantly decrease intensive care unit (ICU) mortality (risk ratio, 2.02 [95% CI: 0.46–8.91], I2 = 0%; n = 75). ICU length of stay and hospital length of stay and muscle strength were not statistically significantly different and no adverse events were reported in both studies. The certainty of the evidence for these outcomes was “very low.” Data on ADL, return to work, and delirium were not available in any of the trials. Rehabilitation of patients with sepsis might not decrease ICU mortality, but might improve QOL. Further, well-designed trials measuring important outcomes will be needed to determine the benefit and harm of rehabilitation among patients with sepsis.