Randomized clinical trial on epidural versus patient-controlled analgesia for laparoscopic colorectal surgery within an enhanced recovery pathway.

OBJECTIVE: To compare epidural analgesia (EDA) to patient-controlled opioid-based analgesia (PCA) in patients undergoing laparoscopic colorectal surgery. BACKGROUND: EDA is mainstay of multimodal pain management within enhanced recovery pathways [enhanced recovery after surgery (ERAS)]. For laparoscopic colorectal resections, the benefit of epidurals remains debated. Some consider EDA as useful, whereas others perceive epidurals as unnecessary or even deleterious. METHODS: A total of 128 patients undergoing elective laparoscopic colorectal resections were enrolled in a randomized clinical trial comparing EDA versus PCA. Primary end point was medical recovery. Overall complications, hospital stay, perioperative vasopressor requirements, and postoperative pain scores were secondary outcome measures. Analysis was performed according to the intention-to-treat principle. RESULTS: Final analysis included 65 EDA patients and 57 PCA patients. Both groups were similar regarding baseline characteristics. Medical recovery required a median of 5 days (interquartile range [IQR], 3-7.5 days) in EDA patients and 4 days (IQR, 3-6 days) in the PCA group (P = 0.082). PCA patients had significantly less overall complications [19 (33%) vs 35 (54%); P = 0.029] but a similar hospital stay [5 days (IQR, 4-8 days) vs 7 days (IQR, 4.5-12 days); P = 0.434]. Significantly more EDA patients needed vasopressor treatment perioperatively (90% vs 74%, P = 0.018), the day of surgery (27% vs 4%, P < 0.001), and on postoperative day 1 (29% vs 4%, P < 0.001), whereas no difference in postoperative pain scores was noted. CONCLUSIONS: Epidurals seem to slow down recovery after laparoscopic colorectal resections without adding obvious benefits. EDA can therefore not be recommended as part of ERAS pathways in laparoscopic colorectal surgery.

Clinical trial designs for rare diseases: studies developed and discussed by the International Rare Cancers Initiative.

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research. SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed. RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design. INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial.

PURPOSE: Rechallenge with temozolomide (TMZ) at first progression of glioblastoma after temozolomide chemoradiotherapy (TMZ/RT→TMZ) has been studied in retrospective and single-arm prospective studies, applying temozolomide continuously or using 7/14 or 21/28 days schedules. The DIRECTOR trial sought to show superiority of the 7/14 regimen. EXPERIMENTAL DESIGN: Patients with glioblastoma at first progression after TMZ/RT→TMZ and at least two maintenance temozolomide cycles were randomized to Arm A [one week on (120 mg/m(2) per day)/one week off] or Arm B [3 weeks on (80 mg/m(2) per day)/one week off]. The primary endpoint was median time-to-treatment failure (TTF) defined as progression, premature temozolomide discontinuation for toxicity, or death from any cause. O(6)-methylguanine DNA methyltransferase (MGMT) promoter methylation was prospectively assessed by methylation-specific PCR. RESULTS: Because of withdrawal of support, the trial was prematurely closed to accrual after 105 patients. There was a similar outcome in both arms for median TTF [A: 1.8 months; 95% confidence intervals (CI), 1.8-3.2 vs. B: 2.0 months; 95% CI, 1.8-3.5] and overall survival [A: 9.8 months (95% CI, 6.7-13.0) vs. B: 10.6 months (95% CI, 8.1-11.6)]. Median TTF in patients with MGMT-methylated tumors was 3.2 months (95% CI, 1.8-7.4) versus 1.8 months (95% CI, 1.8-2) in MGMT-unmethylated glioblastoma. Progression-free survival rates at 6 months (PFS-6) were 39.7% with versus 6.9% without MGMT promoter methylation. CONCLUSIONS: Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation.

Effect Estimation of an Innovative Nursing Intervention to Improve Delirium among Home-Dwelling Older Adults: A Randomized Controlled Pilot Trial.

AIMS: Estimating the effect of a nursing intervention in home-dwelling older adults on the occurrence and course of delirium and concomitant cognitive and functional impairment. METHODS: A randomized clinical pilot trial using a before/after design was conducted with older patients discharged from hospital who had a medical prescription to receive home care. A total of 51 patients were randomized into the experimental group (EG) and 52 patients into the control group (CG). Besides usual home care, nursing interventions were offered by a geriatric nurse specialist to the EG at 48 h, 72 h, 7 days, 14 days, and 21 days after discharge. All patients were monitored for symptoms of delirium using the Confusion Assessment Method. Cognitive and functional statuses were measured with the Mini-Mental State Examination and the Katz and Lawton Index. RESULTS: No statistical differences with regard to symptoms of delirium (p = 0.085), cognitive impairment (p = 0.151), and functional status (p = 0.235) were found between the EG and CG at study entry and at 1 month. After adjustment, statistical differences were found in favor of the EG for symptoms of delirium (p = 0.046), cognitive impairment (p = 0.015), and functional status (p = 0.033). CONCLUSION: Nursing interventions to detect delirium at home are feasible and accepted. The nursing interventions produced a promising effect to improve delirium.

Statistical Reviewers Improve Reporting in Biomedical Articles: a Randomized Trial.

Background. Although peer review is widely considered to be the most credible way of selecting manuscripts and improving the quality of accepted papers in scientific journals, there is little evidence to support its use. Our aim was to estimate the effects on manuscript quality of either adding a statistical peer reviewer or suggesting the use of checklists such as CONSORT or STARD to clinical reviewers or both. Methodology and Principal Findings. Interventions were defined as 1) the addition of a statistical reviewer to the clinical peer review process, and 2) suggesting reporting guidelines to reviewers; with"no statistical expert" and"no checklist" as controls. The two interventions were crossed in a 262 balanced factorial design including original research articles consecutively selected, between May 2004 and March 2005, by the Medicina Clinica (Barc) editorial committee. We randomized manuscripts to minimize differences in terms of baseline quality and type of study (intervention, longitudinal, cross-sectional, others). Sample-size calculations indicated that 100 papers provide an 80% power to test a 55% standardized difference. We specified the main outcome as the increment in quality of papers as measured on the Goodman Scale. Two blinded evaluators rated the quality of manuscripts at initial submission and final post peer review version. Of the 327 manuscripts submitted to the journal, 131 were accepted for further review, and 129 were randomized. Of those, 14 that were lost to follow-up showed no differences in initial quality to the followed-up papers. Hence, 115 were included in the main analysis, with 16 rejected for publication after peer review. 21 (18.3%) of the 115 included papers were interventions, 46 (40.0%) were longitudinal designs, 28 (24.3%) cross-sectional and 20 (17.4%) others. The 16 (13.9%) rejected papers had a significantly lower initial score on the overall Goodman scale than accepted papers (difference 15.0, 95% CI: 4.6- 24.4). The effect of suggesting a guideline to the reviewers had no effect on change in overall quality as measured by the Goodman scale (0.9, 95% CI: 20.3+2.1). The estimated effect of adding a statistical reviewer was 5.5 (95% CI: 4.3-6.7), showing a significant improvement in quality. Conclusions and Significance. This prospective randomized study shows the positive effect of adding a statistical reviewer to the field-expert peers in improving manuscript quality. We did not find a statistically significant positive effect by suggesting reviewers use reporting guidelines.

Frequent users of the emergency department in a universal health coverage system : a randomized controlled trial of a case-management intervention

BACKGROUND: Frequent emergency department users represent a small number of patients but account for a large number of emergency department visits. They should be a focus because they are often vulnerable patients with many risk factors affecting their quality of life (QoL). Case management interventions have resulted in a significant decrease in emergency department visits, but association with QoL has not been assessed. One aim of our study was to examine to what extent an interdisciplinary case management intervention, compared to standard emergency care, improved frequent emergency department users' QoL. METHODS: Data are part of a randomized, controlled trial designed to improve frequent emergency department users' QoL and use of health-care resources at the Lausanne University Hospital, Switzerland. In total, 250 frequent emergency department users (≥5 attendances during the previous 12 months; ≥ 18 years of age) were interviewed between May 2012 and July 2013. Following an assessment focused on social characteristics; social, mental, and somatic determinants of health; risk behaviors; health care use; and QoL, participants were randomly assigned to the control or the intervention group (n=125 in each group). The final sample included 194 participants (20 deaths, 36 dropouts, n=96 in the intervention group, n=99 in the control group). Participants in the intervention group received a case management intervention by an interdisciplinary, mobile team in addition to standard emergency care. The case management intervention involved four nurses and a physician who provided counseling and assistance concerning social determinants of health, substance-use disorders, and access to the health-care system. The participants' QoL was evaluated by a study nurse using the WHOQOL-BREF five times during the study (at baseline, and at 2, 5.5, 9, and 12 months). Four of the six WHOQOL dimensions of QoL were retained here: physical health, psychological health, social relationship, and environment, with scores ranging from 0 (low QoL) to 100 (high QoL). A linear, mixed-effects model with participants as a random effect was run to analyze the change in QoL over time. The effects of time, participants' group, and the interaction between time and group were tested. These effects were controlled for sociodemographic characteristics and health-related variables (i.e., age, gender, education, citizenship, marital status, type of financial resources, proficiency in French, somatic and mental health problems, and behaviors at risk).

Impact of case management on frequent users quality of life : a randomized controlled trial

BACKGROUND: Frequent emergency department users represent a small number of patients but account for a large number of emergency department visits. They should be a focus because they are often vulnerable patients with many risk factors affecting their quality of life (QoL). Case management interventions have resulted in a significant decrease in emergency department visits, but association with QoL has not been assessed. One aim of our study was to examine to what extent an interdisciplinary case management intervention, compared to standard emergency care, improved frequent emergency department users' QoL. METHODS: Data are part of a randomized, controlled trial designed to improve frequent emergency department users' QoL and use of health-care resources at the Lausanne University Hospital, Switzerland. In total, 250 frequent emergency department users (≥5 attendances during the previous 12 months; ≥ 18 years of age) were interviewed between May 2012 and July 2013. Following an assessment focused on social characteristics; social, mental, and somatic determinants of health; risk behaviors; health care use; and QoL, participants were randomly assigned to the control or the intervention group (n=125 in each group). The final sample included 194 participants (20 deaths, 36 dropouts, n=96 in the intervention group, n=99 in the control group). Participants in the intervention group received a case management intervention by an interdisciplinary, mobile team in addition to standard emergency care. The case management intervention involved four nurses and a physician who provided counseling and assistance concerning social determinants of health, substance-use disorders, and access to the health-care system.

Positive Outcomes Influence the Rate and Time to Publication, but Not the Impact Factor of Publications of Clinical Trial Results

Objectives: Publication bias may affect the validity of evidence based medical decisions. The aim of this study is to assess whether research outcomes affect the dissemination of clinical trial findings, in terms of rate, time to publication, and impact factor of journal publications. Methods and Findings: All drug-evaluating clinical trials submitted to and approved by a general hospital ethics committee between 1997 and 2004 were prospectively followed to analyze their fate and publication. Published articles were identified by searching Pubmed and other electronic databases. Clinical study final reports submitted to the ethics committee, final reports synopses available online and meeting abstracts were also considered as sources of study results. Study outcomes were classified as positive (when statistical significance favoring experimental drug was achieved), negative (when no statistical significance was achieved or it favored control drug) and descriptive (for non-controlled studies). Time to publication was defined as time from study closure to publication. A survival analysis was performed using a Cox regression model to analyze time to publication. Journal impact factors of identified publications were recorded. Publication rate was 48·4% (380/785). Study results were identified for 68·9% of all completed clinical trials (541/785). Publication rate was 84·9% (180/212) for studies with results classified as positive and 68·9% (128/186) for studies with results classified as negative (p<0·001). Median time to publication was 2·09 years (IC95 1·61-2·56) for studies with results classified as positive and 3·21 years (IC95 2·69-3·70) for studies with results classified as negative (hazard ratio 1·99 (IC95 1·55-2·55). No differences were found in publication impact factor between positive (median 6·308, interquartile range: 3·141-28·409) and negative result studies (median 8·266, interquartile range: 4·135-17·157). Conclusions: Clinical trials with positive outcomes have significantly higher rates and shorter times to publication than those with negative results. However, no differences have been found in terms of impact factor.

Longitudinal study of informed consent in innovative therapy research: experience and provisional recommendations from a multicenter trial of intracerebral grafting.

BACKGROUND: There is an urgent need to assess and improve the consent process in clinical trials of innovative therapies for neurodegenerative disorders. METHODS: We performed a longitudinal study of the consent of Huntington's disease patients during the Multicenter Fetal Cell Intracerebral Grafting Trial in Huntington's Disease (MIG-HD) in France and Belgium. Patients and their proxies completed a consent questionnaire at inclusion, before signing the consent form and after one year of follow-up, before randomization and transplantation. The questionnaire explored understanding of the protocol, satisfaction with the information delivered, reasons for participating in the trial and expectations regarding the transplant. Forty-six Huntington's disease patients and 27 proxies completed the questionnaire at inclusion, and 27 Huntington's disease patients and 16 proxies one year later. RESULTS: The comprehension score was high and similar for Huntington's disease patients and proxies at inclusion (72.6% vs 77.8%; P > 0.1) but only decreased in HD patients after one year. The information satisfaction score was high (73.5% vs 66.5%; P > 0.1) and correlated with understanding in both patients and proxies. The motivation and expectation profiles were similar in patients and proxies and remained unchanged after one year. CONCLUSIONS: Cognitively impaired patients with Huntington's disease were capable of consenting to participation in this trial. This consent procedure has presumably strengthened their understanding and should be proposed before signing the consent form in future gene or cell therapy trials for neurodegenerative disorders. Because of the potential cognitive decline, proxies should be designated as provisional surrogate decision-makers, even in competent patients.

Fulvestrant with or without selumetinib, a MEK 1/2 inhibitor, in breast cancer progressing after aromatase inhibitor therapy: A multicentre randomised placebo-controlled double-blind phase II trial, SAKK 21/08.

BACKGROUND: Second line endocrine therapy has limited antitumour activity. Fulvestrant inhibits and downregulates the oestrogen receptor. The mitogen-activated protein kinase (MAPK) pathway is one of the major cascades involved in resistance to endocrine therapy. We assessed the efficacy and safety of fulvestrant with selumetinib, a MEK 1/2 inhibitor, in advanced stage breast cancer progressing after aromatase inhibitor (AI). PATIENTS AND METHODS: This randomised phase II trial included postmenopausal patients with endocrine-sensitive breast cancer. They were ramdomised to fulvestrant combined with selumetinib or placebo. The primary endpoint was disease control rate (DCR) in the experimental arm. ClinicalTrials.gov Indentifier: NCT01160718. RESULTS: Following the planned interim efficacy analysis, recruitment was interrupted after the inclusion of 46 patients (23 in each arm), because the selumetinib-fulvestrant arm did not reach the pre-specified DCR. DCR was 23% (95% confidence interval (CI) 8-45%) in the selumetinib arm and 50% (95% CI 27-75%) in the placebo arm. Median progression-free survival was 3.7months (95% CI 1.9-5.8) in the selumetinib arm and 5.6months (95% CI 3.4-13.6) in the placebo arm. Median time to treatment failure was 5.1 (95% CI 2.3-6.7) and 5.6 (95% CI 3.4-10.2) months, respectively. The most frequent treatment-related adverse events observed in the selumetinib-fulvestrant arm were skin disorders, fatigue, nausea/vomiting, oedema, diarrhoea, mouth disorders and muscle disorders. CONCLUSIONS: The addition of selumetinib to fulvestrant did not show improving patients' outcome and was poorly tolerated at the recommended monotherapy dose. Selumetinib may have deteriorated the efficacy of the endocrine therapy in some patients.

Assessment of subjective and hemodynamic tolerance of different high- and low-flux dialysis membranes in patients undergoing chronic intermittent hemodialysis: a randomized controlled trial.

Clinical experience and experimental data suggest that intradialytic hemodynamic profiles could be influenced by the characteristics of the dialysis membranes. Even within the worldwide used polysulfone family, intolerance to specific membranes was occasionally evoked. The aim of this study was to compare hemodynamically some of the commonly used polysulfone dialyzers in Switzerland. We performed an open-label, randomized, cross-over trial, including 25 hemodialysis patients. Four polysulfone dialyzers, A (Revaclear high-flux, Gambro, Stockholm, Sweden), B (Helixone high-flux, Fresenius), C (Xevonta high-flux, BBraun, Melsungen, Germany), and D (Helixone low-flux, Fresenius, Bad Homburg vor der Höhe, Germany), were compared. The hemodynamic profile was assessed and patients were asked to provide tolerance feedback. The mean score (±SD) subjectively assigned to dialysis quality on a 1-10 scale was A 8.4 ± 1.3, B 8.6 ± 1.3, C 8.5 ± 1.6, D 8.5 ± 1.5. Kt/V was A 1.58 ± 0.30, B 1.67 ± 0.33, C 1.62 ± 0.32, D 1.45 ± 0.31. The low- compared with the high-flux membranes, correlated to higher systolic (128.1 ± 13.1 vs. 125.6 ± 12.1 mmHg, P < 0.01) and diastolic (76.8 ± 8.7 vs. 75.3 ± 9.0 mmHg; P < 0.05) pressures, higher peripheral resistance (1.44 ± 0.19 vs. 1.40 ± 0.18 s × mmHg/mL; P < 0.05) and lower cardiac output (3.76 ± 0.62 vs. 3.82 ± 0.59 L/min; P < 0.05). Hypotension events (decrease in systolic blood pressure by >20 mmHg) were 70 with A, 87 with B, 73 with C, and 75 with D (P < 0.01 B vs. A, 0.05 B vs. C and 0.07 B vs. D). The low-flux membrane correlated to higher blood pressure levels compared with the high-flux ones. The Helixone high-flux membrane ensured the best efficiency. Unfortunately, the very same dialyzer correlated to a higher incidence of hypotensive episodes.

Glutamine and antioxidants in the critically ill patient: a post hoc analysis of a large-scale randomized trial.

BACKGROUND: The recent large randomized controlled trial of glutamine and antioxidant supplementation suggested that high-dose glutamine is associated with increased mortality in critically ill patients with multiorgan failure. The objectives of the present analyses were to reevaluate the effect of supplementation after controlling for baseline covariates and to identify potentially important subgroup effects. MATERIALS AND METHODS: This study was a post hoc analysis of a prospective factorial 2 × 2 randomized trial conducted in 40 intensive care units in North America and Europe. In total, 1223 mechanically ventilated adult patients with multiorgan failure were randomized to receive glutamine, antioxidants, both glutamine and antioxidants, or placebo administered separate from artificial nutrition. We compared each of the 3 active treatment arms (glutamine alone, antioxidants alone, and glutamine + antioxidants) with placebo on 28-day mortality. Post hoc, treatment effects were examined within subgroups defined by baseline patient characteristics. Logistic regression was used to estimate treatment effects within subgroups after adjustment for baseline covariates and to identify treatment-by-subgroup interactions (effect modification). RESULTS: The 28-day mortality rates in the placebo, glutamine, antioxidant, and combination arms were 25%, 32%, 29%, and 33%, respectively. After adjusting for prespecified baseline covariates, the adjusted odds ratio of 28-day mortality vs placebo was 1.5 (95% confidence interval, 1.0-2.1, P = .05), 1.2 (0.8-1.8, P = .40), and 1.4 (0.9-2.0, P = .09) for glutamine, antioxidant, and glutamine plus antioxidant arms, respectively. In the post hoc subgroup analysis, both glutamine and antioxidants appeared most harmful in patients with baseline renal dysfunction. No subgroups suggested reduced mortality with supplements. CONCLUSIONS: After adjustment for baseline covariates, early provision of high-dose glutamine administered separately from artificial nutrition was not beneficial and may be associated with increased mortality in critically ill patients with multiorgan failure. For both glutamine and antioxidants, the greatest potential for harm was observed in patients with multiorgan failure that included renal dysfunction upon study enrollment.