Colorectal cancer with Synchronous liver-limited Metastases: the protocol of an Inception Cohort study (CoSMIC).

INTRODUCTION: Colorectal cancer is the fourth most common cancer in the UK and an important cause of cancer-related death. In 20% of patients, there is metastasis to the liver or beyond at the time of diagnosis. The management of synchronous disease is complex. Conventional surgery removes the colorectal primary first, followed by chemotherapy, with resection of liver metastases as a final step. Advances in the availability and safety of liver surgery, anaesthesia and critical care have made two alternative options feasible. The first is synchronous resection of the primary and liver metastases. The second is resection of the metastatic disease as the first step, termed the reverse or liver-first approach. Currently, evidence is inadequate to inform the selection of care pathway for patients with colorectal cancer and synchronous liver-limited metastases. Specifically, optimal pathways are not defined and there is a dearth of prospectively recorded cohort-defining factors influencing treatment selection or outcome. METHODS AND ANALYSIS: Colorectal cancer with Synchronous liver-limited Metastases: an Inception Cohort (CoSMIC) is an inception cohort study of patients with a new diagnosis of colorectal cancer with synchronous liver-limited metastases. The sequence of treatment received, and factors influencing treatment decisions, will be evaluated against European Society of Medical Oncology guidelines. Clinical data will be collected, and quality of life, morbidity, mortality and long-term outcome compared for different treatment sequences adjusted for prognostic factors. Disease-free survival or progression will be measured at 1, 2 and 5 years. A nested qualitative study will ascertain patient experiences and clinician perspectives on delivery of care. ETHICS AND DISSEMINATION: The full study protocol was independently peer reviewed by Professor Kees de Jong (University of Maastricht, Holland). CoSMIC has ethical approval from the National Health Service Research Ethics Committee (14/NW/1397). Results will be disseminated to healthcare professionals and patient groups, and may be used to design a definitive trial addressing areas of equipoise in treatment pathways, as well as optimising current pathways to improve outcomes and experiences. TRIAL REGISTRATION NUMBER: NCT02456285, pre-results.

Habit training versus habit training with direct visual biofeedback in adults with chronic constipation: study protocol for a randomised controlled trial.

BACKGROUND: Constipation affects up to 20% of adults. Chronic constipation (CC) affects 1-2% of adults. Patient dissatisfaction is high; nearly 80% feel that laxative therapy is unsatisfactory and symptoms have significant impact on quality of life. There is uncertainty about the value of specialist investigations and whether equipment-intensive therapies using biofeedback confer additional benefit when compared with specialist conservative advice. METHODS/DESIGN: A three-arm, parallel-group, multicentre randomised controlled trial. OBJECTIVES: to determine whether standardised specialist-led habit training plus pelvic floor retraining using computerised biofeedback is more clinically effective than standardised specialist-led habit training alone; to determine whether outcomes are improved by stratification based on prior investigation of anorectal and colonic pathophysiology. Primary outcome measure is response to treatment, defined as a 0.4-point (10% of scale) or greater reduction in Patient Assessment of Constipation-Quality of Life (PAC-QOL) score 6 months after the end of treatment. Other outcomes up to 12 months include symptoms, quality of life, health economics, psychological health and qualitative experience. HYPOTHESES: (1) habit training (HT) with computer-assisted direct visual biofeedback (HTBF) results in an average reduction in PAC-QOL score of 0.4 points at 6 months compared to HT alone in unselected adults with CC, (2) stratification to either HT or HTBF informed by pathophysiological investigation (INVEST) results in an average 0.4-point reduction in PAC-QOL score at 6 months compared with treatment not directed by investigations (No-INVEST). Inclusion: chronic constipation in adults (aged 18-70 years) defined by self-reported symptom duration of more than 6 months; failure of previous laxatives or prokinetics and diet and lifestyle modifications. Consenting participants (n = 394) will be randomised to one of three arms in an allocation ratio of 3:3:2: [1] habit training, [2] habit training and biofeedback or [3] investigation-led allocation to one of these arms. Analysis will be on an intention-to-treat basis. DISCUSSION: This trial has the potential to answer some of the major outstanding questions in the management of chronic constipation, including whether costly invasive tests are warranted and whether computer-assisted direct visual biofeedback confers additional benefit to well-managed specialist advice alone. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number: ISRCTN11791740. Registered on 16 July 2015.

Biodegradable stent or balloon dilatation for benign oesophageal stricture: pilot randomised controlled trial.

AIM: To undertake a randomised pilot study comparing biodegradable stents and endoscopic dilatation in patients with strictures. METHODS: This British multi-site study recruited seventeen symptomatic adult patients with refractory strictures. Patients were randomised using a multicentre, blinded assessor design, comparing a biodegradable stent (BS) with endoscopic dilatation (ED). The primary endpoint was the average dysphagia score during the first 6 mo. Secondary endpoints included repeat endoscopic procedures, quality of life, and adverse events. Secondary analysis included follow-up to 12 mo. Sensitivity analyses explored alternative estimation methods for dysphagia and multiple imputation of missing values. Nonparametric tests were used. RESULTS: Although both groups improved, the average dysphagia scores for patients receiving stents were higher after 6 mo: BS-ED 1.17 (95%CI: 0.63-1.78) P = 0.029. The finding was robust under different estimation methods. Use of additional endoscopic procedures and quality of life (QALY) estimates were similar for BS and ED patients at 6 and 12 mo. Concomitant use of gastrointestinal prescribed medication was greater in the stent group (BS 5.1, ED 2.0 prescriptions; P < 0.001), as were related adverse events (BS 1.4, ED 0.0 events; P = 0.024). Groups were comparable at baseline and findings were statistically significant but numbers were small due to under-recruitment. The oesophageal tract has somatic sensitivity and the process of the stent dissolving, possibly unevenly, might promote discomfort or reflux. CONCLUSION: Stenting was associated with greater dysphagia, co-medication and adverse events. Rigorously conducted and adequately powered trials are needed before widespread adoption of this technology.

Antioxidant therapy does not reduce pain in patients with chronic pancreatitis: the ANTICIPATE study.

BACKGROUND & AIMS: We investigated whether antioxidant therapy reduces pain and improves quality of life in patients with chronic pancreatitis. METHODS: We performed a double-blind, randomized, controlled trial that compared the effects of antioxidant therapy with placebo in 70 patients with chronic pancreatitis. Patients provided 1 month of baseline data and were followed for 6 months while receiving either antioxidant therapy (Antox version 1.2, Pharma Nord, Morpeth, UK) or matched placebo (2 tablets, 3 times/day). The primary analysis was baseline-adjusted change in pain score at 6 months, assessed by an 11-point numeric rating scale. Secondary analyses included alternative assessments of clinical and diary pain scores, scores on quality-of-life tests (the European Organization for Research and Treatment of Cancer [EORTC-QLQ-C30], Quality of Life Questionnaire-Pancreatic modification [QLQ-PAN28], European Quality of Life questionnaire [EuroQOL EQ-5D], and European Quality of Life questionnaire - Visual Analog Score [EQ-VAS]), levels of antioxidants, use of opiates, and adverse events. Analyses, reported by intention to treat, were prospectively defined by protocol. RESULTS: After 6 months, pain scores reported to the clinic were reduced by 1.97 from baseline in the placebo group and by 2.33 in the antioxidant group but were similar between groups (-0.36; 95% confidence interval [CI], -1.44 to 0.72; P = .509). Average daily pain scores from diaries were also similar (3.05 for the placebo group and 2.93 for the antioxidant group, a difference of 0.11; 95% CI, 1.05-0.82; P = .808). Measures of quality of life were similar between groups, as was opiate use and number of hospital admissions and outpatient visits. Blood levels of vitamin C and E, ß-carotene, and selenium were increased significantly in the antioxidant group. CONCLUSIONS: Administration of antioxidants to patients with painful chronic pancreatitis of predominantly alcoholic origin does not reduce pain or improve quality of life, despite causing a sustained increase in blood levels of antioxidants.

Relaxation therapies for the management of primary hypertension in adults.

BACKGROUND: Lifestyle interventions are often recommended as initial treatment for mild hypertension, but the efficacy of relaxation therapies is unclear. OBJECTIVES: To evaluate the effects of relaxation therapies on cardiovascular outcomes and blood pressure in people with elevated blood pressure. SEARCH STRATEGY: We searched the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, ISI Proceedings, ClinicalTrials.gov, Current Controlled Trials and reference lists of systematic reviews, meta-analyses and randomised controlled trials (RCTs) included in the review. INCLUSION CRITERIA: RCTs of a parallel design comparing relaxation therapies with no active treatment, or sham therapy; follow-up >/=8 weeks; participants over 18 years, with raised systolic blood pressure (SBP) >/=140 mmHg or diastolic blood pressure (DBP) >/=85 mmHg); SBP and DBP reported at end of follow-up. EXCLUSION CRITERIA: participants were pregnant; participants received antihypertensive medication which changed during the trial. DATA COLLECTION AND ANALYSIS: Two reviewers independently extracted data and assessed trial quality. Disagreements were resolved by discussion or a third reviewer. Random effects meta-analyses and sensitivity analyses were conducted. MAIN RESULTS: 29 RCTs, with eight weeks to five years follow-up, met our inclusion criteria; four were excluded from the primary meta-analysis because of inadequate outcome data. The remaining 25 trials assessed 1,198 participants, but adequate randomisation was confirmed in only seven trials and concealment of allocation in only one. Only one trial reported deaths, heart attacks and strokes (one of each). Meta-analysis indicated that relaxation resulted in small, statistically significant reductions in SBP (mean difference: -5.5 mmHg, 95% CI: -8.2 to -2.8, I2 =72%) and DBP (mean difference: -3.5 mmHg, 95% CI: -5.3 to -1.6, I2 =75%) compared to control. The substantial heterogeneity between trials was not explained by duration of follow-up, type of control, type of relaxation therapy or baseline blood pressure. The nine trials that reported blinding of outcome assessors found a non-significant net reduction in blood pressure (SBP mean difference: -3.2 mmHg, 95% CI: -7.7 to 1.4, I(2) =69%) associated with relaxation. The 15 trials comparing relaxation with sham therapy likewise found a non-significant reduction in blood pressure (SBP mean difference: -3.5 mmHg, 95% CI: -7.1 to 0.2, I(2) =63%). AUTHORS' CONCLUSIONS: In view of the poor quality of included trials and unexplained variation between trials, the evidence in favour of causal association between relaxation and blood pressure reduction is weak. Some of the apparent benefit of relaxation was probably due to aspects of treatment unrelated to relaxation.

Randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in severe acute pancreatitis.

BACKGROUND: Based on equivocal clinical data, intravenous antioxidant therapy has been used for the treatment of severe acute pancreatitis. To date there is no randomised comparison of this therapy in severe acute pancreatitis. METHODS: We conducted a randomised, double blind, placebo controlled trial of intravenous antioxidant (n-acetylcysteine, selenium, vitamin C) therapy in patients with predicted severe acute pancreatitis. Forty-three patients were enrolled from three hospitals in the Manchester (UK) area over the period June 2001 to November 2004. Randomisation stratified for APACHE-II score and hospital site, and delivered groups that were similar at baseline. RESULTS: Relative serum levels of antioxidants rose while markers of oxidative stress fell in the active treatment group during the course of the trial. However, at 7 days, there was no statistically significant difference in the primary end point, organ dysfunction (antioxidant vs placebo: 32% vs 17%, p = 0.33) or any secondary end point of organ dysfunction or patient outcome. CONCLUSIONS: This study provides no evidence to justify continued use of n-acetylcysteine, selenium, vitamin C based antioxidant therapy in severe acute pancreatitis. In the context of any future trial design, careful consideration must be given to the risks raised by the greater trend towards adverse outcome in patients in the treatment arm of this study.

Lifestyle interventions to reduce raised blood pressure: a systematic review of randomized controlled trials.

PURPOSE: To quantify effectiveness of lifestyle interventions for hypertension. DATA SOURCES: Electronic bibliographic databases from 1998 onwards, existing guidelines, systematic reviews. STUDY SELECTION AND DATA ABSTRACTION: We included randomized, controlled trials with at least 8 weeks' follow-up, comparing lifestyle with control interventions, enrolling adults with blood pressure at least 140/85 mmHg. Primary outcome measures were systolic and diastolic blood pressure. Two independent reviewers selected trials and abstracted data; differences were resolved by discussion. RESULTS: We categorized trials by type of intervention and used random effects meta-analysis to combine mean differences between endpoint blood pressure in treatment and control groups in 105 trials randomizing 6805 participants. Robust statistically significant effects were found for improved diet, aerobic exercise, alcohol and sodium restriction, and fish oil supplements: mean reductions in systolic blood pressure of 5.0 mmHg [95% confidence interval (CI): 3.1-7.0], 4.6 mmHg (95% CI: 2.0-7.1), 3.8 mmHg (95% CI: 1.4-6.1), 3.6 mmHg (95% CI: 2.5-4.6) and 2.3 mmHg (95% CI: 0.2-4.3), respectively, with corresponding reductions in diastolic blood pressure. Relaxation significantly reduced blood pressure only when compared with non-intervention controls. We found no robust evidence of any important effect on blood pressure of potassium, magnesium or calcium supplements. CONCLUSIONS: Patients with elevated blood pressure should follow a weight-reducing diet, take regular exercise, and restrict alcohol and salt intake. Available evidence does not support relaxation therapies, calcium, magnesium or potassium supplements to reduce blood pressure.