Multi-arm multi-stage (MAMS) randomised selection designs: impact of treatment selection rules on the operating characteristics.

Background: Multi-arm multi-stage (MAMS) randomised trial designs have been proposed to evaluate multiple research questions in the confirmatory setting. In designs with several interventions, such as the 8-arm 3-stage ROSSINI-2 trial for preventing surgical wound infection, there are likely to be strict limits on the number of individuals that can be recruited or the funds available to support the protocol. These limitations may mean that not all research treatments can continue to accrue the required sample size for the definitive analysis of the primary outcome measure at the final stage.

Clinical statistical analysis plan for the ACCURE trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicentre trial.

Background: The primary treatment of ulcerative colitis (UC) is medical therapy using a standard step-up approach. An appendectomy might modulate the clinical course of UC, decreasing the incidence of relapses and reducing need for medication. The objective of the ACCURE trial is to assess the efficacy of laparoscopic appendectomy in addition to standard medical treatment in maintaining remission in UC patients.

Preoperative Chemotherapy for Operable Colon Cancer: Mature Results of an International Randomized Controlled Trial.

Purpose: Neoadjuvant chemotherapy (NAC) has potential advantages over standard postoperative chemotherapy for locally advanced colon cancer but requires formal evaluation.

Methods: Patients with radiologically staged T3-4, N0-2, M0 colon cancer were randomly allocated (2:1) to 6 weeks oxaliplatin-fluoropyrimidine preoperatively plus 18 postoperatively (NAC group) or 24 weeks postoperatively (control group). Patients with -wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC.

Prognostic and Predictive Value of Tumor Budding in Colorectal Cancer.

Background: Tumor budding (TB) is an adverse prognostic factor in colorectal cancer (CRC). International consensus on a standardized assessment method has led to its wider reporting. However, uncertainty regarding its clinical value persists.

Radical surgery versus organ preservation via short-course radiotherapy followed by transanal endoscopic microsurgery for early-stage rectal cancer (TREC): a randomised, open-label feasibility study.

Background: Radical surgery via total mesorectal excision might not be the optimal first-line treatment for early-stage rectal cancer. An organ-preserving strategy with selective total mesorectal excision could reduce the adverse effects of treatment without substantially compromising oncological outcomes. We investigated the feasibility of recruiting patients to a randomised trial comparing an organ-preserving strategy with total mesorectal excision.

A Multicenter Randomized Controlled Trial Comparing Safety, Efficacy, and Cost-effectiveness of the Surgisis Anal Fistula Plug Versus Surgeon's Preference for Transsphincteric Fistula-in-Ano: The FIAT Trial.

Objective: To undertake a randomized comparison of the Biodesign Surgisis anal fistula plug against surgeon's preference in treating cryptoglandular transsphincteric fistula-in-ano.

Summary Background Data: The efficacy of the Biodesign Surgisis anal fistula plug in healing anal fistulae is uncertain.

Methods: Participants were randomized to the fistula plug with surgeon's preference (advancement flap, cutting seton, fistulotomy, Ligation of the Intersphincteric Fistula Tract procedure).

Cardiac structure and function after revascularization versus medical therapy for renal artery stenosis: the ASTRAL heart echocardiographic sub-study.

Background: The ASTRAL trial showed no difference in clinical outcomes between medical therapy and revascularization for atherosclerotic renal vascular disease (ARVD). Here we report a sub-study using echocardiography to assess differences in cardiac structure and function at 12 months.

Methods: ASTRAL patients from 7 participating centres underwent echocardiography at baseline and 12 months after randomisation.

Study protocol for a randomised controlled trial of carvedilol versus variceal band ligation in primary prevention of variceal bleeding in liver cirrhosis (CALIBRE trial).

Introduction: Liver cirrhosis is the fifth largest cause of adult deaths, and a major complication, variceal bleeding is associated with a 1-year mortality of 40%. There is uncertainty on the first-line therapy for prevention of variceal bleeding owing to a lack of adequately powered trials comparing non-selective beta blockers, in particular carvedilol, with variceal band ligation.

Methods And Analysis: CALIBRE is a multicentre, pragmatic, randomised controlled, open-label trial with an internal pilot.

Anal fistula plug versus surgeon's preference for surgery for trans-sphincteric anal fistula: the FIAT RCT.

Background: The aim of fistula surgery is to eradicate the disease while preserving anal sphincter function. The efficacy of the Surgisis anal fistula plug (Cook Medical, Bloomington, IN, USA) in the treatment of trans-sphincteric fistula-in-ano has been variably reported.

Objectives: To undertake a randomised comparison of the safety and efficacy of the Surgisis anal fistula plug in comparison with surgeon's preference for the treatment of trans-sphincteric anal fistulas.

Confirmation that somatic mutations of beta-2 microglobulin correlate with a lack of recurrence in a subset of stage II mismatch repair deficient colorectal cancers from the QUASAR trial.

Aims: Beta2-microglobulin (B2M) forms part of the HLA class I complex and plays a role in metastatic biology. B2M mutations occur frequently in mismatch repair-deficient colorectal cancer (dMMR CRC), with limited data suggesting they may protect against recurrence. Our experimental study tested this hypothesis by investigating B2M mutation status and B2M protein expression and recurrence in patients in the stage II QUASAR clinical trial.

Intravenous remifentanil patient-controlled analgesia versus intramuscular pethidine for pain relief in labour (RESPITE): an open-label, multicentre, randomised controlled trial.

Background: About a third of women receiving pethidine for labour pain subsequently require an epidural, which provides effective pain relief but increases the risk of instrumental vaginal delivery. Remifentanil patient-controlled analgesia (PCA) in labour is an alternative to pethidine, but is not widely used. We aimed to evaluate epidural analgesia progression among women using remifentanil PCA compared with pethidine.

Can we ave the rectum by watchful waiting or ransnal microsurgery following (chemo) adiotherapy versus otal mesorectal excision for early ctal ancer (STAR-TREC study)?: protocol for a multicentre, randomised feasibility study.

Introduction: Total mesorectal excision (TME) is the highly effective standard treatment for rectal cancer but is associated with significant morbidity and may be overtreatment for low-risk cancers. This study is designed to determine the feasibility of international recruitment in a study comparing organ-saving approaches versus standard TME surgery.

Methods And Analysis: STAR-TREC trial is a multicentre international randomised, three-arm parallel, phase II feasibility study in patients with biopsy-proven adenocarcinoma of the rectum.

Intratumoral stromal morphometry predicts disease recurrence but not response to 5-fluorouracil-results from the QUASAR trial of colorectal cancer.

Aims: The biological importance of tumour-associated stroma is becoming increasingly apparent, but its clinical utility remains ill-defined. For stage II/Dukes B colorectal cancer (CRC), clinical biomarkers are urgently required to direct therapeutic options. We report here prognostic/predictive analyses, and molecular associations, of stromal morphometric quantification in the Quick and Simple and Reliable (QUASAR) trial of CRC.

The RESPITE trial: remifentanil intravenously administered patient-controlled analgesia (PCA) versus pethidine intramuscular injection for pain relief in labour: study protocol for a randomised controlled trial.

Background: The commonest opioid used for pain relief in labour is pethidine (meperidine); however, its effectiveness has long been challenged and the drug has known side effects including maternal sedation, nausea and potential transfer across the placenta to the foetus. Over a third of women receiving pethidine require an epidural due to inadequate pain relief. Epidural analgesia increases the risk of an instrumental vaginal delivery and its associated effects.

Effect of renal artery revascularization upon cardiac structure and function in atherosclerotic renal artery stenosis: cardiac magnetic resonance sub-study of the ASTRAL trial.

Background: Cardiac abnormalities are frequent in patients with atherosclerotic renovascular disease (ARVD). The Angioplasty and Stenting for Renal Artery Lesions (ASTRAL) trial studied the effect of percutaneous renal revascularization combined with medical therapy compared with medical therapy alone in 806 patients with ARVD.

Methods: This was a pre-specified sub-study of ASTRAL (clinical trials registration, current controlled trials number: ISRCTN59586944), designed to consider the effect of percutaneous renal artery angioplasty and stenting on change in cardiac structure and function, measured using cardiac magnetic resonance (CMR) imaging.

HER2 overexpression and amplification as a potential therapeutic target in colorectal cancer: analysis of 3256 patients enrolled in the QUASAR, FOCUS and PICCOLO colorectal cancer trials.

HER2 overexpression/amplification is linked to trastuzumab response in breast/gastric cancers. One suggested anti-EGFR resistance mechanism in colorectal cancer (CRC) is aberrant MEK-AKT pathway activation through HER2 up-regulation. We assessed HER2-amplification/overexpression in stage II-III and IV CRC patients, assessing relationships to KRAS/BRAF and outcome.

Dexamethasone reduces emesis after major gastrointestinal surgery (DREAMS).

Background: Postoperative nausea and vomiting is one of the most common complications affecting patients after surgery and causes significant morbidity and increased length of hospital stay. It is accepted that patients undergoing surgery on the bowel are at a higher risk. In the current era of minimally invasive colorectal surgery combined with enhanced recovery, reducing the incidence and severity of postoperative nausea and vomiting is particularly important.

Validation study of a quantitative multigene reverse transcriptase-polymerase chain reaction assay for assessment of recurrence risk in patients with stage II colon cancer.

Purpose: We developed quantitative gene expression assays to assess recurrence risk and benefits from chemotherapy in patients with stage II colon cancer.

Patients And Methods: We sought validation by using RNA extracted from fixed paraffin-embedded primary colon tumor blocks from 1,436 patients with stage II colon cancer in the QUASAR (Quick and Simple and Reliable) study of adjuvant fluoropyrimidine chemotherapy versus surgery alone. A recurrence score (RS) and a treatment score (TS) were calculated from gene expression levels of 13 cancer-related genes (n = 7 recurrence genes and n = 6 treatment benefit genes) and from five reference genes with prespecified algorithms.

Value of mismatch repair, KRAS, and BRAF mutations in predicting recurrence and benefits from chemotherapy in colorectal cancer.

Purpose: It is uncertain whether modest benefits from adjuvant chemotherapy in stage II colorectal cancer justify the toxicity, cost, and inconvenience. We investigated the usefulness of defective mismatch repair (dMMR), BRAF, and KRAS mutations in predicting tumor recurrence and sensitivity to chemotherapy.

Patients And Methods: Immunohistochemistry for dMMR and pyrosequencing for KRAS/BRAF were performed for 1,913 patients randomly assigned between fluorouracil and folinic acid chemotherapy and no chemotherapy in the Quick and Simple and Reliable (QUASAR) trial.

Meta-analysis of the comparative efficacy and safety of adjuvant treatment to levodopa in later Parkinson's disease.

Background: Levodopa initially provides good symptomatic control of the symptoms of Parkinson's disease, but motor complications often develop after long-term use. Other classes of antiparkinsonian drugs including dopamine agonists, catechol-O-methyl transferase inhibitors, or monoamine oxidase type B inhibitors are then added as adjuvant therapy. It is unclear whether one class of drug is more effective than another.

Evaluation of the efficacy and safety of adjuvant treatment to levodopa therapy in Parkinson s disease patients with motor complications.

Background: One of the complications of long-term treatment of Parkinson's disease (PD) with levodopa is the development of motor complications. Generally, when motor complications develop, clinicians add in an additional drug (to the levodopa regimen) from one of three other classes of anti-Parkinsonian treatments (dopamine agonists, catechol-O-methyl transferase inhibitors (COMTIs) or monoamine oxidase type B inhibitors (MAOBIs)). However, despite trials having shown that these drugs are beneficial compared to placebo, it remains unclear as to the best way to treat patients experiencing motor complications and whether one class of drug is more effective than another.