How surgical Trainee Research Collaboratives achieve success: a mixed methods study to develop trainee engagement strategies.

OBJECTIVES: This study aimed to understand the role of surgical Trainee Research Collaboratives (TRCs) in conducting randomised controlled trials and identify strategies to enhance trainee engagement in trials. DESIGN: This is a mixed methods study. We used observation of TRC meetings, semi-structured interviews and an online survey to explore trainees' motivations for engagement in trials and TRCs, including barriers and facilitators. Interviews were analysed thematically, alongside observation field notes. Survey responses were analysed using descriptive statistics. Strategies to enhance TRCs were developed at a workshop by 13 trial methodologists, surgical trainees, consultants and research nurses. SETTING: This study was conducted within a secondary care setting in the UK. PARTICIPANTS: The survey was sent to registered UK surgical trainees. TRC members and linked stakeholders across surgical specialties and UK regions were purposefully sampled for interviews. RESULTS: We observed 5 TRC meetings, conducted 32 semi-structured interviews and analysed 73 survey responses. TRCs can mobilise trainees thus gaining wider access to patients. Trainees engaged with TRCs to improve patient care, surgical evidence and to help progress their careers. Trainees valued the TRC infrastructure, research expertise and mentoring. Challenges for trainees included clinical and other priorities, limited time and confidence, and recognition, especially by authorship. Key TRC strategies were consultant support, initial simple rapid studies, transparency of involvement and recognition for trainees (including authorship policies) and working with Clinical Trials Units and research nurses. A 6 min digital story on YouTube disseminated these strategies. CONCLUSION: Trainee surgeons are mostly motivated to engage with trials and TRCs. Trainee engagement in TRCs can be enhanced through building relationships with key stakeholders, maximising multi-disciplinary working and offering training and career development opportunities.

Transformer-based biomarker prediction from colorectal cancer histology: A large-scale multicentric study.

Deep learning (DL) can accelerate the prediction of prognostic biomarkers from routine pathology slides in colorectal cancer (CRC). However, current approaches rely on convolutional neural networks (CNNs) and have mostly been validated on small patient cohorts. Here, we develop a new transformer-based pipeline for end-to-end biomarker prediction from pathology slides by combining a pre-trained transformer encoder with a transformer network for patch aggregation. Our transformer-based approach substantially improves the performance, generalizability, data efficiency, and interpretability as compared with current state-of-the-art algorithms. After training and evaluating on a large multicenter cohort of over 13,000 patients from 16 colorectal cancer cohorts, we achieve a sensitivity of 0.99 with a negative predictive value of over 0.99 for prediction of microsatellite instability (MSI) on surgical resection specimens. We demonstrate that resection specimen-only training reaches clinical-grade performance on endoscopic biopsy tissue, solving a long-standing diagnostic problem.

The impact of the COVID-19 pandemic upon pancreatic cancer treatment (CONTACT Study): a UK national observational cohort study.

INTRODUCTION: CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic ('COVID' cohort, 16/03/2020-10/05/2020), with 12-month follow-up. RESULTS: Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8-4.1) vs. 4.4 (IQR 3.6-5.2) months, p = 0.093). CONCLUSION: Pathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.

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 RAS-wildtype tumors could also be randomly assigned 1:1 to receive panitumumab or not during NAC. The primary end point was residual disease or recurrence within 2 years. Secondary outcomes included surgical morbidity, histopathologic stage, regression grade, completeness of resection, and cause-specific mortality. Log-rank analyses were by intention-to-treat. RESULTS: Of 699 patients allocated to NAC, 674 (96%) started and 606 (87%) completed NAC. In total, 686 of 699 (98.1%) NAC patients and 351 of 354 (99.2%) control patients underwent surgery. Thirty patients (4.3%) allocated to NAC developed obstructive symptoms requiring expedited surgery, but there were fewer serious postoperative complications with NAC than with control. NAC produced marked T and N downstaging and histologic tumor regression (all P < .001). Resection was more often histopathologically complete: 94% (648/686) versus 89% (311/351), P < .001. Fewer NAC than control patients had residual or recurrent disease within 2 years (16.9% [118/699] v 21.5% [76/354]; rate ratio, 0.72 [95% CI, 0.54 to 0.98]; P = .037). Tumor regression correlated strongly with freedom from recurrence. Panitumumab did not enhance the benefit from NAC. Little benefit from NAC was seen in mismatch repair-deficient tumors. CONCLUSION: Six weeks of preoperative oxaliplatin-fluoropyrimidine chemotherapy for operable colon cancer can be delivered safely, without increasing perioperative morbidity. This chemotherapy regimen, when given preoperatively, produces marked histopathologic down-staging, fewer incomplete resections, and better 2-year disease control. Histologic regression after NAC is a strong predictor of lower postoperative recurrence risk so has potential use as a guide for postoperative therapy. Six weeks of NAC should be considered as a treatment option for locally advanced colon cancer.

Quality-of-life outcomes in older patients with early-stage rectal cancer receiving organ-preserving treatment with hypofractionated short-course radiotherapy followed by transanal endoscopic microsurgery (TREC): non-randomised registry of patients unsuitable for total mesorectal excision.

BACKGROUND: Older patients with early-stage rectal cancer are under-represented in clinical trials and, therefore, little high-quality data are available to guide treatment in this patient population. The TREC trial was a randomised, open-label feasibility study conducted at 21 centres across the UK that compared organ preservation through short-course radiotherapy (SCRT; 25 Gy in five fractions) plus transanal endoscopic microsurgery (TEM) with standard total mesorectal excision in adults with stage T1-2 rectal adenocarcinoma (maximum diameter ≤30 mm) and no lymph node involvement or metastasis. TREC incorporated a non-randomised registry offering organ preservation to patients who were considered unsuitable for total mesorectal excision by the local colorectal cancer multidisciplinary team. Organ preservation was achieved in 56 (92%) of 61 non-randomised registry patients with local recurrence-free survival of 91% (95% CI 84-99) at 3 years. Here, we report acute and long-term patient-reported outcomes from this non-randomised registry group. METHODS: Patients considered by the local colorectal cancer multidisciplinary team to be at high risk of complications from total mesorectal excision on the basis of frailty, comorbidities, and older age were included in a non-randomised registry to receive organ-preserving treatment. These patients were invited to complete questionnaires on patient-reported outcomes (the European Organisation for Research and Treatment of Cancer Quality of Life [EORTC-QLQ] questionnaire core module [QLQ-C30] and colorectal cancer module [QLQ-CR29], the Colorectal Functional Outcome [COREFO] questionnaire, and EuroQol-5 Dimensions-3 Level [EQ-5D-3L]) at baseline and at months 3, 6, 12, 24, and 36 postoperatively. To aid interpretation, data from patients in the non-randomised registry were compared with data from those patients in the TREC trial who had been randomly assigned to organ-preserving therapy, and an additional reference cohort of aged-matched controls from the UK general population. This study is registered with the ISRCTN registry, ISRCTN14422743, and is closed. FINDINGS: Between July 21, 2011, and July 15, 2015, 88 patients were enrolled onto the TREC study to undergo organ preservation, of whom 27 (31%) were randomly allocated to organ-preserving therapy and 61 (69%) were added to the non-randomised registry for organ-preserving therapy. Non-randomised patients were older than randomised patients (median age 74 years [IQR 67-80] vs 65 years [61-71]). Organ-preserving treatment was well tolerated among patients in the non-randomised registry, with mild worsening of fatigue; quality of life; physical, social, and role functioning; and bowel function 3 months postoperatively compared with baseline values. By 6-12 months, most scores had returned to baseline values, and were indistinguishable from data from the reference cohort. Only mild symptoms of faecal incontinence and urgency, equivalent to less than one episode per week, persisted at 36 months among patients in both groups. INTERPRETATION: The SCRT and TEM organ-preservation approach was well tolerated in older and frailer patients, showed good rates of organ preservation, and was associated with low rates of acute and long-term toxicity, with minimal effects on quality of life and functional status. Our findings support the adoption of this approach for patients considered to be at high risk from radical surgery. FUNDING: Cancer Research UK.

The impact of preoperative oral nutrition supplementation on outcomes in patients undergoing gastrointestinal surgery for cancer in low- and middle-income countries: a systematic review and meta-analysis.

Malnutrition is an independent predictor for postoperative complications in low- and middle-income countries (LMICs). We systematically reviewed evidence on the impact of preoperative oral nutrition supplementation (ONS) on patients undergoing gastrointestinal cancer surgery in LMICs. We searched EMBASE, Cochrane Library, Web of Science, Scopus, WHO Global Index Medicus, SciELO, Latin American and Caribbean Health Sciences Literature (LILACS) databases from inception to March 21, 2022 for randomised controlled trials evaluating preoperative ONS in gastrointestinal cancer within LMICs. We evaluated the impact of ONS on all postoperative outcomes using random-effects meta-analysis. Seven studies reported on 891 patients (446 ONS group, 445 control group) undergoing surgery for gastrointestinal cancer. Preoperative ONS reduced all cause postoperative surgical complications (risk ratio (RR) 0.53, 95% CI 0.46-0.60, P < 0.001, I2 = 0%, n = 891), infection (0.52, 0.40-0.67, P = 0.008, I2 = 0%, n = 570) and all-cause mortality (0.35, 0.26-0.47, P = 0.014, I2 = 0%, n = 588). Despite heterogeneous populations and baseline rates, absolute risk ratio (ARR) was reduced for all cause (pooled effect -0.14, -0.22 to -0.06, P = 0.006; number needed to treat (NNT) 7) and infectious complications (-0.13, -0.22 to -0.06, P < 0.001; NNT 8). Preoperative nutrition in patients undergoing gastrointestinal cancer surgery in LMICs demonstrated consistently strong and robust treatment effects across measured outcomes. However additional higher quality research, with particular focus within African populations, are urgently required.

Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy: meta-analysis.

BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.

Can trainees safely perform pancreatoenteric anastomosis? A systematic review, meta-analysis, and risk-adjusted analysis of postoperative pancreatic fistula.

BACKGROUND: The complexity of pancreaticoduodenectomy and fear of morbidity, particularly postoperative pancreatic fistula, can be a barrier to surgical trainees gaining operative experience. This meta-analysis sought to compare the postoperative pancreatic fistula rate after pancreatoenteric anastomosis by trainees or established surgeons. METHODS: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with differences in postoperative pancreatic fistula rates after pancreatoenteric anastomosis between trainee-led versus consultant/attending surgeons pooled using meta-analysis. Variation in rates of postoperative pancreatic fistula was further explored using risk-adjusted outcomes using published risk scores and cumulative sum control chart analysis in a retrospective cohort. RESULTS: Across 14 cohorts included in the meta-analysis, trainees tended toward a lower but nonsignificant rate of all postoperative pancreatic fistula (odds ratio: 0.77, P = .45) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.69, P = .37). However, there was evidence of case selection, with trainees being less likely to operate on patients with a pancreatic duct width <3 mm (odds ratio: 0.45, P = .05). Similarly, analysis of a retrospective cohort (N = 756 cases) found patients operated by trainees to have significantly lower predicted all postoperative pancreatic fistula (median: 20 vs 26%, P < .001) and clinically relevant postoperative pancreatic fistula (7 vs 9%, P = .020) rates than consultant/attending surgeons, based on preoperative risk scores. After adjusting for this on multivariable analysis, the risks of all postoperative pancreatic fistula (odds ratio: 1.18, P = .604) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.85, P = .693) remained similar after pancreatoenteric anastomosis by trainees or consultant/attending surgeons. CONCLUSION: Pancreatoenteric anastomosis, when performed by trainees, is associated with acceptable outcomes. There is evidence of case selection among patients undergoing surgery by trainees; hence, risk adjustment provides a critical tool for the objective evaluation of performance.

External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores. METHODS: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. RESULTS: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. CONCLUSION: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. . Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.

Health-related quality of life, uncertainty and coping strategies in solid organ transplant recipients during shielding for the COVID-19 pandemic.

Strict isolation of vulnerable individuals has been a strategy implemented by authorities to protect people from COVID-19. Our objective was to investigate health-related quality of life (HRQoL), uncertainty and coping behaviours in solid organ transplant (SOT) recipients during the COVID-19 pandemic. A cross-sectional survey of adult SOT recipients undergoing follow-up at our institution was performed. Perceived health status, uncertainty and coping strategies were assessed using the EQ-5D-5L, Short-form Mishel Uncertainty in Illness Scale (SF-MUIS) and Brief Cope, respectively. Interactions with COVID-19 risk perception, access to health care, demographic and clinical variables were assessed. The survey was completed by 826 of 3839 (21.5%) invited participants. Overall, low levels of uncertainty in illness were reported, and acceptance was the major coping strategy (92%). Coping by acceptance, feeling protected, self-perceived susceptibility to COVID-19 were associated with lower levels of uncertainty. Health status index scores were significantly lower for those with mental health illness, compromised access to health care, a perceived high risk of severe COVID-19 infection and higher levels of uncertainty. A history of mental health illness, risk perceptions, restricted healthcare access, uncertainty and coping strategies was associated with poorer HRQoL in SOT recipients during strict isolation. These findings may allow identification of strategies to improve HRQoL in SOT recipients during the pandemic.

Intestinal barrier dysfunction plays an integral role in arthritis pathology and can be targeted to ameliorate disease.

BACKGROUND: Evidence suggests an important role for gut-microbiota dysbiosis in the development of rheumatoid arthritis (RA). The link between changes in gut bacteria and the development of joint inflammation is missing. Here, we address whether there are changes to the gut environment and how they contribute to arthritis pathogenesis. METHODS: We analyzed changes in markers of gut permeability, damage, and inflammation in peripheral blood and serum of RA patients. Serum, intestines, and lymphoid organs isolated from K/BxN mice with spontaneous arthritis or from wild-type, genetically modified interleukin (IL)-10R-/-or claudin-8-/-mice with induced arthritis were analyzed by immunofluorescence/histology, ELISA, and flow cytometry. FINDINGS: RA patients display increased levels of serum markers of gut permeability and damage and cellular gut-homing markers, both parameters positively correlating with disease severity. Arthritic mice display increased gut permeability from early stages of disease, as well as bacterial translocation, inflammatory gut damage, increases in interferon γ (IFNγ)+and decreases in IL-10+intestinal-infiltrating leukocyte frequency, and reduced intestinal epithelial IL-10R expression. Mechanistically, both arthritogenic bacteria and leukocytes are required to disrupt gut-barrier integrity. We show that exposing intestinal organoids to IFNγ reduces IL-10R expression by epithelial cells and that mice lacking epithelial IL-10R display increased intestinal permeability and exacerbated arthritis. Claudin-8-/-mice with constitutively increased gut permeability also develop worse joint disease. Treatment of mice with AT-1001, a molecule that prevents development of gut permeability, ameliorates arthritis. CONCLUSIONS: We suggest that breakdown of gut-barrier integrity contributes to arthritis development and propose restoration of gut-barrier homeostasis as a new therapeutic approach for RA. FUNDING: Funded by Versus Arthritis (21140 and 21257) and UKRI/MRC (MR/T000910/1).

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. This study aimed to (1) confirm the prognostic significance of TB, particularly in stage II CRC; (2) to determine optimum thresholds for TB risk grouping; and (3) to determine whether TB influences responsiveness to chemotherapy. METHODS: TB was assessed in CRC sections from 1575 QUASAR trial patients randomized between adjuvant chemotherapy and observation. Optimal risk group cutoffs were determined by maximum likelihood methods, with their influence on recurrence and mortality investigated in stratified log-rank analyses on exploratory (n = 504), hypothesis-testing (n = 478), and final (n = 593) data sets. RESULTS: The optimal threshold for high-grade TB (HGTB) was ≥ 10 buds per 1.23 mm2. High-grade TB tumors had significantly worse outcomes than those with lower TB: 10-year recurrence 36% versus 22% (risk ratio, 2.00 [95% CI, 1.62-2.45]; 2P < .0001) and 10-year mortality 50% vs. 37% (risk ratio, 1.53 [95% CI, 1.34-1.76]; 2P < .0001). The prognostic significance remained equally strong after allowance for other pathological risk factors, including stage, grade, lymphovascular invasion, and mismatch repair status. There was a nonsignificant trend toward increasing chemotherapy efficacy with increasing bud counts. CONCLUSIONS: TB is a strong independent predictor of recurrence. Chemotherapy efficacy is comparable in patients with higher and lower TB; hence, absolute reductions in recurrence and death with chemotherapy should be about twice as large in patients with ≥ 10 than < 10 TB counts.

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). The primary outcome was faecal incontinence quality of life (FIQoL) at 12-months. Secondary outcomes were fistula healing, incontinence rates, and complication and reintervention rates. RESULTS: Between May 2011 and March 2016, 304 participants were randomized to fistula plug or surgeon's preference. No differences were seen in FIQoL between the 2 groups at 12 months. Clinical fistula healing was reported in 66/122 (54%) of the fistula plug and 66/119 (55%) of the surgeon's preference groups at 12 months. Fecal incontinence rates improved marginally in both the groups. Complications and reinterventions were frequent, with significantly more complications in the fistula plug group at 6-weeks (49/142, 35% vs 25/137, 18%; P=0.002). The mean total costs were £2738 (s.d. £1151) for the fistula plug and £2308 (s.d. £1228) for the surgeon's preference group (mean difference +£430, P=0.0174). The average total quality adjusted life years (QALYs) gained was marginally higher in the fistula plug group. The fistula plug was 35% to 45% likely to be cost-effective across a willingness to pay threshold of £20,000 to £30,000 / QALY. CONCLUSIONS: The Biodesign Surgisis anal fistula plug is associated with similar FIQoL and healing rates to surgeon's preference at 12 months. Higher costs and highly uncertain gains in QALYs mean that the fistula plug may not be considered as a cost-effective treatment in the UK NHS.

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. METHODS: TREC was a randomised, open-label feasibility study done at 21 tertiary referral centres in the UK. Eligible participants were aged 18 years or older with rectal adenocarcinoma, staged T2 or lower, with a maximum diameter of 30 mm or less; patients with lymph node involvement or metastases were excluded. Patients were randomly allocated (1:1) by use of a computer-based randomisation service to undergo organ preservation with short-course radiotherapy followed by transanal endoscopic microsurgery after 8-10 weeks, or total mesorectal excision. Where the transanal endoscopic microsurgery specimen showed histopathological features associated with an increased risk of local recurrence, patients were considered for planned early conversion to total mesorectal excision. A non-randomised prospective registry captured patients for whom randomisation was considered inappropriate, because of a strong clinical indication for one treatment group. The primary endpoint was cumulative randomisation at 12, 18, and 24 months. Secondary outcomes evaluated safety, efficacy, and health-related quality of life assessed with the European Organisation for Research and Treatment of Cancer (EORTC) QLQ C30 and CR29 in the intention-to-treat population. This trial is registered with the ISRCTN Registry, ISRCTN14422743. FINDINGS: Between Feb 22, 2012, and Dec 19, 2014, 55 patients were randomly assigned at 15 sites; 27 to organ preservation and 28 to radical surgery. Cumulatively, 18 patients had been randomly assigned at 12 months, 31 at 18 months, and 39 at 24 months. No patients died within 30 days of initial treatment, but one patient randomly assigned to organ preservation died within 6 months following conversion to total mesorectal excision with anastomotic leakage. Eight (30%) of 27 patients randomly assigned to organ preservation were converted to total mesorectal excision. Serious adverse events were reported in four (15%) of 27 patients randomly assigned to organ preservation versus 11 (39%) of 28 randomly assigned to total mesorectal excision (p=0·04, χ2 test). Serious adverse events associated with organ preservation were most commonly due to rectal bleeding or pain following transanal endoscopic microsurgery (reported in three cases). Radical total mesorectal excision was associated with medical and surgical complications including anastomotic leakage (two patients), kidney injury (two patients), cardiac arrest (one patient), and pneumonia (two patients). Histopathological features that would be considered to be associated with increased risk of tumour recurrence if observed after transanal endoscopic microsurgery alone were present in 16 (59%) of 27 patients randomly assigned to organ preservation, versus 24 (86%) of 28 randomly assigned to total mesorectal excision (p=0·03, χ2 test). Eight (30%) of 27 patients assigned to organ preservation achieved a complete response to radiotherapy. Patients who were randomly assigned to organ preservation showed improvements in patient-reported bowel toxicities and quality of life and function scores in multiple items compared to those who were randomly assigned to total mesorectal excision, which were sustained over 36 months' follow-up. The non-randomised registry comprised 61 patients who underwent organ preservation and seven who underwent radical surgery. Non-randomised patients who underwent organ preservation were older than randomised patients and more likely to have life-limiting comorbidities. Serious adverse events occurred in ten (16%) of 61 non-randomised patients who underwent organ preservation versus one (14%) of seven who underwent total mesorectal excision. 24 (39%) of 61 non-randomised patients who underwent organ preservation had high-risk histopathological features, while 25 (41%) of 61 achieved a complete response. Overall, organ preservation was achieved in 19 (70%) of 27 randomised patients and 56 (92%) of 61 non-randomised patients. INTERPRETATION: Short-course radiotherapy followed by transanal endoscopic microsurgery achieves high levels of organ preservation, with relatively low morbidity and indications of improved quality of life. These data support the use of organ preservation for patients considered unsuitable for primary total mesorectal excision due to the short-term risks associated with this surgery, and support further evaluation of short-course radiotherapy to achieve organ preservation in patients considered fit for total mesorectal excision. Larger randomised studies, such as the ongoing STAR-TREC study, are needed to more precisely determine oncological outcomes following different organ preservation treatment schedules. FUNDING: Cancer Research UK.

STOP-Colitis pilot trial protocol: a prospective, open-label, randomised pilot study to assess two possible routes of faecal microbiota transplant delivery in patients with ulcerative colitis.

INTRODUCTION: Imbalance of the gut microbiome is key to the pathogenesis of ulcerative colitis (UC). Faecal microbiota transplant (FMT) is the transfer of homogenised and filtered faeces from a healthy individual to the gastrointestinal tract of a patient with disease. Published datasets show a positive signal for the use of FMT to treat UC, but the optimal route and dose of FMT remain unanswered. METHODS AND ANALYSIS: This prospective, multi-centre open-label, randomised pilot study will assess two possible routes of FMT delivery, via the nasogastric (NG) route or by delivery to the COLON, in 30 patients with active UC recruited from three sites in the UK. Stool will be collected from healthy screened donors, processed, frozen and stored under a Medicines and Healthcare products Regulatory Agency (MHRA) "specials" manufacturing licence held at the University of Birmingham Microbiome Treatment Centre. Thawed FMT samples will be administered to patients either via eight nasogastric infusions given initially over 4 days starting on the day of randomisation, and then again for 4 days in week 4 for foregut delivery (total of 240 g of stool) or via one colonoscopic infusion followed by seven weekly enemas according to the hindgut protocol (total of 360 g of stool). Patients will be followed up weekly for 8 weeks, and then at 12 weeks. The aims of this pilot study are (1) to determine which FMT administration route (NG or COLON) should be investigated in a randomised double-blind, placebo-controlled trial and (2) to determine if a full randomised controlled trial is feasible. The primary outcome will be a composite assessment of both qualitative and quantitative data based on efficacy (clinical response), acceptability and safety. At the end of the pilot study, decisions will be made regarding the feasibility of a full randomised double-blind, placebo-controlled trial and, if deemed feasible, which route of administration should be used in such a study. ETHICS AND DISSEMINATION: Ethical approval for this study has been obtained from the East Midlands-Nottingham Research Ethics Committee (REC 17/EM/0274). At the end of the study, findings will be reported at national and international gastroenterology meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: ISRCTN74072945.

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. METHODS AND RESULTS: Sanger sequencing was performed for the three coding exons of B2M on 121 dMMR and a subsample of 108 pMMR tumours; 52 with recurrence and 56 without. B2M protein expression was assessed by immunohistochemistry. Mutation status and protein expression were correlated with recurrence and compared to proficient mismatch repair (pMMR) CRCs. Deleterious B2M mutations were detected in 39 of 121 (32%) dMMR tumours. Five contained missense B2M-variants of unknown significance, so were excluded from further analyses. With median follow-up of 7.4 years, none of the 39 B2M-mutant tumours recurred, compared with 14 of 77 (18%) B2M-wild-type tumours (P = 0.005); six at local and eight at distant sites. Sensitivity and specificity of IHC in detecting B2M mutations was 87 and 71%, respectively. Significantly (P < 0.0001) fewer (three of 104, 2.9%) of the 108 pMMR CRCs demonstrated deleterious B2M mutations. One pMMR tumour, containing a frameshift mutation, later recurred. CONCLUSION: B2M mutations were detected in nearly one-third of dMMR cancers, none of which recurred. B2M mutation status has potential clinical utility as a prognostic biomarker in stage II dMMR CRC. The mechanism of protection against recurrence and whether this protection extends to stage III disease remains unclear.

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. DESIGN: A randomised, unblinded, parallel-arm, prospective, multicentre clinical trial. SETTING: Hospitals in the UK NHS involving colorectal surgeons accredited by the Association of Coloproctology of Great Britain and Ireland. PARTICIPANTS: Adult patients suffering from trans-sphincteric fistula-in-ano of cryptoglandular origin. INTERVENTIONS: Patients were randomised on a 1 : 1 basis to either the fistula plug or the surgeon's preference [e.g. fistulotomy, cutting seton, advancement flap or ligation of intersphincteric fistula tract (LIFT) procedure]. MAIN OUTCOME MEASURES: The primary outcome measure was quality of life as measured by the Faecal Incontinence Quality of Life (FIQoL) questionnaire at 12-month follow-up. Secondary outcome measures included clinical and radiological fistula healing rates, faecal incontinence rates, complications rates, reintervention rates and cost-effectiveness. RESULTS: Between May 2011 and March 2016, 304 participants were recruited (152 fistula plug vs. 152 surgeon's preference). No difference in FIQoL score between the two trial groups was seen at the 6-week, 6-month or 12-month follow-up. Clinical evidence of fistula healing was reported in 66 of 122 (54%) participants in the fistula plug group and in 66 of 119 (55%) participants in the surgeon's preference group at 12 months. Magnetic resonance imaging (MRI) showed fistula healing in 54 of 110 (49%) participants in the fistula plug group and in 63 of 112 (56%) participants in the surgeon's preference group. Variation in 12-month clinical healing rates was observed: 55%, 64%, 75%, 53% and 42% for fistula plug, cutting seton, fistulotomy, advancement flap and LIFT procedure, respectively. Faecal incontinence rates were low at baseline, with small improvement in both groups post treatment. Complications and reinterventions were frequent. The mean total costs were £2738 [standard deviation (SD) £1151] in the fistula plug group and £2308 (SD £1228) in the surgeon's preference group. The average total quality-adjusted life-years (QALYs) gain was much smaller in the fistula plug group (0.829, SD 0.174) than in the surgeon's preference group (0.790, SD 0.212). Using multiple imputation and probabilistic sensitivity analysis, and adjusting for differences in baseline EuroQol-5 Dimensions, three-level version utility, there was a 35-45% chance that the fistula plug was as cost-effective as surgeon's preference over a range of thresholds of willingness to pay for a single QALY of £20,000-30,000. LIMITATIONS: Limitations include a smaller sample size than originally calculated, a lack of blinding that perhaps biased patient-reported outcomes and a lower compliance rate with MRI at 12-month follow-up. CONCLUSIONS: The Surgisis anal fistula plug is associated with similar FIQoL score to surgeon's preference at 12-month follow-up. The higher costs and highly uncertain and small gains in QALYs associated with the fistula plug mean that this technology is unlikely to be considered a cost-effective use of resources in the UK NHS. FUTURE WORK: Further in-depth analysis should consider the clinical and MRI characteristics of fistula-in-ano in an attempt to identify predictors of fistula response to treatment. TRIAL REGISTRATION: Current Controlled Trials ISRCTN78352529. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 23, No. 21. See the NIHR Journals Library website for further project information.

Fistula-in-ano is a common condition in which the inside of the anus is in communication with the outside skin. It is a cause of long-term suffering owing to recurrent infection. Many surgical operations have been proposed to treat fistula-in-ano, with varying degrees of success. These carry the risk of faecal incontinence. The aim of the Fistula-In-Ano Trial (FIAT) was to assess the benefits of a new technology, the Surgisis^® anal fistula plug (Cook Medical, Bloomington, IN, USA), compared with other surgical techniques. The FIAT involved 304 participants; 152 participants were treated with the fistula plug and 152 participants were treated with an alternative surgical technique. There were no differences in quality of life (QoL) among participants treated with the fistula plug compared with those receiving other treatments when assessed 12 months following the operation. Successful fistula healing was achieved in 54% of fistula plug-treated participants and in 55% of participants treated with an alternative technique at 12 months following the operation. Few patients suffered from faecal incontinence before their operation and there was a slight improvement following treatment with the fistula plug and other surgical treatments. The only difference seen between the group treated with the fistula plug and those receiving other surgical treatments was in the complication rate at the 6-week assessment time, with the fistula plug group having higher rates of unexpected pain. Economic analysis of the fistula plug compared with the other surgical treatments showed that the fistula plug was more expensive and only produced very small improvements in QoL. On this basis, it is unlikely that decision-makers in the NHS will support the routine use of the fistula plug.

Validation of epigenetic markers to identify colitis associated cancer: Results of module 1 of the ENDCAP-C study.

BACKGROUND: Chronic inflammation caused by ulcerative colitis (UC) causes a pro-neoplastic drive in the inflamed colon, leading to a markedly greater risk of invasive malignancy compared to the general population. Despite surveillance protocols, 50% of cases proceed to cancer before neoplasia is detected. The Enhanced Neoplasia Detection and Cancer Prevention in Chronic Colitis (ENDCaP-C) trial is an observational multi-centre test accuracy study to ascertain the role of molecular markers in improving the detection of dysplasia. We aimed to validate previously identified biomarkers of neoplasia in a retrospective cohort and create predictive models for later validation in a prospective cohort. METHODS: A retrospective analysis using bisulphite pyrosequencing of an 11 marker panel (SFRP1, SFRP2, SRP4, SRP5, WIF1, TUBB6, SOX7, APC1A, APC2, MINT1, RUNX3) in samples from 35 patients with cancer, 78 with dysplasia and 343 without neoplasia undergoing surveillance for UC associated neoplasia across 6 medical centres. Predictive models for UC associated cancer/dysplasia were created in the setting of neoplastic and non-neoplastic mucosa. FINDINGS: For neoplastic mucosa a five marker panel (SFRP2, SFRP4, WIF1, APC1A, APC2) was accurate in detecting pre-cancerous and invasive neoplasia (AUC = 0.83; 95% CI: 0.79, 0.88), and dysplasia (AUC = 0.88; (0.84, 0.91). For non-neoplastic mucosa a four marker panel (APC1A, SFRP4, SFRP5, SOX7) had modest accuracy (AUC = 0.68; 95% CI: 0.62,0.73) in predicting associated bowel neoplasia through the methylation signature of distant non-neoplastic colonic mucosa. INTERPRETATION: This multiplex methylation marker panel is accurate in the detection of ulcerative colitis associated dysplasia and neoplasia and is currently being validated in a prospective clinical trial. FUNDING: The ENDCAP-C study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) Programme (11/100/29).

Low Percentage of Signal Regulatory Protein α/ß+ Memory B Cells in Blood Predicts Development of Anti-drug Antibodies (ADA) in Adalimumab-Treated Rheumatoid Arthritis Patients.

An important goal for personalized treatment is predicting response to a particular therapeutic. A drawback of biological treatment is immunogenicity and the development of antibodies directed against the drug [anti-drug antibodies (ADA)], which are associated with a poorer clinical outcome. Here we set out to identify a predictive biomarker that discriminates rheumatoid arthritis (RA) patients who are more likely to develop ADA in response to adalimumab, a human monoclonal antibody against tumor necrosis factor (TNF)α. By taking advantage of an immune-phenotyping platform, LEGENDScreen™, we measured the expression of 332 cell surface markers on B and T cells in a cross-sectional adalimumab-treated RA patient cohort with a defined ADA response. The analysis revealed seven differentially expressed markers (DEMs) between the ADA+ and ADA- patients. Validation of the DEMs in an independent prospective European cohort of adalimumab treated RA patients, revealed a significant and consistent reduced frequency of signal regulatory protein (SIRP)α/ß-expressing memory B cells in ADA+ vs. ADA- RA patients. We also assessed the predictive value of SIRPα/ß expression in a longitudinal RA cohort prior to the initiation of adalimumab treatment. We show that a frequency of < 9.4% of SIRPα/ß-expressing memory B cells predicts patients that will develop ADA, and consequentially fail to respond to treatment, with a receiver operating characteristic (ROC) area under the curve (AUC) score of 0.92. Thus, measuring the frequency of SIRPα/ß-expressing memory B cells in patients prior to adalimumab treatment may be clinically useful to identify a subgroup of active RA subjects who are going to develop an ADA response and not gain substantial clinical benefit from this treatment.