Karin A. T. G. M. Wasmann

Background: The PISA-II trial showed that short-term anti-TNF therapy followed by surgical closure induces radiological healing of Crohn’s perianal fistulas more frequently than anti-TNF therapy after 18 months. This study aimed to compare long-term outcomes of both treatment arms. Methods: Follow-up data were collected from patients who participated in the PISA-II trial, an international patient preference RCT. Data were collected until May 2022. Primary outcome was radiological (MRI) healing. Findings: Data were collected from 91/94 patients (36/38 anti-TNF+surgical closure, 55/56 anti-TNF). Median follow-up was 6 years (IQR 5-7). Radiological healing occurred significantly more often after anti-TNF+surgical closure (42% versus 18%; P=0·014). Clinical closure was comparable (72% versus 62%; P=0·183). Results were after re-interventions in 15% versus 53%, including (redo-)surgical closure procedures. Recurrences occurred in 0/25 patients with radiological healing versus 27/76 patients with clinical closure only, sometime during follow-up. Anti-TNF serum concentrations were higher in patients with long-term clinical closure in both groups (P=0·01). In 6/11 patients in the anti-TNF group with available serum concentrations, recurrences were diagnosed within three months of a drop under 3.5ug/ml. 36 patients stopped anti-TNF, after which 0/14 patients with radiological healing developed a recurrence and 9/22 with clinical closure only. Continence was comparable between groups, and 79% of patients indicated comparable/improved continence after treatment. Decision-regret analysis showed that all anti-TNF+surgical closure patients (strongly) agreed that surgery was the right decision versus 78% in the anti-TNF arm. All surgical closure patients would go for the same treatment again, whereas this was 89% in the anti-TNF arm. Interpretation: This study confirms that surgical closure should be considered in amenable patients with Crohn’s perianal fistulas as long-term outcomes are favourable, and that radiological healing should be the aim of treatment as recurrences only occurred in patients without radiological healing. In patients with complete MRI closure, anti-TNF could be safely stopped. Funding Information: None. Declaration of Interests: EMMP, MAJB, KLR, KATGMW, JS, MGWD, and AS have nothing to declare. GRH has received grants from Bristol Meiers Squibb, Pfizer and Takeda, has served as a consultant and/or received speaker’s fees from AbbVie, Alimentiv, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Celltrion Healthcare, Cytoki Pharma, Eli Lilly, Ferring, Galapagos, Glaxo SmithKline, Gossamer Bio, Immunic, InDex Pharmaceuticals, Janssen, Johnson & Johnson, Kaleido, Pfizer, Progenity, Prometheus Biosciences, Prometheus Laboratories, Protagonist Therapeutics, Takeda, Tillotts, Ventyx Biosciences. He furthermore received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Pfizer, Boehringer Ingelheim, Takeda and Abbvie, and participated on a Data Safety Monitoring Board or Advisory Board of Astrazeneca, Abbvie and Seres Health. CYP has received grants from Perspectum and Gilead; consulting fees from Shire, and payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Tillotts. KBG has received grants from Pfizer, Galapagos, Celltrion, consultancy fees from AbbVie, Arena Pharmaceuticals, Galapagos, Gilead, ImmunicTherapeutics, Janssen Pharmaceuticals, Novartis, Pfizer Inc., Samsung Bioepis and Takeda, and speaker’s honoraria from Celltrion, Ferring, Janssen Pharmaceuticals, Novartis, Pfizer Inc, Samsung Bioepis, Takeda and Tillotts. SD has received consulting fees from Abbvie, Alimentiv, Allergan, Amgen, AstraZaneca, Athos Therapeutics, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Celltrion, Dr Falk Pharma, Eli Lilly, Enthera, Ferring Pharmaceuticals Inc., Gilead, Hospira, Inotrem, Janssen, Johnson & Johnson, Morphic, MSD, Mundipharma, Mylan, Pfizer, Roche, Sandoz, Sublimity Therapeutics, Takeda, Teladoc Health, TiGenix, UCB Inc., Vial and Vifor. He furthermore received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Abbvie, Amgen, Ferring Pharmaceuticals Inc., Gilead, Janssen, Mylan, Pfizer and Takeda. WAB has received grants from Braun and Vifor, and has served as speaker for Takeda, Johnson and Johnson and Braun. CJB has an unrestricted grant from Boehringer Ingelheim and Roche. She has also received consultancy fees and/or speaker’s honoraria from AbbVie, MSD, Tillotts, Janssen and Takeda. Ethics Approval Statement: The PISA-II2 study received central approval from the Medical Ethical Committee at the Amsterdam University Medical Centers, location University of Amsterdam, and all other participating centres and was conducted in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. For the current study, formal approval and individual patient informed consent was waived by the Medical Ethics Review Committee of the Amsterdam University Medical Centers.

Proctitis after subtotal colectomy with ileostomy for ulcerative colitis [UC] is common, but its impact on short- and long-term outcome after pouch surgery is unknown. The aim of this study was to determine the incidence of proctitis after subtotal colectomy and its impact on postoperative morbidity and pouchitis. The distal margin of the rectal stump of all consecutive patients undergoing completion proctectomy and pouch procedure for UC, between 1999 and 2017, was revised and scored for active inflammation according to the validated Geboes score, and for diversion proctitis. Pathological findings were correlated to complications after pouch surgery and pouchitis [including therapy-refractory] using multivariate analyses. Out of 204 included patients, 167 [82%] had active inflammation in the rectal stump and diversion colitis was found in 170 specimens [83%]. Overall postoperative complications and anastomotic leakage rates were not significantly different between patients with and without active inflammation in the rectal stump [34.7% vs 32.4%, p = 0.79, and 10.2% vs 5.4%, p = 0.54, respectively]. Active inflammation of the rectal stump was significantly associated with the development of pouchitis [54.3% vs 25.5%, plog = 0.02], as well as with therapy refractory pouchitis [14% vs 0%, plog = 0.05]. Following multivariate analysis, active inflammation was an independent predictor for the development of pouchitis. Diversion proctitis showed no association with these outcome parameters. Active inflammation in the rectal stump after subtotal colectomy occurs in 80% of UC patients and is a predictor for the development of pouchitis and therapy-refractory pouchitis.

Resections for Crohn’s disease should be limited and only resect macroscopically affected bowel. However, recent studies suggest microscopic inflammation at resection margins as a predictor for postoperative recurrence. The clinical impact remains unclear, as non-uniform pathological criteria have been used. The aim of this study was to assess the predictive value of pathological characteristics at ileocecal resection margins for recurrence. Both resection margins of 106 consecutive patients undergoing ileocecal resection for Crohn’s disease between 2002 and 2009 were revised and scored for active inflammation, myenteric plexitis, and granulomas. Pathological findings were correlated to recurrence, defined as recurrent disease activity demonstrated by endoscopy (modified Rutgeerts score ≥i2) requiring upscaling medical treatment, using multivariate analysis. Active inflammation was found at the proximal and distal resection margin in 27% and 15% of patients, respectively, myenteric plexitis in 37% and 32%, respectively, and granulomas in 4% and 6%, respectively. In total, 47 out of 106 patients developed recurrence. Only active inflammation at the distal colonic resection margin was an independent significant predictor for recurrence (88% vs 43% vs 51% for distal, proximal, and no involved margins, respectively; P < 0.01). Active inflammation at the distal colonic resection margin after ileocecal resection identifies a patient group at high risk for postoperative recurrence both at the anastomotic site and the colon because it identifies undiagnosed L3 disease. These patients have a different and more aggressive natural history and require more intense medical treatment. Therefore, pathological evaluation of the distal resection margin should be implemented in daily practice.

Background: The transanal approach to ileal pouch-anal anastomosis [Ta-IPAA] provides better access to the lower pelvis with lower short-term morbidity in ulcerative colitis [UC]. The aim of this study was to assess the long-term functional outcomes after Ta-IPAA vs transabdominal IPAA [Abd-IPAA] in UC. Methods: A multicentre cohort analysis was performed between March 2002 and September 2017. Patient characteristics, surgical details and postoperative outcomes were compared. CGQL [Cleveland global quality of life] score at 12 months with a functioning pouch was considered the primary end point. Results: A total of 374 patients [100 Ta-IPAA vs 274 Abd-IPAA] were included. Ta-IPAA demonstrated a comparable overall quality of life [CGQL score] to Abd-IPAA [0.75 ± 0.11 vs 0.71 ± 0.14; respectively, p = 0.1]. Quality of life [7.71 ± 1.17 vs 7.30 ± 1.46; p = 0.04] and energy-level items [7.16 ± 1.52 vs 6.66 ± 1.68; p = 0.03] were significantly better after Ta-IPAA, while the quality of health item was comparable [7.68 ± 1.26 vs 7.64 ± 1.44; p = 0.96]. Analysis excluding anastomotic leaks did not change the overall CGQL scores. Stool frequencies [>10/24 h: 22% vs 21%; p = 1.0] and the rate of a single episode of major incontinence during the following 12-month period [27% vs 26%; p = 0.89] were similar. The differences in 30-day morbidity rates [33% vs 41%; p = 0.2] and anastomotic leak rates were not significant [6% vs 13%; p = 0.09]. Conclusions: This study provides evidence of comparable long-term functional outcome and quality of life after Ta-IPAA and Abd-IPAA for UC.

Objective: Randomised controlled trials (RCT) are the gold standard to provide unbiased data. However, when patients have a treatment preference, randomisation may influence participation and outcomes (eg, external and internal validity). The aim of this study was to assess the influence of patients’ preference in RCTs by analysing partially randomised patient preference trials (RPPT); an RCT and preference cohort combined. Design: Systematic review and meta-analyses. Data sources: MEDLINE, Embase, PsycINFO and the Cochrane Library. Eligibility criteria for selecting studies: RPPTs published between January 2005 and October 2018 reporting on allocation of patients to randomised and preference cohorts were included. Data extraction and synthesis: Two independent reviewers extracted data. The main outcomes were the difference in external validity (participation and baseline characteristics) and internal validity (lost to follow-up, crossover and the primary outcome) between the randomised and the preference cohort within each RPPT, compared in a meta-regression using a Wald test. Risk of bias was not assessed, as no quality assessment for RPPTs has yet been developed. Results: In total, 117 of 3734 identified articles met screening criteria and 44 were eligible (24 873 patients). The participation rate in RPPTs was >95% in 14 trials (range: 48%–100%) and the randomisation refusal rate was >50% in 26 trials (range: 19%–99%). Higher education, female, older age, race and prior experience with one treatment arm were characteristics of patients declining randomisation. The lost to follow-up and cross-over rate were significantly higher in the randomised cohort compared with the preference cohort. Following the meta-analysis, the reported primary outcomes were comparable between both cohorts of the RPPTs, mean difference 0.093 (95% CI −0.178 to 0.364, p = 0.502). Conclusions: Patients’ preference led to a substantial proportion of a specific patient group refusing randomisation, while it did not influence the primary outcome within an RPPT. Therefore, RPPTs could increase external validity without compromising the internal validity compared with RCTs. PROSPERO registration number: CRD42019094438.

Purpose: The aim of this study was to evaluate the impact of a laparoscopic approach on long-term oncological outcomes in curative intent surgery for pT4 colon cancer, in both overall and stratified subgroups with distinct clinical entities. Patients and methods: Patients with a pT4N0-2M0 colon cancer from four centers between 2000 and 2014 were included. Laparoscopic and open approaches were compared according to the intention-to-treat principle. Propensity scores were used to adjust for baseline differences between the groups in three manners: i) as a linear predictor in a Cox regression model, ii) to create a 1:1 matched cohort, and iii) to stratify patients into four groups with an increasing chance of receiving laparoscopy. Results: In total, 424 patients were included. After 1:1 matching, a laparoscopic approach correlated with higher rates of radical resection, lower morbidity, and a higher percentage of patients receiving adjuvant chemotherapy. This translated into better 5-year disease-free survival (52% vs 40%, HR 0.70; 95% CI 0.50–0.96) and 5-year overall survival (68% vs 57%, HR 0.66; 95% CI 0.43–0.99). These results were confirmed in the other two propensity score analyses. In the multivariable models, adjuvant chemotherapy remained independently associated with better survival, whereas surgical approach lost significance. Conclusions: In locally advanced colon cancer, an intentional laparoscopic approach in experienced hands seems to decrease morbidity and to increase the proportion of patients receiving adjuvant chemotherapy. Receiving adjuvant chemotherapy was independently associated with improved survival.