Human type 1 innate lymphoid cells accumulate in inflamed mucosal tissues.

Innate lymphoid cells (ILCs) are effectors of innate immunity and regulators of tissue modeling. Recently identified ILC populations have a cytokine expression pattern that resembles that of the helper T cell subsets T(H)2, T(H)17 and T(H)22. Here we describe a distinct ILC subset similar to T(H)1 cells, which we call 'ILC1'. ILC1 cells expressed the transcription factor T-bet and responded to interleukin 12 (IL-12) by producing interferon-γ (IFN-γ). ILC1 cells were distinct from natural killer (NK) cells as they lacked perforin, granzyme B and the NK cell markers CD56, CD16 and CD94, and could develop from RORγt(+) ILC3 under the influence of IL-12. The frequency of the ILC1 subset was much higher in inflamed intestine of people with Crohn's disease, which indicated a role for these IFN-γ-producing ILC1 cells in the pathogenesis of gut mucosal inflammation.

Interleukin-12 and -23 Control Plasticity of CD127(+) Group 1 and Group 3 Innate Lymphoid Cells in the Intestinal Lamina Propria.

Human group 1 ILCs consist of at least three phenotypically distinct subsets, including NK cells, CD127(+) ILC1, and intraepithelial CD103(+) ILC1. In inflamed intestinal tissues from Crohn's disease patients, numbers of CD127(+) ILC1 increased at the cost of ILC3. Here we found that differentiation of ILC3 to CD127(+) ILC1 is reversible in vitro and in vivo. CD127(+) ILC1 differentiated to ILC3 in the presence of interleukin-2 (IL-2), IL-23, and IL-1ß dependent on the transcription factor RORγt, and this process was enhanced in the presence of retinoic acid. Furthermore, we observed in resection specimen from Crohn's disease patients a higher proportion of CD14(+) dendritic cells (DC), which in vitro promoted polarization from ILC3 to CD127(+) ILC1. In contrast, CD14(-) DCs promoted differentiation from CD127(+) ILC1 toward ILC3. These observations suggest that environmental cues determine the composition, function, and phenotype of CD127(+) ILC1 and ILC3 in the gut.

Optimising surgical anastomosis in ileocolic resection for Crohn's disease with respect to recurrence and functionality: two international parallel randomized controlled trials comparing handsewn (END-to-end or Kono-S) to stapled anastomosis (HAND2END and the End2End STUDIES).

BACKGROUND: The most common intestinal operation in Crohn's disease (CD) is an ileocolic resection. Despite optimal surgical and medical management, recurrent disease after surgery is common. Different types of anastomoses with respect to configuration and construction can be made after resection for example, handsewn (end-to-end and Kono-S) and stapled (side-to-side). The various types of anastomoses might affect endoscopic recurrence and its assessment, the functional outcome, and costs. The objective of the present study is to compare the three types of anastomoses with respect to endoscopic recurrence at 6 months, gastrointestinal function, and health care consumption. METHODS: This is a randomized controlled multicentre superiority trial, allocating patients either to side-to-side stapled anastomosis as advised in current guidelines or a handsewn anastomoses (an end-to-end or Kono-S). It is hypothesized that handsewn anastomoses do better than stapled, and end-to-end perform better than the saccular Kono-S. Two international studies with a similar setup will be conducted mainly in the Netherlands (End2End) and Italy (HAND2END). Patients diagnosed with CD, aged over 16 years in the Netherlands and 18 years in Italy requiring (re)resection of the (neo)terminal ileum are eligible. The first part of the study compares the two handsewn anastomoses with the stapled anastomosis. To detect a clinically relevant difference of 25% in endoscopic recurrence, a total of 165 patients will be needed in the Netherlands and 189 patients in Italy. Primary outcome is postoperative endoscopic recurrence (defined as Rutgeerts score ≥ i2b) at 6 months. Secondary outcomes are postoperative morbidity, gastrointestinal function, quality of life (QoL) and costs. DISCUSSION: The research question addresses a knowledge gap within the general practice elucidating which type of anastomosis is superior in terms of endoscopic and clinical recurrence, functionality, QoL and health care consumption. The results of the proposed study might change current practice in contrast to what is advised by the guidelines. TRIAL REGISTRATION: NCT05246917 for HAND2END and NCT05578235 for End2End ( http://www. CLINICALTRIALS: gov/ ).

Increased Proportion of Colorectal Cancer in Patients With Ulcerative Colitis Undergoing Surgery in the Netherlands.

INTRODUCTION: The aim of the current study was to assess whether there is an indication shift for surgery in patients with ulcerative colitis (UC) from refractory disease to malignant degeneration over the past 3 decades. METHODS: All patients with histologically confirmed UC who underwent a colorectal resection between 1991 and 2020 were extracted from the nationwide Dutch Pathology Registry. The primary outcome was the proportion of colorectal cancer (CRC) in the colon specimens. Outcomes were compared between 3 periods (P1: 1991-2000, P2: 2001-2010, and P3: 2011-2020). RESULTS: Overall, 6,094 patients with UC were included of which 4,854 underwent a (procto)colectomy and 1,240 a segmental resection. In 1,031 (16.9%) patients, CRC was demonstrated in the pathological resection specimen after a median disease duration of 11 years (IQR 3.0-19.0). The proportion of CRC increased from 11.3% in P1, to 16.1% in P2, and 22.8% in P3 ( P < 0.001). Median disease duration at the time of resection increased from 4 years in P1, to 10 years in P2, and 17 years in P3 ( P < 0.001). The proportion of patients diagnosed with advanced malignancy (pT3/T4) (P1: 61.2% vs P2: 65.2% vs P3: 62.4%, respectively, P = 0.633) and lymph node metastasis (N+) (P1: 33.0% vs P2: 41.9% vs P3: 38.2%, respectively, P = 0.113) did not change over time. DISCUSSION: This nationwide pathology study demonstrated an increased proportion of surgery for CRC over the past 3 decades. We hypothesize that the expanding therapeutic armamentarium for UC leads to exhausting medical options and hence postponed colectomy. This, however, might be at the expense of an increased risk of CRC in the long term.

Temporary diverting stoma in therapy-refractory luminal colonic Crohn's disease: an alternative to immediate colorectal resection?

AIM: Creation of a diverting stoma in patients with Crohn's disease (CD) can counteract luminal inflammation. The clinical utility of a diverting stoma with the prospect of restoration of gastrointestinal continuity warrants further investigation. The aim of this work was to evaluate the long-term effects of creation of a diverting stoma on the disease course in patients with luminal colonic CD. METHOD: In this retrospective, multicentre cohort study we investigated the disease course of patients who received a diverting stoma in the biological era. Clinical characteristics, medication use and surgical course were assessed at the time of creation of the diverting stoma and during follow-up. The primary outcome was the rate of successful and lasting reestablishment of gastrointestinal continuity. RESULTS: Thirty six patients with refractory luminal CD from four institutions underwent creation of a diverting stoma. Of the overall cohort, 20 (56%) patients had their gastrointestinal continuity reestablished after initial stoma creation and 14 (39%) who had their stoma reversed remained stoma-free during a median of 3.3 years follow-up (interquartile range 2.1-6.1 years). Absence of stoma reversal was associated with the presence of proctitis (p = 0.02). Colorectal resection after creation of a diverting stoma was performed in 28 (78%) patients, with 7 (19%) having a less extensive resection and 6 (17%) having a more extensive resection compared with the surgical plan before stoma creation. CONCLUSION: A diverting stoma could potentially be an alternative to immediate definitive stoma placement in specific populations consisting of patients with luminal colonic CD, especially in the absence of proctitis.

Incidence and causes of failure in various anatomical pouch designs 20 years after surgical primary ileal-pouch anal anastomosis construction.

PURPOSE: Since the introduction of ileo-pouch anal anastomosis (IPAA) surgery, various pouch designs have been applied. Recently, there has been renewed interest in creating larger pouch designs to reduce defecation frequency after pouch surgery. The aim of this study was to assess chronic pouch failure (PF) rates and causes in alternative S or septated (SP) pouches when compared to J pouches and B- shaped adaptations. METHODS: This retrospective cohort study included patients that underwent primary IPAA construction surgery from 1978-2000. Pouch designs were subdivided in J and B (J/B), and larger pouches (S/SP). PF included need for a pouch excision, redo pouch procedure, revisional pouch surgery, or permanent ileostomy surgery. Outcomes of this study were incidence and causes for PF per pouch design group. RESULTS: Out of 200 patients who underwent IPAA surgery, 19 had an S/SP design and 181 had a J/B design. After a follow-up of 27.0 (IQR 23.3 - 29.0) years, 45/200 (22.5%) patients who underwent IPAA surgery between 1975-2000 developed PF. Some 78.9% of patients with an S/SP pouch developed PF, compared to 16.7% of patients with a J/B pouch (p < 0.01). Mechanical outlet issues occurred more often in S/SP pouches when compared to J/B (42.1% vs. 1.1%, p < 0.01), and were predominantly caused by septal- or pouch wall intussusception and efferent loop kinking (S-pouch). CONCLUSION: Despite an inevitable proportion of bias, the current study revealed that S/SP pouches were characterized by an increased PF incidence due to emptying problems after long-term follow-up when compared to J/B pouches. Constructing an S pouch or large septated reservoir at index surgery should therefore be questioned because of a shorter longevity.

Role of the Mesentery in Crohn's Terminal Ileitis.

Despite the longstanding awareness of the presence of mesenteric alterations in Crohn's disease, the functional and clinical consequences of these alterations remain a topic of debate. Guidelines advise a limited resection without resection of the adjacent mesentery to prevent short bowel syndrome and postoperative complications. However, recently mesenteric resection has been proposed as an alternative to reduce recurrence rates in Crohn's disease patients. Here, we evaluate the data available on this topic in terminal ileitis, both from a fundamental research point of view and clinical perspective.

Laparoscopic wedge resection as an alternative to laparoscopic oncological colon resection for benign endoscopically unresectable colon polyps.

AIM: The aim of this study was to investigate, by comparing clinical and histological outcomes, whether laparoscopic (hybrid) wedge resection (LWR) could be a less invasive and safe alternative to laparoscopic oncological colon resection (OCR) for patients with an endoscopically unresectable, suspected benign, colon polyp. METHOD: All patients with an endoscopically unresectable colon polyp who were referred for surgery between 2009 and 2018 and without biopsy-proven colon cancer were identified from a prospectively maintained database. Patients with macroscopic features of malignancy during endoscopy were excluded. Clinical and histological results for patients who underwent OCR or LWR were reviewed. RESULTS: One hundred-and-twenty-two patients were included. Ninety-seven patients underwent OCR and 25 LWR. Major complications occurred in 16.7% (n = 16) of the OCR group compared with 4.0% (n = 1) of the LWR group (p = 0.06). In the OCR group the anastomotic leakage rate was 6.3% (n = 6) and the mortality rate 3.1% (n = 3). No anastomotic leakage or deaths occurred in the LWR group. The median length of hospital stay after OCR was 5 days [interquartile range (IQR) 5-9 days)] compared with 2 days (IQR 2-4 days) after LWR (p < 0.0001). Definite pathology showed a malignancy rate of 4.2% (n = 4) in the OCR group and 4.0% (n = 1) (without high-risk features) in the LWR group. CONCLUSION: This study shows that LWR was associated with significantly lower complication rates and acceptable oncological risks compared with OCR. Therefore we suggest that LWR is a safe alternative treatment, next to other endoscopic options. The treatment that is most suitable for an individual patient should be discussed in a multidisciplinary meeting.

Video consultation during follow up care: effect on quality of care and patient- and provider attitude in patients with colorectal cancer.

BACKGROUND: Video consultation (VC) is gaining attention as a possible alternative to out-patient clinic visits. However, little is known in terms of attitude, satisfaction and quality of care using VC over a face-to-face (F2F) consultation. The aim of this observational survey study was to compare the attitude and satisfaction with VC amongst patients suffering from colorectal cancer and their treating surgeons at the outpatient surgical care clinic in a tertiary referral centre. METHODS: A patient-preference model was chosen following the concept of shared decision making. A total of fifty patients with colorectal cancer were asked to choose between VC- or a F2F-contact during their follow up at the outpatient surgical care clinic and were subsequently assigned to either the VC-group or the F2F-group. Attitude and satisfaction rates of both groups and their surgeons were measured using a questionnaire administered immediately after the consultation. RESULTS: Out of the 50 patients, 42% chose VC as their preferred follow-up modality. Patients demographics did not differ significantly. Patients who use video calling in their personal life choose VC significantly more often than patients lacking such experience (p = 0.010). These patients scored high on both the attitude- and satisfaction scale of the post-VC questionnaire. Patients who chose a F2F-contact seemed to question the ability of the surgeon to properly assess their healthcare condition by using a video connection more (p = 0.024). Surgeons were highly satisfied with the use of VC. CONCLUSIONS: Based on patient preference, VC is equivalent to a F2F consultation in terms of patient satisfaction and perceived quality of care. Shared decision making is preferred with regard to which contact modality is used during follow up. For easy uptake in other environments it is to be recommended to facilitate VC using the electronic patient portal.

Cost-effectiveness of laparoscopic ileocaecal resection versus infliximab treatment of terminal ileitis in Crohn's disease: the LIR!C Trial.

OBJECTIVE: Evaluate the cost-effectiveness of laparoscopic ileocaecal resection compared with infliximab in patients with ileocaecal Crohn's disease failing conventional therapy. DESIGN: A multicentre randomised controlled trial was performed in 29 centres in The Netherlands and the UK. Adult patients with Crohn's disease of the terminal ileum who failed >3 months of conventional immunomodulators or steroids without signs of critical strictures were randomised to laparoscopic ileocaecal resection or infliximab. Outcome measures included quality-adjusted life-years (QALYs) based on the EuroQol (EQ) 5D-3L Questionnaire and the Inflammatory Bowel Disease Questionnaire (IBDQ). Costs were measured from a societal perspective. Analyses were performed according to the intention-to-treat principle. Missing cost and effect data were imputed using multiple imputation. Cost-effectiveness planes and cost-effectiveness acceptability curves were estimated to show uncertainty. RESULTS: In total, 143 patients were randomised. Mean Crohn's disease total direct healthcare costs per patient at 1 year were lower in the resection group compared with the infliximab group (mean difference €-8931; 95% CI €-12 087 to €-5097). Total societal costs in the resection group were lower than in the infliximab group, however not statistically significant (mean difference €-5729, 95% CI €-10 606 to €172). The probability of resection being cost-effective compared with infliximab was 0.96 at a willingness to pay (WTP) of €0 per QALY gained and per point improvement in IBDQ Score. This probability increased to 0.98 at a WTP of €20 000/QALY gained and 0.99 at a WTP of €500/point of improvement in IBDQ Score. CONCLUSION: Laparoscopic ileocaecal resection is a cost-effective treatment option compared with infliximab. CLINICAL TRIAL REGISTRATION NUMBER: Dutch Trial Registry NTR1150; EudraCT number 2007-005042-20 (closed on 14 October 2015).

The Association of Preoperative Anemia and the Postoperative Course and Oncological Outcome in Patients Undergoing Rectal Cancer Surgery: A Multicenter Snapshot Study.

BACKGROUND: There is still controversy about the relationship between preoperative anemia and outcomes after rectal cancer surgery. OBJECTIVE: The aim of this study was to analyze the association between preoperative anemia and postoperative complications and the survival of patients undergoing surgery for rectal cancer in the era of laparoscopic surgery and modern perioperative care. DESIGN: This was a cohort study. SETTINGS: Data were gathered from 71 hospitals in The Netherlands. PATIENTS: Patients who underwent resection for rectal cancer in 2011, for whom preoperative hemoglobin level was registered, were included. INTERVENTIONS(S): There were no interventions. MAIN OUTCOME MEASURES: Short-term outcome parameters were any postoperative complication or mortality within 30 days postoperatively, and pelvic infectious complications defined as anastomotic leakage and presacral abscess. Long-term outcomes were chronic sinus diagnosed at any time during 3-year follow-up, 3-year local and distant recurrence rates, and 3-year overall survival. RESULTS: Of 2095 patients, 1857 had a registered preoperative hemoglobin level; 576 (31%) of these patients anemic and 1281 (69%) were nonanemic. Preoperative anemia was not independently associated with postoperative complications (HR, 1.1; 95% CI, 0.9-1.4; p = 0·24) or 30-day mortality (HR, 1.4, 95% CI, 0.7-2.8; p = 0·29). Preoperative anemia was associated with 3-year overall survival (HR, 2.1; 95% CI, 1.7-2.5; p < 0.0001), after multivariable analysis (HR, 1.4; 95% CI, 1.1-1.8; p = 0·008), and with local recurrence rate (HR, 1.6; 95% CI, 1.1-2.4; p = 0.026), but not with distant recurrence rate (HR, 1.2; 95% CI, 1.0-1.5; p = 0.054). LIMITATIONS: Preoperative anemia appeared to have only limited association with postoperative and disease-specific outcome after rectal cancer surgery in contrast to published meta-analysis of small historical series. CONCLUSIONS: Anemia is associated with overall survival. It might be considered as one of the warning signs in identifying high-risk patients. See Video Abstract at http://links.lww.com/DCR/A913.

Higher anti-TNF serum levels are associated with perianal fistula closure in Crohn's disease patients.

Objectives: Anti-TNF agents are effective to treat perianal Crohn's disease (CD). Evidence suggests that Crohn's disease patients with perianal fistulas need higher infliximab (IFX) serum concentrations compared to patients without perianal CD to achieve complete disease control. Our aim was to compare anti-TNF serum concentrations between patients with actively draining and closed perianal fistulas. Methods: A retrospective survey was performed in CD patients with perianal disease treated with IFX or adalimumab (ADL). Fistula closure was defined as absence of active drainage at gentle finger compression and/or fistula healing on magnetic resonance imaging. Results: We identified 66 CD patients with a history of perianal fistulas treated with IFX (n = 47) and ADL (n = 19). Median IFX serum trough concentrations ([interquartile range]) were higher in patients with closed fistulas (n = 32) compared to patients with actively draining fistulas (n = 15): 6.0 µg/ml [5.4-6.9] versus 2.3 µg/ml [1.1-4.0], respectively (p < .001)). A similar difference was seen in patients treated with ADL: median serum concentrations were 7.4 µg/ml [6.5-10.8] in 13 patients with closed fistulas versus 4.8 µg/ml [1.7-6.2] in 6 patients with producing fistulas (p = .003). Serum concentrations of ≥5.0 µg/ml for IFX (area under the curve of 0.92; 95% CI: 0.82-1.00)) and 5.9 µg/ml for ADL (area under the curve of 0.89; 95% CI 0.71-1.00) were associated with fistula closure. Conclusion: Cut-off serum concentrations ≥5.0 µg/ml for IFX and ≥5.9 µg/ml for ADL were associated with perianal fistula closure. Hence, patients with producing perianal fistulas may benefit from anti-TNF dose intensification to achieve fistula closure.

Snapshot Study on the Value of Omentoplasty in Abdominoperineal Resection with Primary Perineal Closure for Rectal Cancer.

BACKGROUND: Perineal wound complications are often encountered following abdominoperineal resection (APR). Filling of the pelvic space by omentoplasty (OP) might prevent these complications, but there is scant evidence to support its routine application. OBJECTIVE: The aim of this study was to evaluate the impact of OP on perineal wound complications. METHODS: All patients undergoing APR with primary perineal closure (PPC) for non-locally advanced rectal cancer in 71 Dutch centers in 2011 were selected from a cross-sectional snapshot study. Outcomes were compared between PPC with or without OP, which was based on variability in practice among surgeons. RESULTS: Of 639 patients who underwent APR for rectal cancer, 477 had a non-locally advanced tumor and PPC was performed. Of those, 172 (36%) underwent OP. Patients with OP statistically more often underwent an extralevator approach (32% vs. 14%). Median follow-up was 41 months (interquartile range 22-47). There were no significant differences with or without OP in terms of non-healing of the perineal wound at 30 days (47% vs. 48%), non-healing at the end of follow-up (9% vs. 5%), pelvic abscess (12% vs. 13%) or re-intervention for ileus (5% vs. 3%). Perineal hernia developed significantly more often after OP (13% vs. 7%), also by multivariable analysis (odds ratio 2.61, 95% confidence interval 1.271-5.364; p = 0.009). CONCLUSIONS: In contrast to previous assumptions, OP after APR with PPC appeared not to improve perineal wound healing and seemed to increase the occurrence of perineal hernia. These findings question the routine use of OP for primary filling of the pelvic space.

Transanal Versus Transabdominal Minimally Invasive (Completion) Proctectomy With Ileal Pouch-anal Anastomosis in Ulcerative Colitis: A Comparative Study.

OBJECTIVE: This study aims to compare surgical outcome of transanal ileal pouch-anal anastomosis (ta-IPAA) with transabdominal minimal invasive approach in ulcerative colitis (UC), using the comprehensive complication index (CCI). BACKGROUND: Recent evolutions in rectal cancer surgery led to transanal dissection of the rectum resulting in a better exposure of the distal rectum and presumed better outcome. The same approach was introduced for patients with UC, resulting in decreased invasiveness. METHODS: All patients, undergoing minimally invasive restorative proctocolectomy in 1, 2, or 3 stages between January 2011 and September 2016 in 3 referral centers were included. Only patients who underwent either multiport, single port, single port with 1 additional port, hand-assisted, or robotic (R) laparoscopy were included in the analysis. CCI, registered during 90 days after pouch construction, was compared between the transanal and the transabdominal approach. RESULTS: Ninety-seven patients (male: 52%) with ta-IPAA were compared to 119 (male: 53%) with transabdominal IPAA. Ninety-nine (46%) patients had a defunctioning ileostomy at time of pouch construction. A 2-step model showed that the odds for postoperative morbidity were 0.52 times lower in the ta-IPAA group (95% confidence interval [0.29; 0.92] P = 0.026). In patients with morbidity, mean CCI of the transanal approach was 2.23 points lower than the transabdominal approach (95% confidence interval: [-6.64-3.36] P = 0.13), which was not significant. CONCLUSIONS: Ta-IPAA for UC is a safe procedure, resulting in fewer patients with morbidity, but comparable CCI when morbidity is present. Overall, ta-IPAA led to lower CCI scores.

Single-Port Surgery in Inflammatory Bowel Disease: A Review of Current Evidence.

The majority of patients with Crohn's disease and up to 35 % of patients with ulcerative colitis will ultimately require surgery during the course of their disease. Over the past few years, surgical techniques and experience in minimal invasive surgery have evolved resulting in single-incision laparoscopic surgery. The aim of this approach is to diminish the surgical trauma by reducing the number of incision sites. This review discusses the benefits and disadvantages of single-port surgery in various procedures in patients with inflammatory bowel disease (IBD). Short-term postoperative results, functional outcome, and costs available in the literature will be discussed. Single-port surgery in IBD has several benefits when compared to multi-port laparoscopic surgery. By using fewer incisions, a potential reduction of postoperative pain with less morphine use can be accomplished. In addition, accelerated postoperative recovery can result in a shorter hospital stay. Furthermore, a superior cosmesis can be reached with placement of the port at the future ostomy site or at the umbilicus. Literature on single-port surgery in IBD consists mainly of case series and a few matched case series. These studies demonstrated that single-port surgery seems to be a safe and feasible approach for the surgical treatment of IBD patients.

Emergency Laparoscopic Sigmoidectomy for Perforated Diverticulitis with Generalised Peritonitis: A Systematic Review.

BACKGROUND: Laparoscopic sigmoidectomy for diverticulitis has initially been confined to the elective setting. However, open acute sigmoidectomy for perforated diverticulitis is associated with high morbidity rates that might be reduced after laparoscopic surgery. The aim of this systematic review was to assess the feasibility of emergency laparoscopic sigmoidectomy for perforated diverticulitis. METHODS: We performed a systematic search of PubMed, EMBASE and CENTRAL. All studies reporting on patients with perforated diverticulitis (Hinchey III-IV) treated by laparoscopic sigmoidectomy in the acute phase were included, regardless of design. RESULTS: We included 4 case series and one cohort study (total of 104 patients) out of 1,706 references. Hartmann's procedure (HP) was performed in 84 patients and primary anastomosis in 20. The mean operating time varied between 115 and 200 min. The conversion rate varied from 0 to 19%. The mean length of hospital stay ranged between 6 and 16 days. Surgical re-intervention was necessary in 2 patients. In 20 patients operated upon without defunctioning ileostomy, no anastomotic leakage was reported. Three patients died during the postoperative period. Stoma reversal after HP was performed in 60 out of 79 evaluable patients (76%). CONCLUSIONS: Acute laparoscopic sigmoidectomy for the treatment of perforated diverticulitis is feasible in selected patients provided they are handled by experienced hands.

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BACKGROUND: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. METHODS/DESIGN: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. DISCUSSION: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. TRIAL REGISTRATION NUMBER: NCT02231086 (Clinicaltrials.gov).

The ACCURE-trial: the effect of appendectomy on the clinical course of ulcerative colitis, a randomised international multicenter trial (NTR2883) and the ACCURE-UK trial: a randomised external pilot trial (ISRCTN56523019).

BACKGROUND: Over the past 20 years evidence has accumulated confirming the immunomodulatory role of the appendix in ulcerative colitis (UC). This led to the idea that appendectomy might alter the clinical course of established UC. The objective of this body of research is to evaluate the short-term and medium-term efficacy of appendectomy to maintain remission in patients with UC, and to establish the acceptability and cost-effectiveness of the intervention compared to standard treatment. METHODS/DESIGN: These paired phase III multicenter prospective randomised studies will include patients over 18 years of age with an established diagnosis of ulcerative colitis and a disease relapse within 12 months prior to randomisation. Patients need to have been medically treated until complete clinical (Mayo score <3) and endoscopic (Mayo score 0 or 1) remission. Patients will then be randomised 1:1 to a control group (maintenance 5-ASA treatment, no appendectomy) or elective laparoscopic appendectomy plus maintenance treatment. The primary outcome measure is the one year cumulative UC relapse rate - defined both clinically and endoscopically as a total Mayo-score ≥5 with endoscopic subscore of 2 or 3. Secondary outcomes that will be assessed include the number of relapses per patient at 12 months, the time to first relapse, health related quality of life and treatment costs, and number of colectomies in each arm. DISCUSSION: The ACCURE and ACCURE-UK trials will provide evidence on the role and acceptability of appendectomy in the treatment of ulcerative colitis and the effects of appendectomy on the disease course. TRIAL REGISTRATION: NTR2883 ; ISRCTN56523019.