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/ )

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 degrees 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

The measured distance between tumor cells and the peritoneal surface predicts the risk of peritoneal metastases and offers an objective means to differentiate between pT3 and pT4a colon cancer

Substantial variability exists in what pathologists consider as pT4a in colorectal cancer when tumor cells are within 1 mm of the free peritoneal surface. This study aimed to determine if the measured sub-millimeter distance between tumor cells and the free peritoneal surface would offer an objective means of stratifying patients according to the risk of developing peritoneal metastases. Histological slides of patients included in the COLOPEC trial, with resectable primary c/pT4N0-2M0 colon cancer, were centrally reassessed. Specific tumor morphological variables were collected, including distance from tumor to free peritoneal surface, measured in micrometers (mu m). The primary outcome, 3-year peritoneal metastasis rate, was compared between four groups of patients stratified for relation of tumor cells to the peritoneum: 1) Full peritoneal penetration with tumor cells on the peritoneal surface, 2) 0-99 mu m distance to the peritoneum, 3) 100-999 mu m to the peritoneum, and 4) >= 1000 mu m to the peritoneum, by using Kaplan-Meier analysis. In total, 189 cases were included in the present analysis. Cases with full peritoneal penetration (n = 89), 0-99 mu m distance to the peritoneal surface (n = 34), 100-999 mu m distance (n = 33), and >= 1000 mu m distance (n = 33), showed significantly different 3-year peritoneal metastases rates of 25% vs 29% vs 6% vs 12%, respectively (Log Rank, p = 0.044). N-category did not influence the risk of peritoneal metastases in patients with a tumor distance beyond 100 mu m, while only the N2 category seemed to result in an additive risk in patients with a distance of 0-99 mu m. The findings of this study suggest that the measured shortest distance between tumor cells and the free peritoneal surface is useful as an objective means of stratifying patients according to the risk of developing peritoneal metastases. This simple measurement is practical and may help in providing a precise definition of pT4a. Trial registration: NCT02231086 (Clinicaltrials.gov)

Ligation of the Intersphincteric Fistula Tract and Endorectal Advancement Flap for High Perianal Fistulas in Crohn's Disease: A Retrospective Cohort Study

BACKGROUND AND AIMS: Ligation of the intersphincteric fistula tract [LIFT] and advancement flap [AF] procedures are well-established, sphincter-preserving procedures for closure of high perianal fistulas. As surgical fistula closure is not commonly offered in Crohn's disease patients, long-term data are limited. This study aims to evaluate outcomes after LIFT and AF in Crohn's high perianal fistulas. METHODS: All consecutive Crohn's disease patients ≥18 years old treated with LIFT or AF between January 2007 and February 2018 were included. The primary outcome was clinical healing and secondary outcomes included radiological healing, recurrence, postoperative incontinence and Vaizey Incontinence Score. RESULTS: Forty procedures in 37 patients [LIFT: 19, AF: 21, 35.1% male] were included. A non-significant trend was seen towards higher clinical healing percentages after LIFT compared to AF [89.5% vs 60.0%; p = 0.065]. Overall radiological healing rates were lower for both approaches [LIFT 52.6% and AF 47.6%]. Recurrence rates were comparable: 21.1% and 19.0%, respectively. In AF a trend was seen towards higher clinical healing percentages when treated with anti-tumour necrosis factor/immunomodulators [75.0% vs 37.5%; p = 0.104]. Newly developed postoperative incontinence occurred in 15.8% after LIFT and 21.4% after AF. Interestingly, 47.4% of patients had a postoperatively improved Vaizey Score [LIFT: 52.9% and AF: 42.9%]. The mean Vaizey Score decreased from 6.8 [SD 4.8] preoperatively to 5.3 [SD 5.0] postoperatively [p = 0.067]. CONCLUSIONS: Both LIFT and AF resulted in satisfactory closure rates in Crohn's high perianal fistulas. However, a discrepancy between clinical and radiological healing rates was found. Furthermore, almost half of the patients benefitted from surgical intervention with respect to continence

Propensity Score Adjusted Comparison of Pelviperineal Morbidity with and Without Omentoplasty Following Abdominoperineal Resection for Primary Rectal Cancer

BACKGROUND: Abdominoperineal resection is associated with a high incidence of perineal complications, and whether this is reduced by an omentoplasty is still unclear. OBJECTIVE: This study aimed to investigate the impact of omentoplasty on pelviperineal morbidity in patients undergoing abdominoperineal resection for rectal cancer. DESIGN: This was a retrospective comparative cohort study using propensity score analyses to reduce potential confounding. SETTING: The study was undertaken in 2 teaching hospitals and 1 university hospital. PATIENTS: Patients who underwent abdominoperineal resection for primary rectal cancer between 2000 and 2017 were included. MAIN OUTCOME MEASURES: The main end points were primary perineal wound healing at 30 days and overall and specific pelviperineal morbidity until the end of the study period. RESULTS: Among 254 included patients, 106 had an omentoplasty. The primary perineal wound healing rate at 30 days was similar for omentoplasty and no omentoplasty (65% vs 60%; p = 0.422), also after adjusting for potential confounding by propensity score analysis (OR, 0.89; 95% CI, 0.45-1.75). Being free from any pelviperineal complication at 6 months (75% vs 79%; p = 0.492), absence of any pelviperineal morbidity until 1 year (54% vs 49%; p = 0.484), and incidence of persistent perineal sinus (6% vs 10%; p = 0.256) were also similar in both groups. The unadjusted higher perineal hernia rate after omentoplasty (18% vs 7%; p = 0.011) did not remain statistically significant after regression analysis including the propensity score (OR, 1.34; 95% CI, 0.46-3.88). Complications related to the omentoplasty itself were observed in 8 patients, of whom 6 required reoperation. LIMITATIONS: This study was limited by the retrospective and nonrandomized design causing some heterogeneity between the 2 cohorts. CONCLUSION: In this multicenter study using propensity score analyses, the use of omentoplasty did not lower the incidence or the duration of pelviperineal morbidity in patients undergoing abdominoperineal resection for rectal cancer, and omentoplasty itself was associated with a risk of reoperation. See Video Abstract at http://links.lww.com/DCR/A918

Endoscopic Recurrence or Anastomotic Wound Healing Phenomenon after Ileocolic Resection for Crohn's Disease: The Challenges of Accurate Endoscopic Scoring

BACKGROUND AND AIMS: Adequate endoscopic scoring in Crohn's disease [CD] is crucial, as it dictates the need for initiating postoperative medical therapy and is utilized as an outcome parameter in clinical trials. Here we aimed to observe anastomotic wound healing in relation to endoscopic scoring of both inverted and everted stapled lines in side-to-side anastomoses. METHODS: Two prospective patient cohorts were included: ileocolic resection [ICR] for CD, and right-sided colon resection for colorectal cancer [CRC]. Videos taken during colonoscopy 6 months postoperatively were evaluated. The Simplified Endoscopic Activity Score for Crohn's Disease and modified Rutgeerts score were determined. The primary outcome was the presence of ulcerations in CD patients on both the inverted and the everted stapled lines. Secondary outcomes were the presence of anastomotic ulcerations in CRC patients and the number of cases having ulcerations exclusively at the inverted stapled line. RESULTS: Of the 82 patients included in the CD cohort, ulcerations were present in 63/82 [76.8%] at the inverted- vs 1/71 [1.4%] at the everted stapled line. Likewise in the CRC cohort, ulcerations were present in 4/6 [67.7%] at the inverted vs 0/6 [0%] at the everted stapled line. In total, 27% of the 63 patients in the CD cohort had ulcerations exclusively on the inverted stapled line. CONCLUSION: Inverted stapled lines heal with ulcerations, whereas everted stapled lines heal without any ulcerations, in both CD and non-CD patients. The abnormalities at the inverted stapled line might interfere with endoscopic scoring of recurrence, with potentially an impact on patients' quality of life and on healthcare costs if postoperative treatment is initiated incorrectly

Locally Advanced Colorectal Cancer: True Peritoneal Tumor Penetration is Associated with Peritoneal Metastases

Findings show T4 colorectal cancer (CRC) to be a risk factor for the development of peritoneal metastases (PM). Heterogeneity regarding peritoneal involvement of T4 tumors might explain the wide range of reported PM incidences (8-50%). Hyperplastic and mesothelial inflammatory reactions complicate evaluation of the exact primary tumor involvement of the peritoneal layer. This retrospective cohort study aimed to assess the association between either inflammatory peritoneal reaction or peritoneal involvement of the primary tumor and the risk of PM. Since 2010, pathologists at UZ Leuven have systematically categorized peritoneal involvement in peritoneal reaction with tumor less than 1 mm from the peritoneal surface or true peritoneal penetration. All patients undergoing resection of CRC between January 2010 and July 2013 who fulfilled either of these pathologic criteria were included in this study. The study enrolled 159 CRC patients. Peritoneal reaction with tumor less than 1 mm from the peritoneal surface was present in 43 patients and true peritoneal penetration in 116 patients. Overall, 29 patients (18%) had synchronous PM, and 30 patients (23%) had metachronous PM. In the multivariable analysis, true peritoneal penetration, in contrast to peritoneal reaction with tumor less than 1 mm from the peritoneum, was associated with greater risk of PM (odds ratio [OR], 2.518; range, 1.038-6.111; p = 0.041) and lymph node involvement (N1: OR, 1.572; range, 0.651-3.797 vs N2: OR, 4.046; range, 1.549-10.569; p = 0.014). Histologically confirmed true peritoneal penetration by CRC, rather than inflammatory peritoneal reaction constitutes a high risk for PM. With evolving treatment strategies that aim to treat PM in an earlier phase, identification of high-risk patients becomes highly important clinicall

Evaluation of the effect of storage condition on cell extraction and flow cytometric analysis from intestinal biopsies

Background: Flow cytometric (FC) analysis of intestinal tissue biopsies requires prompt cell isolation and processing to prevent cell death and generate valid data. We examined the effect of storage conditions prior to cell isolation and FC on viable cell yield and the proportions of immune cell phenotypes from intestinal biopsies. Methods: Biopsies (N = 224) from inflamed or non-inflamed ileal and/or colonic tissue from three patients with Crohn's disease were processed and analyzed immediately in duplicate, or stored under different conditions. Cells were isolated and stained for specific markers, followed by FC. Results: Decreased mean live CD45+ cell counts were observed after storage of biopsies at −80 °C dimethyl sulfoxide (DMSO)/citrate buffer compared with immediate processing (1794.3 vs. 19,672.7; p = 0.006]). A non-significant decrease in CD45+ live cell count occurred after storage at −20 °C in DMSO/citrate buffer and cell yield was adequate for subsequent analysis. CD3+ cell proportions were significantly lower after storage at 4 °C in complete medium for 48 h compared with immediate analysis. Mean CD14+ cell proportions were significantly higher after storage of biopsies at −80 °C in DMSO/citrate buffer compared with immediate analysis (2.61% vs. 1.31%, p = 0.007). CD4+, CD8+ and CD4+/CD8+ cell proportions were unaffected by storage condition. Conclusion: Storage of intestinal tissue biopsies at −20 °C in DMSO/citrate buffer for up to 48 h resulted in sufficient viable cell yield for FC analysis without affecting subsequent marker-positive cell proportions. These findings support the potential shipping and storage of intestinal biopsies for centralized FC analysis in multicenter clinical trials

Anatomical Variation in Mesenteric Macrophage Phenotypes in Crohn's Disease

INTRODUCTION: Clinical trials are currently investigating whether an extended mesenteric resection for ileocecal resections could reduce postoperative recurrence in Crohn's disease. Resection of the mesorectum, which contains proinflammatory macrophages, during proct(ocol)ectomy, is associated with reduced recurrent inflammation and improved wound healing. We aimed to characterize the macrophages in the ileocecal mesentery, which were compared with those in the mesorectum, to provide a biological rationale for the ongoing trials. METHODS: In 13 patients with Crohn's disease and 4 control patients undergoing a proctectomy, tissue specimens were sampled at 3 locations from the mesorectum: distal (rectum), middle, and proximal (sigmoid). In 38 patients with Crohn's disease and 7 control patients undergoing ileocecal resections, tissue specimens also obtained from 3 locations: adjacent to the inflamed terminal ileum, adjacent to the noninflamed ileal resection margin, and centrally along the ileocolic artery. Immune cells from these tissue specimens were analyzed by flow cytometry for expression of CD206 to determine their inflammatory status. RESULTS: In the mesorectum, a gradient from proinflammatory to regulatory macrophages from distal to proximal was observed, corresponding to the adjacent inflammation of the intestine. By contrast, the ileocecal mesentery did not contain high amounts of proinflammatory macrophages adjacent to the inflamed tissue, and a gradient toward a more proinflammatory phenotype was seen in the central mesenteric area. DISCUSSION: Although the mesentery is a continuous structure, the mesorectum and the ileocecal mesentery show different immunological characteristics. Therefore, currently, there is no basis to perform an extended ileocecal resection in patients with Crohn's disease