Prominence of ileal mucosa-associated microbiota to predict postoperative endoscopic recurrence in Crohn's disease.

OBJECTIVE: Following ileal resection for Crohn's disease (CD), recurrence is very frequent. Although several clinical risk factors of recurrence have been identified, predicting relapse remains challenging. Performing an ileocolonoscopy within the first year after surgery is currently recommended to assess endoscopic recurrence and to adjust the treatment. We took advantage of a large prospective multicentric cohort to investigate the role of the ileal mucosa-associated microbiota in postoperative endoscopic recurrence. PATIENTS AND METHODS: Ileal mucosa-associated microbiota was analysed by 16S sequencing at the time of surgery and/or of endoscopic evaluation in 201 patients (288 samples in total) prospectively recruited in France. RESULTS: Ileal mucosa-associated microbiota exhibits profound changes following surgery in CD. Compared with non-recurrence setting, endoscopic recurrence is associated with strong changes in ileal mucosa-associated microbiota that are highly reminiscent of those observed generally in ileal CD compared with healthy subjects with a reduction in alpha diversity, an increase in several members of the Proteobacteria phylum and a decrease in several members of the Lachnospiraceae and the Ruminococcaceae families within the Firmicutes phylum. At the time of surgery, we identified several bacterial taxa associated with endoscopic recurrence and that can better predict relapse than usual clinical risk factors. CONCLUSION: Surgery has an important impact on ileal mucosa-associated microbiota. Postoperative endoscopic recurrence is associated with changes in microbiota composition and alpha diversity. The gut microbiota has the potential to predict postoperative evolution and recurrence.

Association Between Microscopic Lesions at Ileal Resection Margin and Recurrence After Surgery in Patients With Crohn's Disease.

BACKGROUND AND AIMS: Different types of histologic lesions at the ileal margin, detected by histology, have been associated with increased rates of recurrence after ileocaecal surgery in patients with Crohn's disease (CD). We aimed to characterize histologic features of the ileal margin and to evaluate their association with disease recurrence. METHODS: We collected histologic data from 211 patients with ileal or ileocolonic CD who underwent ileocolonic resections at hospitals in France from September 2010 through December 2016. Ileal margins were analyzed. Early endoscopic recurrence was defined by a Rutgeerts score of i2 or more, 6 months after surgery. We also collected data from 10 adults with healthy ileum who underwent ileocecal resection for colonic tumors (controls). Clinical relapse was defined by CD-related symptoms confirmed by imaging, endoscopy, therapy intensification, CD-related complication, or subsequent surgery. RESULTS: Six months after surgery, 49% of patients had endoscopic recurrence; 5 years after surgery, 57% of patients had clinical relapse. Ileal margins were macroscopically affected in 20.9% of patients. CD transmural lesions at the margin (defined by mucosal ulceration or cryptitis, submucosal fibrosis and lymphoplasmacytic infiltrate of the subserosa) were observed in 13.6% of patients. Endoscopic recurrence was observed in 75% of patients with CD transmural lesions vs 46% of patients without (P =.005). In multivariate analysis, CD transmural lesions at the margin were independently associated with early endoscopic recurrence (OR, 3.83; 95% CI, 1.47-11.05; P =.008) and clinical recurrence (OR 2.04; 95% CI, 1.09-3.99; P =.026). CONCLUSION: In patients with CD, transmural lesions at the ileal margin were associated with an increased risk of post-operative recurrence. Histologic features of the ileal margin should be included in making decisions about post-operative therapy.

Postoperative Endoscopic Recurrence on the Neoterminal Ileum But Not on the Anastomosis Is Mainly Driving Long-Term Outcomes in Crohn's Disease.

INTRODUCTION: Early ileocolonoscopy within the first year after surgery is the gold standard to evaluate recurrence after ileocolonic resection for Crohn's disease (CD). The aim of the study was to evaluate the association between the presence and severity of anastomotic and ileal lesions at early postoperative ileocolonoscopy and long-term outcomes. METHODS: The REMIND group conducted a prospective multicenter study. Patients operated for ileal or ileocolonic CD were included. An ileocolonoscopy was performed 6 months after surgery. An endoscopic score describing separately the anastomotic and ileal lesions was built. Clinical relapse was defined by the CD-related symptoms, confirmed by imaging, endoscopy or therapeutic intensification; CD-related complications; or subsequent surgery. RESULTS: Among 225 included patients, long-term follow-up was available in 193 (median follow-up: 3.82 years [interquartile range: 2.56-5.41]). Median clinical recurrence-free survival was 47.6 months. Clinical recurrence-free survival was significantly shorter in patients with ileal lesions at early postoperative endoscopy whatever their severity was (I(1) or I(2,3,4)) as compared to patients without ileal lesions (I(0)) (I(0) vs I(2,3,4): P = 0.0003; I(0) vs I(1): P = 0.0008 and I(1) vs I(2,3,4): P = 0.43). Patients with exclusively ileal lesions (A(0)I(1,2,3,4)) had poorer clinical long-term outcomes than patients with exclusively anastomotic lesions (A(1,2,3)I(0)) (P = 0.009). DISCUSSION: A score describing separately the anastomotic and ileal lesions might be more appropriate to define postoperative endoscopic recurrence. Our data suggest that patients with ileal lesions, including mild ones (I(1)), could beneficiate from treatment step-up to improve long-term outcomes.

T cell clonal expansions in ileal Crohn's disease are associated with smoking behaviour and postoperative recurrence.

T cell clonal expansions are present in the inflamed mucosa of patients with Crohn's disease (CD) and may be implicated in postoperative recurrence after ileocolonic resection. METHODS: T cell receptor (TCR) analysis was performed in 57 patients included in a prospective multicentre cohort. Endoscopic recurrence was defined by a Rutgeerts score >i0. DNA and mRNA were extracted from biopsies collected from the surgical specimen and endoscopy, and analysed by high throughput sequencing and microarray, respectively. RESULTS: TCR repertoire in the mucosa of patients with CD displayed diverse clonal expansions. Active smokers at time of surgery had a significantly increased proportion of clonal expansions as compared with non-smokers (25.9%vs17.9%, p=0.02). The percentage of high frequency clones in the surgical specimen was significantly higher in patients with recurrence and correlated with postoperative endoscopic recurrence (area under the curve (AUC) 0.69, 95% CI 0.54 to 0.83). All patients with clonality above 26.8% (18/57) had an endoscopic recurrence. These patients with a high clonality were more frequently smokers than patients with a low clonality (61% vs 23%, p=0.005). The persistence of a similar TCR repertoire at postoperative endoscopy was associated with smoking and disease recurrence. Patients with high clonality showed increased expression of genes associated with CD8 T cells and reduced expression of inflammation-related genes. Expanded clones were found predominantly in the CD8 T cell compartment. CONCLUSION: Clonal T cell expansions are implicated in postoperative endoscopic recurrence. CD patients with increased proportion of clonal T cell expansions in the ileal mucosa represent a subgroup associated with smoking and where pathogenesis appears as T cell driven. TRIAL REGISTRATION NUMBER: NCT03458195.

[Large bowel ganglioneuromatosis associated with neurofibromatosis type 1]. / Ganglioneuromatose du tube digestif dans le cadre d'une neurofibromatose de type 1.

Gastrointestinal tract ganglioneuromatosis is a rare condition, which is isolated or included in a syndromique disease. Multiple endocrine neoplasia type 2 is the most frequently associated syndrome. Association with type 1 neurofibromatosis has also been established, but much rarely. We report the case of large bowel ganglioneuromatosis found incidentally in a patient with type 1 neurofibromatosis.

Postoperative Complications after Ileocecal Resection in Crohn's Disease: A Prospective Study From the REMIND Group.

OBJECTIVES: We sought to determine the frequency of and risk factors for early (30-day) postoperative complications after ileocecal resection in a well-characterized, prospective cohort of Crohn's disease patients. METHODS: The REMIND group performed a nationwide study in 9 French university medical centers. Clinical-, biological-, surgical-, and treatment-related data on the 3 months before surgery were collected prospectively. Patients operated on between 1 September 2010 and 30 August 2014 were included. RESULTS: A total of 209 patients were included. The indication for ileocecal resection was stricturing disease in 109 (52%) cases, penetrating complications in 88 (42%), and medication-refractory inflammatory disease in 12 (6%). A two-stage procedure was performed in 33 (16%) patients. There were no postoperative deaths. Forty-three (21%) patients (23% of the patients with a one-stage procedure vs. 9% of those with a two-stage procedure, P=0.28) experienced a total of 54 early postoperative complications after a median time interval of 5 days (interquartile range, 4-12): intra-abdominal septic complications (n=38), extra-intestinal infections (n=10), and hemorrhage (n=6). Eighteen complications (33%) were severe (Dindo-Clavien III-IV). Reoperation was necessary in 14 (7%) patients, and secondary stomy was performed in 8 (4.5%). In a multivariate analysis, corticosteroid treatment in the 4 weeks before surgery was significantly associated with an elevated postoperative complication rate (odds ratio (95% confidence interval)=2.69 (1.15-6.29); P=0.022). Neither preoperative exposure to anti-tumor necrosis factor (TNF) agents (n=93, 44%) nor trough serum anti-TNF levels were significant risk factors for postoperative complications. CONCLUSIONS: In this large, nationwide, prospective cohort, postoperative complications were observed after 21% of the ileocecal resections. Corticosteroid treatment in the 4 weeks before surgery was significantly associated with an elevated postoperative complication rate. In contrast, preoperative anti-TNF therapy (regardless of the serum level or the time interval between last administration and surgery) was not associated with an elevated risk of postoperative complications.

Identification of Gene Expression Profiles Associated with an Increased Risk of Post-Operative Recurrence in Crohn's Disease.

BACKGROUND AND AIMS: Ileocolonic resection is frequently needed in the course of Crohn's disease [CD] treatment and post-operative recurrence is extremely common. Our main objective was to analyse gene expression in the mucosa of CD patients at the time of surgery and at post-operative endoscopy, in order to identify predictors and mechanisms of early endoscopic recurrence. METHODS: We conducted transcriptome analyses on ileal mucosa samples collected from inflamed sections of the surgical specimens [n = 200], from ileal resection margins [n = 149] and in the neo-terminal ileum 6 months after surgery [n = 122]; these were compared with non-inflammatory bowel disease controls [n = 25]. The primary endpoint was post-operative endoscopic recurrence at 6 months. We applied regression models to identify gene signatures predicting endoscopic recurrence. RESULTS: Chronic inflammation was associated with strong expression of inflammatory genes [IL-6, IL-8, IL-1B] and decreased expression of genes involved in metabolic processes, but with a high inter-individual heterogeneity. Gene signatures associated with early endoscopic recurrence were mainly characterized by upregulation of TNFα, IFNγ, IL23A and IL17A. Pathway analyses showed that upregulation of mitochondrial dysfunction within the inflamed sections and JAK/STAT at the ileal margin were predictive of post-operative recurrence. A combined model integrating these top pathway signatures improved the prediction of endoscopic recurrence [area under the curve of 0.79]. STAT3 phosphorylation at the surgical ileal margin was associated with severe recurrence at 6 months. CONCLUSION: We identified several biological pathways in surgical ileal mucosa specimens associated with an increased risk of disease recurrence. Integration of the JAK/STAT and mitochondrial dysfunction pathways in the clinical model improved the prediction of post-operative recurrence.

Male gender, active smoking and previous intestinal resection are risk factors for post-operative endoscopic recurrence in Crohn's disease: results from a prospective cohort study.

BACKGROUND: After ileocaecal resection for Crohn's disease (CD), inflammatory lesions frequently recur on the anastomosis and/or on the neo-terminal ileum. AIM: To identify predictors of early post-operative endoscopic recurrence. METHODS: From September 2010 to September 2017, the REMIND group conducted a prospective nationwide study in nine French academic centres. Data were collected at the time of surgery and endoscopy, performed 6-12 months after surgery. Endoscopic recurrence was defined as a Rutgeerts score ≥i2. Baseline factors associated with endoscopic recurrence were searched by univariate and multivariate regression analysis. RESULTS: Two hundred and eighty-nine CD patients were included. Endoscopy within 1 year following surgery was performed in 225 (78%) patients (104M/121F). Mean age and disease duration were 35 (12.2) and 8.8 (8.9) years respectively. Seventy (32%) patients were active smokers at surgery. One hundred and forty-two (63%) patients received at least one anti-TNF therapy before surgery. After surgery, 40 (18%) patients received thiopurines and 66 (29%) received an anti-TNF agent. Endoscopic recurrence occurred in 107 (47%) patients. In multivariate analysis, male gender (OR = 2.48 [IC 95% 1.40-4.46]), active smoking at surgery (OR = 2.65 [IC 95% 1.44-4.97]) and previous resection (OR = 3.03 [IC 95% 1.36-7.12]) were associated with a higher risk of endoscopic recurrence. Inversely, post-operative anti-TNF treatment decreased the risk of endoscopic recurrence (OR = 0.50 [IC 95% 0.25-0.96]). CONCLUSIONS: Male gender, active smoking at surgery and previous intestinal resection are associated with a higher risk of endoscopic post-operative recurrence, while post-operative anti-TNF treatment is associated with a lower risk.

Prevalence of Yersinia Species in the Ileum of Crohn's Disease Patients and Controls.

Yersinia are common contaminants of food products, but their prevalence in the human gut is poorly documented. Yersinia have been implicated in Crohn's Disease (CD, an inflammatory bowel disease) however their role in CD is controversial. We performed highly sensitive PCR assays of specific sequences for the gyrB gene of Y. aldovae, Y. bercovieri, Y. enterocolitica, Y. intermedia, Y. mollaretii and the inv gene of Y. pseudotuberculosis. We analyzed a total of 470 ileal samples taken from 338 participants (262 CD patients and 76 controls) belonging to three independent cohorts. All patients and controls were phenotyped and genotyped for the main CD susceptibility variants: NOD2, ATG16L1, and IRGM. Yersinia were found in 7.7% of ileal samples (respectively 7.9 and 7.6% in controls and CD patients) corresponding to 10% of participants (respectively 11.8 and 9.5% in controls and CD patients). Y. enterocolitica, Y. pseudotuberculosis and Y. intermedia were the most frequently identified species. The bacteria were more frequent in resected specimens, lymph nodes and Peyer's patches. Yersinia were no more likely to be detected in CD tissues than tissues from inflammatory and non-inflammatory controls. CD patients treated with immunosuppressants were less likely to be Yersinia carriers. In conclusion, this work shows that Yersinia species are frequently found at low levels in the human ileum in health and disease. The role of Yersinia species in this ecosystem should now be explored.

Role of radiation therapy in non-melanoma cancers, lymphomas and sarcomas of the skin: Systematic review and best practice in 2016.

Radiotherapy (RT) has been used for the treatment of skin cancers since very early after the discovery of X-rays. Indications for radiotherapy in non-melanoma cancers are controversial, and are usually decided according to the tumor type and the possibility of curing the patient with surgery. The introduction of sophisticated surgery techniques and the information of the general population on potential late radiation-induced toxicity and carcinogenesis have led to limiting radiation indications in the dermatologist community. However, radiotherapy has undergone considerable development, including technological advances, to enable limiting doses to the organs at risk. Thus, side effects due to high doses and/or the use of old radiotherapy (RT) techniques have been significantly decreased. In this systematic review we aim to discuss indications of radiotherapy in non-melanoma skin cancers and focus on new advances that may lead to rehabilitating this treatment option according to the tumor's radiosensitivity and the clinical benefit/risk ratio. Finally, for each type of cancer, we suggest "the best RT practice".

Efficacy of modern chemotherapy and prognostic factors in patients with ovarian metastases from gastric cancer: A retrospective AGEO multicentre study.

BACKGROUND: Ovarian metastases from gastrointestinal tumours frequently lead to locoregional complications and undermine quality of life. The chemosensitivity of ovarian metastases from gastric cancer is unknown. AIM: To evaluate the efficacy of modern chemotherapy regimens in first-line treatment for patients with ovarian metastases from gastric cancer. METHODS: All consecutive patients with ovarian metastases from gastric cancer who received at least one cycle of chemotherapy were included in this retrospective study. RESULTS: Thirty-five patients were included (median age, 50.5 years; synchronous ovarian metastases, 60%). Seventeen patients (48.6%) underwent oophorectomy. Patients were treated with first-line chemotherapy based on platinum (n=14), irinotecan (n=8), taxane plus platinum (n=4) or epirubicin plus platinum (n=9). The median PFS and OS were 6.8 and 18.8 months, respectively. The objective response rate (ORR) for extra-ovarian (13.6%) and ovarian (20.9%) metastatic sites was not significantly different (p=0.55). There was no significant difference in terms of ORR on ovarian metastatic site according to the first-line chemotherapy (p=0.21). In multivariate analysis, oophorectomy was an independent prognostic factor for OS (p<0.01). CONCLUSIONS: This study suggests that ovarian metastases from gastric cancer are not more resistant than extra-ovarian metastases, and that oophorectomy is an independent prognostic factor significantly linked to OS. Prospective studies are needed to confirm these results.