Gabriel Rahmi

IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease–associated inflammation and lymphomagenesis

Enteropathy-associated T cell lymphoma is a severe complication of celiac disease (CD). One mechanism suggested to underlie its development is chronic exposure of intraepithelial lymphocytes (IELs) to potent antiapoptotic signals initiated by IL-15, a cytokine overexpressed in the enterocytes of individuals with CD. However, the signaling pathway by which IL-15 transmits these antiapoptotic signals has not been firmly established. Here we show that the survival signals delivered by IL-15 to freshly isolated human IELs and to human IEL cell lines derived from CD patients with type II refractory CD (RCDII) - a clinicopathological entity considered an intermediary step between CD and enteropathy-associated T cell lymphoma - depend on the antiapoptotic factors Bcl-2 and/or Bcl-xL. The signals also required IL-15Rbeta, Jak3, and STAT5, but were independent of PI3K, ERK, and STAT3. Consistent with these data, IELs from patients with active CD and RCDII contained increased amounts of Bcl-xL, phospho-Jak3, and phospho-STAT5. Furthermore, incubation of patient duodenal biopsies with a fully humanized human IL-15-specific Ab effectively blocked Jak3 and STAT5 phosphorylation. In addition, treatment with this Ab induced IEL apoptosis and wiped out the massive IEL accumulation in mice overexpressing human IL-15 in their gut epithelium. Together, our results delineate the IL-15-driven survival pathway in human IELs and demonstrate that IL-15 and its downstream effectors are meaningful therapeutic targets in RCDII.

Long-Term Outcome of Patients Treated With Double Balloon Enteroscopy for Small Bowel Vascular Lesions

OBJECTIVES:Early rebleeding rate after endoscopic therapy with double balloon enteroscopy (DBE) of hemorrhagic small bowel vascular lesions (SBVL) varies between 10 and 50%. In recent reports, long-term follow-up of patients have been described but rebleeding risk factors are still not well established. The aim of the current study was to identify long-term treatment success rate and rebleeding risk factors after DBE therapy in a large cohort.METHODS:We conducted a single-center, retrospective cohort study in a large French tertiary-referral center between January 2004 and December 2007.RESULTS:Among 261 patients presenting with obscure gastrointestinal bleeding (OGIB), SBVL was present in 133 patients and was treated successfully in 129 (97%) using mainly argon plasma coagulation. Ninety-eight patients were followed up for a mean period of 22.6±13.9 months (range 1–52). Rebleeding rate was 46% (45/98 patients) at 36 months. On multivariate analysis, the total number of observed lesions (hazard ratio (HR): 1.15, 95% confidence interval (CI): 1.06–1.25, P=0.001) and the presence of a valvular and/or arrhythmic cardiac disease (HR: 2.50, 95% CI: 1.29–4.87, P=0.007) were significantly associated with the risk of rebleeding. Complication rate of therapeutic DBE was 2.3% with no mortality.CONCLUSIONS:Endoscopic therapy using DBE for SBVL in patients with recurrent OGIB allows a long-term remission in more than half of the patients. Independent rebleeding risk factors after a first endoscopic therapy are an increased number of SBVL and an associated valvular/arrhythmic heart disease.

Diagnostic Yield of Capsule Endoscopy in Refractory Celiac Disease

OBJECTIVES:Capsule endoscopy (CE) allows for the assessment of the small bowel in numerous intestinal diseases, including celiac disease (CD). The main advantage of CE is the complete visualization of the intestinal mucosal surface. The objective of this study was to investigate whether CE can predict the severity of CD and detect complications.METHODS:We retrospectively studied the medical files of 9 patients with symptomatic CD, 11 patients with refractory celiac disease type I (RCDI) and 18 patients with refractory celiac disease type II (RCDII), and 45 patients without CD who were investigated both CE and upper endoscopy or enteroscopy. The type of CD was diagnosed on the basis of a centralized histological review, flow cytometry analysis of intraepithelial lymphocytes, and the analysis of T-cell receptor rearrangement by multiplex polymerase chain reaction.RESULTS:A total of 47 CEs (10, 11, and 26 CEs in the symptomatic CD, RCDI, and RCDII groups, respectively) from the 38 celiac patients and 47 CEs from the 45 nonceliac patients were retrospectively reviewed. Villous atrophy, numerous, or distally located ulcers were more frequent in celiac patients than in controls. Among celiac patients, CE was of acceptable quality in 96% of cases and was complete in 62% of cases. The concordance of CE with histology for villous atrophy was better than that of optic endoscopy (κ coefficient =0.45 vs. 0.24, P<0.001). Extensive mucosal damage on CE was associated with low serum albumin (P=0.003) and the RCDII form (P=0.02). Three cases of overt lymphoma were detected by CE during the follow-up.CONCLUSIONS:CE findings have a satisfactory concordance with histology and nutritional status in patients with symptomatic or refractory CD. Moreover, CE may predict the type of RCD and allows for the early detection of overt lymphoma.

Endoscopic submucosal dissection for superficial rectal tumors: prospective evaluation in France.

BACKGROUND AND STUDY AIMS Endoscopic submucosal dissection (ESD) provides a high en bloc resection rate for superficial colorectal tumors. The aims of this study were to assess the feasibility of ESD in France and to evaluate the complete resection rate at 1 year. PATIENTS AND METHODS Patients with superficial rectal tumors ≥ 10 mm in size were prospectively included in the study at nine French expert centers between February 2010 and June 2012. The study was stopped temporarily because of a high complication rate. Study recruitment resumed following remedial action. RESULTS A total of 45 patients were included (mean age 67 years; 24 males). The immediate perforation rate was 18 % (n = 8), and salvage surgery was not required. Six patients (13 %) had late bleeding, which was treated endoscopically in five patients and surgically in one patient who had required blood transfusion. The mortality rate was zero. The en bloc resection rate was 64 % (29/45), and the curative R0 resection rate was 53 % (24/45). Three patients (7 %) had an invasive tumor (two sm1, one T2). At 1-year follow-up, endoscopic examinations showed complete resection in 38 /43 patients (88 %). At the end of the study, after the remedial action, the en bloc resection rate had increased from 52 % to 82 %, and the perforation rate had decreased significantly from 34 % to 0 %. CONCLUSIONS The study reflects the initial prospective experience of ESD in France, and suggests that curative R0 resection rates should increase and complication rates should decrease with experience and corrective actions.

Multicenter comparison of double-balloon enteroscopy and spiral enteroscopy.

Spiral enteroscopy is a novel technique for small bowel exploration. The aim of this study is to compare double‐balloon and spiral enteroscopy in patients with suspected small bowel lesions.

Long-term follow-up of patients undergoing capsule and double-balloon enteroscopy for identification and treatment of small-bowel vascular lesions: a prospective, multicenter study

BACKGROUND AND STUDY AIMS Few data are available concerning the long-term outcome of patients treated endoscopically for bleeding small-bowel vascular lesions (SBVL). The aim of this study was to evaluate the risk of rebleeding after endoscopic therapy for SBVLs detected by video capsule enteroscopy (VCE). The secondary aim was to assess risk factors for rebleeding. PATIENTS AND METHODS A prospective, multicenter study (15 centers) was conducted, involving patients with obscure gastrointestinal bleeding and SBVL on VCE who were treated during double-balloon enteroscopy (DBE). The likelihood of bleeding was defined according to VCE findings, as high or low. RESULTS A total of 183 patients underwent endotherapy during DBE, and 64 (35 %) had rebleeding during the 1 year follow-up period. Multivariate analysis indicated that cardiac disease (hazard ratio [HR] 2.04, 95 % confidence interval [CI] 1.20 - 3.48; P < 0.01) and the presence of overt bleeding (HR 1.78, 95 %CI 1.07 - 2.97; P = 0.03) at presentation were associated with the risk of rebleeding. The association between chronic renal failure and the risk of rebleeding was close to statistical significance (HR 1.77, 95 %CI 0.94 - 3.33; P = 0.08). Kaplan-Meier analysis suggested that patients treated during DBE for a lesion with low likelihood of bleeding on VCE had higher rebleeding rates than those with a high likelihood of bleeding (HR 1.87, 95 %CI 0.94 - 3.37; P = 0.07). CONCLUSION Despite long-term remission in most patients, about one-third had rebleeding at 1 year. Independent risk factors for rebleeding were cardiac disease and overt bleeding at original presentation. The lesion characteristics on VCE may be useful to evaluate the bleeding potential of the lesion and may be used for better selection of patients for DBE.

Enteropathy-Associated T-Cell Lymphoma Complicating an Autoimmune Enteropathy

Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma frequently associated with celiac disease. We report a case of EATL complicating adult autoimmune enteropathy (AIE). Analysis of phenotype, rearrangements in T-cell receptor genes, and chromosome alterations by high-resolution comparative genomic hybridization identified features distinct from those described for types I and II EATL. Furthermore, EATL arose from a single T-cell clone that had been present for several years in AIE-associated, oligoclonal, intestinal T-cell infiltrate. Emerging T-cell clones should be monitored in patients with AIE who receive long-term immunosuppressive therapy.

Efficacy of endoscopic submucosal dissection for residual or recurrent superficial colorectal tumors after endoscopic mucosal resection

Superficial colorectal tumors can be treated effectively by endoscopic submucosal dissection (ESD). Few data are available on using ESD for residual or recurrent tumors after the first endoscopic resection. This study aimed to evaluate the efficacy of ESD for these lesions.

Impact of chromoscopy on adenoma detection in patients with Lynch syndrome: a prospective, multicenter, blinded, tandem colonoscopy study.

Objectives:In Lynch syndrome, flat and diminutive adenomas are particularly prone to malignant transformation, but they can be missed by standard colonoscopy. It is not known whether chromocolonoscopy is able to detect more adenomas than standard colonoscopy in patients with Lynch syndrome.Methods:We conducted a prospective, multicenter, randomized trial to compare standard colonoscopy with standard colonoscopy followed by pancolonic chromoscopy with indigo carmine in patients with a proven germline mutation in a mismatch-repair gene related to Lynch syndrome and who were undergoing screening or surveillance colonoscopy. Standard colonoscopy was used first to detect visible lesions. Colonoscopy with chromoscopy was then performed by a second gastroenterologist (blinded to the findings of the first colonoscopy) to detect additional lesions. The primary end point was the number of patients in whom at least one adenoma was detected.Results:A total of 78 eligible patients (median age, 45 years) were enrolled at 10 centers from July 2008 to August 2009. Significantly more patients with at least one adenoma were identified by chromocolonoscopy (32/78 (41%)) than by standard colonoscopy (18/78 (23%); P<0.001). The percentage of patients in whom at least one additional adenoma was detected during the chromoscopy was 31% (24/78). Overall, chromocolonoscopy plus colonoscopy detected a total of 55 adenomas in 32 patients (mean number of adenomas detected per patient: 0.7 vs. standard colonoscopy alone: 0.3; P<0.001).Conclusion:The results support the proposition that chromocolonoscopy may significantly improve the detection rate of colorectal adenomas in patients undergoing screening or surveillance colonoscopy for Lynch syndrome.

Bone marrow‐derived mesenchymal stem cell‐loaded fibrin patches act as a reservoir of paracrine factors in chronic myocardial infarction

The combination of mesenchymal stem cells and tissue‐engineered fibrin patches improves the therapeutic efficacy of stem cells. In vivo cardiac magnetic resonance (4.7 Tesla) and ex vivo high‐spatial resolution CMR were used to track the fate of human bone marrow‐derived mesenchymal stem cell (BMSC) delivered on an epicardial scaffold and more specifically assess their potential intramyocardial migration. Fifty‐seven nude rats underwent permanent coronary artery ligation. Two months later, those with a left ventricular ejection fraction ≤55% were randomly allocated to receive a patch loaded with human BMSC (BMSC‐P, n = 10), a patch loaded with BMSCs labelled with iron oxide nanoparticles (BMSC*‐P, n = 12), an acellular patch (A‐P, n = 8) or to serve as sham‐operated animals (SHAM, n = 7). BMSC secretion of cytokines and growth factors was evaluated with flow‐cytometry. Cardiac functional parameters of cell‐treated groups (BMSC*‐P and BMSC‐P) yielded significantly better outcomes than the SHAM group (p = 0.044 and p = 0.026, respectively, for ejection fraction). Angiogenesis was higher in the cell‐patch than in control groups (e.g. BMSC*P vs. SHAM: p = 0.007). No BMSCs were identified into the myocardium on cardiac magnetic resonance or histological sections, although persisting BMSCs were identified on the epicardial surface 21 days post‐transplantation in 10% of rats hearts (Lamin A/C and CD90 positive). Cytokine and growth factor profiling demonstrated an increase in their release by cells seeded in patches. The absence of stem cell migration into the myocardium and the persistence of stem cells on the epicardial surface suggest that fibrin patches are likely to act predominantly as reservoirs of paracrine factors. Copyright