Benoit Terris’s research while affiliated with Université Paris Cité and other places

Autophagy, a cytoprotective mechanism in intestinal epithelial cells, plays a crucial role in maintaining intestinal homeostasis. Beyond its cell-autonomous effects, the significance of autophagy in these cells is increasingly acknowledged in the dynamic interplay between the microbiota and the immune response. In the context of colon cancer, intestinal epithelium disruption of autophagy has been identified as a critical factor influencing tumor development. This disruption modulates the composition of the gut microbiota, eliciting an anti-tumoral immune response. Here, we report that Atg7 deficiency in intestinal epithelial cells shapes the intestinal microbiota leading to an associated limitation of colitis induced by Citrobacter rodentium infection. Mice with an inducible, intestinal epithelial-cell-specific deletion of the autophagy gene, Atg7, exhibited enhanced clearance of C. rodentium , mitigated hyperplasia, and reduced pathogen-induced goblet cell loss. This protective effect is linked to a higher proportion of neutrophils and phagocytic cells in the early phase of infection. At later stages, it is associated with the downregulation of pro-inflammatory pathways and an increase in Th17 and Treg responses—immune responses known for their protective roles against C. rodentium infection, modulated by specific gut microbiota. Fecal microbiota transplantation and antibiotic treatment approaches revealed that the Atg7-deficiency-shapped microbiota, especially Gram-positive bacteria, playing a central role in driving resistance to C. rodentium infection. In summary, our findings highlight that inhibiting autophagy in intestinal epithelial cells contributes to maintaining homeostasis and preventing detrimental intestinal inflammation through microbiota-mediated colonization resistance against C. rodentium . This underscores the central role played by autophagy in shaping the microbiota in promoting immune-mediated resistance against enteropathogens.

Ampullary composite gangliocytoma/neuroma and neuroendocrine tumor (CoGNET), previously called ampullary gangliocytic paragangliomas (GP) are a rare entity, with only few reported cases in the literature. This is a multicentric retrospective cohort of patients treated with endoscopy or surgery for ampullary CoGNET. A literature review of ampullary CoGNET was also performed. Fifteen patients were included, mostly female (n=10) with a median age of 50 y.o. Patients were asymptomatic in 7 cases. Four patients were treated with pancreatoduodenectomy, four with transduodenal ampullectomy and eight with endoscopic papillectomy. Clavien-Dindo III-IV complications occurred in 2 of the 8 surgical cases, but no fatal adverse events were registered. There was only one moderate endoscopic adverse event. Median length of stay was 9 days. Median tumor size was 20 mm, R0 resection rate was 93.8% and 2 patients had nodal involvement. After a median follow-up of 29 months, there was no local or distant recurrence nor death from disease. The literature review confirmed the clinical presentation and excellent outcomes of ampullary CoGNET management, especially regarding survival, even for patients with nodal or distant metastases. Overall, ampullary CoGNET are rare tumors with excellent prognosis, even with incomplete resection or nodal involvement. Treatment should be as minimally invasive as possible and long-term follow-up is needed.

Acyl-CoA binding protein (ACBP), also known as diazepam-binding inhibitor (DBI), is an extracellular checkpoint of autophagy. Here, we report that patients with histologically confirmed metabolic-associated steatohepatitis (MASH) or liver fibrosis exhibit elevated levels of circulating ACBP/DBI protein as compared to non-affected controls. Plasma ACBP/DBI strongly correlated with the NAFLD and FIB4 scores in patients, and these correlations were independent of age and body mass index. We studied the capacity of a monoclonal antibody (mAb) neutralizing mouse ACBP/DBI to combat active liver disease in several mouse models, in which steatohepatitis had been induced by four different protocols, namely, (i) methionine/choline-deficient diet, (ii) Western style diet (WD) alone, (iii) WD combined with the hepatotoxic agent CCl 4 , and (iv) a combination of CCl 4 injections and oral ethanol challenge. Injections of anti-ACBP/DBI mAb attenuated histological, enzymological, metabolomic and transcriptomic signs of liver damage in these four models, hence halting or reducing the progression of non-alcoholic and alcoholic liver disease. Steatosis, inflammation, ballooning and fibrosis responded to ACBP/DBI inhibition at the preclinical level. Altogether, these findings support a causal role of ACBP/DBI in MASH and liver fibrosis, as well as the possibility to therapeutically target ACBP/DBI.

Context and Objective Identifying the risk of malignancy and genetic status in primary paraganglioma or pheochromocytoma (PPGL) is a key challenge. The aim was to assess the diagnostic accuracy of genomic, metabolomic and histopathological biomarkers for predicting metastatic and genetic status. Design, Setting, and Patients COMETE-TACTIC is a prospective study (NCT02672020) conducted from November 2015 to March 2019 across 16 referral centers. Tumor samples and liquid biopsies from 231 consecutive patients with PPGL were collected. Main Outcome Measures Germline and somatic genetic status were determined by NGS. SDHB, SDHA and CA9 immunohistochemistries were performed on tumor tissues. TERT promoter methylation was assessed by pyrosequencing. Metabolomic profile and circulating miRNAs were measured in liquid biopsies by gas chromatography MS/MS and TaqMan assay quantified by droplet digital PCR, respectively. Results Tumor analysis outperformed germline analysis for determining genetic status. Positive SDHA and SDHB staining combined with negative CA9 labeling indicated the absence of SDHx and VHL variants. Plasma succinate levels above 4.94µM identified SDHx mutation carriers with 65% sensitivity and 92% specificity (AUC-ROC 0.82, 95%CI 0.70-0.93). Among circulating miRNAs, miR-483-5p was the best classifier of metastatic status (AUC-ROC 0.64, 95%CI 0.52-0.77). A sum of dinucleotide methylation rate of TERT promoter CpGs above 42% predicted metastatic status (AUC-ROC 0.75, 95%CI 0.65-0.85). Multivariate analyses showed that biomarker combinations significantly predicted SDHx status (AUC-ROC 0.99, 95%CI 0.98-1.00) and metastatic potential (AUC-ROC 0.93, 95%CI 0.84-1). Conclusions Circulating miR-483-5p, plasma succinate, TERT promoter methylation, and SDHB immunostaining are valuable for PPGL risk stratification. Combining biomarkers with clinical data provides excellent diagnostic accuracy for metastatic patients (AUC-ROC 0.97, 95%CI 0.93-1).

Background When FMF patients with cirrhosis were compared with FMF patients without cirrhosis, those with cirrhosis had a significantly later diagnosis of hepatopathy: Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease associated with a mutation in the MEFV gene. The liver may be involved in FMF, but data remain scarce; however, FMF patients may have cirrhosis [1]. The usual metabolic risk factors are not the only explanation, as they were not associated with persistent hepatic cytolysis in a previous work in FMF patients while studying a score of steatosis [2]. Objectives Our aim was to evaluate liver involvement in FMF in a French tertiary centre for adult FMF. Methods In this observational study, we included patients followed for FMF at the National Reference Centre for Adult Autoinflammatory Diseases and Inflammatory Amyloidosis (CEREMAIA) in Paris, France. Heterozygous patients and patients with other identified causes of hepatopathy were not included. Sociodemographic data, underlying characteristics of FMF, laboratory, imaging and pathological features, and complications of cirrhosis, if present, were recorded. Among FMF patients with hepatopathy, we compared patients with and without cirrhosis. Statistical analysis was performed using EasyMedStat. Results Of the 533 adult FMF patients followed, 57 (10.7%) had chronic liver function abnormalities, including 17 (30%) with cirrhosis. Hepatic features developed 47 [24-58] years after FMF onset. All patients were receiving colchicine at a current median daily dose of 1.5 mg [1-2] mg, but 24 patients were colchicine-resistant (42%) and 23 (40%) were receiving interleukin-1 inhibitors, either anakinra (n=17) or canakinumab (n=8). Four patients also had AA amyloidosis. Thirty-five patients had active FMF with a CRP above 5 when liver abnormalities were detected. The median body mass index (BMI) was 26.3 [22.3-29.7] kg/m2. When FMF patients with cirrhosis were compared with FMF patients without cirrhosis, those with cirrhosis had a significantly later diagnosis of hepatopathy, a longer delay in diagnosis of FMF and in starting treatment for their FMF. Patients with colchicine resistance and on interleukin-1 inhibitors were significantly more common in the cirrhosis group. BMI and AA amyloidosis were not significantly different between groups. Liver ultrasound was performed in all but fifteen patients. FibroScan was performed in 32 patients with a median controlled attenuation parameter (CAP) score of 257 [226-303] dB/m and a median liver stiffness measurement (LSM) fibrosis stage score of 11.9 [6-17]. Nineteen patients underwent liver biopsy, including 14 with cirrhosis. The median SAF score was S1A3F4. Seventeen (90%) liver biopsies described inflammation with a variable infiltrate consisting of lymphocytes (n=8/13), neutrophils (n=3/13), monocytes and macrophages (n= 2/13), mononuclear cells (n=4/13) and fifteen had steatosis quantified as 15%, 11 patients had Mallory bodies and 11 patients had ballooning. Iron overload was found in 1 patient, vascular abnormalities in 4 patients and biliary abnormalities in 2 patients. Conclusion FMF patients are at risk of chronic hepatopathy. This complication should be considered and sought because of its frequency in FMF patients, but also because of its morbidity with the risk of progression to cirrhosis and death. Liver function should be monitored in all FMF patients, especially those with uncontrolled inflammation. REFERENCES [1] Fraisse T, Savey L, Hentgen V, Rossi-Semerano L, Koné-Paut I, Grateau G, et al. Non-amyloid liver involvement in familial Mediterranean fever: A systematic literature review. Liver Int. juin 2020;40(6):1269-77.[2] Deshayes S, Fraisse T, Fellahi S, Steichen O, Savey L, Turlin B, et al. Role of non-invasive methods in detecting liver impairment in familial Mediterranean fever adult patients with persistent hepatic cytolysis. Sci Rep. 5 oct 2022;12:16644. Acknowledgements We wish to thank the following geneticians for performing MEFV sequencing at the diagnosis of FMF for French patients: Guilaine Boursier, Isabelle Touitou, Serge Amselem, Irina Giurgea, Isabelle Jeru, Laurence Cuisset. Disclosure of Interests None declared

Gastrointestinal stromal tumors (GISTs) are defined as CD117-positive primary, spindled or epithelioid, mesenchymal tumors of the gastrointestinal tract, omentum, or mesentery. While computed tomography (CT) is the recommended imaging modality for GISTs, overlap in imaging features between GISTs and other gastrointestinal tumors often make radiological diagnosis and subsequent selection of the optimal therapeutic approach challenging. Cinematic rendering is a novel CT post-processing technique that generates highly photorealistic anatomic images based on a unique lighting model. The global lighting model produces high degrees of surface detail and shadowing effects that generate depth in the final three-dimensional display. Early studies have shown that cinematic rendering produces high-quality images with enhanced detail by comparison with other three-dimensional visualization techniques. Cinematic rendering shows promise in improving the visualization of enhancement patterns and internal architecture of abdominal lesions, local tumor extension, and global disease burden, which may be helpful for lesion characterization and pretreatment planning. This article discusses and illustrates the application of cinematic rendering in the evaluation of GISTs and the unique benefit of using cinematic rendering in the workup of GIST with a specific emphasis on tumor characterization and preoperative planning.