Phenotypic characterisation of SMAD4 variant carriers.

BACKGROUND: Both hereditary haemorrhagic telangiectasia (HHT) and juvenile polyposis syndrome (JPS) are known to be caused by SMAD4 pathogenic variants, with overlapping symptoms for both disorders in some patients. Additional connective tissue disorders have also been reported. Here, we describe carriers of SMAD4 variants followed in an HHT reference centre to further delineate the phenotype. METHODS: Observational study based on data collected from the Clinical Investigation for the Rendu-Osler Cohort database. RESULTS: Thirty-three participants from 15 families, out of 1114 patients with HHT, had an SMAD4 variant (3%).Regarding HHT, 26 out of 33 participants (88%) had a definite clinical diagnosis based on Curaçao criteria. Complication frequencies were as follows: epistaxis (n=27/33, 82%), cutaneous telangiectases (n=19/33, 58%), pulmonary arteriovenous malformations (n=17/32, 53%), hepatic arteriovenous malformations (AVMs) (n=7/18, 39%), digestive angiodysplasia (n=13/22, 59%). No cerebral AVMs were diagnosed.Regarding juvenile polyposis, 25 out of 31 participants (81%) met the criteria defined by Jass et al for juvenile polyposis syndrome. Seven patients (21%) had a prophylactic gastrectomy due to an extensive gastric polyposis incompatible with endoscopic follow-up, and four patients (13%) developed a digestive cancer.Regarding connective tissue disorders, 20 (61%) had at least one symptom, and 4 (15%) participants who underwent echocardiography had an aortic dilation. CONCLUSION: We describe a large cohort of SMAD4 variant carriers in the context of HHT. Digestive complications are frequent, early and diffuse, justifying endoscopy every 2 years. The HHT phenotype, associating pulmonary and hepatic AVMs, warrants systematic screening. Connective tissue disorders broaden the phenotype associated with SMAD4 gene variants and justify systematic cardiac ultrasound and skeletal complications screening.

Hereditary Colorectal Cancer and Polyposis Syndromes Caused by Variants in Uncommon Genes.

A substantial number of hereditary colorectal cancer (CRC) and colonic polyposis cannot be explained by alteration in confirmed predisposition genes, such as mismatch repair (MMR) genes, APC and MUTYH. Recently, a certain number of potential predisposition genes have been suggested, involving each a small number of cases reported so far. Here, we describe the detection of rare variants in the NTLH1, AXIN2, RNF43, BUB1, and TP53 genes in nine unrelated patients who were suspected for inherited CRC and/or colonic polyposis. Seven of them were classified as pathogenic or likely pathogenic variants (PV/LPV). Clinical manifestations of carriers were largely consistent with reported cases with, nevertheless, distinct characteristics. PV/LPV in these uncommon gene can be responsible for up to 2.7% of inherited CRC or colonic polyposis syndromes. Our findings provide supporting evidence for the role of these genes in cancer predisposition, and contribute to the determination of related cancer spectrum and cancer risk for carriers, allowing for the establishment of appropriate screening strategy and genetic counseling in affected families.

Impact of Endoscopic Treatment in Severe Duodenal Polyposis: A National Study in Familial Adenomatous Polyposis Patients.

BACKGROUND & AIMS: The majority of patients with familial adenomatous polyposis (FAP) develop duodenal adenomas with a risk of progression to duodenal cancer. Endoscopic management of FAP duodenal adenomas has been proposed as a less-invasive option than surgery, but available data still are limited. Our aims were to assess the feasibility and safety of endoscopic treatment in duodenal polyposis and to evaluate its long-term efficacy in terms of recurrence and malignant degeneration. METHODS: FAP patients with stage IV duodenal polyposis were enrolled in 5 French centers as part of a national cohort and followed up for a median period of 5.66 years (interquartile range, 6.39 y). Primary outcomes were duodenal surgery-free and cancer-free survival. Two groups of patients were identified according to endoscopic procedures: group 1: resection and or destruction (by argon plasma coagulation) of duodenal polyps, and group 2: papillectomy. RESULTS: Fifty-eight patients were enrolled (29 men; median age, 44 y). Endoscopic therapy was performed in 37 patients in group 1 and in 19 patients in group 2. Duodenal cancer-free and surgery-free survival were 95.8% at 5 years and 92.6% at 10 years. Four patients required surgery and 2 patients developed cancers. In the 58 patients, the calculated Spigelman score decreased from 9.24 points at entry to 6.35 at 5 years and then plateaued. Complications (mostly bleeding and perforation) occurred in 20 patients. CONCLUSIONS: In this long-term cohort follow-up evaluation, endoscopic treatment of patients with severe duodenal polyposis appears relatively safe and effective as an alternative to surgery for the prevention of cancer.

Deciphering the clinical spectrum of gastric disease in patients with Juvenile Polyposis Syndrome.

BACKGROUND AND AIMS: Juvenile Polyposis Syndrome (JPS) is a rare hereditary autosomal dominant cancer-predisposition syndrome caused by germline pathogenic variants (PV) located in SMAD4 or BMPR1A genes. Precise clinical and endoscopic presentation as the evolution of gastric lesions remain ill-known. METHODS: Clinical, endoscopic, genetic, pathological data from patients with SMAD4 or BMPR1A PVs included between 2007 and 2020 in the French network on rare digestive polyposis (RENAPOL) database were prospectively collected to address uncertainties regarding gastric involvement. RESULTS: Thirty-six patients were included: 25 (69.5%) had SMAD4 PVs, 11 had BMPR1A PVs. For SMAD4 PV carriers, median age at inclusion was 43.0 years [range 10-78]. At baseline esophagogastroduodenoscopy (EGD), 22/25 (88%) exhibited at least one gastric juvenile polyp, 5/25 (20%) had macroscopic signs of inflammatory gastritis. Early gastric disease was mostly located under the cardia, then progressed to gastric antrum and body. During a mean follow-up period of 55.0 months, 12/25 had gastric disease progression (i.e. new juvenile polyps (91.6%), diffuse gastric involvement (41.6%), inflammatory flat progression (25%)). Among 62 biopsies, low-grade dysplasia was observed in 5 (7.5%) samples from 2 patients. Nine carriers (36%) underwent gastrectomy (mean age of 47.2 years) due to diffuse gastric involvement or worsening clinical symptoms. Gastric adenocarcinoma (T1) was found in one gastrectomy specimen. Among the 11 patients with BMPR1A PVs, 2 had gastric hamartomatomas at baseline EGD, none with dysplasia or symptoms. CONCLUSION: Gastric involvement in JPS appears to be progressive during life, initiating in the cardia area, and mostly concerns SMAD4 PV carriers.

The environmental impact of small-bowel capsule endoscopy.

INTRODUCTION: The environmental impact of endoscopy, including small-bowel capsule endoscopy (SBCE), is a topic of growing attention and concern. This study aimed to evaluate the greenhouse gas (GHG) emissions (kgCO2) generated by an SBCE procedure. METHODS: Life cycle assessment methodology (ISO 14040) was used to evaluate three brands of SBCE device and included emissions generated by patient travel, bowel preparation, capsule examination, and video recording. A survey of 87 physicians and 120 patients was conducted to obtain data on travel, activities undertaken during the procedure, and awareness of environmental impacts. RESULTS: The capsule itself (4 g) accounted for < 6 % of the total product weight. Packaging (43-119 g) accounted for 9 %-97 % of total weight, and included deactivation magnets (5 g [4 %-6 %]) and paper instructions (11-50 g [up to 40 %]). A full SBCE procedure generated approximately 20 kgCO2, with 0.04 kgCO2 (0.2 %) attributable to the capsule itself and 18 kgCO2 (94.7 %) generated by patient travel. Capsule retrieval using a dedicated device would add 0.98 kgCO2 to the carbon footprint. Capsule deconstruction revealed materials (e. g. neodymium) that are prohibited from environmental disposal; 76 % of patients were not aware of the illegal nature of capsule disposal via wastewater, and 63 % would have been willing to retrieve it. The carbon impact of data storage and capsule reading was negligible. CONCLUSION: The carbon footprint of SBCE is mainly determined by patient travel. The capsule device itself has a relatively low carbon footprint. Given that disposal of capsule components via wastewater is illegal, retrieval of the capsule is necessary but would likely be associated with an increase in device-related emissions.

AI-assisted capsule endoscopy reading in suspected small bowel bleeding: a multicentre prospective study.

BACKGROUND: Capsule endoscopy reading is time consuming, and readers are required to maintain attention so as not to miss significant findings. Deep convolutional neural networks can recognise relevant findings, possibly exceeding human performances and reducing the reading time of capsule endoscopy. Our primary aim was to assess the non-inferiority of artificial intelligence (AI)-assisted reading versus standard reading for potentially small bowel bleeding lesions (high P2, moderate P1; Saurin classification) at per-patient analysis. The mean reading time in both reading modalities was evaluated among the secondary endpoints. METHODS: Patients aged 18 years or older with suspected small bowel bleeding (with anaemia with or without melena or haematochezia, and negative bidirectional endoscopy) were prospectively enrolled at 14 European centres. Patients underwent small bowel capsule endoscopy with the Navicam SB system (Ankon, China), which is provided with a deep neural network-based AI system (ProScan) for automatic detection of lesions. Initial reading was performed in standard reading mode. Second blinded reading was performed with AI assistance (the AI operated a first-automated reading, and only AI-selected images were assessed by human readers). The primary endpoint was to assess the non-inferiority of AI-assisted reading versus standard reading in the detection (diagnostic yield) of potentially small bowel bleeding P1 and P2 lesions in a per-patient analysis. This study is registered with ClinicalTrials.gov, NCT04821349. FINDINGS: From Feb 17, 2021 to Dec 29, 2021, 137 patients were prospectively enrolled. 133 patients were included in the final analysis (73 [55%] female, mean age 66·5 years [SD 14·4]; 112 [84%] completed capsule endoscopy). At per-patient analysis, the diagnostic yield of P1 and P2 lesions in AI-assisted reading (98 [73·7%] of 133 lesions) was non-inferior (p<0·0001) and superior (p=0·0213) to standard reading (82 [62·4%] of 133; 95% CI 3·6-19·0). Mean small bowel reading time was 33·7 min (SD 22·9) in standard reading and 3·8 min (3·3) in AI-assisted reading (p<0·0001). INTERPRETATION: AI-assisted reading might provide more accurate and faster detection of clinically relevant small bowel bleeding lesions than standard reading. FUNDING: ANKON Technologies, China and AnX Robotica, USA provided the NaviCam SB system.

Small bowel capsule endoscopy and deep enteroscopy procedure load in France: a nationwide population-based study over 7 years.

Background and study aims Capsule endoscopy (CE) is a diagnostic tool mainly used to explore the small bowel (SB), whereas device-assisted enteroscopy (DAE) is preferred for therapeutics. We aimed to describe the procedure load of SB endoscopy in France from 2015 to 2021. Patients and methods Using the French national health data system and the French national hospital discharge database, we identified all SBCEs and DAEs reported between January 2015 and December 2021. Information on DAEs was crosschecked with data on purchase or maintenance from manufacturers. Centers and procedures were described by type, year, type of practice, and according to the 13 French administrative regions in the mainland and in those overseas. Results A total of 151,096 SBCEs and 6,802 for DAEs were considered over the study period. SBCE service was offered in all regions, in both public and private settings, and the case load increased from 18,956 to 24,183 (+27.6%). The number of DAEs decreased nationwide, from 1,030 to 932 (-9.5%). Eighty-seven percent of all DAEs were performed in public university hospitals. Retrograde route varied between 18.8% and 22.8% of all DAEs yearly. The number of centers offering DAE varied from 0 to 5, over regions and years. DAE caseloads increased in five regions but ended, decreased or the procedure was not yet used in the nine remaining regions. Conclusions SB endoscopy in France is marked by a 22-fold unbalanced procedure load in CE (nationwide coverage) and in DAE (absent in some regions). This gap has widened over the years from 2015 to 2021.