Innate lymphocyte cells (ILCs), a novel family of innate immune cells are considered to function as key orchestrators of immune defences at mucosal surfaces and to be crucial for maintaining an intact intestinal barrier. Accordingly, first data suggest depletion of ILCs to be involved in human immunodeficiency virus (HIV)-associated damage of the intestinal mucosa and subsequent microbial translocation. However, although ILCs are preferentially localized at mucosal surfaces, only little is known regarding distribution and function of ILCs in the human gastrointestinal tract. Here, we show that in HIV(-) individuals composition and functional capacity of intestinal ILCs is compartment-specific with group 1 ILCs representing the major fraction in the upper gastrointestinal (GI) tract, whereas ILC3 are the predominant population in ileum and colon, respectively. In addition, we present first data indicating that local cytokine concentrations, especially that of IL-7, might modulate composition of gut ILCs. Distribution of intestinal ILCs was significantly altered in HIV patients, who displayed decreased frequency of total ILCs in ileum and colon owing to reduced numbers of both CD127(+)ILC1 and ILC3. Of note, frequency of colonic ILC3 was inversely correlated with serum levels of I-FABP and sCD14, surrogate markers for loss of gut barrier integrity and microbial translocation, respectively. Both expression of the IL-7 receptor CD127 on ILCs as well as mucosal IL-7 mRNA levels were decreased in HIV(+) patients, especially in those parts of the GI tract with reduced ILC frequencies, suggesting that impaired IL-7 responses of ILCs might contribute to incomplete reconstitution of ILCs under effective anti-retroviral therapy. This is the first report comparing distribution and function of ILCs along the intestinal mucosa of the entire human gastrointestinal tract in HIV(+) and HIV(-) individuals. Current treatment regimens are very effective in blocking replication of the human immunodeficiency virus (HIV). However, due to ongoing activation of the immune system this often does not fully restore human health. The mechanisms underlying such activation of the immune system are only incompletely understood but are likely to include HIV-induced injury of the gut epithelial barrier and subsequent intrusion of gut flora components into the systemic circulation (microbial translocation). This study looks at the distribution and function of innate lymphoid cells (ILCs) in the gut mucosa of HIV(-) and HIV(+) patients as these cells are important for maintaining an intact gut epithelium. We found that composition of the intestinal ILC pool differs between the specific segments of the digestive tract and is significantly altered in HIV(+) patients. Furthermore, our data suggest a link between dys-regulated intestinal ILCs and loss of intestinal barrier function in HIV infection, thereby allowing for microbial translocation and systemic immune activation. This finding is new and highlights the important role played by the gut immune system in HIV-induced illness.

Background: Lynch syndrome (LS), an autosomal dominant disorder caused by pathogenic germline variants in DNA mismatch repair (MMR) genes, represents the most common hereditary colorectal cancer (CRC) syndrome. Lynch syndrome patients are at high risk of CRC despite regular endoscopic surveillance.Objective: Our aim was to investigate the diagnostic performance of artificial intelligence (AI)‐assisted colonoscopy in comparison to High‐Definition white‐light endoscopy (HD‐WLE) for the first time.Methods: Patients ≥18 years with LS, with a pathogenic germline variant (MLH1, MHS2, MSH6), and at least one previous colonoscopy (interval 10–36 months) were eligible. Patients were stratified by previous CRC and affected MMR gene with a 1:1 allocation ratio (AI‐assisted vs. HD white‐light endoscopy) in this exploratory pilot trial.Results: Between Dec‐2021 and Dec‐2022, 101 LS patients were randomised and 96 patients were finally analyzed after exclusion of 5 patients due to insufficient bowel preparation. In the HD‐WLE arm, adenomas were detected in 12/46 patients compared to 18/50 in the AI arm (26.1% [95% CI 14.3–41.1] vs. 36.0% [22.9–50.8]; p = 0.379). The use of AI‐assisted colonoscopy especially increased detection of flat adenomas (Paris classification 0‐IIb) (examinations with detected flat adenomas: 3/46 [6.5%] vs. 10/50 [20%]; p = 0.07; numbers of detected flat adenomas: 4/20 vs. 17/30, p = 0.018). The median withdrawal time did not differ significantly between HD‐WLE and AI (14 vs. 15 min; p = 0.170).Conclusion: We here present first data suggesting that real‐time AI‐assisted colonoscopy is a promising approach to optimize endoscopic surveillance in LS patients, in particular to improve the detection of flat adenomas.

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Einleitung Das Lynch-Syndrom (LS) ist die häufigste Form des erblichen Darmkrebses und verursacht ca. 3 % aller kolorektalen Karzinome (KRK). Ursächlich ist eine pathogene Sequenzvariante in einem Mismatch-Reparaturgen (MLH1, MSH2, MSH6, PMS2, EPCAM). Nach aktueller Schätzung ist ca. eine von 300 Personen Anlageträger für LS (ca. 300 000 Mutationsträger/Deutschland). Anlageträger haben ein erhöhtes Lebenszeitrisiko für ein KRK mit einer kumulativen Inzidenz von 15 bis 46 % bis zum 75. Lebensjahr. Weiterhin ist auch das Risiko für extrakolonische Tumoren wie Endometrium-, Dünndarm-, Magen-, Urothel- und andere Karzinome erhöht. Methoden Das Deutsche Konsortium Familiärer Darmkrebs besteht aus 14 universitären Zentren in Deutschland. Das Ziel des Konsortiums ist es, geeignete Vorsorgeprogramme zu entwickeln und zu evaluieren, damit diese später in die allgemeine Patientenversorgung übernommen werden können. Wir haben aktuell die Empfehlung zur klinischen Betreuung von LS-Patienten überarbeitet. Ergebnis Eine Koloskopie sollte ab dem 25. Lebensjahr alle 12–24 Monate erfolgen. Bei Diagnose eines KRK ist eine onkologische Resektion notwendig, eine Kolektomie mit ileorektaler Anastomose sollte individuell mit dem Patienten besprochen werden. Das Lebenszeitrisiko für ein Magenkarzinom liegt bei 0,2–13 %. Im Rahmen der endoskopischen Überwachung können signifikant mehr Magenkarzinome in früheren Tumorstadien entdeckt werden im Vergleich zur symptomgetriggerten Endoskopie. Das Lebenszeitrisiko für ein Dünndarmkarzinom liegt bei 4–8 %. Dünndarmkarzinome treten zur Hälfte im Duodenum auf, in 10 % der Fälle vor dem 35. Lebensjahr. Eine ÖGD sollte deshalb ab dem 25. Lebensjahr alle 12–36 Monate erfolgen. Schlussfolgerung Die Früherkennung, Vorsorge und Behandlung von kolonischen und extrakolonischen Karzinomen bei Patienten mit LS reduziert die Mortalität und Morbidität, ist aber komplex und in verschiedenen Aspekten noch nicht umfassend evaluiert. Weitere gen- und geschlechtsspezifische Vorsorgeempfehlungen sind wünschenswert und sollen in prospektiven Studien evaluiert werden. Introduction Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome and accounts for ~3 % of all CRCs. This autosomal dominant disorder is caused by germline mutations in DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS2, and EPCAM). One in 300 individuals of the general population are considered to be mutation carriers (300 000 individuals/Germany). Mutation carriers are at a high CRC risk of 15–46 % till the age of 75 years. LS also includes a variety of extracolonic malignancies such as endometrial, small bowel, gastric, urothelial, and other cancers. Methods The German Consortium for Familial Intestinal Cancer consists of 14 university centers in Germany. The aim of the consortium is to develop and evaluate surveillance programs and to further translate the results in clinical care. We have revisited and updated the clinical management guidelines for LS patients in Germany. Results A surveillance colonoscopy should be performed every 12–24 months starting at the age of 25 years. At diagnosis of first colorectal cancer, an oncological resection is advised, an extended resection (colectomy with ileorectal anastomosis) has to be discussed with the patient. The lifetime risk for gastric cancer is 0.2–13 %. Gastric cancers detected during surveillance have a lower tumor stage compared to symptom-driven detection. The lifetime risk for small bowel cancer is 4–8 %. About half of small bowel cancer is located in the duodenum and occurs before the age of 35 years in 10 % of all cases. Accordingly, patients are advised to undergo an esophagogastroduodenoscopy every 12–36 months starting by the age of 25 years. Conclusion LS colonic and extracolonic clinical management, surveillance and therapy are complex and several aspects remain unclear. In the future, surveillance and clinical management need to be more tailored to gene and gender. Future prospective trials are needed. ^* Autoren teilen sich die Letzt-Autorenschaft.

BACKGROUND: Colectomy and proctocolectomy are the initial standard of care for patients with familial adenomatous polyposis. Pharmacotherapy to prevent the progression of polyposis and surgeries in the lower GI tract would be beneficial to patients with this disease. OBJECTIVE: This analysis aimed to evaluate the impact of eflornithine-sulindac combination versus monotherapy in delaying time to disease progression in the lower GI tract of patients with familial adenomatous polyposis. DESIGN: This is a post hoc analysis of a randomized phase 3 trial. SETTING: This study was conducted in 21 hospitals in 7 countries treating patients with familial adenomatous polyposis. PATIENTS: Adults with familial adenomatous polyposis were randomly assigned 1:1:1 into 3 arms. INTERVENTIONS: Patients received either eflornithine (750 mg), sulindac (150 mg), or both once daily for up to 48 months. MAIN OUTCOME MEASURES: Efficacy was evaluated as the time from randomization to predefined primary disease progression end points. RESULTS: A total of 158 patients were included in the study. Disease progression was observed in 2 of 54 (3.7%), 9 of 53 (17.0%), and 10 of 51 (19.6%) patients with at least partial lower GI tract in the combination, sulindac, and eflornithine arms, corresponding to risk reductions of 80% (p = 0.02) and 83% (p = 0.01) between combination and sulindac or eflornithine. When endoscopic excision of adenomas ≥10 mm in size was censored, the need for major surgery was observed in 0 of 54, 7 of 53 (13.2%), and 8 of 51 (15.7%) patients in the combination, sulindac, and eflornithine arms, corresponding to risk reductions approaching 100% between combination and sulindac (p = 0.005) or combination and eflornithine (p = 0.003). LIMITATIONS: This was a post hoc analysis, the sample size was small, and there were fewer than expected events. CONCLUSIONS: Eflornithine-sulindac combination therapy was superior to either drug alone in delaying or preventing the need for lower GI tract surgery in patients with familial adenomatous polyposis. See Video Abstract at http://links.lww.com/DCR/B658. REGISTRATION: ClinicalTrials.gov, NCT01483144; EU Clinical Trials Register, EudraCT 2012-000427-41 LA COMBINACIÓN DE SULINDAC Y EFLORNITINA RETRASA LA NECESIDAD DE CIRUGÍA DEL TUBO DIGESTIVO BAJO EN PACIENTES CON PAF: ANÁLISIS POST-HOC DE UN ENSAYO CLÍNICO ALEATORIZADO: ANTECEDENTES: La colectomía y la proctocolectomía son el estándar inicial de atención para los pacientes con poliposis adenomatosa familiar. La farmacoterapia para prevenir la progresión de la poliposis y las cirugías en el tracto gastrointestinal inferior sería beneficiosa para los pacientes con esta enfermedad. OBJETIVO: Este análisis tuvo como objetivo evaluar el impacto de la combinación de eflornitina-sulindac versus la monoterapia en el retraso del tiempo hasta la progresión de la enfermedad en el tracto gastrointestinal inferior de pacientes con poliposis adenomatosa familiar. DISEÑO: Este es un análisis posthoc de un ensayo de fase 3 aleatorizado. ENTORNO CLINICO: Veintiún hospitales en 7 países que tratan a pacientes con poliposis adenomatosa familiar. PACIENTES: Adultos con poliposis adenomatosa familiar fueron aleatorizados 1: 1: 1 en 3 brazos. INTERVENCIONES: Los pacientes recibieron eflornitina (750 mg), sulindac (150 mg) o ambos una vez al día durante un máximo de 48 meses. PRINCIPALES MEDIDAS DE VALORACION: La eficacia se evaluó como el tiempo desde la aleatorización hasta los criterios de valoración primarios predefinidos de progresión de la enfermedad. RESULTADOS: Los resultados se informan para la población de estudio excluyendo a los pacientes que se habían sometido a ileostomías permanentes (n = 158). Se observó progresión de la enfermedad en 2/54 (3,7%), 9/53 (17,0%) y 10/51 (19,6%) pacientes con al menos tracto gastrointestinal inferior parcial en los brazos de combinación, sulindac y eflornitina, respectivamente, correspondientes al riesgo de reducciones del 80% (p = 0,02) y del 83% (p = 0,01) entre la combinación y el sulindaco o la eflornitina, respectivamente. Cuando se censuró la escisión endoscópica de adenomas ≥10 mm de tamaño, se observó la necesidad de cirugía mayor en 0/54, 7/53 (13,2%) y 8/51 (15,7%) pacientes en la combinación, sulindac y eflornitina, respectivamente, correspondientes a reducciones de riesgo cercanas al 100% entre combinación y sulindac (p = 0,005) o combinación y eflornitina (p = 0,003). LIMITACIONES: Este fue un análisis posthoc, el tamaño de la muestra fue pequeño y hubo menos eventos de los esperados. CONCLUSIONES: La terapia de combinación de eflornitina-sulindac fue superior a cualquier fármaco solo para retrasar o prevenir la necesidad de cirugía del tracto gastrointestinal inferior en pacientes con poliposis adenomatosa familiar. Consulte Video Resumen en http://links.lww.com/DCR/B658.

Hereditary diffuse gastric cancer (HDGC) is an inherited cancer susceptibility syndrome characterized by an elevated risk for diffuse gastric cancer (DGC) and lobular breast cancer (LBC). Some patients fulfilling the clinical testing criteria harbor a pathogenic CDH1 or CTNNA1 germline variant. However, the underlying mechanism for around 80% of the patients with a family or personal history of DGC and LBC has so far not been elucidated. In this cohort study, patients meeting the 2015 HDGC clinical testing criteria were included, and subsequently, CDH1 sequencing was performed. Of the 207 patients (161 families) in this study, we detected 21 pathogenic or likely pathogenic CDH1 variants (PV) in 60 patients (28 families) and one CTNNA1 PV in two patients from one family. Sixty-eight percent (n = 141) of patients were female. The overall PV detection rate was 18% (29/161 families). Criterion 1 and 3 of the 2015 HDGC testing criteria yielded the highest detection rate of CDH1/CTNNA1 PVs (21% and 28%). PV carriers and patients without proven PV were compared. Risk of gastric cancer (GC) (38/62 61% vs. 102/140 73%) and age at diagnosis (40 ± 13 years vs. 44 ± 12 years) were similar between the two groups. However, GC was more advanced in gastrectomy specimens of patients without PV (81% vs. 26%). LBC prevalence in female carriers of a PV was 20% (n = 8/40). Clinical phenotypes differed strongly between families with the same PV. Emphasis should be on detecting more causative genes predisposing for HDGC and improve the management of patients without a proven pathogenic germline variant.