The present paper reflects the position of the Italian Association for Neuroendocrine Tumors (Itanet), the Italian Society of Gastroenterology (SIGE), and the Italian Society of Digestive Endoscopy (SIED) regarding the management of patients affected by gastric, duodenal, and rectal neuroendocrine neoplasms (NENs) amenable to endoscopic treatment. The key questions discussed in this paper are summarized in Table 1. Data were extracted from the MEDLINE database through searches; expert opinions and recommendations are provided in accordance with the available scientific evidence and the authors' expertise. Recommendations are presented alongside a level of evidence and grade of recommendation based on the GRADE system. This paper specifically focuses on subgroups of NENs considered suitable for endoscopic management according to current international guidelines: i. well-differentiated gastric neuroendocrine tumors (gNET) type 1 < 2 cm and selected cases of type 3; ii. well-differentiated duodenal, non-functioning, non-ampullary NET with size < 2 cm; and well-differentiated rectal NET with size < 2 cm.

Background/Objectives: Gastric cancer (GC) incidence remains high worldwide, and the survival rate is poor. GC develops from atrophic gastritis (AG), associated with Helicobacter pylori (Hp) infection, passing through intestinal metaplasia and dysplasia steps. Since Hp eradication does not exclude GC development, further investigations are needed. New data suggest the possible role of unexplored gastric microbiota beyond Hp in the progression from AG to GC. Aimed to develop a score that could be used in clinical practice to stratify GC progression risk, here was investigate gastric microbiota in AG Hp-negative patients with or without high-grade dysplasia (HGD) or GC. Methods: Consecutive patients undergoing upper endoscopy within an endoscopic follow-up for AG were considered. The antrum and corpus biopsies were used to assess the microbiota composition along the disease progression by sequencing the 16S ribosomal RNA gene. Statistical differences between HGD/GC and AG patients were included in a multivariate analysis. Results: HGD/GC patients had a higher percentage of Bacillus in the antrum and a low abundance of Rhizobiales, Weeksellaceae and Veillonella in the corpus. These data were used to calculate a multiparametric score (Resident Gastric Microbiota Dysbiosis Test, RGM-DT) to predict the risk of progression toward HGD/GC. The performance of RGM-DT in discriminating patients with HGD/GC showed a specificity of 88.9%. Conclusions: The microbiome-based risk prediction model for GC could clarify the role of gastric microbiota as a cancer risk biomarker to be used in clinical practice. The proposed test might be used to personalize follow-up program thanks to a better cancer risk stratification.

INTRODUCTION: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. METHODS: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). RESULTS: During the study period (June 2015–September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. DISCUSSION: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.

Liver fibrosis is a common and reversible feature of liver damage associated with many chronic liver diseases, and its onset is influenced by sex. In this study, we investigated the mechanisms of liver fibrosis and regeneration, focusing on understanding the mechanistic gaps between females and males. We injected increasing doses of carbon tetrachloride into female and male mice and maintained them for a washout period of eight weeks to allow for liver regeneration. We found that male mice were more prone to developing severe liver fibrosis as a consequence of early chronic liver damage, supported by the recruitment of a large number of Ly6C^high MoMφs and neutrophils. Although prolonged liver damage exacerbated the fibrosis in mice of both sexes, activated HSCs and Ly6C^high MoMφs were more numerous and active in the livers of female mice than those of male mice. After eight weeks of washout, only fibrotic females reported no activated HSCs, and a phenotype switching of Ly6C^high MoMφs to anti-fibrogenic Ly6C^low MoMφs. The early stages of liver fibrosis mostly affected males rather than females, while long-term chronic liver damage was not influenced by sex, at least for liver fibrosis. Liver repair and regeneration were more efficient in females than in males.

Many tumors may secondarily involve the pancreas; however, only retrospective autopic and surgical series are available. We retrospectively collected data from all consecutive patients with histologically confirmed secondary tumors of the pancreas referred to five Italian centers between 2010 and 2021. We described clinical and pathological features, therapeutic approach and treatment outcomes. EUS characteristics of the lesions and the tissue acquisition procedures (needle, passages, histology) were recorded. A total of 116 patients (males/females 69/47; mean age 66.7) with 236 histologically confirmed pancreatic metastases were included; kidney was the most common primary site. EUS was performed to confirm the diagnosis in 205 lesions which presented as predominantly solitary (59), hypoechoic (95) and hypervascular (60), with a heterogeneous (n = 54) pattern and well-defined borders (n = 52). EUS-guided tissue acquisition was performed in 94 patients with an overall accuracy of 97.9%. Histological evaluation was possible in 88.3% of patients, obtaining final diagnosis in all cases. When cytology alone was performed, the final diagnosis was obtained in 83.3% of cases. A total of 67 patients underwent chemo/radiation therapy, and surgery was attempted in 45 (38.8%) patients. Pancreatic metastases are a possible event in the natural history of solid tumors, even long after the diagnosis of the primary site. EUS-guided fine needle biopsy may be suggested to implement the differential diagnosis.