Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

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.

Sequential multistenting protocol in biliary stenosis after liver transplantation: a prospective analysis.

BACKGROUND: Biliary complications are a serious source of morbidity after orthotopic and living-related liver transplantation. Endoscopic retrograde cholangiography (ERC) is the gold standard for patients with duct-to-duct anastomosis because it allows a direct approach for interventional procedures. A retrospective study showed results of a sequential multistenting protocol, without stent removal/exchange, with promising results. We conducted a prospective analysis to assess the clinical success, recurrence rate, and adverse event rate related to this protocol. METHODS: From May 2012 to April 2018, all consecutive patients with a diagnosis of anastomotic stenosis following liver transplantation were enrolled in the study, and were followed for a period of at least 6 months after the last ERC. During the first ERC, a maximum number of plastic stents (10 Fr) were placed. In subsequent ERCs, scheduled every 3 months up to a maximum of 1 year, additional stents were inserted, as many as possible, without removing the previously placed stents. RESULTS: From May 2012 to May 2018, 87 patients were included in the study and treated with a sequential multistenting protocol. The mean number of stents placed was 3.7 (SD 1.0). Clinical success (stricture resolution and normalization of cholestasis) was achieved in 86 patients (98.9 %). Seven patients (8.0 %) developed complications. Recurrence was recorded in seven patients (8.0 %) after a mean of 992.7 days (SD 622.1). CONCLUSIONS: This study represents the first prospective demonstration of the efficacy and safety of a sequential multistenting protocol. A key limitation of the study is the lack of a comparative group treated according to the traditional stent exchange approach.

Impact of Ki67 re-assessment at time of disease progression in patients with pancreatic neuroendocrine neoplasms.

BACKGROUND: Although re-assessment of proliferative activity by K67 evaluation during the course of neuroendocrine neoplasms (NENs) is recommended in selected patients, its impact on patients' management is not clear due to the lack of data supporting this practice. AIM: To investigate Ki67 change at time of progressive disease (PD) in entero-pancreatic NENs (EP-NENs). PATIENTS AND METHODS: Retrospective analysis of sporadic EP-NENs which received histological re-assessment after PD once radiologically documented. RESULTS: Forty-three patients were evaluated, including 24 pancreatic NENs (PNENs), and 19 small intestine NENs (SI-NENs). At time of initial histological evaluation, 19 patients had grade 1 (G1) NETs (44.2%), and 24 grade 2 (G2) NETs (55.8%), overall median Ki67 being 3% (range 1%-20%). At time of PD, 13 patients had G1 NETs (30.2%), 26 G2 NETs (60.5%), and 4 had grade 3 (G3) NECs (9.3%), thus resulting in a significant median Ki67 increase (8%, range 1%-70%; p = 0.0006), and a G upgrading in 12 patients (27.9%). A statistically significant Ki67 increase and G grading change at time of PD was observed in PNENs (p = 0.0005 and p = 0.028, respectively). Conversely, no statistically significant change occurred in non-PNENs. CONCLUSIONS: In PNENs with documented PD, Ki67 increase occurs in a significant proportion of patients, providing useful information necessary to choose appropriate therapeutic options.

Functional Imaging in the Follow-Up of Enteropancreatic Neuroendocrine Tumors: Clinical Usefulness and Indications.

Context: Functional imaging tests (FITs) detecting somatostatin receptor expression [i.e., somatostatin receptor scintigraphy, 68Ga-DOTA positron emission tomography/computed tomography (CT)] have a pivotal role in the diagnosis of neuroendocrine tumors (NETs), although their indication during follow-up still needs to be clarified. Objective: Investigate the role of FITs after diagnosis of metastatic enteropancreatic NETs, identifying patients who might benefit from these exams. Design: Multicenter retrospective analysis of metastatic enteropancreatic NETs. Setting: Analysis of imaging tests performed between January 1995 and December 2015 in Rome, Berlin, Milan, Marburg, or Graz. Subjects: One hundred forty-three patients with metastatic pancreatic NETs and small intestine NETs, at least 2-year follow-up, and positive FITs. Interventions: Patients had received CT every 6 months (unless clinical conditions and tumor behavior required shorter intervals) and FIT every 12 months. Main Outcome Measures: Clinical usefulness of FITs, defined as changes in patient management (indication to biopsy, medical therapy, surgery, or further imaging tests) due only to FITs. Results: FITs affected management in 73.4% of patients, mostly when G2 vs G1 [odds ratio (OR), 2.40; 95% confidence interval (CI), 1.09 to 5.27; P = 0.03]. Changes were observed in a 12-month time frame especially with pancreatic NETs vs small intestine NETs (OR, 2.89; 95% CI, 1.09 - 7.67; P = 0.03) or metastases since diagnosis vs developed during follow-up (OR, 4.00; 95% CI, 1.43 to 11.17; P < 0.01). Conclusions: FITs used in addition to CT in the follow-up of stage IV enteropancreatic NETs improve patient management (especially for G2 tumors). Follow-up program should be tailored according to tumor features.

Digestive neuroendocrine neoplasms: A 2016 overview.

Digestive neuroendocrine neoplasms (DNENs) have an incidence of 2.39 per 100,000 inhabitants per year, and a prevalence of 35 cases per 100,000; the gap between these rates is to be referred to the relatively long survival that characterizes the majority of these tumors, which can be thus considered as chronic oncological diseases. Up to 80% of patients are stage IV since the first diagnosis, presenting a 5-yr overall survival rate of 35%-55% and a twice higher mortality than limited disease. DNENs express somatostatin receptors in more than 80% of cases, detected through immunohistochemistry or functional imaging tests (FITs). This feature identifies patients who may benefit from "cold" somatostatin analogs (SSAs) or peptide receptors radionuclide therapy, although SSAs are sometimes used also with a negative uptake at FITs. The therapeutic options have been recently increased after the identification of molecular pathways involved in DNENs pathogenesis, and the subsequent use of targeted therapies (i.e., Everolimus and Sunitinib) for these neoplasms. This review offers an overview about pancreatic and small bowel NENs, critically underlining the issues that still need to be clarified and the future perspectives to be investigated.

Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study.

BACKGROUND: The incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history (FH) of any cancer, smoking and previous cholecystectomy are associated with an increased risk. Such studies investigated small series or examined cancer registries without direct interviews. AIM: We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic SI-NETs. SUBJECTS AND METHODS: We performed a multicenter case-control study. Patients with a histologic diagnosis of SI-NETs were prospectively evaluated, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at gastrointestinal outpatients clinics were matched for sex and age (4:1). All subjects were directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls were compared by Fisher's test or Student's t test for categorical or continuous variables. Explanatory variables were analyzed by simple logistic regression analysis. A multiple logistic regression analysis was performed with an Enter model; p < 0.05 was considered significant. RESULTS: 215 SI-NET patients and 860 controls were enrolled. FH of colorectal cancer (CRC) (8.8 vs. 5.0%) and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking >21 alcohol units per week (7.4 vs. 3.8%) were all significantly more frequent in SI-NET patients than in controls. Multivariate analysis showed that FH of CRC (OR 2.23, 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05, 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47, 95% CI 1.07-2.03, p = 0.01) and in particular heavy smoking (OR 1.94, 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin can be considered a protective factor (OR 0.20, 95% CI 0.06-0.65, p = 0.008). CONCLUSION: FH of colorectal and breast cancer as well as smoking seem to be risk factors for the development of SI-NETs, while use of aspirin might be a protective factor. These factors partially overlap with those associated with CRC, but are different from those previously associated with pancreatic neuroendocrine tumors. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific and similar to those of their exocrine counterparts.