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Hepatitis C virus (HCV) infection has a worldwide incidence of 1.1%. In Italy, 60% of people who inject drugs (PWIDs) and are receiving assistance for substance use disorder are infected with HCV. However, this subset of patients has extremely limited access to care due to multiple factors, including alcohol abuse, psychological comorbidities, and homeless status.To describe the impact of our HCV-dedicated service for substance use disorder (SSUD) service on PWIDs receiving anti-HCV therapy.A dedicated, multidisciplinary team was set up at the SSUD of Trento in October 2020 to provide antiviral treatment to HCV RiboNucleic Acid-positive patients with an active or previous history of substance abuse. The treatment was followed by a health education program. Patients were treated with Direct-Acting Antivirals (DAAs). Data were retrospectively analyzed to assess the efficacy of our dedicated program in terms of therapy completion, HCV eradication, and compliance (primary endpoint). The rate of HCV reinfection and DAA-related toxicity were also assessed (secondary endpoints).A total of 40 patients were enrolled in the study: 28 (70.0%) were treated with Sofosbuvir/Velpatasvir, while 12 (30.0%) received Glecaprevir/Pibrentasvir. At the time of inclusion in the study, 36 patients were receiving opioid agonist maintenance therapy, whilst another 4 had just finished the treatment. 37.5% had a history of alcoholism and 42.5% received concomitant psychiatric treatment. All 40 patients (100.0%) completed the therapy cycle and 92.5% of patients adhered to the program. All patients tested negative for viral load at the end of the treatment. There were no significant drug interactions with common psychiatric treatments and no side effects were observed. The sustained virological response was achieved in 92.5% of cases with good tolerability, although two patients discontinued treatment temporarily. After HCV eradication, one patient died from an overdose, another from complications of cirrhosis, and one reinfection occurred.Very high adherence to therapy and good tolerability was observed in our series of HCV patients treated at the SSUD, regardless of the substance abuse condition. Further validation in a larger population is required.

Although gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) have always been considered rare tumors, their incidence has risen over the past few decades. They represent a highly heterogeneous group of neoplasms with several prognostic factors, including disease stage, proliferative index (Ki67), and tumor differentiation. Most of these neoplasms express somatostatin receptors on the cell surface, a feature that has important implications in terms of prognosis, diagnosis, and therapy. Although International Guidelines propose algorithms aimed at guiding therapeutic strategies, GEP-NEN patients are still very different from one another, and the need for personalized treatment continues to increase. Radical surgery is always the best option when feasible; however, up to 80% of cases are metastatic upon diagnosis. Regarding medical treatments, as GEP-NENs are characterized by relatively long overall survival, multiple therapy lines are adopted during the lifetime of these patients, but the optimum sequence to be followed has never been clearly defined. Furthermore, although new molecular markers aimed at predicting the response to therapy, as well as prognostic scores, are currently being studied, their application is still far from being part of daily clinical practice. As they represent a complex disease, with therapeutic protocols that are not completely standardized, GEP-NENs require a multidisciplinary approach. This review will provide an overview of the available therapeutic options for GEP-NENs and attempts to clarify the possible approaches for the management of these patients and to discuss future perspectives in this field.

Background: Left atrial appendage occlusion is an increasingly proposed treatment for patients with atrial fibrillation and poor tolerance to anticoagulants. All endovascular devices require antithrombotic therapy. Anatomical and clinical variables predisposing to device-related thrombosis, as well as post-procedural peri-device leaks, could mandate the continuation or reintroduction of aggressive antithrombotic treatment. Because of the absence of foreign material inside the heart, epicardial appendage closure possibly does not necessitate antithrombotic therapy, but data of large series are missing. Methods: Multidisciplinary team evaluation for standalone totally thoracoscopic epicardial appendage closure was done in 180 consecutive patients with atrial fibrillation and poor tolerance to antithrombotic therapy. One hundred and fifty-two patients consented (male 66.1%, mean age 76.1 ± 7.4, CHA2DS2VASc mean 5.3 ± 1.6, HASBLED mean 3.8 ± 1.1). Indications were cerebral hemorrhage (48%), gastro-intestinal bleeding (33.3%), and other bleeding (20.7%). No antithrombotic therapy was prescribed from the day of surgery to the latest follow up. Results: Procedural success was 98.7%. At a mean follow up of 38.2 ± 18.8 months, cardioembolic and bleeding events were 1.3% and 0.6%, respectively. Among patients with a history of blood transfusions (41.1%), none needed further transfusions or treatment post procedure. Conclusion: Epicardial appendage occlusion without any antithrombotic therapy appears to be safe and effective. This strategy could be advised when minimization of bleeding risk concomitant to stroke prevention is needed.

OBJECTIVE: To evaluate the impact of multidisciplinary team (MDT) meetings on the management of patients with neuroendocrine neoplasms (NENs).METHODS: All newly referred gastro-entero-pancreatic (GEP)-NEN patients discussed from 1 April to 1 October 2017 in the MDT of seven European expert centres were prospectively included. The impact on patients' management was defined as a change in diagnosis, grade, stage or treatment.RESULTS: A total of 292 patients were included, mainly small intestinal (siNENs) (32%) and pancreatic NENs (28%), with distant metastases in 51%. Patients had received prior surgery in 43% of cases and prior medical treatment in 32%. A significant change occurred in 61% of NENs: 7% changes in diagnosis, 8% in grade and 16% in stage. The MDT recommended a new treatment for 51% of patients, mainly surgery (9%) or somatostatin analogues (20%). A significant change was most frequently observed in patients with Stage IV disease (hazard ratio [HR] 3.6, 95% confidence interval [CI]: 1.9-6.9 vs. Stage I) and G2 NENs (vs. G1, HR 2.1 95% CI: 1.2-3.8).CONCLUSION: NEN-dedicated MDT discussion in expert centres yields significant management changes in over 60% of patients and thus represents the gold standard for the management of these patients.

Neuroendocrine neoplasms (NENs) present with advanced disease at diagnosis in up to 28% of cases, precluding the possibility of curative-intent surgery. Histopathological heterogeneity of this disease can be observed inter-individually as well as intra-individually during disease course. The present study aimed to assess the frequency of Ki-67 change after radical surgery, in a series of patients with radically resected entero-pancreatic neuroendocrine tumors (EP-NETs).We present the analysis of a multicenter, retrospective, series of EP-NETs G1–G2 recurring after radical resection and with histological re-evaluation at disease recurrence (DR). The primary endpoint was the description of Ki-67 change at DR compared to time of surgery. The secondary endpoint was assessment of recurrence-free survival (RFS) rates. In total, 47 patients had a second histological evaluation and could be included in the present study. Median Ki-67 at surgery was 3% (range 1–15%) but, at DR, a significant increase in the value was observed (7%, range 1–30%; p

Acute upper gastrointestinal bleeding (UGIB) is the most common indication for urgent endoscopy, but the correct timing of endoscopy in these patients is still debated. Our systematic review with meta-analysis was aimed at investigating the potential clinical benefit of very early endoscopy for UGIB patients. We performed an electronic literature search of PubMed, Scopus, Web of Science and the Cochrane Library up to 23rd May 2020 and considered only randomised controlled trials (RCTs) comparing management of UGIB patients by very early vs early endoscopy. Only five RCTs were considered eligible for quantitative analysis, with a total population of 926 cases (468 in the very early endoscopy arm and 458 in the early). The meta-analysis showed no statistically significant benefit for very early endoscopy compared to early endoscopy in terms of risk of rebleeding, mortality, ICU admission, blood transfusion, surgery and length of hospital stay. However, our results showed a significantly higher need for haemostatic treatment when very early endoscopy was performed (RR 1.23, 95% CI 1.06–1.42, p

Background Long-acting somatostatin analogs (SSAs) are the primary first-line treatment of well-differentiated advanced gastroenteropancreatic neuroendocrine tumors (NETs), but data about their efficacy in pancreatic NETs (panNETs) with Ki-67 ≥10% are still limited. Materials and Methods To assess the clinical outcomes of advanced, nonfunctioning, well-differentiated panNETs with Ki-67 ≥10% receiving first-line long-acting SSAs in a real-world setting, we carried out a retrospective, multicenter study including patients treated between 2014–2018 across 10 centers of the NET CONNECT Network. The primary endpoints were time to next treatment (TNT) and progression-free survival (PFS), whereas overall survival (OS) and treatment safety were secondary endpoints. Results A total of 73 patients were included (68 grade [G]2, 5 G3), with liver metastases in 61 cases (84%). After a median follow-up of 36.4 months (range, 6–173), the median TNT and PFS were 14.2 months (95% confidence interval [CI], 11.6–16.2) and 11.9 months (95% CI, 8.6–14.1) respectively. No statistically significant difference was observed according to the somatostatin analog used (octreotide vs. lanreotide), whereas increased tumor grade (hazard ratio [HR], 4.4; 95% CI, 1.2–16.6; p = .04) and hepatic tumor load (HR, 2; 95% CI, 1–4; p = .03) were independently associated with shortened PFS. The median OS recorded was 86 months (95% CI, 56.8–86 months), with poor outcomes observed when the hepatic tumor burden was >25% (HR, 3.4; 95% CI, 1.2–10; p = .01). Treatment-related adverse events were reported in 14 patients, most frequently diarrhea. Conclusion SSAs exert antiproliferative activity in panNETs with Ki-67 ≥10%, particularly in G2 tumors, as well as when hepatic tumor load is ≤25%. Implications for Practice The results of the study call into question the antiproliferative activity of somatostatin analogs (SSAs) in pancreatic neuroendocrine tumors with Ki-67 ≥10%. Patients with grade 2 tumors and with hepatic tumor load ≤25% appear to derive higher benefit from SSAs. Prospective studies are needed to validate these results to optimize tailored therapeutic strategies for this specific patient population.

Background Radiofrequency ablation (RFA) and microwave ablation (MWA) represent the standard of care for patients with early hepatocellular carcinoma (HCC) who are unfit for surgery. The incidence of reported adverse events is low, ranging from 2.4% to 13.1% for RFA and from 2.6% to 7.5% for MWA. Gastrointestinal tract (GIT) injury is even more infrequent (0.11%), but usually requires surgery with an unfavourable prognosis. Due to its low incidence and the retrospective nature of the studies, the literature reporting this feared complication is heterogeneous and in many cases lacks information on tumour characteristics, comorbidities and treatment approaches. Case summary A 77-year-old man who had undergone extended right hepatectomy for HCC was diagnosed with early disease recurrence with a small nodule compatible with HCC in the Sg4b segment of the liver with a subcapsular location. He was treated with percutaneous RFA and a few week later he was urgently admitted to the Surgery ward for abdominal pain and fever. A subcutaneous abscess was diagnosed and treated by percutaneous drainage. A fistulous tract was then documented by the passage of contrast material from the gastric antrum to the abdominal wall. The oesophagogastroduodenoscopy confirmed a circular wall defect at the lesser curvature of gastric antrum, leading directly to the purulent abdominal collection. An over-the-scope clip (OTSC) was used to successfully close the defect. Conclusion This is the first reported case of RFA-related GIT injury to have been successfully treated with an OTSC, which highlights the role of this endoscopic treatment for the management of this complication.

Objectives The objective of this study was to investigate the efficacy and tolerability of 5-fluorouracil-oxaliplatin (FOLFOX) in advanced gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). Methods Retrospective analysis of consecutive 72 advanced GEP-NENs treated with FOLFOX between 2005 and 2016 at a single German referral center for NENs was performed. We assessed treatment response by response evaluation criteria in solid tumors 1.0 criteria, progression-free survival by Kaplan-Meyer method, and risk factor analysis by Cox-regression model. Results Patients were 44.5% G1/G2, 55.5% G3, receiving a median of 7 treatment cycles (range, 2-21), and had a median of 18 months of follow-up (range, 3-111 months). Disease control was achieved in 75.0% of cases but 91.3% in the 23 patients receiving FOLFOX as first line (P = 0.04). Median progression-free survival of the overall population was 8 months. A better outcome was significantly related to treatment duration (P = 0.02) and grade of histological differentiation for G3 patients (well differentiated vs poorly differentiated, P = 0.03). Adverse events occurred in 88.8% of patients, mostly grade 1 and 2 hematotoxicity and chemotherapy-induced peripheral sensory neuropathy (84.1% and 50.0% of patients, respectively). Conclusions Our results support FOLFOX as therapeutic option in advanced GEP-NENs with poor prognosis, either at first or further therapy line. Longer duration of therapy was associated with a more durable benefit.

Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, and toxicity profile of PRRT for NEN patients. We will review the most significant studies, such as the phase III NETTER-1 trial, and discuss promising new radiopharmaceuticals, including alpha-emitting radionuclide-labeled somatostatin analogs and SSTR antagonists.

Background: The correct histopathological diagnosis of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) is crucial for treatment selection and prognostication. It is also very challenging due to limited experience in nonexpert centers. Revision of pathology is standard of care for most patients who are referred to NEN expert centers. Objectives: To describe the clinical impact of histopathological revision for GEP-NEN patients referred to an expert center. Methods: Retrospective multicenter analysis of all GEP-NENs receiving a histopathological revision in 6 European NEN expert centers (January 2016 to December 2016) to evaluate the impact on patient management. Results: 175 patients were included and 14.7% referred for a second opinion. Histological samples were 69.1% biopsies, 23.4% surgical specimens, and 7.5% endoscopic resections. Histopathological changes due to revision included first assessment of Ki67 in 8.6% of cases, change in grading in 11.4% (3.4% G1 to G2; 5.7% G2 to G1; 0.6% G2 to G3; 1.7% G3 to G2), definition of tumor invasion in 10.8%, additional immunohistochemical staining in 2.3%, diagnosis of mixed adenoneuroendocrine carcinoma in 3.4%, exclusion of NEN in 3.4%, first diagnosis of NEN in 2.3%, and tumor differentiation for G3 in 1.7%. The revision had a clinical impact in 36.0% of patients, leading to a new therapeutic indication in 26.3%. The indication to then perform a new imaging test occurred in 21.1% and recommendation to follow-up with no further treatment in 6.3%. Conclusions: Histopathological revision in expert centers for NENs can change the diagnosis, with a significant clinical impact in about one third of patients.

Background: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Peritoneal disease control by medical therapies in these patients has been poorly investigated Objectives: To describe, in a consecutive series of GEP-NENs, the clinical impact of PC and to report the effectiveness of available treatments in PC control. Methods: A retrospective, monocenter analysis was performed of 135 GEP-NENs (1993–2016) with at least a 12-month follow-up. Peritoneal disease progression was defined as detection of a significant increase in size or appearance of new implants by imaging. Results: A total of 62.9% of cases had diffuse PC (involving at least 2 abdominal quadrants). According to WHO 2017 classification, cases were 42.3% neuroendocrine tumors NET-G1, 45.5% NET-G2, 6.5% NET-G3, 4.9% neuroendocrine carcinomas NEC-G3, and 0.8% mixed neuroendocrine-nonneuroendocrine neoplasms. Bowel obstruction occurred in 30 (22.2%) patients mainly depending on size of peritoneal implants (HR: 1.10; 95% CI: 1.02–1.20; p = 0.01). Patients with diffuse PC treated with peptide receptor radionuclide therapy (PRRT) showed peritoneal progression in 37.5% of cases, and bowel obstruction or ascites in 28.1%. Better peritoneal disease control was observed in cases receiving somatostatin analogs at first-line therapy, probably due to a less aggressive disease behavior for these patients. Conclusions: Bowel obstruction is not uncommon in GEP-NENs with PC. PRRT should be adopted with caution in GEP-NENs with diffuse PC, but larger series are needed to confirm these data.

Well-differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications. Commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Suggested alternative treatment protocols have not been studied in first-line therapy of NET G3 so far. We performed a retrospective analysis of patients with NET G3 in the databases of 3 German cancer centers. Out of 142 patients, 136 patients received palliative first-line therapy: overall response rate (ORR) was 35.1% for PE (n = 37), 56.4% for FOLFOX (n = 39), 27.3% for temozolomide/capecitabine (TEM/CAP) (n = 22), 45.0% for streptozotocin/5-fluorouracil (STZ/5-FU) (n = 20), and 16.7% for other (n = 18). Median progression-free survival (PFS) for PE was 6.9 months. Compared to PE, PFS in the other treatment groups was 6.9 months for FOLFOX (p = 0.333), 12.0 months for TEM/CAP (p = 0.093), 4.8 months for STZ/5-FU (p = 0.919), and 14.1 months for other (p = 0.014). In a univariate setting, all non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 months, p = 0.049) which could not be confirmed in a multivariate analysis. In conclusion, NET G3 with FOLFOX showed the highest ORR, and with TEM/CAP showed the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this tumor entity is needed.

Introduction The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. Methods A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 Results The main modification in the centers’ activity consisted of decreases in newly diagnosed NEN patients (− 76.8%), decreases in performed surgical procedures (− 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams’ activity (20.8%). A low proportion of centers (

About 40–80% of patients with pancreatic neuroendocrine tumors (PNETs) are metastatic at presentation, usually involving the liver. Here we will provide an up-to-date review of treatment options for patients with metastatic PanNETs. If patients are not suitable for surgery with curative intent, a medical management of disease is need. The availability of different treatment options require personalized therapeutic approach according to the features of individual patients and tumors. Watch and wait strategy is an option just for a limited number of patients with a low burden, asymptomatic and not progressing disease. For well-differentiated (G1–2) and SSTR-positive PanNETs, the treatment of choice is somatostatin analogs (SSTAs) that are effective and well tolerated. After SSTA failure, target therapies (everolimus and sunitinib), chemotherapy, and peptide receptor radionuclide therapy (PRRT) are all adequately supported by strong scientific data, and there are no clear criteria that favor the choice of one treatment over the other. The decision-making process should be conducted as part of a multidisciplinary tumor board and must be based on some key elements: the Grade (G 1,2,3), the proliferation index (Ki67), expression of somatostatin receptors, the rate of growth of the disease over time, and the presence of tumor-related symptoms. Finally in poorly differentiated carcinoma (PanNEC), platinum-based chemotherapy is the only available treatment option although the results in terms of overall survival are disappointing.

Background Stage IV gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) G3 are the NENs with the worst prognosis. According to ENETS guidelines, platinum-based chemotherapy is the standard treatment for this population. Surgery is only considered in highly selected “resectable” NENs with usually lower Ki67. However, the role of surgery with curative intent has been poorly investigated. Objective To describe, in a retrospective series of stage IV GEP-NENs G3, overall survival (OS) and recurrence-free survival (RFS) rates after curatively intended surgery. Methods Multicenter analysis of stage IV GEP-NENs G3 receiving radical resection (R0/R1) from 2007 to 2017, with minimum post-surgical follow-up time of 3 months. Results Fifteen patients from 6 NEN referral centers, with median follow-up of 29 months (8-86), were included. Eight cases had a neuroendocrine carcinoma (NEC) and 7 a neuroendocrine tumor G3 (NET G3). Median OS after radical surgery was 59 months. All patients recurred, with a median RFS of 8 months. Conclusions Radical surgery might be considered for highly selected stage IV GEP-NENs G3. Larger series are needed to confirm these results.

Background: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. Patients and Methods: Multicenter analysis of a series of stage I–III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. Results: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23months (5–187months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. Conclusions: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Background Several risk factors predict clinical outcome in gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs); however, the impact of their combination has not been investigated so far. Patients and Methods A retrospective analysis of stage IV GEP-NENs was performed. Multivariate analysis for progression of disease (PD) was performed by Cox proportional hazards method to obtain a risk score. Area under the curve obtained by receiver operating characteristic analysis was used to assess the score performance. Progression-free survival analysis was performed by Kaplan-Meier method. Results Two hundred eighty-three stage IV GEP-NENs were evaluated, including 93 grade 1 neuroendocrine tumors (32.9%), 153 grade 2 neuroendocrine tumors (54%), and 37 grade 3 neuroendocrine carcinomas (13.1%). Independent risk factors for PD were Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The risk score was calculated as follows: (0.025 × Ki67) + [(0 if no liver metastases or liver involvement 50%)] + [(0 if no extra-abdominal metastases) OR (0.528 if extra-abdominal metastases present)]. The risk score accuracy to predict PD was superior compared with the G grading system (area under the curve: 0.705 and 0.622, respectively). Three subgroups of patients with low, intermediate, and high risk of PD according to risk score were identified, median progression-free survival being 26 months, 19 months, and 12 months, respectively. Conclusion In stage IV GEP-NENs, a risk score able to predict PD was obtained by combining Ki67, proportion of metastatic liver involvement, and presence of extra-abdominal metastases. The score may help to discriminate patients with different progression risk level to plan tailored therapeutic approaches and follow-up programs.

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.

4607 Background: Well differentiated grade 3 neuroendocrine tumors (NET G3) have been distinguished from poorly differentiated neuroendocrine carcinomas (NEC) in the most current WHO classifications from 2017 and 2019. Retrospective data suggest that commonly applied first-line chemotherapy protocols with cisplatin or carboplatin in combination with etoposide (PE) are less effective in NET G3 than NEC. Therefore, current treatment guidelines suggest alternative first-line treatment protocols like temozolomide-based (TEM), streptozotocin-based (STZ) and FOLFOX which have only been studied in second-line so far. The aim of this multicenter analysis was to evaluate treatment outcomes for NET G3 with a focus on the efficacy of different first-line regimens. Methods: We performed retrospective analysis of all patients with NET G3 in the NEN databases of 3 German cancer centers. All histopathological findings were reviewed by the investigators in order to comply with the most current WHO classification. Results: A total of 131 patients could be identified. Median Ki67 was 30 %, primary tumors were located in the pancreas in 71 % of cases, 20 patients had a history of prior NET G1/G2 diagnosis. Median overall survival (OS) was 138.1 months with a median follow-up of 20.4 months. 125 patients received palliative first-line therapy: PE n = 34, FOLFOX n = 36, TEM (mostly temozolomide+capecitabine) n = 21, STZ n = 19, other (including targeted agents, somatostatin analogues, PRRT and multimodal combination approaches) n = 15. Overall response (ORR) and disease control rate was 35.3 % and 67.6 % for PE, 52.8 % and 80.6 % for FOLFOX, 28.6 % and 66.7 % for TEM, 47.4 % and 68.4 % for STZ, 20.0 % and 73.3 % for other respectively. Median progression-free survival for PE was 5.2 months. Compared to PE, PFS in the other treatment groups was 6.0 months for FOLFOX (p = 0.164), 12.0 months for TEM (p = 0.059), 5.7 months for STZ (p = 0.519), 14.1 months for other (p = 0.003). All non-PE patients combined showed a significantly prolonged PFS vs. PE (9.0 vs. 5.2 months; p = 0.011). 89 patients received second-line systemic therapy with a median PFS of 5.3 months. Conclusions: In this first multicenter analysis of different treatment strategies for NET G3, patients receiving upfront treatment with non-PE regimens had a significantly prolonged PFS. Of the single defined protocols, FOLFOX showed the highest ORR, and TEM the longest PFS. Further prospective evaluation of the optimal therapeutic strategy for this newly defined tumor entity is needed.

Background The role of 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) in the diagnostic algorithm of entero-pancreatic neuroendocrine neoplasms (EP NENs) is unclear because most available data derive from heterogeneous populations in terms of tumor biology and disease status at time of examination. The aim of this study was to determine the ability of 18F-FDG PET to identify patients with more aggressive disease among those with advanced EP NENs. Subjects, Materials, and Methods . Patients with advanced EP NENs and known disease status (progressive disease [PD] or stable disease [SD]) according to imaging procedures, who received 18F-FDG PET and computed tomography scans during a time frame of 1 month, were included. Results A total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positive 18F-FDG PET, whereas 18F-FDG PET was negative in the remaining 31 patients (33.3%). Overall, 18F-FDG PET sensitivity and specificity to detect PD were 90.6% and 86.2%, respectively, resulting in a diagnostic accuracy of 89.2%. A positive 18F-FDG PET was significantly associated with PD at the time of study entry (p Conclusion 18F-FDG PET has a high diagnostic accuracy to identify progression of disease with unfavorable clinical outcome in patients with advanced EP NENs. Knowledge of disease status and G grading are key factors for physicians to better select patients for whom 18F-FDG PET is clinically useful. Implications for Practice The findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom 18F-fluorodeoxyglucose positron emission tomography is useful to predict poor clinical outcome.

The role ofA total of 93 patients, including 69 patients with pancreatic NENs and 24 patients with small-intestine NENs, were included. At the time of study entry, 64 patients (68.8%) had PD, and the remaining 29 patients (31.2%) had SD. A total of 62 patients (66.7%) had positiveThe findings of the present study may help physicians dealing with advanced neuroendocrine neoplasms to select patients for whom

OBJECTIVES: The objective of this study was to determine the impact of different metastatic spread patterns on outcome in advanced digestive neuroendocrine tumors (NETs). METHODS: This was a retrospective analysis of patients with stage IV NETs, classified as group 1 (unilobar liver metastases), group 2 (bilobar liver metastases), group 3 (extra-abdominal metastases). End points were overall survival (OS) and progression-free survival (PFS). Risk factor analysis was performed using Cox proportional hazard model. RESULTS: Of the 229 patients, 135 (58.9%) had pancreatic, and 94 (41.1%) small bowel NETs: 32 (13.9%) were included in group 1, 179 (78.2%) in group 2, and 18 (7.9%) in group 3. Median Ki67 was 4.5%. Overall, 5-year OS was 55%. Different OS was observed among the 3 groups: median survival not reached, 81 and 8 months, respectively (P < 0.001). Median PFS was 18 months. Both OS and PFS were significantly affected by Ki67 and metastatic spread pattern. CONCLUSIONS: The stratification of stage IV NET patients based on metastatic patterns, alongside Ki67, predicts the clinical outcome. The extent of metastatic disease is a previously unrecognized variable, which should be considered when evaluating the results of treatments in NET patients with advanced disease.

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.

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.

4094Background: Surgery with radical intent is the only curative option for digestive neuroendocrine neoplasms (DNENs), but clinical practice shows disease-free patients recurring even after years....

Background: Type I gastric carcinoids (TIGCs) are neuroendocrine neoplasms arising from enterochromaffin-like cells in atrophic body gastritis. Data regarding their evolution in prospective series are scarce, thus treatment and follow-up are not codified. Our aim was to evaluate clinical outcome and recurrence in TIGCs managed by endoscopic approach. Methods: 33 patients (24 females; median age 65 years, range 23–81) were included and managed through endoscopic follow-up every 6–12 months, with lesion removal and multiple gastric biopsies. Baseline clinical and histological features were analyzed as risk factors by Cox regression. Results: At diagnosis, 7 tumors were intramucosal carcinoids and 26 were polyps (median diameter 5 mm, range 2–20), multiple in 17 patients. Associated severe atrophy was present in 21 cases (63.6%), while mild atrophy was found in 6 cases (18.2%). During a 46-month median follow-up, survival was 100% and no metastases occurred. One patient developed a less-differentiated carcinoid that was radically treated by surgery. 21 patients (63.6%) had recurrence after a median of 8 months, 14 of these (66.6%) had a second recurrence after a median of 8 months following the previous carcinoid removal. Median recurrence-free survival was 24 months. Neither clinical nor biochemical recurrence-predicting factors were found. Conclusions: Although about 60% of TIGCs had recurrence after endoscopic resection, endoscopic management may be considered safe and effective.

To assess the rate of spontaneous tube migration and to compare the effects of naso-gastric and naso-intestinal (NI) (beyond the ligament of Treitz) feeding in severe acute pancreatitis (SAP).After bedside intragastric insertion, tube position was assessed, and enteral nutrition (EN) started at day 4, irrespective of tube localization. Patients were monitored daily and clinical and laboratory parameters evaluated to compare the outcome of patients with nasogastric (NG) or NI tube.Spontaneous tube migration to a NI site occurred in 10/25 (40%) prospectively enrolled SAP patients, while in 15 (60%) nutrition was started with a NG tube. Groups were similar for demographics and pancreatitis aetiology but computed tomography (CT) severity index was higher in NG tube patients than in NI (mean 6.2 vs 4.7, P = 0.04). The CT index seemed a risk factor for failed obtainment of spontaneous distal migration. EN trough NG or NI tube were similar in terms of tolerability, safety, clinical goals, complications and hospital stay.Spontaneous distal tube migration is successful in 40% of SAP patients, with higher CT severity index predicting intragastric retention; in such cases EN by NG tubes seems to provide a pragmatic alternative opportunity with similar outcomes.

219 Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), which can be detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to evaluate, in metastatic DNENs FU, the diagnostic yield of FITs associated to Computed Tomography scan (CT) in terms of detecting new distant metastases (primary outcome) and of clinical usefulness (secondary outcome). Methods: Retrospective analysis of stage IV DNENs expressing SSTRs and with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), subsequently it was 68Ga-DOTA- PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-“units”, in which each patient had faced at least 1 CT and 1 FIT. Units were analyzed separately and then compared to each other. The gold standard adopted was the result of the imaging tests, the surgical and pathological findings collected for each patient during FU. Clinical usefulness was defined as “appropriate changes” in management (indication to further imaging tests, surgery, biopsy, change in therapy) due to CT and/or FITs. Results: Interim analysis of 381 units (median 3 per patient, range 2-7) obtained from 121 patients included so far (67.8% metastatic since diagnosis). New lesions were detected by CT alone in 82.3% of cases; adding OCT, the diagnostic yield was 9.6%, while adding GaPET 21.7% (P

Background: Digestive Neuroendocrine Neoplasms (DNENs) express in up to 80% of cases somatostatin receptors (SSTRs), that are detected by Functional Imaging Tests (FITs). FITs are needed at DNENs first diagnosis to define therapy but their role in follow-up (FU) is unclear. Moreover, with the introduction of targeted therapies, RECIST criteria are showing difficulties to assess tumor response to these drugs. The aim of this study was to compare the accuracy in detecting new distant metastases (primary outcome) and the clinical usefulness (secondary outcome) of FITs and Computed Tomography scan (CT) in metastatic DNENs FU. Methods Retrospective analysis of stage IV DNENs expressing SSTRs with at least 24 month-FU. From 1995 to 2008 FIT performed was Octreoscan (OCT), from 2008 to 2013 it was 68Ga-DOTANOC PET/CT (GaPET). CT was repeated every 6-12 months, FIT yearly. FU time was divided into 12 month-”units”, in which each patient had at least 1 CT and 1 FIT. Units were analyzed separately and then compared to each other. The gold standard adopted was the result of the imaging tests, the surgical and pathology findings collected for each patient during FU. Clinical usefulness was defined as appropriate changes in management (indication to new imaging test, therapy, surgery or biopsy) due to CT and/or FITs during FU. Results 323 units (median 3 per patient, range 2-7) derived from 99 patients included (66% metastatic since the first diagnosis). New lesions were detected by CT alone in 86.4% of cases, with a positive predictive value (PPV) of 93.3% and a negative predictive value (NPV) of 91.9%; adding OCT, the diagnostic yield was 10.34% (P Citation Format: Elettra Merola, Francesco Panzuto, Gabriele Capurso, Patrizia Kump, Rainer Lipp, Noemi Cicchese, Elsa Iannicelli, Daniela Prosperi, Patrizia Pizzichini, Maria Rinzivillo, Stefano Partelli, Anja Rinke, Massimo Falconi, Gianfranco Delle Fave. Functional imaging tests vs. computed tomography scan: detection of new metastases and clinical usefulness in digestive neuroendocrine neoplasms follow-up. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3455. doi:10.1158/1538-7445.AM2015-3455

Barrett's esophagus (BE) is a metaplastic disorder in which specialized columnar epithelium replaces healthy squamous epithelium (intestinal metaplasia). Even though its pathophysiology and the steps of its neoplastic progression are not completely understood, BE can be considered as a complication of gastroesophageal reflux disease (GERD). Given that esophageal adenocarcinoma, which is continually increasing in the Western world, still has a poor prognosis and suffers from late diagnosis, and because BE is a precancerous lesion, there is a strong need for good molecular markers of malignant progression in Barrett's metaplasia (BM). The aim of this review is to examine the published data regarding the role that assessment of p53 may play in the management of BE, trying to understand if it may be a useful marker to early diagnose BE malignant transformation.

Control of the G1/S-phase transition as well as angiogenic switch are two of the most studied mechanisms in cancer. The current study examined the correlation between the immunohistochemical expression of pRb2/p130, VEGF, EZH2, p53, p16, p21waf-1, p27, and PCNA in Barrett's esophagus (BE). Overall, p53 showed a much higher expression in BE patients (up to 50%) than in controls (1-10%) (P < 0.005). Also p21 showed a downregulation in BE when compared to normal esophagus (70% of cells vs. 65%), but the difference did not show any statistical significance (P = 0.45). pRb2/p130 was detected in 80% of cells in normal controls, but showed positive in only 20% of cells in BE biopsies. Additionally, Rb2/p130 expression was inversely correlated to that of VEGF, EZH2, and PCNA (P < 0.0001, P = 0.0032, P < 0.001, respectively). p27 stained more intensely and in a widespread manner (70%) cells in normal esophageal tissues but about only 30% in BE samples (P < 0.001). Lastly, in accordance with other reports, we also found p16 expressed by immunohistochemistry at high levels in normal controls and at low levels in BE (P < 0.001). In conclusion, p16, p21, p27, and p53 staining confirmed previously published data. Interestingly, pRb2/p130 expression was found significantly decreased in metaplastic epithelium compared to normal controls and showed significant inverse correlation with the expression of other markers, such as VEGF, EZH2, and PCNA. These data, taken together, indicate that these molecular events occurring in Barrett's metaplasia (BM) may represent one of the many steps taking place during esophageal malignant progression such as impairment of cell-cycle control, altered differentiation, and unbalanced angiogenesis.

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