Clinical Outcome of Patients with Gastric, Duodenal, or Rectal Neuroendocrine Tumors after Incomplete Endoscopic Resection.

Objectives: Our aim was to investigate the clinical outcome of patients with well-differentiated gastric, duodenal, and rectal neuroendocrine tumors after treatment with incomplete endoscopic resection due to the finding of microscopic positive resection margins (R1). Methods: This is a retrospective analysis of consecutive patients with type 1 gastric, non-ampullary non-functioning duodenal, or rectal neuroendocrine neoplasms with positive R1 margins after endoscopic resection. The rate of tumor recurrence and progression-free survival were considered to be the study's main endpoints. Statistical analysis was performed using MedCalc® v.17 software and a p-value of <0.05 was considered significant. A Cox proportional-hazard regression was performed to identify risk factors for disease recurrence/progression. Results: After evaluating 110 patients, a total of 58 patients were included in the final analysis (15 gastric NENs, 12 duodenal NENs, and 31 rectal NENs). After evidence of endoscopic R1 resection had been gathered, 26 patients (44.8%) underwent an endoscopic/surgical extension of the previous resection. Tumor progression (all local recurrences) occurred in five out of fifty-eight patients (8.6%) with a median PFS of 36 months. There were no tumor-related deaths. G2 grading and the gastric primary tumor site were the only features significantly associated with the risk of recurrence of the disease (HR: 11.97 [95% CI: 1.22-116.99], HR: 12.54 [95% CI: 1.28-122.24], respectively). Conclusions: Tumor progression rarely occurs in patients with microscopic positive margin excision (R1) after endoscopic resection and does not seem to affect patients' clinical outcomes.

Gastrointestinal side effects of somatostatin analogs in neuroendocrine tumors: a focused review.

Neuroendocrine tumors (NETs) are a group of well-differentiated heterogeneous neoplasms characterized by slow progression and distinct clinical and biological behavior. In the majority of patients with NET, first-line treatment is represented by somatostatin analogs (SSAs) that, despite being drugs with high tolerability (even at high doses) and providing to carcinoid symptoms control and anti-proliferative effects, may present some side effects, with potential impact on quality of life and nutritional status. The most frequent side effects are represented by gastrointestinal events in particular alterations in bowel habits (diarrhea and constipation), abdominal pain, exocrine pancreatic insufficiency, and cholelithiasis. Considering the relative rarity of NETs, literature about frequency and standard clinical management of adverse events SSA-related is still lacking and heterogeneous. The aim of this review is to arm gastroenterologists and other physicians treating NET patients with essential knowledge on the side effects of SSAs. By identifying and managing these adverse events early, healthcare professionals can offer optimal care, avert foreseeable complications, and ensure the best outcomes for patients. Without such early recognition, there is a risk of diminishing the patient's quality of life and their ability to sustain treatment over time.

Type 3 gastric neuroendocrine neoplasms: the rising promise of conservative endoscopic management.

Gastric neuroendocrine neoplasms (g-NENs) are rare tumors arising from the gastric enterochromaffin-like cells. Recent data suggests an increased detection rate, attributed to more frequent esophagogastroduodenoscopies. While type 3 g-NENs were historically deemed aggressive, emerging research indicates potential for conservative management, especially endoscopic resection, in well-differentiated, small tumors. European guidelines now advocate for endoscopic intervention in selected cases, but North American guidelines remain more conservative. Key factors influencing outcomes are tumor size, grading, and depth of gastric wall infiltration. Endoscopic resection has shown promise for tumors confined to submucosal layers without lymphovascular invasion. Given the complexities, a multidisciplinary team approach is essential for management decisions. Current insights are largely based on retrospective studies, underscoring the need for prospective research to optimize endoscopic approaches.

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.

When Should We Adopt EUS-Guided Radiofrequency Ablation in Pancreatic Neuroendocrine Tumors?

Pancreatic neuroendocrine neoplasms (PanNENs) are rare and heterogeneous diseases that account for less than 2% of all cases of pancreatic cancer and only 30% of digestive neuroendocrine neoplasia, even if their incidence and prevalence continue to rise globally [...].

The meaning of R1 resection after endoscopic removal of gastric, duodenal and rectal neuroendocrine tumors.

INTRODUCTION: Well-differentiated gastric, duodenal, and rectal neuroendocrine neoplasms (NETs) are rare diseases usually managed by endoscopic treatment. Although several endoscopic techniques are available, the number of patients with incomplete (R1) resection is significant. AREAS COVERED: This review focuses on the meaning of incomplete R1 findings after endoscopic resection in type I gastric NETs; nonfunctioning, non-ampullary duodenal NETs; and small rectal NETs. Data were identified by MEDLINE database search without publication date limitation. EXPERT OPINION: An incomplete R1 finding may have no significant impact on a patient's clinical outcome, particularly in small G1 type I gastric NETs, which have an indolent course. A 'stepwise approach,' which uses more advanced endoscopic techniques, or minimally invasive surgery may be justified to achieve complete margin-free resection. This approach must balance the tumor features and the procedure-related risk of complications, particularly in the duodenum, where the role of deep endoscopic resections is limited due to the thin duodenal wall. Gastric and rectal NETs that are incompletely removed after initial resection are more easily amenable to deep endoscopic techniques. However, this might not be necessary for patients with comorbidities, elderly, or both due to the uncertainty of how R1 finding impacts a patient's clinical outcome.

Utility of histopathological revision in the management of gastro-entero-pancreatic neuroendocrine neoplasia.

BACKGROUND: Histological evaluation and grading assessment are key points in the diagnostic work-up of gastroentero-pancreatic neuroendocrine neoplasms (GEP-NENs). AIM: To analyze the impact of histopathological revision on the clinical management of patients with GEP-NEN. MATERIALS AND METHODS: Patients referred to our Center of Excellence between 2015 and 2021 were included in this study. Immunohistochemical slides at the time of initial diagnosis were reviewed to assess tumor morphology, diagnostic immunohistochemistry, and Ki67. RESULTS: 101 patients were evaluated, with 65 (64.4%) gastrointestinal, 25 (24.7%) pancreatic, and 11 (10.9%) occult neoplastic lesions suspected to be of GEP origin. The main changes resulting from the revision were: first Ki-67 assessment in 15.8% of patients, Ki-67 change in 59.2% of patients and grading modification in 23.5% of patients. An additional immunohistochemical evaluation was performed in 78 (77.2%) patients, leading to a confirmation of GEP origin in 10 of 11 (90.9%) of unknown primary site neoplastic lesions and an exclusion of NEN diagnosis in 2 (2%) patients. After histopathological revision, a significant modification in clinical management was proposed in 42 (41.6%) patients. CONCLUSIONS: Histopathological revision in a referral NEN center is strongly advised in newly diagnosed GEP-NENs to properly plan prognostic stratification and therapeutic choice.

Management of Functional Pancreatic Neuroendocrine Neoplasms.

OPINION STATEMENT: Functional pancreatic neuroendocrine neoplasms (pNENs) are rare and heterogeneous diseases in terms of both clinical and pathological aspects. These tumors secrete hormones or peptides, which may cause a wide variety of symptoms related to a clinical syndrome. The management of functional pNENs is still challenging for clinicians due to the need to control both tumor growth and specific symptoms. Surgery remains the cornerstone in the management of local disease because it can definitively cure the patient. However, when the disease is not resectable, a broad spectrum of therapeutic options, including locoregional therapy, somatostatin analogs (SSAs), targeted therapies, peptide-receptor radionuclide therapy (PRRT), and chemotherapy, are available. The present review summarizes the main key issues regarding the clinical management of these tumors, providing a specific highlight on their therapeutic approach.

The Antiproliferative Activity of High-Dose Somatostatin Analogs in Gastro-Entero-Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.

Background: The antiproliferative activity of a high dose of somatostatin analogs (HD-SSA) in treating gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) remains under debate. Methods: A systematic review and proportion meta-analysis were made. The primary endpoint was the efficacy measured as incidence density ratio (IDR) at one year. The secondary endpoints were the disease control rate (DCR) and severe adverse events (SAEs). The heterogeneity (I2), when high (>50%), was interpreted by performing a univariate metaregression analysis, analyzing as covariates: type and design of the study, location (Europe or USA), sample size, grading according to 2017 WHO, the metastatic disease rate, previous therapy including surgery, and quality of the study. Results: A total of 11 studies with 783 patients were included. The IDR was 62 new progressions of 100 patients treated with HD-SSA every one year. The heterogeneity was high. The study's year, type and design, primary tumor, grading, previous treatments, and quality of the studies did not influence the IDR. The IDR was significantly higher in USA centers and studies with more than 50 patients. The IDR was lower when a high rate of metastatic patients was present in the studies. The DCR was 45%. The heterogeneity was high. The DCR was lower in USA studies and in prospective trials. Conclusion: Given the limited efficacy of HD-SSA in preventing the disease progression in unresectable GEP-NENs after failure of standard dose SSA, the use of this therapeutic approach is advisable in selected cases when other antiproliferative treatments are not feasible.

CT-based radiomics for prediction of therapeutic response to Everolimus in metastatic neuroendocrine tumors.

AIM: To test radiomic approach in patients with metastatic neuroendocrine tumors (NETs) treated with Everolimus, with the aim to predict progression-free survival (PFS) and death. MATERIALS AND METHODS: Twenty-five patients with metastatic neuroendocrine tumors, 15/25 pancreatic (60%), 9/25 ileal (36%), 1/25 lung (4%), were retrospectively enrolled between August 2013 and December 2020. All patients underwent contrast-enhanced CT before starting Everolimus, histological diagnosis, tumor grading, PFS, overall survival (OS), death, and clinical data collected. Population was divided into two groups: responders (PFS ≤ 11 months) and non-responders (PFS > 11 months). 3D segmentation was performed on whole liver of naïve CT scans in arterial and venous phases, using a dedicated software (3DSlicer v4.10.2). A total of 107 radiomic features were extracted and compared between two groups (T test or Mann-Whitney), radiomics performance assessed with receiver operating characteristic curve, Kaplan-Meyer curves used for survival analysis, univariate and multivariate logistic regression performed to predict death, and interobserver variability assessed. All significant radiomic comparisons were validated by using a synthetic external cohort. P < 0.05 is considered significant. RESULTS: 15/25 patients were classified as responders (median PFS 25 months and OS 29 months) and 10/25 as non-responders (median PFS 4.5 months and OS 23 months). Among radiomic parameters, Correlation and Imc1 showed significant differences between two groups (P < 0.05) with the best performance (internal cohort AUC 0.86-0.84, P < 0.0001; external cohort AUC 0.84-0.90; P < 0.0001). Correlation < 0.21 resulted correlated with death at Kaplan-Meyer analysis (P = 0.02). Univariate analysis showed three radiomic features independently correlated with death, and in multivariate analysis radiomic model showed good performance with AUC 0.87, sensitivity 100%, and specificity 66.7%. Three features achieved 0.77 ≤ ICC < 0.83 and one ICC = 0.92. CONCLUSIONS: In patients affected by metastatic NETs eligible for Everolimus treatment, radiomics could be used as imaging biomarker able to predict PFS and death.

Role of [18F]FDG PET/CT in the management of G1 gastro-entero-pancreatic neuroendocrine tumors.

PURPOSE: Since the role of [18F]FDG PET/CT in low-grade gastroenteropancreatic (GEP) neuroendocrine neoplasia (NET) is not well established, this study was aimed to evaluate the role of [18F]FDG PET/CT in grade 1 (G1) GEP-NETs. METHODS: This is a retrospective study including patients with G1 GEP-NETs who underwent [18F]FDG PET/CT. RESULTS: 55 patients were evaluated, including 24 (43.6%) with pancreatic NETs and 31 (56.4%) with gastrointestinal NETs. At the time of diagnosis, 28 (51%) patients had metastatic disease, and 50 (91%) patients were positive by 68-Ga sstr PET/CT. Overall, 27 patients (49%) had positive findings on [18F]FDG PET/CT. Following [18F]FDG PET/CT, therapeutic management was modified in 29 (52.7%) patients. Progression-free survival was longer in patients with negative [18F]FDG PET/CT compared with positive [18F]FDG PET/CT (median PFS was not reached and 24 months, respectively, p = 0.04). This significance was particularly evident in the pancreatic group (p = 0.008). CONCLUSIONS: Despite having low proliferative activity, approximately half of GEP-NETs G1 showed positive [18F]FDG PET/CT, with a corresponding negative impact on patients' clinical outcomes. These data are in favor of a more "open" attitude toward the potential use of [18F]FDG PET/CT in the diagnostic work-up of G1 GEP-NETs, which may be used in selected cases to detect those at higher risk for an unfavorable disease course.