Gastroenteropancreatic Tract Research Articles

Novel Surgical Initiatives in Gastroenteropancreatic Neuroendocrine Tumours.

Neuroendocrine tumours (NET) are rare entities arising from hormone producing cells in the gastroentero-pancreatic (GEP) tract. Surgery is the most common treatment of GEP-NETs. Improvements in surgical techniques allow for more locally advanced and metastasised GEP-NETs to be resected. Laparoscopic and robotically--assisted approaches are increasingly being utilised in the resection of selected GEP-NETs and are facilitated by novel intraoperative tumour localisation tools and parenchyma-sparing methods. At the same time, some authors suggest that indications for formal resections of small well differentiated non-functioning pancreatic NETs and appendiceal NETs should be more restrictive. Advancements in surgery allows for tissue-sparing resections of GEP-NETs. Indications for surgical resection and the extent of the procedure are highly dependent on GEP-NET size, localisation and grading. Robotically assisted surgeries with intraoperative ultrasound and visualisation methods as well as vessel-sparing radical retrograde lymphadenectomies for small intestinal NETs seem to be the future of GEP-NET surgery.

Surgical Management of Gastroenteropancreatic Neuroendocrine Tumors

Background/Objectives: Neuroendocrine tumors (NETs) are heterogeneous malignancies arising from enterochromaffin cells that can arise from the gastrointestinal (GI) tract and pancreas. Surgical management is the cornerstone of treatment, with the optimal approach tailored by tumor grade, size, location, and presence of metastasis. This review discusses the current strategies for the surgical management of NETs of the gastroenteropancreatic tract. Methods: A review of the available literature was conducted to evaluate surgical approaches to NETs. Consensus guidelines were incorporated to synthesize evidence-based recommendations. Results: For gastric NETs, surgical approach depends on Rindi Classification, WHO grade, and tumor size, with endoscopic approaches favored for smaller and low-grade lesions. Small bowel NETs can be multifocal and thus often require a surgical approach with careful evaluation of the entire intestine. Pancreatic NETs are categorized as functional or non-functional, with enucleation or formal resection strategies based on size, location, functional status, and risk of malignancy. Colorectal NETs are primarily treated with transanal localized or formal surgical resection, depending on lesion size and depth of invasion or presence of lymph node involvement. Appendiceal NETs are either treated with appendectomy or right hemicolectomy, depending on the size, location, and invasiveness of the lesions. For metastatic NETs, cytoreduction, liver transplantation, and targeted therapies offer symptom relief and possible survival benefits. Conclusions: Surgical resection provides curative potential for localized NETs and symptom control in metastatic cases. Future research is essential to refine guidelines for intermediate-risk lesions and multifocal tumors, ensuring optimal outcomes for patients with gastroenteropancreatic NETs.

Nutritional status and gastroenteropancreatic neuroendocrine neoplasms: lights and shadows with a clinical guide from the NIKE Group.

Neuroendocrine neoplasms (NENs) originating in the gastroenteropancreatic (GEP) tract are rare tumors often associated with significant metabolic disturbances and nutritional challenges. This review explores the intricate relationship between nutritional status and the development, progression, and prognosis of GEP-NENs. Through an extensive literature search encompassing studies up to April 2024, we examined various factors, including obesity, malnutrition, metabolic syndrome and type 2 diabetes mellitus, and their roles in the development and progression of GEP-NENs. The review highlights the dual role of obesity, both as a risk factor and a potential prognostic indicator, drawing attention to the 'obesity paradox' observed in cancer research. Additionally, we discuss the impact of malnutrition on patient outcomes and emphasize the need for comprehensive nutritional assessments beyond BMI. This analysis highlights the importance of incorporating nutritional interventions into preventive and therapeutic strategies for GEP-NEN patients. Future research should further clarify these associations and develop personalized nutritional management protocols to improve patient prognosis and quality of life. Acronyms adopted in the text and tables: AOR: adjusted odd ratio, BIA: Bioelectrical Impedance Analysis, BMI: Body Mass Index, CI: confidence interval, CLARINET: Controlled Study of Lanreotide Antiproliferative Response in Neuroendocrine Tumor, FLI: fatty liver index, GEP: gastroenteropancreatic, GLIM: global leadership into malnutrition, HR: hazard ratio, MS: metabolic syndrome, MUST: malabsorption universal screening tool, NEC: neuroendocrine carcinoma, NENs: Neuroendocrine neoplasms, NETs: Neuroendocrine tumors, NRS: Nutritional Risk Screening, OR: odd ratio, OS: overall survival, PFS: progression-free survival, RR: risk ratio, SGA: Subjective Global Assessment, T2DM: type 2 diabetes mellitus, VAI: visceral adiposity index, WD: well-differentiated.

Efficacy and Toxicity Analysis of mFOLFIRINOX in High-Grade Gastroenteropancreatic Neuroendocrine Neoplasms.

High-grade neuroendocrine neoplasms (NENs) comprise both well-differentiated grade 3 neuroendocrine tumors (G3 NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) nearly always include poorly differentiated NEC as the neuroendocrine component. The efficacy and safety of frontline mFOLFIRINOX chemotherapy has never been investigated in patients with high-grade NENs. We conducted a multi-institutional retrospective analysis of patients with advanced high-grade NEN of the gastroenteropancreatic tract or of unknown origin seen between February 2016 and April 2023 who received treatment with frontline mFOLFIRINOX. A total of 35 patients were included (G3 NETs: n=2; NECs: n=25; MiNENs: n=8; stage III: n=5; stage IV: n=30). The objective response rate was 77% (complete response: 3%; partial response: 74%). Median progression-free survival was 12 months (95% CI, 9.2-16.2 months) and median overall survival was 20.6 months (95% CI, 17.2-30.6 months). No significant differences in efficacy were seen according to primary site, histopathology, and Ki-67 proliferative index. All 5 patients with stage III disease who received mFOLFIRINOX obtained an objective response and underwent radical surgery or definitive radiotherapy with curative intent, with a recurrence rate of 40%. Grade 3 or 4 adverse events were observed in 43% of patients (mainly neutropenia and diarrhea). Females were at significantly increased risk of developing severe toxicities. mFOLFIRINOX shows antitumor activity against high-grade NENs. Well-designed, prospective clinical trials are needed to assess the efficacy of mFOLFIRINOX in both the neoadjuvant and metastatic settings.

Mixed neuroendocrine non-neuroendocrine neoplasms in gastroenteropancreatic tract.

Mixed neuroendocrine non-neuroendocrine neoplasms (MiNENs) are a heterogeneous group of malignant neoplasms that can settle in the gastroenteropancreatic tract. They are composed of a neuroendocrine (NE) and a non-NE component in at least 30% of each tumour. The non-NE component can include different histological combinations of glandular, squamous, mucinous and sarcomatoid phenotypes, and one or both of the components can be low-or high grade malignant. Recent changes in the nomenclature of these neoplasms might lead to great deal of confusion, and the lack of specific clinical trials is the main reason why their management is difficult. The review aims to clarify the definition of MiNEN and analyze available evidence about their diagnosis and treatment options according to their location and extension through careful analysis of the available data. It would be important to reach a general consensus on their diagnosis in order to construct a classification that remains stable over time and facilitates the design of clinical trials that, due to their low incidence, will require long recruitment periods.

The global leadership into malnutrition criteria reveals a high percentage of malnutrition which influences overall survival in patients with gastroenteropancreatic neuroendocrine tumours.

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival.

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives.

Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.

DOG1 expression in neuroendocrine neoplasms: Potential applications and diagnostic pitfalls

Neuroendocrine neoplasms represent a heterogeneous group of rare tumors, more frequently arising from gastroenteropancreatic tract and lungs. At the time of diagnosis, 20% of cases are metastatic, and 10% of cases are considered as cancer of unknown primary origin. Several immunohistochemical markers are routinely used to confirm the neuroendocrine differentiation, first among all Synaptophysin and Chromogranin-A; on the other hand, different immunohistochemical markers are used to establish primary anatomical site, as TTF1, CDX2, Islet-1 and Calcitonin, but no marker is available in order to distinguish among different sites of the digestive tract.DOG1 (discovered on GIST-1) is a gene normally expressed in interstitial cells of Cajal and, in routine practice, DOG1 immunostaining is used in diagnosis of GIST (gastrointestinal stromal tumor). DOG1 expression has been described in several neoplasms other than GIST, both in mesenchymal and epithelial neoplasms. In the present study, DOG1 immunostaining has been performed in a large cohort of neuroendocrine neoplasms, including neuroendocrine tumors and neuroendocrine carcinomas, in order to evaluate frequency, intensity and pattern of expression in different anatomical site and in different tumor grade. DOG1 expression was detected in a large percentage of neuroendocrine tumors, with statistically significant association between DOG1 expression and gastrointestinal tract neuroendocrine tumors. As a consequence, DOG1 could be included in marker panel for the identification of primary site in neuroendocrine metastases of unknown primary origin; moreover, these results recommend careful evaluation of DOG1 expression in gastrointestinal neoplasms, in particular in differential diagnosis between epithelioid GIST and neuroendocrine tumors.

Outcome analysis in patients with metastatic gastroenteropancreatic neuroendocrine tumors receiving peptide receptor radionuclide therapy with Lu-177-DOTATATE.

Patients with neuroendocrine tumors (NET) of the gastroenteropancreatic tract (GEP-NET) were effectively treated with peptide receptor radionuclide therapy (PRRT) with Lu-177-DOTATATE in the NETTER-1 trial. The aim of this study was to assess the outcome of metastatic GEP-NET patients within a European Neuroendocrine Tumor Society (ENETS) certified center of excellence after this treatment. A total of 41 GEP-NET patients who received PRRT with Lu-177-DOTATATE between 2012 and 2017 at a single center were included in this analysis. Data on pre- and post-PRRT treatments [selective internal radiation therapy (SIRT), somatostatin analogue therapy (SSA), blood parameters, patient symptomatic burden and overall survival] was extracted from patient records. Overall, PRRT was well tolerated and did not increase patient symptomatic burden. Blood parameters were not significantly affected by PRRT (means before and after therapy: hemoglobin: 125.4 vs. 122.3 mg/L, P=0.201; creatinine: 73.8 vs. 77.7 µmol/L, P=0.146), while leukocytes (6.6 vs. 5.6 G/L, P<0.01) and platelets (269.9 vs. 216.7 G/L, P<0.001) were significantly decreased yet without clinical significance in our study. Seven of 9 patients with SIRT treatment prior to PRRT were deceased (mortality odds ratio =4.083). The mortality odds ratio of patients with a pancreatic tumor and SIRT was 1.33 compared to patients with a different tumor origin. 6 of 15 patients (40%) with post-PRRT SSA were deceased (mortality odds ratio =0.429 without SSA after PRRT). Patients with advanced GEP-NET might benefit from PRRT with Lu-177-DOTATATE as it can provide a valuable treatment modality in advanced disease stages. Safety profiles of PRRT were manageable without increasing the symptomatic burden. SIRT before PRRT or lack of SSA after PRRT seem to impair the response and reduce survival.

Tumour Heterogeneity and the Consequent Practical Challenges in the Management of Gastroenteropancreatic Neuroendocrine Neoplasms.

Tumour heterogeneity is a common phenomenon in neuroendocrine neoplasms (NENs) and a significant cause of treatment failure and disease progression. Genetic and epigenetic instability, along with proliferation of cancer stem cells and alterations in the tumour microenvironment, manifest as intra-tumoural variability in tumour biology in primary tumours and metastases. This may change over time, especially under selective pressure during treatment. The gastroenteropancreatic (GEP) tract is the most common site for NENs, and their diagnosis and treatment depends on the specific characteristics of the disease, in particular proliferation activity, expression of somatostatin receptors and grading. Somatostatin receptor expression has a major role in the diagnosis and treatment of GEP-NENs, while Ki-67 is also a valuable prognostic marker. Intra- and inter-tumour heterogeneity in GEP-NENS, however, may lead to inaccurate assessment of the disease and affect the reliability of the available diagnostic, prognostic and predictive tests. In this review, we summarise the current available evidence of the impact of tumour heterogeneity on tumour diagnosis and treatment of GEP-NENs. Understanding and accurately measuring tumour heterogeneity could better inform clinical decision making in NENs.

Real-world outcomes in patients with gastroenteropancreatic neuroendocrine tumors receiving somatostatin analogue: Data from a public hospital in Brazil.

650 Background: Neuroendocrine tumors are rare malignant neoplasms derived from endocrine cells and known for their heterogeneous behavior and histopathological characteristics; however, largely associated with a favorable clinical outcome. Somatostatin analogues (SSA) were initially used to control the symptoms of secretory neuroendocrine tumors, and later, they were considered effective as a first-line systemic treatment in unresectable or metastatic neuroendocrine tumors of the gastroenteropancreatic tract (NET-GEP). Randomized clinical trials are performed in controlled environments, with strict inclusion and exclusion criteria, and therefore, real-world studies can add to efficacy and safety data in the general population. Methods: To evaluate, in the real world scenario of a tertiary hospital of the public health system, the efficacy and toxicities of first-line treatment with somatostatin analogue in patients diagnosed with unresectable or metastatic NET-GEP, to find real-world progression free survival (rwPFS) and real-world overall survival (rwOS), in addition to the toxicity profile in our population and possible subgroups that benefit from first-line treatment, through the analysis of variables. Results: 29 patients met the study inclusion criteria, which were diagnosed in the period from 2009 to 2017. The median wrSLP and wrSG were 4.4 (95% CI 3.2 – 5.6) and 8.2 years (CI 95% 6.2 – 10.2), respectively. In an adjusted analysis of rwSLP, the HR for patients with hindgut tumors compared to midgut tumors was 4.41 with p 0.05, indicating that these patients had a 4x increased risk for disease progression (p 0 .05). In the adjusted analysis of wrSG, a trend towards a more favorable evolution was observed in the group of patients with well-differentiated tumors, with p 0.05. Assessment of toxicities revealed grade 2 and grade 3 adverse events in 34.48% of patients. Abdominal pain was the most incident toxicity, occurring in 17.24%, followed by headache (13.79%) and diarrhea (10.34%). Conclusions: Treatment with SSA was effective in our sample, with rwPFS and rwOS data above those found in randomized clinical trials. The toxicities were easily manageable and caused no documented harm to patients.

899P Molecular characterization of gastro-entero-pancreatic advanced mixed adeno-neuroendocrine carcinomas: NIRVANA sub-study

Gastro-entero-pancreatic (GEP) mixed adeno-neuroendocrine carcinomas (MANECs) are rare and aggressive neoplasms with a very poor prognosis and their molecular features are still not properly addressed. Our aim is to evaluate clinical, pathological, and biomolecular data of patients with GEP-MANEC in order to identify prognostic and predictive factors which could potentially correlate with clinical outcomes. This cohort of patients is derived from a larger retrospective - prospective observational dataset of patients with pure or mixed extra-pulmonary (EP) high grade neuroendocrine neoplasms. We reviewed clinical and pathological data of advanced GEP-MANECs managed at our Institute between 2015 and 2021 with available surgical/biopsy specimens. All the tumor tissues were tested for 26 genes by next-generation sequencing (NGS) using a targeted multi-genes NGS panel both in neuroendocrine and non-neuroendocrine component. Descriptive analyses will be performed. Primary and secondary endpoints are descriptive in nature, therefore no formal statistical hypotheses were pre-specified. The study is approved by IEO Ethical Committee. Among 55 high grade neuroendocrine neoplasms, 7 patients with GEP-MANEC resulted eligible. The primary sites were: 2 rectum, 1 appendix, 1 caecum, 1 stomach, 1 gallbladder. Almost all cases showed at least one somatic mutation in > 5% of the tissue. The most frequently mutated genes were KRAS and TP53 (4/7 patients) in both components. Other genes, including PI3K and RB1 were mutated, only in one case and only in the NEC component. All MANECs showed TP53 mutation in NEC and non-NEC component. Five out of seven (71%) received at least one line of chemotherapy, mostly represented by cis/carbo-platinum-based regimens. Among them, 4 patients (80%) received a second-line therapy, mainly irinotecan-containing, and then a 3-line therapy (2 capecitabine/temozolomide). Although low numbers, these preliminary data seem to suggest that the carcinogenesis of the MANECs of the GEP tract relies on its biomolecular features and site of origin. Specific targetable alterations indicate a high potential for personalized treatments. The study is ongoing.

Morphological and immunohistochemical features of neuroendocrine neoplasms in gastroenteropancreatic tract

Background and AimsNeuroendocrine neoplasms (NENs) result from neuroendocrine cell neoplastic proliferation, with both characteristics of endocrine and nerve cells. NENs arise in different localizations but the most common site is the gastrointestinal tract, including the pancreas. The morphology and frequency of NENs in our hospital were evaluated, as well as the correlation between lymph node status and Ki67 proliferative index. Materials and MethodsRetrospectively, we analyzed NEN pathohistological reports of patients who underwent surgical excision of gastroenteropancreatic tumors in the Clinical Center of Vojvodina in Novi Sad, from 2011 to 2018. The descriptive and correlation statistics were done. Chromogranin A, synaptophysin, CD56, and Ki67 were usually used as immunohistochemical markers. ResultsThe study registered 78 surgical specimens. The average age of patients was 58.88 (±17) years, whereby 53.8% were males. The most frequent site was the pancreas (29.5%), followed by the large intestine (26.9%). The mean tumor size was 3.71 (±3.13) cm. No significance was found in tumor differentiation degree (G1 = 32.1%, G2 = 26.9%, and G3 = 29.5%). Lymph node metastases were found in 47.44%. Positive correlation was found between the Ki67 index and the percentage of positive lymph nodes (r = 0.343, p = 0.046, p < 0.05, respectively). The correlation between tumor size and lymph node metastases revealed no significance in our study (r = 0.015, p = 0.480, p > 0.05, respectively). ConclusionMost NENs lymph node metastases originated from tumors with a high Ki67 index. The results confirm the use of proliferative index Ki67 as a prognostic marker for the presence of metastases, disease progression, and neuroendocrine tumor prognosis.

Clinicopathological Features of Neuroendocrine Tumors in Gastroenteropancreatic Tract: A Single Center Study.

Background: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors with varying biological, functional, and clinical characteristics that develop from the gastroenteropancreatic tract's diffuse neuroendocrine system. The objective of this study is to determine the clinicopathological features of GEP-NETs at our facility.Methodology: A cross-sectional analysis of 87 biopsies and resection specimens from January 2020 to January 2022 was performed. The histopathological reports as well as patient's demographic and clinic pathological data were obtained. Two pathologists with a special interest in gastroenteropancreatic pathology blindly reviewed all cases. The tumor grade and stage were determined using the WHO classification (2019) and the AJCC TNM system (8th edition). The data were analyzed with SPSS version 22 (IBM Corp., Armonk, NY, USA).Results: Of the total 87 patients, 49 (56.3%) were male. The age range was 11 to 80 years, with a mean of 45.7±16.4 and the majority (56.3%) were under 50 years. The most frequent symptom was abdominal pain (55.2%). The most common site of GEP-NETs was the appendix (21.8%), followed by the ileum (18.4%), with the majority of tumors being non-functional (96.5%). Furthermore, neuroendocrine tumor (NET) grade 1 accounts for 62% of the total, followed by NET grade 2 (24.1%), neuroendocrine carcinoma (NET) grade 3 (10.3%), and mixed neuroendocrine-non-neuroendocrine neoplasms (MINENs) (3.5%). Synaptophysin was found to be positive in 83.9% cases while Chromogranin A was positive in 39.1%. A pathologic tumor (pT) stage was determined in 47 resection specimens in our study and the most common stage was pT3 (36.1%). Nodal metastasis was found in 25.5% of patients.Conclusions: According to our study, appendix and ileum were the most common GEP-NETs sites. The tumor site and grade were shown to significantly correlate among the clinicopathological features but there was no discernible correlation between the tumor grade and the gender, age, or pathological tumor (pT) stage.

Neuroendocrine tumors: Ten years of experience in a Mexican oncology reference center.

503 Background: Neuroendocrine tumors (NETs) are infrequent neoplasms that originate in the neuroendocrine cells of the embryological endoderm. Few data exist about the epidemiology and clinical characteristics of these tumors in the Mexican population. Methods: We performed a retrospective analysis of patients with pathology-confirmed NET treated at an Oncology Reference Center in North-East Mexico from 2010 to 2019. Clinical characteristics were recorded and an evaluation of overall survival (OS) using the Kaplan-Meier method was performed. Results: Fifty-three patients were included in the final analysis. The mean age at diagnosis was 54 +/- 16.36 years and 53% were men. Primarily affected sites were the gastroenteropancreatic tract [GEP] (47%), lung and mediastinum (21%), unknown primary (21%), and others (11%). Regarding the clinical stage at presentation, 22.6% of patients with NETs had localized disease, while 22.6% had regional spread and 54.7% were considered to have metastatic disease at diagnosis. Median OS was 42 months for all patients with NETs. In the GEP group, the median OS was 64 months, whereas for the lung/ mediastinum group was 8 months and for the unknown primary group was 5 months. Median OS stratified by stage was as follows: Localized disease: Not reached (NR), locoregional (20 months), and metastatic disease (8 months). Conclusions: To our knowledge, this is the first study published in English literature reporting the clinical characteristics and survival of Mexican patients with NETs. It is necessary to expand the information regarding these neoplasms to improve access of these patients to standard treatments and therefore improve their outcomes.

Overview of the Updated Evidence of Multiple Endocrinal Neoplasia (MEN) in Children and Adolescents

MEN syndromes are a collection of autosomal dominant disease including MEN 1 and MEN 2. Multiple endocrine neoplasia (MEN) syndromes are infrequent inherited disorders in which more than one endocrine glands develop noncancerous (benign) or cancerous (malignant) tumors or grow excessively without forming tumors. There are 3 famous and well-known forms of MEN syndromes (MEN 1, MEN 2A, and MEN 2B) and a newly documented one (MEN4). These syndromes are infrequent and occurred in all ages and both men and women. MEN1 is the most often happening form of MENs. The information of MEN’s genetic alterations and the connection among genotype and phenotype could be beneficial for MEN disease management. (MEN1) implicated IN primarily by tumors of the parathyroid glands, endocrine gastroenteropancreatic (GEP) tract and anterior pituitary. Before MEN-1 can be diagnosed it must be suspected, genetic screening for MEN-1 is recommended when an individual has 2 or more MEN-1 related tumors, MEN2 associates with medullary thyroid carcinoma, pheochromocytoma, and primaryhype- rparathyroidism. MEN2A and MEN2B should be suspected in any patient diagnosed with MTC or pheochromocytoma, particularly when the age of presentation is very young (younger than 35), the genetic testing for RET proto-oncogene is employed to diagnose and identify a specific type of mutation present. Treatment is mainly surgical in most cases of multiple endocrine neoplasia syndrome.

1098O Nivolumab plus platinum-doublet chemotherapy as first-line therapy in unresectable, locally advanced or metastatic G3 neuroendocrine Neoplasms (NENs) of the gastroenteropancreatic (GEP) tract or unknown (UK) origin: Preliminary results from the phase II NICE-NEC trial (GETNE T1913)

Grade 3 (G3) NENs encompass a heterogeneous group of tumors with aggressive behaviour and poor survival. Standard front-line platinum-based chemotherapy (CT) has limited efficacy, with an ORR of 31%, a median PFS of 4-5 m and a median OS of 11 m. G3 NENs are associated with a high mutational burden and PD-L1 expression that might lead to a favorable response to immunotherapy (IT). The aim of this study is to assess the safety and potential synergy of the combination of CT plus IT in patients with advanced CT-naïve G3 NENs.

Distinct Pattern of NPY in Gastro-Entero-Pancreatic System of Goat Kids Fed with a New Standardized Red Orange and Lemon Extract (RLE).

Simple SummaryIn the last decades the European ban towards antibiotics resulted in an increase of the number of studies on the effects of natural feed additives, that can enhance the health of farm animals intended for human consumption. Polyphenols such as flavanones and anthocyanins (responsible of the red, purple or blue colors) are bioactive compounds found in fruits and vegetables. Polyphenols possess multiple pharmacological characteristics, like antioxidant, anti-inflammatory and immunostimulant properties. Although many of the biological effects of polyphenols are known, only a limited number of studies has been focused on the effects of their supplementation in ruminant diet. Therefore, we evaluated the effect of a diet supplemented with a standardized powder extract, red (blood) orange and lemon extract (RLE), rich in flavanones, anthocyanins and other polyphenols on the neuropeptide Y (NPY) distribution in the gastro–entero–pancreatic system of goat kids. In mammals, NPY occurs in both the central and peripheral nervous systems and it is involved in the control of different physiological processes, including food intake regulation. For the first time, we document that NPY is widely distributed in the abomasum, duodenum and pancreas of goat kids and that significantly increases in the abomasum and pancreas of RLE supplemented feed animals.The use of natural compounds as feed additive is also increasing in farm animals, thanks to the beneficial effect on both animals and consumers health. Here, we questioned whether natural extracts, such as red orange and lemon extract (RLE) rich in flavanones, anthocyanins, and other polyphenols, used as feed additives could display an effect on the neuropeptide Y (NPY) in the gastro–entero–pancreatic tract of goat kids. NPY is one of the most abundant neuropeptides in mammals, known for its orexigenic role although it is involved in many central and peripheral functions. We carried out immunohistochemical analyses on samples of abomasum, duodenum and pancreas collected from two experimental groups: one fed with standard diet and one with standard diet + RLE. For the first time we document NPY distribution in the abomasum, duodenum and pancreas of goats and observe the highest number of NPY positive cells in neuroendocrine cells of duodenum. Remarkably, upon RLE feed supplementation, NPY immunoreactive cells increased significantly in abomasal epithelium and pancreatic islets but not in duodenum, likely due to pH variation of abomasum and duodenum. Our observations represent a baseline for future studies on the interaction between neuropeptides and polyphenols, used as feed additive.

Surgical Strategy Based on Radiological 3D Reconstruction in a Giant Metastatic Neuroendocrine Tumor of the Pancreas: A Case Report of an Interdisciplinary Approach

Background Neuroendocrine tumors (NETs) are a rare entity and are most commonly found in the gastroenteropancreatic tract. The clinical outcome depends on the potential resectability, grade, and stage. Here, we report a case of a tumor debulking in a metastatic NET of the pancreas. A 25-year-old woman with stable metastatic NET of the pancreas G2 T4N1M1 (hepatic, extrahepatic) already underwent several therapies. Case Presentation. A 25-year-old woman with stable metastatic NET of the pancreas G2 T4N1M1 (hepatic, extrahepatic) already underwent several pharmaceutical therapies. Due to the young age, the G2 characteristic, and the stable liver disease, the decision for debulking was made. Based on a 3D CT scan, an embolization was successfully performed directly prior to a pylorus-preserving pancreatic head resection, advanced interaortocaval lymph node dissection, and an atypical liver resection within segment VI. Histological workup revealed a stage pT3, G2, pN1 (29/34), pM1c (hepatic and extrahepatic), L1, V0, Pn0 with complete surgical resection of the primary tumor (180 mm). The excision of the liver segment V showed a completely resected metastasis. Conclusions In this patient, extensive surgery of a pancreatic NET with the aim of a prolonged progression-free survival was performed. Close cooperation between different disciplines is absolutely mandatory. Modern imaging allowed a precise therapy plan to be worked out.

A Subset of Large Cell Neuroendocrine Carcinomas in the Gastroenteropancreatic Tract May Evolve from Pre-existing Well-Differentiated Neuroendocrine Tumors.

In the gastro-entero-pancreatic (GEP) tract, neuroendocrine neoplasms (NENs) include well differentiated neuroendocrine tumors (NETs) and high-grade NE carcinomas (NECs), which are thought to make up separate and mutually exclusive tumor entities. Little is known, however, as to whether there may be any pathogenetic link between them. Clustering analysis of a 10-gene panel generated from a previously reported next-generation sequencing analysis on 48 GEP-NENs with clinical annotations was used in the study. Unsupervised cluster analysis showed three histology-independent clusters, namely, C1, C2, and C3, which accounted for 44% of patients but the entire array of mutations. All but two NECs fell into the clusters, yet with different prevalence rates (p<0.0001). A model was devised according to which NETs were likely to evolve into NECs upon progression of C3 into C1 and C2, despite different morphology. The median Ki-67 labeling index was 5% in C3 showing better prognosis and 50% in C1 and C2 experiencing worse prognosis, with an impressive intra-tumor heterogeneity of diversely proliferating tumor areas. This study suggests that a subset of large cell NECs in the gastroenteropancreatic tract may evolve from pre-existing well-differentiated NETs.