Gastrointestinal Neuroendocrine Tumors Research Articles

Physician-perceived utility of the EORTC QLQ-GINET21 questionnaire in the treatment of patients with gastrointestinal neuroendocrine tumours: a multicentre, cross-sectional survey (QUALINETS)

Background and objectivePatient-reported outcome measures can provide clinicians with valuable information to improve doctor-patient communication and inform clinical decision-making. The aim of this study was to evaluate the physician-perceived utility of the QLQ-GINET21 in routine clinical practice in patients with gastrointestinal neuroendocrine tumours (GI-NETs). Secondary aims were to explore the patient, clinician, and/or centre-related variables potentially associated with perceived clinical utility.MethodsNon-interventional, cross-sectional, multicentre study conducted at 34 hospitals in Spain and Portugal (NCT02853422). Patients diagnosed with GI-NETs completed two health-related quality of life (HRQoL) questionnaires (QLQ-C30, QLQ-GINET21) during a single routine visit. Physicians completed a 14-item ad hoc survey to rate the clinical utility of QLQ-GINET21 on three dimensions: 1)therapeutic and clinical decision-making, 2)doctor-patient communication, 3)questionnaire characteristics.ResultsA total of 199 patients at 34 centres were enrolled by 36 participating clinicians. The highest rated dimension on the QLQ-GINET21 was questionnaire characteristics (86.9% of responses indicating “high utility”), followed by doctor-patient communication (74.4%), and therapeutic and clinical decision-making (65.8%). One physician-related variable (GI-NET patient volume > 30 patients/year) was associated with high clinical utility and two variables (older age/less experience treating GI-NETs) with low clinical utility.ConclusionsClinician-perceived clinical utility of QLQ-GINET21 is high. Clinicians valued the instruments’ capacity to provide a better understanding of patient perspectives and to identify the factors that had the largest influence on patient HRQoL.

Small-bowel obstruction due to a gastrointestinal neuroendocrine tumor – A case report.

Background: Gastrointestinal neuroendocrine tumors (GI-NETs) originate in the cells of the diffuse neuroendocrine system and are the most common neoplasm of the small bowel. GI-NETs are mostly located in the terminal ileum, and are often associated with liver metastasis. They generally follow a more benign clinical course than other gastrointestinal malignancies. GI-NETs are often asymptomatic, with nonspecific abdominal pain being the most frequent symptom. The diagnosis is usually made incidentally or occurs in advanced stages due to mechanical complications such as small-bowel obstruction or as a result of hormone or amines secretion.

Temozolomide and capecitabine (CAPTEM) is effective in metastatic well-differentiated gastrointestinal neuroendocrine tumors.

366 Background: The study aimed to evaluate patients' outcomes and prognosis with metastatic gastrointestinal neuroendocrine tumors (mgNET) who treated temozolomide and capecitabine (CAPTEM). Methods: The data of forty-three patients were retrospectively evaluated. Clinicopathological features and treatment approaches were recorded. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). Prognostic factors were assessed with Cox-regression analysis. Results: Median age was 59 (27-85) years. The number of male and female patients was 23 (%53.5) and 20 (%46.5), respectively. Pancreas (%51.2) was the most common site of the tumor. The number of patients with well- and poorly-differentiated mgNET was 38 (%88.4) and 5 (%11.6), respectively. The most common metastatic sites were liver (%62.8), lymph node (%58.1), and bone (%18.6). Eleven (%25.6) of the patients previously had undergone surgery, and some patients received radiotherapy (%9.5), chemotherapy (%19), and nuclear therapy (%9.3). Also, patients received octreotide (%86) or lanreotide (%14) with CAPTEM. In patients with well-differentiated mgNET, median PFS was 17.4 months, and disease control ratio %79.4 (%3-complete response, %38.2-partial response, and %38.2-stable response). No response observed in patients with poorly differianted mgNET, and the median PFS was calculated as 4.5 months. Grade 1-2 toxicity was observed in 34 (%79.1) of the patients, and grade 3-4 toxicity in 8 (%18.6). Four (%9.5) patients discontinued therapy for the toxicity. The most common toxicities were anemia (%37.2), thrombocytopenia (%25.6), and fatigue (%16.3). At a median follow-up of 33.8 (2.9-172.73) months, the ratio of five-years OS was %61. In multivariate analysis; gender (p=0.008), age (p=0.007), and Ki-67 levels (p=0.011) were a statistically significant for OS. However, the site of the tumor (p=0.186), number of metastatic sites (p=0.255), and type of somatostatin receptor ligand (p=0.903) were not. Conclusions: In the study, we showed that CAPTEM + somatostatin receptor ligands (octreotide or lanreotide) were effective and well-tolerated in patients with well-differentiated mgNET. But, it was not effective in patients with poorly-differentiated mgNET. Male gender, aged over 60 years, and tumor with a high level of Ki-67 were negative prognostic factors.

Incidence and patterns of secondary malignancies in patients with neuroendocrine neoplasms: A SEER database analysis.

374 Background: Neuroendocrine tumors (NETs) are comprised of a group of biologically and clinically heterogenous malignancies arising from a variety of anatomic sites, the majority of which lie within the gastrointestinal tract. Prior literature has reported on the association between NETs and other primary malignancies (OPM), most of which also end up being within the gastrointestinal tract, but these studies are limited by small sample sizes. We aim to further analyze the association of NETs and OPM on a larger scale using a population-based cancer registry. Methods: Malignant primary cancer with NET features were identified from the Surveillance Epidemiology and Ends Results (SEER) registry between 1975 and 2017. The histology/behavior of NET included carcinoid tumor, neuroendocrine carcinoma, pancreatic endocrine tumor, atypical carcinoid tumor, and other including insulinoma, glucagonoma, gastrinoma, VIPoma, somatostatinoma and enterochromaffin cell carcinoid. First NET observation from each patient was examined. Patients with NET were grouped into three categories: only one primary cancer with NET, first primary cancer with NET and first primary cancer without NET based on sequence number of primary cancer recorded in SEER. Distribution of NET between gastrointestinal (GI) and non-GI sites was described. Demographics were compared by NET sequence group and between GI and non-GI sites. Results: 45,896 patients with NET were analyzed (77.9% Caucasian, 47.0% male, median age 62.0 years). More than half (65.7%) of the NETs were observed in GI sites. Within the GI tract, 31.3% were in the small intestine, 25.1% in the rectum, 16.6% in pancreatobiliary, and < 11% in other GI locations. Age at NET diagnosis was younger in those with GI NETs (median 60.0 vs 65.0, p < 0.001 ). 71.2% of NET found in only cancer diagnosis, 10.4% of NET in first followed by a second primary malignancy, and 18.4% in a non-NET primary followed by NET. Mean age was 58.9 for NET primary only, 61.0 for NET primary first and 68.3 for non-NET primary first (p < 0.0001). More Caucasian patients had non-NET primary first (82.3%) compared to NET primary only (76.9%) and NET primary first (75.5%). No gender differences were observed amongst the three groups. Carcinoid tumor histology was more prevalent in NET primary first (78.6%) compared to NET primary only (67.3%) and non-NET primary first (66.6%), while neuroendocrine carcinoma histology was more prevalent in NET only (27.4%) and non-NET first (29.3%) compared to NET first. Conclusions: 28.8% of patients with NETs were found to have OPM, either preceding or following their NET diagnosis. It is imperative that patients with NET undergo age-appropriate cancer screening to help identify any concurrent malignancies. Further research is warranted to identify the location of such additional malignancies and the timeframe in which they occur in relation to the NET.

Ampullary neuroendocrine tumors: A window into a rare tumor using a national database.

373 Background: Ampullary neuroendocrine tumors (NET) make up < 1% of all gastrointestinal NETs. Information about their behavior and prognosis is reliant on small case series. This study set out to describe the population of patients who are diagnosed with ampullary NETs and compare them to patients with duodenal and pancreatic head NETs. Methods: The National Cancer Database (2004 – 2016) was queried for patients with ampullary, duodenal, and pancreatic head NETs. Clinicopathologic and treatment characteristics were compared. Subset analysis was performed on patients who underwent surgery. Kaplan Meier (KM) analysis and Cox regression were used to analyze the survival of patients with ampullary NETs. Results: Overall, 872 patients were identified with ampullary NET, 9692 with duodenal NET, and 6562 with pancreatic head NET. Patients with ampullary NET had an average age of 60.9 +/- 14.5 years, were evenly split among men and women (N = 437, 50.1% vs N = 435, 49.9%, respectively), and primarily Caucasian (N = 663, 76.0%). 72.1% underwent local tumor destruction or surgery (N = 629). Most did not receive radiation (N = 832, 95.4%), chemotherapy (N = 627, 71.9%), or hormone therapy (N = 788, 90.4%). Patients with ampullary NETs had more poorly differentiated tumors (N = 119, 13.6%) than patients with duodenal (N = 159, 1.6%) or pancreatic head (N = 602, 9.2%) NETs. Patients with ampullary NETs had more positive lymph nodes (N = 288, 33%) than patients with duodenal (N = 915, 9.4%) or pancreatic head (N = 1381, 21%) NETs. At five years, the overall survival for patients with ampullary, duodenal, and pancreatic head NETs was 57%, 68%, and 46%, respectively. Within the surgical population, five-year survival for patients with ampullary (N = 367), duodenal (N = 991), and pancreatic head (N = 1961) NETs was 60%, 74%, and 72%, respectively. When compared, there was a statistically significant difference between the mean overall survival of patients with ampullary (98 +/- 4.7 months), duodenal (112 +/- 2.5 months), and pancreatic head (108 +/- 1.7 months) NETs (p < 0.001). In the cox regression analysis, sex, Charlson-Deyo score, lymph node positivity, lymph-vascular invasion, mitotic rate, chromogranin A level, 5-HIAA level, and tumor size did not correlate with survival. Increasing age (HR 1.04, CI 1.01 – 1.07, p = 0.008) and worse tumor differentiation (poorly differentiated HR 3.33, CI 1.38 – 8.04, p = 0.008 and undifferentiated HR 8.31, CI 2.77 – 24.92, p < 0.001 compared to well differentiated) were associated with increased mortality. Conclusions: This study sheds light on a rare tumor histology. When compared to patients who underwent surgical resection for duodenal or pancreatic head NETs, patients with ampullary NETs had a significantly worse prognosis. Identifying prognostic factors allows us to create more concrete treatment recommendations and provide patients with improved prognostic information.

Clinicopathological Features of Primary Neuroendocrine Tumors of Gastrointestinal/Pancreatobiliary Tract With Emphasis on High-Grade (Grade 3) Well-Differentiated Neuroendocrine Tumors.

IntroductionThe two broad subcategories of neuroendocrine neoplasms (NENs) are well-differentiated neuroendocrine tumors (WDNETs) and poorly differentiated neuroendocrine carcinomas (PDNECs), based on tumor architecture and cytology. Grade 3 WDNETs are a subset of WDNETs that not only are high grade by mitotic activity or proliferative index but exhibit a well-differentiated histology. In this study, we evaluated the clinicopathological features of primary neuroendocrine tumors of the gastrointestinal (GI)/pancreatobiliary tract with emphasis on high-grade WDNETs, as it is a newly defined entity.MethodsWe conducted a retrospective observational study, including a total number of 122 cases of primary GI and pancreatobiliary tract NENs. Slides and blocks of all cases were retrieved from the departmental archives. Immunohistochemical stains including Ki67 were applied to selected tissue blocks of all cases. Tumors were then evaluated for their histological differentiation and tumor grade.ResultsOur results showed that the mean age of patients was 46.8 ± 17.1 years. Majority of the NENs were GI tract origin (86.9%). The most common site of tumor in gastroenteropancreatic tract was the small bowel (31.1%), followed by the stomach (26.2%). Ninety five percent of the tumors were WDNETs, of which the most common grade was G2. The mean Ki67 index was 15.8 ± 23.8. Grade 3 WDNETs were noted to have an older mean age than grades 1 and 2 WDNETs. Ten out of 102 (9.8%) WDNETs of GI tract were grade 3, compared with four out of 14 (28.6%) of pancreatobiliary tract. ConclusionIn this study, we found that high-grade (grade 3) WDNETs were more frequent in pancreatobiliary tract than GI tract. Moreover, high-grade WDNETs were associated with a higher mean age than low-grade (grade 1-2) WDNETs. It is extremely important to recognize this subset (high grade) of WDNETs and to distinguish it from PDNECs, as the latter are known to be associated with a worse overall survival. Despite high mitotic rate/proliferative index, high-grade WDNETs are characterized by organoid architecture and monomorphic cell population.

A Comparison of Liver-Directed Therapy and Systemic Therapy for the Treatment of Liver Metastases in Patients with Gastrointestinal Neuroendocrine Tumors: Analysis of the California Cancer Registry

PurposeTo compare the outcomes of patients with gastrointestinal neuroendocrine tumor liver metastases treated with liver-directed therapy (LDT) to those treated with systemic therapy (ST) in a statewide cancer database. Materials and MethodsA retrospective study was performed of patients with metastatic gastrointestinal tract neuroendocrine tumors treated with either LDT or ST alone between the years 2000–2012 in the California Cancer Registry. Overall survival and disease-specific survival were assessed using multivariable Cox proportional hazards analysis and propensity score matching. ResultsA total of 154 patients (ST, n = 87 and LDT, n = 67) were studied. The median overall survival and disease-specific survival for patients that received ST was 29 and 35 months versus 51 and >60 months for patients that received LDT. On multivariate analysis, LDT and the resection of the primary tumor were associated with improved survival (hazard ratio [HR] 0.52, P = .002; HR 0.43, P = .001). Non-white race, Medicaid/uninsured status, and the presence of lung metastases were associated with poor survival (HR 1.76, P = .014; HR 2.29, P = .009; and HR 1.79, P = .031). Propensity score matching demonstrated an improvement in disease-specific survival for LDT compared to ST (HR 0.53, P = .036). The improvement in overall survival on propensity score matching did not achieve statistical significance (HR 0.70, P = .199). ConclusionsLDT is associated with improved overall and disease-specific survival as compared to ST in patients with gastrointestinal neuroendocrine tumor liver metastases. Further investigation is needed to determine whether combination or sequential treatment can improve outcomes in this population.

Resection of Primary Gastrointestinal Neuroendocrine Tumor Among Patients with Non-Resected Metastases Is Associated with Improved Survival: A SEER-Medicare Analysis

BackgroundThe objective of this study was to analyze whether primary tumor resection (PTR) among patients with stage IV gastrointestinal neuroendocrine tumor (GI-NET) and unresected metastases was associated with improved outcomes. MethodsPatients diagnosed with stage IV GI-NETs were identified in the linked SEER-Medicare database from 2004 to 2015. Overall survival (OS) of patients who did versus did not undergo PTR was examined using bivariate and multivariable cox regression analysis as well as propensity score matching (PSM). ResultsAmong 2219 patients with metastatic GI-NETs, 632 (28.5%) underwent PTR, whereas 1587 (71.5%) did not. The majority of individuals had a NET in the pancreas (n = 969, 43.6%); the most common site of metastatic disease was the liver (n = 1064, 47.9%). Patients with stage IV small intestinal NETs most frequently underwent PTR (62.6%) followed by individuals with colon NETs (56.5%). After adjusting for all competing factors, PTR remained independently associated with improved OS (HR = 0.65, 95% CI: 0.56–0.76). Following PSM (n = 236 per group), patients who underwent PTR had improved OS (median OS: 1.3 years vs 0.8 years, p = 0.016). While PTR of NETs originating from stomach, small intestine, colon, and pancreas was associated with improved OS, PTR of rectal NET did not yield a survival benefit. ConclusionPrimary GI-NET resection was associated with a survival benefit among individuals presenting with metastatic GI-NET with unresected metastases. Resection of primary GI-NET among patients with stage IV disease and unresected metastases should only be performed in selected cases following multi-disciplinary evaluation.

Lutetium oxodotreotide (177Lu-Dotatate) for the treatment of unresectable or metastatic progressive gastroenteropancreatic neuroendocrine tumors: a cost-effectiveness analysis for Scotland

BackgroundGastroenteropancreatic neuroendocrine tumors (GEP-NETs) represent a heterogenous group of tumors. Findings from the phase III NETTER-1 trial showed that treatment of unresectable/metastatic progressive gastrointestinal (GI) NETs with 177Lu-Dotatate resulted in a significant improvement in progression-free survival (PFS) and overall survival (OS) compared with best supportive care (BSC) with high dose octreotide long-acting repeatable (LAR) 60 mg. A health economic analysis was performed using input data from clinical studies and data derived from an indirect comparison to determine the cost-effectiveness of 177Lu-Dotatate in the treatment of GI-NETs and pancreatic NETs (P-NETs) in Scotland.MethodsCost-effectiveness analysis was performed from the payer perspective using a three-state partitioned survival model. In the base case 177Lu-Dotatate was compared with BSC in gastrointestinal (GI)-NETs using clinical data from the NETTER-1 trial. A secondary analysis comparing 177Lu-Dotatate with BSC, everolimus or sunitinib in patients with P-NETs was also performed using hazard ratios inferred from indirect comparisons. The base case analysis was performed over a 20-year time horizon with an annual discount rate of 3.5% for both costs and clinical outcomes.ResultsFor unresectable/metastatic progressive GI-NETs treatment with 177Lu-Dotatate led to a gain in quality-adjusted life expectancy of 1.33 quality-adjusted life years (QALYs) compared with BSC due to extended PFS and OS. Mean total lifetime costs were GBP 35,701 higher with 177Lu-Dotatate, leading to an incremental cost-effectiveness ratio (ICER) of GBP 26,830 per QALY gained.In analyses in patients with P-NETs 177Lu-Dotatate was associated with ICERs below GBP 30,000 per QALY gained in comparisons with BSC, sunitinib and everolimus.ConclusionsCost-effectiveness analyses demonstrated that, in Scotland, from the payer perspective, 177Lu-Dotatate at the set acquisition cost is a cost-effective treatment option for patients with unresectable or metastatic progressive GI-NETs or P-NETs.

Endocrine and neuroendocrine tumors

Endokrine Tumoren und hier im Speziellen neuroendokrine Neoplasien des Gastrointestinaltraktes (GEP-NETs), Phäochromozytome (PCs), Paragangliome (PGL) und Schilddrüsentumoren sind Paradebeispiele für die Bedeutung von Molekularpathologie und Molekularbiologie für Diagnostik, Klassifikation und letztendlich auch die (chirurgische) Therapie dieser Erkrankungen. Bei GEP-NETs erfolgt das Grading anhand des Ki-67-Index. Dieser bestimmt die Art der molekularen Bildgebung (DOTA [1,4,7,10-Tetraazacyclododecan‑1,4,7,10-tetraessigsäure]/DOPA [3,4-Dihydroxyphenylalanin]/FDG[Fluordesoxyglukose]-PET[Positronenemissionstomographie]/CT [Computertomographie]), die mögliche Therapie (chirurgisch und/oder Radiopeptidtherapie), antiproliferative und symptomkontrollierende Therapie mit Somatostatinanaloga und letztendlich auch die Prognose. PC/PGL können hereditär auftreten (MEN2A [multiple endokrine Neoplasie Typ 2A], VHL [Von-Hippel-Lindau-Tumorsuppressor], NF1 [Neurofibromatose Typ 1], SDH[Succinat-Dehydrogenase]-Mutationen), was die chirurgische Therapie und die präoperative Medikation maßgeblich beeinflusst. Die molekulare Bildgebung hat einen hohen Stellenwert und kann bei grenzwertiger Biochemie wegweisend sein. Auch Nebennierenrindenkarzinome können genetisch determiniert sein. Bei Schilddrüsentumoren ist v. a. die Pathologie der C‑Zelle (C-Zell-Hyperplasie, medulläres Schilddrüsenkarzinom) hervorzuheben. Bei hereditärer Erkrankung (FMTC [familiäres medulläres Schilddrüsenkarzinom], MEN[multiple endokrine Neoplasie]2) ist häufig eine frühe prophylaktische Operation notwendig und verhindert das Auftreten von fortgeschrittenen Karzinomen. Aber auch die Bestimmung des Resektionsausmaßes bei follikulären Läsionen bzw. die Unterscheidung zwischen „non-invasive follicular thyroid neoplasm with papillary-like nuclear features“ (NIFTPs) und follikulären Varianten des papillären Schilddrüsenkarzinoms kann mithilfe spezifischer Marker erfolgen. Insgesamt hat die Molekularpathologie eine zunehmende Bedeutung bei diesen Entitäten und ist auch Inhalt laufender Forschungsprojekte.

Resection of the primary gastrointestinal neuroendocrine tumor among patients with metastatic neuroendocrine tumors improves overall survival

Introduction: Among patients with metastatic gastrointestinal (GI) neuroendocrine tumor (NET), the role of primary tumor resection remains unknown. We sought to analyze if primary tumor resection of NET was associated improved overall survival (OS).

Neuroendocrine neoplasms of the digestive tract : incorporating the 2019 WHO grading schema in the South African context

Background The classification of gastrointestinal (GI) neuroendocrine neoplasms (NENs) has been updated in the WHO classification of tumours of the digestive tract. Mitotic rate and Ki-67 proliferation index are central to the histopathological grading of these tumours. Assessing these variables is not standardised in local practice. This study addresses this deficit in the South African context. Methods This is a retrospective audit of archival material of resection specimens of GI NENs (excluding appendix) at Groote Schuur Hospital from 2004 to 2017. We performed a mitotic count and immunohistochemistry for Ki-67 to reclassify tumours according to the 2019 WHO criteria. Results Thirty-five resection specimens were examined. These represented stomach (n = 5), jejunoileum (n = 17), colon (n = 7) and rectum (n = 6). The mean age at the time of resection was 56 years (range 32-72). Twenty-one cases (60%) were women and 14 (40%) were men. The majority (24/35) of tumours were classified as grade 1 well-differentiated neuroendocrine tumours (WD NETs), 8/35 were classified as grade 2 WD NETs and 3/35 were classified as small cell poorly differentiated neuroendocrine carcinomas (PD NECs). Re-classification resulted in 7/35 (20%) changes in tumour grade (4 upgraded, 3 downgraded). In most instances (7/8), the Ki-67 proliferation index was the determining factor in assigning tumour grade. Conclusion This study has increased awareness of the recently updated WHO classification system. We conclude that an objective and systematic approach to counting of mitoses and determination of the Ki-67 proliferation index is recommended in routine practice.

Carcinoid Syndrome in a Patient with Duodenal Carcinoid Tumor

Duodenal carcinoid tumors accounts for 5% of all Gastrointestinal Neuroendocrine Tumors (GI-NETs). Only 4% of all duodenal carcinoid tumors present with a full-blown carcinoid syndrome. We report a case of duodenal carcinoid tumor presenting as carcinoid syndrome in a 58 year old man, who presented with upper abdominal discomfort, diarrhoea, hot flushes and occasional wheezing. Histopathology following endoscopic resection of the tumor and 24 hour urinary 5-Hydroxyindolacetic acid (5-HIAA) confirmed the diagnosis. Duodenal carcinoid tumors are one of the rarest tumors of gastrointestinal tract and their association with a typical carcinoid syndrome is not that common. A high level of suspicion is required for an early diagnosis. With proper resection (endoscopic or surgical) of a localized tumor, recurrence and progression of the disease can be halted. Symptoms of carcinoid syndrome should be controlled by antidiarrheal agents, inhaled β-adrenergic agonist bronchodilators and somatostatin analogs (octreotide, lanreotide). Patients should be advised to avoid stress and conditions or substances that precipitate these symptoms. Dietary supplementation with nicotinamide can help in this regard. Patients with hepatic metastases are treated with synthetic analogues of somatostatin (octreotide, lanreotide). Systemic chemotherapy is not recommended in metastatic disease by the current guidelines. Patients should be followed up by monitoring serum chromogranin and urinary 5-HIAA. EUS, CT, MRI & somatostatin receptor scintigraphy can also be used for following up the patients.

B7 immune-checkpoints as targets for the treatment of neuroendocrine tumors.

The B7 family, and their receptors, the CD28 family, are major immune checkpoints that regulate T-cell activation and function. In the present study, we explore the role of two B7 immune-checkpoints: HERV-H LTR-Associating Protein 2 (HHLA2) and B7 Family Member, H4 (B7x), in the progression of gastrointestinal and pancreatic neuroendocrine tumors (GINETs and PNETs). We demonstrated that both HHLA2 and B7x were expressed to a high degree in human GINETs and PNETs. We determined that the expression of B7x and HHLA2 correlates with higher grade and higher incidence of nodal and distant spread. Furthermore, we confirmed that HIF-1α overexpression is associated with the upregulation of B7x both in our in vivo (animal model) and in vitro (cell culture) models. When grown in vitro, islet tumor β-cells lack B7x expression, unless cultured under hypoxic conditions, which results in both hypoxia-inducible factor 1 subunit alpha (HIF-1α) and B7x upregulation. In vivo, we demonstrated that Men1/B7x double knockout (KO) mice (with loss of B7x expression) exhibited decreased islet β-cell proliferation and tumor transformation accompanied by increased T-cell infiltration compared with Men1 single knockout mice. We have also shown that systemic administration of a B7x mAb to our Men1 KO mice with PNETs promotes an antitumor response mediated by increased T-cell infiltration. These findings suggest that B7x may be a critical mediator of tumor immunity in the tumor microenvironment of NETs. Therefore, targeting B7x offers an attractive strategy for the immunotherapy of patients suffering from NETs.

Treatment of ampullary neuroendocrine tumor by Capecitabine (Xeloda®) and Temozolomide (Temodal®).

Neuroendocrine tumors of the gastrointestinal tract and pancreas include a range of rare and diverse neoplasms with unique tumor biology, natural history, and clinical management. Neuroendocrine tumors of the ampulla of Vater are extremely uncommon cancers that account for only about 0.3%-1% of all gastrointestinal neuroendocrine tumors. Approximately 139 cases have been reported to date. In this paper, we describe two patients with low to intermediate grades of ampullary neuroendocrine tumors that underwent multiple courses of chemotherapy with Capecitabine (Xeloda®) and Temozolomide (Temodal®). Our two patients had a dramatic response to this regimen.According to our study, it seems that ampullary neuroendocrine tumors have behavior like pancreatic neuroendocrine tumors which requires further studies in more patients.

Incidence of HIV Cases and Associated Factors in The Northeast Region of Brazil

A 51-year-old female was admitted to the gastroenterology clinic in October 2020 because of a 2-year history of epigastric pain unrelated to food intake. No diarrhea was noted. Her documented medical history was notable for well-controlled hypertension. Her physical examination and Helicobacter pylori antigen detection showed no remarkable abnormalities. A computed tomography scan of the abdomen revealed a 0.5 x 0.5 cm well-defined hyperattenuating structure in the wall of the descending duodenum, which was confirmed by esophagogastroduodenoscopy demonstrating a 0.5 cm nodule in the descending duodenum (Fig. A). The lesion was located within the deep mucosa and submucosa without invasion of adjacent structures detected by endoscopic ultrasound (Fig. B). Endoscopic submucosal dissection was performed to remove the nodule despite the high risk for postoperative complications. Microscopic examination of the specimen by hematoxylin and eosin staining (Fig. C) and the lesion staining strongly immunoreactive for synaptophysin (Fig. D) and chromogranin (Fig. E) by immunohistochemistry were consistent with a well-differentiated grade 2 neuroendocrine neoplasm, which was further defined by a low proliferation index Ki67 around 3% in neoplastic cells (Fig. F). No etiology for patient’s epigastric pain was discovered on esophagogastroduodenoscopic examination. Duodenal neuroendocrine tumors consist of 2% of all gastrointestinal neuroendocrine tumors and 1% of all duodenal tumors, which are very rare (Baliss et al., 2021). The rarity of duodenal neuroendocrine tumors coupled with the absence of neuroendocrine clinical syndromes creates a noteworthy diagnostic challenge (Delle et al., 2016). Patients with nonfunctional and nonmetastatic duodenal neuroendocrine tumors should be considered for resection regardless of tumor size (Sato et al., 2016).

Tratamiento laparoscópico de tres pacientes con tumores neuroendócrinos gástricos.

Los tumores neuroendócrinos gástricos constituyen el 6,9% de todos los tumores neuroendócrinos del tubo digestivo, y el 1% de todas las neoplasias gástricas aproximadamente. Comprenden un amplio grupo de tumores que pueden ser secretantes o no, y con muy distinto comportamiento biológico. Si bien la mayoría de ellos son benignos, un pequeño porcentaje tiene un comportamiento agresivo, con capacidad metastásica y una pobre sobrevida. Dado su curso relativamente indolente, en ocasiones el diagnóstico resulta de un hallazgo fortuito, o menos comúnmente cuando surge alguna complicación (hemorragia u obstrucción). Para el diagnóstico es imprescindible la endoscopía alta con el análisis inmunohistoquímico de la biopsia. La tomografía es de elección para la estadificación. La diseminación ganglionar es infrecuente, y no está indicado un vaciamiento linfático a no ser en casos de tumores indiferenciados o con adenopatías visibles en el intraoperatorio, por lo que el abordaje laparoscópico resulta especialmente atractivo. El objetivo de esta comunicación es presentar tres casos de tumores neuroendócrinos de localización gástrica de resolución laparoscópica en nuestro servicio.

O6-methylguanine DNA methyltransferase and glucose transporter 2 in foregut and hindgut gastrointestinal neuroendocrine neoplasms

BackgroundStreptozocin (STZ) is used for treating both pancreatic (PanNET) and gastrointestinal (GI-NET) neuroendocrine tumors but its therapeutic efficacy is relatively low in GI-NETs. Therefore, it has become pivotal to select GI-NET patients who could benefit from STZ treatment. STZ is transported via the glucose transporter 2 (GLUT2) into the cells and the loss of O6-methylguanine DNA methyltransferase (MGMT) also increases its therapeutic efficacy. Therefore, GLUT2 high and MGMT low status could be the surrogate markers of STZ.MethodsIn this study, we examined the MGMT and GLUT2 status in gastrointestinal neuroendocrine neoplasm (NEN). We studied 84 NEN cases: 33 foregut and 37 hindgut GI-NETs and 14 gastrointestinal neuroendocrine carcinomas (GI-NECs).ResultsIn GI-NETs, MGMT scores of ≥2 and ≥ 3 were 77% (54/70) and 56% (39/70), respectively, and GLUT2 scores of ≥4 and ≥ 6 were 30% (21/70) and 4.3% (3/70), respectively. Methylation-specific polymerase chain reaction revealed that MGMT promoter methylation was detected only in 2/14 GI-NECs but none of the included GI-NETs. GLUT2 (GLUT2 score) and MGMT immunoreactivity (MGMT and H-scores) were both significantly correlated with Ki-67 labeling index (GLUT2 score: P = 0.0045, ρ = − 0.4570; MGMT score: P = 0.0064, ρ = − 0.4399; H-score: P = 0.0110, ρ = − 0.4135) and MGMT immunoreactivity were significantly correlated with GLUT2 immunoreactivity (MGMT score: P = 0.0198; H-score, P = 0.0004, ρ = 0.5483) in hindgut NETs, but not in foregut NETs. However, discrepancies from the above correlation between GLUT2 and MGMT immunoreactivity were detected in several GI-NET cases which could be potential candidates for STZ therapy.ConclusionThe evaluation of MGMT and GLUT2 status could provide an important information in planning STZ therapy in GI-NET patients.

Tuberous Sclerosis Complex with rare associated findings in the gastrointestinal system: a case report and review of the literature

BackgroundTuberous Sclerosis Complex (TSC) is a complex and heterogeneous genetic disease that has well-established clinical diagnostic criteria. These criteria do not include gastrointestinal tumors.Case presentationWe report a 45-year-old patient with a clinical and molecular diagnosis of TSC and a family history of cancer, presenting two rare associated findings: gastrointestinal polyposis and pancreatic neuroendocrine tumor. This patient was subjected to a genetic test with 80 cancer predisposing genes. The genetic panel revealed the presence of a large pathogenic deletion in the TSC2 gene, covering exons 2 to 16 and including the initiation codon. No changes were identified in the colorectal cancer and colorectal polyposis genes.Discussion and conclusionsWe describe a case of TSC that presented tumors of the gastro intestinal tract that are commonly unrelated to the disease. The patient described here emphasizes the importance of considering polyposis of the gastrointestinal tract and low grade neuroendocrine tumor as part of the TSC syndromic phenotype.

Robotic limited local resection of duodenal juxta-ampullary neoplasms.

The unique and complex anatomical location of duodenal juxta-ampullary neoplasms complicates selection of the appropriate surgical strategy. For benign or borderline tumours, surgical local resection can be an appropriate treatment option, and robotic surgical systems can help perform minimally invasive local resection of these lesions. Between December 2014 and December 2019, 10 patients who underwent robotic local resections for duodenal juxta-ampullary tumours were reviewed. All patients successfully underwent robotic local resection of the duodenum, preserving the ampulla of Vater without conversion. The mean tumour size was 2.2 cm. Final pathology consisted of gastrointestinal stromal tumour, neuroendocrine tumour, low grade and high grade dysplasia, ectopic pancreas, and well-differentiated adenocarcinoma (T1a). There were no postoperative complications or recurrences. With accurate preoperative diagnosis and careful selection of patients, local resection of the duodenum for juxta-ampullary benign or borderline tumours using robotic surgical system is an attractive treatment option.