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Background Because of the rarity and variety of pancreatic neuroendocrine tumors (PNETs), there have been few reports regarding the indication for lymph node dissection in patients with these tumors. This study aimed to evaluate the risk of lymph node metastasis of PNETs based on the tumor size and hormonal production. Methods Data for a total of 66 patients who had PNETs resected at our department between 1987 and 2010 were retrospectively studied. The clinicopathological features, including the disease-specific survival rate, were assessed based on the status of lymph node metastasis at the time of initial surgical resection. Then the cut-off point of tumor size to predict lymph node metastasis was estimated. Results There were 12 patients (18%) with lymph node metastasis. The frequency of lymph node metastasis tended to be higher in gastrinomas than that in other tumors (43 vs. 15%; P  = 0.08). The size of PNETs with lymph node metastasis was significantly larger than that of the PNETs without metastasis ( P  = 0.04). The postoperative survival rate in the PNET patients with lymph node metastasis was significantly lower than that in the patients without metastasis ( P  < 0.0001). Only 2 (8%) of 26 PNETs with a tumor size of <15 mm had lymph node metastasis, and both of these were gastrinomas. On the other hand, 10 (25%) of the remaining 40 PNETs with a tumor size of ≥15 mm had lymph node metastasis. Notably, there were no PNETs with lymph node metastasis in 22 non-gastrinomas with a tumor size of <15 mm. Conclusions Non-gastrinomas with a tumor size of ≥15 mm and all gastrinomas would be an indication for pancreatectomy with lymph node dissection.

Background The multiple endocrine neoplasia type 1 syndrome (MEN1) natural history is poorly evaluated, and few single-institution experiences about hereditary gastroenteropancreatic neuroendocrine tumors (GEP-NET) are reported. Our purpose is to analyze the role of GEP-NET in MEN1-related death, as well as the behavior of these lesions during follow-up. Methods The study population consists of 77 patients diagnosed with MEN1 GEP-NET, regularly followed up since 1990. Extensive clinical data were prospectively recorded. Statistical analysis was performed both on the whole population of 77 patients and on two subgroups including patients who, during the long lasting study period, underwent GEP-NET surgery (50 pts) and who did not (27 pts), respectively. Results Twenty-five males (32.5%) and 52 females (67.5%) were enrolled. Sixty-four patients had MEN1 family history (83.1%), and genetic mutation was detected in 67 cases (87%). The mean age at GEP-NET diagnosis was 41.4 years (SD = 13.6); 16 patients (20.8%) had GEP-NET diagnosed before age 30 and 12 cases (15.6%) before 1996. The mean interval time between MEN1 diagnosis and GEP-NET detection was 5.7 years (range −11/37; SD = 8.1 years). Overall, the mean follow-up time from MEN1 diagnosis was 15.8 years (SD = 9.7 years) and from GEP-NET diagnosis was 9.6 years (SD = 6.9 years). Gastrinoma was the most frequent functioning GEP-NET and pancreatoduodenectomy the most adopted surgery. GEP-NET progression affected 12 patients within the non-surgical group, while 18 subjects developed progression after surgery. Conclusions Our single-center data provide information on epidemiologic, clinical and pathological features of GEP-NET in MEN1 making possible to clarify their natural history.

Gastrinoma, distinguished by Zollinger-Ellison Syndrome, is a highly unusual neoplasm. However, understanding of its clinicopathological characteristics and survival at the population level is inadequate. This study aimed to examine the clinicopathological features and survival of gastrinoma patients utilizing the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with gastrinoma from 2000 to 2020 were included in the study. Multiple imputation was used to handle missing data. Chi-square test was employed to analyze the clinicopathological features. The Kaplan-Meier method and Cox proportional hazards models were utilized to evaluate overall survival (OS) and cancer-specific survival (CSS). A total of 160 patients participated in the study. The incidence rate rose with age, peaking at 60-69 years. Notably, the most common site was the pancreas (52.5%), followed by the duodenum (32.5%) and stomach (10.6%). Most gastrinomas were well-differentiated (77.5%). Liver was a frequent metastasis site, with age and tumor size identified as risk factors by multivariate analysis. The 1-, 3-, 5-, and 10-year OS rates were 92.4%, 84.3%, 77.6%, and 62.9%, respectively, with corresponding CSS rates of 94.8%, 89.2%, 86.0%, and 75.2%. Additionally, duodenal gastrinomas showed better differentiation, earlier staging, smaller size, and fewer metastases than pancreatic ones (P < 0.05). Pancreatic gastrinomas had poorer OS (hazard ratio [HR] 2.38, 95% confidence interval [CI] 1.30-4.35, P = 0.005) and CSS (HR 10.70, 95% CI 2.55-44.90, P = 0.001) compared to duodenal ones. Multivariate Cox analysis highlighted N stage, surgery, chemotherapy, and tumor size as risk factors for both OS and CSS. Gastrinomas located in the duodenum and pancreas exhibit distinct clinicopathological characteristics. The prognosis for gastrinomas in the duodenum is better than that for gastrinomas in the pancreas.

PurposeIn patients with metastatic functional gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), it is unknown what degree of tumor reduction is required to eliminate hormonal symptoms. We aimed to reduce hormonal symptoms derived from advanced GEP-NENs by efficient minimal intervention, constructing a hormonal tumor map of liver metastases.MethodsBetween 2013 and 2019, we treated 12 insulinoma or gastrinoma patients with liver metastases. Liver segments containing hormone-producing tumors were identified by injecting calcium gluconate via the hepatic arteries and monitoring the change in serum hormone concentration in the three hepatic veins. A greater-than-twofold increase in hormone concentration indicated a tumor-feeding vessel.ResultsCases included eight insulinomas and four gastrinomas. Primary lesions were functional in three patients and nonfunctional in 9. Nine patients showed hormonal step-up indicating the presence of functional lesions; eight showed step-up in tumor-bearing liver segments, while one with synchronous liver metastases showed step-up only in the pancreatic region. Five patients underwent surgery. Serum hormone concentration decreased markedly after removing the culprit lesions in 3; immediate improvement in hormonal symptoms was achieved in all patients. Three patients with previous surgical treatment who showed step-up underwent transcatheter arterial embolization, achieving temporary improvement of hormonal symptoms. Four patients showed unclear localization of the hormone-producing tumors; treatment options were limited, resulting in poor outcomes.ConclusionHormonal tumor mapping demonstrated heterogeneity in hormone production among primary and metastatic tumors of GEP-NENs. Minimally invasive treatment based on hormonal mapping may be a viable alternative to conventional cytoreduction.

Background Gastrinoma is a rare form of neuroendocrine neoplasm. The presence of a primary lymph node localization of gastrinoma is a much debated and controversial topic in the literature, as regards whether these cases represent metastatic disease from an as yet unidentified primary tumor, or the de novo occurrence of a gastrinoma in a lymph node. Case presentation We report the case of a 24-year-old male with intense epigastric pain treated at the beginning with high dose proton pump inhibitors. Further workup with CT and subsequent laparotomy revealed a single peripancreatic lymph node. Histological examination highlighted a well-differentiated neuroendocrine tumor. Conclusion This case underlines that the primitive lymph node gastrinoma is a distinct nosological entity with a precise location in the context of rare neuroendocrine tumors that should be considered when specific symptoms are associated with the identification of isolated lymph nodes, after excluding any possible primitive locations of neoplastic localization.

Background Studies to identify preoperative prognostic variables for pancreatic neuroendocrine tumor (PNET) have been inconclusive. Specifically, the prevalence and prognostic significance of radiographic calcifications in these tumors remains unclear. Methods From 1998 to 2009, a total of 110 patients with well-differentiated PNET underwent surgical resection at our institution. Synchronous liver metastases present in 31 patients (28%) were addressed surgically with curative intent. Patients with high-grade PNET were excluded. The presence of calcifications in the primary tumor on preoperative computed tomography was recorded and correlated with clinicopathologic variables and overall survival. Results Calcifications were present in 16% of patients and were more common in gastrinomas and glucagonomas (50%), but never encountered in insulinomas. Calcified tumors were larger (median size 4.5 vs. 2.3 cm, P  = 0.04) and more commonly associated with lymph node metastasis (75 vs. 35%, P  = 0.01), synchronous liver metastasis (62 vs. 21%, P  < 0.01), and intermediate tumor grade (80 vs. 31%, P  < 0.01). On multivariate analysis of factors available preoperatively, calcifications ( P  = 0.01) and size ( P  < 0.01) remained independent predictors of lymph node metastasis. Overall survival after resection was significantly worse in the presence of synchronous liver metastasis (5-year, 64 vs. 86%, P  = 0.04), but not in the presence of radiographic calcifications. Conclusions Calcifications on preoperative computed tomography correlate with intermediate grade and lymph node metastasis in well-differentiated PNET. This information is available preoperatively and supports the routine dissection of regional lymph nodes through formal pancreatectomy rather than enucleation in calcified PNET.

Two major forms of gastrin, gastrin-17 (G17) and gastrin-34 (G34), exist in blood. However, conventional immunoassay methods can only quantify total gastrin or G17 alone. Here, we aimed to establish a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify G17 and G34 simultaneously. Serum samples were prepared by anion-exchange solid-phase extraction. The analytical performance of the LC-MS/MS method was validated and the method was compared to chemiluminescence immunoassay (CLIA) and radioimmunoassay (RIA). The G17 and G34 concentrations in 245 serum samples from healthy controls, individuals with gastrinoma, and individuals with other diseases were analyzed. The total runtime of the LC-MS/MS method was 6 min. No substantial matrix effect was observed with internal standard correction. The intraassay coefficients of variation (CVs) for G17 and G34 were 4.0%-14.2% and 4.4%-10.4%, respectively, and total CVs were 5.2%-14.1% and 4.6%-12.4%, respectively. The correlation coefficient between LC-MS/MS and CLIA was 0.87, and between LC-MS/MS and RIA was 0.84. The G17+G34 concentrations for 87.5% of individuals with gastrinoma were higher than the 95th percentile of healthy controls (18.1 pg/mL), whereas the concentrations for individuals with other diseases and gastrinoma overlapped. Based on the Youden indices calculated for G17+G34, G34, and G17, the most specific biomarker was G17 (96.9% clinical specificity at 209.8 pg/mL) for gastrinoma. This method should aid in the diagnosis of diseases associated with increased gastrin concentrations.

Introduction Gastrinoma is a rare tumour of the diffuse neuroendocrine system with the primary invariability located within the duodenum or pancreas. Numerous authors have described gastrinoma apparently isolated to peripancreatic lymph nodes, following exhaustive radiological and operative localisation and examination. Method Two cases of apparent primary lymph node gastrinoma seen in our institution are presented, along with a literature review including 58 other presented cases. Results On prolonged follow-up up to 131 months, 34 patients have remained in remission supporting the diagnosis of primary lymph node gastrinoma. Occult primary disease, usually in the form of microduodenal tumours, have become evident in the remaining 24 cases. Conclusion The existence of primary lymph node gastrinoma is supported by many presented case studies, but long-term follow-up of all patients should occur in the expectation that occult primary disease will become apparent in some.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25–70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10–20 years). Zollinger–Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Purpose Gastrinoma with Zollinger–Ellison syndrome (ZES) may occur sporadically (Sp) or as part of the inherited syndrome of multiple endocrine neoplasia 1 (MEN-1). Data comparing Sp and MEN-1/ZES are scanty. We aimed to identify and compare their clinical features. Methods Consecutive patients with ZES were evaluated between 1992 and 2020 among a monocentric Italian patient cohort. Results Of 76 MEN-1 patients, 41 had gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), 18 of whom had ZES; of 320 Sp-GEP-NEN, 19 had Sp-ZES. MEN-1/ZES patients were younger ( p  = 0.035) and the primary MEN-1/ZES gastrinoma was smaller than Sp-ZES ( p  = 0.030). Liver metastases occurred in both groups, but only Sp-ZES developed extrahepatic metastases. 13 Sp-ZES and 8 MEN-1/ZES underwent surgery. 8 Sp-ZES and 7 MEN-1/ZES received somatostatin analogs (SSAs). Median overall survival (OS) was higher in MEN-1/ZES than in Sp-ZES (310 vs 168 months, p  = 0.034). At univariate-logistic regression, age at diagnosis ( p  = 0.01, OR = 1.1), G3 grading ( p  = 0.003, OR = 21.3), Sp-ZES ( p  = 0.02, OR = 0.3) and presence of extrahepatic metastases ( p  = 0.001, OR = 7.2) showed a significant association with OS. At multivariate-COX-analysis, none of the variables resulted significantly related to OS. At univariate-logistic regression, age ( p  = 0.04, OR = 1.0), size ( p  = 0.039, OR = 1.0), G3 grade ( p  = 0.008, OR = 14.6) and extrahepatic metastases ( p  = 0.005, OR = 4.6) were independently associated with progression-free survival (PFS). In multivariate-COX-analysis, only extrahepatic metastases ( p  = 0.05, OR = 3.4) showed a significant association with PFS. Among SSAs-treated patients, MEN-1/ZES showed better PFS ( p  = 0.0227) . After surgery, the median PFS was 126 and 96 months in MEN-1 and Sp, respectively. Conclusion MEN-1/ZES patients generally show better OS and PFS than Sp-ZES as well as better SSAs response.