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Abstract  Criteria for the staging and grading of neuroendocrine tumors (NETs) of midgut and hindgut origin were established at the second Consensus Conference in Frascati (Rome) organized by the European Neuroendocrine Tumor Society (ENETS). The proposed tumor–node–metastasis (TNM) classifications are based on the recently published ENETS Guidelines for the Diagnosis and Treatment of gastroenteropancreatic NETs and follow our previous proposal for foregut tumors. The new TNM classifications for NETs of the ileum, appendix, colon, and rectum, and the grading system were designed, discussed, and consensually approved by all conference participants. These proposals need to be validated and are meant to help clinicians in the stratification, treatment and follow-up of patients. [ABSTRACT FROM AUTHOR]

Abstract  The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor–node–metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients. [ABSTRACT FROM AUTHOR]

Background: This open-label, phase IB study was undertaken to determine the safety/toxicity profile and recommended dose of oral once-daily PTK787/ZK 222584 (PTK/ZK) combined with oxaliplatin/5-fluorouracil (5-FU)/leucovorin (FOLFOX4) chemotherapy in patients with advanced colorectal cancer. Secondary objectives were to assess full pharmacokinetics and gather preliminary evidence of antitumor activity. Patients and methods: Thirty-five patients received escalating doses of PTK/ZK (range 500–2000 mg daily) continuously. Concurrent FOLFOX4 chemotherapy was administered on days 1 and 2 and repeated every 14 days. Dose escalation of PTK/ZK was continued until maximum tolerated dose (MTD) was established and additional patients were then enrolled at MTD dosage. Results: Mean treatment duration of PTK/ZK was 9.5 months. The MTD was 1250 mg daily with dizziness being the most frequent dose-limiting toxicity (DLT). Hypertension (23%, grade 3) and neutropenia (37%, grades 3 + 4) were the most frequent grade 3 or 4 adverse events. Pharmacokinetic analyses found no evidence for interactions between PTK/ZK and the combination of 5-FU, leucovorin, and oxaliplatin during concomitant use. Median progression-free survival was 11.4 months. Conclusion: The MTD of PTK/ZK in combination with FOLFOX4 in this patient population is 1250 mg daily. The combination is feasible and safe and is not associated with significant pharmacokinetic interactions. [ABSTRACT FROM AUTHOR]

Background: Early diagnosis is key to prevent bowel damage in inflammatory bowel disease (IBD). Risk factor analyses linked with delayed diagnosis in European IBD patients are scarce and no data in German IBD patients exists., Aim: To identify risk factors leading to prolonged diagnostic time in a German IBD cohort., Methods: Between 2012 and 2022, 430 IBD patients from four Berlin hospitals were enrolled in a prospective study and asked to complete a 16-item questionnaire to determine features of the path leading to IBD diagnosis. Total diagnostic time was defined as the time from symptom onset to consulting a physician (patient waiting time) and from first consultation to IBD diagnosis (physician diagnostic time). Univariate and multivariate analyses were performed to identify risk factors for each time period., Results: The total diagnostic time was significantly longer in Crohn's disease (CD) compared to ulcerative colitis (UC) patients (12.0 vs 4.0 mo; P < 0.001), mainly due to increased physician diagnostic time (5.5 vs 1.0 mo; P < 0.001). In a multivariate analysis, the predominant symptoms diarrhea ( P = 0.012) and skin lesions ( P = 0.028) as well as performed gastroscopy ( P = 0.042) were associated with longer physician diagnostic time in CD patients. In UC, fever was correlated ( P = 0.020) with shorter physician diagnostic time, while fatigue ( P = 0.011) and positive family history ( P = 0.046) were correlated with longer physician diagnostic time., Conclusion: We demonstrated that CD patients compared to UC are at risk of long diagnostic delay. Future efforts should focus on shortening the diagnostic delay for a better outcome in these patients., Competing Interests: Conflict-of-interest statement: All authors declare that they have no conflicts of interest related to this paper., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

A subset of neuroendocrine tumors (NETs) can cause an excessive secretion of hormones, neuropeptides, and biogenic amines into the bloodstream. These so-called functional NETs evoke a hormone-related disease and lead to several different syndromes, depending on the factors released. One of the most common functional syndromes, carcinoid syndrome, is characterized mainly by over-secretion of serotonin. However, what distinguishes functional from non-functional tumors on a molecular level remains unknown. Here, we demonstrate that the expression of sortilin, a widely expressed transmembrane receptor involved in intracellular protein sorting, is significantly increased in functional compared to non-functional NETs and thus can be used as a biomarker for functional NETs. Furthermore, using a cell line model of functional NETs, as well as organoids, we demonstrate that inhibition of sortilin reduces cellular serotonin concentrations and may therefore serve as a novel therapeutic target to treat patients with carcinoid syndrome., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bolduan, Wetzel, Giesecke, Eichhorn, Alenina, Bader, Willnow, Wiedenmann and Sigal.)

The gastroesophageal squamocolumnar junction (GE-SCJ) is a critical tissue interface between the esophagus and stomach, with significant relevance in the pathophysiology of gastrointestinal diseases. Despite this, the molecular mechanisms underlying GE-SCJ development remain unclear. Using single-cell transcriptomics, organoids, and spatial analysis, we examine the cellular heterogeneity and spatiotemporal dynamics of GE-SCJ development from embryonic to adult mice. We identify distinct transcriptional states and signaling pathways in the epithelial and mesenchymal compartments of the esophagus and stomach during development. Fibroblast-epithelial interactions are mediated by various signaling pathways, including WNT, BMP, TGF-β, FGF, EGF, and PDGF. Our results suggest that fibroblasts predominantly send FGF and TGF-β signals to the epithelia, while epithelial cells mainly send PDGF and EGF signals to fibroblasts. We observe differences in the ligands and receptors involved in cell-cell communication between the esophagus and stomach. Our findings provide insights into the molecular mechanisms underlying GE-SCJ development and fibroblast-epithelial crosstalk involved, paving the way to elucidate mechanisms during adaptive metaplasia development and carcinogenesis., (© 2024. The Author(s).)

There are no therapeutic predictive biomarkers or representative preclinical models for high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN), a highly aggressive, fatal, and heterogeneous malignancy. We established patient-derived (PD) tumoroids from biobanked tissue samples of advanced high-grade GEP-NEN patients and applied this model for targeted rapid ex vivo pharmacotyping, next-generation sequencing, and perturbational profiling. We used tissue-matched PD tumoroids to profile individual patients, compared ex vivo drug response to patients' clinical response to chemotherapy, and investigated treatment-induced adaptive stress responses.PD tumoroids recapitulated biological key features of high-grade GEP-NEN and mimicked clinical response to cisplatin and temozolomide ex vivo. When we investigated treatment-induced adaptive stress responses in PD tumoroids in silico, we discovered and functionally validated Lysine demethylase 5 A and interferon-beta, which act synergistically in combination with cisplatin. Since ex vivo drug response in PD tumoroids matched clinical patient responses to standard-of-care chemotherapeutics for GEP-NEN, our rapid and functional precision oncology approach could expand personalized therapeutic options for patients with advanced high-grade GEP-NEN., (© 2024. The Author(s).)

Purpose: Osteopontin (OPN), also called secreted phosphoprotein 1 (SPP1) is a matricellular glycoprotein whose expression is elevated in various types of cancer and which has been shown to be involved in tumorigenesis and metastasis in many malignancies. Its role in neuroendocrine neoplasms (NEN) remains to be established. The aim of the study was to analyze plasma concentrations of OPN in patients with NEN and to explore its diagnostic and prognostic value as a clinical biomarker., Methods: OPN plasma concentrations were measured in a total of 38 patients with histologically proven NEN at three different time points during the course of disease and therapy (at the start of the study, after 3 and 12 months, respectively) as well as in healthy controls. Clinical and imaging data as well as concentrations of Chromogranin A (CgA) and Neuron Specific Enolase (NSE) were assessed., Results: OPN levels were significantly higher in patients with NEN compared to healthy controls. High-grade tumors (grade 3) showed the highest OPN levels. OPN levels were neither different between male and female patients nor between different primary tumor sites. OPN correlated significantly with corresponding NSE levels, while there was no correlation with Chromogranin A. High OPN levels above a cutoff value of 200 ng/ml at initial analysis predicted a worsened prognosis with significantly shorter progression-free survival of patients with NEN, which also held true within the subgroup of well-differentiated G1/G2 tumors., Conclusion: Our data indicate that high baseline OPN levels in patients with NEN are predictive of an adverse outcome with shorter progression-free survival, even within the group of well differentiated G1/G2 tumors. Therefore, OPN may be used as a surrogate prognostic biomarker in patients with NEN., (© 2023. The Author(s).)

Hepatocellular carcinoma (HCC) is a major cause of death among patients with liver cirrhosis. The rise of immuno-oncology has revolutionized treatment for advanced HCC. However, most pivotal randomized controlled trials have excluded patients with moderate liver dysfunction (Child-Pugh-Turcotte B), despite the high incidence of liver disease in patients with HCC at the time of diagnosis. Overall survival in patients with HCC and moderate liver dysfunction treated with sorafenib has been found to be only approximately 3-5 months, underlining the need for improved treatment algorithms for this increasingly important subgroup of patients. In this review, we summarize available data on the treatment of patients with HCC and moderate liver dysfunction. Opportunities, as well as clinical challenges, are discussed in detail, highlighting potential changes to the therapeutic landscape., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Clinical management of gastroenteropancreatic neuroendocrine neoplasms remains challenging. We recently introduced the FMS-like tyrosine kinase 3 ligand (FLT3LG) as a possible biomarker for a proinflammatory tumor microenvironment. Here, we put a spotlight on the quantitative assessment of classical dendritic cells (cDC) and T cells in the context of FLT3LG mRNA levels in a retrospective study on neuroendocrine tumor (NET) G2/G3 and neuroendocrine carcinoma (NEC) of pancreatic and gastric origin. The abundance of cDC and T cells and their relevant subpopulations were determined by immunofluorescent staining and correlated with FLT3LG mRNA levels as well as clinical outcomes. Immune cell counts attested to highly variable infiltration densities. Samples with the presence of cDC or high numbers of T cells exhibited increased FLT3LG expression. Abundance of cDC, defined as HLA-DR+CD11c+ cells with CLEC9a (cDC1) or CD1c (cDC2), as well as T cells correlated with FLT3LG mRNA levels and predicted disease-specific survival. Combining FLT3LG and T cell counts further improved this prediction. Therefore, tumor-infiltrating cDC and T cells are prognostic markers in NET G2/G3 or NEC and FLT3LG mRNA may serve as a simple-to-use biomarker for a quantitative estimate of their abundance, mandating prospective evaluation in the context of immune-targeted therapies.

Pancreatic neuroendocrine neoplasms (panNENs) are a rare yet diverse type of neoplasia whose precise clinical-pathological classification is frequently challenging. Since incorrect classifications can affect treatment decisions, additional tools which support the diagnosis, such as machine learning (ML) techniques, are critically needed but generally unavailable due to the scarcity of suitable ML training data for rare panNENs. Here, we demonstrate that a multi-step ML framework predicts clinically relevant panNEN characteristics while being exclusively trained on widely available data of a healthy origin. The approach classifies panNENs by deconvolving their transcriptomes into cell type proportions based on shared gene expression profiles with healthy pancreatic cell types. The deconvolution results were found to provide a prognostic value with respect to the prediction of the overall patient survival time, neoplastic grading, and carcinoma versus tumor subclassification. The performance with which a proliferation rate agnostic deconvolution ML model could predict the clinical characteristics was found to be comparable to that of a comparative baseline model trained on the proliferation rate-informed MKI67 levels. The approach is novel in that it complements established proliferation rate-oriented classification schemes whose results can be reproduced and further refined by differentiating between identically graded subgroups. By including non-endocrine cell types, the deconvolution approach furthermore provides an in silico quantification of panNEN dedifferentiation, optimizing it for challenging clinical classification tasks in more aggressive panNEN subtypes.

Background and study aims  Two different techniques for percutaneous endoscopic gastrostomy (PEG) have been developed: classical pull-through and direct puncture techniques. This study compared the complication rate for both techniques in a large retrospective patient cohort. Patients and methods  Clinical data from patients who received a PEG in four high-volume centers for endoscopy were included retrospectively between January 2016 and December 2018. Patient characteristics and complication rates were correlated in univariate and multivariate analyses. Results  Data from 1014 patients undergoing a PEG insertion by the pull-through technique were compared to 183 patients for whom the direct puncture technique was used. The direct puncture technique was associated with a 50 % reduction in minor and 85.7 % reduction in major complications when compared to the pull-through technique. Multivariate analysis of these data revealed an odds ratio of 0.067 (0.02-0.226; P  < 0.001) for major complications in the direct puncture group. Conclusions  Compared to the pull-through technique, the direct puncture technique resulted in a significant reduction in complications. Despite the retrospective design of this study, these results suggest that the direct puncture technique may be preferable to improve patient safety., Competing Interests: Competing interests The authors declare that they have no conflict of interest., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/).)

Neuroendocrine neoplasms (NENs) present with advanced disease at diagnosis in up to 28% of cases, precluding the possibility of curative-intent surgery. Histopathological heterogeneity of this disease can be observed inter-individually as well as intra-individually during disease course. The present study aimed to assess the frequency of Ki-67 change after radical surgery, in a series of patients with radically resected entero-pancreatic neuroendocrine tumors (EP-NETs). We present the analysis of a multicenter, retrospective, series of EP-NETs G1-G2 recurring after radical resection and with histological re-evaluation at disease recurrence (DR). The primary endpoint was the description of Ki-67 change at DR compared to time of surgery. The secondary endpoint was assessment of recurrence-free survival (RFS) rates. In total, 47 patients had a second histological evaluation and could be included in the present study. Median Ki-67 at surgery was 3% (range 1-15%) but, at DR, a significant increase in the value was observed (7%, range 1-30%; p < .01) and involved 66.0% of cases, with a corresponding increase in tumor grading in 34.0% (p = .05). Median RFS of the overall population was 40 months, and was worse when Ki-67 increased at DR vs. stable Ki-67 value (36 vs. 61 months, respectively; p = .02). In conclusion, in more than half of the cases with relapse after radical surgery, a higher proliferative index with a potentially more aggressive potential was observed. Therefore, histological reassessment should be considered on DR because tailored therapeutic strategies may be required for these patients., (© 2022 British Society for Neuroendocrinology.)

Background: Surgery with radical intent is the only potentially curative option for entero-pancreatic neuroendocrine tumors (EP-NETs) but many patients develop recurrence even after many years. The subset of patients at high risk of disease recurrence has not been clearly defined to date., Objective: The aim of this retrospective study was to define, in a series of completely resected EP-NETs, the recurrence-free survival (RFS) rate and a risk score for disease recurrence., Patients and Methods: This was a multicenter retrospective analysis of sporadic pancreatic NETs (PanNETs) or small intestine NETs (SiNETs) [G1/G2] that underwent R0/R1 surgery (years 2000-2016) with at least a 24-month follow-up. Survival analysis was performed using the Kaplan-Meier method and risk factor analysis was performed using the Cox regression model., Results: Overall, 441 patients (224 PanNETs and 217 SiNETs) were included, with a median Ki67 of 2% in tumor tissue and 8.2% stage IV disease. Median RFS was 101 months (5-year rate 67.9%). The derived prognostic score defined by multivariable analysis included prognostic parameters, such as TNM stage, lymph node ratio, margin status, and grading. The score distinguished three risk categories with a significantly different RFS (p < 0.01)., Conclusions: Approximately 30% of patients with EP-NETs recurred within 5 years after radical surgery. Risk factors for recurrence were disease stage, lymph node ratio, margin status, and grading. The definition of risk categories may help in selecting patients who might benefit from adjuvant treatments and more intensive follow-up programs., (© 2022. Society of Surgical Oncology.)

Background: A recently developed haemostatic peptide gel for endoscopic application has been introduced to improve the management of gastrointestinal bleeding. The aim of this pilot study was to evaluate the feasibility, safety, efficacy and indication profiles of PuraStat in a clinical setting., Methods: In this prospective observational multicentre pilot study, patients with acute non-variceal gastrointestinal bleeding (upper and lower) were included. Primary and secondary application of PuraStat was evaluated. Haemoglobin, prothrombin time, platelets and transfusion behaviour were documented before and after haemostasis. The efficacy of PuraStat was assessed during the procedure, at 3 days and 1 week after application., Results: 111 patients with acute gastrointestinal bleeding were recruited into the study. 70 percent (78/111) of the patients had upper gastrointestinal bleeding and 30% (33/111) had lower gastrointestinal bleeding. After primary application of PuraStat, initial haemostatic success was achieved in 94% of patients (74/79, 95% CI 88-99%), and in 75% of the patients when used as a secondary haemostatic product, following failure of established techniques (24/32, 95% CI 59-91%). The therapeutic success rates (absence of rebleeding) after 3 and 7 days were 91% and 87% after primary use, and 87% and 81% in all study patients. Overall rebleeding rate at 30 day follow-up was 16% (18/111). In the 5 patients who finally required surgery (4.5%), PuraStat allowed temporary haemostasis and stabilisation., Conclusions: PuraStat expanded the therapeutic toolbox available for an effective treatment of gastrointestinal bleeding sources. It could be safely applied and administered without complications as a primary or secondary therapy. PuraStat may additionally serve as a bridge to surgery in order to achieve temporary haemostasis in case of refractory severe bleeding, possibly playing a role in preventing immediate emergency surgery., (© 2021. The Author(s).)

The European Neuroendocrine Tumor Society (ENETS) promotes practices and procedures that aim to improve the standard of care delivered to patients diagnosed with or suspected of having neuroendocrine neoplasia (NEN). At its annual Scientific Advisory Board Meeting in 2018, experts in imaging, pathology and clinical care of patients with NEN drafted guidance for the standardised reporting of diagnostic studies critical to the diagnosis, grading, staging and treatment of NEN. These included pathology, radiology, endoscopy and molecular imaging procedures. In an iterative process, a synoptic reporting template for molecular imaging procedures was developed to guide personalised therapies. Following pilot implementation and refinement within the ENETS Center of Excellence network, harmonisation with specialist imaging societies including the Society of Nuclear Medicine, European Association of Nuclear Medicine and the International Cancer Imaging Society will be pursued., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Secretin was originally discovered as a gastrointestinal peptide that stimulates fluid secretion from the pancreas and liver and delays gastric emptying. In disease, a secretin receptor (SCTR) was found to occur as a splice variant in gastrinoma and pancreatic adenocarcinoma. Overexpression of SCTR has been described for gastrinomas, carcinoid tumors of the lung and cholangiocarcinoma. SCTR therefore is considered a candidate target for molecular tumor imaging as well as for peptide receptor radioligand therapy (PRRT) in a number of oncological indications. The aim of this study was to characterize SCTR expression in esophageal and pancreatic cancer, demonstrating for the first time high SCTR overexpression in these tumor types. In total, 65 of 70 pancreatic ductal adenocarcinoma tissues stained strongly positive for SCTR in immunohistochemistry, as did most of the 151 esophageal cancer samples, with minor influence of grading in both entities. In addition, the aim of this study was to further delineate residues in human secretin that are critical for binding to and activation of human SCTR. For a potential development of short and metabolically stable analogs for clinical use, it was intended to probe the peptide for its capacity to incorporate deletions and substitutions without losing its affinity to SCTR. In a systematic approach, a library of 146 secretin variants containing single amino acid substitutions as well as truncations on either end was tested in β-arrestin2-GFP translocation and fluorescent ligand internalization assays employing high-content analysis, in cAMP assays which run in agonist and antagonist mode, and in radioligand binding. The main structural determinants of SCTR binding and activation were localized to the N-terminus, with His 1 , Asp 3 being among the most sensitive positions, followed by Phe 6 , Thr 7 and Leu 10 . Aminoterminal truncation caused a rapid decline in receptor activity and most of these variants proved to be partial agonists showing antagonistic properties. In this study, the most potent novel antagonist showed an IC 50 of 309 ± 74 nM in the β-arrestin2-GFP translocation assay on human SCTR while remaining a weak partial agonist. Future studies will have to demonstrate the utility of further enhanced secretin analogues as tracers for in vivo imaging and therapy.

Objective: A comprehensive analysis of the immune landscape of pancreatic neuroendocrine tumours (PanNETs) was performed according to clinicopathological parameters and previously defined molecular subtypes to identify potential therapeutic vulnerabilities in this disease., Design: Differential expression analysis of 600 immune-related genes was performed on 207 PanNET samples, comprising a training cohort (n=72) and two validation cohorts (n=135) from multiple transcriptome profiling platforms. Different immune-related and subtype-related phenotypes, cell types and pathways were investigated using different in silico methods and were further validated using spatial multiplex immunofluorescence., Results: The study identified an immune signature of 132 genes segregating PanNETs (n=207) according to four previously defined molecular subtypes: metastasis-like primary (MLP)-1 and MLP-2, insulinoma-like and intermediate. The MLP-1 subtype (26%-31% samples across three cohorts) was strongly associated with elevated levels of immune-related genes, poor prognosis and a cascade of tumour evolutionary events: larger hypoxic and necroptotic tumours leading to increased damage-associated molecular patterns (viral mimicry), stimulator of interferon gene pathway, T cell-inflamed genes, immune checkpoint targets, and T cell-mediated and M1 macrophage-mediated immune escape mechanisms. Multiplex spatial profiling validated significantly increased macrophages in the MLP-1 subtype., Conclusion: This study provides novel data on the immune microenvironment of PanNETs and identifies MLP-1 subtype as an immune-high phenotype featuring a broad and robust activation of immune-related genes. This study, with further refinement, paves the way for future precision immunotherapy studies in PanNETs to potentially select a subset of MLP-1 patients who may be more likely to respond., Competing Interests: Competing interests: ASa, ASc, CR, GN and KY have ownership interest as patent inventors for a patent entitled 'Patient classification and prognostic method' (international patent application number PCT/EP2019/053845). DC have research funding, 4SC (Inst), Amgen (Inst), AstraZeneca (Inst), Bayer (Inst), Celgene (Inst), Clovis Oncology (Inst), Janssen (Inst), Lilly (Inst), MedImmune (Inst), Merck (Inst), Merrimack (Inst) and Sanofi (Inst). NS has research funding: AstraZeneca, Bristol-Myers-Squibb, Merck Serono and Pfizer. ASa - research funding: Bristol-Myers Squibb, Merck KGaA and Pierre Fabre. Patents: (1) ‘Colorectal cancer classification with differential prognosis and personalized therapeutic responses’ (patent number PCT/IB2013/060416) and (2) ‘Prognostic and treatment response predictive method’ (European (EP) patent application number 18792565.6)., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: The clinical management of high-grade gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) is challenging due to disease heterogeneity, illustrating the need for reliable biomarkers facilitating patient stratification and guiding treatment decisions. FMS-like tyrosine kinase 3 ligand (Flt3L) is emerging as a prognostic or predictive surrogate marker of host tumoral immune response and might enable the stratification of patients with otherwise comparable tumor features., Methods: We evaluated Flt3L gene expression in tumor tissue as well as circulating Flt3L levels as potential biomarkers in a cohort of 54 patients with GEP-NEN., Results: We detected a prominent induction of Flt3L gene expression in individual G2 and G3 NEN, but not in G1 neuroendocrine tumors (NET). Flt3L mRNA expression levels in tumor tissue predicted the disease-related survival of patients with highly proliferative G2 and G3 NEN more accurately than the conventional criteria of grading or NEC/NET differentiation. High level Flt3L mRNA expression was associated with the increased expression of genes related to immunogenic cell death, lymphocyte effector function and dendritic cell maturation, suggesting a less tolerogenic (more proinflammatory) phenotype of tumors with Flt3L induction. Importantly, circulating levels of Flt3L were also elevated in high grade NEN and correlated with patients' progression-free and disease-related survival, thereby reflecting the results observed in tumor tissue., Conclusions: We propose Flt3L as a prognostic biomarker for high grade GEP-NEN, harnessing its potential as a marker of an inflammatory tumor microenvironment. Flt3L measurements in serum, which can be easily be incorporated into clinical routine, should be further evaluated to guide patient stratification and treatment decisions.

Introduction: Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive malignant neoplasms, as many cases go undetected until they reach an advanced stage. Integrin αvβ6 is a cell surface receptor overexpressed in PDAC. Consequently, it may serve as a target for the development of probes for imaging diagnosis and radioligand therapy. Engineered cystine knottin peptides specific for integrin αvβ6 have recently been developed showing high affinity and stability. This study aimed to evaluate an integrin αvβ6-specific knottin molecular probe containing the therapeutic radionuclide 177 Lu for targeting of PDAC., Methods: The expression of integrin αvβ6 in PDAC cell lines BxPC-3 and Capan-2 was analyzed using RT-qPCR and immunofluorescence. In vitro competition and saturation radioligand binding assays were performed to calculate the binding affinity of the DOTA-coupled tracer loaded with and without lutetium to BxPC-3 and Capan-2 cell lines as well as the maximum number of binding sites in these cell lines. To evaluate tracer accumulation in the tumor and organs, SPECT/CT, biodistribution and dosimetry projections were carried out using a Capan-2 xenograft tumor mouse model., Results: RT-qPCR and immunofluorescence results showed high expression of integrin αvβ6 in BxPC-3 and Capan-2 cells. A competition binding assay revealed high affinity of the tracer with IC 50 values of 1.69 nM and 9.46 nM for BxPC-3 and Capan-2, respectively. SPECT/CT and biodistribution analysis of the conjugate 177 Lu-DOTA-integrin αvβ6 knottin demonstrated accumulation in Capan-2 xenograft tumors (3.13 ± 0.63%IA/g at day 1 post injection) with kidney uptake at 19.2 ± 2.5 %IA/g, declining much more rapidly than in tumors., Conclusion: 177 Lu-DOTA-integrin αvβ6 knottin was found to be a high-affinity tracer for PDAC tumors with considerable tumor accumulation and moderate, rapidly declining kidney uptake. These promising results warrant a preclinical treatment study to establish therapeutic efficacy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Sachindra, Hellberg, Exner, Prasad, Beindorff, Rogalla, Kimura, Gambhir, Wiedenmann and Grötzinger.)

Background: Rapid quantification of liver metastasis for diagnosis and follow-up is an unmet medical need in patients with secondary liver malignancies. We present a 3D-quantification model of neuroendocrine liver metastases (NELM) using gadoxetic-acid (Gd-EOB)-enhanced MRI as a useful tool for multidisciplinary cancer conferences (MCC)., Methods: Manual 3D-segmentations of NELM and livers (149 patients in 278 Gd-EOB MRI scans) were used to train a neural network ( U -Net architecture). Clinical usefulness was evaluated in another 33 patients who were discussed in our MCC and received a Gd-EOB MRI both at baseline and follow-up examination ( n = 66) over 12 months. Model measurements (NELM volume; hepatic tumor load (HTL)) with corresponding absolute (Δ abs NELM; Δ abs HTL) and relative changes (Δ rel NELM; Δ rel HTL) between baseline and follow-up were compared to MCC decisions (therapy success/failure)., Results: Internal validation of the model's accuracy showed a high overlap for NELM and livers (Matthew's correlation coefficient (φ): 0.76/0.95, respectively) with higher φ in larger NELM volume (φ = 0.80 vs. 0.71; p = 0.003). External validation confirmed the high accuracy for NELM (φ = 0.86) and livers (φ = 0.96). MCC decisions were significantly differentiated by all response variables (Δ abs NELM; Δ abs HTL; Δ rel NELM; Δ rel HTL) ( p < 0.001). Δ rel NELM and Δ rel HTL showed optimal discrimination between therapy success or failure (AUC: 1.000; p < 0.001)., Conclusion: The model shows high accuracy in 3D-quantification of NELM and HTL in Gd-EOB-MRI. The model's measurements correlated well with MCC's evaluation of therapeutic response.

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

Abstract: Immune check-point inhibitors (ICIs) have changed our view on how to treat cancer. Despite their approval in treatment of many different cancers, efficacy of immune check-point inhibitors (ICI) in neuroendocrine neoplasia is limited and poorly understood. Established treatment options of neuroendocrine tumors (NET) and neuroendocrine carcinomas (NECs) are based on surgery, tumor-targeted medical treatments, Peptide Receptor Radionuclide Therapy (PRRT), and locoregional therapies. However, in many patients these treatments lose efficacy over time, and novel therapies are urgently needed. We report on 8 patients diagnosed with neuroendocrine neoplasms (NEN) that were treated with ICI (pembrolizumab, avelumab, nivolumab plus ipilimumab) as salvage therapy. In this cohort, we observed tumor response with partial remission in 3 patients and stable disease in 1 patient. Four patients showed progressive disease. Of note, responses were observed both in PD-L1 positive and PD-L1 negative patients. Here, we discuss clinical courses of these patients in the context of available literature to highlight limitations and drawbacks currently preventing the use of ICI in routine management of patients with NEN., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) are a rare, heterogeneous group of tumors that originate from the endocrine system of the gastrointestinal tract and pancreas. GEP-NENs are subdivided according to their differentiation into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Since GEP-NENs represent rare diseases, only limited data from large prospective, randomized clinical trials are available, and recommendations for treatment of GEP-NEN are in part based on data from retrospective analyses or case series. In this context, tractable disease models that reflect the situation in humans and that allow to recapitulate the different clinical aspects and disease stages of GEP-NET or GEP-NEC are urgently needed. In this review, we highlight available data on mouse models for GEP-NEN. We discuss how these models reflect tumor biology of human disease and whether these models could serve as a tool for understanding the pathogenesis of GEP-NEN and for disease modeling and pharmacosensitivity assays, facilitating prediction of treatment response in patients. In addition, open issues applicable for future developments will be discussed., (© 2020 The Author(s). Published by S. Karger AG, Basel.)

The better understanding of the biological behavior of multiple endocrine neoplasia type 1 (MEN1) organ manifestations and the increase in clinical experience warrant a revision of previously published guidelines. Duodenopancreatic neuroendocrine neoplasias (DP-NENs) are still the second most common manifestation in MEN1 and, besides NENs of the thymus, remain a leading cause of death. DP-NENs are thus of main interest in the effort to reevaluate recommendations for their diagnosis and treatment. Especially over the last 2 years, more clinical experience has documented the follow-up of treated and untreated (natural-course) DP-NENs. It was the aim of the international consortium of experts in endocrinology, genetics, radiology, surgery, gastroenterology, and oncology to systematically review the literature and to present a consensus statement based on the highest levels of evidence. Reviewing the literature published over the past decade, the focus was on the diagnosis of F- and NF-DP-NENs within the MEN1 syndrome in an effort to further standardize and improve treatment and follow-up, as well as to establish a "logbook" for the diagnosis and treatment of DP-NENs. This shall help further reduce complications and improve long-term treatment results in these rare tumors. The following international consensus statement builds upon the previously published guidelines of 2001 and 2012 and attempts to supplement the recommendations issued by various national and international societies., (© 2020 S. Karger AG, Basel.)

This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in neuroendocrine neoplasm (NEN) cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in small-intestinal ( n = 71) NEN tissues compared to controls ( n = 25). NEN cells with high AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gαq inhibition. ATII also stimulated serotonin secretion from BON cells. AGTR1 ligand saralasin was coupled to a near-infrared fluorescent (NIRF) dye and tested for its biodistribution in a nude mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. NIRF imaging showed significantly higher uptake in BON tumors. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for translational chelator-based probes for diagnostic PET imaging and radioligand therapy.

Over the past 5 years, a number of notable research advances have been made in the field of neuroendocrine cancer, specifically with regard to neuroendocrine cancer of the gastrointestinal tract. The aim of this Review is to provide an update on current knowledge that has proven effective for the clinical management of patients with these tumours. For example, for the first time in the tubular gastrointestinal tract, well-differentiated high-grade (grade 3) tumours and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) are defined in the WHO classification. This novel classification enables efficient identification of the most aggressive well-differentiated neuroendocrine tumours and helps in defining the degree of aggressiveness of MiNENs. The Review also discusses updates to epidemiology, cell biology (including vesicle-specific components) and the as-yet-unresolved complex genetic background that varies according to site and differentiation status. The Review summarizes novel diagnostic instruments, including molecules associated with the secretory machinery, novel radiological approaches (including pattern recognition techniques), novel PET tracers and liquid biopsy combined with DNA or RNA assays. Surgery remains the treatment mainstay; however, peptide receptor radionuclide therapy with novel radioligands and new emerging medical therapies (including vaccination and immunotherapy) are evolving and being tested in clinical trials, which are summarized and critically reviewed here.

Background and Aims: Due to its involvement in tumor biology as well as tumor-associated stroma cell responses, recent data suggested a potential role of miR-29 as a biomarker for different malignancies. However, its role in neuroendocrine tumors (NETs) is only poorly understood., Methods: We measured circulating levels of miR-29b in 45 patients with NET and compared them to 19 healthy controls. Results were correlated with clinical records., Results: In our cohort of NET patients treated between 2010 and 2019 at our department, miR-29b serum levels were significantly downregulated when compared to healthy control samples. Further, a significant correlation between chromogranin A (CgA) and relative miR-29b levels was noted. However, serum levels of miR-29b were independent of tumor-related factors such as proliferation activity according to Ki-67 index, tumor grading, the TMN stage of malignant tumors, somatostatin receptor expression or clinical features such as functional or non-functional disease and presence of tumor relapse. Finally, in contrast to previous results from other malignancies, miR-29b serum levels were not a significant predictor of overall survival in NET patients., Conclusion: Our data suggest a role for miR-29b serum levels as a previously unrecognized biomarker for diagnosis of NET. However, miR-29 does not allow for predicting tumor stage or patients' outcome.

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

Background: Stage IV gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) G3 are the NENs with the worst prognosis. According to ENETS guidelines, platinum-based chemotherapy is the standard treatment for this population. Surgery is only considered in highly selected "resectable" NENs with usually lower Ki67. However, the role of surgery with curative intent has been poorly investigated., Objective: To describe, in a retrospective series of stage IV GEP-NENs G3, overall survival (OS) and recurrence-free survival (RFS) rates after curatively intended surgery., Methods: Multicenter analysis of stage IV GEP-NENs G3 receiving radical resection (R0/R1) from 2007 to 2017, with minimum post-surgical follow-up time of 3 months., Results: Fifteen patients from 6 NEN referral centers, with median follow-up of 29 months (8-86), were included. Eight cases had a neuroendocrine carcinoma (NEC) and 7 a neuroendocrine tumor G3 (NET G3). Median OS after radical surgery was 59 months. All patients recurred, with a median RFS of 8 months., Conclusions: Radical surgery might be considered for highly selected stage IV GEP-NENs G3. Larger series are needed to confirm these results., Competing Interests: Declaration of competing interest Authors have no conflicts of interest do declare., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Neuroendocrine neoplasia (NEN) comprises heterogeneous tumors that are challenging to diagnose and, especially in cases of poorly differentiated (G3) NEN, are associated with very limited survival. Novel biomarkers allowing an early diagnosis as well as an optimal selection of suitable treatment options are urgently needed to improve the outcome of these patients. Recently, alterations of soluble urokinase-type plasminogen activator receptor (suPAR) serum levels were described in various types of cancers. However, the role of circulating suPAR as a biomarker in patients with NEN is unknown. In this study, we measured suPAR serum levels in a large and well-characterized cohort of 187 patients with NEN (neuroendocrine carcinomas (NEC) n = 30; neuroendocrine tumors (NET), n = 157) as well as 44 healthy controls. suPAR concentrations were significantly elevated in patients compared to controls. However, suPAR concentrations were independent of tumor-related factors such as the proliferation activity according to Ki-67, tumor grading, TNM (TNM classification of malignant tumors) stage, somatostatin receptor expression or clinical features such as functional or nonfunctional disease and the presence of tumor relapse. Interestingly, suPAR concentrations in NET patients were similar when compared to those measured in NEC patients. In contrast to previous results from other malignancies, in our analysis suPAR levels were not a significant predictor of overall survival. In conclusion, our data suggests that suPAR serum concentrations are elevated in NEN patients but do not allow prediction of outcome.

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

Primary neuroendocrine carcinoma of the breast (NECB) as defined by the World Health Organization (WHO) in 2012 is a rare, but possibly under-diagnosed entity. It is heterogeneous as it entails a wide spectrum of diseases comprising both well-differentiated neuroendocrine tumors of the breast as well as highly aggressive small cell carcinomas. Retrospective screening of hospital charts of 612 patients (2008-2019) from our specialized outpatient unit for neuroendocrine neoplasia revealed five patients diagnosed with NECB. Given the low prevalence of these malignancies, correct diagnosis remains a challenge that requires an interdisciplinary approach. Specifically, NECB may be misclassified as carcinoma of the breast with neuroendocrine differentiation, carcinomas of the breast of no special type/invasive ductal carcinoma, or a metastasis to the breast. Therefore, this study presents multifaceted characteristics as well as the clinical course of these patients and discusses the five cases from our institution in the context of available literature.

Due to the increasing incidence and prevalence of neuroendocrine tumors (NETs), there is a need to assess any gaps in awareness and care. A survey was undertaken in 2017 to identify perceived unmet needs from the perspectives of patients/families, patient advocates and health care professionals (HCPs). The survey consisted of 33-37 questions (depending on type of respondent) across four areas: information, care, treatments and research. In total, 443 participants from 26 countries responded: 338 patients/families, 35 advocates and 70 HCPs. Perceived unmet needs regarding provision of information at diagnosis differed between groups. While 59% of HCPs believed they provided sufficient information, informational needs were mostly/fully met for only 30% of patients and 18% of advocates. Additionally, 91% of patients and 97% of advocates felt that patients had to search for information themselves. Availability of Gallium-68-Dotatate PET/CT scan was limited for the majority of patients (patients: 73%; advocates: 85%; HCP: 86%), as was access to treatments, particularly peptide receptor radionuclide therapy (patients: 42%; advocates: 95%; HCPs: 77%). All groups felt that standards of care, including psychological needs and diagnosis of mental health, were not fully met. Although about two-thirds of patients were managed by a multidisciplinary team, 14% of patients reportedly did not have enough contact. All groups supported more patient involvement in research; patients and advocates prioritized improvement in diagnosis and HCPs focused on clinical trials. This survey revealed significant unmet needs but differing perceptions regarding these among the groups. There is a need for investigation and collaboration to improve standards of care for NET patients., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Background: Parenteral nutrition (PN) is a life-sustaining therapy for patients with chronic intestinal failure (IF) but inevitably has an impact on patients' quality of life (QoL). The purpose of this study was to examine multiple aspects of QoL by utilizing the standardized Short Form 36 (SF-36) health survey., Methods: Between 2014 and 2017, a total of 90 adult patients with IF who were receiving PN were prospectively enrolled in an observational study. All subjects underwent nutrition status assessment, liver assessment, blood tests, and QoL assessment based on the SF-36. Univariate and multivariable analyses were performed to identify determinants of 8 domains and 2 summary scales of the SF-36., Results: Analysis of the SF-36 questionnaire data showed that QoL was significantly worse compared with the general German population across all categories. Multivariable analysis revealed that bioelectrical impedance analysis of phase angle (1/10 categories), stoma/fistula (4/10 categories), oral intake (4/10 categories), infusions per week (1/10 categories), duration of PN (1/10 categories), citrulline (4/10 categories), and hemoglobin levels (1/10 categories) are independent risk factors affecting QoL., Conclusion: This study uses the largest cohort of IF patients assessed by the standardized SF-36 questionnaire to comprehensively analyze QoL. Presence of oral intake, presence of ostomy, and citrulline levels were independently correlated with 4 of 10 categories of the SF-36. These results indicate that to improve QoL for IF patients, clinical care should focus on addressing the social and emotional value of oral intake, educational interventions, early stoma closure, and application of new targeted therapies., (© 2019 American Society for Parenteral and Enteral Nutrition.)

Background & Aims: Intestinal failure associated liver disease (IFALD) is one of the leading complications and causes of deaths in adult patients receiving home parenteral nutrition for chronic intestinal failure (CIF). Early diagnosis of IFALD is key to alleviate the progression of hepatic dysfunction. The aim of this study was to evaluate the capability of noninvasive liver function tests., Methods: 90 adult patients with CIF receiving long-term home parenteral nutrition were included in a prospective cross-sectional study at our department between 2014 and 2017. All participants underwent dynamic liver function assessment (maximum liver function capacity [LiMAx] test, indocyanine green [ICG] test), transient elastography (FibroScan), blood tests and comprehensive nutritional status assessment. Univariate and multivariable analysis were performed to identify predictors of liver function., Results: LiMAx, ICG test, and FibroScan highly correlated with standard liver function tests. Multivariable analysis identified intact ileum (B = 520.895; p = 0.010), digestive anatomy type 3 (B = 75.612; p = 0.025), citrulline level (B = 3.428; p = 0.040), parenteral olive oil intake (B = -0.570; p = 0.043), and oral intake (B = 182.227; p = 0.040) as independent risk factors affecting liver function determined by LiMAx test. ICG test and FibroScan showed no correlation with gastrointestinal and nutrition-related parameters., Conclusion: The LiMAx test is significantly associated with widely accepted risk factors for IFALD by multivariable analysis, whereas ICG test and FibroScan failed to show significant correlations. Liver function assessment by LiMAx test may therefore have the potential to detect alterations in liver function and identify patients at risk for the development of IFALD. Longitudinal studies are needed to investigate the impact of liver function determined by LiMAx test on long-term outcome in patients with CIF., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Peritoneal carcinomatosis (PC) can affect the quality of life of patients with gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs). Peritoneal disease control by medical therapies in these patients has been poorly investigated Objectives: To describe, in a consecutive series of GEP-NENs, the clinical impact of PC and to report the effectiveness of available treatments in PC control., Methods: A retrospective, monocenter analysis was performed of 135 GEP-NENs (1993-2016) with at least a 12-month follow-up. Peritoneal disease progression was defined as detection of a significant increase in size or appearance of new implants by imaging., Results: A total of 62.9% of cases had diffuse PC (involving at least 2 abdominal quadrants). According to WHO 2017 classification, cases were 42.3% neuroendocrine tumors NET-G1, 45.5% NET-G2, 6.5% NET-G3, 4.9% neuroendocrine carcinomas NEC-G3, and 0.8% mixed neuroendocrine-nonneuroendocrine neoplasms. Bowel obstruction occurred in 30 (22.2%) patients mainly depending on size of peritoneal implants (HR: 1.10; 95% CI: 1.02-1.20; p = 0.01). Patients with diffuse PC treated with peptide receptor radionuclide therapy (PRRT) showed peritoneal progression in 37.5% of cases, and bowel obstruction or ascites in 28.1%. Better peritoneal disease control was observed in cases receiving somatostatin analogs at first-line therapy, probably due to a less aggressive disease behavior for these patients., Conclusions: Bowel obstruction is not uncommon in GEP-NENs with PC. PRRT should be adopted with caution in GEP-NENs with diffuse PC, but larger series are needed to confirm these data., (© 2019 S. Karger AG, Basel.)

Although gastric neuroendocrine neoplasias (gNEN) are an orphan disease, their incidence is rising. The heterogeneous clinical course powers the ongoing discussion of the most appropriate classification system and management. Prognostic relevance of proposed classifications was retrospectively analysed in 142 patients from a single tertiary referral centre. Baseline, management and survival data were acquired for statistical analyses. The distribution according to the clinicopathological typification was gNEN-1 (n = 86/60.6%), gNEN-2 (n = 7/4.9%), gNEN-3 (n = 24/16.9%) and gNEN-4 (n = 25/17.6%), while hypergastrinemia-associated gNEN-1 and -2 were all low-grade tumours (NET-G1/2), formerly termed sporadic gNEN-3 could be subdivided into gNEN-3 with grade 1 or 2 and gNEN-4 with grade 3 (NEC-G3). During follow-up 36 patients died (25%). The mean overall survival (OS) of all gNEN was 14.2 years. The OS differed statistically significant across all subgroups with either classification system. According to UICC 2017 TNM classification, OS differed for early and advanced stages, while WHO grading indicated poorer prognosis for NEC-G3. Cox regression analysis confirmed the independent prognostic validity of either classification system for survival. Particularly careful analysis of the clinical course of gNEN-1 (ECLomas, gastric carcinoids) confirmed their mostly benign, but recurrent and extremely slowly progressive behaviour with low risk of metastasis (7%) and an efficient long-term control by repetitive endoscopic procedures. Our study provides evidence for the validity of current classifications focusing on typing, grading and staging. These are crucial tools for risk stratification, especially to differentiate gNEN-1 as well as sporadic gNET and gNEC (gNEN-3 vs -4).

Background & Aims: Teduglutide, a glucagon-like peptide 2 (GLP-2) analog, is an approved medication specific for short bowel syndrome patients with chronic intestinal failure (SBS-IF). Due to its intestinotrophic properties, it improves intestinal absorption of fluids and nutrients, which was shown to reduce the need for parenteral support in clinical trials. The present report aims to describe the experience of teduglutide's effects in routine medical care with focus on clinical and nutritional effects., Methods: Data of adult SBS-IF patients, treated with teduglutide between Sept. 2014 and May 2017 within a structured multidisciplinary program to enhance intestinal rehabilitation, were analyzed retrospectively from a single university medical center., Results: In total, 27 patients were treated with teduglutide. Parenteral nutrition independency was achieved in 4/19 (21%) patients analyzed, with two remaining on intravenous fluids. A clinically significant reduction of parenteral volume was observed in 15/19 patients (79%) with onset between 1 and 45 weeks. Significant parenteral support reductions were observed, ranging from about -20% in patients treated for 3 months to about -45% in patients treated for 2 years. This was accompanied by an increase in parenteral nutrition-free days. We also report on a clinically relevant and significant effect of teduglutide-mediated improvement of stool frequency and consistency. Furthermore, nutritional status subgroup analysis revealed long-term stability in body weight, albumin levels and body composition albeit parenteral support reduction. Structural effects of teduglutide treatment were observed on small intestinal mucosa with significantly increased villus height, crypt depth and plasma citrulline levels., Conclusions: Teduglutide can be applied to anatomically and clinically heterogeneous SBS-IF patients and results in an adaptive response with variable time and effect range in routine medical care. Teduglutide-induced functional and structural changes bring on a gradual reduction of parenteral support at no cost to body composition and suggest an improved intestinal function with compensatory effect on nutritional status., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Wnt signalling stimulated by binding of R-spondin (Rspo) to Lgr-family members is crucial for gastrointestinal stem cell renewal. Infection of the stomach with Helicobacter pylori stimulates increased secretion of Rspo by myofibroblasts, leading to an increase in proliferation of Wnt-responsive Axin2 + Lgr5 - stem cells in the isthmus of the gastric gland and finally gastric gland hyperplasia. Basal Lgr5 + cells are also exposed to Rspo3, but their response remains unclear. Here, we demonstrate that-in contrast to its known mitogenic activity-Rspo3 induces differentiation of basal Lgr5 + cells into secretory cells that express and secrete antimicrobial factors, such as intelectin-1, into the lumen. The depletion of Lgr5 + cells or the knockout of Rspo3 in myofibroblasts leads to hypercolonization of the gastric glands with H. pylori, including the stem cell compartment. By contrast, systemic administration or overexpression of Rspo3 in the stroma clears H. pylori from the gastric glands. Thus, the Rspo3-Lgr5 axis simultaneously regulates both antimicrobial defence and mucosal regeneration.

In recent decades, the incidence of neuroendocrine tumors (NETs) has steadily increased. Due to the slow-growing nature of these tumors and the lack of early symptoms, most cases are diagnosed at advanced stages, when curative treatment options are no longer available. Prognosis and survival of patients with NETs are determined by the location of the primary lesion, biochemical functional status, differentiation, initial staging, and response to treatment. Somatostatin analogue (SSA) therapy has been a mainstay of antisecretory therapy in functioning neuroendocrine tumors, which cause various clinical symptoms depending on hormonal hypersecretion. Beyond symptomatic management, recent research demonstrates that SSAs exert antiproliferative effects and inhibit tumor growth via the somatostatin receptor 2 (SSTR2). Both the PROMID (placebo-controlled, prospective, randomized study in patients with metastatic neuroendocrine midgut tumors) and the CLARINET (controlled study of lanreotide antiproliferative response in neuroendocrine tumors) trial showed a statistically significant prolongation of time to progression/progression-free survival (TTP/PFS) upon SSA treatment, compared to placebo. Moreover, the combination of SSA with peptide receptor radionuclide therapy (PRRT) in small intestinal NETs has proven efficacy in the phase 3 neuroendocrine tumours therapy (NETTER 1) trial. PRRT is currently being tested for enteropancreatic NETs versus everolimus in the COMPETE trial, and the potential of SSTR-antagonists in PRRT is now being evaluated in early phase I/II clinical trials. This review provides a synopsis on the pharmacological development of SSAs and their use as antisecretory drugs. Moreover, this review highlights the clinical evidence of SSAs in monotherapy, and in combination with other treatment modalities, as applied to the antiproliferative management of neuroendocrine tumors with special attention to recent high-quality phase III trials.