Neuroendocrine tumours: what gastroenterologists need to know

Gastroenterologists are intermittently involved in diagnosing and managing patients who have neuroendocrine tumours (NETs). However, few UK gastroenterologists have received extensive training about this topic. This article aims to provide a brief introduction to NETs; it is aimed at a general gastroenterologist audience.NETs present in diverse ways and many symptomatic patients unfortunately experience significant delays in diagnosis. Comprehensive evaluation of a patient with a possible NET involves assessing their symptoms, the tumour’s primary organ of origin, its differentiation status, grade and stage, whether the NET is secreting hormones and whether there is any underlying hereditary predisposition. Such assessment often needs specialist investigations such as nuclear medicine scans. All these factors influence patient management and prognosis, so a patient’s case and investigations should always be discussed by a fully constituted NET multidisciplinary team. Most localised tumours are considered for resection, but there are multiple treatment options for metastatic disease and many patients receive several different therapies during the course of their illness. The most common first line treatment in patients who have metastatic low grade NETs is monthly long acting somatostatin analogue injections. Prognosis is highly variable, but some patients who have inoperable metastases survive for many years on treatment with good quality of life. Gastroenterologists may also be involved in managing the non-tumour associated chronic gastrointestinal problems that some patients experience. Their involvement has been shown to improve patient-reported outcomes and quality of life.</jats:p

RCAN1 regulates vesicle recycling and quantal release kinetics via effects on calcineurin activity

Author version made available in accordance with the publisher's policy.We have previously shown that Regulator of Calcineurin 1 (RCAN1) regulates multiple stages of vesicle exocytosis. However, the mechanisms by which RCAN1 affects secretory vesicle exocytosis and quantal release kinetics remain unknown. Here we use carbon fiber amperometry to detect exocytosis from chromaffin cells and identify these underlying mechanisms. We observe reduced exocytosis with repeated stimulations in chromaffin cells overexpressing RCAN1 (RCAN1ox), but not in wild type (WT) cells, indicating a negative effect of RCAN1 on vesicle recycling and endocytosis. Acute exposure to calcineurin inhibitors, cyclosporine A and FK-506, replicates this effect in WT cells but has no additional effect in RCAN1ox cells. When we chronically expose WT cells to cyclosporine A and FK-506 we find that catecholamine release per vesicle and pre-spike foot (PSF) signal parameters are decreased, similar to that in RCAN1ox cells. Inhibiting calcineurin activity in RCAN1ox cells has no additional effect on the amount of catecholamine release per vesicle but further reduces PSF signal parameters. Electron microscopy studies indicate these changes are not due to altered vesicle number or distribution in RCAN1ox cells but reduced vesicle release may be cause by decreased vesicle and dense core size in RCAN1ox cells. Thus, our results indicate that RCAN1 may negatively affects vesicle recycling and quantal release kinetics via the inhibition of calcineurin activity

Pyridone functionalization: regioselective deprotonation of 6-methylpyridin-2(1H)- and -4(1H)-one derivatives

Selective functionalization at the α-methyl group of 1-substituted pyridin-2(1H)- and 4(1H)-ones (2- and 4-pyridones) can be achieved by appropriate choice of base. n-Butyllithium was found to effect clean 6(2)-methyl deprotonation of 1-benzyl-2- and -4-pyridone derivatives, while potassium hexamethyldisilazide (KHMDS) was the preferred reagent for methyl deprotonation of the corresponding 1-methyl-2- and -4-pyridones. Deprotonation proceeds smoothly at –78 °C, and the resulting anions react readily with a wide range of electrophiles (aldehydes, ketones, alkylating reagents, and an azo compound) under precise temperature control to form usefully functionalized 2- and 4-pyridones and quinolizinones

Gastric Helicobacter infection induces iron deficiency in the INS-GAS mouse

There is increasing evidence from clinical and population studies for a role of H. pylori infection in the aetiology of iron deficiency. Rodent models of Helicobacter infection are helpful for investigating any causal links and mechanisms of iron deficiency in the host. The aim of this study was to investigate the effects of gastric Helicobacter infection on iron deficiency and host iron metabolism/transport gene expression in hypergastrinemic INS-GAS mice. INS-GAS mice were infected with Helicobacter felis for 3, 6 and 9 months. At post mortem, blood was taken for assessment of iron status and gastric mucosa for pathology, immunohistology and analysis of gene expression. Chronic Helicobacter infection of INS- GAS mice resulted in decreased serum iron, transferrin saturation and hypoferritinemia and increased Total iron binding capacity (TIBC). Decreased serum iron concentrations were associated with a concomitant reduction in the number of parietal cells, strengthening the association between hypochlorhydria and gastric Helicobacter-induced iron deficiency. Infection with H. felis for nine months was associated with decreased gastric expression of iron metabolism regulators hepcidin, Bmp4 and Bmp6 but increased expression of Ferroportin 1, the iron efflux protein, iron absorption genes such as Divalent metal transporter 1, Transferrin receptor 1 and also Lcn2 a siderophore-binding protein. The INS-GAS mouse is therefore a useful model for studying Helicobacter-induced iron deficiency. Furthermore, the marked changes in expression of gastric iron transporters following Helicobacter infection may be relevant to the more rapid development of carcinogenesis in the Helicobacter infected INS-GAS model

Cost-effectiveness modelling of use of urea breath test for the management of Helicobacter pylori-related dyspepsia and peptic ulcer in the UK.

Clinical data comparing diagnostic strategies in the management of Helicobacter pylori-associated diseases are limited. Invasive and noninvasive diagnostic tests for detecting H. pylori infection are used in the clinical care of patients with dyspeptic symptoms. Modelling studies might help to identify the most cost-effective strategies. The objective of the study is to assess the cost-effectiveness of a 'test-and-treat' strategy with the urea breath test (UBT) compared with other strategies, in managing patients with H. pylori-associated dyspepsia and preventing peptic ulcer in the UK. Cost-effectiveness models compared four strategies: 'test-and-treat' with either UBT or faecal antigen test (FAT), 'endoscopy-based strategy' and 'symptomatic treatment'. A probabilistic cost-effectiveness analysis was performed using a simulation model in order to identify probabilities and costs associated with relief of dyspepsia symptoms (over a 4-week time horizon) and with prevention of peptic ulcers (over a 10-year time horizon). Clinical and cost inputs to the model were derived from routine medical practice in the UK. For relief of dyspepsia symptoms, 'test-and-treat' strategies with either UBT (€526/success) and FAT (€518/success) were the most cost-effective strategies compared with 'endoscopy-based strategy' (€1317/success) and 'symptomatic treatment' (€1 029/success). For the prevention of peptic ulcers, 'test-and-treat' strategies with either UBT (€208/ulcer avoided/year) or FAT (€191/ulcer avoided/year) were the most cost-effective strategies compared with 'endoscopy-based strategy' (€717/ulcer avoided/year) and 'symptomatic treatment' (€651/ulcer avoided/year) (1 EUR=0,871487 GBP at the time of the study). 'Test-and-treat' strategies with either UBT or FAT are the most cost-effective medical approaches for the management of H. pylori-associated dyspepsia and the prevention of peptic ulcer in the UK. A 'test-and-treat' strategy with UBT has comparable cost-effectiveness outcomes to the current standard of care using FAT in the UK

Landscape of stimulation-responsive chromatin across diverse human immune cells.

A hallmark of the immune system is the interplay among specialized cell types transitioning between resting and stimulated states. The gene regulatory landscape of this dynamic system has not been fully characterized in human cells. Here we collected assay for transposase-accessible chromatin using sequencing (ATAC-seq) and RNA sequencing data under resting and stimulated conditions for up to 32 immune cell populations. Stimulation caused widespread chromatin remodeling, including response elements shared between stimulated B and T cells. Furthermore, several autoimmune traits showed significant heritability in stimulation-responsive elements from distinct cell types, highlighting the importance of these cell states in autoimmunity. Allele-specific read mapping identified variants that alter chromatin accessibility in particular conditions, allowing us to observe evidence of function for a candidate causal variant that is undetected by existing large-scale studies in resting cells. Our results provide a resource of chromatin dynamics and highlight the need to characterize the effects of genetic variation in stimulated cells

Frequency and Causes of False-Positive Elevated Plasma Concentrations of Fasting Gut Hormones in a Specialist Neuroendocrine Tumor Center

IntroductionIn the UK, the fasting plasma concentrations of a panel of gut hormones (comprising vasoactive intestinal peptide (VIP), gastrin, pancreatic polypeptide (PP), glucagon, somatostatin and chromogranin A) are measured to evaluate patients who have or who (due to unexplained and compatible symptoms) are suspected of having neuroendocrine tumors (NETs). False positive elevated hormone concentrations are sometimes found.ObjectiveTo evaluate the frequency and implications of false positive fasting gut hormone results.MethodsRetrospective audit of fasting gut hormone profile results at a large UK university teaching hospital over 12 months.ResultsFasting gut hormone concentrations were measured in 231 patients during 2017. No NETs were found in the 88 patients who had this test performed only to investigate symptoms. 31 false positive gastrin, 8 false positive chromogranin A, two false positive glucagon, three false positive somatostatin, one false positive PP, and one false positive VIP results were found. We extended the audit for glucagon and somatostatin for an additional two years and found seven probable false-positive raised glucagon concentrations and four probable false-positive elevated plasma somatostatin concentrations in total.ConclusionsFalse-positive elevations of plasma gastrin and chromogranin A were common and causes such as proton pump inhibitor use or inadequate fasting accounted for most cases. Elevated plasma concentrations of the other gut hormones were also detected in patients who had no other evidence of NET. Other diagnoses (e.g. cirrhosis and medullary thyroid carcinoma for hypersomatostatinemia and type 2 diabetes mellitus, pancreatitis, liver or renal impairment for hyperglucagonemia) may cause these false positive results.</jats:sec