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

Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer

Contact X-ray Brachytherapy as a sole treatment in selected patients with early rectal cancer Objective The standard management of early rectal cancer is surgical resection. Contact X-ray brachytherapy (CXB) is an alternative treatment for patients who are not suitable or refuse surgery and is usually combined with external beam radiation (EBRT) to treat possible lymphatic spread. We report clinical outcomes from a cohort of patients who, for various reasons, received CXB as the sole treatment for early rectal cancer. Methods From our Clatterbridge Cancer Centre database (2009-2019), we selected patients with early rectal adenocarcinoma (cT1-2, cN0, cM0) and small tumour size (≤ 3cm) who received CXB as their sole treatment. For tumours ≤ 3cm, three fractions of CXB are usually delivered initially and this is followed by EBRT for patients who have residual tumour after CXB. For selected patients with very early rectal cancer who achieved an initial clinical complete response (cCR) after CXB, we did not offer EBRT as the likelihood of lymphatic spread is <20%. In this cohort, we categorised patients into three groups based on their reasons for receiving CXB without EBRT: Group A: 12 patients who refused surgery (of whom 7 also refused EBRT); Group B: 10 patients who were not suitable for surgery due to advanced age and/or comorbidities, and Group C: 11 patients who had received previous pelvic EBRT for other conditions and were therefore not eligible for further EBRT. The CXB treatment regimen consisted of 30Gy/#, a total of 90Gy over 4 weeks and a further dose of 20Gy was added instead of EBRT for patients who still had small volume residual disease. We adopted a watch-and-wait policy for follow-up with endoscopy, digital rectal examination and MRI every 3 months in the first two years and 6-monthly in the third year. Local tumour control rate, disease-free survival, radiation toxicities and sphincter preservation were analysed. Results A total of 33 patients were included, with a median follow-up of 2.9 years [IQR:1.0-5.0]) and there were no significant differences between the groups in terms of age, gender, performance status, T stage or tumour size. The initial cCR was excellent in Groups A and B (both 100%), but was significantly reduced (55%) in Group C (p=0.002). Sustained local tumour control was 83% in Group A, 90% in Group B, and 45% in Group C (p=0.30). Group A had better 5-year disease-free and overall survival rates (82% and 67%) compared to Group B (75% and 52%), and Group C (59% and 18%). The main radiation toxicity was rectal bleeding (21%), but only 6% of all patients required argon beam therapy. The overall organ preservation rate was 94% and only two patients needed a subsequent stoma. Conclusion In patients with early small rectal cancers with no suspicious lymph node spread, who are not suitable for or refuse surgery, it is feasible to offer CXB as the sole definitive treatment without EBRT. No patients relapsed with nodal tumour recurrence and only one patient developed distant metastasis during follow-up

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

Timing of Contact X-ray Brachytherapy in organ-preserving treatment of rectal cancer

Timing of Contact X-ray Brachytherapy in organ-preserving treatment of small rectal cancer Objective For patients with early rectal cancer, who are either at high risk for or refuse surgery, a planned organ preservation treatment involving a combination of external beam radiotherapy (EBRT) and Contact X-ray Brachytherapy (CXB) can be offered as an alternative option to surgery. (1-3) However, the ideal sequence of treatment for small rectal tumours (≤3cm), whether to administer CXB first or after EBRT, has not yet been well established, leading to variable sequences of this organ-preserving treatment being used.(3-5) This study has compared the oncological outcomes between the two treatment approaches using propensity score matching and inverse probability treatment weighting (IPTW) analysis to evaluate whether starting with CXB confers any benefits to patients. Method We analysed patients who had undergone both EBRT and CXB with curative intent, regardless of the treatment sequence, from the prospectively collected database at Clatterbridge Cancer Centre (2008-2019). Only patients who had well to moderately differentiated rectal adenocarcinoma (cT1-3, cN0-1, cM0) and small tumour size (≤ 3cm) were included. The variables of age, sex, fitness for surgery, performance status, tumour stage, nodal stage, EBRT regimen and CXB total dose, were considered possible confounders of the association between treatment regimen and outcomes. The balance of covariates before and after propensity matching and IPTW was assessed by examining the standardised mean difference (SMD) between the groups (Figure 1). The oncological outcomes based on the treatment sequence were first assessed in an unadjusted analysis followed by an adjusted model analysis considering all variables as confounders. Then, we performed propensity score matching (nearest-neighbour method, calliper= 0.25) and calculated IPTW to weigh the full cohort in each regression model. Statistical analysis was performed in R 4.3.1. The primary outcome measures were overall survival (OS) and disease-free survival (DFS). Secondary outcome measures consisted of the local regrowth rate, organ preservation rate, and presence of post-treatment rectal bleeding. Results A total of 251 eligible patients, who received either EBRT (n=103) or CXB (n=148) as their initial treatment with curative intent were included in the study. Patients received a CXB dose of 90-110Gy in 3-4 fractions over 4-6 weeks (each fraction two weeks apart) either before or after EBRT. EBRT was administered either as long-course chemoradiotherapy (45-50Gy/25 #/35 days), long-course radiotherapy alone (45Gy/20#/28days), or short-course radiotherapy (25Gy/5#/5 days). Following treatment, a watch-and-wait policy was adopted for patients who achieved a clinical complete/near response. The median follow-up was 37 [IQR:18-56] months for the EBRT-first group and 32 [IQR:16-54] months for the CXB-first group. In the unadjusted analysis, a higher risk of grade-1(26%) and grade-2(6%) rectal bleeding (p=0.008) was observed in patients who started with CXB, but no significant differences in any of the survival parameters were found. Analysis using the adjusted, propensity matching, and IPTW models, demonstrated a significant improvement of OS (p=0.04, HR (95%CI): 0.69 (0.48-0.98) and a higher risk of grade 1-2 rectal bleeding (p=0.01, OR (95%CI): 2.35(1.16-4.76) in those patients who had been received CXB as their initial treatment (Figure 2). However, DFS (p=0.87), local regrowth rate (p=0.70), and organ preservation rate (p=0.80) were not significantly different between the two groups. Conclusion Small rectal cancer (≤3cm), commencing treatment with CXB, as opposed to EBRT, was associated with improved overall survival, despite an increased risk of grade 1 and 2 rectal bleeding. However, there was no statistically significant improvement in terms of disease-free survival, local regrowth rate, or organ preservation rate with this treatment strategy

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