Neuroendocrine tumors are a heterogeneous group of slow-growing neoplasms arising mainly from the enterochromaffin cells of the digestive and respiratory tract. Although they are relatively rare, their incidence is rising. It has long been observed that they often are associated with the development of fibrosis, both local and distant. Fibrotic complications, such as carcinoid heart disease and mesenteric desmoplasia, may lead to considerable morbidity or even affect prognosis. The elucidation of the pathophysiology of fibrosis would be of critical importance for the development of targeted therapeutic strategies. In this article, the authors review the available evidence regarding the biological basis of fibrosis in neuroendocrine tumors. They explore the role of the tumor microenvironment and the interplay between tumor cells and fibroblasts as a key factor in fibrogenesis and tumor development/progression. They also review the role of serotonin, growth factors, and other peptides in the development of carcinoid-related fibrotic reactions. Cancer 2017;123:4770-90. © 2017 American Cancer Society.

The ward round (WR) is a complex task and medical teachers are often faced with the challenge of finding a balance between service provision and clinical development of learners. The educational value of WRs is an under-researched area. This short communication aims to evaluate the educational role of WRs for junior trainees and provides insight into current practices. It also identifies obstacles to effective teaching/training in this setting and provides suggestions for improving the quality of WR teaching.

Background: Small intestinal neuroendocrine tumours (SI NETs) represent 30–50% of small bowel neoplasms and often present at an advanced stage. To date, there is relatively limited literature regarding prognostic factors affecting overall survival (OS) in stage IV disease. In addition, the prevalence of mesenteric fibrosis (MF) in SI NETs and its effect on OS have not been sufficiently explored in the literature. Aim: The primary aim of this study was to perform a large-scale survival analysis in an institutional cohort of 387 patients with metastatic (stage IV) SI NETs. The secondary aim was to provide epidemiological information regarding the prevalence of MF and to evaluate its effect on OS. Results: The median OS was 101 months (95% CI 84, 118). Age > 65 years, mesenteric metastases with and without desmoplasia, liver metastases, carcinoid heart disease (CHD) and bone metastases were associated with a significantly shorter OS, while primary tumour resection was predictive of a longer OS. The benefit of surgical resection was limited to symptomatic patients. MF was present in approximately 50% of patients with mesenteric lymphadenopathy. Elevated urinary 5-HIAA levels correlated strongly with the presence of CHD (p < 0.001) and to a lesser extent (p = 0.02) with MF. MF and CHD did not usually co-exist, suggesting that different mechanisms are likely to be involved in the development of these fibrotic complications. Conclusions: This study has identified specific prognostic factors in a large cohort of 387 patients with advanced SI NETs and has provided useful epidemiological data regarding carcinoid-related fibrotic complications.

Our data suggest that PEG should be the procedure of choice when considering gastrostomy insertion and RIG should be reserved as a second-line approach for cases in which PEG is technically difficult or contraindicated.

Background:The antiproliferative activity of octreotide LAR in neuroendocrine tumours (NETs) has been demonstrated by small retrospective studies and confirmed by a prospective phase III trial (PROMID). However, there are limited data about the duration and predictors of response. The aim of our retrospective study was to determine the time to radiological progression (TTRP) of disease and the factors that were associated with better response.Methods:A total of 254 treatment naïve patients with advanced NETs and positive somatostatin receptor scintigraphy were included. Mean follow-up period was 42 months.Results:The location of primary was in the small bowel in 204, pancreas in 22, lungs in 14, rectum in 7 and unknown in 7 patients. Most tumours were well-differentiated, G1 (58%) and G2 (23%). The majority of patients commenced octreotide LAR due to functional symptoms (57%), radiological progression (10%) or in the presence of asymptomatic and stable disease on the basis of data from the PROMID trial (18.5%). Partial response occurred in 5%. For all patients, the median TTRP was 37 months (95% confidence interval, CI: 32–52 months). There was a statistically significant shorter TTRP in patients with pancreatic tumours, liver metastases and intermediate grade tumours. Extremely raised (>10 times the upper limit of normal) baseline chromogranin A levels were associated with an unfavourable outcome. In contrast, male sex, carcinoid heart disease and initiation of treatment in the presence of stable disease were predictive of a better response. Age, extra-hepatic metastases, presence of mesenteric desmoplasia, previous resection and functional status of the primary tumour did not affect response.Conclusions:The duration of the antiproliferative effect of octreotide LAR seems to be longer than previously reported. This study has identified several predictors of response in a large cohort of patients with NETs on somatostatin analogue therapy.

<b><i>Background:</i></b> Above-label doses of somatostatin analogs (SSAs) are increasingly utilized in the management of inoperable/metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs), progressing on standard 4-weekly regimens. <b><i>Objective:</i></b> To evaluate the antiproliferative effect of 3-weekly SSA administration in a retrospective GEP-NET cohort. <b><i>Methods:</i></b> Patients with advanced GEP-NET, treated with long-acting release (LAR) octreotide 30 mg or lanreotide Autogel 120 mg at a 3-weekly interval, after disease progression on standard 4-weekly doses, were retrospectively identified. Clinicopathologic and treatment response data were collected. Progression-free survival (PFS; dose escalation to radiographic progression or death) was estimated with the Kaplan-Meier method. Factors associated with PFS were identified with the Cox proportional-hazards model. <b><i>Results:</i></b> The inclusion criteria were fulfilled by 105 patients. Octreotide LAR was administered to 60 (57%) and lanreotide Autogel to 45 (43%). Indications for dose escalation were breakthrough carcinoid symptoms (58%), radiographic progression (35%) and/or increasing biomarkers (11%). Diarrheal and/or flushing symptomatic improvement was identified in 37/67 cases (55%) and 30/55 cases (55%) with available data, respectively. The disease control rate (radiographic partial response or stable disease) was achieved in 53 patients (50%). Median PFS was 25.0 months (95% CI 16.9–33.1). Patients with radiographic progression &#x3c;12 months from 4-weekly SSA initiation had worse PFS after dose escalation (7.0 vs. 17.0 months, <i>p</i> = 0.002). In multivariate analysis, pancreatic NETs, a Ki-67 index ≥5% and multiple extrahepatic metastases were independently associated with inferior PFS. <b><i>Conclusions:</i></b> Above-label doses of SSAs may offer a considerable prolongation of PFS and could be utilized as a bridge to other more toxic treatments. Patients with small bowel/colorectal primaries, a Ki-67 index &#x3c;5% and absence of/limited extrahepatic metastases are more likely to benefit from this approach.

Purpose Mesenteric fibrosis (MF) in small intestinal neuroendocrine neoplasms (SINENs) is often associated with significant morbidity and mortality. The detection of MF is usually based on radiological criteria, but no previous studies have attempted a prospective, multidimensional assessment of mesenteric desmoplasia to determine the accuracy of radiological measurements. There is also a lack of non-invasive biomarkers for the detection of image-negative MF. Methods A multidimensional assessment of MF incorporating radiological, surgical and histological parameters was performed in a prospective cohort of 34 patients with SINENs who underwent primary resection. Pre-operative blood samples were collected in 20 cases to evaluate a set of five profibrotic circulating transcripts-the "fibrosome"-that is included as an "omic" component of the NETest. Results There was a significant correlation between radiological and surgical assessments of MF (p < 0.05). However, there were several cases of image-negative MF. The NETest-fibrosome demonstrated an accuracy of 100% for the detection of microscopic MF. Conclusions The detection of MF by radiological criteria has limitations. The NETest-fibrosome is a promising biomarker for fibrosis detection and further validation of these results would be needed in larger, multicentre studies.

Recent advancements in virtual reality graphics and models have allowed virtual reality simulators to be incorporated into a variety of endoscopic training programmes. Use of virtual reality simulators in training programmes is thought to improve skill acquisition amongst trainees which is reflected in improved patient comfort and safety. Several studies have already been carried out to ascertain the impact that usage of virtual reality simulators may have upon trainee learning curves and how this may translate to patient comfort. This article reviews the available literature in this area of medical education which is particularly relevant to all parties involved in endoscopy training and curriculum development. Assessment of the available evidence for an optimal exposure time with virtual reality simulators and the long-term benefits of their use are also discussed.