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Purpose of Review: This article aims to illustrate the current state of investigations and management of liver metastases in patients with Neuroendocrine Neoplasms. Neuroendocrine tumours (NETs) are rising in incidence globally and have become the second most prevalent gastrointestinal malignancy in UK and USA. Frequently, patients have metastatic disease at time of presentation. The liver is the most common site of metastases for gastro-enteropancreatic NETs. Characterisation of liver metastases with imaging is important to ensure disease is not under-staged., Recent Findings: Magnetic resonance imaging and positron emission tomography are now becoming standard of care for imaging liver metastases. There is an increasing armamentarium of therapies available for management of NETs and loco-regional therapy for liver metastases. The data supporting surgical and loco-regional therapy is reviewed with focus on role of liver transplantation. It is important to use appropriate imaging and classification of NET liver metastases. It is key that decisions regarding approach to treatment is undertaken in a multidisciplinary team and that individualised approaches are considered for management of patients with metastatic NETs., (© 2024. The Author(s).)

Patients with neuroendocrine tumours located in the gastroenteropancreatic tract (GEP-NETs) and treatment with somatostatin analogues (SSA's) are at risk of malnutrition which has been reported previously evaluating weight loss or body mass index (BMI) only. The global leadership into malnutrition (GLIM) criteria include weight loss, BMI, and sarcopenia, for diagnosing malnutrition. These GLIM criteria have not been assessed in patients with GEP-NETs on SSA. The effect of malnutrition on overall survival has not been explored before. The aim of this study is to describe the presence of malnutrition in patients with GEP-NET on SSA based on the GLIM criteria and associate this with overall survival. Cross-sectional study screening all patients with GEP-NETs on SSA's for malnutrition using the GLIM criteria. Body composition analysis for sarcopenia diagnosis were performed. Bloods including vitamins, minerals, and lipid profile were collected. Overall survival since the date of nutrition screening was calculated. Uni- and multivariate Cox regression analysis were performed to identify malnutrition as risk factor for overall survival. A total of 118 patients, 47% male, with median age 67 years (IQR 56.8-75.0) were included. Overall, malnutrition was present in 88 patients (75%); based on low BMI in 26 (22%) patients, based on weight loss in 35 (30%) patients, and based on sarcopenia in 83 (70%) patients. Vitamin deficiencies were present for vitamin D in 64 patients (54%), and vitamin A in 29 patients (25%). The presence of malnutrition demonstrated a significantly worse overall survival (p-value = .01). In multivariate analysis meeting 2 or 3 GLIM criteria was significantly associated with worse overall survival (HR 2.16 95% CI 1.34-3.48, p-value = .002). Weight loss was the most important risk factor out of the 3 GLIM criteria (HR 3.5 95% CI 1.14-10.85, p-value = .03) for worse overall survival. A high percentage (75%) of patients with GEP-NETs using a SSA meet the GLIM criteria for malnutrition. Meeting more than 1 GLIM criterium, especially if there is weight loss these are risk factors for worse overall survival., (© 2024 British Society for Neuroendocrinology.)

Purpose of the Review: To summarise the current literature regarding the presence of sarcopenia in patients with neuroendocrine neoplasms (NENs). These are uncommon cancers separated into well-differentiated neuroendocrine tumours (NETs) and poorly differentiated neuroendocrine carcinoma (NECs). For the diagnosis of sarcopenia, there needs to be low muscle strength and low muscle quantity/quality., Recent Findings: Five studies exist describing either low muscle strength or low muscle quantity in patients with NETs. The studies used different techniques to analyse muscle strength and muscle quantity, included heterogeneous populations, and performed the analysis at different time points following the diagnosis of the NET. Only 2 studies regarding patients with NECs could be found, both included mainly patients with a mixed adenoneuroendocrine carcinoma (MiNEN) and are, therefore, difficult to interpret for patients with a NEC. The main findings of this review are to describe the presence of sarcopenia in patients with NENs. However, results should be interpreted with caution, and future research should focus on the correct technique, homogenous population and same time point., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Multiple recurrent genetic and epigenetic aberrations have been associated with worse prognosis in multiple studies of neuroendocrine tumours (NETs), but these have been mainly small cohorts and univariate analysis. This review and meta-analysis will focus upon the literature available on NETs of the gastrointestinal (GI) tract, liver, biliary tract and pancreas. PubMed and Embase were searched for publications that investigated the prognostic value of (epi)genetic changes of neuroendocrine tumours. A meta-analysis was performed assessing the association of the (epi)genetic alterations with overall survival (OS), disease-free survival (DFS) or locoregional control (LRC). In the pancreas DAXX/ATRX [hazard ratio (HR) = 3.29; 95% confidence interval (CI) = 2.28-4.74] and alternative lengthening telomeres (ALT) activation (HR = 8.20; 95% CI = 1.40-48.07) showed a pooled worse survival. In the small bowel NETs gains on chromosome 14 were associated with worse survival (HR  2.85; 95% CI = 1.40-5.81). NETs from different anatomical locations must be regarded as different biological entities with diverging molecular prognosticators, and epigenetic changes being important to the pathogenesis of these tumours. This review underpins the prognostic drivers of pancreatic NET which lie in mutations of DAXX/ATRX and ALT pathways. However, there is reaffirmation that prognostic molecular biomarkers of small bowel NETs should be sought in copy number variations (CNVs) rather than in single nucleotide variations (SNVs). This review also reveals how little is known about the prognostic significance of epigenetics in NETs., (© 2023 John Wiley & Sons Ltd.)

Somatostatin receptor (SST) PET/CT is the gold standard for well-differentiated neuroendocrine tumours (NET) imaging. Higher grades of neuroendocrine neoplasms (NEN) show preferential [18F]FDG (FDG) uptake, and even low-grade NET may de-differentiate over time. FDG PET/CT's prognostic role is widely accepted; however, its impact on clinical decision-making remains controversial and its use varies widely. A questionnaire-based survey on FDG PET/CT use and perceived decision-making utility in NEN was submitted to the ENETS Advisory Board Meeting attendees (November 2022, response rate = 70%). In 3/15 statements, agreement was higher than 75%: (i) FDG was considered useful in NET, irrespective of grade, in case of mis-matched lesions (detectable on diagnostic CT but negative/faintly positive on SST PET/CT), especially if PRRT is contemplated (80%); (ii) in NET G3 if curative surgery is considered (82%); and (iii) in NEC prior to surgery with curative intent (98%). FDG use in NET G3, even in the presence of matched lesions, as a baseline for response assessment was favoured by 74%. Four statements obtained more than 60% consensus: (i) FDG use in NET G3 if locoregional therapy is considered (65%); (ii) in neuroendocrine carcinoma before initiating active therapy as a baseline for response assessment (61%); (iii) biopsy to re-assess tumour grade prior to a change in therapeutic management (68%) upon detection of FDG-positivity on the background of a prior G1-2 NET; (iv) 67% were in favour to reconsider PRRT to treat residual SST-positive lesions after achieving complete remission on FDG of the SST-negative disease component. Multidisciplinary opinion broadly supports the use of FDG PET/CT for characterisation of disease biology and to guide treatment selection across a range of indications, despite the lack of full consensus in many situations. This may reflect existing clinical access due to lack of reimbursement or experience with this investigation, which should be addressed by further research., (© 2023 British Society for Neuroendocrinology.)

Introduction: Maintaining adequate nutritional status can be a challenge for patients with small bowel neuroendocrine tumours (NETs). Surgical resection could result in short bowel syndrome (SBS), whilst without surgical resection there is a considerable risk of ischemia or developing an inoperable malignant bowel obstruction (IMBO). SBS or IMBO are forms of intestinal failure (IF) which might require treatment with home parenteral nutrition (HPN). Limited data exist regarding the use of HPN in patients with small bowel neuroendocrine tumours, and it is not frequently considered as a possible treatment., Methods: A systematic review was performed regarding patients with small bowel NETs and IF to report on overall survival and HPN-related complications and create awareness for this treatment., Results: Five articles regarding patients with small bowel NETs or a subgroup of patients with NETs could be identified, mainly case series with major concerns regarding bias. The studies included 60 patients (range 1-41). The overall survival time varied between 0.5 and 154 months on HPN. However, 58% of patients were alive 1 year after commencing HPN. The reported catheter-related bloodstream infection rate was 0.64-2 per 1000 catheter days., Conclusion: This systematic review demonstrates the feasibility of the use of HPN in patients with NETs and IF in expert centres with a reasonable 1-year survival rate and low complication rate. Further research is necessary to compare patients with NETs and IF with and without HPN and the effect of HPN on their quality of life.

Background and Aims: Only limited information is available on the use of home parenteral nutrition (HPN) in patients with advanced neuroendocrine tumours (NETs) causing intestinal failure (IF). This study aims to report the outcomes of the explore the use of HPN in this patient cohort, in the largest case series to date., Methods: A retrospective study in the United Kingdom and the Netherlands was performed, using the UK National British Artificial Nutrition Survey (BANS) and local databases in the Netherlands. Data regarding age, sex, NET grading, staging, treatment, HPN characteristics and survival outcomes were collected., Results: Data were collected on 41 patients (n = 18 males, 44%) with a median age of 65. Most primary tumours were in the small bowel (n = 35, 85%). The NETs were Grade 1 (n = 16, 39%), Grade 2 (n = 7, 17%), Grade 3 (n = 1, 2%). In 28 patients (n = 68%) there was stage IV disease with metastases located in the peritoneum, mesentery and or liver. There were two indications for HPN; short bowel syndrome (n = 27, 66%) and inoperable malignant bowel obstruction (n = 14, 34%). The median period on HPN was 11 months (interquartile range 4-25 months). 11 patients were still alive and receiving HPN treatment after 2 years, and 6 patients after 3 years. Six patients (22%) with short bowel syndrome (SBS) could be weaned from HPN. There was a statistically significant improved survival for patients with short bowel syndrome (median 24 months) compared to inoperable malignant bowel obstruction (median 7 months). The catheter-related bloodstream infection rate was comparable to other HPN patient cohorts at 1.0 per 1000 catheter days., Conclusion: This study shows that HPN can be used safely in patients with NET and IF to increase survival beyond that reasonably expected in the context of either short bowel syndrome or inoperable malignant bowel obstruction. Patients with short bowel syndrome are most likely to benefit. Further prospective studies are necessary to validate survival benefits and to demonstrate the effect of HPN on quality of life., Competing Interests: Declaration of competing interest The authors have no conflicts of interest to declare., (Crown Copyright © 2023. Published by Elsevier Ltd. All rights reserved.)

Introduction: Patients with neuroendocrine neoplasms (NENs) may often develop other malignancies. This study aimed to identify the frequency at which these second malignancies occurred in England., Methods: Data were extracted from the National Cancer Registration and Analysis Service (NCRAS) on all patients diagnosed with a NEN at one of eight NEN site groups between 2012 and 2018: appendix, caecum, colon, lung, pancreas, rectum, small intestine, and stomach. WHO International Classification of Disease Edition-10 (ICD-10) codes were used to identify patients who had been diagnosed with an additional non-NEN cancer. Standardized incidence ratios (SIRs) for tumours diagnosed after the index NEN were produced for each non-NEN cancer type by sex and site., Results: A total of 20,579 patients were included in the study. The most commonly occurring non-NEN cancers after NEN diagnosis were the prostate (20%), lung (20%), and breast (15%). Statistically significant SIRs were observed for non-NEN cancer of the lung (SIR = 1.85, 95% CI: 1.55-2.22), colon (SIR = 1.78, 95% CI: 1.40-2.27), prostate (SIR = 1.56, 95% CI: 1.31-1.86), kidney (SIR = 3.53, 95% CI: 2.72-4.59), and thyroid (SIR = 6.31, 95% CI: 4.26-9.33). When stratified by sex, statistically significant SIRs remained for the lung, renal, colon, and thyroid tumours. Additionally, females had a statistically significant SIR for stomach cancer (2.65, 95% CI: 1.26-5.57) and bladder cancer (SIR = 2.61, 95% CI: 1.36-5.02)., Conclusion: This study found that patients with a NEN experienced a metachronous tumour of the lung, prostate, kidney, colon, and thyroid at a higher rate than the general population of England. Surveillance and engagement in existing screening programmes are required to enable earlier diagnosis of second non-NEN tumours in these patients., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Primary renal neuroendocrine neoplasms (NEN) are rare. We aimed to conduct a systematic review, present local cases, and analyse data from the England's National Cancer Registration and Analysis Service (NCRAS) to provide comprehensive evidence on clinical experience, incidence, and survival to better characterize these tumours. First, a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method; second, a synthesis of local cases; and, finally, a retrospective population-based cohort analysis of renal NEN recorded between 2012 and 2018 on NCRAS were performed. Kaplan-Meier estimator was used to calculate overall survival and Cox proportional hazard regression to identify prognostic factors. Systematic review identified 48 articles and the evidence was summarized and presented. We reported data from four local cases presenting with abdominal and back pain but without carcinoid syndrome. In population-based analysis, we identified 63 cases of renal NEN between 2012 and 2018 from the registry. Age-standardized incidence was 0.09-0.32 per million with a median age of 64 years (interquartile range = 48-72 years). Survival was worse in males and those aged 64 years and over. Five-year survival for renal neuroendocrine tumours (NET) was 69.8% (95% confidence interval = 66.6-72.7) and neuroendocrine carcinomas (NEC) was 38.4% (95% confidence interval = 34.6-42.0). No independent predictive factor was identified in the multivariable analyses. We have given a systematic review of evidence, published local experience, and reported incidence and survival of renal NEN in England for the first time. We have provided clinicians with evidence on diagnosis and proposed a treatment algorithm of theses rare tumours. The incidence and median age of presentation in England is similar to other published series. Renal NET has better survival than renal NEC as expected. A uniform classification system would reduce inconsistencies in reporting and standardize treatment decisions for this neoplasia., (© 2022 British Society for Neuroendocrinology.)

Duodenal neuroendocrine neoplasms (dNENs) are rare neoplasms but their incidence is on the rise. They are classified into 5 sub-types but there remains much heterogeneity in behaviour in particular of non-functioning dNENs. To retrospectively analyse outcomes for all types of dNENs, and highlight prognostic factors associated with worse outcome. 102 (57 m/45f.) patients were identified with mean age at diagnosis 62 (range 32-87) years. The majority were non-functioning tumours 87/102 and median size was 10 mm (range 0.9-130 mm). 83 patients had Stage I or II disease, of which 17 underwent endoscopic resection with R1 rate of 45% and complication rate 12%. 36 patients were kept under endoscopic surveillance. There were 11 deaths of which 4 were disease related. Age and Ki67 > 20% were associated with worse OS in all dNENs. In non-functioning dNENs Ki67 > 3% was a predictor of lymph nodes metastases with OR 18.2 (2.54-13) (p < 0.005) in univariate analyses and liver metastases with OR 6.79 (1.56-29.5) (p < 0.05) in the multivariate analysis. Lesions 11-20 mm in size had OR 11.1 (1.16-106) compared to lesions < 11 mm for the prediction of lymph node metastases in the multivariate analysis (p < 0.05). ROC analysis of size of non-functioning dNENs to predict LN metastases found < 15 mm had an AUROC of 0.9 (0.81-0.99) with a sensitivity of 85% and specificity of 88%. dNENs are increasing in incidence, however low grade and smaller lesions have an indolent course and the role of endoscopic resection and active surveillance needs to be reviewed., (© 2022. The Author(s).)

Purpose: NETTER-R aimed to determine the efficacy, safety and tolerability of 177 Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites., Methods: This international study retrospectively included patients with panNETs treated with 177 Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response., Results: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177 Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5-34.5), and the objective response rate was 40.3% (95% CI: 28.1-53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0-123.4 months) after the first cycle of 177 Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6-50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177 Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification., Conclusions: These results reinforce the role of 177 Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs., (© 2022. The Author(s).)

Neuroendocrine liver metastases (LM-NEN) develop in a considerable proportion of patients with gastroenteropancreatic neuroendocrine neoplasms. There is a paucity of experimental models that accurately recapitulate this complex metastatic human liver microenvironment precluding scientific and clinical advancements. Here, we describe the development of a novel personalised immunocompetent precision cut tumour slice (PCTS) model for LM-NEN using resected human liver tissue. The histological assessment throughout the culture demonstrated that slices maintain viability for at least 7 days and retain the cellular heterogeneity of the original tumour. Essential clinical features, such as patient-specific histoarchitecture, tumour grade, neuroendocrine differentiation and metabolic capacity, are preserved in the slices. The PCTS also replicate the tumor-specific immunological profile as shown by the innate and adaptive immunity markers analysis. Furthermore, the study of soluble immune checkpoint receptors in the culture supernatants proves that these immunomodulators are actively produced by LM-NEN and suggests that this process is epithelium-dependent. This model can be employed to investigate these pathways and provides a powerful platform for mechanistic, immunological and pre-clinical studies., 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 © 2022 Doornebal, Harris, Riva, Jagatia, Pizanias, Prachalias, Menon, Preziosi, Zamalloa, Miquel, Zen, Orford, Eaton, Heaton, Ramage, Palma, Srirajaskanthan and Chokshi.)

Background: This European Neuroendocrine Tumor Society (ENETS) Expert Consensus document aims to provide practical guidance and standardization for echocardiography in the screening and follow-up of carcinoid heart disease (CHD) in patients with a neuroendocrine tumour (NET) and carcinoid syndrome., Methods: NET experts within the ENETS Carcinoid Heart Disease Task Force reviewed both general reporting guidelines and specialized scoring systems for transthoracic echocardiography (TTE) in CHD. Based on this review, a dedicated template report was designed by the multidisciplinary working group of cardiologists, oncologists, endocrinologists, gastroenterologists, surgeons and radiologists., Results: We propose a Synoptic Reporting of Echocardiography in Carcinoid Heart Disease which represents an agreed peer reviewed proforma to capture information at the time of referral and enable a detailed outcome of CHD assessment. This includes a systematic and detailed list of structures to evaluate data to capture at the time of reporting of TTE., Conclusions: Adherence to these reporting guidelines aims to promote homogeneous and detailed evaluation of CHD to secure accurate assessment and allow comparison of studies performed intra- and inter-individually. These guidelines could also facilitate CHD assessment as part of prospective clinical trials to enable standardization of the findings seen in response to therapy., (© 2021 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Aim: Rectal neuroendocrine tumours (NETs) are the most common type of gastrointestinal NET. European Neuroendocrine Tumour Society guidelines suggest that rectal NETs measuring ≤10 mm are indolent with low risk of spread. In practice, many patients with lesions ≤1 cm do not undergo complete tumour staging. However, the size of the lesion may not be the only risk factor for nodal involvement/metastases. The aim of this study was to determine if MRI ± nuclear medicine imaging alters tumour stage in patients with rectal NETs ≤10 mm., Methods: Patients referred to a tertiary NET centre between 2005 and 2020 who met the inclusion criteria of a rectal NET ≤10 mm, full cross-sectional imaging, primarily an MRI scan and, if abnormal findings were identified, a subsequent 68 Ga-DOTATATE positron emission tomography scan were included. All patients were followed up at our institution., Results: In all, 32 patients with rectal NETs 10 mm or less were included in the study: 16 women; median age 58 years (range 33-71); 47% (n = 15) were referred from bowel cancer screening procedures. The median size of the lesions was 5 mm (range 2-10 mm). 81% (n = 26) were World Health Organization Grade 1 tumours with Ki67 <3%. Radiological staging confirmed nodal involvement in 25% (8/32); two cases had distant metastatic disease. Lymphovascular invasion was present in 3% (1/32) of patients but none demonstrated peri-neural invasion., Conclusion: This study demonstrates that small rectal NETs can develop nodal metastases; therefore it is important to stage these tumours accurately with MRI at baseline and, if there are concerns regarding potential lymph node metastases, to consider 68 Ga-DOTATATE positron emission tomography imaging., (© 2021 The Association of Coloproctology of Great Britain and Ireland.)

Background/aims: Long-term outcomes are understudied in patients with well-differentiated appendiceal neuroendocrine neoplasms (WD-ANENs). We aimed to evaluate the validity of currently applied criteria for completion prophylactic right hemicolectomy (pRHC) and determine its association with patient outcomes, including health-related quality of life (HRQoL)., Methods: Eligible patients from five European referral centers were divided between those who underwent appendectomy alone and those who underwent completion pRHC. HRQoL EORTC-QLC-C30 questionnaires and cross-sectional imaging data were prospectively collected. Age- and sex-matched healthy controls were recruited for HRQoL analysis' validation., Results: We included 166 patients (119 women [71.2%]: mean age at baseline: 31 ± 16 years). Mean follow-up was 50.9 ± 54 months. Most patients (152 [92%]) had tumors ≤20 mm in size. Fifty-eight patients (34.9%) underwent pRHC that in final analysis was regarded as an overtreatment in 38/58 (65.5%). In multivariable analysis, tumor size >20 mm was the only independent predictor for lymph node (LN) involvement (p = 0.002). No mortality was reported, whereas 2-, 5- and 10-year recurrence-free survival in patients subjected to postoperative cross-sectional imaging (n = 136) was 98.5%, 97.8%, and 97.8%, respectively. Global HRQoL was not significantly impaired in patients with WD-ANEN compared with age- and sex-matched healthy individuals (median scores 0.83[0.08-1] vs 0.83[0.4-1], respectively; p = 0.929). Among patients with WD-ANEN impaired social functioning (p = 0.016), diarrhea (p = 0.003) and financial difficulties (0.024) were more frequently reported in the pRHC group., Conclusions: WD-ANEN is a low-malignant neoplasm with unconfirmed associated mortality, low recurrence rate, and overall preserved HRQoL. pRHC comes at a price of excessive surgery, functional HRQoL issues, and diarrhea. The value per se of a prophylactic surgical approach to patients with WD-ANENs <20 mm is challenged.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177 Lu-Dotatate., Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression., Results: Significantly prolonged median PFS occurred with 177 Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177 Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden., Conclusions: 177 Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Background: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are slow-growing cancers that arise from diffuse endocrine cells in the gastrointestinal tract (GI-NETs) or the pancreas (P-NETs). They are relatively uncommon, accounting for 2% of all gastrointestinal malignancies. The usual treatment options in advanced GEP-NET patients with metastatic disease include chemotherapy, biological therapies, and peptide receptor radionuclide therapy. Understanding the impact of treatment on GEP-NET patients is paramount given the nature of the disease. Health-related quality of life (HRQoL) is increasingly important as a concept reflecting the patients' perspective in conjunction with the disease presentation, severity and treatment., Aim: To conduct a systematic literature review to identify literature reporting HRQoL data in patients with GEP-NETs between January 1985 and November 2019., Methods: The PRISMA guiding principles were applied. MEDLINE, Embase and the Cochrane library were searched. Data extracted from the publications included type of study, patient population data (mid-gut/hind-gut/GI-NET/P-NET), sample size, intervention/comparators, HRQoL instruments, average and data spread of overall and sub-scores, and follow-up time for data collection., Results: Forty-three publications met the inclusion criteria. The heterogeneous nature of the different study populations was evident; the percentage of female participants ranged between 30%-60%, whilst average age ranged from 53.8 to 67.0 years. Eight studies investigated GI-NET patients only, six studies focused exclusively on P-NET patients and the remaining studies involved both patient populations or did not report the location of the primary tumour. The most commonly used instrument was the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 ( n = 28) with consistent results across studies; the GI-NET-specific module Quality of Life Questionnaire-GINET21 was used in six of these studies. A number of randomised trials demonstrated no HRQoL changes between active treatment and placebo arms. The Phase III NETTER-1 study provides the best data available for advanced GEP-NET patients; it shows that peptide receptor radionuclide therapy can significantly improve GEP-NET patients' HRQoL., Conclusion: HRQoL instruments offer a means to monitor patients' general disease condition, disease progression and their physical and mental well-being. Instruments including the commonly used European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 and GINET21 lack, however, validation and a defined minimal clinical important difference specifically for GI-NET and P-NET patients., Competing Interests: Conflict-of-interest statement: All the authors declare that they have no competing interests., (©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.)

Incidence of neuroendocrine neoplasia (NEN) is increasing, as is use of health-related quality of life (HRQoL) measurement in clinical trials. Following development of validated questionnaires, HRQoL is widely used to assess outcomes. This review is intended for healthcare professionals and is based on a selection of data published in the last decade. HRQoL is on par with other clinical endpoints such as performance status. Assessments in clinical trials have been particularly useful for monitoring the symptom burden of NEN, for the effects of treatments on patients' lives, and have provided new data allied to the usual clinical endpoints. QoL expressed as quality-adjusted life years (QALYs) have become the most important primary outcome to establish cost-effectiveness in health economic evaluation. From looking at clinical trials over the last 10 years, we see that the quality of HRQoL evidence reported in published studies has improved and, in general, recent studies are likely to be more methodologically robust. Assessment of HRQoL in clinical trials is likely to become a standard part of clinical practice in NEN, as in other cancers. However, clear methods for calculating the clinical meaningfulness of changes in scores are needed. Other limitations of HRQoL measurement include lack of specificity to certain symptom sets and ease of completion and administration. An international group taking a lead on developing HRQoL research specifically in NEN patients is needed to address limitations of the evidence base. In order for greater weight to be placed on HRQoL data, agreement on optimal, validated scoring systems is needed.

Background: The diagnosis of neuroendocrine neoplasms (NENs) is often delayed. This first UK population-based epidemiological study of NENs compares outcomes with non-NENs to identify any inequalities., Methods: Age-standardised incidence rate (ASR), 1-year overall survival, hazard ratios and standardised mortality rates (SMRs) were calculated for all malignant NENs diagnosed 2013-2015 from UK national Public Health records. Comparison with non-NENs assessed 1-year overall survival (1YS) and association between diagnosis at stage IV and morphology., Results: A total of 15,222 NENs were identified, with an ASR (2013-2015 combined) of 8.6 per 100,000 (95% CI 8.5-8.7); 4.6 per 100 000 (95% CI, 4.5-4.7) for gastro-entero-pancreatic (GEP) NENs. The 1YS was 75% (95% CI, 73.9-75.4) varying significantly by sex. Site and morphology were prognostic. NENs (predominantly small cell carcinomas) in the oesophagus, bladder, prostate, and female reproductive organs had a poorer outcome and were three times more likely to be diagnosed at stage IV than non-NENs., Conclusion: Advanced stage at diagnosis with significantly poorer outcomes of some NENs compared with non-NENs at the same anatomical site, highlight the need for improved access to specialist services and targeted service improvement.

Purpose: To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs)., Methods: Seventy-four patients were recruited from four NEN centers in this observational multicenter study., Results: Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4-395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589-14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14-463) months., Conclusions: Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.

Symptoms of gastroenteropancreatic located neuroendocrine neoplasms (GEP-NENs) are often related to food intake and manifest as abdominal pain or diarrhoea which can influence patients nutritional status. Malnutrition is common in cancer patients and influences quality of life, treatment options and survival but is also present in up to 40% of patients with GEP-NENs. As part of malnutrition there are often deficiencies in fat-soluble vitamins, mainly vitamin D. Little knowledge exists on trace elements. Several factors influence the development of malnutrition such as size and localisation of the primary tumour as well as metastases, side effects from treatment but also hormone production of the tumour itself. One of the main influencing factors leading to malnutrition is diarrhoea which leads to dehydration and electrolyte disturbances. Treatment of diarrhoea should be guided by its cause. Screening for malnutrition should be part of routine care in every GEP-NEN patient. Multidisciplinary treatment including dietician support is necessary for all malnourished patients with GEP-NENs., Competing Interests: Conflict-of-interest statement: No conflict of interest.

Background: Patients with advanced midgut neuroendocrine tumors who have had disease progression during first-line somatostatin analogue therapy have limited therapeutic options. This randomized, controlled trial evaluated the efficacy and safety of lutetium-177 ( 177 Lu)-Dotatate in patients with advanced, progressive, somatostatin-receptor-positive midgut neuroendocrine tumors., Methods: We randomly assigned 229 patients who had well-differentiated, metastatic midgut neuroendocrine tumors to receive either 177 Lu-Dotatate (116 patients) at a dose of 7.4 GBq every 8 weeks (four intravenous infusions, plus best supportive care including octreotide long-acting repeatable [LAR] administered intramuscularly at a dose of 30 mg) ( 177 Lu-Dotatate group) or octreotide LAR alone (113 patients) administered intramuscularly at a dose of 60 mg every 4 weeks (control group). The primary end point was progression-free survival. Secondary end points included the objective response rate, overall survival, safety, and the side-effect profile. The final analysis of overall survival will be conducted in the future as specified in the protocol; a prespecified interim analysis of overall survival was conducted and is reported here., Results: At the data-cutoff date for the primary analysis, the estimated rate of progression-free survival at month 20 was 65.2% (95% confidence interval [CI], 50.0 to 76.8) in the 177 Lu-Dotatate group and 10.8% (95% CI, 3.5 to 23.0) in the control group. The response rate was 18% in the 177 Lu-Dotatate group versus 3% in the control group (P<0.001). In the planned interim analysis of overall survival, 14 deaths occurred in the 177 Lu-Dotatate group and 26 in the control group (P=0.004). Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 1%, 2%, and 9%, respectively, of patients in the 177 Lu-Dotatate group as compared with no patients in the control group, with no evidence of renal toxic effects during the observed time frame., Conclusions: Treatment with 177 Lu-Dotatate resulted in markedly longer progression-free survival and a significantly higher response rate than high-dose octreotide LAR among patients with advanced midgut neuroendocrine tumors. Preliminary evidence of an overall survival benefit was seen in an interim analysis; confirmation will be required in the planned final analysis. Clinically significant myelosuppression occurred in less than 10% of patients in the 177 Lu-Dotatate group. (Funded by Advanced Accelerator Applications; NETTER-1 ClinicalTrials.gov number, NCT01578239 ; EudraCT number 2011-005049-11 .).

Unlabelled: (111)In-diethylenetriaminepentaacetic acid (DTPA)-octreotide scintigraphy is currently the nuclear medicine imaging modality of choice for identifying neuroendocrine tumors. However, there are cohorts of patients in whom scintigraphy findings are negative or equivocal. We evaluated the role of (68)Ga-DOTATATE PET in a selected group of patients with negative or weakly positive findings on (111)In-DTPA-octreotide scintigraphy to determine whether (68)Ga-DOTATATE PET is able to detect additional disease and, if so, whether patient management is altered., Methods: Fifty-one patients with a histologically confirmed diagnosis of neuroendocrine tumors were included. Of the 51 patients, 35 who were negative and 16 equivocal for uptake on (111)In-DTPA-octreotide scintigraphy underwent (68)Ga-DOTATATE PET. Findings were compared using a region-by-region analysis. All findings were verified with CT or MRI. After (68)Ga-DOTATATE PET, all cases were reviewed to determine whether the (68)Ga-DOTATATE PET findings resulted in any alteration in management, in terms of suitability for peptide receptor therapy, somatostatin analogs, and surgery., Results: Of the 51 patients, 47 had evidence of disease on cross-sectional imaging or biochemically. (68)Ga-DOTATATE PET was positive in 41 of these 47 patients (87.2%). No false-positive lesions were identified. (68)Ga-DOTATATE PET detected 168 of the 226 lesions (74.3%) that were identified with cross-sectional imaging. (68)Ga-DOTATATE PET identified significantly more lesions than (111)In-DTPA-octreotide scintigraphy (P < 0.001). There was no correlation between (68)Ga-DOTATATE uptake and histologic grade of neuroendocrine tumors. (68)Ga-DOTATATE imaging changed management in 36 patients (70.6%), who were subsequently deemed suitable for peptide receptor-targeted therapy., Conclusion: In patients with negative or equivocal (111)In-DTPA-octreotide findings, (68)Ga-DOTATATE PET identifies additional lesions and may alter management in most cases.

Neuroendocrine tumors (NETs) can arise from a variety of organs. They can vary widely in clinical behavior; consequently, optimizing their treatment plan can be problematic. NETs display diverse tumor biology; however, most secrete peptides such as chromogranin A into the circulation, consistent with their neuroendocrine origin. In this study, we sought to identify other potential markers for NETs by analyzing the secreted proteomes of three neuroendocrine cell lines. BON-1, NCI-H727, and SHP-77 cells were grown in serum-free media, and the secreted proteins were separated by SDS-PAGE and identified by LC-MS/MS. We identified 205 proteins of which 61 were secreted by two or more of the cell lines and 19 were secreted by all three lines. Mac-2-binding protein (Mac-2BP) was found to be secreted by all three cell lines, and this was confirmed by Western blotting. Immunohistochemical analysis found 29 of 33 NET cases from different primary sites to be positive for Mac-2BP. Serum Mac-2BP was significantly elevated in NET patients compared with healthy controls (p < 0.001). This study demonstrated that analysis of the secreted proteomes of neuroendocrine cell lines can identify potential biomarkers for NET. Initial assessment showed that serum Mac-2BP is significantly elevated in patients with NET and is expressed by the majority of NET tissues.

The type I receptor tyrosine kinase family comprises four homologous members: Epidermal growth factor receptor (EGFR), HER-2, HER-3 and HER-4. Studies have shown that EGFR and HER-2 play a critical role in oncogenesis. In this study we sought to determine the pattern of expression and the prognostic significance of EGFR, HER-2, HER-3 and HER-4 in a variety of neuroendocrine tumours using immunohistochemistry. HER family receptor expression in 82 paraffin-embedded specimens of neuroendocrine tumours using immunohistochemistry was examined. The pattern and protein expression levels for each receptor were correlated with clinical and pathological parameters. EGFR expression was identified in 86.6% samples, HER-2 was not expressed in any samples, HER-3 was expressed in 8.5% samples and HER-4 was expressed 91.5%. EGFR and HER-4 were co-expressed in 79.3% of cases. HER-3 was correlated with better survival. EGFR was not associated with poor prognosis. This study has demonstrated EGFR, HER-2 and HER-4 expression is not associated with poorer survival. HER-3 expression is correlated with better prognosis. Overexpression of EGFR and HER-4 may offer potential new therapeutic targets.

Background/aims: Parathyroid hormone-related peptide (PTHrP) was discovered in 1987 as the tumour product responsible for humoral hypercalcaemia of malignancy (HHM). Pancreatic neuroendocrine tumours (NETs) are uncommon malignancies with an incidence of 1:100,000 population. PTHrP-secreting NETs are rare but are being recognised as a cause of HHM in NETs. We describe the largest series to date and the management of these rare tumours., Methods: One male and 4 female patients were seen in our unit from 1998 to 2006. The average duration of follow-up was 86 months from initial diagnosis. All patients had a histologically confirmed diagnosis of pancreatic NET, all of which were low-grade tumours. PTHrP assay was performed in 4 of 5 cases and was elevated in these patients., Results: Initial management involved surgery in 2 of 5 cases, whilst 2 cases underwent chemotherapy and 1 case was commenced on interferon-alpha. We discuss the further therapies that all patients underwent and the complexities that arose in managing disease progression as well as resistant hypercalcaemia., Conclusion: PTHrP-secreting tumours should be considered in the differential diagnosis of patients with NETs who present with hypercalcaemia and a disproportionately low PTH. PTHrP tumours may well be underestimated as the assay is difficult to perform and may not be requested. In hypercalcaemic patients the standard management acutely includes intravenous fluids, diuretics and intravenous bisphosphonate. In the further management, somatostatin analogue therapy is the first medical option to consider and we discuss the role of other therapies.

Background: In-pentetreotide scan (OctreoScan) is a widely available agent with high sensitivity for imaging neuroendocrine tumours. Negative In-pentetreotide poses diagnostic as well as therapeutic problems in terms of staging and consideration of targeted radionuclide therapy., Aim: To assess the role of Tc-depreotide in patients with negative or weakly positive OctreoScan (Krenning score< or =1; measured on a scale range 0-4). To determine the usefulness of Tc-depreotide scintigraphy for highlighting lesions that may be missed by OctreoScan and/or CT/MRI imaging., Study Design: Prospective analysis of 25 patients with neuroendocrine tumours, with negative or weakly positive In-pentetreotide scans, who were consecutively enrolled to undergo In-pentetreotide and Tc-depreotide imaging. The results were compared with either CT or MRI scans., Results: Histology was available for 20 of 25 patients: of these 40% had high-grade tumours (cellular proliferation marker Ki-67 score >20%), a further 35% had intermediate-grade tumours (Ki-67 2-20%), and the remaining 25% had low-grade tumours (Ki-67 <2%). Fifty-two percent of patients had completely negative and 48% had weakly positive OctreoScan results. Thirty-two percent of these same patients had significantly positive Tc-depreotide scans (Krenning score> or =2), with the histology demonstrating intermediate-grade or high-grade tumours., Conclusion: Tc-depreotide imaging has low sensitivity but is useful in a one-third of OctreoScan-negative patients, displaying significantly better uptake than In-pentetreotide in this patient group. It aids diagnosis by highlighting lesions not seen by OctreoScan and/or CT/MRI imaging, and can possibly identify a group of patients amenable to therapy with radionuclide agents, such as SOM230, targeting somatostatin receptor subtypes 2, 3 and 5.

PurposeTo assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177Lu-Dotatate.MethodsIn the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression.ResultsSignificantly prolonged median PFS occurred with 177Lu-Dotatate versus octreotide LAR 60 mg in patients with low ( 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden.Conclusions177Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

Simple Summary: Rectal neuroendocrine neoplasms are increasing in incidence due in part to increased use of colonoscopy for colon cancer screening. These lesions can be difficult to characterise by endoscopists and, therefore, may be removed using an inappropriate endoscopic technique. Rectal neuroendocrine tumours should be fully staged prior to resection and this will help determine the best endoscopic approach for removal. Post resection, some of these tumours require ongoing surveillance. This article provides a detailed review of current evidence available to optimise assessment and removal of these lesions and approaches to surveillance for patients with rectal neuroendocrine tumours. Rectal neuroendocrine neoplasms are increasing in incidence, in part due to increased endoscopic procedures being performed for bowel cancer screening. Whilst most of these lesions are low-grade well-differentiated neuroendocrine tumours, they can have a varied clinical behaviour. Frequently, these lesions are incorrectly characterised at endoscopy and, therefore, incompletely excised using standard polypectomy techniques. Furthermore, some cases are not fully staged prior to or post resection. In this article we discuss the endoscopic and surgical options available to improve the likelihood of achieving an R0 resection and the staging procedures that should be used in these NETs. We also review factors that may suggest a higher risk of nodal involvement or recurrence. This information may help determine whether endoscopic or surgical resection techniques should be considered. In cases of R1 resection we discuss the management options available and the long-term surveillance options and when these should be offered to patients. [ABSTRACT FROM AUTHOR]

Simple Summary: We conducted a retrospective, population-based study comparing overall survival (OS) between males and females with neuroendocrine neoplasia (NEN). In total, 14,834 cases of NEN recorded in England's National Cancer Registry and Analysis Service (NCRAS)), were analysed. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Females displayed increased survival irrespective of the stage, morphology or level of deprivation, which was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). Stage of tumour mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. Females diagnosed with NEN tend to survive longer than males, and stage at presentation only accounts for part of this effect. Future research in NEN, as well as prognostication and treatment, should consider sex as an important factor. Pre-clinical studies have suggested sex hormone signalling pathways may influence tumorigenesis in neuroendocrine neoplasia (NEN). We conducted a retrospective, population-based study to compare overall survival (OS) between males and females with NEN. A total of 14,834 cases of NEN diagnosed between 2012 and 2018, recorded in England's National Cancer Registry and Analysis Service (NCRAS), were analysed. The primary outcome was OS with 5 years maximum follow-up. Multivariable analysis, restricted mean survival time and mediation analysis were performed. Appendiceal, pulmonary and early-stage NEN were most commonly diagnosed in females; stomach, pancreatic, small intestinal, colonic, rectal and later-stage NEN were more often diagnosed in males. Females displayed increased survival irrespective of the stage, morphology or level of deprivation. On average, they survived 3.62 (95% CI 1.73–5.90) to 10.26 (6.6–14.45) months longer than males; this was statistically significant in NEN of the lung, pancreas, rectum and stomach (p < 0.001). The stage mediated improved survival in stomach, lung, and pancreatic NEN but not in rectal NEN. The reasons underlying these differences are not yet understood. Overall, females diagnosed with NEN tend to survive longer than males, and the stage at presentation only partially explains this. Future research, as well as prognostication and treatment, should consider sex as an important factor. [ABSTRACT FROM AUTHOR]

Simple Summary: Neuroendocrine tumours are rare tumours arising in the digestive system, mainly the small bowel or pancreas. Due to their location in the digestive tract, NETs can cause symptoms of diarrhoea, abdominal pain or weight loss. These symptoms are often correlated with nutrition. Poor nutrition or malnutrition is well described. Sarcopenia is the loss of muscle mass or strength and a phenotype of malnutrition. In patients with cancer and sarcopenia, survival is poorer compared to patients without sarcopenia. There is little knowledge regarding sarcopenia and its effect on survival in patients with NETs. This study aims to describe the presence of sarcopenia at diagnosis of stage IV NET in the digestive system and correlate this with survival. Sarcopenia was present in 69% of patients. When there was a NET in the pancreas, the presence of sarcopenia was correlated with poorer survival. Sarcopenia in patients with cancer is associated with adverse outcomes such as shorter survival. However, there exists little evidence regarding the prevalence of sarcopenia in patients with metastatic gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Patients with a histologically confirmed newly diagnosed metastatic GEP-NET between 2006 and 2018, CT scan, and anthropometric data at diagnosis were included in this study. CT scans were analysed for the presence of sarcopenia and correlated with overall survival (OS). In total, 183 patients, 87 male (48%), with a median age of 62 years (IQR 52–68 years), were included. In 44 patients (24%), there was a pancreas NET, and in 136 patients, there was a small bowel NET (74%). Sarcopenia was present in 128 patients (69%) and unrelated to BMI (median 25.1). There were significant survival differences between patients with pancreatic and small bowel NETs at 86 vs. 141 months, respectively (p = 0.04). For patients with pancreatic NETs, the presence of sarcopenia was independently associated with shorter OS (HR 3.79 95% CI 1.1–13.03, p-value 0.035). A high prevalence of sarcopenia at the time of diagnosis of a metastatic GEP-NET was seen and associated with worse OS in patients with pancreatic NETs. Further research should focus on how to reverse sarcopenia and its impact on OS and/or quality of life. [ABSTRACT FROM AUTHOR]

Purpose: NETTER-R aimed to determine the efficacy, safety and tolerability of 177Lu-DOTATATE in patients with progressive, advanced pancreatic neuroendocrine tumours (panNETs) using retrospective real-world data from multiple sites. Methods: This international study retrospectively included patients with panNETs treated with 177Lu-DOTATATE. The primary endpoint was progression-free survival (PFS) by Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included overall survival (OS), safety and tumour response. Results: In total, 110 patients with panNETs were studied; 65.5% received a cumulative dose of 177Lu-DOTATATE 29.6 GBq ± 10% (median: 7.4 GBq). In 62 patients with available RECIST v1.1 tumour response, the median PFS was 24.8 months (95% confidence interval [CI]: 17.5–34.5), and the objective response rate was 40.3% (95% CI: 28.1–53.6); all responses were partial. With a median follow up of 24.5 months (range: 2.0–123.4 months) after the first cycle of 177Lu-DOTATATE, the median OS in the full analysis set (n = 110) was 41.4 months (95% CI: 28.6–50.2). PFS (hazard ratio [HR]: 3.672; p = 0.0009) and OS (HR: 3.360; p < 0.0001) were longer in patients who received no chemotherapy prior to 177Lu-DOTATATE than those who did. No treatment-emergent adverse events (TEAEs) led to treatment discontinuation. Grade 3 anaemia, lymphopenia and thrombocytopenia occurred in 0.9%, 5.4% and 0.9% of patients, respectively. No acute leukaemia or myelodysplastic syndrome was reported. Six patients (5.5%) had renal TEAEs. All renal grade ≥ 3 events were transient and did not lead to treatment modification. Conclusions: These results reinforce the role of 177Lu-DOTATATE for the treatment of patients with advanced, somatostatin receptor-positive panNETs. [ABSTRACT FROM AUTHOR]

Pancreatic neuroendocrine tumours can have varied and complex presentations. Whilst hormone hypersecretion often induces characteristic clinical syndromes, non-specific symptoms may arise due to localized tumour effects. Malignant invasion of local vasculature is an increasingly recognized complication of these neoplasms and can be associated with significant morbidity. Herein, we present the case of a 47-year-old male with a recurrence of a pancreatic neuroendocrine tumour who presented with unusual upper gastrointestinal bleeding. The tumour had recurred within the superior mesenteric vein, replacing the vessel and invading its branches. This resulted in porto-mesenteric hypertension and the formation of bleeding mesenteric varices. The patient subsequently developed progressive metabolic disturbances and was diagnosed with ectopic Cushing's syndrome, despite his primary tumour having been non-functional. This case demonstrates not only a rare pattern of tumour recurrence but also the potential for pancreatic neuroendocrine tumours to de-differentiate and change from non-functional to hormone secreting, a phenomenon which may complicate diagnosis and management. [ABSTRACT FROM AUTHOR]

Introduction. Small bowel neuroendocrine tumours (NETs) are the most common type of gastrointestinal neuroendocrine tumours. The incidence and prevalence of these tumours are on the rise. The aims of this study were to determine prognostic clinicopathological features and whether the ENETS TNM staging system predicts prognosis and also. Method. Clinical data was collected retrospectively from 138 patients with histologically proven small bowel NETs managed at King's College Hospital. Histology was reviewed and small bowels tumours, were staged according to the ENETS TNM staging system. Results. Median age was 65 years (range 29-87).The 5-year survival was 79.5% and the 10-year survival was 48.5%. Resection of the primary tumour was associated with improved survival (120 versus 56 months, P < 0.05). On multivariate analysis prognostic factors were primary tumour resection and not having a carcinoid heart disease. TNM staging significantly separated survival of stage 2 and stage 3 from stage 4 NETs. Conclusion. Small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors.The ENETS TNM staging and grading system appears to be of prognostic relevance to small bowel NETs. [ABSTRACT FROM AUTHOR]

Neuroendocrine tumours (NETs) are often indolent malignancies that commonly present with metastatic disease in the liver. Surgical, locoregional, and systemic treatment modalities are reviewed. A multidisciplinary approach to patient care is suggested to ensure all therapeutic options explored. [ABSTRACT FROM AUTHOR]