There is a clinical need for 18F -labeled somatostatin analogs for the imaging of neuroendocrine tumors (NET), given the limitations of using [68Ga]Ga-DOTA-peptides, particularly with regard to widespread accessibility. We have shown that [18F]fluoroethyl-triazole-[Tyr3]- octreotate ([18F]FET-beta AG-TOCA) has favorable dosimetry and biodistribution. As a step toward clinical implementation, we conducted a prospective, noninferiority study of [18F]FET-beta AG-TOCA PET/CT compared with [68Ga]Ga-DOTA- peptide PET/CT in patients with NET. Methods: Forty-five patients with histologically confirmed NET, grades 1 and 2, underwent PET/CT imaging with both [18F]FET-beta AG-TOCA and [68Ga]Ga-peptide performed within a 6-mo window (median, 77 d; range, 6-180 d). Whole -body PET/CT was conducted 50 min after injection of 165 MBq of [18F]FET-beta AG-TOCA. Tracer uptake was evaluated by comparing SUVmax and tumor -tobackground ratios at both lesion and regional levels by 2 unblinded, experienced readers. A randomized, blinded reading of both scans was also then undertaken by 3 experienced readers, and consensus was assessed at a regional level. The ability of both tracers to visualize liver metastases was also assessed. Results: A total of 285 lesions were detected on both imaging modalities. An additional 13 tumor deposits were seen in 8 patients on [18F]FET-beta AG-TOCA PET/CT, and [68Ga]Ga-DOTA-peptide PET/CT detected an additional 7 lesions in 5 patients. Excellent correlation in SUVmax was observed between both tracers (r = 0.91; P < 0.001). No difference was observed between median SUVmax across regions, except in the liver, where the median tumor -to -background ratio of [18F]FET-beta AG-TOCA was significantly lower than that of [68Ga]Ga-DOTA-peptide (2.5 +/- 1.9 vs. 3.5 +/- 2.3; P < 0.001). Conclusion: [18F]FET-beta AG-TOCA was not inferior to [68Ga]Ga-DOTA-peptide in visualizing NET and may be considered in routine clinical practice given the longer half-life and availability of the cyclotron -produced fluorine radioisotope.

AbstractNeuroendocrine tumours/neoplasms (NEN) are clinically challenging entities, often due to their late stage at initial diagnosis. Whilst surgery is the cornerstone of curative treatment, many patients are not eligible for a radical surgical approach, and instead other targeted or systemic treatments may be utilised. Neoadjuvant concepts such as downstaging borderline resectable tumours are more established in some adenocarcinomas than in neuroendocrine oncology, yet the diverse armamentarium for the latter offers promise for novel multimodal concepts that may offer prolonged disease control by complementarily targeting micro- and macro-neuroendocrine disease. One promising option, as yet only explored in small case series, is the combination of surgery and peptide receptor radionuclide therapy (PPRT). Here, the authors review the challenges posed by advanced NEN, review the fledgling evidence regarding the combination of PRRT and surgery, and present the case for a wider examination of embedding PRRT and surgery within a multimodal treatment strategy.

Neuroendocrine tumours commonly metastasise to the liver, particularly those arising from the intestinal tract and pancreas. Whilst surgery offers the only approach with intent to cure, the vast majority of patients with neuroendocrine liver metastases are ineligible. Liver-directed interventional therapies seek to exploit the patho-anatomy of the blood supply of hepatic metastases to deliver therapy to liver deposits. This may involve percutaneous ablation, bland embolization, or the selective infusion of chemotherapeutics, targeted agents or radiolabelled embolic material. Retrospective case series evidence has characterised objective response rates, disease control rates, and longer-term outcomes associated with each approach. Recent advances in this field include ongoing comparative trials of different techniques, but more importantly, combinations of interventional liver-directed therapies and other systemic therapy in multimodal treatment concepts.

The aim of the present guidance paper is to update the previous ENETS guidelines on well differentiated appendiceal neuroendocrine tumours (NET), providing practical guidance for the diagnosis and management of appendiceal NET (aNET); poorly differentiated neoplasms are dealt with in a separate guidance paper. This paper is structured on a question-answer format in order to also address controversial issues and areas where uncertainty regarding the management and follow-up of aNET exists. All recommendations are offered on the basis of the best available evidence, along with the authors' experiences in managing these neoplasms. Each recommendation for treatment will provide a level of evidence and grade of recommendation as per the GRADE system (adapted in Infectious Disease Society of United States Public Health Service grading system).

The liver is a common site of metastases from many cancers, particularly those originating in the gastrointestinal tract. Liver transplantation is an uncommonly used but promising and at times controversial treatment option for neuroendocrine and colorectal liver metastases. Transplantation with meticulous patient selection has been associated with excellent long-term outcomes in individuals with neuroendocrine liver metastases, but questions remain regarding the role of transplantation in those who could also be eligible for hepatectomy, the role of neoadjuvant/adjuvant treatments in minimising recurrence, and the optimal timing of the procedure. A prospective pilot study of liver transplantation for unresectable colorectal liver metastases that reported a 5-year overall survival rate of 60% reinvigorated interest in this area following initially dismal outcomes. This has been followed by larger studies, and prospective trials are ongoing to quantify the potential benefits of liver transplantation over palliative chemotherapy. This review provides a critical summary of currently available knowledge on liver transplantation for neuroendocrine and colorectal liver metastases, and highlights avenues for further study to address gaps in the evidence base.

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

OBJECTIVE:To discover serum-based microRNA (miRNA) biomarkers for small-bowel neuroendocrine tumors (SBNET) to help guide clinical decisions. BACKGROUND:MiRNAs are small noncoding RNA molecules implicated in the initiation and progression of many cancers. MiRNAs are remarkably stable in bodily fluids, and can potentially be translated into clinically useful biomarkers. Novel biomarkers are needed in SBNET to determine disease aggressiveness, select patients for treatment, detect early recurrence, and monitor response. METHODS:This study was performed in 3 stages (discovery, validation, and a prospective, longitudinal assessment). Discovery comprised of global profiling of 376 miRNA in sera from SBNET patients (n = 11) versus healthy controls (HCs; n = 3). Up-regulated miRNAs were subsequently validated in additional SBNET (n = 33) and HC sera (n = 14); and then longitudinally after SBNET resection (n = 12), with serial serum sampling (preoperatively day 0; postoperatively at 1 week, 1 month, and 12 months). RESULTS:Four serum miRNAs (miR-125b-5p, -362-5p, -425-5p and -500a-5p) were significantly up-regulated in SBNET (P < 0.05; fold-change >2) based on multiple normalization strategies, and were validated by RT-qPCR. This combination was able to differentiate SBNET from HC with an area under the curve of 0.951. Longitudinal assessment revealed that miR-125b-5p returned towards HC levels at 1 month postoperatively in patients without disease, whereas remaining up-regulated in those with residual disease (RSD). This was also true at 12 months postoperatively. In addition, miR-362-5p appeared up-regulated at 12 months in RSD and recurrent disease (RCD). CONCLUSIONS:Our study represents the largest global profiling of serum miRNAs in SBNET patients, and the first to evaluate ongoing serum miRNA expression changes after surgical resection. Serum miR-125b-5p and miR-362-5p have potential to be used to detect RSD/RCD.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

606 Background: There is no accurate blood biomarker of neuroendocrine tumor (NET) disease. The inability to effectively assess disease in real-time has hindered management. The advance of genomic medicine and the development of molecular biomarkers has provided a strategy – liquid biopsy – to facilitate management. We reviewed the role of a blood mRNA-based NET biomarker, the NETest, as an in vitro diagnostic (IVD) to assess clinical utility. Methods: A systematic review of the literature using PRISMA guidelines was undertaken. The methodological quality was evaluated using the QUADAS-2 tool. We identified 10 original scientific papers, which met inclusion criteria. These were assessed by qualitative analysis, and thereafter meta-analysis. Data were pooled and median (95% CI) diagnostic odds ratio (DOR), positive likelihood ratio (+LR) and negative likelihood ratio (–LR) calculated. For the meta-analysis, a generic inverse variance method was undertaken using the accuracy and AUC data. Results: The ten studies exhibited moderate to high methodological quality. They evaluated NETest usage both as a diagnostic and as a monitoring tool. Meta-analysis identified the diagnostic accuracy of the NETest to be 94.9-96% with a median DOR of 400, +LR of 164 and–LR of 0.05. The NETest was 85.5-86% accurate in differentiating stable from progressive disease. As a marker of natural history, the accuracy was 90-94%. As an interventional/ response biomarker, the accuracy was 94-97%. The pooled AUC for the NETest was 0.954±0.005, with a z-statistic of 175.06 ( p< 0.001). Conclusions: The NETest is an accurate biomarker suitable for clinical use in NET disease management. The meta-analysis supports the utility of the NETest as an IVD to establish a diagnosis and monitor therapeutic efficacy. The use of a multianalyte genomic test as a biomarker provides information relevant to NET management consistent with observations regarding the utility of liquid biopsy in other oncological disciplines.

4093 Background: PRRT represents a step change in NET management, significantly improving survival. However, objective response to PRRT, approximately 20%, is poor. There are no predictive biomarkers of response. Uptake on 68Ga-DOTATATE PET/CT imaging is used to assess patient suitability for PRRT, highlighting the presence of somatostatin receptors (SSTR) to which PRRT selectively binds. We hypothesise that the density of SSTRs, as defined by a minimum SUV uptake, predicts for response to PRRT. Methods: 54 patients underwent PRRT. Modified PERCIST assessment was performed: up to 2 target lesions per organ were identified and volume of interest drawn. Maximum 5 targets were counted. Average SUV (SUVave) was calculated by dividing sum of SUVmax of target lesions by number of lesions. Response was determined by RECIST 1.1. Ki67 and SSTR2 expression were assessed on tumour samples and compared with SUVave. Results: Response to PRRT: partial response (PR) 26%, stable disease (SD) 40% progressive disease (PD) 12%. Response to PRRT predicted progression free survival (PFS) with patients experiencing PR having a PFS 2.5x that of those with SD, and almost 20x as long as PD. Using ROC curve analysis, SUVave of 21.6 predicted for tumour response with high sensitivity (0.74) and specificity (1.0), p = 0.15, 95% CI 0.71-3.96. No association between baseline SUVave and SSTR2 or Ki-67 was observed. SUVave > 21.6 was an independent predictor of clinical outcome. Conclusions: Objective response to PRRT defines a subset of patients with markedly improved PFS. SUVave 21.6 defines a threshold below which patients have a poor response to PRRT. This threshold should be taken forward into prospective study.

A MAFA missense mutation causes familial insulinomatosis and diabetes mellitus 1 2 Donato Iacovazzo, Sarah E. Flanagan, Emily Walker, Rosana Quezado, Fernando Antonio de Sousa 3 Barros, Richard Caswell, Matthew Johnson, Matthew Wakeling, Michael Brändle, Min Guo, Mary N. 4 Dang, Plamena Gabrovska, Bruno Niederle, Emanuel Christ, Stefan Jenni, Bence Sipos, Maike Nieser, 5 Andrea Frilling, Ketan Dhatariya, Philippe Chanson, 13 Wouter de Herder, Björn Konukiewitz, 6 Günter Klöppel, Roland Stein, Márta Korbonits, and Sian Ellard 7 8 Centre for Endocrinology, Barts and The London School of Medicine, Queen Mary University of London, London, EC1M 9 6BQ, UK; Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, EX2 5DW, UK; 10 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee, 37232, USA; Serviço de 11 Endocrinologia e Diabetes, Hospital Universitário Walter Cantídio, Universidade Federal do Ceará, Fortaleza, 60430-372, 12 Brazil; Division of Endocrinology and Diabetes, Department of Internal Medicine, Kantonsspital St. Gallen, St. Gallen, CH13 9007, Switzerland; Section of Endocrine Surgery, Division of General Surgery, Department of Surgery, University of Vienna, 14 Vienna, A-1090, Austria; Division of Diabetes, Endocrinology and Metabolism, University Hospital of Basel, Basel, CH15 4031, Switzerland; Division of Endocrinology, Diabetes and Clinical Nutrition, University Hospital of Bern, Inselspital, 16 Bern, CH-3010, Switzerland; Department of Pathology, University of Tübingen, Tübingen, 72076, Germany; Department 17 of Surgery and Cancer, Imperial College London, London, W12 0HS, UK; Elsie Bertram Diabetes Centre, Norfolk and 18 Norwich University Hospitals NHS Foundation Trust, Norwich, NR4 7UY, UK; Service d'Endocrinologie et des Maladies 19 de la Reproduction, Assistance Publique-Hôpitaux de Paris, Hôpital de Bicêtre, Le Kremlin-Bicêtre, F-94275, France; 20 Inserm 1185, Fac Med Paris Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, F-94276, France; Department of Internal 21 Medicine, Sector of Endocrinology, ENETS Centre of Excellence for Neuroendocrine Tumors, Erasmus MC, Rotterdam, 3015, 22 The Netherlands; Department of Pathology, Consultation Center for Pancreatic and Endocrine Tumors, Technical 23 University of Munich, Munich, 81675, Germany 24 25 These authors contributed equally to this work 26 27

Surgical approaches to hepatic metastases occupy an important role in the management of patients with neuroendocrine neoplasms and may have curative or palliative intentions. Resection of hepatic disease with curative intent is the only modality offering potential cure for patients with liver metastases; however, only a minority of patients are eligible. Regardless of resection margin, disease recurrence almost invariably occurs and novel adjuvant/neoadjuvant therapies are mandated to be included within multimodal treatment concepts. Liver transplantation in meticulously selected patients may be associated with excellent outcomes, but unfortunately demands on donated organs limit the wider utilization of this approach.

configurations (34 vs. 27.6%).Indications for index operations included colorectal cancer (35%), inflammatory bowel disease (34.5%), benign disease (19.7%), and diverticular disease (10.8%).Black patients were nearly twice as likely to have diverticular disease (17.0 vs 9.1%, p<0.05).Black patients were significantly more disadvantaged than white patients with neighborhood summary scores of -3.0 vs 2.31, respectively (p<0.05).Overall, black patients had lower SR rates (58.8 vs 68.6%).Compared with white patients, black patients also had significantly longer median and mean time to reversal, 135 vs 126 days and 253 vs 183 days, respectively (p<0.05).On adjusted analysis for covariate differences, race did not predict overall SR rates.Instead, major predictors for SR included having a loop ileostomy, IBD or diverticular disease, and private insurance.For time to reversal, black race (HR= 0.784) was associated with longer time to SR.Additional predictors for delays included having an end ostomy (0.502), colorectal cancer (HR= 0.705), and being socially disadvantaged.CONCLUSIONS: While overall SR rates are similar, black patients were significantly at risk for delay to SR even after adjustment for patient, social and stoma-level characteristics.Future work is necessary to understand the mechanisms for these observed disparities.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)