Neuroendocrine Tumor Disease Research Articles

ASO Author Reflections: Seeing the Unseen-Predicting Nodal Disease in Pancreatic Neuroendocrine Tumors.

ASO Author Reflections: Seeing the Unseen-Predicting Nodal Disease in Pancreatic Neuroendocrine Tumors.

Successes and challenges in the combined neuroendocrine tumour and carcinoid heart disease service university hospitals birmingham: a neuroendocrine tumour clinical specialist nurse perspective

Successes and challenges in the combined neuroendocrine tumour and carcinoid heart disease service university hospitals birmingham: a neuroendocrine tumour clinical specialist nurse perspective

Outcome of carcinoid heart syndrome in patients enrolled in the SwissNet cohort

BackgroundCarcinoid heart disease is a rare disease which develops in patients with functional neuroendocrine tumors in an advanced tumor state. Patients diagnosed with carcinoid heart disease have a poor longtime prognosis with respect to morbidity and mortality and long-term data on patient outcomes are lacking.Methods and resultsIn this retrospective study, we analyzed outcomes of 23 patients with carcinoid heart disease enrolled into the SwissNet database. We observed that early diagnosis with echocardiographic surveillance of carcinoid heart disease during the course of the neuroendocrine tumor disease was beneficial to overall survival of patients.ConclusionThrough nationwide patient enrollment, the SwissNet registry is a powerful data tool to identify, follow-up and evaluate long-term patient outcomes in patients with rare neuroendocrine tumor driven pathologies including carcinoid heart syndrome with observational methods enabling better therapy optimization to improve patient`s long-term perspectives and survival. In line with the current ESMO recommendations, our data proposes that heart echocardiography should be included as part of the general physical assessment in patients with newly diagnosed NET.

Abstracts

Abstracts

Detection and quantification of a focal fat deposition in a liver undergoing multiple operations for neuroendocrine tumor disease using attenuation imaging: a case report

BackgroundIn patients with history of malignancy, new-onset liver lesions often present diagnostic challenges. We present the case of a patient with history of neuroendocrine tumor and new-onset echo-rich hepatic lesion, in whom attenuation imaging helped to make the diagnosis. Attenuation imaging is an ultrasound-based technique that allows for the quantification of hepatic fat content on the basis of a measurement of sound attenuation.Case presentationWe present the case of a 62-year-old Caucasian female patient who underwent pylorus-preserving pancreaticoduodenectomy Whipple surgery in 2004 for histologically well-differentiated neuroendocrine tumor with a proliferation rate of 3% of the pancreatic head. During the course, single liver metastases were resected in 2009, 2010, and 2013. In 2019, hemihepatectomy was performed when two liver metastases recurred. The liver metastases each showed a proliferation rate of 10% with vigorous expression of chromogranin A, synaptophysin, and somatostatin. The most recent follow-up examinations showed a normal chromogranin A value and the patient reported a good general condition. However, sonography revealed a blurred, echoic lesion in the liver. On contrast-enhanced sonography, the lesion showed identical behavior to the surrounding liver parenchyma. In the asymptomatic patient, liver biopsy did not seem to be indicated at the current time. Measurement of the attenuation coefficient by attenuation imaging showed a significantly higher measurement in the area of the echo-rich lesion than in the rest of the liver. The overall findings are consistent with focal fat deposition.ConclusionsAttenuation imaging appears to be useful in the evaluation of unclear echo-rich liver lesions. In particular, primary non-malignant-appearing liver lesions that are unremarkable on abdominal contrast-enhanced ultrasound can be more accurately assessed.

Gastroenteropancreatic neuroendocrine neoplasm imaging: standard reporting templates.

Standardized reporting in radiology has an established role in numerous disease processes, with added benefits in oncology of reduced variability, and generation of a thorough and pertinent report with a focused and relevant conclusion. Many radiologists are not familiar with the imaging patterns of neuroendocrine neoplasm (NEN) spread and recurrence. This paper will present standardized CT, MRI, and PET templates for reporting gastroenteropancreatic (GEP) NENs and explain the rationale for including specific pertinent positive and negative findings, at various stages of disease management, based on site of origin. Basic templates for initial and follow-up anatomic and molecular GEP NEN imaging were created with input from the multidisciplinary Society of Abdominal Radiology (SAR) Neuroendocrine Tumor Disease Focused Panel (NET-DFP). The templates were further modified and finalized after several iterations. Four main report templates were generated for (i) initial anatomic CT or MR imaging studies, (ii) follow-up anatomic CT or MR imaging studies, (iii) initial Somatostatin Receptor (SSTR) or FDG PET imaging studies, and (iv) follow-up SSTR or FDG PET imaging studies. Each study template was formatted to allow its integration into a dictation software directly and be modified as needed, with internalized instructions indicating where a drop-down menu or macro may be used to personalize the template as necessary. These templates were created through a combination of multidisciplinary expert opinion discussion supported by literature review and provide basic structured reporting standards for GEP NEN anatomic and molecular imaging studies.

A novel tool to predict nodal metastasis in small pancreatic neuroendocrine tumors: A multicenter study

BackgroundNonfunctional pancreatic neuroendocrine tumors display a wide range of biological behavior, and nodal disease is associated with metastatic disease and poorer survival. The aim of this study was to develop a tool to predict nodal disease in patients with small (≤2 cm) nonfunctional pancreatic neuroendocrine tumors. MethodsA multicenter retrospective study was performed on patients undergoing resection for small nonfunctional pancreatic neuroendocrine tumors. Patients with genetic syndromes, metastatic disease at diagnosis, neoadjuvant therapy, or positive resection margin were excluded. Factors associated with nodal disease were identified to develop a predictive model. Internal validation was performed using bootstrap with 1,000 resamples. ResultsNodal disease was observed in 39 (11.1%) of the 353 patients included. Presence of nodal disease was significantly associated with lower 5-year disease-free survival (71.6% vs 96.2%, P < .001). Two predictors were strongly associated with nodal disease: G2 grade (odds ratio: 3.51, 95% confidence interval: 1.71–7.22, P = .001) and tumor size (per mm increase, odds ratio: 1.14, 95% confidence interval: 1.03–1.25, P = .009). Adequate discrimination was observed with an area under the curve of 0.71 (95% confidence interval: 0.63–0.80). Based on risk distribution, 3 risk groups of nodal disease were identified; low (<5%), intermediate (≥5% to <20%), and high (≥20%) risk. The observed mean risk of nodal disease was 3.7% in the low-risk patients, 9.6% in the intermediate-risk patients, and 30.4% in the high-risk patients (P < .001). The 10-year disease-free survival in the low, intermediate, and high-risk groups was 100%, 88.8%, and 50.1%, respectively. ConclusionOur model using tumor grade and size can predict nodal disease in small nonfunctional pancreatic neuroendocrine tumors. Integration of this tool into clinical practice could help guide management of these patients.

19th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, 10 - 11 March 2022.

19th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease, 10 - 11 March 2022.

A multigenomic liquid biopsy biomarker for neuroendocrine tumor disease outperforms CgA and has surgical and clinical utility

Biomarkers are key tools in cancer management. In neuroendocrine tumors (NETs), Chromogranin A (CgA) was considered acceptable as a biomarker. We compared the clinical efficacy of a multigenomic blood biomarker (NETest) to CgA over a 5-year period. An observational, prospective, cross-sectional, multicenter, multinational, comparative cohort assessment. Cohort 1: NETest evaluation in NETs (n = 1684) and cancers, benign diseases, controls (n = 731). Cohort 2: (n= 1270): matched analysis of NETest/CgA in a sub-cohort of NETs (n= 922) versus other diseases and controls (n= 348). Disease status was assessed by response evaluation criteria in solid tumors (RECIST). NETest measurement: qPCR [upper limit of normal (ULN: 20)], CgA (EuroDiagnostica, ULN: 108 ng/ml). Mann-Whitney U-test, AUROC, chi-square and McNemar' test. Cohort 1: NETest diagnostic accuracy was 91% (P < 0.0001) and identified pheochromocytomas (98%), small intestine (94%), pancreas (91%), lung (88%), gastric (80%) and appendix (79%). NETest reflected grading: G1: 40 ± 1, G2 (50 ± 1) and G3 (52 ± 1). Locoregional disease levels were lower (38 ± 1) than metastatic (52 ± 1, P < 0.0001). NETest accurately stratified RECIST-assessed disease extent: no disease (21 ± 1), stable (43 ± 2), progressive (62 ± 2) (P < 0.0001). NETest concordance with imaging (CT/MRI/68Ga-SSA-PET) 91%. Presurgery, all NETs (n= 153) were positive (100%). After palliative R1/R2 surgery (n= 51) all (100%) remained elevated. After curative R0-surgery (n= 102), NETest levels were normal in 81 (70%) with no recurrence at 2 years. In the 31 (30%) with elevated levels, 25 (81%) recurred within 2 years. Cohort #2: NETest diagnostic accuracy was 87% and CgA 54% (P < 0.0001). NETest was more accurate than CgA for grading (chi-square= 7.7, OR= 18.5) and metastatic identification (chi-square= 180, OR= 8.4). NETest identified progressive disease (95%) versus CgA (57%, P < 0.0001). Imaging concordance for NETest was 91% versus CgA (46%) (P < 0.0001). Recurrence prediction after surgery was NETest-positive in >94% versus CgA 11%. NETest accurately diagnoses NETs and is an effective surrogate marker for imaging, grade, metastases and disease status compared to CgA. A multigenomic liquid biopsy is an accurate biomarker of NET disease.

Use of full-dose contrast-enhanced CT for extrahepatic staging using Gallium-68-DOTATATE PET/CT in patients with neuroendocrine tumors.

Studies have demonstrated that positron emission tomography/computed tomography (PET/CT) with Gallium-68 (68Ga)-labeled somatostatin analogues are effective at detecting metastatic disease in neuroendocrine tumors (NET), especially extrahepatic metastases. However, PET in combination with full-dose contrast-enhanced CT (ceCT) exposes patients to higher radiation (~25 mSv). The use of non-contrast-enhanced low-dose CT (ldCT) can reduce radiation to about 10 mSv and may avoid contrast-induced side effects. This study seeks to determine whether ceCT could be omitted from NET assessments. We retrospectively compared the performance of PET/ldCT versus PET/ceCT in 54 patients (26 male, 28 female) who had undergone a 68Ga-DOTATATE PET/CT. The selection criteria were as follows: available ldCT and ceCT, histologically confirmed NET, and follow-up of at least 6 months (median, 12.6 months; range, 6.1-23.2 months). The PET/ldCT and PET/ceCT images were analyzed separately. We reviewed metastases in the lungs, bones, and lymph nodes. The results were compared with the reference standard (clinical follow-up data). The PET/ceCT scans detected 139 true-positive bone lesions compared with 140 lesions detected by the PET/ldCT scans, 106 true-positive lymph node metastases (PET/ceCT) compared with 90 metastases detected by the PET/ldCT scans, and 26 true-positive lung lesions (PET/ceCT) compared with 6 lesions detected by the PET/ldCT scans. The overall lesion-based sensitivity for full-dose PET/ceCT was 97%, specificity 86%, negative predictive value (NPV) 93%, and positive predictive value (PPV) 93%. The overall lesion-based sensitivity for PET/ldCT was 85%, specificity 73%, NPV 72%, and PPV 85%. This study presents the first evidence that ceCT should not be omitted from extrahepatic staging using 68Ga-DOTATATE PET/CT in patients with NET. ceCT alone can be used as a follow-up to reduce radiation exposure when the patient has already undergone PET/ceCT and suffers from non-DOTATATE-avid NET.

Y90 selective internal radiation therapy and peptide receptor radionuclide therapy for the treatment of metastatic neuroendocrine tumors: combination or not?

Peptide receptor radionuclide therapy and selective internal radiation therapy are effective radionuclide therapy modalities for unresectable metastatic neuroendocrine tumor patients that cannot be controlled with somatostatin analogs. The present study is intended to evaluate the therapeutic efficacy and toxicity of the combined therapy of selective internal radiation therapy and peptide receptor radionuclide therapy and stand-alone selective internal radiation therapy in patients with neuroendocrine tumor, a liver-dominant disease. This cohort consists of 27 patients with metastatic neuroendocrine tumor and liver-dominant disease. They were grouped as the patients who were treated with selective internal radiation therapy for unresectable liver metastasis (n = 15) and the patients who received a combination of selective internal radiation therapy and peptide receptor radionuclide therapy (n = 12) for hepatic and extrahepatic metastasis. Treatment efficacy and treatment-associated toxicity were retrospectively assessed in both groups. The objective treatment response and stable disease were found in 13 patients (86.6%) in the selective internal radiation therapy group and eight patients (66.6%) in the selective internal radiation therapy + peptide receptor radionuclide therapy group. The median overall survival rate was found to be 34.9 months, in the selective internal radiation therapy group and 67.5 months in the selective internal radiation therapy + peptide receptor radionuclide therapy group (P = 0.217). The median progression-free survival data was not reached, and the mean values of progression-free survival were 53.1 ± 9.9 months in the selective internal radiation therapy group, and 27.2 ± 5.9 months in the selective internal radiation therapy + peptide receptor radionuclide therapy group (P = 0.561). Temporary lymphopenia was the most common side effect. Grade 1-2 hepatotoxicity was observed to be 6.6% in the selective internal radiation therapy group, while it was not observed in selective internal radiation therapy + peptide receptor radionuclide therapy group. In the neuroendocrine tumors with liver-dominant metastatic disease, personalized selective internal radiation therapy and peptide receptor radionuclide therapy and their combinations result in increased survival rates. Selective internal radiation therapy alone could be an effective treatment in patients with liver-limited and -dominant disease.

Inefficacy of chromogranin a assays as neuroendocrine tumor diagnostic tools compared to the NETest.

4612 Background: Chromogranin A (CgA) remains a commonly used diagnostic and monitoring tool for neuroendocrine tumor disease despite NCCN guidelines identifying it as a category 3 (major concerns about utility) biomarker. Several commercial assays have been developed to measure this protein (or its fragments) and are available both at CLIA-certified laboratories (USA) as well as in NET Centres of Excellence (CoEs - Europe). CgA is typically reimbursed by insurance companies and appears in several guidelines (e.g., ENETS). We sought to directly evaluate the accuracy of detecting NET disease using two different CgA assays, one in the USA (NEOLISA, EuroDiagnostica, IBL-America, CLIA-certified laboratory) and one in an ENETS CoE (CgA ELISA, Demeditec Diagnostics, Germany). We compared the results to the NETest, a circulating mRNA assay, recently validated as an IVD for NETs. Methods: Patients: NETs ( n=258) including lung: n=43; duodenum n=9; gastric: n=44; pancreas: n=67; small bowel: n=40; appendix: n=10; rectum: n=45. No image-evidence of disease ( n=122) (IND) and image-positive disease (IPD) ( n=136). CgA assays (plasma): NEOLISA, ULN &gt;108ng/ml, DD: ULN&gt;99ng/ml. Data mean±SEM. NETest (whole blood): qRT-PCR - multianalyte algorithmic analyses, CLIA-laboratory. All samples de-identified and assessed blinded. Statistics: Mann-Whitney U-test, Pearson correlation &amp; McNemar-test. Results: In the entire group ( n=258), NEOLISA assay CgA levels were significantly ( p&lt;0.0001) higher (216±91ng/ml) vs. the DD-assay (76±8ng/ml). The assays exhibited a high concordance in output (Pearson r=0.81, p&lt;0.0001), but there were 10.9% ( n=31) discordant results. This reflected the NEOLISA assay detecting more CgA-positive samples. IPD group: CgA-positives were detected in 48/136 (35%, NEOLISA) vs. 28 (21%, DD-assay). McNemar’s Chi2=15.04, p&lt;0.001 OR: 11.0, indicating the NEOLISA was significantly better than the DD-assay. The NETest, in contrast, was positive in 135/136 (99%; OR: 87-106, p&lt;0.0001). IND group: CgA-positives were detected in 12/122 (10%, NEOLISA) vs. 9 (7%, DD-assay; p=NS). The majority (75%) of positives were associated with gastric NETs. The NETest was positive in 7 (6%); 4 were gastric NETs and 3 exhibited elevated CgA. Conclusions: Two standard CgA assays used for NET management (one accepted by Medicare in the USA, the second used at a CoE in Europe) only detect NET disease in 21-35% of cases. In contrast, a circulating mRNA fingerprint, the NETest, is ~99% accurate for detecting NET disease.

A Comprehensive Molecular Characterization of the Pancreatic Neuroendocrine Tumor Cell Lines BON-1 and QGP-1.

Experimental models of neuroendocrine tumor disease are scarce, with only a few existing neuroendocrine tumor cell lines of pancreatic origin (panNET). Their molecular characterization has so far focused on the neuroendocrine phenotype and cancer-related mutations, while a transcription-based assessment of their developmental origin and malignant potential is lacking. In this study, we performed immunoblotting and qPCR analysis of neuroendocrine, epithelial, developmental endocrine-related genes as well as next-generation sequencing (NGS) analysis of microRNAs (miRs) on three panNET cell lines, BON-1, QGP-1, and NT-3. All three lines displayed a neuroendocrine and epithelial phenotype; however, while insulinoma-derived NT-3 cells preferentially expressed markers of mature functional pancreatic β-cells (i.e., INS, MAFA), both BON-1 and QGP-1 displayed high expression of genes associated with immature or non-functional β/δ-cells genes (i.e., NEUROG3), or pancreatic endocrine progenitors (i.e., FOXA2). NGS-based identification of miRs in BON-1 and QGP-1 cells revealed the presence of all six members of the miR-17–92 cluster, which have been implicated in β-cell function and differentiation, but also have roles in cancer being both oncogenic or tumor suppressive. Notably, both BON-1 and QGP-1 cells expressed several miRs known to be negatively associated with epithelial–mesenchymal transition, invasion or metastasis. Moreover, both cell lines failed to exhibit migratory activity in vitro. Taken together, NT-3 cells resemble mature functional β-cells, while both BON-1 and QGP-1 are more similar to immature/non-functional pancreatic β/δ-cells or pancreatic endocrine progenitors. Based on the recent identification of three transcriptional subtypes in panNETs, NT-3 cells resemble the “islet/insulinoma tumors” (IT) subtype, while BON-1 and QGP-1 cells were tentatively classified as “metastasis-like/primary” (MLP). Our results provide a comprehensive characterization of three panNET cell lines and demonstrate their relevance as neuroendocrine tumor models.

Abstracts of the 17th Annual ENETS Conference for the Diagnosis and Treatment of Neuroendocrine Tumor Disease

Introduction: Autophagy and mitophagy are key homeostatic machineries linked to cancer development and drug resistance.Aim(s): To assess the levels of autophagy and mitophagy in well differentiated ...

A meta-analysis of the accuracy of a neuroendocrine tumor mRNA biomarker (NETest) in the blood.

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&lt; 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.

Liver transplantation in patients with liver metastases from neuroendocrine tumors.

The prevalence of metastatic disease in neuroendocrine tumors (NETs) is very high (60-80%) and cancer-related death among these patients is generally due to metastatic disease. Numerous treatment options for cure and disease control have been investigated for patients with neuroendocrine liver metastases (NELM). Despite the success of liver directed therapy on slowing tumor progression and palliating symptoms, the chance of being cured by liver resection is 40-50% and only roughly 20% of patients have potentially resectable disease. As such, there has been interest in liver transplantation (LT) as a potentially curative option for patients with unresectable disease. Several criteria have been proposed in order to balance long-term outcomes of patients with NELM and the problem of organ shortage including the Milan-NET criteria, the UNOS criteria and the ENETS guidelines. In the most representative studies, recurrence rate after LT has ranged from 30% to 60% with a 5-year OS ranging from 50% to 97%. This large variability is due to the retrospective nature of the studies available, which used different inclusion criteria. As such, outcomes and the prognostic factors associated with LT for NELM warrant further investigation.

Y90 Clinical Data Update: Cholangiocarcinoma, Neuroendocrine Tumor, Melanoma, and Breast Cancer Metastatic Disease

While the most compelling levels of evidence for the use of Yttrium-90 (90Y) radioembolization are in patients with hepatocellular carcinoma and hepatic metastases from colorectal cancer, a growing body of literature supports its use in other primary and secondary hepatic malignancies. This includes intrahepatic cholangiocarcinoma, as well as hepatic metastases from neuroendocrine cancer, ocular melanoma, and breast cancer. While is it not feasible to conduct prospective, randomized trials for radioembolization in the setting of these malignancies due to the low overall prevalence of liver-only disease, numerous single-arm studies in the last several years make a compelling argument for its use in select situations. This clinical update summarizes those findings.

Predictors of Metastases in Rectal Neuroendocrine Tumors: Results of a National Cohort Study

Rectal neuroendocrine tumors are often found incidentally. Local excision alone has been advocated for lesions ≤2 cm; however, the evidence base for this approach is limited. Associations among tumor size, degree of differentiation, and presence of distant metastatic disease were examined. This was a retrospective cohort study. This study was conducted using a nationwide cohort. A total of 4893 patients with rectal neuroendocrine tumors were identified in the National Cancer Database (2006-2015). Logistic regression analyses were used to evaluate associations among tumor size, degree of differentiation, and presence of regional and distant metastatic disease. Cut point analysis was performed to identify an optimal size threshold predictive of distant metastatic disease. Of patients included for analysis, 3880 (79.3%) had well-differentiated tumors, 540 (11.0%) had moderately differentiated tumors, and 473 (9.7%) had poorly differentiated tumors. On logistic regression, increasing size was associated with a higher likelihood of pathologically confirmed lymph node involvement (among patients undergoing proctectomy), and both size and degree of differentiation were independently associated with a higher likelihood of distant metastatic disease. The association between tumor size and distant metastatic disease was stronger for well-differentiated and moderately differentiated tumors (OR = 1.4; p < 0.001 for both) than for poorly differentiated tumors (OR = 1.1; p = 0.010). For well-differentiated tumors, the optimal cut point for the presence of distant metastatic disease was 1.15 cm (area under the curve = 0.88; 88% sensitive and 88% specific). Tumors ≥1.15 cm in diameter were associated with a substantially increased incidence of distant metastatic disease (72/449 (13.8%)). For moderately differentiated tumors, the optimal cut point was also 1.15 cm (area under the curve = 0.87, 100% sensitive and 75% specific). This study was limited by its retrospective design. Tumor size and degree of differentiation are predictive of regional and distant metastatic disease in rectal neuroendocrine tumors. Patients with tumors >1.15 cm are at substantial risk of distant metastasis and should be staged and managed accordingly. See Video Abstract at http://links.lww.com/DCR/A778.

The neuroendocrine phenotype, genomic profile and therapeutic sensitivity of GEPNET cell lines.

Experimental models of neuroendocrine tumour disease are scarce, and no comprehensive characterisation of existing gastroenteropancreatic neuroendocrine tumour (GEPNET) cell lines has been reported. In this study, we aimed to define the molecular characteristics and therapeutic sensitivity of these cell lines. We therefore performed immunophenotyping, copy number profiling, whole-exome sequencing and a large-scale inhibitor screening of seven GEPNET cell lines. Four cell lines, GOT1, P-STS, BON-1 and QGP-1, displayed a neuroendocrine phenotype while three others, KRJ-I, L-STS and H-STS, did not. Instead, these three cell lines were identified as lymphoblastoid. Characterisation of remaining authentic GEPNET cell lines by copy number profiling showed that GOT1, among other chromosomal alterations, harboured losses on chromosome 18 encompassing the SMAD4 gene, while P-STS had a loss on 11q. BON-1 had a homozygous loss of CDKN2A and CDKN2B, and QGP-1 harboured amplifications of MDM2 and HMGA2. Whole-exome sequencing revealed both disease-characteristic mutations (e.g. ATRX mutation in QGP-1) and, for patient tumours, rare genetic events (e.g. TP53 mutation in P-STS, BON-1 and QGP-1). A large-scale inhibitor screening showed that cell lines from pancreatic NETs to a greater extent, when compared to small intestinal NETs, were sensitive to inhibitors of MEK. Similarly, neuroendocrine NET cells originating from the small intestine were considerably more sensitive to a group of HDAC inhibitors. Taken together, our results provide a comprehensive characterisation of GEPNET cell lines, demonstrate their relevance as neuroendocrine tumour models and explore their therapeutic sensitivity to a broad range of inhibitors.

Clinical Validation of a Pixon-Based Reconstruction Method Allowing a Twofold Reduction in Planar Images Time of 111In-Pentetreotide Somatostatin Receptor Scintigraphy.

The objective of this study was to evaluate the diagnostic efficacy of Pixon-based reconstruction method on planar somatostatin receptor scintigraphy (SRS). All patients with neuroendocrine tumors (NETs) disease who were referred for SRS to our department during 1-year period from January to December 2015 were consecutively included. Three nuclear physicians independently reviewed all the data sets of images which included conventional images (CI; 15 min/view) and processed images (PI) obtained by reconstructing the first 450 s extracted data using Oncoflash® software package. Image analysis using a 3-point rating scale for abnormal uptake of 111 Indium-DTPA-Phe-octreotide in any lesion or organ was interpreted as positive, uncertain, or negative for the evidence of NET disease. A maximum grade uptake of the radiotracer in the lesion was assessed by the Krenning scale method. The results of image interpretation by the two methods were considered significantly discordant when the difference in organ involvement assessment was negative vs. positive or in lesion uptake was ≥2 grades. Agreement between the results of two methods and by different scan observers was evaluated using Cohen κ coefficients. There was no significant (p = 0.403) correlation between data acquisition protocol and quality image. The rates of significant discrepancies for exam interpretation and organs involvement assessment were 2.8 and 2.6%, respectively. Mean κ values revealed a good agreement for concordance between CI and PI interpretation without difference of agreement for inter/intra-observer analysis. Our results suggest the feasibility to use a Pixon-based reconstruction method for SRS planar images allowing a twofold reduction of acquisition time and without significant alteration of image quality or on image interpretation.