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AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC. [ABSTRACT FROM AUTHOR]

We sought to investigate whether N-terminal pro-brain natriuretic peptide (NT-pro-BNP) can be used as a biomarker for the detection of carcinoid heart disease (CHD); 200 patients with carcinoid syndrome were screened for CHD using transthoracic echocardiography. A carcinoid score was formulated to quantify severity of CHD. NT-pro-BNP was measured in all patients before echocardiography. Patients were categorised into New York Heart Association class. CHD was present in 39 patients (19.5%). NT-pro-BNP was significantly higher in those with CHD (median 1,149 pg/ml) than in those without CHD (median 101 pg/ml, p <0.001). The sensitivity and specificity of NT-pro-BNP at a cut-off level of 260 pg/ml for detection of CHD were 0.92 and 0.91, respectively. NT-pro-BNP positively correlated both with carcinoid score (r = 0.81, p <0.001) and New York Heart Association class (p <0.001). The number of patients screened to diagnose 1 case of CHD decreased from 5.1 to 1.4. In conclusion, NT-pro-BNP seems to be an excellent biomarker of CHD. A high negative predictive value may allow it to provide a screening test for CHD. [ABSTRACT FROM AUTHOR]

Prospective data are lacking on early somatostatin analog (SSA) therapy in bronchopulmonary neuroendocrine tumors (BP-NETs; typical carcinoids and atypical carcinoids (TCs and ACs)). SPINET (EudraCT: 2015-004992-62; NCT02683941) was a phase III, double-blind study of lanreotide autogel/depot (LAN; 120 mg every 28 days) plus best supportive care (BSC) vs placebo plus BSC, with an optional open-label treatment phase (LAN plus BSC). Patients had metastatic/unresectable, somatostatin receptor (SSTR)-positive TCs or ACs. Recruitment was stopped early owing to slow accrual; eligible patients from the double-blind phase transitioned to open-label LAN. The adapted primary endpoint was progression-free survival (PFS) during either phase for patients receiving LAN. Seventy-seven patients were randomized (LAN, n = 51 (TCs, n = 29; ACs, n = 22); placebo, n = 26 (TCs, n = 16; ACs, n = 10)). Median (95% CI) PFS during double-blind and open-label phases in patients receiving LAN was 16.6 (11.3; 21.9) months overall (primary endpoint), 21.9 (12.8, not calculable (NC)) months in TCs, and 13.8 (5.4; 16.6) months in ACs. During double-blind treatment, median (95% CI) PFS was 16.6 (11.3; 21.9) months for LAN vs 13.6 (8.3; NC) months for placebo (not significant); corresponding values were 21.9 (13.8; NC) and 13.9 (13.4; NC) months, respectively, in TCs and 13.8 (5.4; 16.6) and 11.0 (2.8; 16.9) months, respectively, in ACs. Patients' quality of life did not deteriorate and LAN was well tolerated. Although recruitment stopped early and the predefined sample size was not met, SPINET is the largest prospective study to date of SSA therapy in SSTR-positive TCs and ACs and suggests clinical benefit in TCs.

[ 18 F]FDG PET/CT and [ 68 Ga]Ga-DOTATATE PET/CT are both used to predict tumor biology in neuroendocrine neoplasms. Although the presence of discordant ([ 18 F]FDG-avid/non-[ 68 Ga]Ga-DOTATATE-avid) disease predicts poor prognosis, the significance of the volume of such discordant disease remains undetermined. The aim of this study is to investigate discordant tumor volume as a potential biomarker in patients with advanced gastroenteropancreatic neuroendocrine neoplasms (GEPNENs). Methods: A multicenter retrospective study in patients with advanced GEPNENs and paired [ 18 F]FDG and [ 68 Ga]Ga-DOTATATE PET/CT no more than 85 d apart was conducted. Patients with discordant disease were identified by the NETPET score, and discordant lesions were contoured with a flat [ 18 F]FDG SUV cutoff of 4. The primary variable of interest was the total discordant volume (TDV), which was the sum of the volumes of discordant lesions. Patients were dichotomized into high- and low-TDV cohorts by the median value. The primary endpoint was overall survival. Results: In total, 44 patients were included (50% men; median age, 60 y), with primary cancers in the pancreas (45%), small bowel (23%), colon (20%), and other (12%). Of the patients, 5% had grade 1 disease, 48% had grade 2 disease, and 48% had grade 3 disease (24% well differentiated, 67% poorly differentiated, 10% unknown within the grade 3 cohort). The overall median survival was 14.1 mo. Overall survival was longer in the low-TDV cohort than in the high-TDV cohort (median volume, 43.7 cm 3 ; survival time, 23.8 mo vs. 9.4 mo; hazard ratio, 0.466 [95% CI, 0.229-0.948]; P = 0.0221). Patients with no more than 2 discordant intrahepatic lesions survived longer than those with 2 or more lesions (31.8 mo vs. 10.2 mo, respectively; hazard ratio, 0.389 [95% CI, 0.194-0.779]; P = 0.0049). Conclusion: TDV is a potential prognostic biomarker in GEPNENs and should be investigated in future neuroendocrine neoplasm trials., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Gastroenteropancreatic neuroendocrine neoplasms (GEPNENs) are heterogeneous in clinical course, biology, and outcomes. The NETPET score predicts survival by scoring uptake on dual [ 68 Ga]DOTATATE and [ 18 F]FDG PET/CT scans. We aimed to validate previous single-centre findings in a multicentre, international study., Methods: Dual scans were assigned a NETPET score of P1 (DOTATATE positive/FDG negative), P2-4 (DOTATATE positive/FDG positive), or P5 (DOTATATE negative/FDG positive). NETPET score, histological grade, age at diagnosis, and presence/absence of extrahepatic disease were compared to overall survival/time to progression on univariate and multivariate analysis., Results: 319 metastatic/unresectable GEPNEN patients were included. The NETPET score was significantly associated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01). Median overall survival/time to progression was 101.8/25.5 months for P1, 46.5/16.7 months for P2-4, and 11.5/6.6 months for P5. Histological grade correlated with overall survival and time to progression on univariate and multivariate analysis (all p < 0.01), while presence/absence of extrahepatic disease did not. Age at diagnosis correlated with overall survival on univariate and multivariate analysis (p < 0.01). The NETPET score also correlated with histological grade (p < 0.001)., Conclusion: This study validates the NETPET score as a prognostic biomarker in metastatic GEPNENs, capturing the complexity of dual PET imaging., (© 2022. The Author(s).)

Purpose of Review: This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients., Recent Findings: In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose of Review: Mesenteric desmoplasia in small intestinal neuroendocrine neoplasms (SINENs) is associated with increased morbidity and mortality. In this paper, we discuss the development of desmoplasia in SINENs., Recent Findings: The fibrotic reactions associated with these tumours could be limited to the loco-regional environment of the tumour and/or at distant sites. Mesenteric fibrotic mass forms around a local lymph node. Formation of desmoplasia is mediated by interactions between the neoplastic cells and its microenvironment via number of profibrotic mediators and signalling pathways. Profibrotic molecules that are mainly involved in the desmoplastic reaction include serotonin, TGFβ (transforming growth factor β) and CTGF (connective tissue growth factor), although there is some evidence to suggest that there are a number of other molecules involved in this process. Desmoplasia is a result of autocrine and paracrine effects of multiple molecules and signalling pathways. However, more research is needed to understand these mechanisms and to develop targeted therapy to minimise desmoplasia., (© 2022. The Author(s).)

Introduction: Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) is considered to be a rare condition associated with lung neuroendocrine tumours (NET), and its natural history is poorly described. We aimed to assess the prevalence and clinicopathologic characteristics of DIPNECH in the lung NET population, and to investigate predictors of time-to-progression (TTP) and overall survival (OS)., Methods: We retrospectively identified patients diagnosed with DIPNECH between April 2005 and December 2020. Clinical data were collected from medical records. The relationship between baseline characteristics and TTP and OS was analysed using the Kaplan-Meier method. Univariate analysis was performed using the Cox proportional hazards model., Results: Of 311 patients with well-differentiated lung NETs, 61 (20%) had DIPNECH and were included in the study. Baseline demographics described 95% female, 59% never smokers and mean body mass index 34.4 kg m -2 ; 77% were typical carcinoids (TC), 13% atypical carcinoids (AC), and 10% both TC and AC (multicentric). At presentation, 54% of patients were asymptomatic. Multicentric NETs were demonstrated in 16 (26%) on histopathology, and a further 32 (52%) had synchronous NETs suggested on imaging (multiple nodules ≥ 5 mm). Seven (11%) patients developed metastases and the median OS from time of first metastasis was 37 months. AC histopathology and NET TNM stage ≥ IIA were associated with poorer TTP and OS. Of the DIPNECH cohort, the 15-year survival rate was 86%., Conclusions: DIPNECH may be more prevalent in the lung NET population than previously appreciated, especially in women. Although our results confirm that DIPNECH is predominantly an indolent disease associated with TC, 23% developed AC and these patients may warrant closer observation., (© 2022 British Society for Neuroendocrinology.)

A healthy diet and dietary supplements have gained attention as potential co-adjuvants in managing and preventing coronavirus disease 2019 (COVID-19). This paper critically reviews the current evidence regarding the impact of diet and supplements on the prevention and progression of COVID-19. According to available data, a healthy diet and normal weight are considered protective factors. Regarding dietary supplementation, the most robust results from human studies are for vitamin C, which appears to decrease inflammatory markers and suppress cytokine storm. A small, randomized trial showed that a high dose of vitamin D significantly reduced the need for intensive care unit treatment of patients requiring hospitalization for COVID-19. According to retrospective human studies, there is limited evidence for vitamin E and selenium supplements. Animal studies have investigated the effects of green tea and curcumin. Xanthohumol and probiotics, interesting for their antiviral, anti-inflammatory, and immunoregulatory properties, need formal clinical study. In summary, there is promising evidence supporting the role of diet and supplements as co-adjuvants in the treatment of COVID-19. Further studies and properly designed clinical trials are necessary to draw more robust conclusions; however, it is not unreasonable to take a pragmatic approach and promote the use of appropriate diet and supplements to counter the effects of COVID-19, ideally with a mechanism to assess outcomes., Competing Interests: AUTHOR DISCLOSURE STATEMENT The authors declare no conflicts of interest., (Copyright © 2022 by The Korean Society of Food Science and Nutrition. All rights Reserved.)

Purpose: Gastroenteropancreatic neuroendocrine neoplasms (GEP NEN) are widely heterogeneous in their biological behavior, and predicting prognosis and optimal treatment strategies can be challenging. 68Ga-DOTATATE PET/CT is a sensitive imaging modality for well-differentiated NEN and indicates a favorable prognosis, whereas 18F-FDG PET/CT avidity indicates disease that is potentially more aggressive. There has been emerging interest in the combined interpretation of 68Ga-DOTATATE and 18F-FDG PET and its prognostic significance. We aimed to assess the prognostic utility of a classification system that incorporates the complex findings of 68Ga-DOTATATE and 18F-FDG PET interpreted side-by-side in patients with metastatic GEP NEN., Methods: We defined 3 68Ga-DOTATATE/18F-FDG "dual-tracer PET" groups: D1 (68Ga-DOTATATE positive/18F-FDG negative), D2 (68Ga-DOTATATE positive/18F-FDG positive), and D3 (68Ga-DOTATATE negative/18F-FDG positive). We retrospectively assessed the association between the dual-tracer PET classification and progression-free and overall survival (OS) using Kaplan-Meier analysis. Univariate and multivariate analyses were performed using the Cox proportional hazards model., Results: Eighty-seven patients with metastatic GEP NEN and contemporaneous 68Ga-DOTATATE and 18F-FDG PET were included. The dual-tracer PET classification was an independent predictor of OS (multivariate P = 0.016) and also predicted progression-free survival (univariate P = 0.030). Other independent predictors of OS included chromogranin A and World Health Organization (WHO) grade. WHO grade was not associated with OS from the time of dual-tracer PET but was an independent predictor of OS from the date of histological diagnosis (multivariate P = 0.003)., Conclusion: Our study demonstrates that a classification system combining the complex findings of 68Ga-DOTATATE and 18F-FDG PET is correlated with prognosis. Further research is needed to prospectively validate these findings and to explore whether dual-tracer PET scores may also be able to predict response to treatment., Competing Interests: Conflicts of interest and sources of funding: This project was funded by the Royal Free Charitable Trust (Quiet Cancer) Grant 311 and the Parasol FoundationTrust. S.N. reports personal fees from AAA, outside the submitted work. G.G. reports personal fees from AAA, outside the submitted work. C.T. reports personal fees (Ipsen, Novartis, AAA) and education grants (Ipsen, Novartis, AAA), outside the submitted work. M.E.C. reports personal fees (Ipsen, Novartis, AAA, Lexicon, Pfizer) and grants (AAA, Ipsen), outside the submitted work. The remaining authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177 Lu-Dotatate plus long-acting octreotide versus high-dose long-acting octreotide alone in patients with advanced midgut neuroendocrine tumours. Here, we report the prespecified final analysis of overall survival and long-term safety results., Methods: This open-label, randomised, phase 3 trial enrolled patients from 41 sites in eight countries across Europe and the USA. Patients were 18 years and older with locally advanced or metastatic, well differentiated, somatostatin receptor-positive midgut neuroendocrine tumours (Karnofsky performance status score ≥60) and disease progression on fixed-dose long-acting octreotide. Patients were randomly assigned (1:1) via an interactive web-based response system to intravenous 177 Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg ( 177 Lu-Dotatate group) or high-dose long-acting octreotide 60 mg every 4 weeks (control group). The primary endpoint of progression-free survival has been previously reported; here, we report the key secondary endpoint of overall survival in the intention-to-treat population. Final overall survival analysis was prespecified to occur either after 158 deaths or 5 years after the last patient was randomised, whichever occurred first. During long-term follow-up, adverse events of special interest were reported in the 177 Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239., Findings: From Sept 6, 2012, to Jan 14, 2016, 231 patients were enrolled and randomly assigned for treatment. The prespecified final analysis occurred 5 years after the last patient was randomly assigned (when 142 deaths had occurred); median follow-up was 76·3 months (range 0·4-95·0) in the 177 Lu-Dotatate group and 76·5 months (0·1-92·3) in the control group. The secondary endpoint of overall survival was not met: median overall survival was 48·0 months (95% CI 37·4-55·2) in the 177 Lu-Dotatate group and 36·3 months (25·9-51·7) in the control group (HR 0·84 [95% CI 0·60-1·17]; two-sided p=0·30). During long-term follow-up, treatment-related serious adverse events of grade 3 or worse were recorded in three (3%) of 111 patients in the 177 Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177 Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177 Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up., Interpretation: 177 Lu-Dotatate treatment did not significantly improve median overall survival versus high-dose long-acting octreotide. Despite final overall survival not reaching statistical significance, the 11·7 month difference in median overall survival with 177 Lu-Dotatate treatment versus high-dose long-acting octreotide alone might be considered clinically relevant. No new safety signals were reported during long-term follow-up., Funding: Advanced Accelerator Applications, a Novartis company., Competing Interests: Declaration of interests JRS has provided consulting or advisory services for Novartis, speakers bureau services for Ipsen, Lexicon and has received research funding from Novartis. MEC has provided consulting or advisory services for Advanced Accelerator Applications (a Novartis company), Ipsen, Sirtex Medical, Novartis, speakers bureau services for Advanced Accelerator Applications, Ipsen, Sirtex Medical, and Pfizer, and has received research funding from Advanced Accelerator Applications. PLK has provided consulting or advisory services for Ipsen, Lexicon, and Advanced Accelerator Applications, and has received research funding from Advanced Accelerator Applications, Lexicon, Ipsen, Xencor, and Brahms. PLK owns stock in Guardant Health. PBR has provided consulting or advisory services for Ipsen, Advanced Accelerator Applications, ITM, and Novartis; has received research funding from Advanced Accelerator Applications, Ipsen, and ITM; and has received travel or accommodation expenses from Ipsen. LB has provided consulting services (non-remunerated) for Advanced Accelerator Applications, ITM, Clovis Oncology, Curium, and Iba; has provided speaker's bureau services (non-remunerated) for Advanced Accelerator Applications, ITM, and Iba; and has received research funding from Advanced Accelerator Applications. AH has provided consulting or advisory services for Novartis, Ipsen, Perthera, Celgene and AbbVie, and has received travel or accommodation expenses from Halozyme and research funding from Ipsen. EM has provided consulting or advisory services for Ipsen and Advanced Accelerator Applications, has received honoraria from Advanced Accelerator Applications and Curium, and has received research funding from Advanced Accelerator Applications and Nordic Nanovector. EMW has provided consulting or advisory services for Advanced Accelerator Applications, Lexicon, and Progenics. JCY has provided consulting or advisory services for Advanced Accelerator Applications, Ipsen, Chiasma, Crinetics, and Hutchinson Medi Pharma, and has received research funding from Advanced Accelerator Applications and Novartis. MEP has provided consulting or advisory services for Advanced Accelerator Applications and Ipsen, and has received honoraria from Ipsen, Hutchison MediPharma, Advanced Accelerator Applications, Riemser, and Boehringer Ingelheim, and travel or accommodation expenses from Ipsen and Hutchison. EG has provided consulting or advisory services for MSD, Pfizer, Ipsen, Roche, and Bristol Myers Squibb; has received honoraria from Pfizer, Bristol Myers Squibb, Ipsen, Roche, Eisai, Eusa Pharma, MSD, Genzyme, Advanced Accelerator Applications, Novartis, Pierre Fabre, Lexicon, Celgene, Janssen-Cilag, Astellas Pharma, AstraZeneca, and Lilly; has received travel or accommodation expenses from Bristol Myers Squibb, Roche/Genentech, Pfizer, Janssen-Cilag, and Ipsen; and has received research funding from Roche, Pfizer, AstraZeneca, Ipsen, Molecular Templates, Lexicon, and Astellas Pharma. EVC has provided consulting or advisory services for Bayer, Lilly, Roche, Servier, Bristol Myers Squibb, Celgene, Merck Sharp & Dohme, Merck KGaA, Novartis, AstraZeneca, Halozyme, Array BioPharma, Biocartis, GlaxoSmithKline, Daiichi Sankyo, Pierre Fabre, Sirtex Medical, Taiho Pharmaceutical, and Incyte, and has received research funding from Amgen, Bayer, Boehringer Ingelheim, Lilly, Novartis, Roche, Celgene, Ipsen, Merck, Merck KGaA, Servier, and Bristol Myers Squibb. GG is an employee of Novartis, owns stock in Novartis, and receives travel or accommodation expenses from Novartis. AB is an employee of Novartis, owns stock in Novartis, and receives travel or accommodation expenses from Novartis. MFM is an employee of Novartis and owns stock in Novartis. AD is an employee of Novartis and owns stock in Novartis. SM is an employee of Novartis and owns stock in Novartis. EPK has an employment interest in Cyclotron Rotterdam BV; has stock or other ownership interest in AstraZeneca, GlaxoSmithKline, Merck and Roche; has patent or intellectual property interest in Advanced Accelerator Applications; and receives travel or accommodation expenses from Advanced Accelerator Applications. ES and HD declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Context: Metastatic medullary thyroid cancer (MTC) is a rare malignancy with minimal treatment options. Many, but not all, MTCs express somatostatin receptors., Objective: Our aim was to explore the role of 68Ga-DOTA-somatostatin analogue (SSA) positron emission tomography (PET)/computed tomography (CT) in patients with metastatic MTC and to determine their eligibility for peptide receptor radionuclide therapy (PRRT)., Methods: We retrospectively identified patients with metastatic MTC who had 68Ga-DOTA-SSA PET/CT at 5 centers. We collected characteristics on contrast-enhanced CT, 68Ga-DOTA-SSA and 18F-FDG PET/CT. The efficacy of PRRT was explored in a subgroup of patients. Kaplan-Meier analysis was used to estimate time to treatment failure (TTF) and overall survival (OS)., Results: Seventy-one patients were included (10 local recurrence, 61 distant disease). Of the patients with distant disease, 16 (26%) had ≥50% of disease sites with tracer avidity greater than background liver, including 10 (10/61, 16%) with >90%. In 19 patients with contemporaneous contrast-enhanced CT, no disease regions were independently identified on 68Ga-DOTA-SSA PET/CT. Thirty-five patients had an 18F-FDG PET/CT, with 18F-FDG positive/68Ga-DOTA-SSA negative metastases identified in 15 (43%). Twenty-one patients had PRRT with a median TTF of 14 months (95% CI 8-25) and a median OS of 63 months (95% CI 21-not reached). Of the entire cohort, the median OS was 323 months (95% CI 152-not reached). Predictors of poorer OS included a short calcitonin doubling-time (≤24 months), strong 18F-FDG avidity, and age ≥60 years., Conclusions: The prevalence of high tumor avidity on 68Ga-DOTA-SSA PET/CT is low in the setting of metastatic MTC; nevertheless, PRRT may still be a viable treatment option in select patients., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: The safety and efficacy of 177 Lu-DOTATATE in older patients with advanced neuroendocrine tumours (NET) are not well understood., Methods: Patients ≥70 years of age and treated with 177 Lu-DOTATATE were included. Toxicity, health-related quality of life (HRQoL), objective response, progression-free survival (PFS) and overall survival (OS) were assessed. The relationship between baseline characteristics and PFS and OS was analysed using the Kaplan-Meier method. Univariate analyses were performed using the Cox proportional hazards model., Results: In total, 71 patients were included (76.1% midgut primary). The median age at diagnosis and age at 177 Lu-DOTATATE treatment were 70 and 74 years, respectively. The majority (78.9%) of patients completed 4 cycles of 177 Lu-DOTATATE. Clinically significant myelosuppression was rare (2.8%). There was no deterioration in HRQoL and 'disease-specific worries' significantly improved (P = 0.029). Radiological response assessment was available in 66 patients. Partial response, stable disease and progression of disease were found in 10 (15.2%), 52 (78.8%) and 4 patients (6.1%), respectively. Median PFS and OS were 36.0 and 47.0 months, respectively. Increased baseline alkaline phosphatase was associated with poorer PFS (P = 0.002) and OS (P = 0.006)., Conclusion: Patients ≥70 years of age with advanced NET treated with 177 Lu-DOTATATE have efficacy and toxicity profiles similar to the wider NET population, without deterioration of HRQoL., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: There is a pressing need to develop clinical management pathways for grade 3 (G3) gastroenteropancreatic neuroendocrine neoplasms (GEP NEN)., Methods: We performed a retrospective study on patients with metastatic G3 GEP NEN. The relationship between baseline characteristics and progression-free survival and overall survival was analyzed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model., Results: We included 142 patients (74 well-differentiated neuroendocrine tumors [WDNETs], 68 poorly differentiated neuroendocrine carcinomas [PDNECs]). Patients with WDNET had prolonged survival compared with PDNEC (median, 24 vs 15 months, P = 0.0001), which persisted in both pancreatic and nonpancreatic cohorts. Well-differentiated morphology, Ki-67 <50% and positive somatostatin receptor imaging were independently associated with prolonged survival. Of the subgroup treated with first-line platinum-based chemotherapy, response rates were favorable (partial response, 47%; stable disease, 30%); there was no significant difference in response rates nor progression-free survival between WDNET and PDNEC despite significantly prolonged overall survival in the WDNET cohort., Conclusions: Our study corroborates the knowledge of 2 prognostically distinct subgroups within the World Health Organization 2019 G3 GEP NEN population, observed in both pancreatic and nonpancreatic gastrointestinal cohorts. Definitive management pathways are needed to reflect the differences between G3 WDNET and PDNEC., Competing Interests: C.To. reports advisory board and speaker honoraria from Ipsen, Novartis and AAA; outside the submitted work. He has received education grants from Ipsen, Novartis and AAA for the Royal Free NET unit. M.E.C. has received advisory board and speaker honoraria from Ipsen, Novartis, AAA, Lexicon and Pfizer; outside the submitted work. C.Th. reports consulting for Ipsen and Boehringer-Ingelheim and conference travel support from Bayer and Novartis; outside the submitted work. The other authors declare no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

We report the impact of 177 Lu DOTATATE treatment on abdominal pain, diarrhea, and flushing, symptoms that patients with advanced midgut neuroendocrine tumors (NETs) often find burdensome. Methods: All patients enrolled in the international randomized phase 3 Neuroendocrine Tumors Therapy (NETTER-1) trial ( 177 Lu-DOTATATE plus standard-dose octreotide long-acting repeatable [LAR], n = 117; high-dose octreotide LAR, n = 114) were asked to record the occurrence of predefined symptoms in a daily diary. Change from baseline in symptom scores (mean number of days with a symptom) was analyzed using a mixed model for repeated measures. Results: Patients (intent-to-treat) who received 177 Lu-DOTATATE experienced a significantly greater decline from baseline in symptom scores than patients who received high-dose octreotide LAR. For 177 Lu-DOTATATE, the mean decline in days with abdominal pain, diarrhea, and flushing was 4.10, 4.55, and 4.52 days per 4 weeks, respectively, compared with 0.99, 1.44, and 2.54 days for high-dose octreotide LAR. The mean differences were 3.11 days (95% confidence interval, 1.35-4.88; P = 0.0007) for abdominal pain, 3.11 days (1.18-5.04; P = 0.0017) for diarrhea, and 1.98 days (0.08-3.88; P = 0.0413) for flushing, favoring 177 Lu-DOTATATE. A positive repeated measures correlation was found between diary-recorded symptom scores and questionnaire-recorded pain, diarrhea, and flushing. Conclusion: In addition to efficacy and quality of life benefits, symptom diaries from NETTER-1 demonstrated that treatment with 177 Lu DOTATATE was associated with statistically significant reductions in abdominal pain, diarrhea, and flushing, constituting the core symptoms of patients with progressive midgut NETs, compared with high-dose octreotide LAR, supporting a beneficial effect of 177 Lu DOTATATE on HRQoL., (Copyright © 2021 by the Society of Nuclear Medicine and Molecular Imaging, Inc.)

Background: Carcinoid heart disease (HD) is a rare form of valvular heart disease, the features of which have not been fully described by cardiac computed tomography (CT)., Methods: All patients with carcinoid HD that underwent cardiac CT, either preoperatively or for assessment of coronary arteries, between Apr-2006 and Dec-2019 at the Royal Free Hospital, UK, were reviewed., Results: Of 32 patients with carcinoid HD, 29 (91%) had heart valve involvement. Abnormalities of the tricuspid and pulmonary valves were present in all patients, affecting all three leaflets in 23/26 (89%) unoperated patients for both valves. The aortic valve was affected in 4/29 (14%) patients and the mitral valve in 5/29 (17%). Left heart valves were affected in 6/29 (21%) patients. One patient (1/29; 3%) had all four valves affected. Severe changes with significant valvular regurgitation were seen in ≥75% of patients with tricuspid, pulmonary, and aortic valve abnormalities. Three patients had carcinoid myocardial metastases (3/32; 9%) and one patient had constrictive pericarditis (1/32; 3%). Ten patients had surgery of whom four (40%) had invasive coronary angiography preoperatively. Ten patients had a patent foramen ovale. Cardiac CT allowed an accurate assessment of damage to different leaflets/cusps, particularly of the pulmonary valve, where visualization with echocardiography was often (3/8; 38%) incomplete., Conclusion: Cardiac CT is a powerful tool for assessment of cardiac valve abnormalities, coronary arteries and the spatial relationship of coronary arteries with myocardial metastasis in patients with carcinoid HD, and should form part of multimodal imaging of this complex pathology., Competing Interests: Declaration of competing interest The authors have no relationships relevant to the contents of this paper to disclose., (Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.)

Purpose: In the phase III CLARINET study (NCT00353496), lanreotide autogel/depot (lanreotide) significantly improved progression-free survival (PFS) vs placebo in patients with non-functioning intestinal or pancreatic neuroendocrine tumours (NETs). The aim of CLARINET open-label extension (OLE) (NCT00842348) was to evaluate long-term safety and efficacy of lanreotide in these patients., Methods: Patients from the CLARINET study were eligible for the OLE if they had stable disease (irrespective of treatment group) or progressive disease (PD) (placebo-treated patients only). All patients in the OLE received lanreotide 120 mg every 28 days. Computed tomography or magnetic resonance imaging scans were conducted every 6 months and assessed locally for PD (the final scan was also assessed centrally)., Results: Overall, 89 patients took part in the OLE (lanreotide, n = 42; placebo, n = 47). Median (range) exposure to lanreotide in patients who received lanreotide in the core study and OLE (LAN-LAN group) was 59.0 (26.0-102.3) months. In this group, the overall incidences of adverse events (AEs) and treatment-related AEs were lower in the OLE than in the core study. Median [95% CI] PFS in the LAN-LAN group was 38.5 [30.9; 59.4] months. In placebo-treated patients with PD at the end of the core study, time to death or subsequent PD during the OLE was 19 [10.1; 26.7] months., Conclusions: This study provides new evidence on the long-term safety profile and sustained anti-tumour effects of lanreotide autogel/depot in indolent and progressive metastatic intestinal or pancreatic NETs.

Background: The number of therapeutic options for patients with pancreatic neuroendocrine neoplasms (PNEN) has increased, but the optimal therapeutic algorithm has not been defined due to lack of randomised trials comparing different modalities., Methods: We performed a retrospective study in patients with metastatic PNEN treated with ≥1 line of systemic therapy. The relationship between baseline characteristics, treatment type, and time to treatment failure (TTF), time to progression (TTP), and overall survival (OS) was analysed using the Kaplan-Meier method. Univariate and multivariate analyses were performed using the Cox proportional hazards model., Results: Two hundred and fifty-five patients with metastatic PNEN had 491 evaluable lines of therapy. Independent predictors of TTF included treatment type, Ki-67, tumour grade, and chromogranin A. To reduce selection bias, a subgroup of 114 patients with grade 2 (G2) metastatic pancreatic neuroendocrine tumours (PNET) was analysed separately. These patients had received 234 lines of treatment (105 chemotherapy, 82 molecular targeted therapy, and 47 peptide receptor radionuclide therapy [PRRT]). In the G2 cohort, TTF and TTP were superior for PRRT compared with both chemotherapy and molecular targeted therapy. OS in the G2 cohort was also superior for those that had received PRRT compared with those that had not (median 84 vs. 56 months; HR 0.55, 95% CI: 0.31-0.98, p = 0.04)., Conclusions: This study suggests that PRRT is associated with superior clinical outcomes relative to other systemic therapies for G2 metastatic PNET. Prospective studies are required to confirm these observations., (© 2020 S. Karger AG, Basel.)

Accessible prognostic tools are needed to individualize treatment of neuroendocrine tumors (NETs). Data suggest neutrophil/lymphocyte ratios (NLRs) have prognostic value in some solid tumors, including NETs. In the randomized double-blind CLARINET study (NCT00353496; EudraCT 2005-004904-35), the somatostatin analog lanreotide autogel/depot increased progression-free survival (PFS) compared with placebo in patients with inoperable or metastatic intestinal and pancreatic NETs (grades 1-2, Ki-67 < 10%). The exploratory post-hoc analyses presented here evaluated the prognostic value of NLR in the CLARINET study cohort, in the context of and independently from treatment. Kaplan-Meier PFS plots were generated for patients with available NLR data, in subgroups based on NLR values, and 24-month survival rates were calculated. P values and hazard ratios for prognostic effects were generated using Cox models. 31216222 Baseline characteristics were balanced between lanreotide autogel/depot 120 mg (n = 100) and placebo (n = 101) arms. Irrespective of treatment, raw 24-month PFS rates were comparable across subgroups based on NLR tertiles [37.3% (low), 38.8% (middle), 38.8% (high); n = 67 per group] and NLR cutoff of 4 [38.1% (NLR ≤ 4; n = 176), 40.0% (NLR > 4; n = 25)]. Furthermore, NLRs were not prognostic in Cox models, irrespective of subgroups used. The therapeutic effect of lanreotide autogel/depot 120 mg was independent of NLRs (P > 0.1). These exploratory post-hoc analyses in patients with advanced intestinal and pancreatic NETs contrast with previous data suggesting NLR has prognostic potential in NETs. This may reflect the inclusion of patients with lower-grade tumors or use of higher NLR cutoff values in the current analysis.

Objective: Paragangliomas are rare tumours of neural crest origin that express high levels of somatostatin receptor. Ga-68 DOTATATE PET/CT is a widely accepted method for imaging of neuroendocrine tumours. This study was performed to review a Ga-68 DOTATATE PET/CT patient database and to establish the impact of the modality on patient treatment., Methods: Demographic data, imaging data and change in management after Ga-68 DOTATATE PET/CT were evaluated., Results: Ga-68 DOTATATE PET/CT scans were performed in 21 patients in whom paragangliomas had been confirmed after biopsy or surgery and in one patient with suspected paraganglioma. In most patients, the primary site was the organ of Zuckerkandl (12/22). Of the 22 Ga-68 DOTATATE PET/CT scans completed, 19 (86.4%) were positive and three (13.6%) negative. In 12 of 14 recurrent cases (90.9%), the treatment plan was changed after the Ga-68 DOTATATE PET/CT scan owing to new, unexpected findings, while it remained unchanged in two (9.1%). Regarding the change in treatment plan, in most instances the new treatment comprised peptide receptor radionuclide therapy (PRRT)., Conclusion: Ga-68 DOTATATE PET/CT findings led to a change in the scheduled treatment plan in 90.9% of patients with suspected recurrence. The most frequent change consisted in initiation of PRRT due to disease recurrence or progression or detection of multiple metastases.

Background: Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience considerable morbidity and mortality; carcinoid syndrome may be associated with shorter survival. Carcinoid syndrome is linked to tumoral secretion of serotonin and other bioactive substances. The subsequent debilitating diarrhea and urgency to defecate pose significant health risks. In previous studies, telotristat ethyl, a tryptophan hydroxylase inhibitor, was effective and well tolerated in treating carcinoid syndrome diarrhea. We present pooled safety data from five clinical trials with telotristat ethyl in patients with carcinoid syndrome., Subjects, Materials, and Methods: Adverse events reported during telotristat ethyl treatment were pooled from two phase II and three phase III clinical trials in 239 patients with carcinoid syndrome. Long-term safety of telotristat ethyl and causes of hospitalization and death were reviewed; overall survival was estimated., Results: Mean (median; range) duration of exposure and follow-up was 1.3 years (1.1 years; 1 week to 5.7 years), with 309 total patient-years of exposure. Leading causes of hospitalization were gastrointestinal disorders or were related to the underlying tumor and related treatment. Survival estimates at 1, 2, and 3 years were 93%, 88%, and 77%. Nearly all deaths were due to progression or complication of the underlying disease; none were attributable to telotristat ethyl. There was one death in year 4., Conclusion: Based on long-term safety data, telotristat ethyl is well tolerated and has a favorable long-term safety profile in patients with carcinoid syndrome., Implications for Practice: Carcinoid syndrome can cause persistent diarrhea, even in patients treated with somatostatin analogs. Across five clinical trials in patients with carcinoid syndrome, telotristat ethyl has been well tolerated and efficacious, providing clinicians with a new approach to help control carcinoid syndrome diarrhea, in addition to somatostatin analog therapy. By reducing the stool frequency in patients with carcinoid syndrome whose diarrhea is refractory to anticholinergics, such as loperamide and atropine/diphenoxylate, and somatostatin analog dose escalation, improvement in quality of life becomes an achievable goal., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Objectives: Vasoactive intestinal peptide-secreting tumors (VIPomas) are rare functioning neuroendocrine tumors often characterized by a difficult-to-control secretory syndrome and high potential to develop metastases. We hereby present the characteristics of 15 cases of VIPomas and provide a recent literature review., Methods: This was a retrospective data analysis of 15 patients with VIPoma from 3 different centers and literature research through PubMed database during the last 10 years., Results: Fifteen patients with VIPomas (9 with hepatic metastases at diagnosis) with watery diarrhea and raised VIP levels were studied. Ten patients (67%) had grade 2 tumors, 6 of 15 had localized disease and underwent potentially curative surgery, whereas the remaining 9 received multiple systemic therapies; 3 patients died during follow-up. The median overall survival was 71 months (range, 41-154 months). Patients who were treated with curative surgery (n = 7) had longer median overall survival compared with patients who were treated with other therapeutic modalities (44 vs 33 months)., Conclusions: The management of VIPomas is challenging requiring the application of multiple treatment modalities. Patients who underwent surgical treatment with curative intent appear to have higher survival rate. Central registration and larger prospective studies are required to evaluate the effect of currently employed therapies in these patients.

Background: Lanreotide depot/autogel antitumor activity in intestinal/pancreatic neuroendocrine tumors (NETs) was demonstrated in the phase-3 CLARINET study (NCT00353496), based on significantly prolonged progression-free survival (PFS) versus placebo., Methods: During CLARINET, patients with metastatic intestinal/pancreatic NETs received lanreotide depot/autogel 120 mg or placebo every 4 weeks for 96 weeks. Imaging data (response evaluation criteria in solid tumors [RECIST] v1.0, centrally reviewed) were re-evaluated in this post hoc analysis of tumor growth rate (TGR) in NETs. TGR (%/month) was calculated from two imaging scans during relevant periods: pre-treatment (TGR 0 ); 12-24 weeks before randomization versus baseline; each treatment visit versus baseline (TGR Tx-0 ); between consecutive treatment visits (TGR Tx-Tx ). To assess TGR as a measure of prognosis, PFS was compared for TGR 0 subgroups stratified by optimum TGR 0 cut-off; a multivariate analysis was conducted to identify prognostic factors for PFS., Results: TGR 0 revealed tumors growing during pre-treatment (median [interquartile range] TGR 0 : lanreotide 2.1%/month [0.2; 6.1]; placebo 2.7%/month [0.15; 6.8]), contrary to RECIST status. TGR was significantly reduced by 12 weeks with lanreotide versus placebo (difference in least-square mean TGR 0-12 of - 2.9 [- 5.1, - 0.8], p = 0.008), a difference that was maintained at most subsequent visits. TGR 0  > 4%/month had greater risk of progression/death than ≤4%/month (hazard ratio 4.1; [95% CI 2.5-6.5]; p < 0.001); multivariate analysis revealed lanreotide treatment, progression at baseline, TGR 0 , hepatic tumor load, and primary tumor type were independently associated with PFS., Conclusions: TGR provides valuable information on tumor activity and prognosis in patients with metastatic intestinal/pancreatic NETs, and identifies early lanreotide depot/autogel antitumor activity., Trial Registration: Retrospective registration, 18 July 2006; EudraCT: 2005-004904-35; ClinicalTrials.gov: NCT00353496 .

Pulmonary carcinoids (PCs) display the common features of all well-differentiated neuroendocrine neoplasms (NEN) and are classified as low- and intermediate-grade malignant tumours (i.e., typical and atypical carcinoid, respectively). There is a paucity of randomised studies dedicated to advanced PCs and management principles are drawn from the larger gastroenteropancreatic NEN experience. There is growing evidence that NEN anatomic subgroups have different biology and different responses to treatment and, therefore, should be investigated as separate entities in clinical trials. In this review, we discuss the existing evidence and limitations of tumour classification, diagnostics and staging, prognostication, and treatment in the setting of PC, with focus on unmet medical needs and directions for the future., (© 2018 S. Karger AG, Basel.)

Carcinoid heart disease remains a major cause of morbidity and mortality among patients with carcinoid syndrome and metastatic neuroendocrine tumors. Screening of all patients with N-terminal pro-B-type natriuretic peptide and transthoracic echocardiography is critical for early detection, as early symptoms and signs have low sensitivity for the disease. Cardiac surgery, in appropriate cases, is the only definitive therapy for advanced carcinoid heart disease, and it improves patient symptoms and survival. Management of carcinoid heart disease is complex, and multidisciplinary assessment of cardiac status, hormonal syndrome, and tumor burden is critical in guiding optimal timing of surgery., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: In the placebo-controlled Phase III TELESTAR (Telotristat Etiprate for Somatostatin Analogue Not Adequately Controlled Carcinoid Syndrome) trial, the oral tryptophan hydroxylase inhibitor telotristat ethyl significantly reduced bowel movement (BM) frequency during a 12-week, double-blind treatment period in 135 patients with metastatic neuroendocrine tumors with carcinoid syndrome and ≥4 BMs per day. Patients (mean [SD] age, 63.5 [8.9] years; mean [SD] body mass index, 24.9 [4.9] kg/m 2 ) received placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg 3 times per day (TID) in addition to somatostatin analogue therapy. Weight loss is associated with uncontrolled carcinoid syndrome and may be associated with reduced survival., Methods: Assessment of the occurrence of weight change ≥3% at week 12 was prespecified in the statistical analysis plan., Findings: In 120 patients with weight data available, weight gain ≥3% was observed in 2 of 39 patients (5.1%) taking placebo TID, 7 of 41 (17.1%) taking telotristat ethyl 250 mg TID, and 13 of 40 (32.5%) taking telotristat ethyl 500 mg TID (P = 0.0017) at week 12. Weight loss ≥3% was observed in 5 of 39 patients (12.8%) taking placebo TID, 4 of 41 (9.8%) taking telotristat ethyl 250 mg TID, and 6 of 40 (15.0%) taking telotristat ethyl 500 mg TID (P = 0.77). Biochemical and metabolic parameters of serum albumin and cholesterol significantly increased (P = 0.02 and P = 0.001, respectively) in patients gaining weight and decreased in patients who lost weight, suggesting an improvement in overall nutritional status., Implications: Up to 32.5% of patients treated with telotristat ethyl experienced significant, dose-dependent weight gain, associated with reduced diarrhea severity and improved biochemical and metabolic parameters. Improved nutritional status could be an additional aspect of telotristat ethyl efficacy among patients with functioning metastatic neuroendocrine tumors. ClinicalTrials.gov identifier: NCT01677910., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Pollution is known to cause and exacerbate a number of chronic respiratory diseases. The World Health Organisation has placed air pollution as the world's largest environmental health risk factor. There has been recent publicity about the role for diet and anti-oxidants in mitigating the effects of pollution, and this review assesses the evidence for alterations in diet, including vitamin supplementation in abrogating the effects of pollution on asthma and other chronic respiratory diseases. We found evidence to suggest that carotenoids, vitamin D and vitamin E help protect against pollution damage which can trigger asthma, COPD and lung cancer initiation. Vitamin C, curcumin, choline and omega-3 fatty acids may also play a role. The Mediterranean diet appears to be of benefit in patients with airways disease and there appears to be a beneficial effect in smokers however there is no direct evidence regarding protecting against air pollution. More studies investigating the effects of nutrition on rapidly rising air pollution are urgently required. However it is very difficult to design such studies due to the confounding factors of diet, obesity, co-morbid illness, medication and environmental exposure.

Introduction: Bronchial neuroendocrine tumors (NETs) are rare tumors representing approximately 20%-30% of all neuroendocrine tumors and 2%-3% of all adult lung cancers. Here, they present a large case series of well-differentiated bronchial NETs with the aim of investigating the behavior of these tumors and long-term outcomes., Methods: A retrospective review was performed of 105 patients with bronchial NETs managed in a tertiary referral center in the period between January 1998 and January 2012., Results: Bronchial NETs are commoner in females and the commonest presenting symptoms were cough (13.9%) and dyspnoea (11.6%). Octreoscan TM and Gallium-68 DOTATATE PET were found to have similar diagnostic sensitivity and FDG PET was more sensitive for higher-grade tumors. Over a median follow-up period of 35.5 months mortality rate was 5.7%. The 5-year survival was 76% and the 10-year survival was 62%. Female patients survived longer but this difference was not statistically significant (P = .59). Older age greater than 50 years (P = .027), higher levels of Chromogranin A (CgA) (P = .034), first-line treatment with surgery (P = .005), ki67 over 10% (P = .037), and tumor stage (P = .036) but not tumor grade (P = .22), were significantly associated with survival., Discussion: Several factors have been identified which are independently associated with survival including CgA levels greater than 100 pmol/L, tumor stage, age greater than 50, ki67 over 10% and having surgery as first-line treatment. There was no difference in survival between typical and atypical carcinoids., (© 2016 John Wiley & Sons Ltd.)

Carcinoid heart disease is a frequent occurrence in patients with carcinoid syndrome and is responsible for substantial morbidity and mortality. The pathophysiology of carcinoid heart disease is poorly understood; however, chronic exposure to excessive circulating serotonin is considered one of the most important contributing factors. Despite recognition, international consensus guidelines specifically addressing the diagnosis and management of carcinoid heart disease are lacking. Furthermore, there is considerable variation in multiple aspects of screening and management of the disease. The aim of these guidelines was to provide succinct, practical advice on the diagnosis and management of carcinoid heart disease as well as its surveillance. Recommendations and proposed algorithms for the investigation, screening, and management have been developed based on an evidence-based review of the published data and on the expert opinion of a multidisciplinary consensus panel consisting of neuroendocrine tumor experts, including oncologists, gastroenterologists, and endocrinologists, in conjunction with cardiologists and cardiothoracic surgeons., (Copyright © 2017 American College of Cardiology Foundation. All rights reserved.)

Purpose Preliminary studies suggested that telotristat ethyl, a tryptophan hydroxylase inhibitor, reduces bowel movement (BM) frequency in patients with carcinoid syndrome. This placebo-controlled phase III study evaluated telotristat ethyl in this setting. Patients and Methods Patients (N = 135) experiencing four or more BMs per day despite stable-dose somatostatin analog therapy received (1:1:1) placebo, telotristat ethyl 250 mg, or telotristat ethyl 500 mg three times per day orally during a 12-week double-blind treatment period. The primary end point was change from baseline in BM frequency. In an open-label extension, 115 patients subsequently received telotristat ethyl 500 mg. Results Estimated differences in BM frequency per day versus placebo averaged over 12 weeks were -0.81 for telotristat ethyl 250 mg ( P < .001) and ‒0.69 for telotristat ethyl 500 mg ( P < .001). At week 12, mean BM frequency reductions per day for placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg were -0.9, -1.7, and -2.1, respectively. Responses, predefined as a BM frequency reduction ≥ 30% from baseline for ≥ 50% of the double-blind treatment period, were observed in 20%, 44%, and 42% of patients given placebo, telotristat ethyl 250 mg, and telotristat ethyl 500 mg, respectively. Both telotristat ethyl dosages significantly reduced mean urinary 5-hydroxyindole acetic acid versus placebo at week 12 ( P < .001). Mild nausea and asymptomatic increases in gamma-glutamyl transferase were observed in some patients receiving telotristat ethyl. Follow-up of patients during the open-label extension revealed no new safety signals and suggested sustained BM responses to treatment. Conclusion Among patients with carcinoid syndrome not adequately controlled by somatostatin analogs, treatment with telotristat ethyl was generally safe and well tolerated and resulted in significant reductions in BM frequency and urinary 5-hydroxyindole acetic acid.

This study aimed to assess the clinical impact of 68 Ga-DOTATATE and 18 F-FDG with respect to the management plan and to evaluate the prognostic value of both tracers., Methods: A total of 104 patients (55 male and 49 female; median age, 58 y; range, 20-90 y) with histologically proven neuroendocrine tumors (NETs) underwent both 68 Ga-DOTATATE and 18 F-FDG PET/CT. Twenty-eight patients (26.9%) had poorly differentiated tumors, and 76 (73.1%) had well-differentiated tumors. PET/CT results and SUVs were compared with prognostic factors such as histologic grade (G1, G2, or G3, for low-grade [well differentiated], intermediate-grade [moderately differentiated], and high-grade [poorly differentiated], respectively), chromogranin A, and proliferation index (Ki-67)., Results: The 68 Ga-DOTATATE and 18 F-FDG PET/CT findings were discordant in 65 patients (62.5%) and concordant in 39 patients (37.5%). The results changed the therapeutic plan in 84 patients (80.8%). In 22 patients (21.1%), decision making was based on the 18 F-FDG findings; in 32 (30.8%), on the findings with both radiotracers; and in 50 (48.1%), on the 68 Ga-DOTATATE findings. The most frequent management decision based on 18 F-FDG was initiation of chemotherapy (10 patients, 47.6%). The most common treatment decision due to 68 Ga-DOTATATE was initiation of peptide receptor radionuclide therapy (14 patients, 27.4%). In 11 (39.2%) of 28 patients with poorly differentiated NETs, the management decision was based on only the 18 F-FDG results. For 68 Ga-DOTATATE, SUV max was higher for G1 tumors and lower for G3 tumors (P = 0.012). However, no significant differences in 18 F-FDG-derived SUVs were observed between different grades (P = 0.38). The Mann-Whitney test showed significant differences in 68 Ga-DOTATATE SUV max between tumors with a Ki-67 of less than 5% and tumors with a Ki-67 of more than 5% (P = 0.004), without significance differences in 18 F-FDG SUV max Log-rank analysis showed statistically significant differences in survival for patients with bone metastasis versus soft-tissue or no metastasis for both 18 F-FDG (P = 0.037) and 68 Ga-DOTATATE (P = 0.047). Overall survival declined rapidly with increasing grade (P = 0.001), at an estimated 91 mo for G1, 59 mo for G2, and 48 mo for G3., Conclusion: 18 F-FDG PET/CT had no clinical impact on G1 NETs and a moderate impact on G2 NETs. However, in poorly differentiated NETs, 18 F-FDG PET/CT plays a significant clinical role in combination with 68 Ga-DOTATATE. 68 Ga DOTATATE SUV max relates to grade and Ki-67 and can be used prognostically., (© 2017 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Neuroendocrine tumours (NET) overexpress somatostatin receptors (SSTR) that can be targeted for therapy. Somatostatin receptor expression is routinely measured by molecular imaging but the resolution is insufficient to define heterogeneity. We hypothesised that SSTR expression could be measured on circulating tumour cells (CTCs) and used to investigate heterogeneity of expression and track changes during therapy., Methods: MCF-7 cells were transfected with SSTR2 or 5 and spiked into donor blood for analysis by CellSearch. Optimum anti-SSTR antibody concentration and exposure time were determined, and flow cytometry was used to evaluate assay sensitivity. For clinical evaluation, blood was analysed by CellSearch, and SSTR2/5 immunohistochemistry was performed on matched tissue samples., Results: Flow cytometry confirmed CellSearch was sensitive and that detection of SSTR was unaffected by the presence of somatostatin analogue up to a concentration of 100 ng ml -l . Thirty-one NET patients were recruited: grade; G1 (29%), G2 (45%), G3 (13%), primary site; midgut (58%), pancreatic (39%). Overall, 87% had SSTR-positive tumours according to somatostatin receptor scintigraphy or 68-Ga-DOTATE PET/CT. Circulating tumour cells were detected in 21 out of 31 patients (68%), of which 33% had evidence of heterogeneous expression of either SSTR2 (n=5) or SSTR5 (n=2)., Conclusions: Somatostatin receptors 2 and 5 are detectable on CTCs from NET patients and may be a useful biomarker for evaluating SSTR-targeted therapies and this is being prospectively evaluated in the Phase IV CALMNET trial (NCT02075606)., Competing Interests: TM has received research funding for this work from Ipsen, MEC has received grant funding and consultancy fees from Ipsen.