ctDNA in Neuroendocrine Carcinoma of Gastroenteropancreatic Origin or of Unknown Primary: The CIRCAN-NEC Pilot Study.

INTRODUCTION: Gastroenteropancreatic neuroendocrine carcinomas (GEPNEC) are characterized by a heterogeneous molecular profile and a poor prognosis. Circulating tumour DNA (ctDNA) analysis may be useful for NEC management. This study aimed at describing ctDNA mutations, to assess their predictive value for response to chemotherapies, and their change according to disease progression. METHODS: The CIRCAN-NEC study included patients with GEPNEC or NEC from an unknown primary, scheduled to begin first- or second-line chemotherapy. Blood samples were collected prior to chemotherapy initiation, at first evaluation, and during disease progression. ctDNA was sequenced by next-generation sequencing (NGS). Molecular response was defined as a decrease of at least 30% of the mutant allele fraction. RESULTS: All 24 patients included received platinum-etoposide first-line chemotherapy; 19 received a FOLFIRI-based post-first-line regimen. Twenty-two patients had at least one driver mutation: TP53 (n = 21), RB1 (n = 2), KRAS (n = 4), and BRAF (n = 3). Ten (42%) had an "adenocarcinoma-like" profile. Five of 6 patients with matching ctDNA/tissue NGS harboured at least one concordant mutation (44% concordance at the gene level). The concordance rate between ctDNA mutation/immunohistochemistry profile was 64% (7/11) for TP53/p53+ and 14% (1/7) for RB1/pRb-. In this pilot study including few patients by subgroups, patients with KRAS (HR = 3.60, 95% CI [1.06-12.04]) and BRAF (HR = 4.25, 95% CI [1.11-16.40]) mutations had shorter progression-free survival (PFS) under platinum-etoposide, while the 2 patients with RB1 mutations had shorter PFS under FOLFIRI-based chemotherapy. Twenty-eight periods of treatment were assessed: 10 patients had a molecular response (7/10 had a morphological response), which was associated with longer PFS (HR = 0.37, 95% CI [0.15; 0.91]). CONCLUSION: This pilot study shows a high sensitivity of ctDNA assessment, which is encouraging for the future management of GEPNEC (tumour molecular diagnosis and evaluation of disease progression).

Elderly Patients with Metastatic Neuroendocrine Tumors Are Undertreated and Have Shorter Survival: The LyREMeNET Study.

INTRODUCTION: The incidence of neuroendocrine tumors (NETs) is rising, especially in elderly patients. The elderly cancer population presents considerable challenges, yet little is known about the characteristics, treatment patterns, and outcomes of metastatic NET (mNET) patients. METHODS: The Lyon Real-life Evidence in Metastatic NeuroEndocrine Tumors study (LyREMeNET, NCT03863106) included consecutive mNET patients, diagnosed between January 1990 and December 2017. The exclusion criteria were nonmetastatic NET, poorly differentiated neuroendocrine carcinoma, and mixed neuroendocrine-nonneuroendocrine neoplasms. We aimed to compare patients ≥70 years old to patients <70 years old. RESULTS: A total of 866 patients were included, 198 (23%) were ≥70 years old. There was no significant difference in characteristics except that elderly patients had synchronous metastasis more frequently. Elderly patients received significantly fewer treatments (median of 2.0 vs. 3.0 lines, respectively, p < 0.0001), were significantly less frequently treated by chemotherapy (32 vs. 54%), targeted therapy (16 vs. 30%), peptide receptor radionuclide therapy (5 vs. 16%), and they underwent significantly less frequently locoregional intervention. Median overall survival was significantly shorter in elderly patients (5.2 vs. 9.6 years). The most frequent cause of death was related to disease progression (71%). Multivariate analysis found that, after adjustment for tumor location, tumor grade, and number of metastatic sites, age remained significantly associated with overall survival (HR 1.66, 95% CI 1.26-2.18), indicating a poorer survival in patients ≥70 years old in comparison with younger patients (p = 0.0003). CONCLUSION: Patients ≥70 years old have a worse survival, die frequently from their disease, and are undertreated compared to younger patients.

Healthcare cost by primary tumour, functioning status and treatment among patients with metastatic neuroendocrine tumours: The LyREMeNET study.

The annual prevalence of metastatic neuroendocrine tumours (mNETs) is rising, leading to significant healthcare costs. The present study aimed to describe healthcare resource use (HRU) and the corresponding costs among patients with mNETs, according to primary tumour location, functioning status and type of treatments. The LyREMeNET study included consecutive mNET patients with a diagnosis performed between January 2010 and December 2017, who were seen at least once in the ENETS center of excellence in Lyon. The median HRU and costs per patient were estimated, up to 3 years before and after the diagnosis. The Cancer database of the center was linked to the French national health data system. HRU and related costs were described per person per month (PPPM). Among 316 patients presenting with a mNET, 48.4% had a small-intestinal mNET, 32.3% had a pancreatic mNET and 39.2% had carcinoid syndrome. The mean overall cost increased from €615 to €2875 PPPM between the years preceding and following the diagnosis, and remained above €2500 in the two subsequent years. The two main cost drivers of total healthcare expenditure were drugs (€1161) and hospital stay (€662). Median costs of mNETs arising from pancreas and small intestine were €2325 and €2540 PPPM, respectively. Costs were higher in patients with a functional mNET (€2807 PPPM for carcinoid syndrome) and during peptide receptor radionuclide therapy (PRRT) (€8835 PPPM). The highest overall cost was found during the first year following the diagnosis. Cost of care was higher for small intestine mNETs, for functional mNETs and during peptide receptor radionuclide therapy.

Improved Glycemic Control Through the Use of a Telehomecare Program in Patients with Diabetes Treated with Insulin.

Background: With the drastic surge in the prevalence of diabetes, the use of medical resources for management of diabetic patients increased markedly. This study aimed to evaluate the impact of telehomecare (THC) use on clinical efficacy, nursing interventions, and medical visits compared with the standard care in insulin-treated diabetic patients. Materials and Methods: A prospective noninferiority clinical trial was designed. Participants were assigned to either an intervention group provided with a THC system during 3 months or to a control group. Main outcome was the difference in A1c at 3 months compared with baseline. Secondary outcomes were the difference in A1c at 6 months compared with baseline, the number of medical visits during the 6-month period of the study, and nursing interventions during the 3 months on THC. Results: A total of 92 participants completed the study. A significant decrease in A1c levels was observed in the THC group (n = 45) compared with the control group (n = 47) at 3 months (-0.61% vs. -0.06%, respectively, P = 0.048) and at 6 months (-0.37% vs. -0.10%, respectively, P = 0.036). The THC group had an average of 0.6 medical visit compared with 1.0 in the control group (P < 0.001). An increase in nursing interventions (mainly e-mails) was noted in THC group (n = 14.7) compared with control group (n = 1.1). Conclusions: This THC program demonstrates improvement in glycemic control and a decrease in the number of medical visits. However, it is important to consider an additional burden in nursing interventions when implementing a THC program.

Demonstrated Cost-Effectiveness of a Telehomecare Program for Gestational Diabetes Mellitus Management.

Background: Prevalence of gestational diabetes mellitus (GDM) has increased steadily in recent years. Pregnant women with GDM are at risk for obstetrical and neonatal complications and require close multidisciplinary follow-up, which implies a significant use of hospital resources. Methods: A prospective noninferiority and controlled clinical trial was designed. The telehomecare (THCa) initiative is a clinical remote patient management project in women with GDM. The main objective was to evaluate the cost-effectiveness of THCa by assessing the direct costs, including the related reduction in medical visits. Secondary outcomes were to evaluate the impact of THCa on diabetes control, GDM-related complications, and patient satisfaction. Results: A total of 161 women were assigned to either an intervention group provided with a THCa system for transmission and online analysis of capillary glucose data (n = 80) or a control group receiving usual care in the clinic (n = 81). A decrease in medical visits by 56% (P < 0.001) in the THCa group was observed. There was no difference between the two groups in diabetes control or maternal and fetal complications. However, results showed a 10-fold increase in nursing interventions in THCa group (mainly by phone calls and e-mails). Satisfaction with care was high. Direct cost analysis revealed savings of 16% in patients followed by THCa compared with the control group. Conclusion: THCa monitoring significantly decreases medical visits and direct costs in GDM women without compromising pregnancy outcomes, quality of care, or patient satisfaction. THCa was shown to be cost-effective despite placing an additional burden on nursing time.

Metformin and everolimus in neuroendocrine tumours: A synergic effect?

OBJECTIVE: To explore potential synergy in effectiveness between metformin and everolimus, 2 inhibitors of the mTOR pathway, for neuroendocrine tumours (NET). DESIGN AND METHODS: A cohort of patients with advanced gastroenteropancreatic or lung NETs treated by everolimus were stratified in to those without diabetes, those with diabetes and without metformin, and those with diabetes with metformin. The primary endpoint was the median progression-free survival (PFS). RESULTS: A total of 213 patients were included, 165 of which were non-diabetic; among diabetic patients, 19 were treated with metformin and 29 with others anti-diabetic drugs. No significant difference in median PFS [95%CI] was found between the three groups: 10.05 months [8.27;11.83] for non-diabetic patients, 15.24 [19.88;49.43] for diabetic w/metformin, and 9.03 months [4.01;14.06] for diabetic w/o metformin group. In univariate analysis, factors significantly associated with longer PFS was a functioning NET, a number of metastatic sites<3, the absence of lung metastasis, and an uptake on Octreoscan®, but not the absence of metformin use; only uptake on Octreoscan® remained significant in multivariate analysis. CONCLUSIONS: In contrast with the literature, we did not find a synergy between everolimus and metformin in NET. Prospective studies are underway to improve the comprehension of the potential synergy regarding population and tumour type.

Pheochromocytoma, paragangliomas, and pituitary adenoma: An unusual association in a patient with an SDHD mutation. Case report.

RATIONALE: Pituitary adenomas and paragangliomas are both rare endocrine diseases. Paragangliomas (PGL)/pheochromocytomas (PHEO) are part of an inherited syndrome in about 30% to 40% of cases. Among familial cases, mutations of the succinate dehydrogenase (SDH) subunit genes (succinate dehydrogenase subunit [SDH]B, SDHC, SDHD, succinate dehydrogenase subunit AF2 [SDHAF2] , and SDHA) are the most common cause. PATIENT CONCERNS: We here report a 31-year-old patient with a known SDHD mutation whose disease has been revealed by a left PHEO during childhood and who presented at age 29 years a large paraganglioma of the right jugular foramen, a concomitant PHEO of the left adrenal and 2 retroperitoneal paragangliomas. A pituitary incidentaloma was found during investigations on a fluorodeoxyglucose (FDG)-positron emission tomography (PET) (FDG-PET). DIAGNOSIS: A pituitary magnetic resonance imaging (MRI) confirmed the presence of a 14 mm pituitary macroadenoma. The pituitary function was normal except for hypogonadotropic hypogonadism. On examination of the fundus, a diagnosis of Pseudo Foster-Kennedy syndrome was made due to a venous compression of the right jugular vein caused by the paraganglioma (PGL). The pituitary adenoma was not compressive to the optic chiasm. INTERVENTIONS: A treatment with acetazolamide was started in order to improve intracranial hypertension. The patient couldn't benefit of a surgical approach for the paraganglioma of the right jugular foramen; the patient has been treated with stereotactic radiosurgery (Gamma Knife). OUTCOMES: The most recent MRI revealed that the right jugular foramen PGL is stable and the latest visual assessment demonstrated stability despite a recent reduction in acetazolamide dosage. A surveillance by MRI of the pituitary adenoma has been planned. LESSONS: The association of a pituitary adenoma to paragangliomas within a same patient is very uncommon and raises the question of related physiopathological mechanisms.

O6-methylguanine-DNA methyltransferase (MGMT) status in neuroendocrine tumors: a randomized phase II study (MGMT-NET).

INTRODUCTION: Neuroendocrine tumors (NETs) are rare, but their incidence is rising. Alkylating agents (ALKY), temozolomide and streptozotocin, are the main chemotherapies used for advanced pancreatic NETs. According to retrospective data, O6-methylguanine-DNA methyltransferase (MGMT) status appears to be a predictive factor of the response to ALKY. AIMS: The main objective is to evaluate the value of tumor MGMT promoter (pMGMT) methylation in the prediction of the objective response (OR) at 3 months in patients treated with ALKY. Secondly, we will evaluate the value of MGMT immunohistochemistry and the efficacy of treatment with ALKY vs. oxaliplatin-based chemotherapy (Ox). MATERIALS AND METHODS: A national, prospective, open-label, randomized, controlled and multicenter trial was designed. Main inclusion criteria are: adult patients with well-differentiated advanced duodeno-pancreatic, lung, or unknown primitive NETs with a validated indication for chemotherapy. pMGMT methylation will be assessed by pyrosequencing, but an ancillary study will compare this technique with others ones including MGMT immunohistochemistry. RESULTS: A total of 104 patients will be randomly assigned (1:1 for unmethylated or 2:1 for methylated pMGMT NETs) to either the ALKY arm or to the Ox arm. CONCLUSION: Recruitment started on October 16, 2018 (NCT03217097) and will be open in 21 centers in France.