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The primary analysis of the phase 3 NETTER-1 trial showed significant improvement in progression-free survival with 177Lu-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. 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 177Lu-Dotatate 7·4 GBq (200 mCi) every 8 weeks (four cycles) plus intramuscular long-acting octreotide 30 mg (177Lu-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 177Lu-Dotatate group only. This trial is registered with ClinicalTrials.gov, NCT01578239. 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 177Lu-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 177Lu-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 177Lu-Dotatate group, but no new treatment-related serious adverse events were reported after the safety analysis cutoff. Two (2%) of 111 patients given 177Lu-Dotatate developed myelodysplastic syndrome, one of whom died 33 months after randomisation (this person was the only the only reported 177Lu-Dotatate treatment-related death). No new cases of myelodysplastic syndrome or acute myeloid leukaemia were reported during long-term follow-up. 177Lu-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 177Lu-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. Advanced Accelerator Applications, a Novartis company.

•Intestinal gas species can be used as biomarkers for specific gut microbiota.•These gases affect the status of the gut and subsequently human health.•Advances in sensors and electronic technologies have led to the development of gas capsules and in vitro fermentation systems.•These novel systems can be used as reliable and cost-effective human health assessment units. The biological and clinical significance of the human gut microbiome is currently attracting worldwide attention. While rRNA and DNA technologies led to a quantum leap in our understanding of the numbers and types of gut microorganisms, much less is known about these microorganisms’ activity in situ and in real time. Accurately measuring their byproducts, including intestinal gases, may offer unique biomarkers for specific gut microbiota, accelerating our understanding of the relationships among intestinal gases, the metabolic activity of the gut microbiome, and human health states. Here we present two novel techniques, namely in vitro fermentation and gas capsule systems, for measuring and assessing selected gas species. We discuss new developments with these technologies and the methods of their implementation and provide an overall review of their operation.

Organogenesis of the ovary is a highly orchestrated process involving multiple lineage determination of ovarian surface epithelium, granulosa cells and theca cells. Although the sources of ovarian surface epithelium and granulosa cells are known, the origin(s) of theca progenitor cells have not been definitively identified. Here we show that theca cells derive from two sources: Wt1 + cells indigenous to the ovary and Gli1 + mesenchymal cells that migrate from the mesonephros. These progenitors acquire theca lineage marker Gli1 in response to paracrine signals Desert hedgehog ( Dhh ) and Indian hedgehog ( Ihh ) from granulosa cells. Ovaries lacking Dhh / Ihh exhibit theca layer loss, blunted steroid production, arrested folliculogenesis and failure to form corpora lutea. Production of Dhh / Ihh in granulosa cells requires growth differentiation factor 9 (GDF9) from the oocyte. Our studies provide the first genetic evidence for the origins of theca cells and reveal a multicellular interaction critical for the formation of a functional theca. Lineage establishment of theca cells is essential for follicle development and morphogenesis of the ovary. Here the authors provide genetic evidence for the origins of theca progenitor cells and study the mechanisms critical for their differentiation.

Sex determination of the gonads begins with fate specification of gonadal supporting cells into either ovarian pre-granulosa cells or testicular Sertoli cells. This fate specification hinges on a balance of transcriptional control. Here we report that expression of the transcription factor RUNX1 is enriched in the fetal ovary in rainbow trout, turtle, mouse, goat, and human. In the mouse, RUNX1 marks the supporting cell lineage and becomes pre-granulosa cell-specific as the gonads differentiate. RUNX1 plays complementary/redundant roles with FOXL2 to maintain fetal granulosa cell identity and combined loss of RUNX1 and FOXL2 results in masculinization of fetal ovaries. At the chromatin level, RUNX1 occupancy overlaps partially with FOXL2 occupancy in the fetal ovary, suggesting that RUNX1 and FOXL2 target common sets of genes. These findings identify RUNX1, with an ovary-biased expression pattern conserved across species, as a regulator in securing the identity of ovarian-supporting cells and the ovary.

A randomized study involving 410 patients with advanced pancreatic neuroendocrine tumors showed that everolimus, as compared with placebo, more than doubled the median progression-free survival (11 months vs. 4.6 months). Most of the adverse events were grade 1 or 2 in severity. The incidence and prevalence of pancreatic neuroendocrine tumors are increasing 1 – 3 ; these tumors represent approximately 1.3% of all cases of pancreatic cancer in incidence and 10% of cases in prevalence. 1 – 3 Pancreatic neuroendocrine tumors are frequently diagnosed at a late stage, with approximately 65% of patients presenting with unresectable or metastatic disease; as a result, these patients have a poor prognosis. The median survival time for patients with distant metastatic disease is 24 months, 2 and limited treatment options are available for this population. Streptozocin is the only approved therapy for pancreatic neuroendocrine tumors in the United States; however, the . . .

Neuroendocrine tumours (NETs) can secrete bioactive amines into the bloodstream, causing carcinoid syndrome, with symptoms including flushing and diarrhoea. However, carcinoid syndrome frequency in the NET population has never been rigorously assessed, nor has its relationship to presenting clinicopathological characteristics. This analysis assessed the proportion of patients with NETs and carcinoid syndrome in the USA and associated clinical factors. We identified patients (≥65 years of age) from the Surveillance, Epidemiology, and End Results-Medicare database, excluding those with pancreatic tumours or small-cell or large-cell lung cancer, as well as those without complete data. We assessed the incidence of patients with at least two insurance claims of flushing, diarrhoea, or carcinoid syndrome during the 3 months before and after NET diagnosis. We compared demographic and clinical characteristics between patients with and without carcinoid syndrome using χ2 tests. We used the Cochran-Armitage trend test to identify trends in carcinoid syndrome incidence and Cox regression to assess the relationship between carcinoid syndrome and survival. Between April 1, 2000, and Dec 31, 2011, 9512 eligible patients were diagnosed with NETs, of whom 1786 (19%) had carcinoid syndrome. The number of patients with NETs and carcinoid syndrome increased from 50 (11%) of 465 patients in 2000 to 160 (19%) of 854 in 2011 (p<0·0001). The proportion of patients with carcinoid syndrome compared with those without did not differ significantly with respect to age at diagnosis (p=0·65), geographical region (p=0·054), or urban versus rural status (p=0·53). Patients with carcinoid syndrome were more frequently female than male (p=0·0003). Race was associated with a significant difference in the reported incidence of carcinoid syndrome (p<0·0001), as was tumour grade, stage, and primary tumour site (all p<0·0001). Patients with carcinoid syndrome had a shorter overall survival (median 5 years [95% CI 4·5–5·4]) than did those without carcinoid syndrome (5·6 years [5·4–5·9]; hazard ratio 1·102 [1·016–1·194]; p=0·019). Use of octreotide (p<0·0001) and chemotherapy (p=0·003) were more common in patients with carcinoid syndrome than in those without it, whereas surgery was used more frequently in patients without carcinoid syndrome (p=0·009); use of radiotherapy was not significantly associated with the presence of carcinoid syndrome at diagnosis (p=0·07). This population-based analysis reveals that carcinoid syndrome is significantly associated with tumour grade, stage, and primary tumour site, and leads to shorter survival compared with those patients without carcinoid syndrome. An improved understanding of the heterogeneity of presenting symptoms among patients with NETs might permit more tailored assessment and management than at present and enable future research into the effect of carcinoid syndrome control on patient survival. Ipsen.

The entorhinal cortex (EC) is one of the most vulnerable brain regions that is attacked during the early stage of Alzheimer's disease (AD). Here, we report that the synaptic terminals of pyramidal neurons in the EC layer II (ECIIPN ) directly innervate CA1 parvalbumin (PV) neurons (CA1PV ) and are selectively degenerated in AD mice, which exhibit amyloid-β plaques similar to those observed in AD patients. A loss of ECIIPN -CA1PV synapses disables the excitatory and inhibitory balance in the CA1 circuit and impairs spatial learning and memory. Optogenetic activation of ECIIPN using a theta burst paradigm rescues ECIIPN -CA1PV synaptic defects and intercepts the decline in spatial learning and memory. These data reveal a novel mechanism of memory loss in AD mice via the selective degeneration of the ECIIPN -CA1PV pathway.

Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), has shown antitumour activity in patients with advanced pancreatic neuroendocrine tumours. We aimed to assess the combination of everolimus plus octreotide long-acting repeatable (LAR) in patients with low-grade or intermediate-grade neuroendocrine tumours (carcinoid). We did a randomised, double-blind, placebo-controlled, phase 3 study comparing 10 mg per day oral everolimus with placebo, both in conjunction with 30 mg intramuscular octreotide LAR every 28 days. Randomisation was by interactive voice response systems. Participants were aged 18 years or older, with low-grade or intermediate-grade advanced (unresectable locally advanced or distant metastatic) neuroendocrine tumours, and disease progression established by radiological assessment within the past 12 months. Our primary endpoint was progression-free survival. Adjusted for two interim analyses, the prespecified boundary at final analysis was p≤0·0246. This study is registered at ClinicalTrials.gov, number NCT00412061. 429 individuals were randomly assigned to study groups; 357 participants discontinued study treatment and one was lost to follow-up. Median progression-free survival by central review was 16·4 (95% CI 13·7–21·2) months in the everolimus plus octreotide LAR group and 11·3 (8·4–14·6) months in the placebo plus octreotide LAR group (hazard ratio 0·77, 95% CI 0·59–1·00; one-sided log-rank test p=0·026). Drug-related adverse events (everolimus plus octreotide LAR vs placebo plus octreotide LAR) were mostly grade 1 or 2, and adverse events of all grades included stomatitis (62% vs 14%), rash (37% vs 12%), fatigue (31% vs 23%), and diarrhoea (27% vs 16%). Everolimus plus octreotide LAR, compared with placebo plus octreotide LAR, improved progression-free survival in patients with advanced neuroendocrine tumours associated with carcinoid syndrome. Novartis Pharmaceuticals.