Towards tailored radiopeptide therapy.

PURPOSE Somatostatin receptor-targeted radiopeptide therapy is commonly performed using single radioisotopes. We evaluated the benefits and harms of combining radioisotopes in radiopeptide therapy in patients with neuroendocrine tumor. METHODS Using multivariable-adjusted survival analyses and competing risk analyses we evaluated outcomes in patients with neuroendocrine tumor receiving (90)Y-DOTATOC, (177)Lu-DOTATOC or their combination. RESULTS (90)Y-DOTATOC plus (177)Lu-DOTATOC treatment was associated with longer survival than (90)Y-DOTATOC (66.1 vs. 47.5 months; n = 1,358; p < 0.001) or (177)Lu-DOTATOC alone (66.1 vs. 45.5 months; n = 390; p < 0.001). (177)Lu-DOTATOC was associated with longer survival than (90)Y-DOTATOC in patients with solitary lesions (HR 0.3, range 0.1 - 0.7; n = 153; p = 0.005), extrahepatic metastases (HR 0.5, range 0.3 - 0.9; n = 256; p = 0.029) and metastases with low uptake (HR 0.1, range 0.05 - 0.4; n = 113; p = 0.001). (90)Y-DOTATOC induced higher hematotoxicity rates than combined treatment (9.5% vs. 4.0%, p = 0.005) or (177)Lu-DOTATOC (9.5 vs. 1.4%, p = 0.002). Renal toxicity was similar among the treatments. CONCLUSIONS Using (90)Y and (177)Lu might facilitate tailoring radiopeptide therapy and improve survival in patients with neuroendocrine tumors.

Brain-borne IL-1 adjusts glucoregulation and provides fuel support to astrocytes and neurons in an autocrine/paracrine manner.

It is still controversial which mediators regulate energy provision to activated neural cells, as insulin does in peripheral tissues. Interleukin-1β (IL-1β) may mediate this effect as it can affect glucoregulation, it is overexpressed in the 'healthy' brain during increased neuronal activity, and it supports high-energy demanding processes such as long-term potentiation, memory and learning. Furthermore, the absence of sustained neuroendocrine and behavioral counterregulation suggests that brain glucose-sensing neurons do not perceive IL-1β-induced hypoglycemia. Here, we show that IL-1β adjusts glucoregulation by inducing its own production in the brain, and that IL-1β-induced hypoglycemia is myeloid differentiation primary response 88 protein (MyD88)-dependent and only partially counteracted by Kir6.2-mediated sensing signaling. Furthermore, we found that, opposite to insulin, IL-1β stimulates brain metabolism. This effect is absent in MyD88-deficient mice, which have neurobehavioral alterations associated to disorders in glucose homeostasis, as during several psychiatric diseases. IL-1β effects on brain metabolism are most likely maintained by IL-1β auto-induction and may reflect a compensatory increase in fuel supply to neural cells. We explore this possibility by directly blocking IL-1 receptors in neural cells. The results showed that, in an activity-dependent and paracrine/autocrine manner, endogenous IL-1 produced by neurons and astrocytes facilitates glucose uptake by these cells. This effect is exacerbated following glutamatergic stimulation and can be passively transferred between cell types. We conclude that the capacity of IL-1β to provide fuel to neural cells underlies its physiological effects on glucoregulation, synaptic plasticity, learning and memory. However, deregulation of IL-1β production could contribute to the alterations in brain glucose metabolism that are detected in several neurologic and psychiatric diseases.Molecular Psychiatry advance online publication, 8 December 2015; doi:10.1038/mp.2015.174.

Application of Ga(68) -DOTA-exendin-4 PET/CT to localise an occult insulinoma

A 49 year old female presented to our Neuroendocrine Tumour (NET) centre with recurrent severe and disabling hypoglycaemia. She had previously been extensively investigated with a clinical and biochemical diagnosis of endogenous hyperinsulinemic hypoglycaemia although the source of hormonal hypersecretion could not be localised with MRI, EUS and (111) In-Octreotide scans. After extensive discussion the patient opted for blind surgical resection undergoing a pylorus-preserving pancreaticoduodenectomy in December 2010. Histological examination of the resected operative specimen demonstrated a normal pancreas with no evidence of neuroendocrine tumour. Consistent with this, post-surgery her hypoglycaemic symptoms persisted with fasting capillary blood glucose of 2.1-6.0 mmol/l with increasing hypoglycaemia unawareness. Consequently she sought alternative clinical opinions from two European Neuroendocrine Tumour Society (ENETS) Centres of Excellence who investigated her collaboratively. This article is protected by copyright. All rights reserved.

The Face of Power

Objective: In humans and other animals, open, expansive postures (compared to contracted postures) are evolutionary developed expressions of power and have been shown to cause neuroendocrine and behavioral changes (Carney, Cuddy, & Yap, 2010). In the present study we aimed to investigate whether power postures have a bearing on the participant’s facial appearance and whether others are able to distinguish faces after “high power posing” from faces after “low power posing”. Methods: 16 models were photographed 4-5 minutes after having adopted high and low power postures. Two different high power and two different low power postures were held for 2 minutes each. Power-posing sessions were performed on two consecutive days. High and low power photographs of each model were paired and an independent sample of 100 participants were asked to pick the more dominant and the more likeable face of each pair. Results: Photographs that were taken after adopting high power postures were chosen significantly more often as being more dominant looking. There was no preference when asked to choose the more likeable photograph (chance level). A further independent sample rated each photograph for head tilt, making it unlikely that dominance ratings were caused merely by the posture of the head. Consistently, facial width-to-height ratio did not differ between faces after high and low power posing. Conclusions: Postures associated with high power affect facial appearance, leading to a more dominant looking face. This finding may have implications for everyday life, for instance when a dominant appearance is needed.

Histopathology of NET: Current concepts and new developments

The diagnosis of neuroendocrine tumors is based on their histopathologic appearance and immunohistochemical profile. With the WHO 2010 classification formal staging and grading was introduced for gastro-entero-pancreatic NET, however, the nomenclature for lung neuroendocrine tumors still relies on the carcinoid term. In this review we also focus on the situation of neuroendocrine carcinoma of unknown primary, tissue biomarkers and actual controversies in the histopathology of NEN.

Prognostic Value of Secretoneurin in Critically Ill Patients With Infections.

OBJECTIVES Secretoneurin is produced in neuroendocrine cells, and the myocardium and circulating secretoneurin levels provide incremental prognostic information to established risk indices in cardiovascular disease. As myocardial dysfunction contributes to poor outcome in critically ill patients, we wanted to assess the prognostic value of secretoneurin in two cohorts of critically ill patients with infections. DESIGN Two prospective, observational studies. SETTING Twenty-four and twenty-five ICUs in Finland. PATIENTS A total of 232 patients with severe sepsis (cohort #1) and 94 patients with infections and respiratory failure (cohort #2). INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS We measured secretoneurin levels by radioimmunoassay in samples obtained early after ICU admission and compared secretoneurin with other risk indices. In patients with severe sepsis, admission secretoneurin levels (logarithmically transformed) were associated with hospital mortality (odds ratio, 3.17 [95% CI, 1.12-9.00]; p = 0.030) and shock during the hospitalization (odds ratio, 2.17 [1.06-4.46]; p = 0.034) in analyses that adjusted for other risk factors available on ICU admission. Adding secretoneurin levels to age, which was also associated with hospital mortality in the multivariate model, improved the risk prediction as assessed by the category-free net reclassification index: 0.35 (95% CI, 0.06-0.64) (p = 0.02). In contrast, N-terminal pro-B-type natriuretic peptide levels were not associated with mortality in the multivariate model that included secretoneurin measurements, and N-terminal pro-B-type natriuretic peptide did not improve patient classification on top of age. Secretoneurin levels were also associated with hospital mortality after adjusting for other risk factors and improved patient classification in cohort #2. In both cohorts, the optimal cutoff for secretoneurin levels at ICU admission to predict hospital mortality was ≈ 175 pmol/L, and higher levels were associated with mortality also when adjusting for Simplified Acute Physiology Score II and Sequential Organ Failure Assessment scores. CONCLUSIONS Secretoneurin levels provide incremental information to established risk indices for the prediction of mortality and shock in critically ill patients with severe infections.