Journal of Neuroendocrinology最新文献

Bone metastases (BMs) were reported in <15% of cases of neuroendocrine neoplasms (NENs). Their clinical behavior is various and clinical management is still undefined. This study aimed to describe the clinical practical management and survival outcome of neuroendocrine neoplasm patients with BMs. This is a retrospective, observational, multicenter, nationwide study, in which clinical-pathological characteristics, diagnostic tools, skeletal-related events (SREs), bone targeted agents (BTAs) and their correlation with clinical outcome were collected. Data from 320 patients from 18 Italian centers diagnosed with bone metastases during 2000–2013 were captured. Most patients had a well/moderately differentiated NEN, with synchronous distant metastases, mostly hepatic, the majority of which originated from a gastroenteropancreatic primary site. Bone was the first metastatic site in 41% of patients. After a median follow-up of 27 months 122 patients died. The median overall survival (OS) was 62 months. In 22% of patients (n = 72), SREs were observed, and 31% of patients received a BTA. At multivariable analysis of factors associated with OS after the development of BMs, primary lung site, Ki-67 ≥55% versus ≤20%, >10 BMs, mixed pattern (osteoblastic/osteolytic) versus osteoblastic, prior lung metastases and SREs were found to be significant poor prognosis factors. At multivariable analysis Ki-67 ≥55% versus ≤20% remains significantly associated with the development of SREs. Our study represents a real-life nationwide scenario of a large series of NEN patients with BMs handled at dedicated centers. Several hypotheses generated by this study are warranted to be tested in future homogeneous studies, including objective criteria for the use of BTAs.

How neuropeptides act within the neural circuits that control social behavior is not well understood. While the prevailing view is that neuropeptides act through synaptic release and then activation of their canonical receptors on postsynaptic membranes, we investigated the role of a very different form of neuropeptide action in a neural circuit regulating social communication. Specifically, we tested the hypothesis that non-synaptically released oxytocin (OT) can act via the non-canonical receptors vasopressin V1a receptors (V1aR) to regulate social communication in Syrian hamsters. Scent marking, a key form of hamster social communication, can be enhanced by the α-melanocortin stimulating hormone (α-MSH), which stimulates OT but not arginine-vasopressin (AVP) release. Here, we employed hypothalamic injections of α-MSH and the α-MSH MC4R receptor antagonist MCL-0020 to determine the role of α-MSH in the expression of flank marking. To determine if these effects were intracellular calcium (iCa²⁺) dependent, hamsters were injected with AVP to induce flank marking and with the iCa²⁺ antagonist TMB-8 to test whether it was possible to block this behavioral effect. Further, a highly selective AVP V1a receptor (V1aR) antagonist and an OT receptor (OTR) antagonist were injected into the hypothalamus to investigate the receptor responsible for activating flank marking. Finally, we employed an in vitro hypothalamic slice preparation using “Sniffer cells” biosensors to confirm that α-MSH induced the release of OT but not AVP. First, we found that the in vivo hypothalamic injection of α-MSH increased odor-stimulated scent marking, whereas blockade of its receptor with MCL-0020 reduced this behavior. Hypothalamic infusion of the iCa²⁺ antagonist TMB-8 significantly reduced both AVP-induced and α-MSH-induced flank marking. Moreover, only the V1aR antagonist, and not the OTR antagonist, significantly decreased scent marking in response to hypothalamic infusion of α-MSH. Finally, biosensor recordings from hypothalamic slices confirmed that α-MSH stimulates OT, but not AVP, release. Together, these results demonstrate that α-MSH triggers non-synaptic OT release that regulates scent marking via V1aR activation, revealing a novel mechanism by which neuropeptides modulate social behavior.

Hypothalamic neuroendocrine neurons control diverse homeostatic functions that are essential for survival. While the cell bodies of these neurons are widely distributed, the nerve terminals converge on one specialised area of the brain called the median eminence. It is here that releasing hormones are secreted into the blood to control the function of the anterior pituitary gland. This current review summarises studies which demonstrate that nerve terminals in the median eminence can undergo unique forms of plasticity under different physiological states. This includes changes in the types of neuropeptides produced, changes in morphology and changes in glial coverage. In addition, median eminence nerve terminals can also act as independent sites of integration of both synaptic and hormonal signals to control the output of the neuroendocrine axis. Together these mechanisms allow for regulation of neurosecretion in response to different physiological demands.

Immune checkpoint inhibitors (ICIs) have significantly improved outcomes in several solid malignancies but are associated with endocrine immune-related adverse events (irAEs), particularly hypophysitis. This retrospective real-world data study aimed to assess the magnetic resonance imaging (MRI) findings in cases with immune-related (ir) hypophysitis. Sixty-six cancer patients treated with ICIs at Laikon General Hospital between January 2016 and September 2024, presenting with anterior pituitary hormone deficiencies, were included. All patients underwent baseline pituitary MRI at the time of ir-hypophysitis diagnosis (median time: 2 weeks post-diagnosis). A follow-up MRI was also available in 37 patients (median time: 1.6 years post-diagnosis). All scans were centrally reviewed by radiologists blinded to clinical data. Baseline MRI abnormalities demonstrated pituitary enlargement (25%), reduced enhancement (10%), empty sella (8.3%), heterogeneous enhancement (5%), reduced size (3.3%), and stalk deviation (1.7%). Among 31 patients with both baseline and follow-up MRIs, 45% showed imaging changes (partially empty sella, size alterations). No specific ICI regimen was associated with characteristic imaging patterns. Patients with multiple hormonal axis deficiencies had more frequent MRI abnormalities than those with isolated ACTH deficiency (68.4% vs. 46.3% initially; 71.3% vs. 56.4% at follow-up). Pituitary MRI abnormalities are present in approximately half of patients with ir-hypophysitis, with dynamic changes observed in follow-up imaging. However, the absence of findings in a substantial proportion highlights the limited sensitivity of MRI in this irAE and underscores the importance of clinical and biochemical evaluation.

Observational studies have reported that thyroid eye disease (TED) may cause structural and functional disorders in the brain, However, it remains uncertain whether this relationship is causal. Genetic data were obtained from the Finn Gen R11 database, yielding 587 imaging-derived phenotypes (IDPs). Single-nucleotide polymorphisms associated with TED were selected as instrumental variables, and multi-variable regression models combined with sensitivity analyses (including Cochran's Q test, MR-Egger regression, and leave-one-out analysis) were applied to evaluate the potential causal relationships between TED and these IDPs. In addition, we recruited 90 patients with TED (49 with mild disease and 41 with moderate to severe disease) along with 50 healthy controls to establish a clinical cohort. White matter microstructural alterations across different disease stages were assessed using tract-based spatial statistics (TBSS) based on diffusion tensor imaging and neurite orientation dispersion and density imaging, and these changes were further correlated with clinical indicators and rating scales. Inverse Mendelian randomization analysis revealed a significant causal relationship between TED and 26 IDPs associated with correlated fibers, brainstem nerve bundles, joint fiber regions, and projection fiber regions (false discovery rate <0.05). TBSS further revealed the evolutionary pattern of white matter structure at different levels of disease and was strongly associated with visual function, ocular symptoms, and emotional state. The combination of the two revealed abnormalities in the microstructure of white matter pathways in the anterior thalamic radiation, superior longitudinal fasciculus, and uncinate fasciculus. This study is the first to systematically assess the causal relationship between TED and cerebral white matter microstructure from both genetic and imaging levels. The two perspectives systematically reveal the potential impact of TED on the central nervous system, providing new evidence for the study of the neural mechanisms of TED and a theoretical basis for future clinical early screening and multidisciplinary intervention strategies.

Somatostatin analogs (SSAs) are an established first-line therapy in intestinal and pancreatic neuroendocrine tumors (NETs). Based on Phase III studies, their use is recommended in NET with a Ki-67 index of up to 10%. The effect of first-line SSA therapy on differentiated NET with a Ki-67 index ≥10% is poorly understood. This study aimed to investigate the outcomes of SSA therapy in differentiated NETs with a Ki-67 index of ≥10%. A retrospective analysis of a prospectively created dataset of consecutive patients with NETs was performed. Patients with first-line SSA monotherapy in advanced NET with a Ki-67 index ≥10% were included. The study endpoints were progression-free survival (PFS), overall survival (OS), and clinical benefit rate, defined as partial remission (PR) or stable disease (SD). Of 362 consecutive patients with a Ki-67 index ≥10%, 67 received first-line SSA therapy. The Ki-67 index was 10–20% (G2) in 57 (85%) patients and >20% (G3) in 10 (15%). SD as the best response was reached in 40 (59.7%) patients and PR in 3 (4.5%), irrespective of the NET origin, time from the diagnosis, or somatostatin receptor-based tracer uptake. The median PFS was 18 (95% confidence interval [CI], 5.7–30.3) months, and the median OS was 60 (95% CI, 38.2–81.8) months after the initiation of SSA therapy. Median PFS was significantly longer in patients with a Ki-67 index of 10–20% (19 months; 95% CI, 6.2–31.8) compared to those with G3 NETs (6 months; 95% CI, 2.9–9.1; p = .015, log-rank test), and in patients with a liver tumor burden of ≤10% (24 months; 95% CI, 12.7–35.3) versus >10% (4 months; 95% CI, 2.3–5.7; p = .007). First-line SSA therapy can provide meaningful disease control in patients with G2 NETs and low tumor burden, despite a Ki-67 index ≥10%. It may be a reasonable alternative to more intensive therapies in selected patients.

Acquired hypothalamic obesity (aHO) is characterized by rapid and persistent weight gain resulting from structural or functional damage to the hypothalamus, typically accompanied by neuroendocrine dysfunction. While aHO is well described in the context of hypothalamic or suprasellar tumors, particularly craniopharyngioma, little is known about its epidemiology in non-tumor–related etiologies such as traumatic brain injury (TBI) or subtle, unrecognized hypothalamic injuries. This study estimates the incidence and clinical characteristics of aHO in patients with traumatic brain injury (TBI-aHO) and hypothalamic–pituitary axis dysfunction of unclear origin, referred to as unspecified microinjury (UM-aHO). We conducted a retrospective cohort study using German statutory health insurance claims data (N = 6.3 million, 2010–2022). Patients were included based on either an incident diagnosis of TBI or a diagnostic algorithm indicating hypothalamic–pituitary axis dysfunction without a documented causal event. aHO was defined via incident obesity coding and validated by concomitant arginine vasopressin deficiency (AVP-D) and desmopressin prescription. For UM-aHO, additional validation required at least three concurrent neuroendocrine replacement therapies. Sensitivity analyses assessed the robustness of case definitions. The estimated incidence of TBI-aHO was 1.78 per million persons (mean age: 42 years; 27% female), corresponding to approximately 520 prevalent cases in Germany. UM-aHO showed a slightly higher incidence of 2.12 per million (mean age: 37 years; 55% female), with an estimated 660 prevalent cases. Following the diagnosis of incident obesity, most patients in both cohorts received at least two neuroendocrine therapies in addition to desmopressin, most commonly including hydrocortisone and levothyroxine sodium. This is the first population-based study to characterize aHO following non-tumor–related hypothalamic injury. Both TBI and subtle, nonspecific hypothalamic microinjuries contribute meaningfully to the burden of aHO in clinical practice. These findings underscore the need for increased clinical awareness and early recognition of hypothalamic dysfunction in patients beyond classical tumor etiologies.

Obesity is a global public health challenge emerging from an energy homeostasis (EO) disruption. EO is primarily driven by neurons residing in the hypothalamus, whose function is critical to integrate neural and humoral signals that account for energy balance. Obesogenic diets induce a loss of function in the mechanism through which these neurons sense the energy status, leading to the systemic accumulation of excess energy. This could result from altered cellular EO involving mitochondria and molecular energy sensors, such as AMP-activated protein kinase (AMPK) and/or K_ATP channels. In this line, hyperglycemia induced by obesogenic diets alters the central regulation of energy balance in the hypothalamus, possibly due to the loss of sensing anorexigenic signals induced by hyperinsulinemia and hyperleptinemia, mediated by deficient energy control involving mitochondria, AMPK, and K_ATP channels. Therefore, reducing elevated glycemia in a mouse model of hypercaloric feeding could restore cellular energy sensing and normalize energy homeostasis. To test this hypothesis, this work aims to evaluate whether the loss of body energy balance induced by hypercaloric 45% high-fat diet (D45%) feeding is prevented by oral hypoglycemiant, metformin (MT), by restoring mitochondrial function, AMPK sensitivity, and K_ATP levels in the hypothalamus of mice. For this purpose, mice were fed a D45% and supplemented with MT for 12 weeks. Metabolic, physiological, and molecular parameters were assessed. The treatment with MT decreased food intake and body weight gain induced by D45% feeding; besides, MT increased horizontal locomotor activity and attenuated insulin resistance and glucose intolerance after 12 weeks of treatment. Regarding energy sensors, MT attenuated the increased phosphorylation of AMPK and reduced the expression of Kir6.2 induced by D45% feeding. These results show that reduced glycemia can partially reverse the decreased energy sensor function and the altered energy metabolism induced by feeding with a hypercaloric diet.

Everolimus is used in the treatment of patients with advanced neuroendocrine tumors (NET) and is administered at fixed doses despite known interpatient pharmacokinetic variability. This may affect both efficacy and tolerability. We wanted to investigate the relationship between prescribed dose, blood trough concentrations (C_trough), and toxicity in NET patients receiving everolimus in routine clinical practice. In this prospective observational study NET patients were treated with everolimus, mostly as third- or fourth-line therapy. Dose was adjusted according to adverse effects and tumor response. Concentrations (C_trough) of everolimus were measured at each routine follow-up and correlated to dose and cumulative adverse event (cAE) scores. Associations were evaluated using linear and generalized linear mixed models which accounted for repeated measurements within patients and varying dose regimens over time. Thirty-six patients were included. Everolimus dose was a significant predictor of C_trough (p < .001), but considerable interindividual variability was observed. Median C_trough levels increased with dose: 3.9, 5.1, 7.4, and 16.4 ng/mL for 2.5, 5.0, 7.5, and 10.0 mg per day, respectively. Considerable overlap in blood concentration was observed across dose groups; patients receiving 2.5 mg reached levels as high as 8.6 ng/mL, while those on 5 mg exhibited a wide range from 1.1 to 21.2 ng/mL. C_trough ≥ 6.0 ng/mL was associated with increased toxicity (p = .03), whereas nominal dose was not a reliable independent predictor of adverse events. Although median blood concentrations increased with higher doses, there was considerable variation between patients, resulting in overlapping concentration ranges across all dose groups. This indicates that fixed-dose regimens may not reliably predict systemic drug exposure. Everolimus blood concentrations were superior to dose levels in predicting adverse events. Therapeutic drug monitoring and individualized dose adjustment may improve the balance between efficacy and toxicity in NET patients treated with everolimus.