Journal of Neuroendocrinology最新文献

Pancreatic neuroendocrine tumors (PNETs) are uncommon malignancies characterized by significant clinical heterogeneity and a pronounced tendency for liver metastasis. Despite this, the cellular mechanisms driving PNET progression remain inadequately elucidated, especially concerning neuroendocrine subpopulations. We analyzed publicly available single-cell RNA sequencing (scRNA-seq) data from 27 samples, including adjacent normal tissues (NT), primary tumors (PT), and hepatic metastases (HM), to explore the heterogeneity of neuroendocrine cells. Our downstream analyses encompassed copy number variation (CNV) inference, pseudotime trajectory modeling using CytoTRACE2 and Monocle3, Single-Cell Regulatory Network Inference and Clustering (SCENIC), cell–cell communication analysis via CellChat, and external validation with bulk RNA-seq datasets. We identified a distinct PCSK1⁺ neuroendocrine cell subpopulation, predominantly found in HM, which exhibited a high CNV burden, low differentiation potential, and significant transcriptional divergence from the NEUROD1⁺ neuroendocrine cells prevalent in primary tumors. The trajectory analysis delineated a developmental continuum commencing from the NEUROD1⁺ subpopulation and culminating in the PCSK1⁺ subpopulation. SCENIC analysis identified ATF6 as a pivotal transcriptional regulator within the PCSK1⁺ subpopulation, while KEGG enrichment of its target genes indicated involvement in stress-related signaling pathways. Furthermore, cell–cell communication analysis demonstrated that fibroblasts were the predominant signaling source to the PCSK1⁺ subpopulation in both primary tumors (PT) and hepatic metastases (HM), with conserved ligand–receptor interactions, including the CD99–CD99 and collagen–integrin axes. Our study identifies a metastasis-enriched, terminally differentiated PCSK1⁺ subpopulation and elucidates its potential regulatory and microenvironmental characteristics. These findings enhance our understanding of the cellular states linked to the progression of PNETs and lay the groundwork for subsequent mechanistic investigations.

There is an unmet need for new methods to predict disease course in patients with neuroendocrine tumors (NET). We investigated 92 putative cancer-related plasma proteins including chromogranin A (CgA) and clinical parameters at the time of diagnosis to identify early factors associated with progressive (PD) or stable disease (SD). Patients with NET grade 1 and 2 of the small intestine (siNET) and pancreas (pNET) were included in this prospective study. Blood samples were obtained at the time of diagnosis before tumor-related therapy was initiated. During 3 years of follow-up, SD or PD was determined according to current clinical practice by each investigator. Association rule mining (ARM) was used to identify combinations of biomarkers and clinical parameters associated with SD or PD. Altogether, 115 patients with siNET and 30 with pNET with complete clinical and biomarker data were included in the analysis representing 3 years of follow-up. Several novel plasma proteins and clinical factors were associated with either PD or SD. In siNET, CgA (>4 upper limits of normal [ULN]) was the most frequent biomarker associated with PD. Females, in contrast to males, with CgA >4 ULN showed a high risk of progression (PPV 100%, NPV 63%). In the siNET cohort, Carboxypeptidase E (CPE) was a discriminating factor between SD and PD. CPE <3.03 was associated with SD, whereas CPE >3.14 was associated with PD (p = 0.003). In the pNET cohort, among clinical variables, only the presence of liver metastasis was associated with PD. CgA was not among the top biomarkers associated with PD. Several parameters, both clinical and biomarker data, as well as combinations of these, were associated with PD or SD 3 years after diagnosis. We identified novel biomarkers improving the association with PD or SD. [Correction added on 28 August 2025, after first online publication: Abstract has been updated.]

Health-related quality of life (HRQoL) has been shown to predict overall survival (OS) in several different malignancies, but not in patients with small intestinal neuroendocrine tumours (siNET). We evaluated the influence of HRQoL on survival in patients with siNET. We included 85 patients with advanced siNET who completed the validated HRQoL instruments, EORTC QLQ-C30 and GI.NET21. We used Cox proportional hazards to calculate the hazard ratio (HR) of survival according to the QLQ-C30 summary score, adjusting for clinical variables selected with causal inference. Flexible parametric modelling using cubic splines was used to illustrate the time-dependent relationship between HRQoL and OS. The QLQ-C30 summary score was correlated with overall survival (OS) with an adjusted HR of 0.62 (95% CI 0.46–0.83, p < .001) for each 10-point increase in summary score. Compared to a model using only clinical variables, the summary score increased predictive accuracy by eight percentage units and improved model fit. The inclusion of GI.NET21 with the summary score yielded similar results. HRQoL predicts overall survival in patients with siNET, providing additional information to clinical variables. Measuring HRQoL might be useful when following patients with siNET.

The mechanism by which photoperiod influences the hypothalamic–pituitary-gonadal (HPG) axis and regulates seasonal reproduction in horses has yet to be fully elucidated. The hypophyseal pars tuberalis (PT) has been indicated as a critical site for the transduction of melatonin signals through melatonin-responsive, PT-specific cells that produce thyroid-stimulating hormone (TSH) in many mammalian species. However, this has yet to be investigated in horses. The objective of this study was to explore the interaction of melatonin and thyroid-stimulating hormone in the equine HPG axis. Pituitaries from mares of light-horse breeds (Quarter Horse, Thoroughbred, etc.) categorized as either breeding season or non-breeding season based on season, gross examination of ovarian structures, and plasma progesterone concentrations were collected post-mortem. In situ hybridization revealed melatonin receptor (MT1r) mRNA abundantly expressed in glandular cells of the PT in both breeding and non-breeding season mares. Immunofluorescent analysis revealed a higher abundance of TSH-ir cells (p = .0043) in PT obtained during the breeding season compared to the non-breeding season. In cycling mares, MT1r mRNA co-localized with TSH-producing cells in the PT, suggesting a role for TSH as a modulator of seasonal reproduction in the mare. These findings support a role for melatonin and TSH in modulating seasonal reproduction in the mare, further evidenced by the increased TSH immunosignal observed during the breeding season. Altogether, this study endorses the PT as the key site for integrating multiple cues to regulate seasonal reproduction in the horse, as this study marks the first investigation of the relationship between melatonin and PT-specific TSH cells and release in an equine model.

Grade 3 neuroendocrine tumours (NET G3) represent approximately 20% of high-grade neuroendocrine neoplasms, and the recent identification of this entity has given rise to many unanswered questions relating to clinical management. The prognosis for these patients is worse than for those with Grade 1–2 well-differentiated NET, but better than for those with Grade 3 poorly differentiated neuroendocrine carcinoma. This consensus statement aims to address some uncertainties and explore unmet needs in the management of patients with NET G3. Firstly, the role of surgery in localised disease will be discussed as well as the dilemma in relation to the use of neo-adjuvant and/or adjuvant treatment in this setting. Treatment of oligometastatic digestive NET G3 will also be examined, including the positioning of surgery and ablative therapy. In the advanced setting, traditionally, chemotherapy in the form of temozolomide/capecitabine or 5-fluorouracil-based therapies, rather than platinum/etoposide, is considered a first-line treatment option, with second-line therapy dependent on what was used first-line. More recently, following the results of the NETTER-2 trial, Peptide Receptor Radionuclide Therapy with ¹⁷⁷Lu-DOTATATE may be an option for selected patients with somatostatin receptor positive NET G3. There is limited data on the use of immunotherapy and targeted therapy in this disease group to date, and some available evidence will be presented. The role for re-biopsy to guide treatment decision-making in patients with digestive NET G3 and whether NET G3 outside of the digestive tract should be treated similarly will also be scrutinised. Prospective studies with translational end-points are required to enable a better understanding of this diagnosis and to facilitate more optimal treatment discoveries.

We aimed to assess the symptoms and impact on overall survival (OS) from bone metastases (BM) diagnosed on Gallium-68-labelled DOTA tyrosine octreotide positron emission tomography with computed tomography (⁶⁸Ga-DOTATOC-PET/CT) in patients with well-differentiated small intestinal neuroendocrine tumours (Si-NETs). Patients with well-differentiated Si-NETs, who underwent ⁶⁸Ga-DOTATOC-PET/CT between 2010 and 2023 at two tertiary referral centres in Sweden, were included. Their number of BM, ≤5 BM versus >5 BM, symptoms and need for analgesics were recorded. To further assess the impact of BM on OS, we used a control group of age- and sex-matched Si-NET patients with liver metastases (Stage IV disease) but without BM. The prevalence of BM in Si-NET patients was 23% (175/753); among these, complete clinical data were available in 138 patients. Synchronous BM were found in 33% (46/138). Sixty-one patients (44%) showed >5 BM at the time of BM detection. Fractures were diagnosed in 4% (n = 6) and 14% (n = 20) needed analgesics for BM-associated pain. In univariable analysis, patients with >5 BM experienced shorter OS from the time of BM detection compared to those with ≤5 BM (18 months vs. 75 months, p < .001). Among patients with Stage IV disease with and without BM, OS was shorter in patients with BM compared to patients with no BM (72 months vs. 288 months, p = .002). In multivariable analysis of patients with BM, higher Ki-67% (hazard ratio [HR] = 1.06, p = .007), older age (HR = 1.07, p < .01), presence of >5 BM (HR = 1.93, p = .021) and synchronous BM (HR = 2.14, p = .016) were identified as independent prognostic factors for shorter OS. In the matched cohort of patients with Stage IV disease with and without BM, presence of BM (HR = 1.94, p = .009), age at diagnosis of Stage IV (HR = 1.08, p < .001) and locoregional surgical resection (HR = 0.47, p = .015) were independent prognostic factors for survival. BM are detected in approximately 25% of Si-NET patients subjected to ⁶⁸Ga-DOTATOC-PET/CT. Pain occurs in approximately 14% and fractures in 4%. The presence of BM among Stage IV patients, the extent of bone disease (>5 BM) and synchronous BM are independent prognostic factors for shorter OS.

Many maternal adaptations occur during pregnancy to support the metabolic demands of the developing fetus and to prepare for the continued metabolic demands of lactation. Among these maternal adaptations are changes in the hypothalamic areas that regulate energy homeostasis: the paraventricular nucleus (PVN), ventromedial hypothalamic nucleus (VMH) and arcuate nucleus (ARC). The adaptive changes in the PVN, VMH, and ARC are believed to be driven by reduced responsiveness to the satiety hormone, leptin, during pregnancy. However, increased maternal metabolism is supported by elevated circulating glucose levels in pregnancy, and glucose itself can alter cell function by O-linked N-acetylglucosamine (O-GlcNAc) post-translational modification of proteins (O-GlcNAcylation). Therefore, we hypothesized that O-GlcNAcylation would be increased within the hypothalamic brain areas that are involved in the maternal adaptations to the increased metabolic demands of pregnancy: the ARC, VMH, and PVN. We completed immunohistochemistry and western blotting for O-GlcNAc in the ARC, VMH, and PVN from non-pregnant, late-pregnant, and lactating rats. Unexpectedly, we found that the number of O-GlcNAc-expressing cells and the levels of O-GlcNAc protein expression were similar within each area in non-pregnant, late-pregnant, and lactating rats. However, western blot analysis showed that the specific proteins that were O-GlcNAcylated appeared to be different between the reproductive states within each area. Further work will be required to identify the specific proteins that are differentially O-GlcNAcylated in each of the areas during pregnancy and lactation to determine whether this might contribute to the maternal adaptations required to cope with the metabolic demands of pregnancy and lactation.

Kisspeptin neurons play a critical role in the estradiol feedback effects on gonadotropin-releasing hormone (GnRH) neurons and luteinizing hormone (LH) secretion. Endogenous opioid peptides regulate LH secretion, but the neuroendocrine mechanisms involved remain elusive. We used RNAscope to characterize the expression of kappa (Oprk1)-, mu (Oprm1)-, and delta (Oprd1)-opioid receptors in GnRH (Gnrh1) neurons and kisspeptin neurons of the rostral periventricular area of the third ventricle (Kiss1^RP3V) and arcuate nucleus (Kiss1^ARC) in cycling mice and rats with physiological low (metestrus) and high (proestrus) levels of ovarian steroids. In mice, all opioid receptors were colocalized with Gnrh1, with increased coexpression of Oprk1 on proestrus compared with metestrus. Most Kiss1^RP3V neurons expressed Oprk1, Oprm1, or Oprd1, with no changes seen during the estrous cycle. The three opioid receptors were also expressed in Kiss1^ARC neurons, and the expression of Oprk1 in Kiss1^ARC neurons was reduced on proestrus compared with metestrus. When investigated in cycling rats, Kiss1^ARC neurons displayed the same pattern of Oprk1 variation as in mice. However, whereas the mouse Kiss1^ARC neurons displayed a predominance of Oprk1 expression, all three opioid receptors were similarly expressed in the rat. Our results show that Oprk1 is the main opioid receptor present in Kiss1^ARC neurons of mice but not rats, whereas Oprk1, Oprm1, and Oprd1 are abundantly expressed in mouse Kiss1^RP3V and GnRH neurons. Fluctuations in ovarian steroids are likely to modulate Oprk1 levels in GnRH and Kiss1^ARC neurons during the ovarian cycle, implicating this opioid receptor in the feedback control of LH secretion in female rodents.

Inferior petrosal sinus sampling (IPSS) is a diagnostic procedure used to differentiate between ectopic adrenocorticotropic hormone (ACTH)-dependent Cushing syndrome (EAS) and pituitary ACTH-dependent Cushing syndrome (CD). This study investigated the diagnostic value of IPSS, focusing on the use of prolactin adjustments and different calculation methods. We retrospectively analyzed data from patients with ACTH-dependent Cushing syndrome and inconclusive pituitary-MRI who underwent IPSS with corticotropin-releasing hormone (CRH) stimulation between 2015 and 2025. The cohort included 19 patients (16 CD, 3 EAS), with diagnoses confirmed by pathology examination and/or biochemical remission 1 year post-surgery. A pituitary source was confirmed in all patients with CD (n = 16) through pathology and/or biochemical remission. An ectopic source was confirmed by pathology in two of three patients with EAS. Using unadjusted ACTH ratios and previously established cut-off values resulted in three incorrect diagnoses out of 20 procedures. In contrast, prolactin-adjusted peak ACTH ratios provided a more distinct separation between CD and EAS, enabling correct diagnosis in all cases. Optimal cut-off values determined by receiver operating characteristic curve analysis were 1.0 for basal and 1.7 for concurrent prolactin-adjusted peak ACTH ratios, yielding 100% sensitivity and specificity. Basal prolactin-adjusted peak ACTH ratios were >1.5 in all patients with CD and <0.6 in all patients with EAS, while concurrent ratios were >1.1 in all patients with CD and <0.3 in all patients with EAS. Prolactin-adjusted peak ACTH ratios improve the diagnostic accuracy of IPSS and can effectively differentiate between ectopic and pituitary sources of ACTH. This study enhances the diagnostic accuracy of inferior petrosal sinus sampling (IPSS) for differentiating pituitary from ectopic ACTH-dependent Cushing syndrome by incorporating prolactin measurements and exploring various calculation methods. The findings contribute to advancing diagnostic techniques and improving clinical management of endocrine disorders. By enabling more accurate identification of the underlying cause of ACTH-dependent Cushing syndrome, this work supports clinicians in selecting optimal treatment strategies.