Neuroendocrinology最新文献

Background: Somatostatin analogs (SSAs) binding to and activating somatostatin receptors (SSTRs) have been extensively used for the treatment of neuroendocrine tumors (NETs). The currently approved synthetic SSAs have high affinity for SSTR2 (octreotide/lanreotide) or for SSTR2 and SSTR5 (pasireotide). These agents have shown symptom control and antiproliferative effects in subsets of NET patients and this was associated with the expression of the targeted SSTRs. Pancreatic NETs (Pan-NETs) are uncommon tumors with a propensity to metastasize. For unresectable advanced Pan-NETs expressing SSTRs, SSAs are the first-line medical therapy. Pan-NETs express mainly SSTR1, SSTR2, and SSTR3 and thus should respond to agonists targeting SSTR3.

Summary: We evaluated the efficacy of ITF2984, a novel multireceptor agonist with specificity for SSTR3, against Pan-NET cells representative of well-differentiated, functioning tumors, and expressing high levels of SSTR3. The effect of ITF2984 on cell proliferation/viability and on its ability to promote apoptosis and suppress hormone secretion was evaluated in 2D and 3D organotypic culture systems. Pasireotide was tested in parallel for comparative purposes.

Key message: We found that ITF2984 is as effective as pasireotide at inhibiting both proliferation/viability and hormone secretion, as well as at inducing apoptosis of Pan-NET cells grown as both 2D monolayers and 3D spheroids. High-dose ITF2984 elicits structural alterations in Pan-NET 3D spheroids compatible with cell death more effectively than pasireotide. Altogether, ITF2984 may represent a useful alternative to pasireotide for the medical treatment of Pan-NETs and other tumors with elevated SSTR3 expression.

Introduction: The gut microbiome, allegedly involved in both healthy homeostasis and development of disease, is found to be associated with several types of cancer. Short-chain fatty acids (SCFAs), important metabolites derived from the gut microbiota, are described to carry both protective and promoting features in cancer development. Limited research exists on neuroendocrine tumors (NETs) and their association with microbiota-derived SCFAs. The aim of this study was to investigate possible alterations in plasma SCFAs/organic acids in NET patients compared to healthy controls.

Methods: We quantified 11 organic acids, including SCFAs, in plasma from 109 NET patients (49 curatively operated patients and 60 patients with distant metastasis) as well as 20 healthy controls. Acids were quantified using liquid chromatography tandem mass spectrometry.

Results: We found that levels of 3OH-propionic acid, 3OH-butyric acid, lactic acid, formic acid, acetic acid, glyoxylic acid, and glycolic acid were significantly altered in NET patients with metastatic disease, as well as curatively operated NET patients, compared to healthy controls (p < 0.05). In addition, a trend displaying increased acid level alterations from healthy controls in curatively operated patients with future recurrence, compared to patients with no documented recurrent disease, was detected.

Conclusion: Our results demonstrating significantly altered levels of multiple organic acids in NET patients represents a novel finding implicating further research on their role in NET pathophysiology.

Introduction: The efferent vestibular system (EVS) originates in brainstem efferent vestibular nuclei (EVN) and modifies afferent vestibular signals at their source, in peripheral vestibular organs. Recent evidence suggests that EVS is also involved in the development of motion sickness symptoms, including vertigo and nausea, but the underlying mechanism is unknown. One possible link between EVN and motion sickness symptoms is through the neuropeptide calcitonin gene-related peptide (CGRP). CGRP often co-exists with substance P and pituitary adenylate cyclase-activating polypeptide (PACAP), two neuropeptides with similar vasodilatory effects. Collectively, these sensory neuropeptides have been associated with vestibular migraine pathophysiology and motion sickness. While CGRP and the fast EVS neurotransmitter, acetylcholine (ACh), have previously been identified in EVN neurons and their peripheral terminals, the presence of substance P and PACAP in the EVN has not yet been described.

Methods: We used fluorescent immunohistochemistry combined with confocal microscopy to examine the distribution of these three neuropeptides in the mouse EVN. In transgenic choline acetyltransferase (ChAT)-gCaMP6f mice, EVN neurons were positively identified using the fluorescent expression of gCaMP6f. In wild-type C57/BL6 mice, EVN neurons were confirmed using ChAT immunolabelling.

Results: Consistent with previous studies, CGRP was labelled in a subset of cholinergic EVN neurons. Additionally, we also show evidence for substance P and PACAP expression in EVN of transgenic and wild-type mice.

Conclusion: The presence of CGRP, substance P, and PACAP in EVN neurons suggests a complex peptidergic modulation of cholinergic signalling, whose release into local blood vessels may contribute to motion sickness symptoms.

Background: Many experimental data in several species clearly demonstrate the important genetic contribution to variations in HPA axis activity. The influence of corticosteroid hormones on adaptive processes and on production traits such as growth rate, feed efficiency, carcass composition, and meat quality is a strong impetus to the search for the molecular bases of these differences for efficient genetic selection.

Summary: Three main sources of genetic variability have been documented so far in farm animal species, the adrenal cortex sensitivity to ACTH-regulating corticosteroid hormone production, the bioavailability of corticosteroid hormones and especially corticosteroid-binding globulin capacity, and glucocorticoid receptor function. The effect of single mutations may be dependent on the genetic background, and genetic variation of cortisol levels may have different functional consequences depending on the molecular mechanisms responsible for this change.

Key messages: Understanding the genetic basis of HPA axis activity allows the development of genomic tools and breeding technologies aimed at improving adaptive capacity and stress tolerance in farm animals and their use as valuable models for the genetic study of the HPA axis and the correlation with adaptation, metabolism, and other functions regulated by adrenal hormones, and associated pathologies (obesity, cardiovascular, etc.). The next step will be to explore HPA axis variability from a system genetics perspective including the multiple sources of variation and their interactions. This multifactorial approach is a prerequisite to the use of the HPA axis phenotypes in the genetic selection for more productive and robust animals, with a high level of production of quality products.

Introduction: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of tumors often detected at the metastatic stage. The aim of this study was to profile the peripheral blood transcriptome through RNA-Seq and investigate the association of the systemic cancer hallmarks with progression-free survival in PRRT-treated GEP-NET patients.

Methods: The cohorts were: discovery cohort [PRRT-naïve well-differentiated GEP-NETs, n=59; age- and sex-matched healthy individuals, n=38], and independent evaluation cohort [GEP-NETs, n=66]. Peripheral blood transcriptomes were profiled through RNA sequencing and cancer hallmarks were identified via Gene Set Enrichment Analysis (GSEA). Activities of cancer hallmarks in each sample were calculated using Gene Set Variation Analysis (GSVA). Differentially expressed genes were identified with DESeq2. Progression-free survival was used as a primary endpoint and prognostic association was evaluated using univariate and multivariate COXPH analyses.

Results: RNA-Seq captured global changes in the peripheral blood transcriptome of GEP-NET patients. Peripheral blood transcriptome of NET patients showed differential enrichment of 30 systemic cancer hallmarks viz., TNF-α signaling via NF-κB, IL2/STAT5 signaling, TNF-α response, TNF-γ response, IL6/JAK/STAT signaling, TGF-β signaling, heme metabolism. etc. In the univariate analyses, two cancer hallmarks were prognostically significant (p<0.05) in GEP-NETs. Heme metabolism and IL2/STAT5 signaling were statistically significant in the Discovery cohort (n=58) and independent evaluation cohort (n=66). In multivariate COXPH analyses, heme metabolism and IL2/STAT5 signaling were independently associated with PFS in GEP-NET patients undergoing PRRT.

Conclusions: This study provides comprehensive coverage of the peripheral blood transcriptome of GEP-NET patients via RNA-Seq and identifies systemic cancer hallmarks as independent prognostic factors in NETs.

Introduction: Lu-PRRT in neuroendocrine tumors is usually delivered with a total cumulative activity (TCA) of 29.6 GBq, divided into 4 cycles and with fixed interval between cycles (IBCs) of 8 weeks. Based on previous radiobiological studies, reducing IBC could improve efficacy without increasing toxicity. The purpose of this study was to evaluate safety of Lu-PRRT with two different IBC: intensive (every 5 weeks) or standard (every 8-10 weeks).

Methods: From May 2016 to July 2018, patients with advanced and progressive GEP and bronchial NENs were enrolled in a prospective randomized phase II study. Patients with risk factors for toxicity (RF) were planned for a TCA of 18.5 GBq, patients without RF of 27.8 GBq, divided into 5 cycles. Patients were then randomly assigned to be treated according to the intensive or to the standard IBC. Toxicity was monitored according to CTCAE.

Results: One hundred and twenty patients (61 in the intensive group and 59 in the standard one) were evaluable for overall toxicity. Five patients (4.1%) had major (G3) hematological toxicity, 2 in the intensive group and 3 in the standard one. Other G3 toxicities related to creatinine, alanine aminotransferase, nausea, and asthenia were observed in the intensive group. 112 patients (54 in the intensive group and 58 in the standard one) performed at least 2 cycles and were also evaluable for cycle-by-cycle toxicity, resulting similar between the two groups.

Conclusion: According to our preliminary results, Lu-PRRT administered intensively could be considered as safe as the standard schedule, when TCA is chosen according to the RF. Further data are needed to confirm these results.

Introduction: Neuroendocrine tumors (NETs) frequently have a genetic basis, and the range of genes implicated in NET development continues to expand. Application of targeted gene panels (TGPs) in next-generation sequencing is a central strategy for elucidating novel variants associated with NET development.

Methods: In this study, we conducted comprehensive molecular genetic analyses using TGP on a cohort of 93 patients diagnosed with various NETs subtypes, mainly accompanied by various endocrine syndromes: insulinoma (n = 26), pheochromocytoma and paraganglioma (PPGL) (n = 38), parathyroid adenoma (n = 18, including three with insulinoma), and NETs of other locations (n = 14). The TGP encompassed genes linked to diverse NETs and other hereditary endocrine disorders, with subsequent variant classification according to the American College of Medical Genetics and Genomics guidelines.

Results: Among the identified variants, 20 were found in genes previously linked to specific tumor types, and 10 were found in genes with a limited likelihood and unclear molecular mecanisms of association with observed NETs. Remarkably, 13 variants were discovered in genes not previously associated with the NETs observed in our patients. These genes, such as ABCC8, KCNJ11, KLF11, HABP2, and APC, were implicated in insulinoma; ZNRF3, GNAS, and KCNJ5 were linked with PPGL; parathyroid adenomas were related to variants in SDHB and TP53; while NETs of other locations displayed variants in APC and ABCC8.

Conclusion: Our study demonstrates that utilizing broad TGP in examining patients with various functioning NETs facilitates the identification of new germinal variants in genes that may contribute to the diseases. The verification of revealed findings requires research in vaster sample.

Background: The pituitary gland is a vital endocrine organ regulating body homoeostasis through six hormone-secreting cell types. Among these, pituitary gonadotrope cells are essential for reproductive function. Throughout pituitary ontogenesis, gonadotrope cells differentiate in a stepwise process, involving both morphogenic cues and transcription factors, which drives specification of progenitor cells into specialised endocrine cells. It is crucial to understand the mechanisms underlying gonadotrope differentiation, as developmental defects and abnormalities in this process can lead to many reproductive pathologies.

Summary: This review offers a detailed overview of the latest advances in gonadotrope cell differentiation. We addressed this question with a specific focus on three important aspects of gonadotrope differentiation: the identification of the progenitor population giving rise to gonadotrope cells, the early mechanisms that initiate Nr5a1 expression and thus gonadotrope fate commitment, and finally, the mechanisms driving the formation of physical and functional gonadotrope networks.

Key messages: Overall, this review aimed to provide new insights into three aspects of the gonadotrope differentiation process by reconsidering pioneering studies in the light of data gained from latest technological developments. Firstly, we re-investigated the long debated developmental trajectory of pituitary gonadotrope cells. Secondly, we reported new regulatory mechanisms of Nr5a1 expression, focusing on the involvement of ERα. Finally, we highlighted the molecular and cellular mechanisms driving gonadotrope network formation during embryogenesis, a process that seems essential for regulation of gonadotrope activity.

Introduction: Multiple endocrine neoplasia type 1 (MEN-1) is the most common inherited syndrome associated with NET development and gender-specific differences are emerging in neuroendocrine tumors (NETs). This study aimed to analyze gender difference in a single cohort of MEN-1 patients focusing on duodeno-pancreatic (DP)-NET and survival rates.

Methods: MEN-1 patients referred to the Endocrinology Unit of the "Federico II" University of Naples, ENETS CoE, were retrospectively evaluated.

Results: Among 100 MEN-1 patients enrolled, 59 (59%) were female and 41 (41%) male, and mean age at diagnosis was 39.4 years (range 5-86). No statistically significant association was identified between MEN-1 clinical manifestations and gender (primary hyperparathyroidism [PHPT] p: 1.0, DP-NET p: 0.83, pituitary adenoma [PA] p: 0.84, lung NET p: 0.64, and thymic NET p: 0.10), and similarly, age at diagnosis of MEN-1 and its individual manifestations was similar between genders. Survival analysis revealed no statistically significant difference between genders in DP-NET patients regarding progression disease p: 1.0 and death p: 1.0. Mean progression-free survival (PFS) of patients with DP-NET was 98.6 months (range 3-288), and mean overall survival (OS) was 130.1 months (range 3-444 months), without differences between genders (PFS p: 0.67 and OS p: 0.60). The Kaplan-Meier survival curves for PFS and OS showed no differences between genders (PFS p: 0.92; OS p: 0.87).

Conclusion: In this MEN-1 cohort, no gender differences in the occurrence of PHPT, PA, DP-NET, lung NET, and thymic NET, nor in survival outcomes including PFS and OS within the DP-NET subcohort, emerged. Therefore, this study supports similar screening and follow-up for both male and female MEN-1 patients.

Introduction: Clinical presentation and genetic profile of gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are highly variable, hampering their management. Sequencing of circulating tumor DNA from liquid biopsy (LB) has been proposed as a less invasive alternative to solid biopsy (SB). Our aim was to compare the mutational profile (MP) provided by LB with that deriving from SB in GEP-NETs.

Methods: SB and LB were derived simultaneously from 6 GEP-NET patients. A comparative targeted next-generation sequencing (NGS) analysis was performed on DNA from SB and LB to evaluate the mutational status of 11 genes (MEN1, DAXX, ATRX, MUTYH, SETD2, DEPDC5, TSC2, ARID1A, CHECK2, MTOR, and PTEN).

Results: Patients (M:F = 2:1; median age 64 years) included 3 with pancreatic and 3 with ileal NETs. NGS detected a median number of 55 variants/sample in SB and 66.5 variants/sample in LB specimens (mutational burden: 0.2-1.9 and 0.3-1.8 mut/Mb, respectively). Missense and nonsense mutations were prevalent in both, mainly represented by C>T transitions. ARID1A, MTOR, and ATRX were consistently mutated in SB, and ARID1A, TSC2, MEN1, PTEN, SETD2, and MUTYH were consistently mutated in LB. DAXX mutations were absent in LB. Seventeen recurrent mutations were shared between SB and LB; in particular, MTOR single-nucleotide variants c.G4731A and c.C2997T were shared by 5 out of 6 patients. Hierarchical clustering supported genetic similarity between SB and LB.

Conclusions: This pilot study explores the applicability of LB in GEP-NET MP evaluation. Further studies with larger cohorts are needed to validate LB and to define the clinical impact.