Neuroendocrinology最新文献

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.

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.

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: Sodium-glucose cotransporter 2 (SGLT2) inhibitors have demonstrated neuroprotective effects and hold potential advantages in enhancing cognitive function. This study aimed to clarify the association between SGLT2 inhibitors and the risk of dementia among individuals diagnosed with type 2 diabetes (T2D).

Methods: All cohort studies concerning the impact of SGLT2 inhibitors on dementia onset in patients with T2D were identified. The literature search encompassed PubMed, Embase, Cochrane Library, and Web of Science from establishment to March 2024, with no language restriction. The quality of the literature was evaluated using the Newcastle-Ottawa Scale (NOS). Meta-analysis was conducted using RevMan 5.4 software, calculating pooled risk ratio (RR) with 95% confidence intervals (CIs) for dichotomous outcomes.

Results: Five cohort studies encompassing a total of 331,908 patients were included in the analysis. The findings showed that individuals receiving SGLT2 inhibitors had a lower risk of dementia (I2 = 42%, p = 0.14; RR: 0.77; 95% CI: 0.71-0.84) compared to the control group. Subgroup analyses confirmed the consistent beneficial effects of SGLT2 inhibitors across different study regions (I2 = 0%, p = 0.60) and genders (I2 = 0%, p = 0.50).

Conclusions: SGLT2 inhibitors may reduce the dementia risk in T2D patients. Given the limitations of the study, further investigations were warranted to confirm the benefits.

Introduction: Chronic cocaine exposure results in changes in circulating steroid hormones, which is known to be associated with cocaine-seeking and cocaine-taking behavior. However, whether cocaine also alters the brain content of these steroid hormones and cholesterol, a precursor to all steroid hormones, has yet to be extensively investigated. Thus, the goal of this study was to determine whether cocaine self-administration (SA) altered the content of cholesterol and steroid hormones (progesterone and testosterone) in both the plasma and the brain of animals.

Methods: Male Sprague-Dawley rats were allowed to self-administer cocaine (1.5 mg/kg/infusion) for a maximum of 40 injections within 6 h per day for 5 consecutive days followed by cue reactivity test and cocaine SA under the progressive ratio schedule as a measure of motivation to acquire cocaine. Eighteen hours after the last behavior test, the blood and brain tissue, including the prefrontal cortex (PFC) and dorsal striatum (CPu), were collected for biochemical assays.

Results: While cocaine SA did not alter the content of cholesterol and progesterone in the plasma, it reduced cholesterol content and almost completely abolished progesterone content in both the PFC and CPu. Further, testosterone levels were reduced in the CPu and plasma. Notably, plasma testosterone was positively correlated with its content in the PFC and CPu.

Conclusions: Cholesterol and progesterone in the brain are more sensitive to changes induced by cocaine SA than those in the plasma. Future studies should focus on understanding the functional consequence of altered brain steroids on neurotransmission and cocaine-seeking and cocaine-taking behavior.

Background: Thymic carcinoids or neuroendocrine neoplasms (t-NEN) are a rare entity with a dismal prognosis. About 25% of the tumors are related to multiple endocrine neoplasia type I (MEN-1), where they contribute significantly to mortality. The tumors are classified according to the WHO classification, TNM classification and Masaoka-Koga staging system, although none of the classifications have been developed for t-NEN. A recently proposed t-NEN specific morphomolecular classification is based on copy number instability scores. Its role is yet to be defined. The prognosis depends on resectability, histological features, metastasis, the amount of copy number instabilities and mitotic activity.

Summary: No study-based therapies exist. The mainstay of therapy is surgical resection as it is associated with significantly improved long-term survival. Based on published cases and small series, for non-resectable and recurring disease, platinum-based chemotherapies are preferred in neuroendocrine carcinoma, while everolimus and temozolomide are recommended in thymic neuroendocrine tumors.

Key messages: This review covers current classification systems and the knowledge of genetic disorders and medical therapies.

Background: The role of gender has gained attention in oncology. In the setting of lung neuroendocrine tumors (L-NETs), the existence of differences between male and females has been suggested, but no clear-cut data are available. We aimed to provide a critical analysis of the existing literature regarding sex roles in L-NETs.

Methods: We performed an extensive search of the available literature to provide a critical narrative review focused on key topics such as epidemiology, histopathological and molecular features, functioning syndromes, prognosis, and response/toxicity to treatments in L-NETs according to sex.

Results: Female patients are more likely to have an L-NET than males. The reasons underlying these gender differences are still unclear; a biologic mechanism for the sex difference is possible, through a role of hormones in regulating gene expression and promoting neuroendocrine cell proliferation. A difference in immunohistochemical biomarkers has been found; thyroid transcription factor-1 (TTF-1) expression appears to be associated with female gender; at the molecular level, in the majority of studies, L-NET mutational profile is not stratified for sex. In terms of prognosis, a correlation between male gender and a more aggressive disease has been found. Patient's gender has been recognized as a key modulator in the response/resistance to anticancer treatments; however, for L-NETs, the available data regarding the activity of different treatments and their toxicities are scarce, as in clinical trials designed for L-NETs, a stratified evaluation of drugs' activity according to patients' sex is largely missing.

Conclusions: There is emerging evidence suggesting a gender role in L-NETs; however, further studies are needed to better understand the pathogenesis of these tumors and to plan tailored treatments. Graphical Abstract: for Graphical Abstract, see https://doi.org/10.1159/000546081.

Background: Neuroendocrine neoplasms (NENs) are consistently referred to as a "relatively" rare heterogenous group of "tumours" with variability in their disease course and outcomes. However, there is a lack of consensus on (a) the group membership, that is, a lack of consistency in which "subtypes" of NEN are included in the group; (b) whether they should continue to be seen as a "heterogenous group," or as separate entities; and (c) whether the term and current definitions of "rare" accurately reflects the true patient population and healthcare requirement.

Summary: This opinion article explores the concept of rare, as applied to NENs: the significance of a rare cancer label and what this means for awareness, healthcare provision and, tangentially, those diagnosed. It briefly explores rare cancer definitions, including incidence thresholds and interpretation of definition as demonstrated in the variability in what subtypes are included in databanks or registries, and it also asks whether the currently utilised rare cancer definitions reflect an accurate representation of the true disease burden and fully inform disease-appropriate healthcare planning and provision.

Key messages: The current definition of "rare cancer" based on incidence alone fails to reflect the true disease burden of NENs and is therefore inadequate, to fully inform healthcare policy, planning and provision for this patient population. This requires either a revision in definition or an alteration in how and what decision-makers utilise and include in their deliberations when assessing and planning service provision.

Background: Neuroendocrine neoplasms (NENs) are comparatively rare tumours. However, prevalence is increasing steeply, related to rising incidence, earlier detection, and prolonged survival in many cases of metastatic NENs, with implications on healthcare resources.

Summary: This commentary/narrative review extracts the relatively scare, available literature related to costs of NEN cancer care, which is mainly based on studies performed in the USA. Key, now implemented or evolving NEN-related treatment options over the last 15 years, is summarised. The commentary further highlights in part preventable aspects that can further contribute to cost pressure in NEN cancer care, including issues related to inappropriate use of available diagnostic tools, and not considering differential diagnoses when assessing people with suspected carcinoid syndrome - with these risks being minimised with access to centres with multi-speciality expertise in the management of people with NENs. Issues observed in people with exocrine and/or endocrine pancreatic deficiencies caused by a NEN or treatment of the NEN are mentioned, as well as some specific aspects related to diagnostics involving 68Ga PET-CT scans and treatment with Lutetium peptide-receptor radionuclide therapy (Lu-PRRT).

Key messages: This commentary summarises factors influencing cost of NEN cancer care, and highlights in part preventable issues mostly related to delayed involvement of a NEN multidisciplinary team, observed in a UK NEN referral centre (ENETS Centre of Excellence certified since 2015) over the last 15 years, resulting in suboptimal management of people with NENs and ultimately adding to cost pressure.