Endocrine-related cancer最新文献

Thyroidectomy is recommended for patients with multiple endocrine neoplasia type 2A (MEN2A). American Thyroid Association 2015 guidelines recommend follow-up of calcitonin values after thyroidectomy. The aim of this study was to determine the natural course of calcitonin levels after total thyroidectomy (TTx) in MEN2A patients. Patients with MEN2A who underwent TTx between 1993 and 2019 and had multiple postoperative calcitonin measurements were retrospectively included from our referral center. Long-term serial calcitonin measurements and clinical outcomes were correlated to the first postoperative calcitonin, histopathology and type of TTx (prophylactic versus non-prophylactic). Fifty-two patients underwent TTx after 1993 at a median age of 10 years (range 0-71). Of these, 23 (44%) had no MTC and 29 (56%) had MTC. The median follow-up time was 12 years (range 3-30). Thirty-eight patients had an 'undetectable' first postoperative calcitonin, seven 'within reference range' and seven 'above reference range'. Of the 38 patients with an 'undetectable' first postoperative calcitonin, 32 remained 'undetectable'. All 21 patients without MTC and 'undetectable' first postoperative calcitonin remained 'undetectable'. Of the 17 patients with MTC and 'undetectable' first postoperative calcitonin, 11 remained 'undetectable' and none developed structural recurrence. Twenty-two of the 25 patients undergoing prophylactic thyroidectomy had repeated 'undetectable' measurements. Persistent MTC or structural recurrence occurred in six patients; all had MTC, had a detectable first postoperative calcitonin and underwent non-prophylactic TTx. In conclusion, the long-term serial calcitonin values remain undetectable in the majority of the patients with an undetectable first postoperative calcitonin. Biochemical follow-up for patients without MTC and an undetectable first postoperative calcitonin may not be necessary.

VIPoma is a rare neuroendocrine tumor (NET) that is challenging to diagnose. While VIP concentrations are elevated in VIPoma, the optimal threshold for diagnostic purposes is not well defined. We aimed to study this in a single-institution population. We obtained results from vasoactive intestinal peptide (VIP) tests from 2011 to 2023 and reviewed the medical record of patients who had concentrations greater than our established assay-specific reference limit of 75 pg/mL. We compared plasma VIP concentrations between patient cohorts with and without VIPoma and determined the optimal threshold for VIP concentrations to predict a VIPoma in this population. Seventy-six patients met the selection criteria. Of these, nine cases of VIPoma were diagnosed. All patients had chronic diarrhea, and five patients had a previous diagnosis of a pancreatic neuroendocrine tumor (PNET). VIP concentrations drawn for acute/episodic diarrhea or flushing/diaphoresis did not lead to a diagnosis of a VIPoma. Mean VIP concentration was increased in patients with a VIPoma relative to those without, but the difference was not statistically significant (508 pg/mL vs 223 pg/mL, P = 0.31). Using the threshold of 75 pg/mL, the positive predictive value for a VIPoma was 12%. The optimal VIP threshold was 442 pg/mL (OR: 11.96, 95% CI: 2.00-79.69, P = 0.01), with statistically significant odds ratios starting at 200 pg/mL. Our findings suggest that elevated VIP concentrations are not predictive for a VIPoma and most patients with elevated VIP do not have a VIPoma. We recommend that VIP only be drawn in certain clinical scenarios to avoid unnecessary medical investigations.

Cabozantinib has significantly improved progression-free survival (PFS) in patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) after lenvatinib and/or sorafenib pre-treatment in the phase 3 COSMIC-311 trial, leading to its approval for sequential treatment. Real-world evidence of cabozantinib remains limited, particularly in poorly differentiated thyroid cancer (PDTC). In this retrospective analysis, we included adult patients with RAIR-DTC or PDTC treated with cabozantinib as further-line treatment at the Essen Endocrine Tumor Center (06/2022 - 07/2025). All patients had received prior targeted therapy and had documented progressive disease at cabozantinib initiation. Best overall response, PFS, overall survival (OS) and adverse events were assessed. Nineteen patients (7 DTC, 12 PDTC) were included in the safety analysis and 17 in the efficacy assessment. Under sequential cabozantinib treatment, partial response (PR) was observed in 4/17 (24%): 3/4 in patients switched due to lenvatinib toxicity and 1/13 in those switched due to progression. Median PFS was 5.4 months in DTC and 3.6 months in PDTC. Median OS from cabozantinib initiation was 13.5 months in DTC and 15.8 months in PDTC. Dose reductions or interruptions were required in 6/19 (31.6%), and 3/19 (15.8%) permanently discontinued cabozantinib due to toxicity. In this real-world cohort, further-line cabozantinib showed limited efficacy in RAIR-(P)DTC, especially in PDTC. Responses were more favorable when cabozantinib was initiated due to prior treatment toxicity rather than progression. The substantial toxicity highlights the need for careful management and improved therapeutic strategies in this population.

The incidence of adrenal tumors rises with age, but the link between adrenal aging and tumorigenesis is still not well defined. This mini-review summarizes age-related changes in both the adrenal cortex and medulla, including structural remodeling, altered steroidogenesis, and shifts in immune and cellular homeostasis. We then examine adrenocortical carcinoma (ACC), where clinical outcomes are poorer in older patients and where senescence, inflammation, and sex-specific immune differences may shape disease behavior. Limited information is available for other adrenocortical tumors, while pheochromocytomas in the elderly are described mainly in case reports, often with diagnostic and perioperative difficulties. For other rare adrenal neoplasms, data are fragmentary. Much of the mechanistic evidence summarized here derives from preclinical models, and robust clinical validation remains limited; accordingly, translational inferences should be regarded as provisional. The evidence suggests that aging influences both the biology and clinical course of adrenal tumors, but systematic studies are lacking. This review brings together what is currently known and highlights many open questions. We hope this will serve as a starting point for further work on how aging affects adrenal function and tumor development, and how this knowledge might be used to improve care of older patients.

Adrenocortical carcinoma (ACC) is a highly aggressive malignancy with poor survival rates and few treatment options. Preclinical models are indispensable to further strengthen our understanding of disease progression and development of novel therapeutic treatments. Here, we report the establishment of a new cell line named ZUC-1 originating from the resection of an advanced primary ACC and its characterization at the genomic, cellular and molecular level. ZUC-1 cells were successfully propagated as monolayer cultures and three-dimensional spheroids. LC-MS/MS analysis revealed for ZUC-1 cells co-secretion of cortisol, aldosterone and testosterone and the model represented in direct comparison with other current ACC pre-clinical models furthermore significantly elevated expression of SF-1, CYP11B1 and CYP11B2 genes. Whole genome sequencing identified various mutations in genes linked to DNA repair/stress response, stemness, but also steroidogenesis. Interestingly, ZUC-1 represents genotypic and phenotypic variations which might be of interest beyond ACC including congenital adrenal hyperplasia (CAH) and polycystic ovary syndrome (PCOS). Moreover, 18OH and 18-oxo-cortisol release was detected in ZUC-1, conditions which are often linked to hyperaldosteronism, but forskolin, potassium and at higher concentration angiotensin II modulability of CYP11B2 for this model is retained. ZUC-1 spheroids exhibited furthermore an intra-spheroidal heterogenous mix of canonical and non-canonical Wnt pathway activation. We conclude that due to its origin and unique geno- and phenotypes, ZUC-1 represents an intriguing model to further gain basic understanding of adrenal function,the pathogenesis of ACC, but it might be also of interest in context of CAH and PCOS.

Lynch syndrome is the result of pathogenic variants in mismatch repair genes that increase the risk of cancer, including adrenocortical carcinoma. Little is known, however, about the clinical characteristics of patients with Lynch Syndrome-associated adrenocortical carcinoma. In order to understand the clinical characteristics and prevalence of Lynch Syndrome-associated adrenocortical carcinoma, we conducted a retrospective chart review of patients with adrenocortical carcinoma and germline genetic testing results indicating pathogenic variants in mismatch repair genes consistent with Lynch Syndrome at a single, academic, tertiary-care institution. In total, 21 patients with Lynch Syndrome-associated adrenocortical carcinoma were identified from 2003 - 2024. Three patients met Amsterdam I criteria, and 12 patients met Amsterdam II criteria (including adrenocortical carcinoma as a Lynch Syndrome-associated cancer). More than 90% of patients with available histopathology had high-grade tumors, suggesting a more aggressive nature. The prevalence of Lynch Syndrome-associated adrenocortical carcinoma is estimated at 2.6%. This study further demonstrates that adrenocortical carcinoma is a Lynch Syndrome-associated cancer and may be associated with high-grade disease. Furthermore, our findings suggest that further research should be pursued to investigate the potential utility of immunotherapy for adrenocortical carcinoma, especially in the presence of microsatellite instability.

Loss-of-function (LOF) germline AIP variants are the main genetic cause of familial isolated pituitary adenoma and gigantism. A role for this defect in other neoplasms has been suggested, but remains unclear. We investigated the frequency, associated phenotypes, and in vitro functional effects of germline AIP variants in a cohort of Mexican patients with neuroendocrine neoplasms (NENs). Blood DNA samples from 101 adults (70.3% females) with isolated or syndromic NENs (50 with pituitary neuroendocrine tumors, PitNETs) were analyzed using a next generation sequencing panel. Targeted Sanger screening was carried out in additional family members and tumor samples. Missense and intronic variants were functionally assessed via cycloheximide chase assays or quantitative polymerase chain reaction plus sequence analysis of blood cDNA, as appropriate. Two rare likely benign defects (c.787 + 9C>T and p.T231M), two variants of uncertain significance (p.R106C and p.V291_L292del), one likely pathogenic (LP, p.C238Y), and one pathogenic (p.R304*) variant were found in six cases (5.9%). One individual was diagnosed with multiple gastric NENs and five carried PitNETs. Variant p.V291_L292del produced an unstable protein (P < 0.0001 for half-life curve, compared with wild type) and was reclassified to LP. Loss of heterozygosity in a gastric neuroendocrine tumor and nonsignificantly increased protein stability were observed for p.R106C. No deleterious effects were documented for c.787 + 9C>T. In conclusion, we determined the prevalence of AIP variants in a cohort of NENs and reclassified one VUS to LP. Our findings support the causal association of AIP LOF with PitNETs, but cannot rule out a role for AIP in other NENs.

There are currently few treatment options available for advanced neuroendocrine neoplasms (NENs). When treating metastatic renal cancer, the combination of lenvatinib with everolimus has shown noticeably greater success than monotherapy. Clarifying the synergistic effects of lenvatinib and everolimus on NENs and investigating the underlying processes were the goals of this study. Lenvatinib and everolimus were tested for their synergistic inhibitory effects on NEN cells in vitro using CCK-8, colony formation, wound healing, flow cytometry, and tube formation. In vivo evaluation of the combined inhibitory effects was conducted using a xenograft mouse model. Western blot analysis was used to look into the main regulatory molecules implicated in this synergy, and clinical case studies were used to quantify the clinical benefits. The combination of lenvatinib and everolimus showed a synergistic anti-tumor impact in vivo and suppressed cell proliferation, colony formation, cell migration, angiogenesis, and promoted apoptosis in vitro. Notably, in patients with advanced NENs who developed resistance after many lines of therapy (>2nd line), this combination successfully postponed the advancement of their disease. Mechanistically, both medications increased the expression of ITGB4 and inhibited 4EBP1 phosphorylation; their combined inhibitory effects on NENs were lessened when ITGB4 was knocked down. These findings indicate that lenvatinib and everolimus act synergistically to inhibit NEN proliferation and migration and to induce apoptosis in vitro, with robust synergistic activity also evident in vivo. This synergy appears to be mediated, at least in part, through the upregulation of ITGB4.

Multiple endocrine neoplasia type 2 (MEN2) is caused by germline RET mutations and is characterized by the presence of medullary thyroid cancer (MTC) associated or not with other endocrine neoplasias. MEN2 is classified as MEN2A, including different variants, and MEN2B. The aim of the present study was to evaluate the impact of the RET genetic screening in redefining the prevalence of the different MEN2 variants inside the MEN2A group. This study included 223 MEN2 families: 202 MEN2A (55 MEN2A classical, 3 MEN2A + lichen cutaneous amyloidosis (CLA), 5 MEN2A + Hirschsprung disease (HD) and 139 FMTC variants) and 21 MEN2B. RET germline mutations found in MEN2A classical variant, as well as in MEN2A + CLA and MEN2A + HD, were the 'high-risk' category in most cases, while only 5/139 RET-mutated FMTC families showed a 'high-risk' category mutation. The most frequent mutation in the FMTC variant was the p.Val804Met (62/139). Among all, 116 families had a known history of hereditary disease (group A) at diagnosis and 107 had an apparently sporadic form of MTC (group B). Different MEN2A variants and RET ATA risk level category mutations were observed in the two groups. In conclusion, we demonstrated that the FMTC is the most prevalent MEN2A variant; 'moderate-risk' RET mutations, particularly non-cysteine mutations, are almost exclusively present in the FMTC variant; about 50% of hereditary MTC kindreds are primarily discovered by the RET genetic screening, confirming the clinical utility of performing this analysis in all cases of MTC.

Phaeochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine, chromaffin cell-derived tumours of the adrenal medulla or paraganglia. Germline pathogenic variants in succinate dehydrogenase subunit B (SDHB) are most prevalent and associated with malignancy and poor prognosis. Treatment options are limited, and therapy development is hindered by knowledge gaps concerning the pathomechanism and lack of suitable models. Previously, homozygous sdhb mutant zebrafish larvae showed disease characteristics, and adult heterozygous mutants represented human heterozygous SDHB carriers, portraying low-grade systemic succinate accumulation. Since spontaneous PPGL formation remains absent, we applied vitamin C supplementation as potential trigger to induce tumourigenesis in adult heterozygous sdhb mutant zebrafish. In addition, sdhb mutant larvae were exposed to vitamin C to investigate dose-dependent effects in an sdhb-deficient context. Twelve percent of vitamin C-supplemented adult sdhb mutants showed local proliferation of chromaffin cells with tissue-specific sdhb deficiency. Furthermore, metabolite profiling showed an increase in succinate/fumarate ratios upon vitamin C in heterozygous sdhb mutants. Gene expression analysis showed activation of the hypoxia-inducible factor pathway in larval and adult zebrafish. In addition, high dose vitamin C increased nrf2a expression, representing oxidative stress, in homozygous and heterozygous sdhb mutants. Ultimately, we have successfully employed vitamin C supplementation to initiate chromaffin cell proliferation in adult heterozygous sdhb mutant zebrafish, resembling early-stage PPGL tumourigenesis. Furthermore, we gained insights into underlying mechanisms, including HIF stabilisation, demethylation, oxidative stress, iron metabolism and glucose transport. Our model provides a unique platform to investigate possible triggers for PPGL development in the human mutation carrier state and investigate early stages of tumourigenesis.