Endocrine-related cancer最新文献

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.

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.

The intracellular molecular networks are highly complex and plastic. Yet, they obey the network principles discovered by systems biology. Precise mathematical models of some networks enable one to predict how molecular properties determine the function and malfunction of the network. However, the complexity is even greater than this: due to selection in evolutionary biology, the molecular networks are not only causal to cell function, but also caused by the requirement that the cell's functions be optimal. We discuss how the combination of complexity, plasticity, and this circular causality makes the networks similar to trained artificial neural networks. Causation by purpose might thereby dominate over causation by mechanism. Comparison of challenges that may cause or cure disease with actual challenges in evolutionary, developmental, or cell biology, and assessment of the learned responses thereto, might add another interesting layer of systems biology.

With increased use of somatostatin analogue (SSA) PET/CT, the prevalence of incidentaloma - at present approximately 4.5% - is anticipated to rise. As malignancy has been reported in 13% of all cases, these incidentaloma are clinically relevant. However, because of publication bias, prevalence is probably underestimated and the malignancy rate overestimated. Therefore, we assessed the prevalence, cause, malignancy rate, and tracer uptake intensity on 68Ga-DOTANOC PET. All 68Ga-DOTANOC PET/CT protocols in adults, performed between 2017 and 2024 at Antwerp University Hospital, were retrospectively screened for incidentaloma. Patient records were examined to determine the cause of non-physiological increased tracer uptake. A total of 1,951 68Ga-DOTANOC PET/CTs were performed in 1,102 subjects. A total of 145 incidentaloma (13.2%) were described in 136 subjects (mean age 64 ± 13 years; F/M 82/54), most commonly in the thyroid (n = 43), brain (n = 31), prostate (n = 23), and breast (n = 11). The cause of pathological tracer uptake was evaluated by additional imaging in 55% of incidentaloma, whereby benign thyroid nodules, meningioma, benign prostatic hyperplasia, and breast fibroma and carcinoma were the most common findings, respectively. The malignancy rate was low (6%), comprising two breast cancers, one prostate cancer, one renal cell carcinoma, and one lung cancer. This is the largest single-centre study describing the prevalence and cause of 68Ga-DOTANOC incidentaloma to date. While the prevalence is significantly higher (13.2%) than described in previous studies (4.5%), the malignancy rate was significantly lower (6 versus 13%), as was expected due to publication bias, and no thyroid cancer was diagnosed.

Locoregional therapies are a standard treatment for neuroendocrine tumors (NET) with predominant liver metastases. The efficacy of transarterial chemoembolization (TACE) using streptozotocin (STZ) has been poorly compared to transarterial embolization (TAE). Predictive biomarkers of TACE efficacy have never been explored. We studied all patients with pancreatic (panNET) or small intestine (siNET) NET and liver metastases treated between 2006 and 2022 using a standardized protocol of TACE-STZ (1,500 mg/m2) or TAE. The primary endpoint was the RECIST 1.1-defined objective response rate (ORR). The variables associated with ORR were explored using a propensity score to account for confounding factors. Secondary endpoints included the impact of tumor expression of O6-methylguanine-methyltransferase (MGMT), alkylpurine-DNA-N-glycosylase (APNG), and carbonic anhydrase IX (CAIX), and progression-free survival (PFS). Among 116 patients, 58 received TACE (15 siNET and 43 panNET) and 58 received TAE (42 siNET and 16 panNET). TACE was associated with a higher ORR than TAE (43 vs 22%, P = 0.045), which remained statistically significant on propensity-adjusted multivariable analysis (OR 2.71, 95% CI: (1.08-7.17), P = 0.038). TACE provided longer PFS than TAE in panNET patients (12.9 vs 6.4 months, P = 0.026), but not in siNET patients (16.1 vs 15.1 months, P = 0.47). Low APNG expression was predictive of higher ORR with TACE (70 vs 16%, P < 0.001), while the expression of MGMT and CAIX had no impact. TACE-STZ provided a higher ORR than TAE, although it yielded longer PFS only in patients with panNET. Low tumor expression of APNG might help select the best candidates for TACE-STZ, although this result was only exploratory.

Epitransciptomic marks, such as N6-methyladenosine (m6A) within RNA transcripts, have been implicated in multiple pro-tumorigenic activities. These modifications are controlled by writers, readers, and erasers, including the METTL3 m6A-methyltransferase. Recently, changes in expression or activity of epitranscriptomic enzymes have been shown to modulate metabolic pathways in multiple tumor types, including within endocrine-sensitive and -resistant estrogen receptor-positive (ERα+) breast cancer (ER+ BC) cells. Yet, a broad analysis of metabolic alterations, specifically with respect to METTL3 inhibition, has not been explored in these BC subtypes. Herein, we investigated the magnitude of pharmacological targeting of METTL3 (STM2457) on overall cellular metabolism in endocrine-sensitive (MCF-7 and ZR-75-1) and -resistant (LCC9 and ZR-75-1-4-OHT) ER+ BC cells. We found that STM2457 selectively decreased glycolytic activity in resistant cells and led to altered hexokinase 2 expression in LCC9 cells. STM2457 suppressed mitochondrial activity, while isotope tracing found diminished tricarboxylic acid (TCA) glucose oxidation in MCF-7 and LCC9 cell lines. This was accompanied by increased glutamine uptake and glutaminolysis, which was more pronounced in the endocrine-resistant LCC9 cells. We also observed differential expression of glutaminase 1 (GLS1) splice variants in the MCF-7 cells and an increase in the ASCT2 glutamine transporter. To determine combinatorial targeting potential, we co-treated cells with STM2457 and CB-839, which is a GLS1 inhibitor. CB-839 increased the potency of STM2457 only in the LCC9 and ZR-75-1-4-OHT endocrine-resistant cells. Our collective findings suggest that METTL3 inhibition leads to selective glycolytic and oxidative metabolic changes between these endocrine-sensitive and -resistant BC cells, which can be exploited for combinatorial therapy.

Current guidelines recommend total thyroidectomy for all T3b differentiated thyroid carcinoma (DTC) with gross strap muscle invasion, yet evidence supporting this universal approach remains limited and conflicting. We analyzed 6,920 T3b DTC patients from the SEER database (2004-2022) who underwent lobectomy (n = 282) or total thyroidectomy (n = 6,638). Overall survival (OS) served as the primary outcome. Random survival forest (RSF) with SHapley Additive exPlanations (SHAP) analysis identified interactions between surgical approach and clinical variables. Cox regression with restricted cubic splines examined age-dependent surgical effects on OS. Neither RSF nor Cox regression (HR 0.96, 95% CI: 0.68-1.37, P = 0.84) showed a significant OS difference between surgical approaches. SHAP interaction analysis revealed significant age-dependent heterogeneity. Restricted cubic splines identified age 45 as the threshold where the surgical benefit converged. In patients <45 years, total thyroidectomy demonstrated significantly superior survival outcomes compared with lobectomy (adjusted HR 3.26, 95% CI: 1.30-8.22, P = 0.012; 10-year survival 95.5 vs 98.4%). Conversely, no difference existed in patients ≥45 years (HR 0.85, 95% CI: 0.58-1.24, P = 0.40). The multiplicative interaction was 0.26 (95% CI: 0.10-0.70, P = 0.008), confirming a negative age-surgery interaction. Although this study demonstrates that surgical approach shows no significant survival difference in T3b DTC, the negative interaction effect between surgical approach and age indicates that the benefit of total thyroidectomy progressively diminishes with advancing age, providing a survival advantage only in patients younger than 45 years. These findings challenge universal total thyroidectomy recommendations and support age-stratified surgical decision-making for T3b DTC.

Abstract: Metastatic pheochromocytoma and paraganglioma (MPP) currently lack definitive curative therapies. The treatment of MPP presents a formidable challenge. Anlotinib hydrochloride, characterized as a multi-targeted tyrosine kinase receptor inhibitor, has demonstrated potential in this domain. This study, a phase 2 trial (NCT04860700), aimed to evaluate the efficacy and safety profiles of anlotinib hydrochloride in patients suffering from MPP. The primary objective was to determine the disease control rate (DCR) and objective response rate (ORR) as determined by the RECIST 1.1 criteria. Secondary objectives were to evaluate the biochemical response, progression-free survival (PFS), and safety. Twenty-nine patients with MPP were enrolled. We found that 24.1% (7/29) of patients discontinued the treatment after 1-2 cycles because of a significant increase in hormone levels or adverse events. Among 22 patients who could be evaluated by the RECIST 1.1 criteria, the overall DCR was 95.5% (21/22), and the ORR was 31.8% (7/22). The PFS was calculated to be 22.6 ± 3.2 months. There is no significant difference in ORR or PFS between patients with and without germline mutations. The most common adverse events included arterial hypertension (24/29, 82.8%), subclinical primary hypothyroidism (11/29, 37.9%), hyperlipidemia (10/29, 34.5%), rash (8/29, 27.6%), and fatigue (8/29, 27.6%). We conclude that among the evaluable patients, anlotinib showed promising efficacy with high DCR. Close monitoring remains essential because of treatment-related adverse events.

Abstract: The purpose of the study was to analyze the differences in the rate of intraoperative and postsurgical complications in patients with pheochromocytoma and sympathetic paraganglioma (PPGL) based on the use or non-use of preoperative beta-blockade. We performed a retrospective multicenter study of patients who underwent PPGL resection in 23 tertiary hospitals. Patients were classified in two groups according to presurgical treatment with beta-blockade or not. A total of 390 surgical resections of PPGLs were included: 226 in the group of beta-blockade and 164 in the group of no blockade. Beta-blockade was more frequently used in patients with higher fasting plasma glucose and plasma metanephrine levels, and treated with higher doses of phenoxybenzamine and doxazosin. The proportion of patients with proper presurgical blood pressure control was higher in patients pretreated with beta-blockade than non-pretreated (70.7 vs 59.1%, P = 0.027). However, the first group had a higher rate of intraoperative arrhythmia (9.3 vs 3.7%, P = 0.031). Nevertheless, when we adjusted for the daily doses of alpha-blockade, the differences disappeared (adjusted odds ratio (OR) 2.55 (0.83-7.89)). In multivariate analysis, the only variables independently associated with intraoperative arrhythmias were the use of phenoxybenzamine vs doxazosin (OR 8.18 (2.28-29.33)) and a lower preoperative heart rate (OR 0.95 (0.90-0.99)). As a conclusion, presurgical beta-blockade was more commonly used in patients with more active tumors. The higher rate of intraoperative arrhythmia in patients pretreated with beta-blockers seems to be related to the more frequent use of phenoxybenzamine in this group and not directly with the use of beta-blocker.

Significance statement: No previous studies have evaluated the impact of presurgical treatment with beta-blockers on patients with pheochromocytomas and sympathetic paragangliomas (PPGLs) receiving alpha-blockade on surgical outcomes, including intraoperative and postsurgical complications. Considering this context, we analyzed the differences in the rate of intraoperative and postsurgical complications in patients with PPGL based on the use or non-use of preoperative beta-blockade. We found that presurgical beta-blockade was more commonly used in patients with more clinically active tumors. The higher rate of intraoperative arrhythmia in patients pretreated with beta-blockers seems to be related to the more frequent use of phenoxybenzamine in this group and not directly with the use of beta-blocker.