Endocrine-related cancer最新文献

Differentiated thyroid carcinoma (DTC) in children and adolescents is a rare but increasingly recognised entity with distinct biological behaviour, clinical presentation, and outcomes compared to adult DTC. While paediatric cases often present with advanced disease, long-term survival is excellent in contrast to adult cases where prognosis declines with age and risk factors. Historically, paediatric management was extrapolated from adult data, but recent guidelines reflect a shift towards age-specific, risk-adapted care. A narrative review was conducted using PubMed (2000-2025), including clinical trials, cohort studies, reviews, and guidelines. We aimed to compare paediatric and adult DTC across epidemiology, clinical presentation, molecular characteristics, treatment strategies, outcomes, and existing guidelines, with the aim of identifying knowledge gaps for future harmonisation. We found that paediatric DTC is characterised by higher rates of multifocal and metastatic disease at diagnosis, distinct molecular drivers (e.g. RET/NTRK fusions), and higher radioiodine avidity. Surgical management is typically more extensive in children, while risk-adapted radioactive iodine therapy is increasingly practised in low-risk paediatric patients. TSH suppression is initially more aggressive, followed by gradual de-escalation. Despite higher recurrence rates in children, survival exceeds 95-98% even with distant metastases. While paediatric-specific guidelines have advanced (ATA 2015, ETA 2022), prospective paediatric data remain limited. We conclude that paediatric DTC is biologically distinct from its adult counterpart and requires tailored management. Coordinated, prospective research is needed to address current evidence gaps and support future harmonised European practice.

Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PTMC; T1aN0M0) in adults was initiated in 1993 at Kuma Hospital (Kobe, Japan) and in 1995 at the Cancer Institute Hospital (Tokyo, Japan). Since then, numerous studies from various countries have reported favorable outcomes for patients managed with AS. Notably, no cases of thyroid carcinoma-related death have been reported among patients who have undergone AS. Young age has been identified as a predictor of high tumor growth activity; however, previous studies have shown that young adult patients may still be suitable candidates for AS. Although surgery for PTMC is not technically complex, it carries risks, even when performed by experienced thyroid surgeons, including permanent recurrent laryngeal nerve paralysis and hypoparathyroidism. No significant difference in prognosis has been observed between patients managed with AS and those who undergo immediate surgery (IS). Some patients initially on AS later opt for conversion surgery (CS) for various reasons. Importantly, the postoperative prognosis and incidence of unfavorable events in patients undergoing CS do not differ significantly from those in patients undergoing IS. However, the overall incidence of unfavorable events has been reported to be higher among patients who initially chose IS than among those who began with AS. Patients managed with AS have demonstrated better physical quality of life (QOL) than those who underwent IS. Although findings on mental QOL have been inconsistent, this may depend on the attitudes and approach of the attending clinicians. Presently, AS is considered an excellent initial management strategy for patients with PTMC.

Prostate cancer (PC) remains a leading cause of cancer-related mortality in men, with recurrence contributing significantly to poor outcomes. Its molecular heterogeneity complicates effective risk stratification. We evaluated Sig27, a novel 27-gene panel, across 13 bulk RNA-seq datasets (n = 3,133 tumors) and 6 single-cell RNA-seq (scRNA-seq) datasets (n = 53 patients). Sig27 expression was elevated in PC compared to normal tissue and further increased in high-grade Gleason tumors, node-positive, and recurrent tumors. Sig27 demonstrated recurrence prediction comparable to Oncotype DX, with strong enrichment in immune regulatory pathways. To further investigate immune associations, we developed SigIC, a 22-gene immune checkpoint panel. Sig27 showed strong correlations with SigIC and individual immune checkpoints (e.g., HAVCR2, CD96, TIGIT) in both primary and metastatic PC. In scRNA-seq data, Sig27 was enriched in tumor-associated monocytes/macrophages (TAMs) and endothelial cells. We identified five key Sig27 genes - TFEC, FPR3, NOD2, LAMP3, and MCTP1 - and constructed Sig27IMG, a multigene panel formed by these five genes, and demonstrated their robust correlations with immune checkpoints and their strong enrichment in TAMs and endothelial cells. Sig27IMG strongly predicted PC recurrence and was dominantly expressed in TAMs, dendritic cells, and endothelial cells across 26 cancer types (n = 386 patients) in scRNA-seq studies and 17 cancer types (n = 5,672 patients) in bulk RNA-seq investigations. Notably, Sig27IMG stratified patients with a poor prognosis risk in these 17 cancer types. In summary, Sig27 and its derivative panel, Sig27IMG, offer a robust assessment of PC recurrence, highlighting immunosuppressive features mediated by TAMs, dendritic cells, and endothelial cells across multiple cancer types.

Malignant pleural effusion (MPE) from differentiated thyroid cancer (DTC) is rare and carries a poor prognosis. This study evaluated clinical outcomes and the impact of multikinase inhibitor (MKI) therapy in patients with MPE from DTC. In this retrospective cohort study of 184 DTC patients with lung metastases, 31 (17%) had MPE. After excluding 10 with non-malignant effusion, 174 were analyzed. Patients with MPE were older (P < 0.001) at DTC diagnosis, had higher T stage (P = 0.004), developed pleural metastases earlier (P = 0.016), and had more frequent macro- and polymetastatic lung lesions (P < 0.001) than those without MPE. All MPE cases were radioactive iodine-refractory and developed a median of 6.3 years after DTC diagnosis. Symptomatic MPE occurred in 22 patients (71%), all requiring drainage, while 9 (29%) had asymptomatic MPE. Symptomatic MPE was associated with worse overall survival (OS) compared to patients without MPE (adjusted hazard ratio (HR) 4.62, 95% confidence interval (CI) 2.49-8.57, P < 0.001). Notably, patients initiating MKI therapy for symptomatic MPE had the worst OS (adjusted HR 9.78, 95% CI: 3.52-27.13, P < 0.001). Median OS after MPE diagnosis was 13 months. Symptomatic MPE also had worse post-MPE survival compared to asymptomatic MPE (adjusted HR 5.73, 95% CI: 1.52-21.52, P = 0.009). MKI therapy did not significantly improve OS or progression-free survival after MPE onset. MPE in DTC patients with lung metastases indicates poor prognosis, especially when symptomatic. MKI therapy showed limited survival benefits after MPE onset. Early identification and proactive management of patients at high risk of MPE may improve outcomes.

DCC protein functions as a tumor suppressor and is altered in various tumors, including neuroendocrine neoplasms. Netrin (NTN)-1 serves as the primary ligand for DCC. Acting as a dependence receptor, DCC induces apoptosis in the absence of NTN and promotes cell survival when NTN is present. In certain cancers, such as small-cell lung cancer and neuroblastoma, the upregulation of NTN-3 has been observed instead of NTN-1. However, the exact role of NTNs and DCC in PNEN remains unclear. We assessed DCC and netrin expression in pancreatic neuroendocrine neoplasm (PNEN) cells (BON-1). We examined the effect of netrin on cell viability using DCC knockdown and NP137, a netrin-inhibiting antibody. In vivo, PNEN cells were injected into nude mice and treated with NP137 or PBS. Tumor RNA sequencing was performed. A population-based analysis using TCGA data evaluated the impact of DCC and NTN3 expression on survival. BON-1 cells exhibited elevated expression of DCC and NTN-3. The addition of NTN-1 augmented BON-1 viability, a response that was lessened upon NTN blockade using NP137. Furthermore, DCC siRNA negated the effect of NTN-1 on cell viability. Mice bearing PNEN BON-1 xenografts treated with NP137 exhibited markedly diminished xenograft growth. RNA sequencing revealed upregulation of small nucleolar RNAs (SNORs) in NP137-treated tumors, with enriched pathways related to RNA processing. TCGA analysis showed a negative correlation between NTN3 expression and survival. In conclusion, our data suggest that NTN-3, NTN-1, and DCC have interdependent oncogenic roles in PNENs, which can be reversed by blocking NTN binding to DCC.

Acromegaly, primarily caused by GH-secreting pituitary neuroendocrine tumors (GH-PitNETs), in about half of cases exhibits resistance to somatostatin receptor ligands (SRLs), making surgery the primary treatment. Recent evidence suggests that glucose-dependent insulinotropic polypeptide receptor (GIPR) overexpression in a subset of GH-PitNETs contributes to disease heterogeneity, particularly in tumors showing a paradoxical GH rise after glucose load, which are associated with a less aggressive phenotype and better first-generation SRLs response. This study investigated the functional role of GIPR in somatotroph cells by generating stable human GIPR-expressing GH3 cells (GH3hGIPR) and comparing them with empty vector controls. Functional assays demonstrated that GIPR activation induces cAMP/PKA and MAPK/ERK signaling, enhances GH and prolactin secretion, and increases intracellular calcium oscillations, dependent on extracellular calcium influx. Transcriptomic analysis revealed differential gene expression patterns linked to cell motility, neuronal development, and extracellular matrix remodeling in GH3hGIPR cells, aligning with clinical observations in GIPR+ tumors. However, GIPR overexpression did not alter cell proliferation or viability, suggesting that its role in tumor behavior may depend on additional molecular or epigenetic factors. These findings highlight the importance of GIPR signaling in somatotroph cell function and its potential influence on therapeutic responses, though further studies are needed to clarify its contribution to tumorigenesis and SRL sensitivity.

The kinase inhibitors lenvatinib and sorafenib represent the first-line options for radioiodine-refractory differentiated thyroid cancer (RR-DTC). Comparative studies in the same study population or between similar cohorts are scarce. Our objective was to compare lenvatinib and sorafenib in naïve RR-DTC in a homogeneous real-life context. We performed a retrospective study involving two institutions from the Italian region Campania. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Secondary endpoints were objective response rate (ORR), disease-control rate, adverse events graded ≥3, toxicity-related treatment withdrawal, and dose reductions/interruptions. Forty-eight RR-DTC patients were included (median follow-up 45.5 months): 24 received lenvatinib from 2015 to 2021 and 24 sorafenib from 2012 to 2016. The sorafenib group showed a higher disease-related symptoms rate (P = 0.022), tumor burden (P = 0.002), and cumulative radioiodine dose compared to lenvatinib. At univariate analysis, median PFS and OS were significantly longer for lenvatinib (30 and 53 months, respectively) compared to sorafenib (10 and 38 months, respectively) (P < 0.001 and = 0.037, respectively). At multivariate analysis, the significance was retained for PFS and lost for OS. ORR was higher for lenvatinib compared to sorafenib (P < 0.001). Dose reductions and interruptions were more frequent for lenvatinib compared to sorafenib (P = 0.003 and 0.01, respectively). In our real-life context, RR-DTC treated with first-line sorafenib had more advanced disease compared to lenvatinib. Lenvatinib exerted stronger antitumor activity (improved PFS and ORR) compared to sorafenib but did not improve OS. Sorafenib was more manageable.

SDHB, one of the four genes encoding the subunits of the Krebs cycle enzyme succinate dehydrogenase (SDH), acts as a tumor suppressor in several human cancers, including pheochromocytomas/paragangliomas. Mutations in SDHB lead to a reduction or complete loss of enzymatic activity, linking SDHB to paraganglioma malignancy. Given the difficulty in curing metastatic paragangliomas and the limited value of surgery, new treatments are needed. Glutamine dehydrogenase 1 (GDH1), a key regulator of glutathione metabolism, and poly (ADP-ribose) polymerase (PARP), essential for repairing single- or double-stranded DNA breaks, are crucial in cancer initiation and progression. We treated the human pheochromocytoma cell line (hPheo1) with knocked-down SDHB using radiation, the GDH inhibitor 'R162', and the PARP inhibitor 'olaparib'. Combining R162 with radiation enhances anticancer effectiveness, reduces cell proliferation, and causes G2/M phase arrest in the wild-type and KD-SDHB hPheo1 cell line. KD-SDHB hPheo1 cells treated with olaparib alone were more resistant than wild-type cells but were more sensitive in combination with radiation, activated repair mechanisms, and halted cell cycle progression at the G2/M phase. These results suggest that enhancing radiation-induced DNA damage could be a potential treatment strategy for metastatic pheochromocytomas/paragangliomas. Inhibiting GDH1 and PARP activities, with radiation, may represent promising strategies for the treatment of SDHB-deficient pheochromocytoma/paraganglioma; however, their effects do not appear to be specific to SDHB-deficient cells and require further validation.

Thyroid cancer (TC) and breast cancer (BC) are common in females, with growing evidence of their higher-than-expected co-occurrence. The purpose of this systematic review and meta-analysis was to evaluate the relationship between TC and BC and to examine the likelihood of developing BC after TC (TC1-BC2) and TC after BC (BC1-TC2). A systematic search was conducted in PubMed and Embase for articles with epidemiological evidence of TC and BC, published until 2024. For BC1-TC2 studies, subgroup analysis was performed on age at diagnosis and treatment type. The standardized incidence ratio (SIR) was used to calculate the risk of second primary malignancy. The MOOSE guidelines were followed, and the Newcastle-Ottawa scale was used to assess the quality of studies. Sixteen studies comprising 511,787 patients were included in the meta-analysis of TC1-BC2 and showed an increased risk of BC after TC (SIR = 1.4, 95% CI: 1.2-1.6, P < 0.01). Moreover, 28 studies with 2,486,870 patients were included for the BC1-TC2 meta-analysis and also demonstrated an increased risk of TC after BC (SIR = 1.5, 95% CI: 1.3-1.7, P < 0.01). The risk of TC was higher in BC patients under 50 (SIR = 1.8, 95% CI: 1.2-2.3) and in those treated with chemotherapy (SIR = 1.6, 95% CI: 1.5-1.7). Radiotherapy for BC was not linked to an increased risk of TC. Here, we demonstrated an increased risk of TC or BC as secondary malignancies. Furthermore, studies are needed to better understand this association and its implications for patient follow-up and management strategies.