Endocrine-related cancer最新文献

Neuroendocrine neoplasms (NENs) originate mainly in the digestive system and lungs and are classified as neuroendocrine carcinomas (NECs) or neuroendocrine tumors (NETs). Breast metastases from NENs are rare, accounting for only 1% of breast neoplasms, but may be more frequent than expected. This study aimed to characterize patients with breast metastatic NENs through a literature review. A systematic review was conducted using PubMed, Embase, LILACS, and OpenGrey databases through July 2024. Eligible studies included case reports, case series, or cross-sectional studies documenting at least one breast metastatic NEN case confirmed by histopathology or imaging. Eighty-one articles with 138 cases were included. The mean age was 52.9 (SD 12.18) years, and three patients were male. NETs were more common than NECs (82.6 vs 14.5%), and the small intestine was the primary site in 45.3% of cases, followed by the lung (26.6%). Breast lesions were the first clinical manifestation in 24.8% of cases. Carcinoid syndrome symptoms occurred in 21.4% of patients. Ultrasonography revealed hypoechoic lesions with irregular margins, and mammography showed poorly defined margins. Chemotherapy was used in 57.4% of patients, typically with etoposide and platinum, and somatostatin analogs were administered to 36.2% of patients. Surgical resection of the primary tumor occurred in 74.6% of cases, and metastasis resection occurred in 73.5%. This review highlights the importance of accurate diagnosis, as a significant number of cases were initially misdiagnosed as primary breast tumors. Proper diagnostic evaluation can improve patient outcomes.

Follicular thyroid carcinoma (FTC) and oncocytic thyroid carcinoma (OTC) are distinct entities with differing biological behaviors, yet optimal surgical and radioactive iodine (RAI) therapy management remains debated. Demographic, clinicopathological, and treatment characteristics were gathered from the Surveillance, Epidemiology, and End Results (SEER) database and compared between FTC and OTC according to tumor size. The Kaplan-Meier method and log-rank test were used to analyze cancer-specific survival (CSS). The effect of potential predictors associated with survival was estimated using the Cox regression model. 13,653 patients were included in our study. OTC patients were older and presented higher rates of extrathyroidal extension (ETE) and lymph node metastases (LNM), while FTC had higher distant metastasis (DM) rates. Increasing tumor size was correlated with worse features in both subtypes. Total thyroidectomy (TT) had no CSS benefit over less than TT (LTT) for FTC ≤2 cm or any OTC size group. TT was paradoxically associated with worse CSS for FTC >2 cm. RAI therapy did not improve CSS for patients with ETE (FTC or OTC) or DM (OTC). Multivariable analysis confirmed that TT was independently associated with worse CSS in FTC but not in OTC, while RAI therapy was beneficial in FTC but not in OTC. FTC and OTC exhibited distinct clinical behaviors. In conclusion, TT did not improve CSS for small FTC (≤2 cm) or any OTC, and appeared to be associated with worse outcomes in larger FTC. RAI therapy provided limited benefit in OTC, especially with DM. Treatment should be individualized, avoiding routine aggressive surgery or RAI.

Primary cilia have emerged as key regulators in cancer biology, influencing tumor progression and therapeutic response through diverse signaling pathways. In this study, we identify WDR60, a component of the dynein-2 complex essential for retrograde intraflagellar transport, as a novel modulator of pancreatic neuroendocrine tumor (Pa-NET) behavior. Transcriptomic analysis of the GEO dataset GSE73338 revealed that WDR60 is significantly upregulated in both primary and metastatic Pa-NETs compared to normal pancreatic islets. Moreover, WDR60 expression is higher in G2 compared to G1 Pa-NETs. Functional analyses in QGP-1 cells following WDR60 silencing demonstrated broad transcriptional reprogramming with enrichment of pathways related to cell adhesion and extracellular matrix (ECM) remodeling. Notably, WDR60 knockdown reduced cell migration and enhanced adhesion without affecting cell viability or proliferation. Among the key upregulated genes were PIK3AP1, RAP1B, and RFLNA, suggesting that WDR60 is involved in regulating PI3K/AKT signaling and cytoskeletal dynamics. To explore potential therapeutic implications, we examined the effects of Ciliobrevin A (HPI-04), an inhibitor of Hedgehog signaling and ciliogenesis. HPI-04 significantly reduced WDR60 expression, impaired cell migration, and increased adhesion. RT-qPCR confirmed overlapping gene expression changes between HPI-04 treatment and WDR60 silencing, although some differences, such as CD164 regulation, suggest WDR60-independent mechanisms. Collectively, these findings identify WDR60 as a critical regulator of cell motility and adhesion in Pa-NETs via ciliary signaling and cytoskeletal remodeling. They also support the therapeutic potential of targeting cilia-associated pathways, including WDR60 and Hedgehog signaling, in the treatment of Pa-NETs.

The thyroid differentiation score (TDS), calculated on the expression levels of 16 thyroid function genes, was reported to be lower in BRAF-like than in RAS-like papillary thyroid cancers, but scanty data are available in either other malignant histotypes or in benign thyroid nodules. The aims of the present study were to investigate the clinical relevance of the TDS in a large series of thyroid neoplasms, and its possible role in the differential diagnosis of cytologically indeterminate nodules. The TDS was calculated in 126 differentiated, 20 undifferentiated, 9 non-invasive follicular thyroid neoplasms with papillary-like nuclear features, and 44 benign neoplasms. Overall, TDS significantly and progressively decreased from benign to differentiated and undifferentiated tumors (P < 0.0001). A lower TDS was found in differentiated tumors with higher stage (P = 0.006) and American Thyroid Association (ATA) risk (P = 0.03), radio-iodine resistance (P = 0.008), and disease persistence (P = 0.009). Moreover, TDS independently correlated with progression-free survival, after adjusting for age at diagnosis and ATA risk (P = 0.02). In Bethesda III and IV nodules, the TDS was significantly lower in nodules found to be malignant at histology compared to benign neoplasms (P = 0.004). The combination of TDS with genetic test showed a sensitivity of 78.4%, a specificity of 77.3%, a PPV of 80%, and a NPV of 75.6% (P = 0.001). In conclusion, we found a lower TDS in malignant compared to benign thyroid neoplasms, and demonstrated the prognostic role of TDS in differentiated tumors. These findings could preoperatively improve both the differential diagnosis of cytologically indeterminate nodules and the selection of the best surgical approach.

The burgeoning metabolic benefits of GLP1 receptor (GLP1R) agonists have led to their widespread use for treatment of type 2 diabetes mellitus and obesity. While the pharmacological GLP1R agonist semaglutide primarily activates GLP1R signaling in the pancreas, GLP1R is also expressed in advanced prostate cancer where GLP1R agonism could directly alter cellular signaling. Because metabolic disorders and their treatment are common among those with prostate cancer, understanding the effects of semaglutide in prostate cells is critical for deciphering its systemic effects and delineating potential impacts on prostate cancer outcomes. In prostate cancer models, semaglutide decreased cell proliferation, glycolytic function, and phosphokinase-mediated signaling. This overall suppression of signaling downstream of GLP1R is consistent with inhibitory GPCR signaling, which was confirmed by reduced cAMP levels. Furthermore, cell proliferation was decreased with semaglutide alone and in combination with enzalutamide, supporting that GLP1R agonism may provide therapeutic benefit as a standalone treatment or to augment the therapeutic benefits of androgen receptor signaling inhibitors. Interestingly, in a trans-differentiation model (n = 55), GLP1R and AR expression were negatively correlated, while GLP1R and NEPC markers (DLL3, ASCL1) were positively correlated, suggesting an association between GLP1R and neuroendocrine differentiation. Bioinformatic analyses on publicly available patient RNA sequencing data (n = 664) identified significantly higher GLP1R expression in advanced prostate cancer vs benign prostate, where it was associated with negative Notch signaling. Taken together, our data support a model wherein GLP1R agonism blocks oncogenic signaling pathways and growth of prostate cancer cells, which could be exploited therapeutically for men with advanced prostate cancer.

Neuroendocrine neoplasms (NENs) are rare tumors with increasing incidence. Data on the prognosis of NEN patients in the real-world setting are limited. We aim to explore survival predictors and the impact of novel treatments in a cohort of patients with NENs from various primary sites. This was a retrospective study of subjects diagnosed with gastroenteropancreatic (GEP) or thoracic NENs and referred to a single institution over more than a decade (2010-2023). The primary objective was to describe the overall survival (OS) and progression-free survival (PFS) of patients with advanced-stage disease undergoing first, second, and third-line therapy. The secondary objectives were to identify predictors of OS and PFS. We included 239 NEN patients. Systemic antineoplastic therapies were administered to 149 subjects (62.3%). In patients treated only with first-line therapy, the OS rate was 75 and 74% at 12 and 18 months, respectively. We observed significant univariable associations between Ki-67 index, primary tumor site, morphology, clinical stage, and OS. The multivariable analysis confirmed a significant association between Ki-67 index, clinical stage, and OS. In patients undergoing second-line therapy, the OS rate was 72 and 61% at 12 and 18 months, respectively, and the Ki-67 index was again associated with OS in the multivariable analysis. GEP NEN patients who received 177Lu-Dotatate showed a numerically higher OS rate at 24 months compared to those who did not receive radioligand therapy. In this real-world study of patients with NENs, we confirmed Ki-67 as a strong prognostic parameter and suggested that 177Lu-Dotatate has the potential to prolong OS.

Paragangliomas (PGLs) are rare neuroendocrine tumors that arise from the paraganglionic tissues and are associated with the autonomic nervous system. Although traditionally classified conjointly, head and neck PGLs (HNPGLs) and PGLs located outside the head and neck (PGLOs) exhibit distinct embryological origins, genetic predispositions, functional profiles, clinical behavior, and therapeutic strategies. HNPGLs are typically nonfunctional and arise from parasympathetic tissues, whereas PGLOs often originate from sympathetic tissues, are frequently functional, and secrete catecholamines. Recent advances in molecular genetics, particularly those involving SDHx mutations, have revealed genotype-phenotype correlations that further differentiate these tumor groups. Despite overlapping histopathological features, the natural history, risk of malignancy, and surveillance strategies differ substantially. Although surgical resection remains the mainstay of treatment for both HNPGLs and PGLOs, the indications, risks, and outcomes vary according to tumor location and genetic context. This review aims to provide a comprehensive clinical comparison between HNPGLs and PGLOs, outlining their unique anatomical, genetic, and clinical characteristics. We emphasize the importance of site-specific management strategies that consider both functional status and prognosis. Based on these distinctions, we propose a revised diagnostic and therapeutic framework that surpasses a uniform classification and emphasizes precision medicine for the management of PGLs. This approach could reduce treatment-related morbidity, optimize long-term outcomes, and guide genetic counseling and surveillance in affected individuals and their families.

Adrenocortical carcinoma (ACC) is a rare and highly aggressive carcinoma with a poor prognosis. The aim of our study is to summarize existing evidence on the potential usefulness of fluorine-18-fluorodeoxyglucose positron/computed tomography (18F-FDG PET/CT) in the management of patients affected with ACC. The current systematic review was registered to the PROSPERO registry (ID1103377). A comprehensive search of the PubMed/MEDLINE, Embase, and Cochrane Library databases was conducted until July 2025. A total of 19 studies that evaluated the role of 18F-FDG PET/CT in ACC were included. One of the fields investigated was the ability of PET/CT to discriminate between adrenal masses, particularly in the differential diagnosis between benign and malignant lesions. 18F-FDG PET/CT demonstrated good sensitivity and specificity but was affected by different cutoff values of SUV and SUV ratio applied. In addition, in the staging/restaging, despite heterogeneity of data, diagnostic performances were good and higher than conventional imaging tools. Moreover, PET/CT modified patient management in 9-21% of cases. The prognostic role of 18F-FDG PET/CT remains controversial, with seven studies reporting heterogeneous findings and different endpoints investigated, primarily OS and PFS. Semiquantitative parameters such as SUVmax and SUV ratio were analyzed, but their prognostic impact was inconsistent. Despite several limitations affecting this analysis, especially related to the heterogeneity of the studies included, 18F-FDG PET/CT seems to be a useful tool for the evaluation of ACC, especially in the differential diagnosis of adrenal masses and in the staging/restaging. Instead, the prognostic impact of PET/CT and its features remains inconclusive.

The CUT/Hox transcription factor ONECUT2 (OC2) promotes lineage plasticity and is a confirmed therapeutic target in prostate cancer and several other malignancies where cell phenotype plays a substantial role in treatment resistance. OC2 governs a broad growth and lineage identity process in prostate cancer that promotes neuroendocrine (NE) differentiation, androgen receptor (AR) suppression, and the emergence of a wide range of treatment-resistant pathways. The mode of action of OC2 includes incorporation of the protein into transcription complexes at gene promoters as an activator and repressor, alteration of chromatin accessibility and epigenetic marks, and extensive alteration of large-scale chromatin modifications, such as super-enhancers and chromatin loops. Notably, OC2 may be unique among NE drivers in that it can promote AR indifference in adenocarcinoma as a direct upstream activator of the glucocorticoid receptor, thus assuming indirect control of a portion of the AR cistrome. OC2 expression and activity increase substantially following hormone therapy in association with aggressive disease in prostate and breast cancer. Experiments in model systems have shown that OC2 has a survival function in both human castration-sensitive and castration-resistant prostate cancer cells. OC2 can be targeted directly with a family of novel small-molecule inhibitors that show therapeutic efficacy in vivo in prostate, breast, and gastric cancer models, including regression of established distant metastases in mice. These findings suggest that inhibition of OC2 clinically may confer substantial therapeutic benefit in some aggressive malignancies, including in localized hormone-sensitive disease.

Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment but can induce immune-related adverse events, most commonly hypothyroidism. The reversibility of ICI-induced hypothyroidism and the potential for discontinuing levothyroxine (LT4) treatment remain unclear. This retrospective study analyzed patients who developed hypothyroidism due to ICI treatment and were prescribed LT4 at a tertiary referral hospital from January 2016 to March 2024. Among 3,753 patients treated with ICIs, 254 (6.8%) developed hypothyroidism requiring LT4 treatment. Of the 184 patients who discontinued ICI, only 10 (5.4%) discontinued LT4 during a median follow-up of 13.2 months, while none did among those continuing ICIs. Multivariable Cox regression analysis revealed that the use of ICIs in early-stage cancer (HR 13.40, 95% CI: 1.99-90.06, P = 0.008) and TSH <20 μIU/mL before starting LT4 (HR 15.16, 95% CI: 2.17-105.85, P = 0.006) significantly increased the likelihood of discontinuing LT4. These findings suggest that while recovery from ICI-induced hypothyroidism is uncommon, patients treated for early-stage cancer and those with lower TSH levels before starting LT4 may have a greater likelihood of recovery.