Endocrine-related cancer最新文献

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.

We reviewed the clinical characteristics of male patients with MEN2B associated medullary thyroid cancer (MTC) with prostate lesions and analyzed available imaging and pathology data.Patients were enrolled on a National Cancer Institute (NCI) natural history protocol (NCT01660984) and a University of Texas (UT) MD Anderson Cancer Center study (DR09-0507).Thirty-six male patients (median age of MEN2B diagnosis 12.0 years, range 1.3-25.6) with the RET p.Met918Thr germline mutation were identified.Pelvic imaging was available for 28/36 (78%) patients. Prostate lesions and/or calcifications were noted in eight patients (28.6%). Lesions were identified at a median age of 20.5 years (range 13-30.5 years). Biopsies in three patients with prostate neoplasms were histologically indistinguishable from primary MTC. Two of these patients did not have other sites of distant disease at the time of prostate biopsy. Prostate lesions in males with MEN2B and MTC are more frequent than previously described. Lesions were identified in patients as young as 14 years and often contained calcifications. The prostate is a more common site of disease in patients with MEN2B than previously appreciated and may represent a distant site of metastatic MTC metastasis or a second primary calcitonin-secreting neuroendocrine tumor. Imaging of the prostate should be considered in post-pubertal MEN2B males, especially in case of unexplained increase in calcitonin or onset of urinary tract symptoms.

Radiotherapy is a mainstay treatment for localized prostate cancer (PCa). Yet, radiation resistance remains a major clinical obstacle. Here, radiation induced a BMP/CD105-dependent metabolic shift in the tumor microenvironment that facilitates PCa cell survival. Using prostate tumor models and fibroblast cultures, we show that radiation enhances epithelial BMP ligand production, which promotes fibroblastic CD105 signaling. Metabolomic analysis upon radiation revealed that fibroblastic CD105 signaling elevated key enzymes involved in mitochondrial biogenesis (PGC1α) and ketogenesis (HMGCS2). The increased production of β-hydroxybutyrate in the tumor microenvironment sustained PCa cell energy metabolism and enhanced DNA repair upon radiation stress. Blocking BMP signaling through carotuximab (ENV105), a CD105-targeting antibody, disrupted epithelial-fibroblast crosstalk, resulting in decreased β-hydroxybutyrate within the tumor microenvironment. This attenuation of fibroblast-mediated metabolic support increased DNA damage and apoptosis, sensitizing PCa cells to radiation. In subcutaneous mouse models, grafting PCa cells with CD105-KO or HMGCS2-KO fibroblasts yielded smaller tumors following radiation compared with wild-type fibroblast controls. Across subcutaneous and orthotopic models, combined treatment with carotuximab and irradiation reproducibly achieved superior tumor volume reduction relative to single-agent therapy. This study identified the BMP/CD105 axis as a key pathway in radiation resistance, highlighting the potential of targeting fibroblastic CD105 with carotuximab to enhance radiation sensitivity.

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.