Endocrine-related cancer最新文献

mTOR inhibitors such as everolimus and BEZ235 have demonstrated efficacy in pancreatic neuroendocrine tumors (PanNET) at the cost of severe side effects, and no biomarker currently predicts response. To identify molecular pathways of resistance, precision-cut slices of 17 fresh well-differentiated PanNET were cultured with everolimus or BEZ235 for 2 days and immunostained with cleaved caspase-3 and mTOR pathway markers. Transcriptomes of sensitive and resistant tumors were compared, and candidate pathways validated by immunohistochemistry. The predictive value of key proteins was then assessed in 26 PanNET patients treated with everolimus. mTOR inhibitors induced significant apoptosis and loss of pS6 and p4EBP1 in tumor slices, with 6/17 tumors considered sensitive. Transcriptomic analysis revealed that sensitive tumors displayed a mitochondrial-based metabolism, whereas resistant tumors exhibited a hypoxic and glycolytic profile, confirmed by high expression of CAIX, GLUT1, ATP5O, and mtTFA. Necrosis was absent and microvessel density similar in both groups, suggesting a pseudohypoxic metabolism in resistant tumors. High expression of CAIX and LDHA, two markers of pseudohypoxia/glycolysis, was associated with shorter progression-free survival in patients treated with everolimus. This study demonstrates that tissue culture can effectively assess drug response in PanNET and identifies a pseudohypoxic/glycolytic profile as a determinant of resistance to mTOR inhibition, detectable by immunohistochemistry and potentially noninvasively by 18F-FDG PET-CT.

Neuroendocrine neoplasms (NEN) are a rare and heterogeneous group of malignancies with rising incidence, requiring multidisciplinary and personalized management. Sex is emerging as a crucial factor in NEN development and progression. Genetic, epigenetic, and hormonal mechanisms have been proposed as potential contributors influencing treatment response and prognosis, but an in-depth analysis of the role of sex hormones and their receptors in NEN is still lacking. This review aims to analyze the impact of sex hormones and their receptors in sporadic NEN to provide potential therapeutic targets in the context of precision medicine. An overview of current preclinical and clinical evidence focused on different primary NEN, including gastroenteropancreatic, lung, prostate, and medullary thyroid cancers, focusing on estrogen, progesterone, and androgen receptors, has been made to clarify their role in NEN. Variable and conflicting results emerged across different primaries. Progesterone receptors appear to play a pivotal role in pancreatic and lung NEN, while estrogen receptors are more frequently involved in small intestine NEN and medullary thyroid carcinoma, suggesting a possible role in metastatic spread. Further studies are required to increase knowledge of the underlying mechanism of sex differences in NEN to define potential therapeutic targets for personalized care.

Age is a major risk factor for a range of diseases, including prostate cancer. Understanding how age influences the susceptibility of normal prostate epithelial cells to cancer initiation is complicated by the fact that aging affects all tissues in the body. Assessing how various aging mechanisms influence the prostate epithelium is a necessary step to determine the critical factors associated with aging that increase prostate cancer risk. Here, we take a broad view of both prostate epithelial cell-intrinsic and cell-extrinsic factors that change with age and are likely to contribute to age-related risk of prostate tumorigenesis. For each factor, we discuss the impact of these age-related changes on cancer risk. We highlight important areas where additional research is required to help decipher the specific age-associated changes that contribute to prostate cancer initiation. Finally, we address the potential impact of various therapeutic interventions on aging phenotypes and cancer risk.

Bone metastases (BMs) are a rare and late event in patients with neuroendocrine tumors (NETs). The aim of our study was to investigate the clinical presentation and outcome of BMs in a large cohort of patients with NETs. A retrospective study was performed at two referral centers of Northern Italy (IRCCS Humanitas Research Hospital in Milan and Santa Maria della Misericordia University Hospital in Udine). Three hundred fifty-two consecutive patients with either gastroenteropancreatic or non-gastroenteropancreatic NETs were included: 52 patients with synchronous or metachronous BMs (BM-positive) and 300 patients with metastatic disease without BMs (BM-negative). Patients with BMs showed a higher prevalence of smoking habit (41.2 vs 21.8%, P = 0.004) and carcinoid syndrome (28.8 vs 5.7%, P <0.001) compared to patients without BMs. In addition, higher levels of chromogranin A (P = 0.001), urinary 5-hydroxyindoleacetic acid (P <0.001), parathyroid hormone (P = 0.022), and alkaline phosphatase (P = 0.018) were found compared to the BM-negative group. Patients with BMs had more frequently a primary lung NET compared to the BM-negative group (19.2 vs 0.7%, P = 0.001) and grade G2 or G3 gastroenteropancreatic tumors (P <0.001) compared to the BM-negative group. During a median follow-up of 4.2 years, a higher mortality rate was registered in the BM-positive group as compared to BM-negative group (42.3 vs 4.0%, P = 0.001). BMs were more common in patients with lung NETs, G2-G3 grade tumors, and in those with carcinoid syndrome. BMs affected patients' prognosis, highlighting the importance of investigating and managing this condition in patients with NETs.

The addition of a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor to endocrine therapy augments biological response in breast cancer. This phase III randomized, double-blind study evaluated the efficacy of adding palbociclib to neoadjuvant endocrine therapy (NET) for operable, hormone receptor-positive human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Patients randomly received 16 weeks of endocrine therapy (letrozole for postmenopausal and tamoxifen plus ovarian function suppression for pre-/perimenopausal patients) plus palbociclib or placebo. The co-primary endpoints included preoperative endocrine prognostic index (PEPI) score and EndoPredict (EPclin) risk score according to the gatekeeping procedure. Of 141 randomized patients, 130 completed the treatment with surgical samples evaluable for endpoints in 126 patients. The proportion of patients with a low, moderate, and high PEPI score was 15.2, 50.0, and 34.8% in the palbociclib arm and 13.3, 55.0, and 31.7% in the placebo arm, respectively, with no statistical difference (one-sided P = 0.563). Statistical analysis was not performed on EPclin risk score. No new safety signals were reported. Permanent treatment discontinuation by adverse events was reported for seven (9.7%) and zero patients in the palbociclib and placebo arms, respectively. In conclusion, the addition of palbociclib to NET did not improve the efficacy. ClinicalTrials.gov NCT03969121.

Activation of signaling pathways that regulate survival, proliferation, motility, inflammation, metabolism, and stemness fuel tumor growth, metastasis, and recurrence. Therapies targeting signaling pathway components, including candidates such as GSK3 and TNFα, drastically affect cellular viability in preclinical cancer models but have limited success in the clinic. However, in recent years, spheroids and organoids have been demonstrated to more accurately reflect tumor characteristics and to be better predictors of therapeutic response than monolayer cultures. Here, we used 3D models from the pancreatic neuroendocrine tumor (pNET) model BON1 to evaluate the effect of GSK3 inhibition along with TNFα or insulin and extended our results in primary gastroenteropancreatic (GEP-)NET culture. The multidimensional configuration of BON1 spheroids imparted aggressive characteristics and a lack of anti-proliferative effects upon single treatments. However, GSK3 inhibition alone resulted in dispersion of spheroids, indicating that GSK3 is necessary for cell-cell adhesions and participates in spheroid architecture. Interestingly, GSK3 inhibition in combination with TNFα or insulin led to drastically reduced cell proliferation. In fresh patient-derived 2D primary cultures from (GEP-)NETs, we demonstrate that insulin has tumor-promoting effects, while GSK3 inhibition and metformin display significant anti-tumor activity mediated through common effects on GSK3/insulin signaling. Both agents show strong efficacy in a patient-derived insulinoma without affecting the corresponding normal pancreatic tissue. We conclude that treatment efficacy depends on three-dimensional architecture and that combinatorial treatments which target cellular dispersion in addition to cellular viability might have beneficial clinical applications, but metastatic potential of remaining single cells needs further characterization before clinical implementation.

The efficacy and tolerability of anlotinib in patients with progressive radioactive iodine refractory differentiated thyroid cancer (RAIR-DTC), especially those with prior VEGFR-targeted therapies, are not fully understood. This study reported the long-term outcomes of anlotinib-treated progressive RAIR-DTC patients and evaluated the prognostic value of 68Ga-NOTA-3PRGD2 and 18F-FDG PET/CT parameters. In this open-label, single-arm, single-center, prospective trial, 20 progressive RAIR-DTC patients were enrolled to receive anlotinib (orally once daily on days 1-14 every 3 weeks). The study endpoints included long-term efficacy and safety. The association between PET/CT parameters at baseline and 6-week assessments and progression-free survival (PFS) was also investigated. The median PFS was 22.5 (95% CI, 16.8-27.9) months, the estimated median overall survival was 38.4 (95% CI, 20.4-56.4) months, the overall response rate was 47.4% (95% CI, 24.4-71.1), the disease control rate was 89.5% (95% CI, 66.9-98.7), and the median time to response was 4.1 (range, 1.3-8.4) months. There were no significant differences in clinicopathological, efficacy, and safety markers between patients with prior VEGFR-targeted agents (treated group, n = 10) or those without (naïve group, n = 10) (P > 0.05). Higher baseline integrin-expressing tumor burden on 68Ga-NOTA-3PRGD2 PET/CT and glucose metabolic progression on 18F-FDG PET/CT 6 weeks after anlotinib treatment were both associated with shorter PFS. Anlotinib showed promise as an effective treatment option for both initial and salvage therapy in progressive RAIR-DTC patients. Integrin- and glucose metabolic-based PET/CT parameters showed predictive potential in anlotinib-treated patients and warrant further study.

The incidence of follicular thyroid carcinoma (FTC) and oncocytic carcinoma of the thyroid has seldom been studied. However, thyroid cancer incidence has experienced significant increases globally over recent decades. This study aims to investigate the incidence of FTC and oncocytic carcinoma of the thyroid in Australia with particular attention to the impact of changes in the World Health Organization (WHO) endocrine tumour classification. Using incidence data from the Australian Institute of Health and Welfare cancer registry (spanning 1982-2019), this descriptive epidemiological study employed joinpoint regression analysis to assess temporal trends in FTC and oncocytic carcinoma of the thyroid. Results were then compared with WHO endocrine tumour classification changes over the same period to identify potential impact(s). FTC and oncocytic carcinoma of the thyroid accounted for 9.4 and 3.2% respectively, of all thyroid carcinomas. Oncocytic carcinoma of the thyroid incidence steadily increased across the study period. Subtype analysis of FTC showed the incidence of widely invasive FTC initially increased significantly before declining and was found to affect older adults primarily. On the other hand, minimally invasive FTC incidence rose sharply for both sexes. Encapsulated angioinvasive FTC, a recently classified subtype, was found predominantly in younger age groups, particularly the 30-34 age bracket. Changes in the incidence of FTC and oncocytic thyroid carcinoma are noted to be influenced by classification updates. To conclude, there is a steady rise in Australian FTC and oncocytic carcinoma of the thyroid incidence, influenced to some degree by WHO classification changes.

Surgical resection is the primary treatment for lung neuroendocrine tumours (NET) but the optimal follow-up is unclear. This is a population-based analysis of 3,307 patients from England (NCRAS database; 2012-2021) and 6,937 patients from the United States (SEER database; 2003-2022) who underwent surgical resection for lung NET, which explores factors affecting post-surgical survival and optimal follow-up duration in these patients. Kaplan-Meier (KM) analysis estimated overall survival (OS). Cox proportional hazards models identified factors affecting survival. Patients were matched to national life tables (UK and US) by age, sex, and year of diagnosis to compare actual versus expected KM plots. In NCRAS, OS at 1, 3, 5, and 10 years was 99.6, 95.3, and 91.2% respectively, and in SEER 99.7, 95.5, and 91.8% respectively. In both England and the US, most patients presented with stage 1 disease. Multivariable Cox regression analyses showed that increasing age, advanced stage, socioeconomic deprivation, and atypical carcinoid morphology were associated with worse survival in both countries. In addition, in the US, male sex and pneumonectomy or wedge resection were also associated with worse survival. No overlap was observed between actual and expected KM plots in England, either overall or in subgroups of stage 1, typical morphology, or tumour <2 cm. In the US, an overlap was observed between actual and expected KM plots for the overall cohort at 240 months (20 years). This analysis of two large national cohorts provides information on the survival of lung NET after surgery, which can contribute to future guideline development on long-term follow-up.

Small intestinal neuroendocrine tumors are often diagnosed at an advanced stage, with up to 70% of patients presenting with stage IV disease. While some guidelines recommend prophylactic resection of the primary tumor and mesenteric lymph node metastasis in patients without abdominal symptoms at diagnosis to prevent future abdominal complications, the benefit of this approach remains uncertain. This retrospective cohort study included 44 asymptomatic patients with stage IV small intestinal neuroendocrine tumors treated at Uppsala University Hospital between 2014 and 2019. Additional ten symptomatic patients who underwent at least two computed tomography scans before planned surgery were included in the analysis of mesenteric metastasis volume change and tumor growth rate. The primary outcomes were abdominal symptoms development requiring surgical intervention and the assessment of mesenteric metastasis size progression. During a 10-year follow-up, only four initially asymptomatic patients (9%) developed symptoms leading to surgery. Among all 54 patients, the median volume change in mesenteric metastases was -298 mm3 (IQR: -2,785-1,294), with no significant difference between baseline and most recent scans (P = 0.38). The median interval between scans was 29 months, and the median tumor growth rate was -0.6% per month (IQR: -3.6-1.9%). Similar results were observed in the asymptomatic group. These findings suggest that a non-operative management in stage IV patients without abdominal symptoms is associated with a low incidence of symptom development and limited progression of mesenteric metastases.