Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy

Background: Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS. Methods: TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV). Results: We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20–42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p < 0.01). In the chemotherapy group cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 × 10−3 vs. 4.04 × 10−3; p = 0.03). Conclusion: Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with “accelerated vascular aging” and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management. Clinical trial registration: The clinical trial registration number is NCT02572934

Cognitive Impairment in Long-Term Survivors of Testicular Cancer More Than 20 Years after Treatment

SIMPLE SUMMARY: Impaired cognition can be a late effect after treatment in long-term testicular cancer survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very-long-term survivors after treatment. In this study, we enrolled testicular cancer survivors with a follow-up duration ≥ 20 years—and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular damage and aging parameters. We included 184 testicular cancer survivors (66 chemotherapy patients, 53 radiotherapy patients, and 65 orchiectomy only patients) and 70 healthy controls. The median follow-up was 26 years. Testicular cancer survivors performed worse on cognitive tests compared to controls. In univariate analysis, the presence of hypogonadism was associated with lower cognitive scores. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment. ABSTRACT: Background: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls. Methods: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)—with a follow-up duration ≥ 20 years—and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs). Results: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20–42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score −0.85; 95% CI −1.39 to −0.33) compared to controls (mean 0.67; 95% CI −0.21 to 1.57, p < 0.01). In univariate analysis, the presence of hypogonadism (β −1.50, p < 0.01), high c-PWV (β −0.35, p = 0.09), and high AGEs (β −1.27, p = 0.02) were associated with lower cognitive scores, while only AGEs (β −1.17, p = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, p < 0.01). Conclusions: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment. Trial Registration: NCT02572934

CD146 increases stemness and aggressiveness in glioblastoma and activates YAP signaling

Glioblastoma (GBM), a highly malignant and lethal brain tumor, is characterized by diffuse invasion into the brain and chemo-radiotherapy resistance resulting in poor prognosis. In this study, we examined the involvement of the cell adhesion molecule CD146/MCAM in regulating GBM aggressiveness. Analyses of GBM transcript expression databases revealed correlations of elevated CD146 levels with higher glioma grades, IDH-wildtype and unmethylated MGMT phenotypes, poor response to chemo-radiotherapy and worse overall survival. In a panel of GBM stem cells (GSCs) variable expression levels of CD146 were detected, which strongly increased upon adherent growth. CD146 was linked with mesenchymal transition since expression increased in TGF-ss-treated U-87MG cells. Ectopic overexpression of CD146/GFP in GG16 cells enhanced the mesenchymal phenotype and resulted in increased cell invasion. Conversely, GSC23-CD146 knockouts had decreased mesenchymal marker expression and reduced cell invasion in transwell and GBM-cortical assembloid assays. Moreover, using GSC23 xenografted zebrafish, we found that CD146 depletion resulted in more compact delineated tumor formation and reduced tumor cell dissemination. Stem cell marker expression and neurosphere formation assays showed that CD146 increased the stem cell potential of GSCs. Furthermore, CD146 mediated radioresistance by stimulating cell survival signaling through suppression of p53 expression and activation of NF-kappa B. Interestingly, CD146 was also identified as an inducer of the oncogenic Yes-associated protein (YAP). In conclusion, CD146 carries out various pro-tumorigenic roles in GBM involving its cell surface receptor function, which include the stimulation of mesenchymal and invasive properties, stemness, and radiotherapy resistance, thus providing an interesting target for therapy