Ex vivo Vitamin D supplementation improves viscoelastic profiles in prostate cancer patients.

BACKGROUND: Increased risk of thromboembolic events is associated with prostate cancer, specifically linked to activation of tissue factor. Vitamin D has potential anticoagulant effects by the downregulation of tissue factor expression. OBJECTIVES: To evaluate the effects on clot formation, the morphological and viscoelastic profiles of prostate cancer patients, before and after ex vivo supplementation of Vitamin D was studied. METHODS: Participants were recruited into a metastatic, non-metastatic and reference group. Whole blood samples were treated ex vivo with a dose of 0.5µg/kg Calcitriol. Clot kinetics were assessed using Thromboelastography®. Morphology of the blood components were studied using scanning electron microscopy (SEM). RESULTS: Results from the Thromboelastography® and SEM indicated no major differences between the non-metastatic group before and after treatment compared to the reference group. The Thromboelastography® showed that the metastatic group had an increased viscoelastic profile relating to a hypercoagulable state. Visible changes with regards to platelet activation and fibrin morphology were demonstrated with SEM analysis of the metastatic group. The viscoelastic and morphological properties for the non-metastatic group after treatment improved to be comparable to the reference group. CONCLUSION: Vitamin D supplementation may lead to a more favorable viscoelastic profile, with less dangerous clots forming.

mCRPC Patients Receiving 225Ac-PSMA-617 Therapy in the Post-Androgen Deprivation Therapy Setting: Response to Treatment and Survival Analysis.

225Ac-PSMA-617, targeting the prostate-specific membrane antigen (PSMA), which is overexpressed on prostate cancer cells, has shown a remarkable therapeutic efficacy in heavily pretreated patients with metastatic castration-resistant prostate carcinoma (mCRPC). Here, we report on treatment outcome and survival using this novel treatment modality in a series of 53 patients with mCRPC directly after their androgen deprivation treatment (ADT). Methods: 225Ac-PSMA-617 was administered to 53 such patients. 68Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle, and on follow-up to select patients for treatment, determine the activity to be administered, and assess their response. Serial prostate-specific antigen (PSA) measurements were obtained for response assessment. Results: The median age of the patients was 63.4 y (range, 45-83 y). In total, 167 cycles were administered (median, 3; range, 1-7). Forty-eight patients (91%) had a PSA decline of at least 50%, and 51 patients (96%) had any decline in PSA. 68Ga-PSMA PET findings became negative in 30 patients. In the multivariate analysis, a PSA decline of at least 50% proved predictive of both progression-free survival (PFS) and overall survival (OS), and platelet count also proved predictive for PFS. The median estimated OS was 9 mo for patients with a PSA decline of less than 50% but was not yet reached at the latest follow-up (55 mo) for patients with a PSA decline of 50% or more. The estimated median PFS was 22 mo for patients with a PSA decline of at least 50% and 4 mo for patients with a PSA decline of less than 50%. No severe hematotoxicity was noted, and only 3 patients had grade III-IV nephrotoxicity. The commonest toxicity seen was grade I-II xerostomia, observed in 81% of patients. Conclusion: In 91% of 53 patients with mCRPC, treatment with 225Ac-PSMA-617 immediately after ADT resulted in at least a 50% decrease in PSA level. Furthermore, a PSA decline of at least 50% proved the single most important factor predicting PFS and OS after 225Ac-PSMA-617 treatment. Of interest, median OS in patients with a PSA decline of at least 50% was not yet reached at the latest follow-up (55 mo). These favorable results suggest that it would be of major clinical relevance to perform a prospective randomized study comparing 225Ac-PSMA-617 with current standard-of-care treatment options such as enzalutamide, abiraterone acetate, and docetaxel after ADT.

Role of Precision Oncology in Type II Endometrial and Prostate Cancers in the African Population: Global Cancer Genomics Disparities.

Precision oncology can be defined as molecular profiling of tumors to identify targetable alterations. Emerging research reports the high mortality rates associated with type II endometrial cancer in black women and with prostate cancer in men of African ancestry. The lack of adequate genetic reference information from the African genome is one of the major obstacles in exploring the benefits of precision oncology in the African context. Whilst external factors such as the geography, environment, health-care access and socio-economic status may contribute greatly towards the disparities observed in type II endometrial and prostate cancers in black populations compared to Caucasians, the contribution of African ancestry to the contribution of genetics to the etiology of these cancers cannot be ignored. Non-coding RNAs (ncRNAs) continue to emerge as important regulators of gene expression and the key molecular pathways involved in tumorigenesis. Particular attention is focused on activated/repressed genes and associated pathways, while the redundant pathways (pathways that have the same outcome or activate the same downstream effectors) are often ignored. However, comprehensive evidence to understand the relationship between type II endometrial cancer, prostate cancer and African ancestry remains poorly understood. The sub-Saharan African (SSA) region has both the highest incidence and mortality of both type II endometrial and prostate cancers. Understanding how the entire transcriptomic landscape of these two reproductive cancers is regulated by ncRNAs in an African cohort may help elucidate the relationship between race and pathological disparities of these two diseases. This review focuses on global disparities in medicine, PCa and ECa. The role of precision oncology in PCa and ECa in the African population will also be discussed.

Prostate cancer racial, socioeconomic, geographic disparities: targeting the genomic landscape and splicing events in search for diagnostic, prognostic and therapeutic targets.

Prostate cancer (PCa) is one of the leading causes of deaths in men globally. This is a heterogeneous and complex disease that urgently warrants further insight into its pathology. Developed countries have thus far the highest PCa incidence rates, with comparatively low mortality rates. Even though PCa in the Asian population seems to have high incidence and mortality rates, the African countries are emerging as the focal center for this disease. It has also been reported that the Sub-Saharan (SSA) countries have both the highest incidence and mortality rates. To date, few studies have reported the link between PCa and African populations. Adequate evidence is still missing to fully comprehend this relationship. While it has been brought to attention that racial, geographical and socioeconomic status are contributing factors, men of African descent across the globe, irrespective of their geographical position have higher PCa incidence and mortality rates compared to their white counterparts. To date, hormone therapy is the mainstay treatment of PCa, while the dysregulation of androgen receptor (AR) signaling is a hallmark of PCa. One of the emerging problems with this therapeutic approach is resistance to antiandrogens, and that AR splice isoforms implicated in the progression of PCa lack the therapeutic ligand-binding domain (LBD) target. AR splice variants targeted therapy is emerging and in clinical trials. Leveraging PCa transcriptomics is key towards PCa precision medicine. The aim of this review is to outline the PCa epidemiology globally and in Africa, PCa associated risk factors, discuss AR signaling and PCa mechanisms, the role of dysregulated splicing in PCa as novel prognostic indicators and therapeutic targets.

Many Voices in a Choir: Tumor-Induced Neurogenesis and Neuronal Driven Alternative Splicing Sound Like Suspects in Tumor Growth and Dissemination.

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.