Introduction: 225 Ac-PSMA-617, targeting the prostate-specific membrane antigen (PSMA) which is overexpressed on prostate cancer cells, has shown a remarkable therapeutic efficacy in heavily pre-treated metastatic castration-resistant prostate carcinoma patients. Here we report on treatment outcome and survival using this novel treatment modality in a series of 53 metastatic castration resistant prostate carcinoma patients directly following their androgen deprivation treatment.Patients and methods: 225 Ac-PSMA-617 was administered to 53 mCRPC patients directly following their androgen deprivation therapy. 68 Ga-PSMA PET/CT was obtained at baseline, before every treatment cycle and on follow-up for selection of patients for treatment, to determine the activity to be administered and for response assessment. Serial prostate specific antigen (PSA) was obtained for PSA response assessment. Results:The median age of the patient population under study was 63.4 yrs (range 45-83 years).A total number of 167 cycles were administered. The median number of cycles administered was 3 (range 1-7). Forty-eight patients (91%) had a PSA decline > 50%, and 51 patients (96%) had any decline in PSA . 68 Ga-PSMA-PET images became negative in 30 patients. In the multivariate analysis a PSA decline > 50 % proved predictive of both PFS and OS whereas platelet count also proved predictive for PFS. Median estimated OS for patients with a PSA decline < 50% was 9 months whereas the median OS of those patients with a PSA decline > 50% was not yet reached at the date of latest follow-up (55 months). Estimated median PFS for patients with a PSA decline > 50% was 22 months whereas that for patients with a PSA decline < 50% was 4 months. No severe of hematotoxicity was noted, whiles only 3 patients had grade III-IV nephrotoxicity. The commonest toxicity seen was grade I-II xerostomia observed in 81% of patients. Conclusion:In this series on 53 patients suffering from mCRPC, treatment with 225 Ac-PSMA-617 administered immediately following ADT, resulted in a > 50% decrease in PSA level in 91% of the patients. Furthermore, a PSA decline of greater than or equal to 50% proved the single most important factor predicting PFS and OS following 225 Ac-PSMA-617 treatment. Of interest, median OS of those patients with a PSA decline > 50% was not yet reached at the date of latest follow-up (55 months). These very favorable results obtained suggest a prospective randomized study comparing 225 Ac-PSMA-617 to current standard of care treatment options, e.g. enzalutamide, abiraterone acetate and docetaxel, post ADT is of major clinical relevance.

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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.