Multiregion human bladder cancer sequencing reveals tumour evolution, bladder cancer phenotypes and implications for targeted therapy.

We present an evolutionary analysis of the relative time of genetic events underlying tumorigenesis in human bladder cancers from 10 whole cystectomy specimens using multiregional whole-exome sequencing. We timed bladder cancer drivers, mutational signatures, ploidy and copy number alterations, provided evidence for kataegis and correlated alterations with tumour areas and histological phenotypes. We found that: (1) heterogeneous tumour areas/phenotypes had distinct driver mutations, (2) papillary-invasive tumours divided early into two parallel evolving branches and (3) parallel evolution of subclonal driver mutations occurred. APOBEC mutational signatures were found to be very early events, active in carcinoma in situ, and often remained a dominant source of mutations throughout tumour evolution. Genetic progression from carcinoma in situ followed driver mutations in NA13/FAT1, ZBTB7B or EP300/USP28/KMT2D. Our results point towards a more diverse mutational trajectory of bladder tumorigenesis and underpin the importance of timing of mutational processes and clonal architecture in bladder cancer as important aspects for successful prognostication and therapy. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Role of Focal Therapy with High-Intensity Focused Ultrasound in the Management of Clinically Localized Prostate Cancer.

Overtreatment of prostate cancer (PC) remains one of the main burdens in uro-oncology. Focal therapy may be a reasonable alternative with less side effects and morbidity. Application of high-intensity focused ultrasound (HIFU) induces immediate and irreversible coagulation. The treatment leads to consecutive necrosis with sharply delineated margins, making HIFU a promising tool for the focal therapy of localized PC. Unlike radiation, the treatment leaves no collateral damage outside of the heated tissue, allowing repeated use of HIFU, if necessary. In case of non-organ-confined relapse, additional radical salvage therapy can be performed. This review gives an overview of the existing evidence on focal HIFU. Today, 3 HIFU devices are approved for the treatment of localized PC: Sonablate™, Ablatherm™ and the FocalOne™ device. In summary, the first published results of focal HIFU are promising. The quality of life and potency of the patients are well preserved. Therefore, HIFU treatment, and especially focal ablation of tumor foci, seems to be a safe alternative to standard treatment, with low side effects. The oncologic results seem satisfactory but need further follow-up to validate this practice of PC control.