E17K substitution in AKT1 in prostate cancer

Background:The phosphatidylinositol 3-kinase (PI3K)-AKT pathway is activated in many cancers. Mutational hotspots in AKT1 and in the regulatory and catalytic subunits of PI3K have been detected in multiple tumour types. In AKT1, the E17K substitution leads to a PI3K-independent activation of AKT1.Methods:A mutational profiling of AKT1 and of the mutational hotspots in PIK3CA and PIK3R1 was carried out in samples from primary and recurrent prostate tumours.Results:We show that, in prostate cancer, AKT1(E17K) had a prevalence of 1.4%. The mutation seemed to be associated with a favourable clinical course but it was not associated with a specific tumour growth pattern. Activating mutations in PIK3CA or PIK3R1 were not found in prostate cancer.Conclusion:The E17K substitution in AKT1 is rare in prostate cancer. It seems associated with a favourable clinical outcome but not with a specific histology of the tumo

Prostate cancer in BRCA2 germline mutation carriers is associated with poorer prognosis

BACKGROUND: The germline BRCA2 mutation is associated with increased prostate cancer (PrCa) risk. We have assessed survival in young PrCa cases with a germline mutation in BRCA2 and investigated loss of heterozygosity at BRCA2 in their tumours. METHODS: Two cohorts were compared: one was a group with young-onset PrCa, tested for germline BRCA2 mutations (6 of 263 cases had a germline BRAC2 mutation), and the second was a validation set consisting of a clinical set from Manchester of known BRCA2 mutuation carriers (15 cases) with PrCa. Survival data were compared with a control series of patients in a single clinic as determined by Kaplan-Meier estimates. Loss of heterozygosity was tested for in the DNA of tumour tissue of the young-onset group by typing four microsatellite markers that flanked the BRCA2 gene, followed by sequencing. RESULTS: Median survival of all PrCa cases with a germline BRCA2 mutation was shorter at 4.8 years than was survival in controls at 8.5 years (P = 0.002). Loss of heterozygosity was found in the majority of tumours of BRCA2 mutation carriers. Multivariate analysis confirmed that the poorer survival of PrCa in BRCA2 mutation carriers is associated with the germline BRCA2 mutation per se. CONCLUSION: BRCA2 germline mutation is an independent prognostic factor for survival in PrCa. Such patients should not be managed with active surveillance as they have more aggressive disease. British Journal of Cancer (2010) 103, 918-924. doi:10.1038/sj.bjc.6605822 www.bjcancer.com Published online 24 August 2010 (C) 2010 Cancer Research U

Pediatric urolithiasis: the current surgical management

Children represent about 1% of all patients with urolithiasis, but 100% of these children are considered high risk for recurrent stone formation, and it is crucial for them to receive a therapy that will render them stone free. In addition, a metabolic workup is necessary to ensure a tailored metaphylaxis to prevent or delay recurrence. The appropriate therapy depends on localization, size, and composition of the calculus, as well as on the anatomy of the urinary tract. In specialized centers, the whole range of extracorporeal shock-wave lithotripsy (ESWL), ureterorenoscopy (URS), and percutaneous nephrolithotomy (PCNL) are available for children, with the same efficiency and safety as in adults

Using the neoadjuvant chemotherapy paradigm to develop precision therapy for muscle-invasive bladder cancer

Background: bladder cancer is a leading cause of morbidity and mortality. Despite recent advances in understanding its molecular biology, the 5-year survival for muscle-invasive disease (muscle-invasive bladder cancer [MIBC]) remains approximately 50%. Although neoadjuvant chemotherapy (NAC) offers an established 5% absolute survival benefit at 5 years, only the 40% of patients with a major tumor response appear to benefit. There remains, therefore, a critical unmet need for predictive markers to determine which patients are best managed with NAC, as well as for novel targeted therapies to overcome resistance to NAC. Methods: the NAC paradigm offers the optimal clinical context for developing precision therapy for MIBC. Abundant tissue is available for analysis before NAC in all patients and after NAC in patients with residual MIBC. Technologic advances have enabled next-generation sequencing and gene expression microarray analysis of routinely collected and even archived tissue specimens. These technologies provide a foundation for the identification of markers of chemoresistance and for the development of rational cotargeting strategies. Results: modern computational methods allow for some measure of target validation, which can be enhanced by the use of patient-derived primary xenografts (PDX). These PDX can be established at the time of radical cystectomy after NAC if there is residual MIBC. By the time a patient recurs clinically, candidate drugs targeting specific molecular changes in the patient tumor and corresponding PDX would have been tested in the PDX model, and only the most efficacious drug(s) would be administered to the patient. Liquid biopsies in the form of circulating tumor DNA and circulating tumor cells allow noninvasive longitudinal monitoring of the molecular landscape of an advanced tumor as it is being treated with successive courses of systemic therapy. Conclusions: these tools combined form the foundation of an evidence-based precision oncology strategy for MIBC.</p

Recommendations for follow-up of muscle-invasive bladder cancer patients: A consensus by the international bladder cancer network

Several guidelines exist that address treatment of patients with nonmetastatic muscle-invasive bladder cancer (MIBC). However, most only briefly mention follow-up strategies for patients and hence the treating physician is often left to infer on what the preferred follow-up schema would be for an individual patient. Herein, we aim to synthesize recommendations for follow-up of patients with MIBC for easy reference.A multidisciplinary MIBC expert panel from the International Bladder Cancer Network was assembled to critically assess currently available major guidelines on surveillance of MIBC patients. Recommendations for follow-up were extracted and critically evaluated. Important considerations for guideline assessment included both aspects of oncological and functional follow-up-frequency of visits, the use of different imaging modalities, the role of cytology and molecular markers, and the duration of follow-up.An International Bladder Cancer Network expert consensus recommendation was constructed for the follow-up of patients with MIBC based on the currently available evidence-based data