Epidemiology ObjectivesTo explore characteristics of urinary stone composition in China, and determine the effects of gender, age, body mass index (BMI), stone location, and geographical region on stone composition. Patients and methodsWe prospectively used Fourier-transform infrared spectroscopy to analyse stones from consecutive patients presenting with new-onset urolithiasis at 46 hospitals in seven geographical areas of China, between 1 June 2010 and 31 May 2015. Chi-squared tests and logistic regression analyses were used to determine associations between stone composition and gender, age, BMI, stone location, and geographical region. ResultsThe most common stone constituents were: calcium oxalate (CaOx; 65.9%), carbapatite (15.6%), urate (12.4%), struvite (2.7%), and brushite (1.7%). CaOx and urate stones occurred more frequently in males, whereas carbapatite and struvite were more common in females (P < 0.01). CaOx and carbapatite were more common in those aged 30-50 and 20-40 years than in other groups. Brushite and struvite were most common amongst those aged <20 and >70 years. The detection rate of urate increased with age, whilst cystine decreased with age. Obese patients were more likely to have urate stones than carbapatite or brushite stones (P < 0.01). CaOx, carbapatite, brushite, and cystine stones were more frequently found in the kidney than other types, whereas urate and struvite were more frequent in the bladder (P < 0.01). Stone composition varied by geographical region. ConclusionsThe most common stone composition was CaOx, followed by carbapatite, urate, struvite, and brushite. Stone composition differed significantly in patients grouped by gender, age, BMI, stone location, and geographical region.

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Purpose Activation of the phosphatidylinositol 3-kinase (PI3K) pathway occurs in over 40% of bladder urothelial cancers. The aim of this study is to determine the therapeutic potential, the underlying action and resistant mechanisms of drugs targeting the PI3K pathway. Experimental Design Urothelial cancer cell lines and patient-derived xenografts (PDXs) were analyzed for alterations of the PI3K pathway and for their sensitivity to the small molecule inhibitor pictilisib alone and in combination with cisplatin and/or gemcitabine. Potential predictive biomarkers for pictilisib were evaluated and RNA-sequencing was performed to explore drug resistance mechanisms. Results The bladder cancer cell line TCCSUP, which harbors a PIK3CA E545K mutation, was sensitive to pictilisib compared to cell lines with wild type PIK3CA. Pictilisib exhibited stronger anti-tumor activity in bladder cancer PDX models with PI3KCA H1047R mutation or amplification than control PDX model. Pictilisib synergized with cisplatin and/or gemcitabine in vitro, significantly delayed tumor growth and prolonged survival compared with single drug treatment in the PDX models. The phosphorylation of ribosomal protein S6 correlated with response to pictilisib both in vitro and in vivo, and could potentially serve as biomarker to predict response to pictilisib. Pictilisib activated the compensatory MEK/ERK pathways that likely contributed to pictilisib resistance, which was reversed by co-treatment with the RAF inhibitor sorafenib. RNA-sequencing of tumors resistant to treatment suggested that LSP1 down-regulation correlated with drug resistance. Conclusion These preclinical results provide new insights into the therapeutic potential of targeting the PI3K pathway for the treatment of bladder cancer.