Radiation resistance in a subset of prostate tumors remains a challenge to prostate cancer radiotherapy. The current study on the effects of radiation on prostate cancer cells reveals that radiation programs an unpredicted resistance mechanism by upregulating acid ceramidase (AC). Irradiated cells demonstrated limited changes of ceramide levels while elevating levels of sphingosine and sphingosine-1-phosphate. By genetically downregulating AC with small interfering RNA (siRNA), we observed radiosensitization of cells using clonogenic and cytotoxicity assays. Conversely, AC overexpression further decreased sensitivity to radiation. We also observed that radiation-induced AC upregulation was sufficient to create cross-resistance to chemotherapy as demonstrated by decreased sensitivity to Taxol and C(6) ceramide compared to controls. Lower levels of caspase 3/7 activity were detected in cells pretreated with radiation, also indicating increased resistance. Finally, utilization of the small molecule AC inhibitor, LCL385, sensitized PPC-1 cells to radiation and significantly decreased tumor xenograft growth. These data suggest a new mechanism of cancer cell resistance to radiation, through upregulation of AC that is, in part, mediated by application of the therapy itself. An improved understanding of radiotherapy and the application of combination therapy achieved in this study offer new opportunities for the modulation of radiation effects in the treatment of cancer.

Objective To assess the ef®cacy and safety of the retrograde ureteropyeloscopic holmium laser for treating renal stones that are too large to treat with extracorporeal shock wave lithotripsy (ESWL). Patients and methods Thirty patients (22 men and eight women, mean age 43 years, range 18±62) with a renal stone burden of >2 cm were selected for laser treatment. The stones were in the renal pelvis in 16 patients, lower calyx in ®ve, middle calyx in two, upper calyx in one and multiple pelvic and calyceal in six. Lithotripsy was undertaken using a holmium laser through 550 mm and 200 mm laser ®bres passed through a semi-rigid ®bre-optic long ureteroscope or the actively de¯ectable¯exible ureteropyeloscope, respectively. Success was de®ned as total fragmentation of the stone to <2 mm in diameter and/or clear imaging on renal ultrasonography and plain ®lms within the 3-month follow-up. Patients in whom the treatment failed received either alternative therapy or complementary ESWL.Results Endoscopic access and complete stone fragmentation was achieved in 23 of the 30 patients (77%). The treatment failed in seven patients because of poor visualization, the initial presence of stones in, or migration of their large fragments to, an inaccessible calyx. There were no major intraoperative complications. Minor complications after treatment included haematuria that persisted for 2 days in one patient and high-grade fever in two patients; all were treated conservatively. Conclusion Large renal calculi that are not amenable to ESWL monotherapy can be safely and effectively treated with a retrograde endoscopic technique that seems to compete well with the more invasive percutaneous or open surgical manoeuvres.

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Complete primary repair with penile disassembly provides a good approach to achieve this purpose without the need for bladder neck reconstruction in some cases. Selection of the proper surgical technique together with adjunctive procedures such as osteotomy and a pain-free early postoperative period can maximize the chance of successful exstrophy repair.

Most children will void efficiently with no straining and no post-void residual (1/2) to 4 years after tubularized incised plate hypospadias repair. Of our patients 68.7% have normal peak flow rate. Intermediate followup of larger series and followup at puberty are recommended to resolve the debate concerning the long-term functional outcome of tubularized incised plate hypospadias repair.