No abstract

The neuroendocrine (NE) cell is a minor cell population in normal human prostate glands. The number of NE cells is increased in advanced hormone-refractory prostate carcinomas (PCA). The mechanism of increased NE cell population in these advanced tumors is poorly understood. We examined molecular mechanisms which may be involved in the regulation of the transdifferentiation process of human PCA cells leading to a NE phenotype. We compared PCA cell lines LNCaP and PC-3 in the following medium conditions: steroid-reduced (SR), interleukin-6 (IL-6)-supplemented, or dibutyrate cAMP (db-cAMP)-supplemented. We found that androgen-responsive C-33 LNCaP cells responded to all treatments, having a neuronal-like morphology. In contrast, C-81 LNCaP cells, having a decreased androgen responsiveness, had a less pronounced effect although followed a similar trend. Androgen-unresponsive PC-3 cells showed little change in their morphology. Grown in the SR condition, the level of neuron-specific enolase (NSE), a marker of neuronal cells, was upregulated in C-33 LNCaP cells, while to a lesser degree in the presence of IL-6. In the presence of db-cAMP, the NSE level in C-33 cells was decreased, lower than that in control cells. An opposite effect was observed for C-81 LNCaP cells. Nevertheless, the NSE level was only elevated in db-cAMP-treated PC-3 cells, but no change was found in PC-3 cells grown in the SR- or IL-6-supplemented medium. Thus, a similar gross phenotypic change may correlate with differential molecular expressions. We also analyzed the expression of protein tyrosine phosphatase alpha (RPTPalpha) since it plays a critical role in normal neuronal differentiation and signaling. Our results showed that the expression of RPTPalpha correlates with the NE phenotypic change of LNCaP cells in the SR condition. In summary, our data clearly show that the molecular process by which cultured human prostate cancer cells undergo a transdifferentiation process to a NE cell-like phenotype is accompanied by differential expressions of different markers, and a gross NE cell-like phenotype can occur by exposing PCA cells to different pharmacological agents.

Word count: 250/250Purpose: To evaluate long-term safety and durability of response to UGN-101, a mitomycincontaining reverse thermal gel, as primary chemoablative treatment for low-grade upper tract urothelial carcinoma (UTUC). Materials and Methods:In this open-label, single-arm, multi-center, phase 3 trial (NCT02793128), patients ≥18 years of age with primary or recurrent biopsy-proven low-grade UTUC received 6 once-weekly instillations of UGN-101 via retrograde catheter to the renal pelvis and calyces. Those with complete response (defined as negative ureteroscopic evaluation, negative cytology, and negative for-cause biopsy) 4-6 weeks after the last instillation were eligible for up to 11 monthly maintenance instillations and were followed for ≥12 months with quarterly evaluation of response durability. Durability of complete response was determined by ureteroscopic evaluation; duration of response was estimated by the Kaplan-Meier method.Treatment-emergent adverse events (TEAEs) were monitored. Results:Of 71 patients who initiated treatment, 41 (58%) had complete response to induction therapy and consented to long-term follow up; 23/41 patients (56%) remained in complete response after 12 months (95% CI: 40, 72), comprising 6/12 (50%) who did not receive any maintenance instillations and 17/29 (59%) who received ≥1 maintenance instillation. Kaplan-Meier analysis of durability was estimated as 82% (95% CI: 66, 91) at 12 months. Ureteric stenosis was the most frequently reported TEAE (31/71, 44%); an increasing number of instillations appeared to be associated with increased incidence of urinary TEAEs.

Primary chemoablation of low-grade intermediate-risk non-muscle-invasive bladder cancer using UGN-102, a mitomycin-containing reverse thermal gel (OPTIMA II): a phase 2b, open-label, single-arm trial,

Transplant-related aneurysms are an unusual complication following pancreas transplantation. We present a case of a pseudoaneurysm developing in a recipient 6 months after bladder-drained pancreas transplantation. The pseudoaneurysm was incidentally found during ultrasonographic evaluation in preparation for a pancreas biopsy. Angiography demonstrated that the origin of the pseudoaneurysm was located near the base of the Y-graft/iliac artery anastomosis. Surgical repair was performed using standard vascular techniques. The patient subsequently recovered without loss of graft exocrine or endocrine function. Review of the literature revealed that aneurysms of various types associated with pancreas transplantation have a high incidence of graft loss and contribute significantly to patient morbidity. However, with prompt diagnostic and surgical management, non-infected pseudoaneurysms can be repaired without loss of pancreatic function.