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Evaluation of pharmacodynamic (PD) markers in vivo.

Supplemental Table S1. IC50 values for Nultin-3a, Carboplatin, and 1:1 Combination; Supplemental Material and Methods; Supplemental Figure Legends

Supplementary Figure Legend

Gene list for Fig.5B, C, D

Acquired and intrinsic resistance to receptor tyrosine kinase inhibitors (RTKi) represents a major hurdle in improving the management of clear cell renal cell carcinoma (ccRCC). Recent reports suggest that drug resistance is driven by tumor adaptation via epigenetic mechanisms that activate alternative survival pathways. The histone methyl transferase EZH2 is frequently altered in many cancers, including ccRCC. To evaluate its role in ccRCC resistance to RTKi, we established and characterized a spontaneously metastatic, patient-derived xenograft model that is intrinsically resistant to the RTKi sunitinib, but not to the VEGF therapeutic antibody bevacizumab. Sunitinib maintained its antiangiogenic and antimetastatic activity but lost its direct antitumor effects due to kinome reprogramming, which resulted in suppression of proapoptotic and cell-cycle–regulatory target genes. Modulating EZH2 expression or activity suppressed phosphorylation of certain RTKs, restoring the antitumor effects of sunitinib in models of acquired or intrinsically resistant ccRCC. Overall, our results highlight EZH2 as a rational target for therapeutic intervention in sunitinib-resistant ccRCC as well as a predictive marker for RTKi response in this disease. Cancer Res; 77(23); 6651–66. ©2017 AACR.

Supplemental data on additional models to support the role of EZH2 in RTKi resistance

Resumen Introduccion y objetivo El carcinoma primario de uretra (CPU) es una enfermedad neoplasica poco frecuente que surge en la uretra, sin evidencia de carcinoma previo o sincronico en todo el tracto urinario. Dado que las enfermedades raras suelen diagnosticarse y tratarse de forma incorrecta, el objetivo de este estudio fue analizar la experiencia de un unico centro urologico en el tratamiento del CPU, centrandose en las neoplasias que surgen de la uretra anterior masculina. Materiales y metodos Se revisaron retrospectivamente las historias clinicas de los pacientes con neoplasias a nivel de la uretra peneana y bulbar que se presentaron en nuestro centro terciario de referencia entre enero de 1988 y diciembre de 2018. Se excluyeron los pacientes con carcinoma de la uretra prostatica. El diagnostico se obtuvo con la ayuda de una uretroscopia y biopsia de la lesion. El estadio patologico local se evaluo mediante resonancia magnetica nuclear (RMN) con contraste en pacientes seleccionados. El estadiaje se evaluo mediante examen clinico, ecografia y tomografia computarizada (TC). La cirugia radical (cistectomia radical + penectomia total + linfadenectomia inguinal bilateral) se propuso a los pacientes con tumores ≥ T2 o cN + con un buen estado funcional, tumor proximal y sin comorbilidades graves. En caso de afectacion ganglionar, se ofrecio adicionalmente quimioterapia neoadyuvante. Los pacientes con enfermedad localizada ( Resultados Se estudiaron retrospectivamente un total de 13 pacientes varones con CPU anterior. Se realizo penectomia total en siete casos, mientras que cinco casos recibieron uretrectomia parcial y un caso, penectomia parcial. De los siete pacientes que se sometieron a una penectomia total, cinco recibieron cistectomia radical junto con linfadenectomia inguinal bilateral. Tres pacientes fueron tratados con quimioterapia sistemica neoadyuvante, de los cuales dos eran cT3N + y 1 era cT3N0. El subtipo histologico predominante fue el carcinoma de celulas escamosas (CCE), encontrado en siete pacientes (53,8%), mientras que el carcinoma urotelial (CU) estaba presente en cinco pacientes (38,5%) y un fibrohistiocitoma maligno en un caso. La mayoria de los pacientes fueron diagnosticados en estadios avanzados de la enfermedad, con tumores T2 en el 15,4% y T3 en el 46,2%. La mediana de seguimiento fue de 24 meses (rango 1-294). Despues del tratamiento quirurgico, ocho pacientes (61,5%) presentaron recidiva de la enfermedad en una mediana de 6,3 meses, con una SLR a cinco anos del 58 ± 14%. La tasa de SG a cinco anos fue del 50 ± 14%, mientras que la tasa de SCE a cinco anos fue del 66 ± 13%. Conclusion Dada su poca frecuencia, el carcinoma uretral debe ser tratado en un centro de referencia. Las opciones de tratamiento incluyen enfoque radical o cirugia de preservacion del pene (uretrectomia o penectomia parcial) en casos de enfermedad localizada. Debido a la alta tasa de recurrencia, el seguimiento estricto es imprescindible.

Background: Kidney autotransplantation is a useful technique to be reserved for cases in which kidney function is compromised by a complex anatomical configuration, such as long ureteral strictures and renal vascular anomalies not suitable for in situ reconstruction. Robot-assisted kidney autotransplantation (RAKAT) presents a novel, minimally invasive, and highly accurate approach. Objective: The aim of this study is to present the largest cohort of patients who underwent either extracorporeal (eRAKAT) or intracorporeal (iRAKAT) RAKAT, to confirm safety and feasibility and to compare the two approaches. Design, setting, and participants: We retrospectively analyzed prospectively followed patients undergoing eRAKAT and totally intracorporeal RAKAT in a total of three institutions. Surgical procedure: Extracorporeal RAKAT and iRAKAT. Measurements: Surgical and functional outcomes of patients subjected to eRAKAT and iRAKAT were measured. Results and limitations: Between January 2017 and February 2021, 29 patients underwent RAKAT: 15 eRAKAT and 14 iRAKAT. No statistical difference in the preoperative data was recorded. The analysis of intraoperative variables showed a statistically significant difference between eRAKAT and iRAKAT in cold ischemia time (median [interquartile range {IQR}]: 151 [125-199] vs 27.5 [20-55]; p < 0.001) and total ischemia time (median [IQR]: 196.2 [182-241] vs 81.5 [73-88]; p < 0.001). However, faster renal function recovery in favor of eRAKAT was observed during the first 90 d, with comparable renal function at 1 yr. The 90-d Clavien-Dindo >2 complications were 13.8%. It is important to stress that RAKAT, and above all iRAKAT, should be performed by surgeons with experience in robotic renal, vascular, and transplant surgery. Conclusions: Both eRAKAT and iRAKAT represent promising minimally invasive techniques in selected cases with acceptable ischemia time and comparable longterm operative outcomes. Patient summary: In selected patients, both extra-and intracorporeal robot-assisted kidney autotransplantation represent valid alternatives in case of long ureteral strictures and renal vascular anomalies not suitable for in situ reconstruction. (c) 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.

Trichomonas vaginalis (TV) is one of the most common sexually transmitted infections (STIs). Overall prevalence is reported to be 3.1%, with rates approaching 12.9-14.4% in high-risk female populations. Although there is a plethora of data on TV in the female population, the corresponding data for the male population are limited.Our aim was to determine the infection rate of TV in male patients seeking care for STIs in the emergency department (ED) and determine the symptoms associated with TV infection in male patients.We conducted a retrospective study of male patients aged 13 years or older who presented to the ED for STI evaluation. Male patients included had nucleic acid amplification test (NAAT) TV testing as part of standard STI evaluation.Of the 2137 male patients included, 95 (4.4%) were positive for TV. Male patients who tested positive were significantly older (mean age 38.9 years vs. 30.7 years for male patients who tested negative; p0.05). Black male patients were more likely than White male patients to be positive for TV (6.3% prevalence vs. 1.8%; p0.05). TV-positive male patients were more likely to have discharge, specifically clear penile discharge, on examination (p0.05), and were less likely to have testicular pain or testicular tenderness (p0.05). Higher rates of TV were seen in an urban (4.9%) compared with suburban ED (1.6%; p0.05).Rates of TV in male patients who receive STI testing in the ED are similar to rates published previously for female patients. We found higher rates among older and African-American male patients. TV among male patients is prevalent and testing should continue when evaluating for STIs.