Hospitalization Burden of Patients with Kidney Stones and Metabolic Comorbidities in Spain during the Period 2017-2020.

Nephrolithiasis has become an increasing worldwide problem during the last decades. Metabolic syndrome, its components, and related dietary factors have been pointed out as responsible for the increasing incidence. The objective of this study was to evaluate the trends in the hospitalization rates of patients with nephrolithiasis, hospitalization features, costs, and how metabolic syndrome traits influence both the prevalence and complications of lithiasic patients. An observational retrospective study was conducted by analyzing hospitalization records from the minimum basic data set, including all patient hospitalizations in Spain in which nephrolithiasis has been coded as a main diagnosis or as a comorbidity during the period 2017-2020. A total of 106,407 patients were hospitalized and coded for kidney or ureteral lithiasis in this period. The mean age of the patients was 58.28 years (CI95%: 58.18-58.38); 56.8% were male, and the median length of stay was 5.23 days (CI95%: 5.06-5.39). In 56,884 (53.5%) patients, kidney or ureteral lithiasis were coded as the main diagnosis; the rest of the patients were coded mostly as direct complications of kidney or ureteral stones, such as "non-pecified renal colic", "acute pyelonephritis", or "tract urinary infection". The hospitalization rate was 56.7 (CI95%: 56.3-57.01) patients per 100,000 inhabitants, showing neither a significant increasing nor decreasing trend, although it was influenced by the COVID-19 pandemic. The mortality rate was 1.6% (CI95%: 1.5-1.7), which was higher, if lithiasis was coded as a comorbidity (3.4% CI95%: 3.2-3.6). Metabolic syndrome diagnosis component codes increased the association with kidney lithiasis when age was higher, reaching the highest in the eighth decade of life. Age, diabetes, and hypertension or lithiasis coded as a comorbidity were the most common causes associated with the mortality of lithiasic patients. In Spain, the hospitalization rate of kidney lithiasis has remained stable during the period of study. The mortality rate in lithiasic patients is higher in elderly patients, being associated with urinary tract infections. Comorbidity conditions such as diabetes mellitus and hypertension are mortality predictors.

Validity and Future of Primary Androgen Deprivation Therapy in Prostate Cancer. Integration in the Era of New Agents Targeting the Androgen Receptor.

The relationship of sex hormones with prostate glandular activity and the evidence of the favourable impact of bilateral orchiectomy in 21 patients with locally advanced or metastatic prostate cancer (PCa), ratified by Huggins C.B. and cols. in 1941, is one of the pillars for the acceptance of androgen deprivation therapy (ADT). Its clinical relevance has withstood the passage of time and remains valid, fundamentally, in advanced PCa. ADT has expanded its use over the years and, after extensive clinical experience, substantial modifications have been incorporated into its indications and options, both of which are increasingly precise. The objective of this review is to update the therapeutic positioning of primary ADT, genetic-molecular advances and future of the developing treatments of PCa.

Hyperthermic Mitomycin C in Intermediate-risk Non-muscle-invasive Bladder Cancer: Results of the HIVEC-1 Trial.

BACKGROUND: Optimising therapeutic strategies of intermediate-risk non-muscle-invasive bladder cancer (IR-NMIBC) is needed. OBJECTIVE: To compare recurrence-free survival (RFS) with adjuvant intravesical mitomycin C (MMC) at normothermia or hyperthermia using the COMBAT bladder recirculation system at 43 °C for 30 and 60 min. DESIGN, SETTING, AND PARTICIPANTS: A prospective open-label, phase 3 randomised controlled trial (HIVEC-1) accrued across 13 centres between 2014 and 2020 in Spain. After complete transurethral resection of the bladder and immediate postoperative MMC instillation, patients with IR-NMIBC were randomised (1:1:1) to four weekly followed by three monthly 40-mg MMC instillations at normothermia (control; n = 106), 43 °C for 30 min (n = 107), or 43 °C for 60 min (n = 106) were investigated. Therapeutic compliance was defined as four or more instillations. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was RFS at 24 mo in the intention-to-treat (ITT) and per-protocol (PP) populations. The secondary outcomes included progression-free survival at 24 mo, safety outcome measures, and changes in health-related quality of life. Log-rank, Fisher, χ2, and analysis of variance tests were used. RESULTS AND LIMITATIONS: The ITT 24-mo RFS was 77% for control, 82% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.6). The PP 24-mo RFS was 77% for control, 83% for 43 °C-30 min, and 80% for 43 °C-60 min (p = 0.59). Six patients progressed to muscle-invasive disease in the ITT population (four in the control, 43 °C-30 min, and 43 °C-60 min groups each) and four in the PP population (all controls). Serious adverse events occurred in 26 patients (8.1%), and we were unable to demonstrate a difference between groups (p = 0.5). Adverse events, mainly dysuria and spasms, occurred in 124 patients (33% in control, 35% in 43 °C-30 min, and 48% in 43 °C-60 min; p = 0.05). The total International Prostate Symptom Score worsened by 1.2 ±â€¯7.3 points, similarly across groups (p = 0.29). The Functional Assessment of Cancer Therapy-Bladder domains and indexes showed no significant change. CONCLUSIONS: Four-month adjuvant hyperthermic MMC using the COMBAT system for 30 and 60 min in IR-NMIBC is well tolerated, but we did not find it to be superior to normothermic MMC at 24 mo. PATIENT SUMMARY: We were unable to demonstrate the effectiveness of hyperthermia using the COMBAT system in intermediate-risk non-muscle-invasive bladder cancer. Further evaluation of long-term recurrence and progression, and maintenance regimens appears mandatory.

Hyperoxaluria Induces Endothelial Dysfunction in Preglomerular Arteries: Involvement of Oxidative Stress.

Urolithiasis is a worldwide problem and a risk factor for kidney injury. Oxidative stress-associated renal endothelial dysfunction secondary to urolithiasis could be a key pathogenic factor, similar to obesity and diabetes-related nephropathy. The aim of the present study was to characterize urolithiasis-related endothelial dysfunction in a hyperoxaluria rat model of renal lithiasis. EXPERIMENTAL APPROACH: Endothelial dysfunction was assessed in preglomerular arteries isolated from control rats and in which 0.75% ethylene glycol was administered in drinking water. Renal interlobar arteries were mounted in microvascular myographs for functional studies; superoxide generation was measured by chemiluminescence and mRNA and protein expression by RT-PCR and immunofluorescence, respectively. Selective inhibitors were used to study the influence of the different ROS sources, xanthine oxidase, COX-2, Nox1, Nox2 and Nox4. Inflammatory vascular response was also studied by measuring the RNAm expression of NF-κB, MCP-1 and TNFα by RT-PCR. RESULTS: Endothelium-dependent vasodilator responses were impaired in the preglomerular arteries of the hyperoxaluric group along with higher superoxide generation in the renal cortex and vascular inflammation developed by MCP-1 and promoted by NF-κB. The xanthine oxidase inhibitor allopurinol restored the endothelial relaxations and returned superoxide generation to basal values. Nox1 and Nox2 mRNA were up-regulated in arteries from the hyperoxaluric group, and Nox1 and Nox2 selective inhibitors also restored the impaired vasodilator responses and normalized NADPH oxidase-dependent higher superoxide values of renal cortex from the hyperoxaluric group. CONCLUSIONS: The current data support that hyperoxaluria induces oxidative stress-mediated endothelial dysfunction and inflammatory response in renal preglomerular arteries which is promoted by the xanthine oxidase, Nox1 and Nox2 pathways.

Risk Factors for Revision After Artificial Urinary Sphincter Implantation in Male Patients With Stress Urinary Incontinence: A 10-Year Retrospective Study.

PURPOSE: To evaluate the preoperative and intraoperative risk factors for revision after artificial urinary sphincter (AUS) implantation in male patients with stress urinary incontinence (SUI). METHODS: A retrospective analysis from a prospectively maintained database was performed. Male patients, with moderate-tosevere SUI, undergoing AUS implantation were included. All patients underwent placement of AMS 800. Cause of revision, type of revision, and time to revision were recorded. Multivariable analyzes were performed using a logistic regression to investigate the risk factors. Competing risk analysis according to Fine-Gray model was used to study time to event data. RESULTS: A total of 70 patients were included. Revision surgery was performed in 22 of 70 patients (31.4%), after a median (interquartile range) time of 26.5 months (6.5-39.3 months). Overall, 19 of 22 repairs (86.4%) and 3 of 22 explants (13.6%) were recorded. Mechanical dysfunction, urethral erosion, urethral atrophy, and device infection were the causes of revision in 11 of 22 (50.0%), 6 of 22 (27.3%), 3 of 22 (13.6%), and 2 of 22 patients (9.1%). Vesicourethral anastomosis stenosis (P=0.02), urethral cuff size of 3.5 cm (P=0.029), and dual implantation (P=0.048) were independent predictors for revision. Vesicourethral anastomosis stenosis (P=0.01) and urethral cuff size of 3.5 cm (P=0.029) predicted a lower survival of the AUS. CONCLUSION: The vesicourethral anastomosis stenosis, urethral cuff size of 3.5 cm, and dual implantation are independent predictors for revision after AUS implantation. However, only the vesicourethral anastomosis stenosis and urethral cuff size of 3.5 cm predict a lower survival of AUS.

Kidney Transplants in Controlled Donation Following Circulatory Death, or Maastricht Type III Donors, With Abdominal Normothermic Regional Perfusion, Optimizing Functional Outcomes.

BACKGROUND: Warm ischemia time and ischemia-reperfusion damage result in higher rates of delayed graft function and primary nonfunction in kidney transplants (KTs) from controlled donation after circulatory death (cDCD). This study aimed to assess early and late kidney function and patient and graft survival of KT from cDCD preserved with normothermic regional perfusion (NRP) and to compare with KT from brain death donors (DBDs) and cDCD preserved with rapid recovery (RR). METHODS: Patients who received a KT at our institution from 2012 to 2018 were included, with a minimum follow-up period of 1 y. They were categorized by donor type and conditioning methods: DBD, cDCD with NRP, and cDCD with RR. Early and late graft function, along with patient and graft survival were analyzed in all groups. RESULTS: A total of 182 KT recipients were included in the study (98 DBD and 84 cDCD). Out of the cDCDs, 24 kidneys were recovered with the use of NRP and 62 with RR; 22 of the 24 kidneys were ultimately transplanted. The cDCD using NRP group showed lower rates of delayed graft function compared with the cDCD with RR group (36.3% versus 46.7%, P = 0.01). Also, primary nonfunction rates were lower in the cDCD using NRP group (4.5% versus 6.4% cDCD-RR and 10.2% DBD). Patient survival rates were >90% in all groups. No differences were found in graft survival rates at 1 y. CONCLUSIONS: The use of abdominal NRP improves early function recovery of KT from cDCD, making their outcomes comparable with those of DBD.

Urolithiasis Develops Endothelial Dysfunction as a Clinical Feature.

An increased risk of cardiovascular morbidity has been reported in lithiasic patients. In this context, endothelial dysfunction (ED), an earlier status of atherogenesis, has been identified in hyperoxaluria rat models of urolithiasis. OBJECTIVE: The purpose of this study was to determine the endothelial vascular function in patients with urolithiasis in relation to systemic inflammatory, oxidative stress, and vascular function serum markers. METHODS: A cross-sectional study was performed between 27 urolithiasic patients, matched for age and sex, with 27 healthy patients. Endothelial function was assessed by measuring flow-mediated dilation (Celermajer method). Fasting blood was collected to determine metabolic parameters (glucose and lipid profile), along with serum CRP, IL-6, MDA, ADMA, and VCAM-1. RESULTS: Both the control and urolithiasis groups were homogenous in anthropometric, exploration, and general laboratory measures. Flow-mediated dilation (%FMD) was 11.85% (SE: 2.78) lower in the lithiasis group (p < 0.001). No significant differences were achieved between groups when CRP, IL-6, MDA, ADMA, and VCAM-1 were compared, although slightly higher values of CRP, ADMA, and VCAM-1 were detected in the lithiasic group. A correlation was not reached in any of the serum markers when they were related to flow-mediated values, although a slight negative correlation trend was observed in MDA, VCAM-1, and IL-6 values. CONCLUSIONS: Endothelial dysfunction constitutes an important disorder related to urolithiasis patients. It must be considered as an early feature responsible for future cardiovascular events. Our study did not find a significant association between inflammatory, oxidative stress, endothelial serum markers, and flow-mediated dilation.

[Local and systhemic immunotherapy for bladder cáncer: from bench to bedside.] / Inmunoterapia local y sistémica en cáncer de vejiga: bases moleculares y traslación clínica.

Therapeutic approaches for treatment of urothelial transitional cell carcinoma based on immune system modulation, as well as the contribution of intravesica Bacillus de Calmette-Guérin (BCG) and the recentin corporation of checkpoint inhibitors had found irrefutable proofs of concept for the indication of antitumoral immunontherapy in such tumors. Its extension and development at the present time covers all the locations of the wide spectrum of presentation and evolution of these tumors. Nowadays, apart for the low grade non muscle-invasive tumors, we are facingan unpredictable development of antitumoral immunotherapy in bladder cancer not only as an option in the primary treatment, but also in other scenarios such asnon-responders when it comes to BCG, or the situation of ineligibility for systemic chemotherapy indication. The main objective of this review article is trying to translate the current basic mechanisms involved in different phases of transitional cell carcinomas antitumoral response, regardless of whether they are muscle-invasive or not, and to establish the rationale for their therapeutic intravesical or systemic administration. The role of the interactions established between urothelial tumor cells and the cellular and molecular elements of the immune system of patients is described, incorporating the relevant and recent advances in immunobiology and the molecular characterization of these tumors thatwill undoubtedly introduce far-reaching modifications intherapeutic regimes that will contrast with the traditional options available. Investigational lines that are already active in the clinical research phase with BCG and, checkpoints inhibitors ofthe immune response are also analyzed, high lighting theneed to find predictive response markers as a real option for treatments personalization. The approach to the knowledge of the individual reactivity of the immune system of each patient as a determining factor to achieve it is proposed.

Los abordajes terapéuticos para los carcinomas de células transicionales del urotelio desarrollados en torno a la modulación del sistema inmune encuentran, en la contribución del Bacillus de Calmettey Guérin (BCG) intravesical y más reciente la de los fármacos inhibidores de los puntos de control de la respuesta inmunitaria, indiscutibles pruebas de concepto de la indicación inmunoterapia antitumoral. Su extensión y desarrollo en el momento actual abarca todas las localizaciones del amplio espectro de presentación y evolución de estos tumores. A excepción, por el momento, de los tumores no-músculo infiltrantes debajo grado, acudimos a un desarrollo impredecible de la inmunoterapia antitumoral en el cáncer de vejiga no solo como opción en el tratamiento primario de alguno de ellos sino también en pacientes no-respondedores cuando se trata del BCG, de la quimioterapia sistémicao la situación de no-elegibilidad para su indicación. El objetivo de este artículo de revisión es intentar trasladar los mecanismos básicos actuales implicados en las distintas fases de la respuesta antitumoral de los carcinomas de células transicionales con independencia de que sean o no músculo infiltrantes y establecer los fundamentos para su traslación terapéutica por vía intravesical o sistémica. Se describe el papel de las interacciones que se establecen entre las células tumorales uroteliales y los elementos celulares y moleculares del sistema inmune de los pacientes incorporando los relevantes y recientes avances de la inmunobiológica y la caracterización molecular de estos tumores que sin duda introducirán modificaciones de alcance en su evolución y tratamiento que contrastaran con las opciones hasta hace poco tiempo disponibles. También se analizan las líneas de futuro ya activas en fase de investigación clínica con BCG y con inhibidores de los puntos de control de la respuesta inmunitaria destacando la necesidad de avanzar en la búsqueda de marcadores predictivos de respuesta como opción real para la personalización de los tratamientos planteando la aproximación al conocimiento de la reactividad individual del sistema inmune de cada paciente como factor determinante para poder alcanzarla.

Inmunoterapia local y sistémica en cáncer de vejiga: bases moleculares y traslación clínica / Local and systhemic immunotherapy for bladder cáncer: from bench to bedside

Los abordajes terapéuticos para los carcinomas de células transicionales del urotelio desarrollados en torno a la modulación del sistema inmune encuentran, en la contribución del Bacillus de Calmette y Guérin (BCG) intravesical y más reciente la de los fármacos inhibidores de los puntos de control de la respuesta inmunitaria, indiscutibles pruebas de concepto de la indicación inmunoterapia antitumoral. Su extensión y desarrollo en el momento actual abarca todas las localizaciones del amplio espectro de presentación y evolución de estos tumores. A excepción, por el momento, de los tumores no-músculo infiltrantes de bajo grado, acudimos a un desarrollo impredecible de la inmunoterapia antitumoral en el cáncer de vejiga no solo como opción en el tratamiento primario de alguno de ellos sino también en pacientes no-respondedores cuando se trata del BCG, de la quimioterapia sistémica o la situación de no-elegibilidad para su indicación. El objetivo de este artículo de revisión es intentar trasladar los mecanismos básicos actuales implicados en las distintas fases de la respuesta antitumoral de los carcinomas de células transicionales con independencia de que sean o no músculo infiltrantes y establecer los fundamentos para su traslación terapéutica por vía intravesical o sistémica. Se describe el papel de las interacciones que se establecen entre las células tumorales uroteliales y los elementos celulares y moleculares del sistema inmune de los pacientes incorporando los relevantes y recientes avances de la inmunobiológica y la caracterización molecular de estos tumores que sin duda introducirán modificaciones de alcance en su evolución y tratamiento que contrastaran con las opciones hasta hace poco tiempo disponibles. También se analizan las líneas de futuro ya activas en fase de investigación clínica con BCG y con inhibidores de los puntos de control de la respuesta inmunitaria destacando la necesidad de avanzar en la búsqueda de marcadores predictivos de respuesta como opción real para la personalización de los tratamientos planteando la aproximación al conocimiento de la reactividad individual del sistema inmune de cada paciente como factor determinante para poder alcanzarla

Therapeutic approaches for treatment of urothelial transitional cell carcinoma based on immune system modulation, as well as the contribution of intravesical Bacillus de Calmette-Guérin (BCG) and the recent incorporation of checkpoint inhibitors had found irrefutable proofs of concept for the indication of antitumoral immunontherapy in such tumors. Its extension and development at the present time covers all the locations of the wide spectrum of presentation and evolution of these tumors. Nowadays, apart for the low grade non muscle-invasive tumors, we are facing an unpredictable development of antitumoral immunotherapy in bladder cancer not only as an option in the primary treatment, but also in other scenarios such as non-responders when it comes to BCG, or the situation of ineligibility for systemic chemotherapy indication. The main objective of this review article is trying to translate the current basic mechanisms involved in different phases of transitional cell carcinomas antitumoral response, regardless of whether they are muscle-invasive or not, and to establish the rationale for their therapeutic intravesical or systemic administration. The role of the interactions established between urothelial tumor cells and the cellular and molecular elements of the immune system of patients is described, incorporating the relevant and recent advances in immunobiology and the molecular characterization of these tumors that will undoubtedly introduce far-reaching modifications in therapeutic regimes that will contrast with the traditional options available. Investigational lines that are already active in the clinical research phase with BCG and, checkpoints inhibitors of the immune response are also analyzed, highlighting the need to find predictive response markers as a real option for treatments personalization. The approach to the knowledge of the individual reactivity of the immune system of each patient as a determining factor to achieve it is proposed

Activation of the AMP-related kinase (AMPK) induces renal vasodilatation and downregulates Nox-derived reactive oxygen species (ROS) generation.

AMP-activated protein kinase (AMPK) is a cellular energy sensor activated during energy stress to stimulate ATP production pathways and restore homeostasis. AMPK is widely expressed in the kidney and involved in mitochondrial protection and biogenesis upon acute renal ischemia, AMPK activity being blunted in metabolic disease-associated kidney disease. Since little is known about AMPK in the regulation of renal blood flow, the present study aimed to assess the role of AMPK in renal vascular function. Functional responses to the selective AMPK activator A769662 were assessed in intrarenal small arteries isolated from the kidney of renal tumour patients and Wistar rats and mounted in microvascular myographs to perform simultaneous measurements of intracellular calcium [Ca2+]i and tension. Superoxide (O2.-) and hydrogen peroxide (H2O2) production were measured by chemiluminescence and fluorescence and protein expression by Western blot. Activation of AMPK with A769662 increased AMPKα phosphorylation at Thr-172 and induced potent relaxations compared to AICAR in isolated human and rat intrarenal arteries, through both endothelium-dependent mechanisms involving nitric oxide (NO) and intermediate-conductance calcium-activated potassium (IKCa) channels, as well as activation of ATP-sensitive (KATP) channels and sarcoplasmic reticulum Ca2+-ATPase (SERCA) in vascular smooth muscle (VSM). Furthermore, AMPK activator reduced NADPH oxidase 4 (Nox4) and Nox2-derived reactive oxygen species (ROS) production. These results demonstrate that A769662 has potent vasodilator and antioxidant effects in intrarenal arteries. The benefits of AMPK activation in rat kidney are reproduced in human arteries and therefore vascular AMPK activation might be a therapeutic target in the treatment of metabolic disease-associated kidney injury.

[The role of intraoperatory ultrasound in laparoscopic partial nephrectomy for intrarenal tumors.] / Nefrectomía parcial laparoscópica en tumores intrarrenales. Papel de la ecografía intraoperatoria.

OBJECTIVES: The use of intraoperatory laparoscopic ultrasound for nephron sparring surgery (partial nephrectomy) in patients with technically challenging tumors has emerged during the last years. The objective of this work is to present a literature review and analysis of the published series, as well as the surgical technique of intraoperatory laparoscopic guided partial nephrectomy. METHODS: Pubmed and Scopus serch was performed in January 2019 including the following keywords: "intraoperative ultrasonography", "laparoscopic ultrasonography" and "partial nephrectomy", the published series are presented. We describe the laparoscopic technique of intraoperatory ultrasound during partial nephrectomy. RESULTS: All the published series present similar results in terms of tumour size which varies from 2.3 to 4 cm. Complications results are also very similar in the comparative series to the ones published in partial nephrectomies. They show promising oncological results during follow up with a rate superior to 90% of negative margins, comparable to those of exophytic tumor partial nephrectomies. CONCLUSIONS: The use of intraoperatory ultrasound during laparoscopic surgery to localize intraparenchymatous renal lesions can expand the indications of partial nephrectomy to more technically challenging tumors. These indications are not yet well standardized. Due to its complexity, the need of previous surgical experience is required to achieve good results and corroborate the security and feasibility of this procedure. Prospective randomized trials are needed to confirm the benefits of intraoperatory laparoscopic ultrasound for nephron sparring surgery (partial nephrectomy).

OBJETIVO: En los últimos años ha emergido el uso de la ecografía laparoscópica intraoperatoria en pacientes con tumores inicialmente complejos para la realización de nefrectomías parciales. El objetivo es realizar una revisión bibliográfica de las series publicadas analizando sus resultados y presentar la técnica quirúrgica de la nefrectomía parcial laparoscópica en los tumores intrarrenales.MÉTODOS: Se realiza una búsqueda bibliográfica en Pumbed y Scopus en Enero de 2019 incluyendo los términos "intraoperative ultrasonography", "laparoscopic ultrasonography" y "partial nephrectomy" en lengua inglesa y se presentan las series de casos publicadas. Descripción de la técnica laparoscópica de ecografía intraoperatoria renal durante la nefrectomía parcial. RESULTADOS: Las diez series publicadas presentan resultados acerca del tamaño medio de las masas intervenidas que oscilan entre los 2,3 y 4 cm. Los resultados de complicaciones son muy similares en las series comparativas a los del resto de nefrectomías parciales. Respecto a la tasa de márgenes negativos en todas las series presenta una tasa superior al 90% con buenos resultados oncológicos en el seguimiento equiparables a la nefrectomía parcial de tumores periféricos. CONCLUSIONES: La utilización durante la cirugía laparoscópica renal de la ecografía intraoperatoria para localización de masas intraparenquimatosas puede expandir la indicación de la nefrectomía parcial a tumores técnicamente más complejos. Las indicaciones de uso de esta técnica no están aún estandarizadas y dada la complejidad precisan de una experiencia quirúrgica previa para ser llevadas a cabo asegurando buenos resultados que corroboren la seguridad y factibilidad de este procedimiento. Son necesarios estudios prospectivos randomizados para confirmar los beneficios de la nefrectomía parcial asistida con ecografía intraoperatoria.

Nefrectomía parcial laparoscópica en tumores intrarrenales. Papel de la ecografía intraoperatoria / The role of intraoperatory ultrasound in laparoscopic partial nephrectomy for intrarenal tumors

Objetivo: En los últimos años ha emergido el uso de la ecografía laparoscópica intraoperatoria en pacientes con tumores inicialmente complejos para la realización de nefrectomías parciales. El objetivo es realizar una revisión bibliográfica de las series publicadas analizando sus resultados y presentar la técnica quirúrgica de la nefrectomía parcial laparoscópica en los tumores intrarrenales. Métodos: Se realiza una búsqueda bibliográfica en Pumbed y Scopus en Enero de 2019 incluyendo los términos "intraoperative ultrasonography", "laparoscopic ultrasonography" y "partial nephrectomy" en lengua inglesa y se presentan las series de casos publicadas. Descripción de la técnica laparoscópica de ecografía intraoperatoria renal durante la nefrectomía parcial. Resultados: Las diez series publicadas presentan resultados acerca del tamaño medio de las masas intervenidas que oscilan entre los 2,3 y 4 cm. Los resultados de complicaciones son muy similares en las series comparativas a los del resto de nefrectomías parciales. Respecto a la tasa de márgenes negativos en todas las series presenta una tasa superior al 90% con buenos resultados oncológicos en el seguimiento equiparables a la nefrectomía parcial de tumores periféricos. Conclusiones: La utilización durante la cirugía laparoscópica renal de la ecografía intraoperatoria para localización de masas intraparenquimatosas puede expandir la indicación de la nefrectomía parcial a tumores técnicamente más complejos. Las indicaciones de uso de esta técnica no están aún estandarizadas y dada la complejidad precisan de una experiencia quirúrgica previa para ser llevadas a cabo asegurando buenos resultados que corroboren la seguridad y factibilidad de este procedimiento. Son necesarios estudios prospectivos randomizados para confirmar los beneficios de la nefrectomía parcial asistida con ecografía intraoperatoria

Objectives: The use of intraoperatory laparoscopic ultrasound for nephron sparring surgery (partial nephrectomy) in patients with technically challenging tumors has emerged during the last years. The objective of this work is to present a literature review and analysis of the published series, as well as the surgical technique of intraoperatory laparoscopic guided partial nephrectomy. Methods: Pubmed and Scopus serch was performed in January 2019 including the following keywords: "intraoperative ultrasonography", "laparoscopic ultrasonography" and "partial nephrectomy", the published series are presented. We describe the laparoscopic technique of intraoperatory ultrasound during partial nephrectomy. Results: All the published series present similar results in terms of tumour size which varies from 2.3 to 4 cm. Complications results are also very similar in the comparative series to the ones published in partial nephrectomies. They show promising oncological results during follow up with a rate superior to 90% of negative margins, comparable to those of exophytic tumor partial nephrectomies. Conclusions: The use of intraoperatory ultrasound during laparoscopic surgery to localize intraparenchymatous renal lesions can expand the indications of partial nephrectomy to more technically challenging tumors. These indications are not yet well standardized. Due to its complexity, the need of previous surgical experience is required to achieve good results and corroborate the security and feasibility of this procedure. Prospective randomized trials are needed to confirm the benefits of intraoperatory laparoscopic ultrasound for nephron sparring surgery (partial nephrectomy)

Surgical Management of Peyronie's Disease With Co-Existent Erectile Dysfunction.

INTRODUCTION: Surgical intervention in Peyronie's disease (PD) should ideally be delayed until the resolution of acute inflammatory phase. AIM: The objective of this review was to highlight the results of penile prosthesis to correct refractory erectile dysfunction (ED) in patients with PD, and the secondary procedures that may be required to correct the penile curvature. METHODS: A systematic search on PubMed online database using Preferred Reporting Items for Systematic Reviews and Meta-Analyses recommendations was done using the MeSH terms "Peyronie's disease" and "erectile dysfunction." MAIN OUTCOME MEASURE: Success and satisfaction rates of various procedures. RESULTS: The search yielded 324 language-specific (English and Spanish language) articles and 58 articles were retained for final review. The following variables were assessed in different studies: number of patients, types of secondary procedure to correct the curvature, satisfaction rates, and follow-up period. CONCLUSION: The aim of the surgery in PD should be to achieve a functionally straight penis (<20 degree curvature) with good erection. Patients with refractory ED in PD are candidates for penile prosthesis. Secondary procedures, like manual modeling, plication, plaque incision, or excision grafting, may be required depending on the degree of penile curvature and penile length. In quest for the best graft, TachoSil graft seems to have gained popularity in Europe. Krishnappa P, Fernandez-Pascual E, Carballido J, et al. Surgical Management of Peyronie's Disease With Co-Existent Erectile Dysfunction. Sex Med 2019;7:361-370.

Association of an organ transplant-based approach with a dramatic reduction in postoperative complications following radical nephrectomy and tumor thrombectomy in renal cell carcinoma.

OBJECTIVES: Our aim was to determine whether using an organ transplant-based(TB) approach reduces postoperative complications(PCs) following radical nephrectomy(RN) and tumor thrombectomy(TT) in renal cell carcinoma(RCC) patients with level II-IV thrombi. METHODS: A total of 390(292 non-TB/98 TB) IRCC-VT Consortium patients who received no preoperative embolization/IVC filter were included. Stepwise linear/logistic regression analyses were performed to determine significant multivariable predictors of intraoperative estimated blood loss(IEBL), number blood transfusions received, and overall/major PC development within 30days following surgery. Propensity to receive the TB approach was controlled. RESULTS: The TB approach was clearly superior in limiting IEBL, blood transfusions, and PC development, even after controlling for other significant prognosticators/propensity score(P < .000001 in each case). Median IEBL for non-TB/TB approaches was 1000 cc/300 cc and 1500 cc/500 cc for tumor thrombus Level II-III patients, respectively, with no notable differences for Level IV patients(2000 cc each). In comparing PC outcomes between non-TB/TB patients with a non-Right-Atrium Cranial Limit, the observed percentage developing a: i) PC was 65.8%(133/202) vs. 4.3%(3/69) for ECOG Performance Status(ECOG-PS) 0-1, and 84.8%(28/33) vs. 25.0%(4/16) for ECOG-PS 2-4, and ii) major PC was 16.8%(34/202) vs. 1.4%(1/69) for ECOG-PS 0-1, and 27.3%(9/33) vs. 12.5%(2/16) for ECOG-PS 2-4. Major study limitation was the fact that all TB patients were treated by a single, experienced, high volume surgeon from one center (non-TB patients were treated by various surgeons at 13 other centers). CONCLUSIONS: Despite this major study limitation, the observed dramatic differences in PC outcomes suggest that the TB approach offers a major breakthrough in limiting operative morbidity in RCC patients receiving RN and TT.

Optimizing collagenase Clostridium histolyticum therapy for Peyronie's disease using a novel approach with percutaneous needle tunnelling.

OBJECTIVES: To compare the efficacy and safety of a combined treatment of percutaneous needle tunnelling (PNT) and a modified collagenase Clostridium histolyticum (CCH) protocol (PNT/CCH) vs the modified protocol alone (CCH) in the treatment of Peyronie's disease (PD). PATIENTS AND METHODS: A prospective registry of patients treated with a modified CCH protocol was maintained between June 2014 and February 2018. The last 50 patients received PNT as an adjuvant therapy (PNT/CCH), and their data were compared with those of the other 94 patients treated previously (CCH). PNT involves the creation of multiple holes made percutaneously in the plaque before each injection. The modified protocol consisted of two collagenase injections, at 1-week intervals, followed by penile modelling. Patients used penile traction therapy, tadalafil and pentoxifylline for the next 2 months and were followed up for 6 months. The main outcome was improvement of curvature. Secondary outcomes were improvements in erectile function, PD symptoms, stretched penile length and satisfaction. RESULTS: Improvement in curvature was greater in patients in the PNT/CCH group than in the CCH group (mean ± sd 19.2 ± 6.1° vs 12.7 ± 5.0°; P < 0.001 [36.2 ± 12.5% vs 28.1 ± 14.5%; P = 0.001]). Compared with baseline, both interventions were associated with significant improvement in secondary outcomes. The main complications were ecchymosis, bruising and penile pain, with no significant differences between groups. CONCLUSIONS: Treatment of PD with CCH using our modified protocol in combination with PNT is safe and more effective than the modified protocol alone, with the potential for improved cost-effectiveness.

Sildenafil/Viagra in the treatment of premature ejaculation.

The arrival of Pfizer's blue pill Sildenafil in 1998 brought a great relief both to patient and physician signalling the start of a great era of medical therapy in sexual medicine. Since then the sexual medicine experts have been prescribing sildenafil in erectile dysfunction with acceptable minor adverse events. But the use of sildenafil in premature ejaculation (PE) is still debated. 2018 being the 20th anniversary of sildenafil, we have compiled interesting facts about the role of sildenafil in PE from various original articles, systematic reviews, meta-analyses, economic brochures and sexual medicine committee guidelines. The major issues in most of these studies were the heterogeneity in the definition of PE and estimating the exact ejaculatory latency time. This perspective article highlights the positive role of sildenafil in the management of PE (even without ED) with acceptable adverse events. Now that we have a standardised definition of PE from International Society of Sexual Medicine (ISSM) and a psychogenic component in PE definition, more randomised placebo-controlled studies are required to further establish its role.

Surgical Technique for Complex Cases of Peyronie's Disease With Implantation of Penile Prosthesis, Multiple Corporeal Incisions, and Grafting With Collagen Fleece.

INTRODUCTION: Patients with Peyronie's disease (PD) and erectile dysfunction (ED) concomitant with shortening or other malformations benefit from prosthesis implantation and penile lengthening procedures. AIM: To evaluate the safety and efficacy of a multi-incisional technique with penile prosthesis implantation with multiple corporeal incisions and collagen grafting for the surgical management of complex cases of PD with ED and severe penile shortening. METHODS: From February 2015-May 2018, 43 consecutive patients with complex PD were treated using this technique. Implantation of a penile prosthesis (malleable or inflatable [IPP]) together with multiple relaxing tunica albuginea incisions and grafting with a self-adhesive collagen-fibrin fleece (TachoSil, Baxter Healthcare) was performed in all patients by a single surgeon (J.I.M.S.). MAIN OUTCOME MEASURE: Penile length and curvature correction, operative time, and incidence of postoperative complications were recorded as outcome measures. Functional outcomes were measured with questionnaires (International Index of Erectile Function-5, Erection Hardness Score, modified Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire, PD Questionnaire) before and 3 and 6 months after surgery. RESULTS: With a median follow-up of 21 months (range 10-31), mean postsurgical penile lengthening was 2.5 (range 1-5) cm, with an improvement in the Bother domain of the PD Questionnaire of 4.4 (range 2-5) points. The average operative time was 86.7 and 71.6 minutes for the IPP and malleable penile prosthesis procedure, respectively. No glans ischemia was recorded; however, 1 IPP infection and 1 delayed distal corporeal erosion were recorded. Hematoma or bruising was observed in 23.2% of patients. The modified Erectile Dysfunction Inventory of Treatment Satisfaction questionnaire was completed by 39 (90.7%) patients. Overall, 89.7% would recommend this surgery. Patient satisfaction with straightness and length was 94.9% and 82.1%, respectively. CLINICAL IMPLICATIONS: The described technique helps restoration of penile length and erectile function in patients with complex PD. STRENGTHS & LIMITATIONS: The strength of the study is that it offers a simple, easy-to-apply technique for surgeons to correct shortening and other malformations in patients with ED and complex PD. The study is limited by the small number of patients, the short follow-up period and the performance of the technique by a single high-volume implanter. CONCLUSION: The implantation of a penile prosthesis (malleable or inflatable) together with multiple incisions of the plaque/tunica albuginea and grafting with a collagen fleece is a safe and efficient treatment for patients with complex PD in addition to ED and significant shortening. Fernández-Pascual E, Gonzalez-García FJ, Rodríguez-Monsalve M, et al. Surgical Technique for Complex Cases of Peyronie's Disease With Implantation of Penile Prosthesis, Multiple Corporeal Incisions, and Grafting With Collagen Fleece. J Sex Med 2019;16:323-332.

Hydrogen peroxide derived from NADPH oxidase 4- and 2 contributes to the endothelium-dependent vasodilatation of intrarenal arteries.

The role of NADPH oxidase (Nox)-derived reactive oxygen species in kidney vascular function has extensively been investigated in the harmful context of oxidative stress in diabetes and obesity-associated kidney disease. Since hydrogen peroxide (H2O2) has recently been involved in the non-nitric oxide (NO) non-prostanoid relaxations of intrarenal arteries, the present study was sought to investigate whether NADPH oxidases may be functional sources of vasodilator H2O2 in the kidney and to assess their role in the endothelium-dependent relaxations of human and rat intrarenal arteries. Renal interlobar arteries isolated from the kidney of renal tumor patients who underwent nephrectomy, and from the kidney of Wistar rats, were mounted in microvascular myographs to assess function. Superoxide (O2.-) and H2O2 production was measured by chemiluminescence and Amplex Red fluorescence, and Nox2 and Nox4 enzymes were detected by Western blotting and by double inmunolabeling along with eNOS. Nox2 and Nox4 proteins were expressed in the endothelium of renal arterioles and glomeruli co-localized with eNOS, levels of expression of both enzymes being higher in the cortex than in isolated arteries. Pharmacological inhibition of Nox with apocynin and of CYP 2C epoxygenases with sulfaphenazol, but not of the NO synthase (NOS), reduced renal NADPH-stimulated O2.- and H2O2 production. Under conditions of cyclooxygenase and NOS blockade, acetylcholine induced endothelium-dependent relaxations that were blunted by the non-selective Nox inhibitor apocynin and by the Nox2 or the Nox1/4 inhibitors gp91ds-tat and GKT136901, respectively. Acetylcholine stimulated H2O2 production that was reduced by gp91ds-tat and by GKT136901. These results suggest the specific involvement of Nox4 and Nox2 subunits as physiologically relevant endothelial sources of H2O2 generation that contribute to the endothelium-dependent vasodilatation of renal arteries and therefore have a protective role in kidney vasculature.

Intrathecal administration of autologous mesenchymal stromal cells for spinal cord injury: Safety and efficacy of the 100/3 guideline.

BACKGROUND AIMS: Cell therapy with autologous mesenchymal stromal cells (MSCs) in patients with spinal cord injury (SCI) is beginning, and the search for its better clinical application is an urgent need. METHODS: We present a phase 2 clinical trial in patients with chronic SCI who received three intrathecal administrations of 100 x 106 MSCs and were followed for 10 months from the first administration. Efficacy analysis was performed on nine patients, and safety analysis was performed on 11 patients. Clinical scales, urodynamic, neurophysiological and neuroimaging studies were performed previous to treatment and at the end of the follow-up. RESULTS: The treatment was well-tolerated, without any adverse event related to MSC administration. Patients showed variable clinical improvement in sensitivity, motor power, spasms, spasticity, neuropathic pain, sexual function or sphincter dysfunction, regardless of the level or degree of injury, age or time elapsed from the SCI. In the course of follow-up three patients, initially classified as ASIA A, B and C, changed to ASIA B, C and D, respectively. In urodynamic studies, at the end of follow-up, 66.6% of the patients showed decrease in postmicturition residue and improvement in bladder compliance. At this time, neurophysiological studies showed that 55.5% of patients improved in somatosensory or motor-evoked potentials, and that 44.4% of patients improved in voluntary muscle contraction together with infralesional active muscle reinnervation. CONCLUSIONS: The present guideline for cell therapy is safe and shows efficacy in patients with SCI, mainly in recovery of sphincter dysfunction, neuropathic pain and sensitivity.

[Mechanism of action of intravesical BCG. Biological bases and clinical applicability.] / Mecanismo de acción de la BCG intravesical. Bases biológicas y aplicabilidad clínica.

The therapeutic approaches developed around immune system modulation find the therapeutic contribution of intravesical Bacillus Calmette Guerin (BCG) for transitional cell bladder cancer an unquestionable example as a proof of concept of antitumor immunotherapy since more than 30 years ago. Intravesical immunotherapy for urothelial carcinomas is considered with periodic intravesical instillations schedules, and the one with longer historic development and wider diffusion is BCG in the form of suspension. BCG is a unique strain obtained from Mycobacterium bovis at the end of the first third of the XX century and represents the historically most successful immunotherapeutic modality of all tumors with a high level body of evidence. Currently, we even see an unpredictable development potential of this therapeutic modality based on immunomodulation related with activation or suppression of T lymphocytes by blocking the immune system checkpoints. This option is at this time a decisive step in the treatment of chemotherapy refractory metastatic urothelial carcinoma. Over the last years, there have been advances in the intimate mechanism of action of intravesical BCG, but there are many open questions that will only be answered from complex basic and translational research platforms. The objective of this review article is to try to translate the basic mechanisms currently implicated in the different phases of antitumor response of BCG in its routine use in clinical practice. Also, to analyze the future lines already active under clinical research with and without implications of the mechanisms of action of BCG. We describe the role of interactions basally established between urothelial tumor cells and cellular and molecular elements of the immune system of the patients with ulterior antitumor effector capacity. After intravesical BCG therapy and its interaction, we describe the various phases of its mechanism of action, namely fixation, internalization and triggering of the lytic cytotoxic antitumor response, and its integration in the current intravesical treatment regimens The implication of all these mechanisms in the varied capacity of clinical response observed in patients, reviewing the current status of knowledge of BCG mechanisms of action, leads unavoidably to the search of better clinical efficacy through eventual immune response markers and to set the approach to the knowledge of the individual reactivity of the immune system of each patient as a determinant factor to be able to adopt adjusted therapeutic patterns.