Immune Predictors of Response after Bacillus Calmette-Guérin Treatment in Non-Muscle-Invasive Bladder Cancer.

Bacillus Calmette-Guérin (BCG) has been the standard of care for the treatment of high-risk, non-muscle-invasive bladder cancer (NMIBC) for decades, but 49.6% of high-risk and very-high-risk patients will experience progression to muscle-invasive disease in five years. Furthermore, cytology and cystoscopy entail a high burden for both patients and health care systems due to the need for very long periods of follow-up. Subsequent adjuvant treatment using intravesical immunotherapy with BCG has been shown to be effective in reducing tumor recurrence and progression, but it is not free of severe adverse effects that ultimately diminish patients' quality of life. Because not all patients benefit from BCG treatment, it is of paramount importance to be able to identify responders and non-responders to BCG as soon as possible in order to offer the best available treatment and prevent unnecessary adverse events. The tumor microenvironment (TME), local immune response, and systemic immune response (both adaptive and innate) seem to play an important role in defining responders, although the way they interact remains unclear. A shift towards a proinflammatory immune response in TME is thought to be related to BCG effectiveness. The aim of this review is to collect the most relevant data available regarding BCG's mechanism of action, its role in modulating innate and adaptive immune responses and the secretion of certain cytokines, and their potential use as immunological markers of response; the aim is also to identify promising lines of investigation.

Toward Tumor Fight and Tumor Microenvironment Remodeling: PBA Induces Cell Cycle Arrest and Reduces Tumor Hybrid Cells' Pluripotency in Bladder Cancer.

Bladder cancer (BC) is the second most frequent cancer of the genitourinary system. The most successful therapy since the 1970s has consisted of intravesical instillations of Bacillus Calmette-Guérin (BCG) in which the tumor microenvironment (TME), including macrophages, plays an important role. However, some patients cannot be treated with this therapy due to comorbidities and severe inflammatory side effects. The overexpression of histone deacetylases (HDACs) in BC has been correlated with macrophage polarization together with higher tumor grades and poor prognosis. Herein we demonstrated that phenylbutyrate acid (PBA), a HDAC inhibitor, acts as an antitumoral compound and immunomodulator. In BC cell lines, PBA induced significant cell cycle arrest in G1, reduced stemness markers and increased PD-L1 expression with a corresponding reduction in histone 3 and 4 acetylation patterns. Concerning its role as an immunomodulator, we found that PBA reduced macrophage IL-6 and IL-10 production as well as CD14 downregulation and the upregulation of both PD-L1 and IL-1ß. Along this line, PBA showed a reduction in IL-4-induced M2 polarization in human macrophages. In co-cultures of BC cell lines with human macrophages, a double-positive myeloid-tumoral hybrid population (CD11b+EPCAM+) was detected after 48 h, which indicates BC cell-macrophage fusions known as tumor hybrid cells (THC). These THC were characterized by high PD-L1 and stemness markers (SOX2, NANOG, miR-302) as compared with non-fused (CD11b-EPCAM+) cancer cells. Eventually, PBA reduced stemness markers along with BMP4 and IL-10. Our data indicate that PBA could have beneficial properties for BC management, affecting not only tumor cells but also the TME.

[Sexual dysfunction secondary to urethral stricture and urethroplasty]. / Disfunciones sexuales secundarias a la estenosis uretral y a la uretroplastia.

OBJECTIVES: Urethral stenosis is a complex pathology that severely affects the quality of life of patients who suffer it. There are multiple therapeutic options, the main objective of which is to eliminate obstruction and improve symptoms, and consequently maintain or improve the quality of life of the patient. The objective of this article is to perform a systematic review of the literature with the aim to evaluate the results regarding the sexual sphere after urethral surgery. METHODS: We performed a bibliographic search in PubMed, identifying studies that analyzed the results in sexual function after various types of urethroplasties. Preference have been given to those articles evaluating sexual function both preoperative and postoperative, to determine the degree of involvement conditioned by surgery. Fourteen articles have been selected, including those making reference to sexual function (sexual desire, erectile and ejaculatory function). RESULTS: A total of 14 studies were selected to perform the analysis; they were divided into two groups depending of the perspective they have to evaluate results: Use of validated tests for data collection before and after surgery and a second group analyzing more qualitative features of the stenosis making the evaluation of results this way. Site of stenosis is not uniformly distributed in these articles, with predominance of those performing anterior urethra surgery. They have a comprehensive analysis of the various features that may affect directly or indirectly the result of the operation both in the short and long term. CONCLUSIONS: Most articles conclude that specific standardized tools are necessary for this type of pathology, with the aim of obtain results that are more adjusted to urethral surgery. Patient perception of the results of urethroplasty is a parameter that has gained great importance lately. Globally the results of postoperative sexual function are very satisfactory, mainly in young patients. It is important to globally analyze the results and surgical techniques currently in use with the aim to minimize deleterious effects on sexual function; moreover taking into account that the objective of surgery is to try to improve the patient's quality of life.

Disfunciones sexuales secundarias a la estenosis uretral y a la uretroplastia / Sexual dysfunction secondary to urethral stricture and urethroplasty

OBJETIVO: La estenosis de uretra es una patología compleja que afecta de manera importante a la calidad de vida de los pacientes que la padecen. Existen múltiples opciones de tratamiento, cuyo objetivo principal es eliminar la obstrucción y mejorar los síntomas que acarrea, consecuentemente manteniendo o mejorando la calidad de vida del paciente. El objetivo de este artículo es hacer una revisión sistemática de la literatura con el fin de evaluar los resultados en relación a la esfera sexual tras la cirugía de uretra. MÉTODOS: Se ha realizado una búsqueda bibliografíca en Pubmed, identificando estudios que analizaban los resultados obtenidos en la función sexual tras diversos tipos de uretroplastias. Se ha dado preferencia a aquellos artículos que evalúan la función sexual tanto pre como postoperatoriamente, para determinar el grado de afectación condicionado por la cirugía. Se han seleccionado catorce artículos, incluyendo aquellos que hacen referencia a la función sexual (deseo sexual, función eréctil y eyaculatoria). RESULTADOS: Un total de catorce estudios fueron seleccionados para realizar dicho análisis, pudiendo ser divididos en dos grupos en función de la perspectiva con la que evalúan los resultados; uso de test validados para recogida de datos antes y después de la cirugía, y un segundo grupo que analiza aspectos mas cualitativos de la estenosis y de esta manera evalúa los resultados. La localización de la estenosis se reparte de manera no uniforme dentro de dichos artículos, predominando aquellos que realizan cirugía de uretra anterior. Se analizan exhaustivamente los distintos aspectos que pueden afectar de manera directa o indirecta al resultado quirúrgico tanto a corto como largo plazo. CONCLUSIONES: La mayoría de los artículos concluyen que son necesarios herramientas estandarizadas específicas para este tipo de patología, con el fin de obtener resultados mas adaptados a la cirugía de uretra. La percepción del paciente en cuanto a los resultados de la uretroplastia es un parámetro que ha cobrado gran importancia en los últimos tiempos. Globalmente los resultados con respecto la función sexual postoperatoria son muy satisfactorios, sobretodo en pacientes jóvenes. Es importante analizar de manera global los resultados y las técnicas quirúrgicas empleadas en la actualidad con el fin de minimizar los efectos deletéreos sobre la función sexual, más aun teniendo en cuenta que se trata de una cirugía cuyo objetivo es intentar mejorar la calidad de vida del paciente

OBJECTIVES: Urethral stenosis is a complex pathology that severely affects the quality of life of patients who suffer it. There are multiple therapeutic options, the main objective of which is to eliminate obstruction and improve symptoms, and consequently maintain or improve the quality of life of the patient. The objective of this article is to perform a systematic review of the literature with the aim to evaluate the results regarding the sexual sphere after urethral surgery. METHODS: We performed a bibliographic search in PubMed, identifying studies that analyzed the results in sexual function after various types of urethroplasties. Preference have been given to those articles evaluating sexual function both preoperative and postoperative, to determine the degree of involvement conditioned by surgery. Fourteen articles have been selected, including those making reference to sexual function (sexual desire, erectile and ejaculatory function). RESULTS: A total of 14 studies were selected to perform the analysis; they were divided into two groups depending of the perspective they have to evaluate results: Use of validated tests for data collection before and after surgery and a second group analyzing more qualitative features of the stenosis making the evaluation of results this way. Site of stenosis is not uniformly distributed in these articles, with predominance of those performing anterior urethra surgery. They have a comprehensive analysis of the various features that may affect directly or indirectly the result of the operation both in the short and long term. CONCLUSIONS: Most articles conclude that specific standardized tools are necessary for this type of pathology, with the aim of obtain results that are more adjusted to urethral surgery. Patient perception of the results of urethroplasty is a parameter that has gained great importance lately. Globally the results of postoperative sexual function are very satisfactory, mainly in young patients. It is important to globally analyze the results and surgical techniques currently in use with the aim to minimize deleterious effects on sexual function; moreover taking into account that the objective of surgery is to try to improve the patient's quality of life

[Patient with testosterone deficit syndrome after radical prostatectomy]. / Paciente con síndrome de déficit de testosterona tras prostatectomía radical.

Testosterone Deficiency Syndrome is associated with age. Recent studies advocate for the safety of hormonal treatment with testosterone in patients with history of Prostate Cancer (PC) ,once disease-free survival is confirmed. A total of five publications describe 110 patients treated with testosterone replacement therapy, having a history of PC, who had undergone radical prostatectomy (RP). Only one patient had biochemical recurrence during replacement therapy. Testosterone replacement therapy must be indicated in selected patients with history of low risk localized prostate cancer treated satisfactorily who are symptomatic and have good oncological control. The testosterone levels to achieve should be the minimum effective to obtain a symptomatic response. Adequate information on the benefits and potential risks must be understood and accepted by the patient.

[Patient with testosterone deficit syndrome and erectile dysfunction non-responder to PDE-5 inhibitors]. / Paciente con sdt y ed no respondedor a inhibidores de la 5PDE.

Androgens play an essential role in the corporo-venous occlusive mechanism that provokes erection. Accordingly to various studies based on animal models,testosterone deficit syndrome causes an endothelial disorder in the corpora cavernosa with diminished secretion of NO, alteration of penile smooth muscle and tunica albuginea structure, and increase of the number of adipocytes within the erectile tissue, which favors fibrosis and impairs erection. All these alterations are reversible with the exogenous administration of androgens. There are not enough studies to get definitive conclusions about androgen supply improving erectile dysfunction in patients with hypogonadism. Studies have been published in which seems that exogenous testosterone could be useful in the treatment of this type of patients. Nevertheless,in most published randomized double blind studies comparing with placebo, testosterone supply does not provide greater benefit on erectile dysfunction than PDE-5 Inhibitors exclusively. All studies coincide in the need to optimize the treatment with PDE-5 Inhibitors since they do have proven to be effective for the treatment of erectile dysfunction in patients with testosterone deficit syndrome.

Paciente con SDT tras prostatectomía radical / Patient with testosterone deficit syndrome after radical prostatectomy

El síndrome de déficit de testosterona (SDT) define un cuadro clínico y bioquímico asociado a la edad que produce un detrimento en la calidad de vida de estos pacientes. Estudios recientes abogan por la seguridad del tratamiento hormonal con testosterona en pacientes con historia de cáncer de próstata (CP) al no haberse demostrado inducción de este tumor. Un total de cinco publicaciones presentan resultados de 110 pacientes tratados con testosterona con historia de CP intervenidos mediante prostatectomía radical (PR). Solo un paciente presentó recidiva bioquímica durante el tratamiento sustitutivo. La terapia de reemplazamiento con testosterona ha de ser indicada en pacientes seleccionados que se encuentren sintomáticos y con historia de cáncer localizado de bajo riesgo tratado de manera satisfactoria y buen control oncológico. Las cifras de testosterona a alcanzar y mantener serán las mínimas eficaces que permitan obtener una respuesta sintomática. Una correcta y adecuada información de los beneficios y potenciales riesgos han de ser entendidos y aceptados por el paciente (AU)

Testosterone Deficiency Syndrome is associated with age. Recent studies advocate for the safety of hormonal treatment with testosterone in patients with history of Prostate Cancer (PC), once disease-free survival is confirmed. A total of five publications describe 110 patients treated with testosterone replacement therapy, having a history of PC, who had undergone radical prostatectomy (RP). Only one patient had biochemical recurrence during replacement therapy. Testosterone replacement therapy must be indicated in selected patients with history of low risk localized prostate cancer treated satisfactorily who are symptomatic and have good oncological control. The testosterone levels to achieve should be the minimum effective to obtain a symptomatic response. Adequate information on the benefits and potential risks must be understood and accepted by the patient (AU)

Paciente con SDT y DE no respondedor a 5IPDE / Patient with testosterone deficit syndrome and erectile dysfunction non-responder to PDE-5 inhibitors

Los andrógenos juegan un papel fundamental en el mecanismo corporo-venooclusivo que provoca la erección. Según diversos estudios basados en modelos animales, el déficit de testosterona provoca una alteración del endotelio de los cuerpos cavernosos con disminución de secreción de NO, alteración en la estructura del músculo liso y la túnica albugínea del pene y aumento de la cantidad de adipocitos en el tejido eréctil lo que favorece la fibrosis y dificulta la erección. Todas estas alteraciones son reversibles con la administración exógena de andrógenos. No existen estudios suficientes que permitan extraer conclusiones definitivas sobre que el aporte de andrógenos en pacientes con hipogonadismo mejore la función eréctil. Se han publicado estudios en los que parece que la testosterona exógena podría ser útil en el tratamiento de este tipo de pacientes. Sin embargo en la mayoría de estudios aleatorizados doble ciego y comparados con placebo publicados, la administración de testosterona no aporta mayor beneficio sobre la función eréctil que el tratamiento con inhibidores de la fosfodiesterasa 5 (PDE5) exclusivamente. En lo que coinciden todos los estudios es en la necesidad de optimizar el tratamiento con inhibidores de la PDE5 ya que éstos sí han demostrado ser efectivos para el tratamiento de la disfunción eréctil en pacientes con síndrome de déficit de testosterona (AU)

Androgens play an essential role in the corporo-venous occlusive mechanism that provokes erection. Accordingly to various studies based on animal models, testosterone deficit syndrome causes an endothelial disorder in the corpora cavernosa with diminished secretion of NO, alteration of penile smooth muscle and tunica albuginea structure, and increase of the number of adipocytes within the erectile tissue, which favors fibrosis and impairs erection. All these alterations are reversible with the exogenous administration of androgens. There are not enough studies to get definitive conclusions about androgen supply improving erectile dysfunction in patients with hypogonadism. Studies have been published in which seems that exogenous testosterone could be useful in the treatment of this type of patients. Never screetheless, in most published randomized double blind studies comparing with placebo, testosterone supply does not provide greater benefit on erectile dysfunction than PDE-5 Inhibitors exclusively. All studies coincide in the need to optimize the treatment with PDE-5 Inhibitors since they do have proven to be effective for the treatment of erectile dysfunction in patients with testosterone deficit syndrome (AU)