Perioperative Immune Checkpoint Blockade for Muscle-Invasive and Metastatic Bladder Cancer.

Checkpoint inhibitors offer promise in treating muscle-invasive and metastatic bladder cancer, but the optimal timing of their administration-neoadjuvant or adjuvant-remains unclear. To determine the efficacy of combining checkpoint inhibition with standard cisplatin-based chemotherapy, we conducted a phase II trial of neoadjuvant anti-PD-1 (αPD-1) and anti-CTLA-4 (αCTLA-4), in combination with cisplatin-gemcitabine, for patients with muscle-invasive bladder cancer prior to radical cystectomy. In addition, a novel murine model of spontaneous metastatic bladder cancer was used to compare the efficacy of neoadjuvant versus adjuvant anti-PD-L1 (αPD-L1) treatment. The clinical trial was closed prematurely due to the industry's withdrawal of drug provision. Adverse events were observed in all patients; however, serious adverse events were not observed in any patient. A complete pathologic response was observed in 50% of the 4 patients enrolled. Response to treatment was significantly associated with elevated urinary T cells including CD8+ and IFNγ+ CD4+ T cells, suggesting potential reinforcement of immune responses by neoadjuvant αPD-1 and αCTLA-4 against bladder tumor cells. These findings suggest that combining chemotherapy and immunotherapy in the neoadjuvant setting could be safe. However, the complete response rate of this four-drug regimen was modest and emphasizes the need for randomized controlled trials to properly assess immunotherapy efficacy in the neoadjuvant setting. In corresponding murine studies, the MB49-met model consistently displayed widespread metastasis, including tumor growth in the lungs, liver, and bowel mesentery, within 20 days of subcutaneous transplantation. Mice receiving surgery plus neoadjuvant αPD-L1 or adjuvant αPD-L1 exhibited improved survival compared to those receiving only αPD-L1. However, no significant difference in survival was observed between the neoadjuvant and adjuvant αPD-L1 cohorts. Furthermore, the timing of neoadjuvant therapy administration (early vs. late) did not significantly impact survival. This study highlights the potential of perioperative immunotherapy in the treatment of locally advanced and metastatic bladder cancer.

Impact of Finasteride on Survival in Bladder Cancer: A Retrospective Multi-institutional Database Analysis.

INTRODUCTION: Androgen suppression therapy has been associated with a lower incidence of bladder cancer (BCa) or improved overall/cancer-specific survival. Results are ofent conflicting; therefore, we aim to assess the impact of use of finasteride on overall survival (OS) for BCa using multi-institutional database. METHODS: The South Texas Veterans Healthcare System from 5 medical centers was queried for patients with BCa with or without use of finasteride after diagnosis of BCa. The primary outcome was the impact of finasteride use after diagnosis on the OS in BCa and in the high-risk Non-muscle invasive BCa (NMIBC) cohort. RESULTS: A total of 1890 patients were included, amongst which 619 (32.8%) men were classified as finasteride users and 1271 (67.2%) men as controls. At a median (IQR) follow up of 53.8 (27.4, 90.9) months, death due to any cause was noted in 272 (43.9%) finasteride-treated, and 672 (49.3%) control groups (P = .028). The patients in the finasteride group had significantly better OS in overall cohort (112.1 months vs. 84.8 months, P < .001) as well as in the NMIBC cohort (129.3months vs. 103.2 months, P = .0046). The use of finasteride was independently associated with improved OS in both, overall cohort (HR 0.74, 95% CI 0.63-0.86; P < .001) and in the NMIBC cohort (HR = 0.71, 95% CI 0.55-0.93; P = .011). CONCLUSION: Finasteride use is associated with the improved overall survival in patients with BCa, specifically in patients with NMIBC. We, further, propose a randomized clinical trial to investigate the use of finasteride in BCa patients.

Development and implementation of competency-based assessment for urological ultrasound training using SonoSim: A preliminary evaluation.

INTRODUCTION: Urology residents are encouraged to learn ultrasound (U/S) imaging, yet there are few tools available for teaching and assessing a resident`s competence. The aim of this study was to test the new SonoSim LiveScan® and to propose a competency-based assessment model for the urology graduate medical education. MATERIALS AND METHODS: Urology residents attended an interactive training session covering the urological U/S techniques guided by the assessment model developed by the authors. Faculty members evaluated the residents using defined objectives, and the residents were surveyed on their comfort level for performing each of the model tasks. A subset of the residents then underwent a structured testing using the SonoSim LiveScan device 6 months following the training. The model developed assessed: general U/S setup, structure identification, and pathologic clinical scenarios. RESULTS: The residents felt most comfortable in identifying the bladder (4.73/5) and the kidneys (4.53/5) during the training sessions. They felt least comfortable while testing for total ureteric obstruction (3.13/5). All the residents were confident that additional U/S training sessions would improve their comfort level in performing the assessed objectives. Resident`s assessment performed at 6 months had a median test score of 15.5/20 and the assessment scores increased with resident seniority. Self-reported comfort, however, did not seem to correlate with seniority. In general, the residents felt that the SonoSim device was highly functional (4.4/5) and the pathologic assessments in particular were very helpful (4.4/5). CONCLUSIONS: Through pilot testing, we propose that a competency-based assessment used with the SonoSim LiveScan could guide the resident`s education through the acquisition of U/S skills and warrants testing in a larger cohort.

Urinary Diversion Disparity Following Radical Cystectomy for Bladder Cancer in the Hispanic Population.

OBJECTIVE: To determine if disparities in quality of surgical care exist between Hispanics and non-Hispanics undergoing radical cystectomy for bladder cancer. MATERIALS AND METHODS: An observational cohort study was conducted retrospectively on patients who underwent radical cystectomy for urothelial carcinoma of the bladder at our institution between January 2005 and July 2018. Data was collected on demographic, clinical, and pathological characteristics of patients, including self-reported ethnicity. Univariable and multivariable logistic or linear regression analyses were used to evaluate the association of ethnicity with receipt of neoadjuvant chemotherapy, utilization of laparoscopic surgery, number of lymph nodes removed, and continent urinary diversion. RESULTS: We identified 507 patients in our database out of which, 136 (27%) were Hispanic and 371 (73%) were non-Hispanic. Compared to non-Hispanics, Hispanics had a higher body mass index (26.9 kg/m2 vs 28.2 kg/m2, P = .006) and lived further away from site of surgery (34 vs 96 miles, P = .02). No significant differences were observed in receipt of neoadjuvant chemotherapy, laparoscopic surgery, or number of lymph nodes removed during cystectomy between ethnicity groups. However, Hispanics were less likely than non-Hispanics to receive a continent urinary diversion on multivariable analysis (odds ratio 0.30, 95% confidence interval 0.10 - 0.92, P = .03). CONCLUSION: Disparity exists in the delivery of continent urinary diversions for Hispanic patients undergoing radical cystectomy for bladder cancer. Further investigation is needed to determine the potential causes for this disparity in care delivered.

Phosphatidylserine on viable sperm and phagocytic machinery in oocytes regulate mammalian fertilization.

Fertilization is essential for species survival. Although Izumo1 and Juno are critical for initial interaction between gametes, additional molecules necessary for sperm:egg fusion on both the sperm and the oocyte remain to be defined. Here, we show that phosphatidylserine (PtdSer) is exposed on the head region of viable and motile sperm, with PtdSer exposure progressively increasing during sperm transit through the epididymis. Functionally, masking phosphatidylserine on sperm via three different approaches inhibits fertilization. On the oocyte, phosphatidylserine recognition receptors BAI1, CD36, Tim-4, and Mer-TK contribute to fertilization. Further, oocytes lacking the cytoplasmic ELMO1, or functional disruption of RAC1 (both of which signal downstream of BAI1/BAI3), also affect sperm entry into oocytes. Intriguingly, mammalian sperm could fuse with skeletal myoblasts, requiring PtdSer on sperm and BAI1/3, ELMO2, RAC1 in myoblasts. Collectively, these data identify phosphatidylserine on viable sperm and PtdSer recognition receptors on oocytes as key players in sperm:egg fusion.

The Microbiome and Prostate Cancer Risk.

PURPOSE OF THE REVIEW: There is an abundance of evidence that the human microbiome plays an important and nuanced role in controlling human metabolism, immunity, and cancer. Herein we aim to review the most current research looking at prostate cancer and its link with the gut and genitourinary microbiome. There is now a host of evidence for a unique genitourinary (GU) microbiome. The prostate microbiota, to include viral, bacterial, fungal, and parasitic contributions, as assessed from formalin-fixed tissue is described nicely in the study by Banerjee et al. Further hierarchical analysis by this group found a unique microbiome signature for higher Gleason score cancers and validation PCR studies noted a marked number of viral genomic insertions into host DNA. Shretha et al. also recently established unique GU microbiomes in patients with prostate cancer or benign prostate pathology based on urine samples. The gut microbiome likely also has an indirect but significant role in prostate cancer development and treatment. Liss et al. and Golombos et al. found significant associations between specific gut microbiota and prostate cancer. Interestingly, the balance of inflammatory and anti-inflammatory bacterial lipopolysaccharides, production of bile salts, and metabolism of dietary fiber to short chain fatty acids all likely play important roles in creating systemic pro- or anti-carcinogenic states. In terms of prostate cancer treatment effects, Sfanos et al. noted a unique microbial signature in patients undergoing oral androgen deprivation therapy (ADT) as compared with prostate cancer patients not on ADT. Patients undergoing ADT also had enrichment of bacterial metabolic pathways promoting androgen synthesis. Together, these studies have identified a unique GU microbiome and linked both the GU microbiome and unique gut microbial signatures with prostate cancer and prostate cancer treatments. Whether this information can be used in cancer prevention, treatment, or diagnosis are areas of ongoing and active research.

Bacillus Calmette-Guérin treatment of bladder cancer: a systematic review and commentary on recent publications.

PURPOSE OF REVIEW: Bacillus Calmette-Guérin (BCG) is the standard immune therapy for nonmuscle invasive bladder cancer. A systematic review of published articles regarding BCG treatment of bladder cancer was conducted and a commentary of these is provided to gain a perspective of the current major developments in the field. RECENT FINDINGS: Several BCG strains are utilized worldwide. As the understanding of genetic and phenotypic differences in these strains is elucidated, inquiries into the potential clinical effects of these various strains have been studied. Data suggest that some strains could be more effective than others but further study is needed. Although response to BCG is heterogenous, current clinical practice does not incorporate use of biomarkers to delegate treatment selection. Thus, biomarker prediction is an important area of research in this area. Novel urine and tissue markers show promise in this endeavor. Notable publications also include mechanistic studies showing a role for T cells, natural killer cells, mast cells, and granulocytes in BCG's antitumor efficacy. SUMMARY: Significant developments have occurred in understanding BCG's response and mechanism of action, which remains incompletely understood. Future work includes efforts to create recombinant BCG strains to decrease side effects, repeated instillations, and increase overall efficacy.

Clomiphene Citrate for the Treatment of Hypogonadism.

INTRODUCTION: Clomiphene citrate (CC) is a selective estrogen receptor modulator that has been used for the treatment of hypogonadism in men since the 1970s. It acts centrally to increase secretion of luteinizing hormone and follicle-stimulating hormone, thereby increasing testosterone production and serum levels. Unlike testosterone replacement therapy, CC does not suppress the hypothalamic-pituitary-gonadal axis, preserving intratesticular testosterone production and spermatogenesis. This is especially useful in treating hypogonadal men who are interested in fertility. AIM: To review the literature regarding the use of CC in the setting of hypogonadism. METHODS: A review of the relevant literature through September 2018 was performed via PubMed. MAIN OUTCOME MEASURE: The data regarding the efficacy and safety of CC when used in the setting of hypogonadism is summarized. RESULTS: Although results are mixed, many studies show CC reduces symptoms in hypogonadal men. Studies have also shown improvement in erectile function and bone mineral density, as well as a reduction in body mass index. There have been few studies investigating fertility rates in hypogonadal men treated with CC, but a metaanalysis of these shows significant improvement in fertility rates. Several studies show improvement in semen parameters. Few studies have investigated adverse effects of the drug. Reports include headache, dizziness, gynecomastia, and exacerbation of psychiatric illnesses. Despite these reports, CC is generally considered to be safe and well tolerated. CONCLUSION: CC is safe and effective and should remain in the armament of urologists treating hypogonadal men, especially men interested in preservation of fertility. Wheeler KM, Sharma D, Kavoussi PK, et al. Clomiphene citrate for the treatment of hypogonadism. Sex Med Rev 2019;7:272-276.

A Comparison of Secondary Polycythemia in Hypogonadal Men Treated with Clomiphene Citrate versus Testosterone Replacement: A Multi-Institutional Study.

PURPOSE: We evaluated the relative prevalence of secondary polycythemia in hypogonadal men treated with clomiphene citrate or testosterone replacement therapy. MATERIALS AND METHODS: In this retrospective, multi-institutional study, we included 188 men who received clomiphene citrate and 175 who received testosterone replacement therapy with symptomatic hypogonadism. The overall prevalence and ORs of secondary polycythemia for clomiphene citrate treatment vs testosterone replacement were primarily measured, as were baseline characteristics. Subset analysis included polycythemia rates for different types of testosterone replacement therapy. RESULTS: Overall, men on testosterone replacement therapy were older than clomiphene citrate treated men (age 51.5 vs 38 years). Men on testosterone replacement had longer treatment duration than clomiphene citrate treated men (19.6 vs 9.2 months). For testosterone replacement therapy and clomiphene citrate the mean change in hematocrit was 3.0% and 0.6%, and the mean change in serum testosterone was 333.1 and 367.6 ng/dl, respectively. The prevalence of polycythemia in men on testosterone replacement was 11.2% vs 1.7% in men on clomiphene citrate (p = 0.0003). This significance remained on logistic regression after correcting for age, site, smoking history and pretreatment hematocrit. CONCLUSIONS: The prevalence of polycythemia in men treated with clomiphene citrate was markedly lower than that in men on testosterone replacement therapy. The improvement in absolute serum testosterone levels was similar to that in men on testosterone replacement. There is no significant risk of polycythemia in men treated with clomiphene citrate for hypogonadism.

Percutaneous microwave ablation of T1a and T1b renal cell carcinoma: short-term efficacy and complications with emphasis on tumor complexity and single session treatment.

PURPOSE: To update the oncologic outcomes and safety for microwave (MW) ablation of T1a (≤4.0 cm) and T1b (4.1-7.0 cm) renal cell carcinoma (RCC) with emphasis on tumor complexity and single session treatment. MATERIALS AND METHODS: Retrospective review of 29 consecutive patients (30 tumors) with localized (NOMO) RCC (23 T1a; 7 T1b) treated with percutaneous MW ablation between 3/2013 and 6/2014. Primary outcomes investigated were technical success, local tumor progression (LTP), and complications. Technical success was assessed with contrast-enhanced computed tomography (CECT) immediately after MW ablation. Presence of LTP was assessed with CECT or contrast-enhanced magnetic resonance at 6-month target intervals for the first two years and annually thereafter. Complications were categorized using the Clavien-Dindo classification system. RESULTS: Median tumor diameter was 2.8 cm [IQR 2.1-3.3] for T1a and 4.7 cm [IQR 4.1-5.7] for T1b tumors. Median RENAL nephrometry score was 7 [IQR 4-8] for T1a tumors and 9 [IQR 6.25-9.75] for T1b tumors. Technical success was achieved for 22 T1a (96%) and 7 T1b (100%) tumors. There were no LTP during a median imaging follow-up of 12.0 months [IQR 6-18] for the 23 patients (24 tumors) with greater than 6 months of follow-up. There were three Clavien-Dindo grade I-II complication (10%) and no Clavien-Dindo grade III-V complications (0%). All but two patients (93%) are alive without metastatic disease; two patients died after 12-month follow-up of causes unrelated to the MW ablation. CONCLUSION: Percutaneous MW ablation appears to be a safe and effective treatment option for low, moderate, and highly complex T1a and T1b RCC in early follow-up.

Boosting Apoptotic Cell Clearance by Colonic Epithelial Cells Attenuates Inflammation In Vivo.

Few apoptotic corpses are seen even in tissues with high cellular turnover, leading to the notion that the capacity for engulfment in vivo is vast. Whether corpse clearance can be enhanced in vivo for potential benefit is not known. In a colonic inflammation model, we noted that the expression of the phagocytic receptor Bai1 was progressively downmodulated. Consistent with this, BAI1-deficient mice had more pronounced colitis and lower survival, with many uncleared apoptotic corpses and inflammatory cytokines within the colonic epithelium. When we engineered and tested transgenic mice overexpressing BAI1, these had fewer apoptotic cells, reduced inflammation, and attenuated disease. Boosting BAI1-mediated uptake by intestinal epithelial cells (rather than myeloid cells) was important in attenuating inflammation. A signaling-deficient BAI1 transgene could not provide a similar benefit. Collectively, these complementary genetic approaches showed that cell clearance could be boosted in vivo, with potential to regulate tissue inflammation in specific contexts.

Occult Radiographically Evident Port-Site Hernia After Robot-Assisted Urologic Surgery: Incidence and Risk Factors.

PURPOSE: Laparoscopic trocar-site hernias (TSH) are rare, with a reported incidence of 1% or less. The incidence of occult radiographically evident hernias has not been described after robot-assisted urologic surgery. We evaluated the incidence and risk factors of this problem. MATERIALS AND METHODS: A single-institution retrospective review of robot-assisted urologic surgery was performed from April 2009 to December 2012. Patients with preoperative and postoperative CT were included for analysis. Imaging was reviewed by two radiologists and one urologist. RESULTS: One hundred four cases were identified, including 60 partial nephrectomy, 38 prostatectomy, and 6 cystectomy. Mean age was 58 years and mean body mass index (BMI) was 29 kg/m(2). The cohort was 77% male. Ten total hernias were identified by CT in 8 patients, 2 of which were clinically evident hernias. Excluding these two hernias, occult port-site hernias were identified radiographically in seven patients. Per-patient incidence of occult TSH was 6.7% (7/104), and per-port incidence was 1.4% (8/564). All hernias were midline and 30% contained bowel. Eight of the 10 occurred at 12 mm sites (p = 0.0065) and 3 of the 10 occurred at extended incisions. Age, gender, BMI, smoking status, diabetes mellitus, immunosuppressive drug therapy, ASA score, procedure, blood loss, prior abdominal surgery, and history of hernia were not significant risk factors. Specimen size >40 g (p = 0.024) and wound infection (p = 0.0052) were significant risk factors. CONCLUSION: While the incidence of clinically evident port-site hernia remains low in robot-assisted urologic surgery, the incidence of CT-detected occult hernia was 6.7% in this series. These occurred most often in sites extended for specimen extraction and at larger port sites. This suggests more attention should be paid to fascial closure at these sites.

Cutting edge: normal regional lymph node enrichment of antigen-specific regulatory T cells with autoimmune disease-suppressive capacity.

Natural CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) effectively prevent autoimmune disease development, but their role in maintaining physiological tolerance against self-Ag of internal organs is not yet defined. In this study, we quantified disease-specific Treg (DS-Treg) as Treg that preferentially suppress one autoimmune disease over another in day 3 thymectomized recipients. A striking difference was found among individual lymph nodes (LN) of normal mice; Treg from draining LN were 15-50 times more efficient than those of nondraining LN at suppressing autoimmune diseases of ovary, prostate, and lacrimal glands. The difference disappeared upon auto-Ag ablation and returned upon auto-Ag re-expression. In contrast, the CD4(+)CD25(-) effector T cells from different individual LN induced multiorgan inflammation with comparable organ distribution. We propose that peripheral tolerance for internal organs relies on the control of autoreactive effector T cells by strategic enrichment of Ag-specific Treg in the regional LN.

Cutting edge: Autoimmune disease in day 3 thymectomized mice is actively controlled by endogenous disease-specific regulatory T cells.

Female B6AF1 mice thymectomized on day 3 (d3tx) develop autoimmune ovarian disease (AOD) and dacryoadenitis. It has been hypothesized that d3tx breaks tolerance by depleting late ontogeny regulatory T cells (Treg). We now report that Treg greatly expand over effector T cells in d3tx mice and adoptively suppress autoimmune disease in d3tx recipients. In the d3tx donors, Treg from ovarian lymph nodes (LN) preferentially suppress AOD and Treg from lacrimal gland LN preferentially suppress dacryoadenitis, suggesting they are strategically positioned for disease control. Indeed, the autologous disease in d3tx mice is dramatically enhanced by in vivo depletion of endogenous Treg. Moreover, normal 3-day-old mice possess Treg that suppress AOD and autoimmune gastritis as efficiently as adult cells. Thus, d3tx mice possess disease-relevant Treg of presumed neonatal origin. They accumulate in the regional LN and actively inhibit concurrent autoimmune disease; however, they cannot fully prevent autoimmune disease development.

Surface electromyographic activity of the submental muscles during swallow and expiratory pressure threshold training tasks.

The use of expiratory muscle strength trainers improves parameters related to pulmonary function, speech, and cough in both healthy and patient populations. Recently, it has been speculated that expiratory strength training may alter the force generation of muscles used during the swallow process. Specifically, the use of the trainer may result in increased activation of the submental muscle complex. Support for this hypothesis was tested by examining the timing and amplitude of submental muscle activity obtained using surface EMG. These muscles are known to be important for normal swallow function. Twenty participants (10 males, 10 females; mean age = 29 years) were recruited to participate in a one-session study. Participants were asked to perform two swallows (saliva swallow and water swallow) and develop an expiratory pressure set at 25% and 75% of their maximum expiratory pressure (MEP) using an expiratory muscle strength trainer. These tasks allowed comparison of muscle activity during both the swallow and expiratory tasks completed with the trainer. Results indicated that the patterns of activation in the submental muscle group while training on the expiratory device had longer duration of activation with higher amplitude of EMG activity when compared with the swallowing condition. These findings indicate that expiratory muscle strength training (EMST) increases motor unit recruitment of the submental muscle complex. Discussion centers on the potential benefit of EMST as a treatment modality for dysphagia characterized by decreased amplitude of hyoid movement during swallowing.

The relationship between VHI scores and specific acoustic measures of mildly disordered voice production.

This study was designed to examine the relationship between the Voice Handicap Index (VHI) and acoustic measures of voice samples common in clinical practice. Fifty participants, 38 women and 12 men, ranging in age from 19 to 80 years, with a mean age of 49 years, served as participants. Of these 50 participants, 17 participants could be included in the acoustic analysis of voice based on measures of error calculated with the TF32 software. All participants completed the VHI and provided voice samples including three trials of the sustained vowel /A/ at a comfortable loudness level as well as a connected speech sample consisting of the Zoo Passage. Acoustic measures were made with TF32 and Cool Edit software and included fundamental frequency, jitter %, shimmer %, signal-to-noise ratio, mean root-mean-square intensity, fundamental frequency standard deviation, aphonic periods, and breath groups. Results indicate that these measures were not predictive of overall VHI score, and no cohesive or predictable pattern was identified when comparing individual measures with overall VHI or with each subscale item. Likely contributions to this lack of correlation and subsequent clinical implications are discussed, as well as the direction for further research.