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Bacillus Calmette–Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.Bacillus Calmette–Guérin (BCG) has been used to prevent tuberculosis for a century and is also a standard approach for the treatment of non-muscle-invasive bladder cancer. However, BCG also has a plethora of non-specific effects that occur via the induction of trained immunity and have raised the hypothesis that BCG vaccination could be used to protect against coronavirus disease 2019 (COVID-19). In this Perspective, the authors describe the history of BCG, discuss the mechanisms of its effects, and consider its potential role during the COVID-19 pandemic.

In addition to its role as a TB vaccine, BCG has been shown to elicit heterologous protection against many other pathogens including viruses through a process termed trained immunity. Despite its potential as a broadly protective vaccine, little has been done to determine if BCG-mediated trained immunity levels can be optimized. Here we re-engineer BCG to express high levels of c-di-AMP, a PAMP recognized by stimulator of interferon genes (STING). We find that BCG overexpressing c-di-AMP elicits more potent signatures of trained immunity including higher pro-inflammatory cytokine responses, greater myeloid cell reprogramming toward inflammatory and activated states, and enhances epigenetic and metabolomic changes. In a model of bladder cancer, we also show that re-engineered BCG induces trained immunity and improved functionality. These results indicate that trained immunity levels and antitumor efficacy may be increased by modifying BCG to express higher levels of key PAMP molecules. Vaccination with BCG has been shown to induce a pre-priming effect in innate immune cells termed trained immunity. Here the authors re-engineer the BCG vaccine and show augmented immune responses, enhanced induction of trained immunity and improved antitumor efficacy in pre-clinical models of bladder cancer.

Non-muscle-invasive bladder cancer (NMIBC) remains one of the most common malignancies and is associated with considerable treatment costs. Patients with intermediate-risk or high-risk disease can be treated with intravesical BCG, but many of these patients will experience tumour recurrence, despite adequate treatment. Standard of care in these patients is radical cystectomy with urinary diversion, but this approach is associated with considerable morbidity and lifestyle modification. As an alternative, perioperative intravesical chemotherapy is recommended for low-risk papillary NMIBC, and induction intravesical chemotherapy is an option for patients with intermediate-risk NMIBC and BCG-unresponsive NMIBC. However, poor pharmaceutical absorption and drug washout during normal voiding can limit sustained drug concentrations in the urothelium, which reduces efficacy, and small-molecule chemotherapeutic agents can be absorbed through the urothelium into the bloodstream, leading to systemic adverse effects. Several novel drug delivery methods — including hyperthermia, mechanical sustained released devices and nanoparticle drug conjugation — have been developed to overcome these limitations. These novel methods have the potential to be combined with established chemotherapeutic agents to change the paradigm of NMIBC treatment.

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette–Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7–73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4–95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9–68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 . In a single-arm phase 2 trial evaluating intravesical delivery of the oncolytic adenovirus cretostimogene grenadenorepvec with systemic anti-PD-1 in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ, the complete response rate at 12 months was 57.1%, meeting the primary endpoint.

Noninvasive approaches for early detection of bladder cancer are actively being investigated. We recently developed a urine- based molecular assay for the detection and surveillance of bladder neoplasms (UroSEEK). UroSEEK is designed to detect alterations in 11 genes that include most common genetic alterations in bladder cancer. In this study, we analyzed 527 cases, including 373 noninvasive and 154 invasive urothelial carcinomas of bladder from transurethral resections or cystectomies performed at four institutions (1991–2016). Two different mutational analysis assays of a representative tumor area were performed: first, a singleplex PCR assay for evaluation of the TERT promoter region (TERTSeqS) and second, a multiplex PCR assay using primers designed to amplify regions of interest of 10 ( FGFR3, PIK3CA , TP53 , HRAS , KRAS , ERBB2 , CDKN2A , MET , MLL , and VHL ) genes (UroSeqS). Overall, 92% of all bladder tumors were positive for at least one genetic alteration in the UroSEEK panel. We found TERT promoter mutations in 77% of low-grade noninvasive papillary carcinomas, with a relatively lower incidence of 65% in high-grade noninvasive papillary carcinomas and carcinomas in situ; p  = 0.017. Seventy-two percent of pT1 and 63% of muscle-invasive bladder tumors harbored TERT promoter mutations with g.1295228C>T alteration being the most common in all groups. FGFR3 and PIK3CA mutations were more frequent in low-grade noninvasive papillary carcinomas compared with high-grade noninvasive papillary carcinomas and carcinomas in situ ( p  < 0.0001), while the opposite was true for TP53 ( p  < 0.0001). Significantly higher rates of TP53 and CDKN2A mutation rates ( p  = 0.005 and 0.035, respectively) were encountered in muscle-invasive bladder tumors compared with those of pT1 stage. The overwhelming majority of all investigated tumors showed at least one mutation among UroSEEK assay genes, confirming the comprehensive coverage of the panel and supporting its potential utility as a noninvasive urine-based assay.

Surgical correction of urethral strictures by substitution urethroplasty — the use of grafts or flaps to correct the urethral narrowing — remains one of the most challenging procedures in urology and is frequently associated with complications, restenosis and poor quality of life for the affected individual. Tissue engineering using different cell types and tissue scaffolds offers a promising alternative for tissue repair and replacement. The past 30 years of tissue engineering has resulted in the development of several therapies that are now in use in the clinic, especially in treating cutaneous, bone and cartilage defects. Advances in tissue engineering for urethral replacement have resulted in several clinical applications that have shown promise but have not yet become the standard of care.Tissue engineering using different cell types and tissue scaffolds offers a promising alternative to substitution urethroplasty, which can be associated with complications, restenosis and poor quality of life. In this Review, the authors describe advances in tissue engineering for urethral replacement and consider the future of the field.

BackgroundCD24 is a cornerstone of tumour progression in urothelial carcinoma of the bladder (UCB). However, its contribution to cancer stem cell (CSC)-like traits and the clinical utility of CD24 as a urinary biomarker for cancer detection have not been determined.MethodsThe functional relevance of CD24 was evaluated using in vitro and in vivo approaches. The clinical utility of CSC-related molecules was assessed in urine samples by quantitative RT-PCR.ResultsThe knockdown of CD24 attenuated cancer stemness properties. The high-CD24-expressing cells, isolated from patient-derived UCB xenograft tumours, exhibited their enhanced stemness properties. CD24 was overexpressed not only in primary tumours but also in urine from UCB subjects. By assessment of 15 candidate CSC-related molecules in urine samples of a training cohort, a panel of three molecules (CD24, CD49f, and NANOG) was selected. The combination of these three molecules yielded a sensitivity and specificity of 81.7% and 74.3%, respectively, in an independent cohort. A combined set of 84 cases and 207 controls provided a sensitivity and specificity of 82% and 76%, respectively.ConclusionCD24 has a crucial role in maintaining the urothelial cancer stem-like traits and a panel of CSC-related molecules has potential as a urinary biomarker for non-invasive UCB detection.

Sudden emotional distress, such as that caused by an unexpected death, can sometimes produce severe transient left ventricular dysfunction. This stress-induced cardiomyopathy appears to be a form of myocardial stunning associated with marked sympathetic stimulation. Sudden emotional distress, such as that caused by an unexpected death, can sometimes produce severe transient left ventricular dysfunction. The potentially lethal consequences of emotional stress are deeply rooted in folk wisdom, as reflected by phrases such as “scared to death” and “a broken heart.” In the past decade, cardiac contractile abnormalities and heart failure have been reported after acute emotional stress, 1 – 6 but the mechanism remains unknown. We evaluated 19 patients with “stress cardiomyopathy,” a syndrome of profound myocardial stunning precipitated by acute emotional stress, in an effort to identify the clinical features that distinguish this syndrome from acute myocardial infarction and the cause of transient stress-induced myocardial dysfunction. Methods Study Patients Nineteen previously healthy patients were admitted . . .

Blue light cystoscopy (BLC) with hexaminolevulinate (HAL) during transurethral resection of bladder cancer improves detection of non-muscle-invasive bladder cancer (NMIBC) and reduces recurrence rates. Flexible BLC was approved by the FDA in 2018 for use in the surveillance setting and was demonstrated to improve detection. Results of a phase III prospective multicentre study of blue light flexible cystoscopy (BLFC) in surveillance of intermediate-risk and high-risk NMIBC showed that 20.6% of malignancies were identified only by BLFC. Improved detection rates in the surveillance setting are anticipated to lead to improved clinical outcomes by reducing future recurrences and earlier identification of tumours that are unresponsive to therapy. Thus, BLFC has a role in surveillance cystoscopy, and determining which patients will benefit from BLFC and optimal and cost-effective ways of incorporating this technology into surveillance cystoscopy must be developed.In this Consensus Statement, experts in the field detail the current evidence regarding blue light flexible cystoscopy for bladder cancer surveillance and make recommendations regarding its use on the basis of conclusions arrived at during the panel discussions at a consensus meeting.

Key Points RhoA–ROCK signalling is important for erectile homeostasis, and acts by potentiating Ca 2+ -dependent contraction to maintain penile flaccidity Dysregulation of the RhoA–ROCK pathway has an important role in the aetiology of erectile dysfunction RhoA–ROCK inhibition improves erectile dysfunction, even for hard-to-treat causes, such as diabetes Several RhoA–ROCK inhibitors are being investigated in clinical trials and could provide new treatment options Treatment of erectile dysfunction by maximizing nitric oxide signalling is not effective for all aetiologies of the condition. In this Review, the authors describe the role of the Rho kinase pathway in erectile dysfunction, its interactions with the nitric oxide pathway and progress towards therapeutic modulation of Rho kinase signalling. Erectile dysfunction (ED) is a common disorder that affects a quarter of US men, and has many causes, including endothelial impairment, low testosterone levels, prior surgical manipulation, and/or psychogenic components. Penile erection is a complex process requiring neurally mediated relaxation of arteriolar smooth muscle and engorgement of cavernosal tissues, mediated by nitric oxide (NO). Current medical therapies for ED largely seek to maximize endogenous NO signalling. Certain aetiologies, including diabetes, are difficult to treat with current modalities, emphasizing the need for new molecular targets. Research has demonstrated the importance of RhoA–Rho-associated protein kinase (ROCK) signalling in maintaining a flaccid penile state, and inhibition of RhoA–ROCK signalling potentiates smooth-muscle relaxation in an NO-independent manner. The mechanisms and effects of RhoA–ROCK signalling and inhibition suggest that the RhoA–ROCK pathway could prove to be a new therapeutic target for the treatment of ED.