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Background and Objective: Management of low-grade (LG) urothelium-confined (Ta stage) non-muscle-invasive bladder cancer (NMIBC) poses a distinct therapeutic challenge. Transurethral resection of bladder tumor (TURBT), the standard treatment, frequently has to be repeated because of high tumor recurrence rates. This places a considerable strain on both patients and health care infrastructure, underscoring the need for alternative management approaches. Herein, the IBCG (International Bladder Cancer Group), conducted a review to explore the efficacy and safety of deintensified treatment strategies for recurrent LG Ta NMIBC., Methods: We conducted a collaborative review of relevant literature in the PubMed/MEDLINE and Cochrane CENTRAL databases. Our focus was on high-quality evidence, including randomized controlled trials, systematic reviews, and meta-analyses. We also reviewed guidelines published by prominent urological associations., Key Findings and Limitations: Active surveillance, chemoablation, and office fulguration are valid treatment options for recurrent LG Ta NMIBC. These deintensified approaches offer several advantages over TURBT: lower complication rates, less morbidity, lower health care costs, and better quality of life for patients. Importantly, these benefits are achieved without compromising oncological safety., Conclusions and Clinical Implications: Our review demonstrates that less intensive treatment strategies for recurrent LG Ta NMIBC are both feasible and valuable. The IBCG recommends use of these approaches for carefully selected patients to help lower health care costs and enhance patients' quality of life., Patient Summary: We reviewed studies on less invasive management options for low-grade noninvasive bladder cancer, including active surveillance, chemical ablation, and heat treatment. Recent results confirm that these less intense treatment options can reduce the treatment burden and costs for patients and preserve their quality of life without negatively affecting cancer control outcomes., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Competing Interests: MSS and NAA have nothing to disclose.

Competing Interests: MSS and NAA have nothing to disclose.

Objectives: To assess whether office-based fulguration (OF) under local anaesthesia for small, recurrent, pathological Ta low-grade (LG) non-muscle-invasive bladder cancer (NMIBC) is an effective alternative to transurethral resection of bladder tumour (TURBT), avoiding the costs and risks of procedure, and anesthesia., Patients and Methods: Of 521 patients with primary TaLG NMIBC, this retrospective study included 270 patients who underwent OF during follow-up for recurrent, small, papillary LG-appearing tumours at a university centre (University Health Network, University of Toronto, Canada). We assessed the cumulative incidence of cancer-specific mortality (CSM) and disease progression (to MIBC or metastases), as well as possible direct cost savings., Results: In the 270 patients with recurrent TaLG NMIBC treated with OF, the mean (sd) age was 64.9 (13.3) years, 70.8% were men, and 60.3% had single tumours. The mean (sd, range) number of OF procedures per patient was 3.1 (3.2, 1-22). The median (interquartile range) follow-up was 10.1 (5.8-16.2) years. Patients also underwent a mean (sd) of 3.6 (3.0) TURBTs during follow-up in case of numerous or bulkier recurrence. In all, 44.4% of patients never received intravesical therapy. The 10-year incidence of CSM and progression were 0% and 3.1% (95% confidence interval 0.8-5.4%), respectively. Direct cost savings in Ontario were estimated at $6994.14 (Canadian dollars) per patient over the study follow-up., Conclusions: This study supports that properly selected patients with recurrent, apparent TaLG NMIBC can be safely managed with OF under local anaesthesia with occasional TURBT for larger or numerous recurrent tumours, without compromising long-term oncological outcomes. This approach could generate substantial cost-saving to healthcare systems, is patient-friendly, and could be adopted more widely., (© 2023 BJU International.)

Competing Interests: Nothing to disclose.

Competing Interests: Nothing to disclose.

Competing Interests: Nothing to disclose.

Objective: Cystoscopy and cauterization performed in the operating room is expensive and exposes patients to anesthesia risks. Patient tolerability during office cystoscopy and cauterization is critical to the office management of bladder cancer (BC) and other urologic diseases. We evaluated the risk factors for pain of flexible cystoscopy in the office-setting with emphasis on a sub-group of BC patients who underwent cauterization., Materials and Methods: Retrospective analyses of 110 anonymous patient surveys completed after cystoscopy and/or cauterization. Survey information included age, gender, indication for cystoscopy, number of prior cystoscopies, number of prior office-based cauterizations, anxiety prior/during cystoscopy, and pain during cystoscopy and/or cauterization. Univariate/multivariate and linear-regression analyses were performed to evaluate the association of pain with clinical parameters., Results: Average pain during cystoscopy (1.75 ± 1.331) was not significantly different when cauterization was also performed (2.37 ± 2.214) (p < 0.001) (p = 0.2840). Patients in the lower age group (<66 years) indicated higher anxiety levels (p = 0.0005), more pain at cystoscopy (P = 0.004) and cauterization (p < 0.001). Although the patients' overall anxiety level was low (1-3/10), it was associated with some pain during cystoscopy (p = 0.0005) and cauterization (p < 0.000). In multivariate analysis, anxiety was the only independent predictor of pain during cystoscopy (p = 0.03, OR: 6.52,95% CI: 1.2-35.6) and cauterization (p = 0.0012, OR: 3.4, 95%CI: 1.6-7.0). In BC patients, pain scores during cystoscopy and cauterization were not significantly different (p = 0.4772) but associated with anxiety., Conclusion: Office-based cystoscopy and cauterization are tolerable with minimal pain. Higher pain levels during cystoscopy were associated with procedure anxiety, and pain during cauterization was associated with procedure anxiety and younger age. Younger and more anxious patients may need more counseling before cystoscopy., (Copyright © 2022 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Competing Interests: MSS and NAA have nothing to disclose.

Background: Hyaluronic acid (HA) promotes cancer metastasis; however, the currently approved treatments do not target HA. Metastatic renal carcinoma (mRCC) is an incurable disease. Sorafenib (SF) is a modestly effective antiangiogenic drug for mRCC. Although only endothelial cells express known SF targets, SF is cytotoxic to RCC cells at concentrations higher than the pharmacological-dose (5-µM). Using patient cohorts, mRCC models, and SF combination with 4-methylumbelliferone (MU), we discovered an SF target in RCC cells and targeted it for treatment., Methods: We analyzed HA-synthase (HAS1, HAS2, HAS3) expression in RCC cells and clinical (n = 129), TCGA-KIRC (n = 542), and TCGA-KIRP (n = 291) cohorts. We evaluated the efficacy of SF and SF plus MU combination in RCC cells, HAS3-transfectants, endothelial-RCC co-cultures, and xenografts., Results: RCC cells showed increased HAS3 expression. In the clinical and TCGA-KIRC/TCGA-KIRP cohorts, higher HAS3 levels predicted metastasis and shorter survival. At > 10-µM dose, SF inhibited HAS3/HA-synthesis and RCC cell growth. However, at ≤ 5-µM dose SF in combination with MU inhibited HAS3/HA synthesis, growth of RCC cells and endothelial-RCC co-cultures, and induced apoptosis. The combination inhibited motility/invasion and an HA-signaling-related invasive-signature. We previously showed that MU inhibits SF inactivation in RCC cells. While HAS3-knockdown transfectants were sensitive to SF, ectopic-HAS3-expression induced resistance to the combination. In RCC models, the combination inhibited tumor growth and metastasis with little toxicity; however, ectopic-HAS3-expressing tumors were resistant., Conclusion: HAS3 is the first known target of SF in RCC cells. In combination with MU (human equivalent-dose, 0.6-1.1-g/day), SF targets HAS3 and effectively abrogates mRCC., (© 2022. The Author(s).)

Competing Interests: Nothing to disclose.

Objective: Patients with low-grade (LG), grade 1-2, Ta bladder cancer (BC) will frequently have a "recurrence". However, they rarely progress in stage. Although current guidelines mention surveillance and office management for these new or recurrent tumors, transurethral resection (TURBT) is the most common treatment. The purpose of this study is to determine if surveillance and/or office cautery is safe., Materials and Methods: This study was conducted as a retrospective case series analysis of 45 patients who had recurrent LG Ta appearing bladder cancer (BC) and were managed primarily with surveillance and/or office cautery. Patients with carcinoma in-situ were excluded. The primary outcome was stage progression., Results: Median follow up was 62 months. 41 (91%) patients did not progress in stage. Three patients recurred with HG T1 BC; one is receiving systemic immunotherapy. One patient developed HG T2 BC and was treated with a bladder preservation protocol. 40 (89%) patients underwent office cauterization. Eleven received BCG and 26 received post-cautery intravesical chemotherapy. Five (11%) patients developed HG BC during follow up. No patients died. None of the 17 (38%) Hispanic patients had progression., Conclusions: Active surveillance and/or office cautery for patients with small recurrent LG Ta bladder tumors is safe, reduces cost and improves quality of life by avoiding TURBTs., (Copyright © 2022 AEU. Published by Elsevier España, S.L.U. All rights reserved.)

Competing Interests: MSS and NAA have nothing to disclose.

Competing Interests: MSS and NAA have nothing to disclose.

Competing Interests: MSS and NAA have nothing to disclose.

Competing Interests: Nothing to disclose.

Competing Interests: Nothing to disclose.

Competing Interests: Nothing to disclose.

Competing Interests: MSS and NAA have nothing to disclose.

The 5-year survival rate of patients with metastatic renal cell carcinoma (mRCC) is <12% due to treatment failure. Therapeutic strategies that overcome resistance to modestly effective drugs for mRCC, such as sorafenib (SF), could improve outcome in mRCC patients. SF is terminally biotransformed by UDP-glucuronosyltransferase-1A9 (A9) mediated glucuronidation, which inactivates SF. In a clinical-cohort and the TCGA-dataset, A9 transcript and/or protein levels were highly elevated in RCC specimens and predicted metastasis and overall-survival. This suggested that elevated A9 levels even in primary tumors of patients who eventually develop mRCC could be a mechanism for SF failure. 4-methylumbelliferone (MU), a choleretic and antispasmodic drug, downregulated A9 and inhibited SF-glucuronidation in RCC cells. Low-dose SF and MU combinations inhibited growth, motility, invasion and downregulated an invasive signature in RCC cells, patient-derived tumor explants and/or endothelial-RCC cell co-cultures; however, both agents individually were ineffective. A9 overexpression made RCC cells resistant to the combination, while its downregulation sensitized them to SF treatment alone. The combination inhibited kidney tumor growth, angiogenesis and distant metastasis, with no detectable toxicity; A9-overexpressing tumors were resistant to treatment. With effective primary tumor control and abrogation of metastasis in preclinical models, the low-dose SF and MU combinations could be an effective treatment option for mRCC patients. Broadly, our study highlights how targeting specific mechanisms that cause the failure of "old" modestly effective FDA-approved drugs could improve treatment response with minimal alteration in toxicity profile.

Purpose: Studies indicate that molecular subtypes in muscle invasive bladder cancer predict the clinical outcome. We evaluated whether subtyping by a simplified method and established classifications could predict the clinical outcome., Materials and Methods: We subtyped institutional cohort 1 of 52 patients, including 39 with muscle invasive bladder cancer, an Oncomine™ data set of 151 with muscle invasive bladder cancer and TCGA (The Cancer Genome Atlas) data set of 402 with muscle invasive bladder cancer. Subtyping was done using simplified panels (MCG-1 and MCG-Ext) which included only transcripts common in published studies and were analyzed for predicting metastasis, and cancer specific, overall and recurrence-free survival. TCGA data set was further analyzed using the Lund taxonomy, the Bladder Cancer Molecular Taxonomy Group Consensus and TCGA 2017 mRNA subtype classifications., Results: Muscle invasive bladder cancer specimens from cohort 1 and the Oncomine data set showed intratumor heterogeneity for transcript and protein expression. MCG-1 subtypes did not predict the outcome on univariate or Kaplan-Meier analysis. On multivariate analysis N stage (p ≤0.007), T stage (p ≤0.04), M stage (p=0.007) and/or patient age (p=0.01) predicted metastasis, cancer specific and overall survival, and/or the cisplatin based adjuvant chemotherapy response. In TCGA data set publications showed that subtypes risk stratified patients for overall survival. Consistently the MCG-1 and MCG-Ext subtypes were associated with overall but not recurrence-free survival on univariate and Kaplan-Meier analyses. TCGA data set included 21 low grade specimens of the total of 402 and subtypes associated with tumor grade (p=0.005). However, less than 1% of muscle invasive bladder cancer cases are low grade. In only high grade specimens the MCG-1 and MCG-Ext subtypes could not predict overall survival. On univariate analysis subtypes according to the Bladder Cancer Molecular Taxonomy Group Consensus, TCGA 2017 and the Lund taxonomy were associated with tumor grade (p <0.0001) and overall survival (p=0.01 to <0.0001). Regardless of classification, subtypes had about 50% to 60% sensitivity and specificity to predict overall and recurrence-free survival. On multivariate analyses N stage and lymphovascular invasion consistently predicted recurrence-free and overall survival (p=0.039 and 0.003, respectively)., Conclusions: Molecular subtypes reflect bladder tumor heterogeneity and are associated with tumor grade. In multiple cohorts and subtyping classifications the clinical parameters outperformed subtypes for predicting the outcome.

Purpose: To update current recommendations on prevention, screening, diagnosis, and evaluation of bladder cancer (BC) based on a thorough assessment of the most recent literature on these topics., Methods: A non-systematic review was performed, including articles until June 2017. A variety of original articles, reviews, and editorials were selected according to their epidemiologic, demographic, and clinical relevance. Assessment of the level of evidence and grade of recommendations was performed according to the International Consultation on Urological Diseases grading system., Results: BC is the ninth most common cancer worldwide with 430,000 new cases in 2012. Currently, approximately 165,000 people die from the disease annually. Absolute incidence and prevalence of BC are expected to rise significantly during the next decades because of population ageing. Tobacco smoking is still the main risk factor, accounting for about 50% of cases. Smoking cessation is, therefore, the most relevant recommendation in terms of prevention, as the risk of developing BC drops almost 40% within 5 years of cessation. BC screening is not recommended for the general population. BC diagnosis remains mainly based on cystoscopy, but development of new endoscopic and imaging technologies may rapidly change the diagnosis algorithm. The same applies for local, regional, and distant staging modalities., Conclusions: A thorough understanding of epidemiology, risk factors, early detection strategies, diagnosis, and evaluation is essential for correct, evidence-based management of BC patients. Recent developments in endoscopic techniques and imaging raise the hope for providing better risk-adopted approaches and thereby improving clinical outcomes.

Background: Aberrantly expressed miRNAs promote renal cell carcinoma (RCC) growth and metastasis and are potentially useful biomarkers for metastatic disease. However, a consensus clinically significant miRNA signature has not been identified. To identify an miRNA signature for predicting clinical outcome in RCC patients, we used a four-pronged interconnected approach. Methods: Differentially expressed miRNAs were identified and analyzed in 113 specimens (normal kidney: 59; tumor: 54). miRNA profiling was performed in matched normal and tumor specimens from 8 patients and extended to 32 specimens. Seven aberrantly expressed miRNAs were analyzed by qPCR, and their levels were correlated with RCC subtypes and clinical outcome. miRNA signature was confirmed in The Cancer Genome Atlas RCC dataset ( n = 241). Results: Discovery phase identified miR-21, miR-142-3p, miR-142-5p, miR-150, and miR-155 as significantly upregulated (2-4-fold) and miR-192 and miR-194 as downregulated (3-60-fold) in RCC; miR-155 distinguished small tumors (<4 cm) from benign oncocytomas. In univariate and multivariate analyses, miRNA combinations (miR-21+194; miR-21+142-5p+194) significantly predicted metastasis and/or disease-specific mortality; miR-21+142-5p+194 (for metastasis): P = 0.0017; OR, 0.53; 95% confidence interval (CI), 0.75-0.33; 86.7% sensitivity; 82% specificity. In the TCGA dataset, combined biomarkers associated with metastasis and overall survival (miR-21+142-5p+194: P < 0.0001; OR, 0.37; 95% CI, 0.58-0.23). Conclusions: The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients. Impact: With 10% survival at 5 years, metastatic disease presents poor prognosis for RCC patients. The three-miRNA signature discovered and validated may potentially at an early stage detect and predict metastasis, to allow early intervention for improving patient prognosis. Cancer Epidemiol Biomarkers Prev; 27(4); 464-72. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Molecular markers of clinical outcome may aid in designing targeted treatments for bladder cancer. However, only a few bladder cancer biomarkers have been examined as therapeutic targets., Methods: Data from The Cancer Genome Atlas (TCGA) and bladder specimens were evaluated to determine the biomarker potential of the hyaluronic acid (HA) family of molecules - HA synthases, HA receptors and hyaluronidase. The therapeutic efficacy of 4-methylumbelliferone (4MU), a HA synthesis inhibitor, was evaluated in vitro and in xenograft models., Results: In clinical specimens and TCGA data sets, HA synthases and hyaluronidase-1 levels significantly predicted metastasis and poor survival. 4-Methylumbelliferone inhibited proliferation and motility/invasion and induced apoptosis in bladder cancer cells. Oral administration of 4MU both prevented and inhibited tumour growth, without dose-related toxicity. Effects of 4MU were mediated through the inhibition of CD44/RHAMM and phosphatidylinositol 3-kinase/AKT axis, and of epithelial-mesenchymal transition determinants. These were attenuated by HA, suggesting that 4MU targets oncogenic HA signalling. In tumour specimens and the TCGA data set, HA family expression correlated positively with β-catenin, Twist and Snail expression, but negatively with E-cadherin expression., Conclusions: This study demonstrates that the HA family can be exploited for developing a biomarker-driven, targeted treatment for bladder cancer, and 4MU, a non-toxic oral HA synthesis inhibitor, is one such candidate.