4-MU is an effective nontoxic, oral chemopreventive, and therapeutic agent that targets PCa development, growth, and metastasis by abrogating HA signaling.

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.

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Study Type – Therapy (case series)
Level of Evidence 4 OBJECTIVE To study guideline recommendation (GR)‐concordance rates of treatment in elderly patients with urothelial carcinoma of the bladder (UCB) and to identify predictors of survival. PATIENTS AND METHODS The records of 206 consecutive patients aged ≥75 years (median age 79 years; range 75–95) were reviewed. All patients underwent transurethral resection (TUR) or biopsy of UCB. The European Association of Urology and American Urological Association guidelines were used as reference when evaluating concordance with GRs and clinical outcome. Univariable and multivariable analyses were performed to identify predictors of survival. RESULTS The overall GR‐concordance rate of treatment was 88.8% (183 of 206 patients). Patients who were older (P= 0.017), who underwent prior treatment for UCB (P= 0.010), and had greater comorbidities (P= 0.001) were less likely to undergo treatment following GRs. With a median (mean; range) follow‐up of 14.7 (22.6; 0.3–111.5) months, 79 patients died (38.3%). More comorbidities (unadjusted Charlson comorbidity index; P= 0.007), a Karnofsky performance status (KPS) score of ≤80 (P= 0.001) and more advanced initial pathological tumour stage (P= 0.019) independently predicted reduced overall survival (OS). In the subgroup of patients with indication for cystectomy (n= 99), there was a trend for longer OS in patients treated with curative intent (cystectomy or radio‐chemotherapy) compared with conservative treatment with TUR ± intravesical therapy only (P= 0.095). CONCLUSIONS The vast majority of elderly patients with UCB received adequate treatment at our tertiary institution. The KPS score, more comorbidities and more advanced pathological tumour stage are predictors for reduced OS and should be considered to optimize patient care.

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