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Purpose: The monocarboxylate transporter 4 (MCT4) is a metabolic target in tumor biology because it mediates lactate transport across membranes resulting in antiapoptotic effects. Cell experiments support the importance of MCT4 in clear cell renal cell carcinoma (ccRCC). In this study, we assessed the prognostic potential of MCT4 expression in ccRCC and its epigenetic regulation by DNA methylation as novel predictive marker for patient outcome using independent ccRCC cohorts.Experimental Design: MCT4 protein expression was quantified in 207 ccRCC and corresponding nontumor tissues. Data of an independent ccRCC cohort from The Cancer Genome Atlas (TCGA) were analyzed on MCT4 mRNA (n ¼ 482) and DNA methylation (n ¼ 283) level. The findings on MCT4 expression and DNA methylation in the SLC16A3 promoter were validated in a third cohort (n ¼ 64). Promoter activity assays were conducted in four RCC cell lines.Results: MCT4 protein expression was upregulated (P < 0.0001) in ccRCC and showed significant association with cancer-related death. Upregulation of MCT4 mRNA expression (P < 0.00001) was confirmed in the TCGA cohort. Single CpG sites correlated inversely with mRNA expression and were associated with overall survival in Kaplan-Meier analyses [HR ¼ 0.39; 95% confidence interval (CI), 0. Conclusion:We identified SLC16A3 promoter DNA methylation as a novel epigenetic mechanism for MCT4 regulation in ccRCC with first evidence of a biological rationale for prognosis and clinical outcome.

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Take-home messageThis retrospective cohort study involved tissue microarrays of 178 bladder-tumor specimens. We found that for patients with non[en] muscle-invasive bladder cancer, hyaluronoglucosaminidase 1 (HYAL-1) expression has potential as an independent predictor of progression to muscle invasion, tumor recurrence, and metastasis.Financial disclosures: I certify that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/ affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Mario Kramer and Judith Knapp are supported by the International Academy of Life Sciences' Biomedical Science Exchange Program fellowship. Author contributions:Vinata Lokeshwar had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kramer, Golshani, Merseburger, Lokeshwar Acquisition of data: Kramer, Golshani, Hennelotter, Garcia Analysis and interpretation of data: Kramer, Golshani, Lokeshwar Drafting of the manuscript: Lokeshwar Critical revision of the manuscript for important intellectual content: Kuczyk, Stenzl, Soloway, Lokeshwar Objective-We evaluated whether HA and HYAL-1 can predict progression to muscle invasion and recurrence among patients with non-muscle-invasive BCa.Design, setting, and participants-Based on tissue availability, tissue microarrays were prepared from a cohort of 178 BCa specimens (144 non-muscle invasive, 34 muscle invasive). Follow-up information was available on 111 patients with non-muscle-invasive BCa (mean followup: 69.5 mo); 58 patients recurred and 25 progressed to muscle invasion (mean time to progress: 22.3 mo).Measurements-HA and HYAL-1 expression was evaluated by immunohistochemistry and graded for intensity and area of staining. Association of HA and HYAL-1 staining with BCa recurrence and muscle invasion was evaluated by univariate and multivariate models.Results and limitations-HA and HYAL-1 expression correlated with tumor grade, stage, and multifocality (p < 0.05). In non-muscle-invasive BCa specimens, HYAL-1 staining was higher (234.3 ± 52.2; 200.6 ± 61.4) if patients experienced progression to muscle invasion or recurrence when compared with no progression or recurrence (164.1 ± 48.2; 172.1 ± 57; p < 0.001). HA staining correlated with muscle ...

Background Although the performance of immunocytology has been established in the surveillance of patients with urothelial carcinoma of the bladder (UCB), its value in the initial detection of UCB in patients with painless hematuria remains unclear. Objective To determine whether immunocytology improves our ability to predict the likelihood of UCB in patients with painless hematuria. Further, to test the clinical benefit of immunocytology in this setting using decision curve analysis. Design, setting, and participants The subjects were 1182 consecutive patients without a history of UCB presenting with painless hematuria and were enrolled at three centres. Intervention All patients underwent upper-tract imaging, cystourethroscopy, voided urine cytology, and immunocytology analysis. Bladder tumors were biopsied and histologically confirmed as UCB. Measurements Multivariable regression models were developed. Area under the curve was measured and compared using the DeLong test. A nomogram was constructed from the full multivariable model. Decision curve analysis was performed to evaluate the clinical benefit associated with use of the multivariable models including immunocytology. Results and limitations Immunocytology had the largest contribution to a multivariable model for the prediction of UCB (odds ratio: 18.3; p < 0.0001), which achieved a 90.8% predictive accuracy. Decision curve analysis revealed that models incorporating immunocytology achieved the highest net benefit at all threshold probabilities. Conclusions Immunocytology is a strong predictor of the presence of UCB in patients who present with painless hematuria. Incorporation of immunocytology into predictive models improves diagnostic accuracy by a statistically and clinically significant margin. The use of immunocytology in the diagnostic workup of patients with hematuria appears promising and should be further evaluated.

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