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.

E 4 4 9What ' s known on the subject? and What does the study add? The surgical implications of renal cell carcinoma with coexisting bland and tumour thrombi of the inferior vena cava is not well described. In this study we review our experience managing these tumours. On multivariate analysis, we found that the presence of bland thrombus was associated with an increased need for surgical interruption of the inferior vena cava. OBJECTIVE• To study the role of interruption of the inferior vena cava (IVC) in patients with renal cell carcinoma (RCC) and associated bland and tumour thrombi. METHODS• We reviewed 129 consecutive patients with the preoperative diagnosis of RCC with tumour thrombus who underwent radical nephrectomy and tumour thrombectomy in one academic institution between May 1997 and February 2011. RESULTS• Percentages of patients with levels I, II, III and IV tumour thrombus were 29%, 13%, 48% and 9%, respectively.• The perioperative mortality rate was 2.3%. There were 29 (22%) perioperative complications recorded.• In all, 19 patients underwent surgical interruption of the IVC by ligation or segmental resection, including one level II, 14 level III and four level IV thrombi.• A total of 15 patients (12%) had bland thrombus associated with the tumour thrombus; four of these underwent intraoperative IVC fi lter placement and eight underwent surgical IVC interruption.• Advanced level of tumour thrombus was the only signifi cant factor predicting association of bland thrombus (odds ratio [ OR ] = 2.09, 95% confi dence interval [ CI ] : 1.082 -4.037, P = 0.028).• On multivariate analysis, level of thrombus (OR = 3.1, 95% CI: 1.30 -7.74, P = 0.011) and association of bland thrombus (OR = 9.07, 95% CI: 2.42 -34.01, P = 0.001) were signifi cant factors for IVC interruption. CONCLUSIONS• Surgical interruption of the IVC is a feasible option in selected patients with chronic IVC obstruction. Association of bland thrombus with tumour thrombus should alert the surgical team to the potential for a challenging surgery.• Precise preoperative imaging to assess the degree of venous obstruction and to help with differentiation between bland and tumour thrombus is key to achieving a surgical outcome with minimal morbidity. KEYWORDSrenal tumour , tumour thrombus , inferior vena cava fi lter , pulmonary emboli , tumour thrombus emboli , bland thrombus emboli Study Type -Therapy (case series) Level of Evidence 4

Purpose Molecular characterization of renal cell carcinoma (RCC) may help in differentiating benign oncocytomas from malignant RCC subtypes and predict metastasis. Chemokines (e.g., interleukin-8 (IL-8)) and chemokine receptors (e.g., CXCR4, CXCR7) promote inflammation and metastasis. Stroma derived factor (SDF-1) is a ligand for CXCR4 and CXCR7, with six known isoforms. We evaluated the expression of these chemokines and chemokine receptors in kidney specimens. Materials and Methods Using quantitative PCR, mRNA levels of IL-8, CXCR4, CXCR7 and SDF1 isoforms α, β and γ were measured in 166 specimens from 86 patients (tumor: 86; matched normal kidney: 80); mean and median follow-up: 18.9 ± 12; Median: 19.5 months. RCC specimens included: clear cell RCC (ccRCC): 65; papillary: 10; chromophobe: 5; oncocytoma: 6; metastasis (+): 17. Results Median levels of CXCR4, CXCR7 and SFD1-γ were 2–10-fold elevated and SDF1-α and SDF1-β levels were either unchanged or lower in ccRCC and papillary tumors when compared to normal tissues. Median SDF1-γ, IL-8, CXCR4 and CXCR7 levels were 3–40-fold elevated in chromophobe tumors when compared to oncocytoma. Both CXCR4 and CXCR7 levels were elevated in tumors < 4-cm (3057±2230; 806±691) when compared to oncocytoma (336±325; 201±281; P≤0.016). In multivariate analyses, CXCR4 (P=0.01), CXCR7 (0.02) and SDF1-β (P=0.005) were independently associated with metastasis. Combined CXCR7+SDF1-α and CXCR7+IL-8 markers showed the highest sensitivity (71–81%) and specificity (75–80%) among all individual or combined markers. Conclusions Chemokines and chemokine receptors differentiate between RCC and oncocytoma. Combined SDF1-α+CXCR7 and IL-8+CXCR7 markers have ~ 80% accuracy in predicting RCC metastasis.

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. 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 ( = 241). 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): = 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: < 0.0001; OR, 0.37; 95% CI, 0.58-0.23). The interconnected discovery-validation approach identified a three-miRNA signature as a potential predictor of disease outcome in RCC patients. 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. .

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