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Purpose Prostate specific membrane antigen is expressed by the endothelium of many tumors. The aim of the study was to find a rationale for prostate specific membrane antigen based imaging and investigate the prognostic role of vascular prostate specific membrane antigen expression in patients with renal cell carcinoma. Materials and Methods A total of 257 patients with renal cell carcinoma were included in study with a median followup exceeding 10.0 years. Prostate specific membrane antigen expression on tumor vessels was detected by immunohistochemistry. Vascular expression of FOLH1 gene (prostate specific membrane antigen) mRNA was investigated in clear cell carcinoma and papillary renal cell carcinoma using TCGA (The Cancer Genome Atlas) data. Results Endothelial prostate specific membrane antigen protein expression was higher in clear cell than in papillary and chromophobe renal cell carcinoma. Higher grade and stage, metastatic and lethal clear cell renal cell carcinoma showed higher prostate specific membrane antigen expression in tumor vessels. On univariate and multivariate analysis the intensity of positive vs negative endothelial prostate specific membrane antigen protein expression was significantly associated with overall survival. TCGA based analyses confirmed the prognostic role of vascular expression of FOLH1 mRNA. The analyses also supported the usefulness of prostate specific membrane antigen based imaging in cases of clear cell but not papillary renal cell carcinoma. Conclusions We provide a rationale for further development of prostate specific membrane antigen targeted imaging in patients with clear cell renal cell carcinoma. The prognostic role of prostate specific membrane antigen was determined at the protein level in clear cell renal cell carcinoma and at the mRNA level in clear cell and papillary renal cell carcinoma. [ABSTRACT FROM AUTHOR]

Purpose In various malignancies RNA fragments are dysregulated. Our study was designed to determine the expression of 4, 5′-tRNA halves in the tissue and serum of patients with clear cell renal cell carcinoma. Materials and Methods Tissue and serum samples of patients with clear cell renal cell carcinoma and nonmalignant disease were collected prospectively in our biobank. We isolated total RNA from 95 clear cell renal cell carcinomas and 50 normal renal tissues as well as serum RNA from 27 patients with clear cell renal cell carcinoma and 13 with nonmalignant urological disease. To specifically determine the expression of 5′-tRNA halves we dephosphorylated and ligated an adaptor nucleotide to the 3′ end of the tRNA halves. The expression levels of 4, 5′-tRNA halves (5′-tRNA-Arg-CCT, 5′-tRNA-Glu-CTC, 5′-tRNA-Leu-CAG and 5′-tRNA-Lys-TTT) were then measured by TaqMan® based quantitative reverse transcription-polymerase chain reaction. Results All studied 5′-tRNA halves were down-regulated in clear cell renal cell carcinoma tissues, indicating a potential role as a tumor suppressor. Furthermore, we noted decreased expression of 5′-tRNA halves in patients with adverse clinicopathological parameters. All 5′-tRNA halves were expressed at lower levels in nonorgan confined clear cell renal cell carcinoma. The 5′-tRNA-Lys-TTT halves inversely correlated with ISUP (International Society of Urological Pathology) grade. In patients with clear cell renal cell carcinoma 5′-tRNA-Arg-CCT, 5′-tRNA-Glu-CTC and 5′-tRNA-Lys-TTT halves circulated at lower levels than in control subjects, indicating relevance as noninvasive biomarkers. Conclusions In patients with clear cell renal cell carcinoma 5′-tRNA halves have potential as diagnostic and prognostic biomarkers. The 5′-tRNA halves may act in a tumor suppressive manner, which requires further research to confirm. [ABSTRACT FROM AUTHOR]

Purpose Classic serum tumor markers (human chorionic gonadotropin, α1-fetoprotein and lactate dehydrogenase) have an important role in managing testicular germ cell tumor. Since only 60% of all patients with testicular germ cell tumor have elevations of these markers, there is a need for new biomarkers with greater sensitivity/specificity. miRNAs are deregulated in cancer and could serve as noninvasive serum biomarkers. We explored the role of serum miRNAs as a novel biomarker in patients with testicular germ cell tumor. Materials and Methods Total RNA was isolated from serum. miRNA levels were quantified by quantitative real-time polymerase chain reaction. We assessed the miRNAs miR-302a-3p, 302b-3p, 302c-3p, 367-3p, 371a-3p, 372-3p and 373-3p in a subcohort of 30 patients with testicular germ cell tumor and 18 healthy subjects. Validation was performed in 76 patients treated with inguinal exploration due to suspicion of testicular germ cell tumor, of whom 59 had cancer and 17 had benign disease, and in 84 healthy male subjects. Results Serum miR-367-3p, 371a-3p, 372-3p and 373-3p levels were significantly increased in patients with testicular germ cell tumor compared to healthy individuals and patients with nonmalignant testicular disease. In particular miR-371a-3p allowed for sensitive (84.7%) and specific (99%) identification of patients with testicular germ cell tumor, thus, outperforming human chorionic gonadotropin or α1-fetoprotein testing. Furthermore, miR-367-3p was increased in nonseminoma compared to seminoma cases. Serum miRNA levels were increased in patients with advanced local stage and metastasis. In 9 patients with localized (clinical stage 1A) testicular germ cell tumor serum miR-371a-3p levels decreased postoperatively, indicating tumor specific release. Conclusions miR-371a-3p allows for better identification of testicular germ cell tumor than α1-fetoprotein and human chorionic gonadotropin. It could be helpful for clinically managing testicular germ cell tumor, especially for monitoring surveillance therapy and residual disease after chemotherapy. [ABSTRACT FROM AUTHOR]

Purpose: Earlier studies indicate that epigenetics contribute to the pathogenesis of penile squamous cell carcinoma. Histone methylation patterns are frequently altered during carcinogenesis. Therefore, we investigated the methylation pattern of the histones H3K4, H3K9 and H3K27 in penile carcinoma and normal tissue. Materials and Methods: A tissue microarray was constructed with 65 penile carcinomas, 6 metastatic lesions and 30 control tissues. Global histone methylation was assessed using immunohistochemistry. Results: Global levels of H3K4me1, H3K9me1, H3K9me2, H3K27me2 and H3K27me3 were decreased, whereas H3K9me3 was increased in penile carcinoma. Histone methylation levels defined an epigenetic entity that allowed accurate differentiation of cancer and normal samples. We observed no correlation of histone methylation levels with clinicopathological parameters or patient outcome. Conclusions: The description of a definite epigenetic entity in penile carcinoma provides a rationale for testing epigenetic agents in patients with metastatic disease. [ABSTRACT FROM AUTHOR]

Purpose: Patients with stage pT3N0 urothelial bladder cancer vary in outcome after radical cystectomy. To improve prognosis estimation a model was recently developed that defines 3 risk groups for recurrence-free survival based on pT substaging, lymphovascular invasion and positive surgical margin. We present what is to our knowledge the first external validation of this risk model. Materials and Methods: Analogous to the risk model derivation cohort our study group comprised 472 patients with stage pT3, pN0, cM0 disease without perioperative chemotherapy and with a median followup of 42 months (IQR 20–75). The primary end point was recurrence-free survival. The effect of variables was determined by univariate and multivariate Cox regression analysis, and predictive accuracy was determined by ROC analysis. Results: Stage pT3aN0 and pT3bN0 cases showed significantly different recurrence-free survival after 5 years (51% vs 29%, p <0.001). In the multivariate Cox model pT3 substage (HR 1.86, p <0.001), lymphovascular invasion (HR 1.48, p = 0.002), positive surgical margins (HR 1.90, p = 0.030) and patient age with a dichotomy at 70 years (HR 1.51, p = 0.001) had an independent effect on recurrence-free survival. In the low (221 patients or 47%), intermediate (184 or 39%) and high (67 or 14%) risk groups the 5-year recurrence-free survival rate was 55%, 45% and 13%, respectively (p <0.001). The concordance index of the risk model to predict recurrence-free survival was 0.64 (95% CI 0.59–0.69). Conclusions: This user friendly risk model can be recommended to estimate prognosis in patients with stage pT3N0 after radical cystectomy. Patients at high risk showed clearly compromised recurrence-free survival and should be included in adjuvant therapy studies. [ABSTRACT FROM AUTHOR]

Purpose: Approximately 15% to 30% of patients with pT1-2N0M0 urothelial carcinoma of the bladder experience disease progression despite radical cystectomy with curative intent. We determined whether p53 expression would improve the prediction of disease progression after radical cystectomy for pT1-2N0M0 UCB. Materials and Methods: In a multi-institutional retrospective cohort we identified 324 patients with pT1-2N0M0 urothelial carcinoma of the bladder who underwent radical cystectomy. Analysis focused on a testing cohort of 272 patients and an external validation of 52. Competing risks regression models were used to test the association of variables with cancer specific mortality after accounting for nonbladder cancer caused mortality. Results: In the testing cohort 91 patients (33.5%) had altered p53 expression (p53alt). On multivariate competing risks regression analysis altered p53 achieved independent status for predicting disease recurrence and cancer specific mortality (each p <0.001). Adding p53 increased the accuracy of multivariate competing risks regression models predicting recurrence and cancer specific mortality by 5.7% (62.0% vs 67.7%) and 5.4% (61.6% vs 67.0%), respectively. Conclusions: Alterations in p53 represent a highly promising marker of disease recurrence and cancer specific mortality after radical cystectomy for urothelial carcinoma of the bladder. Analysis confirmed previous findings and showed that considering p53 can result in substantial accuracy gains relative to the use of standard predictors. The value and the level of the current evidence clearly exceed previous proof of the independent predictor status of p53 for predicting recurrence and cancer specific mortality. [Copyright &y& Elsevier]

Purpose: DNA hypermethylation is a common cancer associated alteration. We analyzed methylation patterns of cell-free serum DNA in patients with testicular cancer. Materials and Methods: Hypermethylation at APC, GSTP1, PTGS2, p14(ARF), p16(INK) and RASSF1A was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment in 73 patients with testicular cancer and 35 healthy individuals. Results: Hypermethylation was more common in patients with testicular cancer than in healthy individuals, including APC 57% and 6%, p16(INK) 53% and 17%, p14(ARF) 53% and 0%, RASSF1A 47% and 0%, PTGS2 45% and 0%, and GSTP1 25% and 0%, respectively (each p <0.01). Methylation frequencies at the investigated gene sites were similar in nonseminoma and seminoma cases (p >0.05). Diagnostic information was increased when multiple gene sites were analyzed in combination (ROC AUC 0.834, 67% sensitivity and 97% specificity). Diagnostic information was superior to the analysis of AFP/HCG/PLAP/LDH (combined sensitivity 58% and AUC 0.791). The sensitivity of hypermethylation in patients with unsuspicious conventional tumor markers was 71% (AUC 0.871, 97% specificity). Hypermethylation at PTGS2 was more common in patients with pT1 stage tumors (p = 0.011). Conclusions: The detection of hypermethylated cell-free serum DNA has the potential of a useful additional diagnostic parameter in patients with testicular germ cell cancer. Furthermore, in cases without conventional tumor marker increases testing CpG island hypermethylation in cell-free circulation DNA may improve the ability to detect early and/or recurrent testicular cancer. [Copyright &y& Elsevier]

Purpose: CpG island hypermethylation is a frequent event in bladder carcinogenesis and progression. We investigated the diagnostic and prognostic value of hypermethylation in cell-free serum DNA of patients with bladder cancer. Materials and Methods: The study cohort consisted of 45 patients with bladder cancer undergoing cystectomy and 45 with histologically confirmed benign prostatic hyperplasia serving as controls. Hypermethylation at APC, DAPK, GSTP1, PTGS2, TIG1 and Reprimo was analyzed using real-time polymerase chain reaction following methylation sensitive restriction endonuclease treatment. Results: Hypermethylation at the APC and GSTP1 promoter was detected in 59% of cases, whereas TIG1 (32%), PTGS2 (24%) and DAPK (2%) were less frequently hypermethylated. In the benign prostatic hyperplasia group 3 patients also harbored methylated GSTP1 DNA, whereas none of the other gene sites was methylated. Hypermethylation at APC, GSTP1 or TIG1 distinguished patients with bladder cancer and controls most accurately with 80% sensitivity and 93% specificity. Hypermethylation significantly correlated with prognostic unfavorable clinicopathological parameters, including APC with pT stage, GSTP1, or GSTP1 or TIG1 with multifocal bladder cancer and APC, or APC or TIG1 with surgical margin positivity. Bladder cancer specific mortality was significantly increased in patients with APC hypermethylation. Conclusions: The detection of hypermethylation in cell-free serum DNA provides valuable diagnostic and prognostic information that can still be improved by combining the results of 3 gene sites (APC, GSTP1 and TIG1). The presence of hypermethylated DNA in the serum of patients with bladder cancer is associated with a worse outcome. Our results suggest that measuring hypermethylation in the serum of patients with bladder cancer is a useful biomarker. [Copyright &y& Elsevier]

Purpose: We prospectively evaluated long-term survival in patients with renal cell carcinoma extending to the inferior vena cava. Materials and Methods: From 1993 and thereafter we followed 86 men and 48 women with a median age of 64 years (range 28 to 86) with renal cell carcinoma and tumor thrombus involvement of the inferior vena cava. Cancer specific survival was analyzed based on clinical therapy, tumor extent, thrombus level and grading. Results: Median followup was 16.4 months (range 0 to 178.9). At the time of this report 97 cancer specific deaths had occurred. Of the 134 patients 111 underwent radical nephrectomy, cavotomy and thrombus extraction, of whom 30 had distant metastases at surgery, and 23 were treated with embolization and immunotherapy. These nonsurgical patients who refused surgery had a high tumor load or a low Karnofsky performance status that may have affected survival. They died at a median of 6.9 months (range 0.1 to 23.6). Patients treated surgically, including those with metastases, had a significantly higher median survival of 19.8 months (range 0 to 178.9). Surgical patients with localized tumor (N0M0) had significantly higher median survival than those with metastatic (NxM1) disease (51.7 months, range 0 to 178.9 vs 6.9, range 0.6 to 149.7). Surgical patients with metastatic disease who underwent interferon and interleukin based immunotherapy had significantly higher median survival than those who did not (13.5 months, range 2.5 to 149.7 vs 5.1, range 0.6 to 24.0). On multivariate analysis localized tumor stage (N0M0) vs advanced tumor stage (N+M0 and NxM1), Fuhrman grade groups 1 and 2 vs 3 and 4, and tumor thrombus levels I and II vs III and IV were independent prognostic factors. Conclusions: Currently radical surgery represents the only chance of long-term survival for patients with renal cell carcinoma and tumor thrombus extension in the inferior vena cava. Median cancer specific survival is significantly higher with localized tumor. However, even with metastatic disease radical surgery can prolong survival, especially when immunotherapy is added. Fuhrman grade and tumor thrombus level are also prognostic factors. [Copyright &y& Elsevier]