Yun-Sok Ha

Safety of Robot-Assisted Radical Prostatectomy with Pneumoperitoneum of 20 mm Hg: A Study of 751 Patients

BACKGROUND AND PURPOSE Early studies describing robot-assisted radical prostatectomy (RARP) reported the use of pneumoperitoneum at a pressure of 15 mm Hg. While higher insufflation pressures (20 mm Hg) may reduce venous oozing and improve visualization, the safety of this method has not been confirmed. This study evaluates the short-term perioperative outcomes of patients undergoing RARP with insufflation pressures of 20 mm Hg. PATIENTS AND METHODS A single-surgeon, prospectively maintained database of patients undergoing RARP was retrospectively analyzed. Patients who underwent RARP with a pneumoperitoneum pressure of 15 and 20 mm Hg for the entire procedure were analyzed. Preoperative and postoperative hemoglobin levels and estimated glomerular filtration rate (eGFR) were compared. Complications, operative time, and estimated blood loss were also examined. RESULTS The number of patients in the experimental (20 mm Hg) and control (15 mm Hg) groups were 550 and 201, respectively. The groups were well matched with respect to age and operative time. The experimental group had a significantly smaller decrease in mean hemoglobin levels after surgery (-1.18 vs-2.13 mg/dL, P<0.0001). There was no significant difference in the eGFR on the first day after surgery (postoperative day [POD]1) (88.4 vs 85.0 mL/min/1.73m(2), P=0.11) or in the change in eGFR from preoperative to POD1 levels (-0.49 vs 1.54 mL/min/1.73m(2), P=0.18). The complication rate in the experimental group was 8.55% vs 8.46% in the control group. CONCLUSION Pneumoperitoneum using a pressure of 20 mm Hg for RARP is safe and has no significant short-term effects on renal function and hemoglobin. Increased insufflation pressure was not associated with a higher complication rate.

Predictive value of progression-related gene classifier in primary non-muscle invasive bladder cancer

BackgroundWhile several molecular markers of bladder cancer prognosis have been identified, the limited value of current prognostic markers has created the need for new molecular indicators of bladder cancer outcomes. The aim of this study was to identify genetic signatures associated with disease prognosis in bladder cancer.ResultsWe used 272 primary bladder cancer specimens for microarray analysis and real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Microarray gene expression analysis of randomly selected 165 primary bladder cancer specimens as an original cohort was carried out. Risk scores were applied to stratify prognosis-related gene classifiers. Prognosis-related gene classifiers were individually analyzed with tumor invasiveness (non-muscle invasive bladder cancer [NMIBC] and muscle invasive bladder cancer [MIBC]) and prognosis. We validated selected gene classifiers using RT-PCR in the original (165) and independent (107) cohorts. Ninety-seven genes related to disease progression among NMIBC patients were identified by microarray data analysis. Eight genes, a progression-related gene classifier in NMIBC, were selected for RT-PCR. The progression-related gene classifier in patients with NMIBC was closely correlated with progression in both original and independent cohorts. Furthermore, no patient with NMIBC in the good-prognosis signature group experienced cancer progression.ConclusionsWe identified progression-related gene classifier that has strong predictive value for determining disease outcome in NMIBC. This gene classifier could assist in selecting NMIBC patients who might benefit from more aggressive therapeutic intervention or surveillance.

The hOGG1 mutant genotype is associated with prostate cancer susceptibility and aggressive clinicopathological characteristics in the Korean population.

BACKGROUND The gene encoding human 8-oxoguanine glycosylase 1 (hOGG1) is involved in DNA base excision repair from oxidatively damaged DNA. A case-control study was conducted to evaluate the correlation between the susceptibility and clinicopathological outcomes of prostate cancer (CaP) and hOGG1 genotype. PATIENTS AND METHODS Subjects were recruited from 266 CaP patients and 266 age-matched benign prostatic hyperplasia patients. The hOGG1 codon 326 genotype was determined by peptide nucleic acid-mediated PCR clamping and compared with Gleason score and tumor stage. RESULTS The Cys allele at codon 326 of hOGG1 was associated with an increased risk of CaP in comparison with the Ser allele (P = 0.005). Gleason scores of 8 or higher were observed more often in patients with the mutant genotypes Ser/Cys and Cys/Cys than in those with a wild-type genotype (P = 0.045), and the Cys/Cys homozygous genotype was associated with a significantly higher risk of metastatic disease in comparison with the Ser/Ser genotype (P = 0.017). CONCLUSIONS These results suggest that hOGG1 is associated with the susceptibility to CaP and its aggressive clinicopathological characteristics.

Methylation of the RUNX3 promoter as a potential prognostic marker for bladder tumor.

PURPOSE DNA methylation is a key regulator of gene transcription and genomic stability, and alterations in DNA methylation patterns are frequently detected in human tumors. Previously we reported that inactivation of RUNX3 by primarily epigenetic alterations in DNA methylation is closely associated with bladder tumor development, recurrence and progression. In the current series we evaluated the association between RUNX3 inactivation and bladder tumors after a long-term followup study. MATERIALS AND METHODS We used previously published data on the methylation patterns of RUNX3 in bladder tumor samples as well as 25 new data sets obtained by methylation specific polymerase chain reaction and direct DNA sequencing. Of the 149 patients examined 118 were followed periodically and included in the final analysis. Median followup was 49.8 months (range 1 to 146). RESULTS RUNX3 promoter methylation was observed in 84 of the 118 tumor samples (71.2%) examined. RUNX3 methylation patterns correlated significantly with the development of invasive tumor, tumor progression, and overall and cancer specific survival (each p <0.05). Kaplan-Meyer curves showed identical results (p <0.05). Multivariate Cox regression models revealed that RUNX3 methylation status was a strong predictor of tumor progression and cancer specific survival. CONCLUSIONS Results strongly suggest that inactivation of RUNX3 by the methylation of its promoter region is a significant risk factor for invasive bladder tumors, tumor progression and cancer specific survival. RUNX3 promoter methylation status could be a promising marker for assessing the prognosis of human bladder tumors.

HOXA9, ISL1 and ALDH1A3 methylation patterns as prognostic markers for nonmuscle invasive bladder cancer: Array‐based DNA methylation and expression profiling

DNA methylation patterns are associated with the development and prognosis of cancer. The aim of this study was to identify novel methylation markers for the prediction of patient outcomes using microarray analysis of DNA methylation and RNA expression patterns in samples from long‐term follow‐up patients with nonmuscle invasive bladder cancer (NMIBC). A total of 187 human bladder specimens were used for microarray array or pyrosequencing (PSQ) analyses: 6 normal controls (NC) and 181 NMIBC. Tumor‐specific hypermethylated genes were selected from a data set comprising 24 matched microarray‐based DNA methylation and gene expression profiles (6 controls and 18 NMIBC), and their clinical relevance was verified by quantitative PSQ analysis. The methylation status of Homeobox A9 (HOXA9), ISL LIM homeobox 1 (ISL1) and Aldehyde dehydrogenase 1 family, member A3 (ALDH1A3) was significantly associated with decreased gene expression levels and aggressive clinicopathological characteristics. Multivariate regression analyses showed that hypermethylation of these genes was an independent predictor of disease recurrence (HOXA9, ISL1 and ALDH1A3, either alone or in combination) and progression (ISL1 and ALDH1A3, either alone or in combination) (each p < 0.05). The results of this study suggest that these novel methylation markers are independent prognostic indicators in NMIBC patients, which may facilitate the assessment of disease recurrence and progression in NMIBC patients and inform clinical decision making regarding treatment.

Gene Signatures for the Prediction of Response to Bacillus Calmette-Guérin Immunotherapy in Primary pT1 Bladder Cancers

Purpose: Intravesical Bacillus Calmette-Guérin (BCG) immunotherapy is effective in the prevention of recurrence and progression in many cases of nonmuscle invasive bladder cancer, but many patients fail to respond. The aim of this study was to identify gene sets of markers that could predict the response to BCG immunotherapy in primary pT1 bladder cancer using microarray gene expression profiling. Experimental Design: We used 80 patients with primary pT1 bladder cancer treated with BCG immunotherapy as training (48) and test (32) sets. Microarray gene expression profiling was done in the training set to identify genes differentially expressed between responder and nonresponder to BCG immunotherapy according to the events (recurrence or progression). Using a real-time reverse-transcriptase PCR, our findings were validated in the test set. Results: In the training set, 424 and 287 genes were significantly associated with recurrence- and progression-free survival, respectively. Functional annotation of these genes included cell-mediated immune response, inflammatory response, cellular growth, and proliferation. From these predictive gene signatures, 24 genes (12 in recurrence and 12 in progression) with the highest score of expression ratio were extracted for validation in the test set. In multivariate regression analyses, predictive gene signatures were the only independent predictors of recurrence (hazard ratio, 3.38; P = 0.048) or progression (hazard ratio, 10.49; P = 0.048) in the test set. Conclusions: Predictive gene signatures have diagnostic value for determining the response to intravesical BCG immunotherapy in primary pT1 bladder cancer. Clin Cancer Res; 16(7); 2131–7. ©2010 AACR.

BMP-6 in Renal Cell Carcinoma Promotes Tumor Proliferation through IL-10–Dependent M2 Polarization of Tumor-Associated Macrophages

Dysregulated bone morphogenetic proteins (BMP) may contribute to the development and progression of renal cell carcinoma (RCC). Herein, we report that BMP-6 promotes the growth of RCC by interleukin (IL)-10-mediated M2 polarization of tumor-associated macrophages (TAM). BMP-6-mediated IL-10 expression in macrophages required Smad5 and STAT3. In human RCC specimens, the three-marker signature BMP-6/IL-10/CD68 was associated with a poor prognosis. Furthermore, patients with elevated IL-10 serum levels had worse outcome after surgery. Together, our results suggest that BMP-6/macrophage/IL-10 regulates M2 polarization of TAMs in RCC.

RUNX3 methylation as a predictor for disease progression in patients with non‐muscle‐invasive bladder cancer

We have previously reported that RUNX3 inactivation by promoter hypermethylation correlated with advanced disease and poor clinical outcome in bladder cancer. In this study, we examined primary tumors from non‐muscle‐invasive bladder cancer (NMIBC) patients in order to investigate the relationship between RUNX3 methylation and disease progression.

HMOX1 is an Important Prognostic Indicator of Nonmuscle Invasive Bladder Cancer Recurrence and Progression

PURPOSE HMOX1, which is highly expressed in various solid tumors, has an important role in rapid tumor growth. We investigated the relationship between HMOX1 expression and clinicopathological parameters in patients with NMIBC. MATERIALS AND METHODS We analyzed 211 primary NMIBC tissue specimens by real-time PCR and compared the results with clinicopathological parameters. Kaplan-Meier survival curves and multivariate Cox regression analysis were used to assess the prognostic value of HMOX1 in NMIBC cases. RESULTS HMOX1 mRNA expression was significantly higher in patients with higher grade and multiple tumors than in those with lower grade and single tumors (each p <0.05, respectively). Kaplan-Meier estimates showed HMOX1 expression was significantly associated with recurrence and progression (log rank test p = 0.010 and <0.001, respectively). A multivariate Cox regression model revealed that HMOX1 mRNA expression was an independent predictor of recurrence (HR 1.832, p = 0.017) and progression (HR 5.241, p = 0.001) in patients with NMIBC. CONCLUSIONS Analysis of HMOX1 expression in 211 NMIBC tissue specimens revealed its potential usefulness as a marker to predict the NMIBC prognosis.

mRNA Expression of S100A8 as a Prognostic Marker for Progression of Non-Muscle-Invasive Bladder Cancer

Purpose S100A8 is a member of the S100 protein family containing 2EF-hand calcium-binding motifs. S100 proteins are involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation. Altered expression of this protein is associated with various diseases and cancers. The present study aimed to evaluate whether S100A8 has prognostic value for non-muscle-invasive bladder cancer (NMIBC). Materials and Methods A total of 103 primary NMIBC samples obtained by transurethral resection were evaluated. mRNA levels were examined by real-time reverse transcriptase polymerase chain reaction (RT-PCR) analysis. The results were compared with clinico-pathological parameters. The Kaplan-Meier method was applied to plot the curves for progression-free survival. The multivariate Cox regression model was used to identify the independent prognostic factors for progression. Results mRNA expression levels of S100A8 were significantly related to the progression of NMIBC. Kaplan-Meier estimates demonstrated significant differences in tumor progression according to the level of S100A8 expression (log-rank test, p<0.001). The multivariate Cox regression model revealed that the S100A8 mRNA expression level (hazard ratio: 12.538; 95% confidence interval: 2.245-70.023, p=0.004) was an independent predictor for disease progression of NMIBC. Conclusions Expression levels of S100A8 might be a useful prognostic marker for disease progression of NMIBC.