Methylation Signature for Prediction of Progression Free Survival in Surgically Treated Clear Cell Renal Cell Carcinoma

BACKGROUND: Little is known about epigenetic silencing of genes by promoter hypermethylation in renal cell carcinoma (RCC). The aim of this study was to identify prognostic methylation markers in surgically treated clear cell RCC (ccRCC). METHODS: Methylation patterns were assayed using the Infinium HumanMethylation450 BeadChip array on pairs of ccRCC and normal tissue from 12 patients. Using quantitative PSQ analysis, tumor-specific hypermethylated genes were validated in 25 independent cohorts and their clinical relevance was also verified in 152 independent cohorts. RESULTS: Using genome-wide methylation array, Zinc finger protein 278 (ZNF278), Family with sequence similarity 155 member A (FAM155A) and Dipeptidyl peptidase 6 (DPP6) were selected for tumor-specific hypermethylated genes in primary ccRCC. The promoter methylation of these genes occurred more frequently in ccRCC than normal kidney in independent validation cohort. The hypermethylation of three genes were associated with advanced tumor stage and high grade tumor in ccRCC. During median follow-up of 39.2 (interquartile range, 15.4–79.1) months, 22 (14.5%) patients experienced distant metastasis. Multivariate analysis identified the methylation status of these three genes, either alone, or in a combined risk score as an independent predictor of distant metastasis. CONCLUSION: The promoter methylation of ZNF278, FAM155A and DPP6 genes are associated with aggressive tumor phenotype and early development of distant metastasis in patients with surgically treated ccRCC. These potential methylation markers, either alone, or in combination, could provide novel targets for development of individualized therapeutic and prevention regimens.

Impact of the ASA Physical Status Score on Adjuvant Chemotherapy Eligibility and Survival of Upper Tract Urothelial Carcinoma Patients: a Multicenter Study

The aim of the present multi-institutional study was to assess the influence of the American Society of Anesthesiologists Physical Status (ASA-PS) classification on adjuvant chemotherapy eligibility and survival in a multi-institutional cohort of patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC). We retrospectively reviewed data from 416 patients who underwent RNU for UTUC at four Korean institutions between 2001 and 2013. The ASA-PS classification was obtained from the anesthesia chart. Locally advanced UTUC was defined as ≥ pT3 and/or pN1 disease. The influence of ASA-PS score on survival was evaluated by Kaplan-Meier analyses and a multivariate Cox regression model. Patients with a higher ASA-PS class were less likely to be eligible for adjuvant chemotherapy in locally advanced UTUC (P = 0.016). Kaplan-Meier estimates showed that the high-risk ASA-PS group has a poorer overallsurvival (OS) and cancer-specific survival (CSS) compared to low risk ASA-PS groups in both the total and locally advanced UTUC cohorts. Based on multivariate Cox regression analysis, the high-risk ASA-PS category was an independent predictor for overall mortality (OM) (hazard ratio [HR], 1.919; 95% confidence interval [CI], 1.017–3.619; P = 0.044) and cancer-specific mortality (CSM) (HR, 2.120; 95% CI, 1.023–4.394; P = 0.043). In conclusion, high-risk ASA-PS score was independently associated with a lower survival rate in patients with UTUC after RNU. However, the influence of ASA-PS classification on survival was limited to locally advanced UTUC. The lower eligibility of patients in the high-risk ASA category for adjuvant chemotherapy may contribute to the lower survival rate in this group.

Chronological Trends in Clinical and Urinary Metabolic Features over 20 Years in Korean Urolithiasis Patients

Urolithiasis is common and is becoming more prevalent worldwide. This study assessed the chronological trends in clinical and urinary metabolic features over 20 years in Korean urolithiasis patients. We performed a retrospective analysis of 4,076 patients treated at our clinic from 1996 to 2015. Urinary metabolic data and stone analysis data were available for 1,421 and 723 patients (34.9% and 17.7%), respectively. Patients were categorized into 4 groups according to the date of initial diagnosis: group 1 (1996–2000, n = 897), group 2 (2001–2005, n = 1,018), group 3 (2006–2010, n = 1,043), and group 4 (2011–2015, n = 1,118). Incidental detection of uric acid renal stones has become more prevalent in the past 10 years, accompanied by an increase in body mass index and age at diagnosis. Similarly, the prevalence of diabetes mellitus and of hypertension increased from one group to the next throughout the study period. Levels of 24-hour urinary excretion of sodium, calcium, uric acid, and oxalate have decreased significantly over the study period. The incidence of urinary metabolic abnormalities also showed an identical tendency. The proportion of stones composed of uric acid increased over the study period. In conclusion, incidental detection of uric acid renal stones has become more prevalent in Korea in the past 20 years. Urinary excretion of lithogenic constituents and the incidence of urinary metabolic abnormalities have decreased significantly over this period.

The Trend of Uro-Oncologist About Blood Test and Imaging Studies for the Diagnosis of Biochemical Recurrence in Korea

PURPOSE: The aim of this study is to investigate the criteria of biochemical recurrence (BCR) and follow-up periods and methods with and without blood and imaging test of urologic oncology before established guidelines of prostate cancer in Korea. MATERIALS AND METHODS: In December 2015, we sent the questionnaire to urologic oncologist in academic hospital and received the answer from 108 urologic oncologist (50%). Also, we analyzed the data of 1,141 patients underwent radical prostatectomy in 2005 from Korean Medical Insurance. RESULTS: In follow-up, 72 physicians (66.7%) performed blood test every 3 months, 51 physicians (47.2%) performed imaging study in case of BCR. Bone scan was the most common imaging study in the follow-up (74 physicians, 68.5%). But, bone scan was only performed in case of BCR (43 physicians, 39.8%). The criteria of BCR was PSA 0.2 ng/mL (75 physician, 69.4%), 76 physicians (70.4%) was performed different follow-up according to risk of patients. In Korean Medical Insurance data analysis, PSA were performed average 2 times every year and magnetic resonance imaging, computed tomography, Bone scan were performed average 0.1, 0.2, 0.1 times every year, respectively. CONCLUSIONS: The criteria of BCR and the follow-up of prostate cancer patients in Korea were similar Korean prostate cancer guidelines. Blood and imaging test might be increased compared to 10 years ago, it is necessary to compare the Korean Medical Insurance data between 10 years ago and present.

Impact of Young Age at Diagnosis on Survival in Patients with Surgically Treated Renal Cell Carcinoma: a Multicenter Study

The prognostic significance of age in renal cell carcinoma (RCC) is a subject of debate. The aim of the present multi-institutional study was to evaluate the impact of age on clinicopathological features and survival in a large cohort of patients with RCC. A total of 5,178 patients who underwent surgery for RCC at eight institutions in Korea between 1999 and 2011 were categorized into three groups according to age at diagnosis as follows: young age (< 40 years, n = 541), middle-age (≥ 40 and < 60 years, n = 2,551), and old age (≥ 60 years, n = 2,096) groups. Clinicopathological variables and survival rates were compared between the three groups. Young patients had lower stage tumors with a low Fuhrman grade, a lower rate of lymphovascular invasion than patients in the other age groups. Regarding histologic type, the young age group had a lower percentage of clear cell histology and a greater incidence of Xp11.2 translocation RCC. Kaplan-Meier estimates showed that cancer-specific survival was significantly better in the young age group than in the other groups (log rank test, P = 0.008). However, age at diagnosis was not an independent predictor of survival in multivariate analysis. In conclusion, young age at diagnosis was associated with favorable pathologic features, although it was not an independent prognostic factor for survival in patients with surgically-treated RCC. Age itself should not be regarded as a crucial determinant for the treatment of RCC.

Methylation Markers in Renal Cell Carcinoma

Many tumor markers in relation to renal cell carcinoma (RCC) have been evaluated for detecting and monitoring diseases outcomes. However, none of these biomarkers reported to date has shown sufficient sensitivity and specificity for as a detector and prognosticator of the whole spectrum of RCC in routine clinical practice. The limited value of the established prognostic markers requires analysis of new molecular parameters of interest in predicting the prognosis of RCC patients; in particular, the high-risk patient groups at risk of recurrence and progression. Abnormal methylation of CpG islands can efficiently repress transcription of the associated gene in a manner akin to mutations and deletions. Recent progress in the understanding of epigenetic modification and gene silencing has provided new opportunities for the detection, treatment, and prevention of cancer. Methylation is an important molecular mechanism in RCC and could be used as a diagnostic and prognostic marker. Aberrant patterns of epigenetic modification would be, in near future, crucial parameters in cancer diagnosis, prognosis and a good target for developing novel therapies while maintaining the quality of life. This review discusses the epigenetic issues involved in the detection and prediction of prognosis in RCC.

Clinical and demographic factors associated with compliance and subsequent urinary metabolic changes in first-time ureteral stone formers / 동물의과학연구지

Dietary and lifestyle modifications are widely prescribed to prevent recurrence of urolithiasis, although little is known about the clinical and demographic factors associated with patient compliance and urinary metabolic changes. The present study assessed the clinical and demographic factors influencing compliance with a modified diet and lifestyle in first-time ureteric stone formers as well as determined the effects of compliance on urinary stone risk factors. We retrospectively reviewed the medical records of 53 patients presenting with ureteric calcium stones. Using a self-completed questionnaire, patients were classified according to compliance with seven recommendations for modifying diet and lifestyle into good compliance group (complied with > or = three recommendations) and poor compliance group. Before (on a random diet) and after prescribing the modifications, 24 hour urine samples were collected from those in the good and poor compliance group. The stone size at presentation and initial treatment modality were closely associated with patient compliance (P=0.019, P=0.027, respectively). Citrate excretion significantly increased in the good compliance group after adopting modifications (P=0.012), whereas the poor compliance group did not show a statistically significant difference. Moreover, patients in the poor compliance group showed significantly increased urinary calcium excretion by the end of the study (P=0.040). After adjustments for age, sex, body mass index, and metabolic abnormality status, poor compliance was found to be an independent risk factor for persistence or development of hypocitraturia (OR: 3.885; 95% CI: 1.102~13.694; P=0.035). In conclusion, our results imply that patient education programs regarding diet and lifestyle should be tailored to the individual's clinical and demographic characteristics.

Association of GATA5 methylation with clinocopathological characteristics in non-muscle invasive bladder cancer / 동물의과학연구지

DNA methylation is the most common and well-characterized epigenetic change in human cancer. Recently, the association between GATA-binding protein 5 (GATA5) methylation and carcinogenesis of various types of tumors was investigated. The aim of the present study was to evaluate the effect of GATA5 methylation status on clinicopathological features and prognosis in primary non-muscle invasive bladder cancer (NMIBC) patients with a long-term followup period. The GATA5 methylation status was determined for 171 human bladder specimens (eight normal controls [NCs] and 163 primary NMIBC patients) using quantitative pyrosequencing analysis. The primary NMIBC tissues were obtained from patients who underwent transurethral resection (TUR) for histologically diagnosed transitional cell carcinomas between 1995 and 2012 at Chungbuk National University Hospital. GATA5 methylation was significantly higher in NMIBC patients than in NCs and was significantly associated with higher grade and more advanced stage of cancer. Kaplan-Meier estimates showed significant differences in tumor recurrence and progression according to GATA5 methylation status (each p<0.05). Our results show that increased methylation of GATA5 was significantly associated with not only aggressive characteristics but also poor prognosis in primary NMIBC patients. Alteration of GATA5 methylation might be used as a biomarker for prognosis of NMIBC patients. However, prospective and functional investigations are necessary to clarify the role of GATA5 methylation in future clinical management of patients with NMIBC.