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Purpose: P21-activated kinase 4 (PAK4), a serine/threonine kinase that regulates a number of fundamental cellular processes, has been suggested as a prognostic factor for various human tumors. The aim of the present study was to evaluate the clinical implications of phospho-Ser474 PAK4 (pPAK4 S474 ), an activated form of PAK4, in surgically treated renal cell carcinoma (RCC)., Materials and Methods: Samples from 131 patients with surgically treated RCC were immunostained to detect PAK4 and pPAK4 S474 . Expression of PAK4 and pPAK4 S474 was compared with clinicopathological characteristics and survival after nephrectomy., Results: PAK4 and pPAK4 S474 were expressed predominantly in the nucleus. Overall, 57.3% (75/131) and 24.4% (29/119) of specimens exhibited high expression of pPAK4 S474 and PAK4, respectively. High expression of pPAK4 S474 was associated with adverse pathologic characteristics, including advanced tumor stage and grade (p=0.036 and p=0.002, respectively), whereas this association was not significant for PAK4 expression (each p>0.05). Kaplan-Meier estimates showed that high expression of pPAK4 S474 was associated with shorter recurrence-free survival in a subgroup with localized RCC and with cancer-specific survival in the total RCC cohort (log-rank test: p=0.001 and p=0.005, respectively), whereas PAK4 expression was not. Multivariate Cox regression analysis identified that high pPAK4 S474 expression was an independent predictor of recurrence in the subgroup with localized RCC., Conclusions: pPAK4 S474 may be a more accurate prognostic factor than total PAK4 in RCC patients. This marker would be useful for identifying patients with pathologically localized disease who may require further interventions., Competing Interests: The authors have nothing to disclose., (© The Korean Urological Association, 2021.)

Background: The objective of this study was to provide more definitive information about the prognostic impact of perioperative blood transfusion (PBT) on patients with surgically treated renal cell carcinoma (RCC)., Methods: A database of 4019 patients with clear cell RCC, all of whom underwent radical or partial nephrectomy as primary therapy as part of a multi-institutional Korean collaboration between 1988 and 2015, was analyzed retrospectively. PBT was defined as transfusion of allogeneic red blood cells during surgery or postsurgical period. Receipt of a PBT, as well as the amount and time of blood transfusion (BT), was compared., Results: Overall, 335 (8.3%) patients received a PBT: 84 received postoperative BT, 202 received intraoperative BT, and 49 received both intraoperative and postoperative BT. Patients receiving a PBT had a poor preoperative immuno-nutritional status, and aggressive tumor characteristics. Multivariate analyses identified PBT as an independent predictor of recurrence-free survival and cancer-specific survival. Prognostic impact of PBT was restricted to those with locally advanced stage (pT3-4), and who underwent radical nephrectomy. Among patients who received a PBT, intraoperative (but not postoperative) BT was a prognostic factor for survival. Among patients who received intraoperative BT, those receiving three or more transfusion units had a significantly worse survival., Conclusion: Receipt of a PBT was an independent predictor of RFS and CSS in patients with surgically treated RCC, specifically locally advanced disease. Regarding the prognostic impact of timing or dose of PBT on survival, intraoperative BT and ≥ 3 pRBC units were associated with adverse oncological outcomes.

The World Health Organization 2016 edition assigned anaplastic lymphoma kinase ( ALK ) rearrangement-associated renal cell carcinoma (ALK-RCC) as an emerging renal tumor entity. Identifying ALK-RCC is important because ALK inhibitors have been shown to be effective in treatment. Here, we report the case of a 14-year-old young man with ALK-RCC. Computed tomography revealed a well-demarcated 5.3-cm enhancing mass at the upper pole of the left kidney. There was no further history or symptoms of the sickle-cell trait. The patient underwent left radical nephrectomy. Pathologically, the mass was diagnosed as an unclassified RCC. Targeted next-generation sequencing identified a TPM3-ALK fusion gene. The present report and literature review demonstrate that TPM3-ALK RCC may be associated with distinct clinicopathological features. Microscopically, the tumors showed diffuse growth and tubulocystic changes with inflammatory cell infiltration. Tumor cells were dis-cohesive and epithelioid with abundant eosinophilic cytoplasm and cytoplasmic vacuoles. If morphological features and TFE3 expression are present in adolescent and young patients, molecular tests for ALK translocation should be performed. This awareness is critically important, because ALK rearrangement confers sensitivity to ALK inhibitors., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Purpose: No study has evaluated the prognostic impact of the age-adjusted Charlson comorbidity index (AACI) in those with renal cell carcinoma (RCC). This study aimed to evaluate the utility of the AACI for predicting long-term survival in patients with surgically treated non-metastatic clear cell RCC (ccRCC)., Methods: Data from 698 patients with non-metastatic ccRCC who underwent radical or partial nephrectomy as primary therapy from a multi-institutional Korean collaboration between 1988 and 2015 were retrospectively analyzed. Clinicopathological variables and survival outcomes of those with AACI scores ≤ 3 (n = 324), 4-5 (n = 292), and ≥ 6 (n = 82) were compared., Results: Patients with a high AACI score were older and more likely to be female. They were also more likely to have diabetes or hypertension, a worse Eastern Cooperative Oncology Group performance status, and lower preoperative hemoglobin, albumin, serum calcium, and serum total cholesterol levels. Regarding pathologic features, a high AACI score was associated with advanced stage. Kaplan-Meier analyses revealed that AACI ≥ 6 was associated with shorter cancer-specific (log-rank test, P < 0.001) and overall survival (log-rank test, P < 0.001), but not with recurrence-free survival (log-rank test, P = 0.134). Multivariate Cox regression analyses identified an AACI score as an independent predictor of overall survival (hazard ratio, 6.870; 95% confidence interval, 2.049-23.031; P = 0.002). The AACI score was a better discriminator of overall survival than the Charlson comorbidity index score., Conclusions: AACI scores may enable more tailored, individualized management strategies for patients with surgically treated non-metastatic ccRCC.

Purpose: To investigated the prognostic significance of the geriatric nutritional risk index (GNRI) in patients with surgically treated clear cell renal cell carcinoma (ccRCC). Patients and methods: We retrospectively selected 4,591 consecutive patients with surgically treated ccRCC from a multi-institutional Korean collaboration between 1988 and 2015. The clinical significance of the GNRI as a continuous and categorical variable was determined. Results: Preoperative low GNRI was significantly associated with older age, low body mass index, presence of diabetes, poor performance status, and presence of symptoms at diagnosis, as well as pathologic features such as aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, sarcomatous differentiation, and tumor necrosis. A low GNRI was significantly associated with a short recurrence-free survival (RFS) in localized (pT1-2N0M0) ccRCC and cancer-specific survival (CSS) in the entire cohort, and with short RFS and CSS in the subgroup analysis according to age categories (≤65 and >65 years). Multivariate Cox regression analysis showed that preoperative GNRI, as a continuous or categorical variable, was an independent predictor of RFS and CSS. Conclusion: Malnutrition as assessed by the preoperative GNRI is associated with aggressive tumor characteristics and poor survival in patients with surgically treated ccRCC.

The present study aimed to identify novel methylation markers of clear cell renal cell carcinoma (ccRCC) using microarray methylation analysis and evaluate their prognostic relevance in patient samples. To identify cancer‑specific methylated biomarkers, microarray profiling of ccRCC samples from our institute (n=12) and The Cancer Genome Atlas (TCGA) database (n=160) were utilized, and the prognostic relevance of candidate genes were investigated in another TCGA dataset (n=153). For validation, pyrosequencing analyses with ccRCC samples from our institute (n=164) and another (n=117) were performed and the potential clinical application of selected biomarkers was examined. We identified 22 CpG island loci that were commonly hypermethylated in ccRCC. Kaplan‑Meier analysis of TCGA data indicated that only 4/22 loci were significantly associated with disease progression. In the internal validation set, Kaplan‑Meier analysis revealed that hypermethylation of two loci, zinc finger protein 492 (ZNF492) and G protein‑coupled receptor 149 (GPR149), was significantly associated with shorter time‑to‑progression. Multivariate Cox regression models revealed that hypermethylation of ZNF492 [hazard ratio (HR), 5.44; P=0.001] and GPR149 (HR, 7.07; P<0.001) may be independent predictors of tumor progression. Similarly, the methylation status of these two genes was significantly associated with poor outcomes in the independent external validation cohort. Collectively, the present study proposed that the novel methylation markers ZNF492 and GPR149 could be independent prognostic indicators in patients with ccRCC.

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., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2019 The Korean Academy of Medical Sciences.)

Purpose: To analyze trends over a period of 28 years in the clinical, operative, and pathologic characteristics of patients with a renal mass who underwent surgical resection in Korea., Materials and Methods: Consecutive patients (n=6,231) with a renal mass who underwent surgical resection at eight Korean institutions between 1988 and 2015 were reviewed. Patients were assigned to one of three groups according to the date of surgery: group 1, 1988-1999; group 2, 2000-2009; and group 3, 2010-2015., Results: Age at the time of surgery, body mass index, smoking status, incidence of diabetes and hypertension, and the number of incidentally identified renal masses increased significantly over time. The proportion of patients undergoing partial nephrectomy (PN) or minimally invasive surgery (MIS) increased sharply during the last two time periods. From 2010, the rate of robot-assisted nephrectomy rose sharply, occurring in 37.8% of MIS cases. Benign pathology was identified in 1.8% and 5.2% of cases in the middle and last periods, respectively; angiomyolipoma was the most common pathology. In later years, tumors were more often localized, although tumor grade increased. Sub-group analysis of small renal masses ≤4 cm revealed similar trends in operative and pathologic characteristics over time., Conclusions: Between 1988 and 2015, there was a substantial change in the clinical, operative, and histological characteristics of patients who underwent resection of a renal mass in Korea. The most notable changes were stage migration towards localized disease and widespread use of PN and MIS., Competing Interests: CONFLICTS OF INTEREST: The authors have nothing to disclose.

Purpose: The prognostic role of the controlling nutritional status (CONUT) score in renal cell carcinoma (RCC) has not been evaluated. The aim of the current study was to clarify the prognostic significance of the CONUT score in Korean patients with surgically treated RCC., Materials and Methods: A database of 1,881 patients with surgically treated RCC from a multiinstitutional Korean collaboration between 1999 and 2015 was analyzed. The preoperative CONUT score was calculated from serum albumin, total cholesterol concentrations, and total lymphocyte count. Clinicopathological variables and survival rates were compared between the CONUT score groups., Results: A high CONUT score was associated with older age, lower body mass index, lower preoperative prognostic nutritional index, and presence of diabetes or hypertension (each P < 0.001). Regarding pathologic features, a high CONUT score was associated with aggressive tumor characteristics including large tumor size, advanced stage, high nuclear grade, lymphovascular invasion, and sarcomatous differentiation (each P < 0.001). Multivariate Cox regression analysis indicated that a high CONUT score (≥ 2) was an independent predictor of cancer-specific mortality (hazard ratio, 1.892; 95% CI: 1.118-3.201; P = 0.018)., Conclusion: The CONUT score, an easily measurable immune-nutritional biomarker, may provide useful prognostic information in patients with surgically treated RCC.

Background: The prognostic implications of preoperative serum total cholesterol (TC) level in patients with renal cell carcinoma (RCC) remain poorly understood. We investigated the prognostic role of preoperative serum TC in patients with surgically treated RCC from a large, multi-institutional Korean collaboration., Patients and Methods: A database of 3064 patients with RCC who underwent radical or partial nephrectomy between 1999 and 2011 at eight academic centers was analyzed. Preoperative serum TC levels were measured in fasting blood samples., Results: Low preoperative serum TC level was associated with aggressive tumor characteristics, including large tumor size, advanced stage, high nuclear grade, lymph node involvement, and sarcomatous differentiation (all P < 0.001). Low TC level was associated with poor recurrence-free or cancer-specific survival (CSS) in the entire cohort, whereas the significance of the association changed after stratification by disease stage and histologic subtype. Multivariate Cox regression analysis showed that preoperative TC, as a continuous or categorical variable, was an independent predictor of CSS., Conclusions: Preoperative low serum TC level was associated with aggressive tumor characteristics and poor CSS in patients with surgically treated RCC. Preoperative TC may provide additional guidance regarding the choice of therapeutic strategies to improve prognosis.

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., Competing Interests: The authors have no potential conflicts of interest to disclose.

Purpose: To assess the risk factors of positive surgical margins (PSM) and the influence of margin status on recurrence in pT1 clear cell renal cell carcinoma (RCC) following partial nephrectomy (PN)., Materials and Methods: Patients (1,831) with pathologically confirmed stage T1 clear cell RCC were retrospectively analyzed following PN at eight institutions in Korea between 1999 and 2011. Demographics, operative data, pathological margin status, and site of recurrence were analyzed., Results: Resection margins were positive in 31 patients (1.7% of the cohort) on final pathology. None of the clinicopathological parameters were significantly related to the marginal status (all P > 0.05). During a median follow-up of 32.5 months, local recurrences were observed in 0.4% of negative surgical margins. There was no local recurrence in any of the cases with PSM. Distant recurrences developed in 1.7% of negative surgical margins and 3.2% of PSM. There were no significant differences in recurrence-free survival by margin status (P = 0.566)., Conclusions: Our multi-institutional data suggest that marginal status does not influence tumor recurrence risk in pT1 clear cell RCC after PN. Careful surveillance seems to be a sufficient strategy in this clinical scenario. J. Surg. Oncol. 2016;114:70-74. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Purpose: Preoperative chronic kidney disease (CKD) status may affect disease outcomes in patients with renal cell carcinoma (RCC). This study evaluated the influence of preoperative CKD status on clinicopathological features and prognosis in patients with RCC., Methods: Between 1999 and 2011, a total of 1855 patients underwent radical nephrectomy at various centers throughout Korea. Of these patients, 1655 had an estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73 m(2) (non-CKD group) and 200 patients had an eGFR ≥30 but <60 ml/min/1.73 m(2) (CKD group). To reduce the effects of selection bias and potential confounding factors, 600 patients in the non-CKD group were selected by propensity-score matching., Results: The median age of all patients was 57.3 years (range 20-94 years) and the median follow-up was 35.0 months (range 1-154 months). Comparisons of the propensity-score-matched cohorts showed that T and N stages were more advanced and tumor size was larger in the CKD group than in the non-CKD group (p < 0.05 each). Kaplan-Meier analyses showed that recurrence-free survival, cancer-specific survival (CSS), and overall survival (OS) were significantly lower in the CKD group (p < 0.01 each). Multivariate regression analysis showed that preoperative CKD status was an independent predictor of CSS and OS in patients with RCC (p < 0.05 each)., Conclusions: Preoperative CKD may be associated with more aggressive features and poorer prognosis in patients with RCC. RCC patients with preoperative CKD should be carefully and frequently followed-up after nephrectomy.

Background: The anticancer effects of selenium may be mediated by selenium-binding proteins, such as SELENBP1. The association between SELENBP1 expression levels and clinicopathologic parameters was assessed in renal cell carcinoma (RCC)., Methods: SELENBP1 mRNA expression was measured with real-time quantitative polymerase chain reaction (qPCR) in 139 specimens of primary RCC and 59 specimens of donor-matched normal-appearing kidney tissues. The prognostic effect of SELENBP1 levels was evaluated with Kaplan-Meier and multivariate Cox regression analyses., Results: SELENBP1 mRNA levels were significantly lower in tumor tissues than in matched normal kidney tissues (P < 0.001) and significantly inversely correlated with pathologic (T-stage and Fuhrman grade) and prognostic variables (progression and cancer-specific death). Kaplan-Meier estimates showed that low SELENBP1 expression was significantly correlated with cancer-specific death (log-rank test, P = 0.014), and a multivariate Cox regression model revealed that SELENBP1 expression was an independent predictor of cancer-specific death (HR, 0.111; P = 0.006)., Conclusions: SELENBP1 might play a role in tumor suppression and could be a useful prognostic factor in RCC.

Background: The purpose of our study was to determine whether preoperative diabetes mellitus (DM) can predict the prognosis of localized clear-cell renal cell carcinoma (RCC)., Methods: At five institutes, 2,597 patients with pT1 and pT2 clear-cell RCC were enrolled. Univariate and multivariable analyses were performed to determine factors that associated with recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). To identify the effect of DM on survival after recurrence, a subgroup of 127 patients who had recurrences was analyzed., Results: In total, 357 patients had DM. Compared with patients without DM, these patients were older, more likely to be male, and had a higher body mass index, lower GFR, and higher incidence of hypertension. Kaplan-Meier curves showed that patients with DM had a significantly worse rate of RFS, CSS, and OS than patients without DM (log-rank test, all P < 0.05). Multivariate analysis revealed that DM was an independent prognostic factor in terms of RFS, CSS, and OS. In the subgroup analysis of 127 patients with recurrence, DM was associated with a lower survival rate after the initial recurrence., Conclusions: DM appeared to be an important determinant of prognosis in clear-cell localized RCC, especially in patients experiencing recurrence.

Objective: Although germline mutations of fumarate hydratase (FH) are a useful molecular marker of hereditary leiomyomatosis and renal cell cancer (RCC) syndrome, their clinical significance in sporadic RCC has not been studied in detail. The aim of the present study was to investigate possible correlations between the expression of FH and the clinical implications of sporadic RCC., Materials and Methods: FH mRNA levels were evaluated in 140 tumor specimens from patients with primary RCC and in 62 specimens of corresponding normal-appearing kidney tissue using real-time quantitative polymerase chain reaction. Immunohistochemical staining was performed on 6 normal surrounding tissues and 71 RCC tissues., Results: FH mRNA levels were significantly lower in tumor tissues than in matched normal-appearing kidney tissues (p = 0.031). In all normal tissues, FH staining intensity was strong. However, the expression of FH showed no significant correlation with the pathological and clinical characteristics of patients with sporadic RCC., Conclusions: Our results showed that FH mRNA expression decreased significantly in correlation with the transition from normal renal parenchyma to RCC. FH may be an indicator or tumorigenesis in sporadic RCC and could be a potential target for therapies against RCC in the future., (Copyright © 2012 S. Karger AG, Basel.)