Yong Mee Cho

University of Ulsan, Ulsan, Ulsan, South Korea

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Publications (63)180.63 Total impact

  • Inkeun Park · Yong Mee Cho · Jae-Lyun Lee · Jin-Hee Ahn · Dae-Ho Lee
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    ABSTRACT: In metastatic renal cell carcinoma (mRCC), the prognostic role of several tumor tissue biomarkers has been evaluated, but the results were controversial. This study aims to verify the prognostic importance of selected tumor tissue biomarkers in patients with mRCC. The clinicopathological features, immunohistochemical staining and scoring for select tissue biomarkers, treatment, and outcome of patients with mRCC treated with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) between July 2006 and March 2011 at Asan Medical Center in Seoul, South Korea, were reviewed. In total, 123 patients met the inclusion criteria. Most patients had clear-cell carcinoma (107 patients, 87.0 %). First-line VEGFR TKIs were sunitinib (97 patients, 78.9 %), sorafenib (23 patients, 18.7 %), and pazopanib (3 patients, 2.4 %). With a median follow-up period of 60.0 months (95 % confidence interval (CI), 56.3-63.6), median overall survival (OS) and progression-free survival (PFS) were 25.6 months (95 % CI, 19.2-32.0) and 12.2 months (95 % CI, 8.1-16.3), respectively. In the multivariable analysis for OS, carbonic anhydrase IX (CAIX; 47.5 % or less vs. more than 47.5 %, p = 0.014), sarcomatoid change (40 % or less vs. more than 40 %, p < 0.001), tumor necrosis (20 % or less vs. more than 20 %, p = 0.006), and Heng's risk group (good vs. intermediate vs. poor, p = 0.011) were identified as independent prognostic factors. In the multivariable analysis for PFS, CAIX (p < 0.001), phosphatase and tensin homolog (PTEN; 45 % or less vs. more than 45 %, p = 0.004), sarcomatoid change (p = 0.002), and tumor necrosis (p = 0.001) were identified as independent factors affecting PFS. CAIX and PTEN had prognostic importance for mRCC patients receiving first-line VEGFR TKI. Future validation and mechanistic studies are required.
    No preview · Article · Nov 2015 · Tumor Biology
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    ABSTRACT: Background: Immune checkpoint blockade therapy targeting programmed death (PD)-1 or PD-ligand1 (L1) has shown promising results in renal cell carcinoma (RCC); however, the prognostic implications and clinicopathological features of PD-L1 and PD-L2 expression in RCC remain unclear. Methods: PD-L1 and PD-L2 expression was immunohistochemically evaluated in 425 resected RCCs of variable histologic subtypes and analyzed according to the clinicopathological status and oncogenic proteins status. Results: PD-L1 expression was observed in 9.4 % with no difference between histologic subtypes, but PD-L2 was observed in 49.6 % with highest frequency in papillary RCC (PRCC) (P < 0.001). In clear cell RCC (CCRCC), PD-L1 expression was associated with adverse features, including higher nuclear grade, necrosis, sarcomatoid transformation, c-MET expression (all, P < 0.001) and VEGF expression (P = 0.002), whereas PD-L2 expression was related with c-MET and VEGF expression (P = 0.008 and P < 0.001). In PRCC, positive correlations between PD-L1 and EGFR expression (P = 0.007) or between PD-L2 and VEGF expression (P < 0.001) were observed. In CCRCC, PD-L1 and PD-L2 positivity were significantly associated with shorter progression-free survival (P < 0.001; P = 0.033) and cancer-specific survival (P < 0.001; P = 0.010), but not in PRCC. Conclusions: PD-L1 and PD-L2 expression predict poor prognosis in CCRCC. Thus, PD-1/PD-L pathway-targeted immunotherapy may be useful for treatment of patients with CCRCC.
    No preview · Article · Oct 2015 · Annals of Surgical Oncology
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    ABSTRACT: Background: Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are used as the first-line treatment for patients with metastatic clear cell renal cell carcinoma (mCCRCC). Recently, programmed death-1 (PD-1) and programmed death ligand-1 (PD-L1) blockade emerged as promising therapy for renal cell carcinoma. However, the expression pattern and prognostic implication of programmed death-ligands (PD-Ls) in mCCRCC patients receiving VEGF-TKI remain unclear. Patients and methods: PD-L1 and PD-L2 expression in tumor cells and the quantities of PD-1+ tumor-infiltrating lymphocytes were immunohistochemically evaluated in 91 mCCRCC patients treated with VEGF-TKI, and their associations with VEGF-TKI responsiveness and clinical outcome were analyzed. Results: PD-L1 immunopositivity was observed in 17.6% and significantly associated with a high International Society of Urological Pathology grade (p = .031) and sarcomatoid features (p = .014). PD-L2 immunopositivity was observed in 39.6% and was not associated with any of the assessed clinicopathological variables. PD-L1-positive cases showed poor VEGF-TKI responsiveness (p = .012) compared with PD-L1-negative cases. In univariate survival analysis, PD-L1 immunopositivity was significantly associated with shorter overall survival (OS) (p = .037) and progression-free survival (PFS) (p = .043). Multivariate survival analysis revealed that PD-L1 expression was independently associated with poor OS (p = .038) and PFS (p = .013) in addition to tumor necrosis (p = .006; p = .029, respectively) and Memorial Sloan Kettering Cancer Center score (p = .018; p = .032, respectively). PD-L2 expression was neither associated with VEGF-TKI responsiveness nor patients' outcome. Conclusion: PD-L1 expression was significantly related to lack of VEGF-TKI responsiveness and independently associated with shorter survival in mCCRCC patients after VEGF-TKI treatment. PD-L1 may have a predictive and prognostic value for determining the value of VEGF-TKI treatment in patients with mCCRCC. Implications for practice: Vascular endothelial growth factor pathway (VEGF)-tyrosine kinase inhibitors (TKIs) are essential for the treatment of metastatic renal cell carcinoma patients, but the treatment suffers from a lack of predictive markers. This study demonstrates that PD-L1 expression is a predictor for unfavorable response to VEGF-TKI and a prognostic indicator for poor overall survival and progression-free survival in patients with metastatic clear cell renal cell carcinoma receiving VEGF-TKI.
    No preview · Article · Oct 2015 · The Oncologist
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    ABSTRACT: We investigated the effects of KML001 (NaAsO2, sodium metaarsenite, Kominox), an orally bioavailable arsenic compound, on the growth and death of human prostate cancer cells and its mechanism of action. Growth inhibition was assessed by cytotoxicity assays in the presence or absence of inhibitor of apoptosis, inhibitor of autophagy or antioxidant N-Acetyl-L-cysteine to study mechanism of cell death induced by KML001 in PC3, DU145 and LNCaP prostate cancer cell lines. Electron microscopy, flow cytometry and Western blotting were used to study apoptotic and autophagic mechanisms. The DU145 xenograft model was used to determine the efficacy of KML001 in vivo. KML001 decreased the viability of cells and increased the percentage of annexin V-positive cells dose-dependently in prostate cancer cells, and LNCaP cells were more sensitive to KML001 than PC3 or DU145 cells. Electron microscopy revealed typical apoptotic characters and autophagic vacuoles in cells treated with KML001. Exposure to KML001 in prostate cancer cells induced apoptosis and autophagy in a time- and dose-dependent manner. KML001 induced dose-dependent accumulation of reactive oxygen species, and scavenging the reactive oxygen species with N-Acetyl-L-cysteine reduced LC3 and cleaved poly (ADP-ribose) polymerase. KML001 significantly inhibited tumor growth in the DU145 xenograft model. In addition, significant decrease of proliferation and significant increases of apoptosis and autophagy were observed in KML001-treated tumors than in vehicle-treated tumors. Exposure of human prostate cancer cells to KML001 induced both apoptosis and autophagic cell death via oxidative stress pathway. And KML001 had an antiproliferative effect on DU145 cells in xenograft mice.
    Preview · Article · Sep 2015 · PLoS ONE
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    ABSTRACT: Purpose: We aimed to compare the pathologic aggressiveness of clinically localized prostate cancer (PCa) treated by radical prostatectomy in Korean and Western (Caucasian and African American [AA]) men by analyzing data from representative hospitals in the capitals of Korea (Seoul) and the United States (Washington, DC). Methods: We performed a retrospective cohort study of 1,939 patients who underwent radical prostatectomy for clinically localized PCa in the Asan Medical Center and Washington Hospital Center. After adjusting for confounding clinical variables, we used multivariate logistic regression analysis to assess differences in the aggressiveness of PCa. Results: We analyzed 1,152 Korean, 473 Caucasian, and 314 AA patients. There were significant differences between Korean and Western patients in terms of age at surgery, preoperative levels of prostate-specific antigen, and clinical stage (P<0.001). Overall, high-grade PCa (Gleason score≥8) was more common in Korean (19.4%) than in AA (6.1%) or Caucasian (5.5%) patients (P<0.001). The incidence of advanced-stage PCa (pT3 or higher) was higher in Korean (34.8%) than in AA (18.2%) or Caucasian (13.3%) patients (P<0.001). After adjusting for age, prostate-specific antigen, prostate volume, and clinical stage, multivariate logistic regression analysis showed that Korean men had a high risk of high-grade PCa (Korean vs. Caucasian, odds ratio [OR] = 3.48, P<0.001; Korean vs. AA, OR=3.14, P<0.001) or advanced-stage PCa (Korean vs. Caucasian, OR=2.40, P<0.001; Korean vs. AA, OR = 1.59, P = 0.009) than Western men. Conclusions: There are differences in PCa aggressiveness between Korean and Western men. The incidence of high-grade or advanced-stage PCa is higher in Korean men.
    No preview · Article · Sep 2015 · Urologic Oncology
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    ABSTRACT: The study aimed to verify the prognostic utility, therapeutic application and clinical benefits of tumor substaging and HER2 status in papillary non-muscle invasive bladder cancer (NMIBC). Select NMIBC transurethral resection specimens from 141 patients were used to construct tissue microarrays for assessing the substaging, HER2 protein expression by immunohistochemistry (HER2-IHC) and gene amplification by dual-color silver in situ hybridization (HER2-SISH). Substages were identified by the differing depth of tumor invasion (pTa / pT1a / pT1b / pT1c). HER2 protein expression was semiquantitatively analyzed and grouped into negative (score 0, 1+) and positive (score 2+, 3+). Other clinicopathological variables were also investigated. For NMIBC, HER2-IHC and HER2-SISH showed positive results in 6/141 (4.3%) and 4/141 (2.8%) respectively, which correlated well with tumor substaging. In multivariate analysis, substaging, HER2-IHC, and HER2-SISH were found to be independent predictors of progression-free survival (P < 0.001, P < 0.001, P = 0.031). HER2-IHC was the sole independent predictor of recurrent free survival in NMIBC (P = 0.017). It is suggested that tumor substaging and HER2 status are independent predictive markers for tumor progression or recurrence, and thus could be included in diagnostic and therapeutic management for NMIBC. Graphical Abstract
    Full-text · Article · Aug 2015 · Journal of Korean medical science
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    ABSTRACT: Sphingosine-1-phosphate receptor 1 (S1PR1) promotes tumour cell survival, invasion, anti-apoptosis, metastasis and radio/chemo-resistance in various cancers. However, the expression pattern and prognostic implications of S1PR1 in urothelial carcinoma remain unclear and thus were addressed here. Tissue microarrays composed of 395 initially diagnosed and transurethral resected urothelial carcinomas of the urinary bladder were immunostained for S1PR1 and phosphor-signal transducer and activator of transcription 3 (pSTAT3). S1PR1 expression was analysed according to clinicopathological features, expression of several anti-apoptosis/proliferation-related markers and patient's survival. S1PR1 positivity was observed in 45.3% of urothelial carcinomas. Among patients with non-muscle invasive urothelial carcinoma (NMIC), S1PR1 positivity was associated with higher grade (P<0.001), higher subepithelial invasive component (P=0.006), lower papillary component (P=0.002), presence of metastasis (P=0.042) and high cancer-specific death (P<0.001). S1PR1 expression was correlated with pSTAT3 (P<0.001), survivin (P=0.008) and Ki-67 (P<0.001) expression. S1PR1 positivity predicted a shorter cancer-specific survival (CSS) in NMICs (P<0.001) and stage T1/high grade (T1HG) tumours (P=0.002). The Cox multivariate model was composed of S1PR1, survivin, lymphovascular invasion and age, and C-index was 0.781. S1PR1 positivity was correlated with shorter CSS in p53-positive T1HG carcinoma (P=0.003) in contrast to p53-negative T1HG carcinoma (P=0.205). In p53-overexpressing NMIC, S1PR1 was the only variable of the survival model and the C-index was 0.719. S1PR1 expression was associated with unfavourable clinicopathological features and the expression of several anti-apoptosis/proliferation-related markers in urothelial carcinoma. S1PR1 serves as an independent predictor of cancer-specific death in NMIC. The model including S1PR1 showed highly accurate prediction for CSS in NMIC patients regardless of the modality of adjuvant therapy. Copyright © 2015 Elsevier Ltd. All rights reserved.
    No preview · Article · Jul 2015 · European journal of cancer (Oxford, England: 1990)
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    ABSTRACT: CD56+ and CD163+ cell infiltration in human kidney transplant biopsies have not been fully evaluated. We investigated the association of CD56+ and CD163+ cell infiltration with human kidney transplant biopsies with antibody- or T-cell-mediated rejection (TCMR) and other histologic lesions. One hundred and seventy four clinically indicated transplant biopsies were included in this analysis. Immunohistochemical staining for C4d, CD56 and CD163 was performed. One hundred and seventy four indication biopsies were divided into early (≤1 year posttransplant; n = 49) and late (>1 year posttransplant; n = 125) biopsies. High numbers of CD56+ cells were uncommon in early biopsies except for those with antibody-mediated rejection (AMR) only. On the other hand, high numbers of CD56+ cells were observed in late biopsies diagnosed as TCMR only, AMR only, and TCMR combined with AMR. In early biopsies, both CD56+ and CD163+ infiltrates correlated strongly with interstitial inflammation, tubulitis, and peritubular capillaritis (ptc) scores. The ci and ct scores, however, were correlated only with the number of CD56+ cells. In late biopsies, on the other hand, the number of CD56+ infiltrates was correlated only with ptc, while the number of CD163+ infiltrates was weakly correlated with any histologic lesion. Multivariable analyses showed that chronic active AMR and the number of CD56+ cells/10 HPF were independently associated with death-censored graft failure post-biopsy. The number of CD163+ cells was not correlated with any pathologic lesion and post-biopsy graft failure. CD56+ infiltrates were also associated with interstitial fibrosis and tubular atrophy. Intragraft CD56+ cell infiltrates were significantly associated with AMR and subsequent poor clinical outcomes. © 2015 S. Karger AG, Basel.
    No preview · Article · Jun 2015 · American Journal of Nephrology
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    ABSTRACT: One of the major challenges in bladder cancer management is in distinguishing aggressive from indolent tumors with similar clinicopathological factors, especially in cases of high-grade T1 stage tumors. To define a set of prognostic factors that can be easily assessed in clinical practice with a high cost-effectiveness, the expressions of 11 proteins were examined immunohistochemically in 403 cases of transurethral resection of bladder tumors, then correlated to clinical outcomes. Based on the protein immunoprofiles, urothelial carcinomas were divided into 4 intrinsic molecular subgroups with different clinical outcomes: subgroups 1 and 4 with the poorest survival, subgroup 2 with the best survival, and subgroup 3 with the intermediate survival outcome. The protein expression patterns of the 4 subgroups were mutually exclusive: overexpression of p53, EZH2, E2F1, and IMP3 and high Ki-67 proliferation index in subgroup 1; overexpression of cytoplasmic survivin in subgroup 4; overexpression of membranous TSP1 and cytoplasmic p27 in subgroup 2; and no representative protein overexpression in subgroup 3. Using these protein immunoprofiles, 3 risk groups were generated, which predicted disease-specific survival not only in total bladder carcinoma cases with 0.737 of predictive accuracy but also in high-grade stage T1 tumors with 0.658 of predictive accuracy. These results showed that urothelial carcinomas were composed of 4 clinically relevant molecular subgroups based on protein expression and that overall survival of those patients could be predicted using a set of a small number of protein expressions not only in total cases but also in high-grade stage T1 tumors. Copyright © 2015. Published by Elsevier Inc.
    No preview · Article · Jun 2015 · Human pathology
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    ABSTRACT: Capicua (CIC) has been implicated in pathogenesis of spinocerebellar ataxia type-1 (SCA1) neurodegenerative disease and some types of cancer; however, the role of CIC in prostate cancer remains unknown. Here we show that CIC suppresses prostate cancer progression. CIC expression was markedly decreased in human prostatic carcinoma. CIC overexpression suppressed prostate cancer cell proliferation, invasion, and migration, whereas CIC RNAi exerted opposite effects. We found that knock-down of CIC derepresses expression of ETV5 and CRABP1 in LNCaP and PC-3 cells, respectively, thereby promoting cell proliferation and invasion. We also discovered that miR-93, miR-106b, and miR-375, which are known to be frequently overexpressed in prostate cancer patients, cooperatively down-regulate CIC levels to promote cancer progression. Altogether, we suggest miR-93/miR-106b/miR-375-CIC-CRABP1 as a novel key regulatory axis in prostate cancer progression.
    Preview · Article · Jun 2015 · Oncotarget
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    ABSTRACT: We evaluated the clinicopathological features and prognosis of 29 cases of prostate ductal carcinoma was considered to be an aggressive subtype of prostate acinar carcinoma. We selected 29 cases who were diagnosed prostate ductal carcinoma and had a radical prostatectomy (RP). The acinar group (n = 116) was selected among 3,980 patients who underwent a prostatectomy. The acinar group was matched to the ductal group for prostate specific antigen (PSA), clinical stage, Gleason score, and age. The mean (range) of the follow-up periods for the ductal and acinar group was 23.8 ± 20.6 and 58 ± 10.5 months, respectively. The mean age of the prostate ductal and acinar carcinoma patients was 67.3 and 67.0 yr and the mean PSA level was 14.7 and 16.2 ng/mL, respectively. No statistical differences were evident between groups in terms of the final pathologic stage or positive resection margin rate other than the postoperative Gleason score. A greater proportion of the ductal group demonstrated a postoperative Gleason score ≥ 8 in comparison with the acinar group (P = 0.024). Additionally, we observed significant prognostic difference in our patient series in biochemical recurrence. The ductal group showed a poorer prognosis than the acinar group (P = 0.016). There were no differences significantly in terms of final pathology and rate of positive resection margin, but a greater proportion of the ductal group demonstrated a Gleason score ≥ 8 than the acinar group after matching for PSA, Gleason score in biopsy and clinical stage. The ductal group also showed a poorer prognosis. Graphical Abstract
    Full-text · Article · Apr 2015 · Journal of Korean medical science
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    ABSTRACT: Background: Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110[gamma] and p110[delta] play important roles in immune cell migration and function, we investigated the effects of PI3K p110[gamma]- and p110[delta]-specific inhibitors in a murine renal IRI model. Methods: Renal function was assessed by serum creatine and hematoxylin-eosin staining. Immune cell migration was assessed by flow cytometry and an in vitro cell migration assay using Transwell plates. Gene expression analysis and a multiplex cytokine/chemokine assay were performed to find cytokines/chemokines whose expression was upregulated in renal IRI and affected by p110[gamma]-specific inhibitor. Results: The PI3K p110[gamma]-specific inhibitor, but not p110[delta]-specific inhibitor, significantly reduced serum creatine levels and acute tubular necrosis. These were accompanied by reduced infiltration of B cells and reduced expression of CXCL9, a CXCR3 ligand, suggesting that p110[gamma] plays an important role in B-cell migration toward injured kidneys. An in vitro cell migration assay revealed for the first time that B-cell migration to injured kidney cells and to CXCL9 requires p110[gamma]. Conclusions: p110[gamma]-specific inhibitor ameliorates renal IRI by reducing necrosis and immune cell migration. This inhibitor may have the potential to reduce renal graft failure caused by renal IRI.
    No preview · Article · Apr 2015 · Transplantation
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    ABSTRACT: High-grade non-muscle-invasive bladder cancer (Non-MIBC) has a high risk of stage progression to muscle-invasive bladder cancer (MIBC) and could be managed either conservatively by transurethral resection of bladder tumor (TURBT) or more aggressively by radical cystectomy. The selection of patients who may benefit from early radical intervention is a challenge. To define useful prognostic markers for progression, we analyzed clinicopathological features and immunohistochemical expression patterns of E2F1, p27, survivin, p53, EZH2, IMP3, TSC1/hamartin, fatty acid synthase, androgen receptor, 14-3-3σ, MAGEA4, and NY-ESO-1 on 118 cases of high-grade Non-MIBC. During the mean follow-up period of 64.3 months, progression occurred in 18 patients (15.3%). Histologically, large amount of invasive component (> 50%) was noted in 35 cases (29.7%) and was strongly associated with progression. Among the 12 biomarkers, high expressions of E2F1 and nuclear p27 were noted in 46 cases (40.0%) and 14 cases (12.7%), respectively, and were associated with frequent progression. Using multivariate analysis, the proportion of invasive component and high E2F1 expression were independent prognostic factors for the prediction of progression. Our results indicated that large amount of invasive carcinoma component and high expressions of p27 and E2F1 were predictive markers for progression in Non-MIBC. Therefore, we suggest that these parameters, especially proportion of invasive carcinoma component and E2F1 expression, should be evaluated during pathologic examination and considered during selection of the appropriate management strategy for high grade Non-MIBC patients.
    No preview · Article · Mar 2015 · International journal of clinical and experimental pathology
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    ABSTRACT: Interstitial cystitis (IC) is a syndrome characterized by urinary urgency, frequency, pelvic pain, and nocturia in the absence of bacterial infection or identifiable pathology. IC is a devastating disease that certainly decreases quality of life. However, the causes of IC remain unknown and no effective treatments or cures have been developed. This study evaluated the therapeutic potency of using human umbilical cord-blood derived mesenchymal stem cells (UCB-MSCs) to treat IC in a rat model and investigate its responsible molecular mechanism. IC was induced in 10-weeks-old female Sprague-Dawley rats via the instillation of 0.1M HCl or PBS (sham). After 1-week, human UCB-MSC (IC+MSC) or PBS (IC) was directly injected into the submucosal layer of the bladder. A single injection of human UCB-MSCs significantly attenuated the irregular and decreased voiding interval in the IC group. Accordingly, denudation of the epithelium and increased inflammatory responses, mast cell infiltration, neurofilament production, and angiogenesis observed in the IC bladders were prevented in the IC+MSC group. The injected UCB-MSCs successfully engrafted to the stromal and epithelial tissues and activated Wnt signaling cascade. Interference with Wnt and epidermal growth factor receptor (EGFR) activity by small molecules abrogated the benefits of MSC therapy. This is the first report that provides an experimental evidence of the therapeutic effects and molecular mechanisms of MSC therapy to IC using an orthodox rat animal model. Our findings not only provide the basis for clinical trials of MSC therapy to IC, but also advance our understanding of IC pathophysiology.
    No preview · Article · Mar 2015 · Stem Cells and Development
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    ABSTRACT: Xp11.2 translocation renal cell carcinoma (RCC) is characterized by various translocations of the TFE3 transcription factor gene. These rare cancers occur predominantly in children and young adults. Here, we review the clinicopathological features of Xp11.2 translocation RCC. We identified 21 patients with Xp11.2 translocation RCC. We retrospectively analyzed patient characteristics, clinical manifestations, and specific pathological features to assess definitive diagnosis, surgical and systemic treatments, and clinical outcomes. The mean age at diagnosis was 43.4±20.0 years (range, 8-80 years; 8 males and 13 females). Eleven patients were incidentally diagnosed, nine patients presented with local symptoms, and one patient presented with systemic symptoms. The mean tumor size was 6.2±3.8 cm (range, 1.9-14 cm). At the time of diagnosis, 11, 1, and 5 patients showed stage I, II, and III, respectively. Four patients showed distant metastasis. At analysis, 15 patients were disease-free after a median follow-up period of 30.0 months. Four patients received target therapy but not effectively. Xp11 translocation RCC tends to develop in young patients with lymph node metastasis. Targeted therapy did not effectively treat our patients. Surgery is the only effective therapy for Xp11 translocation RCC, and further studies are needed to assess systemic therapy and long-term prognosis.
    Full-text · Article · Mar 2015 · Korean journal of urology
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    ABSTRACT: Nephronophthisis 13 (NPHP 13) is associated with mutations in the WDR19 gene, which encodes for a protein in the intraflagellar transport complex. Herein, we describe six additional cases accompanied by Caroli syndrome or disease. Targeted exome sequencing covering 96 ciliopathy-related genes was performed for 48 unrelated Korean patients with a clinical suspicion of NPHP. Mutations were confirmed by Sanger sequencing. We evaluated the expression of WDR19 in the biopsied kidney by immunohistochemistry in patients and controls. We detected three (3/48, 6.3 %) unrelated index cases with WDR19 mutations. One of the cases involved two siblings with the same mutation. Later, we detected an additional index case with a similar phenotype of kidney and liver involvement by Sanger sequencing of WDR19. The p.R1178Q mutation was common in all patients. All of the six affected patients from four families progressed to chronic kidney disease. Of note, all six patients had Caroli syndrome or disease. Immunohistochemistry for WDR19 showed localized expression along the luminal borders of the renal tubular epithelium in controls, whereas it showed diffuse cytoplasmic staining in the affected patients. Caroli disease is a major extra-renal phenotype associated with mutations in WDR19 in the Korean population. In this study, we visually validated the expression pattern of mutant WDR19 protein in the kidneys of NPHP 13 patients. More data are needed to identify the true frequency of p.R1178Q. Functional studies including transfection assay will provide solid grounds for the pathogenicity of each mutation.
    No preview · Article · Mar 2015 · Pediatric Nephrology
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    ABSTRACT: Regarding survival data analysis in regression modeling, multiple conditional quantiles are useful summary statistics to assess covariate effects on survival times. In this study, we consider an estimation problem of multiple nonlinear quantile functions with right censored survival data. To account for censoring in estimating a nonlinear quantile function, weighted kernel quantile regression (WKQR) has been developed by using the kernel trick and inverse-censoring-probability weights. However, the individually estimated quantile functions based on the WKQR often cross each other and consequently violate the basic properties of quantiles. To avoid this problem of quantile crossing, we propose the non-crossing weighted kernel quantile regression (NWKQR), which estimates multiple nonlinear conditional quantile functions simultaneously by enforcing the non-crossing constraints on kernel coefficients. The numerical results are presented to demonstrate the competitive performance of the proposed NWKQR over the WKQR.
    No preview · Article · Dec 2014 · Lifetime Data Analysis
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    ABSTRACT: Hepatoid adenocarcinoma is a rare extrahepatic aggressive tumor defined by morphologic and immunohistochemical evidences of hepatoid differentiation. In this study, clinicopathologic features of three cases of hepatoid renal cell carcinoma (RCC) were analyzed. Case I was a 53-year-old man with stage III, 12 cm-sized RCC showing combined clear cell and papillary RCC with sarcomatoid dedifferentiation, and 1,460 ng/ml of serum alpha-fetoprotein (AFP). Case II was a 62-year-old woman with stage IV, 6.5 cm-sized clear cell RCC, and 40,800 ng/ml of serum AFP. Case III was a 51-year-old woman with stage I, 1.6 cm-sized, Xp11 translocation RCC and 313.3 ng/ml of serum AFP. Cases I and II died of the disease at 26 and 21 months after radical nephrectomy, in each. Case III was alive without the disease for 20 months at the last follow-up. Microscopically, three cases show hepatoid carcinoma areas with eosinophilic to clear tumor cells, arranged in trabeculae separated by thin sinusoidal vessels, in addition to characteristic features of RCC subtypes. Tumor cells in these hepatoid carcinoma areas as well as at least focal corresponding RCC areas were immunopositive for AFP in all three cases, but, immunonegative for other hepatic markers (Hep Par1, polyclonal CEA, and glypican 3). This report suggests that the hepatoid features with AFP production are aberrant differentiation that can be developed in various RCC subtypes. Recognizing hepatoid RCC will help explain abnormal elevation of serum AFP level, which can be used as a serum surveillance marker.
    No preview · Article · Oct 2014 · Annals of Diagnostic Pathology
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    ABSTRACT: Various clinical and laboratory parameters are used to determine the prognosis of patients with renal cell carcinoma (RCC) but prognostic significance of histologic features has not been fully examined in patients with metastatic clear cell RCC receiving vascular endothelial growth factor (VEGF)-tyrosine kinase inhibitor (TKI) (VEGF-TKI)-targeted therapy. To define prognostic clinicopathologic factors, 83 such patients were retrospectively analyzed. Of these patients, 38 (45.8%) showed response to VEGF-TKI, whereas 45 (54.2%) were non-responsive. Response to VEGF-TKI was associated with < 10% sarcomatoid features and < 10% tumor necrosis. Multivariate analysis showed that tumor necrosis was independently prognostic of VEGF-TKI response. During a median follow-up of 18 months (range, 1–62 months), 54 patients (65.1%) showed disease progression and 44 (53.0%) died. Shorter progression-free survival (PFS) and overall survival (OS) were associated with a time period less than 1 year from initial diagnosis to VEGF-TKI initiation, high Fuhrman grade, ≥ 10% sarcomatoid features and ≥ 10% tumor necrosis. In addition, thrombocytosis was associated with shorter OS. Multivariate analysis showed that sarcomatoid features was independently prognostic of PFS, whereas time from initial diagnosis to VEGF-TKI initiation and sarcomatoid features were independent prognostic factors of OS. In summary, sarcomatoid features, tumor necrosis, and tumor grade are histologic prognostic factors and should be considered in determining whether to initiate targeted treatment in patients with metastatic clear cell RCC.
    No preview · Article · Jul 2014 · Human pathology
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    ABSTRACT: We analyzed the clinicopathological data of patients undergoing radical nephrectomy for clear cell type renal cell carcinoma (RCC) who presented with metastasis and were subsequently treated with sunitinib and identified molecular markers in nephrectomy specimens to predict susceptibility to sunitinib. The medical records of 65 patients who underwent nephrectomy for metastatic clear cell type RCC and were then treated with sunitinib were reviewed. The nephrectomy specimens were subjected to prospective immunohistochemical staining for vascular endothelial growth factor, vascular endothelial growth factor receptor-2 (VEGFR-2), platelet-derived growth factor-B, and platelet-derived growth factor receptor-β expression. In 58 evaluable patients, the median value of initial and best overall response was -9.69 and -24.04 %, respectively. VEGFR-2 expression was associated significantly with initial and best overall responses to sunitinib, along with Karnofsky performance status and Memorial Sloan-Kettering Cancer Center prognostic risk group. Multiple linear regression analyses revealed that strong VEGFR-2 expression was positively associated with the best reduction in tumor response (β = -0.275, P = 0.016) and poor Karnofsky performance status was negatively associated it (β = 0.477, P < 0.001). Karnofsky performance status and retroperitoneal lymph node involvement associated independently with progression-free- and overall survivals. None of the molecular markers associated significantly with survival. VEGFR-2 expression might be a useful biomarker for predicting the response to sunitinib by patients with metastatic RCC. Karnofsky performance status and retroperitoneal lymph node involvement were predictive of disease progression and death.
    No preview · Article · Apr 2014 · World Journal of Urology

Publication Stats

467 Citations
180.63 Total Impact Points


  • 2006-2015
    • University of Ulsan
      • • Department of Pathology
      • • College of Medicine
      Ulsan, Ulsan, South Korea
  • 2005-2014
    • Asan Medical Center
      • Department of Pathology
      Sŏul, Seoul, South Korea
  • 2010
    • Ulsan University Hospital
      Urusan, Ulsan, South Korea