Publications by authors named "Yong Mee Cho"

88 Publications

Comparison of clinical outcomes in patients with localized or locally advanced urothelial carcinoma treated with neoadjuvant chemotherapy involving gemcitabine-cisplatin and high dose-intensity MVAC.

J Cancer Res Clin Oncol 2021 Mar 14. Epub 2021 Mar 14.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

Purpose: To compare the efficacy and safety of high dose-intensity combination of methotrexate, vinblastine, adriamycin and cisplatin (HD MVAC) with gemcitabine plus cisplatin (GC) as a neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) or locally advanced upper tract urothelial cancer (UTUC).

Patients And Methods: A retrospective analysis was conducted for patients with UC (cT2-4aN0-1M0) who received NAC from January 2011 and December 2017 at Asan Medical Center. Pathologic complete response (pCR), down-staging (< ypT2 and no N upstaging), disease-free survival (DFS), OS and safety were compared for each regimen.

Results: Out of a total of 277 patients, 176 patients received GC and 41 patients received HD MVAC. With the exception of age (patients receiving HD MVAC were younger; p = 0.002), other baseline characteristics were well balanced between groups. pCR rates were 27.0% for GC and 22.6% for HD MVAC (p = 0.62), and down-staging rate was 50.8% for GC and 58.1% for HD MVAC (p = 0.47). There were no differences in OS (72.1% vs 73.1% for GC vs HD MVAC; p = 0.58) and DFS (54.9% vs 63.3% for GC vs HD MVAC; p = 0.21) at 3 years. HD MVAC with prophylactic G-CSF was associated with a higher incidence of febrile neutropenia (p < 0.001) than GC. The NAC regimen was not an independent prognostic factor for OS.

Conclusion: Oncologic outcomes were not significantly different between the GC and HD MVAC when used as NAC in MIBC/UTUC.
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http://dx.doi.org/10.1007/s00432-021-03582-xDOI Listing
March 2021

Clinical Evaluation of (4S)-4-(3-[F]Fluoropropyl)-L-glutamate (F-FSPG) for PET/CT Imaging in Patients with Newly Diagnosed and Recurrent Prostate Cancer.

Clin Cancer Res 2020 10 21;26(20):5380-5387. Epub 2020 Jul 21.

Molecular Imaging Program at Stanford (MIPS), Department of Radiology, Stanford University, Stanford, California.

Purpose: (4S)-4-(3-[F]Fluoropropyl)--glutamic acid (F-FSPG) is a radiopharmaceutical for PET imaging of system x activity, which can be upregulated in prostate cancer. We present data on the first evaluation of patients with newly diagnosed or recurrent prostate cancer with this radiopharmaceutical.

Experimental Design: Ten patients with primary and 10 patients with recurrent prostate cancer were enrolled in this prospective multicenter study. After injection of 300 MBq of F-FSPG, three whole-body PET/CT scans were obtained. Visual analysis was compared with step-section histopathology when available as well as other imaging studies and clinical outcomes. Metabolic parameters were measured semiquantitatively. Expression levels of xCT and CD44 were evaluated by IHC for patients with available tissue samples.

Results: F-FSPG PET showed high tumor-to-background ratios with a relatively high tumor detection rate on a per-patient (89%) and per-lobe (87%) basis. The sensitivity was slightly higher with imaging at 105 minutes in comparison with 60 minutes. The maximum standardized uptake values (SUV) for cancer was significantly higher than both normal ( < 0.005) and benign pathology ( = 0.011), while there was no significant difference between normal and benign pathology ( = 0.120). In the setting of recurrence, agreement with standard imaging was demonstrated in 7 of 9 patients (78%) and 13 of 18 lesions (72%), and revealed true local recurrence in a discordant case. F-FSPG accumulation showed moderate correlation with CD44 expression.

Conclusions: F-FSPG is a promising tumor imaging agent for PET that seems to have favorable biodistribution and high cancer detection rate in patients with prostate cancer. Further studies are warranted to determine the diagnostic value for both initial staging and recurrence, and how it compares with other investigational radiotracers and conventional imaging modalities.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-0644DOI Listing
October 2020

Involvement of the TNF-α Pathway in TKI Resistance and Suggestion of TNFR1 as a Predictive Biomarker for TKI Responsiveness in Clear Cell Renal Cell Carcinoma.

J Korean Med Sci 2020 Feb 10;35(5):e31. Epub 2020 Feb 10.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Mechanism and predictive biomarkers for tyrosine kinase inhibitor (TKI) resistance of advanced clear cell renal cell carcinoma (ccRCC) have not been fully evaluated.

Methods: We performed gene expression profiling on samples from an acquired TKI resistance cohort that consisted of 10 cases of TKI-treated ccRCC patients with matched tumor tissues harvested at pre-treatment and TKI-resistant post-treatment periods. In addition, a public microarray dataset from patient-derived xenograft model for TKI-treated ccRCC (GSE76068) was retrieved. Commonly altered pathways between the datasets were investigated by Ingenuity Pathway Analysis using commonly regulated differently expressed genes (DEGs). The significance of candidate DEG on intrinsic TKI resistance was assessed through immunohistochemistry in a separate cohort of 101 TKI-treated ccRCC cases.

Results: gene expression and tumor necrosis factor (TNF)-α pathway were upregulated in ccRCCs with acquired TKI resistance in both microarray datasets. Also, high expression (> 10% of labeled tumor cells) of TNF receptor 1 (TNFR1), the protein product of gene, was correlated with sarcomatoid dedifferentiation and was an independent predictive factor of clinically unfavorable response and shorter survivals in separated TKI-treated ccRCC cohort.

Conclusion: TNF-α signaling may play a role in TKI resistance, and TNFR1 expression may serve as a predictive biomarker for clinically unfavorable TKI responses in ccRCC.
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http://dx.doi.org/10.3346/jkms.2020.35.e31DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7008069PMC
February 2020

Genomic Landscape of Young-Onset Bladder Cancer and Its Prognostic Implications on Adult Bladder Cancer.

Cancers (Basel) 2020 Jan 28;12(2). Epub 2020 Jan 28.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea.

Due to the rare occurrence of young-onset bladder cancer (YBC), its genomic characteristics remain largely unknown. Twenty-nine biopsy-proven YBC cases were collected using a nation-wide search for bladder cancer diagnosed at 20 years or younger. Whole exome sequencing and RNA sequencing were carried out in 21 and 11 cases, respectively, and compared with those of adult bladder cancer (ABC) cases obtained from public databases. Almost all YBCs were low grade, non-invasive papillary tumors. YBC had a low mutation burden and less complex copy number alterations. All cases harbored putative driver mutations. Mutations were most commonly found in HRAS (10 cases), with a preference for exon 5. FGFR3 gene fusions were noted with various partner genes (7 cases). The alterations on HRAS and FGFR3 occurred in a mutually exclusive manner. Others included KRAS mutations (2 cases), chromosomes 4p and 10q arm-level deletions (1 case), and ERCC2 mutation (1 case). There were no point mutations in TP53 and FGFR3. The gene expression profiles of YBC were similar to those of the ABC group with good prognosis. None of the YBCs and ABCs with YBC-like mutations showed progression to muscle-invasive tumors. Our results suggest that bladder cancer with YBC-like mutations represents an indolent bladder tumor, regardless of age.
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http://dx.doi.org/10.3390/cancers12020307DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7073191PMC
January 2020

FGFR1 is associated with c-MYC and proangiogenic molecules in metastatic renal cell carcinoma under anti-angiogenic therapy.

Histopathology 2020 May 28;76(6):838-851. Epub 2020 Apr 28.

Department of Pathology, University of Ulsan College of Medicine, Asan Medical Centre, Seoul, Korea.

Aims: This study aimed to investigate the clinicopathological significance of FGFR1 and c-MYC expression, particularly in relation to angiogenesis in clear cell renal cell carcinoma (CCRCC).

Methods And Results: Immunohistochemistry and fluorescence in-situ hybridisation were conducted with tissue microarrays from 91 metastatic CCRCC patients who received VEGF receptor tyrosine kinase inhibitors (VEGFR-TKIs). The expression of angiogenic molecules, FGFR1 and c-MYC, and tumoral vascular density (TVD) and mRNA expression and TVD of 533 CCRCCs in The Cancer Genome Atlas (TCGA) were analysed. FGFR1, pFGFR1 and c-MYC expression was observed in 29.1, 74.4 and 30.8% of tumours, respectively. FGFR1 was an independent worse prognostic factor for overall (HR = 1.871, P = 0.032) and progression-free (HR = 1.976, P = 0.016) survival. FGFR1 was significantly related to VEGFR-TKI responsiveness (P = 0.011). The presence of FGFR1 /c-MYC showed a positive correlation with proangiogenic markers, including VEGF (P = 0.018) and HIF-1α (P < 0.0001). FGFR1 /c-MYC tumours showed higher TVDs together with higher VEGFR2 and PDGFR-β expression (both P < 0.0001). FGFR1 and c-MYC expression was also positively correlated with the expression of hypoxia-related and proangiogenic-related genes in the TCGA data.

Conclusions: FGFR1 and c-MYC may be involved in tumour angiogenesis and FGFR1 may represent a promising therapeutic target in metastatic CCRCC.
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http://dx.doi.org/10.1111/his.14076DOI Listing
May 2020

Recurrent KRAS mutations identified in papillary renal neoplasm with reverse polarity-a comparative study with papillary renal cell carcinoma.

Mod Pathol 2020 04 17;33(4):690-699. Epub 2020 Jan 17.

Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea.

Comprehensive molecular analyses revealed that papillary renal cell carcinoma (PRCC) is a heterogenous entity. Papillary renal neoplasm with reverse polarity (PRNRP) is a subset of PRCC with characteristic histomorphologies such as low-grade nuclear features, inverted nuclear location, eosinophilic cytoplasm, and indolent clinical behavior. We tried to define the molecular, clinicopathological, histologic, and immunohistochemical features of PRNRP by comparing them with type 1 PRCC (PRCC1) and type 2 PRCC (PRCC2). A cohort of 30 PRNRP, 23 PRCC1, and 26 PRCC2 cases was used. Targeted sequencing of 90 cancer-related genes including KRAS was performed in 26 PRNRP tumor samples. PNA-mediated clamping PCR of KRAS was performed using paired normal and tumor DNA from 30 PRNRP, 23 PRCC1, and 26 PRCC2 cases. Tissue microarray slides were made in three cores per tumor, which were stained with cytokeratin 7 (CK7), alpha-methylacyl-CoA racemase (AMACR), epithelial membrane antigen (EMA), E-cadherin, vimentin, and CD10. Recurrent mutations in KRAS were detected in 28 of the 30 PRNRPs. However, there were no KRAS mutations in any PRCC1 or PRCC2 cases. PRNRP exhibited distinct clinicopathological features: small tumor size, lower pathologic T stage, and no disease-specific death during the follow-up period. Histologically, peritumoral lymphoid aggregation, prominent papillary architecture (>80% of tumor), hyalinized papillae, inverted nuclear location, and lower nuclear grade were observed. PRNRP was usually positive for CK7, AMACR, EMA, and E-cadherin, and negative for CD10. The findings suggest that PRNRP is a subtype of papillary renal neoplasm that is different from PRCC1 or PRCC2 in terms of molecular, clinicopathological, histological, and immunohistochemical features.
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http://dx.doi.org/10.1038/s41379-019-0420-8DOI Listing
April 2020

Clinicopathologic study of 60 cases of urothelial neoplasms with inverted growth patterns: Reclassification by international consultation on urologic disease (ICUD) recommendations.

Ann Diagn Pathol 2020 Feb 22;44:151433. Epub 2019 Nov 22.

Department of Pathology and Genomic Medicine, The Methodist Hospital and Weill Medical College of Cornell University, Houston, TX 77030, USA. Electronic address:

Background: Most urothelial neoplasms of the bladder show an exophytic papillary pattern, but some show an inverted growth pattern. In 2004, the World Health Organization (WHO) released a detailed histologic classification system for papillary urothelial neoplasms, but not for inverted forms. The International Consultation on Urologic Disease (ICUD) recommendations of 2012 are applicable to inverted/endophytic papillary lesions as follows: 1) inverted papilloma (IP), 2) inverted papillary urothelial neoplasm of low malignant potential (IPUNLMP), 3) inverted papillary urothelial carcinoma, low grade, non-invasive (IPUCLG-NI), 4) inverted papillary urothelial carcinoma, high grade, non-invasive (IPUCHG-NI), 5) inverted papillary urothelial carcinoma, high grade, invasive (IPUCHG-I). However, only atypical cellular morphology was considered for classification in the 2012 ICUD recommendations, and data to support to validate this new grading system are lacking.

Methods: Sixty cases of inverted urothelial papillary tumors were classified into 5 categories according to 2012 ICUD and 2016 WHO/ISUP recommendations to evaluate their clinical, pathological, and immunohistochemical characteristics. Two subgroups were defined as subgroup 1, IP and IPUNLMP, and subgroup 2, IPUCLG-NI, IPUCHG-NI, and IPUCHG-I. Clinical features (age, sex, history of urothelial carcinoma, smoking history, size, and multifocality) and histologic features (nuclear pleomorphism, mitotic count, mitosis level, apoptosis, luminal necrosis, trabecular thickening, anastomosing trabeculae, hypercellularity, loss of polarity, peripheral palisading, palisading with central streaming, and discohesiveness) were evaluated. Immunohistochemical stains for CK20, CD44, P53, p16, Ki-67, cyclin D1 and c-erbB2 were performed.

Results: A total of 60 cases were classified as 10 cases of IP, 29 cases of IPUNLMPs, 15 cases of IPUCLG-NI, 4 cases of IPUCHG-NI, and 2 cases of IPUCHG-I. Compared to subgroup 1, subgroup 2 showed larger tumor size, more nuclear irregularity, higher mitotic count (hot spot and per 10 high power fields), more upper level mitosis (>1/2), and more frequent apoptosis, luminal necrosis, surface papillary component, trabecular thickening, anastomosing irregular trabeculae, hypercellularity, loss of polarity, peripheral palisading with central streaming, and discohesiveness, and absence of umbrella cells and urothelial eddies. CK20, Ki67, and c-erbB2 were the only markers that were differently expressed in the two subgroups, with more expression in subgroup 2.

Conclusions: The 2012 ICUD recommendations are valid to classify inverted papillary urothelial tumors. However, other histologic features besides atypical cellular morphology should also be considered to distinguish subgroup 1 and subgroup 2 inverted papillary urothelial tumors.
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http://dx.doi.org/10.1016/j.anndiagpath.2019.151433DOI Listing
February 2020

CD56CD57 infiltrates as the most predominant subset of intragraft natural killer cells in renal transplant biopsies with antibody-mediated rejection.

Sci Rep 2019 11 12;9(1):16606. Epub 2019 Nov 12.

Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Little is known about the characteristics and clinical implications of specific subsets of intragraft natural killer (NK) cells in kidney transplant recipients. We analyzed 39 for-cause renal transplant biopsies performed at our center from May 2015 to July 2017. According to histopathologic reports, 8 patients (20.5%) had no rejection (NR), 11 (28.2%) had T cell-mediated rejections (TCMR) only, and 20 (51.3%) had antibody-mediated rejection (ABMR). NK cells were defined as CD3CD56 lymphocytes that are positive for CD57, CD49b, NKG2A, or KIR. The density of NK cells was significantly higher in the ABMR group (2.57 ± 2.58/mm) than in the NR (0.12 ± 0.22/mm) or the TCMR (0.25 ± 0.34/mm) group (P = 0.002). Notably, CD56CD57 infiltrates (2.16 ± 1.89) were the most frequently observed compared with CD56CD49b (0.05 ± 0.13), CD56NKG2A (0.21 ± 0.69), and CD56KIR (0.15 ± 0.42) cells in the ABMR group (P < 0.001). Death-censored graft failure was significantly higher in patients with NK cell infiltration than those without (Log-rank test, P = 0.025). In conclusion, CD56CD57 infiltrates are a major subset of NK cells in kidney transplant recipients with ABMR and NK cell infiltration is significantly associated with graft failure post-transplant.
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http://dx.doi.org/10.1038/s41598-019-52864-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851356PMC
November 2019

Phosphorylation of TFCP2L1 by CDK1 is required for stem cell pluripotency and bladder carcinogenesis.

EMBO Mol Med 2020 01 11;12(1):e10880. Epub 2019 Nov 11.

Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Molecular programs involved in embryogenesis are frequently upregulated in oncogenic dedifferentiation and metastasis. However, their precise roles and regulatory mechanisms remain elusive. Here, we showed that CDK1 phosphorylation of TFCP2L1, a pluripotency-associated transcription factor, orchestrated pluripotency and cell-cycling in embryonic stem cells (ESCs) and was aberrantly activated in aggressive bladder cancers (BCs). In murine ESCs, the protein interactome and transcription targets of Tfcp2l1 indicated its involvement in cell cycle regulation. Tfcp2l1 was phosphorylated at Thr177 by Cdk1, which affected ESC cell cycle progression, pluripotency, and differentiation. The CDK1-TFCP2L1 pathway was activated in human BC cells, stimulating their proliferation, self-renewal, and invasion. Lack of TFCP2L1 phosphorylation impaired the tumorigenic potency of BC cells in a xenograft model. In patients with BC, high co-expression of TFCP2L1 and CDK1 was associated with unfavorable clinical characteristics including tumor grade, lymphovascular and muscularis propria invasion, and distant metastasis and was an independent prognostic factor for cancer-specific survival. These findings demonstrate the molecular and clinical significance of CDK1-mediated TFCP2L1 phosphorylation in stem cell pluripotency and in the tumorigenic stemness features associated with BC progression.
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http://dx.doi.org/10.15252/emmm.201910880DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949511PMC
January 2020

Urinary transglutaminase 2 as a potent biomarker to predict interstitial fibrosis and tubular atrophy of kidney allograft during early posttransplant period in deceased donor kidney transplantation.

Ann Surg Treat Res 2019 Jul 26;97(1):27-35. Epub 2019 Jun 26.

Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: Transglutaminase type 2 (TG2) is an extracellular matrix crosslinking enzyme with a pivotal role in kidney fibrosis. We tested whether quantification of urinary TG2 may represent a noninvasive method to estimate the severity of kidney allograft fibrosis.

Methods: We prospectively collected urine specimens from 18 deceased donor kidney transplant recipients at 1-day, 7-day, 1-month, 3-month, and 6-month posttransplant. In addition, kidney allograft tissue specimens at 0-day and 6-month posttransplant were sampled to analyze the correlation of urinary TG2 and kidney allograft fibrosis.

Results: Thirteen recipients had increased interstitial fibrosis and tubular atrophy (IFTA) scores at the 6-month protocol biopsy (IFTA group). The mean level of urinary TG2 in the IFTA group was higher compared to that of 5 other recipients without IFTA (no IFTA group). Conversely, the mean level of urinary syndecan-4 in the IFTA group was lower than levels in patients without IFTA. In the IFTA group, double immunofluorescent staining revealed that TG2 intensity was significantly upregulated and colocalizations of TG2/heparin sulfate proteoglycan and nuclear syndecan-4 were prominent, usually around tubular structures.

Conclusion: Urinary TG2 in early posttransplant periods is a potent biomarker for kidney allograft inflammation or fibrosis.
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http://dx.doi.org/10.4174/astr.2019.97.1.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609414PMC
July 2019

Factors associated with aggravation of tubulointerstitial damage on repeated biopsies in lupus nephritis patients with treatment failure.

Clin Exp Rheumatol 2020 Mar-Apr;38(2):239-244. Epub 2019 Jun 28.

Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Objectives: Tubulointerstitial damage in lupus nephritis (LN) is an important predictor of renal prognosis. Here, we investigated the factors associated with aggravation of tubulointerstitial damage in patients with LN.

Methods: Patients with LN, who underwent repeated renal biopsy due to treatment failure at a tertiary referral hospital between 1997 and 2017 were identified. Clinicopathologic and laboratory data were collected. Aggravation of tubulointerstitial damage (tubular atrophy and/or interstitial fibrosis) was defined as progression of severity from none-to-mild to moderate-to-severe. Factors associated with aggravation of tubulointerstitial damage were evaluated using logistic regression analysis.

Results: A total of 52 LN patients were included for analysis. Aggravation of tubulointerstitial damage at the second renal biopsy was observed in 19 (36.5%) patients. In multivariable logistic regression analysis, use of hydroxychloroquine (adjusted OR 0.215, 95% CI 0.049-0.941, p=0.041) was inversely associated with aggravation of tubulointerstitial damage, and higher renal component of systemic lupus erythematosus disease activity index (SLEDAI) at first biopsy (adjusted OR 1.331, 95% CI 1.083-1.636, p=0.007) was associated with aggravation of tubulointerstitial damage. In terms of use of HCQ, both length of treatment with HCQ (adjusted OR 0.974, 95% CI 0.951-0.998, p=0.036) and cumulative dose of HCQ (log transferred value) (adjusted OR 0.485, 95% CI 0.262-0.896, p=0.020) were inversely associated with aggravation of tubulointerstitial damage.

Conclusions: Use of hydroxychloroquine was associated with lower risk of aggravation in tubulointerstitial damage, and higher renal component of SLEDAI at first renal biopsy was associated with higher risk of aggravation in tubulointerstitial damage.
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April 2020

Renal flare in class V lupus nephritis: increased risk in patients with tubulointerstitial lesions.

Rheumatol Int 2019 Dec 6;39(12):2061-2067. Epub 2019 Jul 6.

Division of Rheumatology, Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, South Korea.

The objective of this study is to investigate the risk factors of renal flare in patients with membranous lupus nephritis (class V lupus nephritis). Biopsy-proven pure membranous lupus nephritis patients diagnosed between January 1997 and September 2017 were studied. We assessed and compared the clinical and pathological parameters between patients who experienced renal flare and those who did not. To identify risk factors of renal flare, multivariable Cox proportional hazard regression analysis was performed. Out of the 53 patients with pure membranous lupus nephritis, 17 patients (32.1%) experienced renal flare during a median follow-up of 121.5 months (range 44.4-196.9). Patients who experienced renal flare had significantly higher proportion of tubulointerstitial inflammation (76.5% vs. 36.1%, p = 0.006) and tubular atrophy/interstitial fibrosis (70.6% vs. 27.8%, p = 0.003) at baseline. In multivariable Cox proportional hazard regression analysis, the presence of tubulointerstitial inflammation [adjusted hazard ratio (HR) 5.532, 95% confidence interval (CI) 1.722-17.776, p = 0.004] and tubular atrophy/interstitial fibrosis (adjusted HR 4.328, 95% CI 1.450-12.916, p = 0.009) at baseline was significantly associated with increased risk of renal flare. The presence of tubulointerstitial inflammation and tubular atrophy/interstitial fibrosis is associated with increased risk of renal flare in patients with membranous lupus nephritis.
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http://dx.doi.org/10.1007/s00296-019-04369-7DOI Listing
December 2019

Tissue-resident natural killer cells exacerbate tubulointerstitial fibrosis by activating transglutaminase 2 and syndecan-4 in a model of aristolochic acid-induced nephropathy.

BMB Rep 2019 Sep;52(9):554-559

Division of Kidney and Pancreas Transplantation, Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05535, Korea.

Despite reports suggesting that tissue-resident natural killer (trNK) cells cause ischemic kidney injury, their contribution to the development of tubulointerstitial fibrosis has not been determined. This study hypothesized that the depletion of trNK cells may ameliorate renal fibrosis by affecting transglutaminase 2/syndecan-4 interactions. Aristolochic acid nephropathy (AAN) was induced in C57BL/6 mice as an experimental model of kidney fibrosis. The mice were treated with anti-asialo GM1 (ASGM1) or anti-NK1.1 antibodies to deplete NK cells. Although both ASGM1 and NK1.1 antibodies suppressed renal NKp46DX5 NK cells, renal NKp46DX5 cells were resistant to suppression by ASGM1 or NK1.1 antibodies during the development of tubulointerstitial fibrosis in the AAN-induced mouse model. Western blot analysis showed that both antibodies increased the expression of fibronectin, transglutaminase 2, and syndecan-4. These findings indicate that trNK cells played an exacerbating role in tubulointerstitial fibrosis by activating transglutaminase 2 and syndecan-4 in the AAN-induced mouse model. [BMB Reports 2019; 52(9): 554-559].
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774424PMC
September 2019

Epithelial-mesenchymal transition as a mechanism of resistance to tyrosine kinase inhibitors in clear cell renal cell carcinoma.

Lab Invest 2019 05 25;99(5):659-670. Epub 2019 Jan 25.

Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

Tyrosine kinase inhibitors (TKIs) are widely accepted as treatment for metastatic clear cell renal cell carcinoma (ccRCC). However, most patients eventually experience disease progression despite TKI treatment, even if the initial response is favorable. To define the underlying mechanism of TKI resistance, 10 TKI-treated metastatic ccRCC cases in which tumor samples were harvested before treatment and immediately after disease progression were examined. Gene expression profiles and copy number variations of matched pre- and post-treatment tumor samples were investigated. Altered biologic characteristics were confirmed in sunitinib-resistant ccRCC cell lines, which were generated by long-term treatment with sunitinib-containing media. Gene transcript levels related to the cell cycle and epithelial-mesenchymal transition (EMT) were significantly upregulated in the treated tumor samples compared with the pre-treatment samples. The mitotic count and sarcomatoid component were significantly increased in treated tumor samples. Alteration of EMT-related genes was also demonstrated in a sunitinib-resistant ccRCC cell line that showed enhanced migration and invasion compared to the parent cell line. siRNA-induced inhibition of EMT-related gene expression significantly suppressed the migration and invasion capacity of TKI-resistant cell lines. The present study shows that both ccRCC cases that progressed after TKI treatment and sunitinib-resistant ccRCC cell lines demonstrated alteration of EMT-related gene expression and enhancement of EMT-related behavior. These results suggest that EMT may explain the aggressive behavior of TKI-resistant ccRCC.
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http://dx.doi.org/10.1038/s41374-019-0188-yDOI Listing
May 2019

The impact on oncological outcomes after radical prostatectomy for prostate cancer of converting soft tissue margins at the apex and bladder neck from tumour-positive to -negative.

BJU Int 2019 05 26;123(5):811-817. Epub 2018 Jul 26.

Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objectives: To assess the impact of conversion from histologically positive to negative soft tissue margins at the apex and bladder neck on biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) after radical prostatectomy (RP) for prostate cancer.

Materials And Methods: The records of 2 013 patients who underwent RP and intra-operative frozen section (IFS) analysis between July 2007 and June 2016 were reviewed. IFS analysis of the urethra and bladder neck was performed, and if malignant or atypical cells remained, further resection with the aim of achieving histological negativity was carried out. Patients were divided into three groups according to the findings: those with a negative surgical margin (NSM), a positive surgical margin converted to negative (NCSM) and a persistent positive surgical margin (PSM).

Results: Among the 2 013 patients, rates of NSMs, NCSMs and PSMs were 75.1%, 4.9%, and 20.0%, respectively. The 5-year BCRFS rates of patients with NSMs, NCSMs and PSMs were 89.6%, 85.1% and 57.1%, respectively (P < 0.001). In both pathological (p)T2 and pT3 cancers, the 5-year BCRFS rate for patients with NCSMs was similar to that for patients with NSMs, and higher than for patients with PSMs. The 7-year DMFS rates of patients with NSMs, NCSMs and PSMs were 97.8%, 99.1% and 89.4%, respectively (P < 0.001). Among patients with pT3 cancers, the 7-year DMFS rate was significantly higher in the NCSM group than in the PSM group (98.0% vs 86.7%; P = 0.023), but not among those with pT2 cancers (100% vs 96.9%; P = 0.616). The 5-year BCRFS rate for the NCSM group was not significantly different from that of the NSM group among the patients with low- (96.3% vs 95.8%) and intermediate-risk disease (91.1% vs 82.8%), but was lower than that of the NSM group among patients in the high-risk group (73.2% vs 54.7%).

Conclusions: Conversion of the soft tissue margin at the prostate apex and bladder neck from histologically positive to negative improved the BCRFS and DMFS after RP for prostate cancer; however, the benefit of conversion was not apparent in patients in the high-risk group.
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http://dx.doi.org/10.1111/bju.14480DOI Listing
May 2019

Level of invasion into fibromuscular band is an independent factor for positive surgical margin and biochemical recurrence in men with organ confined prostate cancer.

BMC Urol 2018 Feb 2;18(1). Epub 2018 Feb 2.

Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-Ro 43 Gil Songpa-Gu, Seoul, 05505, Republic of Korea.

Background: This study aimed investigate the effect of the level of invasion into fibromuscular band (FMB) of prostate on the positive surgical margin (PSM) and biochemical recurrence (BCR) after radical prostatectomy (RP) in patients with organ-confined (pT2) prostate cancer.

Methods: The clinical and pathological data of 461 consecutive patients with pT2 prostate cancer were evaluated regarding the level of invasion into FMB. The relationship between levels of invasion into FMB and PSM / BCR was assessed.

Results: The rate of PSM at an FMB level of at 2 was 18.8%, which was significantly greater than the rates at levels 0 (5.4%) and 1 (7.8%). The level of FMB (p = 0.007) and percentage of tumor volume (p = 0.012) were identified as independent factors predictive of a positive surgical margin in a multivariate analysis. The 5-year BCR-free survival rates for a level 0-1 FMB with negative surgical margin, level 0-1 FMB with positive surgical margin, level 2 FMB with negative surgical margin, and level 2 FMB with positive surgical margin were 96.6%, 86.4%, 85.6%, and 72.9%, respectively (p <  0.001). A level 2 FMB (p = 0.050), positive surgical margin (p = 0.001), and surgical Gleason score (p = 0.001) were identified as independent predictors of a BCR of pT2 prostate cancer.

Conclusions: Among patients with negative surgical margins, the surgical Gleason score and level of FMB independently affected the incidence of a BCR of pT2 prostate cancer. The level of FMB was an independent predictor of both a positive surgical margin and a BCR of pT2 disease. Accordingly, the level of FMB might help to further stratify the prognosis of patients with pT2 disease.
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http://dx.doi.org/10.1186/s12894-018-0321-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5797402PMC
February 2018

Prognostic Significance of Macroscopic Appearance in Clear Cell Renal Cell Carcinoma and Its Metastasis-Predicting Model.

Pathol Int 2017 Dec 30;67(12):610-619. Epub 2017 Oct 30.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Prognostic significance of macroscopic appearance of clear cell renal cell carcinoma (ccRCC) has not yet been studied. This study aimed to define the prognostic significance of macroscopic appearance and to propose a prognostic model for post-operative metastasis in ccRCC. A total of 1,025 patients with ccRCC were analyzed for the development dataset. A separate cohort of 399 such patients was used as an external validation dataset. Macroscopic appearances were initially divided into four groups, but were later divided into two groups: a simple nodular group (700 cases, 68.3%) and an irregular outline group (325 cases, 32.7%). During the 66.1-month mean follow-up period, 98 patients (9.6%) developed metastasis. Univariate analysis revealed that metastasis was associated with older age, radical nephrectomy, larger tumor size, higher tumor grade and stage, and the irregular outline group. On multivariate analysis, age, tumor size, and macroscopic appearance remained as independent prognostic factors. These factors were used to build a prognostic model, which divided into three risk groups. The probabilities of 5-year metastasis-free survival in the low-, intermediate-, and high-risk groups were 98%, 83%, and 53%, respectively. The results showed prognostic significance of macroscopic appearance in ccRCC and propose a prognostic model to guide post-operative management of patients with ccRCC.
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http://dx.doi.org/10.1111/pin.12606DOI Listing
December 2017

Development of Response Classifier for Vascular Endothelial Growth Factor Receptor (VEGFR)-Tyrosine Kinase Inhibitor (TKI) in Metastatic Renal Cell Carcinoma.

Pathol Oncol Res 2019 Jan 29;25(1):51-58. Epub 2017 Sep 29.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul, 05505, Republic of Korea.

Vascular endothelial growth factor receptor (VEGFR)-targeted therapy improved the outcome of metastatic renal cell carcinoma (mRCC) patients. However, a prediction of the response to VEGFR-tyrosine kinase inhibitor (TKI) remains to be elucidated. We aimed to develop a classifier for VEGFR-TKI responsiveness in mRCC patients. Among 101 mRCC patients, ones with complete response, partial response, or ≥24 weeks stable disease in response to VEGFR-TKI treatment were defined as clinical benefit group, whereas patients with <24 weeks stable disease or progressive disease were classified as clinical non-benefit group. Clinicolaboratory-histopathological data, 41 gene mutations, 20 protein expression levels and 1733 miRNA expression levels were compared between clinical benefit and non-benefit groups. The classifier was built using support vector machine (SVM). Seventy-three patients were clinical benefit group, and 28 patients were clinical non-benefit group. Significantly different features between the groups were as follows: age, time from diagnosis to TKI initiation, thrombocytosis, tumor size, pT stage, ISUP grade, sarcomatoid change, necrosis, lymph node metastasis and expression of pAKT, PD-L1, PD-L2, FGFR2, pS6, PDGFRβ, HIF-1α, IL-8, CA9 and miR-421 (all, P < 0.05). A classifier including necrosis, sarcomatoid component and HIF-1α was built with 0.87 accuracy using SVM. When the classifier was checked against all patients, the apparent accuracy was 0.875 (95% CI, 0.782-0.938). The classifier can be presented as a simple decision tree for clinical use. We developed a VEGFR-TKI response classifier based on comprehensive inclusion of clinicolaboratory-histopathological, immunohistochemical, mutation and miRNA features that may help to guide appropriate treatment in mRCC patients.
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http://dx.doi.org/10.1007/s12253-017-0323-2DOI Listing
January 2019

Diverse Immunoprofile of Ductal Adenocarcinoma of the Prostate with an Emphasis on the Prognostic Factors.

J Pathol Transl Med 2017 Sep 9;51(5):471-481. Epub 2017 Aug 9.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Ductal adenocarcinoma (DAC) of the prostate is an uncommon histologic subtype whose prognostic factors and immunoprofile have not been fully defined.

Methods: To define its prognostic factors and immunoprofile, the clinicopathological features, including biochemical recurrence (BCR), of 61 cases of DAC were analyzed. Immunohistochemistry was performed on tissue microarray constructs to assess the expression of prostate cancer-related and mammalian target of rapamycin (mTOR) signaling-related proteins.

Results: During the median follow-up period of 19.3 months, BCR occurred in 26 cases (42.6%). DAC demonstrated a wide expression range of prostate cancer-related proteins, including nine cases (14.8%) that were totally negative for pan-cytokeratin (PanCK) immunostaining. The mTOR signaling-related proteins also showed diverse expression. On univariate analysis, BCR was associated with high preoperative serum levels of prostate-specific antigen (PSA), large tumor volume, predominant ductal component, high Gleason score (GS), comedo-necrosis, high tumor stage (pT), lymphovascular invasion, and positive surgical margin. High expressions of phospho-mTOR (p-mTOR) as well as low expressions of PSA, phospho-S6 ribosomal protein (pS6) and PanCK were associated with BCR. On multivariable analysis, GS, pT, and immunohistochemical expressions of PanCK and p-mTOR remained independent prognostic factors for BCR.

Conclusions: These results suggest GS, pT, and immunohistochemical expressions of PanCK and p-mTOR as independent prognostic factors for BCR in DAC. Since DAC showed diverse expression of prostate cancer-related proteins, this should be recognized in interpreting the immunoprofile of DAC. The diverse expression of mTOR-related proteins implicates their potential utility as predictive markers for mTOR targeted therapy.
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http://dx.doi.org/10.4132/jptm.2017.06.02DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5611530PMC
September 2017

Level of mitoses in non-muscle invasive papillary urothelial carcinomas (pTa and pT1) at initial bladder biopsy is a simple and powerful predictor of clinical outcome: a multi-center study in South Korea.

Diagn Pathol 2017 Jul 24;12(1):54. Epub 2017 Jul 24.

Department of Pathology, Inje University Sanggye Paik Hospital, 1342, Dongilro, Nowon-gu, Seoul, South Korea.

Background: Histologic grade is the most important predictor of the clinical outcome of non-muscle invasive (Ta, T1) papillary urothelial carcinoma (NMIPUCa), but its ambiguous criteria diminish its power to predict recurrence/progression for individual patients. We attempted to find an objective and reproducible histologic predictor of NMIPUCa that correlates well with the clinical outcome.

Methods: A total of 296 PUCas were collected from the Departments of Surgical Pathology of 11 institutions in South Korea. The clinical outcome was grouped into no event (NE), recurrence (R), and progression (P) categories. All 25 histological parameters were numerically redefined. The clinical pathology of each case was reviewed individually by 11 pathologists from 11 institutions based on the 2004 WHO criteria and afterwards blindly evaluated by two participants, based on our proposed parameters. Univariate and multivariate logistic regression analyses were performed using the R software package.

Results: The level of mitoses was the most reliable parameter for predicting the clinical outcome. We propose a four-tiered grading system based on mitotic count (> 10/10 high-power fields), nuclear pleomorphism (smallest-to-largest ratio of tumor nuclei >20), presence of divergent histology, and capillary proliferation (> 20 capillary lumina per papillary core).

Conclusions: The level of mitoses at the initial bladder biopsy and transurethral resection (TUR) specimen appeared to be an independent predictor of the Ta PUCa outcome. Other parameters include the number of mitoses, nuclear pleomorphism, divergent histology, and capillary proliferation within the fibrovascular core. These findings may improve selection of patients for a therapeutic strategy as compared to previous grading systems.
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http://dx.doi.org/10.1186/s13000-017-0639-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5525253PMC
July 2017

Histopathological characteristics of interstitial cystitis/bladder pain syndrome without Hunner lesion.

Histopathology 2017 Sep 16;71(3):415-424. Epub 2017 Jun 16.

Department of Urology, Asan Medical Centre, University of Ulsan College of Medicine, Seoul, Korea.

Aims: To assess the distinct histopathological characteristics and their clinical significance between non-Hunner-type and Hunner-type interstitial cystitis (IC)/bladder pain syndrome (BPS).

Methods And Results: We prospectively enrolled and classified IC/BPS patients, on the basis of cystoscopic findings, as having non-Hunner-type IC and Hunner-type IC. Specimens obtained from the posterior wall in non-Hunner-type IC cases during hydrodistension or from Hunner/non-Hunner lesions in Hunner-type IC cases during transurethral resection were evaluated. Stress urinary incontinence patients with microscopic haematuria were selected as controls. Biopsy specimens were obtained from 15 non-Hunner-type IC, 15 Hunner-type IC and 5 non-IC patients. Severe and moderate fibrosis was more frequently observed in non-Hunner-type IC than in Hunner-type IC and non-IC cases. However, severe and moderate inflammation was more frequently observed in Hunner-type IC than in non-Hunner-type IC cases. The remnant urothelium was significantly decreased in Hunner-type IC cases as compared with non-Hunner-type IC and non-IC cases (P < 0.05), and non-Hunner-type IC cases showed a higher number of mast cells than Hunner-type IC and non-IC cases (P = 0.035). Accordingly, several fibrosis-promoting genes were highly expressed in bladder tissues of non-Hunner-type IC, as compared with Hunner-type IC. Patients with severe fibrosis showed significantly higher urinary frequency and smaller bladder capacity than those with moderate and mild fibrosis (all P < 0.05).

Conclusions: Non-Hunner-type IC is characterized by severe fibrosis and increased mast cell infiltration, whereas Hunner-type IC is characterized by severe inflammation and urothelial denudation in the entire bladder. Fibrosis in the bladder of IC/BPS patients was correlated with increased urinary frequency and decreased bladder capacity.
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http://dx.doi.org/10.1111/his.13235DOI Listing
September 2017

Lymph node density vs. the American Joint Committee on Cancer TNM nodal staging system in node-positive bladder cancer in patients undergoing extended or super-extended pelvic lymphadenectomy.

Urol Oncol 2017 04 27;35(4):151.e1-151.e7. Epub 2017 Jan 27.

Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. Electronic address:

Purpose: We compared the prognostic value of the American Joint Committee on Cancer (AJCC) TNM nodal staging system with that of lymph node (LN) density in patients with LN-positive bladder cancer who received extended or super-extended pelvic lymphadenectomy.

Methods: Of the 1,018 patients, who underwent radical cystectomy and pelvic lymphadenectomy between February 2005 and August 2014, 110 patients with LN metastases with extended (n = 68) or super-extended (n = 42) pelvic lymphadenectomy were included. All patients were staged using the 2002 (sixth edition) and 2010 (seventh edition) AJCC TNM staging systems. The association of several variables with recurrence-free survival (RFS) and overall survival (OS) was evaluated.

Results: The median number of total LNs removed was 29 (6-118) and the median LN density was 12.5% (1.6%-100%). RFS and OS were not significantly different between the 2002 (pN1-pM1) and 2010 (pN1-N3) AJCC TNM nodal staging systems (sixth edition: P = 0.512 and P = 0.519; seventh edition: P = 0.676 and P = 0.671, respectively). The 2-year RFS and OS rates according to the LN density quartiles were 58.5% and 76.9% in Q1, 39.1% and 70.8% in Q2, 28.8% and 50.1% in Q3, and 12.7% and 20.8% in Q4 (P = 0.001 and P = 0.001, respectively). Multivariate analysis adjusted for the 2010 AJCC TNM staging system showed that LN density was associated with a decreased OS (HR = 1.024; 95% CI: 1.010-1.039; P = 0.001). The nodal staging system (2002 or 2010) was not associated with the RFS and OS.

Conclusions: LN density shows a better prognostic value than the AJCC TNM nodal staging system in patients with LN-positive bladder cancer receiving extended or super-extended pelvic lymphadenectomy.
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http://dx.doi.org/10.1016/j.urolonc.2016.06.021DOI Listing
April 2017

Refinement of the criteria for ultrastructural peritubular capillary basement membrane multilayering in the diagnosis of chronic active/acute antibody-mediated rejection.

Transpl Int 2017 Apr 5;30(4):398-409. Epub 2017 Mar 5.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Chronic active/acute antibody-mediated rejection (cABMR) is the main cause of late renal allograft loss. Severe peritubular capillary basement membrane multilayering (PTCML) assessed on electron microscopy is one diagnostic feature of cABMR according to the Banff 2013 classification. We aimed to refine the PTCML criteria for an earlier diagnosis of cABMR. We retrospectively investigated ultrastructural features of 159 consecutive renal allografts and 44 nonallografts. The presence of serum donor-specific antibodies at the time of biopsy of allografts was also examined. Forty-three patients (27.0%) fulfilled the criteria of cABMR, regardless of PTCML, and comprised the cABMR group. Forty-one patients (25.8%) did not exhibit cABMR features and comprised the non-cABMR allograft control group. In addition, 15 zero-day wedge resections and 29 native kidney biopsies comprised the nonallograft control group. When the diagnostic accuracies of various PTCML features were assessed using the cABMR and non-cABMR allograft control groups, ≥4 PTCML, either circumferential or partial, in ≥2 peritubular capillaries of the three most affected capillaries exhibited the highest AUC value (0.885), greater than the Banff 2013 classification (0.640). None of the nonallograft control groups exhibited PTCML features. We suggest that ≥4 PTCML in ≥2 peritubular capillaries of the three most affected cortical capillaries represents the proper cutoff for cABMR.
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http://dx.doi.org/10.1111/tri.12921DOI Listing
April 2017

Dishevelled segment polarity protein 3 (DVL3): a novel and easily applicable recurrence predictor in localised prostate adenocarcinoma.

BJU Int 2017 09 10;120(3):343-350. Epub 2017 Feb 10.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Objective: To identify new biomarkers for biochemical recurrence (BCR) of prostate adenocarcinoma.

Patients And Methods: Clinical information of 500 patients with prostate adenocarcinoma and their 152 RNA-sequencing and protein-array data from The Cancer Genome Atlas (TCGA) were separated into a discovery set and a validation set. Each dataset was analysed according to the Gleason grade groups reflecting BCR. The results obtained from the analysis using TCGA dataset were confirmed by immunohistochemistry analyses of a confirmation cohort composed of 395 patients with localised prostate adenocarcinoma.

Results: TCGA discovery set was subgrouped into lower- and higher-risk groups for recurrence-free survival (RFS) (P < 0.001). Cyclin B1 (CCNB1), dishevelled segment polarity protein 3 (DVL3), paxillin (PXN), RAF1, transferrin, X-ray repair cross complementing 5 (XRCC5) and BIM had lower expression in the lower-risk group than that in the higher-risk group (all, P < 0.05). In TCGA validation set, CCNB1, DVL3, transferrin, XRCC5 and BIM were also differently expressed between the two groups. Immunohistochemically, DVL3 positivity was associated with high prostate-specific antigen (PSA) levels, resection margin involvement, and BCR (all, P < 0.05). A high Gleason score indicated a marginal relationship (P = 0.055). BIM positivity was related to high PSA levels, lymphovascular invasion, and BCR (all, P < 0.05). Both DVL3 positivity (P = 0.010) and BIM positivity (P = 0.024) were associated with shorter RFS, but statistical significance was lost when the multivariate Cox regression model included all patients. In the lower-risk group, the multivariate Cox model confirmed that DVL3 was an independent predictor for poor RFS (hazard ratio 1.80, P = 0.040), and the concordance index (C-index) was 0.805.

Conclusions: DVL3 and BIM were expressed in patients with a higher risk of BCR. DVL3 may be a novel and easily applicable recurrence predictor of localised prostate adenocarcinoma.
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http://dx.doi.org/10.1111/bju.13783DOI Listing
September 2017

Prognostic value of vascular endothelial growth factor (VEGF), VEGF receptor 2, platelet-derived growth factor-β (PDGF-β), and PDGF-β receptor expression in papillary renal cell carcinoma.

Hum Pathol 2017 03 15;61:78-89. Epub 2016 Dec 15.

Department of Urology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea. Electronic address:

The prognostic value of the expression of vascular endothelial growth factor (VEGF), VEGF receptor 2 (VEGFR2), platelet-derived growth factor (PDGF)-β, and PDGF receptor (PDGFR)-β in papillary renal cell carcinoma (pRCC) is unknown. A total of 145 patients, who were confirmed to have pRCC, were analyzed. Expression levels of molecular markers were assessed via immunohistochemistry. The median follow-up period for all patients was 52.0 (interquartile range, 34.5-90.5) months. Among the cohort of 145 patients, high VEGF expression was observed in 100 (69.0%) patients, whereas high expression of VEGFR2, PDGF-β, and PDGFR-β was observed in 64 (44.1%), 42 (29.0%), and 30 (20.7%) patients, respectively. Only patients with high VEGFR2 expression exhibited improved 10-year recurrence-free survival (85.3% versus 58.1%; P=.005) and cancer-specific survival (86.4% versus 70.1%; P=.014) rates compared with individuals who exhibited low expression. Multivariate analysis revealed that high VEGFR2 expression was an independent prognostic factor for recurrence (hazard ratio, 0.326; P=.006) and cancer-specific mortality (hazard ratio, 0.334; P=.046). During follow-up, 17 patients received targeted drug therapy. Patients with high VEGFR2 expression showed a better initial response (partial response, 40%; stable disease, 20%; progressive disease, 40%) than patients with low expression did (partial response, 0%; stable disease, 58.3%; progressive disease, 41.7%; P=.052). pRCC with high VEGFR2 expression seems to be associated with a better initial response to targeted drug therapy and a better prognostic outcome.
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http://dx.doi.org/10.1016/j.humpath.2016.12.002DOI Listing
March 2017

Clinicopathologic Characteristics and Mutational Status of Succinate Dehydrogenase Genes in Paraganglioma of the Urinary Bladder: A Multi-Institutional Korean Study.

Arch Pathol Lab Med 2017 May 7;141(5):671-677. Epub 2016 Nov 7.

From the Department of Pathology, Ewha Womans University School of Medicine, Seoul, Korea (Drs S. Park, S.H. Sung, and M.S. Cho); the Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University College of Medicine, Seoul, Korea (Drs Kang and G.Y. Kwon); the Department of Pathology, Ajou University School of Medicine, Suwon, Korea (Dr J.E. Kwon); the Department of Pathology, Yonsei University College of Medicine, Seoul, Korea (Dr S.K. Kim and N.H. Cho); the Department of Pathology, Inje University Haeundae Paik Hospital, Pusan, Korea (Dr J.Y. Kim); the Department of Pathology, Korea University School of Medicine, Seoul, Korea (Drs C.H. Kim and Chae); the Department of Pathology, Inje University Sanggye Paik Hospital, Seoul, Korea (Dr H.J. Kim); the Department of Pathology and Kidney Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea (Dr Moon); the Department of Pathology, College of Medicine, Hanyang University Guri Hospital, Guri, Korea (Drs Pyo and Oh); the Department of Pathology, Pusan National University Hospital College of Medicine, Pusan, Korea (Dr W.Y. Park); the Department of Hospital Pathology, Incheon St Mary's Hospital, College of Medicine, Catholic University of Korea, Incheon, Korea (Dr E.S. Park); the Department of Pathology, Kyung Hee University Medical Center, Kyung Hee University School of Medicine, Seoul, Korea (Dr J.Y. Sung); the Department of Pathology, Konkuk University School of Medicine, Seoul, Korea (Dr S.E. Lee); the Department of Pathology, Dankook University College of Medicine, Cheonan, Korea (Dr W. Lee); the Department of Pathology, Dongguk University College of Medicine, Gyeonju, Korea (Dr J.I. Lee); the Department of Pathology, Inje University Busan Paik Hospital, Pusan, Korea (Dr Jung); the Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea (Drs Y.M. Cho and Huh); the Department of Pathology, Gachon University Gil Medical Center, Incheon, Korea (Dr H.Y. Cho); the Department of Pathology, Konyang University School of Medicine, Daejeon, Korea (Dr Cha); the Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seoul, Korea (Dr Choe); the Department of Hospital Pathology, Seoul St Mary's Hospital, The Catholic University of Korea, Seoul, Korea (Dr Choi); and the Department of Pathology and Genomic Medicine, The Methodist Hospital and Weill Medical College of Cornell University, Houston, Texas (Dr Ro).

Context: - Because of the limited number of available primary bladder paraganglioma (PBPG) cases, the rates of succinate dehydrogenase (SDH) mutations and the clinicopathologic characteristics of SDH-deficient tumors have not been fully studied.

Objective: - To define the clinicopathologic and molecular characteristics of PBPGs.

Design: - A total of 52 PBPGs were collected retrospectively. SDHA and SDHB immunohistochemical stains were performed. In cases of SDHB expression loss, mutation analyses of SDHB, SDHC, and SDHD were performed.

Results: - The clinicopathologic features were analyzed for 52 cases (M:F = 27:25), with a mean age of 56 years (range, 22-79 years). Tumor sizes were 0.5 to 8 cm (mean, 2.4 cm). Tumor necrosis was present in 5 of 52 cases (10%), involvement of muscularis propria in 41 (79%), and lymphovascular tumor invasion in 6 (12%). During a mean follow-up period of 41 months (range, 1-161 months), 3 of 52 patients (6%) developed metastases, but no one died from the disease. Immunohistochemistry for SDHA and SDHB showed that all cases were SDHA intact. Among them, 43 cases had intact SDHB, whereas 9 cases were SDHB deficient. Compared with the SDHB-intact cases, the SDHB-deficient cases were characterized by large tumor sizes (4.5 versus 1.9 cm; P < .001), a higher number of mitoses per 10 high-powered fields (2.6 versus 0.1; P = .002), and frequent lymphovascular tumor invasion (33% versus 7%; P = .02) and metastases (22% versus 2%; P = .02). Mutational analyses for SDHB, SDHC, and SDHD were performed in 9 SDHB-deficient cases. Among them, 6 cases were successfully sequenced and revealed SDHB mutations only.

Conclusions: - Large tumor size, a higher number of mitoses, and the presence of lymphovascular tumor invasion and SDHB mutations suggest malignant paraganglioma.
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http://dx.doi.org/10.5858/arpa.2016-0403-OADOI Listing
May 2017

Prognostic tissue biomarker exploration for patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor receptor tyrosine kinase inhibitors.

Tumour Biol 2016 Apr 3;37(4):4919-27. Epub 2015 Nov 3.

Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul, 138-736, Republic of Korea.

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.
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http://dx.doi.org/10.1007/s13277-015-4339-5DOI Listing
April 2016

Clinicopathologic Analysis of PD-L1 and PD-L2 Expression in Renal Cell Carcinoma: Association with Oncogenic Proteins Status.

Ann Surg Oncol 2016 Feb;23(2):694-702

Background: Immune checkpoint blockade therapy targeting programmed death (PD)-1 or PD-ligand 1 (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 PDL2 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.
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http://dx.doi.org/10.1245/s10434-015-4903-7DOI Listing
February 2016

Reduction in Renal Ischemia-Reperfusion Injury in Mice by a Phosphoinositide 3-Kinase p110gamma-Specific Inhibitor.

Transplantation 2015 Oct;99(10):2070-6

1 Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 2 Department of Medicine Graduate School, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 3 Department of Bioscience and Biotechnology, Institute of Bioscience, Sejong University, Seoul, South Korea. 4 Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea. 5 Department of Surgery, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.

Background: Although renal ischemia-reperfusion injury (IRI) can cause delayed graft function, a targeted therapy is not yet available. Because phosphoinositide 3-kinases (PI3K) p110γ and p110δ play important roles in immune cell migration and function, we investigated the effects of PI3K p110γ- and p110δ-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 p110γ-specific inhibitor.

Results: The PI3K p110γ-specific inhibitor, but not p110δ-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 p110γ 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 p110γ.

Conclusions: p110γ-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.
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http://dx.doi.org/10.1097/TP.0000000000000742DOI Listing
October 2015
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