Publications by authors named "Hyo Jeong Kang"

63 Publications

Diagnostic performance of ultrasound attenuation imaging for assessing low-grade hepatic steatosis.

Eur Radiol 2021 Sep 21. Epub 2021 Sep 21.

Department of Radiology, Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul, 03080, South Korea.

Objectives: To investigate the diagnostic performance of attenuation imaging (ATI) for the assessment of low-grade hepatic steatosis using liver biopsy as the reference standard.

Methods: The study included 57 potential donor candidates for living liver transplantation who underwent ATI, transient elastography (TE), and liver biopsy for evaluation of hepatic steatosis between February 2020 and April 2020. The attenuation coefficient (AC) from ATI and the controlled attenuation parameter (CAP) from TE were measured for each participant in a random and blind manner. The histologic hepatic fat fraction (HFF) was graded (S0, < 5%; S1, 5-33%; S2, 33-66%; S3, > 66%). The accuracy of ATI for diagnosing hepatic steatosis was compared with that of CAP using ROC analysis. Correlations between AC and HFF were evaluated, and factors affecting AC were determined by linear regression analysis.

Results: The median HFF was 3% (range: 0-35%), with 31 (54.4%), 24 (42.0%), and 2 (3.5%) participants being graded as S0, S1, and S2, respectively. The AUCs for the ROCs of AC and CAP for the detection of hepatic steatosis were 0.808 (95% CI: 0.682-0.900) and 0.829 (95% CI: 0.706-0.916), respectively, with the difference not being statistically significant (p = 0.762). AC showed 61.5% of sensitivity and 90.3% of specificity. AC was positively correlated with HFF (p < 0.001). HFF was the only factor significantly affecting AC.

Conclusions: ATI showed moderate sensitivity and high specificity in the diagnosis and quantification of hepatic steatosis in low-grade steatosis without fibrosis. Only HFF significantly affected AC.

Key Points: • Attenuation imaging showed moderate sensitivity and high specificity performance in the diagnosis and quantification of hepatic steatosis in low-grade steatosis without fibrosis. • The diagnostic performance of the attenuation coefficient by attenuation imaging did not significantly differ from that of the controlled attenuation parameter by transient elastography in quantifying low-grade steatosis. • The histopathologically determined hepatic fat fraction was the only factor significantly affecting the attenuation coefficient.
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http://dx.doi.org/10.1007/s00330-021-08269-yDOI Listing
September 2021

Comprehensive characterization of viral integrations and genomic aberrations in HBV-infected intrahepatic cholangiocarcinomas.

Hepatology 2021 Sep 3. Epub 2021 Sep 3.

Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.

Background And Aims: Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and hepatitis B virus (HBV) infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA tumors.

Approach And Results: We profiled a cohort of 108 HBV-infected iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with pre-constructed datasets of HBV-infected hepatocellular carcinoma (HBV-HCC; n=167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n=59), and conventional (n=154) and fluke-related iCCAs (n=16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at 9 different sites. The most common insertional hotspot (7 tumors) was in the TERT promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2, and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion, between DMRTA1 and LINC01239 (chr9p21.3), had oncogenic effects through activation of the mTOR/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA.

Conclusions: Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.
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http://dx.doi.org/10.1002/hep.32135DOI Listing
September 2021

Primary hepatic mixed germ cell tumor in an adult.

J Pathol Transl Med 2021 Sep 3;55(5):355-359. Epub 2021 Aug 3.

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

Primary hepatic mixed germ cell tumor (GCT) is very rare, and less than 10 cases have been reported. We report a case of mixed GCT composed of a choriocarcinoma and yolk sac tumor, which occurred in the liver of a 40-year-old woman. A large mass was detected by computed tomography solely in the liver. Serum β-human chorionic gonadotropin (hCG) was highly elevated, otherwise, other serum tumor markers were slightly elevated or within normal limits. For hepatic choriocarcinoma, neoadjuvant chemotherapy was administered, followed by right lobectomy. Histologic features of the resected tumor revealed characteristic choriocarcinoma features with diffuse positivity for hCG in the syncytiotrophoblasts and diffuse positivity for α-fetoprotein and Sal-like protein 4 in the yolk sac tumor components. Primary malignant GCT in the liver is associated with a poor prognosis and requires specific treatment. Therefore, GCT should be considered during a differential diagnosis of a rapidly growing mass in the liver.
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http://dx.doi.org/10.4132/jptm.2021.06.16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8476321PMC
September 2021

Clinicopathological and molecular characterization of chromophobe hepatocellular carcinoma.

Liver Int 2021 10 15;41(10):2499-2510. Epub 2021 Jun 15.

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

Background And Aims: Chromophobe hepatocellular carcinoma (HCC) is a newly included subtype of HCC in the 5th edition of the WHO classification with distinctive histological features (chromophobic cytoplasm with anaplastic nuclei and pseudocyst formation) and is strongly associated with the alternative lengthening of telomeres (ALT) phenotype. However, the clinicopathologic characterization and molecular features of chromophobe HCC are unknown.

Methods: To comprehensively characterize chromophobe HCC, whole exome sequencing, copy number variation, and transcriptomic analyses were performed in 224 surgically resected HCC cases. Additionally, telomere-specific fluorescence in situ hybridization was used to assess ALT. These genomic profiles and ALT status were compared with clinicopathological features among subtypes of HCC, particularly chromophobe HCC and conventional HCC.

Results: Chromophobe HCC was observed in 10.3% (23/224) cases and, compared to conventional HCC, was more frequent in females (P = .023). The overall and recurrence-free survival outcomes were similar between patients with chromophobe HCC and conventional HCC. However, chromophobe HCC displayed significantly more upregulated genes involving cell cycle progression and DNA repair. Additionally, ALT was significantly enriched in chromophobe HCC (87%; 20/23) compared to conventional HCC (2.2%, 4/178; P < .001). Somatic mutations in ALT-associated genes, including ATRX, SMARCAL1, FANCG, FANCM, SP100, TSPYL5, and RAD52 were more frequent in chromophobe HCC (30.4%, 7/23 cases) compared to conventional HCC (11.8%, 21/178 cases; P = .024).

Conclusions: Chromophobe HCC is a unique subtype of HCC with a prevalence of ~10%. Compared to conventional HCC, chromophobe HCC is associated with female predominance and ALT, although overall and recurrence-free outcomes are similar to conventional HCC.
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http://dx.doi.org/10.1111/liv.14975DOI Listing
October 2021

Value of discrepancy of the central scar-like structure between dynamic CT and gadoxetate disodium-enhanced MRI in differentiation of focal nodular hyperplasia and hepatocellular adenoma.

Eur J Radiol 2021 Jun 22;139:109730. Epub 2021 Apr 22.

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

Purpose: To identify the value of discrepancies in the central scar (CS)-like structure between dynamic CT and gadoxetate disodium-enhanced MRI for differentiating FNH from HCA.

Methods: This retrospective study included 113 patients with pathologically-diagnosed FNH (n = 80) or HCA (n = 37). CS-like structures were evaluated on arterial phase (AP) CT and hepatobiliary phase (HBP) MRI. Presence of the CS-like structure, its discrepancy in visibility or size between AP CT and HBP MRI and between AP and HBP MRI, and features of non-scarred tumor portion were evaluated by two radiologists. Inter-observer agreement was evaluated by intraclass correlation coefficients (ICCs) and weighted kappa. Univariable and multivariable logistic regression and ROC analysis were performed to explore features differentiating FNH from HCA.

Results: Inter-observer agreement was moderate-to-excellent (ICCs≥0.74, kappa≥0.65). On univariable analysis, presence of CS-like structures (P < 0.001), discrepancy of the CS-like structures between AP CT and HBP MRI (73.8 % in FNH; 16.2 % in HCA, P < 0.001) and between AP and HBP MRI (70.0 % in FNH; 16.2 % in HCA, P < 0.001), and the features of non-scarred tumor portion (P ≤ 0.011) were significantly different between FNH and HCA. On multivariable analysis, the discrepancy of CS-like structures between AP CT and HBP MRI, and the absence of low SI of the non-scarred tumor portion on HBP MRI, were suggestive of FNH (P = 0.036 and P < 0.001, respectively; area under the ROC curve, 0.96 [95 % CI, 0.93-0.99]).

Conclusion: Evaluation of discrepancy in the visibility or size of CS-like structures between dynamic CT and gadoxetate disodium-enhanced MRI may facilitate the differentiation of FNH from HCA.
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http://dx.doi.org/10.1016/j.ejrad.2021.109730DOI Listing
June 2021

Hepatoid thymic carcinoma: a case report of a rare subtype of thymic carcinoma.

J Pathol Transl Med 2021 May 14;55(3):230-234. Epub 2021 Apr 14.

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

Hepatoid thymic carcinoma is an extremely rare subtype of primary thymus tumor resembling "pure" hepatoid adenocarcinomas with hepatocyte paraffin 1 (Hep-Par-1) expression. A 53-year-old man presented with voice change and a neck mass. Multiple masses involving the thyroid, cervical and mediastinal lymph nodes, and lung were detected on computed tomography. Papillary thyroid carcinoma was confirmed by biopsy, and the patient underwent neoadjuvant chemoradiation therapy. However, the anterior mediastinal mass was enlarged after the treatment whereas the multiple masses in the thyroid and neck decreased in size. Microscopically, polygonal tumor cells formed solid sheets or trabeculae resembling hepatocytes and infiltrated remnant thymus. The tumor cells showed immunopositivity for cytokeratin 7, cytokeratin 19, and Hep-Par-1 and negativity for α-fetoprotein. Possibilities of germ cell tumor, squamous cell carcinoma, and metastasis of thyroid papillary carcinoma were excluded by immunohistochemistry. This report on the new subtype of thymic carcinoma is the third in English literature thus far.
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http://dx.doi.org/10.4132/jptm.2021.03.10DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8141974PMC
May 2021

Prognostic Molecular Indices of Resectable Hepatocellular Carcinoma: Implications of S100P for Early Recurrence.

Ann Surg Oncol 2021 Oct 30;28(11):6466-6478. Epub 2021 Mar 30.

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

Background: Although hepatocellular carcinomas (HCCs) often recur in patients undergoing hepatectomy, there are no reliable biomarkers of this undesirable event. Recent RNA-based efforts have developed valuable genetic indices prognostic of cancer outcomes. We aimed to identify molecular predictors of early recurrence after resection of HCC, and reveal the genomolecular structure of the resected tumors.

Method: Based on the transcriptomic and genomic datasets of 206 HCC samples surgically resected in the Asan Medical Center (AMC), we performed a differential gene expression analysis to identify quantitative markers associated with early recurrence and used the unsupervised clustering method to classify genomolecular subtypes.

Results: Differential gene expression profiling revealed that S100P was the highest-ranked overexpressed gene in HCCs that recurred within 2 years of surgery. This trend was reproduced in immunohistochemical studies of the original cohort and an independent AMC cohort. S100P expression also independently predicted HCC-specific mortality post-resection (adjusted hazard ratio 1.09, 95% confidence interval 1.01-1.19; p = 0.042). Validation in a Chinese cohort and in in vitro experiments confirmed the prognostic value of S100P in HCC. We further identified five discrete molecular subtypes of HCC; a subtype with stem cell features ('AMC-C4') was associated with the worst prognosis, both in our series and another two Asian datasets, and S100P was most strongly upregulated in that subtype.

Conclusion: We identified a promising prognostic biomolecule, S100P, associated with early recurrence after HCC resection, and established the genomolecular architecture of tumors affecting clinical outcomes, particularly in Asian patients. These new insights into molecular mediators should contribute to effective care for affected patients.
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http://dx.doi.org/10.1245/s10434-021-09825-yDOI Listing
October 2021

Development of Colon Cancer in a Patient with Longstanding Colonic Diffuse Ganglioneuromatosis: A Case Report.

Clin Endosc 2021 Mar 4. Epub 2021 Mar 4.

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

Colonic diffuse ganglioneuromatosis is an extremely rare disease in which multiple tumors derived from the ganglion cells, nerve fibers, and supporting cells are distributed in the colon. It is generally considered to be a benign neoplastic condition and is occasionally associated with rare hereditary conditions such as neurofibromatosis type I or multiple endocrine neoplasia type 2B. Here, we report a case of a patient in whom colon cancer developed 12 years after the initial diagnosis of colonic diffuse ganglioneuromatosis, which suggests a possible association between colonic diffuse ganglioneuromatosis and colorectal cancer.
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http://dx.doi.org/10.5946/ce.2021.013DOI Listing
March 2021

Clinical outcomes of systemic therapy in patients with unresectable or metastatic combined hepatocellular-cholangiocarcinoma.

Liver Int 2021 06 11;41(6):1398-1408. Epub 2021 Mar 11.

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

Background & Aims: The optimal systemic chemotherapy for combined hepatocellular-cholangiocarcinoma (cHCC-CCA) has not yet been defined. The definition and classification of cHCC-CCA has changed recently in the 5th edition of WHO classification. We reviewed the pathological findings with the new classification and analysed the efficacy of systemic chemotherapy in patients with unresectable/metastatic cHCC-CCA.

Methods: Among 254 patients with histologically confirmed cHCC-CCA from 1999 to 2015 in Asan Medical Center, Seoul, Korea, 99 patients who received systemic chemotherapy for unresectable/metastatic disease were included. Overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) were retrospectively evaluated.

Results: Sorafenib (n = 62) and cytotoxic chemotherapy (n = 37) were administered as first-line chemotherapies; the ORR was 14.1%, and the median PFS and OS were 3.8 and 10.6 months, respectively, with a median follow-up duration of 39.6 months. The efficacy outcomes were not significantly different between patients who received sorafenib and those who received cytotoxic chemotherapy (ORR, 9.7% vs 21.6%, P = .14; median PFS, 4.2 vs 2.9 months, P = .52; median OS, 10.7 vs 10.6 months, P = .34). In multivariate analysis, large intrahepatic tumour burden (≥30% of liver volume), elevated serum bilirubin and non-platinum containing first-line chemotherapy remained as significant prognostic factors for poorer OS.

Conclusions: The efficacy outcomes according to first-line treatment were not significantly different between sorafenib and cytotoxic chemotherapy, and pathological findings were not found to help for determining appropriate therapeutic agent or assessing the prognosis. To overcome the poor treatment outcomes, further studies are needed to find proper treatment targets, biomarkers and the best treatment strategies.
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http://dx.doi.org/10.1111/liv.14813DOI Listing
June 2021

Diagnostic performance of ultrasonography-guided core-needle biopsy according to MRI LI-RADS diagnostic categories.

Ultrasonography 2021 Jul 3;40(3):387-397. Epub 2020 Nov 3.

Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Purpose: According to the American Association for the Study of Liver Diseases (AASLD) guidelines, biopsy is a diagnostic option for focal hepatic lesions depending on the Liver Imaging Reporting and Data System (LI-RADS) category. We evaluated the diagnostic performance of ultrasonography-guided core-needle biopsy (CNB) according to LI-RADS categories.

Methods: A total of 145 High-risk patients for hepatocellular carcinoma (HCC) who underwent magnetic resonance imaging (MRI) followed by CNB for a focal hepatic lesion preoperatively were retrospectively enrolled. Focal hepatic lesions on MRI were evaluated according to LI-RADS version 2018. Pathologic results were categorized into HCC, non-HCC malignancies, and benignity. The categorization was defined as correct when the CNB pathology and surgical pathology reports were identical. Nondiagnostic results were defined as inadequate CNB pathology findings for a specific diagnosis. The proportion of correct categorizations was calculated for each LI-RADS category, excluding nondiagnostic results.

Results: After excluding 16 nondiagnostic results, 131 lesions were analyzed (45 LR-5, 24 LR-4, 4 LR-3, and 58 LR-M). All LR-5 lesions were HCC, and CNB correctly categorized 97.8% (44/45) of LR-5 lesions. CNB correctly categorized all 24 LR-4 lesions, 16.7% (4/24) of which were non-HCC malignancies. All LR-M lesions were malignant, and 62.1% (36/58) were non-HCC malignancies. CNB correctly categorized 93.1% (54/58) of LR-M lesions, and 12.5% (3/24) of lesions with CNB results of HCC were confirmed as non-HCC malignancies.

Conclusion: In agreement with AASLD guidelines, CNB could be helpful for LR-4 lesions, but is unnecessary for LR-5 lesions. In LR-M lesions, CNB results of HCC did not exclude non-HCC malignancy.
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http://dx.doi.org/10.14366/usg.20110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8217794PMC
July 2021

Interpretation of XIAP Variants of Uncertain Significance in Paediatric Patients with Refractory Crohn's Disease.

J Crohns Colitis 2021 Aug;15(8):1291-1304

Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea.

Background And Aims: Mutations in XIAP can lead to the development of treatment-refractory severe paediatric Crohn's disease [CD], for which haematopoietic stem cell transplantation is the primary therapeutic option. The interpretation of variants of uncertain significance [VUSs] in XIAP needs to be scrutinized.

Methods: Targeted next-generation sequencing was performed for 33 male paediatric patients with refractory CD admitted at a tertiary referral hospital. To obtain functional data, biomolecular cell assays and supercomputing molecular dynamics simulations were performed.

Results: Nine unrelated male patients harboured hemizygous XIAP variants. Four known pathogenic variants and one novel pathogenic variant [p.Lys168Serfs*12] were identified in five patients, and two novel VUSs [p.Gly205del and p.Pro260Ser] and one known VUS [p.Glu350del] were identified in the remaining four. Among children with VUSs, only the subject with p.Gly205del exhibited defective NOD2 signalling. Using molecular dynamics simulation, we determined that the altered backbone torsional energy of C203 in XIAP of p.G205del was ~2 kcal/mol, suggesting loss of zinc binding in the mutant XIAP protein and poor coordination between the mutant XIAP and RIP2 proteins. Elevated auto-ubiquitination of zinc-depleted p.G205del XIAP protein resulted in XIAP protein deficiency.

Conclusion: A high prevalence of XIAP deficiency was noted among children with refractory CD. Advanced functional studies decreased the subjectivity in the case-level interpretation of XIAP VUSs and directed consideration of haematopoietic stem cell transplantation.
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http://dx.doi.org/10.1093/ecco-jcc/jjab013DOI Listing
August 2021

Porto-sinusoidal vascular disease with portal hypertension versus liver cirrhosis: differences in imaging features on CT and hepatobiliary contrast-enhanced MRI.

Abdom Radiol (NY) 2021 05 23;46(5):1891-1903. Epub 2020 Oct 23.

Liver Cancer Center, Asan Medical Center, Seoul, Republic of Korea.

Purpose: To differentiate the computed tomography (CT) and magnetic resonance imaging (MRI) features of porto-sinusoidal vascular disease (PSVD) and liver cirrhosis (LC).

Methods: In this retrospective case-control study of patients with PSVD matched in a 1:3 ratio with LC patients according to liver function, initial diagnosis and time to final diagnosis were analyzed. Imaging features on CT and the parenchymal enhancement on hepatobiliary phase of hepatobiliary agent-enhanced MRI (HBA-MRI) were compared using a generalized linear mixed model. Focal hepatic lesions in the PSVD group were analyzed.

Results: In total, 43 PSVD patients and 129 LC patients were included. Among PSVD patients, 72.1% were initially misdiagnosed with LC. PSVD patients had a longer diagnostic delay than LC patients (32 months vs. 4 months; p < 0.001). Liver surface nodularity was less common in the PSVD group than in the LC group (16.3% vs. 89.2%, p < 0.001). Increased caudate-to-right lobe ratio, heterogeneous parenchymal enhancement, and portal vein abnormalities were more frequently noted in the PSVD group than in the LC group (all p < 0.001). The grade of portal hypertension was significantly higher in the PSVD group than in the LC group (p < 0.001), and they also had brighter parenchymal enhancement during the hepatobiliary phase of HBA-MRI (p < 0.001). In the PSVD group, 14% patients had at least one focal hepatic lesion, primarily a focal nodular hyperplasia (FNH)-like nodule.

Conclusions: Some imaging features on CT and HBA-MRI can distinguish PSVD from LC. Benign focal lesions, most commonly FNH-like nodules, can develop in PSVD.
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http://dx.doi.org/10.1007/s00261-020-02831-wDOI Listing
May 2021

Rationally designed redirection of natural killer cells anchoring a cytotoxic ligand for pancreatic cancer treatment.

J Control Release 2020 10 16;326:310-323. Epub 2020 Jul 16.

Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seongbuk-Gu, Seoul 02792, South Korea; KHU-KIST Department of Converging Science and Technology, Kyung Hee University, Seoul 02447, Republic of Korea. Electronic address:

The emergence of T-cell engineering with chimeric antigen receptors (CARs) has led to attractive therapeutics; however, autologous CAR-T cells are associated with poor clinical outcomes in solid tumors because of low safety and efficacy. Therefore, the aim of our study was to develop a CAR therapy with enhanced cytotoxicity against solid cancer using allogeneic NK cells. In this study, we engineered "off-the-shelf" NK cells to redirect them towards pancreatic ductal adenocarcinoma (PDAC) by improving their target-specific cytotoxic potential. By integrated bioinformatic and clinicopathological analyses, folate receptor alpha (FRα) and death receptor 4 (DR4) were significantly highly expressed in patient-derived tumor cells. The combined expression of FRα and DR4/5 was associated with inferior clinical outcomes, therefore indicating their use as potential targets for biomolecular treatment. Thus, FRα and DR4 expression pattern can be a strong prognostic factor as promising therapeutic targets for the treatment of PDAC. For effective PDAC treatment, allogeneic CAR-NK cells were reprogrammed to carry an apoptosis-inducing ligand and to redirect them towards FRα and initiate DR4/5-mediated cancer-selective cell death in FRα- and DR4/5-positive tumors. As a result, the redirected cytotoxic ligand-loaded NK cells led to a significantly enhanced tumor-selective apoptosis. Accordingly, use of allogeneic CAR-NK cells that respond to FRα and DR4/5 double-positive cancers might improve clinical outcomes based on personal genome profiles. Thus, therapeutic modalities based on allogeneic NK cells can potentially be used to treat large numbers of patients with optimally selective cytotoxicity.
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http://dx.doi.org/10.1016/j.jconrel.2020.07.016DOI Listing
October 2020

Radiologic-Pathologic Correlation of Hepatobiliary Phase Hypointense Nodules without Arterial Phase Hyperenhancement at Gadoxetic Acid-enhanced MRI: A Multicenter Study.

Radiology 2020 08 2;296(2):335-345. Epub 2020 Jun 2.

From the Department of Radiology, Seoul National University Hospital, Seoul, Korea (I.J., J.M.L.); Department of Radiology and Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea (S.Y.K.); Department of Radiology, Samsung Medical Center, Seoul, Korea (T.W.K., Y.K.K.); Department of Radiology, Korea University Anam Hospital, Seoul, Korea (B.J.P.); Department of Radiology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea (Y.J.L.); Department of Radiology, Seoul St. Mary's Hospital, Seoul, Korea (J.I.C.); Department of Radiology, Korea University Guro Hospital, Seoul, Korea (C.H.L.); Department of Radiology, Konkuk University School of Medicine, Seoul, Korea (H.S.P.); Department of Pathology, Seoul National University Hospital and Seoul National University College of Medicine, Seoul, Korea (K.L., H.K.); Department of Pathology, Asan Medical Center, Seoul, Korea (E.Y., H.J.K.); Department of Pathology, Samsung Medical Center, Seoul, Korea (S.Y.H.); Department of Pathology, Korea University Anam Hospital, Seoul, Korea (J.Y.K.); Department of Pathology, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Korea (S.A.); Department of Pathology, Seoul St. Mary's Hospital, Seoul, Korea (E.S.J.); Department of Pathology, Korea University Guro Hospital, Seoul, Korea (B.H.K.); and Department of Pathology, Konkuk University Hospital, Seoul, Korea (H.S.H.).

Background Hepatobiliary phase (HBP) hypointense nodules without arterial phase hyperenhancement (APHE) at gadoxetic acid-enhanced MRI may indicate hepatocellular carcinoma (HCC) or nonmalignant cirrhosis-associated nodules. Purpose To assess the distribution of pathologic diagnoses of HBP hypointense nodules without APHE at gadoxetic acid-enhanced MRI and to evaluate clinical and imaging features in differentiating their histologic grades. Materials and Methods This retrospective multicenter study included pathologic analysis-confirmed HBP hypointense nodules without APHE (≤30 mm) in patients with chronic liver disease or cirrhosis screened between January 2008 and June 2016. Central pathologic review by 10 pathologists determined final histologic grades as progressed HCC, early HCC, high-grade dysplastic nodule (DN), and low-grade DN or regenerative nodule. Gadoxetic acid-enhanced MRI features were analyzed by three radiologists. Multivariable logistic regression analyses with elastic net regularization were performed to identify clinical and imaging features for differentiating histologic grades. Results There were 298 patients (mean age, 59 years ± 10; 226 men) with 334 nodules evaluated, and progressed HCCs were diagnosed in 44.0% (147 of 334), early HCCs in 20.4% (68 of 334), high-grade DNs in 27.5% (92 of 334), and low-grade DNs or regenerative nodules in 8.1% (27 of 334). Serum α-fetoprotein level 100 ng/mL or greater (odds ratio, 2.7; = .01) and MRI features including well-defined margin (odds ratio, 5.5; = .003), hypointensity at precontrast T1-weighted imaging (odds ratio, 3.2; < .001), intermediate hyperintensity at T2-weighted imaging (odds ratio, 3.4; < .001), and restricted diffusion (odds ratio, 1.9; = .04) were independent predictors for progressed HCC at multivariable analysis. Conclusion In patients at high risk for hepatocellular carcinoma (HCC), hepatobiliary phase hypointense nodules without arterial phase hyperenhancement at gadoxetic acid-enhanced MRI corresponded mainly to progressed HCCs, early HCCs, and high-grade dysplastic nodules. High α-fetoprotein level and some imaging features at MRI helped to differentiate progressed HCC from lower grade nodules. © RSNA, 2020 See also the editorial by Motosugi in this issue.
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http://dx.doi.org/10.1148/radiol.2020192275DOI Listing
August 2020

Hepatocyte-Specific Magnetic Resonance Imaging-Based Assessment of Indeterminate Hepatic Nodules in the Liver Transplant Evaluation of Patients With Cirrhosis.

Liver Transpl 2020 03;26(3):359-369

Department of Gastroenterology, University of Ulsan College of Medicine, Seoul, South Korea.

We aimed to determine the identities in explants of indeterminate hepatic nodules (IDNs) that had been scanned by dynamic magnetic resonance imaging (MRI) to establish clinicoradiological parameters predicting which IDNs were hepatocellular carcinomas (HCCs). This study included 88 patients with cirrhosis who underwent gadoxetic acid-enhanced MRI in pre-liver transplantation (LT) workup followed within 90 days by primary LT. The MRI detected 168 hepatic nodules that were classified into 6 benign tumors, 49 HCCs, and 113 IDNs, in 5, 34, and 72 patients, respectively. We compared these pre-LT radiologic diagnoses and stagings with explant pathology on a per-lesion basis to enable us to identify features of IDNs related to malignancy. Of the 168 nodules seen on MRI, 119 that were classified radiologically as consisting of 1 benign nodule (33.3%), 46 HCCs (93.9%), and 72 IDNs (63.7%) all turned out to be pathological HCCs. Of 32 patients inside Milan and 54 without HCC staged by MRI, 11 progressed beyond the criteria after LT. High serum alpha-fetoprotein level (≥20 ng/mL) was the only per-patient factor significantly associated with malignant IDNs. Per-tumor analysis of the MRI signals revealed that arterial hyperintensity, hepatobiliary hypointensity, T -weighted mild-to-moderate intensity, and restricted diffusion-weighted images were significantly correlated with malignant IDN. A model combining these 4 MRI factors with alpha-fetoprotein level had the best performance in predicting the identification of IDNs as HCCs in explanted livers. Over 60% of the IDNs seen on dynamic images of cirrhotic livers proved to be HCCs when explanted livers were examined. It may therefore be possible to identify HCCs with reasonable accuracy by means of their hepatocyte-specific MRI features when patients are being assessed for LT.
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http://dx.doi.org/10.1002/lt.25684DOI Listing
March 2020

Standardized Pathology Report for Colorectal Cancer, 2nd Edition.

J Pathol Transl Med 2020 Jan 13;54(1):1-19. Epub 2019 Nov 13.

Department of Pathology, Kyung Hee University College of Medicine, Seoul, Korea.

The first edition of the 'Standardized Pathology Report for Colorectal Cancer,' which was developed by the Gastrointestinal Pathology Study Group (GIP) of the Korean Society of Pathologists, was published 13 years ago. Meanwhile, there have been many changes in the pathologic diagnosis of colorectal cancer (CRC), pathologic findings included in the pathology report, and immunohistochemical and molecular pathology required for the diagnosis and treatment of colorectal cancer. In order to reflect these changes, we (GIP) decided to make the second edition of the report. The purpose of this standardized pathology report is to provide a practical protocol for Korean pathologists, which could help diagnose and treat CRC patients. This report consists of "standard data elements" and "conditional data elements." Basic pathologic findings and parts necessary for prognostication of CRC patients are classified as "standard data elements," while other prognostic factors and factors related to adjuvant therapy are classified as "conditional data elements" so that each institution could select the contents according to the characteristics of the institution. The Korean version is also provided separately so that Korean pathologists can easily understand and use this report. We hope that this report will be helpful in the daily practice of CRC diagnosis.
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http://dx.doi.org/10.4132/jptm.2019.09.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6986966PMC
January 2020

Validation of a New Point Shear-Wave Elastography Method for Noninvasive Assessment of Liver Fibrosis: A Prospective Multicenter Study.

Korean J Radiol 2019 11;20(11):1527-1535

Department of Radiology, Seoul National University Hospital and Seoul National College of Medicine, Seoul, Korea.

Objective: To validate the diagnostic value of a new point shear-wave elastography method, S-shearwave elastography (S-SWE; Samsung Medison Co., Ltd.), in noninvasive assessment of liver fibrosis.

Materials And Methods: In this prospective multicenter study, liver stiffness (LS) measurements for 600 participants were obtained with both S-SWE and transient elastography (TE). The rates of unsuccessful LS measurements in S-SWE and TE were compared, and correlations between S-SWE and TE measurements were assessed. In 107 patients with histologic reference data, the optimal LS cut-off values for predicting severe fibrosis and cirrhosis on S-SWE were determined using receiver operating characteristic (ROC) curve analysis. The LS cut-off values in S-SWE were then validated in 463 patients without histologic reference data by using TE values as the reference standard, and the sensitivity and specificity of the cut-off values for predicting severe fibrosis and cirrhosis were calculated.

Results: The frequency of unsuccessful LS measurements on TE (4.5%, 27/600) was significantly higher than that (0.7%, 4/600) on S-SWE ( < 0.001). LS measurements on S-SWE showed a significant correlation with TE values (r = 0.880, < 0.001). In 107 patients with histological reference data, the areas under the ROC curves on S-SWE were 0.845 and 0.850, with optimal cut-offs of 7.0 kilopascals (kPa) and 9.7 kPa, for the diagnosis of severe fibrosis and cirrhosis, respectively. Using these cut-off values, S-SWE showed sensitivities of 92.9% and 97.4% and specificities of 89.5% and 83.1% in TE-based evaluations of severe fibrosis and cirrhosis, respectively.

Conclusion: LS measurements on S-SWE were well correlated with those on TE. In addition, S-SWE provided good diagnostic performance for staging of hepatic fibrosis, with a lower rate of unsuccessful LS measurements compared with TE.
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http://dx.doi.org/10.3348/kjr.2019.0109DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6791814PMC
November 2019

Progressive Impairment of NK Cell Cytotoxic Degranulation Is Associated With TGF-β1 Deregulation and Disease Progression in Pancreatic Cancer.

Front Immunol 2019 21;10:1354. Epub 2019 Jun 21.

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

Natural killer (NK) cells are key effectors in cancer immunosurveillance and can be used as a prognostic biomarker in diverse cancers. Nonetheless, the role of NK cells in pancreatic cancer (PC) remains elusive, given conflicting data on their association with disease prognosis. In this study, using conventional K562 target cells and complementary engineered target cells providing defined and synergistic stimulation for NK cell activation, a correlation between impaired NK cell cytotoxic degranulation and PC progression was determined. Peripheral blood mononuclear cells (PBMCs) from 31 patients with newly diagnosed PC, 24 patients with non-malignant tumors, and 37 healthy controls were analyzed by flow cytometry. The frequency, phenotype, and effector functions of the NK cells were evaluated, and correlations between NK cell functions and disease stage and prognosis were analyzed. The results demonstrated that effector functions, but not frequency, of NK cells was progressively decreased on a per-cell basis during PC progression. Impaired cytotoxic degranulation, but not IFN-γ production, was associated with clinical features indicating disease progression, such as high serum CA19-9 and high-grade tumors. Significantly, this impairment correlated with cancer recurrence and mortality in a prospective analysis. Furthermore, the impaired cytotoxic degranulation was unrelated to NKG2D downregulation but was associated with increased circulating and tumor-associated TGF-β1 expression. Thus, NK cell cytotoxic activity was associated with PC progression and may be a favorable biomarker with predictive and prognostic value in PC.
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http://dx.doi.org/10.3389/fimmu.2019.01354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6598013PMC
October 2020

Progressive Familial Intrahepatic Cholestasis in Korea: A Clinicopathological Study of Five Patients.

J Pathol Transl Med 2019 Jul 16;53(4):253-260. Epub 2019 May 16.

1Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.

Background: Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of autosomal recessive liver diseases that present as neonatal cholestasis. Little is known of this disease in Korea.

Methods: The records of five patients histologically diagnosed with PFIC, one with PFIC1 and four with PFIC2, by liver biopsy or transplant were reviewed, and ATP8B1 and ABCB11 mutation status was analyzed by direct DNA sequencing. Clinicopathological characteristics were correlated with genetic mutations.

Results: The first symptom in all patients was jaundice. Histologically, lobular cholestasis with bile plugs was the main finding in all patients, whereas diffuse or periportal cholestasis was identified only in patients with PFIC2. Giant cells and ballooning of hepatocytes were observed in three and three patients with PFIC2, respectively, but not in the patient with PFIC1. Immunostaining showed total loss of bile salt export pump in two patients with PFIC2 and focal loss in two. Lobular and portal based fibrosis were more advanced in PFIC2 than in PFIC1. ATP8B1 and ABCB11 mutations were identified in one PFIC1 and two PFIC2 patients, respectively. One PFIC1 and three PFIC2 patients underwent liver transplantation (LT). At age 7 months, one PFIC2 patient was diagnosed with concurrent hepatocellular carcinoma and infantile hemangioma in an explanted liver. The patient with PFIC1 developed steatohepatitis after LT. One patient showed recurrence of PFIC2 after 10 years and underwent LT.

Conclusions: PFIC is not rare in patients with neonatal cholestasis of unknown origin. Proper clinicopathologic correlation and genetic testing can enable early detection and management.
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http://dx.doi.org/10.4132/jptm.2019.05.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6639708PMC
July 2019

Umbilical cord-derived mesenchymal stem cell extracts ameliorate atopic dermatitis in mice by reducing the T cell responses.

Sci Rep 2019 04 29;9(1):6623. Epub 2019 Apr 29.

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

Mesenchymal stem cells derived from Wharton's jelly of the umbilical cord (UC-MSCs) have immunomodulatory properties. The aim of this study was to explore whether extracts of MSCs (MSC-Ex) could augment the low therapeutic efficacy of the whole cells in an Aspergillus fumigatus (Af)-induced atopic dermatitis (AD) model. LPS- or TNF-α/IFN-γ-stimulated keratinocytes (HaCaT cells) were treated with MSC-Ex, and the Af-induced AD model was established in BALB/c mice. In HaCaT cells, MSC-Ex treatment significantly reduced the inflammatory cytokine (IL-6, IL-1β, IL-4, IL-5 and TNF-α), iNOS and NF-κB levels, and upregulated the anti-inflammatory cytokines (IL-10 and TGF-β1). In the AD mice, the MSC-Ex group showed greatly reduced dermatitis, and lower clinical symptom scores and IgE levels. The histological dermatitis scores were also markedly lower in the MSC-Ex-treated animals compared with the MSC-treated group. Decreased levels of IFN-γ (Th1) and IL-17 (Th17), IL-4 and IL-13 (Th2) were detected in T cells and the skin tissue from the MSC-Ex treated AD mice. The therapeutic capacity of MSC-Ex was preserved after lyophilization and reconstitution. MSC-Ex treatment reproducibly suppresses dermatitis and inhibits the induction of inflammatory cytokines in the skin of AD mice. MSC-Ex is therefore a potential new treatment agent for AD.
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http://dx.doi.org/10.1038/s41598-019-42964-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6488580PMC
April 2019

Immunogenomic landscape of hepatocellular carcinoma with immune cell stroma and EBV-positive tumor-infiltrating lymphocytes.

J Hepatol 2019 07 29;71(1):91-103. Epub 2019 Mar 29.

Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; Asan Liver Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea. Electronic address:

Background & Aims: The immunogenomic characteristics of hepatocellular carcinomas (HCCs) with immune cell stroma (HCC-IS), defined histologically, have not been clarified. We investigated the clinical and molecular features of HCC-IS and the prognostic impact of Epstein-Barr virus (EBV) infection.

Methods: We evaluated 219 patients with conventional HCC (C-HCC) and 47 with HCC-IS using in situ hybridization for EBV, immunohistochemistry, multiplex immunofluorescence staining, and whole exome and transcriptome sequencing. Human leukocyte antigen types were also extracted from the sequencing data. Genomic and prognostic parameters were compared between HCC-IS and C-HCC.

Results: CD8 T cell infiltration was more frequent in HCC-IS than C-HCC (mean fraction/sample, 22.6% vs. 8.9%, false discovery rate q <0.001), as was EBV positivity in CD20-positive tumor-infiltrating lymphocytes (TILs) (74.5% vs. 4.6%, p <0.001). CTNNB1 mutations were not identified in any HCC-IS, while they were present in 24.1% of C-HCC (p = 0.016). Inhibitory and stimulatory immune modulators were expressed at similar levels in HCC-IS and EBV-positive C-HCC. Global hypermethylation, and expression of PD-1 and PD-L1 in TILs, and PD-L1 in tumors, were also associated with HCC-IS (p <0.001), whereas human leukocyte antigen type did not differ according to HCC type or EBV positivity. HCC-IS was an independent factor for favorable recurrence-free survival (adjusted hazard ratio [aHR] 0.23; p = 0.002). However, a subgroup of tumors with a high density of EBV-positive TILs had poorer recurrence-free (aHR 25.48; p <0.001) and overall (aHR 9.6; p = 0.003) survival, and significant enrichment of CD8 T cell exhaustion signatures (q = 0.0296).

Conclusions: HCC-IS is a distinct HCC subtype associated with a good prognosis and frequent EBV-positive TILs. However, paradoxically, a high density of EBV-positive TILs in tumors is associated with inferior prognostic outcomes. Patients with HCC-IS could be candidates for immunotherapy.

Lay Summary: Hepatocellular carcinomas with histologic evidence of abundant immune cell infiltration are characterized by frequent activation of Epstein-Barr virus in tumor-infiltrating lymphocytes and less aggressive clinical behavior. However, a high density of Epstein-Barr virus-positive tumor-infiltrating lymphocytes is associated with inferior prognostic outcomes, possibly as a result of immune escape due to significant CD8 T cell exhaustion.
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http://dx.doi.org/10.1016/j.jhep.2019.03.018DOI Listing
July 2019

Characterization of Hepatocellular Carcinoma Patients with Amplification Assessed by Fluorescence in situ Hybridization: A Large Cohort Study.

Liver Cancer 2019 Feb 22;8(1):12-23. Epub 2018 May 22.

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

Background: amplification is a relatively novel type of genetic aberration that has been proposed to be a driver of hepatocarcinogenesis. Selective inhibitors of , a receptor of , have been developed as targeted therapies for hepatocellular carcinoma (HCC). Despite the role of in mediating HCC progression, the clinicopathological characterization of patients exhibiting amplification remains unclear. Immunohistochemical staining is the simplest and most widely used method of identifying aberrations in the gene, although its specificity is very low.

Methods: This study investigated the prognostic significance of amplification in a large cohort of 989 HCC patients using fluorescence in situ hybridization (FISH), which has a high degree of specificity. In addition, FISH data from formalin-fixed, paraffin-embedded sections were compared with copy number variation (CNV) data obtained from fresh frozen sections to validate the use of FISH as a diagnostic tool.

Results: amplifications were detected by FISH in 51 (5.15%) of the 989 patients, and were independently associated with poor survival and a higher risk of tumor recurrence, as well as with poor prognostic factors such as a high α-fetoprotein level, hepatitis B or C virus infection, a large tumor size, microvascular invasion, and necrosis. In addition, amplification was associated with mutation, and was mutually exclusive with mutation. The results of the FISH and CNV analyses exhibited a significant concordance rate of 96% (κ = 0.618, < 0.001).

Conclusions: These data indicate that amplification represents a unique molecular subtype associated with poor prognostic characteristics, which supports the hypothesis that the signaling pathway plays an important role in hepatocarcinogenesis. We have also demonstrated that FISH is a viable alternative to CNV analysis, offering a number of advantages in the clinical setting.
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http://dx.doi.org/10.1159/000488541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6388559PMC
February 2019

Guanabenz Acetate Induces Endoplasmic Reticulum Stress-Related Cell Death in Hepatocellular Carcinoma Cells.

J Pathol Transl Med 2019 Mar 16;53(2):94-103. Epub 2019 Jan 16.

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

Background: Development of chemotherapeutics for the treatment of advanced hepatocellular carcinoma (HCC) has been lagging. Screening of candidate therapeutic agents by using patient-derived preclinical models may facilitate drug discovery for HCC patients.

Methods: Four primary cultured HCC cells from surgically resected tumor tissues and six HCC cell lines were used for high-throughput screening of 252 drugs from the Prestwick Chemical Library. The efficacy and mechanisms of action of the candidate anti-cancer drug were analyzed via cell viability, cell cycle assays, and western blotting.

Results: Guanabenz acetate, which has been used as an antihypertensive drug, was screened as a candidate anti-cancer agent for HCC through a drug sensitivity assay by using the primary cultured HCC cells and HCC cell lines. Guanabenz acetate reduced HCC cell viability through apoptosis and autophagy. This occurred via inhibition of growth arrest and DNA damage-inducible protein 34, increased phosphorylation of eukaryotic initiation factor 2α, increased activating transcription factor 4, and cell cycle arrest.

Conclusions: Guanabenz acetate induces endoplasmic reticulum stress-related cell death in HCC and may be repositioned as an anti-cancer therapeutic agent for HCC patients.
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http://dx.doi.org/10.4132/jptm.2019.01.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435987PMC
March 2019

High-grade precursor lesions can be used as surrogate markers to identify the epicenter of periampullary carcinomas.

Hum Pathol 2019 02 24;84:92-104. Epub 2018 Sep 24.

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

Identifying the accurate origin of periampullary cancers is important because different origins may trigger different clinicopathological behaviors. The presence of intraepithelial precursor lesions, including high-grade pancreatic intraepithelial neoplasias (PanINs) and/or high-grade biliary intraepithelial neoplasias (BilINs), may be suggestive of the origin of the periampullary carcinoma in challenging cases. To prove the usefulness of high-grade intraepithelial precursor lesions in identifying the origin of ambiguous periampullary cancers, the status and grades of PanINs and BilINs were evaluated in 256 periampullary carcinomas with a well-defined cancer origin as a test set, including 114 pancreatic cancers, 82 distal bile duct cancers, 54 ampullary cancers, and 6 duodenal cancers. One hundred twelve periampullary carcinomas with clinically equivocal epicenter either by radiologic imaging or by endoscopic finding used as a validation set. High-grade PanINs were found more commonly in pancreatic cancers than in distal bile duct, ampullary, and duodenal cancers both in test (P = .002) and validation sets (P < .001). Similarly, high-grade BilINs were identified more frequently in distal bile duct cancers than in ampullary, pancreatic, and duodenal cancers both in test (P < .001) and validation sets (P = .039). High-grade PanINs were found most commonly in pancreatic cancers, whereas high-grade BilINs were seen most frequently in distal bile duct cancers. In addition, both high-grade PanINs and high-grade BilINs are uncommonly noted in ampullary or duodenal cancers. The recognition of high-grade intraepithelial lesions can help identify the primary origin of periampullary cancers, especially when the epicenter of the periampullary cancer is ambiguous.
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http://dx.doi.org/10.1016/j.humpath.2018.09.006DOI Listing
February 2019

Association Between Expression Level of PD1 by Tumor-Infiltrating CD8 T Cells and Features of Hepatocellular Carcinoma.

Gastroenterology 2018 12 24;155(6):1936-1950.e17. Epub 2018 Aug 24.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea; Biomedical Science and Engineering Interdisciplinary Program, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea. Electronic address:

Background & Aims: T-cell exhaustion, or an impaired capacity to secrete cytokines and proliferate with overexpression of immune checkpoint receptors, occurs during chronic viral infections but has also been observed in tumors, including hepatocellular carcinomas (HCCs). We investigated features of exhaustion in CD8 T cells isolated from HCC specimens.

Methods: We obtained HCC specimens, along with adjacent nontumor tissues and blood samples, from 90 patients who underwent surgical resection at Asan Medical Center (Seoul, Korea) from April 2016 through April 2018. Intrahepatic lymphocytes and tumor-infiltrating T cells were analyzed by flow cytometry. Tumor-infiltrating CD8 T cells were sorted by flow cytometry into populations based on expression level of programmed cell death 1 (PDCD1 or PD1): PD1-high, PD1-intermediate, and PD1-negative. Sorted cells were analyzed by RNA sequencing. Proliferation and production of interferon gamma (IFNG) and tumor necrosis factor (TNF) by CD8 T cells were measured in response to anti-CD3 and antibodies against immune checkpoint receptors including PD1, hepatitis A virus cellular receptor 2 (HAVCR2 or TIM3), lymphocyte activating 3 (LAG3), or isotype control. Tumor-associated antigen-specific CD8 T cells were identified using HLA-A*0201 dextramers. PDL1 expression on tumor tissue was assessed by immunohistochemistry.

Results: PD1-high, PD1-intermediate, and PD1-negative CD8 T cells from HCCs had distinct gene expression profiles. PD1-high cells expressed higher levels of genes that regulate T-cell exhaustion than PD1-intermediate cells. PD1-high cells expressed TIM3 and LAG3, and low proportions of TCF1, TBET/eomesodermin, and CD127. PD1-high cells produced the lowest amounts of IFNG and TNF upon anti-CD3 stimulation. Differences in the PD1 expression patterns of CD8 T cells led to the identification of 2 subgroups of HCCs: HCCs with a discrete population of PD1-high cells were more aggressive than HCCs without a discrete population of PD1-high cells. HCCs with a discrete population of PD1-high cells had higher levels of predictive biomarkers of response to anti-PD1 therapy. Incubation of CD8 T cells from HCCs with a discrete population of PD1-high cells with antibodies against PD1 and TIM3 or LAG3 further restored proliferation and production of IFNG and TNF in response to anti-CD3.

Conclusions: We found HCC specimens to contain CD8 T cells that express different levels of PD1. HCCs with a discrete population of PD1-high CD8 T cells express TIM3 and/or LAG3 and produce low levels of IFNG and TNF in response to anti-CD3. Incubation of these cells with antibodies against PD1 and TIM3 or LAG3 further restore proliferation and production of cytokines; HCCs with a discrete population of PD1-high CD8 T cells might be more susceptible to combined immune checkpoint blockade-based therapies.
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http://dx.doi.org/10.1053/j.gastro.2018.08.030DOI Listing
December 2018

Prognostic impact of extranodal extension in stage 1B gastric carcinomas.

Surg Oncol 2018 Jun 8;27(2):299-305. Epub 2018 May 8.

Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, 05505, South Korea.

Background: In addition to the TNM stage, an additional prognostic factor is needed to assess the prognosis of gastric cancer. Moreover, there is no consensus on high-risk group of recurrence and adjuvant strategy in stage 1B gastric cancers. We aimed to investigate the prognostic significance of extranodal extension (ENE) in stage 1B gastric carcinomas and assess whether ENE can indicate the need for adjuvant treatment.

Methods: The clinicopathological characteristics of 1588 patients who underwent curative gastrectomy with more than D1 plus lymphadenectomy for stage 1B gastric cancer from 2003 to 2010 were reviewed. A propensity score matching analysis was performed.

Results: Age over 65 years and the presence of ENE were found to be poor prognostic factors for both overall survival (OS) and disease-free survival (DFS). Adjuvant chemotherapy was related to an increased overall survival. The 5 year OS and DFS rates were 88.7% and 86.2%, respectively. When divided into 3 groups (early gastric cancer with ENE [T1N1 ENE(+)], early cancer without ENE [T1N1 ENE(-)], and advanced tumor without nodal metastasis [T2N0]), the OS and DFS rates of the T1N1 ENE(+) group were significantly worse than those of the other groups (5 year OS rate of 72.7% vs. 88.4% vs. 91.9%, respectively, P < 0.001 and 5 year DFS rate of 67.2% vs. 85.2% vs. 91.5%, respectively, P < 0.001).

Conclusion: ENE is an independent prognostic factor that predicted poor outcomes for stage 1B gastric cancers and it could be an indicator of the need for adjuvant treatment.
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http://dx.doi.org/10.1016/j.suronc.2018.05.014DOI Listing
June 2018

A case with acute-on-chronic liver failure receiving liver transplantation during daclatasvir and asunaprevir therapy in chronic hepatitis C patient.

Gastroenterol Rep (Oxf) 2019 Oct 30;7(5):371-373. Epub 2018 Apr 30.

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

We report a case with hepatitis C virus genotype 1 b liver cirrhosis who received liver transplantation because of acute-on-chronic liver failure during daclatasvir (DSV) and asunaprevir (ASV) combination therapy. To our knowledge, this is the first case received liver transplantation during DSV + ASV therapy. Therefore, clinicians should pay particular attention to the possibility of acute liver failure during DSV and ASV combination therapy.
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http://dx.doi.org/10.1093/gastro/goy012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6821301PMC
October 2019

Poor prognosis in Epstein-Barr virus-negative gastric cancer with lymphoid stroma is associated with immune phenotype.

Gastric Cancer 2018 11 7;21(6):925-935. Epub 2018 Apr 7.

Department of Gastroenterology and Convergence Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 05505, Korea.

Background: Gastric cancer with lymphoid stroma (GCLS) is pathologically characterized by poorly developed tubular structures with a prominent lymphocytic infiltration. Its clinical and prognostic features differ in patients positive and negative for Epstein-Barr virus (EBV) infection. This study analyzed the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD-L1), and the density of tumor-infiltrating lymphocytes (TILs) including CD3+ and CD8+ T cells, as well as their prognostic significance in patients with GCLS.

Methods: The study included 58 patients with GCLS (29 EBV+ and 29 EBV-) who underwent curative resection. Expression of CD3, CD8, PD-1, and PD-L1 in tumor cells and TILs was analyzed using a quantitative multispectral imaging system (Opal™), with these results validated by immuno-histochemical assays for PD-L1 on whole slide sections.

Results: The proportion of tumors overexpressing PD-L1 (31.0 vs. 0%, P = 0.002), TIL density (4548 vs. 2631/mm, P < 0.001), and intra-tumoral CD8+ T-cell density (2650 vs. 1060/mm, P < 0.001) were significantly higher in EBV+ than in EBV- GCLS. In addition, CD8+/CD3+ T-cell ratio was higher in EBV+ than in EBV- GCLS (55.3 vs. 35.8%, P < 0.001). Lower TIL density, defined as < 1350/mm, was a significant negative factor of survival.

Conclusions: Despite histopathological similarity, quantitative multispectral imaging revealed differences in the tumor immune micro-environment between EBV+ and EBV- GCLS, indicating that the underlying pathogenesis differs in these two disease entities. TIL density may be a prognostic marker in patients with GCLS.
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http://dx.doi.org/10.1007/s10120-018-0820-3DOI Listing
November 2018

Validation of the eighth edition of the American Joint Committee on Cancer staging system for ampulla of Vater cancer.

Surgery 2018 05 13;163(5):1071-1079. Epub 2018 Feb 13.

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

Background: The American Joint Committee on Cancer recently proposed the eighth edition of cancer staging system. Validation studies are required to evaluate the prognostic stratification of ampulla of Vater cancer patients.

Methods: In the study, 369 operatively resected patients with ampullary cancers were grouped based on the eighth T (T1a, limited to sphincter of Oddi; T1b, invasion to duodenal submucosa; T2, invasion to duodenal proper muscle; T3a, invasion to pancreas ≤0.5 cm; T3b, invasion to pancreas >0.5 cm; and T4, involvement of celiac axis or superior mesenteric artery) and N (N0, no nodal metastasis; N1, 1-3 nodal metastasis; and N2, ≥4 nodal metastasis) category of ampullary cancer staging.

Results: Overall 5-year survival rates for T and N categories were as followed: T1a, 83%; T1b, 71%; T2, 46%; T3a, 48%; T3b, 28.5%, T4, 7% (P< .001); N0, 44.8%; N1, 20%; N2, 4% (P < .001). Pair-wise comparisons demonstrated significant differences between T1a-b (P = .005), T3a-T3b (P = .03), N0-N1 (P < .001), and N1-N2 (P = .007) tumors, but not between T1b-T2 (P = .20), T2-T3a (P = .84), and T3b-T4 (P = .17) lesions.

Conclusion: The eighth edition T category for ampullary cancer does not stratify patients accurately with regard to prognosis. Modification of the current T category with eliminating subcategories (T1, invasion to duodenal submucosa; T2, invasion to duodenal proper muscle; T3, invasion to pancreas or duodenal subserosa) is a better way for determining prognosis of ampullary cancer. The current N category segregates patient survival well.
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http://dx.doi.org/10.1016/j.surg.2017.12.018DOI Listing
May 2018

Relationships Between Self-awareness and Clinical Diagnostic Findings of Abnormal Foot Arch Height in Koreans.

Ann Rehabil Med 2017 Dec 28;41(6):1013-1018. Epub 2017 Dec 28.

Department of Physical and Rehabilitation Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Objective: To see how people think about their own feet, and evaluate whether there are correlations among self-awareness of the participants and clinical examination findings.

Methods: Adult twins and their families who participated in the Healthy Twin study from May 2008 to April 2010 were recruited. Participants were asked whether they thought their feet were normal, flat, or cavus. The lateral talometatarsal angles were measured on foot X-rays to determine the foot arch height. Using the podoscopic footprints taken with the podobaroscope, the Staheli arch index was also measured. Kappa statistics were used to calculate degree of agreement among the three measurement methods.

Results: Self-awareness and radiographic findings were significantly different (Pearson chi-square test, p=0.000) and only slightly agreed (kappa measure of agreement=0.136, p=0.000). Self-awareness and podoscopy results revealed a significant difference (Pearson chi-square test, p=0.000), with only slight agreement (kappa measure of agreement=0.072, p=0.000).

Conclusion: There is significant disagreement between patients' perception of their feet and actual test results. Many people may have an incorrect assumption about their own foot conditions that may be reflected in improper management. Dissemination of accurate information about foot disorders by foot clinicians would be helpful.
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http://dx.doi.org/10.5535/arm.2017.41.6.1013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5773421PMC
December 2017
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