In November 2021, 14 international travel-related severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant of concern (VOC) patients were detected in South Korea. Epidemiologic investigation revealed community transmission of the omicron VOC. A total of 80 SARS-CoV-2 omicron VOC-positive patients were identified until December 10, 2021 and 66 of them reported no relation to the international travel.There may be more transmissions with this VOC in Korea than reported.

PURPOSE: Multidrug resistance-associated protein (MRP) 2 is a glutathione conjugate in the canalicular membrane of hepatocytes. Early graft damage after liver transplantation (LT) can result in alteration of MRP2 expression. The purpose of this study was to evaluate the relationship between the pattern of MRP2 alteration and graft outcome. METHODS: Forty-one paraffin-embedded liver graft tissues obtained by protocol biopsy within 2 months after LT; these were stained using monoclonal antibodies of MRP2. We selected 15 live donor biopsy samples as a control, that showed homogenous canalicular staining for MRP2. The pattern of canalicular MRP2 staining of graft was classified into 3 types: homogenous (type C0), focal (type C1), and no (type C2,) staining of the canaliculi. RESULTS: In total, 17.1% graft tissues were type C0, 36.6% were type C1, and 46.3% were type C2. The median operation time was longer in patients with type C2 (562.6 minutes) than in patients with type C0 (393.8 minutes) (P = 0.038). The rates of posttransplant complications were higher in patients with type C2 (100%) than in patients with type C0 (42.9%) and C1 (73.3%) (P < 0.001). CONCLUSION: MRP2 expression pattern was altered in 82.9% after LT. The pattern of MRP2 alteration was associated with longer operation time and higher rates of post-LT complications.
Antibodies, Monoclonal ; Biopsy ; Glutathione ; Hepatocytes ; Humans ; Liver Transplantation* ; Liver* ; Membranes ; Multidrug Resistance-Associated Proteins ; Tissue Donors ; Transplants*

BACKGROUND: Liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). The aim of this study was to investigate the recurrence rate of HCC after LT and prognostic factors for recurrence by comparing LT with non-transplanted resection. METHODS: The participants were 338 patients who underwent LT between 1996 and 2012 at Seoul National University Hospital (LT group) and 520 HCC patients who underwent partial hepatectomy between 1995 and 2006 (control group, non-LT group). RESULTS: In the LT group, 68 of 338 patients (19.8%) showed relapse, and the recurrence rate was lower than that in the non-LT group (64.9%, 357/520, p < .001). Stratification analysis by American Joint Committee on Cancer (AJCC) stage showed that the stage I-II LT group had a lower recurrence rate than the non-LT group. Univariate comparative analysis demonstrated that multiplicity of tumor, tumor size, gross type, Edmondson- Steiner (ES) nuclear grade, extent of tumor, angioinvasion, AJCC stage, Milan criteria, University of California at San Francisco criteria on explant pathology (all p < .001), positive expression of cytokeratin 19 (p = .002), and preoperative α-fetoprotein (AFP) (p < .001) were predictors of tumor recurrence. In multivariate analysis, LT, preoperative AFP, multiplicity of tumor, extent of tumor, size of tumor, and ES nuclear grade were independent prognostic factors. CONCLUSIONS: LT might have a protective effect against the late recurrence of stage I-II HCC compared to non-LT, and the prognostic factors for recurrence were similar to previously well-known prognostic factors for HCC.
California ; Carcinoma, Hepatocellular* ; Hepatectomy* ; Humans ; Joints ; Keratin-19 ; Liver Transplantation* ; Liver* ; Multivariate Analysis ; Pathology ; Prognosis* ; Recurrence ; Seoul

Clonorchis sinensis is a Group-I bio-carcinogen, associated with cholangiocarcinoma (CCA). The hamster is the only experimental model of C. sinensis-mediated CCA, but we oblige another animal model. The present study intended to develop a C. sinensis (Cs) mediated CCA model using C3H/He mice, co-stimulated with N-nitrosodimethyl-amine (NDMA) and dicyclanil (DC). The mice were divided into 8 groups with different combinations of Cs, NDMA, and DC. Six months later the mice were sacrificed and subjected to gross and histopathological examination. The body weights were significantly reduced among the groups treated with 2 or more agents (eg. Cs+NDMA, Cs+DC, NDMA+DC, and Cs+NDMA+DC). In contrast, liver weight percentages to body weight were increased in above groups by 4.1% to 4.7%. A Change of the spleen weight was observed only in Cs+NDMA group. Though C. sinensis infection is evident from hyperplastic changes, only 1 worm was recovered. T wo mice, 1 from Cs and the other from Cs+DC group, showed mass forming lesions; 1 (281.2 mm3) from the Cs group was a hepatocellular adenoma and the other (280.6 mm3) from the Cs+DC group was a cystic mass (peliosis). Higher prevalence of gray-white nodules was observed in Cs group (42.9%) followed by Cs+NDMA+DC group (21.4%). The mice of the Cs+NDMA+DC group showed hyper-proliferation of the bile duct with fibrotic changes. No characteristic change for CCA was recognized in any of the groups. In conclusion, C3H/He mice produce no CCA but extensive fibrosis when they are challenged by Cs, NDMA, and DC together.
Adenoma, Liver Cell ; Animals ; Bile Ducts ; Body Weight ; Cholangiocarcinoma* ; Clonorchis sinensis* ; Cricetinae ; Dimethylnitrosamine* ; Fibrosis ; Liver ; Mice* ; Models, Animal ; Models, Theoretical ; Prevalence ; Spleen

BACKGROUND: Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients. METHODS: HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining. RESULTS: The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1-2 HCC subgroup (median, 126 months vs. 35 months; p = .015). CONCLUSIONS: Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.
alpha-Fetoproteins ; Antigens, Surface ; Carcinogenesis ; Carcinoma, Hepatocellular* ; Cytoplasm ; Disease-Free Survival ; Hepatitis B Core Antigens ; Hepatitis B Surface Antigens ; Hepatitis B virus* ; Hepatitis B* ; Hepatitis* ; Hepatocytes ; Humans ; Immunohistochemistry ; Recurrence*

BACKGROUND/AIMS: Protein disulfide isomerase (PDI) has been implicated in the survival and progression of some cancer cells, by compensating for endoplasmic reticulum stress by upregulating the protein-folding capacity. However, its prognostic role in patients with hepatocellular carcinoma (HCC) has not been investigated. METHODS: We collected HCC tissues from 83 HCC patients who underwent surgical resection for an immunohistochemical study of PDI. Overall survival (OS) was measured from the date of surgical resection until the date of death from any cause. Radiological progression was evaluated using the modified Response Evaluation Criteria in Solid Tumors in an independent radiological assessment. RESULTS: PDI expression was found to be increased in human HCC compared to adjacent nontumor tissues. Increased immunopositivity for PDI was associated with a high Edmondson-Steiner grade (p = 0.028). Univariate analysis of patients who had undergone surgical resection for HCC showed that tumor PDI upregulation is a significant risk factor for poor OS (p = 0.016; hazard ratio [HR], 1.980) and time to progression (TTP; p = 0.007; HR, 1.971). Multivariate analyses revealed that high PDI expression was an independent predictor of a shorter TTP (p = 0.015; HR, 1.865) and poor OS (p = 0.012; HR, 2.069). CONCLUSIONS: Upregulated PDI expression is associated with aggressive clinicopathological features of HCC; thus, PDI might serve as an independent prognostic factor and a potential therapeutic target for HCC patients.
Carcinoma, Hepatocellular/*enzymology/pathology ; Female ; Humans ; Kaplan-Meier Estimate ; Liver Neoplasms/*enzymology/pathology ; Male ; Middle Aged ; Prognosis ; Protein Disulfide-Isomerases/*metabolism ; Retrospective Studies ; Tumor Markers, Biological/metabolism

MicroRNAs (miRNAs) participate in diverse biological functions and carcinogenesis by inhibiting specific gene expression. We previously reported that suppression of adenine nucleotide translocase 2 (ANT2) by using the short hairpin RNA (shRNA) approach has an antitumor effect in several cancer cells. We here examined the influence of ANT2 on expression of miRNAs in hepatocellular carcinoma (HCC) to further elucidate the tumor-suppressive mechanism of ANT2 shRNA. We first carried out screening for miRNAs, whose expression is regulated by ANT2 suppression in the Hep3B HCC cell line using miRNA microarrays. Validation of candidate miRNAs was done by incorporating clinical samples, and their effects on the tumorigenesis of HCC were studied in vitro and in vivo. miR-636 was one of the miRNAs whose expression was highly upregulated by ANT2 suppression in miRNA microarray analysis, as confirmed by real-time reverse transcription-polymerase chain reaction. Notably, miR-636 was markedly downregulated in HCC tissues compared with matched non-neoplastic liver in clinical samples. Restoration of miR-636 in Hep3B cells led to significant reduction of cell proliferation and colony formation. miR-636 restoration resulted in a decreased level of Ras, one of the putative targets of miR-636, and inactivation of its signaling pathway. Moreover, tumorigenesis was efficiently suppressed by miR-636 in an in vivo tumor xenograft model of HCC. The data suggest that miR-636 might function as a tumor suppressor miRNA affecting HCC tumorigenesis via downregulation of Ras, and that ANT2 suppression by shRNA could exert an anticancer effect by restoring miR-636 expression in HCC.
Adenine Nucleotide Translocator 2/*metabolism ; Animals ; Carcinoma, Hepatocellular/*genetics/pathology ; Cell Line, Tumor ; Cell Proliferation ; Cell Transformation, Neoplastic/*genetics/pathology ; Down-Regulation/*genetics ; Gene Expression Regulation, Neoplastic ; Gene Knockdown Techniques ; Humans ; Liver Neoplasms/genetics/pathology ; Mice ; Mice, Inbred BALB C ; Mice, Nude ; MicroRNAs/*genetics/metabolism ; Phosphatidylinositol 3-Kinases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; RNA, Small Interfering/*metabolism ; Signal Transduction/genetics ; Transcription, Genetic ; Tumor Stem Cell Assay ; Up-Regulation/genetics ; ras Proteins/*genetics/metabolism

BACKGROUND: Hepatocellular adenoma (HCA) is a rare benign tumor of the liver. A subtype classification of HCA (hepatocyte nuclear factor 1alpha [HNF1alpha]-mutated, beta-catenin-mutated HCA, inflammatory HCA, and unclassified HCA) has recently been established based on a single institutional review of a HCA series by the Bordeaux group. METHODS: We used histologic and immunohistochemical parameters to classify and evaluate eight cases from our institution. We evaluated the new classification method and analyzed correlations between our results and those of other reports. RESULTS: Seven of our eight cases showed histologic and immunohistochemical results consistent with previous reports. However, one case showed overlapping histologic features, as previously described by the Bordeaux group. Four cases showed glutamine synthetase immunohistochemical staining inconsistent with their classification, indicating that glutamine synthetase staining may not be diagnostic for beta-catenin-mutated HCA. HNF1alpha-mutated HCA may be indicated by the absence of liver fatty acid binding protein expression. Detection of amyloid A may indicate inflammatory HCA. HCA with no mutation in the HNF1alpha or beta-catenin genes and no inflammatory protein expression is categorized as unclassified HCA. CONCLUSIONS: Although the new classification is now generally accepted, validation through follow-up studies is necessary.
Adenoma, Liver Cell* ; Amyloid ; beta Catenin ; Fatty Acid-Binding Proteins ; Glutamate-Ammonia Ligase ; Hepatocyte Nuclear Factor 1-alpha ; Liver ; Serum Amyloid A Protein

BACKGROUND: Although chemotherapy-related hepatic injury has been reported in colorectal cancer liver metastasis (CRLM) patients, the morphologic changes caused by chemotherapeutic agents and the effect of chemotherapy on postoperative outcome remain ill-defined. A comprehensive review of the morphologic changes in the post-chemotherapy non-neoplastic liver was performed and the clinical effect of preoperative chemotherapy in CRLM patients was analyzed. METHODS: Hematoxylin-eosin, Masson's trichrome and reticulin-stained slides from non-neoplastic livers obtained from 89 CRLM patients were analyzed, and the clinicopathologic features were correlated with the status of chemotherapy exposure. RESULTS: Histopathologic features of sinusoidal injury (sinusoidal dilatation, centrilobular perivenular fibrosis, parenchymal extinction lesions, small vessel obliteration, and hepatocyte plate disruption) were significantly more frequent in oxaliplatin-exposed livers (p<0.05). The extent of sinusoidal dilatation was positively correlated with increasing numbers of chemotherapy cycles (p=0.022). Abnormal preoperative liver function tests were more frequently seen (p<0.05) and postoperative total bilirubin was higher in the chemotherapy group (p=0.008). Postoperative morbidity was more common in the chemotherapy group (p=0.044). CONCLUSIONS: Sinusoidal injury is frequently seen in oxaliplatin-treated livers, and its presence, especially when extensive, should be documented in surgical pathology practice. The recognition of sinusoidal injury may provide helpful guidelines for surgeons in deciding the extent of hepatic resection.
Bilirubin ; Colorectal Neoplasms ; Dilatation ; Drug-Induced Liver Injury ; Fibrosis ; Glycosaminoglycans ; Hepatocytes ; Humans ; Liver ; Liver Function Tests ; Neoplasm Metastasis ; Pathology, Surgical

DNA methylation is one of the main epigenetic mechanisms and hypermethylation of CpG islands at tumor suppressor genes switches off these genes. To find novel DNA methylation markers in hepatocellular carcinoma (HCC), we performed pharmacological unmasking (treatment with 5-aza-2'-deoxycytidine or trichostatin A) followed by microarray analysis in HCC cell lines. Of the 239 promoter CpG island loci hypermethylated in HCC cell lines (as revealed by methylation-specific PCR), 221 loci were found to be hypermethylated in HCC or nonneoplastic liver tissues. Thirty-three loci showed a 20% higher methylation frequency in tumors than in adjacent nonneoplastic tissues. Correlation of individual cancer-related methylation markers with clinicopathological features of HCC patients (n = 95) revealed that the number of hypermethylated genes in HCC tumors was higher in older than in younger patients. Univariate and multivariate survival analysis revealed that the HIST1H2AE methylation status is closely correlated with the patient's overall survival (P = 0.022 and P = 0.010, respectively). In conclusion, we identified 221 novel DNA methylation markers for HCC. One promising prognostic marker, HIST1H2AE, should be further validated in the prognostication of HCC patients.
Azacitidine/analogs & derivatives/pharmacology ; Carcinoma, Hepatocellular/*genetics/mortality ; Cell Line, Tumor ; CpG Islands ; DNA Methylation/*drug effects ; Down-Regulation ; Female ; Hep G2 Cells ; Humans ; Hydroxamic Acids/pharmacology ; Liver/metabolism ; Liver Neoplasms/*genetics/mortality ; Male ; Middle Aged ; Oligonucleotide Array Sequence Analysis ; Promoter Regions, Genetic ; Survival Analysis ; Tumor Markers, Biological/*genetics