Kyoung Bun Lee

Visceral adipose tissue area is an independent risk factor for hepatic steatosis

Background and Aim:  Recent data indicate that hepatic steatosis is associated with insulin resistance, dyslipidemia and obesity (especially central body fat distribution). There have been few studies on the correlation between biopsy‐proven hepatic steatosis and the above factors in a disease‐free population. The aim of the present study was to evaluate the relation between hepatic steatosis assessed by biopsy and clinical characteristics including regional fat distribution measured by computed tomography (CT) in living liver donors.

Intrahepatic Mass-forming Cholangiocarcinomas: Enhancement Patterns at Multiphasic CT, with Special Emphasis on Arterial Enhancement Pattern—Correlation with Clinicopathologic Findings

PURPOSE To evaluate the imaging features of intrahepatic mass-forming cholangiocarcinomas (IMCCs) at computed tomography (CT), with a special emphasis on the degree and pattern of arterial enhancement, and to determine whether the clinicopathologic features of IMCCs with arterial enhancement differ from those of IMCCs with less arterial enhancement. MATERIALS AND METHODS The institutional review board of Seoul National University Hospital approved this retrospective study, and informed patient consent was waived. Sixty-four patients with 70 pathologically confirmed IMCCs after surgical resection underwent multiphasic CT-unenhanced, hepatic arterial phase (HAP), portal venous phase, and/or equilibrium phase imaging. CT images were retrospectively evaluated for tumor morphology and enhancement features. Patients were placed into typical or atypical enhancement groups according to the presence of enhancement in the largest volume (>50%) of the tumors during the HAP. Imaging features of IMCCs were correlated with pathologic features. The typical and atypical enhancement groups were compared with respect to disease-free survival and overall survival. Survival rates were calculated by using the Kaplan-Meier method, and differences in survival were compared by using the log-rank test. A Cox proportional hazards model was used for multivariate survival analysis. RESULTS Fifty (71%) of 70 IMCCs showed typical arterial enhancement, and 20 (29%) showed atypical enhancement. The mean diameter of atypical IMCCs was significantly smaller than that of typical IMCCs (P = .001). Chronic liver disease was more frequent in the group with atypical lesions (P = .021). During the HAP, the prevalent enhancement pattern in this group was a mixed pattern of peripheral rim and internal heterogeneous enhancement. At pathologic evaluation, atypically enhancing IMCCs showed less central stroma and necrosis and larger cellular areas and more frequently had a cholangiolocellular component than typically enhancing IMCCs. Arterial enhancement of IMCCs was found to be an independent prognostic factor for longer disease-free survival. CONCLUSION Arterially enhancing IMCCs were not rare; thus, enhancement pattern analysis of arterially enhancing IMCCs will be helpful in differentiating them from hepatocellular carcinomas. In addition, arterial enhancement of IMCCs appears to correlate with disease-free survival.

MR elastography for noninvasive assessment of hepatic fibrosis: Experience from a tertiary center in asia

To determine the sensitivity and specificity of MR elastography (MRE) in the staging of hepatic fibrosis (HF) using histopathology as the reference standard in an Asian population.

Long-term prospective cohort study of patients undergoing pancreatectomy for intraductal papillary mucinous neoplasm of the pancreas: implications for postoperative surveillance.

Objective:To evaluate long-term follow-up results after surgical treatment of intraductal papillary mucinous neoplasm (IPMN) to optimize postoperative surveillance strategies. Background:Little is known about the postoperative natural history of IPMN, especially about long-term follow-up results in patients with benign or noninvasive IPMN. Methods:Long-term follow-up was undertaken in a prospective cohort of 403 consecutive patients who underwent surgical treatment of IPMN at Seoul National University Hospital. Of these, 37 patients with ductal adenocarcinoma arising in IPMN were excluded from the analysis. Results:Of the 366 patients, 82 had low-grade dysplasia, 171 had intermediate-grade dysplasia, 45 had high-grade dysplasia, and 68 had IPMN with associated invasive carcinoma. During a median follow-up of 44.4 months, the overall recurrence rate was 10.7%. Pathologic grade of dysplasia was associated with recurrence rate (P < 0.001). IPMNs involving main duct had higher rate of recurrence (P = 0.021). Of the 298 patients with benign or noninvasive IPMN, 16 (5.4%) had recurrences including distant metastasis. Multivariate analysis revealed that the degree of dysplasia was the most important predictor of recurrence (P < 0.001). The overall 5-year disease-free survival rate was 78.9% and was significantly lower in patients with high-grade dysplasia than in those with low- or intermediate-grade dysplasia (P = 0.045). Conclusions:Pancreatic IPMNs recur in 10.7% of patients. Recurrence is correlated with the degree of dysplasia, and 5.4% of patients with benign or noninvasive IPMN have recurrences including distant metastasis. Thorough postoperative surveillance is needed not only for patients with invasive IPMN but also for those with benign or noninvasive IPMN, especially for patients with high-grade dysplasia.

Feasibility and Accuracy of Dual-Source Dual-Energy CT for Noninvasive Determination of Hepatic Iron Accumulation

PURPOSE To retrospectively assess feasibility of dual-source dual-energy (DSDE) computed tomography (CT) for evaluation of hepatic iron accumulation in a liver phantom and liver transplantation candidates and to compare its accuracy with that of 3-T magnetic resonance (MR) imaging. MATERIALS AND METHODS This study was approved by the institutional review board; informed consent was waived. A liver agar phantom containing six tubes of iron (concentrations, 100-5000 mg of iron per 100 mL of solution) was scanned at 80 and 140 kVp with both DSDE mode and single-source dual-energy (SSDE) CT with sequential scanning mode. Difference of averaged attenuation between 80 and 140 kVp at CT (ΔH) was measured and correlated with iron concentration. Thirty-two liver transplant recipients and 55 donors who underwent DSDE CT at 80 and 140 kVp were included. Twenty-three underwent 3-T liver MR with dual-echo in-phase and opposed-phase T1-weighted and spin-echo T2-weighted imaging. Hepatic ΔH was measured at CT. On T1- and T2-weighted MR images, iron indexes were calculated. Degree of iron accumulation and macrosteatosis were determined at histologic examination (reference). Diagnostic performance of ΔH at CT and iron indexes at MR for diagnosing clinically important iron accumulation was evaluated (receiver operating characteristic [ROC] analysis). RESULTS For phantom study, ΔH obtained from both DSDE mode and SSDE CT with sequential scanning mode was correlated with iron concentration (correlation coefficient, 1.00 and 0.943, respectively; P = .173). ΔH (13.53) in 10 patients with clinically important (≥ 10%) iron accumulation was significantly higher than that (7.39) in 77 patients with normal or mild iron deposition (P < .001). ΔH was significantly correlated with degree of iron accumulation (correlation coefficient, 0.430; P < .001) but not with degree of hepatic macrosteatosis (P = .216). Area under the ROC curve for diagnosing clinically important iron accumulation was 0.881 and 0.897 with CT and MR, respectively (P = .851). CONCLUSION DSDE CT is accurate for diagnosing clinically important hepatic iron accumulation without confounding influence of hepatic steatosis, with diagnostic performance on par with MR.

Differential Expression of Matrix Metalloproteinases and Tissue Inhibitors of Metalloproteinases in Thioacetamide-Induced Chronic Liver Injury

Hepatic fibrogenesis, a complex process that involves a marked accumulation of extracellular matrix components, activation of cells capable of producing matrix materials, cytokine release, and tissue remodeling, is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). The MMP-TIMP balance can regulate liver fibrogenesis. The aim of this study was to evaluate the expression patterns of MMPs and TIMPs during thioacetamide (TAA)-induced liver fibrogenesis. Chronic liver injury was induced with TAA (200 mg/kg i.p.) for 4 or 7 weeks in male Sprague-Dawley rats. Hepatic injury and fibrosis were assessed by hematoxylin-eosin (H&E) staining, and collagen deposition was confirmed by Sirius Red staining. The level of hepatic injury was quantified by serological analysis. The transcriptional and translational levels of α-smooth muscle actin (α-SMA), MMPs, and TIMPs in the liver were measured by Western blotting, RT-PCR, and immunohistochemistry. MMP, TIMP, and α-SMA were observed along fibrotic septa and portal spaces around the lobules. TAA treatment increased transcription of both MMPs and TIMPs, but only TIMPs showed increased translation. The dominant expression of TIMPs may regulate the function of MMPs to maintain liver fibrosis induced by TAA.

Evaluation of clinical meaning of histological subtypes of intraductal papillary mucinous neoplasm of the pancreas.

Objectives Prognostic value of histological subtypes of pancreatic intraductal papillary mucinous neoplasm (IPMN) has been reported to have conflicting results. The authors investigated the clinicopathological characteristics and prognostic significance of the histological subtypes of IPMNs with various degrees of dysplasia. Methods Two hundred thirteen patients with surgically treated pancreatic IPMN at a single tertiary care referral center were included. Pathological slides were thoroughly reviewed by a specialized pathologist. Results Of the 213 patients, 38 low-grade, 97 intermediate-grade, and 18 high-grade dysplasia and 59 IPMNs with an associated invasive carcinoma (invasive IPMN) were identified. Histological subtypes consisted of 135 gastric (63.4%), 38 intestinal (17.8%), 38 pancreatobiliary (17.8%), and 2 oncocytic types (0.9%). Histological subtypes were associated with radiological type (P < 0.001), degree of dysplasia (P < 0.001), and T stage (P < 0.001). The proportions of invasive IPMN were 14.1%, 42.1%, 57.9%, and 100% of gastric, intestinal, pancreatobiliary, and oncocytic types, respectively. Disease-specific survival was not affected by histological subtype in overall patients (P = 0.881). For invasive IPMNs, histological subtypes had a marginal significance on survival (P = 0.050), which lost statistical significance after multivariate analysis (P = 0.341). Conclusions Although histological subtypes are associated with the degree of dysplasia, histological subtypes have limited prognostic value for pancreatic IPMNs.

Disease spectrum of intraductal papillary mucinous neoplasm with an associated invasive carcinoma invasive IPMN versus pancreatic ductal adenocarcinoma-associated IPMN.

Objectives Current version of World Health Organization classification introduced the concept of “intraductal papillary mucinous neoplasm (IPMN) with an associated invasive carcinoma.” The authors investigated the clinicopathologic characteristics and prognosis of this disease category according to tumor morphology and percentage of invasive component. Methods Fifty-nine patients who underwent surgical resection of IPMN with an associated invasive carcinoma at Seoul National University Hospital were subgrouped according to the invasive component of less than 5% (minimally invasive [MI] intraductal papillary mucinous carcinoma [IPMC] [MI-IPMC]), 5%–50% (invasive IPMC [IPMC-I]), and 50% or greater (pancreatic ductal adenocarcinoma [PDAC]-associated IPMN [PDAC-IPMN]). Prognosis was compared with 219 curatively resected conventional PDAC. Results Eleven MI-IPMCs (18.6%), 24 IPMC-Is (40.7%), and 24 PDAC-IPMNs (40.7%) were identified. With the transition from MI-IPMC to IPMC-I and PDAC-IPMN, percentage of advanced T (P < 0.001) or N stage (P = 0.001), expression of S100A4 (P = 0.004), p53 (P = 0.028), and CD24 (P = 0.009) increased; and SMAD4 expression decreased (P < 0.001). The overall 5-year survival rates for MI-IPMC, IPMC-I, and PDAC-IPMN were 80.8%, 59.0%, and 29.3%, respectively (P < 0.001). Pancreatic ductal adenocarcinoma-associated IPMN had poor prognosis compared with MI-IPMC (P = 0.011) or IPMC-I (P = 0.026) but had comparable prognosis with conventional PDAC (P = 0.138). Conclusions Pancreatic ductal adenocarcinoma-associated IPMN has different clinicopathological characteristics compared with the IPMC-I. Intraductal papillary mucinous neoplasm with an associated invasive carcinoma is composed of a wide spectrum of disease.

HDAC2 Provides a Critical Support to Malignant Progression of Hepatocellular Carcinoma through Feedback Control of mTORC1 and AKT

Aberrant regulation of histone deacetylase 2 (HDAC2) contributes to malignant progression in various cancers, but the underlying mechanism leading to the activation of oncogenic HDAC2 remains unknown. In this study, we show that HDAC2 expression is upregulated in a large cohort of patients with human hepatocellular carcinoma, and that high expression of HDAC2 was significantly associated with poor prognosis of patients with hepatocellular carcinoma. We found that mTORC1/NF-κBp50 signaling is necessary for the growth factor-induced HDAC2 and is sustained in hepatocellular carcinoma, but not in normal hepatic cells. Growth factor-induced mTORC1 activates the nuclear translocation of NF-κBp50, where it binds to the intragenic sequences of the HDAC2 gene and promotes its transcription. Hepatocellular carcinoma tissues derived from chemical-induced mouse and rat liver cancer models validated that mTORC1 activation and NF-κBp50 nuclear translocation are essential for the transcriptional activation of oncogenic HDAC2 in hepatocellular carcinoma. In addition, we demonstrate that HDAC2 is required to maintain mTORC1 activity by stabilizing the mTOR/RAPTOR complex. Elevated expression of HDAC2 triggers a positive feedback loop that activates AKT phosphorylation via the transcriptional modulation of phosphoinositide signaling molecules. Bioinformatics analysis of HDAC2 signature and immunoblot analysis of mesenchymal genes also evidenced that HDAC2 plays a role in the malignant behavior of tumor cells by Snail induction and simultaneously E-cadherin suppression in hepatocellular carcinoma cells. These findings establish a molecular mechanism responsible for the activation of oncogenic HDAC2, which explains how growth factor-induced HDAC2 maintains mitogenic signaling and function during hepatocellular malignant progression and provide a novel strategy for therapeutic intervention in liver cancer. Cancer Res; 74(6); 1728-38. ©2014 AACR.

Clinical features of 20 patients with curatively resected biliary neuroendocrine tumours.

BACKGROUND Neuroendocrine tumours very rarely occur in the biliary tract; information about them is limited. AIMS To present the clinical characteristics and prognosis of curatively resected biliary neuroendocrine tumours. METHODS Review of medical records dated between 2000 and 2010 of 20 patients from three medical centres with biliary neuroendocrine tumour based on curative resection. RESULTS Based on the World Health Organization 2010 classification, five and one patients had neuroendocrine tumour grades 1 and 2, seven had neuroendocrine carcinoma, and seven were diagnosed with mixed adenoneuroendocrine carcinoma. The locations were the following: seven in the gallbladder, four in the extrahepatic bile duct, and nine in the ampulla of Vater. Lymph node and hepatic metastases were noted in 11 and 4 patients, respectively. Fourteen patients experienced recurrence; most had recurrence in the liver. Patients with neuroendocrine tumour grade 1 had a lower rate of recurrence compared to others (p=0.001). The median disease-free and overall survival times were 5.8 (0.4-53.6) and 13.7 (1.9-102.1) months for all four subtypes. However, the median disease free and overall survival rates of neuroendocrine tumours were significantly longer than those of neuroendocrine carcinomas or mixed adenoneuroendocrine carcinoma. CONCLUSIONS Patients with biliary neuroendocrine tumour showed extremely different clinical outcomes according to histopathologic subtypes by World Health Organization 2010 classification.