Peritumoral Infiltration of T Cells and PD-L1-Expressing Tumor Associated Macrophages as a Potential Predictor of Lenvatinib Response

( Pil Soo Sung ),( Dong Jun Park ),( Gil Won Lee ),( Sung Woo Cho ),( Jaejun Lee ),( Hyun Yang ),( Soon Kyu Lee ),( Hee Chul Nam ),( Jeong Won Jang ),( Si Hyun Bae ),( Jong Young Choi ),( Seung Kew Yo 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: Recently, lenvatinib was demonstrated to be non-inferior to sorafenib in a phase 3 randomized controlled trial in unresectable hepatocellular carcinoma (HCC). In this study, we investigated whether the response to lenvatinib is affected by the immunogenicity of the tumor. Methods: Between April 2019 and March 2020, 10 patients with intermediate-to-advanced HCC who were administered lenvatinib treatment after liver biopsy were enrolled. Immunohistochemical staining and multi-color flow cytometry were performed with the liver biopsy specimen. Results: Among 10 patients enrolled, 4 patients showed objective responses (complete response + partial response). Immunohistochemical staining of CD3, CD68, and PD-L1 demonstrated that patients with objective responses showed marked infiltration of T cells and PD-L1-expressing tumor-associated macrophages in intratumoral and peritumoral tissues than those without objective responses. There was a significant difference in the number of infiltrated T cells in responders than in non-responders (P<0.01). For the number of tumor-associated macrophages, there was no significant difference between the responders and the non-responders, although the number of PD-L1-expressing tumor-associated macrophages was significantly higher in responders than in non-responders (P<0.05). Flow cytometry analyses demonstrated the positive correlation of PD-L1 and HLA-DR (P<0.01), suggesting that PD-L1 expression in tumor-associated macrophages in HCC is associated with the capability of antigen presentation of these cells. Conclusions: Tumor immunogenicity reflected by T cell and PD-L1-positive macrophage infiltration affects the responses to lenvatinib in unresectable HCC. This work was supported by the Scientific Research Fund of the Korean Liver Cancer Study Group. This research was also supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) and funded by the Ministry of Education (NRF-2019R1I1A1A01059642) (P.S.S.). This study was partly supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2020R1A2C3011569).

Synthesis of 2-(4-Hydroxyphenyl)benzofurans and Their Application to $\beta$-Amyloid Aggregation Inhibitor

Choi, Hong-Dae,Seo, Pil-Ja,Son, Byeng-Wha,Kang, Byoung-Won The Pharmaceutical Society of Korea 2004 Archives of Pharmacal Research Vol.27 No.1

The facile synthesis of a series of 2-(4-hydroxyphenyl)benzofurans (4a-e) is described. The one-pot reaction of 4-substituted phenols with the chloride 1 in the presence of zinc chloride afforded 3-methylthio-2-(4-acetoxyphenyl)benzofurans (2a-e). The compounds 4a-e were obtained from the hydrolysis of 2a-e followed by the desulfurization of the resulting 3-methylthio-2-(4-hydroxyphenyl)benzofurans (3a-e). 5-Methyl-3-p-toluoyl-2 -[4-(3-diethylaminopropoxy)phenyl]benzofuran (7), a $\beta$-amyloid aggregation inhibitor, was synthesized by three steps starting from 4a.

Synthesis of 5-Chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2(4-methoxyphenyl)benzofuran as a $\beta-Amyloid$ Aggregation

Choi, Hong-Dae,Seo, Pil-Ja,Son, Byeong-Wha,Kang, Byoung-Won The Pharmaceutical Society of Korea 2003 Archives of Pharmacal Research Vol.26 No.12

An efficient synthesis of 5-chloro-3-[4-(3-diethylaminopropoxy)benzoyl]-2-(4-methoxyphenyl)benzofuran (8), a potent $\beta$-amyloid aggregation inhibitor, is described. 5-Chloro-2-(4-methoxyphenyl)benzofuran (3) was obtained by the one-pot synthesis of 4-chlorophenol with $\omega$(methylsulfinyl)-p-methoxyacetophenone (1) under Pummerer reaction conditions, and it was followed by the desulfurization of the resultant 5-chloro-3-methylthio-2-(4-methoxyphenyl)benzofuran (2e). Acylation of benzofuran 3 with 4-(3-bromopropoxy)benzoyl chloride (6) gave the ketone 7, which was converted into compound 8 by the treatment of diethylamine.

Transarterial Chemolipiodolization for Hepatocellular Carcinoma with Central Bile Duct Invasion Causing Conjugated Hyperbilirubinemia: Safety and Prognostic Factors for Survival

( Pil Soo Sung ),( Jung Suk Oh ),( Ho Jong Chun ),( Jeong Won Jang ),( Si Hyun Bae ),( Jong Young Choi ),( Seung Kew Yoon ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: Bile duct invasion of hepatocellular carcinoma (HCC) is relatively uncommon. For patients with conjugated hyperbilirubinemia caused by HCC with bile duct invasion, it has been reported that effective biliary drainage followed by transarterial chemolipiodolization (TACL) may prolong survival. However, there are few reports comparing the clinical outcomes between tumors with central bile duct invasion causing conjugated hyperbilirubinemia and tumors with central bile duct invasion without hyperbilirubinemia, after TACL. Methods: Between January 2005 and December 2017, a total of 50 patients with HCC invading central bile duct (right or left hepatic duct, common hepatic or bile duct) and treated with TACL were enrolled. Patients were divided into three groups: hyperbilirubinemia (total bilirubin ≥ 2.5mg/dL) with pre-TACL biliary drainage group (n=12), hyperbilirubinemia without biliary drainage group (n=12), and without hyperbilirubinemia group (n=26). Tumor response to TACL, survival outcomes, length of hospitalization, adverse events recorded using Common Terminology Criteria for Adverse Events (CTCAE), and factors affecting overall survival were compared among three groups. Results: The mean length of hospitalization was shorter in patients without hyperbilirubinemia compared to hyperbilirubinemia (10.2 vs 14.5 days, P=0.017), although mean CTCAE grade for laboratory parameters were not significantly increased after TACL among three groups. Significant decrease in serum bilirubin level was observed among patients who underwent pre-TACL biliary drainage (mean of differences: 5.860, P=0.002). However, there were no significant differences in serum bilirubin level between that of the TACL day and highest level within one month after TACL, in all three groups. The tumor response was also not significantly different between patients with hyperbilirubinemia and without hyperbilirubinemia (P=0.573). Survival between patients with hyperbilirubinemia and without hyperbilirubinemia was not significantly different (P=0.097). In multivariate analysis, α-fetoprotein less than 400 ng/dL (HR = 0.477, P=0.048), and highest total bilirubin < 2.5 mg/dL within one month after TACL (HR = 0.335, P=0.004) were significantly associated with longer survival. Conclusions: TACL can be a safe and effective treatment for patients who have HCCs with central bile duct invasion, irrespective of the presence of conjugated hyperbilirubinemia.

Control of Intracranial Disease Is Associated with Improved Survival for Patients with Brain Metastases from Hepatocellular Carcinoma

( Pil Soo Sung ),( Dong Jin Yoon ),( Do Seon Song ),( Jung Hyun Kwon ),( Soon Woo Nam ),( Jeong Won Jang ),( Jong Young Choi ),( Seung Kew Yoon ),( Seok Whan Moon ),( Hong Seok Jang ),( Si Hyun Bae ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: We performed a retrospective study to identify prognostic factors and determine outcomes for patients with brain metastases from hepatocellular carcinoma (HCC). Methods: A total of 72 patients with brain metastases from HCC were identified from two institutions; 26 of 72 patients received tumor-removing surgery or stereotactic radiosurgery with or without whole-brain radiotherapy (WBRT), 23 of 72 received WBRT only, and 23 of 72 received conservative treatment. Estimates for overall survival (OS) after brain metastases were determined and clinical prognostic factors were identified by Cox proportional hazards modeling. Results: Median OS after development of brain metastases was 48 days (one day to 536 days). The median age at the time patients were diagnosed with brain metastasis was 54 years. Fifty-one patients (71%) were male, and 62 patients (86%) were infected with hepatitis B virus. Median time from diagnosis of HCC to brain metastasis was 17.2 months, and 4 patients had brain metastases at the time diagnosis. Intracranial hemorrhage was frequently associated (42%) with brain metastasis. The most common presenting symptoms were motor weakness, mental change, and headache. Sixty-three patients (88%) had lung metastases, 25 patients (35%) had bone metastases, 18 patients (25%) had metastatic lymphadenopathy, and 7 (10%) patients had peritoneal seeding when diagnosed with brain involvement, and there was only one patient without metastasis to other organs. Univariate analyses showed that treatment with curative intent (surgery or SRS) and serum AFP levels were associated with improved survival (P<0.001, and 0.045, respectively), whereas a single brain metastasis, size of metastatic tumor, or intracranial hemorrhage were not. We further divided patients with three groups by the treatment modality; surgery or radiosurgery (group1), WBRT (group 2), or conservative treatment (group 3). Group 1 showed best survival, followed by group 2 and group 3, sequentially (P<0.001). Subgroup analysis with patients with single brain metastasis showed similar results. Multivariate analysis showed that treatment modality was the only factor that is associated with improved OS (P=0.001) Conclusions: When patients with lung metastases from HCC present neurologic symptoms, brain imaging is required to confirm intracranial metastases. Although the overall prognosis of patients with brain metastases from HCC is extremely poor, patients actively treated with surgery or radiosurgery have prolonged survival, suggesting that interventions to control intracranial disease are important treatment modalities.

Reduction of Intrahepatic Tumor Burden by Hepatic Arterial Infusion Chemotherapy Prolongs Survival in Advanced Hepatocellular Carcinoma

( Pil Soo Sung ),( Keungmo Yang ),( Si Hyun Bae ),( Jung Suk Oh ),( Ho Jong Chun ),( Jeong Won Jang ),( Jong Young Choi ),( Seung Kew Yoon ) 대한간학회 2018 춘·추계 학술대회 (KASL) Vol.2018 No.1

Aims: There are limited studies on the impact of intrahepatic tumor control on patient survival in advanced hepatocellular carcinoma (HCC). The purpose of this study is to confirm survival benefits of reduced intrahepatic tumor burden by hepatic arterial infusion chemotherapy (HAIC) in advanced HCC patients. Methods: Between January 2012 and December 2017, a total of 138 consecutive patients with advanced HCC treated with HAIC were enrolled. Thirty-six patients (26.1%) had extrahepatic metastasis when HAIC was started. Survival outcomes and tumor response rate (both intrahepatic and extrahepatic) after HAIC were analyzed. Multivariate analysis was performed to estimate clinical factors associated with survival outcomes. Results: Most of the patients (86.2%) included in the study were on Barcelona Clinic Liver Cancer stage C. The presence of extrahepatic metastasis at the start of HAIC had no significant effect on overall survival (P=0.17). The intrahepatic objective response rate (ORR) (complete response + partial response) of all the enrolled patients to HAIC was 17.4%. The intrahepatic OR was 13.8% for patients with extrahepatic metastasis, and 18.6% for patients without extrahepatic metastasis. Patients with intrahepatic OR by HAIC showed significantly better survival outcomes than those without OR did, irrespective of the initial distant metastases. On multivariate analysis, the achievement of intrahepatic OR by HAIC and Child-Pugh classification at the time of first response evaluation were two independent Conclusions: HAIC-induced intrahepatic tumor reduction prolongs patient survival irrespective of the status of distant metastasis. Our study demonstrates that it is critical to reduce intrahepatic tumor burden in advanced HCC even when patients have initial extrahepatic metastasis.

A Low-Power Two-Line Inversion Method for Driving LCD Panels

Choi, Sung-Pil,Kwon, Kee-Won,Chun, Jung-Hoon The Institute of Electronics and Information Engin 2016 Journal of semiconductor technology and science Vol.16 No.4

A new two-line based inversion driving method is introduced for low power display-driver ICs. By inserting a timing offset between the chopper stabilization and the alternation of LCD polarity, we can reduce power consumption without noticeable degradation in the display quality. By applying the proposed scheme to 12" LCD applications, we achieved 7.5% and 27% power saving in the display-driver IC with white and black patterns, respectively.

Diffusion-Weighted MR Imaging in Hepatocellular Carcinoma as a Predictor of a Response to Cisplatin- Based Hepatic Arterial Infusion Chemotherapy

( Pil Soo Sung ),( Moon Hyung Choi ),( Hyun Yang ),( Ho Jong Chun ),( Soon Kyu Lee ),( Jeong Won Jang ),( Jong Young Choi ),( Seung Kew Yoon ),( Joon-il Choi ),( Young Joon Lee ),( Si Hyun Bae ) 대한간학회 2020 춘·추계 학술대회 (KASL) Vol.2020 No.1

Aims: This study aimed to identify the utility of diffusion- weighted magnetic resonance (MR) imaging with an apparent diffusion coefficient (ADC) map as a predictor of the intrahepatic response of hepatocellular carcinoma (HCC) to cisplatin- based hepatic arterial infusion chemotherapy (HAIC). Methods: We evaluated 113 consecutive patients with HCC who underwent after gadoxetic acid-enhanced and diffusion- weighted MR imaging were retrospectively evaluated. Significant findings for differentiating the two groups were identified at univariate and multivariate analyses. By using receiver operating characteristic analysis, the optimal cut-off values for quantitative variables were determined. The treatment response was evaluated using modified Response Evaluation Criteria in Solid Tumors. Overall survival times after HAIC were also compared between groups by log-rank tests. Results: The appropriate cut-off for the tumor-to-liver ADC ratio was determined as 0.741. Of the 113 patients, 51 (45%) presented with a tumor-to-liver ADC ratio < 0.741. Evaluation of the intrahepatic treatment response after 2-3 cycles of HAIC in these 51 patients revealed that 20 patients (39%) experienced an objective response to HAIC. On the other hand, 10 of the 62 patients with a tumor-to-liver ADC ratio ≥ 0.741 (16%) experienced an objective response. Thus, the objective response rate was significantly higher in patients with a tumor-to-liver ADC ratio < 0.741 than in those with a tumor-to-liver ADC ratio ≥ 0.741 (P=0.006). Multivariate logistic regression analysis using parameters including perfusion alteration, percentage of a non-enhancing portion, and tumor-to-liver ADC ratio revealed that a tumor-to-liver ADC ratio < 0.741 (odds ratio 3.03; P=0.015) is a sole predictor of an objective response to HAIC. Overall survival rates were significantly higher in patients with objective responses to HAIC compared with those without ob jective responses (P=0.001 by log-rank test). Conclusions: Patients with unresectable HCC with tumor-to-liver ADC ratio < 0.741 showed a favorable intrahepatic response to HAIC. Therefore, diffusion-weighted MR imaging can take a critical role as a predictor of a response to cisplatin-based HAIC in unresectable HCC.

Major Achievements and Prospect of the ATLAS Integral Effect Tests

Choi, Ki-Yong,Kim, Yeon-Sik,Song, Chul-Hwa,Baek, Won-Pil Hindawi Limited 2012 Science and technology of nuclear installations Vol.2012 No.-

<P>A large-scale thermal-hydraulic integral effect test facility, ATLAS (Advanced Thermal-hydraulic Test Loop for Accident Simulation), has been operated by KAERI. The reference plant of ATLAS is the APR1400 (Advanced Power Reactor, 1400 MWe). Since 2007, an extensive series of experimental works were successfully carried out, including large break loss of coolant accident tests, small break loss of coolant accident tests at various break locations, steam generator tube rupture tests, feed line break tests, and steam line break tests. These tests contributed toward an understanding of the unique thermal-hydraulic behavior, resolving the safety-related concerns and providing validation data for evaluation of the safety analysis codes and methodology for the advanced pressurized water reactor, APR1400. Major discoveries and lessons found in the past integral effect tests are summarized in this paper. As the demand for integral effect tests is on the rise due to the active national nuclear R&D program in Korea, the future prospects of the application of the ATLAS facility are also discussed.</P>

Dynamic Slew-Rate Control for High Uniformity and Low Power in LCD Driver ICs

Choi, Sung-Pil,Lee, Mira,Jin, Jahoon,Kwon, Kee-Won,Chun, Jung-Hoon The Institute of Electronics and Information Engin 2014 Journal of semiconductor technology and science Vol.14 No.5

A slew-rate control method of LCD driver ICs is introduced to increase uniformity between adjacent driver ICs and reduce power consumption. The slew rate of every voltage follower is calibrated by a feedback algorithm during the non-displaying period. Under normal operation mode, the slew rate is dynamically controlled for improving power efficiency. Experimental results show that the power consumption is reduced by 16% with a white pattern and by 10% with a black pattern, and display defects are successfully eliminated.