Publications by authors named "Hyung Don Kim"

49 Publications

Cervicocerebral atherosclerosis and its hepatic and coronary risk factors in patients with liver cirrhosis.

Clin Mol Hepatol 2021 Oct 12. Epub 2021 Oct 12.

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

Background/aims: This study aimed to investigate the silent atherosclerotic burden of cervicocephalic vessels in cirrhotic patients compared with the general population, and the relevant risk factors including coronary parameters.

Methods: The study population consisted of 993 stroke-free subjects with LC who were screened by magnetic resonance angiography (MRA) of the head and neck as a pre-liver transplant workup, and 6,099 health checkup participants who underwent MRA examination. The two cohorts were matched for cerebrovascular risk factors, and the prevalence rates of atherosclerosis in the major intracranial and extracranial arteries were compared in 755 matched pairs. Also, traditional, hepatic and coronary variables related to the cerebral atherosclerosis were assessed in cirrhotics.

Results: Overall, intracranial atherosclerosis was significantly less prevalent in the LC samples than the matched controls (2.3% vs. 5.4%; P=0.002), whereas the prevalence of extracranial atherosclerosis were similar (4.4% vs. 5.8%; P=0.242). These results were maintained in multivariate analyses in the pooled samples, with the corresponding adjusted odds ratios (ORs) for LC of 0.56 and 0.77 (95% CIs, 0.36-0.88 and 0.55-1.09), respectively. In the cirrhotic series, lower platelet count was inversely correlated with intracranial atherosclerosis (adjusted OR, 0.31; 95% CI, 0.13-0.76). Coronary artery calcium (CAC) score ≥100 was the only factor predicting both intra- and extra-cranial atherosclerosis (adjusted ORs, 4.06 and 5.43; 95% CIs, 1.45-11.41 and 2.68-11.00, respectively).

Conclusions: Our data suggest that LC confers protection against intracranial atherosclerosis, and that thrombocytopenia may be involved in this protection. High CAC score could serve as a potential surrogate for cervicocerebral vascular screening in asymptomatic cirrhotics.
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http://dx.doi.org/10.3350/cmh.2021.0202DOI Listing
October 2021

Reply to D.-C. Mo et al.

J Clin Oncol 2021 Sep 30:JCO2102043. Epub 2021 Sep 30.

Yoon-Koo Kang, MD, PhD, Hyung-Don Kim, MD, PhD, and Min-Hee Ryu, MD, Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea and Sung Hoon Noh, MD, Department of Surgery, Yonsei University College of Medicine, Seoul, Republic of Korea.

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http://dx.doi.org/10.1200/JCO.21.02043DOI Listing
September 2021

Antioxidant and Anti-Melanogenic Activities of Heat-Treated Licorice (Wongam, × ) Extract.

Curr Issues Mol Biol 2021 Sep 18;43(2):1171-1187. Epub 2021 Sep 18.

Department of Herbal Crop Research, National Institute of Horticultural and Herbal Science (NIHHS), Rural Development Administration (RDA), Eumsung 27709, Korea.

Melanin is a brown or black pigment that protects skin from ultraviolet radiation and reactive oxygen species (ROS). However, overproduction of melanin is associated with lentigines, melasma, freckles and skin cancer. Licorice has shown antioxidant, anti-tumor, anti-platelet, anti-inflammatory and immunomodulatory activities and is used as a natural treatment for skin whitening. We aimed to confirm the potential of Wongam, a new cultivar of licorice developed by the Rural Development Administration (RDA), as a whitening agent in cosmetics. In addition, we verified the effect of heat treatment on the bioactivity of licorice by comparing antioxidant and anti-melanogenic activities of licorice extract before and after heating (130 °C). The heat-treated licorice extract (WH-130) showed higher radical-scavenging activities in the ABTS (2,2'-azino-bis-(3-ethylbenzothiazolin-6-sulfonic acid) diammonium salt) and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays. In addition, WH-130 inhibited melanogenesis more effectively due to downregulation of tyrosinase in B16F10 melanoma cells than non-heated licorice extract. Moreover, heat treatment increased total phenolic content. In particular, isoliquiritigenin, an antioxidant and anti-melanogenic compound of licorice, was produced by heat treatment. In conclusion, WH-130, with increased levels of bioactive phenolics such as isoliquiritigenin, has potential for development into a novel skin whitening material with applications in cosmetics.
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http://dx.doi.org/10.3390/cimb43020083DOI Listing
September 2021

Identification of Regorafenib Prognostic Index (REP Index) via Recursive Partitioning Analysis in Patients with Advanced Hepatocellular Carcinoma Receiving Systemic Treatment: A Real-World Multi-Institutional Experience.

Target Oncol 2021 09 7;16(5):653-661. Epub 2021 Sep 7.

Unit of Oncology, IRCCS-San Raffaele Scientific Institute, Università Vita-Salute, Milan, Italy.

Background: The results of the pivotal RESORCE trial led to the approval of the tyrosine kinase inhibitor regorafenib as second-line treatment in advanced hepatocellular carcinoma (HCC) after sorafenib failure. Data about prognostic factors in a second-line HCC setting are scarce.

Objective: The aim of the present study was to investigate prognostic factors in a cohort of patients with advanced HCC treated with regorafenib after progressing on sorafenib.

Methods: We retrieved the data of 259 patients affected by advanced HCC treated with regorafenib as second-line treatment from four different Italian institutions and one South Korean institution and performed a recursive partitioning analysis to build a score system.

Results: At the first-step univariate analysis for overall survival (OS), alkaline phosphatase (ALP) was the most significant parameter and was chosen as the first node in our tree model. In the subpopulation of patients presenting with ALP ≤122 U/L (n=155) at baseline, the most statistically significant split was by progression-free survival (PFS) on previous sorafenib treatment, between patients with a PFS ≥ 6 months (n  =  59) and patients with a PFS < 6 months (n = 96). In the subpopulation of patients with ALP ≤ 122 U/L and PFS to sorafenib ≥ 6 months, the final split was determined between patients with hepatitis B virus (HBV)-related liver disease (n = 22) and patients with no HBV-related liver disease (n = 37). In the subpopulation of patients presenting ALP >122 U/L (n = 104) at baseline, the most statistically significant split was by aspartate aminotransferase (AST) value, between patients with AST ≤ 56 U/L (n = 48) and patients with AST > 56 U/L (n = 56). We built the Regorafenib Prognostic Index (REP index) stratifying the population into "low-risk," "medium-risk," and "high-risk" groups. The difference in median OS between the three risk groups was statistically significant, being 20.8 months (95% confidence interval [CI] 10.0-46.3) in the "low-risk" group, 8.4 months (95% CI 7.2-1435.8) in the "medium-risk" group, and 5.5 months (95% CI 3.5-13.2) in the "high risk" group. The median PFS was 7.7 months (95% CI 3.7-19.3), 2.5 months (95% CI 2.1-28.8), and 2.4 months (95% CI 1.6-9.1) for the "low-risk," "medium-risk," and "high-risk" groups, respectively.

Conclusion: The REP index is an independent prognostic factor for OS and PFS in patients with advanced HCC treated with regorafenib.
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http://dx.doi.org/10.1007/s11523-021-00834-1DOI Listing
September 2021

Radiological criteria for selecting candidates for neoadjuvant chemotherapy for gastric cancer: an exploratory analysis from the PRODIGY study.

Gastric Cancer 2021 Sep 2. Epub 2021 Sep 2.

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

Background: In this exploratory analysis from the PRODIGY study, we aimed to define the radiological criteria to identify patients with gastric cancer who may derive maximal clinical benefit from neoadjuvant chemotherapy.

Patients And Methods: There were 246 patients allocated to receive surgery followed by adjuvant S-1 (SC group) and 238 allocated to receive neoadjuvant chemotherapy (CSC group). As the PRODIGY's radiological method of lymph node (LN) evaluation considers short diameter and morphology (the size and morphology method), a method considering only short diameter was also employed. In the SC group, the correlation between radiologic and pathologic findings was analyzed. The hazard ratio (HR) for the progression-free survival (PFS) of the CSC group was analyzed in subgroups with different cT/N stages.

Results: cT4 disease showed a sensitivity of 85.6% for detecting pT4 and had a low proportion of pathologic stage (pStage) I disease (4.5%). Among the criteria determined by different cT/N stages by each method of LN positivity, those involving cT4Nany or cT4N + by both methods had a minimal proportion of pStage I disease (≤ 5%), while cT4Nany by both methods and cT4N + by the size and morphology method exhibited ≥ 75.9% sensitivity for detecting pStage III disease. The relative risk reduction in PFS of the CSC group was greatest in patients meeting the cT4Nany criterion defined by both methods (HR 0.67, 95% confidence interval 0.48-0.93).

Conclusions: The cT4Nany criterion, regardless of the radiological method used for LN evaluation, may help select patients with resectable gastric cancer for neoadjuvant chemotherapy.
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http://dx.doi.org/10.1007/s10120-021-01243-zDOI Listing
September 2021

Insertion-deletion rate is a qualitative aspect of the tumor mutation burden associated with the clinical outcomes of gastric cancer patients treated with nivolumab.

Gastric Cancer 2021 Sep 1. Epub 2021 Sep 1.

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

Background: We aimed to investigate the clinical implications of the tumor mutation burden (TMB) and insertion-deletion (indel) rate in gastric cancer patients treated with nivolumab.

Methods: A total of 105 patients with advanced gastric cancer who were treated with nivolumab as third or later line of therapy were included as the study population. The indel rate was defined as the proportion of indels making up the TMB.

Results: The median age was 58 (32-78 years), and 65 (61.9%) were men. Patients with TMB > 18.03/Mb showed superior progression-free survival (PFS) and overall survival (OS) compared to those with TMB ≤ 18.03/Mb. Patients with a high indel rate (> 40%) had a favorable PFS and OS compared to those with a lower indel rate (≤ 40%) (P = 0.009 and P = 0.007, respectively). The association between a high indel rate and favorable PFS and OS was prominent in a subgroup with TMB > 18.03/Mb (P < 0.001 and P = 0.007 for PFS and OS, respectively), but not in that with TMB ≤ 18.03/Mb. All five patients with deficient-MMR fell into the category of 'TMB > 18.03/Mb with an indel rate of > 40%. TMB ≥ 18.03/Mb with an indel rate of > 40% was independently associated with a favorable PFS (hazard ratio [HR] 0.07, P = 0.012) and OS (HR 0.09, P = 0.023).

Conclusion: TMB and indel rate should be jointly considered to better predict survival outcomes of gastric cancer patients treated with nivolumab. Our findings deserve further investigation and validation in future studies.
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http://dx.doi.org/10.1007/s10120-021-01233-1DOI Listing
September 2021

Prognostic value of natural killer cell activity for patients with HER2 + advanced gastric cancer treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab.

Cancer Immunol Immunother 2021 Aug 22. Epub 2021 Aug 22.

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

Background: We aimed to evaluate the prognostic value of natural killer (NK) cell activity for patients with HER2 + advanced gastric cancer (AGC) treated with first-line fluoropyrimidine-platinum doublet plus trastuzumab.

Methods: Forty-one patients with HER2 + AGC who received fluoropyrimidine-platinum doublet plus trastuzumab as first-line treatment were prospectively enrolled. NK cell activity was evaluated using the NK Vue®.

Results: The median age was 63.5 years, and 31 patients (75.6%) were male. Patients with low baseline NK cell activity (≤ median, n = 21) were associated worse progression-free survival (PFS) and overall survival (OS) compared with patients with high baseline NK cell activity (> median, n = 20) with a median PFS of 4.21 vs. 9.53 months (P < 0.001), and median OS of 8.15 months vs. 17.82 months (P = 0.025), respectively. In the multivariate analysis, low baseline NK cell activity was independently associated with poor PFS (HR 4.35, P = 0.007). NK cell activity recovered to a normal range in nine patients (47.4%) with a low baseline NK cell activity (n = 19) after two cycles of treatment. The median PFS and OS among patients with recovered NK cell activity were significantly better than that among patients with persistently low NK cell activity (PFS, P = 0.038; OS, P = 0.003).

Conclusion: Our results demonstrated the prognostic value of baseline NK cell activity for patients with HER2 + AGC treated with fluoropyrimidine-platinum doublet plus trastuzumab. The association between treatment outcomes and dynamic changes in NK cell activity suggests that NK cell treatment may improve treatment outcomes, especially for patients with low baseline NK cell activity.
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http://dx.doi.org/10.1007/s00262-021-03035-xDOI Listing
August 2021

Novel anti-4-1BB×PD-L1 bispecific antibody augments anti-tumor immunity through tumor-directed T-cell activation and checkpoint blockade.

J Immunother Cancer 2021 07;9(7)

ABL Bio Inc, Seongnam, Korea

Background: Stimulation of 4-1BB with agonistic antibodies is a promising strategy for improving the therapeutic efficacy of immune checkpoint inhibitors (ICIs) or for overcoming resistance to ICIs. However, dose-dependent hepatotoxicity was observed in clinical trials with monoclonal anti-4-1BB agonistic antibodies due to the activation of 4-1BB signaling in liver resident Kupffer cells.

Methods: To avoid this on-target liver toxicity, we developed a novel bispecific antibody (4-1BB×PD-L1 bispecific antibody, termed "ABL503") uniquely designed to activate 4-1BB signaling only in the context of PD-L1, while also blocking PD-1/PD-L1 signaling.

Results: Functional evaluation using effector cells expressing both 4-1BB and PD-1 revealed superior biological activity of ABL503 compared with the combination of each monoclonal antibody. ABL503 also augmented T-cell activation in in vitro assays and further enhanced the anti-PD-L1-mediated reinvigoration of tumor-infiltrating CD8 T cells from patients with cancer. Furthermore, in humanized PD-L1/4-1BB transgenic mice challenged with huPD-L1-expressing tumor cells, ABL503 induced superior anti-tumor activity and maintained an anti-tumor response against tumor rechallenge. ABL503 was well tolerated, with normal liver function in monkeys.

Conclusion: The novel anti-4-1BB×PD-L1 bispecific antibody may exert a strong anti-tumor therapeutic efficacy with a low risk of liver toxicity through the restriction of 4-1BB stimulation in tumors.
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http://dx.doi.org/10.1136/jitc-2021-002428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8261887PMC
July 2021

Neuroprotective Effects of Flower Extract against Oxidative Stress-Induced Apoptosis in Neuronal Cells and Mice.

Antioxidants (Basel) 2021 Jun 12;10(6). Epub 2021 Jun 12.

Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Eumsung 27709, Korea.

L. is a perennial plant of the family Asteraceae, and its flower is known to contain flavonoids with various bioactivities. We evaluated the effect of L. flower (CLF) extracts on HO-induced oxidative stress (OS) in neuronal cells and mouse neurons. The flowering part of CL was used as CLF1 (70% ethanol extract) and CLF2 (water extract), and 10 types of phenolic compounds were quantified using high-performance liquid chromatography. To evaluate the neuroprotective effects of CLF, the antioxidant activities of the extracts were measured, and the expression levels of antioxidant enzymes and proteins related to OS-induced apoptosis in neuronal cells and mouse neurons treated with the extracts were investigated. In the in vitro study, CLF ameliorated HO-induced oxidative stress and induced the expression of antioxidant enzymes in PC12 cells. Furthermore, CLF1 enhanced the expression of the Bcl-xL protein but reduced the expression of Bax and the cleavage of caspase-3. In the same manner, CLF1 showed neuroprotective effects against OS in vivo. Pretreatment with CLF1 (200 mg/kg) increased the Bcl-2 protein and decreased Bax compared with the 1-methyl-4-phenylpyridinium ion (MPP+)-treated C57BL/6 mice model group. Our results suggest that the protective effects of CLF1 on MPP+-induced apoptosis may be due to its anti-apoptotic activity, through regulating the expression of the Bcl-2 family. CLF1 exerts neuroprotective effects against OS-induced apoptosis in PC12 cells in a Parkinson's disease model mouse. This effect may be attributable to the upregulation of Bcl-2 protein expression, downregulation of Bax expression, and inhibition of caspase-3 activation. These data indicate that CLF may provide therapeutic value for the treatment of progressive neurodegenerative diseases.
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http://dx.doi.org/10.3390/antiox10060951DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8231104PMC
June 2021

Type 17 immunity promotes the exhaustion of CD8 T cells in cancer.

J Immunother Cancer 2021 06;9(6)

Lab of Immune Regulation, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea

Background: Multiple types of immune cells producing IL-17 are found in the tumor microenvironment. However, their roles in tumor progression and exhaustion of CD8 tumor-infiltrating lymphocytes (TILs) remain unclear.

Methods: To determine the role of type 17 immunity in tumor, we investigated the growth of B16F10 melanoma and the exhaustion of CD8 TILs in mice, mice, RORγt inhibitor-treated mice, or their respective control mice. Adoptive transfer of tumor-specific IL-17-producing T cells was performed in B16F10-bearing congenic mice. Anti-CD4 or anti-Ly6G antibodies were used to deplete CD4 T cells or CD11bGr-1 myeloid cells , respectively. Correlation between type 17 immunity and T cell exhaustion in human cancer was evaluated by interrogating TCGA dataset.

Results: Depletion of CD4 T cells promotes the exhaustion of CD8 T cells with a concomitant increase in IL-17-producing CD8 T (Tc17) cells in the tumor. Unlike IFN-γ-producing CD8 T (Tc1) cells, tumor-infiltrating Tc17 cells exhibit CD103KLRG1IL-7Rα tissue resident memory-like phenotypes and are poorly cytolytic. Adoptive transfer of IL-17-producing tumor-specific T cells increases, while depletion of IL-17-producing cells decreases, the frequency of PD-1Tim3TOX terminally exhausted CD8 T cells in the tumor. Blockade of IL-17 or RORγt pathway inhibits exhaustion of CD8 T cells and also delays tumor growth . Consistent with these results, human TCGA analyses reveal a strong positive correlation between type 17 and CD8 T cell exhaustion signature gene sets in multiple cancers.

Conclusion: IL-17-producing cells promote terminal exhaustion of CD8 T cells and tumor progression , which can be reversed by blockade of IL-17 or RORγt pathway. These findings unveil a novel role for IL-17-producing cells as tumor-promoting cells facilitating CD8 T cell exhaustion, and propose type 17 immunity as a promising target for cancer immunotherapy.
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http://dx.doi.org/10.1136/jitc-2021-002603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183213PMC
June 2021

Role of the prognostic nutritional index in predicting survival in advanced hepatocellular carcinoma treated with regorafenib.

Hepatol Res 2021 Jul 26;51(7):796-802. Epub 2021 May 26.

Department of Oncology, IRCCS San Raffaele Scientific Institute Hospital, Milan, Italy.

Aim: A link has been established between malnutrition, immunological status, and hepatocellular carcinoma (HCC). The prognostic nutritional index (PNI) has been recognized as a prognostic indicator in early-stage HCC and in patients treated with first-line therapy. However, to date, the role of the PNI in HCC patients treated with regorafenib has not been reported.

Methods: We undertook a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10 × serum albumin concentration (g/dl) + 0.005 × peripheral lymphocyte count (number/mm ). Univariate and multivariate analyses were used to investigate the association between PNI and survival outcomes.

Results: A PNI cut-off value of 44.45 was calculated by a receiver operating characteristic analysis. The median overall survival was 12.8 and 7.8 months for patients with high (>44.45) and low (≤44.45) PNI, respectively (hazard ratio, 0.58; 95% confidence interval, 0.43-0.77; p = 0.0002). In the univariate and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for overall survival. No differences were found between high and low PNI in terms of progression-free survival (p = 0.14).

Conclusion: If validated, the PNI could represent an easy-to-use prognostic tool able to guide the clinical decision-making process in HCC patients treated with regorafenib.
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http://dx.doi.org/10.1111/hepr.13669DOI Listing
July 2021

The Prognosis and the Role of Adjuvant Chemotherapy for Node-Positive Bladder Cancer Treated with Neoadjuvant Chemotherapy Followed by Surgery.

Cancer Res Treat 2021 May 6. Epub 2021 May 6.

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

Purpose: This study aims to evaluate the prognosis of pathologically node-positive bladder cancer after neoadjuvant chemotherapy, the role of adjuvant chemotherapy in these patients, and the value of preoperative clinical evaluation for lymph node metastases.

Materials And Methods: Patients who received neoadjuvant chemotherapy followed by partial/radical cystectomy and had pathologically confirmed lymph node metastases between Jan 2007 and Dec 2019 were identified and analysed.

Results: A total of 53 patients were included in the study. The median age was 61 years (range, 34-81) with males comprising 86.8%. Among the 52 patients with post-neoadjuvant/pre-operative CT results, only 33 patients (63.5%) were considered positive for lymph node metastasis. Sixteen patients (30.2%) received adjuvant chemotherapy (AC group), and 37 patients did not (no AC group). With the median follow-up duration of 67.7 months, the median recurrence-free survival (RFS) and the median overall survival (OS) was 8.5 months and 16.2 months, respectively. The 2-year RFS and OS rates were 23.3% and 34.6%, respectively. RFS and OS did not differ between the AC group and no AC group (median RFS, 8.8 vs. 6.8 months, p=0.772; median OS, 16.1 vs. 16.3 months, p=0.479). Thirty-eight patients (71.7%) experienced recurrence. Distant metastases were the dominant pattern of failure in both the AC group (91.7%) and no AC group (76.9%).

Conclusion: Patients with lymph node-positive disease after neoadjuvant chemotherapy followed by surgery showed high recurrence rates with limited survival outcomes. Little benefit was observed with the addition of adjuvant chemotherapy.
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http://dx.doi.org/10.4143/crt.2021.365DOI Listing
May 2021

Regorafenib versus cabozantinb as second-line treatment after sorafenib for unresectable hepatocellular carcinoma: matching-adjusted indirect comparison analysis.

J Cancer Res Clin Oncol 2021 Mar 20. Epub 2021 Mar 20.

Department of Medical and Surgical Sciences (DIMEC), University of Bologna, Bologna, Italy.

Background: Recently, three published phase III trials highlighted the superiority of investigational drugs compared to placebo, thus leading to their approval in the second-line setting. We report here a MAIC of second-line MKI options for patients with HCC previously treated with sorafenib using individual real-world data of regorafenib and aggregate data of second-line cabozantinib from the CELESTIAL trial.

Methods: Data from 278 patients who received regorafenib as second-line therapy after sorafenib failure for unresectable HCC were used as IPD. Data inclusion were adapted to those reported in the CELESTIAL trial in the subset of patients who received sorafenib as the only prior therapy. Survival medians and rates were obtained from Kaplan-Meier curves, and differences between regorafenib and cabozantinib groups were explored through Cox regression adjusted for weights originating from MAIC.

Results: The median OS of the weighted regorafenib group was 11.1 months (IQR: 5.6-16.4) and 11.3 (IQR: 6.7-22.4) for cabozantinib; HR 0.83 (95%CI 0.62-1.09). The median PFS of the weighted regorafenib group was 3.0 months (IQR: 1.9-4.8) and 5.5 (IQR: 2.3-9.3) for cabozantinib; HR 0.50 (95%CI 0.41-0.62). In the subgroup who received prior sorafenib for < 3 months, the median OS of the regorafenib group was 6.5 months (IQR: 4.7-10.9) and 9.5 months (IQR: 5.9-18.2) for cabozantinib; HR 0.68 (95%CI 0.39-1.16). In the subgroup receiving prior sorafenib for 3 to < 6 months, the median OS of the regorafenib group was 8.0 months (IQR: 4.2-15.2) and 11.5 (IQR: 6.5-23.9) for cabozantinib; HR 0.66 (95%CI 0.42-1.02). In the subgroup receiving prior sorafenib for ≥ 6 months, the median OS of the regorafenib group was 13.4 (IQR: 8.1-46.5) and 12.3 (IQR: 6.6-22.9) for cabozantinib; HR 0.89 (95%CI 0.52-1.51).

Conclusion: Our results confirmed no differences between regorafenib and cabozantinib in terms of OS. However, in earlier progressors on prior sorafenib a larger benefit might be expected from cabozantinib treatment.
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http://dx.doi.org/10.1007/s00432-021-03602-wDOI Listing
March 2021

Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5.

Cancer Res Treat 2021 Oct 4;53(4):1166-1173. Epub 2021 Mar 4.

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

Purpose: This study aimed to investigate the clinical outcomes with gemcitabine-carboplatin (GCb), the standard treatment for patients with advanced urothelial carcinoma (UC) who are ineligible for cisplatin-based regimens, in advanced UC patients with a glomerular filtration rate (GFR) < 30 mL/min.

Materials And Methods: A retrospective cohort study involving GCb-treated advanced UC patients with GFR < 60 mL/min (n=89) was performed. Clinical outcomes were compared between subgroups with GFR < 30 mL/min and GFR ≥ 30 mL/min but < 60 mL/min.

Results: Most baseline characteristics were comparable between the two subgroups. Patients with GFR < 30 mL/min had a significantly lower objective response rate (12.5%) compared to those with higher GFR levels (56.7%) (p=0.004). The number of GCb cycles was significantly lower in patients with GFR < 30 mL/min (median 2 cycles) than in those with higher GFR levels (median 6 cycles) (p=0.002). Compared to those with GFR ≥ 30 mL/min but < 60 mL/min, patients with GFR < 30 mL/min showed significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.001 for both). Further stratification of patient subgroups according to their GFR (i.e., GFR ≥ 45 mL/min but < 60 mL/min vs. GFR ≥ 30 mL/min but < 45 mL/min vs. GFR < 30 mL/min) revealed significantly different PFS and OS (p < 0.001 for both).

Conclusion: The use of GCb is discouraged in advanced UC patients with GFR < 30 mL/min. Alternative therapeutic approaches with better efficacy are warranted for these patients.
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http://dx.doi.org/10.4143/crt.2021.091DOI Listing
October 2021

Sequential Treatment of Sorafenib-Regorafenib Versus Sorafenib-Physician's Choice: A Propensity Score-Matched Analysis.

Target Oncol 2021 05 1;16(3):401-410. Epub 2021 Mar 1.

Department of Medical Oncology, San Rafaele Scientific Institute IRCCS, Milan, Italy.

Background: Regorafenib has been shown to improve clinical outcomes compared to placebo, becoming a standard second-line therapy for sorafenib-progressed and -tolerated hepatocellular carcinoma (HCC) patients.

Objective: We performed a multicentre, retrospective study in Italy and Korea to evaluate the effectiveness of the treatment sequence sorafenib-regorafenib compared with sorafenib and physician's choice in a real-life setting.

Patients And Methods: A propensity score model was developed to control the results for baseline variable imbalances between the arm treated with sorafenib and regorafenib (S-R) and the arm treated with sorafenib and physician's choice (S-P). Survival analysis was conducted on the matched population.

Results: After the application of propensity score matching, we analysed 99 patients in the arm treated with S-R and 99 patients in the arm treated with S-P. For the S-R group, the median overall survival was 22.2 months (95% CI 17.1-27.4), compared to 17.9 months (95% CI 15.1-50.0) for the S-P group. The results of the univariate analysis showed a 31% reduction of death risk for patients treated with S-R (p = 0.0382) compared to patients treated with S-P. Interaction tests highlighted the predictive role of alpha-fetoprotein (AFP), neutrophil-to-lymphocyte ratio (NLR), and extrahepatic spread.

Conclusion: This study provides additional proof of the superiority of the S-R treatment over the S-P treatment approach in advanced HCC patients from a real-life setting.
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http://dx.doi.org/10.1007/s11523-021-00797-3DOI Listing
May 2021

Implication of CD69 CD103 tissue-resident-like CD8 T cells as a potential immunotherapeutic target for cholangiocarcinoma.

Liver Int 2021 04 23;41(4):764-776. Epub 2021 Feb 23.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

Background: The heterogeneous immune landscapes of intrahepatic cholangiocarcinoma (ICC) remain largely unknown. Here we aimed to investigate the implications of tissue-resident memory (TRM)-related features of tumour-infiltrating CD8 T cells (CD8 TILs) from ICC patients.

Methods: From ICC patients, we obtained blood samples and ICC surgical specimens (n = 33). We performed multicolour flow cytometry, multiplexed immunohistochemistry and RNA sequencing.

Results: When compared to peripheral CD8 T cells, the CD8 TILs included significantly higher proportions of the CD69 CD103 and CD69 CD103 TRM-like subsets (P < .001 for both). Relative to CD69 and CD69 CD103 cells, the CD69 CD103 CD8 TILs harboured higher levels of T-cell markers representing tumour specificity (ie CD39), proliferation (ie Ki-67) and T-cell activation (ie HLA-DR and CD38) (all P < .001). Moreover, compared to the stroma, the tumour margin and core density each had a significantly higher density of CD103 CD8 TILs (P < .001 for both). ICCs with high proportions of CD69 CD103 cells displayed higher levels of parameters associated with response to immune checkpoint inhibitors (ICIs)-including number of CD8 TIL infiltrates (P = .019), PD-L1 expression in the tumour (P = .046) and expression of the T cell-inflamed gene signature (P < .001). ICCs with lower proportions of CD69 CD103 CD8 TILs exhibited significant enrichment of genes related to the Wnt/β-catenin (P < .001) and TGF-β pathways (P = .002).

Conclusion: CD69 CD103 TRM-like CD8 TILs represent prominent tumour-specific immune responses and hold promise as a potential therapeutic target in ICC patients. Differential TRM-related features of ICCs may help develop future immunotherapeutic strategies such as maximizing TRM responses or inhibiting pathways contributing to immune evasion.
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http://dx.doi.org/10.1111/liv.14814DOI Listing
April 2021

Lenvatinib versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: An inverse probability of treatment weighting analysis.

Liver Int 2021 06 20;41(6):1389-1397. Epub 2021 Feb 20.

Division of Internal Medicine, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.

Purpose: Data from common clinical practice were used to generate balanced cohorts of patients receiving either sorafenib or lenvatinib, for unresectable hepatocellular carcinoma, with the final aim to investigate their declared equivalence.

Methods: Clinical features of lenvatinib and sorafenib patients were balanced through inverse probability of treatment weighting (IPTW) methodology, which weights patients' characteristics and measured outcomes of each patient in both treatment arms. Overall survival was the primary endpoint and occurrence of adverse events was the secondary.

Results: The analysis included 385 patients who received lenvatinib, and 555 patients who received sorafenib. In the unadjusted cohort, lenvatinib did not show a survival advantage over sorafenib (HR: 0.85, 95% CI 0.70-1.02). After IPTW adjustment, lenvatinib still not returned a survival advantage over sorafenib (HR: 0.82, 95% CI: 0.62-1.07) even in presence of balanced baseline characteristics. Lenvatinib provided longer survival than sorafenib in patients previously submitted to TACE (HR: 0.69), with PS of 0 (HR: 0.73) or without extrahepatic disease (HR: 0.69).

Conclusion: Present results confirmed randomized controlled trial in the real-life setting, but also suggests that in earlier stages some benefit can be expected.
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http://dx.doi.org/10.1111/liv.14817DOI Listing
June 2021

Root Protects against Aβ-Induced Cognitive Dysfunction and Pathology in Female Models of Alzheimer's Disease.

Antioxidants (Basel) 2021 Feb 1;10(2). Epub 2021 Feb 1.

Department of Biochemistry, College of Medicine, Konyang University, 158, Gwanjeodong-ro, Seo-gu, Daejeon 35365, Korea.

Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by irreversible cognitive dysfunction. Amyloid beta (Aβ) peptide is an important pathological factor that triggers the progression of AD through accumulation and aggregation, which leads to AD-related pathologies that consequently affect cognitive functions. Interestingly, several studies have reported that root extract (PGE), besides exhibiting other bioactive effects, displays neuroprotective, anti-neuroinflammatory, and cognitive-enhancing effects. However, to date, it is not clear whether PGE can affect AD-related cognitive dysfunction and pathogenesis. Therefore, to investigate whether PGE influences cognitive impairment in an animal model of AD, we conducted a Y-maze test using a 5XFAD mouse model. Oral administration of PGE for 3 weeks at a daily dose of 100 mg/kg significantly ameliorated cognitive impairment in 5XFAD mice. Moreover, to elucidate the neurohistological mechanisms underlying the PGE-mediated alleviative effect on cognitive dysfunction, we performed histological analysis of hippocampal formation in these mice. Histopathological analysis showed that PGE significantly alleviated AD-related pathologies such as Aβ accumulation, neurodegeneration, oxidative stress, and neuroinflammation. In addition, we observed a neuroprotective and antioxidant effect of PGE in mouse hippocampal neurons. Our findings suggest that administration of PGE might act as one of the therapeutic agents for AD by decreasing Aβ related pathology and ameliorating Aβ induced cognitive impairment.
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http://dx.doi.org/10.3390/antiox10020207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912782PMC
February 2021

Prognostic Stratification of Patients with Burkitt Lymphoma Using Serum β2-microglobulin Levels.

Cancer Res Treat 2021 Jul 17;53(3):847-856. Epub 2020 Dec 17.

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

Purpose: We aimed to investigate the prognostic value of serum β2-microglobulin for patients with Burkitt lymphoma (BL) and to propose a risk-stratifying classification system.

Materials And Methods: A prospective registry-based cohort study of BL patients treated with dose-intensive or effective dose-adjusted chemotherapies (n=81) was conducted. Survival outcomes were compared based on previously reported risk groups and/or serum β2-microglobulin levels. A risk-stratifying classification system incorporating serum β2-microglobulin levels was proposed and validated in an independent validation cohort (n=60).

Results: The median age was 47 years, and 57 patients (70.4%) were male. Patients with high serum β2-microglobulin levels (> 2 mg/L) had significantly worse progression-free survival (PFS) and overall survival (OS) (p < 0.01 for both). Serum β2-microglobulin levels further stratified patients in the low-risk and high-risk groups in terms of PFS (p=0.010 and p=0.044, respectively) and OS (p=0.014 and p=0.026, respectively). Multivariate analyses revealed that a high serum β2-microglobulin level (> 2 mg/L) was independently associated with a shorter PFS (hazards ratio [HR], 3.56; p=0.047) and OS (HR, 4.66; p=0.043). The new classification system incorporating the serum β2-microglobulin level allowed the stratification of patients into three distinct risk subgroups with 5-year OS rates of 100%, 89.5%, and 62.5%. In an independent cohort of BL, the system was validated by stratifying patients with different survival outcomes.

Conclusion: Serum β2-microglobulin level is an independent prognostic factor for BL patients. The proposed β2-microglobulin-based classification system could stratify patients with distinct survival outcomes, which may help define appropriate treatment approaches for individual patients.
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http://dx.doi.org/10.4143/crt.2020.1060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8291169PMC
July 2021

TOX-expressing terminally exhausted tumor-infiltrating CD8 T cells are reinvigorated by co-blockade of PD-1 and TIGIT in bladder cancer.

Cancer Lett 2021 02 27;499:137-147. Epub 2020 Nov 27.

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

Exhausted T cells in the tumor microenvironment are major targets of immunotherapies. However, the exhaustion status of CD8 tumor-infiltrating lymphocytes (TILs) in bladder cancer has not been comprehensively evaluated. Herein, we examined distinct exhaustion status of CD8 TILs based on the level of programmed cell death-1 (PD-1) and thymocyte selection-associated high mobility group box protein (TOX) expression in urothelial bladder cancer. We also evaluated the reinvigoration of exhausted CD8 TILs upon ex vivo treatment with inhibitory checkpoint blockers. TOX-expressing PD-1CD8 TILs had the highest expression of immune checkpoint receptors (ICRs), the most terminally exhausted features, and the highest tumor antigen reactivity among PD-1CD8 TILs. Bladder cancer patients with a high percentage of PD-1TOXCD8 TILs had more progressed T-cell exhaustion features and higher programmed death-ligand 1 expression in tumor tissues. TIGIT was the most frequent co-expressed ICR on PD-1CD8 TILs, and TIGIT blockade enhanced the PD-1 blockade-mediated cytokine production by CD8 TILs from bladder cancer patients. Our findings provide an improved understanding of the heterogeneous exhaustion status of CD8 TILs and additional immunotherapy strategies to improve outcomes of bladder cancer patients.
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http://dx.doi.org/10.1016/j.canlet.2020.11.035DOI Listing
February 2021

Clinical implications of neutrophil-to-lymphocyte ratio and MDSC kinetics in gastric cancer patients treated with ramucirumab plus paclitaxel.

Chin J Cancer Res 2020 Oct;32(5):621-630

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

Objective: We aimed to investigate the prognostic value of neutrophil-to-lymphocyte ratio (NLR) and myeloid-derived suppressor cells (MDSCs) in gastric cancer patients treated with second-line ramucirumab plus paclitaxel.

Methods: A total of 116 patients with advanced or metastatic gastric cancer who receive ramucirumab plus paclitaxel were prospectively enrolled. Fresh blood samples were collected before and after treatment, and flow cytometry was performed to assess the proportions of monocytic (mMDSCs) and granulocytic MDSCs (gMDSCs).

Results: Median age was 58 years and 71 (61.2%) patients were male. A baseline NLR≥2.94 was associated with significantly poorer progression-free survival (PFS) and overall survival (OS) . an NLR<2.94 (P=0.011 and P=0.002, respectively). In multivariate analysis, an NLR≥2.94 was independently associated with poorer PFS [hazard ratio (HR)=1.58; 95% confidence interval (95% CI): 1.01-2.49, P=0.046] and OS (HR=1.77; 95% CI: 1.04-3.04, P=0.036). While mMDSC counts did not significantly change following two cycles of therapy (P=0.530), gMDSC counts decreased significantly after two treatment cycles (P=0.025) but tended to increase in patients with progressive disease after two treatment cycles (P=0.098). A progressive increase in gMDSC counts (≥44%) was associated with a significantly shorter PFS and OS. a gMDSC count increase <44% (P=0.001 and P=0.003, respectively).

Conclusions: The baseline NLR may help guide clinical decisions during ramucirumab plus paclitaxel therapy for gastric cancer. Our gMDSC kinetics data warrant further clinical validation and mechanistic investigation.
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http://dx.doi.org/10.21147/j.issn.1000-9604.2020.05.07DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666782PMC
October 2020

A prognostic index for extranodal marginal-zone lymphoma based on the mucosa-associated lymphoid tissue International Prognostic Index and serum β2-microglobulin levels.

Br J Haematol 2021 04 20;193(2):307-315. Epub 2020 Nov 20.

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

The mucosa-associated lymphoid tissue (MALT) International Prognostic Index (IPI) was recently proposed as a prognostic index for patients with MALT lymphoma. We aimed to investigate the prognostic value of the serum β2-microglobulin level in the context of MALT-IPI, and we proposed a new prognostic index. Survival outcomes were analysed with regard to β2-microglobulin level, MALT-IPI, and the new prognostic index in MALT lymphoma patients (n = 571). The validity of the new prognostic index was assessed using an independent cohort (n = 216). Patients with high β2-microglobulin levels had significantly worse progression-free survival (PFS) and overall survival (OS) outcomes. A high β2-microglobulin level was independently associated with poor PFS and OS. β2-microglobulin levels further stratified patients in the MALT-IPI intermediate-risk group in terms of PFS and OS. A new prognostic index based on the MALT-IPI and the β2-microglobulin level, MALT-IPI-B, was proposed. The MALT-IPI-B was able to stratify patients into subgroups having distinct PFS and OS outcomes in both the training and validation cohorts. MALT-IPI-B enabled the identification of patients with poor survival outcomes who were classified into the intermediate-risk group by the MALT-IPI. In conclusion, this new β2-microglobulin-based prognostic index may have the specific advantage of identifying high-risk patients who may require systemic treatment.
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http://dx.doi.org/10.1111/bjh.17222DOI Listing
April 2021

Spatial Distribution and Prognostic Implications of Tumor-Infiltrating FoxP3- CD4+ T Cells in Biliary Tract Cancer.

Cancer Res Treat 2021 Jan 31;53(1):162-171. Epub 2020 Aug 31.

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

Purpose: The clinical implications of tumor-infiltrating T cell subsets and their spatial distribution in biliary tract cancer (BTC) patients treated with gemcitabine plus cisplatin were investigated.

Materials And Methods: A total of 52 BTC patients treated with palliative gemcitabine plus cisplatin were included. Multiplexed immunohistochemistry was performed on tumor tissues, and immune infiltrates were separately analyzed for the stroma, tumor margin, and tumor core.

Results: The density of CD8+ T cells, FoxP3- CD4+ helper T cells, and FoxP3+ CD4+ regulatory T cells was significantly higher in the tumor margin than in the stroma and tumor core. The density of LAG3- or TIM3-expressing CD8+ T cell and FoxP3- CD4+ helper T cell infiltrates was also higher in the tumor margin. In extrahepatic cholangiocarcinoma, there was a higher density of T cell subsets in the tumor core and regulatory T cells in all regions. A high density of FoxP3- CD4+ helper T cells in the tumor margin showed a trend toward better progression-free survival (PFS) (p=0.092) and significantly better overall survival (OS) (p=0.012). In multivariate analyses, a high density of FoxP3- CD4+ helper T cells in the tumor margin was independently associated with favorable PFS and OS.

Conclusion: The tumor margin is the major site for the active infiltration of T cell subsets with higher levels of LAG3 and TIM3 expression in BTC. The density of tumor margin-infiltrating FoxP3- CD4+ helper T cells may be associated with clinical outcomes in BTC patients treated with gemcitabine plus cisplatin.
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http://dx.doi.org/10.4143/crt.2020.704DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812013PMC
January 2021

Distinct tumor immune microenvironments in primary and metastatic lesions in gastric cancer patients.

Sci Rep 2020 08 31;10(1):14293. Epub 2020 Aug 31.

Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Republic of Korea.

This study compared the tumor immune microenvironments (TIMEs) of primary gastric cancer (PGC) and paired metastatic gastric cancer (MGC). CD4 and CD8 T-cell density and PD-L1 expression were evaluated by multiplex immunohistochemistry, DNA mismatch repair (MMR) by immunohistochemistry, and immune-related genes by RNA sequencing. Twenty-three patients who underwent surgical treatment for PGC and MGC were enrolled in this study. CD8 T-cell, PD-L1 cell, and PD-L1CK cell densities were significantly lower in MGC than PGC. PD-L1 positivity using a combined positive score (≥ 1%) and deficient MMR were observed in 52.2% and 8.7% of PGC samples, respectively, whereas both occurred in only 4.3% of MGC samples. The most frequent TIME types were inflamed (34.8%) and adaptive immune resistance (34.8%) in PGC, and immune desert (65.2%) and immunological ignorance (73.9%) in MGC. In transcriptome analysis, the expression of the T-cell inflamed gene set and co-stimulatory gene module was down-regulated in MGC compared to PGC. The total CD8 T-cell density was an independent prognostic marker in both PGC and MGC (univariate P = 0.002, multivariate P = 0.006). Our result suggest that the TIME of metastatic tumors was less immunologically active compared to that of primary tumors in gastric cancer patients.
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http://dx.doi.org/10.1038/s41598-020-71340-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7459099PMC
August 2020

Turcz. extract attenuates Alzheimer's disease-associated cognitive deficits and vascular dementia-associated neuronal death.

Anat Cell Biol 2020 Jun;53(2):216-227

Department of Anatomy, College of Medicine, Konyang University, Daejeon, Korea.

Dementia is the common neurodegenerative disorder affecting the elderly, with a progressive cognitive decline and memory loss. Since Alzheimer's disease (AD) and vascular dementia (VD) share key pathologies including oxidative damage, oral supplement of phytochemical medicines, which are well-known for their antioxidant properties, can be a viable therapy for both types of dementia. In this study, the therapeutic potential of the extract (AAE), an oriental drug with multiple medicinal properties, was tested on experimental rat models of AD and VD. After confirming the in vitro attenuation of neuronal excitotoxicity by AAE, rats were orally administered with AAE for 7 days and subsequently tested under 2 different experimental paradigms: efficacy screening against #1 AD and #2 VD. For paradigm #1, the rats received intraperitoneal scopolamine and subsequently underwent 3 different behavior tests i.e., the Y-maze, novel object recognition, and passive avoidance tests. For paradigm #2, the rats were operated with the 2-vessel occlusion and hypovolemia (2VO/H) technique, and at postoperative day 7, their hippocampal neuronal viability and the neuroinflammatory changes were quantified. The results showed that the scopolamine-induced impairment of memory performance was significantly improved by AAE intake. Furthermore, while the 2VO/H operation induced marked hippocampal neuronal death and microglial activation, both these effects were significantly attenuated by AAE supplements. Some of the aforementioned effects of AAE intake were dose-dependent. These results provided evidence that AAE supplements can exert anti-AD and -VD efficacies and suggested that AAE might be used as an edible phytotherapeutic for the 2 major types of dementia.
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http://dx.doi.org/10.5115/acb.20.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343560PMC
June 2020

Regorafenib in patients with advanced Child-Pugh B hepatocellular carcinoma: A multicentre retrospective study.

Liver Int 2020 10 9;40(10):2544-2552. Epub 2020 Jul 9.

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

Introduction: Regorafenib is an approved agent in patients with advanced hepatocellular carcinoma (HCC) who progressed on sorafenib, but little is known about its clinical outcomes in Child-Pugh B patients. We aimed to investigate the safety and effectiveness of regorafenib in Child-Pugh B HCC patients.

Methods: This multicentre retrospective study included 59 patients with Child-Pugh B HCC who received regorafenib. Comparative analyses were performed with an independent cohort of Child-Pugh class A patients from the same registry (n = 440).

Results: The median age was 58 years (range, 19-83). All patients had progression on prior sorafenib. Regorafenib was given as 2nd line, and 3rd-4th line systemic therapy in 37 (62.7%) and 22 (37.3%) patients respectively. Compared to Child-Pugh A cohort, grade 3-4 AEs were more common in the Child-Pugh B cohort (27.1% vs 14.1%, P = .017). The median progression-free survival (PFS) and overall survival (OS) were 1.8 and 4.6 months, respectively, and these were significantly poorer than the Child-Pugh A cohort (P = .008 and P < .001 respectively). Child-Pugh B patients with albumin-bilirubin (ALBI) grade 3 had a significantly higher frequency of increased bilirubin (P = .01 for any grade and P = .01 for grade 3-4) and showed significantly poorer OS (P = .021), compared to those with ALBI grade 1 or 2.

Conclusion: Regorafenib's poor clinical outcomes and increased frequency of severe adverse events lead us to discourage its use in the Child-Pugh B population. In particular, regorafenib should not be used in Child-Pugh B patients with ALBI grade 3.
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http://dx.doi.org/10.1111/liv.14573DOI Listing
October 2020

PD-1 blockade-unresponsive human tumor-infiltrating CD8 T cells are marked by loss of CD28 expression and rescued by IL-15.

Cell Mol Immunol 2021 02 24;18(2):385-397. Epub 2020 Apr 24.

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea.

Blockade of programmed death-1 (PD-1) reinvigorates exhausted CD8 T cells, resulting in tumor regression in cancer patients. Recently, reinvigoration of exhausted CD8 T cells following PD-1 blockade was shown to be CD28-dependent in mouse models. Herein, we examined the role of CD28 in anti-PD-1 antibody-induced human T cell reinvigoration using tumor-infiltrating CD8 T cells (CD8 TILs) obtained from non-small-cell lung cancer patients. Single-cell analysis demonstrated a distinct expression pattern of CD28 between mouse and human CD8 TILs. Furthermore, we found that human CD28CD8 but not CD28CD8 TILs responded to PD-1 blockade irrespective of B7/CD28 blockade, indicating that CD28 costimulation in human CD8 TILs is dispensable for PD-1 blockade-induced reinvigoration and that loss of CD28 expression serves as a marker of anti-PD-1 antibody-unresponsive CD8 TILs. Transcriptionally and phenotypically, PD-1 blockade-unresponsive human CD28PD-1CD8 TILs exhibited characteristics of terminally exhausted CD8 T cells with low TCF1 expression. Notably, CD28PD-1CD8 TILs had preserved machinery to respond to IL-15, and IL-15 treatment enhanced the proliferation of CD28PD-1CD8 TILs as well as CD28PD-1CD8 TILs. Taken together, these results show that loss of CD28 expression is a marker of PD-1 blockade-unresponsive human CD8 TILs with a TCF1 signature and provide mechanistic insights into combining IL-15 with anti-PD-1 antibodies.
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http://dx.doi.org/10.1038/s41423-020-0427-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027446PMC
February 2021

Protects PC12 Neuronal Cells from Oxidative Stress Induced by ROS-Mediated Apoptosis.

Evid Based Complement Alternat Med 2020 6;2020:3945194. Epub 2020 Jan 6.

Department of Herbal Crop Research, National Institute of Horticultural & Herbal Science, Eumsung 27709, Republic of Korea.

Reactive oxygen species (ROS), associated with oxidative stress, are involved in many biological processes such as apoptosis, necrosis, and autophagy. Oxidative stress might induce neuronal damage via ROS generation, causing neurodegenerative diseases. (EA) has antioxidant properties and could protect neurons from oxidative stress. In this study, we investigated the protective effect of the aerial parts (EAA) and flowers (EAF) from EA on ROS-mediated apoptosis in pheochromocytoma 12 cells. We quantified 18 types of phenolic compounds using high-performance liquid chromatography. Pretreatment of the cells with EAA and EAF attenuated ROS generation and induced the expression of antioxidant enzymes such as superoxide dismutase 2, catalase, and glutathione peroxidase. In addition, EAF reduced the expression of apoptotic proteins such as Bax/Bcl-xL, caspase-3, and caspase-8 to a greater extent than that with EAA. These results suggested that the protective effect of EAF against oxidative stress-induced apoptosis might be due to the prevention of ROS generation mediated by oxidative enzymes.
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http://dx.doi.org/10.1155/2020/3945194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6970001PMC
January 2020

VEGF-A drives TOX-dependent T cell exhaustion in anti-PD-1-resistant microsatellite stable colorectal cancers.

Sci Immunol 2019 11;4(41)

Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 34141, Republic of Korea.

Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade-resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors.
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http://dx.doi.org/10.1126/sciimmunol.aay0555DOI Listing
November 2019
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