Sehhoon Park

The in vitro effects of dehydroepiandrosterone on human osteoarthritic chondrocytes

OBJECTIVE To investigate the in vitro effects of dehydroepiandrosterone (DHEA) on human osteoarthritic chondrocytes. DESIGN Chondrocytes isolated from human osteoarthritic knee cartilage were three-dimensionally cultured in alginate beads, except for cell proliferation experiment. Cells were treated with DHEA in the presence or absence of IL-1beta. The effects on chondrocytes were analyzed using a 3-(4,5-dimethylthiazol-2yl)-5-(3-carboxymethoxy-phenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt (MTS) assay (for chondrocyte proliferation), a dimethylmethylene blue (DMB) assay (for glycosaminoglycan (GAG) synthesis), and an indole assay (for DNA amount). Gene expressions of type I and II collagen, metalloproteinase-1 and -3 (MMP-1 and -3), and tissue inhibitor of metalloproteinase-1 (TIMP-1) as well as the IL-1beta-induced gene expressions of MMP-1 and -3 were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). The protein synthesis of MMP-1 and -3 and TIMP-1 was determined by Western blotting. RESULTS The treatment of chondrocytes with DHEA did not affect chondrocyte proliferation or GAG synthesis up to 100 micro M of concentration. The gene expression of type II collagen increased in a dose-dependent manner, while that of type I decreased. DHEA suppressed the expression of MMP-1 significantly at concentrations exceeding 50 micro M. The gene expression of MMP-3 was also suppressed, but this was without statistical significance. The expression of TIMP-1 was significantly increased by DHEA at concentrations exceeding 10 micro M. The effects of DHEA on the gene expressions of MMP-1 and -3 were more prominent in the presence of IL-1beta, in which DHEA suppressed not only MMP-1, but also MMP-3 at the lower concentrations, 10 and 50 micro M, respectively. Western blotting results were in agreement with RT-PCR, which indicates that DHEA acts at the gene transcription level. CONCLUSIONS Our study demonstrates that DHEA has no toxic effect on chondrocytes up to 100 micro M of concentration and has an ability to modulate the imbalance between MMPs and TIMP-1 during OA at the transcription level, which suggest that it has a protective role against articular cartilage loss.

High liver fibrosis index FIB‐4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers

Screening for hepatocellular carcinoma (HCC) is clinically important given that its early detection has remarkable survival benefits. We investigated the possible role of FIB‐4, a recently developed noninvasive marker for liver fibrosis based on routine laboratory tests, as a clinical indicator for predicting future HCC among hepatitis B surface antigen (HBsAg) carriers. Our retrospective cohort study involved 986 Korean HBsAg carriers 40 years of age or older who visited Seoul National University Hospital for a health checkup. National medical service claims data were used to determine HCC incidence. Median follow‐up time was 5.4 years (interquartile range: 4.4 years). Adjusted for age, sex, body mass index, smoking, alcohol, and antiviral medication for hepatitis B, compared to subjects with FIB‐4 <1.25, subjects with 1.7≤ FIB‐4 <2.4 showed an adjusted hazard ratio (aHR) of 4.57 (95% confidence interval [CI]: 1.50‐13.92) and subjects with FIB‐4 ≥2.4 showed an aHR of 21.34 (95% CI: 7.73‐58.92) for HCC incidence. FIB‐4 was shown to have incremental predictive value to ultrasonographic liver cirrhosis for HCC incidence (C‐index: 0.701 vs. 0.831; P = 0.001). FIB‐4 was also better predictive of HCC incidence, compared to that of ultrasonographic liver cirrhosis (C‐index: 0.775 vs. 0.701; P = 0.040). Conclusion: High FIB‐4 is a highly predictive risk factor for HCC incidence among Korean HBsAg carriers. FIB‐4 is a promising, easily applicable, and cost‐effective clinical tool in identifying a subpopulation of HBsAg carriers who are at heightened risk. Our study needs to be replicated in larger future studies on various ethnic groups; nonetheless, our study suggests that FIB‐4 may play a valuable role in HCC screening among HBsAg carriers. (Hepatology 2015;61:1261–1268)

Pretreatment albumin-to-globulin ratio as a predictive marker for tyrosine kinase inhibitor in non-small cell lung cancer

BACKGROUND A low albumin-to-globulin ratio (AGR) has been known as a prognostic factor for cancer-related mortality. However, no study has elucidated its usefulness as a predictive factor in the era of targeted therapy, and so, we evaluated this in the present study. METHODS We retrospectively analyzed 2012 non-small cell lung cancer (NSCLC) patients treated with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). Among these patients, 645 patients who had EGFR mutation and suitable pretreatment laboratory values were included. AGR was calculated 2 months before treatment and 4 months after treatment in each patient. The optimal cutoff value of AGR, and progression free survival (PFS) were also determined. RESULTS The optimal cutoff value of AGR was 1.17, which yielded a highest HR of 1.89 (P< 0.001) for poor PFS. The median PFS was 9.5 months (95% confidential interval [CI] 7.0-10.4) in patients with pretreatment AGR < 1.17 and 13.5 months (95% CI 11.9-14.7) in those with pretreatment AGR ≥ 1.17. Pretreatment AGR showed an independent predictive value (adjusted HR 1.80, P < 0.001) when age, performance status, and pre-TKI systemic treatment was adjusted for. CONCLUSIONS We suggest that patients with NSCLC with EGFR mutations who have AGR values lower than 1.17 at the beginning of EGFR TKI treatment should be considered to have a high risk of early EGFR TKI failure.

Pemetrexed Singlet Versus Nonpemetrexed-Based Platinum Doublet as Second-Line Chemotherapy after First-Line Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitor Failure in Non-small Cell Lung Cancer Patients with EGFR Mutations.

Purpose Platinum-based doublet chemotherapy is the treatment of choice for patients with non-small cell lung cancer (NSCLC); however, the role of a platinum-based doublet as second-line therapy after failure of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) for NSCLC patients has not yet been elucidated. The purpose of this study was to compare the clinical efficacy of pemetrexed versus a platinum-based doublet as second-line therapy after failure of EGFR TKI used as first-line therapy for NSCLC patients with EGFR mutations. Materials and Methods We designed a multicenter retrospective cohort study of 314 NSCLC patients with EGFR mutations who received an EGFR TKI as first-line palliative chemotherapy. Our analysis included 83 patients who failed EGFR TKI therapy and received second-line cytotoxic chemotherapy. Results Forty-six patients were treated using a platinum-based doublet and 37 patients were treated using singlet pemetrexed. The overall response rates of patients receiving a platinum-based doublet and patients receiving pemetrexed were17.4% and 32.4%, respectively (p=0.111). The median progression-free survival (PFS) of patients receiving pemetrexed was significantly longer than that of patients receiving a platinum-based doublet (4.2 months vs. 2.7 months, respectively; p=0.008). The hazard ratio was 0.54 (95% confidence interval, 0.34 to 0.86; p=0.009). Conclusion Our retrospective analysis found that second-line pemetrexed singlet therapy provided significantly prolonged PFS compared to second-line platinum-based doublet chemotherapy for NSCLC patients with EGFR mutations who failed first-line EGFR TKI. Conduct of prospective studies for confirmation of our results is warranted.

Prediction of future hepatocellular carcinoma incidence in moderate to heavy alcohol drinkers with the FIB-4 liver fibrosis index

Although heavy alcoholics are at heightened risk for hepatocellular carcinoma (HCC), there are no guidelines that recommend HCC screening for heavy alcoholics. This study investigated FIB‐4, a noninvasive and easily applicable liver fibrosis index, as a risk factor for HCC incidence among alcohol drinkers without viral hepatitis.

Nutritional status in the era of target therapy: poor nutrition is a prognostic factor in non-small cell lung cancer with activating epidermal growth factor receptor mutations

Background/Aims Pretreatment nutritional status is an important prognostic factor in patients treated with conventional cytotoxic chemotherapy. In the era of target therapies, its value is overlooked and has not been investigated. The aim of our study is to evaluate the value of nutritional status in targeted therapy. Methods A total of 2012 patients with non-small cell lung cancer (NSCLC) were reviewed and 630 patients with activating epidermal growth factor receptor (EGFR) mutation treated with EGFR tyrosine kinase inhibitor (TKI) were enrolled for the final analysis. Anemia, body mass index (BMI), and prognostic nutritional index (PNI) were considered as nutritional factors. Hazard ratio (HR), progression-free survival (PFS) and overall survival (OS) for each group were calculated by Cox proportional analysis. In addition, scores were applied for each category and the sum of scores was used for survival analysis. Results In univariable analysis, anemia (HR, 1.29; p = 0.015), BMI lower than 18.5 (HR, 1.98; p = 0.002), and PNI lower than 45 (HR, 1.57; p < 0.001) were poor prognostic factors for PFS. Among them, BMI and PNI were independent in multi-variable analysis. All of these were also significant prognostic values for OS. The higher the sum of scores, the poorer PFS and OS were observed. Conclusions Pretreatment nutritional status is a prognostic marker in NSCLC patients treated with EGFR TKI. Hence, baseline nutritional status should be more carefully evaluated and adequate nutrition should be supplied to these patients.

Intratumoral heterogeneity characterized by pretreatment PET in non-small cell lung cancer patients predicts progression-free survival on EGFR tyrosine kinase inhibitor

Intratumoral heterogeneity has been suggested to be an important resistance mechanism leading to treatment failure. We hypothesized that radiologic images could be an alternative method for identification of tumor heterogeneity. We tested heterogeneity textural parameters on pretreatment FDG-PET/CT in order to assess the predictive value of target therapy. Recurred or metastatic non-small cell lung cancer (NSCLC) subjects with an activating EGFR mutation treated with either gefitinib or erlotinib were reviewed. An exploratory data set (n = 161) and a validation data set (n = 21) were evaluated, and eight parameters were selected for survival analysis. The optimal cutoff value was determined by the recursive partitioning method, and the predictive value was calculated using Harrell’s C-index. Univariate analysis revealed that all eight parameters showed an increased hazard ratio (HR) for progression-free survival (PFS). The highest HR was 6.41 (P<0.01) with co-occurrence (Co) entropy. Increased risk remained present after adjusting for initial stage, performance status (PS), and metabolic volume (MV) (aHR: 4.86, P<0.01). Textural parameters were found to have an incremental predictive value of early EGFR tyrosine kinase inhibitor (TKI) failure compared to that of the base model of the stage and PS (C-index 0.596 vs. 0.662, P = 0.02, by Co entropy). Heterogeneity textural parameters acquired from pretreatment FDG-PET/CT are highly predictive factors for PFS of EGFR TKI in EGFR-mutated NSCLC patients. These parameters are easily applicable to the identification of a subpopulation at increased risk of early EGFR TKI failure. Correlation to genomic alteration should be determined in future studies.

KRAS G12C mutation as a poor prognostic marker of pemetrexed treatment in non-small cell lung cancer

Background/Aims The predictive and prognostic value of KRAS mutation and its type of mutations in non-small cell lung cancer (NSCLC) are controversial. This clinical study was designed to investigate the predictive value of KRAS mutations and its mutation types to pemetrexed and gemcitabine based treatment. Methods Advanced NSCLC patients tested for KRAS mutation (n = 334) were retrospectively reviewed and 252 patients with wild type epidermal growth factor receptor and no anaplastic lymphoma kinase fusion were enrolled for the analysis. KRAS mutations were observed in 45 subjects with mutation type as followed: G12C (n = 13), G12D (n = 12), G12V (n = 12), other (n = 8). Response rate (RR), progression-free survival (PFS), and overall survival (OS) of pemetrexed singlet and gemcitabine based chemotherapy were analysis. Results Age, sex, performance status were well balanced between subjects with or without KRAS mutations. No difference was observed in RR. Hazard ratio (HR) of PFS for pemetrexed treated subjects with G12C mutation compared to subjects with KRAS wild type was 1.96 (95% confidential interval [CI], 1.01 to 3.79; p = 0.045), but other mutations failed to show clinical significance. By analysis done by PFS, compared to the subjects with transition mutation, HR was 1.48 (95% CI, 0.64 to 3.40; p = 0.360) for subjects with transversion mutation on pemetrexed treatment and 0.41 (95% CI, 0.19 to 0.87; p = 0.020) for subjects treated with gemcitabine based chemotherapy. No difference was observed in OS. Conclusions In this study, different drug sensitivity was observed according to the type of KRAS mutation. NSCLC subpopulations with different KRAS mutation type should be considered as different subgroups and optimal chemotherapy regimens should be searched in further confirmative studies.

Mild form of Guillain-Barré syndrome in a patient with primary Epstein-Barr virus infection.

pISSN 1226-3303 eISSN 2005-6648 http://www.kjim.org Copyright

Early repolarization is associated with significant coronary artery stenosis in asymptomatic adults

The aim of our study was to investigate the relationship between early repolarization (ERP) and coronary heart disease (CHD) by evaluating its association with coronary artery stenosis and plaques. Consecutive asymptomatic adults aged 30 or more without CHD were investigated (n = 3100). Adjusting for major cardiovascular risk factors, ERP was significantly associated with significant coronary stenosis with incremental predictive value (aOR 1.71, 95% CI 1.13-2.60; ROC AUC 0.763 vs. 0.723, P < 0.001; NRI 4.86%, P = 0.042; IDI 0.0030, P = 0.040), specifically in intermediate risk group (aOR 2.33, 95% CI 1.29-4.20; ROC AUC 0.753 vs. 0.708, P = 0.001). ERP was shown to be especially associated with significant coronary stenosis with non-calcified plaque (aOR 2.26, 95% CI 1.28-3.98). Our study is the first to directly show the association of ERP with CHD. Future studies are needed to replicate our results and investigate whether it would be beneficial to include ERP in risk algorithms for CHD screening.