Se Hyun Kim

Role of reactive oxygen species in the induction of apoptosis by alpha-tocopheryl succinate.

α‐Tocopheryl succinate (TOS), a vitamin E analog, is a promising anticancer agent due to its abilities to inhibit proliferation and to induce apoptosis in a variety of human malignant cell lines, while being relatively less active toward normal cells. However, the molecular mechanisms underlying the apoptotic effects of TOS are not precisely understood. Reports that TOS can generate reactive oxygen species (ROS) prompted us to investigate the role of ROS in TOS‐induced apoptosis in cancer cells. We found that the human lung cancer A549 and H460 cell lines were much more sensitive to TOS‐induced apoptosis than the human glioblastoma T98G and U87MG cell lines. Our data suggested that the differential TOS sensitivity was not caused by differences in the uptake and retention of TOS between TOS‐sensitive and –resistant cancer cells. The differential ability of cancer cells to generate ROS in response to TOS appears to be an important factor in determining the susceptibility of cells to TOS‐induced apoptosis. Our results further suggest that TOS‐induced generation of ROS is involved in caspase‐independent apoptosis. Taken together, our findings suggest an important role of ROS generation in TOS‐induced, caspase‐independent apoptosis of cancer cells.

Gastric cancer with initial bone metastasis: A distinct group of diseases with poor prognosis

BACKGROUND Bone metastasis (BM) is reported as a poor prognostic factor in gastric cancer. However, the clinicopathologic characteristics and clinical outcomes of patients with BM compared with patients without BM have not been well described. PATIENTS AND METHODS The medical records of all metastatic or recurrent gastric cancer (MRGC) patients who visited our institution were reviewed. A total of 137 evaluable patients with BM were analysed together with historical control without BM (N=111). RESULTS Of 1342 MRGC patients, 141 (10.5%) had BM. Patients with BM could be divided into initial BM (BM present at initial diagnosis of MRGC; N=90) and late BM (N=47) groups. The median survival after the diagnosis of BM in all patients was 4.4 months (95% confidence interval [CI] 3.69-5.11). However, overall survival after the diagnosis of MRGC was significantly shorter in the initial BM group (5.0 versus 12.2 months, p<0.001). Compared with historical controls, patients with initial BM showed distinct clinicopathologic characteristics. Independent predictors of initial BM were a younger age, signet ring cell histology, primary tumour involving ⩾two-thirds of the stomach, pleural metastasis, thrombocytopenia and elevated alkaline phosphatase. According to a Cox proportional hazard model including both patients with BM and historical controls, initial BM, poor performance status, peritoneal metastasis, hypercalcemia and high carcinoembryonic antigen (CEA) were identified as poor prognostic factors, whereas chemotherapy was identified as a favourable factor (hazard ratio [HR] 0.33, 95% CI 0.22-0.49). CONCLUSION MRGC with initial BM is a distinct group of diseases with specific clinicopathologic characteristics and poor prognosis. Chemotherapy may improve survival in these patients.

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.

Epidemiology and management of primary immune thrombocytopenia: A nationwide population-based study in Korea

INTRODUCTION The epidemiology of immune thrombocytopenia (ITP) is not well characterized in an Asian population. MATERIALS AND METHODS From July 2010 to June 2014, ITP patients were identified using the Korean Health Insurance Review and Assessment Service database. RESULTS The overall incidence rate of ITP was 5.3 per 100,000 person-years (95% CI: 5.1-5.5). The overall incidence rate ratios of children under 15years old to adults and females to males were 3.8 (95% CI: 3.7-3.9) and 1.3 (95% CI: 1.2-1.4), respectively. Of the total 10,814 patients, 3388 patients (31%) needed treatment for ITP; of these, 54% continued treatment for more than three months. First-line therapy consisted of corticosteroids (CS) in 42%, immunoglobulin (IVIg) in 35%, CS with IVIg in 19%, and other immunosuppressive agents (ISA) in 4%. Among treated patients, 75% of adults and 33% of children continued treatment for more than three months. After three months, the most frequently used drug was CS alone in 63% of patients. Only 104 patients underwent splenectomy; of these, 51% received salvage treatment after a median of one month after surgery (range: 0-27). The proportion of patients who received platelet transfusions of 12units or more per month for at least two consecutive months was significantly higher among patients treated for more than three months compared with patients who completed treatment within three months. CONCLUSIONS This population-based study is the first to describe the incidence of ITP and its treatment reality for patients in Korea.

Effects of a DPP4 inhibitor on cisplatin-induced acute kidney injury: study protocol for a randomized controlled trial

BackgroundCisplatin is a potent chemotherapeutic agent, but its nephrotoxicity, which results in acute kidney injury (AKI), often limits its clinical application. Although many studies have attempted to target the mechanism responsible for its nephrotoxicity, no such method has been demonstrated to be effective in clinical trials. Recently, a dipeptidyl peptidase-4 (DPP4) inhibitor has been reported to have a renoprotective effect in a mouse model of cisplatin-induced AKI. Therefore, we will evaluate whether a DPP4 inhibitor protects the kidney from cisplatin-induced injury in humans.Methods/DesignThis is a single-center, prospective, randomized, double-blind, placebo-controlled trial. A total of 182 participants who are scheduled for cisplatin treatment will be enrolled and randomly assigned to receive either a DPP4 inhibitor (gemigliptin) or a placebo. Participants will take the study drugs for 8 days starting 1 day before cisplatin treatment. The primary outcome of interest is the incidence of AKI at 7 days after finishing treatment with cisplatin. The secondary outcomes include changes in serum creatinine levels and estimated glomerular filtration rates from baseline to 7 days after cisplatin treatment.DiscussionThis is the first clinical trial to investigate the effect of a DPP4 inhibitor on cisplatin-induced AKI.Trial registrationClinicalTrials.gov number NCT02250872, December 26, 2014.

Impact of Intratumoral Expression Levels of Fluoropyrimidine-Metabolizing Enzymes on Treatment Outcomes of Adjuvant S-1 Therapy in Gastric Cancer

We analyzed the expression levels of fluoropyrimidine-metabolizing enzymes (thymidylate synthase [TS], dihydropyrimidine dehydrogenase [DPD], thymidine phosphorylase [TP] and orotate phosphoribosyltransferase [OPRT]) to identify potential biomarkers related to treatment outcomes in gastric cancer (GC) patients receiving adjuvant S-1 chemotherapy. In this study, 184 patients who received curative gastrectomy (D2 lymph node dissection) and adjuvant S-1 were included. Immunohistochemistry and quantitative reverse transcription polymerase chain reaction were performed to measure the protein and mRNA levels of TS, DPD, TP, and OPRT in tumor tissue. In univariate analysis, low intratumoral DPD protein expression was related to poorer 5-year disease-free survival (DFS; 78% vs. 88%; P = 0.068). Low intratumoral DPD mRNA expression (1st [lowest] quartile) was also related to poorer DFS (69% vs. 90%; P < 0.001) compared to high intratumoral DPD expression (2nd to 4th quartiles). In multivariate analyses, low intratumoral DPD protein or mRNA expression was related to worse DFS (P < 0.05), irrespective of other clinical variables. TS, TP, and OPRT expression levels were not related to treatment outcomes. Severe non-hematologic toxicities (grade ≥ 3) had a trend towards more frequent development in patients with low intratumoral DPD mRNA expression (29% vs. 16%; P = 0.068). In conclusion, GC patients with high intratumoral DPD expression did not have inferior outcome following adjuvant S-1 therapy compared with those with low DPD expression. Instead, low intratumoral DPD expression was related to poor DFS.

EGFR or HER2 inhibition modulates the tumor microenvironment by suppression of PD-L1 and cytokines release

BACKGROUND Characteristics of tumor microenvironment have been suggested as predictive markers of anti-EGFR or anti-HER2 treatment response. However, the effect of EGFR/HER2 signal blockade on the tumor immune microenvironment is unclear. METHODS EGFR/HER2 pathway signaling and PD-L1 expression in gastric cancer cell lines were screened by western blot analysis. PD-L1 and HER2 expressions in 251 resected gastric tumors were determined by immunohistochemistry, and changes in EFGR, HER2, and PD-L1 expression in paired specimens between pre- and post-chemotherapy were evaluated. PD-L1 expression in HER2-amplified cell lines was evaluated by western blotting, fluorescence-activated cell sorting, reverse transcription, and real-time quantitative PCR analyses before and after afatinib, lapatinib, pictilisib and trametinib treatment. Changes in cytokines were evaluated by reverse transcription, real-time quantitative PCR, and enzyme-linked immunosorbent assay after EGFR/HER2 inhibition. RESULTS Cell lines with pEGFR or pHER2 overexpression showed higher PD-L1 expression. In resected gastric tumors, HER2 expression was significantly associated with PD-L1 expression (p=0.030). PD-L1 overexpression accompanied by increased HER2 expression was identified in a post-chemotherapy specimen from a patient with an initial HER2/PD-L1-negative tumor. In HER2-overexpressing cell lines, PD-L1 expression was decreased in a dose- and time-dependent manner after afatinib and lapatinib treatment. PI3K pathway inhibition by pictilisib, but not MEK pathway inhibition by trametinib, resulted in PD-L1 suppression. After lapatinib treatment, the release of CCL2, CCL21, VEGF and CXCL1 decreased in a dose-dependent manner. CONCLUSIONS Inhibition of the EGFR/HER2 signaling pathway, particularly of downstream PI3K activity, suppressed PD-L1 and release of cytokines, suggesting that EGFR/HER2 inhibition may create a more favorable milieu for tumor immunotherapy.Background Characteristics of tumor microenvironment have been suggested as predictive markers of anti-EGFR or anti-HER2 treatment response. However, the effect of EGFR/HER2 signal blockade on the tumor immune microenvironment is unclear. Methods EGFR/HER2 pathway signaling and PD-L1 expression in gastric cancer cell lines were screened by western blot analysis. PD-L1 and HER2 expressions in 251 resected gastric tumors were determined by immunohistochemistry, and changes in EFGR, HER2, and PD-L1 expression in paired specimens between pre- and post-chemotherapy were evaluated. PD-L1 expression in HER2-amplified cell lines was evaluated by western blotting, fluorescence-activated cell sorting, reverse transcription, and real-time quantitative PCR analyses before and after afatinib, lapatinib, pictilisib and trametinib treatment. Changes in cytokines were evaluated by reverse transcription, real-time quantitative PCR, and enzyme-linked immunosorbent assay after EGFR/HER2 inhibition. Results Cell lines with pEGFR or pHER2 overexpression showed higher PD-L1 expression. In resected gastric tumors, HER2 expression was significantly associated with PD-L1 expression (p=0.030). PD-L1 overexpression accompanied by increased HER2 expression was identified in a post-chemotherapy specimen from a patient with an initial HER2/PD-L1-negative tumor. In HER2-overexpressing cell lines, PD-L1 expression was decreased in a dose- and time-dependent manner after afatinib and lapatinib treatment. PI3K pathway inhibition by pictilisib, but not MEK pathway inhibition by trametinib, resulted in PD-L1 suppression. After lapatinib treatment, the release of CCL2, CCL21, VEGF and CXCL1 decreased in a dose-dependent manner. Conclusions Inhibition of the EGFR/HER2 signaling pathway, particularly of downstream PI3K activity, suppressed PD-L1 and release of cytokines, suggesting that EGFR/HER2 inhibition may create a more favorable milieu for tumor immunotherapy.

A phase II trial of the pan-HER inhibitor poziotinib, in patients with HER2-positive metastatic breast cancer who had received at least two prior HER2-directed regimens: results of the NOV120101-203 trial: pan-HER inhibitor poziotinib for refractory HER2+ MBC patients

Although the introduction of human epidermal growth factor receptor (HER)2‐directed therapy including trastuzumab, pertuzumab, lapatinib and trastuzumab emtansine (T‐DM1) in the treatment of HER2‐positive metastatic breast cancers (mBCs) favorably changed the natural history of this disease, most cases of HER2‐positive mBC will eventually progress. Poziotinib is an oral pan‐HER kinase inhibitor showing potent activity through irreversible inhibition of these kinases. This open‐label, multicenter phase II study was designed to evaluate the efficacy and safety of poziotinib monotherapy in patients with HER2‐positive mBC who had progressed from more than two HER2‐directed therapies. Patients received 12 mg poziotinib once daily on a 14‐day on/7‐day off schedule. Progression‐free survival (PFS) as the primary endpoint, the objective response rate (ORR), overall survival (OS) and safety were evaluated. From April 2015 to February 2016, 106 patients were enrolled in the trial from seven institutes in South Korea. They had a median age of 51 years (range 30–76) and had received a median of four prior therapies including two HER2‐directed therapies for advanced or metastatic cancers. The median follow‐up duration was 12 months. The median PFS was 4.04 months (95% confidence interval [CI], 2.94–4.40 months), and median overall survival has not been reached. The most common treatment‐related adverse events were (total/grade ≥3) diarrhea (96.23%/14.15%), stomatitis (92.45%/12.26%) and rashes (63.21%/3.77%). Poziotinib showed meaningful activity in these heavily treated HER2‐positive mBCs. Diarrhea and stomatitis were the major toxicities. Biomarker studies analyzed are warranted to support further evaluation of this treatment in such cases.

Characteristics and outcomes of ALK+ non‐small cell lung cancer patients in Korea

This study aimed to describe characteristics, treatment patterns and survival among Korean patients diagnosed with locally advanced or metastatic anaplastic lymphoma kinase (ALK)+ non‐small cell lung cancer (NSCLC).

Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer

Purpose Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. Materials and Methods We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. Results Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p<0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p<0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). Conclusion Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.