Publications by authors named "Jun Ho Ji"

49 Publications

Relationship between heavy metal exposure and type 2 diabetes: a large-scale retrospective cohort study using occupational health examinations.

BMJ Open 2021 Mar 4;11(3):e039541. Epub 2021 Mar 4.

Internal Medicine, Dong-A University Medical Center, Busan, The Republic of Korea

Objectives: To investigate the associations between heavy metal exposure and serum ferritin levels, physical measurements and type 2 diabetes mellitus (DM).

Design: A retrospective cohort study.

Setting: Changwon, the location of this study, is a Korean representative industrial city. Data were obtained from medical check-ups between 2002 and 2018.

Participants: A total of 34 814 male subjects were included. Of them, 1035 subjects with lead exposure, 200 subjects with cadmium exposure and the 33 579 remaining were assigned to cohort A, cohort B and the control cohort, respectively. Data including personal history of alcohol and smoking, age, height, weight, the follow-up duration, haemoglobin A1c (HbA1c), fasting blood sugar (FBS), ferritin levels, and lead and cadmium levels within 1 year after exposure were collected.

Primary Outcome Measure: In subjects without diabetes, changes in FBS and HbA1c were analysed through repeated tests at intervals of 1 year or longer after the occupational exposure to heavy metals.

Results: In Cohort A, DM was diagnosed in 33 subjects. There was a significant difference in lead concentrations between the subjects diagnosed with DM and those without DM during the follow-up period (3.94±2.92 mg/dL vs 2.81±2.03 mg/dL, p=0.002). Simple exposure to heavy metals (lead and cadmium) was not associated with DM in Cox regression models (lead exposure (HR) 1.01, 95% CI: 0.58 to 1.77, p 0.971; cadmium exposure HR 1.48, 95% CI: 0.61 to 3.55, p=0.385). Annual changes in FBS according to lead concentration at the beginning of exposure showed a positive correlation (r=0.072, p=0.032).

Conclusion: Our findings demonstrated that simple occupational exposure to heavy metals lead and cadmium was not associated with the incidence of DM. However, lead concentrations at the beginning of the exposure might be an indicator of DM and glucose elevations.
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http://dx.doi.org/10.1136/bmjopen-2020-039541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7934714PMC
March 2021

Durvalumab, with or without tremelimumab, plus platinum-etoposide versus platinum-etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial.

Lancet Oncol 2021 01 4;22(1):51-65. Epub 2020 Dec 4.

Department of Medical Oncology, Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain. Electronic address:

Background: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone.

Methods: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872.

Findings: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]).

Interpretation: First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S1470-2045(20)30539-8DOI Listing
January 2021

rhEGF Treatment Improves EGFR Inhibitor-Induced Skin Barrier and Immune Defects.

Cancers (Basel) 2020 Oct 25;12(11). Epub 2020 Oct 25.

Department of Pathology, Dong-A University College of Medicine, Busan 49201, Korea.

The mechanisms of epidermal growth factor (EGF) affecting EGF receptor inhibitor (EGFRI)-related skin toxicities are as yet unknown. We investigated which mechanisms are involved in EGF's positive effects. Two types of EGFRIs, cetuximab and gefitinib, were used to treat the cells or 3d-cultured human skin tissue with recombinant human EGF (rhEGF). As a result, rhEGF increased EGFR and pEGFR expression. Furthermore, rhEGF induces EGFR signaling by pAKT and pPI3K expression in gefitinib and rhEGF co-treated cells. In addition, rhEGF bound to EGFR after than cetuximab, but cetuximab bound to EGFR more strongly than rhEGF. Moreover, expressions of proliferation and differentiation proteins, both ki-67 and filaggrin, were decreased in EGFRI-treated tissue. However, in rhEGF and EGFRI co-treated tissue, those expressions were increased. Expression of IL-1α, IL-8, and TNF-α was increased by EGFRIs and down-regulated by rhEGF. Furthermore, hBD-2 and hBD-3 protein expressions were inhibited by cetuximab or gefitinib treatment, and those decrements were increased by rhEGF treatment. In patients' tissue evaluation, compared with controls, patients' Ki-67 and EGFR expression were decreased ( = 0.015, = 0.001). Patients' IL-17 and TNF-α expression intensity was higher than that of the control group ( = 0.038, = 0.037). After treatment with EGF ointment, average values of Ki-67, EGFR, and Melan-A were changed to normal values. Oppositely, patients' proportions of IL-17 and TNF-α were decreased to low stain level. In conclusion, treatment of rhEGF improved EGFRI-induced skin eruption via normalizing the proliferation and differentiation of keratinocytes, reducing inflammatory cytokines by the affected EGFRIs.
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http://dx.doi.org/10.3390/cancers12113120DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692663PMC
October 2020

Patient-reported outcomes with first-line durvalumab plus platinum-etoposide versus platinum-etoposide in extensive-stage small-cell lung cancer (CASPIAN): a randomized, controlled, open-label, phase III study.

Lung Cancer 2020 11 10;149:46-52. Epub 2020 Sep 10.

Hospital Universitario 12 de Octubre, H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain.

Objectives: In the phase III CASPIAN study, first-line durvalumab plus etoposide in combination with either cisplatin or carboplatin (EP) significantly improved overall survival (primary endpoint) versus EP alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) at the interim analysis. Here we report patient-reported outcomes (PROs).

Materials And Methods: Treatment-naïve patients with ES-SCLC received 4 cycles of durvalumab plus EP every 3 weeks followed by maintenance durvalumab every 4 weeks until progression, or up to 6 cycles of EP every 3 weeks. PROs, assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) version 3 and its lung cancer module, the Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13), were prespecified secondary endpoints. Changes from baseline to disease progression or 12 months in prespecified key disease-related symptoms (cough, dyspnea, chest pain, fatigue, appetite loss) were analyzed with a mixed model for repeated measures. Time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization was analyzed.

Results: In the durvalumab plus EP and EP arms, 261 and 260 patients were PRO-evaluable. Patients in both arms experienced numerically reduced symptom burden over 12 months or until progression for key symptoms. For the improvements from baseline in appetite loss, the between-arm difference was statistically significant, favoring durvalumab plus EP (difference, -4.5; 99% CI: -9.04, -0.04; nominal p = 0.009). Patients experienced longer TTD with durvalumab plus EP versus EP for all symptoms (hazard ratio [95% CI] for key symptoms: cough 0.78 [0.600‒1.026]; dyspnea 0.79 [0.625‒1.006]; chest pain 0.76 [0.575‒0.996]; fatigue 0.82 [0.653‒1.027]; appetite loss 0.70 [0.542‒0.899]), functioning, and global health status/QoL.

Conclusion: Addition of durvalumab to first-line EP maintained QoL and delayed worsening of patient-reported symptoms, functioning, and global health status/QoL compared with EP.
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http://dx.doi.org/10.1016/j.lungcan.2020.09.003DOI Listing
November 2020

Phase II study of R-CVP followed by rituximab maintenance therapy for patients with advanced marginal zone lymphoma: consortium for improving survival of lymphoma (CISL) study.

Cancer Commun (Lond) 2019 10 16;39(1):58. Epub 2019 Oct 16.

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

Background: The response rate and survival improvement for rituximab, a CD20-targeting monoclonal antibody, have been demonstrated in marginal zone lymphoma (MZL) as monotherapy and in combination with chemotherapeutic regimens, yet relapses still occur despite treatment completion. Thus, extending the period of remission in MZL patients remains an essential goal. This multicenter, single-arm, open-label phase II study evaluated the survival efficacy of 2 years of rituximab-maintenance therapy in patients with stage III-IV CD20-positive MZL who had responded to first-line R-CVP (rituximab, cyclophosphamide, vincristine, and prednisolone). The objective of this study was to determine whether rituximab maintenance following R-CVP warrants further investigation.

Methods: Prior to rituximab-maintenance therapy, patients received 6-8 cycles of first-line R-CVP therapy for stage III-IV MZL. Rituximab (375 mg/m), cyclophosphamide (750 mg/m), and vincristine (1.4 mg/m; maximum 2 mg) were administered via an intravenous infusion on day 1 of each 3-week cycle, while oral prednisolone (100 mg) was given on days 1-5 of each 3-week cycle. The patients who achieved complete response (CR), partial response (PR), or stable disease (SD) to R-CVP treatment, were prescribed rituximab-maintenance therapy which was administered intravenously at a dose of 375 mg/m every 8 weeks for up to 12 cycles. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS) and treatment safety.

Results: 47 patients were enrolled, of whom, 45 (96%) received rituximab-maintenance treatment. Fifteen (33%) patients had nodal MZL. Following R-CVP first-line therapy, 20 (44%), 22 (49%), and 3 (7%) patients achieved CR, PR, and SD, respectively. After a median follow-up of 38.2 months, their observed 3-year PFS rate was 81%. During the rituximab-maintenance, 6 PR and 1 SD patients achieved CR following the administration of R-CVP. Elevated LDH and the presence of B symptoms were found to be significant prognostic factors for PFS (P = 0.003) and demonstrated a 3-year OS rate of 90%. Rituximab-maintenance therapy was well tolerated, and the common treatment-emergent adverse events were sensory neuropathy (18%), myalgia (13%), fatigue (9%), and neutropenia (9%).

Conclusion: Rituximab-maintenance therapy following first-line R-CVP demonstrated good PFS in patients with stage III-IV MZL, in addition to a favorable toxicity profile. Trial registration clinicaltrials.gov: NCT01213095.
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http://dx.doi.org/10.1186/s40880-019-0403-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6796378PMC
October 2019

Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial.

Lancet 2019 11 4;394(10212):1929-1939. Epub 2019 Oct 4.

David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

Background: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC.

Methods: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing.

Findings: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.

Interpretation: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received.

Funding: AstraZeneca.
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http://dx.doi.org/10.1016/S0140-6736(19)32222-6DOI Listing
November 2019

A Randomized Controlled Trial of Epidermal Growth Factor Ointment for Treating Epidermal Growth Factor Receptor Inhibitor-Induced Skin Toxicities.

Oncologist 2020 01 6;25(1):e186-e193. Epub 2019 Sep 6.

Department of Internal Medicine, Gyeongsang National University Hospital, Jinju, Republic of Korea.

Background: The efficacy of epidermal growth factor (EGF) receptor (EGFR) inhibitors in patients with non-small cell lung cancer (NSCLC), pancreatic cancer (PC), or colorectal cancer (CRC) has been demonstrated. However, dermatological reactions to these inhibitors can cause significant physical and psychosocial discomfort. The objective of the present study was to evaluate the efficacy of EGF ointment for EGFR inhibitor-related skin adverse events (ERSEs).

Materials And Methods: This placebo-controlled, double-blind, multicenter, pilot phase III trial enrolled patients with NSCLC, PC, or CRC treated with EGFR inhibitors. Patients with grade ≥2 ERSEs were included. Patients were randomized to three treatment arms: arm 1, placebo; arm 2, 1 ppm of EGF ointment; and arm 3, 20 ppm of EGF ointment. Patients applied ointment to their skin lesions twice daily.

Results: Efficacy evaluation was available for 80 patients (9 for PC, 28 for NSCLC, and 43 for CRC). Responses were 44.4% in arm 1, 61.5% in arm 2, and 77.8% in arm 3. There was a linear correlation between EGF concentrations and responses (p = .012). Quality of life (QoL) was assessed for 74 patients. Maximum changes in composite scores by Skindex-16 after treatment were significantly different among arms (mean ± SD: -5.2 ± 8.6 for arm 1, -11.7 ± 14.2 for arm 2, and - 18.6 ± 17.7 for arm 3; p = .008). EGF arms showed significant improvement in emotions (p = .005) and functioning (p = .044) scores over the placebo arm.

Conclusion: EGF ointment is effective for managing ERSEs. It can also improve patients' QoL compared with placebo. Clinical trial identification number. NCT02284139 IMPLICATIONS FOR PRACTICE: Patients with non-small cell lung cancer, pancreatic cancer, or colorectal cancer who are treated with epidermal growth factor (EGF) receptor (EGFR) inhibitors may experience dermatologic reactions to their treatment. This study investigated the benefit of an EGF ointment in the treatment of these adverse events and observed the ointment to be effective in managing EGFR inhibitor-related skin adverse events.
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http://dx.doi.org/10.1634/theoncologist.2019-0221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6964120PMC
January 2020

Tumor Genomic Profiling Guides Patients with Metastatic Gastric Cancer to Targeted Treatment: The VIKTORY Umbrella Trial.

Cancer Discov 2019 10 17;9(10):1388-1405. Epub 2019 Jul 17.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups ( aberration, mutation, mutation/amplification, amplification, MET overexpression, all negative, deficient, or amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high copy number by ctDNA and response to savolitinib. SIGNIFICANCE: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility..
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http://dx.doi.org/10.1158/2159-8290.CD-19-0442DOI Listing
October 2019

Sedation for terminally ill cancer patients: A multicenter retrospective cohort study in South Korea.

Medicine (Baltimore) 2019 Feb;98(5):e14278

Department of Internal Medicine, Gyeongsang National University Hospital, Jinju.

Sedation therapy is a potential solution to providing relief from refractory symptoms at end of life. The aim of this study was to investigate actual sedation practice and physician characteristics associated with the use of sedation for terminally ill cancer patients in South Korea.A retrospective review was conducted on consecutive patients who had died from cancer at seven tertiary medical centers between January 2010 and October 2015. The use of sedation was defined as the administration of sedative agents to relieve intolerable symptoms within the last 2 weeks preceding death. Patients and physician characteristics and information on the use of sedation were collected.A total of 8309 patients were included in the study. Sedatives were administered in 1334 patients (16.1%) for the following indications: delirium in 39.3%, intractable pain in 23.1%, and dyspnea in 21.9%. Median duration of sedation from initiation to death was 3 days. The use of sedation depended on physician specialty and experience. Family physicians used sedation most often (57.6%), followed by medical oncologists (13.9%), other internists (10.7%), and surgical oncologists (9.4%). The use of sedation was highest for physicians with >5 to 10 years practice experience (22.1%) and lowest for those in practice for 5 years or less (10.2%). The proportion of patients receiving sedation also varied markedly across participating institutions (range, 7.0%-49.7%).This large cohort study provides insight into sedation practice for terminally ill cancer patients in South Korea. Our study shows that the use of sedation depends on physician background and institution. A nation-wide guidelines and continued education on end-of-life sedation are required in South Korea.
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http://dx.doi.org/10.1097/MD.0000000000014278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6380862PMC
February 2019

Efficacy and safety of compound tri-metal stent placement for malignant perihilar biliary obstruction.

Niger J Clin Pract 2018 Sep;21(9):1121-1126

Division of Hematology and Medical Oncology, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea.

Background: Despite many attempts to improve the patency rate of biliary stents in patients with inoperable perihilar cholangiocarcinomas, the longevity of these stents has not been satisfactory. The purpose of the present study is to report technical outcomes and clinical efficacy of the placement of compound tri-metal stent in patients with malignant perihilar biliary obstruction.

Materials And Methods: Retrospective analysis was performed of the medical records of 26 consecutive patients with inoperable malignant perihilar biliary obstruction who underwent compound tri-metal stent placement through a percutaneous transhepatic biliary drainage tube from January 2012 to April 2017.

Results: Placement of the compound tri-metal stent was successfully completed in all 26 patients (technical success, 100%). There was neither procedure-related mortality nor 30-day mortality. None of these patients underwent additional metallic stent placement within 60 days secondary to recurrent cholangitis or stent occlusion. Successful drainage was achieved in 25 (96.2%) of 26 patients who received a compound tri-metal stent. Patients treated with compound tri-metal stent placement had a median stent patency of 145 days (range, 24-426 weeks) and a median survival time of 188 days (range, 37-1732 days).

Conclusions: Placement of compound tri-metal stent in patients with malignant perihilar biliary obstruction may offer a safe and effective alternate technique to improve biliary drainage and stent patency.
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http://dx.doi.org/10.4103/njcp.njcp_290_17DOI Listing
September 2018

Chemotherapy versus Best Supportive Care in Advanced Biliary Tract Carcinoma: A Multi-institutional Propensity Score Matching Analysis.

Cancer Res Treat 2018 Jul 23;50(3):791-800. Epub 2017 Aug 23.

Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.

Purpose: Although chemotherapy is recommended by various guidelines for advanced biliary tract cancer (BTC), the evidence supporting its use over best supportive care (BSC) is limited. The aim of this study was to investigate the survival benefit of chemotherapy over that of BSC in advanced BTC patients.

Materials And Methods: Advanced BTC patientswith a good performance status (Eastern CooperativeOncologyGroup [ECOG] 0-2) were eligible for the study. Data were retrospectively collected from four tertiary cancer centers and analyzed using propensity score matching (PSM). Of the 604 patients enrolled, 206 received BSC and 398 received chemotherapy. PSM analysis was performed using the following variables: age, ECOG status, carcinoembryonic antigen (CEA) level, white blood cell level, albumin level, total bilirubin level, and aspartate aminotransferase level. The sample size of each group was 164 patients after PSM. Median survival was compared between the two groups by using the Kaplan-Meier method, and prognostic factors were investigated using Cox proportional regression analysis.

Results: In post-PSM analysis, the respective median survival for the chemotherapy and BSC groups was dependent on the following prognostic factors: total population, 12.0 months vs. 7.5 months (p=0.001); locally advanced disease, 16.7 months vs. 13.4 months (p=0.490); cancer antigen 19-9 ≤ 100 IU/mL, 12.7 months vs. 10.6 months (p=0.330); and CEA ≤ 3.4 ng/mL, 17.1 months vs. 10.6 months (p=0.052).

Conclusion: Chemotherapy improved overall survival of patients with advanced BTC who had a good performance status. However, this survival benefit was not observed in BTC patients with locally advanced disease or with lower tumor marker. Individualized approach is needed for initiation of palliative chemotherapy in advanced BTC.
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http://dx.doi.org/10.4143/crt.2017.044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6056980PMC
July 2018

Antiemetic Corticosteroid Rotation from Dexamethasone to Methylprednisolone to Prevent Dexamethasone-Induced Hiccup in Cancer Patients Treated with Chemotherapy: A Randomized, Single-Blind, Crossover Phase III Trial.

Oncologist 2017 11 7;22(11):1354-1361. Epub 2017 Jul 7.

Division of Hematology/Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Republic of Korea

Background: To assess whether the rotation of dexamethasone to methylprednisolone decreases the intensity of dexamethasone-induced hiccup (DIH) in cancer patients treated with chemotherapy.

Materials And Methods: Adult patients who experienced DIH within 3 days after the administration of dexamethasone as an antiemetic were screened. Eligible patients were randomly assigned to receive dexamethasone ( = 33) or methylprednisolone ( = 32) as an antiemetic (randomization phase). In the next cycle of chemotherapy, the dexamethasone group received methylprednisolone and vice versa in the methylprednisolone group (crossover phase). The primary endpoint was the difference in hiccup intensity as measured using the numeric rating scale (NRS) between two groups.

Results: No female patients were enrolled, although the study did not exclude them. At the randomization phase, hiccup frequency was 28/33 (84.8%) in the dexamethasone group versus 20/32 (62.5%) in the methylprednisolone group ( = .04). Intensity of hiccup was significantly higher in the dexamethasone group than that in the methylprednisolone group (mean NRS, 3.5 vs. 1.4,  < .001). At the crossover phase, hiccup intensity was further decreased after the rotation of dexamethasone to methylprednisolone in the dexamethasone group (mean NRS, 3.5 to 0.9,  < .001), while it was increased by rotating methylprednisolone to dexamethasone in the methylprednisolone group (mean NRS, 1.4 to 3.3,  = .025). There were no differences in emesis intensity between the two groups at either the randomization or crossover phases. Clinicaltrials.gov identifier: NCT01974024.

Conclusion: Dexamethasone-induced hiccup is a male-predominant phenomenon that can be ameliorated by rotating dexamethasone to methylprednisolone without compromising the antiemetic efficacy.

Implications For Practice: In this randomized, multicenter, phase III trial, hiccup intensity was significantly lower when the antiemetic corticosteroid was rotated from dexamethasone to methylprednisolone without a change in emesis intensity than that when dexamethasone was maintained. At the crossover phase, hiccup intensity was increased again if dexamethasone was readministered instead of methylprednisolone. The present study demonstrated that dexamethasone-induced hiccup can be improved by rotating from dexamethasone to methylprednisolone without compromising its antiemetic efficacy.
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http://dx.doi.org/10.1634/theoncologist.2017-0129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5679820PMC
November 2017

A multi-center, open-label, randomized phase III trial of first-line chemotherapy with capecitabine monotherapy versus capecitabine plus oxaliplatin in elderly patients with advanced gastric cancer.

J Geriatr Oncol 2017 May 21;8(3):170-175. Epub 2017 Jan 21.

Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Objectives: More than half of cases of gastric cancer (GC) are diagnosed in elderly patients (≥70years). While doublet combination with fluoropyrimidines and platinum is currently considered standard first-line chemotherapy in advanced GC, the main goal of chemotherapy remains palliation.

Materials And Methods: In a multi-center phase III trial, patients with chemotherapy-naïve, metastatic GC, aged 70years or older were randomized 1:1 to receive X monotherapy (capecitabine 1000mg/m bid po on days one to fourteen) or XELOX (X plus oxaliplatin 110mg/m iv on D1). Treatment was repeated every 21days until disease progression, unacceptable toxicity, or withdrawal. Primary endpoint was overall survival (OS).

Results: In total, 50 patients with a median age of 77 (range, 70 to 84) were enrolled (X, n=26; XELOX, n=24). No treatment-related serious adverse events or unexpected toxicities were observed. The most frequently observed toxicities were nausea and hand-foot syndrome, with fatigue and peripheral neuropathy more common in XELOX than in X patients. Median OS was 11.1months for XELOX arm and 6.3months for X arm (HR 0.58, 95% CI 0.30-1.12, P=0.108). Although the difference was not significant, on the basis of evidence of superiority of XELOX seen in the first interim analysis, an independent data monitoring committee recommended early stopping of the trial. PFS was significantly longer (HR 0.32, 95% CI 0.17-0.61, P<0.001) with XELOX (7.1months) than with X (2.6months).

Conclusion: Platinum-based combination chemotherapy was associated with survival benefit, as compared with X monotherapy in elderly patients with GC.
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http://dx.doi.org/10.1016/j.jgo.2017.01.002DOI Listing
May 2017

Successful treatment of steroid-refractory immune thrombocytopenia with alemtuzumab.

Blood Res 2016 Dec 23;51(4):297-299. Epub 2016 Dec 23.

Division of Hematology-Oncology, Department of Medicine, Samsung Changwon Hospital, Sungkyunkwan University of School of Medicine, Seoul, Korea.

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http://dx.doi.org/10.5045/br.2016.51.4.297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5234246PMC
December 2016

The role of adjuvant therapy after R0 resection for patients with intrahepatic and perihilar cholangiocarcinomas.

Cancer Chemother Pharmacol 2017 Jan 7;79(1):99-106. Epub 2016 Dec 7.

Division of Hematology/Oncology, Department of Internal Medicine, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, Republic of Korea.

Purpose: There is still debated regarding the optimal treatment strategy for cholangiocarcinoma (CC) after curative resection. The aim of this study was to analyze the role of adjuvant therapy in R0-resected intrahepatic and perihilar CCs.

Methods: We retrospectively reviewed the patients who underwent R0 resection for intrahepatic and perihilar CCs between January 2001 and December 2013 at six tertiary medical centers; adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of our study were recurrence-free survival (RFS) and overall survival (OS).

Results: We included a total of 137 consecutive patients in the analysis; 58.4% of them had intrahepatic CCs, and 25.5% had lymph node (LN) involvement. Seventy-three patients (53.3%) had received adjuvant therapy (CT, CRT, RT: 48, 13, 12, respectively), and most patients who had received adjuvant therapy had stage III or IVA, T3 or 4 tumors, and positive LNs. Multivariable analysis identified positive LN [hazard ratio (HR) 3.47; P < 0.001] and high baseline CA 19-9 level (HR 1.82; P = 0.027) as predictors of decreased OS. The effects of adjuvant therapy varied according to the treatment modality; adjuvant CRT showed significantly longer RFS than surgery only (HR 0.44; P = 0.036), with a nonsignificant trend for better OS (HR 0.46; P = 0.115).

Conclusions: Adjuvant CT and RT were not associated with a survival advantage in R0-resected intrahepatic and perihilar CCs. CRT appears to be appropriate treatment after complete resection.
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http://dx.doi.org/10.1007/s00280-016-3206-4DOI Listing
January 2017

Is There a Role for Adjuvant Therapy in R0 Resected Gallbladder Cancer?: A Propensity Score-Matched Analysis.

Cancer Res Treat 2016 Oct 12;48(4):1274-1285. Epub 2016 Feb 12.

Division of Hematology/Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea.

Purpose: The purpose of this study is to assess the role of adjuvant therapy in stage I-III gallbladder cancer (GBC) patients who have undergone R0 resection.

Materials And Methods: Clinical data were collected on 441 consecutive patients who underwent R0 resection for stage I-III GBC. Eligible patients were classified into adjuvant therapy and surveillance only groups. Propensity score matching (PSM) between the two groups was performed, adjusting clinical factors.

Results: In total, 84 and 279 patients treated with adjuvant therapy and followed up with surveillance only, respectively, were included in the analysis. Before PSM, the 5-year relapse-free survival (RFS) rate was lower in the adjuvant therapy group than in the surveillance only group (50.8% vs. 74.8%, p < 0.001), although there was no statistically significant difference in the 5-year overall survival (OS) rate (66.2% vs. 79.5%, p=0.089). After the PSM, baseline characteristics became comparable and there were no differences in the 5-year RFS (50.8% vs. 64.8%, p=0.319) and OS (66.2% vs. 70.4%, p=0.703) rates between the two groups.

Conclusion: The results suggest that fluoropyrimidine-based adjuvant therapy is not indicated in stage I-III GBC patients who have undergone R0 resection.
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http://dx.doi.org/10.4143/crt.2015.502DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5080804PMC
October 2016

Factors Influencing Clinicians' Choice of Adjuvant S-1 versus Capecitabine plus Oxaliplatin after Curative Gastrectomy in Patients with Gastric Cancer.

J Cancer 2016 27;7(12):1711-1715. Epub 2016 Jul 27.

Department of Surgery, Chung-Ang University College of Medicine, Seoul, South Korea.

Two recent randomized, phase III trials in Asia (ACTS-GC and CLASSIC) documented the survival benefit of postoperative chemotherapy after D2 lymph node dissection in patients with gastric cancer. We sought to determine what factors influenced clinicians' choices of either S-1 or capecitabine plus oxaliplatin (CAPOX) as adjuvant therapy after curative D2 gastrectomy. We retrospectively reviewed the clinicopathologic factors and adjuvant treatments for 435 patients from nine centers in Korea who were treated with either S-1 or CAPOX adjuvant chemotherapy after undergoing curative D2 gastrectomy between January 2013 and July 2014. Of the 435 patients, 204 (46.9%) were treated with S-1 and 231 (53.1%) were treated with CAPOX. The median age at diagnosis was 61 years (range, 30-88). CAPOX was prescribed more often for patients who were 65 years of age or younger than for patients who were age 65 or older (77.1% vs. 22.9%, P<0.0001). Of the patients in stage II, 121 (60.8%) were treated with S-1 and 78 (39.2%) were given CAPOX; however, of those in stage III, 83 (35.2%) received S-1 and 153 (64.8%) were treated with CAPOX (P<0.0001). Clinicians only preferred CAPOX for younger patients with stage III gastric cancer after curative D2 gastrectomy. However, for elderly patients, clinicians more chose S-1 regardless of the stage.
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http://dx.doi.org/10.7150/jca.15598DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5039392PMC
July 2016

Intrinsic resistance to sunitinib in patients with metastatic renal cell carcinoma.

Asia Pac J Clin Oncol 2017 Feb 31;13(1):61-67. Epub 2016 Mar 31.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Aim: Although targeting angiogenesis with vascular endothelial growth factor receptor (VEGFR) inhibitors has demonstrated efficacy in the treatment of renal cell carcinoma, primary, intrinsic resistance to the VEGFR inhibitor sunitinib is not fully understood in a subset of metastatic RCC (mRCC) patients.

Methods: Between 2008 and 2012, a total of 134 patients with mRCC were treated with first-line sunitinib at one of six tertiary centers. Patients in whom progressive disease was the best response were classified as the intrinsic resistance group. Univariate and multivariate analyses were performed on the recognized baseline parameters.

Results: Among 134 patients, 33 (25%) intrinsically resistant to sunitinib were identified. Multivariate logistic regression analyses revealed that the number of metastatic sites (OR = 3.6) and neutrophilia (OR = 7.4) were independently associated with development of intrinsic resistance. There were significant differences with regard to overall survival (P = 0.001) and progression-free survival (P < 0.0001) between the patients with and without intrinsic resistance.

Conclusions: Intrinsic resistance to first-line sunitinib treatment is associated with a dismal prognosis in mRCC patients. Patients with known high-risk factors (poor performance, neutrophilia, elevated lactate dehydrogenase) and multiple metastatic sites including the liver may experience a limited benefit from sunitinib. Greater understanding of the underlying mechanism and molecular biomarkers for detecting intrinsically resistant disease is needed.
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http://dx.doi.org/10.1111/ajco.12465DOI Listing
February 2017

Role of adjuvant therapy after R0 resection for patients with distal cholangiocarcinoma.

Cancer Chemother Pharmacol 2016 05 26;77(5):979-85. Epub 2016 Mar 26.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: The optimal treatment strategy for cholangiocarcinoma (CC) after curative resection remains controversial. The aim of this study was to analyze the role of adjuvant therapy in R0-resected distal CC.

Methods: We retrospectively reviewed the medical records of patients who underwent R0 resection for distal CC at six cancer centers in Korea. Adjuvant therapy consisted of chemotherapy (CT), chemoradiotherapy (CRT), or radiotherapy (RT). The outcomes of the study were overall survival (OS) and recurrence-free survival (RFS).

Results: A total of 158 patients were included in the analysis; 47 patients (29.7 %) had lymph node involvement. Fifty-six patients (35.4 %) received adjuvant therapy (CT/CRT/RT: 27/20/9, respectively). Patients with advanced TNM stage (P < 0.001), T3/T4 disease (P = 0.009), positive lymph nodes (LN; P = 0.052), and elevated baseline carbohydrate antigen 19-9 (P = 0.071) were more likely to receive adjuvant therapy. The effect of adjuvant therapy varied according to treatment modality. A multivariable analysis showed a significant improvement in OS after CT [hazard ratio (HR) 0.21, 95 % confidence interval (CI) 0.08-0.53, P = 0.001] and CRT (HR 0.25, 95 % CI 0.08-0.83, P = 0.024). However, RT alone was associated with shorter OS (HR 2.38, P = 0.040), along with T3/T4 disease (HR 2.12, P = 0.012) and positive LN (HR 2.30, P = 0.008). RFS benefited from adjuvant treatment with CT (HR 0.34, P = 0.002) and CRT (HR 0.33, P = 0.004), but not with RT alone (HR 1.42, P = 0.361). In the subset analysis according to LN status, adjuvant therapy not including RT alone was associated with a significant OS and RFS advantage in both LN-negative and LN-positive patients.

Conclusions: Our results show that patients receiving CT or CRT had significant improvements in OS and RFS. In addition, a benefit of adjuvant therapy (except RT alone) was observed even in LN-negative patients.
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http://dx.doi.org/10.1007/s00280-016-3014-xDOI Listing
May 2016

Treatment outcomes and clinical relevance of the Follicular Lymphoma International Prognostic Index in Korean follicular lymphoma patients treated with chemotherapy.

Korean J Intern Med 2016 May 22;31(3):560-9. Epub 2016 Feb 22.

Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Background/aims: The Follicular Lymphoma International Prognostic Index (FLIPI) and FLIPI2 are well-known prognostic models for patients with follicular lymphoma (FL). However, their prognostic relevance has not been examined before in Korean patients with FL.

Methods: We reviewed clinical and laboratory information from our database of patients between 1995 and 2012. In total, 125 patients were stratified in three categories according to FLIPI or FLIPI2 scores: low-, intermediate-, and high-risk groups. We compared FLIPI and FLIPI2 in terms of progression-free survival (PFS) and overall survival (OS).

Results: Among the 125 patients, the prognostic value of FLIPI and FLIPI2 was evaluated in 73 patients who fulfilled the criteria of both prognostic models. Risk stratification by FLIPI and FLIPI2 showed significant differences in unfavorable parameters among each risk group, particularly between low- and intermediate-risk groups. The high-risk group b was significantly associated with poor PFS on both FLIPI and FLIPI2 (p < 0.05). However, the OS was significantly different only in the risk groups determined by FLIPI2 (p = 0.042). In a subgroup analysis of patients who received rituximab-containing chemotherapy, the risk stratification of both prognostic models showed a significant impact on PFS, especially in the low-risk group.

Conclusions: FLIPI and FLIPI2 are appropriate prognostic models in Korean FL patients, especially for discriminating low-risk patients from intermediate- and high-risk groups.
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http://dx.doi.org/10.3904/kjim.2014.222DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855088PMC
May 2016

Differential expression of heat shock protein 90 isoforms in small cell lung cancer.

Int J Clin Exp Pathol 2015 1;8(8):9487-93. Epub 2015 Aug 1.

Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine Changwon, South Korea.

Heat shock protein 90 (HSP90), a molecular chaperone, plays important roles in cellular protection against various stressful stimuli and in the regulation of cellular growth and apoptosis. HSP90 has 4 different types of human isoforms; HSP90α, HSP90β, glucose related protein 94 (GRP94) and tumor necrosis factor (TNF) receptor-associated protein 1 (TRAP1). We assessed the differential expression of these HSP90 isoforms in small-cell lung cancer (SCLC) and the correlation of their expression levels with clinicopathological factors and patient survival rates. This study included 117 SCLCs, comprised of 108 primary and 9 metastatic tumor tissues. We performed immunohistochemical staining for HSP90α, HSP90β, GRP94 and TRAP1 in 117 tumors and found that HSP90α and HSP90β were positive in 11 (9%) and 61 tumors (52%), respectively, most of which showed weak expression, whereas GRP94 and TRAP1 were positive in 115 (98%) and 117 tumors (100%), respectively, the majority of which showed moderate or strong expression. None of the HSP90 isoforms showed significant associations with clinicopathological factors or survival status in patients with SCLC. Our results indicate that GRP94 and TRAP1 might contribute more to the carcinogenesis or biology of SCLC than HSP90α and HSP90β, and that isoform selectivity should be considered when HSP90 inhibitors are studied or utilized for the treatment of SCLC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4583941PMC
August 2016

A Retrospective Analysis for Patients with HER2-Positive Gastric Cancer Who Were Treated with Trastuzumab-Based Chemotherapy: In the Perspectives of Ethnicity and Histology.

Cancer Res Treat 2016 04 10;48(2):553-60. Epub 2015 Aug 10.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Purpose: While the Trastuzumab for Gastric Cancer (ToGA) trial demonstrated the efficacy and safety of trastuzumab-based chemotherapy in HER2-positive metastatic gastric cancer, the overall survival (OS) benefit was not found in Asian and diffuse-type cancer patients. The aim of the study is to investigate predictive markers for trastuzumab-based chemotherapy.

Materials And Methods: Data of patients with HER2-positive gastric cancer treated with trastuzumab-based chemotherapy were analyzed retrospectively.

Results: A total of 168 Asian patients were included. The median age was 60 years (range, 27 to 85 years) and the male:female ratio was 118 (70.2%):50 (29.8%). Fourteen (8.3%), 63 (37.5%), 75 (44.6%), and 11 (6.5%) patients had well, moderately, poorly-differentiated tubular adenocarcinoma and signet ring cell carcinoma, respectively. With 14 complete responses and 73 partial responses, the response rate was 50.6%. The median progression-free survival (PFS) was 10.2 months (95% confidence interval [CI], 8.7 to 11.7), and the median OS was 18.5 months (95% CI, 16.4 to 50.6). Next, we investigated the effect of poorly-differentiated histology (PDH, poorly-differentiated tubular adenocarcinoma+signet ring cell carcinoma) on clinical outcomes. The median PFS (8.9 months vs. 11.5 months, p=0.16) was slightly inferior in PDH patients, and the median OS was significantly shorter in PDH patients (14.6 months vs. 19.0 months, p=0.025).

Conclusion: While subset analysis of the ToGA trial demonstrated that trastuzumab-based chemotherapy may not be beneficial for Asians and patients with PDH, our data may suggest that even in Asian patients and patients with PDH, trastuzumab-based chemotherapy could be associated with improved clinical outcomes in patients with HER2-positive gastric cancer.
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http://dx.doi.org/10.4143/crt.2015.155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4843742PMC
April 2016

Identification of Driving ALK Fusion Genes and Genomic Landscape of Medullary Thyroid Cancer.

PLoS Genet 2015 Aug 21;11(8):e1005467. Epub 2015 Aug 21.

Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

The genetic landscape of medullary thyroid cancer (MTC) is not yet fully understood, although some oncogenic mutations have been identified. To explore genetic profiles of MTCs, formalin-fixed, paraffin-embedded tumor tissues from MTC patients were assayed on the Ion AmpliSeq Cancer Panel v2. Eighty-four sporadic MTC samples and 36 paired normal thyroid tissues were successfully sequenced. We discovered 101 hotspot mutations in 18 genes in the 84 MTC tissue samples. The most common mutation was in the ret proto-oncogene, which occurred in 47 cases followed by mutations in genes encoding Harvey rat sarcoma viral oncogene homolog (N = 14), serine/threonine kinase 11 (N = 11), v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (N = 6), mutL homolog 1 (N = 4), Kiesten rat sarcoma viral oncogene homolog (N = 3) and MET proto-oncogene (N = 3). We also evaluated anaplastic lymphoma kinase (ALK) rearrangement by immunohistochemistry and break-apart fluorescence in situ hybridization (FISH). Two of 98 screened cases were positive for ALK FISH. To identify the genomic breakpoint and 5' fusion partner of ALK, customized targeted cancer panel sequencing was performed using DNA from tumor samples of the two patients. Glutamine:fructose-6-phosphate transaminase 1 (GFPT1)-ALK and echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusions were identified. Additional PCR analysis, followed by Sanger sequencing, confirmed the GFPT1-ALK fusion, indicating that the fusion is a result of intra-chromosomal translocation or deletion. Notably, a metastatic MTC case harboring the EML4-ALK fusion showed a dramatic response to an ALK inhibitor, crizotinib. In conclusion, we found several genetic mutations in MTC and are the first to identify ALK fusions in MTC. Our results suggest that the EML4-ALK fusion in MTC may be a potential driver mutation and a valid target of ALK inhibitors. Furthermore, the GFPT1-ALK fusion may be a potential candidate for molecular target therapy.
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http://dx.doi.org/10.1371/journal.pgen.1005467DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4546689PMC
August 2015

Workplace Exposure to Titanium Dioxide Nanopowder Released from a Bag Filter System.

Biomed Res Int 2015 1;2015:524283. Epub 2015 Jun 1.

Center for Environment, Health, and Welfare Research, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea ; Green School, Korea University, Seoul 136-713, Republic of Korea ; University of Science and Technology, Daejeon 305-303, Republic of Korea.

Many researchers who use laboratory-scale synthesis systems to manufacture nanomaterials could be easily exposed to airborne nanomaterials during the research and development stage. This study used various real-time aerosol detectors to investigate the presence of nanoaerosols in a laboratory used to manufacture titanium dioxide (TiO2). The TiO2 nanopowders were produced via flame synthesis and collected by a bag filter system for subsequent harvesting. Highly concentrated nanopowders were released from the outlet of the bag filter system into the laboratory. The fractional particle collection efficiency of the bag filter system was only 20% at particle diameter of 100 nm, which is much lower than the performance of a high-efficiency particulate air (HEPA) filter. Furthermore, the laboratory hood system was inadequate to fully exhaust the air discharged from the bag filter system. Unbalanced air flow rates between bag filter and laboratory hood systems could result in high exposure to nanopowder in laboratory settings. Finally, we simulated behavior of nanopowders released in the laboratory using computational fluid dynamics (CFD).
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http://dx.doi.org/10.1155/2015/524283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4466336PMC
March 2016

High-level expression of Hsp90β is associated with poor survival in resectable non-small-cell lung cancer patients.

Histopathology 2015 Oct 26;67(4):509-19. Epub 2015 Mar 26.

Division of Haematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju, Korea.

Aims: The aim of this study was to investigate the expression of Hsp90β and GRP94, and elucidate the clinical significance of their expression, in patients with resectable non-small-cell lung cancer (NSCLC).

Methods And Results: Surgical tissue specimens were obtained from 208 patients with NSCLC who underwent surgical resection. The expression levels of Hsp90β and GRP94 were assessed with tissue microarrays and immunohistochemistry. No correlations were observed between Hsp90β or GRP94 expression and several clinicopathological factors. The high-Hsp90β group [median overall survival (OS) 20.4 months; 95% confidence interval (CI) 0.000-40.864] showed a significant decrease in OS as compared with the low-Hsp90β group (median OS not reached; P = 0.003). In contrast to the Hsp90β analysis, the GRP94 analysis did not show a difference in OS. Moreover, in subgroup analyses of patients with squamous cell carcinoma histology, OS (P = 0.012) and relapse-free survival (P = 0.044) were significantly worse in the high-Hsp90β group than in the low-Hsp90β group. Multivariate analysis suggested that old age [hazard ratio (HR) 1.568; 95% CI 1.019-2.412; P = 0.041], advanced disease (HR 2.066; 95% CI 1.218-3.502; P = 0.007) and high Hsp90β expression (HR 1.802; 95% CI 1.061-3.060; P = 0.029) were independent poor prognostic factors for OS.

Conclusions: Hsp90β expression might be a useful marker of poor OS, although further large prospective studies are warranted to validate our findings.
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http://dx.doi.org/10.1111/his.12675DOI Listing
October 2015

Natural history of metastatic biliary tract cancer (BTC) patients with good performance status (PS) who were treated with only best supportive care (BSC).

Jpn J Clin Oncol 2015 Mar 26;45(3):256-60. Epub 2015 Jan 26.

Division of Hematology-Oncology, Department of Internal Medicine, Gyeongsang National University Hospital, Gyeongsang National University School of Medicine, Jinju

Background: Although chemotherapy is widely recommended for patients with metastatic biliary tract cancer, the natural course of these patients, especially those with good performance status who are indicated for chemotherapy, is not known.

Methods: We retrospectively reviewed patients with metastatic or locally advanced biliary cancer who were diagnosed at six cancer centers. Patients were eligible if they had good performance (ECOG 0-2) and no history of any treatment for cancer. The primary objective was to evaluate the survival time of patients with advanced biliary cancer with good performance who were untreated.

Results: Of the 1677 patients, 204 met the inclusion criteria. The median age and overall survival were 72.0 years and 7.1 months. Overall survival (months) by location was 4.7 for intrahepatic, 9.7 for extrahepatic, 4.4 for gallbladder and 11.2 for ampulla of vater cancer. In subgroup analysis, overall survival of locally advanced biliary cancer was 13.8 months and that of patients with normal carcinoembryonic antigen/carbohydrate antigen 19-9 was 10.6 months. In multivariate analysis, variables that were associated with poor prognosis were metastatic biliary cancer [hazard ratio 2.19 (P = 0.001)], high baseline carcinoembryonic antigen level (defined as >4.0 ng/ml) [hazard ratio 1.51 (P = 0.024)] and high baseline carbohydrate antigen 19-9 level (defined as >100 U/ml) [hazard ratio 1.93 (P = 0.001)].

Conclusions: Advanced biliary tract cancer with good performance status showed modest survival without any treatment. Furthermore, subgroup analysis showed that patients with normal carbohydrate antigen 19-9 or carcinoembryonic antigen level or locally advanced status had favorable survival. Further studies comparing the outcome of chemotherapy with that of best supportive care in patients with unresectable biliary tract cancer are warranted.
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http://dx.doi.org/10.1093/jjco/hyu210DOI Listing
March 2015

Intra-tumoral Metastatic Double Primary Carcinoma: Synchronous Metastatic Tumor in Lung from Breast and Thyroid Carcinoma.

Cancer Res Treat 2014 Apr 22;46(2):200-3. Epub 2014 Apr 22.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Cases of phenotypic heterogeneity of cells within tumors have recently been reported. Here, we report on a patient with characteristic intra-tumor double primary metastases in the lung. This patient was a 40-year-old Korean woman who had been diagnosed with breast cancer (T1N0M0, estrogen receptor/progesterone receptor/HER2 +/+/+) and papillary thyroid cancer three years prior and underwent a complete surgical resection followed by appropriate adjuvant treatment with radiation, hormone, and radioactive iodine. She was recently admitted for newly developed pulmonary nodules. Metastasectomy through video-assisted thoracoscopic surgery revealed recurrent double primary cancer with two different components (metastatic ductal carcinomas from the breast and metastatic papillary carcinomas from the thyroid gland) in each pulmonary nodule in the right upper lobe and right middle lobe. To the best of our knowledge, this is the first report of simultaneous recurrent double metastasis in one organ from different primary origins.
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http://dx.doi.org/10.4143/crt.2014.46.2.200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4022830PMC
April 2014

Detection and characterization of nanomaterials released in low concentrations during multi-walled carbon nanotube spraying process in a cleanroom.

Inhal Toxicol 2013 Dec;25(14):759-65

Center for Environment, Health and Welfare Research, Korea Institute of Science and Technology , Seoul, Korea .

Release of nanomaterials was assessed in a cleanroom workplace designed for the handling of multi-walled carbon nanotubes. During the process, the nanotubes were sprayed in a chamber fitted with an exhaust duct system. The front door of the spraying chamber was completely closed, but rear end of the chamber was partially open. Throughout a series of spray processes, three detectors - an optical particle counter, a nanoparticle aerosol monitor, and an aethalometer - counted and characterized particles escaping the chamber. Concentrations of particle surface area and black carbon emitted by the spraying were assessed assuming zero background aerosol concentration in the cleanroom. Very low concentrations of black carbon, 0.4 μg/m(3), were observed. In conclusion, in a cleanroom, low concentrations of nanomaterials were detected to be emitted from a spraying chamber into the workplace. The level of particles reaching the workplace was sufficiently low to have made their detection difficult in a normal environment. Both target nanomaterial and non-intended incidental nanomaterials were released during spraying. Despite the use of exhaust duct system in the process chamber, workers would be exposed to some particles if the chamber were partially open. The exhaust duct system was not enough to remove all the particles released in the chamber.
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http://dx.doi.org/10.3109/08958378.2013.846951DOI Listing
December 2013

Matched-pair analysis comparing the outcomes of T cell/histiocyte-rich large B cell lymphoma and diffuse large B cell lymphoma in patients treated with rituximab-CHOP.

Acta Haematol 2014 31;131(3):156-61. Epub 2013 Oct 31.

Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.

Background: T cell/histiocyte-rich large B cell lymphoma (THRLBCL) is a rare morphological variant of diffuse large B cell lymphoma (DLBCL), accounting for 1-3% of all DLBCLs. However, its impact on treatment outcome and prognosis is still not clearly defined.

Methods: We compared the clinical outcomes between THRLBCL and DLBCL, not otherwise specified (NOS), in patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP).

Results: Data from 11 patients with THRLBCL were matched to 33 patients with DLBCL-NOS. Patients were matched by five established prognostic factors of the International Prognostic Index, including age, Ann Arbor stage, Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level and the number of extranodal involvement. There was no significant difference in the complete response rate to R-CHOP between THRLBCL (91%, 10/11) and DLBCL-NOS (97%, 32/33; p = 0.442). The 3-year event-free survival rate was 81% for both THRLBCL and DLBCL-NOS (p = 0.813). The 3-year overall survival rates were 75 and 81%, respectively (p = 0.719).

Conclusions: The treatment outcomes of THRLBCL are similar to those of DLBCL-NOS. The addition of rituximab to CHOP seems to be helpful for the management of THRLBCL, as it is for DLBCL-NOS.
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http://dx.doi.org/10.1159/000353787DOI Listing
June 2014

Treatment of dexamethasone-induced hiccup in chemotherapy patients by methylprednisolone rotation.

Oncologist 2013 9;18(11):1229-34. Epub 2013 Oct 9.

Department of Internal Medicine, Institute of Health Science, College of Medicine, Gyeongsang National University, Jinju, South Korea;

Dexamethasone-induced hiccup (DIH) is an underrecognized symptom in patients with cancer, and little information is available about its treatment. The aims of this study were to investigate the feasibility of methylprednisolone rotation as treatment and to confirm the male predominance among those with cancer who experienced DIH during chemotherapy. Methods. Persons with cancer who experienced hiccups during chemotherapy treatment and who were receiving treatment with dexamethasone were presumed to have DIH. The following algorithmic practice was implemented for antiemetic corticosteroid use: rotation from dexamethasone to methylprednisolone in the next cycle and dexamethasone re-administration in the second cycle of chemotherapy after recognition of hiccups to confirm DIH. All other antiemetics except corticosteroid remained unchanged. Patients (n = 40) were recruited from eight cancer centers in Korea from September 2012 to April 2013. Data were collected retrospectively. Results. Hiccup intensity (numeric rating scale [NRS]: 5.38 vs. 0.53) and duration (68.44 minutes vs. 1.79 minutes) were significantly decreased after rotation to methylprednisolone, while intensity of emesis was not increased (NRS: 2.63 vs. 2.08). Median dose of dexamethasone and methylprednisolone were 10 mg and 50 mg, respectively. Thirty-four (85%) of 40 patients showed complete resolution of hiccups after methylprednisolone rotation in the next cycle. Of these 34 patients, 25 (73.5%) had recurrence of hiccups after dexamethasone re-administration. Compared with baseline values, hiccup intensity (NRS: 5.24 vs. 2.44) and duration (66.43 minutes vs. 22.00 minutes) were significantly attenuated after dexamethasone re-administration. Of the 40 eligible patients, 38 (95%) were male. Conclusion. DIH during chemotherapy could be controlled without losing antiemetic potential by replacing dexamethasone with methylprednisolone. We also identified a male predominance of DIH. Further prospective studies are warranted.
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http://dx.doi.org/10.1634/theoncologist.2013-0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3825309PMC
October 2014