[Show abstract][Hide abstract] ABSTRACT: 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.
PLoS ONE 03/2015; 10(3):e0120324. DOI:10.1371/journal.pone.0120324 · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interstitial lung disease (ILD) is a serious adverse effect of gefitinib. We examined the incidence and clinical characteristics of drug-induced ILD in Korean NSCLC patients treated with gefitinib.
A retrospective cohort study was performed in NSCLC patients who started gefitinib treatment at Seoul National University Hospital from January 2002 through December 2011. Patients who developed new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as having possible adverse pulmonary reactions. The patients' medical records were reviewed independently by investigators to identify the causes of pulmonary toxicities.
Among the 1,114 patients evaluated, 128 (11.5%) patients developed pulmonary adverse reactions after taking gefitinib. An infectious complication occurred in 98 (8.8%) patients and 15 (1.3%) patients developed ILD. Nine (60.0%) of the 15 patients with gefitinib-induced ILD experienced a fatal clinical course that met either the Common Terminology Criteria for Adverse Events (CTCAE) grade 4 (n = 3) or grade 5 (n = 6). In the multivariate analysis, a lower serum albumin level (≤ 3.0 g/dL) at baseline was significantly associated with the development of gefitinib-induced ILD (odds ratio = 3.91; 95% confidence interval: 1.20 - 12.71).
s The incidence of gefitinib-induced ILD in Korean NSCLC patients was similar to that reported worldwide, but lower than values reported for Japanese population. ILD was usually a life-threatening adverse effect of gefitinib, and the development of ILD was significantly associated with a lower baseline serum albumin level.
Cancer Research and Treatment 03/2015; DOI:10.4143/crt.2014.201 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The first edition of the Korean treatment guidelines for chronic myelogenous leukemia (CML) was published in 2006. We intend to update those guidelines to include the use of next-generation tyrosine kinase inhibitors (TKIs).
[Show abstract][Hide abstract] ABSTRACT: There are few data on the clinical implications of immunosuppressive protein expression in tumors and immune cell infiltration within the tumor microenvironment in patients with gastric cancer (GC).
In this study, 243 patients with curatively resected GC were included. The levels of immunosuppressive protein expression [programmed cell death 1 ligand 1 (PD-L1), cytotoxic T-lymphocyte antigen 4 (CTLA-4), and indoleamine 2,3-dioxygenase (IDO)] in tumors and the densities of immune cells [CD3(+), CD4(+), CD8(+), or PD-1(+) cells] within the tumor microenvironment were measured using immunohistochemical analysis.
Positive PD-L1, CTLA-4, and IDO expression was observed in 43.6, 65.8, and 47.7 % of the patients, respectively. Expression of PD-L1, CTLA-4, and IDO was related to less advanced stage, intestinal type, and well/moderately differentiated adenocarcinoma (P < 0.05). PD-L1 expression was related to better disease-free survival (DFS) and overall survival (OS) in GC [PD-L1(+) vs. PD-L1(-) tumors: 5-year DFS rate, 82.6 vs. 66.9 %; 5-year OS rate, 83.0 vs. 69.1 % (P values <0.05)]. Survival outcomes were also better in patients with a higher density of CD3(+) cells within the tumor microenvironment than in those with a lower density of CD3(+) cells [5-year DFS rate, 80.9 vs. 67.0 %; 5-year OS rate, 82.5 vs. 68.0 % (P values <0.05)]. In multivariate analysis, these two immune markers had a prognostic impact on survival, independent of other clinical variables.
GC patients with immunosuppressive protein expression (PD-L1, CTLA-4, or IDO) had distinct clinicopathological characteristics. PD-L1(+) expression and a high-CD3 tumor microenvironment are favorable prognostic markers in GC.
Gastric Cancer 11/2014; DOI:10.1007/s10120-014-0440-5 · 4.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: p21-activated kinases (PAKs) are involved in cytoskeletal reorganization, gene transcription, cell proliferation and survival, and oncogenic transformation. Therefore, we hypothesized that PAK expression levels could predict the sensitivity of pancreatic cancer cells to gemcitabine treatment, and PAKs could be therapeutic targets.
Cell viability inhibition by gemcitabine was evaluated in human pancreatic cancer cell lines (Capan-1, Capan-2, MIA PaCa-2, PANC-1, Aspc-1, SNU-213, and SNU-410). Protein expression and mRNA of molecules was detected by immunoblot analysis and reverse transcription polymerase chain reaction. To define the function of PAK4, PAK4 was controlled using PAK4 siRNA.
Capan-2, PANC-1, and SNU-410 cells were resistant to gemcitabine treatment. Immunoblot analysis of signaling molecules reported to indicate gemcitabine sensitivity showed higher expression of PAK4 and lower expression of human equilibrative nucleoside transporter 1 (hENT1), a well-known predictive marker for gemcitabine activity, in the resistant cell lines. Knockdown of PAK4 using siRNA induced the upregulation of hENT1. In resistant cell lines (Capan-2, PANC-1, and SNU-410), knockdown of PAK4 by siRNA resulted in restoration of sensitivity to gemcitabine.
PAK4 could be a predictive marker of gemcitabine sensitivity and a potential therapeutic target to increase gemcitabine sensitivity in pancreatic cancer.
[Show abstract][Hide abstract] ABSTRACT: 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. (c) 2014 Elsevier Ltd. All rights reserved.
European journal of cancer (Oxford, England: 1990) 09/2014; 50(16). DOI:10.1016/j.ejca.2014.08.003 · 4.82 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We previously reported the prevalence of monoclonal gammopathy of undetermined significance (MGUS) to be 3.3% among an elderly Korean urban cohort recruited during 2005-2006. Here, we report a 5-year follow-up study of the previously identified MGUS cohort.
Cancer Research and Treatment 08/2014; 47(2). DOI:10.4143/crt.2013.262 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose
The aim of this study was to develop a pragmatic nomogram for prediction of progressionfree survival (PFS) for the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in EGFR mutant non-small cell lung cancer (NSCLC).
Materials and Methods
A total of 306 recurred or metastatic NSCLC patients with EGFR mutation, who received EGFR TKIs, were enrolled in this study. We developed the nomogram, using a Cox proportional hazard regression model for PFS.
The median PFS was 11.2 months. Response rate to EGFR TKI was 71.9%. Multivariate Cox model identified disease status, performance status, chemotherapy line, response to EGFR TKI, and bone metastasis as independent prognostic factors, and the nomogram for PFS was developed, based on these covariates. The concordance index for a nomogram was 0.708, and the calibration was also good.
We developed a nomogram, based on clinical characteristics, for prediction of the PFS to EGFR TKI in NSCLC patients with EGFR mutation.
Cancer Research and Treatment 07/2014; 46(4). DOI:10.4143/crt.2013.120 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The present study sought to elucidate the role of induction and consolidation therapy in elderly patients. We retrospectively collected data of 477 patients who were aged over 60 years at the time of acute myeloid leukemia (AML) diagnosis. The median overall survival (OS) was 339 days in the induction group (n = 266) and 86 days in the best supportive care group (n = 211) (P < 0.001). In the induction group, the complete remission (CR) rate was 58.3 %, and treatment-related death was 15.4 %. Successful induction was related to good performance [Eastern Cooperative Oncology Group (ECOG <2)] [hazard ratio (HR) 3.215; P = 0.002]. Mortality correlated with failure to achieve CR (HR 4.059; P < 0.001) and poor performance status (ECOG >2) (HR 2.731; P = 0.035). In CR patients, poor karyotype and absence of consolidation (HR 2.313; P = 0.003) correlated with mortality. More than one cycle of consolidation was associated with better OS (P < 0.001). Lack of salvage therapy was associated with mortality in patients who did not achieve CR (HR 3.223; P = 0.005). Intensive induction in patients with good performance and >1 cycle of consolidation after CR may be the best strategy for improving OS in elderly AML patients.
International Journal of Hematology 07/2014; 100(2). DOI:10.1007/s12185-014-1617-8 · 1.68 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aims and background. To evaluate the efficacy of weekly, low-dose paclitaxel chemotherapy after the failure of platinum-based combination chemotherapy in elderly or poor performance status patients with metastatic urothelial carcinoma. Methods. We retrospectively reviewed the medical records of 25 patients. The regimen consisted of paclitaxel, 60 mg/m2 on days 1, 8 and 15, with or without carboplatin (AUC 2). Treatment was repeated every 4 weeks until disease progression. Results. Of 25 patients, the median age was 68 years (range, 47-82), 4 (16%) were female, and 15 (60%) had an ECOG performance status of 2. All patients were ≥65 years or had a performance status of 2 in the cases aged <65 years. Six patients received paclitaxel in combination with carboplatin. The overall response rate was 24% (95% CI, 7.3-40.7) with 6 partial responses. Eight patients (32%) achieved stable disease and 5 (20%) had progressive disease. The median time to progression was 4.0 months (95% CI, 2.9-5.1), and median overall survival was 5.5 months (95% CI, 3.7-7.3). Grade 3-4 toxicities were as follows: neutropenia in 9 patients (36%), anemia in 11 (44%), thrombocytopenia in 2 (8%), neutropenic fever in 2 (8%), asthenia in 4 (16%), anorexia in 2 (8%), nausea in 2 (8%), and peripheral neuropathy in 1 (4%). ECOG performance status (0-1 vs 2) was a significant prognostic factor in multivariate analysis. Conclusions. Low-dose weekly paclitaxel seems to be a meaningful salvage treatment with moderate activity and acceptable toxicity in elderly or poor performance status patients with metastatic urothelial carcinoma. Oncologists should carefully consider the opportunity of chemotherapy versus best supportive care in these patients.
[Show abstract][Hide abstract] ABSTRACT: Waldenström's macroglobulinemia (WM) is a B-cell proliferative malignancy characterized by immunoglobulin M monoclonal gammopathy and bone marrow infiltration by lymphoplasmacytic cells. Clinical features and cytogenetics of WM in Asia including Republic of Korea remain unclear. Moreover, no study has reported treatment outcomes in patients with WM treated with novel agent combined with conventional chemotherapy. This study investigated clinical features and assessed treatment outcomes with novel agent and conventional chemotherapy in Republic of Korea. Data from all (n = 71) patients with newly diagnosed WM at 17 hospitals who received chemotherapy between January 2005 and December 2012 were collected retrospectively. The median age of patients was 66 years (range: 37-92 years) and male to female ratio was 5 : 1. Patients treated with novel agent combined chemotherapy displayed higher overall response rate (ORR) compared to conventional chemotherapy alone (92.9% versus 52.6%, P = 0.006). The 5-year overall survival rate was 62.6% (95% confidence interval: 34.73-111.07). Use of novel agents produced higher ORR but survival benefit was not apparent due to the small number of patients and short follow-up duration. Further studies are needed to confirm the efficacy of novel agents in patients with WM.
BioMed Research International 06/2014; 2014:253243. DOI:10.1155/2014/253243 · 2.71 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Critical care for advanced lung cancer patients is still controversial, and the appropriate method for the selection of patients who may benefit from intensive care unit (ICU) care is not clearly defined. We retrospectively reviewed the medical records of stage IIIB-IV lung cancer patients admitted to the medical ICU of a university hospital in Korea between 2003 and 2011. Of 95 patients, 64 (67 %) had Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2, and 79 (84 %) had non-small-cell lung cancer. In total, 28 patients (30 %) were newly diagnosed or were receiving first-line treatment, and 22 (23 %) were refractory or bedridden. Mechanical ventilation was required in 85 patients (90 %), and ICU mortality and hospital mortality were 57 and 78 %, respectively. According to a multivariate analysis, a PaO2/FiO2 ratio <150 [odds ratio (OR) = 5.51, 95 % confidence interval (CI) 2.10-14.48, p = 0.001] was independently associated with ICU mortality, and an ECOG PS ≥2 (OR = 9.53, 95 % CI 2.03-44.85, p = 0.004) and a need for vasoactive agents (OR = 6.94, 95 % CI 1.61-29.84, p = 0.009) were independently associated with hospital mortality. Refractory or bedridden patients (n = 22) showed significantly poorer overall survival (11.0 vs. 29.0 days, p = 0.005). Among 21 patients who were discharged from the hospital, 11 (52 %) received further chemotherapy. Certain advanced lung cancer patients may benefit from ICU management. However, refractory patients and patients with a poor PS do not seem to benefit from ICU care. Oncologists should try to discuss palliative care and end-of-life issues in advance to avoid futile care.
Medical Oncology 03/2014; 31(3):847. DOI:10.1007/s12032-014-0847-1 · 2.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study assessed the prevalence of, and risk factors for, iron deficiency (ID) and iron deficiency anemia (IDA) among participants of the fifth Korean Health and Nutrition Examination Survey, 2010. Of 8,958 participants, 6,758 individuals ≥10 yr had sufficient data for the analysis of anemia and iron status. ID was defined as a transferrin saturation <10% or serum ferritin <15 µg/L. The prevalence of ID and IDA was 2.0% (95% confidence interval [CI], 1.3%-2.6%) and 0.7% (95% CI, 0.3%-1.0%), respectively, in males, and 22.4% (95% CI, 20.7%-24.2%) and 8.0% (95% CI, 6.8%-9.2%), respectively, in females. In reproductive age females, the prevalence of ID and IDA was 31.4% (95% CI, 28.9%-33.8%) and 11.5% (95% CI, 9.6%-13.4%), respectively. Compared to the prevalence of IDA in adult males 18-49 yr, the relative risks of IDA in adults ≥65 yr, lactating females, premenopausal females, and pregnant females were 8.1, 35.7, 42.8, and 95.5, respectively. Low income, underweight, iron- or vitamin C-poor diets were also associated with IDA. For populations with defined risk factors in terms of age, gender, physiological state and socioeconomic and nutritional status, national health policy to reduce IDA is needed.
Journal of Korean medical science 02/2014; 29(2):224-9. DOI:10.3346/jkms.2014.29.2.224 · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Older patients with cancer may have an increased risk of early discontinuation of active treatment (ED), which results in poor outcome in curative or adjuvant settings. We aimed to determine the association between survival and ED and to identify predictors of ED in palliative setting.
Ninety-eight patients older than 65 years of age who received a comprehensive geriatric assessment (CGA) before palliative first-line chemotherapy were analyzed. Clinical information and CGA results were retrieved from electronic medical record. CGA included Charlson's co-morbidity index, activities of daily living (ADL), instrumental ADL (IADL), Mini-Mental Status Examination, short-form of the geriatric depression scale, timed-get-up-and-go test (TGUG), and mini-nutritional assessment (MNA). ED was defined as no active cancer treatment (radiotherapy and/or chemotherapy) beyond palliative first-line chemotherapy. Predictors of ED were identified using clinical parameters and CGA.
Active treatment was discontinued after first-line chemotherapy in 30 patients during median follow-up period of 15.1 months. ED after first-line chemotherapy was associated with shorter overall survival (OS; median OS = 3.1 vs. 14.7 months in patients with ED compared with patients without ED, p < 0.001). Eastern Cooperative Oncology Group performance status, living alone, ADL, IADL, MNA, and TGUG were associated with ED (p = 0.001, p = 0.048, p = 0.001, p < 0.001, p < 0.001, p = 0.002, respectively). In multivariable analysis, malnutrition and dependent IADL were the independent predictive factors for ED (odds ratio = 5.03; 95 % confidence interval = 1.50-16.87: odds ratio = 3.06; confidence interval = 1.03-9.12, respectively).
ED was associated with shorter OS in older patients with cancer. Malnutrition and dependent IADL were identified as independent predictive factors for ED.
Supportive Care in Cancer 11/2013; 22(3). DOI:10.1007/s00520-013-2033-y · 2.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We conducted a retrospective analysis of lenalidomide with dexamethasone for patients with relapsed/refractory multiple myeloma (RRMM) who were treated within the Korean patient access program. Lenalidomide has been approved for RRMM for several years in Europe and North America, but has not been accessible to Asian patients in the past. Between 2008 and 2012, 110 patients from 20 hospitals were enrolled. The overall response rate (ORR) was 43.6 % with 15.4 % of very good partial response (VGPR) or better. The median time to progression (TTP) in this heavily pretreated patient population was 8.0 months, and median overall survival (OS) was 23 months. Hematologic toxicities, fatigue, anorexia, and constipation were the most common adverse events. The number of previous treatment lines, previous exposure to thalidomide, refractoriness to thalidomide and bortezomib, pretreatment white blood cell count (WBC), platelet count, t(14;16), and 17p deletion were significant prognostic factors for TTP, and creatinine clearance, refractoriness to thalidomide and bortezomib, performance status, platelet count, and 17p deletion were significant for OS in univariate analysis. In multivariate analysis, WBC and platelet count were significant prognostic factors for TTP and performance status for OS. For Korean myeloma patients, lenalidomide showed considerable efficacy, and toxicities were comparable to the data published in Europe and North America.
Annals of Hematology 09/2013; 93(1). DOI:10.1007/s00277-013-1893-z · 2.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Gefitinib was introduced in 2002 for treatment of non-small cell lung cancer (NSCLC); however, it is not clear whether its use in daily practice has changed the outcome of patients. The purpose of this study is to evaluate the question of how molecular understanding regarding gefitinib and epidermal growth factor receptor (EGFR) mutation affect the prescribing patterns and clinical outcomes of treatment with gefitinib in NSCLC, in a real practical field.
We conducted a retrospective analysis of the consecutive database of NSCLC patients who were treated with gefitinib at Seoul National University Hospital between January 2002 and December 2011. Prescribing patterns and clinical outcomes were analyzed by year.
A total of 1,115 NSCLC patients, who received gefitinib at recurred or metastatic setting, were included in this study. Proportion of patients receiving gefitinib, for the first line, showed a gradual increase, from 5.2% in 2002-2003 to 30.6% in 2010-2011. Proportion of patients who underwent EGFR mutation testing showed a rapid increase, from 0.6% in 2004-2005 to 73.5% in 2010-2011. The response rate also showed a gradual increase, from 17.2% in 2002-2003 to 57.1% in 2010-2011 (p<0.001). The median progression-free survival of gefitinib was increased with statistical significance from 2.8 months in 2002-2003 to 9.1 months in 2010-2011 (p<0.001).
We demonstrated that molecular understanding and practical use of EGFR mutation testing have resulted in a change in the prescription patterns of gefitinib. Use of an enrichment strategy can lead to improvement in the efficacy of gefitinib in real practice.
Cancer Research and Treatment 09/2013; 45(3):178-85. DOI:10.4143/crt.2013.45.3.178 · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: There are many complex and rare mutations in the epidermal growth factor receptor (EGFR) gene in non-small cell lung cancer (NSCLC) other than the two classical mutations of L858R and exon 19 deletional mutation. The purpose of this study was to investigate the clinical significance of rare and complex mutations, and the efficacy of EGFR tyrosine kinase inhibitors (TKIs).
We analyzed 1,431 NSCLC patients who were treated with either gefitinib or erlotinib. Exons 18 to 21 of EGFR were analyzed by PCR and subjected to direct sequencing methods.
Of 306 patients who had EGFR mutation, 24 patients (7.3 %) had complex mutations. The frequency of rare mutations was 10.3 %. Four groups were categorized [group A (N = 269): classical mutation alone; group B (N = 16): complex mutation with classical mutation; group C (N = 16): rare mutation alone or complex mutation with rare mutation; group D (N = 5); classical mutation with T790M]; the response rate (RR) to TKI was significantly different between each group (RR = 74.8 % in group A vs. 68.8 % in group B vs. 25.0 % in group C vs. 80.0 % in group D, P < 0.001). Progression-free survival (PFS) was also poorer in rare mutations (median PFS: 11.9 vs. 8.1 vs. 1.4 vs. 8.0 months, respectively, P < 0.001).
NSCLC patients harboring rare mutations did not show consistent and favorable responses to EGFR TKI compared with those harboring classical mutations. However, complex mutations with classical mutations showed similar treatment efficacy toward EGFR TKI to that with classical mutations alone.
International Journal of Clinical Oncology 08/2013; 19(4). DOI:10.1007/s10147-013-0602-1 · 2.17 Impact Factor