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1.  A Phase II Trial of Gemcitabine plus Capecitabine for Patients with Advanced Pancreatic Cancer 
The purpose of this study was to determine the efficacy and safety of treatment using gemcitabine and capecitabine for patients with advanced pancreatic cancer.
Materials and Methods
Patients with advanced unresectable pancreatic adenocarcinoma were enrolled in the study. Inclusion criteria included no prior systemic chemotherapy or radiation therapy, at least one radiographically documented and measurable tumor lesion, and adequate patient organ functions. The patients received 1,000 mg/m2 gemcitabine intravenously on days 1, 8 and 15, and 830 mg/m2 of oral capecitabine twice a day on days 1-21 of a 28-day cycle.
Fifty patients with a median age of 53 years (range, 39 to 76 years) were enrolled in the study. The median follow-up was 10.0 months. The objective response rate of the 50 patients was 48.0% (95% CI, 22.5 to 57.1%). The median time to progression and overall survival were 6.5 months (95% CI, 2.3 to 8.7 months) and 10.0 months (95% CI, 5.7 to 16.7 months), respectively. Grade 3-4 toxicities associated with chemotherapy included neutropenia (22%), anemia (8%), thrombocytopenia (6%), and hand-foot syndrome (10%).
Combination chemotherapy using gemcitabine and capecitabine was well tolerated and demonstrated promising efficacy in the treatment of advanced pancreatic cancer.
PMCID: PMC3394862  PMID: 22802751
Gemcitabine; Capecitabine; Pancreatic neoplasms
2.  The Bone Morphogenesis Protein-2 (BMP-2) is Associated with Progression to Metastatic Disease in Gastric Cancer 
Bone Morphogenetic Proteins (BMPs) are members of the TGF-β superfamily and it has been demonstrated that BMPs enhance migration, invasion and metastasis. The purpose of this study was to identify the association between the serum BMP-2 level and the progression status of gastric cancer.
Materials and Methods
Fifty-five patients with metastatic gastric cancer (metastatic disease group), six patients with early gastric cancer without lymph node metastasis (the EGC group), and ten healthy control subjects were enrolled in this study. The serum BMP-2 level was quantified by use of a commercially available ELISA kit. In EGC group patients and patients with metastatic disease, whole blood was obtained before endoscopic mucosal resection and before the commencement of a scheduled cycle of systemic chemotherapy, respectively.
No significant difference in the mean serum BMP-2 levels was observed between the control subjects and the EGC group patients (87.95 pg/ml for the control subjects and 84.50 pg/ml for the EGC group, p=1.0). However, the metastatic disease group patients had a significantly higher level of serum BMP (179.61 pg/ml) than the control subjects and EGC group patients (87.95 pg/ml for the control subjects and 84.50 pg/ml for the EGC group, p<0.0001). Moreover, the mean serum BMP-2 level from patients with a bone metastasis was significantly higher than the mean serum BMP-2 level from patients without a bone metastasis (204.73 pg/ml versus 173.33 pg/ml, p=0.021).
BMP-2 seems to have a role in progression to metastatic disease in gastric cancer, especially in the late stage of tumorigenesis, including invasion and metastasis. BMP-2 may facilitate bone metastasis in gastric cancer. To confirm these findings, further studies are required with tissue specimens and the use of a cancer cell line.
PMCID: PMC2697466  PMID: 19688119
Bone morphogenesis protein-2; BMP-2; Stomach neoplasms; Invasion; Neoplasm metastasis
3.  Mitochondrial Ribosomal Protein L41 Suppresses Cell Growth in Association with p53 and p27Kip1 
Molecular and Cellular Biology  2005;25(15):6603-6616.
The p53 protein arrests the cell cycle at the G1 phase when stabilized by the interaction between ribosomal proteins and HDM2 under growth-inhibitory conditions. Meanwhile, p53, when translocated to the mitochondria in response to cell death signals, induces apoptosis via transcription-independent mechanisms. In this report, we demonstrate that the mitochondrial ribosomal protein L41 (MRPL41) enhances p53 stability and contributes to p53-induced apoptosis in response to growth-inhibitory conditions such as actinomycin D treatment and serum starvation. An analysis of MRPL41 expression in paired normal and tumor tissues revealed lower expression in tumor tissue. Ectopic MRPL41 expression resulted in inhibition of the growth of cancer cells in tissue culture and tumor growth in nude mice. We discovered that MRPL41 protein is localized in the mitochondria, stabilizes the p53 protein, and enhances its translocation to the mitochondria, thereby inducing apoptosis. Interestingly, in the absence of p53, MRPL41 stabilizes the p27Kip1 protein and arrests the cell cycle at the G1 phase. These results suggest that MRPL41 plays an important role in p53-induced mitochondrion-dependent apoptosis and MRPL41 exerts a tumor-suppressive effect in association with p53 and p27 Kip1.
PMCID: PMC1190350  PMID: 16024796
4.  Genome-wide association analysis identifies new lung cancer susceptibility loci in never-smoking women in Asia 
Lan, Qing | Hsiung, Chao A | Matsuo, Keitaro | Hong, Yun-Chul | Seow, Adeline | Wang, Zhaoming | Hosgood, H Dean | Chen, Kexin | Wang, Jiu-Cun | Chatterjee, Nilanjan | Hu, Wei | Wong, Maria Pik | Zheng, Wei | Caporaso, Neil | Park, Jae Yong | Chen, Chien-Jen | Kim, Yeul Hong | Kim, Young Tae | Landi, Maria Teresa | Shen, Hongbing | Lawrence, Charles | Burdett, Laurie | Yeager, Meredith | Yuenger, Jeffrey | Jacobs, Kevin B | Chang, I-Shou | Mitsudomi, Tetsuya | Kim, Hee Nam | Chang, Gee-Chen | Bassig, Bryan A | Tucker, Margaret | Wei, Fusheng | Yin, Zhihua | Wu, Chen | An, She-Juan | Qian, Biyun | Lee, Victor Ho Fun | Lu, Daru | Liu, Jianjun | Jeon, Hyo-Sung | Hsiao, Chin-Fu | Sung, Jae Sook | Kim, Jin Hee | Gao, Yu-Tang | Tsai, Ying-Huang | Jung, Yoo Jin | Guo, Huan | Hu, Zhibin | Hutchinson, Amy | Wang, Wen-Chang | Klein, Robert | Chung, Charles C | Oh, In-Jae | Chen, Kuan-Yu | Berndt, Sonja I | He, Xingzhou | Wu, Wei | Chang, Jiang | Zhang, Xu-Chao | Huang, Ming-Shyan | Zheng, Hong | Wang, Junwen | Zhao, Xueying | Li, Yuqing | Choi, Jin Eun | Su, Wu-Chou | Park, Kyong Hwa | Sung, Sook Whan | Shu, Xiao-Ou | Chen, Yuh-Min | Liu, Li | Kang, Chang Hyun | Hu, Lingmin | Chen, Chung-Hsing | Pao, William | Kim, Young-Chul | Yang, Tsung-Ying | Xu, Jun | Guan, Peng | Tan, Wen | Su, Jian | Wang, Chih-Liang | Li, Haixin | Sihoe, Alan Dart Loon | Zhao, Zhenhong | Chen, Ying | Choi, Yi Young | Hung, Jen-Yu | Kim, Jun Suk | Yoon, Ho-Il | Cai, Qiuyin | Lin, Chien-Chung | Park, In Kyu | Xu, Ping | Dong, Jing | Kim, Christopher | He, Qincheng | Perng, Reury-Perng | Kohno, Takashi | Kweon, Sun-Seog | Chen, Chih-Yi | Vermeulen, Roel | Wu, Junjie | Lim, Wei-Yen | Chen, Kun-Chieh | Chow, Wong-Ho | Ji, Bu-Tian | Chan, John K C | Chu, Minjie | Li1, Yao-Jen | Yokota, Jun | Li, Jihua | Chen, Hongyan | Xiang, Yong-Bing | Yu, Chong-Jen | Kunitoh, Hideo | Wu, Guoping | Jin, Li | Lo, Yen-Li | Shiraishi, Kouya | Chen, Ying-Hsiang | Lin, Hsien-Chih | Wu, Tangchun | Wu, Yi-Long | Yang, Pan-Chyr | Zhou, Baosen | Shin, Min-Ho | Fraumeni, Joseph F | Lin, Dongxin | Chanock, Stephen J | Rothman, Nathaniel
Nature genetics  2012;44(12):1330-1335.
To identify common genetic variants that contribute to lung cancer susceptibility, we conducted a multistage genome-wide association study of lung cancer in Asian women who never smoked. We scanned 5,510 never-smoking female lung cancer cases and 4,544 controls drawn from 14 studies from mainland China, South Korea, Japan, Singapore, Taiwan, and Hong Kong. We genotyped the most promising variants (associated at P < 5 × 10-6) in an additional 1,099 cases and 2,913 controls. We identified three new susceptibility loci at 10q25.2 (rs7086803, P = 3.54 × 10-18), 6q22.2 (rs9387478, P = 4.14 × 10-10) and 6p21.32 (rs2395185, P = 9.51 × 10-9). We also confirmed associations reported for loci at 5p15.33 and 3q28 and a recently reported finding at 17q24.3. We observed no evidence of association for lung cancer at 15q25 in never-smoking women in Asia, providing strong evidence that this locus is not associated with lung cancer independent of smoking.
PMCID: PMC4169232  PMID: 23143601
5.  Incidence and Risk Factors of Infectious Complications Related to Implantable Venous-Access Ports 
Korean Journal of Radiology  2014;15(4):494-500.
The purpose of this study was to determine the incidence and risk factors of infections associated with implantable venous access ports (IVAPs).
Materials and Methods
From August 2003 through November 2011, 1747 IVAPs were placed in our interventional radiology suite. One hundred forty four IVAPs were inserted in patients with hematologic malignancy and 1603 IVAPs in patients with solid tumors. Among them, 40 ports (23 women and 17 men; mean age, 57.1 years; range, 13-83) were removed to treat port-related infections. We evaluated the incidence of port-related infection, patient characteristics, bacteriologic data, and patient progress. Univariable analyses (t test, chi-square test, and Fisher's exact test) and multiple logistic regression analyses were used to determine the risk factors for IVAP related infection.
Overall, 40 (2.3%) of 1747 ports were removed for symptoms of infection with an incidence rate of 0.067 events/1000 catheter-days. According to the univariable study, the incidences of infection were seemingly higher in the patients who received the procedure during inpatient treatment (p = 0.016), the patients with hematologic malignancy (p = 0.041), and the patients receiving palliative chemotherapy (p = 0.022). From the multiple binary logistic regression, the adjusted odds ratios of infection in patients with hematologic malignancies and those receiving palliative chemotherapy were 7.769 (p = 0.001) and 4.863 (p = 0.003), respectively. Microorganisms were isolated from 26 (65%) blood samples, and two of the most causative organisms were found to be Staphylococcus (n = 10) and Candida species (n = 7).
The underlying hematologic malignancy and the state of receiving palliative chemotherapy were the independent risk factors of IVAP-related infection.
PMCID: PMC4105813  PMID: 25053910
Intravenous access; Cancer patient; Subcutaneous port; Infection; Complication
6.  Case Report of Pulmonary Sarcoidosis Suspected to be Pulmonary Metastasis in a Patient with Breast Cancer 
Standard endocrine therapy and chemotherapy can induce long-term remission in breast cancer patients; however, breast cancer can recur at any site. Pulmonary nodules with lymphadenopathy in advanced cancer patients are likely to be assumed as metastases. A 44-year-old woman with a history of breast cancer was presented to our institution with abnormal findings on 18-fluorodeoxyglucose positron emission tomography imaging, which suggested lung metastasis. She had previously been diagnosed with breast cancer (T1N2M0, Stage IIIa, intraductal carcinoma, triple negative cancer). Histological analysis of the mediastinal lymph node biopsy demonstrated sarcoidosis, showing a chronic, non-caseating, granulomatous inflammation. Our case highlights the need for non-malignant diagnoses in those with prior malignancies, and the need for histological evaluations in the event of first recurrence following potentially curative therapy.
PMCID: PMC4132448  PMID: 25038768
Breast neoplasms; Sarcoidosis; Positron-emission tomography; Neoplasm metastasis
7.  Modified MVAC as a Second-Line Treatment for Patients with Metastatic Urothelial Carcinoma after Failure of Gemcitabine and Cisplatin Treatment 
There is no established standard second-line chemotherapy for patients with advanced or metastatic urothelial carcinoma (UC) who failed gemcitabine and cisplatin (GC) chemotherapy. This study was conducted in order to investigate the efficacy and toxicity of modified methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) in patients with metastatic UC previously treated with GC.
Materials and Methods
We retrospectively analyzed 28 patients who received modified MVAC between November 2004 and November 2012. All patients failed prior, first-line GC chemotherapy.
The median age of patients was 64.0 years (range, 33.0 to 77.0 years), and 23 (82.1%) patients had an Eastern Cooperative Oncology Group performance status of 0 or 1. The overall response rate and the disease control rate were 36.0% and 64.0%, respectively. After a median follow-up period of 38 weeks (range, 5 to 182 weeks), median progression free survival was 21.0 weeks (95% confidence interval [CI], 6.3 to 35.7 weeks) and median overall survival was 49.0 weeks (95% CI, 18.8 to 79.3 weeks). Grade 3 or 4 hematological toxicities included neutropenia (n=21, 75.0%) and anemia (n=9, 32.1%). Grade 3 or 4 non-hematological toxicities did not occur and there was no treatment-related death.
Modified MVAC appears to be a safe and active chemotherapy regimen in patients with stable physical status and adequate renal function after GC treatment.
PMCID: PMC4022826  PMID: 24851109
Urothelial carcinoma; M-VAC protocol; Second-line; Cisplatin failure
8.  Impact of KRAS Mutation Status on Outcomes in Metastatic Colon Cancer Patients without Anti-Epidermal Growth Factor Receptor Therapy 
Activating mutation of the KRAS oncogene is an established negative predictor for anti-epidermal growth factor receptor (anti-EGFR) therapies in metastatic colorectal cancer (CRC). However, KRAS mutation as a prognostic factor of survival outcome remains controversial in CRC, independent of anti-EGFR therapies.
Materials and Methods
We conducted a retrospective analysis of 103 CRC patients who were available for evaluation of KRAS mutation status. None of the patients analyzed had received anti-EGFR therapies. The role of KRAS mutation status was evaluated as a predictive factor for oxaliplatin or irinotecan and as a prognostic factor in CRC patients who did not receive anti-EGFR therapies.
Mutations in KRAS were observed in 48.5% of patients. The response for oxaliplatin- (p=0.664) and irinotecan-based (p=0.255) cytotoxic chemotherapy did not differ according to the KRAS mutation status. In addition, no significant difference in progression free survival (PFS; oxaliplatin, p=0.583 and irinotecan, p=0.426) and overall survival (OS; p=0.258) was observed between the wild and mutant type of the KRAS gene. In univariate and multivariate analyses, KRAS mutations did not have a major prognostic value regarding PFS (oxaliplatin: hazard ratio, 0.892; 95% confidence interval [CI], 0.590 to 1.347; p=0.586 and irinotecan: hazard ratio, 0.831; 95% CI, 0.524 to 1.319; p=0.433) or OS (hazard ratio, 0.754; 95% CI, 0.460 to 1.236; p=0.263). In addition, anti-vascular endothelial growth factor therapies did not affect PFS to oxaliplatin or irinotecan and OS.
KRAS mutation is not a prognostic marker for PFS to oxaliplatin or irinotecan and OS in CRC patients who did not receive anti-EGFR therapies.
PMCID: PMC3629364  PMID: 23613671
KRAS; Anti-EGFR; Colorectal neoplasms
9.  Effects of oral iron chelator deferasirox on human malignant lymphoma cells 
The Korean Journal of Hematology  2012;47(3):194-201.
Iron is essential for cell proliferation and viability. It has been reported that iron depletion by a chelator inhibits proliferation of some cancer cells. Deferasirox is a new oral iron chelator, and a few reports have described its effects on lymphoma cells. The goal of this study was to determine the anticancer effects of deferasirox in malignant lymphoma cell lines.
Three human malignant lymphoma cell lines (NCI H28:N78, Ramos, and Jiyoye) were treated with deferasirox at final concentrations of 20, 50, or 100 µM. Cell proliferation was evaluated by an MTT assay, and cell cycle and apoptosis were analyzed by flow cytometry. Western blot analysis was performed to determine the relative activity of various apoptotic pathways. The role of caspase in deferasirox-induced apoptosis was investigated using a luminescent assay.
The MTT assay showed that deferasirox had dose-dependent cytotoxic effects on all 3 cell lines. Cell cycle analysis showed that the sub-G1 portion increased in all 3 cell lines as the concentration of deferasirox increased. Early apoptosis was also confirmed in the treated cells by Annexin V and PI staining. Western blotting showed an increase in the cleavage of PARP, caspase 3/7, and caspase 9 in deferasirox-treated groups.
We demonstrated that deferasirox, a new oral iron-chelating agent, induced early apoptosis in human malignant lymphoma cells, and this apoptotic effect is dependent on the caspase-3/caspase-9 pathway.
PMCID: PMC3464336  PMID: 23071474
Deferasirox; Malignant lymphoma; Apoptosis
10.  Chemotherapy in Patients Older than or Equal to 75 Years with Advanced Non-small Cell Lung Cancer 
As the number of elderly patients diagnosed with non-small cell lung carcinoma (NSCLC) increases, the number of these patients receiving chemotherapy also increases. However, limited data exists regarding the use of chemotherapy in advanced NSCLC patients who are 75 years of age or older.
Materials and Methods
Between May 2002 and October 2008, data for 48 advanced NSCLC patients who were 75 years of age or older who had been treated with chemotherapy were retrospectively analyzed.
The median age of study participants at the time of first line chemotherapy was 76 years (range, 75 to 87 years) and their median Charlson comorbidity index was 2 (range, 1 to 4). Of the total 48 patients, 43 patients (90%) were treated by platinum-based doublet as a first line chemotherapy regimen. Median progression free survival for first line chemotherapy was 5.7 months (95% confidence interval [CI], 4.93 to 6.47 months) with an overall response rate of 33.3%. After first line chemotherapy, only 14 of the 48 patients (29.2%) received second line chemotherapy. The median overall survival (OS) for these patients was 8.2 months (95% CI, 4.44 to 11.96 months). Multivariate analysis results indicated that female gender and having received second-line or more chemotherapy were independent prognostic factors for increased OS for all 48 patients. Charlson Index was not a significant independent prognostic factor for survival. There were 9 treatment related deaths due to infectious causes (18.8%).
Patients 75 years of age or older with advanced NSCLC may obtain clinical benefit from the administration of platinum-based doublet or single agent chemotherapy. However, oncologists must consider the aspect of safety in relation to the clinical benefits when managing this patient group.
PMCID: PMC3322199  PMID: 22500159
Aged; Non-small-cell lung carcinoma; Drug therapy
11.  An Association Study of Polymorphisms in JAK3 Gene with Lung Cancer in the Korean Population 
The genetic alteration of the janus kinases (JAKs), non-receptor tyrosine kinase, is related to the development of human cancers. However, little is known about how the sequence variation of JAK3 contributes to the development of lung cancer. This study investigated whether polymorphisms at the promoter region of the JAK3 gene are associated with the risk of lung cancer in the Korean population.
Materials and Methods
A total of 819 subjects, including 409 lung cancer patients and 410 healthy controls were recruited. The SNaPshot assay and polymerase chain reaction-restriction fragment length polymorphism analysis were used, and logistic regression analyses were performed to characterize the association between polymorphisms of JAK3 and lung cancer risk.
Three polymorphisms (-672 G>A, +64 A>G and +227 G>A) of JAK3 were analyzed for large-scale genotyping (n=819). Statistical analyses revealed that polymorphisms and haplotypes in the JAK3 gene were not significantly associated with lung cancer.
JAK3 gene was not significantly associated with the risk of lung cancer in the Korean population.
PMCID: PMC3138914  PMID: 21811427
Janus kinase 3; Lung cancer; Polymorphism; Haplotypes; Korea
12.  The 5p15.33 Locus Is Associated with Risk of Lung Adenocarcinoma in Never-Smoking Females in Asia 
PLoS Genetics  2010;6(8):e1001051.
Genome-wide association studies of lung cancer reported in populations of European background have identified three regions on chromosomes 5p15.33, 6p21.33, and 15q25 that have achieved genome-wide significance with p-values of 10−7 or lower. These studies have been performed primarily in cigarette smokers, raising the possibility that the observed associations could be related to tobacco use, lung carcinogenesis, or both. Since most women in Asia do not smoke, we conducted a genome-wide association study of lung adenocarcinoma in never-smoking females (584 cases, 585 controls) among Han Chinese in Taiwan and found that the most significant association was for rs2736100 on chromosome 5p15.33 (p = 1.30×10−11). This finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls (p = 5.38×10−11). A pooled analysis achieved genome-wide significance for rs2736100. This SNP marker localizes to the CLPTM1L-TERT locus on chromosome 5p15.33 (p = 2.60×10−20, allelic risk = 1.54, 95% Confidence Interval (CI) 1.41–1.68). Risks for heterozygote and homozygote carriers of the minor allele were 1.62 (95% CI; 1.40–1.87), and 2.35 (95% CI: 1.95–2.83), respectively. In summary, our results show that genetic variation in the CLPTM1L-TERT locus of chromosome 5p15.33 is directly associated with the risk of lung cancer, most notably adenocarcinoma.
Author Summary
Worldwide, approximately 15% of lung cancer cases occur among nonsmokers. Genome-wide association studies (GWAS) of lung cancer conducted in populations of European background have identified three regions on chromosomes 5, 6, and 15 that harbor genetic variants that confer risk for lung cancer. Prior studies were conducted primarily in cigarette smokers, raising the possibility that the associations could be related to tobacco use, lung carcinogenesis, or both. A GWAS of lung cancer among never-smokers is an optimal setting to discover effects that are independent of smoking. Since most women in Asia do not smoke, we conducted a GWAS of lung adenocarcinoma among never-smoking females (584 cases, 585 controls) in Taiwan, and observed a region on chromosome 5 significantly associated with risk for lung cancer in never-smoking women. The finding was independently replicated in seven studies from East Asia totaling 1,164 lung adenocarcinomas and 1,736 controls. To our knowledge, this study is the first reported GWAS of lung cancer in East Asian women, and together with the replication studies represents the largest genetic association study in this population. The findings provide insight into the genetic contribution of common variants to lung carcinogenesis.
PMCID: PMC2916850  PMID: 20700438
13.  Treatment results including more than third-line chemotherapy for patients with advanced non-small cell lung cancer 
Oncology Letters  2010;1(1):51-55.
Recently, third-line chemotherapy for advanced non-small cell lung cancer (NSCLC) was accepted as a reasonable therapeutic option in patients with a favorable performance status. In practice, however, palliative chemotherapy has been performed for patients with a favorable performance status, even after third-line chemotherapy. Although multiple cycles of palliative chemotherapy were performed for these patients, there are little data of observation for courses of treatment from first-line to the last chemotherapy. We reviewed the courses of treatment for 82 patients with advanced NSCLC that had been admitted for platinum-based chemotherapy as a first-line treatment. Additional cycles of palliative chemotherapy were provided as monotherapy, based on the attending physician’s decision considering patient performance status and toxicity after disease progression for previous chemotherapy. The median number of chemotherapy lines and cycles were 2 and 7, respectively, from first-line to the last chemotherapy. The median overall survival was 24 months in the response group of first-line chemotherapy, compared to 15 months for the entire study group. In the response group, the median number of chemotherapy cycles was 15 and patients received a median of 3 lines of chemotherapy. A total of 33 patients were candidate third-line chemotherapy or more. The median survival was 23 months for patients treated with more than third-line chemotherapy, compared to 7 months for patients treated with less than second-line chemotherapy. We conclude that long-standing chemotherapy is not beneficial to all NSCLC patients. However, patients with a favorable response to first-line chemotherapy tend to receive a higher number and more cycles of chemotherapy than the non-response group. Furthermore, multi-line chemotherapy appears to increase survival in the response group. Further studies will be needed to confirm these results.
PMCID: PMC3436213  PMID: 22966255
more than third-line; chemotherapy; advanced; non-small cell lung cancer
14.  No Association between Promoter Polymorphism of STK11 Gene and Lung Cancer Risk in the Korean Population 
Serine-threonine kinase11 (STK11) was originally identified in 1997 as the causative mutation that's responsible for Peutz-Jeghers Syndrome (PJS). Several recent studies have reported that the STK11 gene is an important human tumor suppressor gene in lung cancer. We evaluated the associations between the polymorphisms of the STK11 promoter region and the risk of lung cancer in 901 Koreans.
Materials and Methods
By direct sequencing, we first discovered three novel polymorphisms (-1,795 T>C, -981 C>T and -160 G>T) and four known polymorphisms (-1,580 C>T, -1,494 A>C, -881 A>G and -458 G>C) of the STK11 promoter region in 24 blood samples of 24 Korean lung cancer patients. Further genotype analyses were then performed on 443 lung cancer patients and 458 controls.
We discovered three novel polymorphisms and we identified four known polymorphisms of the STK11 promoter region in a Korean population. Statistical analyses revealed that the genotypes and haplotypes in the STK11 gene were not significantly associated with the risk of lung cancer in a Korean population.
This is the first study that's focused on the association of STK11 promoter polymorphisms and the risk of lung cancer in a Korean population. To evaluate the role of the STK11 gene for the risk of lung cancer, the genotypes of the STK11 promoter region (-1,795 T>C, -1,494 A>C and -160 G>T) were determined in 901 Koreans, yet the result revealed no significant difference between the lung cancer patients and the controls. These results suggest that the three promoter polymorphisms we studied are not important risk factors for the susceptibility to lung cancer in Koreans.
PMCID: PMC2802846  PMID: 20057966
Serine-threonine kinase11 (STK11); Lung neoplasms; Single nucleotide polymorphism (SNP)
15.  Randomized, Multicenter, Phase III Trial of Heptaplatin 1-hour Infusion and 5-Fluorouracil Combination Chemotherapy Comparing with Cisplatin and 5-Fluorouracil Combination Chemotherapy in Patients with Advanced Gastric Cancer 
Heptaplatin (Sunpla) is a cisplatin derivative. A phase IIb trial using heptaplatin resulted in a 34% response rate with mild nephrotoxicity. We conducted a randomized phase III trial of heptaplatin plus 5-FU compared with cisplatin plus 5-FU in patients with advanced gastric cancer.
Materials and Methods
One hundred seventy-four patients (heptaplatin, n=88; cisplatin, n=86) from 13 centers were enrolled. The eligibility criteria were as follows: patients with pathologically-proven adenocarcinoma, chemonaive patients, or patients who had received only single adjuvant chemotherapy, and who had a measurable or evaluable lesion. On day 1, heptaplatin (400 mg/m2) or cisplatin (60 mg/m2) was given over 1 hour with 5-FU (1 gm/m2) on days 1~5 every 4 weeks.
At the time of survival analysis, the median overall survival was 7.3 months in the 5-FU + heptaplatin (FH) arm and 7.9 months in the 5-FU + cisplatin (FP) arm (p=0.24). Of the FH patients, 34.2% (complete response [CR], 1.3%; partial response [PR], 32.9%) experienced a confirmed objective response compared with 35.9% (CR 0%, PR 35.9%) of FP patients (p=0.78). The median-time-to-progression was 2.5 months in the FH arm and 2.3 months in the FP arm. The incidence of neutropenia was higher with FP (28%) than with FH (16%; p=0.06); grade 3~4 nausea and vomiting were more frequent in the FP than in the FH arm (p=0.01 and p=0.05, respectively). The incidence of increased proteinuria and creatininemia was higher with FH than with FP; however, there was no statistical difference. There were no treatment-related deaths.
Heptaplatin showed similar effects to cisplatin when combined with 5-FU in advanced gastric cancer patients with tolerable toxicities.
PMCID: PMC2699097  PMID: 19688066
Combination chemotherapy; Advanced gastric cancer; Heptaplatin
16.  Clinical Factors Related to Suspected Second Primary Lung Cancer Development in Patients with Head and Neck Cancer 
The rate of second primary lung cancer development for patients with head and neck cancer (HNC) has been noted. The aim of our study was to evaluate the incidence and clinical features of suspected second primary lung cancer that developed in patients with primary HNC.
Materials and Methods
We conducted a retrospective study of 469 patients who were newly diagnosed with HNC at the Korea University Medical Center between January 2000 and December 2006.
A total of 469 patients were included (389 men and 80 women). Eighteen patients (3.8%) had suspected second primary lung cancers. Statistically significant clinical variables for lung cancer development included the origin site for the primary HNC (oro-hypopharynx and larynx) (p=0.048), abnormal chest x-ray findings (p=0.027) and the histological HNC type (squamous cell carcinoma) (p=0.032). When the second primary lung cancers were combined with HNCs, the adjusted overall survival of patients with a second primary lung cancer was 16 months (p<0.001).
Considering the relative risk factors for a second primary lung cancer developing in patients with HNC, advanced diagnostic tools, such as chest CT or PET CT scan, should be applied for the early detection of a second primary lung cancer.
PMCID: PMC2697475  PMID: 19688127
Chest x-ray; Head and neck neoplasms; Second primary cancer
17.  High-dose Immunoglobulin Infusion for Thrombotic Thrombocytopenic Purpura Refractory to Plasma Exchange and Steroid Therapy 
The outcomes of the treatment of thrombotic thrombocytopenic purpura (TTP) have been shown to be improved by the administration of plasma exchange. However, treatment options are currently limited for cases refractory to plasma exchange. The autoantibodies that block the activity of ADAMTS13 have been demonstrated to play a role in the pathogenesis of TTP; therefore, high-dose immunoglobulin, which can neutralize these autoantibodies, may be useful for refractory TTP. However, successful treatment with high-dose immunoglobulin for TTP refractory to plasma exchange and corticosteroids has yet to be reported in Korea. Herein, we describe a refractory case which was treated successfully with high-dose immunoglobulin. A 29-year-old male diagnosed with TTP failed to improve after plasma exchange coupled with additional high-dose corticosteroid therapy. As a salvage treatment, we initiated a 7-day regimen of high-dose immunoglobulin (400 mg/kg) infusions, which resulted in a complete remission, lasting up to the last follow-up at 18 months. High-dose immunoglobulin may prove to be a useful treatment for patients refractory to plasma exchange; it may also facilitate recovery and reduce the need for plasma exchange.
PMCID: PMC2686967  PMID: 18787371
Thrombotic Thrombocytopenic Purpura; Plasma Exchange; Glucocorticoids; Immunoglobulin
18.  Persistent Anemia in a Patient with Diffuse Large B Cell Lymphoma: Pure Red Cell Aplasia Associated with Latent Epstein-Barr Virus Infection in Bone Marrow 
Journal of Korean Medical Science  2007;22(Suppl):S167-S170.
We report a case of pure red cell aplasia (PRCA), which was initially suspected as a result of bone marrow involvement of diffuse large B cell lymphoma. Persistent anemia without an obvious cause was observed in a 47-yr-old man diagnosed with relapsed diffuse large B cell lymphoma. The bone marrow study showed only erythroid hypoplasia without the evidence of bone marrow involvement with lymphoma cells, thus PRCA was suggested. However, parvovirus infection was excluded as a potential cause of PRCA because of negative IgM anti-parvovirus B19 antibody and negative parvovirus PCR in the serum. Latent Epstein-Barr virus (EBV) infection of bone marrow was suggested by in situ hybridization with EBV-encoded small RNA (EBER) that showed a strong positive expression in bone marrow cells. Thus, PRCA was thought to be associated with latent EBV infection in bone marrow cells. Although the finding of unexplained anemia is a possible predictor of bone marrow involvement with lymphoma cells, PRCA as a result of a viral infection including EBV should be considered in lymphoma patients. This is the first report of the occurrence of PRCA associated with latent EBV infection in a patient with non-Hodgkin's lymphoma.
PMCID: PMC2694371  PMID: 17923747
Red-Cell Aplasia; Epstein-Barr Virus; Lymphoma
19.  Glucose Transporter-1 Expression in Squamous Cell Carcinoma of the Tongue 
Tumor cells are known to express hypoxia-related proteins such as glucose transporter-1 (Glut-1). These hypoxia-induced changes may allow tumor cells to survive under sustained hypoxic microenvironments, and the surviving tumor cell under hypoxia may develop a more aggressive phenotype and so result in a poor prognosis.
Materials and Methods
The Glut-1 expression was analyzed by immunohistochemistry, and its association with the prognosis was assessed in 60 patients with squamous cell carcinoma of the tongue.
The Glut-1 expression was diffuse with a membranous pattern, and the median percentage of Glut-1 positive tumor cells was 60% (range: 0.0~90.0%). A high Glut-1 expression (the percentage of positive tumor cells ≥ the median value, 60%) was associated with the location of primary lesion, lymph node metastasis status and disease stage (p<0.05). The expression of Glut-1 was correlated with the Ki-67 expression (r=0.406, p=0.001). Microvessel density, as represented by CD31 staining, was also correlated with the Glut-1 expression although its significance is weak (r=0.267, p=0.039). On the univariate analysis, the group with a high Glut-1 expression showed poorer overall survival than the group with a low Glut-1 expression (p<0.05). However, the Glut-1 expression failed to show any independent prognostic significance on the multivariate analysis.
The expression of Glut-1 may be useful for predicting the prognosis and determining the treatment strategy for the management of squamous cell carcinoma of the tongue.
PMCID: PMC2739325  PMID: 19746220
Tumor hypoxia; Glucose transporter-1; Squamous cell carcinoma; Tongue
20.  The Efficacy and Safety of Padexol® (Paclitaxel) and Cisplatin for Treating Advanced Non-small Cell Lung Cancer 
The authors conducted a multicenter study to evaluate the efficacy and safety of combination chemotherapy with Padexol® and cisplatin for treating patients with advanced non-small cell lung cancer (NSCLC).
Materials and Methods
From November 2003 to April 2005, 42 chemo-naive patients with advanced NSCLC were enrolled into this study from 4 hospitals. The treatment consisted of Padexol® 175 mg/m2 as a 3-hr infusion, and this was followed by cisplatin 75 mg/m2 administered as an intravenous infusion with standard premedication. The treatment was repeated every 3 weeks.
Among the 42 patients (pts), 33 pts were evaluable for response. On the per protocol analysis, 1 patient (pt) (3.0%) achieved complete response (CR), 17 pts (51.5%) achieved partial response (PR), 6 pts (18.2%) achieved stable disease (SD), and 9 pts (27.3%) progressed; therefore, the overall response rate was 54.6% (95% CI: 37.6~71.5%). On the intention-to-treat analysis, 1 pt (2.4%) achieved CR, 18 pts (42.9%) achieved PR, 11 pts (26.2%) achieved SD, and 9 pts (21.4%) progressed; therefore, the overall response rate was 45.2% (95% CI: 30.2~60.3%). The response, as evaluated by the investigators, was independently reviewed by 2 external radiologists and it was as follows; 13 PR (43.3%), 14 SD (46.7%) and 3 progressive disease (10%). The median duration of response was 5.9 months. The median follow-up duration was 10.3 months (range: 1.3 to 22.1 months). The median time to progression was 5.8 months (95% CI: 4.7 to 7.4 months). The median survival time on the intention-to-treat analysis was 10.5 months (95% CI: 8.1 to 18.8 months). The most common grade 3 or 4 hematologic toxicities were neutropenia (26/180 cycles, 14.4%), anemia (7/180 cycles, 3.9%) and febrile neutropenia (2/180 cycles, 1.1%). The most frequent grade 3 or 4 non-hematologic toxicities were nausea (14/42 patients, 14.3%), anorexia (3/42 patients, 7.1%) and myalgia (3/42 patients, 7.1%).
The authors observed that Padexol® was as good as the other paclitaxel (Taxol® or Genexol®) formulations when combined with cisplatin for treating patients with advanced NSCLC.
PMCID: PMC2741668  PMID: 19771262
Non-small cell lung cancer; Chemotherapy; Padexol®; Cisplatin
21.  Hematopoietic Differentiation of Embryoid Bodies Derived from the Human Embryonic Stem Cell Line SNUhES3 in Co-culture with Human Bone Marrow Stromal Cells 
Yonsei Medical Journal  2005;46(5):693-699.
Human embryonic stem (ES) cells can be induced to differentiate into hematopoietic precursor cells via two methods: the formation of embryoid bodies (EBs) and co-culture with mouse bone marrow (BM) stromal cells. In this study, the above two methods have been combined by co-culture of human ES-cell-derived EBs with human BM stromal cells. The efficacy of this method was compared with that using EB formation alone. The undifferentiated human ES cell line SNUhES3 was allowed to form EBs for two days, then EBs were induced to differentiate in the presence of a different serum concentration (EB and EB/high FBS group), or co-cultured with human BM stromal cells (EB/BM co-culture group). Flow cytometry and hematopoietic colony-forming assays were used to assess hematopoietic differentiation in the three groups. While no significant increase of CD34+/CD45- or CD34+/CD38- cells was noted in the three groups on days 3 and 5, the percentage of CD34+/CD45- cells and CD34+/CD38- cells was significantly higher in the EB/BM co-culture group than in the EB and EB/high FBS groups on day 10. The number of colony-forming cells (CFCs) was increased in the EB/BM co-culture group on days 7 and 10, implying a possible role for human BM stromal cells in supporting hematopoietic differentiation from human ES cell-derived EBs. These results demonstrate that co-culture of human ES-cell-derived EBs with human BM stromal cells might lead to more efficient hematopoietic differentiation from human ES cells cultured alone. Further study is warranted to evaluate the underlying mechanism.
PMCID: PMC2810577  PMID: 16259069
Embryonic stem cells; embryoid body; differentiation
22.  Reliability and Validity of the Korean Cancer Pain Assessment Tool (KCPAT) 
Journal of Korean Medical Science  2005;20(5):877-882.
The Korean Cancer Pain Assessment Tool (KCPAT), which was developed in 2003, consists of questions concerning the location of pain, the nature of pain, the present pain intensity, the symptoms associated with the pain, and psychosocial/spiritual pain assessments. This study was carried out to evaluate the reliability and validity of the KCPAT. A stratified, proportional-quota, clustered, systematic sampling procedure was used. The study population (903 cancer patients) was 1% of the target population (90,252 cancer patients). A total of 314 (34.8%) questionnaires were collected. The results showed that the average pain score (5 point on Likert scale) according to the cancer type and the at-present average pain score (VAS, 0-10) were correlated (r=0.56, p<0.0001), and showed moderate agreement (kappa=0.364). The mean satisfaction score was 3.8 (1-5). The average time to complete the questionnaire was 8.9 min. In conclusion, the KCPAT is a reliable and valid instrument for assessing cancer pain in Koreans.
PMCID: PMC2779289  PMID: 16224166
Neoplasms; Pain; Pain Measurement; Reliability; Validity; Reproducibility of Results; Korean
23.  Prevalence of BRCA1 and BRCA2 Mutations in Korean Breast Cancer Patients 
Journal of Korean Medical Science  2004;19(2):269-274.
The incidence of breast cancer in Korea has been increasing in recent years, such that it is now the most common female cancer. Breast cancer in Korea is characterized by an earlier age of onset than in Western countries, suggesting that it would be related with genetic background. We assayed germline mutations in the BRCA genes to evaluate their genetic pathology in Korean breast cancer patients. The study subjects consisted of 173 patients at clinically higher risk and 109 unselected patients. Germline mutations in the entire coding sequences of the BRCA1 and BRCA2 genes were analyzed by Conformation-Sensitive Gel Electrophoresis (CSGE), and any aberrantly-sized band was sequenced. BRCA mutations were present in 12.7% of the high risk patients, compared with 2.8% of the unselected patients. Among high risk patients, mutations were most prevalent in patients with a family history of breast or first-degree ovarian cancer (22.1%), followed by those with male breast cancer (20%), bilateral breast cancer (20%), multiple organ cancer including breast (13%) and younger breast cancer patients (aged <35 yr) (8.1%). Moreover, BRCA mutations were detected in 34.8% of patients having two high-risk factors. These findings suggest that BRCA gene mutation analysis should be performed on Korean patients with high-risk factors for breast cancer.
PMCID: PMC2822310  PMID: 15082902
Breast Neoplasms; Genes, BRCA1; Prevalence; Koreans
24.  ESHAP salvage therapy for relapsed or refractory non-Hodgkin's lymphoma. 
Journal of Korean Medical Science  2002;17(5):621-624.
The ESHAP regimen, a combination of the chemotherapeutic drugs etoposide, methylprednisolone (solumedrol), high-dose cytarabine (ara-C), and cisplatin, has been shown to be active against refractory or relapsed non-Hodgkin's lymphoma (NHL) in therapeutic trials. We undertook this study to determine whether this regimen would be effective and tolerable in Korean patients. A total of 40 patients with refractory or relapsed NHL (8 indolent and 32 aggressive) were enrolled in this study. The overall response rate was 70% (95% confidence interval; 59.8-89.7%); 22.5% of patients achieved a complete response and 47.5% a partial response. The median survival duration was 12 months (95% confidence interval; 5.9-18.1 months) and the median duration of progression-free survival was 9 months (95% confidence interval; 1.1-16.9 months). The median survival duration of patients with relapsed NHL was longer than that of patients with refractory lymphoma (15 months vs 4 months, p=0.02). Myelosuppression was the most frequent complication and treatment-related mortality was noted in two patients. These results suggest that the ESHAP regimen is effective in patients with relapsed NHL who have a sensitive disease. The role of ESHAP chemotherapy in discriminating patients who are more likely to benefit from a subsequent transplant should be evaluated in the future.
PMCID: PMC3054931  PMID: 12378012
25.  Genetic variant in TP63 on locus 3q28 is associated with risk of lung adenocarcinoma among never-smoking females in Asia 
Hosgood, H. Dean | Wang, Wen-Chang | Hong, Yun-Chul | Wang, Jiu-Cun | Chen, Kexin | Chang, I-Shou | Chen, Chien-Jen | Lu, Daru | Yin, Zhihua | Wu, Chen | Zheng, Wei | Qian, Biyun | Park, Jae Yong | Kim, Yeul Hong | Chatterjee, Nilanjan | Chen, Ying | Chang, Gee-Chen | Hsiao, Chin-Fu | Yeager, Meredith | Tsai, Ying-Huang | Wei, Hu | Kim, Young Tae | Wu, Wei | Zhao, Zhenhong | Chow, Wong-Ho | Zhu, Xiaoling | Lo, Yen-Li | Sung, Sook Whan | Chen, Kuan-Yu | Yuenger, Jeff | Kim, Joo Hyun | Huang, Liming | Chen, Ying-Hsiang | Gao, Yu-Tang | Kim, Jin Hee | Huang, Ming-Shyan | Jung, Tae Hoon | Caporaso, Neil | Zhao, Xueying | Huan, Zhang | Yu, Dianke | Kim, Chang Ho | Su, Wu-Chou | Shu, Xiao-Ou | Kim, In-San | Bassig, Bryan | Chen, Yuh-Min | Cha, Sung Ick | Tan, Wen | Chen, Hongyan | Yang, Tsung-Ying | Sung, Jae Sook | Wang, Chih-Liang | Li, Xuelian | Park, Kyong Hwa | Yu, Chong-Jen | Ryu, Jeong-Seon | Xiang, Yongbing | Hutchinson, Amy | Kim, Jun Suk | Cai, Qiuyin | Landi, Maria Teresa | Lee, Kyoung-Mu | Hung, Jen-Yu | Park, Ju-Yeon | Tucker, Margaret | Lin, Chien-Chung | Ren, Yangwu | Perng, Reury-Perng | Chen, Chih-Yi | Jin, Li | Chen, Kun-Chieh | Li, Yao-Jen | Chiu, Yu-Fang | Tsai, Fang-Yu | Yang, Pan-Chyr | Fraumeni, Joseph F. | Seow, Adeline | Lin, Dongxin | Zhou, Baosen | Chanock, Stephen | Hsiung, Chao Agnes | Rothman, Nathaniel | Lan, Qing
Human genetics  2012;131(7):10.1007/s00439-012-1144-8.
A recent genome-wide association study (GWAS) of subjects from Japan and South Korea reported a novel association between the TP63 locus on chromosome 3q28 and risk of lung adenocarcinoma (p = 7.3 × 10−12); however, this association did not achieve genome-wide significance (p < 10−7) among never-smoking males or females. To determine if this association with lung cancer risk is independent of tobacco use, we genotyped the TP63 SNPs reported by the previous GWAS (rs10937405 and rs4488809) in 3,467 never-smoking female lung cancer cases and 3,787 never-smoking female controls from 10 studies conducted in Taiwan, Mainland China, South Korea, and Singapore. Genetic variation in rs10937405 was associated with risk of lung adenocarcinoma [n = 2,529 cases; p = 7.1 × 10−8; allelic risk = 0.80, 95% confidence interval (CI) = 0.74–0.87]. There was also evidence of association with squamous cell carcinoma of the lung (n = 302 cases; p = 0.037; allelic risk = 0.82, 95% CI = 0.67–0.99). Our findings provide strong evidence that genetic variation in TP63 is associated with the risk of lung adenocarcinoma among Asian females in the absence of tobacco smoking.
PMCID: PMC3875137  PMID: 22367405

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