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Volume 48(3); July 2016
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Original Articles
Incidence and Survival of Childhood Cancer in Korea
Hyeon Jin Park, Eun-Kyeong Moon, Ju Young Yoon, Chang-Mo Oh, Kyu-Won Jung, Byung Kiu Park, Hee Young Shin, Young-Joo Won
Cancer Res Treat. 2016;48(3):869-882.   Published online January 21, 2016
DOI: https://doi.org/10.4143/crt.2015.290
AbstractAbstract PDFPubReaderePub
Purpose
An epidemiologic study of childhood cancer would provide useful information on cancer etiology and development of management guidelines.
Materials and Methods
Data from the Korea National Cancer Incidence Database were used to examine the incidence and survival of cancer in patients aged 0-14 years. Patients were grouped according to the International Classification of Childhood Cancer, 3rd edition. Age-specific and age-standardized incidences per million and estimated annual percentage change (APC) were calculated by sex and age. Five-year relative survival was calculated for four periods from 1993 to 2011.
Results
The study comprised 15,113 patients with malignant neoplasms. Age-standardized incidence rates for all cancers were 134.9 per million children in 1999-2011 and 144.0 and 124.9 per million for males and females, respectively (M/F ratio, 1.2; p < 0.05). The highest incidences were observed for ‘leukemias, myeloproliferative diseases, and myelodysplastic diseases’ (group I) (46.4), ‘central nervous system neoplasms’ (group III) (18.3), and ‘lymphomas and reticuloendothelial neoplasms’ (group II) (13.4). Age-standardized incidence increased from 117.9 in 1999 to 155.3 in 2011, with an APC of 2.4% (95% confidence interval, 2.1 to 2.7). There was a significant increase of APC in ‘neuroblastoma and other peripheral nervous cell tumors’ (group IV) (5.6%) and ‘other malignant epithelial neoplasms and malignant melanomas’ (group XI) (5.6%). The 5-year relative survival rate for all childhood cancers improved significantly from 56.2% (1993-1995) to 78.2% (2007-2011) (males, 56.7% to 77.7%; females, 55.5% to 78.8%).
Conclusion
This study provides reliable information on incidence and survival trends for childhood cancer in Korea.

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Responses to Overdiagnosis in Thyroid Cancer Screening among Korean Women
Sangeun Lee, Yoon Young Lee, Hyo Joong Yoon, Eunji Choi, Mina Suh, Boyoung Park, Jae Kwan Jun, Yeol Kim, Kui Son Choi
Cancer Res Treat. 2016;48(3):883-891.   Published online December 28, 2015
DOI: https://doi.org/10.4143/crt.2015.218
AbstractAbstract PDFPubReaderePub
Purpose
Communicating the harms and benefits of thyroid screening is necessary to help individuals decide on whether or not to undergo thyroid cancer screening. This study was conducted to assess changes in thyroid cancer screening intention in response to receiving information about overdiagnosis and to determine factors with the greatest influence thereon.
Materials and Methods
Data were acquired from subjects included in the 2013 Korean National Cancer Screening Survey (KNCSS), a nationwide, population-based, cross-sectional survey. Of the 4,100 respondents in the 2013 KNCSS, women were randomly subsampled and an additional face-to-face interview was conducted. Finally, a total of 586 female subjects were included in this study. Intention to undergo thyroid cancer screening was assessed before and after receiving information on overdiagnosis.
Results
Prior awareness of overdiagnosis in thyroid cancer screening was 27.8%. The majority of subjects intended to undergo thyroid cancer screening before and after receiving information on overdiagnosis (87% and 74%, respectively). Only a small number of subjects changed their intention to undergo thyroid cancer screening from positive to negative after receiving information on overdiagnosis. Women of higher education level and Medical Aid Program recipients reported being significantly more likely to change their intention to undergo thyroid cancer screening afterreceiving information on overdiagnosis,whilewomen with stronger beliefs on the efficacy of cancer screening were less likely to change their intention.
Conclusion
Women in Korea appeared to be less concerned about overdiagnosis when deciding whether or not to undergo thyroid cancer screening.

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The Clinical Status of Radiation Therapy in Korea in 2009 and 2013
Jin-Kyu Kang, Mi-Sook Kim, Won-Il Jang, Hee Jin Kim, Chul Koo Cho, Hyung Jun Yoo, Young Seok Seo, Eun Kyung Paik, Yu Jin Cha
Cancer Res Treat. 2016;48(3):892-898.   Published online December 14, 2015
DOI: https://doi.org/10.4143/crt.2015.370
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study is to estimate the clinical status of radiation therapy (RT) in Korea.
Materials and Methods
We analyzed open claims data from the Health Insurance Review and Assessment Service (HIRA). The subjects were patients with malignant neoplasms who had procedure codes concerning RT in 2009 and 2013.
Results
The total numbers of patients who underwent RT in 2009 and 2013 were 42,483 and 56,850, respectively. The numbers of men and women were 20,012 and 22,471 in 2009 and 26,936 and 29,914 in 2013, respectively. The five most frequent RT sites were metastatic, breast, gastrointestinal, thoracic, and gynecologic cancers in 2009, and metastatic, breast, gastrointestinal, thoracic and head and neck cancers in 2013. The three leading types of cancer among men were metastatic, gastrointestinal, and thoracic, and breast, metastatic, and gynecologic among women. According to age, the most common treatment site was the central nervous system for those aged 20 years or less, the breast for those in their 30s to 50s, and metastatic sites for those in their 60s or older.
Conclusion
Data from this study provide an overview of the clinical status of RT in Korea.

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Changing Patterns of Primary Treatment in Korean Men with Prostate Cancer Over 10 Years: A Nationwide Population Based Study
Jinsung Park, Beomseok Suh, Dong Wook Shin, Jun Hyuk Hong, Hanjong Ahn
Cancer Res Treat. 2016;48(3):899-906.   Published online October 20, 2015
DOI: https://doi.org/10.4143/crt.2015.212
AbstractAbstract PDFPubReaderePub
Purpose
We investigated changing patterns of primary treatment in Korean men with prostate cancer (PC) and impact of sociodemographic factors on treatment choice from a nationwide cohort over 10 years. Materials and Methods We conducted a cohort study of a 2% nationwide random sample of Korean National Health Insurance. A total of 1,382 patients who had undergone active treatments for newly diagnosed PC between 2003 and 2013 were included. Time trends in primary treatment of PC, including radical surgery, radiation therapy (RT), and androgen deprivation therapy (ADT) were analyzed.
Results
Total number of patients undergoing active treatments increased significantly (162%). Surgery cases showed the most significant increase, from 22.4% in 2003 to 45.4% in 2013, while the relative proportion of ADT showed a tendency to decrease from 60.3% in 2003 to 45.4% in 2013, and the relative proportion of RT was variable over 10 years (from 7.2% to 18.4%). While treatment patterns differed significantly according to age (p < 0.001) and income classes (p=0.014), there were differences in primary treatment according to residential area. In multinomial logistic regression analysis, older patients showed significant association with ADT or RT compared to surgery, while patients with higher income showed significant association with surgery. Conclusion Treatment pattern in Korean PC patients has changed remarkably over the last 10 years. Sociodemographic factors do affect the primary treatment choice. Our results will be valuable in overviewing changing patterns of primary treatment in Korean PC patients and planning future health policy for PC.

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The Effect of Induction Chemotherapy Using Docetaxel, Cisplatin, and Fluorouracil on Survival in Locally Advanced Head and Neck Squamous Cell Carcinoma: A Meta-Analysis
Ryul Kim, Seokyung Hahn, Junghoon Shin, Chan-Young Ock, Miso Kim, Bhumsuk Keam, Tae Min Kim, Dong-Wan Kim, Dae Seog Heo
Cancer Res Treat. 2016;48(3):907-916.   Published online November 17, 2015
DOI: https://doi.org/10.4143/crt.2015.359
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The purpose of this study was to compare the survival of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) undergoing concurrent chemoradiotherapy (CRT) alone with that of patients undergoing induction chemotherapy (IC) using docetaxel, cisplatin, and 5-fluorouracil (TPF) followed by CRT.
Materials and Methods
A search of the PubMed, EMBASE, and Cochrane Library databases was performed in April 2015 and abstracts from the American Society of Clinical Oncology meetings (2008-2014) were reviewed. Summaries of the results were pooled using a fixed-effect model, and the risk of bias was evaluated using the Cochrane tool.
Results
A total of six relevant trials comprising 1,280 patients were identified. There was no statistically significant overall survival (OS) advantage for TPF prior to CRT (TPF/CRT) over CRT alone (hazard ratio [HR] 0.92; 95% confidence interval [CI], 0.79 to 1.09; p=0.339). Progression- free survival (PFS) was significantly longer in the TPF/CRT arms (HR, 0.82; 95% CI, 0.70 to 0.95; p=0.009). Patients with non-oropharyngeal LA-HNSCC obtained the greatest OS and PFS benefits from TPF (HR, 0.68; 95% CI, 0.47 to 0.99; p=0.043 and HR, 0.67; 95% CI, 0.48 to 0.94; p=0.022, respectively). The complete response rate was significantly increased (risk ratio [RR], 1.34; 95% CI, 1.14 to 1.56; p < 0.001), and the distant metastasis rate tended to decrease (RR, 0.65; 95% CI, 0.40 to 1.04; p=0.071) in the TPF/CRT arms.
Conclusion
IC with TPF followed by CRT is not superior to CRT alone for OS. However, PFS and the complete response rate were significantly improved in the TPF/CRT arms. TPF/CRT for patients with nonoropharyngeal LA-HNSCC provided clear survival advantages.

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The Role of Neoadjuvant Chemotherapy in the Treatment of Nasopharyngeal Carcinoma: A Multi-institutional Retrospective Study (KROG 11-06) Using Propensity Score Matching Analysis
Jin Ho Song, Hong-Gyun Wu, Bhum Suk Keam, Jeong Hun Hah, Yong Chan Ahn, Dongryul Oh, Jae Myoung Noh, Hyo Jung Park, Chang Geol Lee, Ki Chang Keum, Jihye Cha, Kwan Ho Cho, Sung Ho Moon, Ji-Yoon Kim, Woong-Ki Chung, Young Taek Oh, Won Taek Kim, Moon-June Cho, Chul Seung Kay, Yeon-Sil Kim
Cancer Res Treat. 2016;48(3):917-927.   Published online December 28, 2015
DOI: https://doi.org/10.4143/crt.2015.265
AbstractAbstract PDFPubReaderePub
Purpose
We compared the treatment results and toxicity in nasopharyngeal carcinoma (NPC) patients treated with concurrent chemotherapy (CCRT) alone (the CRT arm) or neoadjuvant chemotherapy followed by CCRT (the NCT arm). Materials and Methods A multi-institutional retrospective study was conducted to review NPC patterns of care and treatment outcome. Data of 568 NPC patients treated by CCRT alone or by neoadjuvant chemotherapy followed by CCRT were collected from 15 institutions. Patients in both treatment arms were matched using the propensity score matching method, and the clinical outcomes were analyzed.
Results
After matching, 300 patients (150 patients in each group) were selected for analysis. Higher 5-year locoregional failure-free survival was observed in the CRT arm (85% vs. 72%, p=0.014). No significant differences in distant failure-free survival (DFFS), disease-free survival (DFS), and overall survival were observed between groups. In subgroup analysis, the NCT arm showed superior DFFS and DFS in stage IV patients younger than 60 years. No significant difference in compliance and toxicity was observed between groups, except the radiation therapy duration was slightly shorter in the CRT arm (50.0 days vs. 53.9 days, p=0.018). Conclusion This study did not show the superiority of NCT followed by CCRT over CCRT alone. Because NCT could increase the risk of locoregional recurrences, it can only be considered in selected young patients with advanced stage IV disease. The role of NCT remains to be defined and should not be viewed as the standard of care.

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The Clinical Usefulness of 18F-Fluorodeoxyglucose Positron Emission Tomography (PET) to Predict Oncologic Outcomes and PET-Based Radiotherapeutic Considerations in Locally Advanced Nasopharyngeal Carcinoma
Hong In Yoon, Kyung Hwan Kim, Jeongshim Lee, Yun Ho Roh, Mijin Yun, Byoung Chul Cho, Chang Geol Lee, Ki Chang Keum
Cancer Res Treat. 2016;48(3):928-941.   Published online December 11, 2015
DOI: https://doi.org/10.4143/crt.2015.275
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We investigated 18F-fluorodeoxyglucose positron emission tomography (PET)-derived parameters as prognostic indices for disease progression and survival in locally advanced nasopharyngeal carcinoma (NPC) and the effect of high-dose radiotherapy for a subpopulation with PET-based poor prognoses.
Materials and Methods
Ninety-seven stage III and Iva-b NPC patients who underwent definitive treatment and PET were reviewed. For each primary, nodal, and whole tumor, maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis (TLG) were evaluated.
Results
Based on the C-index (0.666) and incremental area under the curve (0.669), the whole tumor TLGwas the most useful predictorfor progression-free survival (PFS); thewhole tumor TLG cut-off value showing the best predictive performance was 322.7. In multivariate analysis, whole tumor TLG was a significant prognostic factor for PFS (hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.14 to 0.65; p=0.002) and OS (HR, 0.29; 95% CI, 0.11 to 0.79; p=0.02). Patients with low whole tumor TLG showed the higher 5-year PFS in the subgroup for only patients receiving intensity modulated radiotherapy (77.4% vs. 53.0%, p=0.01). In the subgroup of patients with high whole tumor TLG, patients receiving an EQD2 ≥ 70 Gy showed significantly greater complete remission rates (71.4% vs. 33.3%, p=0.03) and higher 5-year OS (74.7% vs. 19.6%, p=0.02).
Conclusion
Our findings demonstrated that whole tumor TLG could be an independent prognostic factor and high-dose radiotherapy could improve outcomes for NPC showing high whole tumor TLG.

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  • Predictive significance of pretreatment 18F‐FDG PET volumetric parameters on survival outcomes in pediatric patients with locally advanced undifferentiated nasopharyngeal carcinoma
    Gihan El‐Hennawy, Salma ElMenawi, Eman Nasr Said, Wael Zekri, Mohamed Zaghloul, Ahmed Mustafa Abd Elsalam, Habiba El‐Fendy, Ismail Elantably
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    Bedriye Büşra Demirel, Seda Gülbahar Ateş, Ebru Atasever Akkaş, Fatih Göksel, Gülin Uçmak
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TERT Promoter Mutations and Tumor Persistence/Recurrence in Papillary Thyroid Cancer
Jae Kyung Myung, Byung Kuk Kwak, Jung Ah Lim, Myung-Chul Lee, Min Joo Kim
Cancer Res Treat. 2016;48(3):942-947.   Published online December 28, 2015
DOI: https://doi.org/10.4143/crt.2015.362
AbstractAbstract PDFPubReaderePub
Purpose
A telomerase reverse transcriptase (TERT) promoter mutation was identified in thyroid cancer. This TERT promoter mutation is thought to be a prognostic molecular marker, because its association with tumor aggressiveness, persistence/recurrence, and disease-specific mortality in papillary thyroid carcinoma (PTC) has been reported. In this study, we attempted to determine whether the impact of the TERT promoter mutation on PTC persistence/ recurrence is independent of clinicopathological parameters. Materials and Methods Using propensity score matching, 39 patients with PTC persistence or recurrence were matched with 35 patients without persistence or recurrence, with a similar age, sex, tumor size, multifocality, bilaterality, extrathyroidal extension, and lymph node metastasis. The TERT promoter and the BRAF V600E mutations were identified from PTC samples.
Results
The TERT promoter mutation was detected in 18% of PTC patients (13/74). No significant difference in the frequency of the TERT promoter mutation was observed between the persistence/ recurrence group and the non-recurrence group. Conclusion These results suggest that the prognostic implications of the TERT promoter mutation are dependent on clinicopathological parameters.

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  • TERT genetic polymorphism rs2736100 is associated with an aggressive manifestation of papillary thyroid carcinoma
    Xilin Nie, Jinbiao Shang, Wendong Wang
    Frontiers in Surgery.2023;[Epub]     CrossRef
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    Jingxin Mao, Xingliang Huang, Mohammad K. Okla, Mostafa A. Abdel-Maksoud, Ayman Mubarak, Zahid Hameed, Razia Noreen, Aqsa Chaudhary, Shakira Ghazanfar, Yixuan Liao, Yasir Hameed, Chen Li, Min Tang
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    Shalu Sharma, Shantanu Chowdhury
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    Antónia Afonso Póvoa, Elisabete Teixeira, Maria Rosa Bella-Cueto, Rui Batista, Ana Pestana, Miguel Melo, Thalita Alves, Mafalda Pinto, Manuel Sobrinho-Simões, Jorge Maciel, Paula Soares
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  • Suspicious ultrasound and clinicopathological features of papillary thyroid carcinoma predict the status of TERT promoter
    Hui Shi, Le-Hang Guo, Yi-Feng Zhang, Hui-Jun Fu, Jia-Yi Zheng, Han-Xiang Wang, Chong-Ke Zhao, Hui-Xiong Xu
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    Magalie Dosset, Andrea Castro, Hannah Carter, Maurizio Zanetti
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    Tiago Bordeira Gaspar, Ana Sá, José Manuel Lopes, Manuel Sobrinho-Simões, Paula Soares, João Vinagre
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    JiHoon Kang, Kanghee Han, Hyeon Jin Kim, Ju Hui Park, Jun Suk Kong, Sunhoo Park, Jae Kyung Myung
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    Anqi Jin, Jianhao Xu, Yan Wang
    Medicine.2018; 97(29): e11548.     CrossRef
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    Fabio Maino, Raffaella Forleo, Furio Pacini
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    Tiantian Liu, Xiaotian Yuan, Dawei Xu
    Genes.2016; 7(7): 38.     CrossRef
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    Muhammad Ramlee, Jing Wang, Wei Toh, Shang Li
    Genes.2016; 7(8): 50.     CrossRef
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Polymorphic Variants in Oxidative Stress Genes and Acute Toxicity in Breast Cancer Patients Receiving Radiotherapy
Elisa Eugenia Córdoba, Martín Carlos Abba, Ezequiel Lacunza, Eduardo Fernánde, Alba Mabel Güerci
Cancer Res Treat. 2016;48(3):948-954.   Published online January 14, 2016
DOI: https://doi.org/10.4143/crt.2015.360
AbstractAbstract PDFPubReaderePub
Purpose
Reactive oxygen species (ROS) are generated as an indirect product of radiation therapy (RT). Genetic variation in genes related to ROS metabolism may influence the level of RT-induced adverse effects. We evaluated the potential association of single nucleotide polymorphism (SNP)–related response to radiotherapy injury in breast cancer patients undergoing RT. Materials and Methods Eighty patients receiving conventional RT were included. Acute effects were evaluated according to the Radiation Therapy Oncology Group (RTOG) scores. DNA was extracted from blood and buccal swab samples. SNPs were genotyped for GSTP1, GSTA1, SOD2, and NOS3 genes by polymerase chain reaction–based restriction fragment length polymorphism. Univariate analysis (odds ratios [ORs] and 95% confidence interval [CI]) and principal component analysis were used for correlation of SNPs and factors related to risk of developing ≥ grade 2 acute effects.
Results
Sixty-five patients (81.2%) showed side effects, 32 (40%) presented moderate to severe acute skin toxicity, and 33 (41.2%) manifested minimal acute skin reactions by the end of treatment. In both univariate and multivariate analyses, nominally significant associations were found among body mass index (OR, 3.14; 95% CI, 8.5338 to 1.1274; p=0.022), breast size (OR, 5.11; 95% CI, 17.04 to 1.54; p=0.004), and grade ≥ 2 acute radiation skin toxicity. A significant association was also observed between NOS3 G894T polymorphism (OR, 9.8; 95% CI, 211.6 to 0.45; p=0.041) and grade ≥ 2 acute radiation skin toxicity in patients with neo-adjuvant chemotherapy treatment. Conclusion The analysis of the factors involved in individual radiosensitivity contributed to the understanding of the mechanisms underlying this trait.

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Analysis of BRIP1 Variants among Korean Patients with BRCA1/2 Mutation-Negative High-Risk Breast Cancer
Haeyoung Kim, Dae-Yeon Cho, Doo Ho Choi, Gee Hue Jung, Inkyung Shin, Won Park, Seung Jae Huh, Seok Jin Nam, Jeong Eon Lee, Won Ho Gil, Seok Won Kim
Cancer Res Treat. 2016;48(3):955-961.   Published online January 19, 2016
DOI: https://doi.org/10.4143/crt.2015.191
AbstractAbstract PDFPubReaderePub
Purpose
The aim of the current study is to assess the spectrum of genetic variation in the BRIP1 gene among Korean high-risk breast cancer patients who tested negative for the BRCA1/2 mutation.
Materials and Methods
Overall, 235 Korean patientswith BRCA1/2 mutation–negative high-risk breast cancerwere screened for BRIP1 mutations. The entire BRIP1 gene was analyzed using fluorescent-conformation sensitive gel electrophoresis. In silico analysis of BRIP1 variants was performed using PolyPhen-2 and SIFT.
Results
A total of 20 sequence alterations including 12 exonic and eight intronic variantswere found. Among the 12 exonic variants, 10 were missense and two were silent mutations. No protein-truncating mutation was found among the tested patients. Among the 10 missense variants, four (p.L263F, p.L340F, p.L474P, and p.R848H) were predicted to be pathogenic by both PolyPhen-2 and SIFT, and these variants were found in five patients. Of the four missense variants, p.L263F, p.L474P, and p.R848H localize to regions between the helicase motifs, while p.L340F resides in an iron-sulfur domain of BRIP1.
Conclusion
No protein-truncating mutation in BRIP1 was found among the tested patients. The contribution of BRIP1 variants is thought to be minor in Korean non-BRCA1/2 high-risk breast cancer.

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Delay of Treatment Initiation Does Not Adversely Affect Survival Outcome in Breast Cancer
Tae-Kyung Yoo, Wonshik Han, Hyeong-Gon Moon, Jisun Kim, Jun Woo Lee, Min Kyoon Kim, Eunshin Lee, Jongjin Kim, Dong-Young Noh
Cancer Res Treat. 2016;48(3):962-969.   Published online October 22, 2015
DOI: https://doi.org/10.4143/crt.2015.173
AbstractAbstract PDFPubReaderePub
Purpose
Previous studies examining the relationship between time to treatment and survival outcome in breast cancer have shown inconsistent results. The aim of this study was to analyze the overall impact of delay of treatment initiation on patient survival and to determine whether certain subgroups require more prompt initiation of treatment.
Materials and Methods
This study is a retrospective analysis of stage I-III patients who were treated in a single tertiary institution between 2005 and 2008. Kaplan-Meier survival analysis and Cox proportional hazards regression model were used to evaluate the impact of interval between diagnosis and treatment initiation in breast cancer and various subgroups.
Results
A total of 1,702 patients were included. Factors associated with longer delay of treatment initiation were diagnosis at another hospital, medical comorbidities, and procedures performed before admission for surgery. An interval between diagnosis and treatment initiation as a continuous variable or with a cutoff value of 15, 30, 45, and 60 days had no impact on disease-free survival (DFS). Subgroup analyses for hormone-responsiveness, triple-negative breast cancer, young age, clinical stage, and type of initial treatment showed no significant association between longer delay of treatment initiation and DFS.
Conclusion
Our results show that an interval between diagnosis and treatment initiation of 60 days or shorter does not appear to adversely affect DFS in breast cancer.

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In Vitro Adenosine Triphosphate-Based Chemotherapy Response Assay as a Predictor of Clinical Response to Fluorouracil-Based Adjuvant Chemotherapy in Stage II Colorectal Cancer
Hye Youn Kwon, Im-kyung Kim, Jeonghyun Kang, Seung-Kook Sohn, Kang Young Lee
Cancer Res Treat. 2016;48(3):970-977.   Published online October 22, 2015
DOI: https://doi.org/10.4143/crt.2015.140
AbstractAbstract PDFPubReaderePub
Purpose
We evaluated the usefulness of the in vitro adenosine triphosphate-based chemotherapy response assay (ATP-CRA) for prediction of clinical response to fluorouracil-based adjuvant chemotherapy in stage II colorectal cancer. Materials and Methods Tumor specimens of 86 patients with pathologically confirmed stage II colorectal adenocarcinoma were tested for chemosensitivity to fluorouracil. Chemosensitivity was determined by cell death rate (CDR) of drug-exposed cells, calculated by comparing the intracellular ATP level with that of untreated controls. Results Among the 86 enrolled patients who underwent radical surgery followed by fluorouracilbased adjuvant chemotherapy, recurrence was found in 11 patients (12.7%). The CDR ≥ 20% group was associated with better disease-free survival than the CDR < 20% group (89.4% vs. 70.1%, p=0.027). Multivariate analysis showed that CDR < 20% and T4 stage were poor prognostic factors for disease-free survival after fluorouracil-based adjuvant chemotherapy. Conclusion In stage II colorectal cancer, the in vitro ATP-CRA may be useful in identifying patients likely to benefit from fluorouracil-based adjuvant chemotherapy.

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Prospective Study on the Incidence of Postoperative Venous Thromboembolism in Korean Patients with Colorectal Cancer
Eunyoung Lee, Sung-Bum Kang, Sang Il Choi, Eun Ju Chun, Min Jeong Kim, Duck-Woo Kim, Heung-Kwon Oh, Myong Hoon Ihn, Jin Won Kim, Soo-Mee Bang, Jeong-Ok Lee, Yu Jung Kim, Jee Hyun Kim, Jong Seok Lee, Keun-Wook Lee
Cancer Res Treat. 2016;48(3):978-989.   Published online November 17, 2015
DOI: https://doi.org/10.4143/crt.2015.311
AbstractAbstract PDFPubReaderePub
Purpose
Pharmacologic thromboprophylaxis is routinely recommended for Western cancer patients undergoing major surgery for prevention of venous thromboembolism (VTE). However, it is uncertainwhetherroutine administration of pharmacologic thromboprophylaxis is necessary in all Asian surgical cancer patients. This prospective study was conducted to examine the incidence of and risk factors for postoperative VTE in Korean colorectal cancer (CRC) patients undergoing major abdominal surgery. Materials and Methods This study comprised two cohorts, and none of patients received perioperative pharmacologic thromboprophylaxis. In cohort A (n=400), patients were routinely screened for VTE using lower-extremity Doppler ultrasonography (DUS) on postoperative days 5-14. In cohort B (n=148), routine DUS was not performed, and imaging was only performed when there were symptoms or signs that were suspicious for VTE. The primary endpoint was the VTE incidence at 4 weeks postoperatively in cohort A.
Results
The postoperative incidence of VTE was 3.0% (n=12) in cohort A. Among the 12 patients, eight had distal calf vein thromboses and one had symptomatic thrombosis. Age ≥ 70 years (odds ratio [OR], 5.61), ≥ 2 comorbidities (OR, 13.42), and white blood cell counts of > 10,000/μL (OR, 17.43) were independent risk factors for postoperative VTE (p < 0.05). In cohort B, there was one case of VTE (0.7%). Conclusion The postoperative incidence of VTE, which included asymptomatic cases, was 3.0% in Korean CRC patients who did not receive pharmacologic thromboprophylaxis. Perioperative pharmacologic thromboprophylaxis should be administered to Asian CRC patients on a riskstratified basis.

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Splenomegaly and Its Associations with Genetic Polymorphisms and Treatment Outcome in Colorectal Cancer Patients Treated with Adjuvant FOLFOX
Mi-Jung Kim, Sae-Won Han, Dae-Won Lee, Yongjun Cha, Kyung-Hun Lee, Tae-Yong Kim, Do-Youn Oh, Se Hyung Kim, Seock-Ah Im, Yung-Jue Bang, Tae-You Kim
Cancer Res Treat. 2016;48(3):990-997.   Published online January 14, 2016
DOI: https://doi.org/10.4143/crt.2015.296
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Splenomegaly is a clinical surrogate of oxaliplatin-induced sinusoidal obstruction syndrome (SOS). We investigated development of splenomegaly and its association with treatment outcome and genetic polymorphisms following adjuvant 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) in colorectal cancer (CRC) patients.
Materials and Methods
Splenomegaly was determined by spleen volumetry using computed tomography images obtained before initiation of chemotherapy and after completion of adjuvant FOLFOX in CRC patients. Ten genetic polymorphisms in 4 SOS-related genes (VEGFA, MMP9, NOS3, and GSTP1) were analyzed using DNA from peripheral blood mononuclear cells.
Results
Of 124 patients included, increase in spleen size was observed in 109 (87.9%). Median change was 31% (range, –42% to 168%). Patients with splenomegaly had more severe thrombocytopenia compared to patients without splenomegaly during the chemotherapy period (p < 0.0001). The cumulative dose of oxaliplatin and the lowest platelet count during the chemotherapy period were clinical factors associated with splenomegaly. However, no significant associations were found between genetic polymorphisms and development of splenomegaly. Disease-free survival was similar regardless of the development of splenomegaly.
Conclusion
Splenomegaly was frequently observed in patients receiving adjuvant FOLFOX and resulted in more severe thrombocytopenia but did not influence treatment outcome. Examined genetic polymorphisms did not predict development of splenomegaly.

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What Is the Ideal Tumor Regression Grading System in Rectal Cancer Patients after Preoperative Chemoradiotherapy?
Soo Hee Kim, Hee Jin Chang, Dae Yong Kim, Ji Won Park, Ji Yeon Baek, Sun Young Kim, Sung Chan Park, Jae Hwan Oh, Ami Yu, Byung-Ho Nam
Cancer Res Treat. 2016;48(3):998-1009.   Published online October 22, 2015
DOI: https://doi.org/10.4143/crt.2015.254
AbstractAbstract PDFPubReaderePub
Purpose
Tumor regression grade (TRG) is predictive of therapeutic response in rectal cancer patients after chemoradiotherapy (CRT) followed by curative resection. However, various TRG systems have been suggested, with subjective categorization, resulting in interobserver variability. This study compared the prognostic validity of four different TRG systems in order to identify the most ideal TRG system. Materials and Methods This study included 933 patients who underwent preoperative CRT and curative resection. Primary tumors alone were graded according to the American Joint Committee on Cancer (AJCC), Dworak, and Ryan TRG systems, and both primary tumors and regional lymph nodes were graded according to a modified Dworak TRG system. The ability of each TRG system to predict recurrence-free survival (RFS) and overall survival (OS) was analyzed using chisquare and C statistics.
Results
All four TRG systems were significantly predictive of both RFS and OS (p < 0.001 each), however none was a better predictor of prognosis than ypStage. Among the four TRGs, the mDworak TRG system was a better predictor of RFS and OS than the AJCC, Dworak, and Ryan TRG systems, and both the chi-square and C statistics were higher for the former, although the differences were not statistically significant. The combination of ypStage and the modified Dworak TRG better predicted RFS and OS than ypStage alone. Conclusion The modified Dworak TRG system for evaluation of entire tumors including regional lymph nodes is a better predictor of survival than current TRG systems for evaluation of the primary tumor alone.

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Cost Effectiveness of Colorectal Cancer Screening Interventions with Their Effects on Health Disparity Being Considered
Kwang-Sig Lee, Eun-Cheol Park
Cancer Res Treat. 2016;48(3):1010-1019.   Published online December 28, 2015
DOI: https://doi.org/10.4143/crt.2015.279
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The purpose of this study was to evaluate the cost effectiveness of colorectal cancer screening interventions with their effects on health disparity being considered.
Materials and Methods
Markov cohort simulation was conducted with the cycle/duration of 1/40 year(s). Data came from the results of randomized trials and others. Participants were hypothetical cohorts aged 50 years as of year 2013 in 16 Korean provinces. The interventions until the age of 80 were annual organized fecal occult blood test (FOBT) (standard screening), annual FOBT with basic reminders for provinces with higher mortalities than the national average (targeted reminder) and annual FOBT with basic/enhanced reminders for all provinces (universal reminder 1 and 2). The comparison was non-screening, the outcome was quality-adjusted life years, and only medical costs for screening and treatment were considered from a societal perspective. The Atkinson incremental cost effectiveness ratio (Atkinson ICER), the incremental cost effectiveness ratio adjusted by the Atkinson Inequality Index, was used to evaluate the cost effectiveness of the four interventions with their impacts on regional health disparity being considered.
Results
Health disparity was smallest (or greatest) in non-screening (or the standard screening). The targeted reminder had smaller health disparity, and smaller Atkinson ICER with respect to standard screening, than did the universal reminder 1 and 2.
Conclusion
The targeted reminder might be more cost effective than the universal reminders with their effects on health disparity being considered. This study helps to develop promotional effort for colorectal cancer screening with both the greatest cost effectiveness and the smallest health disparity

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    Amirhossein Fouladi, Amin Asadi, Eric A. Sherer, Mahboubeh Madadi
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    Thomas Ward, Ruben E. Mujica-Mota, Anne E. Spencer, Antonieta Medina-Lara
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    Qin Zhou, Hai-lin Li, Yan Li, Yu-ting Gu, Ying-ru Liang, Hua-zhang Liu, Ke Li, Hang Dong, Yuan-yuan Chen, Guo-zhen Lin
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Effect of Helicobacter pylori Eradication on Long-Term Survival after Distal Gastrectomy for Gastric Cancer
Young-Il Kim, Soo-Jeong Cho, Jong Yeul Lee, Chan Gyoo Kim, Myeong-Cherl Kook, Keun Won Ryu, Young-Woo Kim, Il Ju Choi
Cancer Res Treat. 2016;48(3):1020-1029.   Published online November 17, 2015
DOI: https://doi.org/10.4143/crt.2015.264
AbstractAbstract PDFPubReaderePub
Purpose
Negative Helicobacter pylori status has been identified as a poor prognostic factor for survival in gastric cancer (GC) patients who underwent surgery. The aim of this study was to examine the effect of H. pylori eradication on long-term outcomes after distal gastrectomy for GC.
Materials and Methods
We analyzed the survival of 169 distal GC patients enrolled in a prospective randomized trial evaluating histologic changes of gastric mucosa after H. pylori eradication in the remnant stomach. The outcomes measured were overall survival (OS) and GC recurrence rates.
Results
The median follow-up duration was 9.4 years. In the modified intention-to-treat analysis including patients who underwent H. pylori treatment (n=87) or placebo (n=82), 5-year OS rates were 98.9% in the treatment group and 91.5% in the placebo group, and KaplanMeier analysis showed no significant difference in OS (p=0.957) between groups. In multivariate analysis, no difference in overall mortality was observed between groups (adjusted hazard ratio [aHR] for H. pylori treatment, 0.75; p=0.495) or H. pylori-eradicated status (aHR for positive H. pylori status, 1.16; p=0.715), while old age, male sex, and advanced stage ≥ IIIa were independent risk factors. Six patients in the treatment group (6.9%) and seven patients in the placebo group (8.5%) had GC recurrences, and GC recurrence rates were not different according to H. pylori treatment (5-year GC recurrence rates, 4.6% in the treatment group vs. 8.5% in the placebo group; p=0.652).
Conclusion
H. pylori eradication for GC patients who underwent distal gastrectomy did not compromise long-term survival after surgery.

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  • Anti–Helicobacter pylori Treatment in Patients With Gastric Cancer After Radical Gastrectomy
    Zhoukai Zhao, Ruopeng Zhang, Guoming Chen, Man Nie, Feiyang Zhang, Xiaojiang Chen, Jun Lin, Zewei Chen, Feizhi Lin, Chengzhi Wei, Ziqi Zheng, Shenghang Ruan, Bowen Huang, Yingbo Chen, Runcong Nie
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    Zhifang Jia, Min Zheng, Jing Jiang, Donghui Cao, Yanhua Wu, Yuzheng Zhang, Yingli Fu, Xueyuan Cao
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    Kentaro Matsuo, Sang-Woong Lee, Ryo Tanaka, Yoshiro Imai, Kotaro Honda, Kohei Taniguchi, Hideki Tomiyama, Kazuhisa Uchiyama
    World Journal of Surgical Oncology.2021;[Epub]     CrossRef
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    Farid Rahimi, Amin Talebi Bezmin Abadi
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    Bo Li, Xiaoqian Lan, Li Wang, Jiani Zhao, Jingli Ding, Hao Ding, Jun Lei, Yiping Wei, Wenxiong Zhang
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    Yonghoon Choi, Nayoung Kim, Chang Yong Yun, Yoon Jin Choi, Hyuk Yoon, Cheol Min Shin, Young Soo Park, Sang-Hoon Ahn, Do Joong Park, Hye Seung Lee, Ji-Won Kim, Jin Won Kim, Keun-Wook Lee, Won Chang, Ji Hoon Park, Yoon Jin Lee, Kyoung Ho Lee, Young Hoon Kim
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    Minoosh Moghimi, Yousef Mortazavi, Saeed Razavi-Dizaji, Shahrbanoo Keyhanian, Zahra Ghadimi, Sahar Baba Ali, Saeideh Mazloomzadeh, Sattar Jafari, Reza Mansouri, Masoud Asadi-Khiavi
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    Il Ju Choi, Myeong-Cherl Kook, Young-Il Kim, Soo-Jeong Cho, Jong Yeul Lee, Chan Gyoo Kim, Boram Park, Byung-Ho Nam
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    Bum Jun Kim, Hyeong Su Kim, Hyun Joo Jang, Jung Han Kim
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    Sang Kil Lee
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Chronological Changes of Quality of Life in Long-Term Survivors after Gastrectomy for Gastric Cancer
Wansik Yu, Ki Bum Park, Ho Young Chung, Oh Kyoung Kwon, Seung Soo Lee
Cancer Res Treat. 2016;48(3):1030-1036.   Published online January 6, 2016
DOI: https://doi.org/10.4143/crt.2015.398
AbstractAbstract PDFPubReaderePub
Purpose
A few studies have prospectively evaluated changes in quality of life (QoL) after surgery in short-term survivors; however, no prospective study has evaluated the longitudinal changes in QoL in long-terms survivors. We prospectively evaluated the chronological changes in QoL after a gastrectomy over a 5-year postoperative period in a large group of patients. Materials and Methods QoL data from the European Organization for Research and Treatment of Cancer QLQ-C30 and the QLQ-STO22 questionnaires were obtained from 254 patients who completed the entire series of QoL assessments preoperatively and at 1, 2, 3, 4, and 5 years after surgery.
Results
There was no statistically significant change in global health status/QoL during the 5-year postoperative period. Decreases in QoL from upper gastrointestinal symptoms including diarrhea (p < 0.001), dysphagia (p < 0.001), reflux symptoms (p=0.029), and eating restrictions (p < 0.001) were observed among the long-term survivors. Decreased physical functioning (p < 0.001), role functioning (p < 0.001), and cognitive functioning (p < 0.001), along with fatigue (p=0.045) and a poor body image (p=0.003), negatively impacted the patients’ QoL for a long time. Conclusion Management of gastrointestinal symptoms should be specifically targeted as a part of longterm patient care after a gastrectomy. Proper nutritional care will improve food intake resulting in weight gain and improved physical functioning, role functioning, and body image. In addition, patients should be encouraged to preserve self-esteem and maintain social activity.

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Relationship between Salt Preference and Gastric Cancer Screening: An Analysis of a Nationwide Survey in Korea
Ji-Yeon Shin, Jeongseon Kim, Kui Son Choi, Mina Suh, Boyoung Park, Jae Kwan Jun
Cancer Res Treat. 2016;48(3):1037-1044.   Published online December 11, 2015
DOI: https://doi.org/10.4143/crt.2015.333
AbstractAbstract PDFPubReaderePub
Purpose
Epidemiological studies have demonstrated an association between excessive salt intake and gastric cancer risk, and this potential risk increases the need for adequate gastric cancer screening in individuals with high salt intake. However, the association between salt intake and gastric cancer screening in the general population has rarely been investigated. We explored the association between salt preference and participation in gastric cancer screening among a nationally representative Korean population.
Materials and Methods
The study population was derived from the Korean National Cancer Screening Survey (KNCSS) 2006-2007, an annual nationwide interview survey investigating cancer screening rates. Of 4,055 individuals who participated in the KNCSS 2006-2007, 3,336 individuals aged over 40 years were included in our analysis. The odds ratio (OR) and 95% confidence interval (CI) were estimated using polytomous logistic regression.
Results
Individuals with higher salt preference were less likely to participate in regular gastric cancer screening. After adjusting for age, sex, monthly household income, education, family history of cancer, and self-rated health status, ORs for undergoing regular gastric cancer screening were 1.00, 0.82 (95% CI, 0.61 to 1.12), 0.74 (95% CI, 0.54 to 1.00), 0.77 (95% CI, 0.56 to 1.05), and 0.38 (95% CI, 0.16 to 0.92) according to the level of salt preference (p for trend=0.048).
Conclusion
Individuals with higher salt preference showed suboptimal gastric cancer screening adherence compared to those with a lower salt preference. These findings highlight the need for better delivery of educational messages to change risk perceptions regarding gastric cancer screening practice.

Citations

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  • Socio-economic factors and medical conditions affecting regular stomach cancer screening in Korea: a retrospective longitudinal study using national public health data for 11 years
    J.-Y. Kim, J.Y. Hong, S.M. Kim, K.H. Ryu, D.S. Kim, S.H. Lee, J.H. Na, H.H. Cho, J. Yu, J. Lee
    Public Health.2024; 227: 70.     CrossRef
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    Martin C. S. Wong, Eman Yee‐man Leung, Sarah T. Y. Yau, Sze Chai Chan, Shaohua Xie, Wanghong Xu, Junjie Huang
    Cancer Medicine.2023; 12(21): 20544.     CrossRef
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    Jeeyoo Lee, Aesun Shin, Woo-Kyoung Shin, Ji-Yeob Choi, Daehee Kang, Jong-Koo Lee
    Epidemiology and Health.2023; 45: e2023070.     CrossRef
  • Dietary Salt Intake and Gastric Cancer Risk: A Systematic Review and Meta-Analysis
    Bo Wu, Dehua Yang, Shuhan Yang, Guangzhe Zhang
    Frontiers in Nutrition.2021;[Epub]     CrossRef
  • The Science of Salt: A focused review on salt‐related knowledge, attitudes and behaviors, and gender differences
    Briar McKenzie, Joseph Alvin Santos, Kathy Trieu, Sudhir Raj Thout, Claire Johnson, JoAnne Arcand, Jacqui Webster, Rachael McLean
    The Journal of Clinical Hypertension.2018; 20(5): 850.     CrossRef
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Concurrent Chemoradiotherapy Versus Chemotherapy Alone for Unresectable Locally Advanced Pancreatic Cancer: A Retrospective Cohort Study
Younak Choi, Do-Youn Oh, Kyubo Kim, Eui Kyu Chie, Tae-Yong Kim, Kyung-Hun Lee, Sae-Won Han, Seock-Ah Im, Tae-You Kim, Sung Whan Ha, Yung-Jue Bang
Cancer Res Treat. 2016;48(3):1045-1055.   Published online October 16, 2015
DOI: https://doi.org/10.4143/crt.2015.226
AbstractAbstract PDFPubReaderePub
Purpose
The optimal treatment strategy for locally advanced pancreatic cancer (LAPC), particularly the role of concurrent chemoradiotherapy (CCRT), remains debatable. We compared the clinical outcomes of CCRT and palliative chemotherapy alone (CA) in patients with unresectable LAPC. Materials and Methods Patients with LAPC who were consecutively treated between 2003 and 2010 were included. Resectability was evaluated according to National Comprehensive Cancer Network ver. 1.2012. The clinical outcomes for each treatment group (CCRT vs. CA) were evaluated retrospectively.
Results
Sixty-three patients (58.9%) and 44 patients (41.1%) were treated with CCRT and CA, respectively. The CCRT cohort included patients who were treated with CCRT with or without chemotherapy backbone (CCRT alone, induction chemotherapy-CCRT, CCRT-maintenance chemotherapy, and induction-CCRT-maintenance chemotherapy). Median progression-free survival (PFS) and overall survival (OS) of all patients were 7.2 months and 13.1 months. PFS of the CCRT and CA groups was 9.0 months and 4.4 months, respectively (p=0.020). OS of the CCRT and CA groups was 15.4 months and 9.3 months, respectively (p=0.011). In multivariate analysis, the adjusted hazard ratio of CCRT was 0.536 (p=0.003) for OS and 0.667 (p=0.078) for PFS. Although the pattern of failure was similar in the CCRT and CA groups, the times to both local and distant failure were significantly longer in the CCRT group. Conclusion In patients with unresectable LAPC, those who underwent CCRT during their entire treatment courses had longer OS than patients treated with chemotherapy alone.

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    B. Salas, L. Ferrera-Alayón, A. Espinosa-López, A. Vera-Rosas, E. Salcedo, A. Kannemann, A. Alayon, R. Chicas-Sett, M. LLoret, P.C. Lara
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Serum Concentrations of Selenium and Copper in Patients Diagnosed with Pancreatic Cancer
Marcin R. Lener, Rodney J. Scott, Anna Wiechowska-Kozłowska, Pablo Serrano-Fernández, Piotr Baszuk, Katarzyna Jaworska-Bieniek, Grzegorz Sukiennicki, Wojciech Marciniak, Magdalena Muszyńska, Józef Kładny, Tomasz Gromowski, Katarzyna Kaczmarek, Anna Jakubowska, Jan Lubiński
Cancer Res Treat. 2016;48(3):1056-1064.   Published online December 28, 2015
DOI: https://doi.org/10.4143/crt.2015.282
AbstractAbstract PDFPubReaderePub
Purpose
Understanding of the etiology and pathogenesis of pancreatic cancer (PaCa) is still insufficient. This study evaluated the associations between concentrations of selenium (Se) and copper (Cu) in the serum of PaCa patients.
Materials and Methods
The study included 100 PaCa patients and 100 control subjects from the same geographical region in Poland. To determine the average concentration of Se, Cu, and ratio Cu:Se in the Polish population, assay for Se and Cu was performed in 480 healthy individuals. Serum levels of Se and Cu were measured using inductively coupled plasma mass spectrometry.
Results
In the control group, the average Se level was 76 µg/L and Cu 1,098 µg/L. The average Se level among PaCa patients was 60 µg/L and the mean Cu level was 1,432 µg/L. The threshold point at which any decrease in Se concentration was associated with PaCa was 67.45 µg/L. The threshold point of Cu level above which there was an increase in the prevalence of PaCa was 1,214.58 µg/L. In addition, a positive relationship was observed between increasing survival time and Se plasma level.
Conclusion
This retrospective study suggests that low levels of Se and high levels of Cu might influence development of PaCa and that higher levels of Se are associated with longer survival in patients with PaCa. The results suggest that determining the level of Se and Cu could be incorporated into a risk stratification scheme for the selection and surveillance control examination to complement existing screening and diagnostic procedures.

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The Overexpression of CCAR1 in Hepatocellular Carcinoma Associates with Poor Prognosis
Sang Yun Ha, Jeong Hoon Kim, Jung Wook Yang, Jimin Kim, Binnari Kim, Cheol-Keun Park
Cancer Res Treat. 2016;48(3):1065-1073.   Published online October 16, 2015
DOI: https://doi.org/10.4143/crt.2015.302
AbstractAbstract PDFPubReaderePub
Purpose
Cell division cycle and apoptosis regulator 1 (CCAR1) plays a dynamic role in regulation of cell growth and apoptosis by serving as a cofactor of steroid/thyroid nuclear receptors, β- catenin, and p53 in a variety of cell types including different cancer cells. However, whether CCAR1 protein is overexpressed in hepatocellular carcinoma (HCC) and the prognostic significance of CCAR1 protein expression in HCC have not been reported. Materials and Methods In 167 HCC patients with long-term follow-up, CCAR1 protein expression was examined by immunohistochemistry.
Results
High CCAR1 protein expression was observed in 149 of the 167 HCC cases (89.2%) and showed significant correlation with microvascular invasion, intrahepatic metastasis, higher American Joint Committee on Cancer (AJCC) T stage, and early recurrence. High CCAR1 expression showed an unfavorable effect on recurrence-free survival (RFS) (p=0.002). In subgroup analysis, among patients with α-fetoprotein ≤ 20 ng/mL (n=54) and patients with AJCC T stage 1 (n=62), significant differences in RFS were observed between high CCAR1 expression groups and low CCAR1 expression groups (p=0.015 and p=0.004, respectively). High CCAR1 expression tended to be an independent predictor of shorter RFS (p=0.054) and showed an unfavorable effect on overall survival (OS) (p=0.015). In subgroup analysis, among patients with α-fetoprotein ≤ 20 ng/mL (n=54), significant difference in OS was observed between high CCAR1 expression group and low CCAR1 expression group (p=0.046). Conclusion CCAR1 protein could be a potential biomarker predicting RFS in HCC patients after curative hepatectomy. In addition, CCAR1 had prognostic values in HCC patients with normal serum α-fetoprotein levels or early stage HCC.

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Adjuvant Treatment after Surgery in Stage IIIA Endometrial Adenocarcinoma
Mee Sun Yoon, Seung Jae Huh, Hak Jae Kim, Young Seok Kim, Yong Bae Kim, Joo-Young Kim, Jong-Hoon Lee, Hun Jung Kim, Jihye Cha, Jin Hee Kim, Juree Kim, Won Sup Yoon, Jin Hwa Choi, Mison Chun, Youngmin Choi, Kang Kyoo Lee, Myungsoo Kim, Jae-Uk Jeong, Sei Kyung Chang, Won Park
Cancer Res Treat. 2016;48(3):1074-1083.   Published online October 29, 2015
DOI: https://doi.org/10.4143/crt.2015.356
AbstractAbstract PDFPubReaderePub
Purpose
We evaluated the role of adjuvant therapy in stage IIIA endometrioid adenocarcinoma patients who underwent surgery followed by radiotherapy (RT) alone or chemoradiotherapy (CTRT) according to risk group. Materials and Methods A multicenter retrospective study was conducted including patients with surgical stage IIIA endometrial cancertreated by radical surgery and adjuvant RT or CTRT. Disease-free survival (DFS) and overall survival (OS) were analyzed.
Results
Ninety-three patients with stage IIIA disease were identified. Nineteen patients (20.4%) experienced recurrence, mostly distant metastasis (17.2%). Combined CTRT did not affect DFS (74.1% vs. 82.4%, p=0.130) or OS (96.3% vs. 91.9%, p=0.262) in stage IIIA disease compared with RT alone. Patients with age ≥ 60 years, grade G2/3, and lymphovascular space involvement had a significantly worse DFS and those variables were defined as risk factors. The high-risk group showed a significant reduction in 5-year DFS (≥ 2 risk factors) (49.0% vs. 88.0%, p < 0.001) compared with the low-risk group (< 2). Multivariate analysis confirmed that more than one risk factor was the only predictor of worse DFS (hazard ratio, 5.45; 95% confidence interval, 2.12 to 13.98; p < 0.001). Of patients with no risk factors, a subset treated with RT alone showed an excellent 5-year DFS and OS (93.8% and 100%, respectively). Conclusion We identified a low-risk subset of stage IIIA endometrioid adenocarcinoma patients who might be reasonable candidates for adjuvant RT alone. Further randomized studies are needed to determine which subset might benefit from combined CTRT.

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Cisplatin, Gemcitabine, and Lapatinib as Neoadjuvant Therapy for Muscle-Invasive Bladder Cancer
Vivek Narayan, Ronac Mamtani, Stephen Keefe, Thomas Guzzo, S. Bruce Malkowicz, David J. Vaughn
Cancer Res Treat. 2016;48(3):1084-1091.   Published online December 2, 2015
DOI: https://doi.org/10.4143/crt.2015.405
AbstractAbstract PDFPubReaderePub
Purpose
We sought to investigate the safety and efficacy of gemcitabine, cisplatin, and lapatinib (GCL) as neoadjuvant therapy in patients with muscle-invasive bladder cancer (MIBC) planned for radical cystectomy.
Materials and Methods
Four cycles of GCL were administered as neoadjuvant therapy for patients with MIBC. Although initially designed as a phase II efficacy study with a primary endpoint of pathologic complete response at the time of radical cystectomy, the dose selected for investigation proved excessively toxic. A total of six patients were enrolled.
Results
The initial four patients received gemcitabine 1,000 mg/m2 intravenously on days 1 and 8 and cisplatin 70 mg/m2 intravenously on day 1 of each 21-day treatment cycle. Lapatinib was administered as 1,000 mg orally daily starting one week prior to the initiation of cycle 1 of gemcitabine and cisplatin (GC) and continuing until the completion of cycle 4 of GC. These initial doses were poorly tolerated, and the final two enrolled patients received a reduced lapatinib dose of 750 mg orally daily. However, reduction of the lapatinib dose did not result in improved tolerance or drug-delivery, and the trial was terminated early due to excessive toxicity. Grade 3/4 toxicities included diarrhea (33%), nausea/vomiting (33%), and thrombocytopenia (33%).
Conclusion
The addition of lapatinib to GC as neoadjuvant therapy for MIBC was limited by excessive treatment-related toxicity. These findings highlight the importance of thorough dose-escalation investigation of combination therapies prior to evaluation in the neoadjuvant setting, as well as the limitations of determination of maximum tolerated dose for novel targeted combination regimens.

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Systemic Treatments for Metastatic Renal Cell Carcinoma: 10-Year Experience of Immunotherapy and Targeted Therapy
Sung Han Kim, Weon Seo Park, Sun Ho Kim, Jae Young Joung, Ho Kyung Seo, Kang Hyun Lee, Jinsoo Chung
Cancer Res Treat. 2016;48(3):1092-1101.   Published online January 28, 2016
DOI: https://doi.org/10.4143/crt.2015.316
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study is to compare the outcomes of first-line systemic targeted therapy (TT) and immunotherapy (IT) in patients with metastatic renal cell carcinoma (mRCC).
Materials and Methods
This study was a retrospective review of the data of 262 patients treated with systemic IT or TT with tyrosine kinase inhibitors between 2003 and 2013. The objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were assessed using Response Evaluation Criteria in Solid Tumor ver. 1.0 criteria and the Kaplan-Meier method with log-rank test.
Results
During the median 4.3-month treatment and the 24-month follow-up period, the ORR/PFS/OS of the overall first-line and second-line therapy were 41.9%/8.1 months/16.8 months and 27.5%/6.5 months/15.3 months, respectively. The first-line TT/IT/sequential IT had a PFS of 9.3/6.4/5.7 months and an OS of 15.8/16.5/40.6 months (all p < 0.05). The second-line of TT/IT had a PFS of 7.1/2.1 months (both p < 0.05) and an OS of 16.6/8.6 months (p=0.636), respectively. Pazopanib provided the best median PFS of 11.0 months (p < 0.001) and a quadruple IT regimen had a superior PFS (p=0.522). For OS, sequential treatment with IT and TT was superior compared to treatment with either IT or TT alone (40.6/16.5/15.8 months, p=0.014). The prognosis according to the Memorial Sloan Kettering Cancer Center model showed that favorable/intermediate/poor risk groups had a PFS of 8.5/10.4/2.3 months, and an OS of 43.1/20.4/5.6 months, respectively. The prognosis calculated using the Heng model showed that the favorable/intermediate/poor risk groups had a PFS of 9.2/3.9/2.7 months, and an OS of 32.4/16.5/6.1months, respectively (all p < 0.001).
Conclusion
In patients with mRCC, TT provided a better PFS and OS compared with IT.

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Variation in Practice Patterns of Korean Radiation Oncologists for Spine Metastasis between 2009 and 2014
Jeong Il Yu, Hee Chul Park, Yong Chan Ahn, Yoonsun Chung, Woong Sub Koom, Si Yeol Song
Cancer Res Treat. 2016;48(3):1102-1109.   Published online December 2, 2015
DOI: https://doi.org/10.4143/crt.2015.207
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The Korean Society of Radiation Oncologists (KOSRO) conducted the Patterns of Care Study (PCS) of radiotherapy (RT) for spine metastases in 2009. The current study was conducted to investigate current practice patterns and compare them with the results of the PCS.
Materials and Methods
The survey questionnaire was composed of 10 questions regarding general information and seven questions for each of two clinical scenarios.
Results
Fifty-four members of the KOSRO answered at least one question on the web-based questionnaire. The yearly number of patients treated who underwent palliative spine RT was greater than 200 in 14 (25.9%), 51 to 100 in 13 (24.1%), and 31 to 50 in 11 respondents (20.4%). Scenario 1 described a patient presenting with cord compressive spine metastasis in multiple bones and liver metastasis from non-small cell lung cancer. Thirty gray (Gy) in 10 fractions was chosen by 35 respondents (64.8%). Scenario 2 described a case of a single spine metastasis without progression after targeted therapy. Thirty Gy in 10 fractions was chosen by 19 respondents (35.2%), and a single fraction or less than four fractions of stereotactic ablative radiotherapy (SABR) were selected by 18 respondents (33.3%). When compared with the 2009 PCS, practice patterns of Korean radiation oncologists had not changed significantly over 5 years, except that SABR emerged as a new treatment modality in the selected population.
Conclusion
The 2014 PCS demonstrated that multiple fraction RT is still preferred in a considerable proportion of Korean radiation oncologists.

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Clinical Characteristics and Continued Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Administration in EGFR-mutated Non-Small Cell Lung Cancer with Skeletal Metastasis
Sook-Hee Hong, Yeon-Sil Kim, Ji Eun Lee, In-ho Kim, Seung Joon Kim, Daehee Han, Ie Ryung Yoo, Yang-Guk Chung, Young-Hoon Kim, Kyo-Young Lee, Jin-Hyoung Kang
Cancer Res Treat. 2016;48(3):1110-1119.   Published online January 6, 2016
DOI: https://doi.org/10.4143/crt.2015.289
AbstractAbstract PDFPubReaderePub
Purpose
The aim of this study was to analyze clinical characteristics of skeletal metastasis in epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) and treatment outcomes of continued EGFR tyrosine kinase inhibitor (TKI) therapy in patients presenting with skeletal metastasis progression. Materials and Methods Of the 216 patients treated with EGFR-TKI for management of stage III-IV NSCLC between 2006 and 2012 in Seoul St. Mary’s Hospital, 76 patients with confirmed EGFR-mutated NSCLC with skeletal metastases during therapy were analyzed retrospectively.
Results
Of 76 patients with EGFR mutant lung cancer with skeletal metastasis, 37 patients developed first progressive disease (PD) in skeletal regions. EGFR-TKI was continued in these 37 patients after first PD in skeletal regions. Median time to first PD of skeletal regions was 8.9 months (95% confidence interval [CI], 4.8 to 13.0). Median time of continued EGFR-TKI after first PD of skeletal regions was 8.0 months (95% CI, 2.9 to 13.0) in patients with disease progression of preexisting regions, 5.6 months (95% CI, 4.5 to 6.7) in patients showing new localized regions, and 3.3 months (95% CI, 1.1 to 5.5) in patients with multiple new metastatic regions (p=0.006). Median time of postskeletal metastasis progression survival was 23.0 months (95% CI, 13.5 to 32.5), 15.0 months (95% CI, 3 to 34.7), and 7.0 months (95% CI, 6.0 to 8.0) (p=0.004) in the above described patient groups, respectively. Overall, seven patients (18.9%) had more than one episode of skeletal progression of disease without extraskeletal PD. Conclusion Continued EGFR-TKI treatment with adequate local treatment after progression of skeletal metastasis may be considered for patients who show disease progression in preexisting regions or local progression.

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A Multi-centric Bioequivalence Trial in Ph+ Chronic Myeloid Leukemia Patients to Assess Bioequivalence and Safety Evaluation of Generic Imatinib Mesylate 400 mg Tablets
Rachna Arora, Manju Sharma, Tausif Monif, Sunil Iyer
Cancer Res Treat. 2016;48(3):1120-1129.   Published online February 12, 2016
DOI: https://doi.org/10.4143/crt.2015.436
AbstractAbstract PDFPubReaderePub
Purpose
This study was designed to characterize the pharmacokinetic profile and to assess bioequivalence of the sponsor’s test formulation (imatinib mesylate 400 mg tablets) with an innovator product (Gleevec 400 mg tablets, Novartis Pharmaceuticals) under fed conditions, in adult patients of Philadelphia chromosome positive chronic myeloid leukemia (Ph+ CML) stabilized on imatinib mesylate 400 mg. In addition, the aim of this study was to monitor the safety profile of investigational medicinal products (IMPs).
Materials and Methods
A multicenter, randomized, open label, two-period, crossover, single dose bioequivalence study was designed for conduct under fed conditions in 42 adult Ph+ CML patients already stabilized on imatinib 400 mg tablets. Pharmacokinetic parameters Tmax, Cmax, and AUC0-24 were calculated using a non-compartmental model on validated WinNonlin software. Validated SAS software was used for statistical evaluation of data. The safety profile of investigational products was monitored during the course of study by applying a clinical process for recording observed untoward effects postadministration of investigational products.
Results
The 90% confidence intervals for the test/reference mean ratios of the ln-transformed PK variables Cmax (99.0%) and AUC0-24 (99.2%) were within an acceptable range of 80%-125%, as per bioequivalence assumptions. Both formulations were well tolerated after oral administration of IMPs.
Conclusion
The test product was found to be bioequivalent and safe, and thus can be used interchangeably in clinical practice.

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Isotype-Specific Inhibition of Histone Deacetylases: Identification of Optimal Targets for Radiosensitization
Jin Ho Kim, Sung Ho Moon, Mina No, Jae Jin Kim, Eun Jung Choi, Bong Jun Cho, Jae Sung Kim, Il Han Kim, In Ah Kim
Cancer Res Treat. 2016;48(3):1130-1140.   Published online November 17, 2015
DOI: https://doi.org/10.4143/crt.2015.206
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Histone deacetylase (HDAC) inhibitors radiosensitize tumor cells. To elucidate mechanisms underlying radiosensitization by HDAC inhibition, understanding of differential contributions of HDAC isotypes is needed. The aim of this study was to investigate involvement of known HDAC isotypes in modulation of cellular radiosensitivity. Materials and Methods Because pharmacologic HDAC inhibitors lack isotype-specificity, RNA interference against 11 HDAC isotypes was used to inhibit HDAC in an isotype-specific manner. Radiation cell survival was evaluated using a clonogenic assay in SQ20B cells transfected with small interfering RNA specifically targeting HDAC isotypes. Immunocytochemistry was performed for detection of γH2AX foci. Protein expression was measured using Western blotting.
Results
Among 11 HDAC isotypes tested, specific inhibition of 7 isotypes (HDAC1, HDAC3, HDAC4, HDAC6, HDAC7, HDAC10, and HDAC11) enhanced radiation lethality in SQ20B cells. Radiosensitization by inhibition of these HDAC isotypes was accompanied by delay of DNA double strand break repair. Radiosensitivity of SQ20B cells was not altered by selective inhibition of the remaining four isotypes (HDAC2, HDAC5, HDAC8, and HDAC9). Inhibition of HDAC isotypes resulted in downregulation of various proteins involved in pro-survival and DNA damage repair pathways. Conclusion Isotype-specificity exists in HDAC inhibition-induced radiosensitization. Different HDAC isotypes are differentially involved in modulation of cellular radiosensitivity.

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Dexamethasone Inhibits TGF-β1–Induced Cell Migration by Regulating the ERK and AKT Pathways in Human Colon Cancer Cells Via CYR61
Sanghoon Han, Ngoc Thuy Bui, Manh Tin Ho, Young Mee Kim, Moonjae Cho, Dong Bok Shin
Cancer Res Treat. 2016;48(3):1141-1153.   Published online December 15, 2015
DOI: https://doi.org/10.4143/crt.2015.209
AbstractAbstract PDFPubReaderePub
Purpose
One of the features in cancer development is the migration of cancer cells to form metastatic lesions. CYR61 protein promotes migration and the epithelial-mesenchymal transition in several cancer cell types. Evidence suggests that CYR61 and dexamethasone are relevant to colorectal cancer. However, relationships between them and colorectal cancer are still unclear. Understanding the molecular mechanism of colorectal cancer progression related with CYR61 and dexamethasone, which is widely used for combination chemotherapy, is necessary for improved therapy. Materials and Methods We used colorectal cancer cells, HCT116, co-treated with transforming growth factor β1 (TGF-β1) and dexamethasone to examine the inhibitory migration effect of dexamethasone by migratory assay. Alternatively, both migratory pathways, expression of AKT and ERK, and the target factor CYR61 was also tested by co-treatment with TGF-β1 and dexamethasone.
Results
We report that dexamethasone significantly inhibited TGF-β1–induced cell migration, without affecting cell proliferation. Importantly, we observed that TGF-β1 promoted the epithelial- mesenchymal transition process and that dexamethasone co-treatment abolished this effect. ERK and AKT signaling pathways were found to mediate TGF-β1–induced migration, which was inhibited by dexamethasone. In addition, TGF-β1 treatment induced CYR61 expression whereas dexamethasone reduced it. These observations were compatible with the modulation of migration observed following treatment of HCT116 cells with human recombinant CYR61 and anti-CYR61 antibody. Our results also indicated that TGF-β1 enhanced collagen I and reduced matrix metalloproteinase 1 expression, which was reversed by dexamethasone treatment. Conclusion These findings suggested that dexamethasone inhibits AKT and ERK phosphorylation, leading to decreased CYR61 expression, which in turn blocks TGF-β1–induced migration.

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