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Volume 49(1); January 2017
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Special Article
How Can We Treat Cancer Disease Not Cancer Cells?
Kyu-Won Kim, Su-Jae Lee, Woo-Young Kim, Ji Hae Seo, Ho-Young Lee
Cancer Res Treat. 2017;49(1):1-9.   Published online December 26, 2016
DOI: https://doi.org/10.4143/crt.2016.606
AbstractAbstract PDFPubReaderePub
Since molecular biology studies began, researches in biological science have centered on proteins and genes at molecular level of a single cell. Cancer research has also focused on various functions of proteins and genes that distinguish cancer cells from normal cells. Accordingly, most contemporary anticancer drugs have been developed to target abnormal characteristics of cancer cells. Despite the great advances in the development of anticancer drugs, vast majority of patients with advanced cancer have shown grim prognosis and high rate of relapse. To resolve this problem, we must reevaluate our focuses in current cancer research. Cancer should be considered as a systemic disease because cancer cells undergo a complex interaction with various surrounding cells in cancer tissue and spread to whole body through metastasis under the control of the systemic modulation. Human body relies on the cooperative interaction between various tissues and organs, and each organ performs its specialized function through tissue-specific cell networks. Therefore, investigation of the tumor-specific cell networks can provide novel strategy to overcome the limitation of current cancer research. This review presents the limitations of the current cancer research, emphasizing the necessity of studying tissue-specific cell network which could be a new perspective on treating cancer disease, not cancer cells.

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Original Articles
A Phase II Study of Poziotinib in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma Who Have Acquired Resistance to EGFR–Tyrosine Kinase Inhibitors
Ji-Youn Han, Ki Hyeong Lee, Sang-We Kim, Young Joo Min, Eunkyung Cho, Youngjoo Lee, Soo-Hyun Lee, Hyae Young Kim, Geon Kook Lee, Byung Ho Nam, Hyesun Han, Jina Jung, Jin Soo Lee
Cancer Res Treat. 2017;49(1):10-19.   Published online May 3, 2016
DOI: https://doi.org/10.4143/crt.2016.058
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
We examined the efficacy of poziotinib, a second-generation epidermal growth factor receptor (EGFR)–tyrosine kinase inhibitor (TKI) in patients with lung adenocarcinoma with activating EGFR mutations, who developed acquired resistance (AR) to EGFR-TKIs.
Materials and Methods
This single-arm phase II study included EGFR-mutant lung adenocarcinoma with AR to erlotinib or gefitinib based on the Jackman criteria. Patients received poziotinib 16 mg orally once daily in a 28-day cycle. The primary endpoint was progression-free survival (PFS). Prestudy tumor biopsies and blood samples were obtained to determine resistance mechanisms.
Results
Thirty-nine patients were treated. Tumor genotyping was determined in 37 patients; 19 EGFR T790M mutations and two PIK3CAmutations were detected in the prestudy tumors, and seven T790M mutations were detected in the plasma assay. Three (8%; 95% confidence interval [CI], 2 to 21) and 17 (44%; 95% CI, 28 to 60) patients had partial response and stable disease, respectively. The median PFS and overall survival were 2.7 months (95% CI, 1.8 to 3.7) and 15.0 months (95% CI, 9.5 to not estimable), respectively. A longer PFS was observed for patients without T790M or PIK3CA mutations in tumor or plasma compared to those with these mutations (5.5 months vs. 1.8 months, p=0.003). The most frequent grade 3 adverse events were rash (59%), mucosal inflammation (26%), and stomatitis (18%). Most patients required one (n=15) or two (n=15) dose reductions.
Conclusion
Low activity of poziotinib was detected in patients with EGFR-mutant non-small cell lung cancer who developed AR to gefitinib or erlotinib, potentially because of severe-toxicityimposed dose limitation.

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Minimally Invasive Stereotactical Radio-ablation of Adrenal Metastases as an Alternative to Surgery
Ciro Franzese, Davide Franceschini, Luca Cozzi, Giuseppe D’Agostino, Tiziana Comito, Fiorenza De Rose, Pierina Navarria, Pietro Mancosu, Stefano Tomatis, Antonella Fogliata, Marta Scorsetti
Cancer Res Treat. 2017;49(1):20-28.   Published online April 27, 2016
DOI: https://doi.org/10.4143/crt.2016.057
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to study the clinical outcome for patients with metastases of the adrenal gland treated with stereotactic body radiation therapy.
Materials and Methods
Forty-six patients were studied retrospectively. The dose prescription was 40 Gy in four fractions. Dosimetric analysis was performed using the dose volume histograms while clinical outcome was assessed using actuarial analysis with determination of the overall survival (OS) and local control (LC) rates.
Results
The planning objectives were met for all patients. With a median follow-up period of 7.6 months, at the last follow-up 42 patients (91.3%) were alive and four had died because of distant progression. The actuarial mean OS was 28.5±1.6 months, the median was not reached. One-year and 2-year OS were 87.6±6.1%. None of the risk factors was significant in univariate analysis. Actuarial mean LC was 14.6±1.8 months (95% confidence interval [CI], 11.0 to 18.2) and median LC was 14.5±2.0 months (95% CI, 10.5 to 18.5). One-year and 2-year LC were 65.5±11.9% and 40.7±15.8%, respectively. A mild profile of toxicity was observed in the cohort of patients. Forty patients (86.9%) showed no complication (grade 0); two patients reported asthenia, six patients (13.1%) reported either pain, nausea, or vomiting. Of these six patients, five patients (10.9%) were scored as grade 1 toxicity while one patient (2.2%) was scored as grade 2.
Conclusion
Stereotactic body radiation therapy treatment provided an adequate clinical response in the management of adrenal gland metastases.

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    Cihan YB
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Association between Metformin Use and Survival in Nonmetastatic Rectal Cancer Treated with a Curative Resection: A Nationwide Population Study
Young-Jun Ki, Hyo Jeong Kim, Mi-Sook Kim, Chan Mi Park, Min Jung Ko, Young Seok Seo, Sun Mi Moon, Jin A Choi
Cancer Res Treat. 2017;49(1):29-36.   Published online July 4, 2016
DOI: https://doi.org/10.4143/crt.2016.128
AbstractAbstract PDFPubReaderePub
Purpose
Metformin is associated with an anticancer effect. However, the effects of metformin in rectal cancer are controversial. This study investigated the impact of metformin on the survival of patients with diabetes mellitus and nonmetastatic rectal cancer who underwent curative surgery.
Materials and Methods
The database was provided by the Korea Center Cancer Registry and National Health Insurance Service of the Republic of Korea. A cohort of patients with newly diagnosed rectal cancer between 2005 and 2011 was identified. Drug exposure was defined as receiving the oral hypoglycemic agent for at least 90 days over the period from 6 months before the initial diagnosis of rectal cancer to the last follow-up.
Results
A total of 4,503 patients were prescribed oral hypoglycemic agents and classified as the diabetic group, of which 3,694 patients received metformin for at least 90 days. Unadjusted analyses showed a significantly higher overall survival (hazard ratio, 0.596; 95% confidence interval, 0.506 to 0.702) and rectal cancer-specific survival (hazard ratio, 0.621; 95% confidence interval, 0.507 to 0.760) in the metformin group than in the nonmetformin group. The adjusted overall survival (hazard ratio, 0.631; 95% confidence interval, 0.527 to 0.755) and cancer-specific survival (hazard ratio, 0.598; 95% confidence interval, 0.479 to 0.746) in the group with a medication possession ratio of 80% or greater was significantly higher than in the group with a medication possession ratio of less than 80%.
Conclusion
Metformin use is associated with overall and cancer-specific survival in diabetic patients with a nonmetastatic rectal cancer treated with a curative resection.

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Use of a High-Throughput Genotyping Platform (OncoMap) for RAS Mutational Analysis to Predict Cetuximab Efficacy in Patients with Metastatic Colorectal Cancer
Dalyong Kim, Yong Sang Hong, Jeong Eun Kim, Kyu-pyo Kim, Jae-Lyun Lee, Sung-Min Chun, Jihun Kim, Se Jin Jang, Tae Won Kim
Cancer Res Treat. 2017;49(1):37-43.   Published online April 27, 2016
DOI: https://doi.org/10.4143/crt.2016.069
AbstractAbstract PDFPubReaderePub
Purpose
Cetuximab demonstrates improved efficacy outcomes in patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS exon 2. Resistance to cetuximab is mediated by activating less frequent mutations in the RAS genes beyond KRAS exon 2. We performed extended RASmutational analysis using a high -throughput genotyping platform (OncoMap) and evaluated extended RAS analysis for predicting cetuximab efficacy in patients harboring wild-type KRAS exon 2 tumors following Sanger sequencing.
Materials and Methods
Extended RAS analysis was performed on 227 wild-type KRAS exon 2 mCRC patients who received cetuximab as salvage treatment using OncoMap ver. 4.0. Targeted genes included exon 2, exon 3, and exon 4, both in KRAS and NRAS, and included BRAF exon 15. We assessed efficacy by the new RAS mutation status.
Results
The OncoMap detected 57 additional mutations (25.1%): 25 (11%) in KRAS exon 2 and 32 (14.1%) beyond KRAS exon 2. Survival differences were observed after dividing patients into the wild-type RAS group (n=170) and mutant RAS group (n=57) using OncoMap. Progression-free survival was 4.8 months versus 1.8 months (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.32 to 0.61), and overall survival was 11.9 months versus 8.4 months (HR, 0.65; 95% CI, 0.47 to 0.88).
Conclusion
Sanger sequencing is not sufficient for selecting candidates for cetuximab treatment. High-throughput extended RAS genotyping is a feasible approach for this purpose and identifies patients who might benefit from cetuximab treatment.

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Ipilimumab Real-World Efficacy and Safety in Korean Melanoma Patients from the Korean Named-Patient Program Cohort
Minkyu Jung, Jeeyun Lee, Tae Min Kim, Dae Ho Lee, Jin Hyung Kang, Sung Young Oh, Soo Jung Lee, Sang Joon Shin
Cancer Res Treat. 2017;49(1):44-53.   Published online April 27, 2016
DOI: https://doi.org/10.4143/crt.2016.024
AbstractAbstract PDFPubReaderePub
Purpose
Ipilimumab improves survival in advanced melanoma patients. However, the efficacy and safety of ipilimumab has not been evaluated in Asian melanoma patients with a high frequency of mucosal and acral melanoma subtypes.
Materials and Methods
Advanced melanoma patients treated with 3 mg/kg ipilimumab in a Korean multicenter named-patient program (NPP) were evaluated between September 2014 and July 2015. Baseline characteristics and blood parameters including neutrophil to lymphocyte ratio (NLR) were assessed, and outcome and adverse events were evaluated according to subtypes.
Results
A total of 104 advanced melanoma patients were treated. The primary sites were acral (31.7%), mucosal (26%), cutaneous (26%), uveal (9.6%), and unknown (6.7%). Sixty-eight patients (65.4%) experienced adverse events, and the most common toxicity was skin rash (22.1%), 10 patients (9.6%) experienced adverse events of grade 3 or higher. The median progression-free survival (PFS) was 2.73 months (95% confidence interval, 2.67 to 2.85), and there was no difference in PFS according to subtypes. Poor performance status, liver metastasis, and NLR (≥5) were independent poor prognostic factors by multivariate analysis.
Conclusion
In the Korean NPP cohort, ipilimumab showed similar efficacy and tolerability compared to Western patients, regardless of subtypes. All subtypes should benefit from ipilimumab with consideration of performance status, liver metastasis, and NLR.

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Estimation of the Incidence of Hepatocellular Carcinoma and Cholangiocarcinoma in Songkhla, Thailand, 1989-2013, Using Multiple Imputation Method
Seesai Yeesoonsang, Surichai Bilheem, Edward McNeil, Sophon Iamsirithaworn, Chuleeporn Jiraphongsa, Hutcha Sriplung
Cancer Res Treat. 2017;49(1):54-60.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2016.045
AbstractAbstract PDFPubReaderePub
Purpose
Histological specimens are not required for diagnosis of liver and bile duct (LBD) cancer, resulting in a high percentage of unknown histologies. We compared estimates of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) incidences by imputing these unknown histologies.
Materials and Methods
A retrospective study was conducted using data from the Songkhla Cancer Registry, southern Thailand, from 1989 to 2013. Multivariate imputation by chained equations (mice) was used in re-classification of the unknown histologies. Age-standardized rates (ASR) of HCC and CCA by sex were calculated and the trends were compared. Results Of 2,387 LBD cases, 61% had unknown histology. After imputation, the ASR of HCC in males during 1989 to 2007 increased from 4 to 10 per 100,000 and then decreased after 2007. The ASR of CCA increased from 2 to 5.5 per 100,000, and the ASR of HCC in females decreased from 1.5 in 2009 to 1.3 in 2013 and that of CCA increased from less than 1 to 1.9 per 100,000 by 2013.
Results
of complete case analysis showed somewhat similar, although less dramatic, trends.
Conclusion
In Songkhla, the incidence of CCA appears to be stable after increasing for 20 years whereas the incidence of HCC is now declining. The decline in incidence of HCC among males since 2007 is probably due to implementation of the hepatitis B virus vaccine in the 1990s. The rise in incidence of CCA is a concern and highlights the need for case control studies to elucidate the risk factors.

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  • Comparison of Cholangiocarcinoma and Hepatocellular Carcinoma Incidence Trends from 1993 to 2012 in Lampang, Thailand
    Pianpian Cao, Laura S. Rozek, Donsuk Pongnikorn, Hutcha Sriplung, Rafael Meza
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    Nima Fattahi, Negar Rezaei, Mohsen Asadi-Lari, Moein Yousefi, Zahra Madadi, Kimiya Gohari, Ali Sheidaei, Esmaeil Mohammadi, Nazila Rezaei, Mahboubeh Parsaeian, Farzad Kompani, Farshad Farzadfar, Amir Radfar
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  • Trends in Incidence of Two Major Subtypes of Liver and Bile Duct Cancer: Hepatocellular Carcinoma and Cholangiocarcinoma in Songkhla, Southern Thailand, 1989-2030
    Seesai Yeesoonsang, Edward McNeil, Shama Virani, Surichai Bilheem, Chakrarat Pittayawonganon, Chuleeporn Jiraphongsa, Hutcha Sriplung
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    Shama Virani, Surichai Bilheem, Wasan Chansaard, Imjai Chitapanarux, Karnchana Daoprasert, Somsak Khuanchana, Atit Leklob, Donsuk Pongnikorn, Laura Rozek, Surattaya Siriarechakul, Krittika Suwanrungruang, Sukit Tassanasunthornwong, Patravoot Vatanasapt, H
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Clinical Practice Patterns of Radiotherapy in Patients with Hepatocellular Carcinoma: A Korean Radiation Oncology Group Study (KROG 14-07)
Hyejung Cha, Hee Chul Park, Jeong Il Yu, Tae Hyun Kim, Taek-Keun Nam, Sang Min Yoon, Won Sup Yoon, Jun Won Kim, Mi Sook Kim, Hong Seok Jang, Youngmin Choi, Jin Hee Kim, Chul Seung Kay, Inkyung Jung, Jinsil Seong
Cancer Res Treat. 2017;49(1):61-69.   Published online June 13, 2016
DOI: https://doi.org/10.4143/crt.2016.097
AbstractAbstract PDFPubReaderePub
Purpose
The aim of this study was to examine patterns of radiotherapy (RT) in Korean patients with hepatocellular carcinoma (HCC) according to the evolving guideline for HCC established by the Korean Liver Cancer Study Group-National Cancer Center (KLCSG-NCC).
Materials and Methods
We reviewed 765 patients with HCC who were treated with RT between January 2011 and December 2012 in 12 institutions.
Results
The median follow-up period was 13.3 months (range, 0.2 to 51.7 months). Compared with previous data between 2004 and 2005, the use of RT as a first treatment has increased (9.0% vs. 40.8%). Increased application of intensity-modulated RT resulted in an increase in radiation dose (fractional dose, 1.8 Gy vs. 2.5 Gy; biologically effective dose, 53.1 Gy10 vs. 56.3 Gy10). Median overall survival was 16.2 months, which is longer than that reported in previous data (12 months). In subgroup analysis, treatments were significantly different according to stage (p < 0.001). Stereotactic body RT was used in patients with early HCC, and most patients with advanced stage were treated with three-dimensional conformal RT.
Conclusion
Based on the evolving KLCSG-NCC practice guideline for HCC, clinical practice patterns of RT have changed. Although RT is still used mainly in advanced HCC, the number of patients with good performance status who were treated with RT as a first treatment has increased. This change in practice patterns could result in improvement in overall survival.

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Risk Factors for Thyroid Cancer: A Hospital-Based Case-Control Study in Korean Adults
Seung-Kwon Myung, Chan Wha Lee, Jeonghee Lee, Jeongseon Kim, Hyeon Suk Kim
Cancer Res Treat. 2017;49(1):70-78.   Published online June 23, 2016
DOI: https://doi.org/10.4143/crt.2015.310
AbstractAbstract PDFPubReaderePub
Purpose
Although the incidence of thyroid cancer in Korea has rapidly increased over the past decade, few studies have investigated its risk factors. This study examined the risk factors for thyroid cancer in Korean adults.
Materials and Methods
The study design was a hospital-based case-control study. Between August 2002 and December 2011, a total of 802 thyroid cancer cases out of 34,211 patients screened from the Cancer Screenee. Cohort of the National Cancer Center in South Korea were included in the analysis. A total of 802 control cases were selected from the same cohort, and matched individually (1:1) by age (±2 years) and area of residence for control group 1 and additionally by sex for control group 2.
Results
Multivariate conditional logistic regression analysis using the control group 1 showed that females and those with a family history of thyroid cancer had an increased risk of thyroid cancer, whereas ever-smokers and those with a higher monthly household income had a decreased risk of thyroid cancer. On the other hand, the analysis using control group 2 showed that a family history of cancer and alcohol consumption were associated with a decreased risk of thyroid cancer, whereas higher body mass index (BMI) and family history of thyroid cancer were associated with an increased risk of thyroid cancer.
Conclusion
These findings suggest that females, those with a family history of thyroid cancer, those with a higher BMI, non-smokers, non-drinkers, and those with a lower monthly household income have an increased risk of developing thyroid cancer.

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Anti-proliferative Effect of Engineered Neural Stem Cells Expressing Cytosine Deaminase and Interferon-β against Lymph Node–Derived Metastatic Colorectal Adenocarcinoma in Cellular and Xenograft Mouse Models
Geon-Tae Park, Seung U. Kim, Kyung-Chul Choi
Cancer Res Treat. 2017;49(1):79-91.   Published online May 3, 2016
DOI: https://doi.org/10.4143/crt.2015.503
AbstractAbstract PDFPubReaderePub
Purpose
Genetically engineered stem cells may be advantageous for gene therapy against various human cancers due to their inherent tumor-tropic properties. In this study, genetically engineered human neural stem cells (HB1.F3) expressing Escherichia coli cytosine deaminase (CD) (HB1.F3.CD) and human interferon-β (IFN-β) (HB1.F3.CD.IFN-β) were employed against lymph node–derived metastatic colorectal adenocarcinoma.
Materials and Methods
CD can convert a prodrug, 5-fluorocytosine (5-FC), to active 5-fluorouracil, which inhibits tumor growth through the inhibition of DNA synthesis,while IFN-β also strongly inhibits tumor growth by inducing the apoptotic process. In reverse transcription polymerase chain reaction analysis, we confirmed that HB1.F3.CD cells expressed the CD gene and HB1.F3.CD.IFN-β cells expressed both CD and IFN-β genes.
Results
In results of a modified trans-well migration assay, HB1.F3.CD and HB1.F3.CD.IFN-β cells selectively migrated toward SW-620, human lymph node–derived metastatic colorectal adenocarcinoma cells. The viability of SW-620 cells was significantly reduced when co-cultured with HB1.F3.CD or HB1.F3.CD.IFN-β cells in the presence of 5-FC. In addition, it was found that the tumor-tropic properties of these engineered human neural stem cells (hNSCs) were attributed to chemoattractant molecules including stromal cell-derived factor 1, c-Kit, urokinase receptor, urokinase-type plasminogen activator, and C-C chemokine receptor type 2 secreted by SW-620 cells. In a xenograft mouse model, treatment with hNSC resulted in significantly inhibited growth of the tumor mass without virulent effects on the animals.
Conclusion
The current results indicate that engineered hNSCs and a prodrug treatment inhibited the growth of SW-620 cells. Therefore, hNSC therapy may be a clinically effective tool for the treatment of lymph node metastatic colorectal cancer.

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Comparison of Total Body Irradiation (TBI) Conditioning with Non-TBI for Autologous Stem Cell Transplantation in Newly Diagnosed or Relapsed Mature T- and NK-Cell Non-Hodgkin Lymphoma
Chi Hoon Maeng, Young Hyeh Ko, Do Hoon Lim, Eun Suk Kang, Joon Young Choi, Won Seog Kim, Seok Jin Kim
Cancer Res Treat. 2017;49(1):92-103.   Published online May 9, 2016
DOI: https://doi.org/10.4143/crt.2015.476
AbstractAbstract PDFPubReaderePub
Purpose
This retrospective study was conducted for comparison of survival outcomes and toxicities of autologous stem cell transplantation (ASCT) based on the use of total body irradiation (TBI) as a part of the conditioning regimen in patients with mature T- and natural killer (NK)-cell lymphomas.
Materials and Methods
Patients who underwent ASCT in the upfront or salvage setting between January 2000 and December 2013 were analyzed. Patients were dichotomized according to the TBI group (n=38) and non-TBI group (n=60) based on the type of conditioning regimen for ASCT.
Results
Patients with responsive disease underwent upfront ASCT (TBI, n=16; non-TBI, n=29) whereas patients with refractory disease (TBI, n=9; non-TBI, n=12) or relapsed disease (TBI, n=13; non-TBI, n=19) underwent ASCT after salvage treatment. Hematologic and non-hematologic toxicities were manageable, and the median cumulative toxicity score according to Seattle criteria was estimated as 2 (range, 0 to 7) in both groups. No significant difference in 100-day mortality was observed between the TBI (13%, 5/38) and non-TBI (12%, 12/60) groups, and most deaths were related to disease progression. There was no difference in overall and progression-free survival; however, the TBI group showed a trend of better survival in upfront and salvage ASCT than the non-TBI group. However, patients with refractory disease showed the worst outcome regardless of the use of TBI. Patients who showed complete response before ASCT showed better progression-free survival than thosewho showed partial response.
Conclusion
TBI could be used as an effective part of conditioning for ASCT in patients with mature T- and NK-cell lymphomas.

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  • Whole body irradiation with intensity-modulated helical tomotherapy prior to haematopoietic stem cell transplantation: analysis of organs at risk by dose and its effect on blood kinetics
    Mümtaz Köksal, Jonathan Baumert, Danny Jazmati, Felix Schoroth, Stephan Garbe, David Koch, Davide Scafa, Gustavo R. Sarria, Christina Leitzen, Gregor Massoth, Achilles Delis, Annkristin Heine, Tobias Holderried, Peter Brossart, Thomas Müdder, Leonard C. S
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    Mümtaz Köksal, Jonathan Baumert, Felix Schoroth, Thomas Müdder, Davide Scafa, David Koch, Christina Leitzen, Gustavo R. Sarria, Leonard C. Schmeel, Frank A. Giordano
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Curative Resection for Metachronous Pulmonary Metastases from Colorectal Cancer: Analysis of Survival Rates and Prognostic Factors
Myong Hoon Ihn, Duck-Woo Kim, Sukki Cho, Heung-Kwon Oh, Sanghoon Jheon, Kwhanmien Kim, Eun Shin, Hye Seung Lee, Jin-Haeng Chung, Sung-Bum Kang
Cancer Res Treat. 2017;49(1):104-115.   Published online May 9, 2016
DOI: https://doi.org/10.4143/crt.2015.367
AbstractAbstract PDFPubReaderePub
Purpose
Prognostic factors in patients with pulmonary metastases (PM) from colorectal cancer (CRC) are still controversial. This study assessed oncologic outcomes and prognostic factors in patients with metachronous PM from CRC.
Materials and Methods
Between June 2003 and December 2011, 122 patients with CRC underwent curative resection of PM detected at least 4 months after CRC resection. Clinico-pathological factors selected from the prospectively maintained database were analyzed retrospectively.
Results
The median disease-free interval (DFI) between resection of the primary tumor and detection of PM was 22.0 months (range, 4 to 85 months). Solitary PM were detected in 77 patients (63.1%), with a median maximal tumor diameter of 12.0 mm (range, 2 to 70 mm). Of 52 patients who underwent mediastinal lymph node (LN) dissection, eight patients had LN involvement. Five-year overall survival and disease-free survival (DFS) rates after initial pulmonary metastasectomy were 66.4% and 50.9%, respectively. DFI, mediastinal LN involvement, and the number and distribution of PM were significantly prognostic factors for DFS. In multivariable analysis DFI ≥ 12 months, solitary lesion, and absence of mediastinal LN involvement were independently prognostic for DFS. Of the 122 patients, 48 patients (39.3%) developed recurrent PM a median 13.0 months after initial pulmonary metastasectomy. Recurrent DFI was independently prognostic of DFS in patients who underwent repeated pulmonary metastasectomy.
Conclusion
There is a potential survival benefit for patients with metachronous PM from CRC who undergo pulmonary metastasectomy, even those with recurrent PM. Pulmonary metastasectomy should be considered in selected patients, particularly those with longer DFI, solitary lesions, and absence of mediastinal LN involvement.

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Use of a Combined Gene Expression Profile in Implementing a Drug Sensitivity Predictive Model for Breast Cancer
Xianglan Zhang, In-Ho Cha, Ki-Yeol Kim
Cancer Res Treat. 2017;49(1):116-128.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2016.085
AbstractAbstract PDFPubReaderePub
Purpose
Chemotherapy targets all rapidly growing cells, not only cancer cells, and thus is often associated with unpleasant side effects. Therefore, examination of the chemosensitivity based on genotypes is needed in order to reduce the side effects. Materials and Methods Various computational approaches have been proposed for predicting chemosensitivity based on gene expression profiles. A linear regression model can be used to predict the response of cancer cells to chemotherapeutic drugs, based on genomic features of the cells, and appropriate sample size for this method depends on the number of predictors. We used principal component analysis and identified a combined gene expression profile to reduce the number of predictors
Results
The coefficients of determinanation (R2) of prediction models with combined gene expression and several independent gene expressions were similar. Corresponding F values, which represent model significances were improved by use of a combined gene expression profile, indicating that the use of a combined gene expression profile is helpful in predicting drug sensitivity. Even better, a prediction model can be used even with small samples because of the reduced number of predictors. Conclusion Combined gene expression analysis is expected to contribute to more personalized management of breast cancer cases by enabling more effective targeting of existing therapies. This procedure for identifying a cell-type-specific gene expression profile can be extended to other chemotherapeutic treatments and many other heterogeneous cancer types.

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Post-bevacizumab Clinical Outcomes and the Impact of Early Discontinuation of Bevacizumab in Patients with Recurrent Malignant Glioma
Yongjun Cha, Yu Jung Kim, Se-Hoon Lee, Tae-Min Kim, Seung Hong Choi, Dong-Wan Kim, Chul-Kee Park, Il Han Kim, Jee Hyun Kim, Eunhee Kim, Byungse Choi, Chae-Yong Kim, In Ah Kim, Dae Seog Heo
Cancer Res Treat. 2017;49(1):129-140.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2015.466
AbstractAbstract PDFPubReaderePub
Purpose
Bevacizumab±irinotecan is effective for treatment of recurrent malignant gliomas. However, the optimal duration of treatment has not been established.
Materials and Methods
Ninety-four consecutive patients with recurrent malignant glioma who were treated with bevacizumab at our institutions were identified. Patients who continued bevacizumab until tumor progression were enrolled in a late discontinuation (LD) group, while those who stopped bevacizumab before tumor progression were enrolled in an early discontinuation (ED) group. Landmark analyses were performed at weeks 9, 18, and 26 for comparison of patient survival between the two groups.
Results
Among 89 assessable patients, 62 (69.7%) and 27 (30.3%) patients were categorized as the LD and ED groups, respectively. According to landmark analysis, survival times from weeks 9, 18, and 26 were not significantly different between the two groups in the overall population. However, the LD group showed a trend toward increased survival compared to the ED group among responders. In the ED group, the median time from discontinuation to disease progression was 11.4 weeks, and none of the patients showed a definite rebound phenomenon. Similar median survival times after disease progression were observed between groups (14.4 weeks vs. 15.7 weeks, p=0.251). Of 83 patients, 38 (45.8%) received further therapy at progression, and those who received further therapy showed longer survival in both the LD and ED groups.
Conclusion
In recurrent malignant glioma, duration of bevacizumab was not associated with survival time in the overall population. However, ED of bevacizumab in responding patients might be associated with decreased survival.

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  • The Vascular Microenvironment in Glioblastoma: A Comprehensive Review
    Alejandra Mosteiro, Leire Pedrosa, Abel Ferrés, Diouldé Diao, Àngels Sierra, José Juan González
    Biomedicines.2022; 10(6): 1285.     CrossRef
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    Tiziana Annese, Mariella Errede, Antonio d’Amati, Michelina De Giorgis, Loredana Lorusso, Roberto Tamma, Domenico Ribatti
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  • Identification of diverse tumor endothelial cell populations in malignant glioma
    Jeff C Carlson, Manuel Cantu Gutierrez, Brittney Lozzi, Emmet Huang-Hobbs, Williamson D Turner, Burak Tepe, Yiqun Zhang, Alexander M Herman, Ganesh Rao, Chad J Creighton, Joshua D Wythe, Benjamin Deneen
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    Charlotte Bronnimann, Cristina Izquierdo, Stéphanie Cartalat, Laure Thomas, Bastien Joubert, Laura Delpech, Marc Barritault, David Meyronet, Jérôme Honnorat, François Ducray
    Journal of Neuro-Oncology.2018; 138(1): 141.     CrossRef
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Reactive Oxygen Species Modulator 1 (Romo1) Predicts Poor Outcomes in Advanced Non-small Cell Lung Cancer Patients Treated with Platinum-Based Chemotherapy
Seung Hyeun Lee, Sue In Choi, Ji Sung Lee, Chul Hwan Kim, Won Jai Jung, Eun Joo Lee, Kyung Hoon Min, Gyu Young Hur, Seung Heon Lee, Sung Yong Lee, Je Hyeong Kim, Sang Yeub Lee, Chol Shin, Jae Jeong Shim, Kyung Ho Kang, Kwang Ho In
Cancer Res Treat. 2017;49(1):141-149.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2016.133
AbstractAbstract PDFPubReaderePub
Purpose
Reactive oxygen species modulator 1 (Romo1) is a key mediator of intracellular reactive oxygen species production. However, examination of the clinical usefulness of Romo1 in cancers has been limited. We evaluated the association of Romo1 expression with clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients treated with platinum-based chemotherapy.
Materials and Methods
Romo1 expression in tumor tissue was examined by immunohistochemistry and evaluated by histological score. Survival analyses were performed according to Romo1 expression and the association between Romo1 expression and clinical parameters was evaluated.
Results
A total of 88 tumor specimens were analyzed. Significantly shorter median progression-free survival (PFS) was observed in the high Romo1 group compared with the low Romo1 group (4.5 months vs. 9.8 months, p < 0.001), and the median overall survival (OS) of the high Romo1 group was also significantly shorter than that of the low Romo1 group (8.4 months vs. 15.5 months, p < 0.001). Results of multivariate analyses showed significant association of high Romo1 expression with both poor PFS (hazard ratio [HR], 2.75; 95% confidence interval [CI], 1.71 to 4.44) and poor OS (HR, 3.99; 95% CI, 2.36 to 6.74). Results of the subgroup analysis showed a similar association regardless of tumor histology. Romo1 expression showed no association with any clinical parameter including age, sex, smoking status, stage, differentiation, or tumor histology.
Conclusion
Romo1 overexpression was associated with poor response to treatment and shorter survival in advanced NSCLC patients treated with platinum-based chemotherapy. Romo1 could be a potential adverse predictive marker in this setting.

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  • Prognostic Impact of Reactive Oxygen Species Modulator 1 in Surgically Resected Epidermal Growth Factor Receptor-Mutant Lung Adenocarcinomas
    Tae-Woo Kim, Kiyong Na, Junyang Jung, Heejin Lim, Hyewon Seo, Seung Hyeun Lee
    Oncology.2024; : 1.     CrossRef
  • ROMO1 – a potential immunohistochemical prognostic marker for cancer development
    Eva Tsoneva, Mariela B. Vasileva-Slaveva, Stoyan G. Kostov, Angel D. Yordanov
    Oncologie.2023; 25(6): 753.     CrossRef
  • Serum Reactive Oxygen Species Modulator 1 as a Novel Predictive Biomarker for Resected Lung Adenocarcinoma: A Retrospective Pilot Study
    Boksoon Chang, In Kyung Hwang, Seung Hyeun Lee
    OncoTargets and Therapy.2021; Volume 14: 5097.     CrossRef
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    Won Gun Kwack, Ji-Youn Sung, Seung Hyeun Lee
    Frontiers in Oncology.2021;[Epub]     CrossRef
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    Hadi Ghasemi, Mohammad Amin Amini, Atefeh Pegah, Ebrahim Azizi, Heidar Tayebinia, Shima Khanverdilou, Seyed Habibollah Mousavibahar, Aida Alizamir
    Molecular Biology Reports.2020; 47(9): 6497.     CrossRef
  • Reactive Oxygen Species Modulator 1 is Associated with Poor Survival in Patients with Non-Small Cell Lung Cancer After Stereotactic Fractionated Radiosurgery: A Retrospective Pilot Study


    Moonkyoo Kong, Ji-Youn Sung, Seung Hyeun Lee
    OncoTargets and Therapy.2020; Volume 13: 8173.     CrossRef
  • Reactive oxygen species modulator 1 expression predicts lymph node metastasis and survival in early-stage non-small cell lung cancer
    Taehee Kim, Yoon Jin Cha, Ji Hyun Park, Arum Kim, Yong Jun Choi, Hye Jung Park, Jung Weon Lee
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    Mohammad Amin Amini, Seyed Saman Talebi, Jamshid Karimi
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  • Reactive oxygen species modulator 1 (Romo1) as a novel diagnostic marker for lung cancer-related malignant effusion
    Seung Hyeun Lee, Myung Jae Park, Sue In Choi, Eun Joo Lee, Sang Yeub Lee, Kwang Ho In
    Medicine.2017; 96(4): e5975.     CrossRef
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  • 182 Download
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Gastric Carcinogenesis in the miR-222/221 Transgenic Mouse Model
Boram Choi, Jieun Yu, Tae-Su Han, Young-Kook Kim, Keun Hur, Byeong-Cheol Kang, Woo-Ho Kim, Dae-Yong Kim, Hyuk-Joon Lee, V. Narry Kim, Han-Kwang Yang
Cancer Res Treat. 2017;49(1):150-160.   Published online June 23, 2016
DOI: https://doi.org/10.4143/crt.2015.462
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
MicroRNAs (miRNAs) regulate various cellular functions, including development, cell proliferation, apoptosis, and tumorigenesis. Different signatures associated with various tissue types, diagnosis, progression, prognosis, staging, and treatment response have been identified by miRNA expression profiling of human tumors. miRNAs function as oncogenes or as tumor suppressors. The relationship between gastric cancer and miRNA garnered attention due to the high incidence of gastric cancer in Asian countries. miR-222/221 expression increases in gastric tumor tissues. The oncogenic effect of miR-222/221 was previously determined in functional studies and xenograft models. In this study, transgenic mice overexpressing miR-222/221 were generated to confirm the effect of miR-222/221 on gastric carcinogenesis. Materials and Methods At 6 weeks of age, 65 transgenic mice and 53 wild-type mice were given drinking water containing N-nitroso-N-methylurea (MNU) for 5 alternating weeks to induce gastric cancer. The mice were euthanized at 36 weeks of age and histologic analysis was performed.
Results
Hyperplasia was observed in 3.77% of the wild-type mice and in 18.46% of the transgenic mice (p=0.020). Adenoma was observed in 20.75% of the wild-type mice and 26.15% of the transgenic mice (p=0.522). Carcinoma was observed in 32.08% of the wild-type mice and 41.54% of the transgenic mice (p=0.341). The frequency of hyperplasia, adenoma, and carcinoma was higher in transgenic mice, but the difference was statistically significant only in hyperplasia. Conclusion These results suggest that hyperplasia, a gastric pre-cancerous lesion, is associated with miR-222/221 expression but miR-222/221 expression does not affect tumorigenesis itself.

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    Experimental and Therapeutic Medicine.2017;[Epub]     CrossRef
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Paired Primary and Metastatic Tumor Analysis of Somatic Mutations in Synchronous and Metachronous Colorectal Cancer
Kyu-pyo Kim, Jeong-Eun Kim, Yong Sang Hong, Sung-Min Ahn, Sung Min Chun, Seung-Mo Hong, Se Jin Jang, Chang Sik Yu, Jin Cheon Kim, Tae Won Kim
Cancer Res Treat. 2017;49(1):161-167.   Published online July 4, 2016
DOI: https://doi.org/10.4143/crt.2015.490
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
Although the mutation status of KRAS is highly concordant in primary and metastatic lesions, it has not been generalized to other major pathway genes.
Materials and Methods
In this study, 41 genes were evaluated and the mutational profiles were compared in 46 colorectal cancer patients with paired surgical specimens of primary and metastatic lesions: synchronous (n=27) and metachronous (n=19) lesions. A high-throughput mass spectrometry-based genotyping platform validated by orthogonal chemistry, OncoMap v.4.4, was used to evaluate the formalin-fixed, paraffin-embedded surgical specimens. The patients’ demographics, tumor characteristics, and microsatellite instability status were analyzed by a retrospective chart review.
Results
In this study,with OncoMap, mutationswere identified in 80.4% of patientswith the following frequency: KRAS (39.1%), TP53 (28.3%), APC (28.3%), PIK3CA (6.5%), BRAF (6.5%), and NRAS (4.3%). Although 19.6% (9/46) of the patients showed no gene mutations, 43.5% (20/46) and 37.0% (17/46) had mutations in one and two or more genes, respectively. The synchronous and metachronous lesions showed similar mutational profiles. Paired samples between primary and metastatic tumors differed in 7.4% (2/27) and 10.5% (2/19) for synchronous and metachronous according to OncoMap.
Conclusion
These findings indicate the major pathway genes, including KRAS, TP53, APC, PIK3CA, BRAF, and NRAS, are often concordant between the primary and metastatic lesions regardless of the temporal relationship of metastasis.

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    Chiara Molinari, Giorgia Marisi, Alessandro Passardi, Laura Matteucci, Giulia De Maio, Paola Ulivi
    International Journal of Molecular Sciences.2018; 19(12): 3733.     CrossRef
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Optimal Adjuvant Treatment for Curatively Resected Thoracic Esophageal Squamous Cell Carcinoma: A Radiotherapy Perspective
Kyung Hwan Kim, Jee Suk Chang, Ji Hye Cha, Ik Jae Lee, Dae Joon Kim, Byoung Chul Cho, Kyung Ran Park, Chang Geol Lee
Cancer Res Treat. 2017;49(1):168-177.   Published online June 23, 2016
DOI: https://doi.org/10.4143/crt.2016.142
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to evaluate the benefits of adjuvant treatment for curatively resected thoracic esophageal squamous cell carcinoma (ESCC) and determine the optimal adjuvant treatments.
Materials and Methods
One hundred ninety-five patients who underwent a curative resection for thoracic ESCC between 1994 and 2014 were reviewed retrospectively. Postoperatively, the patients received no adjuvant treatment (no-adjuvant group, n=68), adjuvant chemotherapy (AC group, n=62), radiotherapy (RT group, n=41), or chemoradiotherapy (CRT group, n=24). Chemotherapy comprised cisplatin and 5-fluorouracil administration every 3 weeks. The median RT dose was 45.0 Gy (range, 34.8 to 59.4 Gy). The overall survival (OS), disease-free survival (DFS), locoregional recurrence (LRR), and distant metastasis (DM) rates were estimated.
Results
At a median follow-up duration of 42.2 months (range, 6.3 to 215.2 months), the 5-year OS and DFS were 37.6% and 31.4%, respectively. After adjusting for other clinicopathologic variables, the AC and CRT groups had a significantly better OS and DFS compared to the no-adjuvant group (p < 0.05). The LRR rate was significantly lower in the RT and CRT groups than in the no-adjuvant group (p < 0.05), whereas no significant difference was observed in the AC group. In the no-adjuvant and AC groups, 25% of patients received high-dose salvage RT due to LRR. The DM rates were similar. The anastomotic stenosis and leakage were similar in the treatment groups.
Conclusion
Adjuvant treatment might prolong survival after an ESCC resection, and RT contributes to a reduction of the LRR. Overall, the risks and benefits should be weighed properly when selecting the optimal adjuvant treatment.

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Tumor Stage-Related Role of Radiotherapy in Patients with an External Auditory Canal and Middle Ear Carcinoma
Jinhyun Choi, Se-Heon Kim, Yoon Woo Koh, Eun Chang Choi, Chang Geol Lee, Ki Chang Keum
Cancer Res Treat. 2017;49(1):178-184.   Published online July 4, 2016
DOI: https://doi.org/10.4143/crt.2016.165
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to evaluate the clinical outcomes of patients treated with radiotherapy (RT) for a carcinoma of the external auditory canal (EAC) and middle ear.
Materials and Methods
The records of 32 patients who received RT from 1990 to 2013 were reviewed retrospectively. The Pittsburgh classification was used to stage all the cancers (early stage, T1/T2 [n=12]; advanced stage, T3/T4 or N positive [n=20]). Twenty-one patients (65.6%) were treated with postoperative RT and 11 patients (34.4%) were treated with definitive RT. The median radiation doses for postoperative and definitive RT were 60 Gy and 64.8 Gy, respectively. Chemotherapy was administered to seven patients (21.9%).
Results
The 5-year overall survival and disease-free survival rates for all patients were 57% and 52%, respectively. The disease control rates for the patients with early stage versus advanced stage carcinomawere 55.6% (5/9) and 50% (6/12) in the postoperative RT group and 66.7% (2/3) and 37.5% (3/8) in the definitive RT group, respectively. Overall, 15 cases (14 patients, 46.7%) experienced treatment failure; these failures were classified as local in four cases, regional in one case, and distant in 10 cases. The median follow-up period after RT was 51 months (range, 7 to 286 months).
Conclusion
Patients with early stage carcinoma achieved better outcomes when definitive RT was used. Advanced stage carcinoma patients experienced better outcomes with postoperative RT. The high rate of distant failure after RT, with or without surgery, reflected the lack of a consensus regarding the best therapeutic approach for treating carcinoma of the EAC and middle ear.

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Rare Incidence of ROS1 Rearrangement in Cholangiocarcinoma
Sun Min Lim, Jeong Eun Yoo, Kiat Hon Lim, David Wai Meng Tai, Byoung Chul Cho, Young Nyun Park
Cancer Res Treat. 2017;49(1):185-192.   Published online April 27, 2016
DOI: https://doi.org/10.4143/crt.2015.497
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
The recent discovery and characterization of an oncogenic ROS1 gene rearrangement has raised significant interest because small molecule inhibitors are effective in these tumors. The aim of this study was to determine frequency and clinicopathological features associated with ROS1 rearrangement in patients with cholangiocarcinoma (CCA).
Materials and Methods
A total of 261 patients who underwent surgery for CCA between October 1997 and August 2013 were identified from an international, multi-institutional database. ROS1 rearrangement was evaluated by break-apart fluorescence in situ hybridization using tissue microarrays of these patients.
Results
Of 261 CCA evaluated, three cases (1.1%) showed ROS1 rearrangement by fluorescence in situ hybridization (FISH), all of which were derived from intrahepatic origin. ROS1 protein expression was observed in 38 samples (19.1%). Significantly larger tumor size was observed in ROS1 immunohistochemistry (IHC)–negative patients compared with ROS1 IHC–positive patients. ROS1 FISH–positive patients had a single tumor with a median size of 4 cm and well-to-moderate differentiation. Overall, there was no difference in terms of baseline characteristics, overall survival, and recurrence-free survival between ROS1-positive and -negative patients.
Conclusion
ROS1 rearrangement was detected in 1.1% of CCA patients. Although rare, conduct of clinical trials using ROS1 inhibitors in these genetically unique patients is warranted.

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Concurrent Chemoradiotherapy with Temozolomide Followed by Adjuvant Temozolomide for Newly Diagnosed Glioblastoma Patients: A Retrospective Multicenter Observation Study in Korea
Byung Sup Kim, Ho Jun Seol, Do-Hyun Nam, Chul-Kee Park, Il Han Kim, Tae Min Kim, Jeong Hoon Kim, Young Hyun Cho, Sang Min Yoon, Jong Hee Chang, Seok-Gu Kang, Eui Hyun Kim, Chang-Ok Suh, Tae-Young Jung, Kyung-Hwa Lee, Chae-Yong Kim, In Ah Kim, Chang-Ki Hong, Heon Yoo, Jin Hee Kim, Shin-Hyuk Kang, Min Kyu Kang, Eun-Young Kim, Sun-Hwan Kim, Dong-Sup Chung, Sun-Chul Hwang, Joon-Ho Song, Sung Jin Cho, Sun-Il Lee, Youn-Soo Lee, Kook-Jin Ahn, Se Hoon Kim, Do Hun Lim, Ho-Shin Gwak, Se-Hoon Lee, Yong-Kil Hong
Cancer Res Treat. 2017;49(1):193-203.   Published online June 27, 2016
DOI: https://doi.org/10.4143/crt.2015.473
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study was to investigate the feasibility and survival benefits of combined treatment with radiotherapy and adjuvant temozolomide (TMZ) in a Korean sample.
Materials and Methods
A total of 750 Korean patients with histologically confirmed glioblastoma multiforme, who received concurrent chemoradiotherapy with TMZ (CCRT) and adjuvant TMZ from January 2006 until June 2011, were analyzed retrospectively.
Results
After the first operation, a gross total resection (GTR), subtotal resection (STR), partial resection (PR), biopsy alone were achieved in 388 (51.7%), 159 (21.2%), 96 (12.8%), and 107 (14.3%) patients,respectively. The methylation status of O6-methylguanine-DNA methyltransferase (MGMT) was reviewed retrospectively in 217 patients. The median follow-up period was 16.3 months and the median overall survival (OS) was 17.5 months. The actuarial survival rates at the 1-, 3-, and 5-year OS were 72.1%, 21.0%, and 9.0%, respectively. The median progression-free survival (PFS) was 10.1 months, and the actuarial PFS at 1-, 3-, and 5-year PFS were 42.2%, 13.0%, and 7.8%, respectively. The patients who received GTR showed a significantly longer OS and PFS than those who received STR, PR, or biopsy alone, regardless of the methylation status of the MGMT promoter. Patients with a methylated MGMT promoter also showed a significantly longer OS and PFS than those with an unmethylated MGMT promoter. Patients who received more than six cycles of adjuvant TMZ had a longer OS and PFS than those who received six or fewer cycles. Hematologic toxicity of grade 3 or 4 was observed in 8.4% of patients during the CCRT period and in 10.2% during the adjuvant TMZ period.
Conclusion
Patients treated with CCRT followed by adjuvant TMZ had more favorable survival rates and tolerable toxicity than those who did not undergo this treatment.

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Analysis of the Clinicopathological Characteristics of Gastric Cancer in Extremely Old Patients
Il Woong Sohn, Da Hyun Jung, Jie-Hyun Kim, Hyun Soo Chung, Jun Chul Park, Sung Kwan Shin, Sang Kil Lee, Yong Chan Lee
Cancer Res Treat. 2017;49(1):204-212.   Published online June 27, 2016
DOI: https://doi.org/10.4143/crt.2016.163
AbstractAbstract PDFPubReaderePub
Purpose
Gastric cancer is the third-leading cause of cancer-related death in Korea. As the Korean population is ageing, the number of extremely old patients with this disease is increasing. This study examined the clinicopathological characteristics of gastric cancer in extremely old (over 85 years) patients who received treatment or conservative observations and compared the treatment outcomes according to the treatment modality.
Materials and Methods
A total of 170 patients over 85 years of age were diagnosed with gastric cancer. Of these, 81 underwent treatment for gastric cancer and 89 received conservative observations. The clinicopathological characteristics of the treatment and conservative groupswere compared.
Results
The mean age of the patients was 86.5 years. The conservative group included significantly more patients with older ages, macroscopically advanced cancer and upper-middle located cancer. The overall survival rate of the treatment group was significantly higher than that of the conservative group. The disease-specific mortality rate was significantly lower in the treatment group than in the conservative group. Multivariate analysis revealed the clinical course, alarm sign, and macroscopic classification to be independent prognosis factors.
Conclusion
By itself, the chronological age should not be used as a strategy to determine whether treatmentwill be administered for gastric cancer. Patientswho have early gastric cancer or lower-risk preexisting comorbidities should not be discouraged from treatment, even if they are older than 85 years.

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Clinicopathological Features of Low-Grade Thyroid-like Nasopharyngeal Papillary Adenocarcinoma
Minhua Li, Jiangguo Wei, Xiaofei Yao, Cheng Wang
Cancer Res Treat. 2017;49(1):213-218.   Published online July 4, 2016
DOI: https://doi.org/10.4143/crt.2016.195
AbstractAbstract PDFPubReaderePub
Purpose
Primary low-grade thyroid-like papillary adenocarcinomas are extremely rare neoplasms that generally originate in the nasopharynx. Here, we describe a novel case of a 15-year-old Chinese girl who was diagnosed with low-grade thyroid-like papillary adenocarcinoma, including a brief review of the literature to reveal the clinicopathological features of low-grade thyroid-like nasopharyngeal papillary adenocarcinoma.
Materials and Methods
Immunohistochemistry was used to evaluate the expression of pan-cytokeratin (CKpan), cytokeratin (CK) 7, thyroid transcription factor 1 (TTF-1), vimentin, epithelial membrane antigen (EMA), thyroglobulin, CD15, S100, P40, CK20, CDX-2, glial fibrillary acidic protein (GFAP), and Ki-67. Additionally, in situ hybridization investigation was utilized to identify the presence of small Epstein-Barr virus (EBV)–encoded RNA.
Results
Histopathological analysis revealed florid proliferation of papillary structures lined by columnar epithelial cells with fibrovascular cores. Immunohistochemically, the neoplastic cells were positive for CKpan, CK7, TTF-1, vimentin, and EMA, but negative for thyroglobulin, CD15, S100, P40, CK20, CDX-2, and GFAP. The Ki-67–labeling index reached 5% in the most concentrated spot. In situ hybridization for EBV was negative.
Conclusion
Due to the distinct rarity of low-grade thyroid-like papillary adenocarcinomaswith a favorable clinical outcome, a nationwide effort to raise public awareness of this neoplasm is required.

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Anti-cancer Effects of a Novel Quinoline Derivative 83b1 on Human Esophageal Squamous Cell Carcinoma through Down-Regulation of COX-2 mRNA and PGE2
Ivan Ho Yuen Pun, Dessy Chan, Sau Hing Chan, Po Yee Chung, Yuan Yuan Zhou, Simon Law, Alfred King Yin Lam, Chung Hin Chui, Albert Sun Chi Chan, Kim Hung Lam, Johnny Cheuk On Tang
Cancer Res Treat. 2017;49(1):219-229.   Published online July 18, 2016
DOI: https://doi.org/10.4143/crt.2016.190
AbstractAbstract PDFSupplementary MaterialPubReaderePub
Purpose
83b1 is a novel quinoline derivative that has been shown to inhibit cancer growth in human esophageal squamous cell carcinoma (ESCC). This study was conducted to comprehensively evaluate the cytotoxic effects of 83b1 on a series of ESCC cell lines and investigate the mechanisms by which 83b1 suppresses cancer growth based on molecular docking analysis.
Materials and Methods
A series of ESCC and nontumor immortalized cell lines were exposed to 83b1 and cisplatin (CDDP) in a dose-dependent manner, and the cytotoxicity was examined by a MTS assay kit. Prediction of the molecular targets of 83b1 was conducted by molecular docking analysis. Expression of cyclooxygenase 2 (COX-2) mRNA and COX-2–derived prostaglandin E2 (PGE2) were measured by quantitative real-time polymerase chain reaction and enzymelinked immuno-sorbent assay, respectively. In vivo anti-tumor effect was determined using a nude mice xenografted model transplanted with an ESCC cell line, KYSE-450.
Results
83b1 showed the significant anti-cancer effects on all ESCC cell lines compared to CDDP; however, 83b1 revealed much lower toxic effects on non-tumor cell lines than CDDP. The predicted molecular target of 83b1 is peroxisome proliferator-activated receptor delta (PPARδ), which is a widely known oncoprotein. Additionally the expression of COX-2 mRNA and COX-2–derived PGE2 were down-regulated by 83b1 in a dose-dependent manner in ESCC cell lines. Furthermore, 83b1 was shown to significantly reduce the tumor size in nude mice xenograft.
Conclusion
The results of this study suggest that the potential anti-cancer effects of 83b1 on human esophageal cancers occur through the possible oncotarget, PPARδ, and down-regulation of the cancer related genes and molecules.

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Studying the Effect of Downregulating Autophagy-Related Gene LC3 on TLR3 Apoptotic Pathway Mediated by dsRNA in Hepatocellular Carcinoma Cells
Guilan Wang, Maona Zhang, Yunlong Li, Jiaming Zhou, Li Chen
Cancer Res Treat. 2017;49(1):230-245.   Published online June 13, 2016
DOI: https://doi.org/10.4143/crt.2015.506
AbstractAbstract PDFPubReaderePub
Purpose
The purpose of this study is to examine the role of the double-stranded RNA (dsRNA) activated Toll–interleukin-1 receptor domain-containing adaptor inducing interferon β (TRIF) signal pathway in triggering apoptosis in hepatocellular carcinoma (HCC) cells.
Materials and Methods
First, siRNA targeted autophagy–related gene LC3 (pU6H1-LC3 siRNA and siLC3) and a dsRNA used as a Toll-like receptor 3 (TLR3) ligand was constructed and synthesized, respectively. Then, a human HCC cell line was transfected with dsRNA, siLC3, and cotransfected with siLC3 and dsRNA (siLC3+dsRNA), respectively. Finally, quantification real-time polymerase chain reaction, western blotting, and immunofluorescence staining were used in the HCC line (SMMC7721), and MTT assay, flow cytometry, terminal deoxynucleotidyl transferase-mediated dUTP nick-end-labeling, and transmission electron microscopy were used in an HCC xenograft model of nude mice. Human umbilical vein endothelial cell tube forming assay, color Doppler ultrasonographic flow image examination, and CD34-positive microvessel density were used in vitro and in vivo.
Results
Compared with untreated cells, the protein and mRNA expression of TLR3 and TRIF was up-regulated, in order, siLC3+dsRNA, dsRNA, and siLC3. Expression of LC3 was obviously down-regulated and the autophagosomes were significantly decreased in siLC3+dsRNA and siLC3, whereas in dsRNA (p < 0.05). LC3 and TRIF colocation was observed in HepG2 cells. Decreased cell viability, increased apoptosis, decrease in xenograft tumor volume, and angiogenesis potential were also observed in order (p < 0.05).
Conclusion
Suppression of intracellular autophagy resulted in decreased degradation of TRIF protein, which can promote triggering of apoptosis by the TLR3-TRIF pathway. dsRNA and siLC3 could play anticancer roles in coordination.

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Overexpression of PD-L1 and PD-L2 Is Associated with Poor Prognosis in Patients with Hepatocellular Carcinoma
Hae Il Jung, Dongjun Jeong, Sanghee Ji, Tae Sung Ahn, Sang Ho Bae, Susie Chin, Jun Chul Chung, Hyung Chul Kim, Moon Soo Lee, Moo-Jun Baek
Cancer Res Treat. 2017;49(1):246-254.   Published online July 7, 2016
DOI: https://doi.org/10.4143/crt.2016.066
AbstractAbstract PDFPubReaderePub
Purpose
Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Recently, the overexpression of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has been shown to correlate with poor prognosis in many cancers. However, the expression of PD-L1 or PD-1 ligand 2 (PD-L2) and clinical outcomes have not been fully investigated in HCC.
Materials and Methods
Formalin-fixed paraffin-embedded samples were obtained from 85 patients with HCC who underwent surgery. The expression of PD-Ls (PD-L1, PD-L2) was evaluated by immunohistochemical analysis.
Results
The proportion of high expression groups of PD-L1 and PD-L2 was 27.1% and 23.5%, respectively. Univariate analysis revealed that tumor size (p < 0.001), histological differentiation (p=0.010), PD-L1 expression (p < 0.001), and PD-L2 expression (p=0.039) were significant prognostic factors of overall survival in patients with HCC. Multivariate analysis revealed that overall tumor size (hazard ratio [HR], 4.131; 95% confidence interval [CI], 2.233 to 7.643; p < 0.001 and HR, 3.455; 95% CI, 1.967 to 6.067; p < 0.001) and PD-L1 expression (HR, 5.172; 95% CI, 2.661 to 10.054; p < 0.001 and HR, 3.730; 95% CI, 1.453 to 9.574; p=0.006) were independent prognostic values for overall and disease-free survival. Patients with high expression of PD-Ls had a significantly poorer survival than those with low expression (p < 0.001, p=0.034).
Conclusion
The overexpression of PD-Ls in HCC patients is correlated with survival and tumor recurrence. Further evaluation of PD-1 and PD-Ls as therapeutic targets and predictive biomarkers for HCC is warranted.

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Meta-Analysises
Irinotecan Monotherapy Versus Irinotecan-Based Combination as Second-Line Chemotherapy in Advanced Gastric Cancer: A Meta-Analysis
Yo-Han Cho, So Young Yoon, Soo-Nyung Kim
Cancer Res Treat. 2017;49(1):255-262.   Published online May 18, 2016
DOI: https://doi.org/10.4143/crt.2015.452
AbstractAbstract PDFPubReaderePub
Purpose
A meta-analysis was conducted to examine the question of whether combination regimens are more effective than monotherapy as a second-line chemotherapy in advanced gastric cancer.
Materials and Methods
The MEDLINE and the EMBASE databases and the Cochrane Central Register for Controlled Trials were searched using appropriate keywords. Only randomized controlled trials were eligible.
Results
Taxane-based study is rare; thus, four irinotecan-based studies were finally included in the meta-analysis. Out of 661 patients, 331 patients were assigned to combination therapy and 330 to monotherapy. Cisplatin or fluoropyrimidine (S-1 or 5-fluorouracil) was used as a combination partner to irinotecan. The pooled hazard ratio (HR) for overall survival (OS) and for progression-free survival (PFS) was 0.938 (95% confidence interval [CI], 0.796 to 1.104; p=0.442) and 0.815 (95% CI, 0.693 to 0.958; p=0.013). In subgroup analysis according to previous exposure to a partner agent, the PFS benefit of combination was observed only in the partially exposed group (HR, 0.784; 95% CI, 0.628 to 0.980; p=0.032).
Conclusion
Second-line irinotecan-based combination was not associated with increased OS, but with PFS benefit, which seemed particularly significant for patients receiving combination with a new agent.

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Adjuvant Chemotherapy for Advanced Gastric Cancer in Elderly and Non-elderly Patients: Meta-Analysis of Randomized Controlled Trials
Seong-Hwan Chang, Soo-Nyung Kim, Hye Jung Choi, Misuk Park, Rock Bum Kim, Se-Il Go, Won Sup Lee
Cancer Res Treat. 2017;49(1):263-273.   Published online July 5, 2016
DOI: https://doi.org/10.4143/crt.2016.054
AbstractAbstract PDFPubReaderePub
Purpose
This study evaluated the benefits of adjuvant chemotherapy on elderly patients with advanced gastric cancer (AGC) using meta-analysis of well-designed randomized controlled clinical studies.
Materials and Methods
PubMed, Embase, and Cochrane were searched to retrieve clinical studies evaluating the benefits of adjuvant chemotherapy in the elderly with AGC. Hazards ratios (HRs) with 95% confidence intervals (CIs) were pooled across studies using a fixed-effects model.
Results
Two studies were included in this meta-analysis to estimate HR for the overall survival (OS), and relapse-free survival (RFS) between adjuvant chemotherapy and surgery in elderly and non-elderly patients. HR for OS in the elderly and non-elderly was 0.745 (95% CI, 0.552 to 1.006, p=0.055) and 0.636 (95% CI, 0.522 to 0.776; p < 0.001), respectively, which showed no heterogeneity regarding HR between the two groups (pinteraction=0.389). HR for RFS in the elderly and non-elderly was 0.613 (95% CI, 0.466 to 0.806; p < 0.001) and 0.633 (95% CI, 0.533 to 0.753; p < 0.001), respectively (pinteraction=0.846).
Conclusion
Meta-analysis suggests that the benefit of adjuvant chemotherapy to the elderly is not big enough to reach statistical significance while the HR for OS is less than 1 (0.745) and no heterogeneity are observed regarding the HR between the elderly and non-elderly patients.

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Case Reports
Human Herpesvirus 8–Unrelated Primary Effusion Lymphoma–Like Lymphoma in an Elderly Korean Patient with a Good Response to Rituximab Plus Cyclophosphamide, Doxorubicin, Vincristine, and Prednisolone
Junghoon Shin, Jeong-Ok Lee, Ji-Young Choe, Soo-Mee Bang, Jong-Seok Lee
Cancer Res Treat. 2017;49(1):274-278.   Published online June 10, 2016
DOI: https://doi.org/10.4143/crt.2016.076
AbstractAbstract PDFPubReaderePub
Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin’s lymphoma arising from a B-cell lineage characterized by the formation of malignant effusion in body cavities without evidence of a detectable tumor. The effusion contains tumor cells universally infected with human herpesvirus 8 (HHV8), which is the critical factor differentiating PEL from HHV8-unrelated PEL-like lymphoma (PEL-LL). This report describes a 77-year-old male patient with pleural effusion and ascites, containing lymphoma cells expressing a B-cell phenotype, but without markers of HHV8 in immunocytochemical analysis. The patient was diagnosed with PEL-LL and treated with six cycles of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP), which resulted in a complete remission. The patient is currently disease-free 15 months post-treatment. To the best of our knowledge, this is the first report on administration of R-CHOP in a PEL-LL patient in South Korea.

Citations

Citations to this article as recorded by  
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    Kenta Hayashino, Yusuke Meguri, Ryouya Yukawa, Aya Komura, Makoto Nakamura, Chikamasa Yoshida, Kazuhiko Yamamoto, Wakako Oda, Kenji Imajo
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  • Targeting VEGF with bevacizumab inhibits malignant effusion formation of primary human herpesvirus 8‐unrelated effusion large B‐cell lymphoma in vivo
    Fumiya Ogasawara, Tomonori Higuchi, Tomohiro Nishimori, Yumiko Hashida, Kensuke Kojima, Masanori Daibata
    Journal of Cellular and Molecular Medicine.2022; 26(22): 5580.     CrossRef
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    Soichiro Nakako, Mitsushige Nishimura, Yoshiro Murakami, Atsuko Mugitani
    Clinical Case Reports.2020; 8(12): 3215.     CrossRef
  • Body Cavity–Based Lymphoma in a Country with Low Human Immunodeficiency Virus Prevalence: A Series of 17 Cases from the Consortium for Improving Survival of Lymphoma
    Junghoon Shin, Young Hyeh Ko, Sung Yong Oh, Dok Hyun Yoon, Jeong-Ok Lee, Jin Seok Kim, Yong Park, Ho Jin Shin, Seok Jin Kim, Jong Ho Won, Sung-Soo Yoon, Won Seog Kim, Youngil Koh
    Cancer Research and Treatment.2019; 51(4): 1302.     CrossRef
  • Age and CD20 Expression Are Significant Prognostic Factors in Human Herpes Virus-8-negative Effusion-based Lymphoma
    Tomomi Kubota, Yosuke Sasaki, Eisuke Shiozawa, Masafumi Takimoto, Tsunekazu Hishima, Ja-Mun Chong
    American Journal of Surgical Pathology.2018; 42(12): 1607.     CrossRef
  • A Case of Diffuse Large B-Cell Lymphoma Mimicking Primary Effusion Lymphoma-Like Lymphoma
    Daisuke Usuda, Masahisa Arahata, Kento Takeshima, Ryusho Sangen, Akiteru Takamura, Yasuhiro Kawai, Yuji Kasamaki, Yoshitsugu Iinuma, Tsugiyasu Kanda
    Case Reports in Oncology.2017; 10(3): 1013.     CrossRef
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Treatment of Pulmonary Tumor Embolism from Choriocarcinoma: Extracorporeal Membrane Oxygenation as a Bridge through Chemotherapy
Jae Heun Chung, Hye Ju Yeo, Hyun Myung Cho, Jin Ook Jang, Byung Min Ye, Gun Yoon, Dong Hoon Shin, Dohyung Kim, Woo Hyun Cho
Cancer Res Treat. 2017;49(1):279-282.   Published online June 24, 2016
DOI: https://doi.org/10.4143/crt.2016.125
AbstractAbstract PDFPubReaderePub
A 22-year-old woman with a 1-month history of shortness of breath that was treated as a case of tuberculosis and pulmonary embolism was referred to the authors’ hospital. Because of the hemodynamic instability in this patient, venoarterial extracorporeal membrane oxygenation (ECMO) was administered in the intensive care unit. She underwent a pulmonary embolectomy for the treatment of progressive circulatory collapse secondary to a pulmonary embolism. The histopathologic result was consistent with a metastatic choriocarcinoma. Despite the surgical management, persistent refractory cardiogenic shock occurred. Subsequently, the patient was treated with chemotherapy in the presence of ECMO and responded well to chemotherapy. She was discharged after 3 months. This case suggests that metastatic choriocarcinoma should be considered as a differential diagnosis in women of childbearing age presenting with a pulmonary embolism, and ECMO may be beneficial in patients with pulmonary embolism for bridging to surgical embolectomy and chemotherapy.

Citations

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    Simon Doran, Ronan Kernan, Niall McEniff
    Radiology Case Reports.2024; 19(8): 3525.     CrossRef
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    Alejandra Portillo-Romero, Eric Cuevas-Medina, Maria Jose Santa Ana-Bayona, Santiago Saenz-Ancira, Costantino Mancusi, Megha Agarwal, A Shaheer Ahmed, Federico B Blasi, Polyvios Demetriades, Jonathan Senior
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    Xiangnan Teng, Jiali Wu, Jing Liao, Shanling Xu
    Cancer Medicine.2023; 12(15): 16243.     CrossRef
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    Pengcheng Wang, Dunqiang Ren, Caihong Guo, Xiaoqian Ding, Yiwei Cao, Peige Zhao, Qiang Wang, Wenjuan Xu
    Oncology Letters.2023;[Epub]     CrossRef
  • Extracorporeal Membrane Oxygenator Failure in a Patient With Gestational Trophoblastic Neoplasm: Possible Mechanisms and Considerations in Critical Care
    Nathan J. Smith, Beth A. Nance, Lucian A. Durham, Lindsey A. McAlarnen, Erin A. Bishop, M. Tracy Zundel
    Journal of Cardiothoracic and Vascular Anesthesia.2022; 36(8): 2583.     CrossRef
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    Seung Soo Yoo, Shin Yup Lee, Sun Ha Choi
    World Journal of Clinical Cases.2022; 10(25): 8974.     CrossRef
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    Respiratory Medicine Case Reports.2021; 34: 101527.     CrossRef
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    Praveena Tathineni, Mauna Pandya, Bassem Chaar
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  • Lessons from a patient with cardiac arrest due to massive pulmonary embolism as the initial presentation of Wilms tumor: a case report and literature review
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    Mei Yang, Li Peng
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  • Antineoplastics

    Reactions Weekly.2017; 1643(1): 32.     CrossRef
  • 9,143 View
  • 190 Download
  • 17 Web of Science
  • 19 Crossref
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