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Naito S.,Kyushu University | Tomita Y.,Yamagata University | Rha S.Y.,Cancer Metastasis Research Center | Uemura H.,Kinki University | And 4 more authors.
Japanese Journal of Clinical Oncology | Year: 2010

Kidney cancer accounts for approximately 2% of all cancers worldwide, with renal cell carcinoma being the most common form and this report is focused on renal cell carcinoma. Globally, the incidence and mortality rates are increasing by 2-3% per decade. Kidney cancer is less common in Asia compared with the West. Cigarette smoking, obesity, acquired cystic kidney disease and inherited susceptibility are known risk factors for kidney cancer. The National Comprehensive Cancer Network Guidelines recommend surgical excision as first line of treatment for Stage I, II or III kidney cancer patients and Stage IV patients with resectable tumours. Immunotherapy has a 20-year history in treatment of metastatic kidney cancer. Highdose interleukin-2 (IL-2) is administered in some countries, whereas low-dose IL-2 and interferon-alpha (IFN-α) are popular in Japan. Molecular-targeted drugs, including sunitinib, bevacizumab and sorafenib, are being used for previously untreated and refractory patients. Asian and non-Asian populations have shown large differences in the incidences of adverse events with sorafenib and sunitinib. Consensus Statement: Kidney cancer is relatively uncommon in Asia compared with the West, but its incidence is increasing in more developed Asian nations. Guidelines from the National Comprehensive Cancer Network, etc., for treating metastatic renal cell carcinoma are based on Phase III clinical trials conducted primarily in Western patients. Targeted therapies are now becoming primary recommendations, but efficacy/toxicity data from Asian patients are lacking. Some drugs cause adverse effects in Asians because their recommended dosages are optimal for Caucasians but may be too high for Asians. Further research is necessary to develop optimal treatment strategies for Asians. © The Author (2010). Published by Oxford University Press. All rights reserved.


Kim S.H.,Cancer Metastasis Research Center | Shin S.J.,Cancer Metastasis Research Center | Kim S.Y.,Research Institute and Hospital | Lee S.H.,Samsung | And 6 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2012

Purpose: Capecitabine plus oxaliplatin (XELOX) is an effective second-line regimen for advanced colorectal carcinoma (CRC) patients pretreated with irinotecan. Previous studies have shown supra-additive anti-tumor activity of gemcitabine (GEM) when administered with oxaliplatin. We investigated the dose, toxicity, and efficacy of a second-line XELOXGEM regimen in CRC patients pretreated with irinotecan. Methods: Patients with metastatic or recurrent CRC who failed after a first-line irinotecan-containing regimen received escalating doses of gemcitabine (600, 800, 1,000 mg/m 2 d1, d8) followed by capecitabine (1,000 mg/m 2 b.i.d d1-14) and oxaliplatin (100 mg/m 2 d1) on a 21-day cycle. Results: A total of 38 patients were treated. At 800 mg/m 2, two of six patients experienced dose-limiting toxicities (diarrhea and thrombocytopenia). Therefore, the clinically recommended dose was defined as 600 mg/m 2 gemcitabine (d1, d8) followed by 1,000 mg/m 2 capecitabine (b.i.d dl-14) and 100 mg/m 2 oxaliplatin (d1). The most common grade 3/4 toxicities were neutropenia (32%), thrombocytopenia (13%), anemia (11%), and peripheral neuropathy (11%). Ten (26.3%) and 23 (60.5%) patients experienced partial response and stable disease, respectively. The median progression-free survival and overall survival were 5.4 months (95% CI 3.8-6.9 months) and 17.7 months (95% CI 8.4-26.9 months), respectively. Conclusions: The XELOXGEM triplet combination is an active and safe second-line regimen for advanced CRC patients pretreated with irinotecan. © 2011 Springer-Verlag.


Sun H.-H.,Yanbian University | Cui H.,Yanbian University | Jin Y.-M.,Yanbian University | Cui X.,Yanbian University | And 5 more authors.
Asian Pacific Journal of Cancer Prevention | Year: 2011

Metastasis is the major feature of malignant tumors that causes 90% of cancer deaths. Our laboratory has already established liver metastatic clones with YCC-16, isolated from the blood of a gastric cancer patient and expanded in vitro culture using a repeated orthotopic implantation method, and had reported biologic behaviour of the parental YCC-16, the orthotopic primary S1L0, and S1L1, S2L2 and S3L3 liver metastatic clones. Here, using these cell lines, we screened from chromosomal abnormalities using karyotype analysis and micro-CGH matching. There were 31 genes screened using PCA method which were functionally related to cell adhesion. Also, there were 23 genes selected which were related to the liver specific metastasis but excluded genes related to adhesion. There were 4 genes which demonstrated reduced or increased expression stepwise with passage. In conclusion, our results should contribute to exploring the mechanisms of liver metastasis by gastric cancer.


Noh S.,Cancer Metastasis Research Center | Jung J.-J.,Cancer Metastasis Research Center | Jung J.-J.,National Biochip Research Center | Jung M.,Cancer Metastasis Research Center | And 18 more authors.
Hepato-Gastroenterology | Year: 2011

Background/Aims: We evaluated matrix metalloproteinase (MMP)-2 and -9 as novel biomarkers in the body fluid of advanced gastric cancer with peritoneal and pleural metastasis. Methodology: MMPs activity from zymography was quantified with ELISA to determine the cut-off expression levels of MMPs. The expression of MMPs in patient samples were evaluated with ELISA and compared with clinical parameters. Ascitic CEA (aCEA) and pleural CEA (pCEA) were measured by chemiluminescent enzyme immunoassay. Results: MMP-2 and -9 cut-off levels were 8.6ng/mL and 0.14ng/mL, respectively. Ascitic fluid cytology of 93 patients revealed a positivity of 55.9% while for MMP-2 it was 93.3%, for MMP-9 35.2% and for aCEA 86.7%. Combining biomarkers, the positivity increased to 99.1% in patients with MMP-2 and aCEA expression. We found a negative correlation between MMP-2 expression and survival when a new prognostic cut-off of 22.6ng/mL was used. Patients with high MMP-2 expression (≥22.6ng/mL) had a median survival of 45 days and those with low MMP-2 expression (<22.6ng/mL) had a median survival of 69 days (p<0.01). Conclusions: These results suggest that MMPs could be used as diagnostic markers in body fluid and MMP-2 might be a prognostic marker in ascites of advanced gastric patients with disseminated metastasis. © H.G.E. Update Medical Publishing S.A.


Jeung H.-C.,Yonsei Cancer Center | Jeung H.-C.,Cancer Metastasis Research Center | Rha S.Y.,Yonsei Cancer Center | Rha S.Y.,Cancer Metastasis Research Center | And 7 more authors.
Anti-Cancer Drugs | Year: 2011

Determination of significant associations between gene expression and predefined endpoints might improve treatment tailoring for advanced gastric cancer. We investigated the mRNA expression of 5-fluorouracil (5-FU) pathway genes in prechemotherapeutic tumor samples of primary gastric cancer to try to predict the treatment outcome of S-1 monotherapy. 5-FU pathway genes, dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidylate synthase (TS), and thymidine phosphorylase (TP), were analyzed using quantitative real-time PCR of RNA extracted from archived formalin-fixed paraffin-embedded tissues. We selected the median value for each gene as a cutoff to separate patients into high and low gene expression groups. High OPRT gene expression was significantly associated with tumor response (P=0.014). In a combined analysis including OPRT, patients with high OPRT and TP showed a higher overall response rate than did the remaining patients (40 vs. 10%, respectively; P=0.002). For survival, patients with high OPRT and low TS levels showed prolonged survival in both progression-free survival (3.4 vs. 2.4 months, P=0.024) and overall survival (11.0 vs. 8.2 months, P=0.007). In a multivariate analysis, the combinations of OPRT and TP for response and OPRT and TS for both progression-free survival and overall survival were independent variables. To conclude, mRNA expression levels of molecular markers in formalin-fixed paraffin-embedded specimens of primary gastric tumors can be useful for identifying patients with advanced gastric cancer who would most likely benefit from S-1 treatment. © 2011 Wolters Kluwer Health | Lippincott Williams & Wilkins.


Kim J.H.,Yonsei Cancer Research Institute | Kim J.H.,Cancer Metastasis Research Center | Kim J.H.,Yonsei University | Kim H.S.,Yonsei Cancer Research Institute | And 17 more authors.
Annals of Oncology | Year: 2012

Background: Nomograms are statistics-based tools that provide the overall probability of a specific outcome. In our previous study, we developed a nomogram that predicts recurrence of early gastric cancer (EGC) after curative resection. We carried out this study to externally validate our EGC nomogram. Patients and methods: The EGC nomogram was established from a retrospective EGC database that included 2923 consecutive patients. This nomogram was independently externally validated for a cohort of 1058 consecutive patients. For the EGC nomogram validation, we assessed both discrimination and calibration. Results: Within the follow-up period (median 37 months), a total of 11 patients (1.1%) experienced recurrence. The concordance index (c-index) was 0.7 (P = 0.02) and the result of the overall C index was 0.82 [P = 0.006, 95% confidence interval (CI) 0.59-1.00]. The goodness of fit test showed that the EGC nomogram had significantly good fit for 1- and 2-year survival intervals (P = 0.998 and 0.879, respectively). The actual and predicted survival outcomes showed good agreement, suggesting that the survival predictions from the nomogram are well calibrated externally. Conclusions: A preexisting nomogram for predicting disease-free survival (DFS) of EGC after surgery was externally validated. The nomogram is useful for accurate and individual prediction of DFS, patient prognostication, counseling, and follow-up planning. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Lee W.S.,Cancer Metastasis Research Center | Lee W.S.,Yonsei University | Jung J.J.,Cancer Metastasis Research Center | Jung J.J.,Yonsei University | And 15 more authors.
Hepato-Gastroenterology | Year: 2012

Background/Aims: Epigenetic regulations play a role in the development and progression of cancer. Therefore, discovering novel epigenetically regulated genes could provide useful information in understanding cancer. Lamin A/C is an intermediate filament protein whose expression is reported to be suppressed in tissues of gastro-intestinal malignancies. We examined expression of lamin A/C in gastric and colorectal cancer cell lines and its association with DNA methylation. Methodology: The methylation status of CpG island in 19 gastric, 5 colorectal cancer cells and 1 normal colon cell line were examined with methylation-specific PCR using paired methylated and unmethylated primers. The level of mRNA expression of lamin A/C was detected using RT-PCR. Results: Eighteen gastric cancer cell lines showed 95% unmethylation of lamin A/C and 1 cell line showed partial methylation. In colorectal cancer, only 1 out of 5 cancer cell lines (20%) was partially methylated and the remaining cell lines, including 1 normal colon cell line was unmethylated. With RT-PCR, all cell lines demonstrated mRNA expression of lamin A/C regardless of methylation status. Conclusions: We observed that the expression of lamin A/C was not suppressed in gastrointestinal cancer cell lines different from hematologic malignant cells and it is not regulated through DNA methylation. © H.G.E. Update Medical Publishing S.A.


PubMed | Cancer Metastasis Research Center
Type: Journal Article | Journal: Hepato-gastroenterology | Year: 2012

We evaluated matrix metalloproteinase (MMP)-2 and -9 as novel biomarkers in the body fluid of advanced gastric cancer with peritoneal and pulmonary metastasis.MMPs activity from zymography was quantified with ELISA to determine the cut-off expression levels of MMPs. The expression of MMPs in patient samples were evaluated with ELISA and compared with clinical parameters. Ascitic CEA (aCEA) and pleural CEA (pCEA) were measured by chemiluminescent enzyme immunoassay.MMP-2 and -9 cut-off levels were 8.6ng/mL and 0.14ng/mL, respectively. Ascitic fluid cytology of 93 patients revealed a positivity of 55.9% while for MMP-2 it was 93.3%, for MMP-9 35.2% and for aCEA 86.7%. Combining biomarkers, the positivity increased to 99.1% in patients with MMP-2 or aCEA expression. We found a negative correlation between MMP-2 expression and survival when a new prognostic cut-off of 22.6ng/mL was used. Patients with high MMP-2 expression (22.6ng/mL) had a median survival of 45 days and those with low MMP-2 expression (<22.6ng/mL) had a median survival of 69 days (p<0.01).These results suggest that MMPs could be used as diagnostic markers in body fluid and MMP-2 might be a prognostic marker in ascites of advanced gastric patients with disseminated metastasis.


PubMed | Cancer Metastasis Research Center
Type: Journal Article | Journal: Hepato-gastroenterology | Year: 2012

Epigenetic regulations play a role in the development and progression of cancer. Therefore, discovering novel epigenetically regulated genes could provide useful information in understanding cancer. Lamin A/C is an intermediate filament protein whose expression is reported to be suppressed in tissues of gastro-intestinal malignancies. We examined expression of lamin A/C in gastric and colorectal cancer cell lines and its association with DNA methylation.The methylation status of CpG island in 19 gastric, 5 colorectal cancer cells and 1 normal colon cell line were examined with methylation-specific PCR using paired methylated and unmethylated primers. The level of mRNA expression of lamin A/C was detected using RT-PCR.Eighteen gastric cancer cell lines showed 95% unmethylation of lamin A/C and 1 cell line showed partial methylation. In colorectal cancer, only 1 out of 5 cancer cell lines (20%) was partially methylated and the remaining cell lines, including 1 normal colon cell line was unmethylated. With RT-PCR, all cell lines demonstrated mRNA expression of lamin A/C regardless of methylation status.We observed that the expression of lamin A/C was not suppressed in gastrointestinal cancer cell lines different from hematologic malignant cells and it is not regulated through DNA methylation.

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