Institute of Innovative Cancer Research

Seoul, South Korea

Institute of Innovative Cancer Research

Seoul, South Korea
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Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research | Lee J.L.,University of Ulsan | Lee J.L.,Institute of Innovative Cancer Research | Park S.H.,University of Ulsan
Diseases of the Colon and Rectum | Year: 2017

BACKGROUND: Since the introduction of indocyanine green angiography more than 25 years ago, few studies have presented interpretative guidelines for indocyanine green fluorescent imaging. OBJECTIVE: We aimed to provide interpretative guidelines for indocyanine green fluorescent imaging through quantitative analysis and to suggest possible indications for indocyanine green fluorescent imaging during robot-assisted sphincter-saving operations. DESIGN: This is a retrospective observational study. SETTINGS: This study was conducted at a single center. PATIENTS: A cohort of 657 patients with rectal cancer who consecutively underwent curative robot-assisted sphincter-saving operations was enrolled between 2010 and 2016, including 310 patients with indocyanine green imaging (indocyanine green fluorescent imaging+ group) and 347 patients without indocyanine green imaging (indocyanine green fluorescent imaging-group). MAIN OUTCOME MEASURES: We tried to quantitatively define the indocyanine green fluorescent imaging findings based on perfusion (mesocolic and colic) time and perfusion intensity (5 grades) to provide probable indications. RESULTS: The anastomotic leakage rate was significantly lower in the indocyanine green fluorescent imaging+ group than in the indocyanine green fluorescent imaging-group (0.6% vs 5.2%) (OR, 0.123; 95% CI, 0.028-0.544; p = 0.006). Anastomotic stricture was closely correlated with anastomotic leakage (p = 0.002) and a short descending mesocolon (p = 0.003). Delayed perfusion (>60 s) and low perfusion intensity (1-2) were more frequently detected in patients with anastomotic stricture and marginal artery defects than in those without these factors (p ≤ 0.001). In addition, perfusion times greater than the mean were more frequently observed in patients aged >58 years, whereas low perfusion intensity was seen more in patients with short descending mesocolon and high ASA classes (≥3). LIMITATIONS: The 300 patients in the indocyanine green fluorescent imaging-group underwent operations 3 years before indocyanine green fluorescent imaging. CONCLUSIONS: Quantitative analysis of indocyanine green fluorescent imaging may help prevent anastomotic complications during robot-assisted sphincter-saving operations, and may be of particular value in high-class ASA patients, older patients, and patients with a short descending mesocolon. © 2016 The ASCRS.

Xiao H.,University of Ulsan | Xiao H.,Beijing United Family Hospital | Yoon Y.S.,University of Ulsan | Yoon Y.S.,Beijing United Family Hospital | And 8 more authors.
American Journal of Clinical Pathology | Year: 2013

Objectives: To evaluate the association of microsatellite instability (MSI) with clinicopathologic features and oncologic outcomes in patients with poorly differentiated colorectal cancer (PD). Methods: Study patients were divided into well-differentiated colorectal cancer (WD) and PD, which were compared according to histologic differentiation and MSI status. Results: Among 1,941 patients, PD was more frequent among microsatellite-unstable tumors (23.6%) than among microsatellite-stable (MSS) tumors (4.2%, P < .001). Patients with PD had worse 4-year overall survival rates than patients with WD (78.6% vs 88.2%, P = 0.010). Compared with MSS-PD tumors, MSI-PD tumors were characterized by right-colon predilection, larger size, and infrequent lymph node metastasis (P < .001 to P = .007). Conclusions: The clinicopathologic characteristics of PD were closely associated with those of MSI. The outcomes of MSI-PD tumors were better than those of MSS-PD tumors, but this finding did not reach statistical significance. © American Society for Clinical Pathology.

Kim J.,Research Center for Womens Diseases | Lee S.-D.,Research Center for Womens Diseases | Chang B.,Research Center for Womens Diseases | Jin D.-H.,Institute of Innovative Cancer Research | And 8 more authors.
Free Radical Biology and Medicine | Year: 2012

Ascorbate is an important natural antioxidant that can selectively kill cancer cells at pharmacological concentrations. Despite its benefit, it is quite difficult to predict the antitumor effects of ascorbate, because the relative cytotoxicity of ascorbate differs between cancer cell lines. Therefore, it is essential to examine the basis for this fundamental disagreement. Because p53 is activated by DNA-damaging stress and then regulates various cellular conditions, we hypothesized that p53 can sensitize cancer cells to ascorbate. Using isogenic cancer cells, we observed that the presence of p53 can affect ascorbate cytotoxicity, and also reactivation of p53 can make cancer cells sensitive to ascorbate. p53-dependent enhancement of ascorbate cytotoxicity is caused by increased reactive oxygen species generation via a differentially regulated p53 transcriptional network. We also found that transcriptionally activated p53 was derived from MDM2 ubiquitination by ascorbate and subsequently its signaling network renders cancer cells more susceptible to oxidative stress. Similar to the p53 effect on in vitro ascorbate cytotoxicity, inhibition of tumor growth is also stronger in p53-expressing tumors than in p53-deficient ones in vivo. This is the first observation that ascorbate cytotoxicity is positively related to p53 expression, activating its transcriptional network to worsen intracellular oxidative stress and consequently enhancing its cytotoxicity. Based on our study, reactivation of p53 may help to achieve more consistent cytotoxic effects of ascorbate in cancer therapies. © 2012 Elsevier Inc.

PubMed | Institute of Innovative Cancer Research, University of Ulsan and Korea Research Institute of Bioscience and Biotechnology
Type: Journal Article | Journal: PloS one | Year: 2016

Using our data set (GSE50760) previously established by RNA sequencing, the present study aimed to identify upregulated genes associated with colorectal cancer (CRC) liver metastasis (CLM) and verify their biological behavior. The potential roles of candidate genes in tumors were assessed using cell proliferation and invasion assays. Tissue samples were collected from 18 CRC patients with synchronous CLM and two CRC cell lines (SW480 and SW620) were used for transfection and cloning. The roles of the genes identified in CLM were verified using immunohistochemistry in 48 nude mice after intrasplenic transplantation of CRC cells. mRNA and protein expression was determined by quantitative real-time reverse transcription polymerase chain reaction and western blot, respectively. Nine genes were initially selected according to the relevance of their molecular function and biological process and, finally, ALDH1A1 and IGFBP1 were chosen based on differential mRNA expression and a positive correlation with protein expression. The overexpression of ALDH1A1 and IGFBP1 significantly and time-dependently decreased cell proliferation (p 0.001-0.003) and suppressed invasiveness by 3-fold over control cells (p < 0.001) in the SW480 cell line, whereas they had a slight effect on reducing SW620 cell proliferation. The protein expression levels of E-cadherin, N-cadherin, claudin-1, and vimentin were significantly higher in CLM than in primary tumor tissues (p < 0.05). However, the cadherin switch, namely, N-cadherin overexpression with reduced E-cadherin expression, was not observed in CLM tissues and transfected CRC cells. Irrespective of reduced proliferation and invasion found on in vitro cell assays, persistent overexpression of -catenin, vimentin, and ZO-1 in IGFBP1-overexpressing SW480 cells possibly contributed to CLM development in mice implanted with IGFBP1-overexpressing SW480 cells (CLM occurrences: SW480/IGFBP1-transfected mice vs. SW480/vector- and SW480/ALDH1A1-transfected mice, 4/8 vs. 0/10, p = 0.023). In conclusion, ALDH1A1 and IGFBP1 are differentially overexpressed in CLM and may play a dual role, functioning as both tumor suppressors and metastasis promoters in CRC.

PubMed | Institute of Innovative Cancer Research, University of Ulsan and Kyung Hee University
Type: Journal Article | Journal: Annals of surgical treatment and research | Year: 2016

The purpose of this study was to evaluate the prognostic significance of serum CEA (s-CEA) changes in colorectal cancer (CRC) patients with sustained elevated postoperative s-CEA levels.Between January 1999 and December 2008, 9,380 CRC patients underwent surgery. Curative resection was performed in 1,242 CRC patients with high preoperative s-CEA levels (>6 ng/mL). High s-CEA levels were normalized in 924 patients (74.4%) within 2 weeks from surgery, whereas high s-CEA levels were persistent in 318 patients (25.6%). Patients were divided into 2 groups according to their postoperative s-CEA levels: group 1 (37 patients with a 1-year postoperative s-CEA>6 ng/mL) and group 2 (281 patients with a 1-year postoperative s-CEA6 ng/mL).A postoperative recurrence was identified in 24 patients (64.9%) in group 1 and 65 patients (23.1%) in group 2 (P < 0.001). A curative resection after recurrence was performed in 22 patients (33.8%) from group 2, but no patients from group 1 (P = 0.001). The 5-year overall survival and time to recurrence were significantly lower in patients with recurrent cancer in group 1 (P < 0.001).Patients with persistent elevated postoperative s-CEA levels are at high risk for recurrence and a low survival rate. More intensive surveillance of patients with high postoperative s-CEA levels should be mandatory.

Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research | Ha Y.J.,University of Ulsan | Ha Y.J.,Institute of Innovative Cancer Research | And 14 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2013

Purpose: Studies aimed at predicting individual responsiveness to preoperative chemoradiation therapy (CRT) are urgently needed, especially considering the risks associated with poorly responsive patients. Methods and Materials: A 3-step strategy for the determination of CRT sensitivity is proposed based on (1) the screening of a human genome-wide single-nucleotide polymorphism (SNP) array in correlation with histopathologic tumor regression grade (TRG); (2) clinical association analysis of 113 patients treated with preoperative CRT; and (3) a cell-based functional assay for biological validation. Results: Genome-wide screening identified 9 SNPs associated with preoperative CRT responses. Positive responses (TRG 1-3) were obtained more frequently in patients carrying the reference allele (C) of the SNP CORO2A rs1985859 than in those with the substitution allele (T) (P=.01). Downregulation of CORO2A was significantly associated with reduced early apoptosis by 27% (P=.048) and 39% (P=.023) in RKO and COLO320DM colorectal cancer cells, respectively, as determined by flow cytometry. Reduced radiosensitivity was confirmed by colony-forming assays in the 2 colorectal cancer cells (P=.034 and.015, respectively). The SNP FAM101A rs7955740 was not associated with radiosensitivity in the clinical association analysis. However, downregulation of FAM101A significantly reduced early apoptosis by 29% in RKO cells (P=.047), and it enhanced colony formation in RKO cells (P=.001) and COLO320DM cells (P=.002). Conclusion: CRT-sensitive SNP markers were identified using a novel 3-step process. The candidate marker CORO2A rs1985859 and the putative marker FAM101A rs7955740 may be of value for the prediction of radiosensitivity to preoperative CRT, although further validation is needed in large cohorts. © 2013 Elsevier Inc. All rights reserved.

Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research | Yu J.H.,University of Ulsan | Yu J.H.,Institute of Innovative Cancer Research | And 10 more authors.
Breast Cancer Research and Treatment | Year: 2012

Small proline rich repeat protein 3 (SPRR3), a member of the SPRR family of cornified envelope precursor proteins, is a marker for terminal squamous cell differentiation. Previously, this laboratory showed that SPRR3 is strongly upregulated in colorectal tumors, and is involved in the tumorigenesis. The current study was performed to investigate the expression status and effect of SPRR3 in breast cancers (BCs). SPRR3 expression was examined by immunohistochemistry in 241 tumor samples from BC patients. SPRR3 was overexpressed in more than half of all BC samples. SPRR3 overexpression was significantly associated with less advanced stage (0-1 vs. II=III) and the absence of lymph node metastasis (P = 0.004 and 0.013, respectively). HER2/neu overexpression was closely correlated with SPRR3 overexpression in a multivariate analysis (OR, 3.23, P = 0.017). To assess the influence of SPRR3 on cell proliferation and related signaling pathways, SPRR3-transfected clones from the SPRR3-negative T-47D human BC cell line were generated. Among the total of six SPRR3-overexpressing clones, five showed marked proliferation compared with SPRR3-nonexpressing control cells from day 3 of culture (P < 0.001). The SPRR3-over-expressing BC clones showed increased phosphorylation of AKT and MDM2, p21 overexpression, and p53 downregu-lation. Furthermore, phosphorylation of MEK and M APK was markedly increased. This study demonstrates that SPRR3 promotes BC cell proliferation by enhancing p53 degradation via the AKT and MAPK pathways and is, therefore, a potential novel therapeutic target for less advanced stages of BC. © 2012 Springer Science+Business Media, LLC.

Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research | Kwak J.Y.,University of Ulsan | Kwak J.Y.,Institute of Innovative Cancer Research | And 6 more authors.
International Journal of Colorectal Disease | Year: 2014

Purpose: This study was to ascertain whether a robot-assisted (RA) approach to APR might facilitate a cylindrical APR by enabling a deeper pelvic dissection during an abdominal approach, concurrently comparing the feasibility and short-term oncologic outcomes. Methods: Forty-eight consecutive patients with lower rectal cancer who had undergone curative APR (21 RA vs. 27 open) were prospectively enrolled. The short-term operative outcomes and oncologic feasibility were evaluated and compared. A levator muscle excision was performed concomitantly with the abdominal procedure in the RA group and with the perineal procedure in the open group. Results: No patients in the RA group experienced intraoperative perforation or required conversion to open APR. Overall, a cylindrical APR was performed in 72 % of patients, and subtotal excision of the levator muscle, i.e., either one or both sides of the puborectalis and pubococcygeus muscles, was more likely in the RA group (P=0.019). A positive CRM was exclusively identified in four open APR patients. The mean number of retrieved lymph nodes was greater in the RA group (20 vs. 16, P=0.035). There was no difference in perineal morbidity between the two groups (P=0.445). Conclusions: The RA approach facilitates an efficient excision in the pelvic region than open APR during the abdominal procedure. The RA approach also demonstrated a trend toward improved oncologic outcomes with equivalent postoperative morbidities than with the open approach. © 2014 Springer-Verlag.

Kim J.C.,University of Ulsan | Kim J.C.,Institute of Innovative Cancer Research | Kim S.Y.,Institute of Innovative Cancer Research | Kim S.Y.,Korea Research Institute of Bioscience and Biotechnology | And 12 more authors.
Clinical Cancer Research | Year: 2011

Purpose: Methods for predicting individual responsiveness to targeted chemotherapy are urgently needed, considering the frequent resistance and extremely high cost. Experimental Design: A chemosensitive single-nucleotide polymorphism (SNP) discovery schema is presented that utilizes (i) genome-wide SNP screening with a human SNP array and an in vitro chemosensitivity assay in 118 colorectal cancers, (ii) clinical association analysis in the other 98 patients who had received chemotherapy for metastatic cancer, and (iii) biological utility assessment using cell viability assays of transfected colorectal cancer (CRC) cells. Results: Nine SNPs related to bevacizumab and cetuximab regimen sensitivity were chosen during screening. Overall responses for bevacizumab regimens revealed that patients carrying the TT genotype at ANXA11 rs1049550 or at least one G allele at LINS1 rs11247226 seemed greater chemosensitive than those carrying at least one C allele or the AA genotype, respectively (P < 0.05). For cetuximab regimens, patients carrying the GG genotype at DFNB31 rs2274159 or LIFR rs3729740 seemed greater chemosensitive than those carrying at least one A allele (P = 0.025 and P = 0.07). Cytotoxicity analyses showed that all RKO and HCT116 CRC clones transfected with the G allele at LIFR rs3729740 and the C allele at ISX rs361863 were more sensitive to cetuximab regimens than those with the A and T allele, respectively (P ≤ 0.001-0.024). Conclusions: Chemosensitive SNP markers were identified using a novel three-step process. The candidate marker LIFR rs3729740 and possibly ISX rs361863 will hopefully predict responsive patients to cetuximab regimens, although further validation is needed in large cohorts.©2011 AACR.

Kim J.C.,Asan Medical Center | Kim J.C.,Institute of Innovative Cancer Research | Choi J.S.,Asan Medical Center | Choi J.S.,Institute of Innovative Cancer Research | And 8 more authors.
Annals of Surgical Oncology | Year: 2010

Background. Promoter methylation of colorectal cancerrelated genes were examined with respect to phenotype and tumor progression. Materials and Methods. We assayed promoter methylation of 11 genes including established CpG island methylator phenotype (CIMP) markers (MLH1, MINT1, MINT2, MINT31, p16 INK4a, p14ARF, and CACNA1G) and four genes (COX2, DAPK, MGMT, and APC) frequently methylated in colorectal cancer in 285 patients with sporadic colorectal cancer. Results. CIMP+ tumors were more than two times more frequent among high-frequency microsatellite instability tumors (MSI-H) than in tumors without MSI (P ≤.0001-.002). COX2 and DAPK methylation were significantly associated with CIMP+ and MSI. KRAS showed tendency toward more frequent codon 12-13 mutations identified in tumors with APC and p16 INK4a methylation than in those with unmethylation (P =.033 and.05, respectively). Additionally, tumors with synchronous adenoma were associated with p16INK4a methylation (P =.004). The p16INK4a methylation was significantly associated with poor overall and disease-free survival in 131 rectal cancer patients who underwent curative operation, according to multivariate analyses (relative risk [RR] = 0.317 and 0.349; P =.033 and.024, respectively). Specifically, in 175 stage II and III patients receiving adjuvant-based fluoropyrimidine chemotherapy, p16INK4a methylation and MINT31 unmethylation showed a significant or tendency toward an association with recurrence and DFS (P =.007-.032). Conclusions. The study suggests that specific CIMP markers, such as p16INK4a and MINT31, should be further verified as potential epigenetic targets for the design of efficient chemotherapy regimens. We also identified a subset of colorectal cancer, possibly comprising APC methylation-KRAS mutation-p16INK4a methylation. © Society of Surgical Oncology 2010.

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