[Show abstract][Hide abstract] ABSTRACT: MicroRNAs (miRNAs) are important components of cellular signaling pathways, acting either as pathway regulators or pathway targets. Currently, only a limited number of miRNAs have been functionally linked to specific signaling pathways. Here, we explored if gene expression signatures could be used to represent miRNA activities and integrated with genomic signatures of oncogenic pathway activity to identify connections between miRNAs and oncogenic pathways on a high-throughput, genome-wide scale. Mapping >300 gene expression signatures to >700 primary tumor profiles, we constructed a genome-wide miRNA-pathway network predicting the associations of 276 human miRNAs to 26 oncogenic pathways. The miRNA-pathway network confirmed a host of previously reported miRNA/pathway associations and uncovered several novel associations that were subsequently experimentally validated. Globally, the miRNA-pathway network demonstrates a small-world, but not scale-free, organization characterized by multiple distinct, tightly knit modules each exhibiting a high density of connections. However, unlike genetic or metabolic networks typified by only a few highly connected nodes ("hubs"), most nodes in the miRNA-pathway network are highly connected. Sequence-based computational analysis confirmed that highly-interconnected miRNAs are likely to be regulated by common pathways to target similar sets of downstream genes, suggesting a pervasive and high level of functional redundancy among coexpressed miRNAs. We conclude that gene expression signatures can be used as surrogates of miRNA activity. Our strategy facilitates the task of discovering novel miRNA-pathway connections, since gene expression data for multiple normal and disease conditions are abundantly available.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Liver transplantation (LT) is a curative treatment for localized hepatocellular carcinoma (HCC), but the recurrence rate after LT is about 10-20%, with a dismal prognosis. Little data exist as to the natural history, treatment outcome and optimal treatment of recurrent HCC after LT. We reviewed various treatment modalities given to patients with recurrent HCC after LT.
Among 132 patients who underwent LT for localized HCC, we retrospectively reviewed medical records of 39 of the 132 patients who developed recurrent HCC after LT. We analyzed the clinical outcome of various treatment modalities and treatment-related adverse events.
A total of 39 (29%) of the original 132 patients had recurrent HCC, most recurrences (82%) having occurred within 1 year after LT and involved extrahepatic lesions. Only seven patients had recurrent disease limited to the liver. The median overall survival from the initial treatment of all relapsed patients was 6.9 months. There were various initial treatment modalities, namely palliative systemic chemotherapy, trans-catheter arterial chemo-embolization/infusion (TACE/I), radiation therapy (RT), surgical resection and no treatment. The median overall survival was 9.5 months for first-line chemotherapy, including those who had prior local therapy, 6.3 months TACE/I and 6.9 months for RT.
Various clinical approaches have been used to treat patients with recurrent HCC after LT in a clinical setting. More effective strategies and clinical guidelines for recurrent HCC following LT must be established.
[Show abstract][Hide abstract] ABSTRACT: We aimed to describe the efficacy and safety of sunitinib in unselected Korean advanced renal cell carcinoma (RCC) patients.
From November 2005 to August 2008, 132 histologically confirmed advanced RCC patients (100 in the global expanded access program) were enrolled. Response and toxicity were assessed regularly according to the protocol.
Within this population, 82.6% had clear cell RCC, and 28.8% were treatment naïve. Patients received a median of 5 cycles of sunitinib (range 1-30), and the mean relative dose intensity was 82.0 ± 14.20 (SD). The progression-free survival (PFS) and overall survival rates were 8.2 and 23.1 months, respectively. For the 130 evaluable patients, the objective response rate was 34.1% (n = 45); 44.7% (n = 59) exhibited stable disease. Reasons for discontinuation were disease progression (75.0%) and toxicity (7.6%). The most frequent adverse events were thrombocytopenia (75.0%), neutropenia (70.5%), and anemia (69.7%). Low body surface area (OR = 4.2, 95% CI 1.2-13.8, p = 0.02) and previously treated status (OR = 3.1, 95% CI 1.3-7.4, p = 0.01) were highly predictive of grade 3-4 toxicities. Based on these findings, a nomogram predicting the probability of 12-month PFS was constructed, giving a concordance index of 0.675.
Despite the different toxicity profiles, maintaining adequate dose modifications and a careful follow-up enables comparable treatment outcomes for unselected Korean advanced RCC patients.
[Show abstract][Hide abstract] ABSTRACT: Laparoscopic colectomy has clinical benefits such as short hospital stay, less postoperative pain, and early return of bowel function. However, objective evidence of its immunologic and oncologic benefits is scarce. We compared functional recovery after open versus laparoscopic sigmoidectomy and investigated the effect of open versus laparoscopic surgery on acute inflammation as well as tumor stimulation.
A total of 57 patients who were diagnosed with sigmoid colon cancer were randomized for elective conventional or laparoscopically assisted sigmoidectomy. Serum samples were obtained preoperatively and on postoperative day 1. C-reactive protein (CRP) and interleukin-6 (IL-6) were measured as inflammation markers, and vascular endothelial growth factor (VEGF) and insulin-like growth factor binding protein-3 (IGFBP-3) were used as tumor stimulation factors. Clinical parameters and serum markers were compared.
Postoperative hospital stay (p=0.031), the first day of gas out (p=0.016), and the first day of soft diet (p<0.001) were significantly shorter for the laparoscopic surgery group than the open surgery group. The levels of CRP, IL-6, and VEGF rose significantly, and the concentration of IGFBP-3 fell significantly after both open and laparoscopic surgery. However, there were no significant differences in the preoperative and postoperative levels of CRP, IL-6, VEGF, and IGFBP-3 between the two groups.
Our data suggest that both open and laparoscopic surgeries are accompanied by significant changes in IL-6, CRP, IGFBP-3, and VEGF levels. Acute inflammation markers and tumor stimulating factors may not reflect clinical benefits of laparoscopic surgery.
Yonsei medical journal 07/2011; 52(4):635-42. DOI:10.3349/ymj.2011.52.4.635 · 1.26 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The clinicopathological manifestations and treatment outcomes of bone metastasis of gastric cancer are largely unknown. We delineated a prognostic model to identify different risk groups on the basis of clinical parameters.
Patients who had bone metastasis at the time of diagnosis of gastric cancer (synchronous metastasis) or who developed bone metastasis during follow-up (metachronous metastasis) were retrospectively reviewed from January 1998 to May 2008.
Bone metastasis was identified in 203 (2.4%) of 8,633 patients: 126 patients (62%) with synchronous metastasis and 77 patients with metachronous metastasis. The median time to event was 16 months (range 4-87). As for treatment, 120 patients (59%) received systemic chemotherapy. The median survival time was 103 days (95% CI 80-126). Poor performance status [Eastern Cooperative Oncology Group 3-4; relative risk (RR) = 1.91, p = 0.011], multiple bone metastasis (RR = 2.593, p = 0.002), and abnormal carcinoembryonic antigen (RR = 1.779, p = 0.004) implied independent factors for survival. For patients who had zero to two of these factors identified, chemotherapy had a beneficial effect (175 vs. 43 days; p < 0.0001).
We recommend that the therapeutic approach with bone metastasis be customized to facilitate the risk stratification, so as to consequently provide the most appropriate therapy for each patient.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to compare 2 weekly docetaxel-based regimens as first-line treatments for advanced gastric cancer and to investigate the expression of secreted protein acidic and rich in cysteine (SPARC) and its abilities to predict treatment-related clinical outcomes.
Patients were randomly selected to receive 3 weekly cycles of docetaxel (35 mg/m(2) on days 1 and 8) plus S-1 (35 mg/m(2) each twice daily on days 1-14) (DS), or docetaxel plus cisplatin (35 mg/m(2) each on days 1 and 8) (DC). Endpoints included overall response rate (primary), survival, toxicity, and quality of life (secondary). SPARC expression in prechemotherapy specimens of primary gastric tumors was evaluated via immunohistochemical analysis.
Eighty patients were enrolled in the study. Confirmed overall response rates were 46% (95% confidence interval, 30%-62%) for DS and 24% (95% confidence interval, 11%-38%) for DC via intent-to-treat analysis. Median progression-free survival was 7.3 and 4.9 months and overall survival was 16.0 and 8.3 months for DS and DC, respectively. The most common grade ≥ 3 toxicity was neutropenia. Grade ≥ 3 mucositis (18%) and hand-foot syndrome (8%) were the toxicities most associated with DS, whereas anorexia (20%) and lethargy (20%) were more common with DC. High SPARC expression was related to early progression (hazard ratio, 3.67; P = .042) and poor overall survival (hazard ratio, 2.01; P = .010) in docetaxel chemotherapy on multivariate analysis.
The outcomes in this study favored DS over DC for further phase 3 study. The findings suggest that split-dose weekly docetaxel alleviates hematological toxicity without compromising efficacy, and that SPARC expression may help individualize therapy in advanced gastric cancer.
Cancer 05/2011; 117(10):2050-7. DOI:10.1002/cncr.25729 · 4.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: TSU-68 is a novel multiple tyrosine kinase inhibitor that inhibits VEGFR-2, FGF and PDGF receptors. We conducted a phase I study to evaluate the safety and pharmacokinetic of TSU-68 when used with S-1 and oxaliplatin (SOX) in metastatic colorectal cancer (mCRC) patients. Patients with mCRC were treated with TSU-68 200 mg (Level 1) or 400 mg (Level 2) b.i.d. daily, S-1 35 mg/m(2) b.i.d. on Days 1-14 and oxaliplatin 130 mg/m(2) i.v. on Day 1 repeatedly every 3 weeks. Of eleven patients enrolled, two patients were excluded from dose limiting toxicity (DLT) assessment. Six patients at Level 1 experienced no DLT. Of three patients at Level 2, two patients experienced DLTs (one patient: grade 3 hiccup and palmar-plantar erythrodysaesthesia syndrome, another one: grade 2 neutropenia which prevented the initiation of next cycle within 14 days). The maximal tolerated dose (MTD) and recommended dose (RD) of TSU-68 was 200 mg b.i.d. C(max) and AUC(0-t) of TSU-68 at Level 2 were higher than those at Level 1, but doubling the dose of TSU-68 increased C(max) and AUC(0-t) less than two-fold. There was no appreciable difference in the PK of S-1 components (FT, CDHP and Oxo), 5-FU and oxaliplatin-derived platinum between Levels 1 and 2. A significant decrease in PDGF after TSU-68 treatment was identified and it might serve as pharmacodynamic marker of TSU-68. Administration of TSU-68 in combination with SOX is generally well tolerated. The MTD and RD of TSU-68 in this study was 200 mg b.i.d. daily.
Investigational New Drugs 05/2011; 30(4):1501-10. DOI:10.1007/s10637-011-9683-8 · 2.93 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: This study primarily aimed to investigate the prevalence and associated factors of psychological distress among Korean cancer patients. Its secondary objective was to classify mental illnesses among cancer patients with significant psychological distress.
We administered the Modified Distress Thermometer (MDT), Hospital Anxiety and Depression Scale (HADS), and Center for Epidemiologic Studies-Depression Scale (CES-D) to consecutive, newly diagnosed cancer patients and conducted subsequent psychiatric interviews. A multiple logistic regression produced a discriminate profile of individuals with psychological distress.
Among 295 participants, 85 (28.8%) were identified as patients with psychological distress. Female gender [odds ratio (OR)=1.97], low educational level (OR=2.25) and low performance status (OR=4.10) were significantly associated with this condition. Among the 38 patients with psychological distress who received psychiatric assessment, the most common mental illness was adjustment disorder (n=23, 69.7%).
The results of this study showed that approximately one-third of the cancer patients suffered from psychological distress. We recommend that physicians focus on the psychological status of female cancer patients with low levels of education and poor performance status.
General hospital psychiatry 05/2011; 33(3):246-52. DOI:10.1016/j.genhosppsych.2011.02.008 · 2.90 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fusion genes are chimeric genes formed in cancers through genomic aberrations such as translocations, amplifications, and rearrangements. To identify fusion genes in gastric cancer, we analyzed regions of chromosomal imbalance in a cohort of 106 primary gastric cancers and 27 cell lines derived from gastric cancers. Multiple samples exhibited genomic breakpoints in the 5' region of SLC1A2/EAAT2, a gene encoding a glutamate transporter. Analysis of a breakpoint-positive SNU16 cell line revealed expression of a CD44-SLC1A2 fusion transcript caused by a paracentric chromosomal inversion, which was predicted to produce a truncated but functional SLC1A2 protein. In primary tumors, CD44-SLC1A2 gene fusions were detected in 1 to 2% of gastric cancers, but not in adjacent matched normal gastric tissues. When we specifically silenced CD44-SLC1A2, cellular proliferation, invasion, and anchorage-independent growth were significantly reduced. Conversely, CD44-SLC1A2 overexpression in gastric cells stimulated these pro-oncogenic traits. CD44-SLC1A2 silencing caused significant reductions in intracellular glutamate concentrations and sensitized SNU16 cells to cisplatin, a commonly used chemotherapeutic agent in gastric cancer. We conclude that fusion of the SLC1A2 gene coding region to CD44 regulatory elements likely causes SLC1A2 transcriptional dysregulation, because tumors expressing high SLC1A2 levels also tended to be CD44-SLC1A2-positive. CD44-SLC1A2 may represent a class of gene fusions in cancers that establish a pro-oncogenic metabolic milieu favoring tumor growth and survival.
Science translational medicine 04/2011; 3(77):77ra30. DOI:10.1126/scitranslmed.3001423 · 14.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mucinous colorectal carcinoma exhibits distinct clinicopathological features compared to non-mucinous colorectal carcinoma. Previous studies have discovered several molecular genetic features in mucinous colorectal carcinomas, but have limitations as they are confined to a small number of molecules. To understand the mucinous colorectal carcinoma system, this study was designed to identify genes that are differentially expressed in mucinous colorectal carcinoma compared to non-mucinous colorectal carcinoma using cDNA microarrays. cDNA microarray experiments were performed using human cDNA 17k chips with 25 mucinous and 27 non-mucinous cancer tissues. Differentially expressed genes (DEGs) were determined by Welch's t-test and more accurate classifiers were selected from the DEGs using the prediction analysis for microarrays (PAM) software package. Array results were validated using quantitative real-time RT-PCR. The identified gene set was functionally investigated through in silico analysis. Sixty-two DEGs were identified and the 50 highest ranking genes could be used to accurately classify mucinous and non-mucinous colorectal carcinomas. The identified gene set included up-regulated TFF1 (4-fold), AGR2 (3.3-fold), FSCN1 (2.2-fold), CD44 (1.5-fold) and down-regulated SLC26A3 (0.2-fold) in MC. TFF1, AGR2 and SLC26A3 were validated by quantitative real-time RT-PCR. The functions of these DEGs were related to tumorigenesis (14 genes), cell cycle progression (6 genes), invasion (2 genes), anti-apoptosis (7 genes), cell adhesion and proliferation (5 genes) and carbohydrate metabolism (3 genes). We suggest that MC has distinct molecular characteristics from NMC and therefore, that the expression signatures of DEGs may improve the understanding of molecular pathogenesis and clinical behaviors in MC.
[Show abstract][Hide abstract] ABSTRACT: To evaluate prognostic factors in estrogen receptor (ER)-positive, operable breast cancer focusing on the progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2).
A total of 819 patients with ER-positive, operable breast cancer were enrolled. All patients received upfront adjuvant tamoxifen, as stipulated by eligibility criteria. Prognostic values of the PR status and HER2 status were evaluated using Cox regression.
Of all patients enrolled, 72% were PR positive and 20% were HER2 positive. PR and HER2 status were inversely correlated (P = 0.014). PR-negative tumors were associated with older age over 50 years (P < 0.001) and higher histologic grade (P = 0.024). HER2 overexpression correlated with older age over 50 years (P = 0.007), higher T stage (P = 0.010), and higher histologic grade (P = 0.047). For recurrence, PR negativity was a poor prognostic factor before 5 years postsurgery (hazard ratio = 1.57; P = 0.049) and HER2 overexpression was a consistent poor prognostic factor over all time periods (hazard ratio = 1.93; P = 0.001) in the multivariate model adjusted by age, T/N stage, and histologic grade.
In ER-positive, operable breast cancer, PR negativity may provide additional information on poor prognosis or tamoxifen resistance during adjuvant tamoxifen therapy within 5 years postsurgery. HER2 overexpression was a poor prognostic factor consistently throughout time. This suggests that an alternative adjuvant strategy, possibly incorporating prolonged HER2-targeted therapy, needs to be evaluated for HER2-overexpressing tumors.
Journal of Cancer Research and Clinical Oncology 02/2011; 137(7):1123-30. DOI:10.1007/s00432-011-0976-2 · 3.01 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This phase II trial first describes the combination chemotherapy of biweekly irinotecan plus S-1 (biweekly IRIS) for pretreated advanced gastric cancer (AGC) patients.
Patients who had previously been treated with greater than or equal to one regimen were enrolled. They received S-1 35 mg/m(2) twice daily on days 1-14 and irinotecan 150 mg/m(2) on days 1 and 15, every 4 weeks. The primary endpoint was overall survival (OS).
Among the 38 patients enrolled, 18 patients were treated as second line, and the remaining 20 patients were enrolled as third- or fourth line. A total of 208 cycles were administered with the median being four cycles (range 1-16). The median OS was 8.7 months [95% confidence interval (CI) 7.5-10.3], and the median progression-free survival was 6.3 months (95% CI 5.3-7.3). Low serum albumin (<3.5 mg/dL) was an independent adverse prognosticator for survival. Overall response rate was 17% (95% CI 4-30%). The major grade 3/4 toxicities were neutropenia (26%) and diarrhea (18%).
Biweekly IRIS showed the moderate activity as salvage treatment in AGC. Considering high neutropenia and gastrointestinal toxicity, patient selection should be warranted; serum albumin may be a predictive factor for treatment decision.
Cancer Chemotherapy and Pharmacology 02/2011; 68(4):991-9. DOI:10.1007/s00280-011-1560-9 · 2.57 Impact Factor