[Show abstract][Hide abstract] ABSTRACT: Overexpression of cyclooxygenase 2 (COX-2) is thought to promote survival of transformed cells. Transforming growth factor β (TGF-β) exerts anti-proliferative effects on a broad range of epithelial cells. In the current study, we investigated whether TGF-β can regulate COX-2 expression in A549 human lung adenocarcinoma cells, which are TGF-β-responsive and overexpress COX-2.
Western blotting, Northern blotting, and mRNA stability assays were performed to demonstrate that COX-2 protein and mRNA expression were suppressed by TGF-β. We also evaluated the effects of tristetraprolin (TTP) on COX-2 mRNA using RNA interference.
We demonstrated that COX-2 mRNA and protein expression were both significantly suppressed by TGF-β. An actinomycin D chase experiment demonstrated that COX-2 mRNA was more rapidly degraded in the presence of TGF-β, suggesting that TGF-β-induced inhibition of COX-2 expression is achieved via decreased mRNA stability. We also found that TGF-β rapidly and transiently induced the expression of TTP, a well-known mRNA destabilizing factor, before suppression of COX-2 mRNA expression was observed. Using RNA interference, we confirmed that increased TTP levels play a pivotal role in the destabilization of COX-2 mRNA by TGF-β. Furthermore, we showed that Smad3 is essential to TTP-dependent down-regulation of COX-2 expression in response to TGF-β.
The results of this study show that TGF-β down-regulated COX-2 expression via mRNA destabilization mediated by Smad3/TTP in A549 cells.
Cancer Research and Treatment 10/2014; · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate the outcome of adjuvant chemoradiotherapy (CRT) after distal pancreatectomy (DP) in patients with pancreatic adenocarcinoma, and to identify the prognostic factors for these patients.
We performed a retrospective review of 62 consecutive patients who underwent curative DP followed by adjuvant CRT between 2000 and 2011. There were 31 men and 31 women, and the median age was 64 years (range, 38 to 80 years). Adjuvant radiotherapy was delivered to the tumor bed and regional lymph nodes with a median dose of 50.4 Gy (range, 40 to 55.8 Gy). All patients received concomitant chemotherapy, and 53 patients (85.5%) also received maintenance chemotherapy. The median follow-up period was 24 months.
Forty patients (64.5%) experienced relapse. Isolated locoregional recurrence developed in 5 patients (8.1%) and distant metastasis in 35 patients (56.5%), of whom 13 had both locoregional recurrence and distant metastasis. The median overall survival (OS) and disease-free survival (DFS) were 37.5 months and 15.4 months, respectively. On multivariate analysis, splenic artery (SA) invasion (p=0.0186) and resection margin (RM) involvement (p=0.0004) were identified as significant adverse prognosticators for DFS. Also, male gender (p=0.0325) and RM involvement (p=0.0007) were associated with a significantly poor OS. Grade 3 or higher hematologic and gastrointestinal toxicities occurred in 22.6% and 4.8% of patients, respectively.
Adjuvant CRT may improve survival after DP for pancreatic body or tail adenocarcinoma. Our results indicated that SA invasion was a significant factor predicting inferior DFS, as was RM involvement. When SA invasion is identified preoperatively, neoadjuvant treatment may be considered.
Cancer research and treatment : official journal of Korean Cancer Association. 09/2014;
[Show abstract][Hide abstract] ABSTRACT: To evaluate the prognostic significance of phosphorylated Akt (p-Akt), phosphorylated mammalian target of rapamycin (p-mTOR), and total phosphatase and tensin homolog deleted on chromosome 10 (PTEN) expressions in patients undergoing adjuvant chemoradiotherapy (CRT) for proximal extrahepatic bile duct (EHBD) cancer.
American Journal of Clinical Oncology 08/2014; · 2.61 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to evaluate treatment patterns, outcome and prognosticators for patients with leptomeningeal metastases from solid tumor. Medical records of 80 patients from January 1, 2004 to May 31, 2011 were retrospectively reviewed. Most frequent site of origin was the lung (59%) followed by the breast (25%). Most patients were treated with intrathecal chemotherapy (90%) and/or whole brain radiotherapy (67.5%). Systemic therapy was offered to 27 patients (33.8%). Percentage of patients treated with single, dual, and triple modality were 32.5%, 43.8%, and 23.8%, respectively. Median survival was 2.7 months and 1 yr survival rate was 11.3%. Multivariate analysis showed that negative cerebrospinal fluid cytology, fewer chemotherapy regimen prior to leptomeningeal metastases, whole brain radiotherapy, systemic therapy, and combined modality treatment (median survival; single 1.4 vs. dual 2.8 vs. triple 8.3 months, P<0.001) had statistical significance on survival. Subgroup analysis of non-small cell lung cancer (NSCLC) patients showed that targeted therapy had significant independent impact on survival (median survival; 10.5 vs. 3.0 months, P=0.008). Unlike previous reports, survival of patients with NSCLC primary was comparable to breast primary. Furthermore, combined modality treatment for all patients and additionally targeted therapy for NSCLC patients should be considered in the treatment of leptomeningeal metastases from solid tumor.
Journal of Korean Medical Science 08/2014; 29(8):1094-101. · 1.25 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Aim: To identify immunohistochemical (IHC) features associated with sensitivity to lapatinib-plus-capecitabine (LX) and resistance to trastuzumab in human epidermal growth factor receptor (HER)-2-positive metastatic breast cancer. Patients and Methods: Expression levels of estrogen receptor, progesterone receptor, epidermal growth factor receptor, HER2, HER3/phosphorylated HER3 (pHER3), phosphatase and tensin homolog, thymidylate synthase (TYMS), and thymidine phosphorylase by IHC were compared between patients treated with LX following trastuzumab failure. Results: In 35 patients, HER2 was the only biomarker associated with LX treatment outcomes. A high HER2 level was associated with significantly longer survival and a tendency towards longer time-to-progression and higher response rates. Acquisition of trastuzumab resistance was associated with higher pHER3 and TYMS expression. Elevated pHER3 was predictive of superior treatment outcomes. Conclusion: Up-regulation of pHER3 and TYMS was associated with trastuzumab resistance. High HER2 and increased pHER3 IHC levels correlated with favourable LX treatment outcomes in patients with HER2-positive metastatic breast cancer.
Anticancer research 08/2014; 34(8):4275-4280. · 1.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers.
Cancer Research and Treatment 07/2014; 46(3):234-242. · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A newly isolated mediastinal lymph node (LN) or a small pulmonary nodule, which appears during breast cancer surveillance, may pose a diagnostic dilemma with regard to malignancy. We conducted this study to determine which clinical factors were useful for the differentiation of malignant lesions from benign lesions under these circumstances.
Cancer Research and Treatment 07/2014; 46(3):280-287. · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the efficacy of gemcitabine plus uracil-tegafur (UFT) combination chemotherapy as a salvage treatment in patients with metastatic colorectal cancer (MCRC).
Cancer Chemotherapy and Pharmacology 06/2014; · 2.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although KRAS mutation has a predictive role in stage IV colorectal cancer (CRC) patients treated with anti-EGFR therapy, there have been controversies in the prognostic impact of KRAS mutation in stage II or III disease. The purpose of this study was to assess the prognostic impact of KRAS and BRAF mutation in patients treated with adjuvant 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX).
Annals of Surgical Oncology 06/2014; · 3.94 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To analyze the outcome of patients with ampullary cancer who had undergone curative surgery followed by adjuvant chemoradiotherapy and to identify the prognostic factors for these patients METHODS:: Between January 1991 and August 2006, 71 patients with ampullary cancer underwent curative resection followed by adjuvant radiotherapy. There were 38 males and 33 females, and median age was 56 years (range, 28 to 77 y). Postoperative radiotherapy was delivered to tumor bed and regional lymph nodes up to 40 to 50 Gy at 2 Gy/fraction; 67 patients also received intravenous 5-fluorouracil as a radiosensitizer. Median follow-up duration was 72 months for survivors.
There were 5 isolated locoregional recurrences, 20 isolated distant metastases, and 11 combined locoregional and distant relapses. The 5-year locoregional relapse-free and overall survival rates were 76.2% and 64.5%, respectively. On multivariate analysis, nodal ratio and histologic differentiation were significant prognostic factors for overall survival (P=0.0382 and 0.0331, respectively).
Adjuvant chemoradiotherapy after curative resection can achieve a long-term survival rate in patients with ampullary cancer. Nodal ratio and histologic differentiation are independent prognostic factors for these patients.
American journal of clinical oncology 04/2014; · 2.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: High body mass index (BMI) is linked to an increased risk of developing pancreatic cancer (PC). However, in patients with advanced PC (APC), especially those receiving palliative chemotherapy, the impact of BMI on survival has not been investigated fully.
To assess changes in BMI during the course of APC and their impact on patient survival, specifically for those receiving palliative chemotherapy.
Consecutive patients with APC, all of whom were treated with palliative chemotherapy, were enrolled during 2003-2010. Clinical characteristics and prognoses were analyzed.
A total of 425 patients participated (median age, 60.1 years). At diagnosis of APC, patients' BMI distribution of patients was as follow: <18.5 (45, 10.6%); 18.5-19.9 (67, 15.8%); 20.0-22.4 (156, 36.7%); 22.5-24.9 (107, 25.2%); 25.0-29.9 (49, 11.5%); and ≥30.0 (1, 0.2%). Median overall survival (OS) was 8.1 months (95% confidence interval 7.2, 9.1). Precancer BMI and baseline BMI (at diagnosis) had no impact on OS. Weight loss at diagnosis (precancer weight minus weight at diagnosis) and weight loss during first-line chemotherapy (both stipulated as BMI change ≥1) were associated with shortened OS (hazard ratio, 1.300; P = 0.012 and hazard ratio, 1.367; P = 0.010, respectively).
In patients with APC undergoing palliative chemotherapy, decreases in BMI at APC diagnosis and during chemotherapy are more hazardous for OS than precancer BMI or baseline BMI (at diagnosis) as absolute values. Further studies are needed to validate this finding and investigate strategies to maintain BMI during chemotherapy in this setting.
Journal of pain and symptom management 12/2013; · 2.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Circumferential resection margin (CRM) and distal resection margin (DRM) have different impact on clinical outcomes after preoperative chemoradiotherapy (CRT) followed by surgery. Effect and adequate length of resection margin as well as impact of treatment response after preoperative CRT was evaluated.
Total of 403 patients with rectal cancer underwent preoperative CRT followed by total mesorectal excision between January 2004 and December 2010. After applying the criterion of margin less than 0.5 cm for CRM or less than 1 cm for DRM, 151 cases with locally advanced rectal cancer were included as a study cohort. All patients underwent conventionally fractionated radiation with radiation dose over 50 Gy and concurrent chemotherapy with 5-fluorouracil or capecitabine. Postoperative chemotherapy was administered to 142 patients (94.0%). Median follow-up duration was 43.1 months.
The 5-year overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS) rates, and locoregional control rates (LRC) were 84.5%, 72.8%, 74.2%, and 86.3%, respectively. CRM of 1.5 mm and DRM of 7 mm were cutting points showing maximal difference in a maximally selected rank method. In univariate analysis, CRM of 1.5 mm was significantly related with worse clinical outcomes, whereas DRM of 7 mm was not. In multivariate analysis, CRM of 1.5 mm, and ypN were prognosticators for all studied endpoints. However, CRM was not a significant prognostic factor for good responders, defined as patients with near total regression or T down-staging, which was found in 16.5% and 40.5% among studied patients, respectively. In contrast, poor responders demonstrated a significant difference according to the CRM status for all studied end-points.
Close CRM, defined as 1.5 mm, was a significant prognosticator, but the impact was only prominent for poor responders in subgroup analysis. Postoperative treatment strategy may be individualized based on this finding. However, findings from this study need to be validated with larger cohort.
BMC Cancer 12/2013; 13(1):576. · 3.32 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Vascular endothelial growth factor (VEGF)-A, VEGF165b, interleukin (IL)-1β, and transforming growth factor (TGF)-β1 are known to influence tumor angiogenesis. Clinical implications of these cytokines need to be elucidated.
Using clinical data and baseline serum samples of 140 consecutive patients with advanced non-small cell lung cancer who received platinum-based combination chemotherapy, we investigated the association among serum cytokine levels, treatment outcomes, as well as leukocyte and platelet counts.
The median age of patients was 64 years (range, 26 to 86 years). The male to female ratio was 104:36. High TGF-β1 and IL-1β levels were associated with shorter progression-free survival, and high VEGF-A and IL-1β levels were associated with shorter overall survival in the univariate analysis. VEGF165b was not related to the treatment outcomes. Leukocytosis and thrombocytosis were associated with shorter overall survival. The multivariate analysis demonstrated that VEGF-A, IL-1β, and leukocytosis were significant prognostic factors (p=0.0497, p=0.047, and p<0.001, respectively). Leukocytosis was not associated with recent pneumonia (p=0.937) and correlated with VEGF-A (p<0.001) and TGF-β1 (p=0.020) levels.
Serum VEGF-A, TGF-1β, and IL-1β levels, in addition to leukocyte and platelet counts, are shown to be associated with clinical outcomes. Leukocyte and platelet counts are correlated with serum VEGF-A and TGF-β1 levels.
Cancer Research and Treatment 12/2013; 45(4):325-33. · 2.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To develop nomograms for predicting the overall survival (OS) and relapse-free survival (RFS) in patients with extrahepatic bile duct cancer undergoing adjuvant chemoradiation therapy after curative resection.
From January 1995 through August 2006, a total of 166 consecutive patients underwent curative resection followed by adjuvant chemoradiation therapy. Multivariate analysis using Cox proportional hazards regression was performed, and this Cox model was used as the basis for the nomograms of OS and RFS. We calculated concordance indices of the constructed nomograms and American Joint Committee on Cancer (AJCC) staging system.
The OS rate at 2 years and 5 years was 60.8% and 42.5%, respectively, and the RFS rate at 2 years and 5 years was 52.5% and 38.2%, respectively. The model containing age, sex, tumor location, histologic differentiation, perineural invasion, and lymph node involvement was selected for nomograms. The bootstrap-corrected concordance index of the nomogram for OS and RFS was 0.63 and 0.62, respectively, and that of AJCC staging for OS and RFS was 0.50 and 0.52, respectively.
We developed nomograms that predicted survival and recurrence better than AJCC staging. With caution, clinicians may use these nomograms as an adjunct to or substitute for AJCC staging for predicting an individual's prognosis and offering tailored adjuvant therapy.
International journal of radiation oncology, biology, physics 11/2013; 87(3):499-504. · 4.59 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Epidermal growth factor (EGF) is a ligand for the epidermal growth factor receptor (EGFR). Human epidermal growth factor receptor 2 (HER2) shares common signal pathways and forms a heterodimer with EGFR. In this study, we investigated the clinical and pathologic implications of serum EGF levels in patients with HER2-positive metastatic breast cancer (MBC).
We analyzed serum EGF levels from baseline serum samples of consecutive patients with HER2-positive MBC who received first-line trastuzumab plus taxane chemotherapy and correlated them with treatment outcomes and pathologic features.
A total of 50 women were analyzed. The median age was 47 years (range 27-72 years). Patients with high serum EGF levels (≥10.0 pg/mL) had significantly longer overall survival (47.0 months (95 % confidence interval (CI) 28.3-65.7 months) vs. 23.3 months (95 % CI 13.5-33.1 months); p = 0.009) with a tendency toward longer progression-free survival (p = 0.123). Serum EGF levels were not associated with hematologic or cardiac adverse events. Progesterone receptor-positive patients had significantly higher serum EGF levels than progesterone receptor-negative patients (24.3 pg/mL (range 9.5-69.0 pg/mL) vs. 12.3 pg/mL (range 0.0-59.5 pg/mL); p = 0.006).
Our data suggest that high serum EGF levels may be associated with good prognosis in patients with HER2-positive MBC receiving trastuzumab plus taxane chemotherapy. In addition, serum EGF levels were associated with progesterone receptor positivity.
Cancer Chemotherapy and Pharmacology 09/2013; 72(5). · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent advance in sequencing technology has enabled comprehensive profiling of genetic alterations in cancer. We have established a targeted sequencing platform using next-generation sequencing (NGS) technology for clinical use, which can provide mutation and copy number variation data. NGS was performed with paired-end library enriched with exons of 183 cancer-related genes. Normal and tumor tissue pairs of 60 colorectal adenocarcinomas were used to test feasibility. Somatic mutation and copy number alteration were analyzed. A total of 526 somatic non-synonymous sequence variations were found in 113 genes. Among these, 278 single nucleotide variations were 232 different somatic point mutations. 216 SNV were 79 known single nucleotide polymorphisms in the dbSNP. 32 indels were 28 different indel mutations. Median number of mutated gene per tumor was 4 (range 0-23). Copy number gain (>X2 fold) was found in 65 genes in 40 patients, whereas copy number loss (<X0.5 fold) was found in 103 genes in 39 patients. The most frequently altered genes (mutation and/or copy number alteration) were APC in 35 patients (58%), TP53 in 34 (57%), and KRAS in 24 (40%). Altered gene list revealed ErbB signaling pathway as the most commonly involved pathway (25 patients, 42%). Targeted sequencing platform using NGS technology is feasible for clinical use and provides comprehensive genetic alteration data.
PLoS ONE 05/2013; 8(5):e64271. · 3.53 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: PURPOSE: This study aimed to elucidate the clinical implication of human epidermal growth factor receptor 2/centromeric probe for chromosome 17 (HER2/CEP17) ratio and HER2 immunohistochemistry (IHC) results in patients with HER2 fluorescence in situ hybridization (FISH)-positive metastatic breast cancer (MBC) who received first-line trastuzumab plus taxane chemotherapy. METHODS: Using clinical data of patients with HER2 FISH-positive MBC who received first-line trastuzumab plus taxane chemotherapy, we analyzed the clinical outcome according to the HER2/CEP17 ratio and HER2 IHC analysis. RESULTS: Fifty-two women were analyzed. The median age was 50 years (range 27-69 years). Patients with a HER2/CEP17 ratio ≥3.0 had significantly longer progression-free survival (PFS) (17.2 vs. 7.4 months; p = 0.002) with a tendency toward higher response rate (RR) (p = 0.325) and longer overall survival (OS) (p = 0.129). Patients with HER2 IHC 1+ had significantly shorter OS (14.0 vs. 42.4 months; p = 0.013) along with a tendency toward lower RR (p = 0.068) and shorter PFS (p = 0.220). In the multivariate analysis, HER2/CEP17 ratio <3.0 (p = 0.004) and Eastern Cooperative Oncology Group (ECOG) PS 2 (p = 0.015) were significant factors for shorter PFS, and HER2 IHC 1+ (p = 0.015) and ECOG PS 2 (p = 0.036) were significant factors for poor OS. CONCLUSIONS: Our data support that HER2/CEP17 ratios and HER2 IHC scores may predict clinical outcome after first-line trastuzumab plus taxane chemotherapy in patients with HER2 FISH-positive MBC.
Cancer Chemotherapy and Pharmacology 05/2013; 72(1). · 2.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: BACKGROUND: We aimed to investigate the role of BRCA1 nuclear expression in sporadic gastric cancer; currently, the role remains unknown. METHODS: Patients with gastric cancer who received curative operation with D2 dissection were enrolled in this study. Adjuvant chemotherapy was administered at the discretion of the physician. According to BRCA1 nuclear expression analysis by immunohistochemistry (IHC) on tissue microarrays using anti-BRCA1 antibody MS110, BRCA1 expression was classified as negative, low expression, and high expression. RESULTS: Among 318 cases, 155 cases (48.7 %) were identified as BRCA1-negative by IHC and 96 cases (30.2 %) revealed BRCA1 low expression, 67 cases (21.0 %) showed BRCA1 high expression. The negative or reduced expression of BRCA1 was more frequent in more advanced-stage disease (p < 0.001) and was associated with perineural invasion (p = 0.032). Disease-free survival (DFS) was significantly decreased with reduced BRCA1 expression (p = 0.027). This tendency was also observed in overall survival (OS), although the difference was not significant. The poorer prognosis of BRCA1-negative tumors was overcome through adjuvant chemotherapy. The benefit of adjuvant chemotherapy for DFS and OS in stage III was enhanced only in BRCA1-negative tumors (p < 0.001, p < 0.001, respectively), but not in BRCA1-positive tumors (p = 0.236, p = 0.148, respectively). CONCLUSION: The reduction of BRCA1 nuclear expression is associated with advanced stage and perineural invasion. Moreover, negative BRCA1 nuclear expression is a predictive marker regarding the benefit of adjuvant chemotherapy in sporadic gastric cancer; these novel findings are of great importance, and further, larger studies are warranted.
Cancer Chemotherapy and Pharmacology 04/2013; · 2.80 Impact Factor