Chih-Chien Chin

The oncologic benefit of high ligation of the inferior mesenteric artery in the surgical treatment of rectal or sigmoid colon cancer

PurposeIt remains controversial as to whether high ligation of the inferior mesenteric artery (IMA) should be performed during surgical treatment for sigmoid colon or rectal cancer. The purpose of this study is to attempt to clarify the extent of the oncologic benefit of high ligation of the IMA.Materials and methodsFrom January 1995 to July 2001, a total of 1,389 patients underwent high ligation of the IMA; 387 patients featured non-disseminated sigmoid colon cancer and 1,002 patients had rectal cancer. Pathology of the primary tumors, IMA nodes, and clinical outcome were reviewed.ResultsForty-three patients (3.1%) revealed IMA node metastasis. Of these 43 patients, 29 (67.4%) featured tumor recurrences/metastases. After a minimum 5-year follow-up, 11 of these 43 patients (25.6%) were alive and disease free. Of these 43 patients, the 5-year disease-free survival rate for patients featuring sigmoid cancer was 50% and for patients with rectal cancer 13.8%. The beneficial rate of high ligation of the IMA for non-disseminated sigmoid colon cancer and rectal cancer was 0.8%, for non-disseminated sigmoid colon cancer 1.8%, and for non-disseminated rectal cancer, the rate was only 0.4%. The rates of IMA metastasis in patients with T stage tumors were 0% (pT1), 1.0% (pT2), 2.6% (pT3), and 4.3% (pT4).ConclusionsAlthough patients afflicted with IMA node metastasis revealed a rather high incidence of tumor recurrence/metastasis, 25.6% of these patients remained disease free following IMA node dissection after a minimum 5-year follow-up. We consider that IMA node dissection is more beneficial in patients with non-disseminated sigmoid pT4 tumor.

Metastatic lymph node ratio is a more precise predictor of prognosis than number of lymph node metastases in stage III colon cancer

ObjectiveThe objective of this study is to assess the value of metastatic lymph node ratio (LNR) in predicting disease-free survival (DFS) in patients with stage III adenocarcinoma of the colon.Materials and methodsFrom 1995 to 2003 inclusively, a total of 624 patients featuring stage III adenocarcinoma of the colon underwent curative resection. Of the 624 patients, an adequate number of lymph nodes (n ≥ 12) had been harvested in 490 patients. These patients were stratified into LNR groups 1 (LNR ≤ 0.4), 2 (0.4 < LNR ≤ 0.7), and 3 (LNR > 0.7). Kaplan–Meier survival curve and log-rank test were used to evaluate the prognostic value of LNR. A Cox regression model was used for multivariate analyses.ResultsThe 5-year DFS rate was 66.7% for patients with LNR1, 35.1% for those with LNR2, and 0% for patients with LNR3 (p < 0.0001). In T3/4LNR1 patients (n = 411), there was no difference in survival between those with N1 stage and those with N2 stage. Cox proportional hazards regression analysis revealed that N stage (number of positive lymph nodes) was not a significant factor when LNR was taken into consideration.ConclusionsLNR is a more precise predictor of 5-year DFS than number of positive lymph nodes (N stage) in patients with stage III colon cancer.

Proteomic analysis of the effects of baicalein on colorectal cancer cells.

Baicalein is the flavonoids with multiple pharmacological activities. The aim of our study was to investigate the effects of baicalein on colorectal cancer (CRC) and to recognize the targets of baicalein treatment. To better understand baicaleins target, proteomic approaches were used to purify and identify the protein substrates using 2D difference gel electrophoresis (2D SDS‐PAGE) to elucidate proteins differential display. Results from this study investigate that baicalein treatment of CRC cells results in reduced cell proliferation. As a result, differential protein displays between baicalein‐treated and untreated CRC were determined and validated. There were 11 differentially expressed proteins between baicalein‐treated and untreated CRC. Furthermore, we demonstrate that baicalein inhibits cancer cell proliferation and reduced reactive oxygen species (ROS) by up‐regulating the levels of peroxiredoxin‐6 (PRDX6). Knockdown of PRDX6 in baicalein‐treated CRC cells by specific small interfering RNA resulted in ROS production and proliferation, opposite of the baicalein treatment scenario as indicated by cell cycle distribution. These results illustrate that baicalein up‐regulates the expression of PRDX6, which attenuates the generation of ROS and inhibits the growth of CRC cells, whereas baicalein treatment have no effect on normal epithelial cells.

Resistin-induced stromal cell-derived factor-1 expression through Toll-like receptor 4 and activation of p38 MAPK/ NFκB signaling pathway in gastric cancer cells

BackgroundStromal cell-derived factor-1 (SDF-1) (CXC chemokine ligand-12)/CXC chemokine receptor 4 (CXCR4) is involved in the carcinogenesis of human gastric cancer, where it stimulates angiogenesis and favors metastasis of tumor cells to distant organs. In addition, resistin is suggested to be an important link between obesity and the development of gastric cancer. Resistin has identified as an important player in inflammatory responses, and emerged as a mediator in inflammation-associated cancer. A limited number of studies have investigated the association of resistin and SDF-1 with gastric cancer. Herein, we investigated the molecular mechanisms by which resistin influences the expression of SDF-1 in gastric carcinoma cells.ResultsHuman gastric cancer cell lines were exposed to doses of resistin; SDF-1 expression and secretion levels were then determined. Real-time polymerase chain reaction and western blotting analyses were performed to clarify molecular changes. Inhibition of Toll-like receptor 4 (TLR4) by a competitive antagonist inhibited resistin-induced SDF-1 expression. Pharmacological inhibitors and small interfering RNA (siRNA) demonstrated that activation of the p38 mitogen-activated protein kinase (MAPK) pathway is critical for resistin-induced SDF-1 expression mediated by TLR4. The promoter activity and transcription factor enzyme-linked immunosorbent assay revealed that resistin induced expression of SDF-1 mediated by NF-κB in gastric cancer cells. Inhibition of p38 MARK activation blocked the SDF-1-induced expression and the SDF-1 promoter activity in the cancer gastric cells. Chromatin immunoprecipitation assay revealed that inhibition of p38 MARK activation also blocked the resistin-increased NF-κB-DNA-binding activity.ConclusionsResistin-induced SDF-1 upregulation by activation of TLR4, p38 MARK and NF-κB may explain a new role of resistin in the link of obesity and gastric cancer.

Stromal cell‐derived factor‐1/CXC receptor 4 and β1 integrin interaction regulates urokinase‐type plasminogen activator expression in human colorectal cancer cells

The stromal cell‐derived factor‐1 (SDF‐1)/CXC receptor 4 (CXCR4) axis has been shown to play a role in colorectal cancer progression. In addition, the protease urokinase‐type plasminogen activator (uPA) is an important factor in tumor cell invasion and metastasis. However, the mechanism by which SDF‐1 mediates uPA expression in human colorectal cancer cells remains unknown. We investigated the molecular mechanism governing the interaction between SDF‐1 stimulation and uPA expression in three human colon cancer cell lines (DLD‐1, SW48, and COLO 205). We found that SDF‐1 stimulation led to an increase in the expression and secretion of uPA in these cells. Experiments involving specific inhibitors and small interfering RNA demonstrated that the activation of p38 mitogen‐activated protein kinase (MAPK) and phosphatidylinositol 3‐kinase (PI3K)/Akt pathways are critical for SDF‐1‐induced uPA expression. Analysis of transcription factor binding using ELISA and chromatin immunoprecipitation assays revealed that SDF‐1 increased Sp1‐ and AP‐1‐DNA‐binding activities in DLD‐1 cells. Inhibition of Sp1 and AP‐1 activation blocked the SDF‐1‐induced expression and activity of the uPA promoter. The effect of SDF‐1 on DLD‐1 signaling and uPA expression was mediated by the CXCR4/β1 integrin axis. In summary, our findings elucidate the mechanisms of SDF‐1/CXCR4 downstream signaling and provide insights into the function of SDF‐1 in colon cancer cells. J. Cell. Physiol. 227: 1114–1122, 2012.

Role of Peroxiredoxin I in Rectal Cancer and Related to p53 Status

BACKGROUND Neoadjuvant chemoradiotherapy is widely accepted for the treatment of localized rectal cancer. Although peroxiredoxin I (PrxI) and p53 have been implicated in carcinogenesis and cancer treatment, the role of PrxI and its interaction with p53 in the prognosis and treatment response of rectal cancer remain relatively unstudied. METHODS AND MATERIALS In the present study, we examined the levels of PrxI and p53 in rectal cancer patients using membrane arrays and compared them with normal population samples. To demonstrate the biologic changes after manipulation of PrxI expression, we established stable transfectants of HCT-116 (wild-type p53) and HT-29 (mutant p53) cells with a PrxI silencing vector. The predictive capacities of PrxI and p53 were also assessed by relating the immunohistochemical staining of a retrospective series of rectal cancer cases to the clinical outcome. RESULTS The membrane array and immunochemical staining data showed that PrxI, but not p53, was significantly associated with the tumor burden. Our immunochemistry findings further indicated that PrxI positivity was linked to a poor response to neoadjuvant therapy and worse survival. In cellular and animal experiments, the inhibition of PrxI significantly decreased tumor growth and sensitized the tumor to irradiation, as indicated by a lower capacity to scavenge reactive oxygen species and more extensive DNA damage. The p53 status might have contributed to the difference between HCT-116 and HT-29 after knockdown of PrxI. CONCLUSION According to our data, the level of PrxI combined with the p53 status is relevant to the prognosis and the treatment response. We suggested that PrxI might be a new biomarker for rectal cancer.

Role of body mass index in colon cancer patients in Taiwan

AIM To determine the effect of body mass index (BMI) on the characteristics and overall outcome of colon cancer in Taiwan. METHODS From January 1995 to July 2003, 2138 patients with colon cancer were enrolled in this study. BMI categories (in kg/m²) were established according to the classification of the Department of Health of Taiwan. Postoperative morbidities and mortality, and survival analysis including overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) were compared across the BMI categories. RESULTS There were 164 (7.7%) underweight (BMI < 18.5 kg/m²), 1109 (51.9%) normal-weight (BMI = 18.5-23.9 kg/m²), 550 (25.7%) overweight (BMI = 24.0-26.9 kg/m²), and 315 (14.7%) obese (BMI ≥ 27 kg/m²) patients. Being female, apparently anemic, hypoalbuminemic, and having body weight loss was more likely among underweight patients than among the other patients (P < 0.001). Underweight patients had higher mortality rate (P = 0.007) and lower OS (P < 0.001) and DFS (P = 0.002) than the other patients. OS and DFS did not differ significantly between normal-weight, overweight, and obese patients, while CSS did not differ significantly with the BMI category. CONCLUSION In Taiwan, BMI does not significantly affect colon-CSS. Underweight patients had a higher rate of surgical mortality and a worse OS and DFS than the other patients. Obesity does not predict a worse survival.

Carcinoma obstruction of the proximal colon cancer and long-term prognosis—obstruction is a predictor of worse outcome in TNM stage II tumor

PurposeColon obstruction is suggested to be a predictor of poor outcome in colon cancer. However, the effect of obstruction on outcome in patients with different tumor–nodes–metastases (TNM) stage cancer has not been fully addressed. The aim of this study is to determine whether colon obstruction predicts surgical and long-term oncologic outcomes in patients with proximal colon cancer.MethodsA total of 1,492 consecutive patients underwent open resection of primary adenocarcinoma of right colon in a single institution between January 1995 and December 2005. Clinical and follow-up data were extracted from a prospective colorectal cancer database. Univariate and multivariate analyses were performed to identify colon obstruction and other predictors of surgical and oncologic outcomes.ResultsAmong 1,492 patients, 306 (20.5%) patients presented with colon obstruction. The rates of surgical morbidity and mortality were greater in patients with an obstruction as compared to patients without an obstruction (22.2% and 3.9% vs. 14.1% and 1.9%; p = 0.0005 and 0.041, respectively). Obstruction predicted a worse long-term disease-free survival (DFS) among patients with stage II–III disease (log-rank test, p = 0.0003). The data were stratified by TNM stage. Obstruction predicted a worse DFS among patients with TNM stage II cancer (598 patients; log-rank test, p = 0.001; Cox regression, p = 0.012), but it was not a predictor in TNM stage III cancer patients (424 patients; p = 0.116; p = 0.108).ConclusionsColon obstruction was an independent predictor of long-term outcome only in TNM stage II but not in stage III proximal colon cancer. Patients with TNM stage II obstructive colon cancer could be included in future trials of adjuvant therapies.

Selective β2-AR Blockage Suppresses Colorectal Cancer Growth Through Regulation of EGFR-Akt/ERK1/2 Signaling, G1-Phase Arrest, and Apoptosis.

The stress‐upregulated catecholamines‐activated β1‐ and β2‐adrenergic receptors (β1/2‐ARs) have been shown to accelerate the progression of cancers such as colorectal cancer (CRC). We investigated the underlying mechanism of the inhibition of β1/2‐ARs signaling for the treatment of CRC and elucidated the significance of β2‐AR expression in CRC in vitro and in clinical samples. The impacts of β1/2‐AR antagonists in CRC in vitro and CRC‐xenograft in vivo were examined. We found that repression of β2‐AR but not β1‐AR signaling selectively suppressed cell viability, induced G1‐phase cell cycle arrest, caused both intrinsic and extrinsic pathways‐mediated apoptosis of specific CRC cells and inhibited CRC‐xenograft growth in vivo. Moreover, the expression of β2‐AR was not consistent with the progression of CRC in vitro or in clinical samples. Our data evidence that the expression profiles, signaling, and blockage of β2‐AR have a unique pattern in CRC comparing to other cancers. β2‐AR antagonism selectively suppresses the growth of CRC accompanying active β2‐AR signaling, which potentially carries wild‐type KRAS, in vitro and in vivo via the inhibition of β2‐AR transactivated EFGR‐Akt/ERK1/2 signaling pathway. Thus, β2‐AR blockage might be a potential therapeutic strategy for combating the progressions of β2‐AR‐dependent CRC. J. Cell. Physiol. 231: 459–472, 2016.

Pursestring Closure versus Conventional Primary Closure Following Stoma Reversal to Reduce Surgical Site Infection Rate: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: Stoma reversal is a surgical procedure commonly used following temporary defunctioning stoma surgery. Surgical site infection is one of the most common postoperative morbidities. A few skin closure methods have been developed to decrease surgical site infection. However, the optimal skin closure method is still in debate. OBJECTIVE: The aim of this study was to compare the surgical site infection rate and other postoperative outcomes between the pursestring closure and conventional primary closure techniques. DATA SOURCES: We searched the MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials for relevant trials. STUDY SELECTION: We conducted a meta-analysis of randomized controlled trials that compared the surgical outcomes following pursestring closure and conventional primary closure techniques. INTERVENTION: We conducted the meta-analysis by using the random-effects model. MAIN OUTCOME MEASURES: The primary outcome of interest was surgical site infection following stoma reversal within 30 days after operation. RESULTS: This meta-analysis included 4 randomized controlled trials with a total of 319 participants (162 in the pursestring closure group and 157 in the conventional primary closure group). Compared with the conventional primary closure group, the pursestring closure group had a significant decrease in surgical site infection (risk difference, –0.25; 95% CI, –0.36 to –0.15; p < 0.00001; number needed to treat = 4) and higher satisfaction with cosmetic outcomes (standard mean difference, 0.7; 95% CI, 0.13–1.27; p = 0.02). No other significant differences in operative time, length of hospital stay, and wound healing time were found between the 2 groups. LIMITATIONS: This study was limited to the lack of double blinding and long-term follow-up in the included trials. CONCLUSIONS: Pursestring closure has significantly fewer surgical site infections and achieves better cosmetic outcomes following stoma reversal than conventional primary closure.