Huann-Sheng Wang

Overexpression of the thymosin β-4 gene is associated with increased invasion of SW480 colon carcinoma cells and the distant metastasis of human colorectal carcinoma

Cell–matrix and cell–cell adhesive interactions play important roles in the normal organization and stabilization of the cell layer in epithelial tissue. Alterations in the expression and function of these adhesion systems that cause a switch to a migratory phenotype in tumor invasion and metastasis are critical for the malignant conversion of epithelial cells. Thymosin β-4 (Tβ-4) is the major actin-sequestering protein that has been shown to be upregulated in a wide variety of human carcinomas and has been implicated to be involved in altering the motility of certain tumors. We have recently demonstrated that the growth rate, colony formation in soft agar, and motility, all good indicators for malignant progression, of SW480 colon carcinoma cells are dramatically increased by enforced Tβ-4 expression. To test the hypothesis that overexpression of this G-actin sequestering peptide also promotes tumor invasion, we examined not only the invasion capability of Tβ-4-overexpressing SW480 cells, but also the expression levels of Tβ-4 as well as several proteins that participate in different stages of tumor progression in matched samples of human primary colorectal adenocarcinoma and liver metastases from several patients. A marked increase on the invasiveness in Tβ-4-overexpressing SW480 cells with increased levels and activity of matrix metalloproteinase-7 (MMP-7) was observed. Furthermore, the levels of Fas as well as the susceptibility to Fas ligand-mediated apoptosis in Tβ-4-overexpressing cells were significantly decreased. Interestingly, the levels of Tβ-4 mRNA, β-catenin, c-Myc, and MMP-7 in metastatic liver lesions were relatively higher, whereas the levels of E-cadherin and Fas were significantly lower than those in the matched primary colorectal tumors. These results suggest that upregulation of Tβ-4, by promoting the disruption of cell–cell adhesion and a consequential activation of the β-catenin signaling, could be a key event in the acquisition of growth advantages as well as invasive phenotypes in human colorectal carcinomas.

UGT1A1*28 Polymorphism Predicts Irinotecan-induced Severe Toxicities Without Affecting Treatment Outcome and Survival in Patients With Metastatic Colorectal Carcinoma

It is known that the uridine‐diphosphoglucuronosyl transferase 1A1 (UGT1A1)*28 polymorphism reduces UGT1A1 enzyme activity, which may lead to severe toxicities in patients who receive irinotecan. This study was conducted to assess the influence of this polymorphism on the efficacy and toxicity of irinotecan treatment in Chinese patients with metastatic colorectal carcinoma (CRC).

Influence of GSTP1 I105V polymorphism on cumulative neuropathy and outcome of FOLFOX-4 treatment in Asian patients with colorectal carcinoma

Glutathione S‐transferase P1 (GSTP1) participates in detoxification of potentially genotoxic compounds that may alter the efficacy and toxicity of platinum‐based chemotherapy. We analyzed the influence of I105V polymorphism of GSTP1 on clinico‐pathological features and outcomes in 166 Chinese patients with metastatic colorectal carcinoma who had been treated with first‐line FOLFOX‐4. Combined analysis of GSTP1 I105V, ERCC1‐118, and XPD‐751 polymorphisms was also conducted. The results showed that, in comparison with Caucasian populations, a remarkably lower prevalence of Val105 allele variants was noted (24.7%). Patients with Val105 allele variants had a higher response to FOLFOX‐4 (56.1%vs 37.6%, P = 0.04), and a longer progression‐free (P < 0.01) as well as overall (P < 0.01) survival. By adjusted analysis, this polymorphism was identified as an independent prognostic factor (P = 0.01). In combined analysis, patients without any risk genotype, including GSTP1‐105 Ile/Ile, ERCC1‐118 C/T or T/T, and XPD‐751 Lys/Gln, had significantly longer progression‐free and overall survivals (P < 0.01). In addition, patients with Val105 allele variants had a higher incidence of grade 3/4 cumulative neuropathy after different cycles of treatment. These data suggest that Asian populations have a lower prevalence of I105V polymorphism in GSTP1. I105V polymorphism in GSTP1, by reducing its enzymatic activity and consequential detoxification to oxaliplatin, could be a key determinant for a better outcome, but more neurotoxicity, to FOLFOX‐4 treatment. (Cancer Sci 2009)

ERCC1 codon 118 C→T polymorphism associated with ERCC1 expression and outcome of FOLFOX‐4 treatment in Asian patients with metastatic colorectal carcinoma

We analyzed the influence of codon 118 C→T polymorphism of ERCC1 on its protein expression levels, clinicopathological features, and outcome of 168 Chinese patients with metastatic colorectal carcinoma that had been treated with first‐line FOLFOX‐4 chemotherapy. A high prevalence of C/C genotype was noted (47.6%, n = 80; 168 patients in total). A marked increase of ERCC1 protein expression levels was also noted in patients with C/T or T/T genotypes (70%vs 20%; P < 0.01), which was associated with significantly lower response to FOLFOX‐4 (36.4%vs 57.5%; p = 0.01), and shorter progression‐free (7 months vs 13 months; P < 0.01) and overall (16 months vs 25 months; P < 0.01) survival times. By multivariate analysis, this polymorphism was also identified as an independent prognostic factor (P = 0.02). These data suggest that Asian populations have a significantly higher prevalence of the C/C genotype in ERCC1 codon 118, which could be a key determinant for good responses to oxaliplatin‐based treatment and favorable outcomes. (Cancer Sci 2009; 100: 278–283)

The Influence of Fecal Diversion and Anastomotic Leakage on Survival after Resection of Rectal Cancer

BackgroundWe analyzed factors associated with the occurrence of anastomotic leakage (AL) and its impact on long-term survival in patients who have undergone resection for rectal cancer. We also investigated the effect of fecal diversion on survival.MethodClinical data of patients who received surgery for rectal cancer were reviewed. The difference in AL incidence among different groups was compared and survival rates were calculated. Cox’s proportional hazards model was used to compare survival in patients who developed AL or received diversion stoma with those who did not.ResultsOf 999 patients who received resection and anastomosis, 53 patients experienced AL. Multivariate analysis revealed advanced age (P = 0.009) and operative method (P = 0.002) were independent risk factors for AL. Anastomotic leakage was an independent risk factor for overall recurrence (HR 2.30; 95% CI 1.12–4.73). Anastomotic leakage and fecal diversion were independent prognostic factors of overall survival (P = 0.002 and P < 0.001, respectively), cancer-specific survival (P = 0.002 and P < 0.001, respectively), and disease-free survival (P < 0.001, respectively).ConclusionsPatients who are older and have anastomosis at the anorectal junction or dentate line have an increased risk of AL. A diversion stoma does not appear to decrease the incidence of anastomotic leakage, but may decrease the need of reoperation when leakage occurred. Anastomotic leakage and fecal diversion are independent prognostic factors of overall, cancer-specific, and disease-free survival.

Analysis of the seventh edition of American Joint Committee on colon cancer staging

PurposeThe seventh edition of the American Joint Committee on Cancer (AJCC) staging system has new substages for colon cancer. We used survival data from a single medical center to analyze this new AJCC edition.MethodsThe colon cancer database of Taipei Veterans General Hospital provided 1,865 patient records covering from 1999 to 2005. Survival rates were evaluated using the Kaplan–Meier method.ResultsThere were 268, 607, 561, and 421 patients in stages I, II, III, and IV disease with 5-year observed survival rates of 86.3%, 79.2%, 65.4%, and 12.8%, respectively. Survival rates were not significantly different between those with T4a and T4b disease (P = 0.806). The outcome of N1c disease was similar to N1a and N1b but worse than N0 (P = 0.004). Survival rates for M1a and M1b disease became different after reclassifying solely peritoneal seeding as M1a (P < 0.001). No discrepancy of outcomes between stage IIIA and stage IIB/IIC remained in the seventh edition.ConclusionsEvolution from the fifth to seventh edition of the AJCC staging system is successful in separating prognostic groups by substaging. But some issues remain unresolved, including the subdivision of T4, N1, and M1.

Very low prevalence of XPD K751Q polymorphism and its association with XPD expression and outcomes of FOLFOX-4 treatment in Asian patients with colorectal carcinoma.

Xeroderma pigmentosum group D (XPD) participates in DNA unwinding during nucleotide excision repair, which may alter the efficacy of platinum‐based chemotherapy. We analyzed the influence of codon 751 Lys→Gln polymorphism of XPD on its protein expression levels, clinico‐pathological features, and outcome of 188 Chinese patients with metastatic colorectal carcinoma (CRC) that had been treated with first‐line Oxaliplatin + Leucovorin + 5‐Fluorouracil (FOLFOX‐4) chemotherapy. The results showed that in comparison with Caucasian populations, a remarkably lower prevalence of Lys/Gln genotype was noted (16%, n = 30). No between‐group difference in XPD protein expression of patients with or without this polymorphism was noted (56.5%vs 59.7%; P = 0.783). Patients with Gln751 allele have a significantly lower response to FOLFOX‐4 treatment (36.7%vs 58.2%, P = 0.03), and shorter progression‐free (7 vs 11 months; P < 0.01) and overall (14 vs 22 months; P < 0.01) survivals. The incidence of grade 3/4 oxaliplatin‐neuropathies was very similar in both groups (13.3%vs 16.5%; P = 0.67). By adjusted analysis, this polymorphism was further identified as an independent prognostic factor (P = 0.03). These data suggest that Asian populations have a significantly lower prevalence of codon 751 Lys/Gln polymorphism in XPD, which could be a key determinant for good response to oxaliplatin‐based treatment and favorable outcomes. (Cancer Sci 2009; 100: 1261–1266)

Carcinoembryonic antigen (CEA) level, CEA ratio, and treatment outcome of rectal cancer patients receiving pre-operative chemoradiation and surgery

BackgroundTo investigate serum carcinoembryonic antigen (CEA) as a prognostic factor for rectal cancer patients receiving pre-operative chemoradiotherapy (CRT).MethodsBetween 2000 and 2009, 138 patients with advanced rectal cancer receiving CRT before surgery at our hospital were retrospectively classified into 3 groups: pre-CRT CEA <6 ng/ml (group L; n = 87); pre-CRT CEA ≥ 6 ng/ml and post-CRT CEA <6 ng/ml (group H-L; n = 32); and both pre- and post-CRT CEA ≥ 6 ng/ml (group H-H; n = 19). CEA ratio (defined as post-CRT CEA divided by pre-CRT CEA), post-CRT CEA level and other factors were reviewed for prediction of pathologic complete response (pCR).ResultsFive-year disease-free survival (DFS) was better in groups L (69.0%) and H-L (74.5%) than in group H-H (44.9%) (p = 0.024). Pathologic complete response was observed in 19.5%, 21.9% and 5.3% of groups L, H-L and H-H respectively (p = 0.281). Multivariate analysis showed that ypN stage and pCR were independent prognostic factors for DFS and that post-CRT CEA level was independently predictive of pCR. As a whole, post-CRT CEA <2.61 ng/ml predicted pCR (sensitivity 76.0%; specificity 58.4%). For those with pre-CRT CEA ≥6 ng/ml, post-CRT CEA and CEA ratio both predicted pCR (sensitivity 87.5%, specificity 76.7%).ConclusionsIn patients with pre-CRT serum CEA ≥6 ng/ml, those with “normalized” CEA levels after CRT may have similar DFS to those with “normal” (<6 ng/ml) pre-CRT values. Post-CRT CEA level is a predictor for pCR, especially in those with pre-CRT CEA ≥6 ng/ml.

Mutations in the RAS and PI3K pathways are associated with metastatic location in colorectal cancers.

Identification of mutations in the downstream epidermal growth factor receptor (EGFR) signaling pathway could provide important insights of EGFR‐targeted therapies in colorectal cancers. We analyzed the mutation spectra of the PI3K/PTEN/AKT and RAS/RAF/MAPK pathways in colorectal cancers and the associations of these mutations with sites of metastases or recurrence.

The prognostic role of microsatellite instability, codon-specific KRAS, and BRAF mutations in colon cancer

This study aimed to establish a correlation between MSI, KRAS mutations, and BRAFV600E in colon cancer and to investigate the prognostic effect.