Shih-Ching Chang

Aldehyde dehydrogenase 1 is a putative marker for cancer stem cells in head and neck squamous cancer

Aldehyde dehydrogenase 1 (ALDH1) has been considered to be a marker for cancer stem cells. However, the role of ALDH1 in head and neck squamous cell carcinoma (HNSCC) has yet to be determined. In this study, we isolated ALDH1-positive cells from HNSCC patients and showed that these HNSCC-ALDH1+ cells displayed radioresistance and represented a reservoir for generating tumors. Based on microarray findings, the results of Western blotting and immunofluorescent assays further confirmed that ALDH1+-lineage cells showed evidence of having epithelial-mesenchymal transition (EMT) shifting and endogenously co-expressed Snail. Furthermore, the knockdown of Snail expression significantly decreased the expression of ALDH1, inhibited cancer stem-like properties, and blocked the tumorigenic abilities of CD44+CD24(-)ALDH1+ cells. Finally, in a xenotransplanted tumorigenicity study, we confirmed that the treatment effect of chemoradiotherapy for ALDH1+ could be improved by Snail siRNA. In summary, it is likely that ALDH1 is a specific marker for the cancer stem-like cells of HNSCC.

Curative Resection of T1 Colorectal Carcinoma: Risk of Lymph Node Metastasis and Long-Term Prognosis

PURPOSEThe features of T1 colorectal adenocarcinoma and the risk determination of lymph node metastasis were reviewed. Prognostic factors were assessed to verify whether the risk of lymph node metastasis would influence the long-term prognosis.METHODSPatients undergoing curative resection of T1 colorectal adenocarcinoma at the Taipei Veterans General Hospital from December 1969 to August 2002 were retrospectively studied. Patients with synchronous colorectal cancer, distant metastasis, familiar adenomatous polyposis, or inflammatory bowel disease were excluded. The associations between lymph node metastasis and clinicopathologic variables were evaluated univariately using chi-squared test, Fisher’s exact test, or Student’s t -test, and multivariately using logistic regression. Univariate analysis by the log-rank test and multivariate analysis by Cox regression hazards model determined the factors influencing the overall survival.RESULTSA total of 159 patients were included. Sixteen patients (10.1 percent) had lymph node metastasis. The risk of lymph node metastasis included histologic grade (P = 0.005), lymphatic vessel invasion (P = 0.023), inflammation around cancer (P = 0.049), and budding at the invasive front of tumor (P = 0.022). Age (P = 0.001) and number of total sampling lymph nodes (P < 0.0001) were found to be the factors influencing the overall survival.CONCLUSIONSVariables that predict lymph node metastasis in surgically resected T1 colorectal carcinoma may not impact the long-term prognosis.

Inhibition of tumorigenicity and enhancement of radiochemosensitivity in head and neck squamous cell cancer-derived ALDH1-positive cells by knockdown of Bmi-1

Bmi-1, a member of the Polycomb family of transcriptional repressors, is essential for maintaining the self-renewal abilities of adult stem cells. Bmi-1 has been demonstrated to play a role in tumorigenesis in head and neck squamous cell carcinomas (HNSCCs). A recent study has further suggested that ALDH1 may be considered to be a putative marker for HNSCC-derived cancer stem cells. However, the role that Bmi-1 plays in HNSCC-derived ALDH1-positive cells (HNSCC-ALDH1(+)) has yet to be determined. In this study, we demonstrated that HNSCC-ALDH1(+) cells possess tumor initiating properties, are capable of self-renewal, and express higher levels of Bmi-1 as compared to HNSCC-ALDH1(-) cells. To further explore the functional role of Bmi-1 in HNSCC-ALDH1(+) cells, we used a lentiviral vector expressing shRNA to knock down Bmi-1 expression (sh-Bmi-1) in HNSCC-ALDH1(+) cells. Silencing of Bmi-1 significantly enhanced the sensitivity of HNSCC-ALDH1(+) cells to chemoradiation and increased the degree of chemoradiation-mediated apoptosis that occurred. Importantly, knockdown of Bmi-1 increased the effectiveness of radiotherapy and led to the inhibition of tumor growth in nude mice transplanted with HNSCC-ALDH1(+) cells. Kaplan-Meier survival analysis indicated that the mean survival rate of HNSCC-ALDH1(+) tumor-bearing immunocompromised mice treated with radiotherapy was significantly improved by treatment with sh-Bmi-1 as well. In summary, these results suggest that Bmi-1 is a potential target for increasing the sensitivity of HNSCC cancer stem cells to chemoradiotherapy.

Rectal perforation: a life-threatening complication of stapled hemorrhoidectomy: report of a case.

Stapled hemorrhoidectomy is considered to be safe and carries advantages. We describe a patient with rectal perforation and fecal peritonitis after stapled hemorrhoidectomy. We suggest that it should be performed by experienced colorectal surgeons who are familiar with the technique and aware of possible complications.

BRAF mutation is a prognostic biomarker for colorectal liver metastasectomy

In metastatic colorectal cancer, v‐Ki‐ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) is a predictive biomarker for anti‐epidermal growth factor receptor (EGFR) treatment and V‐raf murine sarcoma viral oncogene homolog B1 (BRAF) is a prognostic biomarker. We aimed to determine the impact of KRAS and BRAF mutation as determined from liver metastases specimens on overall survival (OS) in patients following colorectal liver metastasectomy.

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.

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.

Loss of heterozygosity and DNA aneuploidy in colorectal adenocarcinoma.

AbstractBackground: This study evaluated the relationship between DNA aneuploidy and loss of heterozygosity (LOH) at different genetic loci in colorectal adenocarcinoma. Methods: A total of 112 patients with surgically removed colorectal adenocarcinoma in Taipei Veterans General Hospital from January 1999 to July 2001 were included in this study. The pattern of DNA ploidy was determined with DNA flow cytometry, and the LOH of various genetic loci was determined with fluorescence polymerase chain reaction and denaturing gradient gel electrophoresis. The relationship between DNA ploidy, LOH of various genetic loci, and clinicopathologic variables was analyzed with the χ2 test with Yates’ correction as well as by multivariate binary logistic regression analysis. Results: Seventy-one (63.4%) of the 112 carcinomas had DNA aneuploidy. The DNA aneuploidy was not associated with any clinicopathologic variable. Ninety-one tumors (81.3%) exhibited LOH in at least one genetic locus. In the univariate analysis, the DNA aneuploidy was associated with LOH of Tp53-penta, D8S254, D5S346, and high-frequency LOH (P = .001, P = .016, P = .041, and P < .001, respectively). In the multivariate analysis, the most significant factor influencing DNA aneuploidy was D8S254, followed by Tp53-penta, high-frequency LOH, and D5S346. Conclusions: DNA aneuploidy is strongly associated with LOH at specific genetic loci.

Oct4-related cytokine effects regulate tumorigenic properties of colorectal cancer cells

Oct4, a member of the POU-domain transcription factor family, has been implicated in the cancer stem cell (CSC)-like properties of various cancers. However, the precise role of Oct4 in colorectal CSC initiation remains uncertain. Numerous studies have demonstrated a strong link between inflammation and tumorigenesis in colorectal cancers. In this study, we demonstrated that Oct4 overexpression enhances CSC-like properties of colorectal cancer cells (CRCs), including sphere formation, cell colony formation, cell migration, invasiveness, and drug resistance. In addition, putative CSC markers, stemness genes, drug-resistant genes, as well as interleukin (IL)-8 and IL-32 were upregulated. Microarray-based bioinformatics of CRCs showed higher expression levels of embryonic stem cell-specific genes in cells that overexpressed Oct4. Neutralization of either IL-8 or IL-32 with specific antibodies partially blocked the tumorigenic effects induced by either Oct4 overexpression or by the addition of conditioned media from Oct4-overexpressing CRCs. In addition, the presence of Oct4-overexpressing CRCs enhanced the tumorigenic potential of parental CRCs in vivo. In summary, these data suggest that IL-8 and IL-32 play a role in regulating the CSC-like properties that promote tumorigenesis of CRCs in both autocrine and paracrine manners.