Zhen Hai Lu

Elevated preoperative neutrophil to lymphocyte ratio predicts risk of recurrence following curative resection for stage IIA colon cancer

Background and ObjectivesAdjuvant chemotherapy for stage II colon cancer remains controversial but may be considered for patients with high-risk features. Recent studies have shown that elevated neutrophil to lymphocyte ratio (NLR) is a worse prognostic factor and a predictor of response to chemotherapy in patients with advanced colorectal cancer. The purpose of this study was to evaluate whether NLR predicts risk of recurrence in patients with stage IIA colon cancer undergoing curative resection without adjuvant chemotherapy.MethodsWe retrospectively reviewed 141 consecutive patients with stage IIA colon cancer treated with curative surgery alone from 2002 to 2006. NLR, as well as demographics, clinical, histopathologic, and laboratory data were analyzed. Univariate and multivariate analyses were conducted to identify prognostic factors associated with recurrent-free survival (RFS).ResultsCox’s regression analysis demonstrated that elevated NLR (>4) (hazard ratio, 4.88; P < 0.01) and less lymph node sampling (<15 lymph nodes; hazard ratio, 3.80; P < 0.05) were adverse prognostic factors for RFS. The 5-year RFS was 91.4% (95% CI, 88.6–94.2%) for patients with normal NLR and 63.8% (51.1–76.3%) for patients with elevated NLR. The 5-year RFS for patients with 0, 1, and 2 of the identified risk factors was 95.1%, 87.4%, and 33.3%, respectively (P < 0.001).ConclusionsElevated preoperative NLR is an independent predictor of worse RFS for patients with stage IIA colon cancer and a potential biomarker to identify candidates for adjuvant chemotherapy.

Prognostic impact of ERβ and MMP7 expression on overall survival in colon cancer

Estrogen receptor beta (ERβ) is the most highly expressed protein in patients with colon cancer. Matrix metalloproteinase 7 (MMP7) is consistently expressed throughout cancer progression. We have previously shown that endocrine therapy can inhibit MMP7 expression in colon cancer cells. In this study, we aim to identify the prognostic effects and correlation of ERβ and MMP7 in the context of colon cancer. ERβ and MMP7 levels were assessed by immunohistochemistry in normal mucosa and tumoral tissues from 423 patients with stage I-III colon cancer. The Cox proportional hazards regression model was applied to analyze the lifetime data, including overall survival (OS) and cause-specific survival (CSS). The 5-year survival rate was significantly higher in patients with high expression of nuclear ERβ than in patients with low expression (84.3% vs. 63.9%, respectively, p < 0.05). High expression of MMP7 was related to decreased OS (72% vs. 90%, respectively, p = 0.008) and 5-year survival (86.6% vs. 88.8%, respectively, p = 0.005) compared to patients with low expression of MMP7. In the subset of patients with high expression levels of tumoral nuclear ERβ, high expression of MMP7 was related to OS and CSS among colon cancer patients with high expression of ERβ. In conclusion, our results suggest that low expression of ERβ was a risk factor in colon cancer, and high expression of MMP7 was an independent prognostic factor of ERβ-positive patients with colon cancer.

The Dihydrouracil/Uracil Ratios in Plasma and Toxicities of 5-Fluorouracil-Based Adjuvant Chemotherapy in Colorectal Cancer Patients

Background: This study was designed to measure the dihydrouracil (UH2)/uracil (U) ratio in plasma as a surrogate marker for dihydropyrimidine dehydrogenase (DPD) activity and to investigate the relationships of the UH2/U ratios in plasma with the toxicities of 5-fluorouracil (5-FU)-based adjuvant chemotherapy and 5-FU plasma concentrations in colorectal cancer patients. Methods: Thirty colorectal cancer patients received adjuvant chemotherapy of leucovorin plus 5-FU after operations. The concentrations of UH2, U and 5-FU were assayed by the high-performance liquid chromatography method. The relationships of the UH2/U ratios with the 5-FU toxicities and 5-FU plasma concentrations were analyzed.Results: There was a negative relationship between the UH2/U ratios and 5-FU plasma concentrations (p <0.001). 5-FU toxicities had a negative correlation with the UH2/U ratios and a positive correlation with 5-FU plasma concentrations (p < 0.05). Conclusion: The UH2/U ratio in plasma has close correlations with the 5-FU plasma concentration and 5-FU toxicity during chemotherapy, which may highlight the theoretical base of individual therapy for patients with colorectal cancer.

MMP7 expression regulated by endocrine therapy in ERβ-positive colon cancer cells

BackgroundMany studies have shown that colon cancer is an estrogen-dependent carcinoma. This study explored the efficacy of endocrine therapy in colon cancer cells with high metastatic potential (HT29). We investigated the proliferation of HT29 cells after exposure to endocrine therapy (tamoxifen) and 5-FU.MethodsApoptosis was evaluated using flow cytometry. The expression of matrix metalloproteinases 7 (MMP-7) and estrogen receptor beta (ERβ) was measured by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. The migration capability of treated cells was determined with wound scratch assay.ResultsTamoxifen alone, 5-FU alone, and the combination of the two drugs can significantly inhibit HT29 cell proliferation and migration, block the cells in G2/M phase and induce cell apoptosis. These drugs also can down-regulate MMP7 and ERβ expression.ConclusionOur findings suggest that endocrine therapy is an efficient therapy for inhibiting ERβ-positive colon cancer cell proliferation and migration via down-regulation of MMP7.

Hospital-Based Colorectal Cancer Survival Trend of Different Tumor Locations from 1960s to 2000s

Background Our aim is to explore the trend of association between the survival rates of colorectal cancer (CRC) and the different clinical characteristics in patients registered from 1960s to 2000s. We hypothesized that the survival rate of CRC increases over time and varies according to anatomic subsites. Methods Information from a total of 4558 stage T(1-4)N(1-2)M0 CRC patients registered from 1960s to 2008 were analyzed. The association of CRC overall survival with age, gender, tumor locations, time, histopathology types, pathology grades, no. of examined lymph nodes, the T stage, and the N stage was analyzed. The assessment of the influence of prognostic factors on patient survival was performed using Cox’s proportional hazard regression models. Results From 1960 to 2008, the studied CRC patients included 2625 (57.6%) and 1933 (42.4%) males and females, respectively. These included 1896 (41.6%) colon cancers, and 2662 (58.4%) rectum cancers. The 5-year survival rate was 49%, 58%, 58%, 70%, and 77% for the time duration of 1960s, 1970s, 1980s, 1990s and 2000s, respectively. An increased 5-year survival rate was observed in the colon cancer and rectum cancer patients. Patients older than 60 years of age were more likely to develop colonic cancer (sigmoid) than rectum cancer (49.2% vs. 39.9%). The Cox regression model showed that only rectum cancer survival was related to time duration. Conclusion The overall survival and 5-year survival rates showed an increase from the 1960s to 2000s. There is a trend of rightward shift of tumor location in CRC patients.

Depth of Tumor Invasion Independently Predicts Lymph Node Metastasis in T2 Rectal Cancer

ObjectiveThe aim of this study was to identify risk factors of lymph node metastasis (LNM) for T2 rectal cancer.MethodsFrom a prospectively maintained single-institution database, we identified 346 consecutive pT2 rectal cancers treated with total mesorectal excision from 1998 to 2009. Univariate and multivariate analyses were performed to identify risk factors associated with overall and intermediate/apical LNM. The incidence of overall and intermediate/apical LNM was analyzed by tree analysis.ResultsAge, tumor location, pathological features, and depth of invasion were independent predictors for overall LNM. Tumor location, pathological features, and depth of invasion were independent predictors for intermediate/apical LNM. Tree analysis showed that the incidence of LNM was 7.7% for upper rectal cancer with favorable pathological features, and 3.4% for mid/lower rectal cancer without other identified risk factors. The incidence of intermediate/apical LNM was 5.7% for superficial T2 rectal cancer with favorable pathological features, and 3.1% for deep T2 rectal cancer locating in upper rectum with favorable pathological features.ConclusionsDepth of invasion is an independent predictor for LNM in T2 rectal cancer. Using tree analysis, we identified a subset of patients with low risk of LNM who may be candidates of local excision.

The loss-of-function mutations and down-regulated expression of ASB3 gene promote the growth and metastasis of colorectal cancer cells

BackgroundAnkyrin repeat and SOCS box protein 3 (ASB3) is a member of ASB family and contains ankyrin repeat sequence and SOCS box domain. Previous studies indicated that it mediates the ubiquitination and degradation of tumor necrosis factor receptor 2 and is likely involved in inflammatory responses. However, its effects on oncogenesis are unclear. This study aimed to investigate the effects of ASB3 on the growth and metastasis of colorectal cancer (CRC).MethodsWe used next-generation sequencing or Sanger sequencing to detect ASB3 mutations in CRC specimens or cell lines, and used real-time quantitative polymerase chain reaction, Western blotting, and immunohistochemical or immunofluorescence assay to determine gene expression. We evaluated cell proliferation by MTT and colony formation assays, tested cell cycle distribution by flow cytometry, and assessed cell migration and invasion by transwell and wound healing assays. We also performed nude mouse experiments to evaluate tumorigenicity and hepatic metastasis potential of tumor cells.ResultsWe found that ASB3 gene was frequently mutated (5.3%) and down-regulated (70.4%) in CRC cases. Knockdown of endogenous ASB3 expression promoted CRC cell proliferation, migration, and invasion in vitro and facilitated tumorigenicity and hepatic metastasis in vivo. Conversely, the ectopic overexpression of wild-type ASB3, but not that of ASB3 mutants that occurred in clinical CRC tissues, inhibited tumor growth and metastasis. Further analysis showed that ASB3 inhibited CRC metastasis likely by retarding epithelial-mesenchymal transition, which was characterized by the up-regulation of β-catenin and E-cadherin and the down-regulation of transcription factor 8, N-cadherin, and vimentin.ConclusionASB3 dysfunction resulted from gene mutations or down-regulated expression frequently exists in CRC and likely plays a key role in the pathogenesis and progression of CRC.

The role of adjuvant chemotherapy for colorectal liver metastasectomy after pre-operative chemotherapy: Is the treatment worthwhile?

Peri-operative chemotherapy has been proposed to improve the survival of patients with colorectal cancer hepatic metastases (CRCHM). However, the role of the adjuvant chemotherapy post-metastasectomy for CRCHM patients who have undergone pre-operative chemotherapy is still undetermined. We retrospectively analyzed the role of adjuvant chemotherapy post-metastasectomy on relapse-free survival (RFS) and overall survival (OS) in 163 CRCHM patients who received pre-operative chemotherapy using a Kaplan-Meier curve and univariate/multiple Cox model. Ten patients with rapidly progressing disease were further excluded in a sensitivity analysis. Seven risk factors (metachronous/synchronous metastases, differentiated grade of the primary tumor, number of metastases, size of the max metastasis, duration of pre-operative chemotherapy, radiologic response and pathologic regression) were used to stratify patients and investigate the beneficial features of adjuvant chemotherapy post-metastasectomy. The results indicated that adjuvant chemotherapy post-metastasectomy prolonged both RFS (median RFS: 3.3 vs. 10.2 m, P = 0.002) and OS (median OS: 28.1 vs. 40.7 m, P = 0.005) in CRCHM patients who received pre-operative chemotherapy. After adjusting for other risk factors in a multiple Cox model, the adjuvant chemotherapy group was estimated to have a 54.0 % relapse-free survival (hazard ratio (HR) = 0.46, 95 % confidence interval (CI) 0.31 - 0.69, P < 0.001) and a 55.0 % overall survival (HR [95 % CI]: 0.45 [0.26 - 0.78], P = 0.005) advantage compared to patients without adjuvant chemotherapy. Additionally, the benefit of adjuvant chemotherapy post-liver resection remained in sensitivity analysis. After the risk stratification, patients with synchronous metastases, poor differentiation, ≥ 3 metastases per patient, size of the maximum metastasis >3 cm, a short duration of pre-operative chemotherapy, radiologic response and poor pathologic regression seem to benefit more from adjuvant chemotherapy. To sum up, adjuvant chemotherapy post-metastasectomy might be considered for CRCHM patients who have received preoperative chemotherapy, especially for those with high-risk factors.

Dihydroartemisinin inhibits colon cancer cell viability by inducing apoptosis through up-regulation of PPARγ expression

The present study was aimed to investigate the effect of dihydroartemisinin on the colon cancer cell proliferation and apoptosis. The results from MTT assay revealed a concentration and time dependent relation between the inhibition of SW 948 cell viability and dihydroartemisinin addition. The viability of SW 948 cells was reduced to 45 and 24% on treatment with 30 and 50 µM, respectively concentrations of dihydroartemisinin after 48 h. Morphological examination of SW 948 cells showed attainment of rounded shape and cluster formation on treatment with dihydroartemisinin. Western blot analysis showed a significant increase in the activation of caspase-3 and expression of cleaved PARP by dihydroartemisinin treatment. The activation of PPARγ was increased significantly in SW 948 cells by treatment with dihydroartemisinin. Compared to control, the migration potential of SW 948 cells was reduced significantly (p < 0.005) and the expression levels of MMP-2 and -9 inhibited by dihydroartemisinin at 50 µM concentration. In the dihydroartemisinin treatment group colon tumor formation was significantly inhibited on treatment with 20 mg/kg doses of dihydroartemisinin after 30 days. Therefore, dihydroartemisinin inhibits colon cancer growth by inducing apoptosis and increasing the expression of PPARγ. Thus dihydroartemisinin can be used for the treatment of colon cancer.

A scoring system based on artificial neural network for predicting 10-year survival in stage II A colon cancer patients after radical surgery

Nearly 20% patients with stage II A colon cancer will develop recurrent disease post-operatively. The present study aims to develop a scoring system based on Artificial Neural Network (ANN) model for predicting 10-year survival outcome. The clinical and molecular data of 117 stage II A colon cancer patients from Sun Yat-sen University Cancer Center were used for training set and test set; poor pathological grading (score 49), reduced expression of TGFBR2 (score 33), over-expression of TGF-β (score 45), MAPK (score 32), pin1 (score 100), β-catenin in tumor tissue (score 50) and reduced expression of TGF-β in normal mucosa (score 22) were selected as the prognostic risk predictors. According to the developed scoring system, the patients were divided into 3 subgroups, which were supposed with higher, moderate and lower risk levels. As a result, for the 3 subgroups, the 10-year overall survival (OS) rates were 16.7%, 62.9% and 100% (P < 0.001); and the 10-year disease free survival (DFS) rates were 16.7%, 61.8% and 98.8% (P < 0.001) respectively. It showed that this scoring system for stage II A colon cancer could help to predict long-term survival and screen out high-risk individuals for more vigorous treatment.