Tiancheng Zhan

MicroRNA-181a promotes tumor growth and liver metastasis in colorectal cancer by targeting the tumor suppressor WIF-1

BackgroundGiven the emerging role of microRNA in tumor disease progression, we investigated the association between microRNA expression, liver metastasis and prognosis of colorectal cancer.MethodsColorectal cancer tissues from patients with or without liver metastases were profiled to identify differentially expressed microRNA. Expression profile was further assessed using quantitative reverse transcription PCR and in situ hybridization. Correlation between miR-181a expression, the most differentially expressed microRNA, between patients with and without liver metastasis, and its downstream target genes were investigated using qRT-PCR. Luciferase reporter assay was conducted to establish functional association between miR-181a and its target genes. Manipulation of miR-181a expression and its consequences in tumor growth and metastasis were demonstrated in various in vitro and in vivo models.ResultsmiR-181a was revealed being the most elevated in CRC with liver metastases. miR-181a expression correlated with advanced stage, distant metastasis, and served as an independent prognostic factor of poor overall survival. Stable transfection of CRC cell lines with miR-181a promoted cell motility and invasion, as well as tumor growth and liver metastasis,while silencing its expression resulted in reduced migration and invasion. Additionally, we identified WIF-1 as direct and functional targets of miR-181a. Ectopic expression of miR-181a suppressed the epithelial markers E-cadherin and β-catenin, while enhanced the mesenchymal markers vimentin.ConclusionOur data demonstrate that miR-181a expression is associated with CRC liver metastasis and survival. miR-181a has strong tumor-promoting effects through inhibiting the expression of WIF-1, and its potential role in promoting epithelial-mesenchymal transition.

Prognostic role of serum AZGP1, PEDF and PRDX2 in colorectal cancer patients

This study was designed to develop novel and better reliable serum prognostic biomarkers for colorectal cancer (CRC). A 50 sample set including CRC, adenoma and healthy control sera was used to identify the serum proteins involved in CRC carcinogenesis using serum proteomic approach. Alpha-2-glycoprotein 1, zinc-binding (AZGP1), pigment epithelium derived factor (PEDF) and peroxiredoxin 2 (PRDX2) were selected as good candidates. Two independent cohorts of 868 individuals were enrolled. The expression of selected proteins in serum from cohort 1 (n = 534) was quantified with enzyme-linked immunosorbent assays. CRC sera of this cohort (n = 405) were assigned to training and test sets, which were used to identify and verify the prognostic markers. The prognostic values of identified proteins were further validated in cohort 2 (n = 334) using quantitative reverse transcription PCR and immunohistochemical staining. Our data showed that the elevated AZGP1 and decreased PEDF and PRDX2 expressions in CRC serum and tissues were correlated with liver metastases. In the training set, higher AZGP1 and lower PEDF levels in sera were significantly associated with a poorer overall survival (OS), higher AZGP1 was also associated with a poorer disease-free survival (DFS). This association was verified in the testing set and further validated in patients in cohort 2. Patients with lower PEDF or PRDX2 levels in their CRC tissues had a significantly poorer DFS or OS than patients with high levels of these proteins in cohort 2. Univariate and multivariate analyses indicated that the prognostic performance of serum AZGP1 and PEDF was independent of other clinicopathological factors. We propose that they may serve as prognostic markers and potential therapeutic targets in CRC.

Risk Factors for Nonclosure of a Temporary Defunctioning Ileostomy Following Anterior Resection of Rectal Cancer.

BACKGROUND: In patients with colorectal cancer, a defunctioning ileostomy is commonly constructed to reduce anastomotic complications. However, many patients do not undergo a subsequent procedure to have their temporary stoma closed. OBJECTIVE: This study investigated the incidence of nonclosure of ileostomies and identified factors associated with nonclosure. DESIGN: This study is a retrospective analysis of prospectively collected data. SETTING: This study was conducted at a tertiary referral cancer hospital. PATIENTS: A total of 296 patients who received anterior resection with a defunctioning ileostomy with protective intention from 2006 to 2013 were included. MAIN OUTCOME MEASURES: The primary outcomes measured were the incidence of nonclosure of ileostomy and associated risk factors. RESULTS: Patients were followed for a median time of 29 months (range, 21–100 months). At the end of the study, 51 (17.2%) patients were left with a permanent ileostomy. The median time interval from the creation of a defunctioning ileostomy to closure was 192 days (range, 14–865 days). Multivariate analyses using a logistic regression model showed that metastatic diseases (OR, 0.179, p < 0.001), Charlson Comorbidity Index score >1 (OR, 0.268; p < 0.01), and complications from the index surgery (OR, 0.391; p = 0.013) were significant independent risk factors for failing to close a defunctioning ileostomy. LIMITATIONS: Although our study has a large patient cohort, it is limited by its retrospective nature. It is difficult to fully evaluate stoma complications after hospital discharge, and the prevalence may be underestimated. CONCLUSION: One in 6 temporary ileostomies constructed during an elective anterior resection for rectal cancer was not closed. Patients should be told before the index surgery that there is a risk of nonclosure and possible complications associated with permanent ileostomy.

Intermediate-fraction neoadjuvant radiotherapy for rectal cancer.

BACKGROUND: In China, standard neoadjuvant chemoradiation therapy has not been well accepted, not only because of financial constraints but also because of the poorly-tolerated long duration of the regimen. OBJECTIVE: The current study aimed to evaluate the impact of a modified neoadjuvant radiation regimen on the prognosis of rectal cancer patients in China. DESIGN: This was a nonrandomized cohort study evaluating outcomes of patients who chose to undergo preoperative radiotherapy compared with those who chose not to undergo preoperative radiotherapy (controls). SETTINGS: The study was carried out in Peking University Cancer Hospital, a tertiary care cancer center in China. PATIENTS: Records of patients with locally advanced, mid-to-low rectal cancer who underwent total mesorectal excision at Peking University Cancer Hospital from 2001 through 2005 were analyzed in this study. INTERVENTION: Patients who chose preoperative radiotherapy received a total dose of 30 Gy delivered in 10 once-daily fractions of 3.0 Gy each, with at least a 14-day delay of surgery after delivery of the last fraction. MAIN OUTCOME MEASURES: Tumor downstaging was evaluated. Local recurrence, distant metastases, and disease-free and overall survival were analyzed with the Kaplan-Meier method. RESULTS: A total of 101 patients accepted and 162 patients declined the modified preoperative radiotherapy regimen. Of the 101 patients receiving preoperative radiotherapy, 5 (5%) had a complete response, and 50 (50%) achieved TNM downstaging. The local recurrence rate was 5% with preoperative radiotherapy and 18% in the control groups (p = 0.02). Within the preoperative radiotherapy group, 5-year disease-free survival and overall survival rates were significantly higher in patients with T-, N-, or TNM-downstaging than in patients without downstaging. Evaluation of literature reports indicated that clinical safety and effectiveness of the modified protocol are comparable to results of standard neoadjuvant procedures. LIMITATIONS: The allocation to study groups was not randomized, and patient self-selection may have introduced bias, particularly because patients with greater financial means were more likely to choose to undergo the preoperative radiotherapy regimen. CONCLUSIONS: Compared with surgery alone, this modified preoperative radiotherapy regimen is associated with significantly reduced local recurrence and complication rates, with improved survival in patients who show downstaging. The modified protocol offers a clinical outcome equivalent to standard preoperative radiotherapy regimens while offering an alternative for increasing the flexibility of preoperative radiation regimens in China.

Intermediate Neoadjuvant Radiotherapy Combined With Total Mesorectal Excision for Locally Advanced Rectal Cancer: Outcomes After a Median Follow-Up of 5 Years

BACKGROUND We previously reported the oncologic results for intermediate neoadjuvant radiotherapy (nRT) plus total mesorectal excision (TME) for locally advanced rectal cancer in a retrospective study. The objective of the present study was to further investigate the efficacy and long-term outcomes after this nRT regimen. PATIENTS AND METHODS From 2002 to 2011, 382 patients with resectable locally advanced rectal cancer were treated at the Peking University Cancer Hospital with 30 Gy of intermediate nRT in 10 fractions (biologic equivalent dose, 36 Gy) plus TME. Surgery, RT, and pathologic examination were standardized. The primary endpoints were local recurrence-free survival (LRFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS The median patient age at the initial treatment was 58 years (range, 22-85 years). The median patient follow-up time was 5.5 years. The estimated 5-year LRFS, CSS, and OS were 93.6%, 79.0%, and 73.6%, respectively. Of the 382 patients, 4 (1%), 4 (1%), 4 (1%), and 11 (2.9%) patients died of postoperative complications, secondary malignancies, cardiovascular and/or neurologic events, or other causes, respectively. Seven patients (1.8%) developed late-onset ileus and died after conservative treatment in peripheral hospitals. CONCLUSION The 10-fraction intermediate nRT regimen reported in the present study is efficient and safe. The long-term outcome is acceptable. This treatment schedule is useful as an alternative that provides efficiency, patient convenience, and low medical costs.

A multidisciplinary clinical treatment of locally advanced rectal cancer complicated with rectovesical fistula: a case report

IntroductionRectal cancer with rectovesical fistula is a rare and difficult to treat entity. Here, we describe a case of rectal cancer with rectovesical fistula successfully managed by multimodality treatment. To the best of our knowledge, this is the first such case report in the literature.Case presentationA 51-year-old Chinese man was diagnosed as having rectal cancer accompanied by rectovesical fistula. He underwent treatment with neoadjuvant radiochemotherapy combined with total pelvic excision and adjuvant chemotherapy, as recommended by a multimodality treatment team. Post-operative pathology confirmed the achievement of pathological complete response.ConclusionsThis case suggests that a proactive multidisciplinary treatment is needed to achieve complete cure of locally advanced rectal cancer even in the presence of rectovesical fistula.

Prognostic Value of Lymph Node Number and Ratio Staging System inStage ⢠Rectal Cancer Following Neoadjuvant Radiochemotherapy

Objective: To compare the prognostic value of positive lymph node number (LNN) and lymph node ratio (LNR) in stage III rectal cancer following neoadjuvant radiochemotherapy. Methods: From 2008 to 2010, 99 rectal cancer cases in our hospital received neoadjuvant radiochemotherapy or radiotherapy. Radical surgery was performed after neoadjuvant therapy. LNN distinguished four stages of lymph node involvement by TNM stage system and LNR divided patients into quartiles. The prognosis value of LNN and LNR to the patients was evaluated by Kaplan-Meier method and Cox regression. We evaluated the prognosis value of LNN and LNR for those with inadequate lymph nodes (<12). Results: The patients were staged according to lymph node number (LNN=1, 2 ≤ LNN ≤ 3, 4 ≤ LNN ≤ 6 and LNN ≥ 7) and lymph node ratio (LNR<0.075, 0.075 ≤ LNR<0.15, 0.15 ≤ LNR<0.35 and LNR ≥ 0.35). 3 year overall survival rates were different among different LNN groups and different LNR groups. Multivariate analysis showed that LNR ≥ 0.15 was an independent prognostic factor of overall survival (P=0.029). 26 patients with less than 12 lymph nodes harvest were divided into four groups (LNR<0.15, 0.15 ≤ LNR<0.25, 0.25 ≤ LNR<0.50 and LNR ≥ 0.50), LNR was proved to be a better predictor of survival. 3 year overall survival rates were significant different between LNR<0.50 and LNR ≥ 0.50 (P=0.018). Conclusion: The study showed LNR was an independent prognostic factor for rectal cancer after neoadjuvant radiochemotherapy, LNR 0.15 was a cutoff point for overall survival. LNR might be a better prognostic factor than LNN, especially in patients with less than 12 lymph nodes harvest.