Icariin-mediated inhibition of NF-κB activity enhances the in vitro and in vivo antitumour effect of 5-fluorouracil in colorectal cancer.

Colorectal cancer (CRC) is an aggressive malignancy that has a poor prognosis. 5-Fluorouracil (5-FU) is a first line chemotherapeutic medication used in the treatment of gallbladder cancer; however, the efficacy is below satisfactory. Icariin is a natural compound that is conventionally reported to have activity against a variety of cancers. This study was carried out to investigate the anti-cancer effect of icariin in CRC cells and to determine whether the compound can enhance the antitumour activity of 5-FU. Cell proliferation and apoptosis were measured using an MTT assay and flow cytometry, respectively. The activity of transcription factor NF-κB was determined by EMSA method. The expression of apoptosis- and proliferation-related proteins was determined by western blotting. The in vivo antitumour effect of combination treatment with icariin and 5-FU on CRC was also assessed using a murine model of CRC. Icariin sensitized the CRC cells to 5-FU both in vitro and in vivo. The antitumour activity of icariin and its potentiating effect on the antitumour activity of 5-FU implicated the suppression of NF-κB activity and consequent down-regulation of the gene products regulated by NF-κB. Our results showed that icariin, suppressed tumour growth and enhanced the antitumour activity of 5-FU in CRC by inhibiting NF-κB activity. Therefore, we suggest that combination of icariin with 5-FU might offer a therapeutic benefit to the patients with CRC; however, further studies are required to ascertain this proposition.

Short-term outcomes of laparoscopic total mesorectal excision compared to open surgery.

AIM: To investigate the short-term outcome of laparoscopic total mesorectal excision (TME) in patients with mid and low rectal cancers. METHODS: A consecutive series of 138 patients with middle and low rectal cancer were randomly assigned to either the laparoscopic TME (LTME) group or the open TME (OTME) group between September 2008 and July 2011 at the Department of Colorectal Cancer of Shanghai Cancer Center, Fudan University and pathological data, as well as surgical technique were reviewed retrospectively. Short-term clinical and oncological outcome were compared in these two groups. Patients were followed in the outpatient clinic 2 wk after the surgery and then every 3 mo in the first year if no adjuvant chemoradiation was indicated. Statistical analysis was performed using SPSS 13.0 software. RESULTS: Sixty-seven patients were treated with LTME and 71 patients were treated with OTME (sex ratio 1.3:1 vs 1.29:1, age 58.4 ± 13.6 years vs 59.6 ± 9.4 years, respectively). The resection was considered curative in all cases. The sphincter-preserving rate was 65.7% (44/67) vs 60.6% (43/71), P = 0.046; mean blood loss was 86.9 ± 37.6 mL vs 119.1 ± 32.7 mL, P = 0.018; postoperative analgesia was 2.1 ± 0.6 d vs 3.9 ± 1.8 d, P = 0.008; duration of urinary drainage was 4.7 ± 1.8 d vs 6.9 ± 3.4 d, P = 0.016, respectively. The conversion rate was 2.99%. The complication rate, circumferential margin involvement, distal margins and lymph node yield were similar for both procedures. No port site recurrence, anastomotic recurrence or mortality was observed during a median follow-up period of 21 mo (range: 9-56 mo). CONCLUSION: Laparoscopic TME is safe and feasible, with an oncological adequacy comparable to the open approach. Further studies with more patients and longer follow-up are needed to confirm the present results.

[Prospective study on the use of nickel-titanium temperature-dependent memory-shape device (CAR27) for anastomosis after colorectal surgery].

OBJECTIVE: To prospectively evaluate the safety and efficacy of nickel- titanium temperature-dependent memory-shape device(CAR27) for colorectal anastomosis. METHODS: Sixty colorectal cancer patients were randomly divided into two groups and received colorectal anastomosis with CAR27 or traditional stapling device. Complications, bowel function return, and the extrusion of anastomosis ring were prospectively monitored. RESULTS: Both CAR27 and stapler group had one case of anastomotic leakage. Other complications such as stricture or obstruction were not found. Time for anastomosis of the two groups were (10.1±1.2) minutes and (11.2±2.1) minutes respectively. Time to first flatus was(3.2±1.2) days and (3.5±1.4) days respectively. Time to food intake resumption was (4.0±1.4) days and (4.3±1.3) days respectively. The differences above between the two groups were not statistically significant(P>0.05). The ring was expelled with stool within 7-16 days. The two groups were similar in operative time and the return of bowel function. CONCLUSION: CAR27 is safe and simple for colorectal anastomosis.

S100A4 over-expression underlies lymph node metastasis and poor prognosis in colorectal cancer.

AIM: To develop lymph node metastasis (LNM)-associated biomarkers for colorectal cancer (CRC) using quantitative proteome analysis. METHODS: Differences in protein expression between primary CRC with LNM (LNM CRC) and without LNM (non-LNM CRC) were assessed using methyl esterification stable isotope labeling coupled with 2D liquid chromatography followed by tandem mass spectrometry (2D-LC-MS/MS). The relationship to clinicopathological parameters and prognosis of candidate biomarkers was examined using an independent sample set. RESULTS: Forty-three proteins were found to be differentially expressed by at least 2.5-fold in two types of CRC. S100A4 was significantly upregulated in LNM CRC compared with non-LNM CRC, which was confirmed by Western blotting, immunohistochemistry and real-time quantitative polymerase chain reaction. Further immunohistochemistry on another 112 CRC cases showed that overexpression of S100A4 frequently existed in LNM CRC compared with non-LNM CRC (P<0.001). Overexpression of S100A4 was significantly associated with LNM (P<0.001), advanced TNM stage (P<0.001), increased 5-year recurrence rate (P<0.001) and decreased 5-year overall survival rate (P<0.001). Univariate and multivariate analyses indicated that S100A4 expression was an independent prognostic factor for recurrence and survival of CRC patients (P<0.05). CONCLUSION: S100A4 might serve as a powerful biomarker for LNM and a prognostic factor in CRC.

[Compression anastomosis ring: a novel technique for colorectal anastomosis].

OBJECTIVE: To evaluate the safety and efficacy of a novel nickel-titanium memory alloy compression anastomosis ring(CAR27) for colorectal anastomosis. METHODS: One sigmoid cancer patient undergone lower anterior resection(LAR) received colorectal anastomosis with CAR27 on November 12, 2009. The following parameters were recorded during 4 weeks postoperative follow-up:colorectal anastomotic complication,first post-operation flatus and bowel movement, extrusion of ring device. RESULTS: The total operation time was 42 minutes, including 11 minutes for colorectal anastomosis. The patient had flatus at the first day and began feeding at the second day postoperatively. The ring was expelled with stool at the 10th day postoperatively. Patient didn't have anastomotic complications such as leakage or obstruction during 1 month postoperative follow-up. CONCLUSION: This case study primarily indicates CAR27 is safe and feasible for colorectal anastomosis.

[Relationship between CpG island methylator phenotype and genetic instability in sporadic colorectal cancer].

OBJECTIVE: To explore the relationship between CpG island methylator phenotype(CIMP) and genetic instability in sporadic colorectal cancer(SCRC). METHODS: Seventy-one SCRC patients were enrolled in this study. Promotor methylation status of five genes including P14(ARF ), hMLH1, P16(INK4a), MGMT and MINT1 was detected with methylation specific PCR to confirm CIMP. Microsatellite instability (MSI) status was evaluated with two microsatellite loci of BAT25 and BAT26, and the ploidy was detected with flow cytometry. The association between CIMP and MSI as well as chromosomal instability(CIN) was examined. RESULTS: The positive rates of CIMP, MSI and aneuploidy were 21.1% (15/71), 9.9% (7/71) and 73.5% (50/68) respectively. The positive rate of MSI in positive CIMP patients was higher than that in negative CIMP ones, but the difference was not significant (20.0% vs 7.1%,P=0.158). The positive rate of MSI was 57.1% in patients with hMLH1 gene promotor hypermethylation, which was significantly higher than that (4.7%) in patients without hMLH1 gene promotor hypermethylation (P=0.001). SCRCs with positive CIMP displayed significant inclination of diploidy (P=0.003). The positive rate of diploidy among SCRCs with CIMP was 61.5% while only 18.2% of cases without CIMP demonstrated diploid. CONCLUSIONS: SCRCs with positive CIMP are significantly more likely to be diploid. Simultaneous multiple genes hypermethylation represented by CIMP may be an epigenetic mechanism competing with the genetic mechanism of CIN.

Predicting prognosis of rectal cancer patients with total mesorectal excision using molecular markers.

AIM: To explore the prognostic variables in rectal cancer patients undergoing curative total mesorectal excision and the effect of postoperative chemotherapy in advanced rectal cancer. METHODS: A total of 259 consecutive rectal cancer patients treated with curative total mesorectal excision between 1999 and 2004 were collected. p53, p21, PCNA, and CD44v6 were examined using immunohistochemistry (IHC). The correlation between clinicopathological or molecular variables and clinical outcomes, including local recurrence, metastasis, disease-free survival and overall survival, was analyzed. RESULTS: The median follow-up was 44 mo. Five-year survival rates and 5-year disease free survival rates were 75.43% and 70.32%, respectively. Multi-analysis revealed TNM staging, preoperative CEA, and CD44v6 level were independent risk factors predicting overall survival or disease free survival. The hazard ratio of peroperative CEA was 2.65 (95% CI 1.4-5) and 3.10 (95% CI 1.37-6.54) for disease free survival and overall survival, respectively. The hazard ratio of CD44v6 was 1.93 (95% CI 1.04-3.61) and 2.21 (95% CI 1.01-4.88) for disease free survival and overall survival, respectively. TNM staging was the only risk factor predicting local recurrence. Postoperative chemotherapy without radiotherapy did not improve patients' outcome. CONCLUSION: TNM staging, preoperative CEA and CD44v6 were independent prognostic factors for rectal cancer patients with total mesorectal excision. Postoperative chemotherapy may be only used together with radiotherapy for rectal cancer patients.

Clinical characteristics and diagnosis of patients with hereditary nonpolyposis colorectal cancer.

AIM: To study the clinical characteristics of hereditary nonpolyposis colorectal cancer (HNPCC) in the Chinese population and discuss the identification and management of the patients with HNPCC. METHODS: A series of 140 patients with colorectal cancers (CRC) and HNPCC associated tumors from 30 families fulfilling the Amsterdam criteria were analyzed. RESULTS: A total of 118 patients had CRC. Average age at diagnosis of the first CRC was 45.7 years, 56.8 % and 23.4 % of the first CRC were located proximal to the splenic flexure and in the rectum respectively. Twenty-three (19.5 %) had synchronous and metachronous CRC. Twenty-seven patients were found to have extracolonic tumors. Gastric carcinoma was the most common tumor type in our series (44.4 %). CONCLUSION: The frequency of HNPCC was 2.6 % in our series of patients. The main features are an excess of early onset with a propensity to involve the proximal colon, and high frequency of multiple foci. Management and surveillance for these patients should be different from sporadic CRC. Contrary to American and European reports, gastric cancer seems more frequent than endometrial cancer in Chinese. It is necessary to formulate a new HNPCC criterion for Chinese patients.