Laparoscopic vs open abdominoperineal resection in the multimodality management of low rectal cancers.

AIM: To evaluate the safety and feasibility of laparoscopic abdominoperineal resection compared with the open procedure in multimodality management of rectal cancer. METHODS: A total of 106 rectal cancer patients who underwent open abdominoperineal resection (OAPR) were matched with 106 patients who underwent laparoscopic abdominoperineal resection (LAPR) in a 1 to 1 fashion, between 2009 and 2013 at Fudan University Shanghai Cancer Center. Propensity score matching was carried out based on age, gender, pathological staging of the disease and administration of neoadjuvant chemoradiation. Data regarding preoperative staging, surgical technique, pathological results, postoperative recovery and complications were reviewed and compared between the LAPR and OAPR groups. Perineal closure around the stoma and pelvic floor reconstruction were performed only in OAPR, not in LAPR. Therefore, abdominoperineal resection procedure-specific surgical complications including parastomal hernia and perineal wound complications were compared between the open and laparoscopic procedure. Regular surveillance of the two cohorts was carried out to gather prognostic data. Disease-free survival was analyzed using Kaplan-Meier estimate and log-rank test. Subgroup analysis was performed in patients with locally advanced disease treated with preoperative chemoradiation followed by surgical resection. RESULTS: No significant difference was found between the LAPR group and the OAPR group in terms of clinicopathological features. The operation time (180.8 ± 47.8 min vs 172.1 ± 49.2 min, P = 0.190), operative blood loss (93.9 ± 60.0 mL vs 88.4 ± 55.2 mL, P = 0.494), total number of retrieved lymph nodes (12.9 ± 6.9 vs 12.9 ± 5.4, P = 0.974), surgical complications (12.3% vs 15.1%, P = 0.549) and pathological characteristics were comparable between the LAPR and OAPR group, respectively. Compared with OAPR patients, LAPR patients showed significantly shorter postoperative analgesia (2.4 ± 0.7 d vs 2.7 ± 0.6 d, P < 0.001), earlier first flatus (57.3 ± 7.9 h vs 63.5 ± 9.2 h, P < 0.001), shorter urinary drainage time (6.5 ± 3.4 d vs 7.8 ± 1.3 d, P < 0.001), and shorter postoperative admission (11.2 ± 4.7 d vs 12.6 ± 4.0 d, P = 0.014). With regard to APR-specific complications (perineal wound complications and parastomal hernia), there were no significant differences between the two groups. Similar results were found in the 26 pairs of patients administered neoadjuvant chemoradiation in subgroup analysis. During the follow-up period, no port site recurrences were observed. CONCLUSION: Laparoscopic abdominoperineal resection for multidisciplinary management of rectal cancer is safe, and is associated with earlier recovery and shorter admission time in combination with neoadjuvant chemoradiation.

RNA-seq identifies determinants of oxaliplatin sensitivity in colorectal cancer cell lines.

Oxaliplatin-based chemotherapy, such as FOLFOX, is the first-line therapy for advanced colorectal cancer (CRC) or metastatic CRC patients. However, the partial response of patients to these regimes and the severe peripheral neuropathy toxicity induced by oxaliplatin makes it urgent to figure out biomarkers for oxaliplatin sensitivity to select suitable patients who benefit from these treatments. In present work, 21 CRC cell lines with different sensitivities to oxaliplatin were applied to RNA-seq. The basal expression profiles of these cell lines were correlated to their response to oxaliplatin. Bioinformatics analysis suggested that expression of 58 genes was correlated, negatively or positively, to oxaliplatin response across the 21 CRC cell lines. These 58 genes were mainly enriched in small molecules biochemistry, Wnt/ß-catenin signaling and EMT pathways. The latter two pathways were predicted to be activated in oxaliplatin-resistant CRC cell lines. Moreover, 15 genes were validated by qPCR that their expression levels were actually closely correlated to their response to oxaliplatin, in line with the biocomputation prediction. Taken together, our work might provide potential biomarkers for oxaliplatin sensitivity in CRC cell lines and therapeutic targets for combinational therapy with oxaliplatin.

Laparoscopic segmental colectomy for colonic lymphangiomas: a definitive, minimally invasive surgical option.

Colonic lymphangioma is an unusual benign malformation. We herein describe two cases. A 36-year-old woman was admitted with one year of intermittent abdominal pain; colonoscopy, abdominopelvic computed tomography and endoscopic ultrasonography (EUS) revealed enlarged cystic masses at the ascending colon. In another 40-year-old man, colonoscopy and EUS revealed an asymptomatic lobulated cystic mass with four small sessile polyps at the sigmoid colon. Both patients underwent laparoscopic segmental colectomy. Both masses were histologically confirmed as cystic lymphangiomas, and the patients were discharged without complications. The management of colonic lymphangioma depends on the individual situation; close surveillance or endoscopic therapy may be appropriate for asymptomatic lesions smaller than 2.5 cm in diameter. Surgical intervention can be considered for larger lesions or in patients who develop complication risks. Laparoscopic segmental colon resection may be recommended to excise relatively large submucosal lesions because it is a definitive, minimally invasive intervention with a fast postoperative recovery.

High expression of lncRNA MALAT1 suggests a biomarker of poor prognosis in colorectal cancer.

OBJECTIVE: This study sought to investigate the role of the long noncoding RNA MALAT1 in the prognosis of stage II/III colorectal cancer (CRC) patients. METHODS: The expression of MALAT1 was evaluated in cancer tissues from 146 stage II/III CRC patients undergoing radical resection and 23 paired normal colonic mucosa samples using quantitative real-time reverse transcriptase PCR. Differences in the expression of MALAT1 between 23 CRC and paired normal colonic mucosa samples were analysed with the Wilcoxon test. Relationships between the expression level of MALAT1, patient clinicopathological parameters and disease-free survival (DFS) and overall survival (OS) were analysed using the univariate Kaplan-Meier method and the multivariate COX regression model. RESULTS: The MALAT1 levels in cancerous tissues were 2.26 times higher than those measured in noncancerous tissues, and this difference was statistically significant (P = 0.0004). Based on their expression level of MALAT1, the patients were divided into a high MALAT1 expression group (n = 73) and a low expression group (n = 73). Patients with tumours harbouring higher expression of MALAT1 showed a significantly worse prognosis with a hazard ratio (HR) of 2.863 (95% CI, 1.659 to 4.943; P < 0.001) for DFS and 3.968 (95% CI, 1.665 to 9.456; P = 0.002) for OS. Furthermore, patients with perineural invasion demonstrated significantly worse DFS (HR = 3.459, 95% CI 2.008 to 5.957; P < 0.001) and OS (HR = 3.750, 95% CI 1.743 to 8.069; P = 0.001) than those without perineural invasion. Multivariate analyses indicated that MALAT1 expression and perineural invasion were two independent prognostic risk factors for patients with CRC. CONCLUSION: The expression of MALAT1 is upregulated in CRC tissues, and a higher expression level of MALAT1 might serve as a negative prognostic marker in stage II/III CRC patients.

Silencing of CXCR7 gene represses growth and invasion and induces apoptosis in colorectal cancer through ERK and ß-arrestin pathways.

The CXC chemokine receptor 7 (CXCR7) has been reported to be involved in cell growth, metastasis and apoptosis in certain cancers. However, the function and molecular mechanisms of CXCR7 in human colorectal cancer (CRC) are still undefined. In the present study, sixty-eight cases of CRC tissues and corresponding adjacent non-cancer tissues (ANCT) were collected, and the expression of CXCR7 was assessed using immunohistochemistry (IHC) in biopsy samples. Furthermore, CXCR7 gene was silenced by small hairpin RNA-mediated lentiviral vector (Lv-shCXCR7), by transfection into human CRC cells (SW480 and HT-29). The levels of p-ERK, ß-arrestin, proliferating cell nuclear antigen (PCNA), matrix metallopeptidase-2 (MMP-2) and caspase-3 (CAS-3) were detected by western blotting. Cell proliferative activities and invasive capability were respectively measured by MTT and Transwell assays. Cell apoptosis was analyzed by flow cytometry. The results demonstrated that CXCR7 expression was significantly upregulated in CRC tissues compared with the ANCT (54.4 vs. 36.8%, P=0.041), and correlated with Dukes staging and depth of invasion (P=0.007; P=0.002). Silencing of CXCR7 gene suppressed cell proliferation and invasion, and induced cell apoptosis in CRC cells with decreased expression of p-ERK, ß-arrestin, PCNA and MMP-2 but increased expression of CAS-3. The tumor volumes in the SW480 subcutaneous tumor models treated with Lv-shCXCR7 were significantly smaller than those of the negative control (NC) and PBS groups (P<0.01). In conclusion, our findings indicate that upregulation of CXCR7 expression is associated with tumor invasion, and silencing of the CXCR7 gene represses the development of CRC cells through ERK and ß-arrestin pathways, suggesting that CXCR7 may serve as a potential therapeutic target for the treatment of CRC.

RNA-seq reveals determinants for irinotecan sensitivity/resistance in colorectal cancer cell lines.

Irinotecan is a topoisomerase I inhibitor approved worldwide as a first- and second-line chemotherapy for advanced or recurrent colorectal cancer (CRC). Although irinotecan showed significant survival advantage for patients, a relatively low response rate and severe adverse effects demonstrated the urgent need for biomarkers searching to select the suitable patients who can benefit from irinotecan-based therapy and avoid the adverse effects. In present work, the irinotecan response (IC50 doses) of 20 CRC cell lines were correlated with the basal expression profiles investigated by RNA-seq to figure out genes responsible for irinotecan sensitivity/resistance. Genes negatively or positively correlated to irinotecan sensitivity were given after biocomputation, and 7 (CDC20, CTNNAL1, FZD7, CITED2, ABR, ARHGEF7, and RNMT) of them were validated in two CRC cell lines by quantitative real-time PCR, several of these 7 genes has been proposed to promote cancer cells proliferation and hence may confer CRC cells resistance to irinotecan. Our work might provide potential biomarkers and therapeutic targets for irinotecan sensitivity in CRC cells.

Klotho suppresses growth and invasion of colon cancer cells through inhibition of IGF1R-mediated PI3K/AKT pathway.

Klotho (KL) was originally characterized as an aging suppressor gene, and has been identified as a tumor suppressor gene in a variety of cancers including colon cancer. However, the potential role and molecular events for KL in colon cancer remain unclear. The present study aimed to investigate the expression of KL in human colon cancer by immunohistochemistry, and to analyze the correlation between KL expression and clinicopathological characteristics of patients with colon cancer. Functional analysis after lentivirus-mediated gain of KL expression was used to assess the tumor growth and invasion in colon cancer cells in vitro and in vivo. The rate of KL expression was significantly decreased in cancer tissues compared with that in adjacent non-cancer tissues (ANCT) (60.3 vs.77.9%, P=0.022), and KL expression was negatively associated with Dukes staging (P=0.034) and depth of tumor invasion (P=0.008). Overexpression of KL in vitro inhibited cell proliferative activities and invasive potential in colon cancer cells, companied with decreased expression of p-IGF1R, p-PI3K, p-AKT, PCNA and MMP-2. In addition, the tumor volumes in the HT-29 subcutaneous tumor model treated with lentivirus­mediated KL vector (Lv-KL) was significantly smaller than those of the negative control (NC) group (P<0.01). Taken together, our findings indicate that the expression of KL is downregulated in human colon caner and correlates with tumor invasion and Dukes staging, while overexpression of KL suppresses growth and invasion through inhibition of IGF1R-mediated PI3K/AKT pathway in colon cancer cells, suggesting that KL may serve as a potential therapeutic target for the treatment of colon cancer.

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.

[Study on clinical value of three localization methods in laparoscopic colorectal tumor surgery].

OBJECTIVE: To evaluate the clinical effectiveness of three localization methods, including methylene blue, metal clips and intraoperative colonoscopy in laparoscopic colorectal surgery. METHODS: A retrospective analysis was performed to review the clinical data of 64 patients who underwent the laparoscopic colorectal operations in Cancer Hospital of Fudan University from December 2009 to June 2012. Three methods of tumor localization were used perioperatively, including 23 cases of methylene blue, 20 of metal clips and 21 of colonoscopy. RESULTS: Operations were successfully performed in this cohort and there were no deaths or complications. In methylene blue group, intraoperative colonoscopy was performed in two cases because of the inability to visualize blue dye on the serosal surface of the intestinal wall, another 2 cases were converted to open operation because of methylene blue diffusion and inability to identify resection margin. Intraoperative colonoscopic localization was required for 3 cases of sigmoid colon or upper rectal tumor because of inaccurate tumor localization by metal clips. Poor operative exposure due to obvious bowel distension prompted the conversion to open surgery in 2 cases of colonoscopy localization group, and the accurate position of the lesion was not found in another 2 cases due to long pedunculated adenoma. CONCLUSIONS: Colorectal tumor can be localized effectively by endoscopic methylene blue tattooing at a maximum of 2 tumors before operation and the method of 4-point positioning can significantly improve the accuracy of colorectal tumor localization. Tumor localization preoperatively on the day of surgery by metal clip is accurate for the right or left colon cancer. Intraoperative colonoscopy can localize tumor accurately and rapidly for rectosigmoid or descending tumor, and the incidence of bowel distension can be significantly reduced. Localization method should be considered according to the tumor location and surgical procedure.

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.

[Short to midterm results of endovascular for 105 case of infrarenal abdominal aortic aneurysms].

OBJECTIVE: To assess short to midterm outcome of endovascular aneurysm repair (EVAR) of infrarenal abdominal aortic aneurysms (AAA) in 105 cases. METHODS: Stent-grafts were placed into 105 patients with infrarenal AAA between January 2001 and February 2007. The clinical data of those cases were retrospectively analyzed. RESULTS: Primary technical success rate was 100%. Eighty-two cases (78.09%) were followed-up for 1 to 73 months (mean, 8.9 +/- 5.8 months). Three cases (2.86%) died during peri-operative period, from acute cardiac infarction, multi-organ failure and significant upper gastrointestinal bleeding, respectively. Another one died from hepatic cancer 30 months after EVAR. Twenty-one cases experienced primary endoleak. Eighteen were type I, among which 10 underwent secondary intervention in the form of balloon dilatation (n = 9) and stent-graft placement (n = 1), 8 sealed spontaneously. Two cases were type II and sealed spontaneously. One type III was treated by placing a stent-graft. An emergent femorofemoral crossover was performed for one graft limb thrombosis 2 weeks after EVAR. Four late type I endoleaks occurred. One stent-graft migration without endoleak was cured conservatively. Two stent-graft infections occurred 1 month and 3 months after EVAR respectively, and were cured with debridement, drainage and antibiotics. Nine femorofemoral or iliofemoral bypass and three internal iliac bypasses were all patent during the follow-up period. CONCLUSION: Endovascular repair is a safe and effective method for infrarenal AAA with perfect short to midterm outcomes.

[Endovascular repair of descending thoracic aortic aneurysm: preliminary experience].

OBJECTIVE: To report an initial experience with the endovascular repair of descending thoracic aortic aneurysm (DTAA). METHODS: Endoprostheses were placed into 41 patients with DTAA between January 2001 and July 2007 which were retrospectively analyzed. The preliminary right-left carotid and left carotid-subclavian bypass was performed in 4 cases in which the distances from the proximal aneurysm to the origin of the left common carotid artery were no longer than 15 mm. EVAR was conducted 1 week after the bypass or immediately. RESULTS: All stent grafts were deployed in proper position. There were two deaths (4.9%) during perioperative period, resulting from multiorgan failure and acute cardiac infarction, respectively. Eighteen endoleaks occurred immediately after EVAR (43.9%), four disappeared after balloon dilatation. There were two acute renal insufficiencies (4.9%), one requiring hemodialysis for more than 30 days. Follow-up, which ranged from 1 to 60 months [median, (18.6 +/- 4.2) months] was carried out in 26 patients (63.4%). Type-I endoleak and type-III endoleak were detected in two patients in 4 years and 2 years after EVAR, might because of migration, and were corrected using another stent-graft each. Two patients died of other diseases during follow-up. Complete thrombosis of the thoracic aneurysm sac with no late migration or endoleaks was revealed on CT at 3 months postoperatively in the remaining patients. The decrease in maximal aneurysm diameter was 0-22 mm [median, (8.3 +/- 4.5) mm] and the prosthetic vascular grafts in four patients with preliminary carotid subclavian bypass surgery were patent during the follow-up period. CONCLUSIONS: The treatment of descending thoracic aortic aneurysm with an endovascular approach is feasible with less trauma, quick recovery and less complications. It may offer the best means of therapy for high risk patients.