BackgroundBRAF mutation has been investigated as a prognostic factor in metastatic colorectal cancer (mCRC) undergoing anti-EGFR monoclonal antibodies (moAbs), but current results are still inconclusive. The aim of this meta-analysis was to evaluate the relationship between BRAF mutation status and the prognosis of mCRC patients treated with moAbs.MethodsEligible studies were identified by systematically searching Pubmed, the Cochrane Library, Web of Knowledge, and OVID. Risk ratio (RR) for overall response rate (ORR), Hazard ratios (HRs) for Progression free survival (PFS) and Overall survival (OS) were extracted or calculated. Prespecified subgroup analyses were conducted in KRAS wild-type and in different study types. The source of between-trial variation was explored by sensitivity analyses. Quality assessment was conducted by the Hayden’s criteria.ResultsA total of twenty one trials including 5229 patients were identified for the meta-analysis. 343 patients displayed BRAF mutations of 4616 (7.4%) patients with known BRAF status. Patients with BRAF wild-type (WT) showed decreased risks of progression and death with an improved PFS(HR 0.38, 95% confidence intervals 0.29–0.51) and an improved OS (HR 0.35 [0.29–0.42]), compared to BRAF mutant. In KRAS WT population, there were even larger PFS benefit (HR 0.29[0.19,0.43]) and larger OS benefit (HR 0.26 [0.20,0.35]) in BRAF WT. A response benefit for BRAF WT was observed (RR 0.31[0.18,0.53]) in KRAS WT patients, but not observed in unselected patients (RR 0.76 [0.43–1.33]). The results were consistent in the subgroup analysis of different study types. Heterogeneity between trials decreased in the subgroup and explained by sensitivity analysis. No publication bias of ORR, PFS and OS were detected.ConclusionsThe results indicate that BRAF mutant is a predictive biomarker for poor prognosis in mCRC patients undergoing anti-EGFR MoAbs therapy, especially in KRAS WT patients. Additional large prospective trials are required to confirm the predictive role of BRAF status.

Preoperative radiotherapy increases the risk of anastomotic leakage and stenosis after rectal cancer resection. Clinical leakage independently contributes to the development of stenosis.

Bowel function deteriorates frequently after low anterior resection for rectal cancer. Severe bowel dysfunction is significantly associated with preoperative long-course radiotherapy and a lower-third tumor, and the thickening of rectal wall after radiation is a strong predictor. Treatment decisions and patient consent should be implemented with raising awareness of bowel symptom burdens. See Video Abstract at http://links.lww.com/DCR/A317.

Human antigen R (HuR) is an RNA-binding protein that posttranscriptionally regulates many cancer-trait genes. CDC6, a central regulator of DNA replication, is regulated by HuR. In this study, we investigated the role of HuR in colorectal cancer tumorigenesis and oxaliplatin (L-OHP) resistance, as well as the underlying mechanisms involving CDC6. We detected increased HuR and CDC6 expression, along with a positive correlation between the two in human colorectal cancer tissues. HuR overexpression increased colorectal cancer cell proliferation in vitro and xenograft tumor growth in vivo, and induced resistance to L-OHP. In contrast, HuR knockdown sensitized colorectal cancer cells to L-OHP. CDC6 over-expression increased while CDC6 knockdown decreased colorectal cancer cell malignant behaviors (growth, DNA synthesis, EMT, migration, and invasion) and L-OHP resistance in vitro. Moreover, L-OHP resistance induced by HuR overexpression was reversed by CDC6 knockdown. Mechanistically, the results from our luciferase reporter and ribonucleoprotein immunoprecipitation assays indicated that HuR upregulates CDC6 by binding to CDC6 3 0 -UTR. Taken together, our findings identified HuR's regulation of CDC6 as an essential mechanism driving colorectal cancer tumorigenesis and L-OHP resistance, and this mechanism may represent a potential target for overcoming drug resistance in colorectal cancer.

5-fluorouracil (5-FU)-based chemotherapy is the main chemotherapeutic approach for colorectal cancer (CRC) treatment. Because chemoresistance occurs frequently and significantly limits CRC therapies, a novel agent is needed. Pseudolaric acid B (PAB), a small molecule derived from the Chinese medicinal herb ''Tujinpi'', exhibits strong cytotoxic effects on a variety of cancers. However, the detailed mechanisms by which PAB inhibits CRC cell growth and its potential role in overcoming 5-FU resistance have not been well studied. In this study, we showed that PAB significantly inhibited the viability of various CRC cell lines but induced minor cytotoxicity in normal cells. Both the in vitro and in vivo results showed that PAB induced proliferation inhibition, mitotic arrest and subsequently caspase-dependent apoptosis in both 5-FU-sensitive and -resistant CRC cells. Moreover, PAB was shown to interfere with CRC cell mitotic spindle apparatus and activate the spindle assembly checkpoint. Finally, CDK1 activity was involved in PAB-induced mitotic arrest and apoptosis in CRC cells. Taken together, these data reveal that PAB induces CRC cell mitotic arrest followed by apoptosis and overcomes 5-FU resistance in vitro and in vivo, suggesting that PAB may be a potential agent for CRC treatment, particularly for 5-FU-resistant CRC.