Optimal management of malignant left-sided large bowel obstruction: do international guidelines agree?

Background: Approximately 20% of patients diagnosed with colorectal cancer will present with left-sided large bowel obstruction. The optimal management of this cohort of patients remains unclear. We aimed to review international guidelines to see if there was a consensus on the treatment of this surgical emergency. Methods: The PubMed and Medline databases were searched for guidelines on the management of left-sided, malignant large bowel obstruction (MBO) between 2010 and 2018. Results: Nineteen guidelines were identified spanning a range of continents. There was no clear consensus on the management of potentially resectable disease. Eight guidelines (42%) suggested primary surgery, two guidelines (11%) suggested stenting as a bridge to surgery and nine guidelines (47%) suggested surgery or stenting could be performed. Primary resection with or without anastomosis was the most frequently recommended procedure (n = 6 35%), but over a third of guidelines gave no operative recommendations. There was very limited detail on the stenting procedure and how long elective surgery should be deferred. In the palliative situation, there was general agreement that stents should be offered in preference to surgery. Conclusion: International guidelines offer limited and contrasting recommendations on the management of left-sided MBO. There is a lack of high-quality evidence to support whether emergency surgery or stenting as a bridge to surgery is the optimal procedure in terms of morbidity, mortality and long-term oncological outcome.

AZD1775 induces toxicity through double-stranded DNA breaks independently of chemotherapeutic agents in p53-mutated colorectal cancer cells.

AZD1775 is a small molecule WEE1 inhibitor used in combination with DNA-damaging agents to cause premature mitosis and cell death in p53-mutated cancer cells. Here we sought to determine the mechanism of action of AZD1775 in combination with chemotherapeutic agents in light of recent findings that AZD1775 can cause double-stranded DNA (DS-DNA) breaks. AZD1775 significantly improved the cytotoxicity of 5-FU in a p53-mutated colorectal cancer cell line (HT29 cells), decreasing the IC50 from 9.3 µM to 3.5 µM. Flow cytometry showed a significant increase in the mitotic marker pHH3 (3.4% vs. 56.2%) and DS-DNA break marker γH2AX (5.1% vs. 50.7%) for combination therapy compared with 5-FU alone. Combination therapy also increased the amount of caspase-3 dependent apoptosis compared with 5-FU alone (4% vs. 13%). The addition of exogenous nucleosides to combination therapy significantly rescued the increased DS-DNA breaks and caspase-3 dependent apoptosis almost to the levels of 5-FU monotherapy. In conclusion, AZD1775 enhances 5-FU cytotoxicity through increased DS-DNA breaks, not premature mitosis, in p53-mutated colorectal cancer cells. This finding is important for designers of future clinical trials when considering the optimal timing and duration of AZD1775 treatment.