ABSTRACT
Resistance to neoadjuvant chemoradiation therapy, is a major challenge in the management of rectal cancer. Increasing evidence supports a role for altered energy metabolism in the resistance of tumours to anti-cancer therapy, suggesting that targeting tumour metabolism may have potential as a novel therapeutic strategy to boost treatment response. In this study, the impact of metformin on the radiosensitivity of colorectal cancer cells, and the potential mechanisms of action of metformin-mediated radiosensitisation were investigated. Metformin treatment was demonstrated to significantly radiosensitise both radiosensitive and radioresistant colorectal cancer cells in vitro. Transcriptomic and functional analysis demonstrated metformin-mediated alterations to energy metabolism, mitochondrial function, cell cycle distribution and progression, cell death and antioxidant levels in colorectal cancer cells. Using ex vivo models, metformin treatment significantly inhibited oxidative phosphorylation and glycolysis in treatment naïve rectal cancer biopsies, without affecting the real-time metabolic profile of non-cancer rectal tissue. Importantly, metformin treatment differentially altered the protein secretome of rectal cancer tissue when compared to non-cancer rectal tissue. Together these data highlight the potential utility of metformin as an anti-metabolic radiosensitiser in rectal cancer.
ABSTRACT
Robotic surgery enhances the precision of minimally invasive surgery through improved three-dimensional views and articulated instruments. There has been increasing interest in adopting this technology to colorectal surgery and this has recently been introduced to the Irish health system. This paper gives an account of our early institutional experience with adoption of robotic colorectal surgery using structured training. Analysis was conducted of a prospectively maintained database of our first 55 consecutive robotic colorectal cases, performed by four colorectal surgeons, each at the beginning of his robotic surgery experience, using the Da Vinci Si® system and undergoing training as per the European Academy of Robotic Colorectal Surgery (EARCS) programme. Overall surgical and oncological outcomes were interrogated. Fifty-five patients underwent robotic surgery between January 2017 and January 2018, M:F 34:21, median age (range) 60 (35-87) years. Thirty-three patients had colorectal cancer and 22 had benign pathologies. Eleven rectal cancer patients had neoadjuvant chemoradiotherapy. BMI was > 30 in 21.8% of patients and 56.4% of patients had previous abdominal surgery. Operative procedures performed were low anterior resection (n = 19), sigmoid colectomy (n = 9), right colectomy (n = 22), ventral mesh rectopexy (n = 3), abdominoperineal resection (n = 1) and reversal of Hartmann's procedure (n = 1). Median blood loss was 40 ml (range 0-400). Mean operative time (minutes) was 233 (SD 79) for right colectomy and 368 (SD 105) for anterior resection. Median length of hospital stay was 6 days (IQR 5-7). There was no 30-day mortality, intraoperative complications, conversion to laparoscopic or open, or anastomotic leakage. Median lymph nodes harvest was 15 in non-neoadjuvant cases (range 7-23) and 8 in neoadjuvant cases (2-14). Our early results demonstrate that colorectal robotic surgery can be adopted safely for both benign and neoplastic conditions using a structured training programme without compromising clinical or oncological outcomes. The early learning curve can be time intensive.
