Complement is increased in treatment resistant rectal cancer and modulates radioresistance.

Resistance to neoadjuvant chemoradiation therapy (neo-CRT) is a significant clinical problem in the treatment of locally advanced rectal cancer. Identification of novel therapeutic targets and biomarkers predicting therapeutic response is required to improve patient outcomes. Increasing evidence supports a role for the complement system in resistance to anti-cancer therapy. In this study, increased expression of complement effectors C3 and C5 and increased production of anaphylatoxins, C3a and C5a, was observed in radioresistant rectal cancer cells. Modulation of the central complement effector, C3, was demonstrated to functionally alter the radioresponse, with C3 overexpression significantly enhancing radioresistance, whilst C3 inhibition significantly increased sensitivity to a clinically-relevant dose of radiation. Inhibition of C3 was demonstrated to increase DNA damage and alter cell cycle distribution, mediating a shift towards a radiosensitive cell cycle phenotype suggesting a role for C3 in reprogramming of the tumoural radioresponse. Expression of the complement effectors C3 and C5 was significantly increased in human rectal tumour tissue, as was expression of CFB, a component of the alternative pathway of activation. Elevated levels of C3a and C5b-9 in pre-treatment sera from rectal cancer patients was associated with subsequent poor responses to neo-CRT and poorer survival. Together these data demonstrate a role for complement in the radioresistance of rectal cancer and identify key complement components as potential biomarkers predicting response to neo-CRT and outcome in rectal cancer.

Metformin is a metabolic modulator and radiosensitiser in rectal cancer.

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.

Safe adoption of robotic colorectal surgery using structured training: early Irish experience.

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.