Systems biology analysis identifies molecular determinants of chemotherapy-induced diarrhoea.

Chemotherapy-induced diarrhoea (CID) is a common dose-limiting adverse event in patients with cancer. Here, we hypothesise that chemotherapy evokes apoptosis in normal gut epithelium, contributes to CID and that patients with increased risk of CID can be identified using a systems model of BCL-2 protein interactions (DR_MOMP) that calculates the sensitivity of cells to undergo apoptosis. Normal adjacent gut epithelium tissue was collected during resection surgery from a cohort of 35 patients with stage II-III colorectal cancer (CRC) who were subsequently treated with capecitabine, XELOX or FOLFOX. Clinical follow-up, type and grade of adverse events during adjuvant chemotherapy were recorded. The level of five BCL-2 proteins required for the calculation of the DR_MOMP score was quantified together with 62 additional signalling proteins related to apoptotic pathways. Odds ratios for the occurrence of diarrhoea were determined using multinomial logistic regression (MLR). Patients treated with capecitabine who had a DR_MOMP score equal or higher than the mean had a significantly lower frequency of diarrhoea significantly compared to patients below the mean. High DR_MOMP scores indicate high apoptosis resistance. No statistical difference was observed in patients treated with XELOX or FOLFOX. Using MLR, we found that levels of apoptosis-related proteins caspase-8, p53 and XIAP statistically interacted with the DR_MOMP stress dose. Markers of MAPK signalling were prognostic for diarrhoea independently of DR_MOMP. In conclusion, apoptosis sensitivity and MAPK signalling status of the adjacent normal gut epithelium of chemotherapy-naïve patients represent promising biomarkers to identify patients with CRC with increased risk of CID.

Incidence, risks and outcome of radiological leak following early contrast enema after anterior resection.

INTRODUCTION: Anastomotic leak (AL) is a major complication following anterior resection for colorectal cancer. Early contrast enema may diagnose subclinical anastomotic leakage. Knowledge of factors concerning AL is vital to its detection. The aim of this study was to define the incidence, risks and outcome of radiological leak following routine early contrast enema after anterior resection. METHODS: A cohort of 129 patients who underwent anterior resection for colorectal cancer and had an early Gastrografin enema between July 2008 and December 2012 in a tertiary referral centre was identified from a prospective database. The severity of AL was defined using the International Study Group of Rectal Cancer (ISREC) grading system. RESULTS: Of the 129 patients, 65.1 % were male, and the mean age at surgery was 64.6 ± 1.1 years. Gastrografin enema was performed on average on post-operative day 4.8 ± 0.2. Eighteen patients (14.0 %) had a radiological leak on Gastrografin enema, and nine patients (7.0 %) had a clinical AL. On multivariate analysis, only being of male sex and having a loop ileostomy increased the risk of radiological AL. Gastrografin enema had a sensitivity of 100 % (95 % CI 66-100 %) and specificity of 93 % (95 % CI 86-97 %) for predicting clinical AL. Of the 18 patients with radiological leaks, 11 were ISREC grade A, 3 were grade B and 4 were grade C. CONCLUSIONS: In the current series, early Gastrografin enema following anterior resection identifies a 14 % radiological leak rate and has a high sensitivity and specificity for predicting clinical AL. The majority of radiological leaks may be managed conservatively.

Early outcomes for rectal cancer surgery in the republic of ireland following a national centralization program.

BACKGROUND: Following a national audit of rectal cancer management in 2007, a national centralization program in the Republic of Ireland was initiated. In 2010, a prospective evaluation of rectal cancer treatment and early outcomes was conducted. METHODS: A total of 29 colorectal surgeons in 14 centers prospectively collated data on all patients with rectal cancer who underwent curative surgery in 2010. RESULTS: Data were available on 447 patients who underwent proctectomy with curative intent for rectal cancer in 2010; 23.7 % of patients underwent abdominoperineal excision. The median number of lymph nodes identified was 12. The 30-day mortality rate was 1.1 %. Compared with 2007, there was a reduction in positive circumferential margin rate (15.8 vs 4.5 %, P < 0.001), clinical anastomotic leak rate (10.8 vs 4.3 %, P = 0.002), and postoperative radiotherapy use (17.8 vs 4.0 %, P < 0.001). Also, 53.9 % received preoperative radiotherapy in 2010. Four centers gave statistically more patients (high-administration), and four centers gave fewer patients (low-administration) preoperative radiotherapy for T2/T3 tumors (P < 0.05). On multivariate analysis, being treated in a "high-administration center" increased the likelihood (likelihood ratio [LR], 2.9; 95 % CI 1.7-4.8; P < 0.001) while attending a "low-administration center" (LR, 0.3; 95 % CI 0.2-0.5; P < 0.001) reduced the likelihood of receiving preoperative radiotherapy for a T2/T3 rectal cancer. CONCLUSIONS: Patients undergoing rectal cancer surgery in hospitals following a national centralization initiative received high-quality surgery. Significant heterogeneity exists in radiotherapy administration, and evidence-based guidelines should be developed and implemented.

Clinical application of a systems model of apoptosis execution for the prediction of colorectal cancer therapy responses and personalisation of therapy.

OBJECTIVE: Key to the clinical management of colorectal cancer is identifying tools which aid in assessing patient prognosis and determining more effective and personalised treatment strategies. We evaluated whether an experimental systems biology strategy which analyses the susceptibility of cancer cells to undergo caspase activation can be exploited to predict patient responses to 5-fluorouracil-based chemotherapy and to case-specifically identify potential alternative targeted treatments to reactivate apoptosis. DESIGN: We quantified five essential apoptosis-regulating proteins (Pro-Caspases 3 and 9, APAF-1, SMAC and XIAP) in samples of Stage II (n = 13) and III (n=17) tumour and normal colonic (n = 8) tissue using absolute quantitative immunoblotting and employed systems simulations of apoptosis signalling to predict the susceptibility of tumour cells to execute apoptosis. Additional systems analyses assessed the efficacy of novel apoptosis-inducing therapeutics such as XIAP antagonists, proteasome inhibitors and Pro-Caspase-3-activating compounds in restoring apoptosis execution in apoptosis-incompetent tumours. RESULTS: Comparisons of caspase activity profiles demonstrated that the likelihood of colorectal tumours to undergo apoptosis decreases with advancing disease stage. Systems-level analysis correctly predicted positive or negative outcome in 85% (p=0.004) of colorectal cancer patients receiving 5-fluorouracil based chemotherapy and significantly outperformed common uni- and multi-variate statistical approaches. Modelling of individual patient responses to novel apoptosis-inducing therapeutics revealed markedly different inter-individual responses. CONCLUSIONS: Our study represents the first proof-of-concept example demonstrating the significant clinical potential of systems biology-based approaches for predicting patient outcome and responsiveness to novel targeted treatment paradigms.

The effects of low-frequency endo-anal electrical stimulation on faecal incontinence: a prospective study.

BACKGROUND AND AIMS: Faecal incontinence is a distressing problem that is often not amenable to surgical correction. Chronic low-frequency electrical stimulation of damaged axons is thought to reduce synaptic resistance, increase the size of motor units by axonal sprouting and increase the rate of conduction of the pudendal nerve. The aim of this study was to prospectively evaluate the effect of chronic low-frequency endo-anal electrical stimulation on faecal incontinence using a home-based unit and hospital-supervised therapy. MATERIALS AND METHODS: Forty-eight patients with faecal incontinence completed a prospective randomised trial. Patients were allocated randomly to one of two groups; group 1 was exposed to endo-anal pudendal nerve stimulation daily at home with a portable home unit, group 2 attended the physiotherapy department for endo-anal electrical stimulation under supervision. RESULTS: Continence scores improved significantly after treatment in both groups (p<0.001). Both groups showed improved manometric scores, although only group 1 showed significant improvement in both resting and squeeze pressures (mean total resting pressure 184-224 mmHg, p<0.001; mean total squeeze pressure 253-337 mmHg, p<0.001). This was also reflected by an improvement in quality of life in both groups. CONCLUSIONS: Low-frequency endo-anal electrical stimulation significantly improves continence scores and quality of life in patients with faecal incontinence not amenable to surgical correction. It leads to improved manometric values when carried out on a daily basis with a portable home unit.