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.

Acceptance and Commitment Therapy Reduces Psychological Stress in Patients With Inflammatory Bowel Diseases.

BACKGROUND & AIMS: Patients with Crohn's disease or ulcerative colitis have relatively high levels of stress and psychological dysfunction. Acceptance and commitment therapy (ACT) is a psychological intervention that comprises acceptance and mindfulness procedures, along with commitment and behavior change strategies, to increase psychological flexibility and reduce stress. We performed a randomized controlled trial to investigate the effect of ACT on stress in patients with inflammatory bowel diseases (IBD). METHODS: A total of 122 patients with quiescent or stable, mildly active IBD were randomly assigned to an 8-week ACT program or treatment as usual (control group). Clinical, demographic, disease activity, and psychological data and blood and feces were collected at baseline and at 8 weeks and 3 months after the intervention (week 20). Scalp hair was collected at baseline and week 20 for measurement of steroid concentrations. The primary endpoint was change in stress symptoms, assessed with the Depression Anxiety Stress Scale. Secondary endpoints included changes in perceived stress, anxiety, depression, quality-of-life domains, disease activity, and cortisol concentration in hair. RESULTS: Overall, 79 participants were included in the complete case intention-to-treat analysis. There were 39% and 45% reductions in stress in the treatment group from baseline to 8 and 20 weeks, respectively, compared with 8% and 11% in the control group (group × time interaction, P = .001). ACT was associated with reduced perceived stress (P = .036) and depression (P = .010), but not anxiety (P = .388), compared with control individuals. In the intention-to-treat analysis, changes in all 4 quality-of-life domains over time were similar in the ACT and control groups. In the per-protocol analysis, the overall well-being quality-of-life domain improved in the ACT group compared with the control group (P = .009). Subjective and objective disease activity measurements were similar between groups over the study period (all P values >.05). Hair cortisol concentrations correlated with stress (rs = 0.205, P = .050) and anxiety (rs = 0.208, P = .046) at baseline but did not change significantly in the ACT group over the study period compared with the control group (P = .831). CONCLUSION: In a randomized controlled trial of patients with IBD, an 8-week ACT therapy course improved stress and other indices of psychological health.ClinicalTrials.gov Identifier: NCT02350920.

Targeting EGFR in metastatic colorectal cancer beyond the limitations of KRAS status: alternative biomarkers and therapeutic strategies.

Patients with metastatic colorectal cancer have a very poor prognosis. Incorporation of targeted molecular therapies, such as the anti-EGFR receptor monoclonal antibodies cetuximab and panitumumab, into treatment regimens has improved outcomes for patients with wild-type RAS tumors. Yet, response rates remain low and overall survival times are short. Increased understanding of oncogenic signaling pathways within the tumor, and how these are regulated by the inflammatory tumor microenvironment, is a priority to facilitate the development of biomarkers to better guide the use of existing therapies and to develop new ones. Here, we review recent preclinical and clinical progress in the development of biomarkers for predicting response to anti-EGFR therapy in metastatic colorectal cancer.