Evaluating predictive pharmacogenetic signatures of adverse events in colorectal cancer patients treated with fluoropyrimidines

The potential clinical utility of genetic markers associated with response to fluoropyrimidine treatment in colorectal cancer patients remains controversial despite extensive study. Our aim was to test the clinical validity of both novel and previously identified markers of adverse events in a broad clinical setting. We have conducted an observational pharmacogenetic study of early adverse events in a cohort study of 254 colorectal cancer patients treated with 5-fluorouracil or capecitabine. Sixteen variants of nine key folate (pharmacodynamic) and drug metabolising (pharmacokinetic) enzymes have been analysed as individual markers and/or signatures of markers. We found a significant association between TYMP S471L (rs11479) and early dose modifications and/or severe adverse events (adjusted OR = 2.02 [1.03; 4.00], p = 0.042, adjusted OR = 2.70 [1.23; 5.92], p = 0.01 respectively). There was also a significant association between these phenotypes and a signature of DPYD mutations (Adjusted OR = 3.96 [1.17; 13.33], p = 0.03, adjusted OR = 6.76 [1.99; 22.96], p = 0.002 respectively). We did not identify any significant associations between the individual candidate pharmacodynamic markers and toxicity. If a predictive test for early adverse events analysed the TYMP and DPYD variants as a signature, the sensitivity would be 45.5 %, with a positive predictive value of just 33.9 % and thus poor clinical validity. Most studies to date have been under-powered to consider multiple pharmacokinetic and pharmacodynamic variants simultaneously but this and similar individualised data sets could be pooled in meta-analyses to resolve uncertainties about the potential clinical utility of these markers

Neutrophil/lymphocyte ratio predicts chemotherapy outcomes in patients with advanced colorectal cancer

BACKGROUND: Advances in the treatment of metastatic colorectal cancer (mCRC) in the last decade have significantly improved survival; however, simple biomarkers to predict response or toxicity have not been identified, which are applicable to all community oncology settings worldwide. The use of inflammatory markers based on differential white-cell counts, such as the neutrophil/ lymphocyte ratio (NLR), may be simple and readily available biomarkers. METHODS: Clinical information and baseline laboratory parameters were available for 349 patients, from two independent cohorts, with unresectable mCRC receiving first-line palliative chemotherapy. Associations between baseline prognostic variables, including inflammatory markers such as the NLR and tumour response, progression and survival were investigated. RESULTS: In the training cohort, combination-agent chemotherapy (P ¼ 0.001) and NLRp5 (P ¼ 0.003) were associated with improved clinical benefit. The ECOG performance status X1 (P ¼ 0.002), NLR45 (P ¼ 0.01), hypoalbuminaemia (P ¼ 0.03) and single-agent chemotherapy (Po0.0001) were associated with increased risk of progression. The ECOG performance status X1 (P ¼ 0.004) and NLR45 (P ¼ 0.002) predicted worse overall survival (OS). The NLR was confirmed to independently predict OS in the validation cohort (Po0.0001). Normalisation of the NLR after one cycle of chemotherapy in a subset of patients resulted in improved progression-free survival (P ¼ 0.012). CONCLUSION: These results have highlighted NLR as a potentially useful clinical biomarker of systemic inflammatory response in predicting clinically meaningful outcomes in two independent cohorts. Results of this study have also confirmed the importance of a chronic systemic inflammatory response influencing clinical outcomes in patients with mCRC

Optimal Placement of STATCOMs Against Short-Term Voltage Instability

Short-term voltage stability is an increasing concern in today's power systems given growing penetration of induction motors. The instability can lead to catastrophic consequences such as cascading failures and/or wide-spread blackouts. STATCOMs are able to provide rapid and dynamic reactive power (VAr) support into the system and therefore improve system's short-term voltage performance following a large disturbance. Importantly, the sizing and locating of the STATCOM integration determine how much the short-term voltage performance can be improved. This chapter presents a novel systematic method for optimal placement of STATCOMs against short-term voltage instability. The problem is formulated as a multi-objective optimization model minimizing two conflicting objectives: (1) total investment cost and (2) expected unacceptable short-term voltage performance subject to a set of probable contingencies. Indices for quantifying short-term voltage stability and the related risk level are proposed for problem modeling. Candidate buses for STATCOM installations are analytically selected based on trajectory sensitivity technique. Load dynamics are fully considered using a composite load model comprising induction motor and other typical components. For the proposed model, rather than a single solution, a set of trade-off solutions called Pareto optimal solutions can be obtained, and the decision-maker may select one from them depending on practical needs. A relatively new and superior multiobjective evolutionary algorithm called multi-objective evolutionary algorithm based on decomposition (MOEA/D) is introduced and employed to find the Pareto optimal solutions to the model. The proposed method is verified on the New England 10-machine 39-bus system using industry-grade simulation tool and system models. Simulation results have validated the effectiveness of the proposed method. The method can be practically applied to provide decision-support for STATCOM installations