Optimisation of pharmacy content in clinical cancer research protocols: Experience of the United Kingdom Chemotherapy and Pharmacy Advisory Service

Background: Clarity and accuracy of the pharmacy aspects of cancer clinical trial protocols is essential. Inconsistencies and ambiguities in such protocols have the potential to delay research and jeopardise both patient safety and collection of credible data. The Chemotherapy and Pharmacy Advisory Service was established by the UK National Cancer Research Network, currently known as National Institute for Health Research Clinical Research Network, to improve the quality of pharmacy-related content in cancer clinical research protocols. This article reports the scope of Chemotherapy and Pharmacy Advisory Service, its methodology of mandated protocol review and pharmacy-related guidance initiatives and its current impact. Methods: Over a 6-year period (2008–2013) since the inception of Chemotherapy and Pharmacy Advisory Service, cancer clinical trial protocols were reviewed by the service, prior to implementation at clinical trial sites. A customised Review Checklist was developed and used by a panel of experts to standardise the review process and report back queries and inconsistencies to chief investigators. Based on common queries, a Standard Protocol Template comprising specific guidance on drug-related content and a Pharmacy Manual Template were developed. In addition, a guidance framework was established to address ‘ad hoc’ pharmacy-related queries. The most common remarks made at protocol review have been summarised and categorised through retrospective analysis. In order to evaluate the impact of the service, chief investigators were asked to respond to queries made at protocol review and make appropriate changes to their protocols. Responses from chief investigators have been collated and acceptance rates determined. Results: A total of 176 protocols were reviewed. The median number of remarks per protocol was 26, of which 20 were deemed clinically relevant and mainly concerned the drug regimen, support medication, frequency and type of monitoring and drug supply aspects. Further analysis revealed that 62% of chief investigators responded to the review. All responses were positive with an overall acceptance rate of 89% of the proposed protocol changes. Conclusion: Review of pharmacy content of cancer clinical trial protocols is feasible and exposes many undetected clinically relevant issues that could hinder efficient trial conduct. Our service audit revealed that the majority of suggestions were effectively incorporated in the final protocols. The refinement of existing and development of new pharmacy-related guidance documents by Chemotherapy and Pharmacy Advisory Service might aid in better and safer clinical research

Oxaliplatin-induced coronary artery spasm: first report of an important side-effect

A 67-year-old woman with metastatic colorectal cancer was given her first oxaliplatin infusion as part of the XELOX protocol. She developed chest pain with ECG changes leading subsequently to a diagnosis of coronary artery spasm. To our knowledge, this is the first report of oxaliplatin-induced coronary artery spasm

Quantification of metabolites by NMR spectroscopy in the presence of protein

The high reliability of NMR spectroscopy makes it an ideal tool for large-scale metabolomic studies. However, the complexity of biofluids and, in particular, the presence of macromolecules poses a significant challenge. Ultrafiltration and protein precipitation are established means of deproteinization and recovery of free or total metabolite content, but neither is ever complete. In addition, aside from cost and labor, all deproteinization methods constitute an additional source of experimental variation. The Carr-Purcell-Meiboom-Gill (CPMG) echo-train acquisition of NMR spectra obviates the need for prior deproteinization by attenuating signals from macromolecules, but concentration values of metabolites measured in blood plasma will not necessarily reflect total or free metabolite content. Here, in contrast to approaches that propose the determination of individual T1 and T2 relaxation times for the computation of correction factors, we demonstrate their determination by spike-in experiments with known amounts of metabolites in pooled samples of the matrix of interest to facilitate the measurement of total metabolite content. Provided that the protein content does not vary too much among individual samples, accurate quantitation of metabolites is feasible. Moreover, samples with significantly deviating protein content may be readily recognized by inclusion of a standard that shows moderate protein binding. It is also shown that urinary proteins when present in high concentrations may effect detection of common urinary metabolites prone to strong protein binding such as tryptophan

Outcome of advanced lung cancer with central airway obstruction versus without central airway obstruction

Patients with central airway obstruction (CAO) from advanced lung cancer present with significant morbidity and are assumed to have lower survival. Hence, they are offered only palliative support. We asked if patients who have advanced lung cancer with CAO (recanalised and treated) will behave similarly to those with advanced lung cancer without CAO. This study was a retrospective review of the medical records of the patients managed for advanced lung cancer during 2010 and 2015 at our institution. 85 patients were studied. Median survival and 1-, 2- and 5-year survival were 5.8 months, 30.3%, 11.7% and 2.3% versus 9.3 months, 35.7%, 9.6% and 4.7%, respectively, in the CAO and no CAO groups (p=0.30). More patients presented with respiratory failure (15 (35%) versus none; p=0.0001) and required assisted mechanical ventilation (10 (23.3%) versus none; p=0.001) in the CAO group compared with the no CAO group. Fewer patients received chemotherapy in the CAO group (11 (25.5%)) compared with the no CAO group (23 (54.7%); p=0.008). There was no difference in survival among patients with advanced lung cancer whether they presented with CAO or without CAO. Survival was similar to those without CAO in patients with recanalised CAO despite greater morbidity and lesser use of chemotherapy, strongly advocating bronchoscopic recanalisation of CAO. These findings dispel the nihilism associated with such cases

Lung Cancer in Singapore

10.1016/j.jtho.2020.11.020JOURNAL OF THORACIC ONCOLOGY166906-91

Machine learning unveils an immune-related DNA methylation profile in germline DNA from breast cancer patients

Abstract Background There is an unmet need for precise biomarkers for early non-invasive breast cancer detection. Here, we aimed to identify blood-based DNA methylation biomarkers that are associated with breast cancer. Methods DNA methylation profiling was performed for 524 Asian Chinese individuals, comprising 256 breast cancer patients and 268 age-matched healthy controls, using the Infinium MethylationEPIC array. Feature selection was applied to 649,688 CpG sites in the training set. Predictive models were built by training three machine learning models, with performance evaluated on an independent test set. Enrichment analysis to identify transcription factors binding to regions associated with the selected CpG sites and pathway analysis for genes located nearby were conducted. Results A methylation profile comprising 51 CpGs was identified that effectively distinguishes breast cancer patients from healthy controls achieving an AUC of 0.823 on an independent test set. Notably, it outperformed all four previously reported breast cancer-associated methylation profiles. Enrichment analysis revealed enrichment of genomic loci associated with the binding of immune modulating AP-1 transcription factors, while pathway analysis of nearby genes showed an overrepresentation of immune-related pathways. Conclusion This study has identified a breast cancer-associated methylation profile that is immune-related to potential for early cancer detection