Analytical validation and clinical utilization of K-4CARE™: a comprehensive genomic profiling assay with personalized MRD detection.

Background: Biomarker testing has gradually become standard of care in precision oncology to help physicians select optimal treatment for patients. Compared to single-gene or small gene panel testing, comprehensive genomic profiling (CGP) has emerged as a more time- and tissue-efficient method. This study demonstrated in-depth analytical validation of K-4CARE, a CGP assay that integrates circulating tumor DNA (ctDNA) tracking for residual cancer surveillance. Methods: The assay utilized a panel of 473 cancer-relevant genes with a total length of 1.7 Mb. Reference standards were used to evaluate limit of detection (LOD), concordance, sensitivity, specificity and precision of the assay to detect single nucleotide variants (SNVs), small insertion/deletions (Indels), gene amplification and fusion, microsatellite instability (MSI) and tumor mutational burden (TMB). The assay was then benchmarked against orthogonal methods using 155 clinical samples from 10 cancer types. In selected cancers, top tumor-derived somatic mutations, as ranked by our proprietary algorithm, were used to detect ctDNA in the plasma. Results: For detection of somatic SNVs and Indels, gene fusion and amplification, the assay had sensitivity of >99%, 94% and >99% respectively, and specificity of >99%. Detection of germline variants also achieved sensitivity and specificity of >99%. For TMB measurement, the correlation coefficient between whole-exome sequencing and our targeted panel was 97%. MSI analysis when benchmarked against polymerase chain reaction method showed sensitivity of 94% and specificity of >99%. The concordance between our assay and the TruSight Oncology 500 assay for detection of somatic variants, TMB and MSI measurement was 100%, 89%, and 98% respectively. When CGP-informed mutations were used to personalize ctDNA tracking, the detection rate of ctDNA in liquid biopsy was 79%, and clinical utility in cancer surveillance was demonstrated in 2 case studies. Conclusion: K-4CARE™ assay provides comprehensive and reliable genomic information that fulfills all guideline-based biomarker testing for both targeted therapy and immunotherapy. Integration of ctDNA tracking helps clinicians to further monitor treatment response and ultimately provide well-rounded care to cancer patients.

Implementation of C-reactive protein point of care testing to improve antibiotic targeting in respiratory illness in Vietnamese primary care (ICAT): a study protocol for a cluster randomised controlled trial.

INTRODUCTION: C-reactive protein (CRP), a biomarker of infection, has been used widely in high-income settings to guide antibiotic treatment in patients presenting with respiratory illnesses in primary care. Recent trials in low- and middle-income countries showed that CRP testing could safely reduce antibiotic use in patients with non-severe acute respiratory infections (ARIs) and fever in primary care. The studies, however, were conducted in a research-oriented context, with research staff closely monitoring healthcare behaviour thus potentially influencing healthcare workers' prescribing practices. For policy-makers to consider wide-scale roll-out, a pragmatic implementation study of the impact of CRP point of care (POC) testing in routine care is needed. METHODS AND ANALYSIS: A pragmatic, cluster-randomised controlled trial, with two study arms, consisting of 24 commune health centres (CHC) in the intervention arm (provision of CRP tests with additional healthcare worker guidance) and 24 facilities acting as controls (routine care). Comparison between the treatment arms will be through logistic regression, with the treatment assignment as a fixed effect, and the CHC as a random effect. With 48 clusters, an average of 10 consultations per facility per week will result in approximately 520 over 1 year, and 24 960 in total (12 480 per arm). We will be able to detect a reduction of 12% to 23% or more in immediate antibiotic prescription as a result of the CRP POC intervention. The primary endpoint is the proportion of patient consultations for ARI resulting in immediate antibiotic prescription. Secondary endpoints include the proportion of all patients receiving an antibiotic prescription regardless of ARI diagnosis, frequency of re-consultation, subsequent antibiotic use when antibiotics are not prescribed, referral and hospitalisation. ETHICS AND DISSEMINATION: The study protocol was approved by the Oxford University Tropical Research Ethics Committee (OxTREC, Reference: 53-18), and the ethical committee of the National Hospital for Tropical Diseases in Vietnam (Reference:07/HDDD-NDTW/2019). Results from this study will be disseminated via meetings with stakeholders, conferences and publications in peer-reviewed journals. Authorship and reporting of this work will follow international guidelines. TRIAL REGISTRATION DETAILS: NCT03855215; Pre-results.

Factors influencing choices of empirical antibiotic treatment for bacterial infections in a scenario-based survey in Vietnam.

BACKGROUND: Antimicrobial stewardship (AMS) programmes have been implemented around the world to guide rational use of antibiotics but implementation is challenging, particularly in low- and middle-income countries, including Vietnam. Understanding factors influencing doctors' prescribing choices for empirical treatment can help design AMS interventions in these settings. OBJECTIVES: To understand doctors' choices of antibiotics for empirical treatment of common bacterial infections and the factors influencing decision-making. METHODS: We conducted a cross-sectional survey among medical professionals applying for a postgraduate programme at Hanoi Medical University, Vietnam. We used a published survey developed for internal medicine doctors in Canada. The survey was self-administered and included four clinical scenarios: (i) severe undifferentiated sepsis; (ii) mild undifferentiated sepsis; (iii) severe genitourinary infection; and (iv) mild genitourinary infection. RESULTS: A total of 1011/1280 (79%), 683/1188 (57.5%), 718/1157 (62.1%) and 542/1062 (51.0%) of the participants selected combination therapy for empirical treatment in scenarios 1, 2, 3 and 4, respectively. Undifferentiated sepsis (OR 1.82, 95% CI 1.46-2.27 and 2.18, 1.51-3.16 compared with genitourinary) and severe infection (1.33, 1.24-1.43 and 1.38, 1.21-1.58 compared with mild) increased the likelihood of choosing a combination therapy and a carbapenem regimen, respectively. Participants with higher acceptable minimum threshold for treatment coverage and young age were also more likely to prescribe carbapenems. CONCLUSIONS: Decision-making in antibiotic prescribing among doctors in Vietnam is influenced by both disease-related characteristics and individual factors, including acceptable minimum treatment coverage. These findings are useful for tailoring AMS implementation in Vietnam and other, similar settings.