Detection of circulating tumour DNA after neoadjuvant chemoradiotherapy in patients with locally advanced oesophageal cancer

Active surveillance instead of standard surgery after neoadjuvant chemoradiotherapy (nCRT) has been proposed for patients with oesophageal cancer. Circulating tumour DNA (ctDNA) may be used to facilitate selection of patients for surgery. We show that detection of ctDNA after nCRT seems highly suggestive of major residual disease. Tumour biopsies and blood samples were taken before, and 6 and 12 weeks after, nCRT. Biopsies were analysed with regular targeted next-generation sequencing (NGS). Circulating cell-free DNA (cfDNA) was analysed using targeted NGS with unique molecular identifiers and digital polymerase chain reaction. cfDNA mutations matching pre-treatment biopsy mutations confirmed the presence of ctDNA. In total, 31 patients were included, of whom 24 had a biopsy mutation that was potentially detectable in cfDNA (77%). Pre-treatment ctDNA was detected in nine of 24 patients (38%), four of whom had incurable disease progression before surgery. Pre-treatment ctDNA detection had a sensitivity of 47% (95% CI 24–71) (8/17), specificity of 85% (95% CI 42–99) (6/7), positive predictive value (PPV) of 89% (95% CI 51–99) (8/9), and negative predictive value (NPV) of 40% (95% CI 17–67) (6/15) for detecting major residual disease (>10% residue in the resection specimen or progression before surgery). After nCRT, ctDNA was detected in three patients, two of whom had disease progression. Post-nCRT ctDNA detection had a sensitivity of 21% (95% CI 6–51) (3/14), specificity of 100% (95% CI 56–100) (7/7), PPV of 100% (95% CI 31–100) (3/3), and NPV of 39% (95% CI 18–64) (7/18) for detecting major residual disease. The addition of ctDNA to the current set of diagnostics did not lead to more patients being clinically identified with residual disease. These results indicate that pre-treatment and post-nCRT ctDNA detection may be useful in identifying patients at high risk of disease progression. The addition of ctDNA analysis to the current set of diagnostic modalities may not improve detection of residual disease after nCRT. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Expanding the boundaries of previously obtained informed consent in research: Views from participants in the Personalised Risk-based Mammascreening study

Introduction

Understanding participants' concerns and information needs regarding broadened consent is crucial to ensure transparency and participant autonomy. Our study qualitatively examined these issues in women participating in the Personalized RISk-based MAmmascreening study (PRISMA). The original PRISMA informed consent was project-specific (i.e., breast cancer research), limiting the scope of secondary research. We explored participants' needs for broadened consent to preserve informed decision-making while maximising the potential re-use of data.

Methods

Focus groups (FGs) were performed following a semistructured discussion guide. Two independent researchers analysed the data thematically using an inductive approach.

Findings

Twenty-three asymptomatic women and 13 women diagnosed with breast cancer were randomly divided into six FGs. Four superordinate themes were identified: (1) Normalization, (2) Attitude towards the pharmaceutical industry, (3) Privacy and (4) Knowledge. Our participants viewed data sharing as an important conduit for advancing medical science. Perceived integrity was more often attributed to noncommercial than commercial parties, with a marked mistrust towards the pharmaceutical industry. Most requested information needs related to data protection. Participants' ideal consent process would confer a range of options; for example, they would be able to choose with whom data can be shared, whether data will be de-identified or anonymous, the expiration date of their consent and how, if requested, general and personal study results would be disclosed.

Conclusion

Our participants expressed clear information needs and a strong desire to be actively engaged in future data sharing decisions. Given that many researchers collaborate with commercial parties, building public confidence in these institutions would be beneficial. Illustrative examples addressing privacy concerns and clarifying difficult terms would aid consent decision-making. Although our participants displayed great altruism in sharing their data and accepted that broad consent would ultimately facilitate future research, broad consent did not reflect their ideal situation. Dynamic consent may be an option but warrants further feasibility research.

Patient and Public Contribution

Women were recruited from the general breast cancer screening population. Their perceptions and information needs, as reported in this study, will not only inform broadened consent for PRISMA but ideally guide other consent templates and decisions regarding consent processes.     

Refining the therapeutic range of posaconazole and isavuconazole for efficient therapeutic drug monitoring using a bioassay approach

Therapeutic drug monitoring (TDM) of antifungal triazole was recommended, except for isavuconazole (ISA) whose target trough concentrations (C_min) need to be specified. Concerning posaconazole (POS), tablet formulation results in higher exposure but no upper C_min threshold has been yet proposed. We aimed to investigate the pharmacokinetic–pharmacodynamic relationship of POS and ISA, using a bioassay approach as surrogate marker of antifungal activity, in order to refine the therapeutic C_min of both antifungals. A bioassay using a cellulose disk diffusion method was performed to determine the growth inhibition zone (GIZ) of POS and ISA on Aspergillus fumigatus and Candida parapsilosis (ISA only). GIZs of plasma from patients undergoing TDM for POS (n = 136) or ISA (n = 40) were determined. GIZs of plasma patients and antifungal C_min were highly correlated for ISA (A. fumigatus: ρ = 0.942, P < 0.0001; C. parapsilosis: ρ = 0.949, P < 0.0001) and POS (ρ = 0.922, P < 0.0001), and these relationships were represented with a Michaelis–Menten model. Based on this modeling, the recommended thresholds of 0.7, 1, and 1.25 mg/L for the POS C_min corresponded to 50.1, 55.2, and 59.1% of the maximal GIZ, respectively. We propose an upper threshold of 4.8 mg/L for the POS C_min and a lower threshold of 2.0 mg/L for the C_min of ISA, as they respectively corresponded to concentrations leading to 90% and 50% of the maximal GIZ on A. fumigatus. The determination of antifungal activity using this bioassay allowed refining target C_min of POS and ISA, especially the upper threshold of POS (4.8 mg/L) and the lower threshold of ISA (2.0 mg/L).     

Identifying a motivational process surrounding adherence to exercise and diet among adults with type 2 diabetes

ABSTRACT

Objectives: This paper aims to provide physicians with knowledge about the motivational processes surrounding exercise and diet for patients with type 2 diabetes and to offer patient support measures to favor self-management. To respond to this objective, the links between two kind of motivators (i.e., promotion and prevention foci), the Selection, Optimization and Compensation (SOC) self-management strategy, and adherence to exercise and diet of patients with type 2 diabetes were investigated for the first time in the literature.

Method: A cross-sectional study was conducted with 491 French volunteer participants with type 2 diabetes diagnosed for at least 3 months (Age = 61.66 ± 9.63; BMI = 29.8 ± 5.9). Participants completed an online self-report survey measuring SOC strategy, promotion and prevention foci, and adherence to exercise and diet.

Results: The main results of path and bootstrapping analysis demonstrated that promotion focus was positively related with SOC strategy (β = .69, p < .001) whereas prevention focus was not (β = ?.01, ns.). On the other hand, SOC strategy was positively related with exercise (β = .20, p < .05), general diet (β = .49, p < .001), fruit and vegetable consumption (β = .27, p < .001), and spacing of carbohydrates (β = .40, p < .001), and mediated the positive link between promotion focus and these behaviors (bootstrapped 95% CI: [.11; .40], [.52; .81], [.22; .54], [.37; .70], respectively).

Conclusion: This paper addresses a gap in previous research by evidencing a motivator that promotes self-management for exercise and diet among patients with type 2 diabetes. Our results suggest that physicians should privilege an interaction with patients oriented toward promotional motivation so as to favor their patients’ self-management regarding exercise and diet.