Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma: The PROACT Clinical Trial.

Background: Cardiotoxicity is a concern for cancer survivors undergoing anthracycline chemotherapy. Enalapril has been explored for its potential to mitigate cardiotoxicity in cancer patients. The dose-dependent cardiotoxicity effects of anthracyclines can be detected early through the biomarker cardiac troponin. Objectives: The PROACT (Preventing Cardiac Damage in Patients Treated for Breast Cancer and Lymphoma) clinical trial assessed the effectiveness of enalapril in preventing cardiotoxicity, manifesting as myocardial injury and cardiac function impairment, in patients undergoing high-dose anthracycline-based chemotherapy for breast cancer or non-Hodgkin lymphoma. Methods: This prospective, multicenter, open-label, randomized controlled trial employed a superiority design with observer-blinded endpoints. A total of 111 participants, scheduled for 6 cycles of chemotherapy with a planned dose of ≥300 mg/m2 doxorubicin equivalents, were randomized to receive either enalapril (titrated up to 20 mg daily) or standard care without enalapril. Results: Myocardial injury, indicated by cardiac troponin T (≥14 ng/L), during and 1 month after chemotherapy, was observed in 42 (77.8%) of 54 patients in the enalapril group vs 45 (83.3%) of 54 patients in the standard care group (OR: 0.65; 95% CI: 0.23-1.78). Injury detected by cardiac troponin I (>26.2 ng/L) occurred in 25 (47.2%) of 53 patients on enalapril compared with 24 (45.3%) of 53 in standard care (OR: 1.10; 95% CI: 0.50-2.38). A relative decline of more than 15% from baseline in left ventricular global longitudinal strain was observed in 10 (21.3%) of 47 patients on enalapril and 9 (21.9%) of 41 in standard care (OR: 0.95; 95% CI: 0.33-2.74). An absolute decline of >10% to <50% in left ventricular ejection fraction was seen in 2 (4.1%) of 49 patients on enalapril vs none in patients in standard care. Conclusions: Adding enalapril to standard care during chemotherapy did not prevent cardiotoxicity in patients receiving high-dose anthracycline-based chemotherapy. (PROACT: Can we prevent Chemotherapy-related Heart Damage in Patients With Breast Cancer and Lymphoma?; NCT03265574).

The influence of blood lactate sample site on exercise prescription.

The aims of this study were first to determine the level of agreement between the fingertip and earlobe for the measurement of blood lactate, and second, to examine whether these sample sites may be used interchangeably when distinguishing lactate parameters routinely used in the physiological assessment and exercise prescription. Twenty healthy men performed an incremental cycle ergometry step test. Capillary blood samples were taken simultaneously at the end of each increment from the earlobe and the fingertip to determine blood lactate concentration. The power output and the heart rate at different lactate parameters (LT, LT1, 2, and 4 mMol·L(-1)) were calculated from the lactate values. The average bias in blood lactate concentration measured from the fingertip and the earlobe was 9.2% with 95% of measures differing by between -24.9 and 58.7%. There were no significant differences between sample sites (p = 0.201); however, there was a strong positive relationship (R2 = 0.9455). At the different lactate parameters, there were no differences in determining the heart rate (except at 4 mMol·L(-1) [p = 0.028], equating to 2 b·min(-1)) and power output between sample sites. In conclusion, this high level of agreement and negligible differences in prescribing exercise using power output and heart rate from commonly used lactate parameters, determined from the earlobe and the fingertip indicate that these sample sites could be used interchangeably for physiological assessment during cycle ergometry.

Adjuvant Rituximab-Exploratory Trial in Young People With Graves Disease.

CONTEXT: Remission rates in young people with Graves hyperthyroidism are less than 25% after 2 years of thionamide antithyroid drug (ATD). OBJECTIVE: We explored whether rituximab (RTX), a B-lymphocyte-depleting agent, would increase remission rates when administered with a short course of ATD. METHODS: This was an open-label, multicenter, single-arm, phase 2 trial in young people (ages, 12-20 years) with Graves hyperthyroidism. An A'Hern design was used to distinguish an encouraging remission rate (40%) from an unacceptable rate (20%). Participants presenting with Graves hyperthyroidism received 500 mg RTX and 12 months of ATD titrated according to thyroid function. ATDs were stopped after 12 months and primary outcome assessed at 24 months. Participants had relapsed at 24 months if thyrotropin was suppressed and free 3,5,3'-triiodothyronine was raised; they had received ATD between months 12 and 24; or they had thyroid surgery/radioiodine. RESULTS: A total of 27 participants were recruited and completed the trial with no serious side effects linked to treatment. Daily carbimazole dose at 12 months was less than 5 mg in 21 of 27 participants. Thirteen of 27 participants were in remission at 24 months (48%, 90% one-sided CI, 35%-100%); this exceeded the critical value (9) for the A'Hern design and provided evidence of a promising remission rate. B-lymphocyte count at 28 weeks, expressed as a percentage of baseline, was related to likelihood of remission. CONCLUSION: Adjuvant RTX, administered with a 12-month course of ATD, may increase the likelihood of remission in young people with Graves hyperthyroidism. A randomized trial of adjuvant RTX in young people with Graves hyperthyroidism is warranted.

BIOlogical Factors that Limit sustAined Remission in rhEumatoid arthritis (the BIO-FLARE study): protocol for a non-randomised longitudinal cohort study.

BACKGROUND: Our knowledge of immune-mediated inflammatory disease (IMID) aetiology and pathogenesis has improved greatly over recent years, however, very little is known of the factors that trigger disease relapses (flares), converting diseases from inactive to active states. Focussing on rheumatoid arthritis (RA), the challenge that we will address is why IMIDs remit and relapse. Extrapolating from pathogenetic factors involved in disease initiation, new episodes of inflammation could be triggered by recurrent systemic immune dysregulation or locally by factors within the joint, either of which could be endorsed by overarching epigenetic factors or changes in systemic or localised metabolism. METHODS: The BIO-FLARE study is a non-randomised longitudinal cohort study that aims to enrol 150 patients with RA in remission on a stable dose of non-biologic disease-modifying anti-rheumatic drugs (DMARDs), who consent to discontinue treatment. Participants stop their DMARDs at time 0 and are offered an optional ultrasound-guided synovial biopsy. They are studied intensively, with blood sampling and clinical evaluation at weeks 0, 2, 5, 8, 12 and 24. It is anticipated that 50% of participants will have a disease flare, whilst 50% remain in drug-free remission for the study duration (24 weeks). Flaring participants undergo an ultrasound-guided synovial biopsy before reinstatement of previous treatment. Blood samples will be used to investigate immune cell subsets, their activation status and their cytokine profile, autoantibody profiles and epigenetic profiles. Synovial biopsies will be examined to profile cell lineages and subtypes present at flare. Blood, urine and synovium will be examined to determine metabolic profiles. Taking into account all generated data, multivariate statistical techniques will be employed to develop a model to predict impending flare in RA, highlighting therapeutic pathways and informative biomarkers. Despite initial recruitment to time and target, the SARS-CoV-2 pandemic has impacted significantly, and a decision was taken to close recruitment at 118 participants with complete data. DISCUSSION: This study aims to investigate the pathogenesis of flare in rheumatoid arthritis, which is a significant knowledge gap in our understanding, addressing a major unmet patient need. TRIAL REGISTRATION: The study was retrospectively registered on 27/06/2019 in the ISRCTN registry 16371380 .