Arterial effects of anthracycline: structural and inflammatory assessments in non-human primates and lymphoma patients using 18F-FDG positron emission tomography.

Background: Anthracyclines, such as doxorubicin, are important anti-cancer therapies but are associated with arterial injury. Histopathological insights have been limited to small animal models and the role of inflammation in the arterial toxic effects of anthracycline is unclear in humans. Our aims were: 1) To evaluate aortic media fibrosis and injury in non-human primates treated with anthracyclines; 2) To assess the effect of anthracycline on aortic inflammation in patients treated for lymphoma. Methods: 1) African Green monkeys (AGM) received doxorubicin (30-60 mg/m2/biweekly IV, cumulative dose: 240 mg/m2). Blinded histopathologic analyses of collagen deposition and cell vacuolization in the ascending aorta were performed 15 weeks after the last doxorubicin dose and compared to 5 age- and gender-matched healthy, untreated AGMs. 2) Analysis of the thoracic aorta of patients with diffuse large B-cell lymphoma (DLBCL), at baseline and after doxorubicin exposure, was performed using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this observational study. The primary outcome was change in maximal tissue-to-background ratio (TBRmax) of the thoracic aorta from baseline to their end-of-treatment clinical PET/CT. Results: In AGMs, doxorubicin exposure was associated with greater aortic fibrosis (collagen deposition: doxorubicin cohort 6.23±0.88% vs. controls 4.67±0.54%; p=0.01) and increased intracellular vacuolization (doxorubicin 66.3 ± 10.1 vs controls 11.5 ± 4.2 vacuoles/field, p<0.0001) than untreated controls.In 101 patients with DLBCL, there was no change in aortic TBRmax after anthracycline exposure (pre-doxorubicin TBRmax 1.46±0.16 vs post-doxorubicin TBRmax 1.44±0.14, p=0.14). The absence of change in TBRmax was consistent across all univariate analyses. Conclusions: In a large animal model, anthracycline exposure was associated with aortic fibrosis. In patients with lymphoma, anthracycline exposure was not associated with aortic inflammation.Further research is required to elucidate the mechanisms of anthracycline-related vascular harm.

'ACOPP' chemotherapy for older and less fit patients with Hodgkin lymphoma-A multicentre, retrospective study.

Management of classical Hodgkin lymphoma in older patients is challenging due to poor tolerance of the chemotherapy regimens used in younger patients. We modified the BEACOPP regimen (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisolone), whereby bleomycin and etoposide were removed and cyclophosphamide dose was reduced, for older patients with co-morbidities. Here we present data from the first 41 patients treated with 'ACOPP' across 3 centres, demonstrating that it can be delivered, with a favourable toxicity profile (TRM 2%) and promising efficacy (2-year PFS and OS, 73% (95% CI: 52-94) and 93% (95% CI: 80-100) respectively).

Dynamical-statistical seasonal forecasts of winter and summer precipitation for the Island of Ireland.

Seasonal precipitation forecasting is highly challenging for the northwest fringes of Europe due to complex dynamical drivers. Hybrid dynamical-statistical approaches offer potential to improve forecast skill. Here, hindcasts of mean sea level pressure (MSLP) from two dynamical systems (GloSea5 and SEAS5) are used to derive two distinct sets of indices for forecasting winter (DJF) and summer (JJA) precipitation over lead-times of 1-4 months. These indices provide predictors of seasonal precipitation via a multiple linear regression model (MLR) and an artificial neural network (ANN) applied to four Irish rainfall regions and the Island of Ireland. Forecast skill for each model, lead time, and region was evaluated using the correlation coefficient (r) and mean absolute error (MAE), benchmarked against (a) climatology, (b) bias corrected precipitation hindcasts from both GloSea5 and SEAS5, and (c) a zero-order forecast based on rainfall persistence. The MLR and ANN models produced skilful precipitation forecasts with leads of up to 4 months. In all tests, our hybrid method based on MSLP indices outperformed the three benchmarks (i.e., climatology, bias corrected, and persistence). With correlation coefficients ranging between 0.38 and 0.81 in winter, and between 0.24 and 0.78 in summer, the ANN model outperformed MLR in both seasons in most regions and lead-times. Forecast skill for summer was comparable to that in winter and for some regions/lead times even superior. Our results also show that climatology and persistence performed better than direct use of bias corrected dynamical outputs in most regions and lead-times in terms of MAE. We conclude that the hybrid dynamical-statistical approach developed here-by leveraging useful information about MSLP from dynamical systems-enables more skilful seasonal precipitation forecasts for Ireland, and possibly other locations in western Europe, in both winter and summer.