ESTRO 2025 - Abstract Book

S3942

Radiobiology - Normal tissue radiobiology

ESTRO 2025

Conclusion: Our clinically-mimetic focal duodenal radiation injury model is safe and well-tolerated. We uncover biogeographically-distinct microbiome perturbations in the duodenum that are not apparent in the stool. Gut biogeography should be considered in future studies examining bowel radiation injury as stool alone may not accurately represent community dynamics at the site of injury.

Keywords: Microbiome, Enteritis, Duodenum

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Proffered Paper Combination of Captopril, Ambrisentan and Sildenafil mitigates long-term side effects of combined heart and lung irradiation Julia Wiedemann 1 , Uilke Brouwer 2 , Herman H.W. Silljé 3 , Michael G. Dickinson 3 , Robert P Coppes 1,2 , Peter van Luijk 1 1 Radiation Oncology, UMCG, Groningen, Netherlands. 2 Biomedical Science, UMCG, Groningen, Netherlands. 3 Cardiology, UMCG, Groningen, Netherlands Purpose/Objective: Thoracic radiotherapy unavoidably also delivers radiation doses to heart and lung, leading to side effects compromising quality of life and possibly even survival in patients. In rat, lung irradiation can cause vascular remodeling resembling pulmonary hypertension (PH). Heart irradiation causes left ventricle (LV) remodeling and additional pulmonary vascular remodeling. The combination of these effects prevents recovery, resulting in long term reduced cardiopulmonary function. Interestingly, these effects have been observed in the ongoing clinical CLARIFY study (NCT03978377). Since dose reduction is not always possible, pharmacological interventions are needed to prevent this. We previously reported that if the lung is spared, the angiotensin-converting-enzyme (ACE) inhibitor Captopril reduces late fibrosis and LV remodeling after heart irradiation. Furthermore, Sildenafil and Ambrisentan which are used in PH patients to target the endothelin and nitric oxide pathways improve LV and RV function early after irradiation. Therefore, we hypothesize that the reduction of early damage by Ambrisentan and Sildenafil may facilitate protection from late irradiation effects by Captopril even after combined heart and lung irradiation and aim to test this in our rat model. Material/Methods: The heart, 50% of the lateral lung, or both were irradiated using protons. Animals were randomly assigned to receive a combination of Captopril, Ambrisentan and Sildenafil, only Ambrisentan and Sildenafil or normal food and drinking water (n>9). Echocardiography, LV pressure measurements and tissue collection were performed 38 weeks after irradiation. Results: Treatment with all three medications improved left ventricle end-diastolic pressure from 17.3±0.8mmHg after heart and lung irradiation to 13.3±0.9mmHg (p=0.006; Figure1) and reduced LV wall thickness in this irradiation setting from 2.49±0.11mm to 2.01±0.07mm (p=0.03), resembling non-irradiated controls (2.03±0.05mm). Furthermore, TAPSE, a measure for RV contraction improved significantly from 2.12±0.09mm after combined irradiation to 2.82±0.01mm (p=0.0002), again close to control levels (2.88±0.08mm). However, surprisingly long-term use of Ambrisentan and Sildenafil without Captopril caused mortality after combined heart and lung irradiation (Figure2), possibly related to interactions with developing radiation fibrosis. Further optimization of the administration scheme preventing late mortality, while preserving early protection is required.