Radiation-induced cardiac side-effects:The lung as target for interacting damage and intervention

Radiotherapy is part of the treatment for many thoracic cancers. During this treatment heart and lung tissue can often receive considerable doses of radiation. Doses to the heart can potentially lead to cardiac effects such as pericarditis and myocardial fibrosis. Common side effects after lung irradiation are pneumonitis and pulmonary fibrosis. It has also been shown that lung irradiation has effects on cardiac function. In a rat model lung irradiation caused remodeling of the pulmonary vasculature increasing resistance of the pulmonary vascular bed, leading to enhanced pulmonary artery pressure, right ventricle hypertrophy and reduced right ventricle performance. Even more pronounced effects are observed when both, lung and heart are irradiated. The effects observed after lung irradiation show striking similarities with symptoms of pulmonary arterial hypertension. In particular, the vascular remodeling in lung tissue seems to have similar underlying features. Here, we discuss the similarities and differences of vascular remodeling observed after thoracic irradiation compared to those in pulmonary arterial hypertension patients and research models. We will also assess how this knowledge of similarities could potentially be translated into interventions which would be beneficial for patients treated for thoracic tumors, where dose to lung tissue is often unavoidable

Regional Responses in Radiation-Induced Normal Tissue Damage

Simple SummarySide effects caused by the concomitant irradiation of normal tissue during radiotherapy for cancer treatment can negatively affect the patient's quality of life and limit the radiation dose that can safely be administered to the tumor. Recently, considerable developments have been achieved in radiotherapy and imaging technologies, allowing the selective sparing of the regions within organs that contribute most to the development of these side effects. This review discusses regional variation in the response to radiation in several organs, including the brain, salivary glands, cardiopulmonary system, pancreas, and bladder. Regional responses are shown to originate from general principles, such as the localization of target cells or function. We conclude that regional responses are a general phenomenon that should be studied in other organs. This will facilitate further optimization of the use of modern radiotherapy technologies.Normal tissue side effects remain a major concern in radiotherapy. The improved precision of radiation dose delivery of recent technological developments in radiotherapy has the potential to reduce the radiation dose to organ regions that contribute the most to the development of side effects. This review discusses the contribution of regional variation in radiation responses in several organs. In the brain, various regions were found to contribute to radiation-induced neurocognitive dysfunction. In the parotid gland, the region containing the major ducts was found to be critical in hyposalivation. The heart and lung were each found to exhibit regional responses while also mutually affecting each other's response to radiation. Sub-structures critical for the development of side effects were identified in the pancreas and bladder. The presence of these regional responses is based on a non-uniform distribution of target cells or sub-structures critical for organ function. These characteristics are common to most organs in the body and we therefore hypothesize that regional responses in radiation-induced normal tissue damage may be a shared occurrence. Further investigations will offer new opportunities to reduce normal tissue side effects of radiotherapy using modern and high-precision technologies.</p

Radiation-induced cardiac side-effects: The lung as target for interacting damage and intervention

Radiotherapy is part of the treatment for many thoracic cancers. During this treatment heart and lung tissue can often receive considerable doses of radiation. Doses to the heart can potentially lead to cardiac effects such as pericarditis and myocardial fibrosis. Common side effects after lung irradiation are pneumonitis and pulmonary fibrosis. It has also been shown that lung irradiation has effects on cardiac function. In a rat model lung irradiation caused remodeling of the pulmonary vasculature increasing resistance of the pulmonary vascular bed, leading to enhanced pulmonary artery pressure, right ventricle hypertrophy and reduced right ventricle performance. Even more pronounced effects are observed when both, lung and heart are irradiated.The effects observed after lung irradiation show striking similarities with symptoms of pulmonary arterial hypertension. In particular, the vascular remodeling in lung tissue seems to have similar underlying features. Here, we discuss the similarities and differences of vascular remodeling observed after thoracic irradiation compared to those in pulmonary arterial hypertension patients and research models. We will also assess how this knowledge of similarities could potentially be translated into interventions which would be beneficial for patients treated for thoracic tumors, where dose to lung tissue is often unavoidable

Academic achievement of children with autistic symptoms compared to typically developing children

Children with autistic symptoms experience challenges in school settings, yet little is known about their academic profiles and the mechanisms underlying the association between autistic symptoms and academic achievement. This study examined the association between autistic symptoms and academic achievement in a population-based sample of children with and without (sub)clinical autism spectrum disorder (ASD). We also investigated potential sex differences and assessed if the association is mediated by vocabulary skills and behavior problems. Information was available for 2038 participants (48.3% boys), and autistic symptoms were assessed using the Social Responsiveness Scale (M = 6.8 years). Diagnosis of ASD was clinically confirmed in 28 children. Academic achievement was determined by a nationwide, standardized test assessed at the end of primary school (M = 11.8 years). Children with more autistic symptoms in early childhood had lower achievement scores in language, mathematics, and world orientation by the end of primary education. There were no sex differences. Furthermore, vocabulary skills and behavior problems partly mediated the association between autistic symptoms and academic achievement. Then, by using propensity matching technique, we compared 140 matched typically developing peers with 28 children diagnosed with ASD. These results indicated no differences in academic achievement between children diagnosed with ASD and their matched typically developing peers. We conclude that autistic symptoms associate with lower academic achievement but by carefully matching on background variables and potential confounders, the academic achievement of children with clinical ASD might not differ from that of their typically developing peers.</p

A new CT-based method to quantify radiation-induced lung damage in patients

SummaryA new method to assess radiation-induced lung toxicity (RILT) using CT-scans was developed. It is more sensitive in detecting damage and corresponds better to physician-rated radiation pneumonitis than routinely-used methods. Use of this method may improve lung toxicity assessment and thereby facilitate development of more accurate predictive models for RILT

The Acute and Early Effects of Whole-Brain Irradiation on Glial Activation, Brain Metabolism, and Behavior:a Positron Emission Tomography Study

Purpose: Radiotherapy is a frequently applied treatment modality for brain tumors. Concomitant irradiation of normal brain tissue can induce various physiological responses. The aim of this study was to investigate whether acute and early-delayed effects of brain irradiation on glial activation and brain metabolism can be detected with positron emission tomography (PET) and whether these effects are correlated with behavioral changes. Procedures: Rats underwent 0-, 10-, or 25-Gy whole-brain irradiation. At 3 and 31 days post irradiation, 1-(2-chlorophenyl)-N-[11C]methyl-(1-methylpropyl)-3-isoquinoline carboxamide ([11C]PK11195) and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG) PET scans were acquired to detect changes in glial activation (neuroinflammation) and glucose metabolism, respectively. The open-field test (OFT) was performed on days 6 and 27 to assess behavioral changes. Results: Twenty-five-gray-irradiated rats showed higher [11C]PK11195 uptake in most brain regions than controls on day 3 (striatum, hypothalamus, accumbens, septum p < 0.05), although some brain regions had lower uptake (cerebellum, parietal association/retrosplenial visual cortex, frontal association/motor cortex, somatosensory cortex, p < 0.05). On day 31, several brain regions in 25-Gy-irradiated rats still showed significantly higher [11C]PK11195 uptake than controls and 10-Gy-irradiated group (p < 0.05). Within-group analysis showed that [11C]PK11195 uptake in individual brain regions of 25-Gy treated rats remained stable or slightly increased between days 3 and 31. In contrast, a significant reduction (p < 0.05) in tracer uptake between days 3 and 31 was found in all brain areas of controls and 10-Gy-irradiated animals. Moreover, 10-Gy treatment led to a significantly higher [18F]FDG uptake on day 3 (p < 0.05). [18F]FDG uptake decreased between days 3 and 31 in all groups; no significant differences between groups were observed anymore on day 31, except for increased uptake in the hypothalamus in the 10-Gy group. The OFT did not show any significant differences between groups. Conclusions: Non-invasive PET imaging indicated that brain irradiation induces neuroinflammation and a metabolic flare, without causing acute or early-delayed behavioral changes

Mouse parotid salivary gland organoids for the in vitro study of stem cell radiation response

Objective: Hyposalivation-related xerostomia is an irreversible, untreatable, and frequent condition after radiotherapy for head and neck cancer. Stem cell therapy is an attractive option of treatment, but demands knowledge of stem cell functioning. Therefore, we aimed to develop a murine parotid gland organoid model to explore radiation response of stem cells in vitro. Materials and Methods: Single cells derived from murine parotid gland organoids were passaged in Matrigel with defined medium to assess self-renewal and differentiation potential. Single cells were irradiated and plated in a 3D clonogenic stem cell survival assay to assess submandibular and parotid gland radiation response. Results: Single cells derived from parotid gland organoids were able to extensively self-renew and differentiate into all major tissue cell types, indicating the presence of potential stem cells. FACS selection for known salivary gland stem cell markers CD24/CD29 did not further enrich for stem cells. The parotid gland organoid-derived stem cells displayed radiation dose–response curves similar to the submandibular gland. Conclusions: Murine parotid gland organoids harbor stem cells with long-term expansion and differentiation potential. This model is useful for mechanistic studies of stem cell radiation response and suggests similar radiosensitivity for the parotid and submandibular gland organoids

Radiation-Induced Myocardial Fibrosis in Long-Term Esophageal Cancer Survivors

Purpose: Radiation-induced cardiac toxicity is a potential lethal complication. The aim of this study was to assess whether there is a dose-dependent relationship between radiation dose and myocardial fibrosis in patients who received neoadjuvant chemoradiation (nCRT) for esophageal cancer (EC). Methods and Materials: Forty patients with EC treated with a transthoracic esophagectomy with (n = 20) or without (n = 20) nCRT (CROSS study regimen) were included. Cardiovascular magnetic resonance imaging (1.5 Tesla) for left ventricular (LV) function, late gadolinium enhancement, and T1 mapping were performed. Extracellular volume (ECV), as a surrogate for collagen burden, was measured for all LV segments separately. The dose-response relationship between ECV and mean radiation dose per LV myocardial segment was evaluated using a mixed-model analysis. Results: Seventeen nCRT and 16 control patients were suitable for analysis. The mean time after treatment was 67.6 +/- 8.1 (nCRT) and 122 +/- 35 (controls) months (P = .02). In nCRT patients, we found a significantly higher mean global ECV of 28.2% compared with 24.0% in the controls (P < .001). After nCRT, LV myocardial segments with elevated ECV had received significantly higher radiation doses. In addition, a linear dose-effect relation was found with a 0.136% point increase of ECV for each Gy (P < .001). There were no differences in LV function measures and late gadolinium enhancement between both groups. Conclusions: Myocardial ECV was significantly higher in long-term EC survivors after nCRT compared with surgery only. Moreover, this ECV increase was linear with the radiation dose per LV segment, indicating radiation-induced myocardial fibrosis. (C) 2021 The Author(s). Published by Elsevier Inc

ACE inhibition attenuates radiation-induced cardiopulmonary damage

BACKGROUND AND PURPOSE: In thoracic irradiation, the maximum radiation dose is restricted by the risk of radiation-induced cardiopulmonary damage and dysfunction limiting tumor control. We showed that radiation-induced sub-clinical cardiac damage and lung damage in rats mutually interact and that combined irradiation intensifies cardiopulmonary toxicity. Unfortunately, current clinical practice does not include preventative measures to attenuate radiation-induced lung or cardiac toxicity. Here, we investigate the effects of the ACE inhibitor captopril on radiation-induced cardiopulmonary damage.MATERIAL AND METHODS: After local irradiation of rat heart and/or lungs captopril was administered orally. Cardiopulmonary performance was assessed using biweekly breathing rate measurements. At 8weeks post-irradiation, cardiac hemodynamics were measured, CT scans and histopathology were analyzed.RESULTS: Captopril significantly improved breathing rate and cardiopulmonary density/structure, but only when the heart was included in the radiation field. Consistently, captopril reduced radiation-induced pleural and pericardial effusion and cardiac fibrosis, resulting in an improved left ventricular end-diastolic pressure only in the heart-irradiated groups.CONCLUSION: Captopril improves cardiopulmonary morphology and function by reducing acute cardiac damage, a risk factor in the development of radiation-induced cardiopulmonary toxicity. ACE inhibition should be evaluated as a strategy to reduce cardiopulmonary complications induced by radiotherapy to the thoracic area.</p

Can we safely reduce the radiation dose to the heart while compromising the dose to the lungs in oesophageal cancer patients?

PURPOSE: The aim of this study was to evaluate which clinical and treatment-related factors are associated with heart and lung toxicity in oesophageal cancer patients treated with chemoradiation (CRT). The secondary objective was to analyse whether these toxicities are associated with overall survival (OS) MATERIALS AND METHODS: The study population consisted of a retrospective cohort of 216 oesophageal cancer patients treated with curative CRT. Clinical and treatment related factors were analysed for OS and new pulmonary and cardiac events by multivariable regression analyses. The effect of these toxicities on OS was assessed by Kaplan Meyer analyses. RESULTS: Multivariable analysis revealed that pulmonary toxicity was best predicted by the mean lung dose. Cardiac complications were diverse; the most frequently occurring complication was pericardial effusion. Several cardiac dose parameters correlated with this endpoint. Patients developing radiation pneumonitis had significantly worse OS than patients without radiation pneumonitis, while no difference was observed in OS between patients with and without pericardial effusion. OS was best predicted by the V45 of the lung and tumour stage. None of the cardiac dose parameters predicted OS in multivariable analyses. CONCLUSION: Cardiac dose volume parameters predicted the risk of pericardial effusion and pulmonary dose volume parameters predicted the risk of radiation pneumonitis. However, in this patient cohort, pulmonary DVH parameters (V45) were more important for OS than cardiac DVH parameters. These results suggest that reducing the cardiac dose at the expense of the dose to the lungs might not always be a good strategy in oesophageal cancer patients