Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung

Cella, Laura; D’Avino, Vittoria; Palma, Giuseppe; Conson, Manuel; Liuzzi, Raffaele; Picardi, Marco; Pressello, M.C.; Boboc, Genoveva Ionela; Battistini, Roberta; Donato, Vittorio; Pacelli, Roberto

doi:10.1016/j.radonc.2015.07.051

Cited by 56 publications

(35 citation statements)

References 36 publications

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“…In particular, we implemented a procedure to explore dosimetric lung regional differences associated with the development of late RILD. The procedure was applied to a cohort of HL survivors treated with post–chemoradiation therapy in the supradiaphragmatic region (13). Thoracic irradiation, also at the relatively low dose range inherent to HL treatments, may be responsible for late-phase subclinical lung radiation-induced injuries such as fibrosis, resulting in radiologic density changes detectable on radiographic studies or by computed tomography.…”

Section: Discussionmentioning

confidence: 99%

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A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

Palma

Monti

D’Avino

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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Purpose To apply a voxel-based (VB) approach aimed at exploring local dose differences associated with late radiation-induced lung damage (RILD). Methods and Materials An interinstitutional database of 98 patients who were Hodgkin lymphoma (HL) survivors treated with postchemotherapy supradiaphragmatic radiation therapy was analyzed in the study. Eighteen patients experienced late RILD, classified according to the Radiation Therapy Oncology Group scoring system. Each patient’s computed tomographic (CT) scan was normalized to a single reference case anatomy (common coordinate system, CCS) through a log-diffeomorphic approach. The obtained deformation fields were used to map the dose of each patient into the CCS. The coregistration robustness and the dose mapping accuracy were evaluated by geometric and dose scores. Two different statistical mapping schemes for nonparametric multiple permutation inference on dose maps were applied, and the corresponding P<.05 significance lung subregions were generated. A receiver operating characteristic (ROC)-based test was performed on the mean dose extracted from each subregion. Results The coregistration process resulted in a geometrically robust and accurate dose warping. A significantly higher dose was consistently delivered to RILD patients in voxel clusters near the peripheral medial-basal portion of the lungs. The area under the ROC curves (AUC) from the mean dose of the voxel clusters was higher than the corresponding AUC derived from the total lung mean dose. Conclusions We implemented a framework including a robust registration process and a VB approach accounting for the multiple comparison problem in dose-response modeling, and applied it to a cohort of HL survivors to explore a local dose–RILD relationship in the lungs. Patients with RILD received a significantly greater dose in parenchymal regions where low doses (~6 Gy) were delivered. Interestingly, the relation between differences in the high-dose range and RILD seems to lack a clear spatial signature.

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Section: Discussionmentioning

confidence: 99%

“…A detailed description of patients’ and treatment characteristics has been previously reported (13, 14). …”

Section: Methodsmentioning

confidence: 99%

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

Palma

Monti

D’Avino

et al. 2016

International Journal of Radiation Oncology*Biology*Physics

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“…This makes it less likely that they will be able to deal with future cardiopulmonary stresses effectively. In addition to this, they found that the amount of radiation delivered to cardiac tissue correlates with the incidence of RILF 3. From this, we can conclude that when it comes to the effects of radiotherapy, the heart and lungs are intimately linked.…”

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confidence: 68%

“…According to one study, the incidence of RILF in patients treated for breast cancer has been shown to be 35.5%,2 while other studies suggest rates of 15% in both patients with breast cancer and patients with lymphoma 3. This proportion of the patient cohort is small, but significant enough to be considered in a clinical situation.…”

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confidence: 98%

Considering lung fibrosis in the context of radiation-induced coronary artery disease

Sluijters

Bhatti

2018

Heart

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“…Previous methods of modeling human radio-sensitivities include coupling empirical evidence with radiative transfer models [12] , biophysical models [13] or normal tissue complication probabilities. [14] However, these models only utilize uniform irradiation of populations at high doses whereas Ward et. al [15] has proven even significant effects can occur at low doses.…”

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confidence: 99%

Gamma-radiation exposure alters the cardiovascular extracellular matrix.

Allen¹

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Ionizing radiation has been associated with various cardiovascular complications; however, the associated molecular changes from radiation exposure still remain largely uncharacterized. Alterations to the cardiovascular tissue microenvironment, i.e. the extracellular matrix (ECM), directly affect the function of integrated vascular cells, including cell adhesion, potential to form vessels, and endothelial permeability, which can promote cardiovascular pathologies. The ECM is constantly remodeled in response to stimuli, such as TGF-β1, which leads to excessive ECM accumulation. We hypothesize that radiation exposure will alter the cardiovascular ECM. Human Cardiac Fibroblasts (HCFs) were utilized to produce ECM as an in vitro model to study changes in cardiovascular ECM from exposure to 0 and 1 Gy of γ-radiation. We verified that the ECM produced by these cells over 7 days of culture contained collagen and fibronectin. HCFs were radiosensitive to 1 Gy of radiation, as the irradiated cells exhibited γ-H2AX foci. Intracellular reactive oxygen species (ROS), a known activator of latent TGF-β1, was increased in HCF immediately after radiation. In addition, irradiated HCF contained SMAD 2/3 in their nuclei and expressed α-smooth muscle actin, which are indicative of TGF-β1 activation. Measurement of total ECM protein and morphology demonstrated an increase in ECM protein production and an altered ECM structure from HCF exposed to 1 Gy radiation compared to sham control. In conclusion, we demonstrate that ionizing radiation induces structural and molecular changes in cardiovascular ECM. Our data vi further indicates that γ-irradiation activates TGF-β1 downstream signaling cascades, which may be a primary contributor of ECM remodeling in vascular tissue. Future studies relating ECM remodeling and cardiovascular cell function may help improve our understanding of cardiovascular risks from radiation exposure.vii

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Modeling the risk of radiation-induced lung fibrosis: Irradiated heart tissue is as important as irradiated lung

Cited by 56 publications

References 36 publications

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

A Voxel-Based Approach to Explore Local Dose Differences Associated With Radiation-Induced Lung Damage

Considering lung fibrosis in the context of radiation-induced coronary artery disease

Gamma-radiation exposure alters the cardiovascular extracellular matrix.

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