Abstract 38: Radiation Exposure And Coronary Atherosclerosis: Differential Effect Of The Radiation Site

Background: Thoracic radiation is commonly used in breast cancer, Hodgkin’s lymphoma, head and neck and lung cancer patients. Accelerated coronary artery atherosclerosis is a common complication of thoracic radiation as a result of unintended cardiac radiation. It is unclear however whether specific areas of the heart are more susceptible to the effects of radiation (RT). In this study we hypothesize that accelerated development of lesions post RT is dependent upon differential sensitivity of specific areas of the heart to the effects of RT. Methods: Male Apolipoprotein E knockout mice on a high fat diet received 16Gy cardiac RT targeted to the whole or partial (apical or basal) region of the heart at 9 or 16 weeks of age (n=5 per group). Atherosclerotic lesions in H&E stained slides and inflammatory infiltrates in the hearts by IHC were assessed 8 weeks following RT and compared to control unirradiated mice. Results: Our studies show that: (1) Subendocardial atherosclerotic lesions at the base of heart in mice irradiated at 9 weeks of age after basal irradiation (7.8±2.49) were comparable to whole heart irradiation (12.2±3.29). (2) A greater number of atherosclerotic lesions were present in the basal coronary arteries (29.33±5.48 vs 9±2.70) and basal subendocardial vasculature (6.66±2.07 vs 0.2±0.2) after irradiation of the cardiac base as compared to unirradiated controls in mice irradiated at 16 weeks of age. (3) Apical or whole heart irradiation had no impact on the development of lesions in the basal region of the hearts of older mice. (4) IL-6 was significantly increased in the serum of mice 6 hours post basal cardiac irradiation (105.10±17.56 pg/ml) when compared to unirradiated controls (29.85±11.63 pg/ml), demonstrating an acute inflammatory response. (5) Infiltration of inflammatory cells (CD45 and CD3) and enhanced expression of endothelial adhesion molecules (CD31) were differentially and locally regulated based upon the site of irradiation. Conclusion: Our results indicate that the base of the heart is more prone to development of RT induced atherosclerotic lesions likely due to acute and delayed inflammatory responses. Avoiding this area from direct radiation exposure may improve the quality of life for cancer patients receiving thoracic RT.

Radiation Therapy Planning of Thoracic Tumors: A Review of Challenges Associated With Lung Toxicities and Potential Perspectives of Gallium-68 Lung PET/CT Imaging

Despite the introduction of new radiotherapy techniques, such as intensity modulated radiation therapy or stereotactic body radiation therapy, radiation induced lung injury remains a significant treatment related adverse event of thoracic radiation therapy. Functional lung avoidance radiation therapy is an emerging concept in the treatment of lung disease to better preserve lung function and to reduce pulmonary toxicity. While conventional ventilation/perfusion (V/Q) lung scintigraphy is limited by a relatively low spatial and temporal resolution, the recent advent of 68Gallium V/Q lung PET/CT imaging offers a potential to increase the accuracy of lung functional mapping and to better tailor lung radiation therapy plans to the individual's lung function. Lung PET/CT imaging may also improve our understanding of radiation induced lung injury compared to the current anatomical based dose–volume constraints. In this review, recent advances in radiation therapy for the management of primary and secondary lung tumors and in V/Q PET/CT imaging for the assessment of functional lung volumes are reviewed. The new opportunities and challenges arising from the integration of V/Q PET/CT imaging in radiation therapy planning are also discussed.

High-dose thoracic radiation therapy for non-small cell lung cancer: a novel grading scale of radiation-induced lung injury for symptomatic radiation pneumonitis

Background Symptomatic radiation pneumonitis (RP) may be a serious complication after thoracic radiation therapy (RT) for non-small cell lung cancer (NSCLC). This prospective observational study sought to evaluate the utility of a novel radiation-induced lung injury (RILI) grading scale (RGS) for the prediction of RP. Materials and methods Data of 41 patients with NSCLC treated with thoracic RT of 60–66 Gy were analysed. CT scans were scheduled before RT, one month post-RT, and every three months thereafter for one year. Symptomatic RP was defined as Common Terminology Criteria for Adverse Events grade ≥ 2. RGS grading ranged from 0 to 3. The inter-observer variability of the RGS was assessed by four senior radiologists. CT scans performed 28 ± 10 days after RT were used to analyse the predictive value of the RGS. The change in the RGS severity was correlated to dosimetric parameters. Results The CT obtained one month post-RT showed RILI in 36 (88%) of patients (RGS grade 0 [5 patients], 1 [25 patients], 2 [6 patients], and 3 [5 patients]). The inter-observer agreement of the RGS grading was high (Kendall’s W coefficient of concordance = 0.80, p < 0.01). Patients with RGS grades 2–3 had a significantly higher risk for development of RP (relative risk (RR): 2.4, 95% CI 1.6–3.7, p < 0.01) and RP symptoms within 8 weeks after RT (RR: 4.8, 95% CI 1.3–17.6, p < 0.01) compared to RGS grades 0–1. The specificity and sensitivity of the RGS grades 2–3 in predicting symptomatic RP was 100% (95% CI 80.5–100%) and 45.4% (95% CI 24.4–67.8%), respectively. Increase in RGS severity correlated to mean lung dose and the percentage of the total lung volume receiving 5 Gy. Conclusions The RGS is a simple radiologic tool associated with symptomatic RP. A validation study is warranted.

Sox9-expressing cells promote regeneration after radiation-induced lung injury via the PI3K/AKT pathway

Background Radiation-induced lung injury (RILI) is considered one of the most common complications of thoracic radiation. Recent studies have focused on stem cell properties to obtain ideal therapeutic effects, and Sox9 has been reported to be involved in stem cell induction and differentiation. However, whether Sox9-expressing cells play a role in radiation repair and regeneration remains unknown. Methods We successfully obtained Sox9CreER, RosatdTomato and RosaDTA mice and identified Sox9-expressing cells through lineage tracing. Then, we evaluated the effects of the ablation of Sox9-expressing cells in vivo. Furthermore, we investigated the underlying mechanism of Sox9-expressing cells during lung regeneration via an online single-cell RNA-seq dataset. Results In our study, we demonstrated that Sox9-expressing cells promote the regeneration of lung tissues and that ablation of Sox9-expressing cells leads to severe phenotypes after radiation damage. In addition, analysis of an online scRNA-Seq dataset revealed that the PI3K/AKT pathway is enriched in Sox9-expressing cells during lung epithelium regeneration. Finally, the AKT inhibitor perifosine suppressed the regenerative effects of Sox9-expressing cells and the AKT pathway agonist promotes proliferation and differentiation. Conclusions Taken together, the findings of our study suggest that Sox9-expressing cells may serve as a therapeutic target in lung tissue after RILI.