Lung Irradiation Research Articles

155 Advanced Practice Clinical technologist contouring GTV volumes for radical lung radiotherapy

155 Advanced Practice Clinical technologist contouring GTV volumes for radical lung radiotherapy

Low-dose radiation therapy for COVID-19 pneumonia: Comparison of dosimetry and life-time attributable risk of cancer with conventional AP-PA fields and bone marrow sparing VMAT.

Low-dose radiation therapy (LDRT) to lungs did show encouraging results in COVID-19 patients in some clinical trials. However, there has been some concern regarding the long-term risk of radiation-induced cancer (RIC). Compared to the conventional AP-PA field technique, volumetric modulated arc therapy (VMAT) can potentially reduce the dose to the marrow and other organs at risk (OARs) and thus minimize the risk of cancer. We designed a dosimetry study to study if VMAT can reduce the exposure to the marrow and other OAR doses and curtail the estimated life-time attributable risk (LAR) of cancer. We retrieved the computed tomography scan data of 10 patients (aged 40-60 years, median 48 years) who have been already treated for any malignancy in the region of the thorax. A dose of 1.0 Gy in single fraction was prescribed to both lungs. All the organs were delineated as per the established guidelines. The dosimetry achieved by the two plans was compared to find the difference. Mean OAR doses were used to estimate the LAR for both plans and compared. Planning target volume coverage parameters like conformity index and homogeneity index were significantly better with VMAT (P value < 0.05 for all). The mean dose to most OARs was significantly lower with VMAT (P value < 0.05 for all). The mean dose to the marrow was significantly lower with VMAT (59.05 vs 81.9 cGy with P value < 0.05). The overall LAR was significantly lower with VMAT as compared to the conventional plan (0.357% vs 0.398%, P value < 0.05). Compared to the conventional technique, VMAT provides better OAR dosimetry for lung irradiation (a prescription dose of 1.0 Gy or more) in COVID-19 pneumonia. VMAT significantly reduces the risk of RIC. We therefore suggest if lung LDRT is used for COVID-19 patients, VMAT is the preferred technique for a prescription dose of ≥1.0 Gy.

DIBH reduces right coronary artery and lung radiation dose in right breast cancer loco-regional radiotherapy

To determine whether deep inspiratory breath-hold (DIBH) reduces dose to organs-at-risk (OAR), in particular the right coronary artery (RCA), in women with breast cancer requiring right-sided post-mastectomy radiotherapy (PMRT) including internal mammary chain (+IMC) radiotherapy (RT). Fourteen consecutive women requiring right-sided PMRT + IMC were retrospectively identified. Nodal delineation was in accordance with European Society for Radiology and Oncology (ESTRO) guidelines and tangential chest wall fields marked. Patients were planned with Anisotropic Analytical Algorithm using free-breathing (FB) and DIBH datasets. Dose was calculated using Acuros External Beam algorithm. FB and DIBH dose comparisons were analyzed for heart, RCA and right lung, as were chest wall and IMC planning target volumes (PTVs). DIBH vs FB resulted in median decreases of: the RCA mean dose by 0.6Gray (Gy) (interquartile range (IQR) 0.1, 1.9) (p = 0.002), RCA max dose by 1.8Gy (IQR 0.8, 6.1) (p = 0.002), and V5Gy by 2.9% (IQR 0.0, 37.2) (p = 0.016). RCA data indicated no statistically significant dosimetric reduction ≥10Gy. A median reduction of 1.7Gy (c -0.0, 7.1) (p = 0.019) in maximum heart dose was recorded with DIBH vs FB; no significant difference was observed in other heart and left anterior descending coronary artery parameters. The median reduction in right lung mean dose was 2.8Gy for DIBH vs FB plans (IQR 1.6, 3.6) (p = 0.001); significant median reductions of V5Gy, V20Gy, and V30Gy were all achieved with DIBH. Chest wall PTV coverage did not significantly differ between DIBH and FB plans; IMC dosimetric coverage improved with use of DIBH (V47.5Gy, V45Gy, V42Gy). DIBH reduced OAR dose in right-sided PMRT + IMC patients. A novel finding was that DIBH decreased RCA dose. Heart and right lung dose were also decreased with DIBH, whilst optimally dosed PTVs were maintained.

Setup time analysis for stereotactic body radiotherapy in O-ring linear accelerator without rotational correction.

This study analyse setup time (ST) and frequency of on-board imaging for stereotactic abdomen (liver, stomach), lung, and spine radiotherapy in the absence of automatic rotational correction. Total 53 stereotactic body radiotherapy (SBRT) patients, 28 of abdomen, 19 lung, and 6 spine treated for 230 sessions in O-ring gantry accelerator were evaluated for ST analysis. The mean setup time for all patients, abdomen, lung, and spine cases were 7.7 ± 7.4min, 9.2 ± 9.2min, 6.3 ± 4.1min, and 5.5 ± 3.3min, respectively. Median number CBCT was 2. 96% of cases had a CBCT between 1 and 3, and 9 (4%) had ≥ 4 CBCTs. Overall, 38.1%, 35.5%, 22.1%, 2.2%, and 2.2% of setup time fall intowindow of 0-5min, 5-10min, 10-20min, 20-30min, and > 30min. Most difficult challenge is to negotiate with unknown rotational errors. It will be easy to dealt with them without automatic rotational correction if values are known.

Abstract 7396: Development of deep neural networks that guide more individualized radiotherapy to the lung

Abstract Introduction: Radiotherapy is dependent on an expert-based model that impedes implementation of many potentially useful applications that could aid decision makers. This model is a barrier to a learning healthcare system due to noise introduced by decision-maker variation. Surmounting this barrier will require compelling clinical outcome data and highly useful and accurate information systems. We sought to develop new augmented-intelligence capabilities to better predict both high-dose lung irradiation treatment efficacy (i.e., local tumor control) and toxicity (i.e., radiation-induced pneumonitis). Methods: We curated one of the largest datasets of lung stereotactic body radiotherapy (SBRT) datasets globally (~1200 cases). We input pre-therapy lung computed tomography (CT) images using a bounding box approach that captures the gross tumor volume and adjacent normal lung into a multi-task deep neural network to generate an image fingerprint that predicts local failures after treatment. Separately, we input axial slices from CT scans of the lung into convolutional neural network (CNN) and trained using an outcome per slice method. We then aggregated intra-patient slices into a recurrent neural network (RNN) to estimate individual patient risk for pneumonitis. We validated our findings with the independent study cohort. Risk scores for local failure and pneumonitis were combined with clinical variables to assess the relative contribution of the deep learning-derived image risk scores. Results: A total of 1045 patients met our eligibility criteria. Radiation treatments in patients with high local failure risk scores failed at a significantly higher rate than in patients with low scores; 3-year cumulative incidence of local failure in the internal study cohort was 20·3% (16·0-24·9) in patients with high scores and 5·7% (95% CI 3·5-8·8) in patients with low scores (hazard ratio [HR]=3·64 [95% CI 2·19-6·05], p&amp;lt;0·0001). Models that included the local failure risk score and clinical variables predicted treatment failures with a concordance index (C-index) of 0·72 (95% CI 0·67-0·77), a significant improvement compared with classical radiomics (p&amp;lt;0·0001) or clinical variables (p&amp;lt;0·0001) alone. Radiation pneumonitis risk scores were highly predictive of toxicity, with an accuracy and CI of 0.78 (95% CI 0.72-0.85). A model that includes dosimetry variates (V20), improved the CI to 0.85 (95% CI 0.80-0.90). Conclusions: The image-based deep learning frameworks developed herein represent the first opportunity to use medical images to individualize radiotherapy dose and toxicity predictions. Our results signify a new roadmap for deep learning-guided predictions and treatment guidance in the image-replete and highly standardized discipline of radiation oncology. A phase 2 study assessing machine-derived dose predictions is currently enrolling patients. Citation Format: Mohamed Abazeed. Development of deep neural networks that guide more individualized radiotherapy to the lung [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7396.

Heart and Lung Dose as Predictors of Overall Survival in Patients With Locally Advanced Lung Cancer. A National Multicenter Study

IntroductionIt is an ongoing debate how much lung and heart irradiation impact overall survival (OS) after definitive radiotherapy for lung cancer. This study uses a large national cohort of patients with locally advanced NSCLC to investigate the association between OS and irradiation of lung and heart. MethodsTreatment plans were acquired from six Danish radiotherapy centers, and patient characteristics were obtained from national registries. A hybrid segmentation tool automatically delineated the heart and substructures. Dose-volume histograms for all structures were extracted and analyzed using principal component analyses (PCAs). Parameter selection for a multivariable Cox model for OS prediction was performed using cross-validation based on bootstrapping. ResultsThe population consisted of 644 patients with a median survival of 26 months (95% confidence interval [CI]: 24–29). The cross-validation selected two PCA variables to be included in the multivariable model. PCA1 represented irradiation of the heart and affected OS negatively (hazard ratio, 1.14; 95% CI: 1.04–1.26). PCA2 characterized the left-right balance (right atrium and left ventricle) irradiation, showing better survival for tumors near the right side (hazard ratio, 0.92; 95% CI: 0.84–1.00). Besides the two PCA variables, the multivariable model included age, sex, body-mass index, performance status, tumor dose, and tumor volume. ConclusionsBesides the classic noncardiac risk factors, lung and heart doses had a negative impact on survival, while it is suggested that the left side of the heart is a more radiation dose–sensitive region. The data indicate that overall heart irradiation should be reduced to improve the OS if possible.

Protective Effects of Alpha-lipoic Acid, Resveratrol, and Apigenin Against Oxidative Damages, Histopathological Changes, and Mortality Induced by Lung Irradiation in Rats.

This study investigated the protective effects of three antioxidants on radiationinduced lung injury. Oxidative stress is one of the key outcomes of radiotherapy in normal tissues. It can induce severe injuries in lung tissue, which may lead to pneumonitis and fibrosis. Recently, interest in natural chemicals as possible radioprotectors has increased due to their reduced toxicity, cheaper price, and other advantages. The present study was undertaken to evaluate the radioprotective effect of Alpha-lipoic Acid (LA), Resveratrol (RVT), and Apigenin (APG) against histopathological changes and oxidative damage and survival induced by ionizing radiation (IR) in the lung tissues of rats. First, the lung tissue of 50 mature male Wistar rats underwent an 18 Gy gamma irradiation. Next, the rats were sacrificed and transverse sections were obtained from the lung tissues and stained with hematoxylin and eosin (H and E) and Mason trichrome (MTC) for histopathological evaluation. Then, the activity of Glutathione peroxidase (GPx), Superoxide Dismutase (SOD), and Malondialdehyde (MDA) was measured by an ELISA reader at 340, 405, and 550 nm. Based on the results of this study, IR led to a remarkable increase in morphological changes in the lung. However, APG, RVT, and LA could ameliorate the deleterious effects of IR in lung tissue. IR causes an increase in GPX level, and APG+IR administration causes a decrease in the level of GPX compared to the control group. Also, the results of this study showed that RVT has significant effects in reducing MDA levels in the short term. In addition, compared to the control group, IR and RVT+IR decrease the activity of SOD in the long term in the lung tissues of rats. Also, the analysis of results showed that weight changes in IR, LA+IR, APG+IR, and control groups were statistically significant. APG and RVT could prevent tissue damage induced by radiation effects in rat lung tissues. Hence, APG, LA, and RVT could provide a novel preventive action with their potential antioxidant anti-inflammatory properties, as well as their great safety characteristic.

Lung Function Evaluated By Structured Light Plethysmography in Children After Lung Surgery: A Preliminary Analysis.

Background: Structured light plethysmography (SLP) is a novel light-based method that captures chest wall movements to evaluate tidal breathing. Methods: Thirty-two children who underwent lung surgery were enrolled. Their clinical history was collected along with spirometry and SLP. Results: Median age of surgery was 9 months (interquartile range 4-30). Most frequent diagnosis was congenital pulmonary airway malformation (14/32), then pulmonary sequestration (9/32), tumor (5/32), and bronchogenic cyst (4/32). The most frequent surgical approach was lobectomy (59%), segmentectomy (38%), and complete resection (3%). More than 80% had surgery when younger than 3 years of age. Eight patients had short-term complications (pleural effusion was the most frequent), while long-term effects were reported in 15 patients (19% recurrent cough, 13% thoracic deformities, 13% airway infections, 9% wheezing, 6% reduced exercise tolerance, and 3% columnar deformities). Spirometry was normal in 9/22 patients. Nine patients had a restrictive pattern, while 4 showed a mild bronco-reactivity. Ten patients did not perform spirometry because of young age. SLP revealed the presence of obstructive pattern in 10% of patients (IE50 > 1.88) and showed a significant difference between the two hemithorax in 29% of patients. Discussion: SLP may be a new method to evaluate lung function, without collaboration and radiation exposure, in children who underwent lung resection, also in preschool age.

A 3D-printed phantom for stereotactic body radiation therapy simulation.

In modern radiation therapy for lung cancer, examining the uncertainty between tumor motion and beam delivery is vitally important. To lower the radiation dose delivery to the patient's normal tissue, narrowing the irradiation field margin to hit the tumor accurately is critical. Thus we proposed a phantom that simulates the thorax and lung tumor's motions by employing a 3D printing technique. The lung tumor is controlled by a linear miniature Delta robot arm, with a maximum displacement of 20 mm in each direction. When we simulated the thoracic breathing movements at 12 mm in A-P (Anterior-Posterior), the control errors were within 10%. The average tracking errors of the prosthetic tumor were within 1.1 mm. Therefore, the 3D-printed phantom with a robot arm can provide a reliable simulation for training and dosimetry measurement before lung radiotherapy, especially SBRT.

Development of a Radiation-induced Pulmonary Fibrosis Partial Body Irradiation Model in C57BL/6 Mice.

With the current volatile geopolitical climate, the threat of nuclear assault is high. Exposure to ionizing radiation from either nuclear incidents or radiological accidents often lead to major harmful consequences to human health. Depending on the absorbed dose, the symptoms of the acute radiation syndrome and delayed effects of acute radiation exposure (DEARE) can appear within hours, weeks to months. The lung is a relatively radiosensitive organ with manifestation of radiation pneumonitis as an acute effect, followed by apparent fibrosis in weeks or even months. A recently developed, first-of-its-kind murine model for partial-body irradiation (PBI) injury, which can be used to test potential countermeasures against multi-organ damage such as gastrointestinal (GI) tract and lungs was used for irradiation, with 2.5% bone marrow spared (BM2.5-PBI) from radiation exposure. Long-term damage to lungs from radiation was evaluated using µ-CT scans, pulmonary function testing, histopathological parameters and molecular biomarkers. Pulmonary fibrosis was detected by ground glass opacity observed in µ-CT scans of male and female C57BL/6J mice 6-7 months after BM2.5-PBI. Lung mechanics assessments pertaining to peripheral airways suggested fibrotic lungs with stiffer parenchymal lung tissue and reduced inspiratory capacity in irradiated animals 6-7 months after BM2.5-PBI. Histopathological evaluation of the irradiated lungs revealed presence of focal and diffuse pleural, and parenchymal inflammatory and fibrotic lesions. Fibrosis was confirmed by elevated levels of collagen when compared to lungs of age-matched naïve mice. These findings were validated by findings of elevated levels of pro-fibrotic biomarkers and reduction in anti-inflammatory proteins. In conclusion, a long-term model for radiation-induced pulmonary fibrosis was established, and countermeasures could be screened in this model for survival and protection/mitigation or recovery from radiation-induced pulmonary damage.

Inverse planning of lung radiotherapy with photon and proton beams using a discrete ordinates Boltzmann solver

Objective. A discrete ordinates Boltzmann solver has recently been developed for use as a fast and accurate dose engine for calculation of photon and proton beams. The purpose of this study is to apply the algorithm to the inverse planning process for photons and protons and to evaluate the impact that this has on the quality of the final solution. Approach. The method was implemented into an iterative least-squares inverse planning optimiser, with the Boltzmann solver used every 20 iterations over the total of 100 iterations. Elemental dose distributions for the intensity modulation and the dose changes at the intermediate iterations were calculated by a convolution algorithm for photons and a simple analytical model for protons. The method was evaluated for 12 patients in the heterogeneous tissue environment encountered in radiotherapy of lung tumours. Photon arc and proton arc treatments were considered in this study. The results were compared with those for use of the Boltzmann solver solely at the end of inverse planning or not at all. Main results. Application of the Boltzmann solver at the end of inverse planning shows the dose heterogeneity in the planning target volume to be greater than calculated by convolution and empirical methods, with the median root-mean-square dose deviation increasing from 3.7 to 5.3 for photons and from 1.9 to 3.4 for proton arcs. Use of discrete ordinates throughout inverse planning enables homogeneity of target coverage to be maintained throughout, the median root-mean-square dose deviation being 3.6 for photons and 2.3 for protons. Dose to critical structures is similar with discrete ordinates and conventional methods. Time for inverse planning with discrete ordinates takes around 1–2 h using a contemporary computing environment. Significance. By incorporating the Boltzmann solver into an iterative least squares inverse planning optimiser, accurate dose calculation in a heterogeneous medium is obtained throughout inverse planning, with the result that the final dose distribution is of the highest quality.

Access to and Timeliness of Lung Cancer Surgery, Radiation Therapy, and Systemic Therapy in New Zealand: A Universal Health Care Context.

Lung cancer is the biggest cancer killer of indigenous peoples worldwide, including Māori people in New Zealand. There is some evidence of disparities in access to lung cancer treatment between Māori and non-Māori patients, but an examination of the depth and breadth of these disparities is needed. Here, we use national-level data to examine disparities in access to surgery, radiation therapy and systemic therapy between Māori and European patients, as well as timing of treatment relative to diagnosis. We included all lung cancer registrations across New Zealand from 2007 to 2019 (N = 27,869) and compared access with treatment and the timing of treatment using national-level inpatient, outpatient, and pharmaceutical records. Māori patients with lung cancer appeared less likely to access surgery than European patients (Māori, 14%; European, 20%; adjusted odds ratio [adj OR], 0.82 [95% CI, 0.73 to 0.92]), including curative surgery (Māori, 10%; European, 16%; adj OR, 0.72 [95% CI, 0.62 to 0.84]). These differences were only partially explained by stage and comorbidity. There were no differences in access to radiation therapy or systemic therapy once adjusted for confounding by age. Although it appeared that there was a longer time from diagnosis to radiation therapy for Māori patients compared with European patients, this difference was small and requires further investigation. Our observation of differences in surgery rates between Māori and European patients with lung cancer who were not explained by stage of disease, tumor type, or comorbidity suggests that Māori patients who may be good candidates for surgery are missing out on this treatment to a greater extent than their European counterparts.

Technical note: A small animal irradiation platform for investigating the dependence of the FLASH effect on electron beam parameters.

The recent rediscovery of the FLASH effect, a normal tissue sparing phenomenon observed in ultra-high dose rate (UHDR) irradiations, has instigated a surge of research endeavors aiming to close the gap between experimental observation and clinical treatment. However, the dependences of the FLASH effect and its underpinning mechanisms on beam parameters are not well known, and large-scale in vivo studies using murine models of human cancer are needed for these investigations. To commission a high-throughput, variable dose rate platform providing uniform electron fields(≥15cm diameter) at conventional (CONV) and UHDRs for in vivo investigations of the FLASH effect and its dependences on pulsed electron beam parameters. A murine whole-thoracic lung irradiation (WTLI) platform was constructed using a 1.3cm thick Cerrobend collimator forming a 15 × 1.6 cm2 slit. Control of dose and dose rate were realized by adjusting the number of monitor units and couch vertical position, respectively. Achievable doses and dose rates were investigated using Gafchromic EBT-XD film at 1cm depth in solid water and lung-density phantoms. Percent depth dose (PDD) and dose profiles at CONV and various UHDRs were also measured at depths from 0 to 2cm. A radiation survey was performed to assess radioactivation of the Cerrobend collimator by the UHDR electron beam in comparison to a precision-machined copper alternative. This platform allows for the simultaneous thoracic irradiation of at least three mice. A linear relationship between dose and number of monitor units at a given UHDR was established to guide the selection of dose, and an inverse-square relationship between dose rate and source distance was established to guide the selection of dose rate between 20 and 120Gy·s-1 . At depths of 0.5 to 1.5cm, the depth range relevant to murine lung irradiation, measured PDDs varied within±1.5%. Similar lateral dose profiles were observed at CONV and UHDRs with the dose penumbrae widening from 0.3mm at 0cm depth to 5.1mm at 2.0cm. The presence of lung-density plastic slabs had minimal effect on dose distributions as compared to measurements made with only solid water slabs. Instantaneous dose rate measurements of the activated copper collimator were up to two orders of magnitude higher than that of the Cerrobend collimator. A high-throughput, variable dose rate platform has been developed and commissioned for murine WTLI electron FLASH radiotherapy. The wide field of our UHDR-enabled linac allows for the simultaneous WTLI of at least three mice, and for the average dose rate to be modified by changing the source distance, without affecting dose distribution. The platform exhibits uniform, and comparable dose distributions at CONV and UHDRs up to 120Gy·s-1 , owing to matched and flattened 16 MeV CONV and UHDR electron beams. Considering radioactivation and exposure to staff, Cerrobend collimators are recommended above copper alternatives for electron FLASH research. This platform enables high-throughput animal irradiation, which is preferred for experiments using a large number of animals, which are required to effectively determine UHDR treatment efficacies.

The Predictive Value of 8-Hydroxy-Deoxyguanosine (8-OHdG) Serum Concentrations in Irradiated Non-Small Cell Lung Carcinoma (NSCLC) Patients.

Ionizing radiation is strongly linked to direct or indirect DNA damage, as with the production of reactive oxygen species (ROS), which in turn produce DNA damage products, such as 8-hydroxy-2-deoxyguanosine (8-OHdG). In this study, we aimed to investigate the formation of 8-OHdG after irradiation in patients with non-small cell cancer (NSCLC) and its use as a biomarker. Sixteen patients with squamous and thirty-six patients with non-squamous pathology were included. An enzyme-linked-immunosorbent assay (ELISA) was performed before and after radiation. A dose-dependent relationship was confirmed: 8-OHdG plasma concentrations, increased in the total of NSCLC patients and specifically with a linear correlation in non-squamous pathology; in squamous histology, after an initial increase, a significant decrease followed after 20 Gy dose of irradiation. The pretreatment total irradiated tumor volume (cm3) was positively correlated with 8-OHdG levels in patients with squamous histology. When plotting the 8-OHdG plasma concentration at a 10 Gy irradiation dose to the baseline, the AUC was 0.873 (95% CI 0.614-0.984), p < 0.0001, with an associated criterion value of >1378 as a cutoff (sensitivity 72.7%, specificity 100%). When normalizing this ratio to BSA, the associated criterion cutoff value was >708 (sensitivity of 100%, specificity 80%). Lastly, 8-OHdG levels were closely related with the development of radiation-induced toxicities.

Multi-phase failure modes and effects analysis for low dose bilateral whole lung irradiation of COVID-19 positive patients requiring respiratory ventilation.

To identify high-priority risks in a clinical trial investigating the use of radiation to alleviate COVID-19 pneumonia using a multi-phase failure modes and effects analysis (FMEA). A comprehensive FMEA survey of 133 possible causes of failure was developed for the clinical trial workflow (Phase I). The occurrence, severity, and detection risk of each possible cause of failure was scored by three medical physicists. High-risk potential failure modes were identified using the risk priority number (RPN) and severity scores, which were re-scored by 13 participants in radiation oncology (Phase II). Phase II survey scores were evaluated to identify steps requiring possible intervention and examine risk perception patterns. The Phase II participants provided consensus scores as a group. Thirty high-priority failure modes were selected for the Phase II survey. Strong internal consistency was shown in both surveys using Cronbach's alpha (αc≥0.85). The 10 failures with the largest median RPN values concerned SARS-CoV-2 transmission (N=6), wrong treatment (N=3), and patient injury (N=1). The median RPN was larger for COVID-related failures than other failure types, primarily due to the perceived difficulty of failure detection. Group re-scoring retained 8/10 of the highest-priority risk steps that were identified in the Phase II process, and discussion revealed interpretation differences of process steps and risk evaluation. Participants who were directly involved with the trial working group had stronger agreement on severity scores than those who were not. The high ranking of failures concerning SARS-CoV-2 transmission suggest that these steps may require additional quality management intervention when treating critically ill COVID-19+ patients. The results also suggest that a multi-phase FMEA survey led by a facilitator may be a useful tool for assessing risks in radiation oncology procedures, supporting future efforts to adapt FMEA to clinical procedures.

Low-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma.

A tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy. Tissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs. TLS+, TLSHigh, TLS+GC+ and CD8High within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs. We successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.

Dosimetric characterization of a novel UHDR megavoltage X-ray source for FLASH radiobiological experiments

A first irradiation platform capable of delivering 10 MV X-ray beams at ultra-high dose rates (UHDR) has been developed and characterized for FLASH radiobiological research at TRIUMF. Delivery of both UHDR (FLASH mode) and low dose-rate conventional (CONV mode) irradiations was demonstrated using a common source and experimental setup. Dose rates were calculated using film dosimetry and a non-intercepting beam monitoring device; mean values for a 100 μA pulse (peak) current were nominally 82.6 and 4.40 × 10−2 Gy/s for UHDR and CONV modes, respectively. The field size for which > 40 Gy/s could be achieved exceeded 1 cm down to a depth of 4.1 cm, suitable for total lung irradiations in mouse models. The calculated delivery metrics were used to inform subsequent pre-clinical treatments. Four groups of 6 healthy male C57Bl/6J mice were treated using thoracic irradiations to target doses of either 15 or 30 Gy using both FLASH and CONV modes. Administration of UHDR X-ray irradiation to healthy mouse models was demonstrated for the first time at the clinically-relevant beam energy of 10 MV.

Rosmarinic Acid Alleviates Radiation-Induced Pulmonary Fibrosis by Downregulating the tRNA N7-Methylguanosine Modification-Regulated Fibroblast-to-Myofibroblast Transition Through the Exosome Pathway.

Radiation-induced pulmonary fibrosis (RIPF) is a common complication after radiotherapy in thoracic cancer patients, and effective treatment methods are lacking. The purpose of this study was to investigate the protective effect of rosmarinic acid (RA) on RIPF in mice as well as the mechanism involved. m7G-tRNA-seq and tRNA-seq analyses were conducted to identify m7G-modified tRNAs. Western blotting, immunohistochemistry, northwestern blotting, northern blotting, immunofluorescence, wound-healing assays and EdU experiments were performed to explore the molecular mechanism by which RA regulates fibroblast-to-myofibroblast transformation (FMT) by affecting the exosomes of lung epithelial cells. Ribo-seq and mRNA-seq analyses were used to explore the underlying target mRNAs. Seahorse assays and immunoprecipitation were carried out to elucidate the effects of RA on glycolysis and FMT processes via the regulation of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) acetylation. We found that RA had an antifibrotic effect on the lung tissues of RIPF model mice and inhibited the progression of FMT through exosomes derived from lung epithelial cells. Mechanistically, RA reduced the transcription and translation efficiency of sphingosine kinase 1 in lung fibroblasts by decreasing N7-methylguanosine modification of tRNA, downregulating the expression of tRNAs in irradiated lung epithelial cell-derived exosomes, and inhibiting the interaction between sphingosine kinase 1 and the N-acetyltransferase 10 protein in fibroblasts. Furthermore, the acetylation and cytoplasmic translocation of PFKFB3 were reduced by exosomes derived from irradiated lung epithelial cells, which following RA intervention. This suppression of the FMT process, which is triggered by glycolysis, and ultimately decelerating the progression of RIPF. These findings suggest that RA is a potential therapeutic agent for RIPF.

Patient-specific Effective Dose Estimation from Dose-Length Product in Lung Computed Tomography Using Monte Carlo Simulation.

Computed tomography (CT) imaging has a large portion in the dose of patients from radiological procedures; therefore, accurate calculation of radiation risk estimation in this modality is inevitable. In this study, a method for determining the patient-specific effective dose using the dose-length product (DLP) index in lung CT scan using Monte Carlo (MC) simulation is introduced. EGSnrc/BEAMnrc MC code was used to simulate a CT scanner. The DOSxyznrc simulation code was used to simulate a specific voxelized phantom from the patient's lungs and irradiate it according to X-ray parameter of routing lung CT scan, and dose delivered to thorax organs was calculated. Three types of phantoms were simulated according to three different body habits (slim, standard, and fat patients) in two groups of men and women. A factor was used to convert the relative dose per particle in MC code to the absolute dose. The dose was calculated in all lung organs, and the effective dose was calculated for all three groups of patient body habits. DLP index and volume CT dose index (CTDIvol) were extracted from the patient's dose report in the CT scanner. The DLP to effective dose conversion factor (k-factor) for patients with different body habitus was calculated. Lung radiation dose in slim, standard, and fat patients in men was 0.164, 0.103, and 0.078 mGy/mAs and in women was 0.164, 0.105, and 0.079 mGy/mAs, respectively. The k-factor in the group of slim patients, especially in women, was higher than in other groups. CT scan dose indexes for slim patients are reported to be underestimated in studies. The dose report in CT scan systems should be modified in proportion to the patient's body habitus, to accurately estimate the radiation risk.

Dosimetric Comparison of 3D Conformal Radiotherapy (3D-CRT), Intensity-Modulated Radiotherapy (IMRT), and Volumetric-Modulated Arc Therapy (VMAT) in Cardiac-Sparing Whole Lung Irradiation.

Introduction Whole lung irradiation (WLI) is used for the treatment of lung metastasis in Wilms tumor and Ewing sarcoma; however, cardiac complications are one of the concerns. We report the dosimetric advantages of WLI using volumetric-modulated arc therapy (VMAT) and present a dosimetric comparison of VMAT with anteroposterior-posteroanterior (AP-PA) and static-field intensity-modulated radiation therapy (IMRT). Additionally, we evaluated the dosimetric impact of respiratory motion and intra-fractional motion during VMAT treatment. Methods Seven patients were recruited in this study. AP-PA, IMRT, one-isocenter (1-IC) VMAT, and 2-IC VMAT were planned on the maximum inspiration and expiration CT, respectively. The prescribed dose was 15 Gy in 10 fractions. To determine the effects of respiratory motion, the CT series was replaced and the dose was evaluatedwhile maintaining the beam information. To determine the effect of patient motion, perturbed dose calculations were performed using a two-IC VMAT. The perturbation doses were calculated by shifting only the IC of the one side beam by 3mm or 5 mm in the right-to-left (RL) direction. Results The mean heart dose was 1467.0 cGy, 790.0 cGy, 764.2 cGy, and 738.4 cGy for AP-PA, IMRT, 1-IC VMAT, and 2-IC VMAT, respectively. When the expiration CT plan was recalculated with inspiration CT, Dmax increased approximately by 8%. In the 2-IC VMAT plan, the D50%, D98%, and D2% dose differences were within ±2%, even with a 5 mm IC shift. Conclusion We confirmed a significant dosimetric advantage of VMAT over other techniques. 2-IC VMAT should be consideredan effective treatment option during irradiation for large target volumes.