Predicting Radiation Pneumonitis Integrating Clinical Information, Medical Text, and 2.5D Deep Learning Features in Lung Cancer.

Exploring radiation pneumonitis associated with immune checkpoint inhibitors: Insights from the FAERS pharmacovigilance database

Hypofractionated radiotherapy (RT) is the standard adjuvant treatment for breast cancer patients after surgery. The recent results of the FAST-FORWARD trial on ultra-hypofractionated RT, delivered over one week, support a viable alternative regimen for early-stage breast cancer. Whether the addition of a tumor bed boost could further improve patient outcomes is still under investigation. We report the results of a single-center prospective study involving 26 early-stage (T1, 2N0) breast cancer patients treated with whole-breast RT consisting of five daily fractions of 5.2 Gy (FAST-FORWARD regimen) followed by a tumor-bed boost of three daily fractions of 3 Gy. Grade 1 early breast toxicity (skin changes and altered breast consistency) was documented in 20% of patients within the first 3 months after treatment completion. No events of acute pneumonitis were reported. Whole-breast and tumor-bed boost volumes did not affect the occurrence of breast toxicity. Minimal radiation-induced lung injury (grade 1) was noted in 95.8% of patients, while one patient (4.2%) developed grade 2 lung toxicity, which was later downgraded to grade 1 at the 12-month post-RT time point. With a median follow-up of 72 months, none of the patients presented with locoregional recurrence or distant metastases. The present study highlights the safety of a hypofractionated RT boost to the tumor bed after ultra-hypofractionated whole-breast RT. No clear evidence exists to date regarding the superiority of delivering a tumor bed boost after ultra-hypofractionated RT or the specific patient subgroups to which a boost should be prescribed.

Background: Radiation-induced pulmonary fibrosis (RPF) remains a major burden of successful lung cancer radiotherapy. Clinically validated drugs targeting RPF remains scarce. Methods: We employed a transcriptome-based drug repurposing approach using REMEDY, a computational platform built on the Library of Integrated Network-Based Cellular Signatures (LINCS). Differentially expressed genes (DEGs) derived from radiation-induced lung injury (RILI) models were used as a query to identify compounds capable of reversing pro-fibrotic expression profile. Among top-ranked candidates, homoharringtonine (HHT), an FDA-approved protein synthesis inhibitor, was selected for experimental validation. Anti-fibrotic effects of HHT were assessed using an optimized in vitro fibrotic model based on activation of MRC-5 human lung fibroblasts. Complementary in silico molecular docking analyses were also conducted to explore the mechanistic basis of HHT’s actions. This represents the first transcriptome-guided, LINCS-based drug repurposing study applied specifically to radiation-induced pulmonary fibrosis, utilizing RPF-derived molecular signatures rather than general fibrosis-related datasets. Results: HHT significantly attenuated key fibrotic phenotypes, including fibroblast proliferation, myofibroblast differentiation, and extracellular matrix (ECM) production. Notably, HHT suppressed expression of cyclin D1 and α-smooth muscle actin (α-SMA), and reduced collagen deposition. Mechanistic investigations revealed that HHT modulates two pro-fibrotic pathways: RhoA/ROCK and Wnt/β-catenin signaling. Molecular docking further suggested that HHT may directly interact with fibrosis-related receptors such as integrins and Frizzled, providing structural insight into its anti-fibrotic potential. These findings underscore the novelty of reassigning HHT to a radiation-specific fibrotic context using a signature-reversal strategy uniquely tailored to RPF biology. Conclusions: Our findings identify HHT as a promising treatment of RPF, offering a dual mechanism of action—interruption of protein synthesis and targeted inhibition of fibrotic signaling pathways. This study highlights the value of computational drug repurposing platforms for accelerating therapeutic discovery. Further preclinical investigations are warranted to evaluate HHT’s in vivo efficacy and clinical applicability in RPF.

Programmed cell death (PCD) has been implicated in the development and progression of radiation-induced lung injury (RILI). However, the specific PCD subtype most relevant to RILI remains unclear. We integrated bulk transcriptome datasets (GSE25295, GSE41789) and a single-cell RNA sequencing dataset (GSE211713) from lung tissue to analyze the cell type-specific PCD patterns in RILI. Differentially expressed genes (DEGs) were identified using limma for bulk data and Seurat for scRNA-seq data. PCD-related DEGs were extracted based on curated gene sets, followed by functional enrichment analyzes. Intercellular communication was assessed using CellChat, and transcription factor (TF) regulatory networks were constructed using RcisTarget and AUCell. Bulk transcriptome analyzes revealed 465 radiation-responsive genes enriched in inflammatory and immune pathways. Among multiple PCD subtypes, NETosis, a specialized form of neutrophil-driven PCD characterized by the release of neutrophil extracellular traps (NETs) composed of DNA and granule proteins, was the most significantly enriched in irradiated lung tissue (FDR < 0.05). Neutrophils showed the highest NETosis scores, accompanied by activation of MAPK, IL-17, TNF, and TLR signaling. CellChat analysis revealed enhanced bidirectional communication between neutrophils and AM1/IM1 through SPP1-CD44, ANXA1-FPR, and CCL/CXCL signaling. NETosis strongly correlated with M2 polarization, and key TFs (Mafg, Mxd4, Klf4, Max, Cux1, and Irf9) were identified as putative upstream regulators driving M2 macrophage polarization and neutrophil activation. Our findings highlight NETosis, mediated by enhanced neutrophil-macrophage crosstalk and TF-driven immune polarization.

Background: Cancer is listed among the leading causes of mortality and morbidity worldwide, with approx 19.97 million newly diagnosed cases and 9.74 million cancer deaths in 2022. 6,66,103 cases died out of 2.29 million new cases of breast cancer diagnosed in 2022. Radiotherapy is an integral component of the multidisciplinary management of breast cancer. Hypofractionated radiation therapy is radiation treatment in which the total dose of radiation is divided into large doses and treatments are given once a day or less often. This study is intended to compare a hypo-fractionated radiotherapy regimen delivered over 2.5 weeks as 39 Gy in 13 fractions at 3Gy per fraction against 40 Gy in 15 fractions at 2.67Gy per fraction over 3 weeks after mastectomy for early adverse reactions as radiation pneumonitis, dermatitis, dysphagia, and arm edema. Material and Methods: The study was conducted at Acharya Tulsi Regional Cancer Treatment and Research Institute, Sardar Patel Medical College, Bikaner. It was done on 60 histologically proven postoperative, post-chemotherapy, early breast cancer with a mean age of 50.7 years and 54.1 years respectively Arm A and Arm B. Patients were treated by radiotherapy and randomized into either of the two arms Arm A(Study) and Arm B(Control). On ARM A Hypo-fractionated radiotherapy 39Gy/13# in 3Gy/# and on ARM B Hypo-fractionated radiotherapy 40Gy/15# in 2.67Gy/# postoperative, post-chemotherapy in terms of radiation pneumonitis, dysphagia, skin reaction and arm edema were given. Toxicities were graded at 1st week, 3rd week, 1st, 3rd, 6th and 9th months. Data was analyzed using percentage, mean, and p-value. Results: The majority of the patients were in their 51 to 60 years of life and all patients were female. Majority of the population had ECOG Performance Score of 1. Histologically, patients had infiltrating ductal carcinoma non otherwise specified. In study vs control arm where 3(10%) vs 3(10%) patients were I, 21(70%) vs 20(66.67%) in II A, 6(20%) vs 7(23.33%) in II B respectively. All 30(100%) patients in both arms completed treatment. In this study pneumonitis was not found to be statistically significant in both arms during follow-up of radiotherapy at 1st week, 3rd week,1st month, 3rd month, 6th month, and 9th month as evident by p-value (≥ 1.000 in grade 0, 0.268 for Grade 1, ≥1.000 in grade 2). The grade of dysphagia was not statistically significant when compared to both arms. (p ≥ 1.000 in grade 0, p ≥ 0.200 in grade 1, p ≥ 0.721 in grade 2). Dysphagia grade 2 toxicity was found only in 2 patients (6.6%) in each arm. Arm edema was not statistically significant in both arms. In both arms, patients of grade 2 arm edema increased at every follow-up and maximum [8(26.6%) in Arm-A and 5 (16.6%) in Arm-B] at 9-month follow-up (P value 0.185). Grade 1st skin reaction was observed in 26.66% of patients in arm A and 20.00% of patients in arm B which is statistically significant (P value 0.049). Conclusions: In conclusion, both hypo-fractionated arms were comparable in terms of acute toxicity. However, more such trials with a larger sample size and larger follow-up are required to have more concrete evidence for late toxicities and locoregional control.

Abstract In contemporary oncologic care, ionizing radiation (IR) is a crucial therapeutic modality for a wide range of cancers. However, a significant challenge in thoracic radiotherapy is the unavoidable exposure of adjacent lung tissue, which has a high intrinsic radiosensitivity. This often results in radiation-induced lung injury (RILI), a common and dose-limiting clinical complication. The pathogenesis of RILI is mechanistically associated with IR-induced cytosolic double-strand DNA (dsDNA) breaks, which strongly enhance the activation of the stimulator of interferon genes (STING) signaling pathway. Nevertheless, the persistent activation of this innate immune cascade leads to an excessive production of type I interferons (IFN-α/β) and numerous pro-inflammatory cytokines. We summarize the current evidence on the role of IR-stimulated cyclic GMP-AMP synthase (cGAS)-STING signaling in driving the pathological progression from radiation pneumonitis to pulmonary fibrosis. The elucidation of IR-mediated cGAS-STING signaling in RILI is crucial for developing innovative adjuvant strategies aimed at improving the therapeutic ratio of radiotherapy by simultaneously enhancing tumor cell kill and reducing normal lung injury. Additionally, this review discusses the emergence of cGAS-STING inhibitors as a promising new approach for managing RILI. We aim to provide a critical framework for exploring novel RILI management strategies and to inform the rational development of therapeutics targeting the cGAS-STING axis.

ObjectiveImmune checkpoint inhibitors plus thoracic radiotherapy (RT) may magnify the radiation pneumonitis (RP) risk. Data on the risk for symptomatic RP in small cell lung cancer (SCLC) patients following RT after induction immunochemotherapy using anti-programmed cell death protein-1 monoclonal antibody Serplulimab, cisplatin plus etoposide are limited.MethodsThis retrospective study included 443 SCLC patients from two hospitals who finished thoracic intensity-modulated radiation therapy or volumetric modulated arc therapy between April 1, 2022 and March 31, 2025. The primary endpoint was the incidence of grade 2 or worse (grade 2+) RP. Fine-Gray competing risks regression analyses were used to identify the potential risk factors of RP2+.ResultsThe follow-up duration was (15.8 ± 4.6) weeks since the end of RT. In detail, 87 (19.6%), 35 (7.9%), and 6 (1.4%) patients developed grade 2, grade 3, and grade 4 RP respectively. Six patients died from non-RP-related diseases were treated as competing events. On univariate analysis, male, pneumoconiosis, ECOG status, concurrent chemoradiotherapy (CCRT) were positively correlated with the incidence of RP2+, with subdistribution hazard ratio (SHR) and 95% confidence interval (CI) of 1.81 (1.29–2.55), 2.56 (1.35–4.87), 1.53 (1.17–1.99) and 2.15 (1.35–3.42), respectively (all P < 0.05), while VO2max, left ventricular ejection fraction (LVEF), and forced expiratory volume in one second (FEV1) were negatively correlated with RP2+, with SHR and 95%CI of 0.89 (0.84–0.935), 0.98 (0.96-1.00), and 0.34 (0.19–0.61), respectively (all P < 0.05). Further multivariate competing risks analysis revealed that male, CCRT, and VO2max were independent predictors of RP2+, with SHR and 95% as 1.84 (1.22–2.78), 1.72 (1.04–2.87), and 0.92 (0.86–0.98), respectively (all P < 0.05). Additionally, immunochemotherapy before RT, preexisting pulmonary co-morbidities and smoking history were not significant indicators of RP2+ (P > 0.05, respectively).ConclusionThe incidence of RP2 + following sequential immunochemotherapy and RT was positively associated with male and CCRT, but negatively correlated with VO2 max in SCLC patients.Clinical trial numberNot applicable.

Pirfenidone for grade 2 and grade 3 radiation-induced lung injury: a multicentre, open-label, randomised, phase 2 trial.

Macrophage-specific deletion of HO-1 aggravates radiation-induced lung injury through an PP2A-dependent manner.

Integrated bulk and single-cell RNA sequencing identifies oxidative stress signatures of radiation-induced lung injury in mice through machine learning.

Radiation therapy is a crucial method used to treat various tumors, but it can lead to radiation pneumonitis. Shashen Maidong Decoction (SMD) is clinically used to treat radiation pneumonitis, but the exact mechanism remains unclear. Herbal components and targets of SMD were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP), the Encyclopedia of Traditional Chinese Medicine (ETCM), and Swiss Target Prediction platforms. Moreover, disease-related targets were retrieved from the GeneCards database. A Protein-protein Interaction (PPI) network was constructed using the STRING database and analyzed using the Cytoscape software. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed using the DAVID database. Subsequently, the disease-active component-target network and drug-pathway-target network were constructed using Cytoscape. The molecular docking results were validated and visualized using Auto Dock and PyMOL software. In this study, 115 conserved active ingredients, 316 drug targets, and 355 radiation pneumonitis targets were identified. Among these, 75 targets were identified as intersecting targets. GO enrichment analysis revealed 494 biological processes, 36 cell components, and 59 molecular functions. KEGG analysis uncovered 118 signaling pathways, including the IL17 signaling pathway, TNF signaling pathway, HIF-1 signaling pathway, etc. The molecular docking results showed the core active ingredients of SMD, including quercetin, kaempferol, beta-carotene, and naringenin, to have strong binding ability with the core targets. This study preliminarily confirmed that SMD may act on the TNF, IL17, and HIF-1 signaling pathways to exert its therapeutic effects on radiation pneumonitis by regulating the expression of inflammatory factors.

Neoadjuvant immunotherapy plus chemotherapy in locally advanced stage III NSCLC patients undergoing definitive chemo-radiotherapy---a real‑world multicenter retrospective study.

Molecular pathways of radiation-induced lung damage: Effects of X-ray and Anti-PD-1 combination in a murine model.

Real-world evaluation of interstitial lung disease/pneumonitis in patients treated with trastuzumab deruxtecan for HER2-positive advanced or recurrent gastric cancer: a postmarketing surveillance study in Japan.

The helical tomotherapy (HT) system can expose more normal lung tissue to low radiation doses, resulting in extensive low-dose distribution in both lungs which may induce radiation pneumonitis (RP). This study aims to optimize dosimetric parameters and identify a clinically feasible treatment plan by analyzing the impact of different block settings and modulation factor (MF) combinations on HT plans for lung cancer to reduce the low-dose exposure volumes in normal lung tissue. We retrospectively reviewed 14 lung cancer patients who received radiotherapy. These cases were optimized using different modulation factors (MFs: 3, 4, 5) and block techniques (Unblocked, Directional, Complete). The impact of MF and block combinations on reducing low-dose bath (e.g., V5, V10) in lung tissue was evaluated by analyzing dose distribution maps, dose-volume histograms (DVH), homogeneity index (HI), conformity index (CI), and treatment time for each optimized HT plan combination. Block settings and higher MF exerted minimal influence on the average dose to the target volume. With stricter block constraints and higher MF, HI increased (range: 17.39%-27.54%) and CI decreased (range: 2.76%-17.43%); although both indices showed slight deterioration, they remained within acceptable clinical limits. Treatment time increased substantially (range: 15.77%-131.58%). The block technique significantly reduced V5 in the bilateral lungs and the contralateral (healthy) lung, with less impact on the ipsilateral (affected) lung. The combination of block and high MF effectively reduced V5. To balance target volume coverage (high dose), dose distribution uniformity, and treatment duration while reducing low-dose irradiation to normal lung tissue, we recommend implementing Directional block with an MF range of 3-4 to optimize the HT plan for patients with unilateral lung cancer.

Relative Biological Effectiveness Derived from NTCP Analysis of Carbon Ion vs. Photon Radiation Therapy in Locally Advanced Non-Small Cell Lung Cancer.

Pirfenidone: a new option for radiation-induced lung injury?

Revealing the Mechanisms of Compound Kushen Injection on Oxidative Stress Regulation in the Treatment of Radiation-Induced Lung Injury

Mai-Men-Dong decoction alleviates radiation-induced lung injury by regulating ferroptosis through modulation of the STAT6/p53/SLC7A11 axis.