Abstract Lung cancer is the leading cause of cancer-related deaths worldwide, and radiotherapy, a commonly used treatment for lung cancer, is associated with a variety of complications while treating cancer, among which radiotherapy-induced pneumonia is a common complication whose underlying mechanism remains unclear and requires further investigation. To address this, cell lines with ATMLP overexpression and knockdown were created using gene editing techniques, and Western blot, immunofluorescence and trans-well co-culture were used to explore the role of mitochondria-derived vesicles (MDVs) in mediating radiotherapy-induced inflammation, as well as the effects of ATMLP, DRP-1 and PGAM5 on MDVs. Ionizing radiation promoted the expression of ATMLP and the release of ATMLP-mediated MDVs. Up-regulation of ATMLP expression led to increased levels of PGAM5 and activation of phosphorylation at the Ser616 site of DRP-1. The increased number of MDVs further promoted macrophage polarization toward the M1 phenotype. Overall, ionizing radiation induces ATMLP expression, which enhances MDVs release through the PGAM5/DRP-1 axis. This process leads to macrophage polarization toward the M1 phenotype, contributing to the inflammatory response.
ABSTRACT This study investigates the radiobiological damage and microdosimetry of non-uniform distributions of 177Lu and 161Tb in the nucleus of targeted cell. The Geant4-DNA toolkit (version 11.3) was utilized to model PC-3 M prostate cancer cells. In these simulations, both uniform and non-uniform distributions of 177Lu and 161Tb within the cell nucleus were considered (10 MBq·s disintegrations were considered). To model the heterogeneity in radiopharmaceutical distribution at cellular scales, a Gaussian distribution function with a mean of zero and a standard deviation of 0.1–0.5 was used. Our simulations assess cell absorbed dose and direct and indirect DNA double-strand breaks (DSBs) based on the level of radionuclide heterogeneity. At a uniform radionuclide distribution, the number of DSBs and the absorbed dose from 161Tb were 0.035 decay−1 and 40.62 uGy/decay, respectively, while for 177Lu, they were 0.0093 decay−1 and 11.18 uGy/decay. As the heterogeneity of radionuclide distribution within the cell nucleus increased, the cell nucleus absorbed dose and the number of direct and indirect DSBs per cell nucleus absorbed dose remained constant for 177Lu, whereas the cell nucleus absorbed dose and the number of direct DSBs per cell nucleus absorbed dose decreased for 161Tb (P-value <0.05). Meanwhile, the radiobiological effectiveness of 161Tb is highly sensitive to its spatial distribution within the nucleus. Overall, our in silico study suggests that 161Tb is a highly promising radionuclide for radiopharmaceutical therapy, particularly when efficient nuclear targeting and a relatively uniform intranuclear distribution can be achieved. Accurately predicting the therapeutic efficacy of 161Tb-based agents requires careful consideration of their subcellular distribution.
Abstract Treatment-related lymphopenia is an established prognostic factor in glioblastoma, yet the anatomical origin remains unclear. This retrospective single-center study compared the whole brain, dural venous sinus and cranial bone marrow as organs at risk for predicting lymphocyte depletion and evaluated the prognostic significance of nadir absolute lymphocyte count (ALC). The cohort comprised 155 patients with IDH-wildtype glioblastoma treated with concurrent chemoradiotherapy. V20 Gy was extracted for each structure. Cox proportional hazards regression evaluated associations between nadir ALC and overall survival. Multiple linear regression predicted nadir ALC from dosimetric parameters adjusted for clinical factors and regimen. Nadir ALC independently predicted overall survival (HR 0.897 per 100 cells/μl; P = 0.004), and severe lymphopenia (ALC < 500 cells/μl) was associated with shorter median overall survival (15.1 vs 21.1 months; P = 0.012). Whole brain and skull V20 Gy were each significantly associated with nadir ALC (both P < 0.01), whereas dural venous sinuses V20 Gy was not (P = 0.194). Brain and skull models showed equivalent predictive performance (AIC 185 vs 184, R2 0.351 vs 0.353). The two doses were strongly correlated (Spearman ρ = 0.925), and neither remained significant when entered simultaneously, so the responsible structure cannot be determined. In regimen-stratified analyses, both structures remained significant in the 40 Gy cohort, but not in the 60 Gy cohort. Cranial bone marrow dose predicts nadir ALC comparably to, but inseparably from, whole brain dose, and nadir ALC is independently prognostic for survival. These hypothesis-generating findings require validation before adopting skull-sparing strategies in glioblastoma radiotherapy.
Abstract Carbon-ion radiotherapy (CIRT) is a non-surgical treatment option for early-stage non-small cell lung cancer (NSCLC). However, the association between operability and outcomes in real-world CIRT cohorts has not been systematically evaluated. This study aimed to evaluate the association between clinically assessed operability and outcomes in patients with stage I NSCLC treated with CIRT. This multicenter prospective registry study analyzed 231 patients with stage I NSCLC treated with CIRT at five institutions between May 2016 and June 2018. Patients were categorized as operable or inoperable based on multidisciplinary tumor board decisions before CIRT. Patients who could undergo lobectomy were considered operable. Survival outcomes, including overall survival (OS), cause-specific survival (CSS) and progression-free survival (PFS), were analyzed using Kaplan–Meier and Cox proportional hazards models. Local recurrence was evaluated using a competing-risk approach, treating death without prior local recurrence as a competing event. The 5-year OS, CSS and PFS rates were 69.6, 85.6 and 54.8%, respectively. Operable patients showed superior 5-year OS (83.5 vs. 49.1%, P < 0.001), CSS (91.9 vs. 75.0%, P < 0.001) and PFS (66.5 vs. 38.0%, P < 0.001) compared with inoperable patients. The 5-year cumulative incidence of local recurrence was 3.8% in operable patients and 12.1% in inoperable patients (Gray’s test, P = 0.008). Clinically assessed operability was associated with outcomes after CIRT and may serve as a useful composite baseline clinical marker when counseling patients, interpreting treatment outcomes and designing future clinical studies.
