Radiotherapy and Oncology

Proton beam therapy (PBT) offers a unique potential for dose conformity to tumors while sparing surrounding healthy tissues. Current PBT accuracy, however, is fundamentally limited by range uncertainties from tissue density variations and anatomical changes, yet no clinically viable methods exist for localizing the dose delivery pulse-by-pulse inside patients during pencil beam scanning (PBS). We developed and clinically demonstrated a first-of-its-kind radiation acoustic beam localization (iRABL) system for real-time tracking PBS trajectory and mapping dose deposition deep in patients body during PBT. A clinical-grade compact iRABL system featuring high speed, super-resolution, and high sensitivity was specifically designed for PBT applications. Its clinical feasibility was validated through the first-in-human study on prostate cancer patients, demonstrating the capability for in vivo proton dose mapping without interfering with treatment delivery. System performance, including spatial resolution, imaging speed for tracking beam trajectory and temporal dose accumulation, and dosimetric accuracy, was quantitatively characterized using tissue-equivalent phantoms and clinical treatment plans. This iRABL system achieved displacement resolution of 0.1 mm laterally and 0.2 mm axially, exceeding the acoustic diffraction limit by an order of magnitude and surpassing typical proton beam spot sizes. This super-resolution capability, combined with GPU-accelerated image reconstruction and processing, enabled single-pulse detection at a frame rate of 1 kHz, matching the proton systems pulse repetition rate. Dosimetric validation using clinical M-shaped treatment plans met clinical criteria with gamma index passing rates exceeding 90% at 3 mm/3% tolerance, confirming high accuracy for mapping delivered dose distributions. For the first time, by leveraging the high sensitivity and the high speed of our newly developed iRABL system, we are able to localize proton beam and map the proton dose deposition during PBS with sub-diffraction-limit spatial resolution, pulse-by-pulse imaging speed, and clinical grade accuracy. This capability, which addresses fundamental limitations in current treatment monitoring, holds promise for advancing PBT toward image-guided "proton surgery".

Background and PurposeQuantitative relaxometry on the integrated MRI / linear accelerator (MR-Linac) at high isotropic resolution is currently limited due to prohibitively long scan times and limited field-of-views. Therefore, the purpose of this study was to assess the technical feasibility of the 3D-QALAS technique on the 1.5T MR-Linac which has the ability to acquire whole-brain 1 mm isotropic quantitative T1, T2, and PD maps along with multiple synthetic images in a 7 minute acquisition time. Materials and MethodsA 1 mm isotropic 3D-QALAS acquisition was scanned in both phantoms and a healthy volunteer on the 1.5T Elekta Unity MR-Linac device with scan times around seven minutes. A test-retest protocol across five independent sessions for the phantom was conducted. The correlation, repeatability, and reproducibility between measured and reference quantitative T1, T2, and PD values were determined in the phantom. Distortion was also studied. Vendor-provided reconstruction through SyMRI was performed to extract synthetic images and brain volume metric assessments on a healthy volunteer. ResultsThe slope and concordance between the measured and phantom reference values was 1.02 (1.00), 1.09 (0.90), and 0.99 (1.00) for T1, T2, and PD, respectively. Median distortion across the phantom remained below 2 mm. The repeatability and reproducibility coefficient-of-variation (CoV) was under 8% for all measured values. The measured brain volumes in the healthy volunteer was within expected age-adjusted reference values. DiscussionThe technical feasibility of using 3D-QALAS on the integrated 1.5T MR-Linac was confirmed. Applying this technique to the head and neck adaptive radiation therapy workflow will provide new opportunities to integrate quantitative imaging relaxometry biomarkers at 1 mm isotropic resolution. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/26347967v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@1f43093org.highwire.dtl.DTLVardef@a1320eorg.highwire.dtl.DTLVardef@dd750eorg.highwire.dtl.DTLVardef@1300853_HPS_FORMAT_FIGEXP M_FIG C_FIG

Optimizing radiotherapy dose distributions remain a resource-intensive bottleneck. Existing AI-based dose prediction methods often have limited generalizability because they rely on small, heterogeneous datasets. We present nnDoseNetv2, an auto-configured, end-to-end framework for dose prediction across diverse disease sites (head and neck, prostate, breast, and lung), prescription levels (1.5-84 Gy), and treatment modalities (IMRT, VMAT, and 3D-CRT). By integrating machine-specific beam geometry with 3D structural information, the framework is designed to generalize across varied clinical scenarios. A single multi-site model was trained on 1,000 clinical plans. On sites seen during training, performance was comparable to specialized site-specific models. On unseen sites (liver and whole brain), the model outperformed site-specific models, with mean absolute errors of 2.46% and 6.97% of prescription, respectively. These results suggest that geometric awareness can bridge disparate anatomical domains while eliminating the need for site-specific model maintenance, providing a scalable and high-fidelity approach for personalized radiotherapy planning.

Humanized mice (hu-mice), which recapitulate the human immune system, have become increasingly important for preclinical immunotherapy studies. Among these models, the human peripheral blood mononuclear cells (PBMC)-engrafted hu-mice model is the simplest and fastest. However, its utility is hindered by the development of lethal graft-versus-host disease (GvHD) and the insufficient reconstitution of human leukocytes. To address these limitations, we developed PBMC hu-mice models using a novel strain, NOD-CD47nullRag2nullIL-2r{gamma}null (RTKO) focusing on the immunological defects of the NOD strain and the immunotolerance provided by CD47 deficiency. Six-week-old female NOD-Rag2nullIL-2r{gamma}null (RID) and RTKO mice were intravenously injected with three different PBMC doses (3x106, 5x106, and 1x107 cells). At standard doses (5x106 and 1x107 cells), RTKO mice exhibited enhanced engraftment of human leukocytes, though GvHD was more severe compared to the RID strain, resulting in a limited experimental window. However, in a subsequent trial using a lower dose of PBMCs (3 x 106 cells), RTKO mice demonstrated notable advantages, including stable reconstitution of human leukocytes, milder GvHD symptoms without life-threatening lesions, and a markedly prolonged experimental window. Considering the difficulties in generating hematopoietic stem cell (HSC)-engrafted hu-mice, the extended experimental window provided by this model, which is comparable to HSC hu-mice, is a significant improvement. Moreover, the radiation tolerance conferred by the Rag gene mutation in this model offers another advantage for radiotherapy research. Consequently, the low-dose PBMC RTKO model serves as a versatile and valuable platform for a broad spectrum of immunotherapy studies, especially in the field of immuno-oncology.

BackgroundFLASH-RT defines a promising treatment modality against medulloblastoma, as it minimizes treatment-related complications. To support its clinical translation, we dissected the cellular and molecular determinants of the FLASH response in the tumor-microenvironment (TME) and healthy hippocampus using an orthotopic human medulloblastoma mouse model treated with a hypo-fractionated FLASH regimen. MethodsFive cohorts of 4 weeks-old UW228-MB-bearing female nude mice (n=57) were irradiated, or sham-irradiated using 3x10 Gy (BED=60), delivered 48h apart at 0.1 Gy/s (CONV) or 5.5x106 Gy/s (FLASH) using an electron beam (eRT6). Digital spatial profiling (DSP) was performed 24h after radiotherapy in one cohort, while the four other cohorts were followed for long-term tumor response, cognition, and neuroinflammation. ResultsBoth CONV and FLASH-RT induced a complete and long-lasting anti-tumor response in 100% of animals associated with cognitive decline. However, more mice maintained a very good discrimination score after FLASH exposure (38%) than CONV (7%). DSP revealed a sustained microglial activation in the cerebellar tumor micro-environment, where FLASH enhanced expression of genes with phagocytic and proteolytic activity. In the tumor free hippocampus, FLASH exposure induced a preferential neuron/astrocyte transcriptional crosstalk, which manifested over protracted times to minimize neuroinflammation and cognitive complications. ConclusionThe study shows the tumor-ablative efficacy of hypo-fractionated FLASH-RT in a human medulloblastoma mouse model. It is associated with qualitatively distinct transcriptional signatures prone to tumor and debris clearance mediated by microglial cells of the TME. Moreover, in the hippocampus, FLASH mitigates radiation-induced neurotoxicity by enhancing genes involved in synaptic plasticity, attenuating neuroinflammation, and preserving metabolic function. Key PointsO_LIComplete response of medulloblastoma and reduction of neurotoxicity with hypo-fractionated FLASH regimen. C_LIO_LIClearance-prone phagocytic and proteolytic activity in the microglia of the TME. C_LIO_LINeuron/astrocyte transcriptional crosstalk in the hippocampus. C_LI Importance of the studyThis study constitutes a milestone for the future implementation of FLASH-RT in the treatment of children with brain cancer. It shows that FLASH does not protect medulloblastoma and on the contrary can be ablative when delivered in 3 fractions of 10 Gy. FLASH promotes a metabolically active, phagocytosis-prone phenotype in microglial cells consistent with immune activation and tumor surveillance, in contrast to the proliferative and immunosuppressive signaling programs induced by CONV. It also shows how FLASH may differentially shape long-term brain function in patients with brain tumors by modifying the transcriptional program of hippocampal subregions known to be critical for memory encoding, pattern separation, and consolidation. In summary, this study supports the idea that FLASH has the potential to shift treatment paradigms and change the dismal therapeutic outcome in patients with brain cancer.

Abstract: Purpose: Recurrence in high grade glioma (HGG) predominantly occurs within the high dose radiation field, raising the question of whether treatment failure reflects limitations in radiation target delineation or is driven by intrinsic tumor biology. This study evaluated recurrence patterns following standard chemoradiotherapy and their treatment implications. Material and Methods: This retrospective single center study included 41 patients with histologically confirmed HGG treated with surgery followed by radiotherapy with concurrent and adjuvant temozolomide (TMZ). Patients were followed through August 2018; those with recurrence were included in the analysis. Recurrence patterns were classified based on their spatial relationship to the 60 Gy isodose line as central, infield, marginal, or distant. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log rank test. Results: The most common pattern of recurrence was central (15 patients, 36.5%), followed by infield (11, 26.8%), distant (6, 14.6%), marginal (5, 12.1%), and multicentric (4, 9.8%). Central and in field recurrences (local failures) accounted for 26 patients (63%). Median overall survival (OS) was 27 months, and median progression-free survival (PFS) was 12 months. Survival differed significantly by recurrence pattern (log-rank p = 0.018), with marginal recurrence associated with more favorable outcomes. Conclusion: The predominance of central and infield recurrences within the high-dose region suggests that treatment failure in HGG is not solely explained by inadequate target delineation and may also be driven, in part, by intrinsic tumor biology, including radioresistant subpopulations and tumor heterogeneity. Future strategies may benefit from incorporating biologically guided approaches alongside optimization of radiation treatment parameters.

PurposeThis study evaluated the safety and effectiveness of an intraoral light-emitting diode (LED)-based photobiomodulation (PBM) device to reduce the incidence and severity of oral mucositis (OM) from intensity modulated radiation therapy (IMRT) for head and neck cancer (HNC). MethodsThis randomized, double-blind, sham-controlled trial enrolled patients with HNC undergoing high-dose IMRT over 6-8 weeks, with or without concurrent chemotherapy. Participants received daily 10-minute PBM or sham treatments immediately before IMRT sessions. Assessments were conducted at baseline, daily and weekly during IMRT, and two weeks post-IMRT. ResultsEighty-five participants (42 PBM; 43 sham) were enrolled across 12 US sites. No device-related adverse events were observed, and 99.5% of initiated sessions were completed. In the intent-to-treat population, severe OM (WHO Grade [≥]3) incidence was significantly lower with PBM across six weeks of IMRT (36.8% vs 57.1%; p = 0.046) and at two weeks post-treatment (10.8% vs 36.4%; p = 0.042). In the per-protocol population, the PBM arm reported significantly greater taste preservation (p = 0.034), lower increases in mouth/throat soreness (p = 0.029) and throat pain (p = 0.028) and needed fewer feeding tube placements (p = 0.073) than the control arm. ConclusionDaily intraoral PBM therapy using an LED-based device was safe, well tolerated, and significantly reduced the incidence of severe OM and associated complications in HNC patients undergoing IMRT with or without concurrent chemotherapy. These findings align with guidelines recommending daily intraoral PBM therapy for preventing cancer therapy-related OM, a dose-limiting toxicity for which effective preventive interventions are needed. Trial RegistrationClinicalTrials.gov Registration Number NCT03972527. Registered on June 3, 2019. Concise SummaryDaily intraoral PBM therapy using an LED-based device was safe, well tolerated, and significantly reduced the incidence of severe OM and associated complications in HNC patients undergoing IMRT with or without concurrent chemotherapy. These findings align with guidelines recommending daily intraoral PBM therapy for preventing cancer therapy-related OM, a dose-limiting toxicity for which effective preventive interventions are needed.

BACKGROUNDSubcutaneous white adipose tissue (scWAT), a key metabolic and endocrine organ, is inevitably exposed during radiotherapy (RT). While RT is a cornerstone of cancer treatment, its efficacy is limited by toxicity to surrounding healthy tissues. Ultra-high dose rate (FLASH) RT has emerged as a promising modality capable of preserving tumor control while reducing normal tissue damage - the so-called FLASH effect. Clinical evidence indicates that childhood exposure to conventional (CONV) RT is associated with long-term dysmetabolism and WAT dysfunction. However, the impact of FLASH-RT on WAT has not been investigated. AIMTo compare the effects of FLASH- and CONV-RT on adipocyte function and scWAT homeostasis, and to identify molecular and structural changes associated with each modality. METHODSWe evaluated the effects of FLASH- and CONV-RT on adipocytes and scWAT using a dedicated linear accelerator capable of delivering both modalities. Experiments were performed in the human SGBS preadipocyte/adipocyte cell line and in a mouse model subjected to proximal hind limb irradiation, with analyses conducted 70 days post-exposure. RESULTSRT impaired adipogenic differentiation in a dose-dependent manner, with a relative sparing effect of FLASH at 4-8 Gy. Mature adipocytes exhibited radioresistance, with protection by FLASH at 8 Gy. In vivo, both regimens reduced fat mass without affecting body weight, with greater loss following CONV-RT. Transcriptomic profiling of scWAT revealed inflammatory and neurodegenerative signatures after CONV-RT, whereas FLASH-RT induced minimal transcriptional changes. Histological and ultrastructural analyses confirmed increased cellular damage, vacuolization, lipid spill-over, and reduced PLIN1 expression, predominantly in CONV-treated mice. CONCLUSIONSWAT homeostasis is sensitive to conventional RT, whereas FLASH-RT better preserves tissue structure and function, with implications for long-term metabolic health in cancer survivors.

Purpose: Manual verification of AI-based auto-contouring is labor-intensive and prone to fatigue-related errors. This study developed the large language model (LLM)-based automated Quality Assurance (QA) for auto-contouring (LAQUA) system using a multimodal LLM, Gemini 2.5 Pro, and evaluated its feasibility as a clinical primary screening tool to streamline the QA workflow. Methods: Twenty male pelvic CT scans from an open dataset were utilized. Three distinct auto-contouring software packages (OncoStudio, RatoGuide prototype and syngo.via) were evaluated. Auto-contouring results for each slice were exported as PDF images with overlaid contours and input into Gemini 2.5 Pro. The LLM was instructed to rate the contour quality on a 5-point clinical scale (5: Optimal; 4: Acceptable; 3: Suboptimal; 2: Unacceptable; redraw from scratch; 1: Unacceptable; organ not detected). Using evaluations by two board-certified radiation oncologists as ground truth, Spearman's rank correlation coefficients ({rho}) and weighted kappa coefficients ({kappa}) were calculated. Additionally, to assess screening performance, sensitivity and specificity were calculated by dichotomizing the scores into "Pass" and "Fail" using two different cutoffs (scores [≥] 3 and [≥] 4 as "Pass"). Finally, the alignment of the rationales provided by the LLM with the auto-contouring quality was evaluated by two board-certified radiation oncologists. This was conducted using a Likert scale assessing four domains (error detection, hallucination, clinical relevance, and anatomical understanding), each scored out of 2 points. Results: The LAQUA system demonstrated moderate to strong agreement with expert judgments across all evaluated organs ({rho}: 0.567 - 0.835; quadratic weighted {kappa} : 0.639 - 0.804), with the rectum showing the highest correlation. Regarding screening performance, a cutoff of [≥]3 as "Pass" achieved the highest sensitivity and specificity in specific subgroups, but with wide 95% confidence intervals (CIs). A cutoff of [≥]4 as "Pass" narrowed the CIs, yielding the highest sensitivity in the rectum (0.976) and the highest specificity in the left femoral head (0.933). Qualitatively, the LLM's rationales achieved an overall mean score of 1.70 {+/-} 0.48 (out of 2), with 155 of 291 outputs receiving perfect scores across all criteria. Conclusions: The LAQUA system demonstrated substantial agreement with expert evaluations in AI-based auto-contouring quality assessment. While potential overestimation bias (risk of missing "Fail" cases) warrants caution, the observed sensitivity suggests its feasibility as a primary screening QA tool to efficiently filter acceptable contours, thereby reducing the clinical workload.

Background and PurposeThe use of MRI-based fat quantification can be applied to automatically identify red bone marrow which is highly sensitive to radiation and systemic therapies and could be used as an organ-of-interest for adaptive radiation therapy. Currently, the tradeoff of scan time and PDFF/R2* quantification accuracy from the 2-/3-/6-point methods, particularly for the time-constrained MR-Linac, remain unanswered. Therefore, the purpose of this study was to investigate the technical feasibility and quantitative performance of quantitative Dixon-based imaging for scanners within the radiation oncology department. Materials and MethodsA 2-/3-/6-point version of the quantitative Dixon sequence was developed and scanned on a 1.5T MR-Simulation, 3T MR-Simulation, and 1.5T MR-Linac scanner for five repetitions using the Calimetrix Model 725 PDFF-R2* phantom as a nominal reference for quantitative PDFF/R2* values. The image geometric distortion as well as the quantitative concordance, Bland-Altman agreement, repeatability, and reproducibility of both the PDFF/R2* values were determined. Each sequence was evaluated in both the pelvis and head and neck across both healthy volunteers and patients. ResultsThe most severe geometric distortion was less than 2 mm except for the 1.5T MR-Linac when using the 2-point Dixon sequence with distortions exceeding 5 mm. The 6-point Dixon sequence showed the highest concordance at above 0.97 across all scanners for both PDFF and R2* followed by the 3-point and 2-point sequence. The 2-point Dixon sequence exhibited significant PDFF biases particularly at the higher R2* values since it did not correct for it during reconstruction. For the Bland-Altman analysis, the 2-point Dixon sequence had the widest 95% limits of agreement followed by the 3-point and 6-point Dixon sequence with the narrowest bands. The goodness-of-fit is generally lowest at higher PDFF values and lower R2* values. Both repeatability and reproducibility were the lowest for the 6-point Dixon sequence. DiscussionThe 6-point quantitative Dixon sequence demonstrated superiority for the chosen evaluation metrics. The results of this work can be used to determine the threshold for true quantitative changes of PDFF/R2* while considering acquisition variabilities, enabling future biomarker studies and clinical trials. Further, this work provides validation for future investigations into quantitative bone marrow characterization. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=81 SRC="FIGDIR/small/26347965v1_ufig1.gif" ALT="Figure 1"> View larger version (35K): org.highwire.dtl.DTLVardef@8b2139org.highwire.dtl.DTLVardef@322a97org.highwire.dtl.DTLVardef@18a3a46org.highwire.dtl.DTLVardef@1f7ef62_HPS_FORMAT_FIGEXP M_FIG C_FIG

BackgroundRadiation therapy is a standard-of-care oncological treatment for central nervous system (CNS) malignancies. However, as survival outcomes improve, radiation-induced injury to normal brain tissue has increased in clinical significance. CNS radiation injury is a delayed, multifactorial process characterized by impaired neurogenesis, reactive gliosis, and persistent functional deficits. Mechanistic exploration and development of effective radiation mitigators have been limited by the lack of scalable, human-relevant models. MethodsMature human iPSC-derived cortical organoids were exposed to single-dose or clinically relevant fractionated radiation (5 x 2 Gy). DNA damage, apoptosis, and growth dynamics were assessed longitudinally. Structural organization, synaptic integrity, and neuroinflammatory responses were evaluated by immunofluorescence and real-time PCR. Transcriptomic profiling was performed at 72 hours and 2 weeks after fractionated radiation to capture acute and delayed effects. Two candidate radiation mitigators, NSPP and amisulpride, were tested for their therapeutic effects within the organoid system. ResultsCortical organoids exhibited partial recovery following single doses up to 4 Gy or fractioned irradiation. Transcriptomic analyses revealed that radiation not only reduced overall cell viability but also reshaped lineage trajectories, characterized by depletion of neural stem/progenitor populations, loss of neuronal identity, enhanced gliogenesis, increased inflammatory cytokines, and disrupted cortical layering and synaptic integrity. Treatment with NSPP or amisulpride attenuated injury-associated transcriptional and structural alterations. ConclusionHuman cortical organoids recapitulate key features of radiation-induced neural injury, recovery, and therapeutic modulation, providing a robust, scalable, and human-relevant platform for studying CNS radiation biology and preclinical screening of candidate radiation mitigators. Key pointsO_LIHuman iPSC-derived cortical organoids enable study of human CNS radiation responses. C_LIO_LIOrganoids recover after single-dose and fractionated radiation relevant to clinical exposure. C_LIO_LIThe platform supports scalable, human-relevant testing of radiation mitigation strategies. C_LI

Radiation-induced intestinal injury is a widely used model for studying mechanisms regulating tissue injury and regeneration. Traditionally, Cesium (137Cs) radiation has been used in research applications, but over the past decade, X-ray irradiation has become increasingly favored due to its improved safety and non-radioactive profile. Since each type of radiation has distinct physical characteristics that drive its performance, we sought to systematically compare the effects of the X-ray and 137Cs irradiators on intestinal epithelial injury and regeneration. Using established in vitro models, including colorectal cancer cell lines such as HCT116, RKO, and DLD-1, and mouse intestinal organoids, alongside an in vivo model, Bmi1-CreER;Rosa26eYFP, we evaluated differences in transcriptional, protein, and histopathological responses to irradiation. Our results demonstrate that X-ray produced intestinal injury and regenerative responses comparable to those induced by 137Cs, supporting its reliability as an alternative modality for studying intestinal radiation.

BackgroundLarge Language Models (LLMs) have demonstrated expert-level performance across many medical domains, suggesting potential utility in clinical practice. However, their reliability in the highly specialized domain of moderate hyperthermia (HT) remains unknown. We therefore evaluated the performance of three modern LLMs in answering HT-related questions. MethodsWe conducted an evaluation study by posing 40 open-ended questions--22 clinical and 18 physics-related--to three modern LLMs (DeepSeek-V3, Llama-3.3-70B-Instruct, and GPT-4o). Responses were blinded, randomized, and evaluated by 19 international experts with either a clinical or physics background for quality (5-point Likert scale: 1=very bad, 2=bad, 3=acceptable, 4=good to 5=very good) and for potential harmfulness in clinical decision-making. ResultsA total of 1144 quality evaluation responses were collected. Overall reported mean quality scores were similar across models, with DeepSeek scoring 3.26, Llama 3.18, and GPT-4o 3.07, corresponding to an "acceptable" rating. Across expert evaluations, responses were considered potentially harmful in 17.8% of cases for DeepSeek, 19.3% for Llama, and 15.3% for GPT-4o. Notably, despite "acceptable" mean scores, approximately 25% of responses were rated "bad" to "very bad," and potentially harmful answers occurred in [~]15-19% of evaluations, indicating a non-trivial risk if used without domain expertise. ConclusionOur findings indicate that the performance of LLMs in HT in versions available at the time of investigation is only partially satisfactory. The proportion of poor-quality responses is too high and may lead non-domain experts to misinterpret the available clinical evidence and draw inappropriate clinical conclusions.

Definitive radiotherapy (RT) for prostate cancer (PC) with dose intensification and/or focal boosting has excellent oncologic outcomes, but many patients experience adverse events. Dose escalation to the whole prostate improves outcomes at the expense of increased late adverse events. Intraprostatic recurrence after definitive RT typically occurs at the site of the primary tumor, suggesting that dose to the site of the dominant lesion is an important predictor of future failure. The efficacy and safety of tumor-focused RT compared to that of standard RT for definitive treatment of localized PC has not been assessed. RadTARGET (RAdiation Dose TAiloRing Guided by Enhanced Targeting) is a phase II randomized trial that aims to demonstrate superior safety of image-guided, tumor-focused RT compared to standard RT for acute genitourinary (GU) or gastrointestinal (GI) in the setting of definitive RT for intermediate- and high-risk PC. The study intervention is image-guided, tumor-focused RT with dose intensification of cancer visible on imaging and dose de-intensification to remaining prostate. Patients will be randomized to two arms: those who receive standard RT dose and those that receive tumor-focused RT. The study population will be patients with intermediate- or high-risk PC planning to undergo definitive RT with or without systemic therapy. The primary endpoint to compare between randomized arms is acute GU or GI grade [≥]2 adverse events. Participant and study duration are 5 years and 8 years, respectively. RadTARGET will compare the efficacy and safety of tumor-focused RT to that of standard RT for definitive treatment of localized PC. We hypothesize that the tumor-focused approach will substantially reduce adverse events after prostate RT while retaining high efficacy. If this hypothesis is confirmed, we will conclude that a phase III randomized control trial is warranted to formally establish oncologic non-inferiority compared to the current standard of whole-gland dose escalation.

Accurate assessment of low-dose neutron radiation exposure remains a central challenge in biodosimetry, particularly for applications requiring non-invasive sample types such as skin. Here, we characterized the transcriptional response of a three-dimensional in vitro human skin model (EpiDermFT) to neutron irradiation at doses up to 0.75 Gy, measured from pre-exposure through a 14-day post-exposure period. RNA sequencing revealed greater than 800 significantly altered genes, including upregulation of FOS, FOSB, CDKN1A, MDM2, and GADD45A, and downregulation of NRG1, H3C11, and CENPX. Gene ontology enrichment indicated activation of DNA damage checkpoint signaling, cell cycle arrest, and stress-response pathways, alongside suppression of nucleosome assembly and DNA replication processes. Machine learning models trained on transcriptomic features exhibited strong predictive performance across biodosimetric endpoints. Classification models accurately distinguished irradiated from sham samples (AUC > 0.99), and regression models achieved high accuracy for estimating both absorbed dose (R2 = 0.97) and days post-exposure (R2 = 0.99). The latter, while highly predictive, may partially reflect transcriptional shifts associated with progressive degradation of the in vitro tissue model over time. Collectively, these findings demonstrate that RNA-based molecular signatures from human skin tissue provide a robust framework for quantitative estimation of neutron radiation exposure and temporal response dynamics.

Ultra-high-dose-rate therapy enhances the protection of normal tissues and reduces side effects while effectively controlling tumors. This biological phenomenon is called the FLASH effect, and when observed, therapy is called FLASH Radiotherapy (FLASH-RT). Various hypotheses have been proposed to explain how ultra-high dose rates achieve these effects under different conditions, with the impact of tissue oxygen perfusion still needing further investigation. FLASH-RT involves brief exposure to radiation, which results in fewer heartbeats occurring during the irradiation period, which could lead to reduced tissue oxygen perfusion occurring during the treatment timeframe. Therefore, we developed a compartmental model to simulate oxygen transfer and its interaction with radiation. The proposed model consists of three compartments: 1) the heart and arteries; 2) the irradiated brains blood vessels and capillaries; and 3) the irradiated brain tissue. We employed a system of differential equations, incorporating experimental data from in vivo oxygen measurements using the Oxyphor probe in the brain, to fit the model parameters to the experimental results. This model shows how dose rate and oxygen perfusion could influence chemical processes such as lipid peroxidation, potentially leading to differential biological effects. Our analysis of lipid peroxidation as a function of dose rate revealed a sigmoidal dose-rate-response curve that correlates well with several published biological response datasets. Our results indicate that the differential chemical effects of FLASH-RT compared with conventional dose rates may depend on factors such as oxygen perfusion, consumption, and tissue oxygen tension. This suggests that the temporal dynamics of oxygen could play a crucial role in enhancing the therapeutic window for FLASH-RT treatments. Furthermore, it suggests that the magnitude of some observed FLASH effects may vary across tissues or tumors and across experimental models, given differential oxygen dynamics.

Background Cardiovascular adverse events (CVAEs) after chemoradiotherapy (CRT) for lung cancer are major concerns in Appalachia due to high rates of smoking and pre-existing cardiovascular diseases (CVD). The objectives of this study were to characterize the incidence of CVAEs in this population and evaluate machine learning (ML) models for CVAEs risk stratification and mortality prediction. Methods A retrospective study was conducted among Appalachian patients with lung cancer treated with definitive CRT at a single institution between 2013 and 2025. Baseline clinical variables, including demographics, smoking status, pre-existing CVD, and post-CRT CVAEs were collected. Heart dosimetric parameters were also obtained. ML models [Random Forest (RF), Gradient Boosting (GBM), Support Vector Machine (SVM), Logistic Regression (LR)] were trained using 5 fold cross validation and evaluated using AUC, sensitivity, specificity, and F1 score. Feature importance was assessed using permutation analysis. Wilcoxon and Chi-squared tests were used for descriptive comparisons. Results Eighty-six patients (mean age 66 years, 47% male) were included. At diagnosis, 80% (n=69) had NSCLC and 20% (n=17) had LS-SCLC. CVAEs occurred in 51 patients (59%). The most frequent events were NSTEMI (n=15, 29.4%), pericardial disease (n=15, 29.4%), and arrhythmia (n=8, 15.7%). Mean heart dose was higher in the CVAE group (13.4 vs 9.4 Gy, p=0.27). For CVAE prediction, GBM achieved the highest AUC (0.55, 95% CI 0.44-0.69) and sensitivity (75%), while RF showed the highest sensitivity (80%, 95% CI 69-90%). Key predictors included age and cardiac dosimetrists (Heart V20, V40, V50, and mean heart dose). For mortality prediction, RF achieved the highest discrimination (AUC = 0.63, 95% CI 0.496-0.750). Age, cardiac dosimetry, disease stage, and cardiovascular comorbidity were the most influential predictors. Conclusion High incidence of CVAEs occurred among patients with lung cancer treated with CRT in this Appalachian cohort. While ML models demonstrated modest predictive performance, tree-based approaches demonstrated high sensitivity for identifying patients at risk for CVAEs and mortality. Age and cardiac radiation dose metrics consistently emerged as key predictors, highlighting the importance of cardiac dose optimization and ML-based risk stratification for cardio-oncology surveillance.

Head and neck cancer (HNC) requires accurate tumor delineation for effective radiotherapy planning. Manual segmentation of tumor regions is time-consuming and subject to considerable inter-observer variability. Although several automated approaches have been proposed, many rely on multimodal imaging such as PET/CT, which is expensive, less accessible in many clinical settings, and increases the burden on patients. In this work, we investigate a CT-only three-dimensional segmentation framework that provides a clinically practical and resource-efficient alternative. CT images of 136 head and neck cancer patients from the publicly available HN1 dataset in The Cancer Imaging Archive (TCIA) were used along with 30 additional cases from a private dataset collected at a tertiary care centre, Christian Medical College (CMC), Vellore, India. A fully automated segmentation model was developed to delineate the primary gross tumor volume (GTV) using the 3D nnU-Net framework. The models were trained using the HN1 dataset and an extended HN1+CMC dataset that included the additional private cases. Performance was evaluated using three-fold cross-validation with standard segmentation metrics including Dice Similarity Coefficient (DSC), Intersection over Union (IoU), and the 95th percentile Hausdorff Distance (HD95). The proposed CT-based model achieved a Global Dice of 0.63 and a Median Dice of 0.60 on the HN1 dataset. When the additional CMC cases were incorporated during training, the performance improved to a Global Dice of 0.65 and a Median Dice of 0.71. These results demonstrate that 3D nnU-Net can effectively segment head and neck tumors from CT images alone. The proposed CT-only approach provides a cost-effective and scalable solution that can support radiotherapy treatment planning and help reduce variability in clinical workflows.

International guidelines for low-frequency electromagnetic field exposure (LF EMF) are primarily intended to prevent substantiated adverse effects. In the frameworks, limits on internal electric fields are linked to external exposure levels through computational dosimetry. However, the relationship between internal electric fields and these adverse effects remains incompletely understood. In particular, current approaches often overlook the morphological complexity and diversity of cortical neurons, which may limit the realism of neuronal activation estimates used to support these assessments. This study evaluates LF EMF-induced neural activation using 25 morphologically realistic neuron models spanning all cortical layers, embedded within 11 detailed human head models. The internal electric fields were simulated for uniform magnetic field exposures (100 Hz-100 kHz) along the three anatomical directions, and excitation thresholds were computed using a multi-scale framework combining voxel-based dosimetry with biophysical neuron simulations. A real-world exposure scenario involving a child near an acousto-magnetic article-surveillance deactivator was also analyzed. Thresholds varied across cell type, morphology, cortical location, subject anatomy, frequency, and exposure direction, with L2/3 pyramidal, L4 basket, and L5 thick-tufted pyramidal cells showing the lowest thresholds. Despite this variability, all simulated thresholds were conservative with respect to the basic restrictions and dosimetric reference limits set by IEEE ICES and ICNIRP. The smallest margin occurred at 100 kHz, where the threshold remained a factor of 2.8 above the corresponding limit. These findings indicate that current LF EMF exposure limits remain conservative when evaluated using highly detailed, morphology-based CNS activation models.

BackgroundPatient radiation exposure in diagnostic radiology is an important concern for radiation protection and patient safety. Monitoring radiation dose levels during radiographic examinations is essential to ensure compliance with diagnostic reference levels (DRLs) and to optimize radiological practices. ObjectiveThe aim of this study was to evaluate patient radiation dose during conventional lumbar spine radiography and compare the obtained values with diagnostic reference levels. MethodsA descriptive cross-sectional multicenter study was conducted in four hospitals in the Sous Massa region, Morocco, between April and June 2017. Data were collected from 142 patients undergoing lumbar spine radiography examinations and from 20 radiology technicians. Exposure parameters including tube voltage, tube current, exposure time, focus-to-film distance, and field size were recorded. Entrance surface dose (ESD) was estimated using MICADO software, and dose area product (DAP) values were subsequently calculated. The 75th percentile values were determined and compared with diagnostic reference levels. ResultsThe regional 75th percentile ESD values were 5.33 mGy for the anteroposterior projection and 7.38 mGy for the lateral projection. Corresponding DAP values were 1840.9 mGy.cm2 and 2783.65 mGy.cm2, respectively. All obtained values were below the diagnostic reference levels used for comparison. However, variations between hospitals were observed, likely due to differences in imaging protocols and equipment. ConclusionRadiation doses associated with lumbar spine radiography in the evaluated hospitals were within acceptable limits according to diagnostic reference levels. Continuous monitoring of patient radiation exposure and optimization of radiographic techniques remain essential to ensure effective radiation protection.