International Journal of Radiation Oncology*Biology*Physics

Purpose: To quantify the dosimetric effect of residual intrafraction motion during gated MR-guided prostate stereotactic body radiotherapy with simultaneous integrated boost to the dominant intraprostatic lesion, and to derive and evaluate target-specific, population-based margins designed to mitigate motion-induced coverage loss. Materials and Methods: Thirty patients were treated on a 1.5-T MR-Linac with 36.25, 40, and 45 Gy prescribed to the planning target volume, clinical target volume (CTV), and gross tumor volume (GTV), in 5 fractions. Across 150 fractions, segment-level dose matrices synchronized with time-resolved target displacements were combined to reconstruct per-fraction and cumulative dose. Directional prescription-isodose deviations were used to derive internal target volume margins, which were evaluated through offline replanning, gating-envelope analysis, and dose reconstruction. Results: Median 95th-percentile motion ranges were 0.5, 1.4, and 2.9 mm in the left-right, anterior-posterior, and superior-inferior directions; these exceeded 3 mm in 0.7%, 13.2%, and 47.7% of fractions, respectively. The median treatment time was 13.2 min (IQR, 12.0-15.1 min) with a median gating duty cycle of 93.2% (80.6%-97.8%). Per-fraction median GTV deviations were -1.2% (-2.4% to -0.1%) for D95 and -5.6% (-15.3% to -0.2%) for V45Gy; corresponding CTV deviations were -0.5% (-1.1% to -0.1%) and -2.1% (-4.1% to -0.4%). Cohort-derived margins of 2/2/1/2/1/2 mm for the GTV and 1/1/1/2/1/2 mm for the CTV in the left/right/anterior/posterior/superior/inferior directions achieved sufficient coverage in approximately 94% of fractions in each direction. Gated delivery using the proposed margins improved coverage but may reduce duty cycle by an average of 6.9 +/- 4.7 %. Conclusion: Residual intrafraction motion produced directionally asymmetric coverage loss, with the largest effect on the boosted GTV. Motion-inclusive dose reconstruction enabled derivation of practical asymmetric margins that improved robustness while identifying the tradeoff between target coverage and delivery efficiency.

Abstract Purpose: To compare scalar circulating blood dose summaries, assess whether associations with grade 3 or higher lymphopenia and overall survival persisted after planning target volume (PTV) adjustment, and distinguish scalar from exploratory dynamic blood dose analyses. Methods and Materials: The assembled dataset included 133 patients from 2 retrospective thoracic radiation cohorts; 121 entered the dosimetric main analysis and 116 passed a post hoc dosimetric gate. Six scalar exposures were compared: an ICE3 (Immune Circulation radiation Exposure Estimator Engine) 10 compartment mean-dose metric, corrected effective dose to immune cells (EDIC), body remainder dose, a hematological dose (HEDOS) derived organ-mean approximation, mean lung dose, and mean heart dose. Logistic base models included baseline absolute lymphocyte count, concurrent chemotherapy, and cohort; PTV was then added. Overall survival used cohort-stratified Cox models on an endpoint-specific common set. Benjamini Hochberg correction was applied within prespecified 6exposure families and, separately, across 3 selected post hoc bootstrap contrasts. Results: The lymphopenia analysis included 94 patients and 69 events. After PTV adjustment, the HEDOS derived approximation remained nominally associated (odds ratio, 2.54; 95% confidence interval, 1.18-5.45; P=.017; q=.102), but no exposure survived false-discovery-rate control. The survival set contained 92 patients and 42 deaths; no PTV adjusted scalar exposure was associated with survival (all q>=.531). In post hoc analyses, the standardized association of mean heart dose with overall survival was more positive than that of ICE3 (difference in log hazard ratios, 0.44; 95% CI, 0.13 0.94; multiplicity-adjusted q=.024). The corresponding contrast with the HEDOS derived approximation did not meet the adjusted significance threshold (q=.053). These coefficient contrasts do not establish superior predictive performance or causality. Exported ICE3 kinetic summaries had no false-discovery-rate-significant residual associations. A 13 case HEDOS bDVH audit showed little change under one continuous versus 10 second gap perturbation. Conclusions: PTV adjustment attenuated scalar blood-dose associations with severe lymphopenia, and no scalar exposure retained a multiplicity-robust survival association. The selected mean heart dose coefficient contrast is hypothesis generating and does not establish superior prediction. The primary cohort comparison evaluated a HEDOS derived organ-mean approximation rather than the full dynamic HEDOS framework; therefore, these findings should not be interpreted as evidence against the potential value of particle level blood dose distributions or time-dependent blood-flow modeling.

Objectives: To estimate the absolute benefit of adding and prolonging androgen deprivation therapy (ADT) to radiation therapy (RT) for men with localized prostate cancer by integrating cancer-specific risk, other-cause mortality (OCM) risk, and relative treatment efficacy. Subjects and Methods: Individualized risks were estimated by integrating cause-specific hazard estimates from a validated staging system (STAR-CAP) with those from a validated non-cancer mortality model (OCCAM). ADT treatment efficacy was then incorporated using published hazard ratio estimates from the MARCAP meta-analysis. Model utility was illustrated using the Prostate, Lung, Colon, and Ovarian (PLCO) cancer screening trial cohort (n=5468 prostate cancer patients with complete covariates). The primary outcome was the estimated 10-year absolute risk reduction (ARR) in distant metastasis (DM) from adding short-term ADT (STADT) to RT or extending STADT to long term ADT (LTADT). Results: Within PLCO, model estimated risk of DM at 10 years ranged from <1% to 56% under guideline concordant care and OCM risk ranged from 3% to 80% independent of treatment. For patients with NCCN unfavorable intermediate-risk (n=1814), adding STADT to RT reduced estimated 10 year DM risk by a median of 4%, but the ARR estimates for individuals ranged from <1% to almost 15%. Similar variation was seen within NCCN high-risk patients (n=1289) with a median ARR of 9% [Range: 0.4%-17.2%] when prolonging ADT treatment. Moreover, 25% of NCCN unfavorable intermediate-risk patients have less than a 2.4% ARR while 25% of NCCN high-risk patients experience less than a 5% ARR. Conclusion: An integrated model accounting for both prostate cancer aggressiveness and comorbidities demonstrates substantial heterogeneity in the estimated absolute benefit of ADT within conventional risk groups. This approach provides individualized estimates to support treatment discussions; external validation is needed before clinical implementation.

Background. Treatment of locally advanced rectal cancer (LARC) increasingly varies in radiotherapy use, sequence, and intensity. Pretreatment biomarkers for the mismatch-repair-proficient majority remain limited: the biopsy-adapted Immunoscore predicts neoadjuvant response and recurrence risk, but no available biomarker estimates intrinsic tumor radiosensitivity or guides radiotherapy dose, use, or sequence. Genomic Adjusted Radiation Dose (GARD) combines the biopsy-derived Radiosensitivity Index (RSI) with the prescribed dose-fractionation schedule through the linear-quadratic model to estimate tumor-specific modeled radiation effect. We sought to evaluate whether pretreatment GARD is prognostic for outcomes in radiotherapy-treated LARC. Patients and methods. We performed a retrospective pooled analysis of 497 patients with LARC drawn from four prospective clinical trial and institutional cohorts; 335 patients (67%) were prospectively enrolled in clinical trials. The cohort spanned induction chemotherapy followed by chemoradiotherapy (CRT) (n=142), CRT followed by consolidation chemotherapy (n=120), and CRT without sequential chemotherapy (n=235). Pretreatment gene expression was measured by microarray or RNA sequencing and harmonized across platforms before GARD calculation. The primary endpoint was disease-free survival (DFS). GARD was evaluated continuously using cohort-stratified Cox regression and dichotomized at the outcome-blind pooled-cohort median of 19.3. Multivariable models adjusted for age, sex, and clinical stage. Results. Median follow-up was 5.3 years. Among 456 patients evaluable for DFS, 99 experienced an event. Higher GARD was associated with longer DFS as a continuous variable (hazard ratio [HR] per 1-unit increase, 0.92; 95% CI, 0.86-0.99; p=0.027) and at the median threshold (GARD >19.3 versus <19.3: HR, 0.62; 95% CI, 0.41-0.92; p=0.021). Five-year DFS was 81% versus 73%, and 10-year DFS was 80% versus 66%, respectively. GARD remained independently associated with DFS after adjustment for age, sex, and clinical stage (HR, 0.92; p=0.023). Overall survival (OS) was directionally consistent but not statistically significant (HR per 1-unit increase, 0.94; p=0.18). Among 445 patients with evaluable Neoadjuvant Rectal (NAR) scores, higher-GARD patients had lower median NAR scores (8.4 versus 15.0; p=0.004), were more frequently classified as low risk (34% versus 21%), and were less frequently classified as high risk (23% versus 31%). Among 460 patients evaluable for pathologic complete response (pCR), the pCR rate was numerically higher with higher GARD (22% versus 15%; odds ratio per 1-unit increase, 1.07; p=0.09). Conclusions. Pretreatment GARD, a biology-based model of tumor-specific radiation effect, stratified DFS independently of clinical stage and was associated with NAR-defined pathologic response across contemporary treatment sequences. These findings provide multicohort evidence of prognostic validity but do not establish prediction of radiotherapy benefit. Prospective GARD-stratified trials should test whether incorporating tumor radiosensitivity into decisions about radiotherapy use, dose, and sequence improves tumor control and organ preservation while reducing treatment-related morbidity.

Bone marrow chimeras are widely used to study immune development and function. As the field moves from cesium-137 (137Cs)-based irradiators to X-ray irradiators for safety reasons, it is essential to determine if there are differences in immune system reconstitution after irradiating mice with one of these two radiation sources. Here, we performed a comprehensive immunological comparison of mice lethally irradiated with 137Cs or one of two different X-ray platforms and reconstituted with congenic bone marrow. Mice received 12 Gy total body radiation in two 6 Gy sessions followed by intravenous transfer of donor hematopoietic stem cells and were analyzed eight weeks post-transplant. We assessed mouse survival, donor chimerism, immune cell subset distribution, and activation states across multiple organs (bone marrow, spleen, lymph nodes, liver, and lung). All groups exhibited comparable survival and high levels of donor chimerism, with expected organ-specific reconstitution patterns. Immune lineage distributions, CD4/CD8 ratios, and activation states did not differ by irradiation type. Host-derived radioresistant cells were also similar across all irradiation groups and were predominantly composed of T cells skewed toward an activated phenotype. Overall, our data show that X-ray irradiation with proper filters and energy levels (225 KVp and 320 KVp) can yield equivalent immunological outcomes, including immune reconstitution and activation states, as compared to the same radiation dose from 137Cs-based irradiation in bone marrow chimera models. These results support the continued adoption of X-ray irradiation systems in place of 137Cs for generating bone marrow chimeras to be used across a wide range of immunologic studies.

Background: Radiotherapy is a cornerstone of treatment for pediatric central nervous system (CNS) tumors, but dose selection remains largely uniform despite substantial interpatient variability in tumor radiosensitivity. This limitation is particularly consequential in children, in whom radiation-associated toxicity has lifelong impact. The genomic-adjusted radiation dose (GARD), which integrates tumor genomics with delivered radiation dose, quantifies the biological effect of radiotherapy and has been validated across multiple adult malignancies. Its relevance in pediatric CNS tumors remains unknown. Methods: We performed a retrospective cohort study using gene expression and clinical data from 246 pediatric patients with high-grade glioma, medulloblastoma, or ependymoma from the Childrens Brain Tumor Network. GARD was calculated using a sequencing-adapted radiosensitivity index integrated with radiation dose via the linear-quadratic model. Associations between GARD, physical radiation dose, and clinical outcomes (event-free survival and overall survival) were evaluated using Cox proportional hazards models stratified by tumor type and anatomic location. Patients who did not receive radiotherapy were analyzed as a negative control cohort (sham-GARD). Results: Among patients receiving radiotherapy, physical radiation dose was relatively uniform, yet GARD demonstrated substantial interpatient variability in predicted biological effect. Higher GARD was significantly associated with improved event-free survival (hazard ratio [HR] 0.90, 95% CI 0.83-0.97; p=0.004) and overall survival (HR 0.90, 0.83-0.99; p=0.018). By contrast, physical radiation dose was not associated with either endpoint. In patients who did not receive radiotherapy, sham-GARD was not associated with outcomes, supporting its role as a treatment-specific predictor rather than a general prognostic biomarker. Conclusions: In pediatric CNS tumors, the biological effect of radiotherapy as quantified by GARD is associated with clinical outcomes, whereas physical dose alone is not. These findings challenge the current paradigm of uniform radiotherapy dosing and support a genomically informed approach to dose individualization. Prospective evaluation of GARD-guided radiotherapy is warranted to optimize tumor control while minimizing long-term toxicity in children.

Purpose: Clinical assessment of vertebral lesion quality (osteolytic, osteoblastic, mixed) remains subjective, with limited interobserver reliability. This study evaluated a novel application of 3D convolutional neural networks (3D-CNNs) for classifying lesion quality from CT volumes in metastatic cancer patients. Materials and Methods: This retrospective study used CT data from 151 cancer patients planned for radiotherapy for metastatic spine disease (September 2020-July 2024). Leveraging vertebra-level expert annotations, we introduced an unconventional U-Net-based strategy converting coarse voxel-wise predictions into vertebra-level lesion classifications. The final dataset comprised 2,125 vertebrae across four classes (no lesion, osteolytic, osteoblastic, mixed), split into a 3-fold cross-validation set and an independent holdout test set. Model performance was benchmarked against a DenseNet121 baseline and a musculoskeletal radiologist, with Cohen's kappa assessing inter-rater agreement. Results: The 3D model achieved an ensemble accuracy of 84.7%, outperforming DenseNet121 (72.1%), with substantial gains in F1 score, precision, and balanced accuracy. It showed high concordance with the radiologist (Cohen's kappa = 0.76) and comparable sensitivity and specificity across all lesion subtypes. We found both models and the radiologist to struggle with osteolytic lesions, reflecting the difficulty of distinguishing this class from age-related changes in vertebral bone density and architecture caused by benign bone lesions, age-related systemic skeletal disorders and cancer treatments. Conclusions: 3D-CNNs trained with vertebra-level labels can accurately and reliably classify vertebral metastatic lesion quality from CT scans, offering a scalable path toward automated characterization of metastatic spine disease to support clinical decision-making and large-scale radiomics research.

Purpose: Biochemical recurrence (BCR) after radical prostatectomy (RP) presents heterogeneous recurrence patterns and variable outcomes following salvage radiotherapy (sRT). We evaluated clinicopathologic determinants of PSMA-PET/CT detection, anatomical recurrence distribution, and biochemical disease-free survival (bDFS) following PSMA-PET-guided sRT. Methods: This retrospective single-institution study included 140 patients with BCR after RP who underwent Ga-PSMA-PET/CT prior to sRT with or without androgen deprivation therapy. PSMA-PET-positive findings were categorized as prostate bed only (PBO) or pelvic nodal involvement with or without the prostate bed (PLNI). Receiver operating characteristic (ROC) analysis, logistic regression, and Cox proportional hazards models were employed. Results: PSMA-PET detected locoregional recurrence in 77/140 patients (55%). On multivariable analysis, PSA at recurrence (OR=2.07; p=0.003) and age (OR=1.07; p=0.016) were the sole independent predictors of PSMA-PET positivity. ROC analysis yielded AUC=0.74 (optimal threshold of 0.58 ng/mL). Among PSMA-positive patients, PBO was associated with a longer time to BCR (tBCR) (37.5 versus 15 months; p=0.006). Seminal vesicle invasion (SVI) and pT-stage predicted PLNI on univariable analysis. Among 124 of 140 evaluable patients (median follow-up 31 months), estimated bDFS at 24, 36, and 60 months was 89.7%, 80.2%, and 54.1%, respectively. SVI (HR=2.39; p=0.031), EPE (HR=2.82; p=0.012), pT-stage (HR=1.64; p=0.021), and pN-stage (HR=1.83; p=0.045) were associated with increased failure on univariable Cox regression, though none retained independent significance. Conclusion: PSA burden and age independently predicted PSMA-PET detection. Recurrence patterns reflected disease behavior, as PBO was associated with longer tBCR. Adverse pathologic features were associated with pelvic nodal disease and reduced biochemical control; none remained independently predictive.

BACKGROUND AND PURPOSE: ROAM/EORTC-1308 is an international (Europe and Australasia) phase III randomised controlled trial (RCT) comparing radiotherapy (60Gy/30#) to observation after surgery for atypical meningioma. The treatment plans of all the patients randomised to radiotherapy were reviewed and approved prior to treatment delivery, either by the UK RTTQA group (European sites) or the Australian TROG (Australia and New Zealand). Pretrial credentialling included outlining and planning a benchmark case (DR). MATERIALS AND METHODS: Variations from the guidelines were noted in quality assurance (QA) reports both for DR and for the on-trial Individual Case Reviews (ICRs) and classed as major or minor. After recruitment had finished, a random 10% of the ICRs were independently reviewed for audit purposes. We used the QA reports to analyse the variations in the DR and in the ICRs RESULTS: 56 sites (20 UK, 25 EORTC, 11 TROG) undertook the DR of which 13 (23%) had major variations. During the trial 64 patients at 28 sites received radiotherapy, the median being 2 patients per site. Overall, 25 (39%) patient cases needed resubmitting: 22 (36%) sets of outlines (2 cases twice) and 12 (14%) treatment plans (1 plan twice). CONCLUSIONS: For complex radiotherapy of rare tumours, a DR is insufficient and prospective ICRs of all patients is required. The consistent high-quality radiotherapy in ROAM/EORTC1308 ensures the primary outcome (progression free survival) will be a robust assessment and any difference between treatment arms cannot be attributed to variation in radiotherapy treatment.

Purpose: Digital-twin frameworks can potentially offer a pathway toward individualized treatment but remain largely untested in radiation oncology. We present a causal digital-twin model for head-and-neck (H&N) cancer that estimates patient-specific survival benefit from chemoradiotherapy (CRT) versus radiotherapy (RT) alone, stratified by HPV status. Methods: Using the public RADCURE cohort (n = 3,346), we developed a causal digital-twin framework in which patients were divided into HPV-positive and HPV-negative groups and assigned to training (RT start year [&le;] 2007) and test sets (RT start year > 2007). Bayesian-network structure learning identified each cohort's Markov Blanket around the 2-year survival endpoint (SVy2), yielding the minimal causally relevant feature set. A causal-forest model (double machine learning, DML framework) estimated the individualized treatment effect {tau}=P(SVy_2|CRT,X)-P(SVy_2|RT,X), with {tau} denoting the model-estimated effect. Overlap restrictions were applied to mitigate extrapolation. Predictive discrimination (AUC, C-index), average treatment effects (ATE), individualized effects (ITE), and decision-curve analyses were computed. Results: For HPV-negative disease, internal evaluation demonstrated strong discriminative performance (test AUC = 0.72; C-index = 0.81, p < 0.01). The estimated test-set ATE favored CRT with a modest but positive improvement in SVy2 (mean {tau} = 0.13). Patterns in {tau} were clinically coherent, including increased benefit in node-positive and good-performance patients and reduced benefit in high-burden or poor-performance presentations. Decision-curve analysis showed that a {tau} -guided selective-CRT strategy provided higher net benefit than uniform treatment policies. In HPV-positive disease, treatment-effect heterogeneity was attenuated, consistent with its more uniformly favorable prognosis. Conclusion: This study demonstrates a proof-of-concept causal digital-twin framework for interpretable, patient-specific survival simulation in H&N cancer. The model captures clinically plausible treatment-effect heterogeneity and establishes a foundation for multi-cohort validation and future integration into individualized treatment decision support.

Background: Patient-specific dosimetry in targeted radionuclide therapy (TRT) is increasingly supported by quantitative imaging; however, voxel-scale dose estimates cannot resolve cellular and subcellular heterogeneity present within tumor tissue. Conventional cellular dosimetry models often represent cells as regularly packed spheres, which may not capture realistic tumor microarchitecture. This study investigated how histopathology-informed three-dimensional (3D) tumor microarchitecture influences cellular absorbed-dose distributions, predicted radiobiological response, and treatment-related conclusions in TRT. Methods: Realistic 3D cellular tumor models were constructed from thick-section 3D cyclic immunofluorescence (3D CyCIF) imaging data. Monte Carlo radiation-transport simulations were performed for Lu-177, Pd-103, Tb-161 and Y-90, with activity localized in cancer-cell subcellular compartments and in non-cancer targets. Absorbed dose per total cluster decay was calculated individually for each cell nucleus and compared with corresponding simplified spherical tumor models. Cell survival fractions were estimated using the linear-quadratic model, and tumor control probability (TCP) was calculated from the individual cancer-cell survival probabilities. Results: Simplified model overestimated mean cancer-cell nuclear absorbed dose by 9.54% to 14.51% for nuclear localization and by 33.23% to 44.88% for cytoplasmic and membrane localization. In larger tissue models, simplified and realistic geometries produced comparable mean absorbed doses in several cases; however, the realistic models consistently generated broader cellular dose distributions, including low-dose cancer-cell subpopulations not captured by the simplified models. These dose-distribution differences propagated into wider survival-fraction distributions and altered TCP predictions. In the spatially heterogeneous tumor region, the realistic model required 1.11- to 1.33-fold higher activity to reach TCP90 for nuclear localization, and 1.49- to 5.93-fold higher activity for cytoplasmic and membrane localization. For similar tumor control, the radionuclide and source-localization combination associated with the greatest preservation of surrounding non-cancer cells differed between the simplified and realistic models. The intra-voxel analysis further showed that homogeneous voxel-scale activity assumptions can obscure biologically relevant microscopic dose heterogeneity. Conclusion: Native 3D tumor microarchitecture substantially influences cellular absorbed-dose distributions, predicted biological response, and treatment-related conclusions. Histopathology-informed 3D cellular models can be used as a complementary framework for characterizing cellular dose heterogeneity and may improve the evaluation of radionuclides and subcellular targeting strategies in heterogeneous tumor tissue.

Background: Chimeric antigen receptor (CAR) T cell therapy has had clinical success in hematologic malignancies, but limited efficacy is seen in solid tumors. In this study, we investigated whether systemic CAR T cell therapy could be enhanced in metastatic models of neuroblastoma when combined with radiopharmaceutical therapy (RPT). Methods: Non-irradiated or irradiated tumor cells were co-cultured with CAR T cells (1:1) in vitro and supernatant media was subsequently collected for cytokines analyses. CAR T cell phenotypes were characterized by flow cytometry including checkpoint marker expression. Xenograft models of metastatic neuroblastoma were generated in NOD-Rag1nullIL2rgnull (NRG) mice. Tumor-bearing mice received 1.8 Gy of radiation delivered by 177Lu-NM600 RPT five days after tumor implantation. Nine days after RPT, CAR T cells were administered intravenously. To evaluate tumor burden, mice were imaged weekly for 4 weeks. Results: In models of metastatic neuroblastoma, 177Lu-NM600 RPT significantly increased overall survival when combined with CAR T cell therapy in vivo. Pre-treatment of tumor cells with 177Lu also significantly increased CAR T cell cytotoxicity while decreasing production of IL-4 and IL-10 in vitro. Co-culture of CAR T cells with irradiated tumors led to increases in PD-1+TIM3+LAG3+ T cells, suggesting that further combination with immune checkpoint inhibitors may enhance clinical efficacy. Conclusions: Our findings demonstrate that low-dose RPT can potentiate the anti-tumor efficacy of CAR T cells in metastatic neuroblastoma. To our knowledge, this is the first report of dosimetry-based RPT being combined with CAR T cells in a metastatic solid tumor setting. These findings underscore the potential of combining RPT and CAR T cells to overcome the unique challenges of solid tumors, particularly when treating metastatic disease.

Routine H&E-histopathology captures spatial snapshots of tumor ecosystems, yet computational pathology largely treats them as textures without explicit links to underlying kinetics. We show that patient-specific parameters of a mechanistic reaction-diffusion model can be inferred from a single biopsy. Cell-nucleus point patterns are fitted jointly to the analytical two-point correlation function and power spectral density, recovering patient-specific mechanistic proliferation and diffusion rates across eleven multicenter cohorts. Derived dispersion length and front velocity define mechanistic phenotypes stratifying progression-free and overall survival and adding information independent of routine covariates. We illustrate counterfactual radiotherapy simulations in glioblastoma and show that a virtual clinical trial deescalating histology-calibrated faster-growing tumors to hypofractionation while dose-intensifying slower-growing tumors adds 96.7 days of restricted mean progression-free in silico survival over standard of care (permutation p<0.001 against random allocation to the same arms). This provides a low-barrier transition from routine histopathology to mechanistically interpretable model-based forward simulations.

Radiosensitizing nanoparticles represent a promising approach for enhancing the efficacy of proton radiotherapy; however, their performance is constrained by restricted penetration into tumor tissue, resulting in preferential perivascular accumulation. Here, we develop a spatially distributed mathematical model of a growing tumor undergoing proton therapy with intravenously administered radiosensitizing nanoparticles to investigate treatment optimization strategies. Using physiologically plausible parameter ranges informed by our own experimental measurements and published data, we demonstrate that co-administration of targeted nanoparticles with antibodies binding to the same tumor receptors can overcome transport-induced localization and promote a more uniform intratumoral redistribution of nanoparticles before irradiation. Population-level simulations across heterogeneous parameter sets suggest that moderate antibody doses consistently prolong tumor regrowth time, whereas higher antibody doses produce a pronounced and robust increase in tumor cure probability under a single high-dose irradiation regimen representative of preclinical settings. A key conceptual result of our analysis is the asymmetric risk associated with antibody co-administration. In contrast to antibody--drug conjugates, for which excessive dosing of unconjugated antibodies may severely compromise therapeutic efficacy, co-administration of antibodies with nanoparticle-based radiosensitizers constitutes a "safe-by-design" strategy with respect to tumor cell kill in the modeled single high-dose irradiation setting: although excessive antibody doses may yield suboptimal outcomes, they cannot reduce tumor cell kill below that achieved with targeted nanoparticles administered without antibodies. These findings identify antibody-mediated spatial redistribution of radiosensitizing nanoparticles as a favorable strategy that is expected to provide robust therapeutic benefit despite substantial variability in tumor characteristics.

Radiopharmaceutical therapies (RPT) deliver non-uniform radiation dose in tumors and the impact of this on response is poorly understood. Dose heterogeneity could engender treatment resistance in low dose regions, yet we hypothesize that a broader array of dose-dependent immuno-radiobiological mechanisms in tumor microenvironments (TME) and preservation of immune function in low-dose regions could promote adaptive anti-tumor immunity and response. In murine models, non-uniform lutetium-177 delivering <2.5 Gy to >20 Gy in a TME induced broader immunomodulatory effects and T cell-dependent survival improvement compared to more uniform distributions. Preserving low-dose regions promoted dendritic cell activation and TME infiltration of clonally expanded CD8+ T cells. In three independent cohorts of patients with prostate cancer, heterogeneous tumor dose distribution strongly correlated with improved clinical outcomes. These findings defy expected radiobiological dose-response and define a novel mechanism of action for RPT, supporting clinical investigation of dose distribution for optimizing patient selection and personalized dosing.

Background: Brachytherapy delivers localized radiation from sources placed within or adjacent to tissue at risk. In brain tumor surgery, intracavitary implantation can begin at resection and concentrate dose along the cavity wall, where many recurrences arise. Current preoperative GammaTile tools estimate tile requirements but not patient-specific placement, resulting dose, or adjacent anatomy. We developed an integrated software framework for patient-specific virtual GammaTile planning. Methods: The framework incorporates AI-assisted tumor and cavity segmentation with user approval, converts accepted masks into patient-derived surfaces, supports virtual tile placement, calculates lifetime Cs-131 dose using TG-43, maps dose distributions to HCP-MMP cortical parcels and normative HCP-1065 white-matter bundles, and supports AI-assisted synthesis of the resulting complex anatomical and connectomic output for clinician review. We retrospectively applied it to three patients with glioblastoma. Tile requirements were compared with the GammaTile Cavity Surface Area Calculator. For Patient 1, calculated 60- and 80-Gy volumes were compared with the clinical plan. Results: Preoperative layouts required 6.5, 7, and 4 tile equivalents for Patients 1-3; calculator estimates were higher by 1.5, 4, and 1 tiles. Postoperative differences narrowed to 1, 1, and 0 tiles. The plans generated patient-specific lifetime dose distributions at 60, 80, and [&ge;]120 Gy. In Patient 1, calculated and clinical 60- and 80-Gy volumes were similar despite incomplete spatial overlap. Atlas mapping revealed distinct cortical and white-matter exposure patterns across cases beyond lobar description. Conclusions: Patient-specific virtual GammaTile planning can connect anticipated tile placement with calculated dose and adjacent neuroanatomy. These cases demonstrate feasibility and establish a framework for prospective validation and future comparison of candidate implant arrangements.

Purpose/Objective There is paucity of data reporting outcomes of breast cancers with initial internal mammary nodal involvement and no visceral metastases, treated with curative hypofractionated radiotherapy . We report the outcomes from a tertiary centre alongside spatial patterns of recurrences in the above group Material/Methods For this retrospective cross-sectional study, consecutive patients contoured as per the ESTRO 2013 guidelines, treated between 2016-2022 were eligible if their diagnostic imaging demonstrated involvement of the internal mammary nodes. Radiotherapy (40 Gy/15#/3 weeks) was delivered to the residual breast / thoracic wall, SCF region corresponding to the ESTRO lymph node level 4 and internal mammary chain nodes. Residual IMN/ level 4 nodes received a boost of 10Gy/5#. Spatial mapping of sites of recurrence at the local site and three nodal sites (axilla, SCF and IMN) was performed using deformable image registration. Sites of recurrence at the local site and three nodal levels were contoured separately. Volumetric intersection of the recurrent gross tumour volume (GTV_recurrence) with treated clinical target volume (CTV) was calculated. Actuarial overall (OS), disease free survival (DFS) & cumulative incidence of local (LR), regional (RR) and loco-regional recurrence(LRR) were calculated using Kaplan Meier method. Univariate comparison of outcomes with or without residual disease was performed using the log rank test. Results The median age of the 61 eligible women was 49 years. 77% received neoadjuvant chemotherapy and the rest adjuvant chemotherapy. 82% patients had a mastectomy. Axillary lymph node dissection was done in 96.7%. Boosts to residual IMN and SCF nodes were delivered to 21(34.4%) and 2 (3.3%) respectively. Median follow up was 3.6 years. Out of the 61 patients, 42 patients were disease free with an estimated 3 year disease free survival of 75% (95% CI 64, 88%). Spatial mapping of locoregional recurrence was possible in all but 1 patient with local (only) recurrence who was lost to follow-up after mammogram only. Among the patients with loco regional recurrence 1 had recurrence in local site + SCF +axilla, 3 had recurrence in the SCF+axilla, 2 in the SCF+IMN and 1 in the axilla+SCF+IMN. Only one patient had isolated axillary recurrence or isolated SCF recurrence. There were no IMN only recurrences. Among the 8 patients with nodal recurrence, a total of 27 individual GTV_recurrence were identified in the axilla(n=11), SCF(n=11) and IMN (n=5). IMN recurrences showed complete or partial overlap with CTV. SCF recurrences were a mix with predominantly in-field recurrences while axillary recurrences occurred outside the treated volume.Four (6.6%) patients had Grade 2 lymphoedema as documented late side effect. Conclusion Aggressive treatment of IMN disease with adjuvant radiation is effective with good locoregional control. Systemic recurrences are common and may benefit from intensification strategies.

Herein, we assess the potential of low-dose stereotactic radiosurgery (SRS) to modulate neuronal network states without apparent damage to cellular integrity. Using a small animal radiation research platform (SARRP), a 1 mm3 focal target in the mouse visual cortex was irradiated with doses of 5, 20, and 40 Gy. One-month later a significant dose-dependent increase in excitatory synapse numbers was observed, notably limited to the treated visual cortex and not the adjacent somatosensory cortex. Six months post-irradiation, cortical neuronal microcircuit activity was monitored in awake mice using high sensitivity two-photon calcium imaging. A single 5 Gy dose resulted in a significant microcircuit-wide increase of spontaneous neuronal activity, consistent with a lasting shift in the functional architecture of the irradiated nodal network. At higher SRS doses (40 Gy) this neuromodulatory window appears to close. In aggregate, these data suggest that low-dose radiation could, in some circumstances, be exploited by selected high precision SRS technologies to durably modulate neuronal circuit disorders. Some, or even all the clinical benefits reported in the companion article by Zhao et al. are likely attributable to the biological properties we sought to characterize in our research. One Sentence SummaryLow-dose stereotactic radiosurgery effectively and durably modulates neuronal excitability via synaptic re-organization and could open new clinical possibilities for neuromodulation.

Background: Prostate cancer enzalutamide treatment is approved at a standard dose of 160 mg daily. Concerns for real-world patients -- older and more fragile than those enrolled in clinical trials -- have prompted consideration of initiating treatment with lower doses, but the long-term efficacy of this approach remains unknown. We evaluate the long-term survival and longevity in patients treated with standard versus upfront low-dose enzalutamide. Methods: Retrospective analysis of 151 patients treated with enzalutamide (102 receiving 160 mg; 49 receiving [&le;]80 mg) between 2014--2021 at the Centre Hospitalier Universitaire de Martinique, with complete follow-up through end of life (98.7% completeness of follow-up). Primary outcomes were overall survival (OS), progression-free survival (PFS), and longevity (attained age). Results: Doses [&le;]80 mg were associated with longer median OS (36.3 vs. 20.7 months), improved restricted mean OS (difference of 0.7 years, p=0.05), and enhanced longevity (median 82.5 vs. 78.3 years, p=0.004). PSA response rate at 12 weeks was higher with lower-dose (71.4% vs. 48.8%, p=0.016). In multivariable models adjusted for prognostic factors, [&le;]40 mg compared with 160 mg was non-inferior regarding OS (HR=0.61, 95% CI 0.36--1.06), superior regarding PFS (HR=0.59, 95% CI 0.35--0.99), and superior regarding longevity (HR=0.48, 95% CI 0.28--0.84). Bone metastasis, poor performance status, PSA response, time to PSA nadir, and disease duration were independent predictors of outcomes. A post-hoc analysis revealed a strong association between dose and physician-prescribing profiles, ranging from "endorse-lowest-dose" to "never-deviate-from-full-dose". Conclusions: Lower doses of enzalutamide were non-inferior to full-dose. Dose-adapted strategies warrant further investigation.

Background: Trophoblast cell surface antigen 2 (TROP2, encoded by TACSTD2) is a transmembrane glycoprotein overexpressed in multiple aggressive epithelial carcinomas. While antibody drug conjugates targeting TROP2 have achieved regulatory approvals, acquired payload resistance and systemic off-target toxicities limit sustained remissions. Radionuclide Drug Conjugates (RDCs) represent a potent alternative modality capable of delivering cytotoxic ionizing radiation directly to target cells. However, selecting the optimal therapeutic radioisotope between long-range beta emitters (177Lu) and short-range, high linear energy transfer (LET) alpha emitters (225Ac) under heterogeneous TROP2 spatial distributions remains an unaddressed clinical challenge. Methods: We developed an automated computational pathology and spatial microdosimetry pipeline to resolve microscopic TROP2 expression gradients and simulate absorbed radiation dose distributions from digitized whole-tissue immunohistochemistry (IHC) sections (N = 14). Optical density matrices were de-convoluted in Hematoxylin-Eosin-DAB (HED) color space to isolate the DAB chromogen. Continuous 2D spatial density distributions and topological surface profiles were reconstructed. Physical radiation energy deposition was modeled using radial dose point kernels for 177Lu (mean range ~670 m, LET 0.2 keV/m) and 225Ac (mean range ~65 m, LET 100 keV/m, 4 alpha particles per decay cascade). Therapeutic Index (TI, ratio of mean target to non-target absorbed dose), target coverage, and spatial specificity were quantified across all specimens. Results: Quantitative image deconvolution revealed that TROP2 expression across the cohort was characteristically focal and clustered, with a mean positive area fraction of 1.55 +/- 2.22% (range: 0.08% to 6.85%) and mean DAB signal intensity of 0.256 +/- 0.043. In all 14 evaluated specimens (100%), 225Ac-labeled RDCs demonstrated superior tumor-to-stroma dose localization compared to 177Lu-labeled RDCs. The cohort-wide mean Therapeutic Index was significantly higher for 225Ac (1.26 +/- 0.14) than for 177Lu (1.01 +/- 0.02, p < 0.0001, paired two-tailed t-test). Because the path length of 177Lu beta particles exceeded target cell nest dimensions by up to 30-fold, 177Lu suffered from severe off-target crossfire spillover into antigen-negative stroma. In contrast, 225Ac confined high-LET ionization tracks strictly within the micro-geographic boundaries of TROP2-expressing clusters. Conclusions: In tumors displaying focal or sparse TROP2 micro-architecture, Targeted Alpha Therapy with 225Ac-RDCs offers a superior biophysical profile over beta-emitting 177Lu-RDCs, maximizing cluster cell kill while sparing adjacent normal tissue stroma. This computational microdosimetry framework provides a practical tool to guide rational isotope pairing in RDC drug design.