International Journal of Radiation Oncology*Biology*Physics

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.

Purpose/Objective: Genitourinary (GU) adverse events (AEs) are common during and after pelvic radiation therapy (RT) for prostate cancer and can substantially impact quality of life. We convened an international committee to establish consensus in the prevention, mitigation, and management of radiation-related acute and late GU AEs, as there are no relevant evidence-based consensus guidelines to inform treating providers. Materials/Methods: A systematic evidence review focused on mitigation and management of radiation-related acute and late GU AEs was performed in PubMed, Embase and Cochrane. The following topics were addressed: management of acute GU AEs in the intact and post-operative settings; RT techniques; bladder outlet obstruction procedures; and indications for urology referral or hyperbaric oxygen therapy (HBO). Evidence-based consensus recommendations were developed using a Delphi process. We highlight the current state of evidence and evidence gaps worthy of future study. Results: Consensus was reached for 31 key questions. For management of lower urinary tract symptoms (LUTS), most evidence comes from trials in patients without cancer and not undergoing RT. A consensus algorithm for medical management of acute GU AEs was developed with the following highlights: (a) alpha blockers as 1st-line for obstructive symptoms in the intact setting, (b) anti-spasmodics as 1st -line for irritative symptoms in the intact setting, and (c) anti-spasmodics as 1st -line in the post-operative setting. The consensus algorithm provides an ordered list of medications to offer if 1st -line options afford inadequate relief. For RT fractionation, randomized clinical trial (RCT) data are available. 40% of panelists rarely or never use standard fractionation over moderate hypofractionation for patients with baseline LUTS, but most consider moderate hypofractionation over SBRT for AUA IPSS > 15. For patients with severe obstructive LUTS (most commonly AUA IPSS >20), the panel recommends a prophylactic bladder outlet obstruction procedure and, if obstructive symptoms improve, consideration of moderate hypofractionation or SBRT, based on retrospective data. There is one RCT supporting use of HBO for late radiation cystitis. Conclusions: The consensus guideline synthesizes available evidence and expert opinion across key clinical decision points to provide practical guidance in the prevention, mitigation, and management of radiation-related acute and late GU AEs in prostate cancer RT. Envisioned as a living document with periodic updates, this guideline serves as a resource for practicing radiation oncologists by outlining expert-derived consensus recommendations of evidence-based care in areas where high-quality data is limited.

Background: Deep Inspiration Breath Hold (DIBH) is a widely used respiratory motion management technique for minimizing cardiac dose in left-sided breast radiotherapy. In the Breast HYPORT Adjuvant study, DIBH was employed for cardiac sparing in patients without nodal irradiation using a standardized institutional protocol with the Varian Real-time Position Management (RPM) system. Both moderate-hypofractionation (control arm - 40Gy in 15 fractions) and one-week hypofractionation (experimental arm - 26 Gy in 5 fractions) regimens were delivered using this protocol. This study aimed to evaluate the robustness of DIBH by analyzing intra-fraction stability and inter-fraction reproducibility of breath-hold amplitude across the two treatment regimens. Methods: Respiratory waveforms acquired during each treatment session were analyzed to determine the median breath-hold amplitude and its standard deviation during beam delivery. Intra-fraction stability was assessed from vari- ations within individual treatment sessions, while inter-fraction reproducibility was evaluated relative to the simula- tion waveform amplitude across all treatment sessions. These parameters were compared between the two HYPORT regimens to examine breath-hold consistency during treatment delivery. Moreover, an additional comparison was made between the one-week hypofractionation regimen and the first five fractions of the moderate-hypofractionation regimen to evaluate the effect of treatment duration . Lung volumes from free-breathing and DIBH CT scans were analyzed to assess the effectiveness of patient breath-hold training. Results: Both arms demonstrated an average 1.7-fold increase of air volume in lung during the breath-hold position, confirming the effective implementation of DIBH during treatment planning and delivery. Structured training resulted in increased breath-hold amplitudes, with gains of 22.87% and 24.16% with respect to the first trial session in the experimental and control arms, respectively. Both regimens receive equivalent doses for approximately the same air volume in lung . Despite the different prescription doses in the two arms (26 Gy vs. 40 Gy), the experimental arm achieved an equivalent mean heart dose of 2.91% (75.6 cGy) compared with 2.95% (118.51 cGy) in the control arm, suggesting a similar cardiac preservation protocol adopted during treatment planning. Intra-fraction stability was similar between the control arm and the experimental arm, with median amplitude variations of 1.006 mm (95% CI: [0.998-1.015]) and 1.079 mm (95% CI: [1.067-1.097]), respectively. In contrast, inter-fraction reproducibility improved in the experimental arm, with lower deviation from simulation amplitude (0.44 {+/-} 0.24 mm vs. 0.66 {+/-} 0.25 mm) for the entire treatment schedule. The stability and reproducibility of experimental arm were further compared with the first five fractions of the control arm. The results were similar to those of the experimental arm. Conclusion: In this study, we compared two treatment regimens in terms of intra-fraction stability and inter-fraction reproducibility during DIBH radiotherapy. Both regimens demonstrated comparable intra-fraction stability, indicating effective motion management irrespective of treatment duration. However, the experimental arm showed better inter- fraction reproducibility, suggesting more consistent breath-hold performance throughout the treatment course. Based on stability and reproducibility, a reasonable narrowing of the DIBH gating window may be implemented with minor changes to the institutional protocol. The observed trend highlights the potential for improved consistency with the experimental approach and supports further investigation to better understand the underlying factors and strengthen these findings in future studies.

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: Glioblastoma (GBM) remains associated with poor outcomes, with most recurrences occurring within the high-dose radiation field, suggesting persistent radioresistance. Exportin 1 (XPO1) inhibition with Selinexor has demonstrated radiosensitizing effects in preclinical models. We conducted a phase I trial to evaluate the safety, tolerability, and preliminary efficacy of Selinexor in combination with standard chemoradiation for newly diagnosed GBM. Methods: This investigator-initiated phase I dose-escalation trial (3+3 design) enrolled adults with newly diagnosed GBM or gliosarcoma. Patients received standard radiotherapy (60 Gy in 30 fractions) with concurrent temozolomide and escalating doses of Selinexor. Three dose levels were evaluated: 80 mg weekly (weeks 1, 2, 4, 5); 60 mg twice weekly (weeks 1, 2, 4, 5); and 60 mg twice weekly (weeks 1-6) throughout radiotherapy. The primary endpoint was determination of the maximum tolerated dose (MTD) based on dose-limiting toxicities (DLTs). Secondary endpoints included progression-free survival (PFS), overall survival (OS), patterns of failure, and patient-reported outcomes (MDASI-BT). Results: Eleven patients were enrolled. Median age was 58 years, and median KPS was 90. The MTD was established at Selinexor 60 mg twice weekly during weeks 1, 2, 4, and 5 of chemoradiation. Dose level 3 exceeded the MTD with two DLTs. Treatment compliance was high, with minimal missed radiotherapy fractions. Median PFS was 15.9 months (95% CI, 6.2 28.5), and median OS was 17.4 months (95% CI, 14.1 not reached). Most recurrences were central (5/6 evaluable patients). Notably, multiple cases of delayed pseudoprogression were observed at 5, 9, 10, and 23 months post-radiotherapy. Patient-reported symptom burden remained stable over time. Conclusions: Selinexor can be safely combined with standard chemoradiation in patients with newly diagnosed GBM, with an MTD of 60 mg twice weekly during select treatment weeks. Preliminary efficacy signals and an increased incidence of delayed pseudoprogression suggest a potential radiosensitizing effect. These findings support further investigation of Selinexor in larger, prospective studies.

Background: Cognitive impairment is a prevalent long-term sequela in glioma patients, yet its cerebrovascular correlates remain poorly characterized. Arterial spin labeling (ASL) perfusion MRI offers a non-invasive means to quantify cerebral blood flow (CBF) and may serve as a sensitive correlate of radiotherapy (RT)-induced neurovascular injury. Methods: Fifty WHO Grade 2/3 glioma patients and 50 matched healthy controls underwent pseudo-continuous ASL (pCASL) MRI and a standardized cognitive test battery. Regional CBF was compared between patients (n=44, after quality control) and controls (n=50) using ANCOVA with age, sex, and deep white matter CBF as covariates. In irradiated patients (~5 years post-RT), RT dose-CBF associations were assessed using region-wise regression, and regional CBF was compared among controls and low-dose ([&le;]15 Gy) versus high-dose ([&ge;]40 Gy) regional RT exposure groups. Cognition-CBF associations were evaluated in a priori domain-specific regions of interest. Results: Compared with controls, patients showed frontoparietal cortical hypoperfusion, with significantly lower CBF in middle frontal and superior/inferior parietal cortices (all q<0.01; partial -squared=0.128-0.147). Region-wise regression showed no significant linear RT dose-CBF associations after correction. However, subgroup analyses identified RT dose-sensitive regions with [&ge;]40 Gy exposure that showed lower adjusted CBF than controls, most prominently in the left precentral and caudal middle frontal cortices (q<0.01; adjusted-{Delta}CBF{approx}-27.2--28.8 mL/100g/min). Perfusion in the left precentral and postcentral gyri of irradiated patients correlated positively with motor performance. Conclusions: pCASL reveals persistent cortical hypoperfusion in glioma patients that spatially corresponds with RT dose exposure and associates with cognitive performance, positioning ASL as a promising non-invasive biomarker of RT-related neurovascular injury.

The purpose of this work is to analyze the 2-year overall survival (OS2y) of limited-stage small cell lung cancer (LS-SCLC) treated with chemoradiotherapy (CRT), aiming at characterizing the response of LS-SCLC, and in particular the /{beta} value and proliferation parameters. Through a systematic analysis of the literature, we collated a dataset containing 57 entries (3363 patients) of response of LS-SCLC treated with CRT. Radiotherapy schedules ranged from hyper- to hypofractionation. Four radiobiological models to describe the OS2y were investigated, with progressive levels of complexity including the effect of radiotherapy, chemotherapy, treatment year and toxicity. The Akaike Information Criterion (AIC) was used to compare models, and the profile likelihood methodology to compute confidence intervals. Model 4, which includes the effect of radiotherapy, chemotherapy, treatment year and dose-dependent toxicity, provided the best fits of the experimental data (lowest AIC value). While being the best model, model 4 still fails to provide a good prediction of the OS2y, in particular failing to predict the survival of the schedules achieving the lower/higher survivals. The radiobiological analysis of the dose-response of LS-SCLC to CRT does not allow to narrowly constrain the value of response parameters. We attribute this limitation to the large heterogeneity of this disease. Nonetheless, our analysis shows a large /{beta} value (>9 Gy, 95% CI), which implies a low fractionation effect in the radiotherapy of LS-SCLC. and an accelerated proliferation of tumor cells, {lambda}' > 1.6 Gy/day (95% CI), after a kick-off time of ~4-5 weeks, which supports the use of accelerated protocols to avoid the effect of tumor proliferation on the clinical outcome.

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.

Background and purpose. Patients with oropharyngeal cancer (OPC) treated with radiotherapy (RT) exhibit heterogeneous courses of radiation-associated dysphagia (RAD) during recovery, yet most survivorship models typically treat RAD uniformly. This study aimed to identify distinct, data-driven RAD longitudinal Phenotypes based on imaging-graded swallow function from pre-treatment to 30 months post-RT and to characterize their baseline predictors. Materials and methods. Heterogeneous linear mixed-effects latent class trajectory modeling was applied to longitudinal DIGEST scores from the Stiefel MDA-OPC prospective registry. Eligible patients had [&ge;]3 Modified Barium Swallow (MBS) assessments between baseline and 30 months post-RT. Models were evaluated across functional forms and 1-5 latent classes; final selection used the Bayesian Information Criterion. Baseline predictors of class membership were identified via binary logistic regression. Results. The cohort comprised 650 OPC patients (2,116 MBS assessments; mean age 61 years, 89% male, 93% HPV-positive). Four RAD Phenotypes were identified: No/Minimal RAD (n=385/650, 59%), Mild/Moderate RAD (n=104/650, 16%), Moderate/Severe Transient RAD (n=94/650, 15%), and Moderate/Severe Progressing RAD (n=67/650, 10%). Classification quality was acceptable (mean posterior probabilities 0.78-0.89; entropy 0.69). Baseline DIGEST impairment, base-of-tongue primary, advanced T stage, and age [&ge;]60 independently predicted membership in higher-burden Phenotypes (AUC=0.845; 10-fold CV-AUC=0.835). Conclusion. RAD following RT for OPC comprises four biologically and clinically distinct longitudinal Phenotypes, predictable from pre-treatment characteristics. These findings support trajectory phenotyping as outcome framework for RAD research and risk-adaptive survivorship care.

Purpose. The radiosensitivity index (RSI) and genomic-adjusted radiation dose (GARD) are increasingly treated as quantitative inputs to radiotherapy dose calculation. Two reproducibility issues bear on this use: whether CT radiomics can non-invasively recover RSI, and whether one coefficient of the equation is uniquely specified (printed CDK1 but implemented as PAK2). We examine both on public data. Methods. In GEO GSE103584 RNA-seq (n = 130 non-small cell lung cancer [NSCLC]), we recomputed RSI with the Eschrich 2009 coefficients using CDK1 or PAK2 in the disputed slot and derived GARD under four fixed dose/fractionation schemas. In the paired TCIA NSCLC-Radiogenomics cohort (n = 117), we trained cross-validated Elastic Net and Random Forest models to predict continuous RSI and a median-split RSI label from IBSI-conformant, scanner-corrected CT radiomic features, under a pre-set viability rule. Results. CT radiomics did not recover RSI (Spearman rho = 0.05 and 0.03; binary AUC = 0.43), below the pre-set viability threshold. Separately, the two probesets listed for the disputed coefficient in the founding paper's Table 3 both map to PAK2; using the printed CDK1 left rank correlation high (rho = 0.980) but reclassified 6.2% and 9.2% of patients (median and tertile) and shifted GARD by 4.1 to 6.3 Gy. Conclusions. CT radiomics is not a viable RSI surrogate in this public cohort, so imaging-GARD should not assume radiomic recovery of RSI. The disputed coefficient resolves to PAK2; implementing the printed CDK1 shifts GARD and reclassifies patients despite high rank correlation. Outcome-directed, dose-adjusted imaging is the more defensible next step.

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.

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.

Purpose: To examine the relative contributions of insurance, county-level poverty, and other socioeconomic factors, as compared with Appalachian geography, to receipt of guideline-concordant therapy for early-stage non-small cell lung cancer (NSCLC) in Appalachian and non-Appalachian Ohio. Methods: Retrospective population-based cohort study using the Ohio Cancer Incidence Surveillance System. We identified adults diagnosed with early-stage NSCLC between 2004 and 2015 (N=26,756). The primary outcome was receipt of guideline-concordant local therapy (surgery or definitive radiation). Rural-urban classification used USDA Rural-Urban Continuum Codes. Multivariable logistic regression and Cox proportional hazards models assessed predictors of treatment and survival, with E-values, race-stratified models, and propensity score weighting as sensitivity analyses. Findings: Median age was 71 years; 50.3% were male, 83.8% non-Hispanic White, and 20.4% Appalachian. Overall, 83.6% received guideline-concordant local therapy (59.6% surgery, 24.0% radiation). In adjusted analysis, Medicaid (adjusted odds ratio [OR] 0.53, 95% confidence interval [CI] 0.44-0.63; adjusted risk ratio [RR] 0.94, 0.91-0.96), county-level poverty >20% (OR 0.77, 95% CI 0.68-0.87; RR 0.96, 0.95-0.98), and unmarried status were independently associated with lower therapy receipt, whereas Appalachian residence was associated with modestly higher receipt (OR 1.17, 95% CI 1.06-1.29; RR 1.02, 1.01-1.04). Therapy rates converged across regions over the study period (year x Appalachian interaction p<0.001). Mortality was independently associated with lack of local therapy (adjusted hazard ratio [HR] 4.33, 95% CI 4.10-4.56), Medicaid (HR 1.25, 95% CI 1.14-1.37), and poverty >20% (HR 1.13, 95% CI 1.07-1.20). Conclusions: Socioeconomic factors, particularly Medicaid insurance and county-level poverty, were the patient characteristics most strongly associated with lower receipt of guideline-concordant therapy, whereas Appalachian residence was not a barrier. Findings support targeted interventions addressing insurance-related and poverty-related barriers to lung cancer care in high-poverty communities regardless of geographic designation.

Radiation oncology has a long history of developing in-house health information technology (HIT) tools such as quality assurance (QA) checklists, yet there is little guidance from professional bodies on how to implement these tools in complex clinical environments. Building on our previous work that used human-centered participatory co-design, the Task-User-Representation-Function (TURF) framework, and multi-method usability evaluations to design and develop an enhanced dosimetry QA checklist (DQC), this study investigated the barriers and facilitators (determinants) to implementing the enhanced DQC in a radiation oncology clinic, examined implementation strategies, proposed an implementation framework for QA checklists in radiation oncology, and assessed four implementation outcomes: acceptability, appropriateness, feasibility, and adoption. We conducted a qualitative implementation study using an abductive research approach at an academic medical center. All key stakeholders (dosimetrists, physicists, trainees, and software developers) participated in semi-structured interviews, field observations, and surveys across pre-implementation, implementation, and post-implementation phases. Data were analyzed using a hybrid inductive-deductive approach, with deductive coding guided by an adapted Consolidated Framework for Implementation Research (CFIR) mapped to the Unified Theory of Acceptance and Use of Technology and by the Expert Recommendations for Implementing Change (ERIC) compilation. We identified 4 CFIR constructs and 12 sub-constructs as barriers, with structural characteristics and planning showing the highest negative valence, and 5 CFIR constructs and 19 sub-constructs as facilitators, with relative advantage, culture, and leadership engagement showing the highest positive valence. Participants' suggestions mapped to 19 ERIC strategies in 7 clusters, and the CFIR-ERIC matching tool identified 14 evidence-based strategies in 4 clusters that informed a proposed phased implementation framework. Acceptability, appropriateness, and feasibility scores improved significantly from pre-implementation to implementation for all professional roles (p<0.05), yet adoption reached 100% only in the sixth week of implementation. These findings highlight the value of combining subjective and objective implementation outcomes and provide a practical, evidence-based framework for implementing in-house QA checklists in radiation oncology that warrants validation in diverse settings.