Clinical and Translational Radiation Oncology

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.

BackgroundMen with aggressive, localized prostate cancer (PC) undergo definitive radiotherapy (RT) with androgen deprivation therapy (ADT). The prospective, phase II ARIEL trial evaluates a quantitative MRI biomarker, Restriction Spectrum Imaging restriction score (RSIrs), at three time points (before treatment, after ADT and after RT) for treatment response assessment. RSIrs highlights intracellular restricted diffusion and is correlated with high-grade PC. DesignParticipants are men with unfavorable-intermediate-risk or high-risk localized PC undergoing definitive RT with neoadjuvant and concurrent ADT, and MRI-RSI acquisitions at three time points: before therapy, after neoadjuvant ADT but before RT, and after RT. The primary aim is to evaluate performance of RSIrs for identifying patients who will experience early biochemical recurrence. Change in RSIrs within visible tumors after ADT and RT is the primary independent variable. Results97 patients met inclusion criteria and received [&ge;]1 MRI. On central review, visible PI-RADS lesions were identified in 88 patients: 80 patients had one lesion, and 8 patients had two lesions. After neoadjuvant ADT, 40% of lesions were not clearly visible. Those still visible had shrank by median 55.8% (IQR: 42.8-69.0%), much more than the prostate volume decrease of 21.5% (11.9-31.6%). RSIrs maximum within visible lesions decreased from mean 329 (SD:185) pre-ADT to 209 (SD:125) pre-RT (p<0.01), and to 107 (SD:61) post-RT (p<0.01). Conventional apparent diffusion coefficient (ADC) changes were less consistent. Follow-up is ongoing to assess whether imaging response is related to future recurrence risk. ConclusionARIEL has completed accrual and preliminary results demonstrate changes in RSIrs after treatment, which may indicate tumor response. Primary results will be presented when the primary endpoint is reached. With neoadjuvant ADT, both pre- and post-ADT MRI are likely necessary for accurate focal RT boost targeting. Concurrent commencement of ADT and RT simplifies workflows and facilitates accurate gross tumor volume delineation.

Purpose: Radiation-associated lower cranial neuropathy (LCNP) is a debilitating late complication among head and neck cancer (HNC) survivors, leading to progressive dysphagia, aspiration, and loss of nutritional independence. No proven therapies exist to reverse LCNP. This Phase I dose-finding trial (XXXX, XXXX) and parallel registry study prospectively evaluated the safety, feasibility, tolerability, and symptomatic response of high-dose corticosteroid therapy for radiation-associated LCNP. Methods and Materials: Eligible participants were disease-free oropharyngeal cancer survivors [&ge;]2 years post-radiotherapy with LCNP involving CN XII +/- X and no structural or malignant etiology. Phase I trial participants received oral prednisone 1 mg/kg (Dose 1, n = 3) or 3 mg/kg (Dose 2, n = 5) daily for 5 days followed by a 2-week taper. A parallel registry (n = 6) enrolled broader HNC survivors treated with 1 mg/kg. Phase I dose escalation decisions were based on the balance of tolerability and symptom response. The primary endpoint was change in MDASI-HN Top 5 mean symptom score from baseline to 1-2 weeks post-taper; a [&ge;] 1.315 unit decrease indicated clinically meaningful improvement. Secondary endpoints included clinician-graded measures of bulbar function, electromyography (EMG) and patient-report outcome measures. Results: All regimens were feasible and well tolerated. Insomnia (n = 4, Grade 1) was the most frequent adverse event and there were no treatment discontinuations. At 1-2 weeks post-taper, the median MDASI-HN Top 5 change was -0.2 in Dose 1 and -1.6 in Dose 2; three of five Dose 2 patients achieved clinically meaningful improvement versus one in Dose 1. By 6-10 weeks, symptom improvement persisted in a subset but diminished overall. Dose 2 met pre-specified criteria for Phase II progression. No consistent improvements were observed in objective functional or electrophysiologic measures, though exploratory trends favored higher dosing. Conclusions: High-dose corticosteroid therapy at 3 mg/kg/day was feasible and tolerable in long-term HNC survivors with LCNP and showed preliminary evidence of short-term symptomatic benefit. Phase II evaluation is warranted.

Background and purposePrecise manual annotation of the left ventricular myocardial (LVM) wall is essential for cardiac substructure research, wall-specific radiation dosimetry, and segmentation model development. However, existing radiotherapy-oriented atlases and conventional CT viewing planes lack an explicit framework for reproducible, wall-level LVM delineation. To address this gap, we developed an anatomy-guided manual segmentation protocol for delineating the five LVM walls on non-contrast-enhanced CT (NECT) or contrast-enhanced CT (CECT) scans. Materials and methodsThis protocol was developed using 60 chest CT scans from two prospective cohorts at Heidelberg University Hospital, including 50 CECTs from IMRT-MC2 cohort and 10 NECTs from MAGELLAN cohort. Manual contouring was performed in 3D Slicer. Segmentation rules were established through review by a radiation oncologist and a cardiology expert, based on the American Heart Association 17-segment model, and were tested on additional CT scans before final protocol definition. ResultsThe protocol centers on three geometric steps: (1) defining the LV long axis using the endocardial apex and the center of the mitral annulus; (2) constructing an apical delimitation plane based on LV geometry; and (3) partitioning wall regions via intersections of the right ventricular and LV cavity centers in the short-axis view. This workflow enables structured segmentation of the anterior, septal, lateral, inferior, and apical LVM walls, supporting anatomically coherent 3D reconstruction. ConclusionThis study provides contouring steps and a representative atlas as a methodological basis for standardized annotation, with potential applications in dose-mapping cardiotoxicity analysis and deep-learning modeling for radiotherapy.

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: Reirradiation (reRT) is increasingly offered following progression in diffuse intrinsic pontine glioma (DIPG) and diffuse midline glioma (DMG), though optimal patient selection remains a challenge. This study evaluated clinical outcomes after reRT in a contemporary cohort of patients with DIPG/DMG. Methods: Patients <26 years old with DMG/DIPG treated with radiation therapy between 2011-2025 were retrospectively reviewed. Primary endpoints included overall survival (OS2) and progression-free survival (PFS2), measured from first progression, and change in neurologic symptoms after reRT. Survival was estimated using Kaplan Meier methods, with Cox proportional hazards modeling for prognostic factors. Results: Fifty eight patients were included; 37 (63.8%) underwent reRT. Tumors were predominantly pontine (74.1%). ReRT was associated with improvement in motor function (51.4% vs. 9.5%, p=0.002), cranial nerve function (29.7% vs. 4.8%, p=0.044), and gait ataxia (35.1% vs. 9.5%, p=0.059). Median OS2 and PFS2 were improved with reRT (OS2: 9.67 vs. 2.57 months, p<0.001; PFS2: 5.63 vs. 1.57 months, p<0.001). OS2 was independently associated with reRT (HR 0.27, p<0.0001), pontine location (HR 2.94, p=0.004), and steroid use at progression (HR 4.12, p=0.001). PFS2 was independently associated with reRT (HR 0.23, p < .0001) and distant pattern of failure (HR 2.83, p=.037). Among reRT patients, non-pontine location was associated with improved OS2 (p=0.02), and local failure was associated with improved PFS2 (p=0.003). Conclusion: ReRT was associated with neurologic improvement and prolonged survival. Patients with non-pontine tumors or local-only failure might derive the greatest benefit. Prospective studies are warranted to define optimal dose/fractionation and refine patient selection.

Purpose: Elective nodal (EN) irradiation (ENI) during radiotherapy for locally advanced head-and-neck squamous cell carcinoma (LA-HNSCC) influences hematotoxicity, anti-tumor immunity, and synergy with immunotherapy. We evaluated whether EN-sparing upfront boosts affect DNA damage, systemic immune signaling in peripheral blood lymphocytes (PBLs), and radiation-induced lymphopenia (RIL). Methods and Materials: Twenty-eight patients with LA-HNSCC were randomized to either adjuvant or definitive chemoradiotherapy with standard ENI or EN-sparing upfront boost (adjuvant: 2x2 Gy; definitive: 5x2 Gy). Blood was collected pre-radiotherapy, 15 min, and 24 h after the first fraction, and before the sixth fraction. DNA damage in PBLs was assessed via {gamma}H2AX and 53BP1 foci and dicentric chromosome (DIC) assay. RNA sequencing was performed in two patients per group (definitive setting) at pre-CRT, before the sixth fraction, and at therapy end. Absolute lymphocyte counts (ALCs) were monitored weekly to assess RIL. Results: DNA damage in PBLs correlated with planning target volume and whole-body dose, both of which were reduced by EN-sparing by 9.9-fold and 4.4-fold, respectively (p < 0.001 each). Correspondingly, EN-sparing significantly reduced radiation-induced foci and DIC levels in PBLs (3-4-fold, p < 0.001) and lowered the fraction of radiation-damaged PBLs per fraction (11% vs. 23% with ENI, p < 0.001). EN-sparing preserved baseline ALCs during week 1 of chemoradiotherapy and delayed RIL, whereas ENI caused an immediate ALC decline and RIL. Lymphocyte counts after week 1 negatively correlated with planning target volume, whole-body dose, and DNA damage in PBLs (p < 0.01). Transcriptomics showed metabolic and interferon signaling associated with EN-sparing, versus sterile inflammatory and damage-associated patterns with ENI. Conclusions: EN-sparing by an upfront boost significantly reduced PBL damage and early RIL with distinct immune responses associated with lymphocyte viability and immune maturation. These findings support upfront EN-sparing strategies to mitigate RIL and improve radiotherapy-immunotherapy synergy in HNSCC.

PurposeRecurrence 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 MethodsThis 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, in-field, marginal, or distant. Survival outcomes were estimated using the Kaplan-Meier method and compared using the log-rank test. ResultsThe most common pattern of recurrence was central (15 patients, 36.5%), followed by in-field (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. ConclusionThe predominance of central and in-field 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.

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: 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.

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 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.

Clinical studies of prostate cancer treated with radically hypofractionated highdose-rate brachytherapy (HDR-BT) have reported a significant loss of tumor control that contradicts the standard linear-quadratic (LQ) and low /{beta} ratio paradigm for prostate cancer. In a previous study by our group, we showed that the linear-quadraticlinear (LQL) model could describe this response, but the underlying biological drivers remained unclear. In this follow-up study, we further investigate whether the interplay between hypoxia and reoxygenation kinetics can explain the poor response to extreme hypofractionation. We analyzed a large dataset of 3,239 patients (44 schedules) using a three-compartment reoxygenation model (the MSK model) that simulates the dynamics of oxic, intermediate, and hypoxic cell populations. Results show that the MSK model achieves an excellent fit to the clinical data (p > 0.99) while maintaining a biologically plausible low /{beta} ratio ([&le;] 8 Gy). The reoxygenation model provided a performance comparable to the LQL model for low-risk prostate cancer, being slightly inferior to the LQL model to describe the response of intermediate-risk. This suggests that the observed reduction in tumor control is not necessarily a failure of the LQ formalism, but rather a consequence of oxygen dynamics associated with ultra-fractionated schedules, and provides a mechanistic basis for designing clinical trials exploring the response of prostate cancer to ultra-hypofractionation and the role of reoxygenation.

Accurate segmentation of thin-wall organs-at-risk (OARs)-the cochlea, vestibular semicircular canals, internal auditory canal, tympanic cavity, and middle ear-is clinically relevant for head-and-neck radiotherapy planning, yet these small, thin-wall structures remain among the most challenging targets for automated delineation. Dual-frequency feature fusion is a promising direction for boundary-sensitive representation, but under the investigated FP16 FFT-FcaNet setting, we observe an approximately 863-fold activation-scale mismatch between the FFT and FcaNet branches, causing a nominal 5 percent residual coefficient to behave as an approximately 43-fold dominant term. We propose FreqFuseNet, which resolves this mismatch by normalizing the FcaNet branch to the FFT activation scale before residual injection with a fixed low-amplitude coefficient (beta = 0.05), restoring beta as an interpretable 5 percent residual-amplitude coefficient relative to the FFT feature scale. Under a controlled binary per-OAR ROI protocol on the SegRap2023 head-and-neck CT benchmark across 10 clinically prioritized thin-wall OARs, FreqFuseNet achieves Dice of 0.849, HD95 of 0.824 mm, and SDice@1mm of 0.959 in the primary seed, with comparable performance in an independent second seed (Dice 0.843, HD95 0.823 mm). FreqFuseNet yields statistically significant case-level aggregate improvements over 3D U-Net and MedNeXt-S (Wilcoxon p < 0.01 and p < 0.05, respectively), using only 29.7 million parameters versus 414.6 million for the full wavelet baseline.

The PRESERVE trial (NCT04972097) is a prospective, single-arm pivotal IDE study evaluating focal irreversible electroporation (IRE) using the NanoKnife System for intermediate-risk prostate cancer. Men with Gleason Grade Group 2-3 disease underwent focal IRE and were followed for durability of oncologic control and safety. At 24 months, 68 patients completed follow-up with no new treatment failures identified. PSA levels were below baseline in 97% of patients, and one clinically triggered biopsy was negative for cancer. No new device- or procedure-related adverse events occurred beyond 12 months. These findings demonstrate durable efficacy and sustained safety of focal IRE.

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.

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.

Tumor habitat imaging aims to capture intratumoral heterogeneity by grouping voxels with similar radiomic properties into spatially coherent subregions. However, radiomic features are known to be sensitive to small variations in image acquisition and processing, which can affect the stability of the resulting habitat maps. Feature repeatability is usually evaluated using test-retest scans, but such data are rarely available in clinical practice. To overcome this, we adopted an image perturbation framework, which simulates test-retest conditions by applying small, controlled changes to a single image. In head and neck cancer (HNC), where imaging is further complicated by complex anatomy, dental artifacts, and variability in tumor delineation, dedicated stability analyses are still missing. In this study, we evaluated how the repeatability of radiomic features affects habitat stability in 390 oropharyngeal cancer patients (discovery cohort). For each patient, 11 perturbed CT volumes were generated using small in-plane rotations, sub-voxel translations, and tumor-adaptive Gaussian noise. Ninety-three radiomic features were extracted from each image set, and their repeatability was assessed using the lower confidence limit of the intraclass correlation coefficient (ICC-LCL), grouped into poor, moderate, good, and excellent categories. Tumor habitats were then generated using K-means clustering (H = 3) for each feature subset, and habitat stability was measured by the Dice similarity coefficient (DSC) between habitat maps obtained from original and perturbed images. Overall, 48.4% of features were poorly repeatable and only 6.5% reached the excellent category, with first-order features being more stable than texture-based ones. Habitat stability followed a clear monotonic trend with feature repeatability: the median DSC was 0.93 for habitats generated from excellent features, 0.84 for good features, 0.75 for moderate features, and dropped to 0.41 for poorly repeatable features. Habitats generated using all features (without any repeatability-based filtering) yielded an intermediate median DSC of 0.52. All pairwise comparisons between feature subsets were statistically significant (p < 0.001). To evaluate the generalizability of these findings, the analysis was repeated in an independent external validation cohort of 372 oropharyngeal cancer patients treated at the H. Lee Moffitt Cancer Center. The stability classification showed substantial feature-level concordance between the discovery and validation cohorts (overall agreement 67.7%, quadratic-weighted Cohen's kappa = 0.78), with no feature shifting by more than two stability classes. The habitat-stability hierarchy was fully preserved in the validation cohort (median DSC of 0.87, 0.73, 0.69, and 0.39 for excellent, good, moderate, and poor features, respectively; all pairwise p < 0.001). These results show that selecting features with higher repeatability clearly improves the spatial consistency of habitat maps in HNC and support the use of perturbation-based stability analysis as a routine step in habitat imaging studies.

Our study evaluated whether a deep learning auto segmentation model combined with machine learning triage can streamline radiotherapy clinical trial quality assurance (QA). We analyzed 107 stereotactic ablative radiotherapy (SABR) cases from a multi-institutional phase II clinical trial of neurovascular sparing prostate SABR, focusing on physician contours of the internal pudendal artery (IPA) as a novel organ-at-risk with substantial interobserver variability. Contours were scored by the trial principal investigator as Per-Protocol or Minor Deviation/Unacceptable. We applied a deep learning model for IPA auto-segmentation. Agreement between human and AI contours was then quantified using 14 overlap, distance, and surface metrics, and a supervised classifier was trained on these metrics to flag clinical trial protocol deviations. While AI segmentation achieved only modest geometric accuracy with mean Dice similarity coefficient of 0.446 and 95th percentile Hausdorff distance of 14.23, when incorporating all 14 metrics, a machine learning classifier yielded AUROC of 0.836, flagging all Minor Deviation/Unacceptable cases with 100% sensitivity on the 27 case hold-out set with 6 false positives and no false negatives. AI segmentation combined with metrics-based machine learning can triage protocol deviations within a multi-institution radiotherapy clinical trial, supporting prospective evaluation of AI-assisted trial QA.

Computed tomography is the largest contributor to population radiation dose from medical imaging, yet no diagnostic reference levels (DRLs) have been published from Kosovo or the Western Balkans. This retrospective audit analyzed all CT examinations performed on a 128- slice scanner at the University Clinical Centre of Kosovo between January and March 2026. After exclusions, 1,535 acquisitions from 1,092 patients across nine examination categories were analyzed. Local DRLs were defined as the 75th percentile and compared against German (BfS 2022) and Turkish (Kahraman et al., 2024) reference values. Head CT (n = 590) demonstrated CTDIvol 4.7% below the BfS DRL yet scan length 98.5% above the orientation value (median 25.8 vs 13 cm). Abdomen-pelvis CTDIvol matched the BfS reference while scan length exceeded it by 28%. Coronary CTA showed CTDIvol +377%, consistent with retrospective ECG gating. Excess scan length, not CTDIvol, is the major driver of elevated dose at this institution. The identified excesses are correctable through technologist landmarking training, protocol review, and enabling iterative reconstruction.