arXiv subjects

Robert Timmerman

Publications and source records attributed to Robert Timmerman.

13 recordsLinked to original sources

arXiv2026

Exploring Strategies for Personalized Radiation Therapy Part IV: An Interaction-Picture Approach to Quantify the Abscopal Effect

We revisit the controversial "abscopal" effect in the context of Personalized Ultra-Fractionated Stereotactic Adaptive Radiotherapy (PULSAR). By allowing long interval between fractions, PULSAR may enhance systemic immune activation and increase the likelihood of abscopal responses compared with conventional daily fractionation. To quantify treatment-induced effects, we introduce an interaction-picture transformation adapted from quantum mechanics, which separates intrinsic tumor growth from radiation and immune-mediated perturbations. In this preliminary study, we tested this method to two preclinical bilateral tumor models (4T1 and MC38). Our model provides a quantitative measure of the interaction strength between primary and secondary tumors at the individual level, capturing dynamics over time rather than relying solely on cohort averages. This approach frames the abscopal effect as a continuous, stochastic phenomenon rather than a binary response. The framework is flexible for future studies, particularly in concurrent radiation and immunotherapy with PULSAR, where different radiation doses and fractionation schedules can be compared, and immune checkpoint inhibitors (ICIs) can be incorporated to further enhance systemic anti-tumor immunity. The framework can also help us make cross-study comparison of abscopal effects and standardizes the reporting of abscopal magnitude beyond simple statistical significance.

q-bio.QM↗

arXiv2025

Integrated Transcriptomic-proteomic Biomarker Identification for Radiation Response Prediction in Non-small Cell Lung Cancer Cell Lines

To develop an integrated transcriptome-proteome framework for identifying concurrent biomarkers predictive of radiation response, as measured by survival fraction at 2 Gy (SF2), in non-small cell lung cancer (NSCLC) cell lines. RNA sequencing (RNA-seq) and data-independent acquisition mass spectrometry (DIA-MS) proteomic data were collected from 73 and 46 NSCLC cell lines, respectively. Following preprocessing, 1,605 shared genes were retained for analysis. Feature selection was performed using least absolute shrinkage and selection operator (Lasso) regression with a frequency-based ranking criterion under five-fold cross-validation repeated ten times. Support vector regression (SVR) models were constructed using transcriptome-only, proteome-only, and combined transcriptome-proteome feature sets. Model performance was assessed by the coefficient of determination (R2) and root mean square error (RMSE). Correlation analyses evaluated concordance between RNA and protein expression and the relationships of selected biomarkers with SF2. RNA-protein expression exhibited significant positive correlations (median Pearson's r = 0.363). Independent pipelines identified 20 prioritized gene signatures from transcriptomic, proteomic, and combined datasets. Models trained on single-omic features achieved limited cross-omic generalizability, while the combined model demonstrated balanced predictive accuracy in both datasets (R2=0.461, RMSE=0.120 for transcriptome; R2=0.604, RMSE=0.111 for proteome). This study presents the first proteotranscriptomic framework for SF2 prediction in NSCLC, highlighting the complementary value of integrating transcriptomic and proteomic data. The identified concurrent biomarkers capture both transcriptional regulation and functional protein activity, offering mechanistic insights and translational potential.

cs.LG↗

arXiv2025

Leveraging Support Vector Regression, Radiomics and Dosiomics for Outcome Prediction in Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR)

Personalized ultra-fractionated stereotactic adaptive radiotherapy (PULSAR) is a novel treatment that delivers radiation in pulses of protracted intervals. Accurate prediction of gross tumor volume (GTV) changes through regression models has substantial prognostic value. This study aims to develop a multi-omics based support vector regression (SVR) model for predicting GTV change. A retrospective cohort of 39 patients with 69 brain metastases was analyzed, based on radiomics (MRI images) and dosiomics (dose maps) features. Delta features were computed to capture relative changes between two time points. A feature selection pipeline using least absolute shrinkage and selection operator (Lasso) algorithm with weight- or frequency-based ranking criterion was implemented. SVR models with various kernels were evaluated using the coefficient of determination (R2) and relative root mean square error (RRMSE). Five-fold cross-validation with 10 repeats was employed to mitigate the limitation of small data size. Multi-omics models that integrate radiomics, dosiomics, and their delta counterparts outperform individual-omics models. Delta-radiomic features play a critical role in enhancing prediction accuracy relative to features at single time points. The top-performing model achieves an R2 of 0.743 and an RRMSE of 0.022. The proposed multi-omics SVR model shows promising performance in predicting continuous change of GTV. It provides a more quantitative and personalized approach to assist patient selection and treatment adjustment in PULSAR.

cs.LG↗

arXiv2025

Exploring Strategies for Personalized Radiation Therapy: Part III Identifying genetic determinants for Radiation Response with Meta Learning

Radiation response in cancer is shaped by complex, patient specific biology, yet current treatment strategies often rely on uniform dose prescriptions without accounting for tumor heterogeneity. In this study, we introduce a meta learning framework for one-shot prediction of radiosensitivity measured by SF2 using cell line level gene expression data. Unlike the widely used Radiosensitivity Index RSI a rank-based linear model trained on a fixed 10-gene signature, our proposed meta-learned model allows the importance of each gene to vary by sample through fine tuning. This flexibility addresses key limitations of static models like RSI, which assume uniform gene contributions across tumor types and discard expression magnitude and gene gene interactions. Our results show that meta learning offers robust generalization to unseen samples and performs well in tumor subgroups with high radiosensitivity variability, such as adenocarcinoma and large cell carcinoma. By learning transferable structure across tasks while preserving sample specific adaptability, our approach enables rapid adaptation to individual samples, improving predictive accuracy across diverse tumor subtypes while uncovering context dependent patterns of gene influence that may inform personalized therapy.

physics.med-ph↗

arXiv2025

Exploring Strategies for Personalized Radiation Therapy Part I Unlocking Response-Related Tumor Subregions with Class Activation Mapping

Personalized precision radiation therapy requires more than simple classification, it demands the identification of prognostic, spatially informative features and the ability to adapt treatment based on individual response. This study compares three approaches for predicting treatment response: standard radiomics, gradient based features, and convolutional neural networks enhanced with Class Activation Mapping. We analyzed 69 brain metastases from 39 patients treated with Gamma Knife radiosurgery. An integrated autoencoder classifier model was used to predict whether tumor volume would shrink by more than 20 percent at a three months follow up, framed as a binary classification task. The results highlight their strength in hierarchical feature extraction and the classifiers discriminative capacity. Among the models, pixel wise CAM provides the most detailed spatial insight, identifying lesion specific regions rather than relying on fixed patterns, demonstrating strong generalization. In non responding lesions, the activated regions may indicate areas of radio resistance. Pixel wise CAM outperformed both radiomics and gradient based methods in classification accuracy. Moreover, its fine grained spatial features allow for alignment with cellular level data, supporting biological validation and deeper understanding of heterogeneous treatment responses. Although further validation is necessary, these findings underscore the promise in guiding personalized and adaptive radiotherapy strategies for both photon and particle therapies.

physics.med-ph↗

arXiv2025

Exploring Strategies for Personalized Radiation Therapy Part II Predicting Tumor Drift Patterns with Diffusion Models

Radiation therapy outcomes are decided by two key parameters, dose and timing, whose best values vary substantially across patients. This variability is especially critical in the treatment of brain cancer, where fractionated or staged stereotactic radiosurgery improves safety compared to single fraction approaches, but complicates the ability to predict treatment response. To address this challenge, we employ Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR), a strategy that dynamically adjusts treatment based on how each tumor evolves over time. However, the success of PULSAR and other adaptive approaches depends on predictive tools that can guide early treatment decisions and avoid both overtreatment and undertreatment. However, current radiomics and dosiomics models offer limited insight into the evolving spatial and temporal patterns of tumor response. To overcome these limitations, we propose a novel framework using Denoising Diffusion Implicit Models (DDIM), which learns data-driven mappings from pre to post treatment imaging. In this study, we developed single step and iterative denoising strategies and compared their performance. The results show that diffusion models can effectively simulate patient specific tumor evolution and localize regions associated with treatment response. The proposed strategy provides a promising foundation for modeling heterogeneous treatment response and enabling early, adaptive interventions, paving the way toward more personalized and biologically informed radiotherapy.

physics.med-ph↗

arXiv2024

Multiomics-based Outcome Prediction for the Treatment of Brain Metastases with Personalized Ultra-fractionated Stereotactic Adaptive Radiotherapy (PULSAR)

Purpose: We aimed to develop a data-driven multiomics approach integrating radiomics, dosiomics, and delta features to predict treatment response at an earlier stage (intra-treatment) for brain metastases (BMs) patients treated with PULSAR. Methods: We conducted a retrospective study of 39 patients with 69 BMs treated with PULSAR. Radiomics, dosiomics, and delta features were extracted from pretreatment and intra-treatment MRI scans and dose distributions. Six individual models and an ensemble feature selection (EFS) model were constructed using SVM and evaluated via stratified 5-fold cross-validation. The classification task distinguished lesions with >20% volume reduction at follow-up. We assessed performance metrics including sensitivity, specificity, accuracy, precision, F1 score, and AUC. Various feature extraction and ensemble selection scenarios were explored to enhance model robustness and reduce overfitting. Results: The EFS model, integrating features from pre-treatment radiomics and dosiomics, intra-treatment radiomics, and delta-radiomics, outperformed six individual models. It achieved an AUC of 0.979, accuracy of 0.917, and F1 score of 0.821. Among the top 9 features, six were derived from post-wavelet transformation, and three from original images. The discrete wavelet transform decomposes volumetric images into multi-resolution components, offering a more comprehensive characterization of underlying structures. Conclusion: Our study demonstrated the feasibility of employing a data-driven multiomics approach to predict tumor volume changes in BMs patients with PULSAR. The EFS model demonstrates enhanced performance compared with six individual models, emphasizing the importance of integrating both pretreatment and intra-treatment data. This application holds promise for optimizing BMs management, potentially mitigating risks associated with under- or over-treatment.

physics.med-ph↗

arXiv2024

Understanding the PULSAR Effect in Combined Radiotherapy and Immunotherapy through Attention Mechanisms with a Transformer Model

PULSAR (personalized, ultra-fractionated stereotactic adaptive radiotherapy) is the adaptation of stereotactic ablative radiotherapy towards personalized cancer management. For the first time, we applied a transformer-based attention mechanism to investigate the underlying interactions between combined PULSAR and PD-L1 blockade immunotherapy based on a murine cancer model (Lewis Lung Carcinoma, LLC). The proposed approach is able to predict the trend of tumor volume change semi-quantitatively, and excels in identifying the potential causal relationships through both self-attention and cross-attention scores.

physics.med-ph↗

arXiv2024

PULSAR Effect: Revealing Potential Synergies in Combined Radiation Therapy and Immunotherapy via Differential Equations

PULSAR (personalized ultrafractionated stereotactic adaptive radiotherapy) is a form of radiotherapy method where a patient is given a large dose or pulse of radiation a couple of weeks apart rather than daily small doses. The tumor response is then monitored to determine when the subsequent pulse should be given. Pre-clinical trials have shown better tumor response in mice that received immunotherapy along with pulses spaced 10 days apart. However, this was not the case when the pulses were 1 day apart. Therefore, a synergistic effect between immunotherapy and PULSAR is observed when the pulses are spaced out by a certain number of days. In our study, we aimed to develop a mathematical model that can capture the synergistic effect by considering a time-dependent weight function that takes into account the spacing between pulses. By determining feasible parameters, and applying reasonable conditions, we utilize our model to simulate murine trials with varying sequencing of pulses. We successfully demonstrate that our model is simple to implement and can generate tumor volume data that is consistent with the pre-clinical trial data. Our model has the potential to aid in the development of clinical trials of PULSAR therapy.

q-bio.QM↗

arXiv2023

Mathematical Modeling of the Synergetic Effect between Radiotherapy and Immunotherapy

Achieving effective synergy between radiotherapy and immunotherapy is critical for optimizing tumor control and treatment outcomes. To explore the underlying mechanisms of this synergy, we have investigated a novel treatment approach known as personalized ultra-fractionated stereotactic adaptive radiation therapy (PULSAR), which emphasizes the impact of radiation timing on treatment efficacy. However, the precise mechanism remains unclear. Building on insights from small animal PULSAR studies, we developed a mathematical framework consisting of multiple ordinary differential equations to elucidate the temporal dynamics of tumor control resulting from radiation and the adaptive immune response. The model accounts for the migration and infiltration of T-cells within the tumor microenvironment. This proposed model establishes a causal and quantitative link between radiation therapy and immunotherapy, providing a valuable in-silico analysis tool for designing future PULSAR trials.

q-bio.QM↗

arXiv2023

Performance Deterioration of Deep Learning Models after Clinical Deployment: A Case Study with Auto-segmentation for Definitive Prostate Cancer Radiotherapy

We evaluated the temporal performance of a deep learning (DL) based artificial intelligence (AI) model for auto segmentation in prostate radiotherapy, seeking to correlate its efficacy with changes in clinical landscapes. Our study involved 1328 prostate cancer patients who underwent definitive radiotherapy from January 2006 to August 2022 at the University of Texas Southwestern Medical Center. We trained a UNet based segmentation model on data from 2006 to 2011 and tested it on data from 2012 to 2022 to simulate real world clinical deployment. We measured the model performance using the Dice similarity coefficient (DSC), visualized the trends in contour quality using exponentially weighted moving average (EMA) curves. Additionally, we performed Wilcoxon Rank Sum Test to analyze the differences in DSC distributions across distinct periods, and multiple linear regression to investigate the impact of various clinical factors. The model exhibited peak performance in the initial phase (from 2012 to 2014) for segmenting the prostate, rectum, and bladder. However, we observed a notable decline in performance for the prostate and rectum after 2015, while bladder contour quality remained stable. Key factors that impacted the prostate contour quality included physician contouring styles, the use of various hydrogel spacer, CT scan slice thickness, MRI-guided contouring, and using intravenous (IV) contrast. Rectum contour quality was influenced by factors such as slice thickness, physician contouring styles, and the use of various hydrogel spacers. The bladder contour quality was primarily affected by using IV contrast. This study highlights the challenges in maintaining AI model performance consistency in a dynamic clinical setting. It underscores the need for continuous monitoring and updating of AI models to ensure their ongoing effectiveness and relevance in patient care.

eess.IV↗

arXiv2019

MRI-only brain radiotherapy: assessing the dosimetric accuracy of synthetic CT images generated using a deep learning approach

Purpose: This study assessed the dosimetric accuracy of synthetic CT images generated from magnetic resonance imaging (MRI) data for focal brain radiation therapy, using a deep learning approach. Material and Methods: We conducted a study in 77 patients with brain tumors who had undergone both MRI and computed tomography (CT) imaging as part of their simulation for external beam treatment planning. We designed a generative adversarial network (GAN) to generate synthetic CT images from MRI images. We used Mutual Information (MI) as the loss function in the generator to overcome the misalignment between MRI and CT images (unregistered data). The model was trained using all MRI slices with corresponding CT slices from each training subject s MRI/CT pair. Results: The proposed GAN method produced an average mean absolute error (MAE) of 47.2 +- 11.0 HU over 5-fold cross validation. The overall mean Dice similarity coefficient between CT and synthetic CT images was 80% +- 6% in bone for all test data. Though training a GAN model may take several hours, the model only needs to be trained once. Generating a complete synthetic CT volume for each new patient MRI volume using a trained GAN model took only one second. Conclusions: The GAN model we developed produced highly accurate synthetic CT images from conventional, single-sequence MRI images in seconds. Our proposed method has strong potential to perform well in a clinical workflow for MRI-only brain treatment planning.

physics.med-ph↗

arXiv2017

Shell feature: a new radiomics descriptor for predicting distant failure after radiotherapy in non-small cell lung cancer and cervix cancer

Purpose To develop and demonstrate a novel tumor shell feature for predicting distant failure in non-small cell lung cancer (NSCLC) and cervical cancer (CC) patients. Patients and Methods The shell predictive model was constructed using pretreatment positron emission tomography (PET) images from 48 NSCLC patients received stereotactic body radiation therapy (SBRT) and 52 CC patients underwent external beam radiation therapy and concurrent chemotherapy followed with high-dose-rate intracavitary brachytherapy. A shell feature, consisting of outer voxels around the tumor boundary, was extracted from a series of axial PET slices. The hypothesis behind this feature is that non-invasive and invasive tumors may have different morphologic patterns in the tumor periphery, in turn reflecting the differences in radiological presentations in the PET images. The utility of the shell was evaluated by the support vector machine (SVM) classifier in comparison with intensity, geometry, gray level co-occurrence matrix (GLCM) based texture, neighborhood gray tone difference matrix (NGTDM) based texture, and a combination of these four features. The results were assessed in terms of accuracy, sensitivity, specificity, and the area under the receiver operating curve (AUC). Results For NSCLC, the AUC achieved by the shell feature was 0.82 while the highest AUC achieved by the other features was 0.76. Similarly, for CC, the AUC achieved by the shell feature was 0.83 while the highest AUC achieved by the other features was 0.76. Also, the difference in performance between shell and the other features was significant (P < 0.005) in all cases. Conclusions We propose a boundary-based shell feature that correlates with tumor metastasis. The shell feature showed better predictive performance than all the other features for distant failure prediction in both NSCLC and CC.

physics.med-ph↗