Robert Timmerman

Biling Wang, Michael Dohopolski, Ti Bai et al.

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.

Hao Peng, Steve Jiang, Robert Timmerman

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.

Hao Peng, Steve Jiang, Robert Timmerman

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.

Yajun Yu, Guoping Xu, Steve Jiang et al.

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.

Yajun Yu, Steve Jiang, Robert Timmerman et al.

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.

Hao Peng, Yuanyuan Zhang, Steve Jiang et al.

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.

Hao Peng, Casey Moore, Debabrata Saha et al.

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.