The complexity of DNA damage by radiation follows a Gamma distribution: insights from the Microdosimetric Gamma Model.

Introduction: DNA damage is the main predictor of response to radiation therapy for cancer. Its Q8 quantification and characterization are paramount for treatment optimization, particularly in advanced modalities such as proton and alpha-targeted therapy. Methods: We present a novel approach called the Microdosimetric Gamma Model (MGM) to address this important issue. The MGM uses the theory of microdosimetry, specifically the mean energy imparted to small sites, as a predictor of DNA damage properties. MGM provides the number of DNA damage sites and their complexity, which were determined using Monte Carlo simulations with the TOPAS-nBio toolkit for monoenergetic protons and alpha particles. Complexity was used together with a illustrative and simplistic repair model to depict the differences between high and low LET radiations. Results: DNA damage complexity distributions were were found to follow a Gamma distribution for all monoenergetic particles studied. The MGM functions allowed to predict number of DNA damage sites and their complexity for particles not simulated with microdosimetric measurements (yF) in the range of those studied. Discussion: Compared to current methods, MGM allows for the characterization of DNA damage induced by beams composed of multi-energy components distributed over any time configuration and spatial distribution. The output can be plugged into ad hoc repair models that can predict cell killing, protein recruitment at repair sites, chromosome aberrations, and other biological effects, as opposed to current models solely focusing on cell survival. These features are particularly important in targeted alpha-therapy, for which biological effects remain largely uncertain. The MGM provides a flexible framework to study the energy, time, and spatial aspects of ionizing radiation and offers an excellent tool for studying and optimizing the biological effects of these radiotherapy modalities.

Evaluating the effect of setup uncertainty reduction and adaptation to geometric changes on normal tissue complication probability using online adaptive head and neck intensity modulated proton therapy.

Objective. To evaluate the impact of setup uncertainty reduction (SUR) and adaptation to geometrical changes (AGC) on normal tissue complication probability (NTCP) when using online adaptive head and neck intensity modulated proton therapy (IMPT).Approach.A cohort of ten retrospective head and neck cancer patients with daily scatter corrected cone-beam CT (CBCT) was studied. For each patient, two IMPT treatment plans were created: one with a 3 mm setup uncertainty robustness setting and one with no explicit setup robustness. Both plans were recalculated on the daily CBCT considering three scenarios: the robust plan without adaptation, the non-robust plan without adaptation and the non-robust plan with daily online adaptation. Online-adaptation was simulated using an in-house developed workflow based on GPU-accelerated Monte Carlo dose calculation and partial spot-intensity re-optimization. Dose distributions associated with each scenario were accumulated on the planning CT, where NTCP models for six toxicities were applied. NTCP values from each scenario were intercompared to quantify the reduction in toxicity risk induced by SUR alone, AGC alone and SUR and AGC combined. Finally, a decision tree was implemented to assess the clinical significance of the toxicity reduction associated with each mechanism.Main results. For most patients, clinically meaningful NTCP reductions were only achieved when SUR and AGC were performed together. In these conditions, total reductions in NTCP of up to 30.48 pp were obtained, with noticeable NTCP reductions for aspiration, dysphagia and xerostomia (mean reductions of 8.25, 5.42 and 5.12 pp respectively). While SUR had a generally larger impact than AGC on NTCP reductions, SUR alone did not induce clinically meaningful toxicity reductions in any patient, compared to only one for AGC alone.SignificanceOnline adaptive head and neck proton therapy can only yield clinically significant reductions in the risk of long-term side effects when combining the benefits of SUR and AGC.

Neural network based ensemble model to predict radiation induced lymphopenia after concurrent chemo-radiotherapy for non-small cell lung cancer from two institutions.

The use of adjuvant Immune Checkpoint Inhibitors (ICI) after concurrent chemo-radiation therapy (CCRT) has become the standard of care for locally advanced non-small cell lung cancer (LA-NSCLC). However, prolonged radiotherapy regimens are known to cause radiation-induced lymphopenia (RIL), a long-neglected toxicity that has been shown to correlate with response to ICIs and survival of patients treated with adjuvant ICI after CCRT. In this study, we aim to develop a novel neural network (NN) approach that integrates patient characteristics, treatment related variables, and differential dose volume histograms (dDVH) of lung and heart to predict the incidence of RIL at the end of treatment. Multi-institutional data of 139 LA-NSCLC patients from two hospitals were collected for training and validation of our suggested model. Ensemble learning was combined with a bootstrap strategy to stabilize the model, which was evaluated internally using repeated cross validation. The performance of our proposed model was compared to conventional models using the same input features, such as Logistic Regression (LR) and Random Forests (RF), using the Area Under the Curve (AUC) of Receiver Operating Characteristics (ROC) curves. Our suggested model (AUC=0.77) outperformed the comparison models (AUC=0.72, 0.74) in terms of absolute performance, indicating that the convolutional structure of the network successfully abstracts additional information from the differential DVHs, which we studied using Gradient-weighted Class Activation Map. This study shows that clinical factors combined with dDVHs can be used to predict the risk of RIL for an individual patient and shows a path toward preventing lymphopenia using patient-specific modifications of the radiotherapy plan.

Predictive Model of Liver Toxicity to Aid the Personalized Selection of Proton Versus Photon Therapy in Hepatocellular Carcinoma.

PURPOSE: Our objective was to develop an externally validated model for predicting liver toxicity after radiation therapy in patients with hepatocellular carcinoma (HCC) that can integrate both photon and proton dose distributions with patient-specific characteristics. METHODS AND MATERIALS: Training data consisted of all patients with HCC treated between 2008 and 2019 at our institution (n = 117, 60%/40% photon/proton). We developed a shallow convolutional neural network (CNN) to predict posttreatment liver dysfunction from the differential dose-volume histogram (DVH) and baseline liver metrics. To reduce bias and improve robustness, we used ensemble learning (CNNE). After a preregistered study analysis plan, we evaluated stability using internal bootstrap resampling and generalizability using a data set from a different institution (n = 88). Finally, we implemented a class activation map method to characterize the critical DVH subregions and benchmarked the model against logistic regression and XGBoost. The models were evaluated using the area under the receiver operating characteristic curve and area under the precision-recall curve. RESULTS: The CNNE model showed similar internal performance and robustness compared with the benchmarks. CNNE exceeded the benchmark models in external validation, with an area under the receiver operating characteristic curve of 0.78 versus 0.55 to 0.70, and an area under the precision-recall curve of 0.6 versus 0.43 to 0.52. The model showed improved predictive power in the photon group, excellent specificity in both modalities, and high sensitivity in the photon high-risk group. Models built solely on DVHs confirm outperformance of the CNNE and indicate that the proposed structure efficiently abstracts features from both proton and photon dose distributions. The activation map method demonstrates the importance of the low-dose bath and its interaction with low liver function at baseline. CONCLUSIONS: We developed and externally validated a patient-specific prediction model for hepatic toxicity based on the entire DVH and clinical factors that can integrate both photon and proton therapy cohorts. This model complements the new American Society for Radiation Oncology clinical practice guidelines and could support value-driven integration of proton therapy into the management of HCC.

Weekly Nowcasting of New COVID-19 Cases Using Past Viral Load Measurements.

The rapid spread of the coronavirus disease COVID-19 has imposed clinical and financial burdens on hospitals and governments attempting to provide patients with medical care and implement disease-controlling policies. The transmissibility of the disease was shown to be correlated with the patient's viral load, which can be measured during testing using the cycle threshold (Ct). Previous models have utilized Ct to forecast the trajectory of the spread, which can provide valuable information to better allocate resources and change policies. However, these models combined other variables specific to medical institutions or came in the form of compartmental models that rely on epidemiological assumptions, all of which could impose prediction uncertainties. In this study, we overcome these limitations using data-driven modeling that utilizes Ct and previous number of cases, two institution-independent variables. We collected three groups of patients (n = 6296, n = 3228, and n = 12,096) from different time periods to train, validate, and independently validate the models. We used three machine learning algorithms and three deep learning algorithms that can model the temporal dynamic behavior of the number of cases. The endpoint was 7-week forward number of cases, and the prediction was evaluated using mean square error (MSE). The sequence-to-sequence model showed the best prediction during validation (MSE = 0.025), while polynomial regression (OLS) and support vector machine regression (SVR) had better performance during independent validation (MSE = 0.1596, and MSE = 0.16754, respectively), which exhibited better generalizability of the latter. The OLS and SVR models were used on a dataset from an external institution and showed promise in predicting COVID-19 incidences across institutions. These models may support clinical and logistic decision-making after prospective validation.

Predictive Modeling of Survival and Toxicity in Patients With Hepatocellular Carcinoma After Radiotherapy.

PURPOSE: To stratify patients and aid clinical decision making, we developed machine learning models to predict treatment failure and radiation-induced toxicities after radiotherapy (RT) in patients with hepatocellular carcinoma across institutions. MATERIALS AND METHODS: The models were developed using linear and nonlinear algorithms, predicting survival, nonlocal failure, radiation-induced liver disease, and lymphopenia from baseline patient and treatment parameters. The models were trained on 207 patients from Massachusetts General Hospital. Performance was quantified using Harrell's c-index, area under the curve (AUC), and accuracy in high-risk populations. Models' structures were optimized in a nested cross-validation approach to prevent overfitting. A study analysis plan was registered before external validation using 143 patients from MD Anderson Cancer Center. Clinical utility was assessed using net-benefit analysis. RESULTS: The survival model stratified high-risk versus low-risk patients well in the external validation cohort (c-index = 0.75), better than existing risk scores. Predictions of 1-year survival and nonlocal failure were excellent (external AUC = 0.74 and 0.80, respectively), especially in the high-risk group (accuracy > 90%). Cause-of-death analysis showed differential modes of treatment failure in these cohorts and indicated that these models could be used to stratify RT patients for liver-sparing treatment regimen or combination approaches with systemic agents. Predictions of liver disease and lymphopenia were good but less robust (external AUC = 0.68 and 0.7, respectively), suggesting the need for more comprehensive consideration of dosimetry and better predictive biomarkers. The liver disease model showed excellent accuracy in the high-risk group (92%) and revealed possible interactions of platelet count with initial liver function. CONCLUSION: Machine learning approaches can provide reliable outcome predictions in patients with hepatocellular carcinoma after RT in diverse cohorts across institutions. The excellent performance, particularly in high-risk patients, suggests novel strategies for patient stratification and treatment selection.

Lymphocyte dynamics during and after chemo-radiation correlate to dose and outcome in stage III NSCLC patients undergoing maintenance immunotherapy.

PURPOSE: We investigated the dynamics of lymphocyte depletion and recovery during and after definitive concurrent chemoradiotherapy (CCRT), dose to which structures is correlated to them, and how they affect the prognosis of stage III non-small cell lung cancer (NSCLC) patients undergoing maintenance immunotherapy. METHODS AND MATERIALS: In this retrospective study, absolute lymphocyte counts (ALC) of 66 patients were obtained before, during, and after CCRT. Persistent lymphopenia was defined as ALC < 500/µL at 3 months after CCRT. The impact of regional dose on lymphocyte depletion and recovery was investigated using voxel-based analysis (VBA). RESULTS: Most patients (n = 65) experienced lymphopenia during CCRT: 39 patients (59.0%) had grade (G) 3+ lymphopenia. Fifty-nine patients (89.3%) recovered from treatment-related lymphopenia at 3 months after CCRT, whereas 7 (10.6%) showed persistent lymphopenia. Patient characteristics associated with persistent lymphopenia were older age and ALC before and during treatment. In multivariable Cox regression analysis, recovery from lymphopenia was identified as a significant prognostic factor for Progression Free Survival (HR 0.35, 95% CI 0.13-0.93, p = 0.034) and Overall Survival (HR 0.24, 95% CI 0.08-0.68, p = 0.007). Voxel-based analysis showed strong correlation of dose to the upper mediastinum with lymphopenia at the end of CCRT, but not at 3 months after CCRT. CONCLUSION: Recovery from lymphopenia is strongly correlated to improved survival of patients undergoing CCRT and adjuvant immunotherapy, and is correlated to lymphocyte counts pre- and post-CCRT. VBA reveals high correlation of dose to large vessels to lymphopenia at the end of CCRT. Therefore, efforts should be made not only for preventing lymphocyte depletion during CCRT but also for helping lymphocyte recovery after CCRT.

Using Parallel Coordinates in Optimization of Nano-Particle Drug Delivery.

Nanoparticle drug delivery better targets neoplastic lesions than free drugs and thus has emerged as a safer form of cancer therapy. Nanoparticle design variables are important determinants of efficacy as they influence the drug biodistribution and pharmacokinetics. Previously, we determined optimal designs through mechanistic modeling and optimization. However, the numerical nature of the tumor model and numerous candidate nanoparticle designs hinder hypothesis generation and treatment personalization. In this paper, we utilize the parallel coordinates technique to visualize high-dimensional optimal solutions and extract correlations between nanoparticle design and treatment outcomes. We found that at optimality, two major design variables are dependent, and thus the optimization problem can be reduced. In addition, we obtained an analytical relationship between optimal nanoparticle sizes and optimal distribution, which could facilitate the utilization of tumors models in preclinical studies. Our approach has simplified the results of the previously integrated modeling and optimization framework developed for nanotherapy and enhanced the interpretation and utilization of findings. Integrated mathematical frameworks are increasing in the medical field, and our method can be applied outside nanotherapy to facilitate the clinical translation of computational methods.

Collective Cell Migration in a Fibrous Environment: A Hybrid Multiscale Modelling Approach.

The specific structure of the extracellular matrix (ECM), and in particular the density and orientation of collagen fibres, plays an important role in the evolution of solid cancers. While many experimental studies discussed the role of ECM in individual and collective cell migration, there are still unanswered questions about the impact of nonlocal cell sensing of other cells on the overall shape of tumour aggregation and its migration type. There are also unanswered questions about the migration and spread of tumour that arises at the boundary between different tissues with different collagen fibre orientations. To address these questions, in this study we develop a hybrid multi-scale model that considers the cells as individual entities and ECM as a continuous field. The numerical simulations obtained through this model match experimental observations, confirming that tumour aggregations are not moving if the ECM fibres are distributed randomly, and they only move when the ECM fibres are highly aligned. Moreover, the stationary tumour aggregations can have circular shapes or irregular shapes (with finger-like protrusions), while the moving tumour aggregations have elongate shapes (resembling to clusters, strands or files). We also show that the cell sensing radius impacts tumour shape only when there is a low ratio of fibre to non-fibre ECM components. Finally, we investigate the impact of different ECM fibre orientations corresponding to different tissues, on the overall tumour invasion of these neighbouring tissues.

A Dual Nanoparticle Delivery Strategy for Enhancing Drug Distribution in Cancerous Tissue.

Nanoparticle-mediated drug delivery may be a promising alternative to traditional chemotherapy of high systemic toxicity. Tumor tissue architecture poses a challenge to delivery of nanoparticles. Small and spherical nanoparticles have poor adherence to the tumor vasculature, while larger and more eccentric ones create high heterogeneity in tissue-to-drug exposure. In previous work, we quantified these tradeoffs using numerical optimization. In this study, we demonstrate that simultaneous delivery of multiple nanoparticle designs can enhance drug distribution in the cancerous tissue without compromising nanoparticle tumoral accumulation. We formulate and solve optimization problems to find the optimal constituent of the heterogeneous injection in terms of nanoparticle design diversity that increases drug distribution by 14%.

Multi-objective optimization of tumor response to drug release from vasculature-bound nanoparticles.

The pharmacokinetics of nanoparticle-borne drugs targeting tumors depends critically on nanoparticle design. Empirical approaches to evaluate such designs in order to maximize treatment efficacy are time- and cost-intensive. We have recently proposed the use of computational modeling of nanoparticle-mediated drug delivery targeting tumor vasculature coupled with numerical optimization to pursue optimal nanoparticle targeting and tumor uptake. Here, we build upon these studies to evaluate the effect of tumor size on optimal nanoparticle design by considering a cohort of heterogeneously-sized tumor lesions, as would be clinically expected. The results indicate that smaller nanoparticles yield higher tumor targeting and lesion regression for larger-sized tumors. We then augment the nanoparticle design optimization problem by considering drug diffusivity, which yields a two-fold tumor size decrease compared to optimizing nanoparticles without this consideration. We quantify the tradeoff between tumor targeting and size decrease using bi-objective optimization, and generate five Pareto-optimal nanoparticle designs. The results provide a spectrum of treatment outcomes - considering tumor targeting vs. antitumor effect - with the goal to enable therapy customization based on clinical need. This approach could be extended to other nanoparticle-based cancer therapies, and support the development of personalized nanomedicine in the longer term.

Hybrid modeling frameworks of tumor development and treatment.

Tumors are complex multicellular heterogeneous systems comprised of components that interact with and modify one another. Tumor development depends on multiple factors: intrinsic, such as genetic mutations, altered signaling pathways, or variable receptor expression; and extrinsic, such as differences in nutrient supply, crosstalk with stromal or immune cells, or variable composition of the surrounding extracellular matrix. Tumors are also characterized by high cellular heterogeneity and dynamically changing tumor microenvironments. The complexity increases when this multiscale, multicomponent system is perturbed by anticancer treatments. Modeling such complex systems and predicting how tumors will respond to therapies require mathematical models that can handle various types of information and combine diverse theoretical methods on multiple temporal and spatial scales, that is, hybrid models. In this update, we discuss the progress that has been achieved during the last 10 years in the area of the hybrid modeling of tumors. The classical definition of hybrid models refers to the coupling of discrete descriptions of cells with continuous descriptions of microenvironmental factors. To reflect on the direction that the modeling field has taken, we propose extending the definition of hybrid models to include of coupling two or more different mathematical frameworks. Thus, in addition to discussing recent advances in discrete/continuous modeling, we also discuss how these two mathematical descriptions can be coupled with theoretical frameworks of optimal control, optimization, fluid dynamics, game theory, and machine learning. All these methods will be illustrated with applications to tumor development and various anticancer treatments. This article is characterized under: Analytical and Computational Methods > Computational Methods Translational, Genomic, and Systems Medicine > Therapeutic Methods Models of Systems Properties and Processes > Organ, Tissue, and Physiological Models.

Design Optimization of Tumor Vasculature-Bound Nanoparticles.

Nanotherapy may constitute a promising approach to target tumors with anticancer drugs while minimizing systemic toxicity. Computational modeling can enable rapid evaluation of nanoparticle (NP) designs and numerical optimization. Here, an optimization study was performed using an existing tumor model to find NP size and ligand density that maximize tumoral NP accumulation while minimizing tumor size. Optimal NP avidity lies at lower bound of feasible values, suggesting reduced ligand density to prolong NP circulation. For the given set of tumor parameters, optimal NP diameters were 288 nm to maximize NP accumulation and 334 nm to minimize tumor diameter, leading to uniform NP distribution and adequate drug load. Results further show higher dependence of NP biodistribution on the NP design than on tumor morphological parameters. A parametric study with respect to drug potency was performed. The lower the potency of the drug, the bigger the difference is between the maximizer of NP accumulation and the minimizer of tumor size, indicating the existence of a specific drug potency that minimizes the differential between the two optimal solutions. This study shows the feasibility of applying optimization to NP designs to achieve efficacious cancer nanotherapy, and offers a first step towards a quantitative tool to support clinical decision making.

Nanoparticle Optimization for Enhanced Targeted Anticancer Drug Delivery.

Nanoparticle (NP)-based drug delivery is a promising method to increase the therapeutic index of anticancer agents with low median toxic dose. The delivery efficiency, corresponding to the fraction of the injected NPs that adhere to the tumor site, depends on NP size a and aspect ratio AR. Values for these variables are currently chosen empirically, which may not result in optimal targeted drug delivery. This study applies rigorous optimization to the design of NPs. A preliminary investigation revealed that delivery efficiency increases monotonically with a and AR. However, maximizing a and AR results in nonuniform drug distribution, which impairs tumor regression. Therefore, a multiobjective optimization (MO) problem is formulated to quantify the trade-off between NPs accumulation and distribution. The MO is solved using the derivative-free mesh adaptive direct search algorithm. Theoretically, the Pareto-optimal set consists of an infinite number of mathematically equivalent solutions to the MO problem. However, interesting design solutions can be identified subjectively, e.g., the ellipsoid with a major axis of 720 nm and an aspect ratio of 7.45, as the solution closest to the utopia point. The MO problem formulation is then extended to optimize NP biochemical properties: ligand-receptor binding affinity and ligand density. Optimizing physical and chemical properties simultaneously results in optimal designs with reduced NP sizes and thus enhanced cellular uptake. The presented study provides an insight into NP structures that have potential for producing desirable drug delivery.