Technical feasibility of novel immunostimulatory low-dose radiation for polymetastatic disease with CBCT-based online adaptive and conventional approaches.

PURPOSE: A workflow/planning strategy delivering low-dose radiation therapy (LDRT) (1 Gy) to all polymetastatic diseases using conventional planning/delivery (Raystation/Halcyon = "conventional") and the AI-based Ethos online adaptive RT (oART) platform is developed/evaluated. METHODS: Using retrospective data for ten polymetastatic non-small cell lung cancer patients (5-52 lesions each) with PET/CTs, gross tumor volumes (GTVs) were delineated using PET standardized-uptake-value (SUV) thresholding. A 1 cm uniform expansion of GTVs to account for setup/contour uncertainty and organ motion-generated planning target volumes (PTVs). Dose optimization/calculation used the diagnostic CT from PET/CT. Dosimetric objectives were: Dmin,0.03cc ≥ 95% (acceptable variation (Δ) ≥ 90%), V100% ≥ 95% (Δ ≥ 90%), and D0.03cc ≤ 120% (Δ ≤ 125%). Additionally, online adaptation was simulated. When available, subsequent diagnostic CT was used to represent on-treatment CBCT. Otherwise, the CT from PET/CT used for initial planning was deformed to simulate clinically representative changes. RESULTS: All initial plans generated, both for Raystation and Ethos, achieved clinical goals within acceptable variation. For all patients, Dmin,0.03cc ≥ 95%, V100% ≥ 95%, and D0.03cc ≤ 120% goals were achieved for 84.8%/99.5%, 97.7%/98.7%, 97.4%/92.3%, in conventional/Ethos plans, respectively. The ratio of 50% isodose volume to PTV volume (R50% ), maximum dose at 2 cm from PTV (D2cm ), and the ratio of the 100% isodose volume to PTV volume (conformity index) in Raystation/Ethos plans were 7.9/5.9; 102.3%/88.44%; and 0.99/1.01, respectively. In Ethos, online adapted plans maintained PTV coverage whereas scheduled plans often resulted in geographic misses due to changes in tumor size, patient position, and body habitus. The average total duration of the oART workflow was 26:15 (min:sec) ranging from 6:43 to 57:30. The duration of each oART workflow step as a function of a number of targets showed a low correlation coefficient for influencer generation and editing (R2  = 0.04 and 0.02, respectively) and high correlation coefficient for target generation, target editing and plan generation (R2  = 0.68, 0.63 and 0.69, respectively). CONCLUSIONS: This study demonstrates feasibility of conventional planning/treatment with Raystation/Halcyon and highlights efficiency gains when utilizing semi-automated planning/online-adaptive treatment with Ethos for immunostimulatory LDRT conformally delivered to all sites of polymetastatic disease.

Predicting Radiotherapy Patient Outcomes with Real-Time Clinical Data Using Mathematical Modelling.

Longitudinal tumour volume data from head-and-neck cancer patients show that tumours of comparable pre-treatment size and stage may respond very differently to the same radiotherapy fractionation protocol. Mathematical models are often proposed to predict treatment outcome in this context, and have the potential to guide clinical decision-making and inform personalised fractionation protocols. Hindering effective use of models in this context is the sparsity of clinical measurements juxtaposed with the model complexity required to produce the full range of possible patient responses. In this work, we present a compartment model of tumour volume and tumour composition, which, despite relative simplicity, is capable of producing a wide range of patient responses. We then develop novel statistical methodology and leverage a cohort of existing clinical data to produce a predictive model of both tumour volume progression and the associated level of uncertainty that evolves throughout a patient's course of treatment. To capture inter-patient variability, all model parameters are patient specific, with a bootstrap particle filter-like Bayesian approach developed to model a set of training data as prior knowledge. We validate our approach against a subset of unseen data, and demonstrate both the predictive ability of our trained model and its limitations.

Essentially unedited deep-learning-based OARs are suitable for rigorous oropharyngeal and laryngeal cancer treatment planning.

Quality of organ at risk (OAR) autosegmentation is often judged by concordance metrics against the human-generated gold standard. However, the ultimate goal is the ability to use unedited autosegmented OARs in treatment planning, while maintaining the plan quality. We tested this approach with head and neck (HN) OARs generated by a prototype deep-learning (DL) model on patients previously treated for oropharyngeal and laryngeal cancer. Forty patients were selected, with all structures delineated by an experienced physician. For each patient, a set of 13 OARs were generated by the DL model. Each patient was re-planned based on original targets and unedited DL-produced OARs. The new dose distributions were then applied back to the manually delineated structures. The target coverage was evaluated with inhomogeneity index (II) and the relative volume of regret. For the OARs, Dice similarity coefficient (DSC) of areas under the DVH curves, individual DVH objectives, and composite continuous plan quality metric (PQM) were compared. The nearly identical primary target coverage for the original and re-generated plans was achieved, with the same II and relative volume of regret values. The average DSC of the areas under the corresponding pairs of DVH curves was 0.97 ± 0.06. The number of critical DVH points which met the clinical objectives with the dose optimized on autosegmented structures but failed when evaluated on the manual ones was 5 of 896 (0.6%). The average OAR PQM score with the re-planned dose distributions was essentially the same when evaluated either on the autosegmented or manual OARs. Thus, rigorous HN treatment planning is possible with OARs segmented by a prototype DL algorithm with minimal, if any, manual editing.

Accurate, repeatable, and geometrically precise diffusion-weighted imaging on a 0.35 T magnetic resonance imaging-guided linear accelerator.

Background and purpose: Diffusion weighted imaging (DWI) allows for the interrogation of tissue cellularity, which is a surrogate for cellular proliferation. Previous attempts to incorporate DWI into the workflow of a 0.35 T MR-linac (MRL) have lacked quantitative accuracy. In this study, accuracy, repeatability, and geometric precision of apparent diffusion coefficient (ADC) maps produced using an echo planar imaging (EPI)-based DWI protocol on the MRL system is illustrated, and in vivo potential for longitudinal patient imaging is demonstrated. Materials and methods: Accuracy and repeatability were assessed by measuring ADC values in a diffusion phantom at three timepoints and comparing to reference ADC values. System-dependent geometric distortion was quantified by measuring the distance between 93 pairs of phantom features on ADC maps acquired on a 0.35 T MRL and a 3.0 T diagnostic scanner and comparing to spatially precise CT images. Additionally, for five sarcoma patients receiving radiotherapy on the MRL, same-day in vivo ADC maps were acquired on both systems, one of which at multiple timepoints. Results: Phantom ADC quantification was accurate on the 0.35 T MRL with significant discrepancies only seen at high ADC. Average geometric distortions were 0.35 (±0.02) mm and 0.85 (±0.02) mm in the central slice and 0.66 (±0.04) mm and 2.14 (±0.07) mm at 5.4 cm off-center for the MRL and diagnostic system, respectively. In the sarcoma patients, a mean pretreatment ADC of 910x10-6 (±100x10-6) mm2/s was measured on the MRL. Conclusions: The acquisition of accurate, repeatable, and geometrically precise ADC maps is possible at 0.35 T with an EPI approach.

A head and neck treatment planning strategy for a CBCT-guided ring-gantry online adaptive radiotherapy system.

PURPOSE: A planning strategy was developed and the utility of online-adaptation with the Ethos CBCT-guided ring-gantry adaptive radiotherapy (ART) system was evaluated using retrospective data from Head-and-neck (H&N) patients that required clinical offline adaptation during treatment. METHODS: Clinical data were used to re-plan 20 H&N patients (10 sequential boost (SEQ) with separate base and boost plans plus 10 simultaneous integrated boost (SIB)). An optimal approach, robust to online adaptation, for Ethos-initial plans using clinical goal prioritization was developed. Anatomically-derived isodose-shaping helper structures, air-density override, goals for controlling hotspot location(s), and plan normalization were investigated. Online adaptation was simulated using clinical offline adaptive simulation-CTs to represent an on-treatment CBCT. Dosimetric comparisons were based on institutional guidelines for Clinical-initial versus Ethos-initial plans and Ethos-scheduled versus Ethos-adapted plans. Timing for five components of the online adaptive workflow was analyzed. RESULTS: The Ethos H&N planning approach generated Ethos-initial SEQ plans with clinically comparable PTV coverage (average PTVHigh V100%  = 98.3%, Dmin,0.03cc  = 97.9% and D0.03cc  = 105.5%) and OAR sparing. However, Ethos-initial SIB plans were clinically inferior (average PTVHigh V100%  = 96.4%, Dmin,0.03cc  = 93.7%, D0.03cc  = 110.6%). Fixed-field IMRT was superior to VMAT for 93.3% of plans. Online adaptation succeeded in achieving conformal coverage to the new anatomy in both SEQ and SIB plans that was even superior to that achieved in the initial plans (which was due to the changes in anatomy that simplified the optimization). The average adaptive workflow duration for SIB, SEQ base and SEQ boost was 30:14, 22.56, and 14:03 (min: sec), respectively. CONCLUSIONS: With an optimal planning approach, Ethos efficiently auto-generated dosimetrically comparable and clinically acceptable initial SEQ plans for H&N patients. Initial SIB plans were inferior and clinically unacceptable, but adapted SIB plans became clinically acceptable. Online adapted plans optimized dose to new anatomy and maintained target coverage/homogeneity with improved OAR sparing in a time-efficient manner.

Framework for Quality Assurance of Ultrahigh Dose Rate Clinical Trials Investigating FLASH Effects and Current Technology Gaps.

FLASH radiation therapy (FLASH-RT), delivered with ultrahigh dose rate (UHDR), may allow patients to be treated with less normal tissue toxicity for a given tumor dose compared with currently used conventional dose rate. Clinical trials are being carried out and are needed to test whether this improved therapeutic ratio can be achieved clinically. During the clinical trials, quality assurance and credentialing of equipment and participating sites, particularly pertaining to UHDR-specific aspects, will be crucial for the validity of the outcomes of such trials. This report represents an initial framework proposed by the NRG Oncology Center for Innovation in Radiation Oncology FLASH working group on quality assurance of potential UHDR clinical trials and reviews current technology gaps to overcome. An important but separate consideration is the appropriate design of trials to most effectively answer clinical and scientific questions about FLASH. This paper begins with an overview of UHDR RT delivery methods. UHDR beam delivery parameters are then covered, with a focus on electron and proton modalities. The definition and control of safe UHDR beam delivery and current and needed dosimetry technologies are reviewed and discussed. System and site credentialing for large, multi-institution trials are reviewed. Quality assurance is then discussed, and new requirements are presented for treatment system standard analysis, patient positioning, and treatment planning. The tables and figures in this paper are meant to serve as reference points as we move toward FLASH-RT clinical trial performance. Some major questions regarding FLASH-RT are discussed, and next steps in this field are proposed. FLASH-RT has potential but is associated with significant risks and complexities. We need to redefine optimization to focus not only on the dose but also on the dose rate in a manner that is robust and understandable and that can be prescribed, validated, and confirmed in real time. Robust patient safety systems and access to treatment data will be critical as FLASH-RT moves into the clinical trials.

Evaluation of an MRI linac magnetic isocenter walkout with gantry rotation in the presence of angle-specific corrections.

Objective. To reduce the magnetic isocenter position variation with gantry rotation on an 0.35 T MRI-guided linac to a practically negligible level.Approach. Central fRequency (CF) offset, eddy current calibration, cross-term calibration, gradient delay, and gradient offsets are tuned for each MR linac installation at every 30° of gantry rotation and stored in a look-up table (LUT). During treatment, the CF is tuned only once in the beginning at an arbitrary gantry angle. After that, imaging paramters are offset based on the stored LUT values for any given gantry angle.Main results. For the same hardware configuration, the implementation of the gantry-angle-specific parameter corrections reduced the total isocenters range of travel in the transverse plane from 1.1 to 0.3 mm and from 0.8 to 0.2 mm in horizontal and vertical directions, respectively. With the longitudinal shift always being negligible (≤0.2 mm), the radius of the sphere encompassing the isocenter locations was reduced from 0.6 to 0.2 mm. Geometric distortion improved as well; in particular, the gantry-angle-averaged maximum longitudinal distortion within a 35 cm diameter sphere was reduced from 1.4 to 0.8 mm. Since the CF is tuned only once during treatment, imaging may resume promptly after the gantry reaches the next target position.Significance. The MRI-guided linear accelerator was conceived primarily as an instrument for precision image-guided therapy. Thus, it is important to keep the treatment and imaging isocentres as close as possible while minimizing the geometric distortion. The described solution reduces the walkout of the imaging isocenter to a fraction of 1 mm, while keeping geometric distortion in a substantial volume below 1 mm. The approach is robust and does not increase the overall procedure time.

Real-time, volumetric imaging of radiation dose delivery deep into the liver during cancer treatment.

Ionizing radiation acoustic imaging (iRAI) allows online monitoring of radiation's interactions with tissues during radiation therapy, providing real-time, adaptive feedback for cancer treatments. We describe an iRAI volumetric imaging system that enables mapping of the three-dimensional (3D) radiation dose distribution in a complex clinical radiotherapy treatment. The method relies on a two-dimensional matrix array transducer and a matching multi-channel preamplifier board. The feasibility of imaging temporal 3D dose accumulation was first validated in a tissue-mimicking phantom. Next, semiquantitative iRAI relative dose measurements were verified in vivo in a rabbit model. Finally, real-time visualization of the 3D radiation dose delivered to a patient with liver metastases was accomplished with a clinical linear accelerator. These studies demonstrate the potential of iRAI to monitor and quantify the 3D radiation dose deposition during treatment, potentially improving radiotherapy treatment efficacy using real-time adaptive treatment.

Comparative evaluation of a prototype deep learning algorithm for autosegmentation of normal tissues in head and neck radiotherapy.

PURPOSE: To introduce and validate a newly developed deep-learning (DL) auto-segmentation algorithm for head and neck (HN) organs at risk (OARs) and to compare its performance with a published commercial algorithm. METHODS: A total of 864 HN cancer cases were available to train and evaluate a prototype algorithm. The algorithm is based on a fully convolutional network with combined U-Net and V-net. A Dice loss plus Cross-Entropy Loss function with Adam optimizer was used in training. For 75 validation cases, OAR sets were generated with three DL-based models (A: the prototype model trained with gold data, B: a commercial software trained with the same data, and C: the same software trained with data from another institution). The auto-segmented structures were evaluated with Dice similarity coefficient (DSC), Hausdorff distance (HD), voxel-penalty metric (VPM) and DSC of area under dose-volume histograms. A subjective qualitative evaluation was performed on 20 random cases. RESULTS: Overall trend was for the prototype algorithm to be the closest to the gold data by all five metrics. The average DSC/VPM/HD for algorithms A, B, and C were 0.81/84.1/1.6 mm, 0.74/62.8/3.2 mm, and 0.66/46.8/3.3 mm, respectively. 93% of model A structures were evaluated to be clinically useful. CONCLUSION: The superior performance of the prototype was validated, even when trained with the same data. In addition to the challenges of perfecting the algorithms, the auto-segmentation results can differ when the same algorithm is trained at different institutions.

Robustness Assessment of Images From a 0.35T Scanner of an Integrated MRI-Linac: Characterization of Radiomics Features in Phantom and Patient Data.

Purpose: Radiomics entails the extraction of quantitative imaging biomarkers (or radiomics features) hypothesized to provide additional pathophysiological and/or clinical information compared to qualitative visual observation and interpretation. This retrospective study explores the variability of radiomics features extracted from images acquired with the 0.35 T scanner of an integrated MRI-Linac. We hypothesized we would be able to identify features with high repeatability and reproducibility over various imaging conditions using phantom and patient imaging studies. We also compared findings from the literature relevant to our results. Methods: Eleven scans of a Magphan® RT phantom over 13 months and 11 scans of a ViewRay Daily QA phantom over 11 days constituted the phantom data. Patient datasets included 50 images from ten anonymized stereotactic body radiation therapy (SBRT) pancreatic cancer patients (50 Gy in 5 fractions). A True Fast Imaging with Steady-State Free Precession (TRUFI) pulse sequence was selected, using a voxel resolution of 1.5 mm × 1.5 mm × 1.5 mm and 1.5 mm × 1.5 mm × 3.0 mm for phantom and patient data, respectively. A total of 1087 shape-based, first, second, and higher order features were extracted followed by robustness analysis. Robustness was assessed with the Coefficient of Variation (CoV < 5%). Results: We identified 130 robust features across the datasets. Robust features were found within each category, except for 2 second-order sub-groups, namely, Gray Level Size Zone Matrix (GLSZM) and Neighborhood Gray Tone Difference Matrix (NGTDM). Additionally, several robust features agreed with findings from other stability assessments or predictive performance studies in the literature. Conclusion: We verified the stability of the 0.35 T scanner of an integrated MRI-Linac for longitudinal radiomics phantom studies and identified robust features over various imaging conditions. We conclude that phantom measurements can be used to identify robust radiomics features. More stability assessment research is warranted.

Heat-induced SIRT1-mediated H4K16ac deacetylation impairs resection and SMARCAD1 recruitment to double strand breaks.

Hyperthermia inhibits DNA double-strand break (DSB) repair that utilizes homologous recombination (HR) pathway by a poorly defined mechanism(s); however, the mechanisms for this inhibition remain unclear. Here we report that hyperthermia decreases H4K16 acetylation (H4K16ac), an epigenetic modification essential for genome stability and transcription. Heat-induced reduction in H4K16ac was detected in humans, Drosophila, and yeast, indicating that this is a highly conserved response. The examination of histone deacetylase recruitment to chromatin after heat-shock identified SIRT1 as the major deacetylase subsequently enriched at gene-rich regions. Heat-induced SIRT1 recruitment was antagonized by chromatin remodeler SMARCAD1 depletion and, like hyperthermia, the depletion of the SMARCAD1 or combination of the two impaired DNA end resection and increased replication stress. Altered repair protein recruitment was associated with heat-shock-induced γ-H2AX chromatin changes and DSB repair processing. These results support a novel mechanism whereby hyperthermia impacts chromatin organization owing to H4K16ac deacetylation, negatively affecting the HR-dependent DSB repair.

Maintaining dosimetric quality when switching to a Monte Carlo dose engine for head and neck volumetric-modulated arc therapy planning.

Head and neck cancers present challenges in radiation treatment planning due to the large number of critical structures near the target(s) and highly heterogeneous tissue composition. While Monte Carlo (MC) dose calculations currently offer the most accurate approximation of dose deposition in tissue, the switch to MC presents challenges in preserving the parameters of care. The differences in dose-to-tissue were widely discussed in the literature, but mostly in the context of recalculating the existing plans rather than reoptimizing with the MC dose engine. Also, the target dose homogeneity received less attention. We adhere to strict dose homogeneity objectives in clinical practice. In this study, we started with 21 clinical volumetric-modulated arc therapy (VMAT) plans previously developed in Pinnacle treatment planning system. Those plans were recalculated "as is" with RayStation (RS) MC algorithm and then reoptimized in RS with both collapsed cone (CC) and MC algorithms. MC statistical uncertainty (0.3%) was selected carefully to balance the dose computation time (1-2 min) with the planning target volume (PTV) dose-volume histogram (DVH) shape approaching that of a "noise-free" calculation. When the hot spot in head and neck MC-based treatment planning is defined as dose to 0.03 cc, it is exceedingly difficult to limit it to 105% of the prescription dose, as we were used to with the CC algorithm. The average hot spot after optimization and calculation with RS MC was statistically significantly higher compared to Pinnacle and RS CC algorithms by 1.2 and 1.0 %, respectively. The 95% confidence interval (CI) observed in this study suggests that in most cases a hot spot of ≤107% is achievable. Compared to the 95% CI for the previous clinical plans recalculated with RS MC "as is" (upper limit 108%), in real terms this result is at least as good or better than the historic plans.

Triggered kV Imaging During Spine SBRT for Intrafraction Motion Management.

Purpose: To monitor intrafraction motion during spine stereotactic body radiotherapy(SBRT) treatment delivery with readily available technology, we implemented triggered kV imaging using the on-board imager(OBI) of a modern medical linear accelerator with an advanced imaging package. Methods: Triggered kV imaging for intrafraction motion management was tested with an anthropomorphic phantom and simulated spine SBRT treatments to the thoracic and lumbar spine. The vertebral bodies and spinous processes were contoured as the image guided radiotherapy(IGRT) structures specific to this technique. Upon each triggered kV image acquisition, 2D projections of the IGRT structures were automatically calculated and updated at arbitrary angles for display on the kV images. Various shifts/rotations were introduced in x, y, z, pitch, and yaw. Gantry-angle-based triggering was set to acquire kV images every 45°. A group of physicists/physicians(n = 10) participated in a survey to evaluate clinical efficiency and accuracy of clinical decisions on images containing various phantom shifts. This method was implemented clinically for treatment of 42 patients(94 fractions) with 15 second time-based triggering. Result: Phantom images revealed that IGRT structure accuracy and therefore utility of projected contours during triggered imaging improved with smaller CT slice thickness. Contouring vertebra superior and inferior to the treatment site was necessary to detect clinically relevant phantom rotation. From the survey, detectability was proportional to the shift size in all shift directions and inversely related to the CT slice thickness. Clinical implementation helped evaluate robustness of patient immobilization. Based on visual inspection of projected IGRT contours on planar kV images, appreciable intrafraction motion was detected in eleven fractions(11.7%). Discussion: Feasibility of triggered imaging for spine SBRT intrafraction motion management has been demonstrated in phantom experiments and implementation for patient treatments. This technique allows efficient, non-invasive monitoring of patient position using the OBI and patient anatomy as a direct visual guide.

Dynamics-Adapted Radiotherapy Dose (DARD) for Head and Neck Cancer Radiotherapy Dose Personalization.

Standard of care radiotherapy (RT) doses have been developed as a one-size-fits all approach designed to maximize tumor control rates across a population. Although this has led to high control rates for head and neck cancer with 66-70 Gy, this is done without considering patient heterogeneity. We present a framework to estimate a personalized RT dose for individual patients, based on pre- and early on-treatment tumor volume dynamics-a dynamics-adapted radiotherapy dose (DDARD). We also present the results of an in silico trial of this dose personalization using retrospective data from a combined cohort of n = 39 head and neck cancer patients from the Moffitt and MD Anderson Cancer Centers that received 66-70 Gy RT in 2-2.12 Gy weekday fractions. This trial was repeated constraining DDARD between (54, 82) Gy to test more moderate dose adjustment. DDARD was estimated to range from 8 to 186 Gy, and our in silico trial estimated that 77% of patients treated with standard of care were overdosed by an average dose of 39 Gy, and 23% underdosed by an average dose of 32 Gy. The in silico trial with constrained dose adjustment estimated that locoregional control could be improved by >10%. We demonstrated the feasibility of using early treatment tumor volume dynamics to inform dose personalization and stratification for dose escalation and de-escalation. These results demonstrate the potential to both de-escalate most patients, while still improving population-level control rates.

Forecasting Individual Patient Response to Radiation Therapy in Head and Neck Cancer With a Dynamic Carrying Capacity Model.

PURPOSE: To model and predict individual patient responses to radiation therapy. METHODS AND MATERIALS: We modeled tumor dynamics as logistic growth and the effect of radiation as a reduction in the tumor carrying capacity, motivated by the effect of radiation on the tumor microenvironment. The model was assessed on weekly tumor volume data collected for 2 independent cohorts of patients with head and neck cancer from the H. Lee Moffitt Cancer Center (MCC) and the MD Anderson Cancer Center (MDACC) who received 66 to 70 Gy in standard daily fractions or with accelerated fractionation. To predict response to radiation therapy for individual patients, we developed a new forecasting framework that combined the learned tumor growth rate and carrying capacity reduction fraction (δ) distribution with weekly measurements of tumor volume reduction for a given test patient to estimate δ, which was used to predict patient-specific outcomes. RESULTS: The model fit data from MCC with high accuracy with patient-specific δ and a fixed tumor growth rate across all patients. The model fit data from an independent cohort from MDACC with comparable accuracy using the tumor growth rate learned from the MCC cohort, showing transferability of the growth rate. The forecasting framework predicted patient-specific outcomes with 76% sensitivity and 83% specificity for locoregional control and 68% sensitivity and 85% specificity for disease-free survival with the inclusion of 4 on-treatment tumor volume measurements. CONCLUSIONS: These results demonstrate that our simple mathematical model can describe a variety of tumor volume dynamics. Furthermore, combining historically observed patient responses with a few patient-specific tumor volume measurements allowed for the accurate prediction of patient outcomes, which may inform treatment adaptation and personalization.

Pretreatment CT and PET radiomics predicting rectal cancer patients in response to neoadjuvant chemoradiotherapy.

BACKGROUND: The purpose of this study was to characterize pre-treatment non-contrast computed tomography (CT) and 18F-fluorodeoxyglucose positron emission tomography (PET) based radiomics signatures predictive of pathological response and clinical outcomes in rectal cancer patients treated with neoadjuvant chemoradiotherapy (NACR T). MATERIALS AND METHODS: An exploratory analysis was performed using pre-treatment non-contrast CT and PET imaging dataset. The association of tumor regression grade (TRG) and neoadjuvant rectal (NAR) score with pre-treatment CT and PET features was assessed using machine learning algorithms. Three separate predictive models were built for composite features from CT + PET. RESULTS: The patterns of pathological response were TRG 0 (n = 13; 19.7%), 1 (n = 34; 51.5%), 2 (n = 16; 24.2%), and 3 (n = 3; 4.5%). There were 20 (30.3%) patients with low, 22 (33.3%) with intermediate and 24 (36.4%) with high NAR scores. Three separate predictive models were built for composite features from CT + PET and analyzed separately for clinical endpoints. Composite features with α = 0.2 resulted in the best predictive power using logistic regression. For pathological response prediction, the signature resulted in 88.1% accuracy in predicting TRG 0 vs. TRG 1-3; 91% accuracy in predicting TRG 0-1 vs. TRG 2-3. For the surrogate of DFS and OS, it resulted in 67.7% accuracy in predicting low vs. intermediate vs. high NAR scores. CONCLUSION: The pre-treatment composite radiomics signatures were highly predictive of pathological response in rectal cancer treated with NACR T. A larger cohort is warranted for further validation.

Lipophilicity Determines Routes of Uptake and Clearance, and Toxicity of an Alpha-Particle-Emitting Peptide Receptor Radiotherapy.

Lipophilicity is explored in the biodistribution (BD), pharmacokinetics (PK), radiation dosimetry (RD), and toxicity of an internally administered targeted alpha-particle therapy (TAT) under development for the treatment of metastatic melanoma. The TAT conjugate is comprised of the chelator DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), conjugated to melanocortin receptor 1 specific peptidic ligand (MC1RL) using a linker moiety and chelation of the 225Ac radiometal. A set of conjugates were prepared with a range of lipophilicities (log D 7.4 values) by varying the chemical properties of the linker. Reported are the observations that higher log D 7.4 values are associated with decreased kidney uptake, decreased absorbed radiation dose, and decreased kidney toxicity of the TAT, and the inverse is observed for lower log D 7.4 values. Animals administered TATs with lower lipophilicities exhibited acute nephropathy and death, whereas animals administered the highest activity TATs with higher lipophilicities lived for the duration of the 7 month study and exhibited chronic progressive nephropathy. Changes in TAT lipophilicity were not associated with changes in liver uptake, dose, or toxicity. Significant observations include that lipophilicity correlates with kidney BD, the kidney-to-liver BD ratio, and weight loss and that blood urea nitrogen (BUN) levels correlated with kidney uptake. Furthermore, BUN was identified as having higher sensitivity and specificity of detection of kidney pathology, and the liver enzyme alkaline phosphatase (ALKP) had high sensitivity and specificity for detection of liver damage associated with the TAT. These findings suggest that tuning radiopharmaceutical lipophilicity can effectively modulate the level of kidney uptake to reduce morbidity and improve both safety and efficacy.