Time structures of proton pencil beam scanning delivery on a microsecond scale measured with a pixelated semiconductor detector Timepix3.

PURPOSE: The time structures of proton spot delivery in proton pencil beam scanning (PBS) radiation therapy are essential in many clinical applications. This study aims to characterize the time structures of proton PBS delivered by both synchrotron and synchrocyclotron accelerators using a non-invasive technique based on scattered particle tracking. METHODS: A pixelated semiconductor detector, AdvaPIX-Timepix3, with a temporal resolution of 1.56 ns, was employed to measure time of arrival of secondary particles generated by a proton beam. The detector was placed laterally to the high-flux area of the beam in order to allow for single particle detection and not interfere with the treatment. The detector recorded counts of radiation events, their deposited energy and the timestamp associated with the single events. Individual recorded events and their temporal characteristics were used to analyze beam time structures, including energy layer switch time, magnet switch time, spot switch time, and the scanning speeds in the x and y directions. All the measurements were repeated 30 times on three dates, reducing statistical uncertainty. RESULTS: The uncertainty of the measured energy layer switch times, magnet switch time, and the spot switch time were all within 1% of average values. The scanning speeds uncertainties were within 1.5% and are more precise than previously reported results. The measurements also revealed continuous sub-milliseconds proton spills at a low dose rate for the synchrotron accelerator and radiofrequency pulses at 7 µs and 1 ms repetition time for the synchrocyclotron accelerator. CONCLUSION: The AdvaPIX-Timepix3 detector can be used to directly measure and monitor time structures on microseconds scale of the PBS proton beam delivery. This method yielded results with high precision and is completely independent of the machine log files.

Enhanced IDOL segmentation framework using personalized hyperspace learning IDOL.

BACKGROUND: Adaptive radiotherapy (ART) workflows have been increasingly adopted to achieve dose escalation and tissue sparing under shifting anatomic conditions, but the necessity of recontouring and the associated time burden hinders a real-time or online ART workflow. In response to this challenge, approaches to auto-segmentation involving deformable image registration, atlas-based segmentation, and deep learning-based segmentation (DLS) have been developed. Despite the particular promise shown by DLS methods, implementing these approaches in a clinical setting remains a challenge, namely due to the difficulty of curating a data set of sufficient size and quality so as to achieve generalizability in a trained model. PURPOSE: To address this challenge, we have developed an intentional deep overfit learning (IDOL) framework tailored to the auto-segmentation task. However, certain limitations were identified, particularly the insufficiency of the personalized dataset to effectively overfit the model. In this study, we introduce a personalized hyperspace learning (PHL)-IDOL segmentation framework capable of generating datasets that induce the model to overfit specific patient characteristics for medical image segmentation. METHODS: The PHL-IDOL model is trained in two stages. In the first, a conventional, general model is trained with a diverse set of patient data (n = 100 patients) consisting of CT images and clinical contours. Following this, the general model is tuned with a data set consisting of two components: (a) selection of a subset of the patient data (m < n) using the similarity metrics (mean square error (MSE), peak signal-to-noise ratio (PSNR), structural similarity index (SSIM), and the universal quality image index (UQI) values); (b) adjust the CT and the clinical contours using a deformed vector generated from the reference patient and the selected patients using (a). After training, the general model, the continual model, the conventional IDOL model, and the proposed PHL-IDOL model were evaluated using the volumetric dice similarity coefficient (VDSC) and the Hausdorff distance 95% (HD95%) computed for 18 structures in 20 test patients. RESULTS: Implementing the PHL-IDOL framework resulted in improved segmentation performance for each patient. The Dice scores increased from 0.81 ± $ \pm $ 0.05 with the general model, 0.83 ± 0.04 $ \pm 0.04$ for the continual model, 0.83 ± 0.04 $ \pm 0.04$ for the conventional IDOL model to an average of 0.87 ± 0.03 $ \pm 0.03$ with the PHL-IDOL model. Similarly, the Hausdorff distance decreased from 3.06 ± 0.99 $ \pm 0.99$ with the general model, 2.84 ± 0.69 $ \pm 0.69$ for the continual model, 2.79 ± 0.79 $ \pm 0.79$ for the conventional IDOL model and 2.36 ± 0.52 $ \pm 0.52$ for the PHL-IDOL model. All the standard deviations were decreased by nearly half of the values comparing the general model and the PHL-IDOL model. CONCLUSION: The PHL-IDOL framework applied to the auto-segmentation task achieves improved performance compared to the general DLS approach, demonstrating the promise of leveraging patient-specific prior information in a task central to online ART workflows.

Particle arc therapy: Status and potential.

There is a rising interest in developing and utilizing arc delivery techniques with charged particle beams, e.g., proton, carbon or other ions, for clinical implementation. In this work, perspectives from the European Society for Radiotherapy and Oncology (ESTRO) 2022 physics workshop on particle arc therapy are reported. This outlook provides an outline and prospective vision for the path forward to clinically deliverable proton, carbon, and other ion arc treatments. Through the collaboration among industry, academic, and clinical research and development, the scientific landscape and outlook for particle arc therapy are presented here to help our community understand the physics, radiobiology, and clinical principles. The work is presented in three main sections: (i) treatment planning, (ii) treatment delivery, and (iii) clinical outlook.

NRG Oncology White Paper on the Relative Biological Effectiveness in Proton Therapy.

This position paper, led by the NRG Oncology Particle Therapy Work Group, focuses on the concept of relative biologic effect (RBE) in clinical proton therapy (PT), with the goal of providing recommendations for the next-generation clinical trials with PT on the best practice of investigating and using RBE, which could deviate from the current standard proton RBE value of 1.1 relative to photons. In part 1, current clinical utilization and practice are reviewed, giving the context and history of RBE. Evidence for variation in RBE is presented along with the concept of linear energy transfer (LET). The intertwined nature of tumor radiobiology, normal tissue constraints, and treatment planning with LET and RBE considerations is then reviewed. Part 2 summarizes current and past clinical data and then suggests the next steps to explore and employ tools for improved dynamic models for RBE. In part 3, approaches and methods for the next generation of prospective clinical trials are explored, with the goal of optimizing RBE to be both more reflective of clinical reality and also deployable in trials to allow clinical validation and interpatient comparisons. These concepts provide the foundation for personalized biologic treatments reviewed in part 4. Finally, we conclude with a summary including short- and long-term scientific focus points for clinical PT. The practicalities and capacity to use RBE in treatment planning are reviewed and considered with more biological data in hand. The intermediate step of LET optimization is summarized and proposed as a potential bridge to the ultimate goal of case-specific RBE planning that can be achieved as a hypothesis-generating tool in near-term proton trials.

Impact of Relative Biologic Effectiveness for Proton Therapy for Head and Neck and Skull-Base Tumors: A Technical and Clinical Review.

Proton therapy has emerged as a crucial tool in the treatment of head and neck and skull-base cancers, offering advantages over photon therapy in terms of decreasing integral dose and reducing acute and late toxicities, such as dysgeusia, feeding tube dependence, xerostomia, secondary malignancies, and neurocognitive dysfunction. Despite its benefits in dose distribution and biological effectiveness, the application of proton therapy is challenged by uncertainties in its relative biological effectiveness (RBE). Overcoming the challenges related to RBE is key to fully realizing proton therapy's potential, which extends beyond its physical dosimetric properties when compared with photon-based therapies. In this paper, we discuss the clinical significance of RBE within treatment volumes and adjacent serial organs at risk in the management of head and neck and skull-base tumors. We review proton RBE uncertainties and its modeling and explore clinical outcomes. Additionally, we highlight technological advancements and innovations in plan optimization and treatment delivery, including linear energy transfer/RBE optimizations and the development of spot-scanning proton arc therapy. These advancements show promise in harnessing the full capabilities of proton therapy from an academic standpoint, further technological innovations and clinical outcome studies, however, are needed for their integration into routine clinical practice.

Optimizing spot intensity with lower bound constraints for IMPT: Exposing shortcomings and introducing an enhanced strategy.

BACKGROUND: Intensity Modulated Proton Therapy (IMPT) is a sophisticated radiation treatment allowing for precise dose distributions. However, conventional spot selection strategies in IMPT face challenges, particularly with minimum monitor unit (MU) constraints, affecting planning quality and efficiency. PURPOSE: This study introduces an innovative Two-Stage Mixed Integer Linear Programming (MILP) method to optimize spot intensity in IMPT with Lower Bound (LB) constraints. This method seeks to improve treatment planning efficiency and precision, overcoming limitations of existing strategies. METHODS: Our approach evaluates prevalent IMPT spot selection strategies, identifying their limitations, especially concerning MU constraints. We integrated LB constraints into a MILP framework, using a novel three-phase strategy for spot pool selection, to enhance performance over traditional heuristic methods and L1 + L∞ strategies. The method's efficacy was tested in eight study cases, using Dose-Volume Histograms (DVHs), spot selection efficiency, and computation time analysis for benchmarking against established methods. RESULTS: The proposed method showed superior performance in DVH quality, adhering to LB constraints while maintaining high-quality treatment plans. It outperformed existing techniques in spot selection, reducing unnecessary spots and balancing precision with efficiency. Cases studies confirmed the method's effectiveness in producing clinically feasible plans with enhanced dose distributions and reduced hotspots, especially in cases with elevated LB constraints. CONCLUSIONS: Our Two-Stage MILP strategy signifies a significant advancement in IMPT treatment planning. By incorporating LB constraints directly into the optimization process, it achieves superior plan quality and deliverability compared to current methods. This approach is particularly advantageous in clinical settings requiring minimum spot number and high MU LB constraints, offering the potential for improved patient outcomes through more precise and efficient radiation therapy plans.

Investigation of dosimetric effect of beam current fluctuations in synchrotron-based proton PBS continuous scanning.

Objective.In proton pencil beam scanning (PBS) continuous delivery, the beam is continuously delivered without interruptions between spots. For synchrotron-based systems, the extracted beam current exhibits a spill structure, and recent publications on beam current measurements have demonstrated significant fluctuations around the nominal values. These fluctuations potentially lead to dose deviations from those calculated assuming a stable beam current. This study investigated the dosimetric implications of such beam current fluctuations during proton PBS continuous scanning.Approach.Using representative clinical proton PBS plans, we performed simulations to mimic a worst-case clinical delivery environment with beam current varies from 50% to 250% of the nominal values. The simulations used the beam delivery parameters optimized for the best beam delivery efficiency of the upcoming particle therapy system at Mayo Clinic Florida. We reconstructed the simulated delivered dose distributions and evaluated the dosimetric impact of beam current fluctuations.Main results.Despite significant beam current fluctuations resulting in deviations at each spot level, the overall dose distributions were nearly identical to those assuming a stable beam current. The 1 mm/1% Gamma passing rate was 100% for all plans. Less than 0.2% root mean square error was observed in the planning target volume dose-volume histogram. Minimal differences were observed in all dosimetric evaluation metrics.Significance.Our findings demonstrate that with our beam delivery system and clinical planning practice, while significant beam current fluctuations may result in large local move monitor unit deviations at each spot level, the overall impact on the dose distribution is minimal.

radioGWAS links radiome to genome to discover driver genes with somatic mutations for heterogeneous tumor image phenotype in pancreatic cancer.

Addressing the significant level of variability exhibited by pancreatic cancer necessitates the adoption of a systems biology approach that integrates molecular data, biological properties of the tumors, medical images, and clinical features of the patients. In this study, a comprehensive multi-omics methodology was employed to examine a distinctive collection of patient dataset containing rapid autopsy tumor and normal tissue samples as well as longitudinal imaging with a focus on pancreatic cancer. By performing a whole exome sequencing analysis on tumor and normal tissues to identify somatic gene variants and a radiomic feature analysis to tumor CT images, the genome-wide association approach established a connection between pancreatic cancer driver genes and relevant radiomic features, enabling a thorough and quantitative assessment of the heterogeneity of pancreatic tumors. The significant association between sets of genes and radiomic features revealed the involvement of genes in shaping tumor morphological heterogeneity. Some results of the association established a connection between the molecular level mechanism and their outcomes at the level of tumor structural heterogeneity. Because tumor structure and tumor structural heterogeneity are related to the patients' overall survival, patients who had pancreatic cancer driver gene mutations with an association to a certain radiomic feature have been observed to experience worse survival rates than cases without these somatic mutations. Furthermore, the association analysis has revealed potential gene mutations and radiomic feature candidates that warrant further investigation in future research endeavors.

Impact of proton PBS machine operating parameters on the effectiveness of layer rescanning for interplay effect mitigation in lung SBRT treatment.

BACKGROUND: Rescanning is a common technique used in proton pencil beam scanning to mitigate the interplay effect. Advances in machine operating parameters across different generations of particle therapy systems have led to improvements in beam delivery time (BDT). However, the potential impact of these improvements on the effectiveness of rescanning remains an underexplored area in the existing research. METHODS: We systematically investigated the impact of proton machine operating parameters on the effectiveness of layer rescanning in mitigating interplay effect during lung SBRT treatment, using the CIRS phantom. Focused on the Hitachi synchrotron particle therapy system, we explored machine operating parameters from our institution's current (2015) and upcoming systems (2025A and 2025B). Accumulated dynamic 4D dose were reconstructed to assess the interplay effect and layer rescanning effectiveness. RESULTS: Achieving target coverage and dose homogeneity within 2% deviation required 6, 6, and 20 times layer rescanning for the 2015, 2025A, and 2025B machine parameters, respectively. Beyond this point, further increasing the number of layer rescanning did not further improve the dose distribution. BDTs without rescanning were 50.4, 24.4, and 11.4 s for 2015, 2025A, and 2025B, respectively. However, after incorporating proper number of layer rescanning (six for 2015 and 2025A, 20 for 2025B), BDTs increased to 67.0, 39.6, and 42.3 s for 2015, 2025A, and 2025B machine parameters. Our data also demonstrated the potential problem of false negative and false positive if the randomness of the respiratory phase at which the beam is initiated is not considered in the evaluation of interplay effect. CONCLUSION: The effectiveness of layer rescanning for mitigating interplay effect is affected by machine operating parameters. Therefore, past clinical experiences may not be applicable to modern machines.

Proton Therapy in the Treatment of Men with Breast Cancer.

Purpose: Male breast cancer treatment involves multimodality therapy, including radiation therapy; nevertheless, few men have received proton therapy (PT) for it. Further, heart disease is an established leading cause of death in men, and radiation therapy heart dose correlates with cardiac toxicity, highlighting the need for cardiac-sparing radiation techniques. Thus, we provide a descriptive analysis of PT in a male breast cancer cohort. Patients and Methods: Men who received PT for localized breast cancer between 2012 and 2022 were identified from a prospective database. Toxicities were prospectively recorded by using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Results: Five male patients were identified. All had estrogen receptor (ER)-positive, Her2neu-negative disease and received adjuvant endocrine therapy. One had genetic testing positive for BRCA2, one had a variant of unknown significance (VUS) in the APC gene, and one had a VUS in MSH2. Median age was 73 years (range, 41-80). Baseline comorbidities included obesity (n = 1), diabetes (n = 1), hypertension (n = 4), history of deep vein thrombosis (n = 1), personal history of myocardial infarction (n = 3; 1 with a pacemaker), and a history of lung cancer (n = 1). All received PT to the left chest wall and comprehensive regional lymphatics. One received passive-scattering PT, and 4 received pencil beam scanning. One patient received a boost to the mastectomy incision via electrons. Median heart dose was 1 GyRBE (range, 0-1.0), median 0.1-cm3 dose to the left anterior descending artery was 7.5 GyRBE (range, 0-14.2), and median follow-up was 2 years (range, 0.75-6.5); no patient experienced a new cardiac event, and all remain free from breast cancer recurrence and progression. Conclusion: In a small case series for a rare diagnosis, PT to the chest wall and regional lymphatics, including internal mammary nodes, resulted in low cardiac exposure, high local regional disease control rates, and minimal toxicity. Proton therapy should be considered for treating men with breast cancer to achieve cardiac sparing.

radioGWAS: link radiome to genome to discover driver genes with somatic mutations for heterogeneous tumor image phenotype in pancreatic cancer.

Addressing the significant level of variability exhibited by pancreatic cancer necessitates the adoption of a systems biology approach that integrates molecular data, biological properties of the tumors, and clinical features of the patients. In this study, a comprehensive multi-omics methodology was employed to examine a distinctive collection patient dataset containing rapid autopsy tumor and normal tissue samples as well as longitudinal imaging with a focus on pancreatic cancer. By performing a whole exome sequencing analysis on tumor and normal tissues to identify somatic gene variants and a radiomics feature analysis to tumor CT images, the genome-wide association approach established a connection between pancreatic cancer driver genes and relevant radiomics features, enabling a thorough and quantitative assessment of the heterogeneity of pancreatic tumors. The significant association between sets of genes and radiomics features revealed the involvement of genes in shaping tumor morphological heterogeneity. Some results of the association established a connection between the molecular level mechanism and their outcomes at the level of tumor structural heterogeneity. Because tumor structure and tumor structural heterogeneity are related to the patients' overall survival, patients who had pancreatic cancer driver gene mutations with an association to a certain radiomics feature have been observed to experience worse survival rates than cases without these somatic mutations. Furthermore, the outcome of the association analysis has revealed potential gene mutations and radiomics feature candidates that warrant further investigation in future research endeavors.

A high-resolution cone beam computed tomography (HRCBCT) reconstruction framework for CBCT-guided online adaptive therapy.

BACKGROUND: Kilo-voltage cone-beam computed tomography (CBCT) is a prevalent modality used for adaptive radiotherapy (ART) due to its compatibility with linear accelerators and ability to provide online imaging. However, the widely-used Feldkamp-Davis-Kress (FDK) reconstruction algorithm has several limitations, including potential streak aliasing artifacts and elevated noise levels. Iterative reconstruction (IR) techniques, such as total variation (TV) minimization, dictionary-based methods, and prior information-based methods, have emerged as viable solutions to address these limitations and improve the quality and applicability of CBCT in ART. PURPOSE: One of the primary challenges in IR-based techniques is finding the right balance between minimizing image noise and preserving image resolution. To overcome this challenge, we have developed a new reconstruction technique called high-resolution CBCT (HRCBCT) that specifically focuses on improving image resolution while reducing noise levels. METHODS: The HRCBCT reconstruction technique builds upon the conventional IR approach, incorporating three components: the data fidelity term, the resolution preservation term, and the regularization term. The data fidelity term ensures alignment between reconstructed values and measured projection data, while the resolution preservation term exploits the high resolution of the initial Feldkamp-Davis-Kress (FDK) algorithm. The regularization term mitigates noise during the IR process. To enhance convergence and resolution at each iterative stage, we applied Iterative Filtered Backprojection (IFBP) to the data fidelity minimization process. RESULTS: We evaluated the performance of the proposed HRCBCT algorithm using data from two physical phantoms and one head and neck patient. The HRCBCT algorithm outperformed all four different algorithms; FDK, Iterative Filtered Back Projection (IFBP), Compressed Sensing based Iterative Reconstruction (CSIR), and Prior Image Constrained Compressed Sensing (PICCS) methods in terms of resolution and noise reduction for all data sets. Line profiles across three line pairs of resolution revealed that the HRCBCT algorithm delivered the highest distinguishable line pairs compared to the other algorithms. Similarly, the Modulation Transfer Function (MTF) measurements, obtained from the tungsten wire insert on the CatPhan 600 physical phantom, showed a significant improvement with HRCBCT over traditional algorithms. CONCLUSION: The proposed HRCBCT algorithm offers a promising solution for enhancing CBCT image quality in adaptive radiotherapy settings. By addressing the challenges inherent in traditional IR methods, the algorithm delivers high-definition CBCT images with improved resolution and reduced noise throughout each iterative step. Implementing the HR CBCT algorithm could significantly impact the accuracy of treatment planning during online adaptive therapy.

Selecting Optimal Proton Pencil Beam Scanning Plan Parameters to Reduce Dose Discrepancy between Discrete Spot Plan and Continuous Scanning: A Proof-of-Concept Study.

Pencil beam scanning delivered with continuous scanning has several advantages over conventional discrete spot scanning. Such advantages include improved beam delivery efficiency and reduced beam delivery time. However, a move dose is delivered between consecutive spots with continuous scanning, and current treatment planning systems do not take this into account. Therefore, continuous scanning and discrete spot plans have an inherent dose discrepancy. Using the operating parameters of the state-of-the-art particle therapy system, we conducted a proof-of-concept study in which we systematically generated 28 plans for cubic targets with different combinations of plan parameters and simulated the dose discrepancies between continuous scanning and a planned one. A nomograph to guide the selection of plan parameters was developed to reduce the dose discrepancy. The effectiveness of the nomograph was evaluated with two clinical cases (one prostate and one liver). Plans with parameters guided by the nomograph decreased dose discrepancy than those used standard plan parameters. Specifically, the 2%/2 mm gamma passing rate increased from 96.3% to 100% for the prostate case and from 97.8% to 99.7% for the liver case. The CTV DVH root mean square error decreased from 2.2% to 0.2% for the prostate case and from 1.8% to 0.9% for the liver case. The decreased dose discrepancy may allow the relaxing of the delivery constraint for some cases, leading to greater benefits in continuous scanning. Further investigation is warranted.

Incidence of Rib Fracture following Treatment with Proton Therapy for Breast Cancer.

Purpose: To determine the rib fracture rate in a cohort of patients with breast cancer treated with proton therapy. Patient and Methods: From a prospective database, we identified 225 patients treated with proton therapy between 2012 and 2020 (223 women; 2 men). Clinical and dosimetric data were extracted, the cumulative incidence method assessed rib fracture rate, and Fine-Gray tests assessed prognostic significance of select variables. In-field rib fracture was defined as a fracture that occurred in a rib located within the 10% isodose line. Out-of-field rib fracture was defined as a fracture occurring in a rib location outside of the 10% isodose line. Results: Of the patients, 74% had left-sided breast cancer; 5%, bilateral; and 21%, right-sided. Dual-energy x-ray absorptiometry scans showed normality in 20%, osteopenia in 34%, and osteoporosis in 6% (test not performed in 40%). Additionally, 57% received an aromatase inhibitor. Target volumes were breast ± internal mammary nodes (IMNs) (16%), breast and comprehensive regional lymphatics (32%), chest wall ± IMNs (1%), and chest wall/comprehensive regional lymphatics (51%). Passive-scattered proton therapy was used for 41% of patients, 58% underwent pencil-beam scanning (PBS), and 1% underwent a combination (passive scattering/PBS), with 85% of patients receiving a boost. Median follow-up was 3.1 years, with 97% having >12-month follow-up. The 3-year cumulative in-field rib fracture incidence was 3.7%. Eight patients developed in-field rib fractures (1 symptomatic, 7 imaging identified) for a 0.4% symptomatic rib fracture rate. Median time from radiation completion to rib fracture identification was 1.8 years (fractures were identified within 2.2 years for 7 of 8 patients). No variables were associated with rib fracture on univariate analysis. Three fractures developed outside the radiation field (0.9% cumulative incidence of out-of-field rib fracture). Conclusion: In this series of patients with breast cancer treated with proton therapy, the 3-year rib fracture rates remain low (in-field 3.7%; symptomatic 0.4%). As in photon therapy, the asymptomatic rate may be underestimated owing to a lack of routine surveillance imaging. However, patients experiencing symptomatic rib fractures after proton therapy for breast cancer are rare.

Proton Therapy for Bilateral Breast Cancer Maximizes Normal-Tissue Sparing.

Purpose: Treatment for bilateral breast cancer with radiation therapy is technically challenging. We evaluated the clinical and dosimetric outcomes of a small series of patients with synchronous bilateral breast cancer, including a photon dosimetric comparison, to identify optimal treatment planning approaches. Materials and Methods: We reviewed a registry of patients (simultaneously) diagnosed with synchronous bilateral breast cancers who underwent postoperative definitive adjuvant proton therapy at our institution between 2012 and 2021. All patients were treated with double-scattered proton or pencil-beam scanning therapies. For comparison, intensity-modulated radiation therapy photon plans optimized for organ sparing and coverage were generated after treatment. Results: Six patients were included. The median patient age was 66 years; all were female with no history of breast cancer or radiation therapy. Two (33%) patients received breast/chest wall-only treatments, 1 (17%) required breast plus level I axillary treatment to one side and breast plus regional nodal irradiation (RNI) to the other, and 3 (50%) received bilateral breast/chest plus RNI; dosimetric results are reported for each group's median. Analysis showed clinical target coverage was comparable between proton and photon techniques (V95% of 96.4% with proton, 97.8% with photon). However, protons could deliver superior organ sparing at clinically relevant dose metrics for virtually all structures: a 6.7 Gy absolute reduction in the mean heart dose (7.5 Gy with photons to 0.7 Gy with protons), a 47% to 57% relative reduction in D0.1cm3 to coronary arteries, a 54% relative reduction in lung V20 Gy, and an absolute 7.6 Gy reduction to the brachial plexus. There was also greater esophagus and spinal cord sparing. The overall survival rate was 100% at 1.5 years of median follow-up (0.5-4.9), and all patients were free of disease. For toxicity, all patients had some form of acute side effects: 66% experienced grade 2 breast/chest pain or soreness; 100% had grade 2 radiation dermatitis or skin induration; 33% had grade 2 fatigue; and 17% had grade 2 esophagitis (per the Common Terminology Criteria for Adverse Events [CTCAE] version 5.0; US National Cancer Institute, Bethesda, Maryland). Subacute toxicity (within 6 months) was observed for 17% of patients with delayed onset of grade 3 dermatitis in the setting of preexisting lupus, 17% with a delayed surgical wound complication, and 17% with grade 2 soft tissue fibrosis. No grade 4 or 5 events were observed. Conclusions: Substantial dose reductions to multiple organs at risk while maintaining target coverage make proton the preferred modality for bilateral breast cancer treatment when available.

Radiation Therapy for Primary Adenoid Cystic Carcinoma of the Trachea: Photons, Protons, or Carbon.

Primary adenoid cystic carcinoma of the trachea (ACC-T) is an extremely rare cancer of the central bronchial system. It is usually associated with an excellent prognosis. Surgery is the standard treatment for resectable tumors, while radiation therapy is used for unresectable tumors or medically inoperable patients. Radiation therapy can be delivered with photons, protons, or carbon ion therapy. In this report, we review a case of unresectable ACC-T in a middle-aged female patient who was treated with radiation therapy and review the potential benefits of the different types of radiation therapy.

Technical note: Delivery benefit and dosimetric implication of synchrotron-based proton pencil beam scanning using continuous scanning mode.

BACKGROUND: Discrete spot scanning (DSS) is the commonly used method for proton pencil beam scanning (PBS). There is lack of data on the dose-driven continuous scanning (DDCS). PURPOSE: To investigate delivery benefits and dosimetric implications of DDCS versus DSS for PBS systems. METHODS: The irradiation duty factor, beam delivery time (BDT), and dose deviation were simulated for eight treatment plans in prostate, head and neck, liver, and lung, with both conventional fractionation and hypofractionation schemes. DDCS results were compared with those of DSS. RESULTS: The DDCS irradiation duty factor (range, 11%-41%) was appreciably improved compared to DSS delivery (range, 4%-14%), within which, hypofractionation schemes had greater improvement than conventional fractionation. With decreasing stop ratio constraints, the DDCS BDT reduction was greater, but dose deviation also increased. With stop ratio constraints of 2, 1, 0.5, and 0, DDCS BDT reduction reached to 6%, 10%, 12%, and 15%, respectively, and dose deviation reached to 0.6%, 1.7%, 3.0%, and 5.2% root mean square error in PTV DVH, respectively. The 3%/2-mm gamma passing rate was greater than 99% with stop ratio constraints of 2 and 1, and greater than 95% with a stop ratio of 0.5. When the stop ratio constraint was removed, five of the eight treatment plans had a 3%/2-mm gamma passing rate greater than 95%, and the other three plans had a 3%/2-mm gamma passing rate between 90% and 95%. CONCLUSIONS: The irradiation duty factor was considerably improved with DDCS. Smaller stop ratio constraints led to shorter BDTs, but with the cost of larger dose deviations. Our finding suggested that a stop ratio of 1 constraint seems to yield acceptable DDCS dose deviation.

A Geant4 shielding design for the first US carbon multi-ion hybrid synchrotron facility.

The Mayo Clinic Florida Integrated Oncology Building will be the home of the first spot-scanning only carbon/proton hybrid therapy system by Hitachi, Ltd. It will provide proton beams up to kinetic energies of 230 MeV and carbon beams up to 430 MeV n-1for clinical deployment. To provide adequate radiation protection, the Geant4 (v10.6) Monte Carlo toolkit was utilized to quantify the ambient dose equivalent at a 10 mm depth (H*(10)) for photons and neutrons. To perform accurate calculations of the ambient dose equivalent, three-dimensional computer-aided design files of the entire planned facility were imported into Geant4, as well as certain particle system components such as the bending magnets, fast Faraday cup, and gantry. Particle fluence was scored using 60 cm diameter spheres, which were strategically placed throughout areas of interests. Analytical calculations were performed as first-pass design checks. Major shielding slabs were optimized using Geant4 simulations iteratively, with more than 20 alternative designs evaluated within Geant4. The 430 MeV n-1carbon beams played the most significant role in concrete thickness Requirements. The primary wall thickness for the carbon fixed beam room is 4 meters. The presence of the proton gantry structure in the simulation caused the ambient dose equivalent to increase by around 67% at the maze entrance, but a decrease in the high energy beam transport corridor. All shielding primary and secondary goals for clinical operations were met per state regulation and national guidelines.

Binding of Licochalcone A to Whey Protein Enhancing Its Antioxidant Activity and Maintaining Its Antibacterial Activity.

Incorporating LA into whey protein by forming whey protein isolate-LA (WPI-LA) and polymerized whey protein-LA (PWP-LA) complexes is a good way to maintain its bioactivity and improve its functional performance within food matrices. Herein, we found that WPI and PWP were able to interact with LA as suggested by multi-spectroscopy, molecular docking, and molecular dynamics simulations. The interaction between whey protein and LA was a spontaneous non-covalent binding process, while PWP had a higher affinity for LA than WPI, resulting from its more negatively binding free energy with LA. Hydrogen bonds, van der Waals forces, and electrostatic interactions were responsible for WPI-LA interactions. Hydrophobic forces, van der Waals, and hydrogen bonds positively accounted for PWP-LA interactions. The antioxidant activity of LA was improved by complexation with whey proteins as identified by DPPH and ABTS. The antimicrobial efficiency of LA was partially screened by complexation with whey protein with MIC values increased by seven-fold compared to free LA but successfully recovered to its original efficiency upon isolating it from the complex. This work demonstrates the promising antioxidant and antibacterial activities of the whey protein-LA complex and provides a good candidate for developing a new class of natural functional ingredients for food systems.

Investigation of the impact of machine operating parameters on beam delivery time and its correlation with treatment plan characteristics for synchrotron-based proton pencil beam spot scanning system.

Purpose: To investigate the beam delivery time (BDT) reduction due to the improvement of machine parameters for Hitachi synchrotron-based proton PBS system. Methods: BDTs for representative treatment plans were calculated to quantitatively estimate the BDT improvement from our 2015 system at Mayo Clinic in Arizona to our system to be implemented in 2025 at Mayo Clinic in Florida, and to a hypothetical future system. To specifically assess how each incremental improvement in the operating parameters reduced the total BDT, for each plan, we simulated the BDT 10,368 times with various settings of the nine different operating parameters. The effect of each operating parameter on BDT reduction and its correlation with treatment plan characteristics were analyzed. The optimal number of multiple energy extraction (MEE) layers per spill for different systems was also investigated. Results: The median (range) decrease in BDT was 60% (56%-70%) from the 2015 to the 2025 system. The following incremental improvement in parameters of the 2015 system for the 2025 system played an important role in this decreased BDT: beam intensity (8 to 20 MU/s), recapture efficiency (50% to 80%), number of MEE layers per spill (4 to 8), scanning magnet preparation and verification time (1.9 to 0.95 msec), and MEE layer switch time (200 to 100 msec). Reducing the total spill change time and scanning magnet preparation and verification time from those of the 2025 system further reduced BDT in the hypothetical future system. 8 MEE layers per spill is optimal for a system with 50% recapture efficiency; 16 MEE layers per spill is optimal for a system with 80% recapture efficiency; and more than 16 MEE layers per spill is beneficial only for a system close to 100% recapture efficiency. Conclusions: We systematically studied the effect of each machine operating parameter on the reduction in total BDT and its correlation with treatment plan characteristics. Our findings will aid new and existing synchrotron-based proton beam therapy centers to make balanced decisions on BDT benefits vs. costs when considering machine upgrade or new system selection.