Proton Beam Therapy for Pancreatic Tumors: A Consensus Statement from the Particle Therapy Cooperative Group Gastrointestinal Subcommittee.

Objectives: Radiotherapy manages pancreatic cancer in various settings; however, the proximity of gastrointestinal (GI) luminal organs-at-risk (OAR) poses challenges to conventional radiotherapy. Proton beam therapy (PBT) may reduce toxicities compared to photon therapy. This consensus statement summarizes PBT's safe and optimal delivery for pancreatic tumors.

Self-organization of the hematopoietic vascular niche and emergent innate immunity on a chip.

Here, we present a bioengineering approach to emulate the human bone marrow in vitro. Our developmentally inspired method uses self-organization of human hematopoietic stem and progenitor cells and vascular endothelial cells cultured in a three-dimensional microphysiological system to create vascularized, perfusable tissue constructs that resemble the hematopoietic vascular niche of the human marrow. The microengineered niche is capable of multilineage hematopoiesis and can generate functionally mature human myeloid cells that can intravasate into perfused blood vessels, providing a means to model the mobilization of innate immune cells from the marrow.

Proton radiation boosts the efficacy of mesothelin-targeting chimeric antigen receptor T cell therapy in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) represents a challenge in oncology, with limited treatment options for advanced-stage patients. Chimeric antigen receptor T cell (CAR T) therapy targeting mesothelin (MSLN) shows promise, but challenges such as the hostile immunosuppressive tumor microenvironment (TME) hinder its efficacy. This study explores the synergistic potential of combining proton radiation therapy (RT) with MSLN-targeting CAR T therapy in a syngeneic PDAC model.

FLASH proton reirradiation, with or without hypofractionation, mitigates chronic toxicity in the normal murine intestine, skin, and bone.

Background And Purpose: The normal tissue sparing afforded by FLASH radiotherapy (RT) is being intensely investigated for potential clinical translation. Here, we studied the effects of FLASH proton RT (F-PRT) in the reirradiation setting, with or without hypofractionation. Chronic toxicities in three murine models of normal tissue toxicity including the intestine, skin, and bone were investigated.

Proton FLASH Radiotherapy Ameliorates Radiation-induced Salivary Gland Dysfunction and Oral Mucositis and Increases Survival in a Mouse Model of Head and Neck Cancer.

Head and neck cancer radiotherapy often damages salivary glands and oral mucosa, severely negatively impacting patients' quality of life. The ability of FLASH proton radiotherapy (F-PRT) to decrease normal tissue toxicity while maintaining tumor control compared with standard proton radiotherapy (S-PRT) has been previously demonstrated for several tissues. However, its potential in ameliorating radiation-induced salivary gland dysfunction and oral mucositis and controlling orthotopic head and neck tumor growth has not been reported.

FLASH Radiotherapy: What Can FLASH's Ultra High Dose Rate Offer to the Treatment of Patients With Sarcoma?

FLASH is an emerging treatment paradigm in radiotherapy (RT) that utilizes ultra-high dose rates (UHDR; >40 Gy)/s) of radiation delivery. Developing advances in technology support the delivery of UHDR using electron and proton systems, as well as some ion beam units (eg, carbon ions), while methods to achieve UHDR with photons are under investigation. The major advantage of FLASH RT is its ability to increase the therapeutic index for RT by shifting the dose response curve for normal tissue toxicity to higher doses.

FLASH Proton Radiation Therapy Mitigates Inflammatory and Fibrotic Pathways and Preserves Cardiac Function in a Preclinical Mouse Model of Radiation-Induced Heart Disease.

Purpose: Studies during the past 9 years suggest that delivering radiation at dose rates exceeding 40 Gy/s, known as "FLASH" radiation therapy, enhances the therapeutic index of radiation therapy (RT) by decreasing normal tissue damage while maintaining tumor response compared with conventional (or standard) RT. This study demonstrates the cardioprotective benefits of FLASH proton RT (F-PRT) compared with standard (conventional) proton RT (S-PRT), as evidenced by reduced acute and chronic cardiac toxicities.

Methods And Materials: Mice were imaged using cone beam computed tomography to precisely determine the heart's apex as the beam isocenter.

Unedited allogeneic iNKT cells show extended persistence in MHC-mismatched canine recipients.

Allogeneic invariant natural killer T cells (allo-iNKTs) induce clinical remission in patients with otherwise incurable cancers and COVID-19-related acute respiratory failure. However, their functionality is inconsistent among individuals, and they become rapidly undetectable after infusion, raising concerns over rejection and limited therapeutic potential. We validate a strategy to promote allo-iNKT persistence in dogs, an established large-animal model for novel cellular therapies.

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.

A phenomenological model of proton FLASH oxygen depletion effects depending on tissue vasculature and oxygen supply.

Introduction: Radiation-induced oxygen depletion in tissue is assumed as a contributor to the FLASH sparing effects. In this study, we simulated the heterogeneous oxygen depletion in the tissue surrounding the vessels and calculated the proton FLASH effective-dose-modifying factor (FEDMF), which could be used for biology-based treatment planning.

Methods: The dose and dose-weighted linear energy transfer (LET) of a small animal proton irradiator was simulated with Monte Carlo simulation.

Radiomic Phenotypes for Improving Early Prediction of Survival in Stage III Non-Small Cell Lung Cancer Adenocarcinoma after Chemoradiation.

We evaluate radiomic phenotypes derived from CT scans as early predictors of overall survival (OS) after chemoradiation in stage III primary lung adenocarcinoma. We retrospectively analyzed 110 thoracic CT scans acquired between April 2012-October 2018. Patients received a median radiation dose of 66.

Patient-derived organoids as a platform for modeling a patient's response to chemoradiotherapy in esophageal cancer.

3D patient-derived organoids (PDOs) have been utilized to evaluate potential therapies for patients with different cancers. However, the use of PDOs created from treatment-naive patient biopsies for prediction of clinical outcomes in patients with esophageal cancer has not yet been reported. Herein we describe a pilot prospective observational study with the goal of determining whether esophageal cancer PDOs created from treatment naive patients can model or predict clinical outcomes.

The current status of preclinical proton FLASH radiation and future directions.

We review the current status of proton FLASH experimental systems, including preclinical physical and biological results. Technological limitations on preclinical investigation of FLASH biological mechanisms and determination of clinically relevant parameters are discussed. A review of the biological data reveals no reproduced proton FLASH effect in vitro and a significant in vivo FLASH sparing effect of normal tissue toxicity observed with multiple proton FLASH irradiation systems.

Characterization of a high-resolution 2D transmission ion chamber for independent validation of proton pencil beam scanning of conventional and FLASH dose delivery.

Introduction: Ultra-high dose rate (FLASH) radiotherapy has become a popular research topic with the potential to reduce normal tissue toxicities without losing the benefit of tumor control. The development of FLASH proton pencil beam scanning (PBS) delivery requires accurate dosimetry despite high beam currents with correspondingly high ionization densities in the monitoring chamber. In this study, we characterized a newly designed high-resolution position sensing transmission ionization chamber with a purpose-built multichannel electrometer for both conventional and FLASH dose rate proton radiotherapy.

Current delivery limitations of proton PBS for FLASH.

Purpose: Proton Pencil Beam Scanning (PBS) is an attractive solution to realize the advantageous normal tissue sparing elucidated from FLASH high dose rates. The mechanics of PBS spot delivery will impose limitations on the effective field dose rate for PBS.

Methods: This study incorporates measurements from clinical and FLASH research beams on uniform single energy and the spread-out Bragg Peak PBS fields to extrapolate the PBS dose rate to high cyclotron beam currents 350, 500, and 800 nA.

Machine learning highlights the deficiency of conventional dosimetric constraints for prevention of high-grade radiation esophagitis in non-small cell lung cancer treated with chemoradiation.

Background And Purpose: Radiation esophagitis is a clinically important toxicity seen with treatment for locally-advanced non-small cell lung cancer. There is considerable disagreement among prior studies in identifying predictors of radiation esophagitis. We apply machine learning algorithms to identify factors contributing to the development of radiation esophagitis to uncover previously unidentified criteria and more robust dosimetric factors.

Design, Implementation, and in Vivo Validation of a Novel Proton FLASH Radiation Therapy System.

Purpose: Recent studies suggest that ultrahigh-dose-rate, "FLASH," electron radiation therapy (RT) decreases normal tissue damage while maintaining tumor response compared with conventional dose rate RT. Here, we describe a novel RT apparatus that delivers FLASH proton RT (PRT) using double scattered protons with computed tomography guidance and provide the first report of proton FLASH RT-mediated normal tissue radioprotection.

Methods And Materials: Absolute dose was measured at multiple depths in solid water and validated against an absolute integral charge measurement using a Faraday cup.

Building more accurate decision trees with the additive tree.

The expansion of machine learning to high-stakes application domains such as medicine, finance, and criminal justice, where making informed decisions requires clear understanding of the model, has increased the interest in interpretable machine learning. The widely used Classification and Regression Trees (CART) have played a major role in health sciences, due to their simple and intuitive explanation of predictions. Ensemble methods like gradient boosting can improve the accuracy of decision trees, but at the expense of the interpretability of the generated model.

Design and commissioning of an image-guided small animal radiation platform and quality assurance protocol for integrated proton and x-ray radiobiology research.

Small animal x-ray irradiation platforms are expanding the capabilities and future pathways for radiobiology research. Meanwhile, proton radiotherapy is transitioning to a standard treatment modality in the clinician's precision radiotherapy toolbox, highlighting a gap between state-of-the-art clinical radiotherapy and small animal radiobiology research. Comparative research of the biological differences between proton and x-ray beams could benefit from an integrated small animal irradiation system for in vivo experiments and corresponding quality assurance (QA) protocols to ensure rigor and reproducibility.

Predicting radiation pneumonitis in locally advanced stage II-III non-small cell lung cancer using machine learning.

Background And Purpose: Radiation pneumonitis (RP) is a radiotherapy dose-limiting toxicity for locally advanced non-small cell lung cancer (LA-NSCLC). Prior studies have proposed relevant dosimetric constraints to limit this toxicity. Using machine learning algorithms, we performed analyses of contributing factors in the development of RP to uncover previously unidentified criteria and elucidate the relative importance of individual factors.

Dermatopathology effects of simulated solar particle event radiation exposure in the porcine model.

The space environment exposes astronauts to risks of acute and chronic exposure to ionizing radiation. Of particular concern is possible exposure to ionizing radiation from a solar particle event (SPE). During an SPE, magnetic disturbances in specific regions of the Sun result in the release of intense bursts of ionizing radiation, primarily consisting of protons that have a highly variable energy spectrum.

Effect of electron radiation on vasomotor function of the left anterior descending coronary artery.

The left anterior descending (LAD, interventricular) coronary artery provides the blood supply to the mid-region of the heart and is a major site of vessel stenosis. Changes in LAD function can have major effects on heart function. In this report, we examined the effect of electron simulated solar particle event (eSPE) radiation on LAD function in a porcine animal model.