Single Irradiation Research Articles

Identifying Common Topics in Patient Portal Messages with Unsupervised Natural Language Processing.

Patient portal messaging is an increasingly important form of communication between patients and medical providers. This has become particularly relevant in oncology, where patients undergo intense longitudinal treatments that require frequent communication regarding symptoms, appointments, and diagnostic results. The rise in the volume of these messages has significantly increased the workload of medical providers and consequent physician burn-out. Natural language processing (NLP), particularly transformer-based models, may offer an automated approach to characterize the content of patient messages and improve message triage and routing. In this study, we employed a state-of-the-art language model (Bidirectional Encoder Representations from Transformers; BERT) to identify data-derived categories of representative topics from real-world data thereby providing basic information to build an appropriate routing system. Patient-generated portal messages sent to a messaging pool for a single institution radiation oncology department from 2014 to 2023 were extracted. BERTopic, an NLP-based topic modeling technique based on BERT was optimized for topic modeling of patient messages. Uniform Manifold Approximation and Projection (UMAP) was used to reduce dimensionality and visualize topic relationships across messages. The BERTopic-identified topic categories were subsequently labeled manually by one of the physician investigators. Differences of number of messages over time were assessed using t-tests. A total of 47,492 messages were retrieved. The average number of messages per month from a single patient ranged from 1 to 18 (median 1.67, interquartile range 1.0-2.4). The total volume of patient messages showed a ten-fold increase over the study period, with 101 messages per month sent in 2014 and 999 messages per month in 2022 (p<0.001). BERTopic initially identified 35 topics whose relationships and degrees of overlap were visualized by UMAP. Due to physician-identified similarities, these topics were reduced into 13 categories. The most frequent topic category was messages about laboratory tests or imaging studies: 24.3%, followed by messages expressing appreciation: 18.9%, scheduling discussions: 15.6%, symptom-related messages: 11%, and treatment-related messages: 10.7%. Patient portal messages sent to a single institution radiation oncology department have increased dramatically in volume since implementation, corresponding to a broader national trend. NLP successfully identified common subject themes across patient messages, many of which are related to scheduling. This presents potential opportunities to apply NLP to automate message routing in the future.

TFAM Modulates Cardiomyocytes Pyroptosis Induced by Ionizing Radiation through mtDNA/TLR9/NF-kB Pathway

Mitochondrial transcription factor A (TFAM) is a pivotal factor for regulating mitochondrial DNA (mtDNA) replication, transcription and biogenesis. Previous studies have reported that cytosolic mtDNA stress can lead to cardiomyocytes pyroptosis, which is characterized by inflammasome formation. In this study, we attempted to investigate the mechanism of TFAM regulate cardiomyocytes pyroptosis induced by ionizing radiation. The peripheral blood serum of patients with esophageal cancer before and after definitive chemoradiotherapy was collected for Luminex multiplex cytokine assays. C57BL/6 mice were irradiated with the whole heart using small animal radiation research platform (SARRP) to construct a radiation-induced myocardial damage (RIMD) mouse model, and the ventricular function was evaluated using 9.4T Bruker magnetic resonance (MR) scanner. The function changes of cardiomyocytes exposed to radiation were observed in vitro and in vivo after knocking out GSDMD. Furthermore, the changes of mitochondrial function, the levels of cytosolic mtDNA, and the protein levels of NF-kB and pyroptosis pathway in irradiated cardiomyocytes were analyzed by knockdown and overexpression of TFAM in vitro and in vivo. By multifactor cytokine assays we found that pyroptosis related IL-1β and IL-18 were significantly increased in patients with high mean heart dose (MHD) after radiotherapy, while those with low MHD were not significantly increased after radiotherapy. Next, we successfully constructed the RIMD mouse model using a single heart irradiation of 20 Gy. We found that the gene expression of pyroptosis pathway was significantly up-regulated after cardiac irradiation by myocardial tissue transcriptomic sequencing. Compared with wild-type (WT) mice, cardiac systolic function of Gsdmd-/- mice was significantly improved at 1, 2, 6, 12, and 24 weeks after heart irradiation. In vitro, we also demonstrated increased viability of irradiated cardiomyocytes by knocking out GSDMD. In vitro and in vivo experiments confirmed the expression of TFAM decreased after radiation. By overexpression of TFAM, we found that irradiated cardiomyocytes showed improved mitochondrial function, decreased release of mtDNA into cytoplasm through mitochondrial permeability transition pores (mPTPs), decreased binding of cytosolic mtDNA to TLR9, and decreased expression of NF-kB and pyroptosis pathway proteins. Dual luciferase gene reporter assays and Chromatin immunoprecipitation (CHIP) assay confirmed that p65 could bind the NLRP3 promoter region. In addition, we found that ventricular function deteriorated and improved in mice with knockdown and overexpression of TFAM through adeno-associated virus serotype 9 (AAV9), respectively. Our study indicated that TFAM regulate irradiated cardiomyocytes pyroptosis through mtDNA/TLR9/NF-kB pathway. We provide a novel mechanism of RIMD, revealing an underappreciated intervention target for RIMD.

Dosimetric Validation of 3D-Printed Bolus at Different Printing Infill Percentage in VMAT Plan

The 3D printed bolus technology is rapidly evolving in external beam radiotherapy and printing parameters can have a significant impact on absorbed dose. In this study, a novel 3D printed bolus was designed to evaluate the time and material cost effects, dosimetry differences, and surface dose modulation capabilities in the volumetric-modulated arc therapy (VMAT) plan at different print filling percentages. A hollow-type bolus, the middle 2.36 mm of 5 mm thickness infilled with different ratio, was designed and printed with polylactic acid (PLA). The ratio of printed material was defined by the infill percentage parameter ranging from 10% to 90%. For each bolus, two treatment plans were designed with AAA algorithm, considering the real computed tomography (CT) scan of the 3D printed bolus and modeling the 3D printed bolus as a virtual bolus structure. Percentage depth dose (PDD) profiles were calculated to build up the mapping equivalent CT value in treatment plan system (TPS). Measurement dose was performed by radiographic films. The PDD profiles were then compared between measured and calculated. A simulation VMAT treatment plan with planning target volume (PTV) close to the body surface was designed on a water-equivalent phantom, and the modulation capabilities of epidermal dose under different filling percentage was compared. Compared with 100% percent infill 3D printed bolus, The maximum printing time could be reduced by 47.8% and material consumption could be reduced by 42.5%. The surface dose at single field irradiation can reach 69.6% to 85.8% of the maximum dose in different filling boluses. The PDD measurement and mapping equivalent CT calculation deviation was less than 3% when the infill percentage of the middle region is greater than 30%. The dose distribution of the VMAT plan is satisfying for infill percentages greater than 30%. Using the 3D printing technology is possible to modulate the amount of shift of the build-up region by tuning the infill percentage of the 3D printed bolus. Patients could undergo CT simulation without bolus. Appropriate bolus could be selected according to the location of the PTV region and dose requirement.

Financial Toxicity and Patient Experience Outcomes on a Multi-Institutional Phase I Single Fraction Stereotactic Partial Breast Irradiation Protocol for Early-Stage Breast Cancer

Given the demonstrated financial toxicity (FT) of radiation treatment on breast cancer patients shown in both conventional and our recent 5 fraction stereotactic APBI (S-PBI) study, we assessed the FT, as well as patient-reported utility, quality-of-life and patient experience measures, on patients treated in our phase I single fraction S-PBI trial. A phase I single fraction dose escalation trial of S-PBI for early-stage breast cancer was conducted. Women with in-situ or stage I-II (AJCC 6) invasive breast cancer following breast conserving surgery were treated with S-PBI in 1 fraction to a total dose of 22.5, 26.5 or 30 Gy (Clinical trials.gov ID NCT02685332). At one month follow-up, patients were asked to complete our novel "Patient Perspective Cost and Convenience of Care Questionnaire". Patients also completed the EQ-5D-5L, including the visual analogue scale of overall health (VAS), at enrollment, 6, 12-, 24-, 36-, and 48-month follow-up. Of 29 patients enrolled and treated, questionnaire data was available for all patients. Our trial encompassed a wide range of annual household incomes, education, and employment status. Overall, 44.8% (n = 13/29) of patients reported that radiation treatment presented a financial burden. Interestingly, no demographic information, such as patient race, marital status, education, household income, or employment during treatment predicted perceived FT. Patients reporting FT trended towards younger age (median 64 vs 70.5) and having a cancer related co-pay similar to our 5 fraction S-PBI FT trial; however, due to the small size of this study, this did not reach significance (p = 0.24 and 0.10, respectively). VAS and utility scores were calculated per the EQ-5D-5L and remained unchanged from baseline through 4-year follow-up. Likewise, there was no difference in the utility or VAS between patients who reported FT and those who did not. Interestingly, while patient reported cosmesis was similar for all patients at enrollment, patients who reported FT noted significantly worse cosmesis scores (fair/poor vs good/excellent) at 6 month and 2-year follow-ups (p = 0.01 and 0.04, respectively). Finally, patients were surveyed on treatment related disruption to their daily activities and enjoyment of life. The median values were 0 (scale 0-10, with 0 being no disruption) regardless of perceived FT. Patients were also uniformly satisfied with treatment time with a median score of 10 (scale 0-10, 10 being most satisfied). Here, we show that despite using SPBI in a single fraction, nearly half of the patients treated still reported FT of treatment. Importantly, single fraction S-PBI has no negative impact on patient VAS or utility scores, and all patients were uniformly satisfied with treatment time without significant disruption to their life.

High Risk Prognostic Factors Predictive of Outcome Following Stereotactic Body Radiation Therapy (SBRT) for Early-Stage Lung Cancer

High risk prognostic factors for outcomes following SBRT for early-stage lung cancer per SWOG/NRG 1914 include: tumor size > 2cm; moderately/poorly/undifferentiated histology; or high metabolic activity on PET/CT defined as SUV > 6.2. The purpose of this IRB approved retrospective study is to assess outcome for stage I lung cancer and to validate SWOG risk stratification in a single community-based radiation department. A total of 132 patients with 139 tumors treated with SBRT between 2014 and 2019 were stratified by SWOG risk group (high vs. low). To assess differences by risk group in estimated overall survival (OS) at the patient level, as well as Freedom from Local Failure (FFLF), Freedom from Regional Failure (FFRF) and Freedom from Distant Failure (FFDF) at the tumor level, Kaplan-Meier methodology and Cox proportional hazards (PH) modeling for correlated data were used. Statistical significance was concluded at the 0.05 level. Median follow-up for the entire group is 56 months. 77% of patients had high risk tumors. The median patient age was 75 years with 57% female. Patients with high-risk tumors were older (p = 0.023) compared to patients with low-risk tumors. At the tumor level, high risk tumors were more likely to have biopsies performed (91% vs 57% p = 0.002) and more likely to experience regional failure (28% vs 7% p = 0.005). High risk tumors were more likely to experience local failure (8% vs 0% p = NS) and distant failure (27% vs 14% p = NS). Median survival was 49 months for the whole group (46.0 months high risk, 65.1 months low risk). Actuarial OS at 5 years is 38% (35% high risk, 51% low risk). Actuarial FFLF at 5 years is 94% (93% high risk, 100% low risk). Actuarial FFRF at 5 years is 77% (72% high risk, 93% low risk). Actuarial FFDF at 5 years is 74% (70% high risk, 88% low risk). Cox PH models revealed no statistically significant differences in FFRF by risk group (p = 0.08). Excellent local control but higher regional and distant failure was demonstrated for high-risk lung tumors as defined by SWOG/NRG 1914. Clinically important decrement in outcomes were consistently noted for high-risk tumors in this sample which did not demonstrate statistical significance due to lack of events and statistical power. However, our data supports the prognostic importance of tumor size/grade and SUV for identifying patients at high risk. Further validation with larger sample sizes would contribute to our knowledge regarding risk stratification for early-stage lung cancer treated with SBRT.

Predictors of Long-Term Survival in Patients Treated for Oligometastases

The purpose of this work is to report the long-term outcomes of patients with oligometastases treated with curative intent radiotherapy in the context of the recently developed ESTRO EORTC classification schema. This retrospective, single institution study consists of consecutive adult patients with oligometastases from solid tumor malignancy referred to a single high volume radiation oncologist. Oligometastases were defined as 5 or fewer extracranial or intracranial metastatic lesions where all sites of active disease are amenable to treatment. Patients with a history of distant metastases requiring treatment of the primary tumor ± regional lymph nodes were included. Radical local therapies utilized included stereotactic radiotherapy (53% of patients, median dose 27 Gy in 3 fractions), intensity modulated radiotherapy (64% of patients; median dose 50 Gy in 15 fractions), surgery and/or ablation. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Predictors of survival were assessed using log-rank test for categorical variables and Cox regression for continuous variables for univariable analysis and Cox multivariable analyses. The study population consists of 130 patients with 207 treated distant metastases referred to radiation oncology between 1/2014 and 12/2021. Key patient characteristics include median age 71, median pre-radiation albumin 3.7 g/dl, 72% ECOG 0-1 performance status, 35% lung primary, 12% prostate primary, median of 1 distant metastasis treated, 31% bone metastases, 30% brain metastases, 47% required treatment to primary tumor ± regional lymph nodes and 71% received systemic therapy after radiation. The most frequent ESTRO EORTC oligometastatic groups were synchronous oligometastases (40%) and metachronous oligorecurrence (29%). At a median follow-up of 28.8 months (IQR 16.0 to 56.3 months), the median overall survival is 37.9 months with a 4-year overall survival of 41.1%. The median progression-free survival was 12.3 months with a 4-year progression-free survival of 22.6%. On multivariable analysis, the strongest predictors of overall survival are age (HR 1.05 [1.02-1.08]; CI: 95%; p<0.001), ECOG performance status (HR 1.69 [1.15-2.47]; CI: 95%; p = 0.007), primary prostate, breast or kidney tumor (HR 2.79 [1.29-6.03]; CI: 95%; p = 0.009) and pre-radiation serum albumin (HR 0.55 [0.35-0.87]; CI: 95%; p = 0.01). The strongest predictors of progression free survival on multivariable analysis are albumin (HR 0.59 [0.39-0.88]; CI: 95%; p = 0.009) and primary prostate, breast or kidney tumor (HR 1.90 [1.06-3.38]; CI: 95%; p = 0.03). Long-term overall survival is not uncommon after radical treatment for oligometastases. The ESTRO EORTC classification provides an enriched nomenclature for oligometastases but is not independently predictive of survival.

Clinical Trials of Carbon Ion Radiotherapy for Early-Stage Breast Cancer

Our institute conducted a clinical trial of curative partial breast irradiation using carbon ion radiotherapy (CIRT) to patients with stage 0 and I breast cancer since 2013. The purpose of this report is to evaluate treatment outcomes up to now. To date, we have conducted three clinical trials and one advanced medical treatment (NIRS 9404 Comprehensive Research). The first study (UMIN000010848: commonly known as Breast I trial) was 4-split irradiation for stage I low-risk patients aged 60 years or older, and the next clinical study (UMIN000029478: commonly known as Breast II trial) was for Tis-1N0M0 cases of 2 cm or less. On the other hand, 4-split irradiation using standard adjuvant drug therapy according to risk combined with whole breast irradiation by X-ray, the latest clinical trial (UMIN000046859: commonly known as Breast III trial) is a single irradiation for Tis-1N0M0 patients aged 50 years or older. be. In each phase I, the dose increase test was performed, and in phase II, treatment was performed with the recommended dose determined in phase I. Advanced medical care was provided in parallel with breast I for stage I breast cancer that was difficult or rejected to participate in breast I trial. By January 2023, 60 cases were enrolled. A total of 19 were enrolled In Breast I, 7 in Phase I, 12 in Phase II of the recommended dose of 60.0 Gy (RBE). A total of 14 were enrolled in the 9404 Comprehensive Research. A total of 17 were enrolled In Breast II, 5 cases in Phase I, 12 cases in Phase II of recommended dose 60.0 Gy (RBE). A total of 10 were enrolled in Breast III, 6 cases in Phase I, and 4 in Phase II of recommended dose 50.0 Gy (RBE). As acute adverse events, grade 2 of acute radiation dermatitis were observed in 1 case, grade 1 of acute radiation dermatitis was observed in 31 cases, and grade 1 of mastitis was observed in 6 cases. As a late adverse event, grade 3 of pneumonia of unknown causality were observed in one case, but there were no other problematic adverse events, and breast cosmetic outcome was excellent in all cases. Tumor disappearance after CIRT took 3 to 24 months. Local recurrence and axillary lymph node metastasis were observed in one high-risk case of advanced medical treatment who refused any other therapy. Two cases had ipsilateral intramammary metachronous breast cancer with different subtypes. To date, no other recurrences or metastases have been observed. CIRT for early-stage breast cancer is expected to be effective with mild adverse events, and it is considered meaningful to continue research.

A Simulation-Based Approach for Strategic Evaluation of Resource Allocation for Improving Spatial Access to Radiation Oncology

Access to radiation therapy is essential to oncologic care. Prior studies have examined geographic distribution of radiation oncologists and centers but with methodologies that fail to account for patient movement across artificially constructed boundaries. This analysis utilizes an approach agnostic to geographic boundaries as well as a mathematical metric to assess the equality of access to care and quantify the impact additional resource allocation would have on a geographic area. Government databases were utilized to collect information on supply of radiation oncologists and population over 65 years old as a surrogate for demand. Addresses were geocoded to create coordinates for spatial analysis. US Census Centers of Population files were used to assign population data to spatial coordinates. Isochrone lines for driving time around population centers were generated using an internet road maps programming interface. Enhanced two-step floating catchment area (E2SFCA) analysis was performed with catchment area defined as a 120-minute drive from the population centers. A distance decay factor was applied. Spatial access ratios (SPARs), defined as the ratio of a given county's access to care against the mean across all counties, were calculated for each of the 3143 US counties, where a value <1 represents underserved and >1 represents overserved areas. A Gini coefficient was calculated to create a value representing spatial access equality (SPAE) for the current geographic distribution of supply and demand across the US. The incremental impact on SPAE was determined by iteratively simulating the addition of a single radiation oncologist in each of the 3143 US counties, and subsequently used to quantifiably rank areas by magnitude and direction of impact. Olmsted County, MN and the surrounding counties represent 8 of the 10 most overserved in the US (SPAR: 4.03 - 5.84). There are 1713 underserved counties with SPARs <1 and 130 counties with a SPAR of 0. Thomas County, KS would have greatest benefit on SPAE from the addition of a single radiation oncologist as it would introduce access to numerous neighboring underserved counties. Conversely, introduction of a single radiation oncologist negatively impacted SPAE in 173 of the previously underserved counties by shifting SPAR to overserved without significant positive effect on neighboring counties due to having a small population and isolated location. E2SFCA and SPAE provide a method for evaluating spatial access and a mathematical framework for assessing areas with the greatest potential benefit from new resource allocation. In some instances, resource allocation to a previously underserved area paradoxically has a negative impact on equal access to care. Better solutions such as travel/lodging programs and appropriate hypofractionation would do more to improve issues of access inequality for these areas.

Hippocampal Sparing Whole Brain Radiation Therapy: 2 Arc Coplanar and 4 Arc Noncoplanar Planning Comparison

Whole brain radiation therapy (WBRT) has been shown to provide palliation but with negative neurocognitive effects associated with radiation-induced damage to the hippocampus. Sparing of the hippocampus has been shown to reduce the risk of neurocognitive deficit. Hippocampal sparing WBRT plan optimization is commonly done using 2 arc coplanar technique. The purpose of this work is to show that 4 arc noncoplanar plans will improve hippocampal sparing without compromising PTV coverage. Retrospective WBRT with hippocampal sparing using 2 arc coplanar and 4 arc noncoplanar VMAT technique were done on 10 patients previously treated for intracranial lesions. CT and MRI fused images were used to delineate the whole brain and hippocampus. Strictly following RTOG 0933 atlas guidelines, the hippocampus was manually delineated by a single Radiation Oncologist. Plans with prescription dose of 30 Gy in 10 fractions were generated using the 2 techniques. The 4 arc noncoplanar plan included 2 partial field arcs with couch angle at 90 degrees and 2 coplanar arcs. The 2 noncoplanar partial arcs consisted of a clockwise arc and a counterclockwise arc with gantry angles between 5 and 179 degrees. Lens were kept to < 7 Gy and pituitary gland to < 30 Gy. Dosimetric parameters from both techniques were compared by paired t-test. Radiation dose to the hippocampus was significantly reduced using 4 arc noncoplanar plan when compared to 2 arc coplanar plan. While hippocampus D100% were similar (7.25 Gy vs 7.32 Gy, p = 0.557), the mean dose (9.46 Gy vs 9.87 Gy, p = 0.003) and D0.03cc (12.48 Gy vs 12.94 Gy, p < 0.001) were significantly reduced with 4 arc noncoplanar plans. Whole brain PTV coverage remained at V100% = 95% for both techniques. However, the 4 arc noncoplanar plans showed significantly improved D2% (32.56 Gy vs 32.97 Gy, P = 0.003), D98% (28.11 Gy vs 27.91 Gy, P = 0.01), and homogeneity index (0.141 vs 0.159, P < 0.001). The 4 arc noncoplanar plans improved hippocampal sparing without compromising PTV coverage or compromise to other nearby organs at risk.

Combination of irinotecan silicasome nanoparticles with radiation therapy sensitizes immunotherapy by modulating the activation of the cGAS/STING pathway for colorectal cancer

Our previous clinical trial (Identifier: NCT02605265) revealed that addition of irinotecan (IRIN) to neoadjuvant chemoradiotherapy for rectal cancer could improve the curative effect. However, the adverse effects caused by IRIN limited the wide application of IRIN chemoradiotherapy. This study aimed to explore the mechanism under the synergistic effects of IRIN plus radiation therapy in colorectal cancer (CRC) cells and optimization of IRIN delivery via a silicasome nanocarrier in vivo. Our results revealed that compared with single IRIN or radiation treatment, IRIN combined with radiation therapy remarkably activated the intracellular cGAS/STING pathway, and promoted the expression levels of major histocompatibility complex class I (MHC-I) and programmed death ligand 1 (PD-L1). Further, a silicasome (mesoporous silica nanoparticle coated with lipid bilayer) nanocarrier was utilized to improve the delivery of IRIN with enhanced efficacy and reduced side effects. In the MC38 CRC syngeneic tumor model, IRIN silicasome combined with radiation therapy demonstrated a greater antitumor efficacy than free IRIN plus radiation therapy. Flow cytometry showed the increased number of CD4+ T cells, CD8+ T cells, and dendritic cells (DCs) in tumor in the IRIN silicasome plus radiation group. The immunofluorescence staining further confirmed the activated immune microenvironment with the elevated interferon-γ (IFN-γ) deposition. Besides, the antitumor effect of IRIN silicasome plus radiation therapy was synergistically enhanced by anti-PD-1 immunotherapy. These findings indicated that the combination of IRIN silicasome with radiation therapy could sensitize immunotherapy by manipulating the cGAS/STING pathway serving as a new strategy for CRC treatment.

Diamond detectors for dose and instantaneous dose-rate measurements for ultra-high dose-rate scanned helium ion beams.

The possible emergence of the FLASH effect-the sparing of normal tissue while maintaining tumor control-after irradiations at dose-rates exceeding several tens of Gy per second, has recently spurred a surge of studies attempting to characterize and rationalize the phenomenon. Investigating and reporting the dose and instantaneous dose-rate of ultra-high dose-rate (UHDR) particle radiotherapy beams is crucial for understanding and assessing the FLASH effect, towards pre-clinical application and quality assurance programs. The purpose of the present work is to investigate a novel diamond-based detector system for dose and instantaneous dose-rate measurements in UHDR particle beams. Two types of diamond detectors, a microDiamond (PTW 60019) and a diamond detector prototype specifically designed for operation in UHDR beams (flashDiamond), and two different readout electronic chains, were investigated for absorbed dose and instantaneous dose-rate measurements. The detectors were irradiated with a helium beam of 145.7 MeV/u under conventional and UHDR delivery. Dose-rate delivery records by the monitoring ionization chamber and diamond detectors were studied for single spot irradiations. Dose linearity at 5cm depth and in-depth dose response from 2 to 16cm were investigated for both measurement chains and both detectors in a water tank. Measurements with cylindrical and plane-parallel ionization chambers as well as Monte-Carlo simulations were performed for comparisons. Diamond detectors allowed for recording the temporal structure of the beam, in good agreement with the one obtained by the monitoring ionization chamber. A better time resolution of the order of few μs was observed as compared to the approximately 50 μs of the monitoring ionization chamber. Both diamonds detectors show an excellent linearity response in both delivery modalities. Dose values derived by integrating the measured instantaneous dose-rates are in very good agreement with the ones obtained by the standard electrometer readings. Bragg peak curves confirmed the consistency of the charge measurements by the two systems. The proposed novel dosimetric system allows for a detailed investigation of the temporal evolution of UHDR beams. As a result, reliable and accurate determinations of dose and instantaneous dose-rate are possible, both required for a comprehensive characterization of UHDR beams and relevant for FLASH effect assessment in clinical treatments.

Flash-Thermal Shock Synthesis of High-Entropy Alloys Toward High-Performance Water Splitting.

High-entropy alloys (HEAs) provide unprecedented physicochemical properties over unary nanoparticles (NPs). According to the conventional alloying guideline (Hume-Rothery rule), however, only size-and-structure similar elements can be mixed, limiting the possible combinations of alloying elements. Recently, it has been reported that based on carbon thermal shocks (CTS) in a vacuum atmosphere at high temperature, ultrafast heating/cooling rates and high-entropy environment play a critical role in the synthesis of HEAs, ruling out the possibility of phase separation. Since the CTS requires conducting supports, the Joule-heating efficiencies rely on the carbon qualities, featuring difficulties in uniform heating along the large area. This work proposes a photo-thermal approach as an alternative and innovative synthetic method that is compatible with ambient air, large-area, remote process, and free of materials selection. Single flash irradiation on carbon nanofibers induced momentary high-temperature annealing (>1800°C within 20ms duration, and ramping/cooling rates >104 Ks-1 ) to successfully decorate HEA NPs up to nine elements with excellent compatibility for large-scale synthesis (6.0 × 6.0 cm2 of carbon nanofiber paper). To demonstrate their feasibility toward applications, senary HEA NPs (PtIrFeNiCoCe) are designed and screened, showing high activity (ηoverall = 777mV) and excellent stability (>5000 cycles) at the water splitting, including hydrogen evolution reactions and oxygen evolution reactions.

Systematics and biogeography of snakes of the genus (Boa) in the Lesser Antilles

The genus Boa is represented in the Lesser Antilles by a range of fossil, recently extinct, and extant formsoccupying adjacent island banks in the center of the archipelago. Our multigene molecular phylogeny indicates reciprocal monophyly for these extant forms, and colonization from South America rather than Central America. The timing of the colonization of the Lesser Antilles by this genus indicates a late Miocene or Pliocene event, which is earlier than the Pleistocene event suggested for the Corallus treeboas, which are also represented by two extant nominal species. The compact distribution of Boa on adjacent island banks suggests a single colonization and radiation, but this cannot be tested due to widespread extinction of boas across the island banks.

Blue and green light responsive caged glutamate

Glutamate (Glu) is an excitatory neurotransmitter that plays a critical role in memory. Brain mapping activities of such pathways relied heavily on the ability to release Glu with spatiotemporal precision. Several photo-protecting groups (PPGs), referred to as photocages or cages, were designed to accomplish the release of Glu upon irradiation. Previously reported Glu cages responded to UV upon irradiation with single photons, which limited their use in vivo experiments due to cytotoxicity. Other caged designs suffered from lower quantum efficiency (QE) of release necessitating higher concentrations and/or longer photoirradiation times. There have been limited examples of cages that respond to visible light with single photon irradiation. Herein, we report the efficient preparation of 11 caged Glu examples that respond to two visible wavelengths, 467 nm (thiocoumarin based) and 515–540 nm (BODIPY based). The kinetics of photo-uncaging were studied for all caged designs, and we report all quantum efficiencies, i.e., quantum yields (Φ), that ranged from 0.0001 to 0.65. Two of the BODIPY cages are reported here for the first time, and one, Me-BODIPY-Br-Glu, shows the most efficient Glu release with a QE of 0.65. Similar caged designs can be extended to the inhibitory neurotransmitter, GABA. This would enable the use of two visible wavelengths to modulate the release of excitatory and inhibitory neurotransmitters upon demand via optical control.

A methodology for measuring heat transfer coefficient and self-similarity of thermal regulation in microvascular material systems

Fluid transport through microvascular networks—a hallmark for homeostasis in living systems—has transcended to engineered materials, primarily made possible because of modern manufacturing advancements. Vascular-enabled multifunctionality, including thermal regulation and self-healing, holds great potential for extending the lifetime of structural materials and expanding the operational envelope. Prior studies on vascular-based active cooling use a “combined” heat transfer coefficient (HTC): a single parameter lumps convection and radiation effects. Although the resulting mathematical models are linear—an attractive feature for computational modeling, the combined coefficient approach may not be accurate or even applicable if the operating temperature is unknown, which is the case with many thermal regulation applications (e.g., space probes). In this paper, we illustrate the remarked limitations of the lumped approach and advocate the need to use a decoupled HTC by splitting convective and radiative heat transfer modes. We show the broad applicability of the proposed method by applying it to three material systems: glass and carbon fiber-reinforced polymer composites and an additive manufactured metal. We show, using numerical simulations, the differences in the predictions from the decoupled approach with that of the combined HTC; these differences are prominent at higher heat fluxes. Also, the decoupling has enabled us to establish a scaling law that allows transferring of solutions fields across material systems, strengthening further the validity and utility of our approach. This work's significance is two-fold. First, the research is fundamental, providing accurate measurement protocols for critical model parameters. Second, this work facilitates the development of mathematical models for vascular-based thermal regulation that are predictive even for hostile environments (which are often difficult to realize in laboratories), such as outer space.

Irradiation Affects Adipose-Derived Stem Cells and Wound Healing Depending on Radiation Dose and Frequency.

Radiation therapies are often associated with permanent devitalization in the surrounding tissue. The authors hypothesized that stem cells are damaged depending on each irradiation dose and frequency of fractionated radiotherapies, which results in impaired tissue function, including wound-healing capacity. Susceptibility of human adipose-derived stem cells (ASCs) to a single irradiation (0 to 10 Gy) was assessed in vitro. In vivo chronic radiation effects were also assessed on mouse dorsal skin ( n = 4 to 5) for 6 months after a total of 40 Gy irradiation (0 Gy as control) using 1 of 3 fractionated protocols (2 Gy daily for 20 days, 10 Gy weekly for 4 weeks, or 10 Gy monthly for 4 months). Oxygen partial pressure, oxygen saturation of hemoglobin, and dorsal skin viscoelasticity were measured periodically, and wound healing and tissue immunohistology were compared at 6 months. A single irradiation of cultured human ASCs resulted in a dose-dependent increase in cell death up to 2 Gy but with no further increases between 2 and 10 Gy. Most of the apoptotic ASCs were in the proliferation phase. Among the 3 in vivo irradiation protocols, the 2 Gy×20 group had the most severe chronic tissue damage (ie, skin dysfunction, subcutaneous atrophy, depletion of CD34 + stem cells) 6 months after the irradiation. Wound healing was also impaired most significantly in the 2 Gy×20 group. These results have important clinical implications for surgeons and radiotherapists in the timing of surgical interventions and the optimization of fractionation protocols. Irradiation damages stem cells depending on the radiation dose and frequency. Using the ultimately optimized protocol, surgeons can minimize the long-term functional deficits of radiated tissue without losing the anticancer efficacy of radiation therapy.

Enhancement of Radiation Therapy through Blockade of the Immune Checkpoint, V-domain Ig Suppressor of T Cell Activation (VISTA), in Melanoma and Adenocarcinoma Murine Models.

Radiation therapy (RT) has recently demonstrated promise at stimulating an enhanced immune response. The recent success of immunotherapies, such as checkpoint inhibitors, CART cells, and other immune modulators, affords new opportunities for combination with radiation. The aim of this study is to evaluate whether and to what extent blockade of VISTA, an immune checkpoint, can potentiate the tumor control ability of radiation therapy. Our study is novel in that it is the first comparison of two VISTA-blocking methods (antibody inhibition and genetic knockout) in combination with RT. VISTA was blocked either through genetic knockout (KO) or an inhibitory antibody and combined with RT in two syngeneic murine flank tumor models (B16 and MC38). Selected mRNA, immune cell infiltration, and tumor growth delay were used to assess the biological effects. When combined with a single 15Gy radiation dose, VISTA blockade via genetic knockout in the B16 model and via anti-VISTA antibodies in the MC38 model significantly improved survival compared to RT alone by an average of 5.5 days and 6.3 days, respectively (p < 0.05). The gene expression data suggest that the mechanism behind the enhanced tumor control is primarily a result of increased apoptosis and immune-mediated cytotoxicity. VISTA blockade significantly enhances the anti-tumor effect of a single dose of 15Gy radiation through increased expression and stimulation of cell-mediated apoptosis pathways. These results suggest that VISTA is a biologically relevant immune promoter that has the potential to enhance the efficacy of a large single radiation dose in a synergic manner.

Photo-induced flexible semiconductor CdSe/CdS quantum rods alignment

The anisotropic absorption and emission from semiconductor CdSe/CdS quantum rods (QRs) provide extra benefits among other photoluminescence nanocrystals. Using photo-induced alignment technique, the QRs can be oriented in liquid crystal polymer matrix at a large scale. In this article, a 2D Dammann grating pattern, within “SKL” characters domains aligned QRs in composite film, was fabricated by multi-step photo exposure using several photo masks, and a continuous geometric lens profile pattern aligned QRs was realized by the single step polarization converting holographic irradiation method. Both polarized optical microscope and fluorescence microscope are employed to determine the liquid crystal director profiles and QRs anisotropic excitation properties. We have been able to orient the QRs in fine binary and continuous patterns that confirms the strong quantum rod aligning ability of the proposed method. Thus, the proposed approach paves a way for photo-induced flexible QRs alignments to provide a highly specific and difficult-to-replicate security application at a large scale.

77 Single Pre-Operative Radiation Therapy (SPORT-CK) Trial for Low-Risk Breast Cancer: Early Results of a Phase 2 Study

77 Single Pre-Operative Radiation Therapy (SPORT-CK) Trial for Low-Risk Breast Cancer: Early Results of a Phase 2 Study

216 Impact of Intra-Fraction Motion Correction on Target and Oar Dosimetry in Single Fraction Lung Stereotactic Ablative Radiation Therapy

216 Impact of Intra-Fraction Motion Correction on Target and Oar Dosimetry in Single Fraction Lung Stereotactic Ablative Radiation Therapy