Reduction of post-radiotherapy urinary toxicity via intrafractional MV-kV prostate location monitoring.

PURPOSE/OBJECTIVE(S): We hypothesized that an in-house developed system using MV and kV image guidance (MKIG) to ensure correct prostate positioning during SBRT could potentially avoid unwanted doses to non-target tissues, leading to reduced toxicities. MATERIALS/METHODS: We built a 3D MKIG platform that accurately tracks prostate implanted fiducials in real-time and clinically translated the system to replace a commercial approach, intrafraction motion review (IMR), which only tracks fiducials in the 2D kV views. From 2017 to 2019, 150 prostate cancer patients were treated with SBRT and monitored by MKIG. The motion trace of the fiducials alerts therapists to interrupt and reposition the prostate when displacement exceeds a 1.5 mm threshold. A comparison cohort of 121 patients was treated with the same dose regimen and treatment technique but managed by IMR. Statistics of intrafractional patient shifts and delivery time were collected to evaluate the workflow efficacy. The incidence of grade ≥2 urinary toxicities was analyzed to assess clinical complications. The median follow-up time was 3.7 years (0.2 to 8.2 years). RESULTS: MKIG treatments had more treatment shifts (1.09 vs. 0.28) and a longer average delivery time per fraction (579±205s vs. 357±117s) than IMR treatments. Three-quarters (75%) of shifts resulting from MKIG were ≤3mm, vs. 51% in IMR, indicating that MKIG detected and corrected smaller deviations. The incidence of grade ≥2 urinary toxicity was lower in the MKIG than IMR cohort: 10.7% vs. 19.8% (p=0.047). On multivariate analysis of late urinary toxicity, only high (>7) pre-RT IPSS (p<0.043) and the use of MKIG were selected (p< 0.029). CONCLUSIONS: Automated and quantitative MKIG introduced minimal workflow impact and was superior to IMR in localizing the prostate during SBRT, which correlated with a clinically significant reduction in late urinary toxicity. Further clinical testing via randomized trial will be required to validate the impact on outcomes.

Genetic Findings in Short Turkish Children Born to Consanguineous Parents.

INTRODUCTION: The diagnostic yield of genetic analysis in the evaluation of children with short stature depends on associated clinical characteristics, but the additional effect of parental consanguinity has not been well documented. METHODS: This observational case series of 42 short children from 34 consanguineous families was collected by six referral centres of paediatric endocrinology (inclusion criteria: short stature and parental consanguinity). In 18 patients (12 families, group 1), the clinical features suggested a specific genetic defect in the growth hormone (GH) insulin-like growth factor I (IGF-I) axis, and a candidate gene approach was used. In others (group 2), a hypothesis-free approach was chosen (gene panels, microarray analysis, and whole exome sequencing) and further subdivided into 11 patients with severe short stature (height <-3.5 standard deviation score [SDS]) and microcephaly (head circumference <-3.0 SDS) (group 2a), 10 patients with syndromic short stature (group 2b), and 3 patients with nonspecific isolated GH deficiency (group 2c). RESULTS: In all 12 families from group 1, (likely) pathogenic variants were identified in GHR, IGFALS, GH1, and STAT5B. In 9/12 families from group 2a, variants were detected in PCNT, SMARCAL1, SRCAP, WDR4, and GHSR. In 5/9 families from group 2b, variants were found in TTC37, SCUBE3, NSD2, RABGAP1, and 17p13.3 microdeletions. In group 2c, no genetic cause was found. Homozygous, compound heterozygous, and heterozygous variants were found in 21, 1, and 4 patients, respectively. CONCLUSION: Genetic testing in short children from consanguineous parents has a high diagnostic yield, especially in cases of severe GH deficiency or insensitivity, microcephaly, and syndromic short stature.

How strongly does diet variation explain variation in isotope values of animal consumers?

Analysis of stable isotopes in consumers is used commonly to study their ecological and/or environmental niche. There is, however, considerable debate regarding how isotopic values relate to diet and how other sources of variation confound this link, which can undermine the utility. From the analysis of a simple, but general, model of isotopic incorporation in consumer organisms, we examine the relationship between isotopic variance among individuals, and diet variability within a consumer population. We show that variance in consumer isotope values is directly proportional to variation in diet (through Simpson indices), to the number of isotopically distinct food sources in the diet, and to the baseline variation within and among the isotope values of the food sources. Additionally, when considering temporal diet variation within a consumer we identify the interplay between diet turnover rates and tissue turnover rates that controls the sensitivity of stable isotopes to detect diet variation. Our work demonstrates that variation in the stable isotope values of consumers reflect variation in their diet. This relationship, however, can be confounded with other factors to the extent that they may mask the signal coming from diet. We show how simple quantitative corrections can recover a direct 1:1 correlation in some situations, and in others we can adjust our interpretation in light of the new understanding arising from our models. Our framework provides guidance for the design and analysis of empirical studies where the goal is to infer niche width from stable isotope data.

Athletes' Perspectives of the Classification System in Para Alpine Skiing for Those With Visual Impairment.

This study explored the classification experiences and views of Para Alpine skiers with visual impairment. Data from 11  interviews were analyzed using reflexive thematic analysis to generate three themes: Suitability-The skiers questioned the suitability of the visual measurements, testing environment, and the information they received regarding classification; Exclusivity-Skiers felt certain aspects of the system remain exclusive due to the restrictions of sport classes and lack of the athlete voice; and (Dis)trust-Skiers felt distrust in those implementing the system and in other athletes due to intentional misrepresentation. Speculation surrounding this resulted in the skiers' feeling doubt in their own classification. While there is not a "one size fits all" approach to classification, understanding skiers' experiences can be a vital first step and will help to guide future research into the evolution of this sport's classification.

Surgical treatment of headshaking by removal of a paracondylar process fragment via modified hyovertebrotomy approach: A detailed anatomical and surgical description in an adult horse.

OBJECTIVE: To describe, in detail, the relevant anatomy and surgical approach to access the paracondylar process (PCP) and report its application in a clinical case of headshaking. ANIMAL: A seven-year-old, mixed breed mare. STUDY DESIGN: Experimental study/case report. METHODS: A seven-year-old mixed breed mare was presented for investigation of acute onset progressing violent headshaking, resulting in the horse falling on multiple occasions. The horse was highly reactive to palpation over the right PCP. Standing computed tomographic (CT) investigation and ultrasonographic examination of the head detected a fracture of the right PCP. Five equine heads of mixed breeds and sizes were dissected to demonstrate the relevant anatomy surrounding the PCP with regard to surgical access. A modified hyovertebrotomy approach was used to remove the fracture fragment under general anesthesia. RESULTS: The anatomy surrounding the PCP was described. The fragment was successfully removed resulting in gradual resolution of clinical signs. The horse recovered well postoperatively and was back into light levels of work with no signs of headshaking present two and a half years following surgery. CONCLUSION: The caudal meningeal artery and vein as well as the glossopharyngeal and hypoglossal nerves are adjacent to the PCP and must be avoided during dissections. The modified hyovertebrotomy approach allows safe surgical access to the PCP. Surgical excision of a PCP fragment can result in complete resolution of clinical signs of headshaking. Computed tomography and ultrasonography are valuable diagnostic tools to identify a fracture of the PCP.

Radiation Dose-Volume-Response Relationships for Adverse Events in Childhood Cancer Survivors: Introduction to the Scientific Issues in PENTEC.

At its very core, radiation oncology involves a trade-off between the benefits and risks of exposing tumors and normal tissue to relatively high doses of ionizing radiation. This trade-off is particularly critical in childhood cancer survivors (CCS), in whom both benefits and risks can be hugely consequential due to the long life expectancy if the primary cancer is controlled. Estimating the normal tissue-related risks of a specific radiation therapy plan in an individual patient relies on predictive mathematical modeling of empirical data on adverse events. The Pediatric Normal-Tissue Effects in the Clinic (PENTEC) collaborative network was formed to summarize and, when possible, to synthesize dose-volume-response relationships for a range of adverse events incident in CCS based on the literature. Normal-tissue clinical radiation biology in children is particularly challenging for many reasons: (1) Childhood malignancies are relatively uncommon-constituting approximately 1% of new incident cancers in the United States-and biologically heterogeneous, leading to many small series in the literature and large variability within and between series. This creates challenges in synthesizing data across series. (2) CCS are at an elevated risk for a range of adverse health events that are not specific to radiation therapy. Thus, excess relative or absolute risk compared with a reference population becomes the appropriate metric. (3) Various study designs and quantities to express risk are found in the literature, and these are summarized. (4) Adverse effects in CCS often occur 30, 50, or more years after therapy. This limits the information content of series with even very extended follow-up, and lifetime risk estimates are typically extrapolations that become dependent on the mathematical model used. (5) The long latent period means that retrospective dosimetry is required, as individual computed tomography-based radiation therapy plans gradually became available after 1980. (6) Many individual patient-level factors affect outcomes, including age at exposure, attained age, lifestyle exposures, health behaviors, other treatment modalities, dose, fractionation, and dose distribution. (7) Prospective databases with individual patient-level data and radiation dosimetry are being built and will facilitate advances in dose-volume-response modeling. We discuss these challenges and attempts to overcome them in the setting of PENTEC.

Reporting Standards for Complication Studies of Radiation Therapy for Pediatric Cancer: Lessons From PENTEC.

The major aim of Pediatric Normal Tissue Effects in the Clinic (PENTEC) was to synthesize quantitative published dose/-volume/toxicity data in pediatric radiation therapy. Such systematic reviews are often challenging because of the lack of standardization and difficulty of reporting outcomes, clinical factors, and treatment details in journal articles. This has clinical consequences: optimization of treatment plans must balance between the risks of toxicity and local failure; counseling patients and their parents requires knowledge of the excess risks encountered after a specific treatment. Studies addressing outcomes after pediatric radiation therapy are particularly challenging because: (a) survivors may live for decades after treatment, and the latency time to toxicity can be very long; (b) children's maturation can be affected by radiation, depending on the developmental status of the organs involved at time of treatment; and (c) treatment regimens frequently involve chemotherapies, possibly modifying and adding to the toxicity of radiation. Here we discuss: basic reporting strategies to account for the actuarial nature of the complications; the reporting of modeling of abnormal development; and the need for standardized, comprehensively reported data sets and multivariate models (ie, accounting for the simultaneous effects of radiation dose, age, developmental status at time of treatment, and chemotherapy dose). We encourage the use of tools that facilitate comprehensive reporting, for example, electronic supplements for journal articles. Finally, we stress the need for clinicians to be able to trust artificial intelligence models of outcome of radiation therapy, which requires transparency, rigor, reproducibility, and comprehensive reporting. Adopting the reporting methods discussed here and in the individual PENTEC articles will increase the clinical and scientific usefulness of individual reports and associated pooled analyses.

The speed of sight: Individual variation in critical flicker fusion thresholds.

The critical flicker fusion threshold is a psychophysical measure commonly used to quantify visual temporal resolution; the fastest rate at which a visual system can discriminate visual signals. Critical flicker fusion thresholds vary substantially among species, reflecting different ecological niches and demands. However, it is unclear how much variation exists in flicker fusion thresholds between healthy individuals of the same species, or how stable this attribute is over time within individuals. In this study, we assessed both inter- and intra-individual variation in critical flicker fusion thresholds in a cohort of healthy human participants within a specific age range, using two common psychophysical methods and three different measurements during each session. The resulting thresholds for each method were highly correlated. We found a between-participant maximum difference of roughly 30 Hz in flicker fusion thresholds and we estimated a 95% prediction interval of 21 Hz. We used random-effects models to compare between- and within-participant variance and found that approximately 80% of variance was due to between-individual differences, and about 10% of the variance originated from within-individual differences over three sessions. Within-individual thresholds did not differ significantly between the three sessions in males, but did in females (P<0.001 for two methods and P<0.05 for one method), indicating that critical flicker fusion thresholds may be more variable in females than in males.

Multi-centre evaluation of variation in cumulative dose assessment in reirradiation scenarios.

BACKGROUND AND PURPOSE: Safe reirradiation relies on assessment of cumulative doses to organs at risk (OARs) across multiple treatments. Different clinical pathways can result in inconsistent estimates. Here, we quantified the consistency of cumulative dose to OARs across multi-centre clinical pathways. MATERIAL AND METHODS: We provided DICOM planning CT, structures and doses for two reirradiation cases: head & neck (HN) and lung. Participants followed their standard pathway to assess the cumulative physical and EQD2 doses (with provided α/ß values), and submitted DVH metrics and a description of their pathways. Participants could also submit physical dose distributions from Course 1 mapped onto the CT of Course 2 using their best available tools. To assess isolated impact of image registrations, a single observer accumulated each submitted spatially mapped physical dose for every participating centre. RESULTS: Cumulative dose assessment was performed by 24 participants. Pathways included rigid (n = 15), or deformable (n = 5) image registration-based 3D dose summation, visual inspection of isodose line contours (n = 1), or summation of dose metrics extracted from each course (n = 3). Largest variations were observed in near-maximum cumulative doses (25.4 - 41.8 Gy for HN, 2.4 - 33.8 Gy for lung OARs), with lower variations in volume/dose metrics to large organs. A standardised process involving spatial mapping of the first course dose to the second course CT followed by summation improved consistency for most near-maximum dose metrics in both cases. CONCLUSION: Large variations highlight the uncertainty in reporting cumulative doses in reirradiation scenarios, with implications for outcome analysis and understanding of published doses. Using a standardised workflow potentially including spatially mapped doses improves consistency in determination of accumulated dose in reirradiation scenarios.

A practical review of barriers and challenges to a definitive randomised trial of grafts versus fistula.

A definitive randomised controlled trial of arteriovenous fistula (AVF) versus arteriovenous grafts (AVG) has been advocated for more than a decade, but as yet, none has been completed. The aim of this article is to summarise the theoretical barriers, review the difficulties in trial design and practicalities that have thus far prevented this from occurring.

AAV8 vector induced gliosis following neuronal transgene expression.

Introduction: Expression of light sensitive ion channels by selected neurons has been achieved by viral mediated transduction with gene constructs, but for this to have therapeutic uses, for instance in treating epilepsy, any adverse effects of viral infection on the cerebral cortex needs to be evaluated. Here, we assessed the impact of adeno-associated virus 8 (AAV8) carrying DNA code for a soma targeting light activated chloride channel/FusionRed (FR) construct under the CKIIa promoter. Methods: Viral constructs were harvested from transfected HEK293 cells in vitro and purified. To test functionality of the opsin, cultured rodent neurons were transduced and the light response of transduced neurons was assayed using whole-cell patch-clamp recordings. In vivo expression was confirmed by immunofluorescence for FR. Unilateral intracranial injections of the viral construct were made into the mouse neocortex and non-invasive fluorescence imaging of FR expression made over 1-4 weeks post-injection using an IVIS Spectrum system. Sections were also prepared from injected mouse cortex for immunofluorescence staining of FR, alongside glial and neuronal marker proteins. Results: In vitro, cortical neurons were successfully transduced, showing appropriate physiological responses to light stimulation. Following injections in vivo, transduction was progressively established around a focal injection site over a 4-week period with spread of transduction proportional to the concentration of virus introduced. Elevated GFAP immunoreactivity, a marker for reactive astrocytes, was detected near injection sites associated with, and proportional to, local FR expression. Similarly, we observed reactive microglia around FR expressing cells. However, we found that the numbers of NeuN+ neurons were conserved close to the injection site, indicating that there was little or no neuronal loss. In control mice, injected with saline only, astrocytosis and microgliosis was limited to the immediate vicinity of the injection site. Injections of opsin negative viral constructs resulted in comparable levels of astrocytic reaction as seen with opsin positive constructs. Discussion: We conclude that introduction of an AAV8 vector transducing expression of a transgene under a neuron specific promotor evokes a mild inflammatory reaction in cortical tissue without causing extensive short-term neuronal loss. The expression of an opsin in addition to a fluorescent protein does not significantly increase neuroinflammation.

Quality assurance in surgical trials of arteriovenous grafts for haemodialysis: A systematic review, a narrative exploration and expert recommendations.

BACKGROUND: Introducing new procedures and challenging established paradigms requires well-designed randomised controlled trials (RCT). However, RCT in surgery present unique challenges with much of treatment tailored to the individual patient circumstances, refined by experience and limited by organisational factors. There has been considerable debate over the outcomes of arteriovenous grafts (AVG) compared to AVF, but any differences may reflect differing practice and potential variability. It is essential, therefore, when considering an RCT of a novel surgical procedure or device that quality assurance (QA) is defined for both the new approach and the comparator. The aim of this systematic review was to evaluate the QA standards performed in RCT of AVG using a multi-national, multi-disciplinary approach and propose an approach for future RCT. METHOD: The methods of this have been previously registered (PROSPERO: CRD420234284280) and published. In summary, a four-stage review was performed: identification of RCT of AVG, initial review, multidisciplinary appraisal of QA methods and reconciliation. QA measures were sought in four areas - generic, credentialing, standardisation and monitoring, with data abstracted by a multi-national, multi-speciality review body. RESULTS: QA in RCT involving AVG in all four domains is highly variable, often sub-optimally described and has not improved over the past three decades. Few RCT established or defined a pre-RCT level of experience, none documented a pre-trial education programme, or had minimal standards of peri-operative management, no study had a defined pre-trial monitoring programme, and none assessed technical performance. CONCLUSION: QA in RCT is a relatively new area that is expanding to ensure evidence is reliable and reproducible. This review demonstrates that QA has not previously been detailed, but can be measured in surgical RCT of vascular access, and that a four-domain approach can easily be implemented into future RCT.

Brain and Brain Stem Necrosis After Reirradiation for Recurrent Childhood Primary Central Nervous System Tumors: A PENTEC Comprehensive Review.

PURPOSE: Reirradiation is increasingly used in children and adolescents/young adults (AYA) with recurrent primary central nervous system tumors. The Pediatric Normal Tissue Effects in the Clinic (PENTEC) reirradiation task force aimed to quantify risks of brain and brain stem necrosis after reirradiation. METHODS AND MATERIALS: A systematic literature search using the PubMed and Cochrane databases for peer-reviewed articles from 1975 to 2021 identified 92 studies on reirradiation for recurrent tumors in children/AYA. Seventeen studies representing 449 patients who reported brain and brain stem necrosis after reirradiation contained sufficient data for analysis. While all 17 studies described techniques and doses used for reirradiation, they lacked essential details on clinically significant dose-volume metrics necessary for dose-response modeling on late effects. We, therefore, estimated incidences of necrosis with an exact 95% CI and qualitatively described data. Results from multiple studies were pooled by taking the weighted average of the reported crude rates from individual studies. RESULTS: Treated cancers included ependymoma (n = 279 patients; 7 studies), medulloblastoma (n = 98 patients; 6 studies), any CNS tumors (n = 62 patients; 3 studies), and supratentorial high-grade gliomas (n = 10 patients; 1 study). The median interval between initial and reirradiation was 2.3 years (range, 1.2-4.75 years). The median cumulative prescription dose in equivalent dose in 2-Gy fractions (EQD22; assuming α/ß value = 2 Gy) was 103.8 Gy (range, 55.8-141.3 Gy). Among 449 reirradiated children/AYA, 22 (4.9%; 95% CI, 3.1%-7.3%) developed brain necrosis and 14 (3.1%; 95% CI, 1.7%-5.2%) developed brain stem necrosis with a weighted median follow-up of 1.6 years (range, 0.5-7.4 years). The median cumulative prescription EQD22 was 111.4 Gy (range, 55.8-141.3 Gy) for development of any necrosis, 107.7 Gy (range, 55.8-141.3 Gy) for brain necrosis, and 112.1 Gy (range, 100.2-117 Gy) for brain stem necrosis. The median latent period between reirradiation and the development of necrosis was 5.7 months (range, 4.3-24 months). Though there were more events among children/AYA undergoing hypofractionated versus conventionally fractionated reirradiation, the differences were not statistically significant (P = .46). CONCLUSIONS: Existing reports suggest that in children/AYA with recurrent brain tumors, reirradiation with a total EQD22 of about 112 Gy is associated with an approximate 5% to 7% incidence of brain/brain stem necrosis after a median follow-up of 1.6 years (with the initial course of radiation therapy being given with conventional prescription doses of ≤2 Gy per fraction and the second course with variable fractionations). We recommend a uniform approach for reporting dosimetric endpoints to derive robust predictive models of late toxicities following reirradiation.

CYTOP® 366: A Tertiary Phosphine Inaccessible by Most Traditional Hydrophosphination Methods.

Homogenous catalysis is an essential tool within the commercial manufacture of bulk and fine chemicals. Within this, phosphine ligands, such as tricyclohexylphosphine, otherwise known as CYTOP® 366, are a crucial component. When designing a pathway to your ligand of choice, some key considerations include safety, yield and quality, but at commercial volumes we must also balance cost and consider the technologies readily available. Herein, we report the synthetic route that was chosen to manufacture tricyclohexylphosphine at commercial scale. We also consider, with the use of computational calculations, why traditional hydrophosphination methods failed, where the selected pathway succeeded.

Improving Pediatric Normal Tissue Radiation Dose-Response Modeling in Children With Cancer: A PENTEC Initiative.

The development of normal tissue radiation dose-response models for children with cancer has been challenged by many factors, including small sample sizes; the long length of follow-up needed to observe some toxicities; the continuing occurrence of events beyond the time of assessment; the often complex relationship between age at treatment, normal tissue developmental dynamics, and age at assessment; and the need to use retrospective dosimetry. Meta-analyses of published pediatric outcome studies face additional obstacles of incomplete reporting of critical dosimetric, clinical, and statistical information. This report describes general methods used to address some of the pediatric modeling issues. It highlights previous single- and multi-institutional pediatric dose-response studies and summarizes how each PENTEC taskforce addressed the challenges and limitations of the reviewed publications in constructing, when possible, organ-specific dose-effect models.

Accreditation of analogue quantum simulators.

We present an accreditation protocol for analogue, i.e., continuous-time, quantum simulators. For a given simulation task, it provides an upper bound on the variation distance between the probability distributions at the output of an erroneous and error-free analogue quantum simulator. As its overheads are independent of the size and nature of the simulation, the protocol is ready for immediate usage and practical for the long term. It builds on the recent theoretical advances of strongly universal Hamiltonians and quantum accreditation as well as experimental progress toward the realization of programmable hybrid analogue-digital quantum simulators.

What are the observed procedural costs of vascular access surgery? Protocol for a systematic review.

INTRODUCTION: A central component in the introduction of a novel surgical procedure or technique is an evaluation of its cost efficiency when compared with a benchmark standard of care. Accurate assessment of costs is thus essential in ensuring appropriate allocation of resources within a healthcare system. The treatment of kidney failure requires a significant volume of resources, and vascular access provision is the main modifiable cost. The costs of providing this service are obscured by generic NHS reference costs, which lack adequate granularity to allow meaningful comparisons between treatments. The aim of this systematic review will be to assess the reporting of procedural costs in all published economic analyses of vascular access surgery and perform a comparison of the reported procedural costs involved in arteriovenous fistula (AVF) and arteriovenous graft (AVG) creation. This will provide an estimate as to the accuracy of the NHS reference costs in this field. METHODS AND ANALYSIS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines will be followed. A systematic search will be performed of the MEDLINE, Embase and Cochrane databases to identify full-text economic analyses of vascular access for haemodialysis in which the procedural cost of AVF or AVG creation is reported. Publications in English from 1 January 2000 to 30 August 2023, will be eligible for inclusion. Studies will be selected by title and abstract review, followed by a full-text review using inclusion and exclusion criteria. Studies not reporting the procedural costs of surgery will be excluded. Data collected will pertain to procedural costs of AVF and AVG creation. Costs will be adjusted to a common currency using a gross domestic product (GDP) deflator index and conversion rates based on purchasing power parities for GDP. Comparison with NHS reference costs will indicate their reliability for use in future economic analyses in this field. ETHICS AND DISSEMINATION: Ethical approval is not required for this systematic review. Findings will be disseminated through peer-reviewed publications and conference presentations. PROSPERO REGISTRATION NUMBER: CRD42023458779.

Clinical and Dosimetric Risk Factors Associated With Radiation-Induced Lung Toxicities After Multiple Courses of Lung Stereotactic Body Radiation Therapy.

Purpose: Data are limited on radiation-induced lung toxicities (RILT) after multiple courses of lung stereotactic body radiation therapy (SBRT). We herein analyze a large cohort of patients to explore the clinical and dosimetric risk factors associated with RILT in such settings. Methods and Materials: A single institutional database of patients treated with multiple courses of lung SBRT between January 2014 and December 2019 was analyzed. Grade 2 or higher (G2+) RILT after the last course of SBRT was the primary endpoint. Composite plans were generated with advanced algorithms including deformable registration and equivalent dose adjustment. Logistic regression analyses were performed to examine correlations between patient or treatment factors including dosimetry and G2+ RILT. Risk stratification of patients and lung constraints based on acceptable normal tissue complication probability were calculated based on risk factors identified. Results: Among 110 eligible patients (56 female and 54 male), there were 64 synchronous (58.2%; defined as 2 courses of SBRT delivered within 30 days) and 46 metachronous (41.8%) courses of SBRT. The composite median lung V20, lung V5, and mean lung dose were 9.9% (interquartile range [IQR], 7.3%-12.4%), 32.2% (IQR, 25.5%-40.1%), and 7.0 Gy (IQR, 5.5 Gy-8.6 Gy), respectively. With a median follow-up of 21.1 months, 30 patients (27.3%) experienced G2+ RILT. Five patients (4.5%) developed G3 RILT, and 1 patient (0.9%) developed G4 RILT, and no patients developed G5 RILT. On multivariable regression analysis, female sex (odds ratio [OR], 4.35; 95% CI, 1.49%-14.3%; P = .01), synchronous SBRT (OR, 8.78; 95% CI, 2.27%-47.8%; P = .004), prior G2+ RILT (OR, 29.8; 95% CI, 2.93%-437%; P = .007) and higher composite lung V20 (OR, 1.18; 95% CI, 1.02%-1.38%; P = .030) were associated with significantly higher likelihood of G2+ RILT. Conclusions: Our data suggest an acceptable incidence of G2+ RILT after multiple courses of lung SBRT. Female sex, synchronous SBRT, prior G2+ RILT, and higher composite lung V20 may be risk factors for G2+ RILT.