Abstract Objective: The recently introduced Gamma Knife (GK) Lightning (Elekta) fast inverse planning dose optimizer allows concurrent optimization of multiple targets, but the optimizer’s use for generating a simultaneous integrated boost (SIB) plan has not been described and validated for accuracy of dose delivery. Here, we describe a method for creating an SIB using the GK Lightning optimizer and conduct validation of dose delivery. Materials and Methods: Radiochromic film was positioned in an anthropomorphic phantom. A 15.7-cm3 irregular contour was drawn to represent a brain metastasis resection cavity, a uniform 2-mm radial-expansion contour created, and a 1.6-cm3 contour drawn representing a nodule of residual disease within the cavity. Targets were prescribed 3 Gy (2-mm expansion), 4 Gy (cavity), and 5 Gy (residual disease) in 1 fraction. Within the GammaPlan Lightning optimizer, “beam-on time” and “low-dose” settings were iteratively adjusted to create a clinically acceptable plan. Treatment was delivered using the GK Icon system. The film was scanned and calibrated for absolute dosimetry. Global gamma index analyses were performed at various dose and distance tolerances. Results: An 18-minute treatment plan with 40 shots was delivered. Prescription isodose lines were 3 Gy at 55% (2-mm expansion), 4 Gy at 69% (resection cavity), and 5 Gy at 75% (residual disease). All target volumes had greater than or equal to 99% prescription dose coverage and the maximum dose was 6.9 Gy. Paddick conformality indices were 0.79 (2-mm expansion), 0.74 (resection cavity), and 0.15 (residual disease). Gamma index pass rate, mean, and median values were 77%, 0.68, and 0.54 at 1%/1-mm tolerance, 85%, 0.58, and 0.49 at 2%/1-mm tolerance, and 97%, 0.34, and 0.28 at 2%/2-mm tolerance. Conclusion: We successfully created an SIB plan with the GK Lightning optimizer, verifying dose delivery within clinically acceptable tolerances. Future work is needed to determine optimal dose levels for use in clinical practice and determine what disease entities may benefit from an SIB.

PURPOSE: Highlight safety considerations in intravascular brachytherapy (IVBT) programs, provide relevant quality assurance (QA) and safety measures, and establish their effectiveness. METHODS AND MATERIALS: Radiation oncologists, medical physicists, and cardiologists from three institutions performed a failure modes and effects analysis (FMEA) on the radiation delivery portion of IVBT. We identified 40 failure modes and rated the severity, occurrence, and detectability before and after consideration of safety practices. Risk priority numbers (RPN) and relative risk rankings were determined, and a sample QA safety checklist was developed. RESULTS: We developed a process map based on multi-institutional consensus. Highest-RPN failure modes were due to incorrect source train length, incorrect vessel diameter, and missing prior radiation history. Based on these, we proposed QA and safety measures: ten of which were not previously recommended. These measures improved occurrence and detectability: reducing the average RPN from 116 to 58 and median from 84 to 40. Importantly, the average RPN of the top 10% of failure modes reduced from 311 to 172. With QA considered, the highest risk failure modes were from contamination and incorrect source train length. CONCLUSIONS: We identified several high-risk failure modes in IVBT procedures and practical safety and QA measures to address them. (c) 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

PURPOSE: Coronary stents reduce IVBT radiation dose with a single layer by 10-30%. However, the impact of multiple stent layers and stent expansion remains unexplored. Individualized dose adjustments considering variations in stent layers and expansion could improve radiation delivery effectiveness. METHODS: EGSnrc was used to compute the delivered vessel wall dose in various IVBT scenarios. Stent effects were modeled for the stent density of 25%, 50%, and 75% with 1, 2, and 3 layers respectively. Doses were calculated at 1.75 to 5.00 mm away from the source center, normalized to 100% at 2 mm. RESULTS: Dose fall-off increased with increasing stent density. With a single layer, the dose at 2 mm from source fell from 100% of prescription to 92%, 83% and 73% at 25%, 50% and 75% density, respectively. The computed dose to points with increasing radial distance from the source decreased progressively with increasing stent layers. With three layers, at 75% stent density, the dose at 2 mm from source center fell to 38%. CONCLUSIONS: A schema for image-guided IVBT dose adjustment is described. While it would be an improvement over current standard of care, myriad factors remain to be addressed in a comprehensive effort to optimize IVBT. (c) 2023 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.

Nebulized thrombolysis offers locally targeted therapy with potentially lower bleeding risk than systemic administration for coronavirus disease 2019 (COVID-19) respiratory failure. In a proof-of-concept safety study, adult patients with COVID-19-induced respiratory failure and a <300mmHg PaO2/FiO2 (P/F) ratio, requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care during the first two UK COVID-19 waves. Matched historical controls (MHC; n=18) were used in C1. Safety co-primary endpoints were treatment-related bleeds and fibrinogen reduction to <1.0–1.5 g/L. A dose escalation strategy for improved efficacy with the least safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA per day for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeding events (one severe and three mild) in three patients were considered treatment-related. No significant fibrinogen reductions were reported. Greater improvement in mean P/F ratio from baseline to end of study was observed in C1 compared with MHC [C1; 154 to 299 vs MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in P/F ratio was observed in NIRS patients [NIRS; 126 to 240 vs IMV; 120 to 188) and they required fewer treatment days (NIRS; 7.86 vs IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, showing a trend of improved oxygenation and faster recovery in patients with acute COVID-19-induced respiratory failure requiring respiratory support; this effect was more pronounced in the NIRS group. Further investigation is required to study the potential of this novel treatment approach.

Acute lung injury in COVID-19 results in diffuse alveolar damage with disruption of the alveolar-capillary barrier, coagulation activation, alveolar fibrin deposition and pulmonary capillary thrombi. Nebulized recombinant tissue plasminogen activator (rt-PA) has the potential to facilitate localized thrombolysis in the alveolar compartment and improve oxygenation. In this proof-of-concept safety study, adults with COVID-19-induced respiratory failure and a <300 mmHg PaO2/FiO2 (P/F) ratio requiring invasive mechanical ventilation (IMV) or non-invasive respiratory support (NIRS) received nebulized rt-PA in two cohorts (C1 and C2), alongside standard of care, between 23 April–30 July 2020 and 21 January–19 February 2021, respectively. Matched historical controls (MHC; n = 18) were used in C1 to explore efficacy. Safety co-primary endpoints were treatment-related bleeds and <1.0–1.5 g/L fibrinogen reduction. A variable dosing strategy with clinical efficacy endpoint and minimal safety concerns was determined in C1 for use in C2; patients were stratified by ventilation type to receive 40–60 mg rt-PA daily for ≤14 days. Nine patients in C1 (IMV, 6/9; NIRS, 3/9) and 26 in C2 (IMV, 12/26; NIRS, 14/26) received nebulized rt-PA for a mean (SD) of 6.7 (4.6) and 9.1(4.6) days, respectively. Four bleeds (one severe, three mild) in three patients were considered treatment related. There were no significant fibrinogen reductions. Greater improvements in mean P/F ratio from baseline to study end were observed in C1 compared with MHC (C1; 154 to 299 vs. MHC; 154 to 212). In C2, there was no difference in the baseline P/F ratio of NIRS and IMV patients. However, a larger improvement in the P/F ratio occurred in NIRS patients (NIRS; 126 to 240 vs. IMV; 120 to 188) and fewer treatment days were required (NIRS; 7.86 vs. IMV; 10.5). Nebulized rt-PA appears to be well-tolerated, with a trend towards improved oxygenation, particularly in the NIRS group. Randomized clinical trials are required to demonstrate the clinical effect significance and magnitude.

Abstract BACKGROUND The novel Gamma Knife (GK) Lightning optimizer allows simultaneous automated optimization of multiple intracranial radiotherapy targets. We used this optimizer to create a dose-painting treatment plan where an escalated dose was prescribed to residual disease within a brain metastasis resection cavity. We validated this method by measuring dose-delivery accuracy using radiochromic film in an anthropomorphic phantom. METHODS A 15.7cc irregular contour was drawn to represent a brain metastasis resection cavity, a 2mm expansion contour created, and a 1.6cc contour drawn representing a nodule of residual disease. In GammaPlan v11.3.1, three targets were created with overlapping dose matrices. Targets were prescribed 3Gy (2mm expansion), 4Gy (resection cavity), and 5Gy (residual disease) in one fraction. On the GK Icon system, an occipital mold was made, an unexposed film placed in the phantom’s cranium, cone-beam coregistration conducted, and treatment delivered. The film was scanned and calibrated for absolute dosimetry. To evaluate dose-painting accuracy, global gamma index (GI) analyses were performed at various dose and distance tolerances, excluding points below 30% of the maximum dose. RESULTS An 18-minute treatment plan with 40 shots was created and delivered. Prescription isodose lines were 3Gy at 55% (2mm expansion, mean 4.8Gy), 4Gy at 69% (resection cavity, mean 5.2Gy), and 5Gy at 75% (residual disease, mean 6.1Gy). All target volumes had ≥ 99% prescription dose coverage and the maximum dose was 6.9Gy. Paddick conformality indices were 0.79 (2mm expansion), 0.74 (resection cavity), and 0.15 (residual disease). Gamma index pass rate/mean GI/median GI were 73%/0.68/0.55 at 1%/1mm tolerance, 85%/0.58/0.48 at 2%/1mm tolerance, and 97%/0.34/0.28 at 2%/2mm tolerance. An average of 17,883 points were evaluated per analysis. CONCLUSIONS We successfully performed GK dose painting with the Lightning optimizer, verifying dose delivery within clinically acceptable tolerances. Future work is needed to determine optimal dose levels for use in clinical practice.

Evaluating cardiac dose during total body irradiation (TBI) is of increasing interest. A three-dimensional beam model for TBI was commissioned and lung shielding was simulated in a treatment planning system with the cardiac silhouette partially blocked and unblocked. When blocked, the median heart dose decreased by 6% (IQR = 6%) and the median cardiac V12Gy decreased by 27% (IQR = 17%). The median left anterior descending artery dose decreased 20% (IQR = 12%) for blocked cases. Because using partial heart shielding may result in considerable changes in dose to cardiac structures, TBI protocols should explicitly consider lung block design parameters and their potential effects.

AbstractPurposeTotal body irradiation (TBI) is an integral part of stem cell transplant. However, patients are at risk of treatment‐related toxicities, including radiation pneumonitis. While lung dose is one of the most crucial aspects of TBI dosimetry, currently available data are based on point doses. As volumetric dose distribution could be substantially altered by lung block parameters, we used 3D dosimetry in our treatment planning system to estimate volumetric lung dose and measure the impact of various lung block designs.Materials and methodsWe commissioned a TBI beam model in RayStation that matches the measured tissue‐phantom ratio under our clinical TBI setup. Cerrobend blocks were automatically generated in RayStation on thoracic Computed Tomography (CT) scans from three anonymized patients using the lung, clavicle, spine, and diaphragmatic contours. The margin for block edge was varied to 0, 1, or 2 cm from the superior, lateral, and inferior thoracic borders, with a uniform margin 2.5 cm lateral to the vertebral bodies. The lung dose was calculated and compared with a prescription dose of 1200 cGy in six fractions (three with blocks and three without).ResultThe point dose at midplane under the block and the average lung dose are at the range of 73%–76% and 80%–88% of prescription dose respectively regardless of the block margins. In contrast, the percent lung volume receiving 10 Gy increased by nearly two‐fold, from 31% to 60% over the margins from 0 to 2 cm.ConclusionsThe TPS‐derived 3D lung dose is substantially different from the nominal dose assumed with HVL lung blocks. Point doses under the block are insufficient to accurately gauge the relationship between dose and pneumonitis, and TBI dosimetry could be highly variable between patients and institutions as more descriptive parameters are not included in protocols. Much progress remains to be made to optimize and standardize technical aspects of TBI, and better dosimetry could provide more precise dosimetric predictors for pneumonitis risk.

One objective of a lander mission to Jupiter's icy moon Europa is to detect liquid water within 30 km as well as characterizing the subsurface ocean. In order to satisfy this objective, water within the ice shell must also be identified. Inductive electromagnetic (EM) methods are optimal for water detection on Europa because even a small fraction of dissolved salts will make water orders of magnitude more electrically conductive than the ice shell. Compared to induction studies by the Galileo spacecraft, measurements of higher-frequency ambient EM fields are necessary to resolve the shallower depths of intrashell water. Although these fields have been mostly characterized by prior missions, their unknown source structures and plasma properties do not allow EM sounding using a single surface magnetometer or the orbit-to-surface magnetic transfer function, respectively. Instead, broadband EM sounding can be accomplished from a single surface station using the magnetotelluric (MT) method, which measures horizontal electric fields as well as the three-component magnetic field. We have developed a prototype Europa Magnetotelluric Sounder (EMS) to meet the measurement requirements in the relevant thermal, vacuum, and radiation environment. EMS comprises central electronics, a fluxgate magnetometer on a mast, and three ballistically deployed electrodes to measure differences in surface electric potential. In this paper, we describe EMS development and testing as well as providing supporting information on the concept of operations and calculations on water detectability. EMS can uniquely determine the occurrence of intrashell water on Europa, providing important constraints on habitability.

Radiation therapy is a complex process involving multiple professionals and steps from simulation to treatment planning to delivery, and these procedures are prone to error. Additionally, the imaging and treatment delivery equipment in radiotherapy is highly complex and interconnected and represents another risk point in the quality of care. Numerous quality assurance tasks are carried out to ensure quality and to detect and prevent potential errors in the process of care. Recent developments in artificial intelligence provide potential tools to the radiation oncology community to improve the efficiency and performance of quality assurance efforts. Targets for artificial intelligence enhancement include the quality assurance of treatment plans, target and tissue structure delineation used in the plans, delivery of the plans and the radiotherapy delivery equipment itself. Here we review recent developments of artificial intelligence applications that aim to improve quality assurance processes in radiation therapy and discuss some of the challenges and limitations that require further development work to realise the potential of artificial intelligence for quality assurance.

Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4–9.8) and median overall survival was 14.7 months (95% CI: 11.7–16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

This work has shown that margins of lung blocks could affect the dose to lungs and heart substantially, despite the indifference that the commonly used point dose parameter, point dose behind the blocks, indicates. A 3D TBI model could provide more dosimetry data to help future studies to correlate TBI-associated toxicity to the heart and lungs.

Abstract Introduction: FLT180a (verbrinacogene setparvovec) is an investigational, liver-directed AAV gene therapy for the treatment of patients with hemophilia B (HB). FLT180a consists of a novel, potent, engineered capsid (AAVS3) containing an expression cassette encoding a Factor IX (FIX) gain-of-function protein variant ('Padua'; FIX-R338L). The B-AMAZE study was designed to identify a dose of FLT180a that maintains FIX activity within the normal range (50-150%) and thereby protect patients with severe HB from spontaneous and traumatic bleeds. Methods: B-AMAZE was a multicentre, open-label Phase 1/2 clinical trial (NCT03369444; sponsored by UCL) that evaluated FLT180a dose levels using an escalating/descending adaptive design in patients with severe (FIX activity <1%) or moderately severe (FIX activity 1-2%) HB who were negative for AAVS3 neutralizing antibodies. A novel regimen of prophylactic corticosteroids with/without tacrolimus was implemented to mitigate the impact of vector-related transaminitis on FIX expression. Patients who completed the 26-week B-AMAZE study were eligible for the ongoing long-term follow-up study (NCT03641703; sponsored by Freeline). Results: Ten HB patients received a single dose of FLT180a. Four FLT180a doses ranging from 3.84e11 vg/kg to 1.28e12 vg/kg were assessed. As of the data cut-off date, all patients have been followed for ≥16 months. FLT180a demonstrated a favorable safety profile, without evidence of inhibitors against FIX, infusion-related or allergic reactions. The most common treatment-related adverse event was transient elevation in alanine aminotransferase. An event of AV fistula thrombosis occurred in a 67-year-old patient who received the highest dose of 1.28e12 vg/kg (total dose of 1.15e14 vg) and had supranormal FIX levels; this patient was treated with anticoagulants. While these FIX levels demonstrate the potency of our proprietary AAVS3 capsid, this dose will not be used in future hemophilia studies. At Week 26 after FLT180a administration, a dose-response relationship was observed with mean FIX activity of 45.0%, 35.5%, 141.5%, and 175.5% for 3.84e11, 6.4e11, 8.32e11, and 1.28e12 vg/kg doses, respectively (Table); FIX activity levels ≥50% were achieved in 7 of 8 patients treated with the three highest doses. One patient (Patient 4) who received 6.4e11 vg/kg lost transgene expression early due to transaminitis and resumed routine factor prophylaxis. The 8.32e11 vg/kg cohort received an extended immune management regimen (9-18 weeks) with prophylactic tacrolimus in addition to prednisolone to prevent breakthrough vector-related transaminitis. However, after cessation of the immune management regimen, transaminitis with concomitant reductions in FIX activity was observed in all patients in the 8.32e11 vg/kg cohort. The combination of prophylactic tacrolimus and prednisolone appeared to have suppressed immune-mediated transaminitis while administered, but recurrence of transaminitis developed soon after cessation. This unique and previously unreported observation suggests that the longer-duration prophylactic immune management regimen may have prevented tolerization to the vector because this was not observed in earlier cohorts where a brief course of tacrolimus was given reactively for breakthrough transaminitis. All patients (including the 8.32e11 vg/kg cohort) have achieved steady state. Patients in the earliest cohort who received the lowest dose (3.84e11 vg/kg) have shown stable FIX activity for >3 years. There were no spontaneous bleeds that required FIX supplementation in patients who maintained FIX activity above 50%; Patient 4 in the 6.4e11 vg/kg cohort experienced two bleeds (cause unknown) after he lost transgene expression, which were treated with exogenous FIX. One patient received exogenous FIX for treatment of a traumatic bleed, but his FIX activity level was 57% at the time of the event. Additional efficacy and safety results with >3.5 years of follow-up will be presented. Conclusions: B-AMAZE is the first HB gene therapy study to achieve normal levels of FIX activity using relatively low vector doses. Results suggest that a dose of 7.7e11 vg/kg, coupled with a short course of prophylactic immune management, has the potential to achieve durable FIX activity in the normal range (50-150%) and thereby prevent spontaneous bleeds and normalize hemostasis in the event of traumatic bleeds. Figure 1 Figure 1. Disclosures Chowdary: Sanofi: Honoraria; Roche: Honoraria; CSL Behring: Honoraria, Research Funding; Freeline: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; SOBI: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria; Chugai: Honoraria; Spark: Honoraria; Bayer: Honoraria, Research Funding. Shapiro: Roche: Honoraria; CSL Bering: Honoraria; Takeda: Honoraria, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau. Makris: Freeline: Consultancy. Dolan: Takeda: Speakers Bureau; Roche-Chugai: Speakers Bureau; Spark Therapeutics: Speakers Bureau; Octapharma: Speakers Bureau; CSL: Speakers Bureau; Biomarin: Speakers Bureau; Bayer: Research Funding, Speakers Bureau; Novo Nordisk: Research Funding, Speakers Bureau; Pfizer: Research Funding. Tuddenham: Freeline: Consultancy, Current holder of individual stocks in a privately-held company. Long: Freeline: Current Employment. Krop: Freeline: Current Employment. Nathwani: Freeline: Current holder of individual stocks in a privately-held company, Other: Board of directors.

The recent explosion in machine learning efforts in the quality assurance (QA) space has produced a variety of proofs-of-concept many with promising results. Expected outcomes of model implementation include improvements in planning time, plan quality, advanced dosimetric QA, predictive machine maintenance, increased safety checks, and developments key for new QA paradigms driven by adaptive planning. In this article, we outline several areas of research and discuss some of the unique challenges each area presents.

Ontologies are a formal, computer-compatible method for representing scientific knowledge about a given domain. They provide a standardized vocabulary, taxonomy and set of relations between concepts. When formatted in a standard way, they can be read and reasoned upon by computers as well as by humans. At the 2019 International Conference on the Use of Computers in Radiation Therapy, there was a session devoted to ontologies in radiation therapy. This paper is a compilation of the material presented, and is meant as an introduction to the subject. This is done by means of a didactic introduction to the topic followed by a series of applications in radiation therapy. The goal of this article is to provide the medical physicist and related professionals with sufficient background that they can understand their construction as well as their practical uses.

This chapter reviews new approaches to quality and safety improvement in radiation oncology with a specific focus on big data. One way to conceptualize big data's aspects of quality and safety is through the well-established quality model proposed by Avedis Donebedian and colleagues at the University of Michigan in the 1960s. In this paradigm, quality and safety measures fall into one of three categories: Structure, Process, and Outcomes. In the context of big data and oncology, most of the outcomes studies to date have focused on new methods to provide prognostic accuracy using radiomics signatures and the like. The chapter presents an effort to develop a semiautomatic method to identify anomalies in a patient's electronic medical record. There are a number of ways to approach the quality assurance problem programmatically, the two most common being rules-based systems and probabilistic models.