Drivers of Memory Loss Underreport in Mild Cognitive Impairment Due to Alzheimer Versus Vascular Disease.

BACKGROUND: We examined drivers of self and study partner reports of memory loss in mild cognitive impairment (MCI) from Alzheimer (AD-MCI) and vascular disease (Va-MCI). METHODS: We performed retrospective cross-sectional analyses of participants with AD-MCI (n=2874) and Va-MCI (n=376) from the National Alzheimer Coordinating Center data set. Statistical analysis utilized 2-sided t test or the Fisher exact test. RESULTS: Compared with AD-MCI, Va-MCI subjects (24.5% vs. 19.7%, P =0.031) and study partners (31.4% vs. 21.6%, P <0.0001) were more likely to deny memory loss. Black/African Americans were disproportionately represented in the group denying memory loss in AD-MCI (20.0% vs. 13.2%, P <0.0001) and Va-MCI (33.7% vs. 18.0%, P =0.0022). Study partners of participants with these features also disproportionately denied memory loss: female (AD-MCI: 60.1% vs. 51.7%, P =0.0002; Va-MCI: 70.3% vs. 52.3%, P =0.0011), Black/African American (AD-MCI: 23.5% vs. 11.98%, P <0.0001; Va-MCI: 48.8% vs. 26.5%, P =0.0002), and <16 years of education (AD-MCI only: 33.9% vs. 16.3%, P =0.0262). In AD-MCI and Va-MCI, participants with anxiety were disproportionately represented in the group endorsing memory loss (AD: 28.2% vs. 17.4%, P <0.0001; Va: 31.5% vs. 16.1%, P =0.0071), with analogous results with depression. CONCLUSION: The findings would suggest extra vigilance in interview-based MCI detection of persons at-risk for self-based or informant-based misreport.

Lymphatic expression of the proliferation marker Ki67 is linked to sentinel node positivity, recurrence and mortality in primary cutaneous melanoma.

Lymphangiogenesis is a precursor to lymphovascular invasion, and may therefore signal a higher risk of metastasis and mortality in primary cutaneous melanoma. This retrospective longitudinal study aimed to evaluate whether emergent lymphangiogenesis, as measured through co-expression of endothelial proteins with the proliferation marker Ki67, was associated with poorer prognosis in a cohort of patients with single primary cutaneous melanoma. We screened all patients with a single locally invasive primary cutaneous melanoma who received sentinel lymph node biopsy at a tertiary dermatology centre in Brisbane, Australia between 1994 and 2007. Primary melanoma sections were stained via Opal multiplex immunofluorescence, and categorized according to the presence of Ki67 within either CD31+ or D2-40+ endothelial cells. Multivariate Cox regression modelling was used to evaluate associations between endothelial Ki67 positivity and clinical outcomes, with adjustment for age, sex, Breslow depth, ulceration, and anatomical location. Overall, 264 patients were available for analysis, with a median follow-up duration of 7.1 years. The presence of D2-40+ /Ki67+ co-expression was associated with greater melanoma-specific mortality (adjusted hazard ratio [HR]: 2.03; 95% confidence interval [CI]: 1.33-3.10; p = 0.001) and recurrence (adjusted HR: 1.70; 95% CI: 1.33-3.10; p = 0.001) relative to absence. CD31+ /Ki67+ co-expression was not prognostic in this cohort. Lymphatic proliferation, as measured through D2-40+ /Ki67+ co-expression, predicted greater melanoma-specific mortality and recurrence in this cohort of primary cutaneous melanoma.

Microcanonical treatment of HCl dissociative chemisorption on Au(111): Reactive dampening through inefficient translational energy coupling and an active surface.

Microcanonical unimolecular rate theory is applied to Shirhatti and Wodtke's recent supersonic molecular beam experiments examining the activated dissociative chemisorption of HCl on Au(111). A precursor mediated microcanonical trapping (PMMT) model (where the surface vibrates and HCl rotations, vibration, and translation directed along the surface normal are treated as active degrees of freedom) gave dissociative sticking coefficient predictions that are several orders of magnitude higher than experimental values but in good accord with prior quantum and molecular dynamics simulations. Density functional theory (DFT) electronic structure calculations using the Perdew-Burke-Ernzerhof (PBE) functional served to fix the vibrational frequencies of the reactive transition state and the threshold energy for dissociation, E0 = 72.9 kJ/mol. To explore the possibilities of varying threshold energy, coupling to phonons, and dynamics, a three-parameter [E0, s, ɛn] dynamically biased (d-) PMMT model was fit to the experiments. A dynamical bias was introduced using an efficiency, ɛn, of normal translational energy to contribute to the active exchangeable energy capable of promoting reactivity. To achieve the low sticking probabilities observed in experiment, severe normal translational energy dampening (ɛn → 0.26) was imposed, leading to a large vibrational efficacy of ηv = εv/εn = 3.85. The optimal threshold energy for dissociation was E0 = 30.88 kJ/mol, some 40 kJ/mol below the PBE-DFT prediction, and the optimal number of Au surface oscillators was s = 1. The d-PMMT modeling indicates that HCl/Au(111) reactivity can be consistent with electronically adiabatic passage across a relatively low and late transition state that dynamically disfavors normal translational energy.

iCare - a self-directed, interactive online program to improve health and wellbeing for people living with upper gastrointestinal or hepato-pancreato-biliary cancers, and their informal carers: the study protocol for a Phase II randomised controlled trial.

BACKGROUND: Up to 70% of people diagnosed with upper gastrointestinal (GI) tract or hepato-pancreato-biliary (HPB) cancers experience substantial reductions in quality of life (QoL), including high distress levels, pain, fatigue, sleep disturbances, weight loss and difficulty swallowing. With few advocacy groups and support systems for adults with upper GI or HPB cancers (i.e. pancreas, liver, stomach, bile duct and oesophageal) and their carers, online supportive care programs may represent an alternate cost-effective mechanism to support this patient group and carers. iCare is a self-directed, interactive, online program that provides information, resources, and psychological packages to patients and their carers from the treatment phase of their condition. The inception and development of iCare has been driven by consumers, advocacy groups, government and health professionals. The aims of this study are to determine the feasibility and acceptability of iCare, examine preliminary efficacy on health-related QoL and carer burden at 3- and 6-months post enrolment, and the potential cost-effectiveness of iCare, from health and societal perspectives, for both patients and carers. METHODS AND ANALYSIS: A Phase II randomised controlled trial. Overall, 162 people with newly diagnosed upper GI or HPB cancers and 162 carers will be recruited via the Upper GI Cancer Registry, online advertisements, or hospital clinics. Patients and carers will be randomly allocated (1:1) to the iCare program or usual care. Participant assessments will be at enrolment, 3- and 6-months later. The primary outcomes are i) feasibility, measured by eligibility, recruitment, response and attrition rates, and ii) acceptability, measured by engagement with iCare (frequency of logins, time spent using iCare, and use of features over the intervention period). Secondary outcomes are patient changes in QoL and unmet needs, and carer burden, unmet needs and QoL. Linear mixed models will be fitted to obtain preliminary estimates of efficacy and variability for secondary outcomes. The economic analysis will include a cost-consequences analysis where all outcomes will be compared with costs. DISCUSSION: iCare provides a potential model of supportive care to improve QoL, unmet needs and burden of disease among people living with upper GI or HPB cancers and their carers. AUSTRALIAN AND NEW ZEALAND CLINICAL TRIALS REGISTRY: ACTRN12623001185651. This protocol reflects Version #1 26 April 2023.

Focusing a realist evaluation of peer support for paediatric mental health.

OBJECTIVE: Mental health problems are a leading and increasing cause of health-related burden in children across the world. Peer support interventions are increasingly used to meet this need using the lived experience of people with a history of mental health problems. However, much of the research underpinning this work has focused on adults, leaving a gap in knowledge about how these complex interventions may work for different children in different circumstances. Realist research may help us to understand how such complex interventions may trigger different mechanisms to produce different outcomes in children. This paper reports on an important first step in realist research, namely the construction of an embryonic initial programme theory to help 'focus' realist evaluation exploring how children's peer support services work in different contexts to produce different outcomes in the West Midlands (UK). METHODS: A survey and preliminary semi-structured realist interviews were conducted with 10 people involved in the delivery of peer support services. Realist analysis was carried out to produce context-mechanism-outcome configurations (CMOC). RESULTS: Analysis produced an initial programme theory of peer support for children's mental health. This included 12 CMOCs. Important outcomes identified by peer support staff included hope, service engagement, wellbeing, resilience, and confidence; each generated by different mechanisms including contextualisation of psychoeducation, navigating barriers to accessing services, validation, skill development, therapeutic relationship, empowerment, and reducing stigma. CONCLUSION: These data lay the groundwork for designing youth mental health realist research to evaluate with nuance the complexities of what components of peer support work for whom in varying circumstances.

Contour subregion error detection methodology using deep learning auto-segmentation.

BACKGROUND: Inaccurate manual organ delineation is one of the high-risk failure modes in radiation treatment. Numerous automated contour quality assurance (QA) systems have been developed to assess contour acceptability; however, manual inspection of flagged cases is a time-consuming and challenging process, and can lead to users overlooking the exact error location. PURPOSE: Our aim is to develop and validate a contour QA system that can effectively detect and visualize subregional contour errors, both qualitatively and quantitatively. METHODS/MATERIALS: A novel contour subregion error detection (CSED) system was developed using subregional surface distance discrepancies between manual and deep learning auto-segmentation (DLAS) contours. A validation study was conducted using a head and neck public dataset containing 339 cases and evaluated according to knowledge-based pass criteria derived from a clinical training dataset of 60 cases. A blind qualitative evaluation was conducted, comparing the results from the CSED system with manual labels. Subsequently, the CSED-flagged cases were re-examined by a radiation oncologist. RESULTS: The CSED system could visualize the diverse types of subregional contour errors qualitatively and quantitatively. In the validation dataset, the CSED system resulted in true positive rates (TPR) of 0.814, 0.800, and 0.771; false positive rates (FPR) of 0.310, 0.267, and 0.298; and accuracies of 0.735, 0.759, and 0.730, for brainstem and left and right parotid contours, respectively. The CSED-assisted manual review caught 13 brainstem, 19 left parotid, and 21 right parotid contour errors missed by conventional human review. The TPR/FPR/accuracy of the CSED-assisted manual review improved to 0.836/0.253/0.784, 0.831/0.171/0.830, and 0.808/0.193/0.807 for each structure, respectively. Further, the time savings achieved through CSED-assisted review improved by 75%, with the time for review taking 24.81 ± 12.84, 26.75 ± 10.41, and 28.71 ± 13.72 s for each structure, respectively. CONCLUSIONS: The CSED system enables qualitative and quantitative detection, localization, and visualization of manual segmentation subregional errors utilizing DLAS contours as references. The use of this system has been shown to help reduce the risk of high-risk failure modes resulting from inaccurate organ segmentation.

How much rotational error is clinically acceptable for single-isocenter/two-lesion lung SBRT treatment on halcyon ring delivery system (RDS)?

PURPOSE: SBRT treatment of two separate lung lesions via single-isocenter/multi-target (SIMT) plan on Halcyon RDS could improve patient comfort, compliance, patient throughput, and clinic efficiency. However, aligning two separate lung lesions synchronously via a single pre-treatment CBCT scan on Halcyon can be difficult due to rotational patient setup errors. Thus, to quantify the dosimetric impact, we simulated loss of target(s) coverage due to small, yet clinically observable rotational patient setup errors on Halcyon for SIMT treatments. METHODS: Seventeen previously treated 4D-CT based SIMT lung SBRT patients with two separate lesions (total 34 lesions, 50 Gy in five fractions to each lesion) on TrueBeam (6MV-FFF) were re-planned on Halcyon (6MV-FFF) using a similar arc geometry (except couch rotation), dose engine (AcurosXB algorithm), and treatment planning objectives. Rotational patient setup errors of [± 0.5° to ± 3.0°] on Halcyon were simulated via Velocity registration software in all three rotation axes and recalculated dose distributions in Eclipse treatment planning system. Dosimetric impact of rotational errors was evaluated for target coverage and organs at risk (OAR). RESULTS: Average PTV volume and distance to isocenter were 23.7 cc and 6.1 cm. Average change in Paddick's conformity indexes were less than -5%, -10%, and -15% for 1°, 2°, and 3°, respectively for yaw, roll, and pitch rotation directions. Maximum drop off of PTV(D100%) coverage for 2° rotation was -2.0% (yaw), -2.2% (roll), and -2.5% (pitch). With ±1° rotational error, no PTV(D100%) loss was found. Due to anatomical complexity: irregular and highly variable tumor sizes and locations, highly heterogenous dose distribution, and steep dose gradient, no trend for loss of target(s) coverage as a function of distance to isocenter and PTV size was found. Change in maximum dose to OAR were acceptable per NRG-BR001 within ±1.0° rotation, but were up to 5 Gy higher to heart with 2° in the pitch rotation axis. CONCLUSION: Our clinically realistic simulation results show that rotational patient setup errors up to 1.0° in any rotation axis could be acceptable for selected two separate lung lesions SBRT patients on Halcyon. Multivariable data analysis in large cohort is ongoing to fully characterize Halcyon RDS for synchronous SIMT lung SBRT.

Impact of white matter hyperintensities on subjective cognitive decline phenotype in a diverse cohort of cognitively normal older adults.

OBJECTIVES: Subjective cognitive decline (SCD) is a preclinical stage of AD. White matter hyperintensities (WMH), an MRI marker of cerebral small vessel disease, associate with AD biomarkers and progression. The impact of WMH on SCD phenotype is unclear. METHODS/DESIGN: A retrospective, cross-sectional analysis was conducted on a diverse cohort with SCD evaluated at the NYU Alzheimer's Disease Research Center between January 2017 and November 2021 (n = 234). The cohort was dichotomized into none-to-mild (n = 202) and moderate-to-severe (n = 32) WMH. Differences in SCD and neurocognitive assessments were evaluated via Wilcoxon or Fisher exact tests, with p-values adjusted for demographics using multivariable logistic regression. RESULTS: Moderate-to-severe WMH participants reported more difficulty with decision making on the Cognitive Change Index (1.5 SD 0.7 vs. 1.2 SD 0.5, p = 0.0187) and worse short-term memory (2.2 SD 0.4 vs. 1.9 SD 0.3, p = 0.0049) and higher SCD burden (9.5 SD 1.6 vs. 8.7 SD 1.7, p = 0.0411) on the Brief Cognitive Rating Scale. Moderate-to-severe WMH participants scored lower on the Mini-Mental State Examination (28.0 SD 1.6 vs. 28.5 SD 1.9, p = 0.0491), and on delayed paragraph (7.2 SD 2.0 vs. 8.8 SD 2.9, p = 0.0222) and designs recall (4.5 SD 2.3 vs. 6.1 SD 2.5, p = 0.0373) of the Guild Memory Test. CONCLUSIONS: In SCD, WMH impact overall symptom severity, specifically in executive and memory domains, as well as objective performance on global and domain-specific tests in verbal memory and visual working/associative memory.

Benchmarking halcyon ring delivery system for hypofractionated breast radiotherapy: Validation and clinical implementation of the fast-forward trial.

PURPOSE: The aim of this study was to demonstrate the feasibility and efficacy of an iterative CBCT-guided breast radiotherapy with Fast-Forward trial of 26 Gy in five fractions on a Halcyon Linac. This study quantifies Halcyon plan quality, treatment delivery accuracy and efficacy by comparison with those of clinical TrueBeam plans. MATERIALS AND METHODS: Ten accelerated partial breast irradiation (APBI) patients (four right, six left) who underwent Fast-Forward trial at our institute on TrueBeam (6MV beam) were re-planned on Halcyon (6MV-FFF). Three site-specific partial coplanar VMAT arcs and an Acuros-based dose engine were used. For benchmarking, PTV coverage, organs-at-risk (OAR) doses, beam-on time, and quality assurance (QA) results were compared for both plans. RESULTS: The average PTV was 806 cc. Compared to TrueBeam plans, Halcyon provided highly conformal and homogeneous plans with similar mean PTVD95 (25.72  vs. 25.73 Gy), both global maximum hotspot < 110% (p = 0.954) and similar mean GTV dose (27.04  vs. 26.80 Gy, p = 0.093). Halcyon provided lower volume of ipsilateral lung receiving 8 Gy (6.34% vs. 8.18%, p = 0.021), similar heart V1.5 Gy (16.75% vs. 16.92%, p = 0.872), V7Gy (0% vs. 0%), mean heart dose (0.96  vs. 0.9 Gy, p = 0.228), lower maximum dose to contralateral breast (3.2  vs. 3.6 Gy, p = 0.174), and nipple (19.6  vs. 20.1 Gy, p = 0.363). Compared to TrueBeam, Halcyon plans provided similar patient-specific QA pass rates and independent in-house Monte Carlo second check results of 99.6% vs. 97.9% (3%/2 mm gamma criteria) and 98.6% versus 99.2%, respectively, suggesting similar treatment delivery accuracy. Halcyon provided shorter beam-on time (1.49  vs. 1.68 min, p = 0.036). CONCLUSION: Compared to the SBRT-dedicated TrueBeam, Halcyon VMAT plans provided similar plan quality and treatment delivery accuracy, yet potentially faster treatment via one-step patient setup and verification with no patient collision issues. Rapid delivery of daily APBI on Fast-Forward trial on Halcyon with door-to-door patient time < 10 min, could reduce intrafraction motion errors, and improve patient comfort and compliance. We have started treating APBI on Halcyon. Clinical follow-up results are warranted. We recommend Halcyon users consider implementing the protocol to remote and underserved APBI patients in Halcyon-only clinics.

The spatial accuracy of ring-mounted halcyon linac versus C-arm TrueBeam linac for single-isocenter/multi-target SBRT treatment.

Stereotactic body radiotherapy (SBRT) treatment of oligometastatic lesions via single-isocenter/multi-target (SIMT) plan is more efficient than using multi-isocenter/multitarget SBRT. This study quantifies the spatial positioning accuracy of 2 commercially available LINAC systems for SIMT treatment pertaining to the potential amplification of error as a function of the target's distance-to-isocenter. We compare the Ring-Gantry Halcyon LINAC equipped with the fast iterative conebeam-CT (iCBCT) for image-guided SIMT treatment, and the SBRT-dedicated C-Arm TrueBeam with standard pretreatment CBCT imaging. For both systems, Sun Nuclear's MultiMet Winston-Lutz Cube phantom with 6 metallic BBs distributed at different planes up to 7 cm away from the isocenter was used. The phantom was aligned and imaged via CBCT, and then couch corrections were applied. To treat all 6 BBs, an Eclipse 10-field 3D-conformal Field-in-Field (2×2 cm2 MLC field to each BB) plan for varying gantry, collimator, and couch (TrueBeam only) positions was developed for both machines with 6MV-FFF beam. The plan was delivered through ARIA once a week. The EPID images were analyzed via Sun Nuclear's software for spatial positioning accuracy. On TrueBeam, the treatment plan was delivered twice: once with 3DoF translational corrections and once with PerfectPitch 6DoF couch corrections. The average 3D spatial positioning accuracy was 0.55 ± 0.30 mm, 0.54 ± 0.24 mm, and 0.56 ± 0.28 mm at isocenter, and 0.59 ± 0.30 mm, 0.69 ± 0.30 mm, and 0.70 ± 0.35 mm at 7 cm distance-to-isocenter for Halcyon, TrueBeam 3DoF, and TrueBeam 6DoF, respectively. This suggests there are no clinically significant deviations of spatial uncertainty between the platforms with the distance-to-isocenter. On both platforms, our weekly independent measurements demonstrated the reproducibility for less than 1.0 mm positional accuracy of off-axis targets up to 7 cm from the isocenter. Due to this, no additional PTV-margin is suggested for lesions within 7 cm of isocenter. This study confirms that Halcyon can deliver similar positional accuracy to SBRT-dedicated TrueBeam to off-axis targets up to 7 cm from isocenter. These results further benchmark the spatial uncertainty of our extensively used SBRT-dedicated TrueBeam LINAC for SIMT SBRT treatments.

Contouring quality assurance methodology based on multiple geometric features against deep learning auto-segmentation.

BACKGROUND: Contouring error is one of the top failure modes in radiation treatment. Multiple efforts have been made to develop tools to automatically detect segmentation errors. Deep learning-based auto-segmentation (DLAS) has been used as a baseline for flagging manual segmentation errors, but those efforts are limited to using only one or two contour comparison metrics. PURPOSE: The purpose of this research is to develop an improved contouring quality assurance system to identify and flag manual contouring errors. METHODS AND MATERIALS: DLAS contours were used as a reference to compare with manually segmented contours. A total of 27 geometric agreement metrics were determined from the comparisons between the two segmentation approaches. Feature selection was performed to optimize the training of a machine learning classification model to identify potential contouring errors. A public dataset with 339 cases was used to train and test the classifier. Four independent classifiers were trained using five-fold cross validation, and the predictions from each classifier were ensembled using soft voting. The trained model was validated on a held-out testing dataset. An additional independent clinical dataset with 60 cases was used to test the generalizability of the model. Model predictions were reviewed by an expert to confirm or reject the findings. RESULTS: The proposed machine learning multiple features (ML-MF) approach outperformed traditional nonmachine-learning-based approaches that are based on only one or two geometric agreement metrics. The machine learning model achieved recall (precision) values of 0.842 (0.899), 0.762 (0.762), 0.727 (0.842), and 0.773 (0.773) for Brainstem, Parotid_L, Parotid_R, and mandible contours, respectively compared to 0.526 (0.909), 0.619 (0.765), 0.682 (0.882), 0.773 (0.568) for an approach based solely on Dice similarity coefficient values. In the external validation dataset, 66.7, 93.3, 94.1, and 58.8% of flagged cases were confirmed to have contouring errors by an expert for Brainstem, Parotid_L, Parotid_R, and mandible contours, respectively. CONCLUSIONS: The proposed ML-MF approach, which includes multiple geometric agreement metrics to flag manual contouring errors, demonstrated superior performance in comparison to traditional methods. This method is easy to implement in clinical practice and can help to reduce the significant time and labor costs associated with manual segmentation and review.

Sensitized 1-Acyl-7-nitroindolines with Enhanced Two-Photon Cross Sections for Release of Neurotransmitters.

Precise photochemical control, using two-photon excitation (2PE), of the timing and location of activation of glutamate is useful for studying the molecular and cellular physiology of the brain. Antenna-based light harvesting strategies represent a general method to increase the sensitivity to 2PE of otherwise insensitive photoremovable protecting groups (PPGs). This was applied to the most commonly used form of "caged" glutamate, MNI-Glu. Computational investigation showed that a four- or six-carbon linker attached between the 4-position of thioxanthone (THX) and the 4-position of the 5-methyl derivative of MNI-Glu (MMNI-Glu) would position the antenna and PPG close to one another to enable Dexter energy transfer. Nine THX-MMNI-Glu conjugates were prepared and their photochemical properties determined. Installation of the THX antenna resulted in a red shift of the absorption (λmax = 385-405 nm) along with increased quantum yield compared to the parent compound MNI-Glu (λmax = 347 nm). The THX-MMNI-Glu conjugate with a four-carbon linker and attachment to the 4-position of THX underwent photolysis via 1PE at 405 and 430 nm and via 2PE at 770 and 860 nm, yielding glutamate. The two-photon uncaging action cross section (δu) was 0.11 and 0.29 GM at 770 and 860, respectively, which was greater than for MNI-Glu (0.06 and 0.072 GM at 720 and 770 nm, respectively). The THX sensitizer harvested the light via 2PE and transferred its resulting triplet energy to MMNI-Glu. Release of glutamate through 2PE at 860 nm from the compound (100 µM) activated iGluSnFR, a genetically encoded, fluorescent glutamate sensor, on the surface of cells in culture, portending its usefulness in studies of neurophysiology in acute brain slice.

Clinical validation of novel lightning dose optimizer for gamma knife radiosurgery of irregular-shaped arteriovenous malformations and pituitary adenomas.

PURPOSE: To demonstrate the clinical feasibility of a novel treatment planning algorithm via lightning dose optimizer (LDO) on Leksell Gamma Knife (LGK) GammaPlan with significantly faster planning times for stereotactic radiosurgery (SRS) of the complex and difficult arteriovenous malformations (AVMs) and pituitary adenomas. METHODS AND MATERIALS: After completing the in-house end-to-end phantom testing and independent dose verification of the recently upgraded LDO algorithm on GammaPlan using the MD Anderson's IROC anthropomorphic SRS head phantom irradiation credentialing, 20 previously treated GK-SRS patients (10 AVM, average volume 3.61 cm3 and 10 pituitary adenomas, average volume 0.86 cm3 ) who underwent manual forward planning on GammaPlan were retrospectively replanned via LDO. These pathologies were included because of the need for adequate dose delivery with organs at risk in very close proximity. LDO finds the target curvature boundary by well-formulated linear programing objectives and inversely optimizes the GK-SRS plan by isocenter placement, optimization, and sequencing. For identical target coverage, the LDO and original manual plans were compared for target conformity, gradient index, dose to critical organs, and surrounding normal brain. Additionally, various treatment delivery parameters, including beam-on time were recorded. RESULTS: For both patient cohorts, LDO provided similar target coverage with better dose conformity, tighter radiosurgical dose distribution with a lower value of gradient indices (all p < 0.001), and lower dose to critical organs. For AVMs, there was a significant reduction of normal brain V10Gy , V12Gy , and V14Gy by 4.74, 3.67, and 2.67 cm3 (all p < 0.001). LDO had twice the number of shots (p < 0.001), and longer beam-on time (p = 0.012) by a factor of 1.44. For pituitary adenomas, LDO provided systematically lower values of V10Gy , V12Gy , and V14Gy by 1.08, 0.86, and 0.68 cm3 (all p < 0.001), and lower maximum dose to optic pathway by 0.7 Gy (p = 0.005), but had almost twice the numbers of shots (p < 0.001) and increased beam-on time (p = 0.005) by a factor of 1.2. However, for both patient groups, the average planning time for the LDO was <5 min, compared to the estimated 30-90 min of manual planning times. CONCLUSION: GK-SRS treatment on Leksell Perfexion GammaPlan using the LDO provided highly conformal target coverage with a steep dose gradient, spared critical organs, and significantly reduced normal brain dose for complex targets at the cost of slightly higher treatment times. LDO generated high-quality treatment plans and could significantly reduce planning time. If available, the LDO algorithm is suggested for validation and clinical use for complex and difficult GK cases.

Feasibility Study of Stereotactic Radiosurgery Treatment of Glomus Jugulare Tumors via HyperArc VMAT.

This study aims to report on the clinical validation and feasibility of utilizing a novel fully automated treatment planning and delivery system, HyperArc VMAT stereotactic radiosurgery (SRS) for glomus jugulare tumors (GJT). Independent dose verification of the HyperArc module via the MD Anderson's SRS head phantom irradiation and credentialing results showed compliance with the SRS treatment requirements per IROC MD Anderson's standard. Following the Alliance clinical trial, AAPM, RTOG protocols, and QUANTEC requirements, utilizing selected three-partial arc geometry of HyperArc module on TrueBeam Linac with 6MV-FFF beam, GJT SRS plans were generated for nine previously treated Gamma Knife (GK) radiosurgery patients using advanced Acuros-based algorithm to account for tissue inhomogeneity corrections and frameless immobilization with Q-fix mask and Encompass device insert. HyperArc VMAT produced highly conformal SRS dose distributions to GJT, a steep dose gradient around the GJT, and spared adjacent critical organs including the spinal cord (< 3.0 Gy). Due to faster patient setup and less MLC modulation through the target (average beam-on time, 6.2 minutes), the HyperArc VMAT plan can deliver a single high-dose of 18 Gy to the GJT in less than 15 minutes overall treatment time, significantly improving patient comfort and clinic workflow. Pretreatment portal dosimetry quality assurance results and independent dose verification via Monte Carlo-based physics second check met our clinical SRS protocol's requirements for treatment. Due to the highly conformal dose distribution, rapid dose fall-off, excellent sparing of adjacent critical organs, and highly precise and accurate treatment, clinical implementation of frameless HyperArc VMAT for GJT patients who may not have access to nor tolerate frame-based GK SRS treatment are underway.

Conebeam CT-guided 3D MLC-based spatially fractionated radiation therapy for bulky masses.

For fast, safe, and effective management of large and bulky (≥8 cm) non-resectable tumors, we have developed a conebeam CT-guided three-dimensional (3D)-conformal MLC-based spatially fractionated radiation therapy (SFRT) treatment. Using an in-house MLC-fitting algorithm, Millennium 120 leaves were fitted to the gross tumor volume (GTV) generating 1-cm diameter holes at 2-cm center-to-center distance at isocenter. SFRT plans of 15 Gy were generated using four to six coplanar crossfire gantry angles 60° apart with a 90° collimator, differentially weighted with 6- or 10-MV beams. A dose was calculated using AcurosXB algorithm, generating sieve-like dose channels without post-processing the physician-drawn GTV contour within an hour of CT simulation allowing for the same day treatment. In total, 50 extracranial patients have been planned and treated using this method, comprising multiple treatment sites. This novel MLC-fitting algorithm provided excellent dose parameters with mean GTV (V7.5 Gy) and mean GTV doses of 53.2% and 7.9 Gy, respectively, for 15 Gy plans. Average peak-to-valley dose ratio was 3.2. Mean beam-on time was 3.32 min, and treatment time, including patient setup and CBCT to beam-off, was within 15 min. Average 3D couch correction from original skin-markers was <1.0 cm. 3D MLC-based SFRT plans enhanced target dose for bulky masses, including deep-seated large tumors while protecting skin and adjacent critical organs. Additionally, it provides the same day, safe, effective, and convenient treatment by eliminating the risk to therapists and patients from heavy gantry-mounted physical GRID-block-we recommend other centers to use this simple and clinically useful method. This rapid SFRT planning technique is easily adoptable in any radiation oncology clinic by eliminating the need for plan optimization and patient-specific quality assurance times while providing dosimetry information in the treatment planning system. This potentially allows for dose-escalation to deep-seated masses to debulk unresectable large tumors providing an option for neoadjuvant treatment. An outcome study of clinical trial is underway.

HyperArc VMAT stereotactic radiotherapy for locally recurrent previously-irradiated head and neck cancers: Plan quality, treatment delivery accuracy, and efficiency.

PURPOSE: This paper demonstrates the clinical feasibility and efficacy of HyperArc VMAT treatments for locally recurrent, locally advanced, or previously irradiated head and neck cancers treated with stereotactic radiotherapy (SRT). MATERIALS/METHODS: First, an anthropomorphic SRS head phantom from the MD Anderson's IROC credentialing laboratory containing a 1.9 cm diameter spherical target, including in vivo dosimetry system, was imaged, planned, and irradiated (25 Gy in 1 fraction) using HyperArc VMAT with a 6 MV flattening filter free (FFF) beam. Second, RANDO phantom was imaged, planned, and irradiated (35 Gy in 5 fractions) by generating eight HyperArc VMAT plans (4 right, 4 left neck tumors) at different anatomical locations (C1-C4). Average tumor volume was 21.7 cm3 up to 32.3 cm3 . Distance to isocenter from the central marker of the Encompass device down to neck was 25.8 cm up to 28.0 cm and 24.3 cm up to 27.1 cm for left- and right-sided neck tumors, respectively, and 9 cm from both lateral markers defined by the patient protection zone. Third, seven recurrent head and neck cancer patients with 80.3 cm3 tumors on average, and up to 159 cm3 , were imaged, planned, and treated with 30-40 Gy in 5 fractions with HyperArc SRT. Plan quality, treatment delivery accuracy, and efficiency are reported herein. RESULTS: Phantom irradiation results met all the compliance requirements set forth by the IROC for HyperArc SRS treatment. For end-to-end RANDO phantom tests, a highly conformal target dose distribution with 50% isodose fall-off within 5 mm from the surface of the target was obtained. Average beam modulation factor, beam-on-time, and overall treatment time were 2.9, 2.56 min, and 13.96 min with 99.1% pre-treatment quality assurance pass rate for the 2%/2 mm gamma criteria, respectively. Immediately adjacent critical structures, such as the spinal cord (maximum, 3.9 Gy and 0.35 cm3 of cord, 3.7 Gy) and skin (maximum, 10.3 Gy and 10 cm3 of skin, 5.7 Gy), were spared. Similar results were found on the patient's HyperArc VMAT plans including highly conformal target coverage, sharp dose fall-off, and low doses to the adjacent critical organs such as the spinal cord (< 5 Gy). Average perfect pitch couch correction was <1.5 mm and 2° in each direction. Average beam-on-time was approximately 3.21 min and treatments were completed within 15 min. CONCLUSION: For recurrent head and neck SRT treatments, HyperArc VMAT provided highly conformal dose distributions, rapid dose fall-off, excellent sparing of adjacent critical organs, and highly accurate treatments that could be delivered down to the C4 vertebral level. This could potentially allow for delivery of HyperArc SRT to patients with glomus tumors as well to those who may not tolerate frame-based SRS treatment. Clinical follow up of these patients is ongoing to confirm the therapeutic benefits of this novel treatment option.

Evaluating the clinical acceptability of deep learning contours of prostate and organs-at-risk in an automated prostate treatment planning process.

BACKGROUND: Radiation treatment is considered an effective and the most common treatment option for prostate cancer. The treatment planning process requires accurate and precise segmentation of the prostate and organs at risk (OARs), which is laborious and time-consuming when contoured manually. Artificial intelligence (AI)-based auto-segmentation has the potential to significantly accelerate the radiation therapy treatment planning process; however, the accuracy of auto-segmentation needs to be validated before its full clinical adoption. PURPOSE: A commercial AI-based contouring model was trained to provide segmentation of the prostate and surrounding OARs. The segmented structures were input to a commercial auto-planning module for automated prostate treatment planning. This study comprehensively evaluates the performance of this contouring model in the automated prostate treatment planning process. METHODS AND MATERIALS: A 3D U-Net-based model (INTContour, Carina AI) was trained and validated on 84 computed tomography (CT) scans and tested on an additional 23 CT scans from patients treated in our local institution. Prostate and OARs contours generated by the AI model (AI contour) were geometrically evaluated against reference contours. The prostate contours were further evaluated against AI, reference, and two additional observer contours for comparison using inter-observer variation (IOV) and 3D boundaries discrepancy analyses. A blinded evaluation was introduced to assess subjectively the clinical acceptability of the AI contours. Finally, treatment plans were created from an automated prostate planning workflow using the AI contours and were evaluated for their clinical acceptability following the Radiation Therapy Oncology Group-0815 protocol. RESULTS: The AI contours demonstrated good geometric accuracy on OARs and prostate contours, with average Dice similarity coefficients (DSC) for bladder, rectum, femoral heads, seminal vesicles, and penile bulb of 0.93, 0.85, 0.96, 0.72, and 0.53, respectively. The DSC, 95% directed Hausdorff distance (HD95), and mean surface distance for the prostate were 0.83 ± 0.05, 6.07 ± 1.87 mm, and 2.07 ± 0.73 mm, respectively. No significant differences were found when comparing with IOV. In the double-blinded evaluation, 95.7% of the AI contours were scored as either "perfect" (34.8%) or "acceptable" (60.9%), while only one case (4.3%) was scored as "unacceptable with minor changes required." In total, 69.6% of the AI contours were considered equal to or better than the reference contours by an independent radiation oncologist. Automated treatment plans created from the AI contours produced similar and clinically acceptable dosimetric distributions as those from plans created from reference contours. CONCLUSIONS: The investigated AI-based commercial model for prostate segmentation demonstrated good performance in clinical practice. Using this model, the implementation of an automated prostate treatment planning process is clinically feasible.

Feasibility of using ring-mounted Halcyon Linac for single-isocenter/two-lesion lung stereotactic body radiation therapy.

PURPOSE: To demonstrate the plan quality and delivery efficiency of volumetric-modulated arc therapy (VMAT) with the Halcyon Linac ring delivery system (RDS) in the treatment of single-isocenter/two-lesion lung stereotactic body radiation therapy (SBRT). MATERIALS/METHODS: Sixteen previously treated non-coplanar VMAT single-isocenter/two-lesion lung SBRT plans delivered with SBRT-dedicated C-arm TrueBeam Linac were selected. Prescribed dose was 50 Gy to each lesion over five fractions with treatment delivery every other day and AcurosXB algorithm as the final dose calculation algorithm. TrueBeam single-isocenter plans were reoptimized for Halcyon Linac with coplanar geometry. Both TrueBeam and Halcyon plans were normalized for identical combined target coverage and evaluated. Conformity indices (CIs), heterogeneity index (HI), gradient index (GI), gradient distance (GD), and D2cm were compared. The normal lung V5Gy, V10Gy, V20Gy, mean lung dose (MLD), and dose to organs at risk (OAR) were evaluated. Treatment delivery parameters, including beam-on time, were recorded. RESULTS: Halcyon plans were statistically similar to clinically delivered TrueBeam plans. No statistical differences in target conformity, dose heterogeneity, or intermediate-dose spillage were observed (all, p > 0.05). Halcyon plans, on average, demonstrated statistically insignificant reduced maximum dose to most adjacent OAR and normal lung. However, Halcyon yielded statistically significant lower maximal dose to the ribs (p = 0.041) and heart (p = 0.026), dose to 1 cc of ribs (p = 0.035) and dose to 5 cc of esophagus (p = 0.043). Plan complexity slightly increased as seen in the average increase of total monitor units, modulation factor, and beam-on time by 480, 0.48, and 2.78 min, respectively. However, the estimated overall treatment time was reduced by 2.22 min, on average. Mean dose delivery accuracy of clinical TrueBeam plans and the corresponding Halcyon plans was 98.9 ± 0.85% (range: 98.1%-100%) and 98.45 ± 0.99% (range: 97.9%-100%), respectively, demonstrating similar treatment delivery accuracy. CONCLUSION: SBRT treatment of synchronous lung lesions via single-isocenter VMAT on Halcyon RDS is feasible and dosimetrically equivalent to clinically delivered TrueBeam plans. Halcyon provides excellent plan quality and shorter overall treatment time that may improve patient compliance, reduce intrafraction movement, improve clinic efficiency, and potentially offering lung SBRT treatments for underserved patients on a Halcyon only clinic.

Double-vertebral segment SBRT via novel ring-mounted Halcyon Linac: Plan quality, delivery efficiency and accuracy.

To evaluate the plan quality, treatment delivery efficiency, and accuracy of single-isocenter/multi-target (SIMT) volumetric modulated arc therapy (VMAT) of double-vertebral segments stereotactic body radiation therapy (SBRT) on Halcyon ring delivery system (RDS). In-house multi-target end-to-end phantom testing and independent dose verification using the MD Anderson's single-isocenter/multi-target (lung/spine targets) thorax phantom were completed. Six previously treated patients with 2-vertebral segments on thoracic and/or lumber spine were replanned on Halcyon RDS with 6MV-FFF beam using a single-isocenter placed between the vertebral segments. Three full VMAT arcs with 0° and ±10° collimator angles and advanced Acuros-based dose engine for heterogeneity corrections were used. Prescription was 35 Gy in 5 fractions to each vertebral-segment, simultaneously. For comparison, Halcyon VMAT-SBRT plans were retrospectively created on SBRT-dedicated Truebeam with a 6MV-FFF beam using identical planning geometry and optimization objectives. Target coverage, conformity index (CI), heterogeneity index (HI), gradient index (GI), dose to 2-cm away from each target (D2-cm), and dose to adjacent organs-at-risk (OAR) were evaluated per NRG-BR002 protocol. Treatment delivery parameters were evaluated for both plans. In-house phantom measurements showed acceptable spatial accuracy (< 1mm within 5-cm from the isocenter) of conebeam CT-guided Halcyon SBRT treatments. The MD Anderson phantom irradiation credentialing results met IROC requirements for protocol patients. Mean isocenter-to-tumor center distance was 3.3 ± 0.6-cm (range 2.4 to 4.3-cm). Mean combined PTV was 57.3 ± 31.3 cc (range 20.1 to 99.9 cc). Both Halcyon and Truebeam SIMT-VMAT plans met NRG-BR002 compliance criteria and show similar CI, HI, GI, D2-cm. Maximal and volumetric doses to adjacent OAR including dose to partial spinal cord were lower with Halcyon RDS. Average total monitor units, modulation, and overall treatment time were lower with Halcyon plans by 130 MU, 0.2, 3.8 min, respectively, with similar beam-on time. Average pre-treatment patient-specific portal-dosimetry QA results on Halcyon showed a high pass rate of 99.6%, compared to SBRT-dedicated Truebeam pass rate of 96.8%, for 2%/2 mm clinical gamma passing criteria, suggesting more accurate treatment delivery on Halcyon RDS. SBRT treatment of double-vertebral segments via SIMT-VMAT plans on Halcyon for selected patients is feasible and dosimetrically superior to Truebeam Linac. Faster treatment delivery (<10 min) of double-vertebral segment SBRT on Halcyon could reduce patient intolerance due to severe back pain, potentially reduce intra-fraction motion errors, and improve patient throughput, and clinic workflow.