Reduction of patient specific quality assurance through plan complexity metrics for VMAT plans with an open-source TPS script

PURPOSE Volumetric modulated arc therapy (VMAT) is a widespread technique for the delivery of normo-fractionated radiation therapy (NFRT) and stereotactic body radiation therapy (SBRT). It is associated with a significant hardware burden requiring dose rate modulation, collimator movement and gantry rotation synchronisation. Patient specific quality assurance (PSQA) guarantees that the linacs can precisely and accurately deliver the planned dose. However, PSQA requires a significant time allocation and class solutions to reduce this while guaranteeing the deliverability of the plans should be investigated. METHODS In this study, an in-house developed Eclipse Scripting API (ESAPI) script was used to extract five independent plan complexity metrics from N = 667 VMAT treatment fields. The correlation between metrics and portal dosimetry measurements was investigated with Pearson correlation, box plot analysis and receiver operating characteristic curves, which were used to defined the best performing metric and its threshold. RESULTS The incidence of fields failing the clinical PSQA criteria of 3%/2mm (NFRT) and 3%/1.5mm (SBRT) was low (N = 1). The mean MLC opening was the metric with the highest correlation with the portal dosimetry data and among the best in discriminating the requirement of PSQA. The thresholds of 16.12 mm (NFRT) and 7.96 mm (SBRT) corresponded to true positive rates higher than 90%. CONCLUSIONS This work presents a quantitative approach to reduce the time allocation for PSQA by identifying the most complex plans demanding a dedicated measurement. The proposed method requires PSQA for approximately 10% of the plans. The ESAPI script is distributed open-source to ease the investigation and implementation at other institutions

Using endogenous saccades to characterize fatigue in multiple sclerosis

Purpose Multiple Sclerosis (MS) is likely to cause dysfunction of neural circuits between brain regions increasing brain working load or a subjective overestimation of such working load leading to fatigue symptoms. The aim of this study was to investigate if saccades can reveal the effect of fatigue in patients with MS. Methods Patients diagnosed with MS (EDSS<=3) and age matched controls were recruited. Eye movements were monitored using an infrared eyetracker. Each participant performed 40 trials in an endogenous generated saccade paradigm (valid and invalid trials). The fatigue severity scale (FSS) was used to assess the severity of fatigue. FSS scores were used to define two subgroups, the MS fatigue group (score above normal range) and the MS non-fatigue. Differences between groups were tested using linear mixed models. Results Thirty-one MS patients and equal number of controls participated in this study. FSS scores were above the normal range in 11 patients. Differences in saccade latency were found according to group (p<0.001) and trial validity (p=0.023). Differences were 16.9 ms, between MS fatigue and MS non-fatigue, 15.5 ms between MS fatigue and control. The mean difference between valid and invalid trials was 7.5 ms. Differences in saccade peak velocity were found according to group (p<0.001), the difference between MS fatigue and control was 22.3°/s and between MS fatigue and non-fatigue was 12.3°/s. Group was a statistically significant predictor for amplitude (p<0.001). FSS scores were correlated with peak velocity (p=0.028) and amplitude (p=0.019). Conclusion Consistent with the initial hypothesis, our study revealed altered saccade latency, peak velocity and amplitude in patients with fatigue symptoms. Eye movement testing can complement the standard inventories when investigating fatigue because they do not share similar limitations. Our findings contribute to the understanding of functional changes induced by MS and might be useful for clinical trials and treatment decisions.We would like to acknowledge that part of this work has been presented at 3rd International Porto Congress of Multiple Sclerosis, February 27–28, 2015, Porto, Portugal and ECEM 2015 | XVIII. European Conference on Eye Movements, August 16–21, 2015, Viena, Austria. We thank the Multiple Sclerosis Association “Todos com a Esclerose Multiple (TEM)” and the Clinical and Academic Centre (CAA-Hospital de Braga) for their support financial support and for providing facilities for data collection, respectively. We also acknowledge: i) Carla Sofia for recruiting all the MS participants and most of the controls, ii) Two anonymous reviewers for their opinion about an early version of this manuscript and iii) Liz Pearce for proofreading the manuscript. Vision Rehabilitation Lab. receives founding from Shamir Portugal and from grant PTDC/DTP-EPI/0412/2012, Fundação para a Ciência e a Tecnologia, co-financiado pelo FEDER através do COMPETE.info:eu-repo/semantics/publishedVersio

Ribosomal protein l13a as a reference gene for human bone marrow-derived mesenchymal stromal cells during expansion, adipo-, chondro-, and osteogenesis

In the field of human mesenchymal stromal cell (MSC) research, quantitative real-time reverse transcription-polymerase chain reaction (qPCR) is the method of choice to study changes in gene expression patterns upon differentiation, application of stimuli, or of factors such as inhibitors or siRNAs. To reliably detect small changes, the use of a reference gene (RG) that is stably expressed under all conditions is essential. The large number of different RGs used in the field and the lack of validation of their suitability make the comparison between studies impossible. Therefore, this work aims to establish one single RG for mesodermal differentiation studies that use MSCs. Seven commonly used RGs (glyceraldehyde-3-phosphate dehydrogenase [GAPDH], ribosomal protein L13a [RPL13a], beta-actin [ACTB], tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, zeta-polypeptide [YWHAZ], eukaryotic translational elongation factor 1 alpha [EF1α], β2-microglobulin [B2M], and 18S ribosomal RNA [18S]) were investigated concerning their mRNA expression stability during expansion of bone marrow-derived MSCs up to four passages as well as during their adipo-, chondro-, and osteogenenic differentiation on days 9, 16, and 22 after induction. RPL13a was validated for qPCR studies of MSCs (bone marrow- and placenta-derived) and, additionally, for primary human bone cells (HBCs) and the osteosarcoma cell line MG-63. GAPDH and ACTB, the two most frequently used RGs, showed the highest expression variance. The superior performance of RPL13a should make it the RG of choice for all MSC studies addressing mesodermal differentiation

MR-guided beam gating: Residual motion, gating efficiency and dose reconstruction for stereotactic treatments of the liver and lung

PURPOSE This study aims to investigate the efficiency and the geometric as well as the dosimetric benefit of magnetic-resonance guided beam gating for stereotactic treatments in moving organs. METHOD Patients treated with MR-guided (MRIdian system) SBRT for lung (n = 10) and liver (n = 10) targets were analyzed. Breath-hold gating was performed based on lesion tracking in sagittal cine MRI images. The target offset from the geometric center of the gating window with and without gating was evaluated. A dose reconstruction workflow based on convolution of these 2D position-probability maps and the daily 3D dose distribution was used to estimate the daily delivered dose including motion. The dose to the clinical target volume (CTV) and to a 2-cm ring structure around the planning target volume were evaluated. RESULTS The applied gating protocol resulted in a mean (±standard deviation) gating efficiency of 55%±16%. Over all patients, the mean target offset (2D-root-mean-square error) was 8.3 ± 4.3 mm, which reduced to 2.4 ± 0.6 mm during gating. The dose reconstruction showed a mean deviation in CTV coverage (D95) from the static plans of -1.7%±1.8% with gating and -12.0%±8.4% if no gating would have been used. The mean dose (Dmean) in the ring structure, with respect to the static plans, showed mean deviations of -0.1%±0.3% with gating and -1.6%±1.8% without gating. CONCLUSION The MRIdian system enables gating based on the inner anatomy and the implemented dose reconstruction workflow demonstrated geometric robust delivery of the planned radiation doses

Modeling and performance evaluation of a robotic treatment couch for tumor tracking

Tumor motion during radiation therapy increases the irradiation of healthy tissue. However, this problem may be mitigated by moving the patient via the treatment couch such that the tumor motion relative to the beam is minimized. The treatment couch poses limitations to the potential mitigation, thus the performance of the Protura (CIVCO) treatment couch was characterized and numerically modeled. The unknown parameters were identified using chirp signals and verified with one-dimensional tumor tracking. The Protura tracked chirp signals well up to 0.2 Hz in both longitudinal and vertical directions. If only the vertical or only the longitudinal direction was tracked, the Protura tracked well up to 0.3 Hz. However, there was unintentional yet substantial lateral motion in the former case. And during vertical motion, the extension caused rotation of the Protura around the lateral axis. The numerical model matched the Protura up to 0.3 Hz. Even though the Protura was designed for static positioning, it was able to reduce the tumor motion by 69% (median). The correlation coefficient between the tumor motion reductions of the Protura and the model was 0.99. Therefore, the model allows tumor-tracking results of the Protura to be predicted

Intra- and inter-fraction breath-hold variations and margins for radiotherapy of abdominal targets

Radiotherapy in expiration breath-hold (EBH) has the potential to reduce treatment volumes of abdominal targets compared to an internal target volume concept in free-breathing. The reproducibility of EBH and required safety margins were investigated to quantify this volumetric benefit. Pre- and post-treatment diaphragm position difference and the positioning variability were determined on computed tomography. Systematic and random errors for EBH position reproducibility and positioning variability were calculated, resulting in margins of 7 to 12 mm depending on the prescription isodose and fractionation. A reduced volume was shown for EBH for lesions with superior-inferior breathing motion above 4 to 8 mm

Dose escalation for stereotactic arrhythmia radioablation of recurrent ventricular tachyarrhythmia - a phase II clinical trial

BACKGROUND: Stereotactic arrhythmia radioablation (STAR) is delivered with a planning target volume (PTV) prescription dose of 25 Gy, mostly to the surrounding 75-85% isodose line. This means that the average and maximum dose received by the target is less than 35 Gy, which is the minimum threshold required to create a homogenous transmural fibrosis. Similar to catheter ablation, the primary objective of STAR should be transmural fibrosis to prevent heterogenous intracardiac conduction velocities and the occurrence of sustained ventricular arrhythmias (sVA) caused by reentry. We hypothesize that the current dose prescription used in STAR is inadequate for the long-term prevention of sVA and that a significant increase in dose is necessary to induce transmural scar formation. OBJECTIVE: A single arm, multi-center, phase II, dose escalation prospective clinical trial employing the i3 + 3 design is being conducted to examine the safety of a radiation dose-escalation strategy aimed at inducing transmural scar formation. The ultimate objective of this trial is to decrease the likelihood of sVA recurrence in patients at risk. METHODS: Patients with ischemic or non-ischemic cardiomyopathy and recurrent sVA, with an ICD and history of ≥ 1 catheter ablation for sVA will be included. This is a prospective, multicenter, one-arm, dose-escalation trial utilizing the i3 + 3 design, a modified 3 + 3 specifically created to overcome limitations in traditional dose-finding studies. A total of 15 patients will be recruited. The trial aims to escalate the ITV dose from 27.0 Gy to an ITV prescription dose-equivalent level of maximum 35.1 Gy by keeping the PTV prescription dose constant at 25 Gy while increasing the dose to the target (i.e. the VT substrate without PTV margin) by step-wise reduction of the prescribing isodose line (85% down to 65%). The primary outcome of this trial is safety measured by registered radiation associated adverse events (AE) up to 90 days after study intervention including radiation associated serious adverse events graded as at least 4 or 5 according to CTCAE v5, radiation pneumonitis or pericarditis requiring hospitalization and decrease in LVEF ≥ 10% as assessed by echocardiography or cardiac MRI at 90 days after STAR. The sample size was determined assuming an acceptable primary outcome event rate of 20%. Secondary outcomes include sVA burden at 6 months after STAR, time to first sVA recurrence, reduction in appropriate ICD therapies, the need for escalation of antiarrhythmic drugs, non-radiation associated safety and patient reported outcome measures such as SF-36 and EQ5D. DISCUSSION: DEFT-STAR is an innovative prospective phase II trial that aims to evaluate the optimal radiation dose for STAR in patients with therapy-refractory sVA. The trial has obtained IRB approval and focuses on determining the safe and effective radiation dose to be employed in the STAR procedure

Quality assurance process within the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial for the fusion of electroanatomical mapping and radiotherapy planning imaging data in cardiac radioablation

A novel quality assurance process for electroanatomical mapping (EAM)-to-radiotherapy planning imaging (RTPI) target transport was assessed within the multi-center multi-platform framework of the RAdiosurgery for VENtricular TAchycardia (RAVENTA) trial. A stand-alone software (CARDIO-RT) was developed to enable platform independent registration of EAM and RTPI of the left ventricle (LV), based on pre-generated radiotherapy contours (RTC). LV-RTC were automatically segmented into the American-Heart-Association 17-segment-model and a manual 3D-3D method based on EAM 3D-geometry data and a semi-automated 2D-3D method based on EAM screenshot projections were developed. The quality of substrate transfer was evaluated in five clinical cases and the structural analyses showed substantial differences between manual target transfer and target transport using CARDIO-RT

Refining Treatment Planning in STereotactic Arrhythmia Radioablation: Benchmark Results and Consensus Statement From the STOPSTORM.eu Consortium

PURPOSE STereotactic Arrhythmia Radioablation (STAR) showed promising results in patients with refractory ventricular tachycardia. However, clinical data are scarce and heterogeneous. The STOPSTORM.eu consortium was established to investigate and harmonize STAR in Europe. The primary goal of this benchmark study was to investigate current treatment planning practice within the STOPSTORM project as a baseline for future harmonization. METHODS AND MATERIALS Planning target volumes (PTVs) overlapping extracardiac organs-at-risk and/or cardiac substructures were generated for 3 STAR cases. Participating centers were asked to create single-fraction treatment plans with 25 Gy dose prescriptions based on in-house clinical practice. All treatment plans were reviewed by an expert panel and quantitative crowd knowledge-based analysis was performed with independent software using descriptive statistics for International Commission on Radiation Units and Measurements report 91 relevant parameters and crowd dose-volume histograms. Thereafter, treatment planning consensus statements were established using a dual-stage voting process. RESULTS Twenty centers submitted 67 treatment plans for this study. In most plans (75%) intensity modulated arc therapy with 6 MV flattening filter free beams was used. Dose prescription was mainly based on PTV D_{95%} (49%) or D_{96%-100%} (19%). Many participants preferred to spare close extracardiac organs-at-risk (75%) and cardiac substructures (50%) by PTV coverage reduction. PTV D$_{0.035cm3}$ ranged from 25.5 to 34.6 Gy, demonstrating a large variety of dose inhomogeneity. Estimated treatment times without motion compensation or setup ranged from 2 to 80 minutes. For the consensus statements, a strong agreement was reached for beam technique planning, dose calculation, prescription methods, and trade-offs between target and extracardiac critical structures. No agreement was reached on cardiac substructure dose limitations and on desired dose inhomogeneity in the target. CONCLUSIONS This STOPSTORM multicenter treatment planning benchmark study not only showed strong agreement on several aspects of STAR treatment planning, but also revealed disagreement on others. To standardize and harmonize STAR in the future, consensus statements were established; however, clinical data are urgently needed for actionable guidelines for treatment planning