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Abstract Background Cysteine proteinases perform multiple functions in seeds, including participation in remodelling polypeptides and recycling amino acids during maturation and germination. Currently, few details exist concerning these genes and proteins in coffee. Furthermore, there is limited information on the cysteine proteinase inhibitors which influence the activities of these proteinases. Results Two cysteine proteinase (CP) and four cysteine proteinase inhibitor (CPI) gene sequences have been identified in coffee with significant expression during the maturation and germination of coffee grain. Detailed expression analysis of the cysteine proteinase genes CcCP1 and CcCP4 in Robusta using quantitative RT-PCR showed that these transcripts accumulate primarily during grain maturation and germination/post germination. The corresponding proteins were expressed in E. coli and purified, but only one, CcCP4, which has a KDDL/KDEL C-terminal sequence, was found to be active after a short acid treatment. QRT-PCR expression analysis of the four cysteine proteinase inhibitor genes in Robusta showed that CcCPI-1 is primarily expressed in developing and germinating grain and CcCPI-4 is very highly expressed during the late post germination period, as well as in mature, but not immature leaves. Transcripts corresponding to CcCPI-2 and CcCPI-3 were detected in most tissues examined at relatively similar, but generally low levels. Conclusions Several cysteine proteinase and cysteine proteinase inhibitor genes with strong, relatively specific expression during coffee grain maturation and germination are presented. The temporal expression of the CcCP1 gene suggests it is involved in modifying proteins during late grain maturation and germination. The expression pattern of CcCP4, and its close identity with KDEL containing CP proteins, implies this proteinase may play a role in protein and/or cell remodelling during late grain germination, and that it is likely to play a strong role in the programmed cell death associated with post-germination of the coffee grain. Expression analysis of the cysteine proteinase inhibitor genes suggests that CcCPI-1 could primarily be involved in modulating the activity of grain CP activity; while CcCPI-4 may play roles modulating grain CP activity and in the protection of the young coffee seedlings from insects and pathogens. CcCPI-2 and CcCPI-3, having lower and more widespread expression, could be more general "house-keeping" CPI genes.

Hypomethylating agents are the most widely used upfront therapy for patients with myelodysplastic syndrome (MDS) who are not suitable for hematopoietic stem cell transplantation. In Australia, azacitidine was, until recently, the only approved and subsidized treatment for patients with intermediate-2 and high-risk MDS, chronic myelomonocytic leukemia, and low blast acute myeloid leukemia. We analyzed prescription data to evaluate the real-world persistence and overall survival (OS) of patients prescribed azacitidine for the first time in Australia. A retrospective cohort analysis of patients who had been prescribed Pharmaceutical Benefits Scheme (PBS)-listed azacitidine for the first time, between January 2016 and April 2021, was conducted using the PBS 10% dataset. Treatment persistence and OS were estimated using Kaplan-Meier methods. The impact of the number of treatment cycles and treatment adherence on OS was also estimated. There were 351 patients in the PBS 10% dataset who initiated treatment with azacitidine. The average age (standard deviation [SD]) at azacitidine initiation was 71.9 (11.1) years and the average number (SD) of azacitidine prescriptions was 5.6 (0.2). The median persistence on azacitidine was 15.6 months, and the OS was 13.4 months. The median OS for patients who had six or more cycles of azacitidine treatment was greater compared to patients who had five or less cycles of treatment. The data from this real-world study illustrate the unmet medical needs of patients with MDS treated with azacitidine in Australia. The majority of patients are not treated with the optimal number of cycles of azacitidine, which is negatively correlated with patient outcomes., Competing Interests: Anoop Enjeti has acted as an advisor and received honoraria on speaker panel for ASTEX/OTSUKA. The authors declare no conflicts of interest specifically related to this retrospective review. Francesco Castaldi and Taleisha Paine are employees of ASTEX/OTSUKA but are not the commercial manufacturers of any of the drugs analyzed in this PBS dataset analysis. Harold Keer was employed by ASTEX Pharmaceuticals, Inc. (USA) during manuscript development. Harold Keer is currently employed by Taiho Oncology, Inc. (USA). Asma Ashraf, Jonathan Silar, Vincent Caillet, and Arif Alam declare they have no conflicts of interest., (© 2024 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Aim: Gout is the most common form of inflammatory arthritis in men. Despite the availability of effective urate-lowering therapies (ULT), the management of gout is suboptimal due to poor persistence with ULT. This study examined national prescribing patterns of ULT to determine persistence with allopurinol in Australia., Methods: A 10% sample of the Australian Pharmaceutical Benefits Scheme dispensing claims database was used to identify individuals initiated on allopurinol between April 2014 and December 2019. The number of allopurinol scripts dispensed was used to estimate persistence with allopurinol. Persistence was defined as the number of months from initiation until discontinuation (last prescription with no further scripts acquired for a period thereafter). Kaplan-Meier curves were used to examine persistence, while Cox regression analysis was used to examine the influence of gender, concomitant colchicine and age., Results: The largest drop in persistence occurred immediately after initiation, with 34% of patients discontinuing allopurinol 300-mg therapy in the first month. Median persistence with allopurinol 300 mg was 5 months (95% confidence interval 4.76-5.24), with around 63% of individuals not persisting with this therapy for more than 12 months. Concomitant prescription of colchicine on the day of allopurinol initiation only occurred in 7% of allopurinol initiations. No increase in persistence was observed for those co-prescribed colchicine., Conclusion: Persistence with allopurinol was poor. More effective methods targeting prescribers, patients and systems are required to promote persistence with allopurinol. Improving persistence to allopurinol is an important public health goal given the proven potential of this medication to eliminate gout., (© 2022 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Background: Fiducial markers are used as surrogates for tumor location during radiation therapy treatment. Developments in lung fiducial marker and implantation technology have provided a means to insert markers endobronchially for tracking of lung tumors. This study quantifies the surrogacy uncertainty (SU) when using endobronchially implanted markers as a surrogate for lung tumor position., Methods: We evaluated SU for 17 patients treated in a prospective electromagnetic-guided MLC tracking trial. Tumor and markers were segmented on all phases of treatment planning 4DCTs and all frames of pretreatment kilovoltage fluoroscopy acquired from lateral and frontal views. The difference in tumor and marker position relative to end-exhale position was calculated as the SU for both imaging methods and the distributions of uncertainties analyzed., Results: The mean (range) tumor motion amplitude in the 4DCT scan was 5.9 mm (1.7-11.7 mm) in the superior-inferior (SI) direction, 2.2 mm (0.9-5.5 mm) in the left-right (LR) direction, and 3.9 mm (1.2-12.9 mm) in the anterior-posterior (AP) direction. Population-based analysis indicated symmetric SU centered close to 0 mm, with maximum 5th/95th percentile values over all axes of -2.0 mm/2.1 mm with 4DCT, and -2.3/1.3 mm for fluoroscopy. There was poor correlation between the SU measured with 4DCT and that measured with fluoroscopy on a per-patient basis. We observed increasing SU with increasing surrogate motion. Based on fluoroscopy analysis, the mean (95% CI) SU was 5% (2%-8%) of the motion magnitude in the SI direction, 16% (6%-26%) of the motion magnitude in the LR direction, and 33% (23%-42%) of the motion magnitude in the AP direction. There was no dependence of SU on marker distance from the tumor., Conclusion: We have quantified SU due to use of implanted markers as surrogates for lung tumor motion. Population 95th percentile range are up to 2.3 mm, indicating the approximate contribution of SU to total geometric uncertainty. SU was relatively small compared with the SI motion, but substantial compared with LR and AP motion. Due to uncertainty in estimations of patient-specific SU, it is recommended that population-based margins are used to account for this component of the total geometric uncertainty., (© 2021 American Association of Physicists in Medicine.)

Purpose: In multileaf collimator (MLC) tracking, the MLC positions from the original treatment plan are continuously modified to account for intrafraction tumor motion. As the treatment is adapted in real time, there is additional risk of delivery errors which cannot be detected using traditional pretreatment dose verification. The purpose of this work is to develop a system for real-time geometric verification of MLC tracking treatments using an electronic portal imaging device (EPID)., Methods: MLC tracking was utilized during volumetric modulated arc therapy (VMAT). During these deliveries, treatment beam images were taken at 9.57 frames per second using an EPID and frame grabber computer. MLC positions were extracted from each image frame and used to assess delivery accuracy using three geometric measures: the location, size, and shape of the radiation field. The EPID-measured field location was compared to the tumor motion measured by implanted electromagnetic markers. The size and shape of the beam were compared to the size and shape from the original treatment plan, respectively. This technique was validated by simulating errors in phantom test deliveries and by comparison between EPID measurements and treatment log files. The method was applied offline to images acquired during the LIGHT Stereotactic Ablative Body Radiotherapy (SABR) clinical trial, where MLC tracking was performed for 17 lung cancer patients. The EPID-based verification results were subsequently compared to post-treatment dose reconstruction., Results: Simulated field location errors were detected during phantom validation tests with an uncertainty of 0.28 mm (parallel to MLC motion) and 0.38 mm (perpendicular), expressed as a root-mean-square error (RMS Error ). For simulated field size errors, the RMS Error was 0.47 cm 2 and field shape changes were detected for random errors with standard deviation ≥ 2.5 mm. For clinical lung SABR deliveries, field location errors of 1.6 mm (parallel MLC motion) and 4.9 mm (perpendicular) were measured (expressed as a full-width-half-maximum). The mean and standard deviation of the errors in field size and shape were 0.0 ± 0.3 cm 2 and 0.3 ± 0.1 (expressed as a translation-invariant normalized RMS). No correlation was observed between geometric errors during each treatment fraction and dosimetric errors in the reconstructed dose to the target volume for this cohort of patients., Conclusion: A system for real-time delivery verification has been developed for MLC tracking using time-resolved EPID imaging. The technique has been tested offline in phantom-based deliveries and clinical patient deliveries and was used to independently verify the geometric accuracy of the MLC during MLC tracking radiotherapy., (© 2020 American Association of Physicists in Medicine.)

Background and Purpose: The purpose of this work is to present the clinical experience from the first-in-human trial of real-time tumor targeting via MLC tracking for stereotactic ablative body radiotherapy (SABR) of lung lesions., Methods and Materials: Seventeen patients with stage 1 non-small cell lung cancer (NSCLC) or lung metastases were included in a study of electromagnetic transponder-guided MLC tracking for SABR (NCT02514512). Patients had electromagnetic transponders inserted near the tumor. An MLC tracking SABR plan was generated with planning target volume (PTV) expanded 5 mm from the end-exhale gross tumor volume (GTV). A clinically approved comparator plan was generated with PTV expanded 5 mm from a 4DCT-derived internal target volume (ITV). Treatment was delivered using a standard linear accelerator to continuously adapt the MLC based on transponder motion. Treated volumes and reconstructed delivered dose were compared between MLC tracking and comparator ITV-based treatment., Results: All seventeen patients were successfully treated with MLC tracking (70 successful fractions). MLC tracking treatment delivery time averaged 8 minutes. The time from the start of CBCT to the end of treatment averaged 22 minutes. The MLC tracking PTV for 16/17 patients was smaller than the ITV-based PTV (range -1.6% to 44% reduction, or -0.6 to 18 cc). Reductions in mean lung dose (27 cGy) and V20Gy (50 cc) were statistically significant (p < 0.02). Reconstruction of treatment doses confirmed a statistically significant improvement in delivered GTV D98% (p < 0.05) from planned dose compared with the ITV-based plans., Conclusion: The first treatments with lung MLC tracking have been successfully performed in seventeen SABR patients. MLC tracking for lung SABR is feasible, efficient and delivers high-precision target dose and lower normal tissue dose., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: The purpose of this work was to report on the geometric uncertainty for patients treated with multi-leaf collimator (MLC) tracking for lung SABR to verify the accuracy of the system., Methods: Seventeen patients were treated as part of the MLC tracking for lung SABR clinical trial using electromagnetic beacons implanted around the tumor acting as a surrogate for target motion. Sources of uncertainties evaluated in the study included the surrogate-target positional uncertainty, the beam-surrogate tracking uncertainty, the surrogate localization uncertainty, and the target delineation uncertainty. Probability density functions (PDFs) for each source of uncertainty were constructed for the cohort and each patient. The total PDFs was computed using a convolution approach. The 95% confidence interval (CI) was used to quantify these uncertainties., Results: For the cohort, the surrogate-target positional uncertainty 95% CIs were ±2.5 mm (-2.0/3.0 mm) in left-right (LR), ±3.0 mm (-1.6/4.5 mm) in superior-inferior (SI) and ±2.0 mm (-1.8/2.1 mm) in anterior-posterior (AP). The beam-surrogate tracking uncertainty 95% CIs were ±2.1 mm (-2.1/2.1 mm) in LR, ±2.8 mm (-2.8/2.7 mm) in SI and ±2.1 mm (-2.1/2.0 mm) in AP directions. The surrogate localization uncertainty minimally impacted the total PDF with a width of ±0.6 mm. The target delineation uncertainty distribution 95% CIs were ±5.4 mm. For the total PDF, the 95% CIs were ±5.9 mm (-5.8/6.0 mm) in LR, ±6.7 mm (-5.8/7.5 mm) in SI and ±6.0 mm (-5.5/6.5 mm) in AP., Conclusion: This work reports the geometric uncertainty of MLC tracking for lung SABR by accounting for the main sources of uncertainties that occurred during treatment. The overall geometric uncertainty is within ±6.0 mm in LR and AP directions and ±6.7 mm in SI. The dominant uncertainty was the target delineation uncertainty. This geometric analysis helps put into context the range of uncertainties that may be expected during MLC tracking for lung SABR (ClinicalTrials.gov registration number: NCT02514512).

Background and Purpose: To test the hypothesis that 4DCT and 4DCBCT-measured target motion ranges predict target motion ranges during lung cancer SABR., Materials and Methods: Ten lung SABR patients were implanted with Calypso beacons. 4DCBCT was reconstructed for 29 fractions (1-4fx/patient) from a 1 min CBCT scan. The beacon centroid motion segmented for all 4DCT and 4DCBCT bins was compared with the real-time imaging and treatment beacon centroid ("target") motion range (4SDs) for each fraction. We tested the hypotheses that (1) 4DCT and 4CBCT predict treatment motion range and (2) there is no difference between 4DCT and 4DCBCT for predicting treatment motion range. Phase-wise root-mean-square errors (RMSEs) between imaging and treatment motion and reconstructed motion (4DCT, 4DCBCT) were calculated. Relationships between motion ranges in 4DCT and 4DCBCT and imaging and treatment motion ranges were investigated for the superior-inferior (SI), left-right (LR) and anterior-posterior (AP) directions. Baseline drifts and amplitude variability were investigated as potential factors leading to motion misrepresentation., Results: SI 4DCT, 4DCBCT, imaging and treatment motion ranges were 6.3 ± 3.6 mm, 7.1 ± 4.5 mm, 11.1 ± 7.5 mm and 10.9 ± 6.9 mm, respectively. Similar 4DCT and 4DCBCT under-predictions were observed in the LR and AP directions. Hypothesis (1) was rejected (p < 0.0001). Treatment target motion range was under-predicted in 4DCT by factors of 1.7, 1.9 and 1.7 and in 4DCBCT by factors of 1.5, 1.6 and 1.6 in the SI, LR, and AP directions, respectively. RMSEs were generally lower for end-exhale than inhale. 4DCBCT showed higher correlations with the imaging and treatment target motion than 4DCT and testing hypothesis (2) a statistically significant difference between 4DCT and 4DCBCT was shown in the SI direction (p = 0.03)., Conclusion: For lung SABR patients both 4DCT and 4DCBCT significantly under-predict treatment target motion ranges., (Copyright © 2019 Elsevier B.V. All rights reserved.)

In this study we develop and characterise a six degree-of-freedom (6 DoF) robotic motion system for quality assurance of real-time image-guided radiotherapy techniques. The system consists of a commercially available robotic arm, an acrylic phantom with embedded Calypso markers, a custom base plate to mount the robot to the treatment couch, and control software implementing the appropriate sequence of transformations to reproduce measured tumour motion traces. The robotic motion system was evaluated in terms of the set-up and motion trace repeatability, static localization accuracy and dynamic localization accuracy. Four prostate, two liver and three lung motion traces, representing a range of tumor motion trajectories recorded in real patient treatments, were executed using the robotic motion system and compared with motion measurements from the clinical Calypso motion tracking system. System set-up and motion trace repeatability was better than 0.5 deg and 0.3 mm for rotation and translation, respectively. The static localization accuracy of the robotic motion system in the LR, SI and AP directions was 0.09 mm, 0.08 mm and 0.02 mm for translations, respectively, and 0.2°, 0.06° and 0.06° for rotations, respectively. The dynamic localization accuracy of the robotic motion system was  <0.2 mm and  <0.6° for translations and rotations, respectively. Thus, we have demonstrated the ability to accurately mimic rigid-body tumor motion using a robotically controlled phantom to provide precise geometric QA for advanced radiotherapy delivery approaches.

Purpose: Multileaf collimator (MLC) tracking is being clinically pioneered to continuously compensate for thoracic and pelvic motion during radiotherapy. The purpose of this work was to characterize the performance of two MLC leaf-fitting algorithms, direct optimization and piecewise optimization, for real-time motion compensation with different plan complexity and tumor trajectories., Methods: To test the algorithms, both in silico and phantom experiments were performed. The phantom experiments were performed on a Trilogy Varian linac and a HexaMotion programmable motion platform. High and low modulation VMAT plans for lung and prostate cancer cases were used along with eight patient-measured organ-specific trajectories. For both MLC leaf-fitting algorithms, the plans were run with their corresponding patient trajectories. To compare algorithms, the average exposure errors, i.e., the difference in shape between ideal and fitted MLC leaves by the algorithm, plan complexity and system latency of each experiment were calculated., Results: Comparison of exposure errors for the in silico and phantom experiments showed minor differences between the two algorithms. The average exposure errors for in silico experiments with low/high plan complexity were 0.66/0.88 cm 2 for direct optimization and 0.66/0.88 cm 2 for piecewise optimization, respectively. The average exposure errors for the phantom experiments with low/high plan complexity were 0.73/1.02 cm 2 for direct and 0.73/1.02 cm 2 for piecewise optimization, respectively. The measured latency for the direct optimization was 226 ± 10 ms and for the piecewise algorithm was 228 ± 10 ms. In silico and phantom exposure errors quantified for each treatment plan demonstrated that the exposure errors from the high plan complexity (0.96 cm 2 mean, 2.88 cm 2 95% percentile) were all significantly different from the low plan complexity (0.70 cm 2 mean, 2.18 cm 2 95% percentile) (P < 0.001, two-tailed, Mann-Whitney statistical test)., Conclusions: The comparison between the two leaf-fitting algorithms demonstrated no significant differences in exposure errors, neither in silico nor with phantom experiments. This study revealed that plan complexity impacts the overall exposure errors significantly more than the difference between the algorithms., (© 2019 American Association of Physicists in Medicine.)

Purpose: Four-dimensional cone beam computed tomography (4DCBCT) facilitates verification of lung tumor motion before each treatment fraction and enables accurate patient setup in lung stereotactic ablative body radiation therapy. This work aims to quantify the real-time motion represented in 4DCBCT, depending on the reconstruction algorithm and the respiratory signal utilized for reconstruction., Methods and Materials: Eight lung cancer patients were implanted with electromagnetic Calypso beacons in airways close to the tumor, enabling real-time motion measurements. 4DCBCT scans were reconstructed from projections for treatment setup CBCT for 1 to 2 fractions of 8 patients with the Feldkamp-Davis-Kress (FDK) algorithm or the prior image constrained compressed sensing (PICCS) method and internal real-time Calypso beacon trajectories or an external respiratory signal (bellows belt). The real-time beacon centroid ("target") motion was compared with beacon centroid positions segmented in the 4DCBCT reconstructions. We tested the hypotheses that (1) the actual target motion was accurately represented in the reconstructions and (2) the reconstruction/respiratory signal combinations performed similarly in the representation of the real-time motion., Results: On average the target motion was significantly underrepresented and exceeded the 4DCBCT motion for 48%, 25%, and 40% of the time in the left-right (LR), superior-inferior (SI), and anterior-posterior (AP) directions, respectively. The average underrepresentation for the LR, SI, and AP direction was 1.7 mm, 4.2 mm, and 2.5 mm, respectively. No difference could be shown between the reconstruction algorithms or respiratory signals in LR direction (FDK vs PICCS: P = .47, Calypso vs bellows: P = .19), SI direction (FDK vs PICCS: P = .49, Calypso vs bellows: P = .22), and AP direction (FDK vs PICCS: P = .62, Calypso vs bellows: P = .34)., Conclusions: The 4DCBCT scans all underrepresented the real-time target motion. The selection of the reconstruction algorithm and respiratory signal for the 4DCBCT reconstruction does not have an impact on the reconstructed motion range., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Increasing evidence shows that intrafraction tumour motion monitoring must include both six degrees of freedom (6DoF): 3D translations and 3D rotations. Existing real-time algorithms for 6DoF target motion estimation require continuous intrafraction fluoroscopic imaging at high frequency, thereby exposing patients to additional high imaging dose. This paper presents the first method capable of 6DoF motion monitoring using intermittent 2D kV imaging and a continuous external respiratory signal. Our approach is to optimise a state-augmented linear correlation model between an external signal and internal 6DoF motion. In standard treatments, the model can be built using information obtained during pre-treatment cone beam CT (CBCT). Real-time 6DoF tumor motion can then be estimated using just the external signal. Intermittent intrafraction kV images are used to update the model parameters, accounting for changes in correlation and baseline shifts. The method was evaluated in silico using data from 6 lung SABR patients, with the internal tumour motion recorded with electromagnetic beacons and the external signal from a bellows belt. Projection images from CBCT (10 Hz) and intermittent kV images were simulated by projecting the 3D Calypso beacon positions onto an imager. IMRT and VMAT treatments were simulated with increasing imaging update intervals: 0.1 s, 1 s, 3 s, 10 s and 30 s. For all the tested clinical scenarios, translational motion estimates with our method had sub-mm accuracy (mean) and precision (standard deviation) while rotational motion estimates were accurate to  <[Formula: see text] and precise to [Formula: see text]. Motion estimation errors increased as the imaging update interval increased. With the largest imaging update interval (30 s), the errors were [Formula: see text] mm, [Formula: see text] mm and [Formula: see text] mm for translation in the left-right, superior-inferior and anterior-posterior directions, respectively, and [Formula: see text], [Formula: see text] and [Formula: see text] for rotation around the aforementioned axes for both VMAT and IMRT treatments. In conclusion, we developed and evaluated a novel method for highly accurate real-time 6DoF motion monitoring on a standard linear accelerator without requiring continuous kV imaging. The proposed method achieved sub-mm and sub-degree accuracy on a lung cancer patient dataset.

Stereotactic arrhythmia radioablation (STAR) is an emerging treatment option for atrial fibrillation (AF). However, it faces possibly the most challenging motion compensation scenario: both respiratory and cardiac motion. Multi-leaf collimator (MLC) tracking is clinically used for lung cancer treatments but its capabilities with intracardiac targets is unknown. We report the first experimental results of MLC tracking for intracardiac targets. Five AF STAR plans of varying complexity were created. All delivered 5  ×  10 Gy to both pulmonary vein antra. Three healthy human target motion trajectories were acquired with ultrasound and programmed into a motion platform. Plans were delivered with a linac to a dosimeter placed on the motion platform. For each motion trace, each plan was delivered with no MLC tracking and with MLC tracking with and without motion prediction. Dosimetric accuracy was assessed with γ-tests and dose metrics. MLC tracking improved the dosimetric accuracy in all measurements compared to non-tracking experiments. The average 2%/2 mm γ-failure rate was improved from 13.1% with no MLC tracking to 5.9% with MLC tracking (p  <  0.001) and 7.2% with MLC tracking and no motion prediction (p  <  0.001). MLC tracking significantly improved the consistency between planned and delivered target dose coverage. The 95% target coverage with the prescription dose (V100) was improved from 60% of deliveries with no MLC tracking to 80% of deliveries with MLC tracking (p  =  0.03). MLC tracking was successfully implemented for the first time for intracardiac motion compensation. MLC tracking provided significant dosimetric accuracy improvements in AF STAR experiments, even with challenging cardiac and respiratory-induced target motion and complex treatment plans. These results warrant further investigation and optimisation of MLC tracking for intracardiac target motion compensation.

Purpose: Radiation treatments delivered with real-time multileaf collimator (MLC) tracking currently lack fast pretreatment or real-time quality assurance. The purpose of this study is to test a 2D silicon detector, MagicPlate-512 (MP512), in a complex clinical environment involving real-time reconfiguration of the MLC leaves during target tracking., Methods: MP512 was placed in the center of a solid water phantom and mounted on a motion platform used to simulate three different patient motions. Electromagnetic target tracking was implemented using the Calypso system (Varian Medical Systems, Palo Alto, CA, USA) and an MLC tracking software. A two-arc VMAT plan was delivered and 2D dose distributions were reconstructed by MP512, EBT3 film, and the Eclipse treatment planning system (TPS). Dose maps were compared using gamma analysis with 2%/2 mm and 3%/3 mm acceptance criteria. Dose profiles were generated in sup-inf and lateral directions to show the agreement of MP512 to EBT3 and to highlight the efficacy of the MLC tracking system in mitigating the effect of the simulated patient motion., Results: Using a 3%/3 mm acceptance criterion for 2D gamma analysis, MP512 to EBT3 film agreement was 99% and MP512 to TPS agreement was 100%. For a 2%/2 mm criterion, the agreement was 95% and 98%, respectively. Full width at half maximum and 80%/20% penumbral width of the MP512 and EBT3 dose profiles agreed within 1 mm and 0.5 mm, respectively. Patient motion increased the measured dose profile penumbral width by nearly 2 mm (with respect to the no-motion case); however, the MLC tracking strategy was able to mitigate 80% of this effect., Conclusions: MP512 is capable of high spatial resolution 2D dose reconstruction during adaptive MLC tracking, including arc deliveries. It shows potential as an effective tool for 2D small field dosimetry and pretreatment quality assurance for MLC tracking modalities. These results provide confidence that detector-based pretreatment dosimetry is clinically feasible despite fast real-time MLC reconfigurations., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: To report on the primary and secondary outcomes of a prospective clinical trial of electromagnetic-guided multileaf collimator (MLC) tracking radiation therapy for prostate cancer., Methods and Materials: Twenty-eight men with prostate cancer were treated with electromagnetic-guided MLC tracking with volumetric modulated arc therapy. A total of 858 fractions were delivered, with the dose per fraction ranging from 2 to 13.75 Gy. The primary outcome was feasibility, with success determined if >95% of fractions were successfully delivered. The secondary outcomes were (1) the improvement in beam-target geometric alignment, (2) the improvement in dosimetric coverage of the prostate and avoidance of critical structures, and (3) no acute grade ≥3 genitourinary or gastrointestinal toxicity., Results: All 858 planned fractions were successfully delivered with MLC tracking, demonstrating the primary outcome of feasibility (P < .001). MLC tracking improved the beam-target geometric alignment from 1.4 to 0.90 mm (root-mean-square error). MLC tracking improved the dosimetric coverage of the prostate and reduced the daily variation in dose to critical structures. No acute grade ≥3 genitourinary or gastrointestinal toxicity was observed., Conclusions: Electromagnetic-guided MLC tracking radiation therapy for prostate cancer is feasible. The patients received improved geometric targeting and delivered dose distributions that were closer to those planned than they would have received without electromagnetic-guided MLC tracking. No significant acute toxicity was observed., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: Until now, real-time image guided adaptive radiation therapy (IGART) has been the domain of dedicated cancer radiotherapy systems. The purpose of this study was to clinically implement and investigate real-time IGART using a standard linear accelerator., Materials/methods: We developed and implemented two real-time technologies for standard linear accelerators: (1) Kilovoltage Intrafraction Monitoring (KIM) that finds the target and (2) multileaf collimator (MLC) tracking that aligns the radiation beam to the target. Eight prostate SABR patients were treated with this real-time IGART technology. The feasibility, geometric accuracy and the dosimetric fidelity were measured., Results: Thirty-nine out of forty fractions with real-time IGART were successful (95% confidence interval 87-100%). The geometric accuracy of the KIM system was -0.1 ± 0.4, 0.2 ± 0.2 and -0.1 ± 0.6 mm in the LR, SI and AP directions, respectively. The dose reconstruction showed that real-time IGART more closely reproduced the planned dose than that without IGART. For the largest motion fraction, with real-time IGART 100% of the CTV received the prescribed dose; without real-time IGART only 95% of the CTV would have received the prescribed dose., Conclusion: The clinical implementation of real-time image-guided adaptive radiotherapy on a standard linear accelerator using KIM and MLC tracking is feasible. This achievement paves the way for real-time IGART to be a mainstream treatment option., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Purpose: Most modern radiotherapy machines are built with a 2D kV imaging system. Combining this imaging system with a 2D-3D inference method would allow for a ready-made option for real-time 3D tumor tracking. This work investigates and compares the accuracy of four existing 2D-3D inference methods using both motion traces inferred from external surrogates and measured internally from implanted beacons., Method: Tumor motion data from 160 fractions (46 thoracic/abdominal patients) of Synchrony traces (inferred traces), and 28 fractions (7 lung patients) of Calypso traces (internal traces) from the LIGHT SABR trial (NCT02514512) were used in this study. The motion traces were used as the ground truth. The ground truth trajectories were used in silico to generate 2D positions projected on the kV detector. These 2D traces were then passed to the 2D-3D inference methods: interdimensional correlation, Gaussian probability density function (PDF), arbitrary-shape PDF, and the Kalman filter. The inferred 3D positions were compared with the ground truth to determine tracking errors. The relationships between tracking error and motion magnitude, interdimensional correlation, and breathing periodicity index (BPI) were also investigated., Results: Larger tracking errors were observed from the Calypso traces, with RMS and 95th percentile 3D errors of 0.84-1.25 mm and 1.72-2.64 mm, compared to 0.45-0.68 mm and 0.74-1.13 mm from the Synchrony traces. The Gaussian PDF method was found to be the most accurate, followed by the Kalman filter, the interdimensional correlation method, and the arbitrary-shape PDF method. Tracking error was found to strongly and positively correlate with motion magnitude for both the Synchrony and Calypso traces and for all four methods. Interdimensional correlation and BPI were found to negatively correlate with tracking error only for the Synchrony traces. The Synchrony traces exhibited higher interdimensional correlation than the Calypso traces especially in the anterior-posterior direction., Conclusion: Inferred traces often exhibit higher interdimensional correlation, which are not true representation of thoracic/abdominal motion and may underestimate kV-based tracking errors. The use of internal traces acquired from systems such as Calypso is advised for future kV-based tracking studies. The Gaussian PDF method is the most accurate 2D-3D inference method for tracking thoracic/abdominal targets. Motion magnitude has significant impact on 2D-3D inference error, and should be considered when estimating kV-based tracking error., (© 2018 American Association of Physicists in Medicine.)

Background and Purpose: To perform a quantitative analysis of the accuracy and precision of Kilovoltage Intrafraction Monitoring (KIM) six degree-of-freedom (6DoF) prostate motion measurements during treatments., Material and Methods: Real-time 6DoF prostate motion was acquired using KIM for 14 prostate cancer patients (377 fractions). KIM outputs the 6DoF prostate motion, combining 3D translation and 3D rotational motion information relative to its planning position. The corresponding groundtruth target motion was obtained post-treatment based on kV/MV triangulation. The accuracy and precision of the 6DoF KIM motion estimates were calculated as the mean and standard deviation differences compared with the ground-truth., Results: The accuracy ± precision of real-time 6DoF KIM-measured prostate motion were 0.2 ± 1.3° for rotations and 0.1 ± 0.5 mm for translations, respectively. The magnitude of KIM-measured motion was well-correlated with the magnitude of ground-truth motion resulting in Pearson correlation coefficients of  ≥0.88 in all DoF., Conclusions: The results demonstrate that KIM is capable of providing the real-time 6DoF prostate target motion during patient treatments with an accuracy ± precision of within 0.2 ± 1.3° and 0.1 ± 0.5 mm for rotation and translation, respectively. As KIM only requires a single X-ray imager, which is available on most modern cancer radiotherapy devices, there is potential for widespread adoption of this technology., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Patient motion can cause misalignment of the tumour and toxicities to the healthy lung tissue during lung stereotactic body radiation therapy (SBRT). Any deviations from the reference setup can miss the target and have acute toxic effects on the patient with consequences onto its quality of life and survival outcomes. Correction for motion, either immediately prior to treatment or intra-treatment, can be realized with image-guided radiation therapy (IGRT) and motion management devices. The use of these techniques has demonstrated the feasibility of integrating complex technology with clinical linear accelerator to provide a higher standard of care for the patients and increase their quality of life., (Copyright © 2017 Associazione Italiana di Fisica Medica. All rights reserved.)

Purpose: Assess the dosimetric impact of multi-leaf collimator (MLC) tracking and mid-ventilation (midV) planning compared with the internal target volume (ITV)-based planning approach for lung Stereotactic Ablative Body Radiotherapy (SABR)., Method: Ten lung SABR patients originally treated with an ITV-based plan were re-planned according to MLC tracking and midV planning schemes. All plans were delivered on a linac to a motion phantom in a simulated treatment with real lung motions. Delivered dose was reconstructed in patient planning scans. ITV-based, tracking and midV regimes were compared at the planning and delivered stages based on PTV volume and dose metrics for the GTV and OAR., Results: MLC tracking and midV schemes yielded favourable outcomes compared with ITV-based plans. Average reduction in PTV volume was (MLC tracking/MidV) 33.9%/22%. GTV dose coverage performed better with MLC tracking than the other regimes. Reduction in dose to OAR were for the lung (mean lung dose, 0.8Gy/0.2Gy), oesophagus (D3cc, 1.9Gy/1.4Gy), great vessels (D10cc, 3.2Gy/1.3Gy), trachea (D4cc, 1.1Gy/0.9Gy), heart (D1cc, 2.0Gy/0.5Gy) and spinal cord (D0.03cc, 0.5Gy/-0.1Gy)., Conclusion: MLC tracking showed reduction in PTV volume, superior GTV dose coverage and organ dose sparing than MidV and ITV-based strategies., (Copyright © 2017 Elsevier B.V. All rights reserved.)

The ability to monitor tumor motion without implanted markers can potentially enable broad access to more accurate and precise lung radiotherapy. A major challenge is that kilovoltage (kV) imaging based methods are rarely able to continuously track the tumor due to the inferior tumor visibility on 2D kV images. Another challenge is the estimation of 3D tumor position based on only 2D imaging information. The aim of this work is to address both challenges by proposing a Bayesian approach for markerless tumor tracking for the first time. The proposed approach adopts the framework of the extended Kalman filter, which combines a prediction and measurement steps to make the optimal tumor position update. For each imaging frame, the tumor position is first predicted by a respiratory-correlated model. The 2D tumor position on the kV image is then measured by template matching. Finally, the prediction and 2D measurement are combined based on the 3D distribution of tumor positions in the past 10 s and the estimated uncertainty of template matching. To investigate the clinical feasibility of the proposed method, a total of 13 lung cancer patient datasets were used for retrospective validation, including 11 cone-beam CT scan pairs and two stereotactic ablative body radiotherapy cases. The ground truths for tumor motion were generated from the the 3D trajectories of implanted markers or beacons. The mean, standard deviation, and 95th percentile of the 3D tracking error were found to range from 1.6-2.9 mm, 0.6-1.5 mm, and 2.6-5.8 mm, respectively. Markerless tumor tracking always resulted in smaller errors compared to the standard of care. The improvement was the most pronounced in the superior-inferior (SI) direction, with up to 9.5 mm reduction in the 95th-percentile SI error for patients with  >10 mm 5th-to-95th percentile SI tumor motion. The percentage of errors with 3D magnitude  <5 mm was 96.5% for markerless tumor tracking and 84.1% for the standard of care. The feasibility of 3D markerless tumor tracking has been demonstrated on realistic clinical scenarios for the first time. The clinical implementation of the proposed method will enable more accurate and precise lung radiotherapy using existing hardware and workflow. Future work is focused on the clinical and real-time implementation of this method.

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary cancer syndrome that predisposes affected individuals to the development of multiple benign and malignant tumors. One of the main manifestations of VHL is renal cell carcinoma (RCC). RCC is increasingly being treated with targeted therapies, which offer an alternative treatment option for patients with VHL disease. This study investigated the effectiveness of sunitinib in VHL patients with advanced tumors or tumors unsuitable for surgery.This multicenter, phase II, open-label study from the PREDIR VHL network, treated patients with genetically-confirmed advanced VHL disease with oral sunitinib (50 mg/day for 28 days then a 2-week rest period) until progression. Lesions were performed using magnetic resonance imaging (MRI) and computed tomographic (CT) scan. The primary endpoint was objective response rate; secondary endpoints included tolerability and overall survival.All five patients showed stable disease as best response at 6 months. Two patients showed impressive transitory clinical improvement during early cycles. No patient died during sunitinib treatment. Reasons for discontinuing sunitinib therapy were disease progression (n=1), unacceptable toxicity (n=3) and lack of clinical improvement after 7 cycles (10.5 months) with unacceptable toxicity (n=1).In conclusion, sunitinib was of limited benefit in patients with advanced VHL disease, but had better efficacy against metastatic RCC than other VHL-related lesions. Treatment-related toxicity is an important limiting factor in this frail patient population. New agents with different mechanisms of action are required to treat this disease.

This study presents estimation of typical kV fluoroscopic imaging doses for image-guided real-time adaptive radiotherapy. For a cohort of 10 lung SABR patients the estimated imaging dose to ipsi-lateral lung with real-time adaptation is 9.9-15.1cGy, which is less than the extra lung dose from treatment with potentially larger ITV-based PTV approach., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: Real time adaptive radiotherapy that enables smaller irradiated volumes may reduce pulmonary toxicity. We report on the first patient treatment of electromagnetic-guided real time adaptive radiotherapy delivered with MLC tracking for lung stereotactic ablative body radiotherapy., Materials and Methods: A clinical trial was developed to investigate the safety and feasibility of MLC tracking in lung. The first patient was an 80-year old man with a single left lower lobe lung metastasis to be treated with SABR to 48Gy in 4 fractions. In-house software was integrated with a standard linear accelerator to adapt the treatment beam shape and position based on electromagnetic transponders implanted in the lung. MLC tracking plans were compared against standard ITV-based treatment planning. MLC tracking plan delivery was reconstructed in the patient to confirm safe delivery., Results: Real time adaptive radiotherapy delivered with MLC tracking compared to standard ITV-based planning reduced the PTV by 41% (18.7-11cm 3 ) and the mean lung dose by 30% (202-140cGy), V20 by 35% (2.6-1.5%) and V5 by 9% (8.9-8%)., Conclusion: An emerging technology, MLC tracking, has been translated into the clinic and used to treat lung SABR patients for the first time. This milestone represents an important first step for clinical real-time adaptive radiotherapy that could reduce pulmonary toxicity in lung radiotherapy., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Kilovoltage intrafraction monitoring (KIM) is a new real-time 3-dimensional image guidance method. Unlike previous real-time image guidance methods, KIM uses a standard linear accelerator without any additional equipment needed. The first prospective clinical trial of KIM is underway for prostate cancer radiation therapy. In this paper we report on the measured motion accuracy and precision using real-time KIM-guided gating., Methods and Materials: Imaging and motion information from the first 200 fractions from 6 patient prostate cancer radiation therapy volumetric modulated arc therapy treatments were analyzed. A 3-mm/5-second action threshold was used to trigger a gating event where the beam is paused and the couch position adjusted to realign the prostate to the treatment isocenter. To quantify the in vivo accuracy and precision, KIM was compared with simultaneously acquired kV/MV triangulation for 187 fractions., Results: KIM was successfully used in 197 of 200 fractions. Gating events occurred in 29 fractions (14.5%). In these 29 fractions, the percentage of beam-on time, the prostate displacement was >3 mm from the isocenter position, reduced from 73% without KIM to 24% with KIM-guided gating. Displacements >5 mm were reduced from 16% without KIM to 0% with KIM. The KIM accuracy was measured at <0.3 mm in all 3 dimensions. The KIM precision was <0.6 mm in all 3 dimensions., Conclusions: Clinical implementation of real-time KIM image guidance combined with gating for prostate cancer eliminates large prostate displacements during treatment delivery. Both in vivo KIM accuracy and precision are well below 1 mm., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Laparoscopic-assisted colon surgery is a safe alternative to conventional open colectomy. Using the laparoscopic approach, the surgeon uses tools through port sites to mobilize the section of colon to be removed, avoiding a large laparotomy incision. Usually, two to three 5-mm port site are created. Although this procedure often requires a small incision to remove the diseased portion of the colon, the incision is much smaller, causing less postoperative pain and shortening the hospital stay. This leads to a faster return to activities of daily living for the patient., ((c) AORN, Inc, 2008.)