Electrochemical Degradation of Molecularly Imprinted Polymers for Future Applications of Inflammation Sensing in Cochlear Implants.

After cochlear implant (CI) insertion, there is a possibility of postoperative inflammation, which may involve proinflammatory markers such as interleukin-6. Detecting this inflammation promptly is crucial for administering anti-inflammatory drugs, if required. One potential method for detecting inflammation is using molecular imprinted polymers (MIPs). These MIPs, which can be deposited on the CI electrode, provide readout employing impedance measurements, a feature already available on the CI circuit. MIPs designed for this purpose should possess biocompatibility, conductivity, and degradability. The degradability is crucial because there is a limitation on the number of electrodes available, and once the inflammation sensor degrades after the acute inflammation period, it should remain usable as a regular electrode. In this work, conductive poly(3,4-ethylenedioxythiophene) polystyrenesulfonate-based MIPs were synthesized against biotin as a surrogate target marker. Specific biotin binding with MIPs was determined before and after degradation using electrochemical impedance spectroscopy (EIS) and compared with the control nonimprinted polymers (NIPs). Subsequently, MIPs were electrochemically degraded by EIS with different potentials, wherein a potential dependence was observed. With decreasing potential, fewer dissolved polymers and more monomer molecules were detected in the solution in which degradation took place. At a potential of 0.205 V a negligible amount of dissolved polymer in addition to the dissolved monomer molecules was measured, which can be defined as the limiting potential. Below this potential, only dissolved monomer molecules are obtained, which enables renal clearance. Biocompatibility testing revealed that both the polymer and the solution with dissolved monomer molecules do not exceed the ISO 10993-5 cytotoxicity threshold. Based on these findings, we have developed conductive, biocompatible, and controllably degradable MIPs capable of detecting biotin. This research work paves the way for the advancement of CIs, where inflammation can be detected using molecular imprinting technology without compromising the stability and biosafety of the product.

Challenges and opportunities for proton therapy during pregnancy.

During pregnancy, the use of radiation therapy for cancer treatment is often considered impossible due to the assumed associated fetal risks. However, suboptimal treatment of pregnant cancer patients and unjustifiable delay in radiation therapy until after delivery can be harmful for both patient and child. In non-pregnant patients, proton-radiation therapy is increasingly administered because of its favorable dosimetric properties compared with photon-radiation therapy. Although data on the use of pencil beam scanning proton-radiation therapy during pregnancy are scarce, different case reports and dosimetric studies have indicated a more than 10-fold reduction in fetal radiation exposure compared with photon-radiation therapy. Nonetheless, the implementation of proton-radiation therapy during pregnancy requires complex fetal dosimetry for the neutron-dominated out-of-field radiation dose and faces a lack of clinical guidelines. Further exploration and standardization of proton-radiation therapy during pregnancy will be necessary to improve radiotherapeutic management of pregnant women with cancer and further reduce risks for their offspring.

Extended in-field and out-of-field validation of a compact Monte Carlo model of an IBA PROTEUS®ONE proton beam in TOPAS/GEANT4.

Objective:This study evaluates a compact Monte Carlo (MC) model of a pencil beam scanning clinical proton beam using TOPAS to estimate the dose out-of-field (OOF). Compact modelling means that the model starts from a pristine proton beam at the nozzle exit, customised based on acceptance and commissioning data, instead of modelling the full treatment head and room.Approach: First, in-field validation tests were performed. Then, the OOF dose was validated in an RW3 phantom with bubble detectors for personal neutron dosimetry (measuring the neutron dose equivalent) and thermoluminiescent detectors (measuring the absorbed dose by protons and gammas). Measurements were performed at 15 and 35 cm from the distal edge of the field for five different irradiation plans, covering different beam orientations, proton energies and a 40 mm range shifter. TOPAS simulations were performed with QGSP Binary Cascade HP (BIC) and QGSP Bertini HP (Bertini) hadron physics lists.Main results: In-field validation shows that MC simulations agree with point dose measurements within -2.5 % and +1.5 % at locations on- and off-axis and before, in and after the Bragg peak or plateau. The gamma passing rate 2%/3mm of four simulated treatment plans compared to the dose distribution calculated by the TPS exceeds 97 % agreement score. OOF dose simulations showed an average overestimation of 27 % of the neutron dose equivalent for the BIC hadron physics list and an average underestimation of 20 % for the Bertini hadron physics list. The simulated absorbed dose of protons and gammas showed a systematic underestimation which was on average 21 % and 51 % for BIC and Bertini respectively.Significance: Our study demonstrates that a compact MC model can reliably produce in-field data, while out-of-field dose data are within the uncertainties of the detector systems and MC simulations nuclear models, and do so with shorter modelling and faster calculation time.

"Scan-(pre)Plan-Treat" Workflow for Bone Metastases Using the Ethos Therapy System: A Single-Center, In Silico Experience.

Purpose: To report on the accuracy of automated delineation, treatment plan quality, and duration of an in-silico "scan-(pre)plan-treat" (SPT) workflow for vertebral bone metastases using a 1 × 8 Gy regimen. Method and Materials: The cloud-based emulator system of the Ethos therapy system was used to adapt an organ-at-risk-sparing preplan created on the diagnostic CT to the anatomy-of-the-day using the cone beam CT made before treatment. Results: SPT using the Ethos emulator system resulted in relatively good coverage of the PTV and acceptable dose to the OAR. Delivery time and plan homogeneity was the best for 7-field IMRT plan template. Conclusions: A SPT workflow formula results in a highly conformal treatment delivery while maintaining an acceptable timeframe for the patient on the treatment couch.

A Review on Bio- and Chemosensors for the Detection of Biogenic Amines in Food Safety Applications: The Status in 2022.

This article provides an overview on the broad topic of biogenic amines (BAs) that are a persistent concern in the context of food quality and safety. They emerge mainly from the decomposition of amino acids in protein-rich food due to enzymes excreted by pathogenic bacteria that infect food under inappropriate storage conditions. While there are food authority regulations on the maximum allowed amounts of, e.g., histamine in fish, sensitive individuals can still suffer from medical conditions triggered by biogenic amines, and mass outbreaks of scombroid poisoning are reported regularly. We review first the classical techniques used for selective BA detection and quantification in analytical laboratories and focus then on sensor-based solutions aiming at on-site BA detection throughout the food chain. There are receptor-free chemosensors for BA detection and a vastly growing range of bio- and biomimetic sensors that employ receptors to enable selective molecular recognition. Regarding the receptors, we address enzymes, antibodies, molecularly imprinted polymers (MIPs), and aptamers as the most recent class of BA receptors. Furthermore, we address the underlying transducer technologies, including optical, electrochemical, mass-sensitive, and thermal-based sensing principles. The review concludes with an assessment on the persistent limitations of BA sensors, a technological forecast, and thoughts on short-term solutions.

Proton therapy of a pregnant patient with nasopharyngeal carcinoma.

Background and purpose: Radiotherapy during pregnancy is rarely administered due to lack of data and practical challenges. This is the first detailed report of proton therapy as cancer treatment for a pregnant patient with nasopharyngeal carcinoma. Materials and methods: Pencil beam scanning proton therapy was prescribed to a pregnant patient to a total dose of 70 Gy (RBE) to the therapeutic CTV and 54.25 Gy to the prophylactic CTV, delivered in 35 fractions with a simultaneous integrated boost technique. Results: Phantom measurements showed a thirty-fold decrease in fetal radiation dose when using proton compared to photon therapy, with a total fetal dose of 5.5 mSv for the complete proton treatment, compared to 185 and 298 mSv for the photon treatment with and without lead shielding, respectively. After adminstering proton therapy during pregnancy, at 39 weeks of gestation, a healthy boy with a birthweight on the 83th percentile was delivered. Pediatric follow-up at 2 months of age of the offspring showed normal growth and age-adequate motor development with no signs of neurological problems. MR follow-up of the tumor 3 months after the end of treatment showed complete remission. Conclusion: This case demonstrates the potential of proton therapy for treatment during pregnancy.Compared to photon therapy, proton therapy can significantly limit fetal dose, while simultaneously offering a more optimized treatment to the patient.

Experimental investigation of dynamic real-time rotation-including dose reconstruction during prostate tracking radiotherapy.

BACKGROUND: Hypofractionation in prostate radiotherapy is of increasing interest. Steep dose gradients and a large weight on each individual fraction emphasize the need for motion management. Real-time motion management techniques such as multileaf collimator (MLC) tracking or couch tracking typically adjust for translational motion while rotations remain uncompensated with unknown dosimetric impact. PURPOSE: The purpose of this study is to demonstrate and validate dynamic real-time rotation-including dose reconstruction during radiotherapy experiments with and without MLC and couch tracking. METHODS: Real-time dose reconstruction was performed using the in-house developed software DoseTracker. DoseTracker receives streamed target positions and accelerator parameters during treatment delivery and uses a pencil beam algorithm with water density assumption to reconstruct the dose in a moving target. DoseTracker's ability to reconstruct motion-induced dose errors in a dynamically rotating and translating target was investigated during three different scenarios: (1) no motion compensation and translational motion correction with (2) MLC tracking and (3) couch tracking. In each scenario, dose reconstruction was performed online and in real time during delivery of two dual-arc volumetric-modulated arc therapy prostate plans with a prescribed fraction dose of 7 Gy to the prostate and simultaneous intraprostatic lesion boosts with doses of at least 8 Gy, but up to 10 Gy as long as the organs at risk dose constraints were fulfilled. The plans were delivered to a pelvis phantom that replicated three patient-measured motion traces using a rotational insert with 21 layers of EBT3 film spaced 2.5 mm apart. DoseTracker repeatedly calculated the actual motion-including dose increment and the planned static dose increment since the last calculation in 84 500 points in the film stack. The experiments were performed with a TrueBeam accelerator with MLC and couch tracking based on electromagnetic transponders embedded in the film stack. The motion-induced dose error was quantified as the difference between the final cumulative dose with motion and without motion using the 2D 2%/2 mm γ-failure rate and the difference in dose to 95% of the clinical target volume (CTV ΔD95% ) and the gross target volume (GTV ΔD95% ) as well as the difference in dose to 0.1 cm3 of the urethra, bladder, and rectum (ΔD0.1CC ). The motion-induced errors were compared between dose reconstructions and film measurements. RESULTS: The dose was reconstructed in all calculation points at a mean frequency of 4.7 Hz. The root-mean-square difference between real-time reconstructed and film-measured motion-induced errors was 3.1%-points (γ-failure rate), 0.13 Gy (CTV ΔD95% ), 0.23 Gy (GTV ΔD95% ), 0.19 Gy (urethra ΔD0.1CC ), 0.09 Gy (bladder ΔD0.1CC ), and 0.07 Gy (rectum ΔD0.1CC ). CONCLUSIONS: In a series of phantom experiments, online real-time rotation-including dose reconstruction was performed for the first time. The calculated motion-induced errors agreed well with film measurements. The dose reconstruction provides a valuable tool for monitoring dose delivery and investigating the efficacy of advanced motion-compensation techniques in the presence of translational and rotational motion.

Urethral and bladder dose-effect relations for late genitourinary toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

PURPOSE OR OBJECTIVES: The FLAME trial (NCT01168479) showed that by adding a focal boost to conventional fractionated EBRT in the treatment of localized prostate cancer, the five-year biochemical disease-free survival increased, without significantly increasing toxicity. The aim of the present study was to investigate the association between radiation dose to the bladder and urethra and genitourinary (GU) toxicity grade ≥2 in the entire cohort. MATERIAL AND METHODS: The dose-effect relations of the urethra and bladder dose, separately, and GU toxicity grade ≥2 (CTCAE 3.0) up to five years after treatment were assessed. A mixed model analysis for repeated measurements was used, adjusting for age, diabetes mellitus, T-stage, baseline GU toxicity grade ≥1 and institute. Additionally, the association between the dose and separate GU toxicity subdomains were investigated. RESULTS: Dose-effect relations were observed for the dose (Gy) to the bladder D2 cm3 and urethra D0.1 cm3, with adjusted odds ratios of 1.14 (95% CI 1.12-1.16, p < 0.0001) and 1.12 (95% CI 1.11-1.14, p < 0.0001), respectively. Additionally, associations between the dose to the urethra and bladder and the subdomains urinary frequency, urinary retention and urinary incontinence were observed. CONCLUSION: Further increasing the dose to the bladder and urethra will result in a significant increase in GU toxicity following EBRT. Focal boost treatment plans should incorporate a urethral dose-constraint. Further treatment optimization to increase the focal boost dose without increasing the dose to the urethra and other organs at risk should be a focus for future research, as we have shown that a focal boost is beneficial in the treatment of prostate cancer.

Intra-fraction motion monitoring during fast modulated radiotherapy delivery in a closed-bore gantry linac.

BACKGROUND AND PURPOSE: New closed-bore linacs allow for highly streamlined workflows and fast treatment delivery resulting in brief treatment sessions. Motion management technology has only recently been integrated inside the bore, yet is required in future online adaptive workflows. We measured patient motion during every step of the workflow: image acquisition, evaluation and treatment delivery using surface scanning. MATERIALS AND METHODS: Nineteen patients treated for breast, lung or esophageal cancer were prospectively monitored from the end of setup to the end of treatment delivery in the Halcyon linac (Varian Medical Systems). Motion of the chest was tracked by way of 6 degrees-of-freedom surface tracking. Baseline drift and rate of drift were determined. The influence of fraction number, patient and fraction duration were analyzed with multi-way ANOVA. RESULTS: Median fraction duration was 4 min 48 s including the IGRT procedure (kV-CBCT acquisition and evaluation) (N = 221). Baseline drift at the end of the fraction was -1.8 ± 1.5 mm in the anterior-posterior, -0.0 ± 1.7 mm in the cranio-caudal direction and 0.1 ± 1.8 mm in the medio-lateral direction of which 75% occurred during the IGRT procedure. The highest rate of baseline drift was observed between 1 and 2 min after the end of patient setup (-0.62 mm/min). Baseline drift was patient and fraction duration dependent (p < 0.001), but fraction number was not significant (p = 0.33). CONCLUSION: Even during short treatment sessions, patient baseline drift is not negligible. Drift is largest during the initial minutes after completion of patient setup, during verification imaging and evaluation. Patients will need to be monitored during extended contouring and re-planning procedures in online adaptive workflows.

Anorectal dose-effect relations for late gastrointestinal toxicity following external beam radiotherapy for prostate cancer in the FLAME trial.

BACKGROUND AND PURPOSE: The phase III FLAME trial (NCT01168479) showed an increase in five-year biochemical disease-free survival, with no significant increase in toxicity when adding a focal boost to external beam radiotherapy (EBRT) for localized prostate cancer [Kerkmeijer et al. JCO 2021]. The aim of this study was to investigate the association between delivered radiation dose to the anorectum and gastrointestinal (GI) toxicity (grade ≥2). MATERIAL AND METHODS: All patients in the FLAME trial were analyzed, irrespective of treatment arm. The dose-effect relation of the anorectal dose parameters (D2cm3 and D50%) and GI toxicity grade ≥2 in four years of follow-up was assessed using a mixed model analysis for repeated measurements, adjusted for age, cardiovascular disease, diabetes mellitus, T-stage, baseline toxicity grade ≥1, hormonal therapy and institute. RESULTS: A dose-effect relation for D2cm3 and D50% was observed with adjusted odds ratios of 1.17 (95% CI 1.13-1.21, p < 0.0001) and 1.20 (95% CI 1.14-1.25, p < 0.0001) for GI toxicity, respectively. CONCLUSION: Although there was no difference in toxicity between study arms, a higher radiation dose to the anorectum was associated with a statistically significant increase in GI toxicity following EBRT for prostate cancer. This dose-effect relation was present for both large and small anorectal volumes. Therefore, further increase in dose to the anorectum should be weighed against the benefit of focal dose escalation for prostate cancer.

Automated treatment planning of prostate stereotactic body radiotherapy with focal boosting on a fast-rotating O-ring linac: Plan quality comparison with C-arm linacs.

PURPOSE: The integration of auto-segmentation and automated treatment planning methods on a fast-rotating O-ring linac may improve the time efficiency of online adaptive radiotherapy workflows. This study investigates whether automated treatment planning of prostate SBRT with focal boosting on the O-ring linac could generate plans that are of similar quality as those obtained through manual planning on clinical C-arm linacs. METHODS: For 20 men with prostate cancer, reference treatment plans were generated on a TrueBeam STx C-arm linac with HD120 MLC and a TrueBeam C-arm linac with Millennium 120 MLC using 6 MV flattened dual arc VMAT. Manual planning on the Halcyon fast-rotating O-ring linac was performed using 6 MV FFF dual arc VMAT (HA2-DL10) and triple arc VMAT (HA3-DL10) to investigate the performance of the dual-layer MLC system. Automated planning was performed for triple arc VMAT on the Halcyon linac (ET3-DL10) using the automated planning algorithms of Ethos Treatment Planning. The prescribed dose was 35 Gy to the prostate and 30 Gy to the seminal vesicles in five fractions. The iso-toxic focal boost to the intraprostatic tumor nodule(s) was aimed to receive up to 50 Gy. Plan deliverability was verified using portal image dosimetry measurements. RESULTS: Compared to the C-arm linacs, ET3-DL10 shows increased seminal vesicles PTV coverage (D99% ) and reduced high-dose spillage to the bladder (V37Gy ) and urethra (D0.035cc ) but this came at the cost of increased high-dose spillage to the rectum (V38Gy ) and a higher intermediate dose spillage (D2cm). No statistically significant differences were found when benchmarking HA2-DL10 and HA3-DL10 with the C-arm linacs. All plans passed the patient-specific QA tolerance limit. CONCLUSIONS: Automated planning of prostate SBRT with focal boosting on the fast-rotating O-ring linac is feasible and achieves similar plan quality as those obtained on clinical C-arm linacs using manual planning.

Six degrees of freedom dynamic motion-including dose reconstruction in a commercial treatment planning system.

PURPOSE: Intrafractional motion during radiotherapy delivery can deteriorate the delivered dose. Dynamic rotational motion of up to 38 degrees has been reported during prostate cancer radiotherapy, but methods to determine the dosimetric consequences of such rotations are lacking. Here, we create and experimentally validate a dose reconstruction method that accounts for dynamic rotations and translations in a commercial treatment planning system (TPS). Interplay effects are quantified by comparing dose reconstructions with dynamic and constant rotations. METHODS: The dose reconstruction accumulates the dose in points of interest while the points are moved in six degrees of freedom (6DoF) in a precalculated time-resolved four-dimensional (4D) dose matrix to emulate dynamic motion in a patient. The required 4D dose matrix was generated by splitting the original treatment plan into multiple sub-beams, each representing 0.4 s dose delivery, and recalculating the dose of the split plan in the TPS (Eclipse). The dose accumulation was performed via TPS scripting by querying the dose of each sub-beam in dynamically moving points, allowing dose reconstruction with any dynamic motion. The dose reconstruction was validated with film dosimetry for two prostate dual arc VMAT plans with intra-prostatic lesion boosts. The plans were delivered to a pelvis phantom with internal dynamic rotational motion of a film stack (21 films with 2.5 mm separation). Each plan was delivered without motion and with three prostate motion traces. Motion-including dose reconstruction was performed for each motion experiment using the actual dynamic rotation as well as a constant rotation equal to the mean rotation during the experiment. For each experiment, the 3%/2 mm γ failure rate of the TPS dose reconstruction was calculated with the film measurement being the reference. For each motion experiment, the motion-induced 3%/2 mm γ failure rate was calculated using the static delivery as the reference and compared between film measurements and TPS dose reconstruction. DVH metrics for RT structures fully contained in the film volume were also compared between film and TPS. RESULTS: The mean γ failure rate of the TPS dose reconstructions when compared to film doses was 0.8% (two static experiments) and 1.7% (six dynamic experiments). The mean (range) of the motion-induced γ failure rate in film measurements was 35.4% (21.3-59.2%). The TPS dose reconstruction agreed with these experimental γ failure rates with root-mean-square errors of 2.1% (dynamic rotation dose reconstruction) and 17.1% (dose reconstruction assuming constant rotation). By DVH metrics, the mean (range) difference between dose reconstructions with dynamic and constant rotation was 4.3% (-0.3-10.6%) (urethra D 2 % ), -0.6% (-5.6%-2.5%) (urethra D 99 % ), 1.1% (-7.1-7.7%) (GTV D 2 % ), -1.4% (-17.4-7.1%) (GTV D 95 % ), -1.2% (-17.1-5.7%) (GTV D 99 % ), and -0.1% (-3.2-7.6%) (GTV mean dose). Dose reconstructions with dynamic motion revealed large interplay effects (cold and hot spots). CONCLUSIONS: A method to perform dose reconstructions for dynamic 6DoF motion in a TPS was developed and experimentally validated. It revealed large differences in dose distribution between dynamic and constant rotations not identifiable through dose reconstructions with constant rotation.

Spirometer-guided breath-hold breast VMAT verified with portal images and surface tracking.

BACKGROUND AND PURPOSE: Fast rotating closed-bore gantry linacs are ideally suited for breath-hold treatments due to reduced imaging and delivery times. We evaluated the reproducibility and stability of spirometer-guided breath-hold breast treatments, using intra-bore surface monitoring and portal imaging on Halcyon (Varian Medical Systems). MATERIALS AND METHODS: Seven left-sided breast cancer patients were treated in breath-hold using the SDX spirometer (Dyn'R) with an integrated boost volumetric arc protocol on Halcyon. A dual depth-camera surface scanning system monitored the left breast. The interfraction, intrafraction and intrabreath-hold motion was determined in the anterior-posterior (AP) and superior-inferior (SI) direction. Portal images (PI), acquired at a tangential gantry angle were manually registered to the planning-CT to determine inter- and intrafraction breath-hold errors for the SI and tangential-anterior-posterior ("AP") axis. Correlations between PI and surface imaging deviations were investigated. To evaluate workflow efficiency, the total time and the number of breath-holds were recorded. RESULTS: Systematic and random variability of breath-hold amplitude was below 0.7 mm for the AP and below 1.2 mm for the SI component as detected by surface monitoring (N = 130). Systematic and random errors retrieved from portal images (N = 140) were below 1.2 mm for the "AP" and 2.1 mm for SI axis. A limited correlation was found between PI and surface monitoring deviations for both the SI and "AP" axes (R2 = 0.27/0.38, p < 0.01). 75% of fractions were completed using four breath-holds and 82% within 10 min. CONCLUSION: Surface imaging indicated spirometer-guided breath-hold VMAT breast radiotherapy can be accurately and quickly performed on a closed-bore gantry linac. Intra-bore surface scanning proved a valuable technique for monitoring breathing motion in closed-bore systems.

Dosimetric impact of intrafraction prostate rotation and accuracy of gating, multi-leaf collimator tracking and couch tracking to manage rotation: An end-to-end validation using volumetric film measurements.

BACKGROUND AND PURPOSE: Both gating and tracking can mitigate the deteriorating dosimetric impact of intrafraction translation during prostate stereotactic body radiotherapy (SBRT). However, their ability to manage intrafraction rotation has not yet been thoroughly investigated. The dosimetric accuracy of gating, MLC tracking and couch tracking to manage intrafraction prostate rotation was investigated. MATERIALS AND METHODS: Treatment plans for end-to-end tests of prostate SBRT with focal boosting were generated for a dynamic anthropomorphic pelvis phantom. The phantom applied internal lateral rotation (up to 25°) and coupled vertical and longitudinal translation of a radiochromic film stack that was used for dose measurements. Dose was delivered for each plan while the phantom applied motion according to three typical prostate motion traces without compensation (i), with gating (ii), with MLC tracking (iii) or with couch tracking (iv). Measured doses for the four motion compensation strategies were compared with the planned dose in terms of γ-index analysis, target coverage and organs at risk (OAR) sparing. RESULTS: Intrafraction rotation reduced the 3%(global)/2mm γ-index passing rate (γPR) for the prostate target volume by median (range) -33.2% (-68.6%, -4.1%) when no motion compensation was applied. The use of motion compensation improved the γPR by 13.2% (-0.4%, 32.9%) for gating, by 6.0% (-0.8%, 27.7%) for MLC tracking and by 11.1% (1.2%, 22.9%) for couch tracking. The three compensation techniques improved the target coverage in most cases. Gating showed better OAR sparing than MLC tracking or couch tracking. CONCLUSIONS: Compensation of intrafraction prostate rotation with gating, MLC tracking and couch tracking was investigated experimentally for the first time. All three techniques improved the dosimetric accuracy, but residual motion-related dose errors remained due to the lack of rotation correction.

openPR - A computational tool for CT conversion assessment with proton radiography.

PURPOSE: One of the main sources of uncertainty in proton therapy is the conversion of the Hounsfield Units of the planning CT to (relative) proton stopping powers. Proton radiography provides range error maps but these can be affected by other sources of errors as well as the CT conversion (e.g., residual misalignment). To better understand and quantify range uncertainty, it is desirable to measure the individual contributions and particularly those associated to the CT conversion. METHODS: A workflow is proposed to carry out an assessment of the CT conversion solely on the basis of proton radiographs of real tissues measured with a multilayer ionization chamber (MLIC). The workflow consists of a series of four stages: (a) CT and proton radiography acquisitions, (b) CT and proton radiography registration in postprocessing, (c) sample-specific validation of the semi-empirical model both used in the registration and to estimate the water equivalent path length (WEPL), and (d) WEPL error estimation. The workflow was applied to a pig head as part of the validation of the CT calibration of the proton therapy center PARTICLE at UZ Leuven, Belgium. RESULTS: The CT conversion-related uncertainty computed based on the well-established safety margin rule of 1.2 mm + 2.4% were overestimated by 71% on the pig head. However, the range uncertainty was very much underestimated where cavities were encountered by the protons. Excluding areas with cavities, the overestimation of the uncertainty was 500%. A correlation was found between these localized errors and HUs between -1000 and -950, suggesting that the underestimation was not a consequence of an inaccurate conversion but was probably rather due to the resolution of the CT leading to material mixing at interfaces. To reduce these errors, the CT calibration curve was adapted by increasing the HU interval corresponding to the air up to -950. CONCLUSION: The application of the workflow as part of the validation of the CT conversion to RSPs showed an overall overestimation of the expected uncertainty. Moreover, the largest WEPL errors were found to be related to the presence of cavities which nevertheless are associated with low WEPL values. This suggests that the use of this workflow on patients or in a generalized study on different types of animal tissues could shed sufficient light on how the contributions to the CT conversion-related uncertainty add up to potentially reduce up to several millimeters the uncertainty estimations taken into account in treatment planning. All the algorithms required to perform the workflow were implemented in the computational tool named openPR which is part of openREGGUI, an open-source image processing platform for adaptive proton therapy.

Primary endpoint analysis of the multicentre phase II hypo-FLAME trial for intermediate and high risk prostate cancer.

BACKGROUND AND PURPOSE: Local recurrences after radiotherapy for prostate cancer (PCa) often originate at the location of the macroscopic tumour(s). Since PCa cells are known to be sensitive to high fraction doses, hypofractionated whole gland stereotactic body radiotherapy (SBRT) in conjunction with a simultaneous ablative microboost to the macroscopic tumour(s) within the prostate could be a way to reduce the risk of local failure. We investigated the safety of this treatment strategy. MATERIALS AND METHODS: Patients with intermediate or high risk PCa were enrolled in a prospective phase II trial, called hypo-FLAME. All patients were treated with extreme hypofractionated doses of 35 Gy in 5 weekly fractions to the whole prostate gland with an integrated boost up to 50 Gy to the multiparametric (mp) MRI-defined tumour(s). Treatment-related toxicity was measured using the CTCAE v4.0. The primary endpoint of the trial was treatment-related acute toxicity. RESULTS: Between April 2016 and December 2018, 100 men were treated in 4 academic centres. All patients were followed up for a minimum of 6 months. The median mean dose delivered to the visible tumour nodule(s) on mpMRI was 44.7 Gy in this trial. No grade ≥3 acute genitourinary (GU) or gastrointestinal (GI) toxicity was observed. Furthermore, 90 days after start of treatment, the cumulative acute grade 2 GU and GI toxicity rates were 34.0% and 5.0%, respectively. CONCLUSION: Simultaneous focal boosting to the macroscopic tumour(s) in addition to whole gland prostate SBRT is associated with acceptable acute GU and GI toxicity.

Stereotactic body radiation therapy with optional focal lesion ablative microboost in prostate cancer: Topical review and multicenter consensus.

Stereotactic body radiotherapy (SBRT) for prostate cancer (PCa) is gaining interest by the recent publication of the first phase III trials on prostate SBRT and the promising results of many other phase II trials. Before long term results became available, the major concern for implementing SBRT in PCa in daily clinical practice was the potential risk of late genitourinary (GU) and gastrointestinal (GI) toxicity. A number of recently published trials, including late outcome and toxicity data, contributed to the growing evidence for implementation of SBRT for PCa in daily clinical practice. However, there exists substantial variability in delivering SBRT for PCa. The aim of this topical review is to present a number of prospective trials and retrospective analyses of SBRT in the treatment of PCa. We focus on the treatment strategies and techniques used in these trials. In addition, recent literature on a simultaneous integrated boost to the tumor lesion, which could create an additional value in the SBRT treatment of PCa, was described. Furthermore, we discuss the multicenter consensus of the FLAME consortium on SBRT for PCa with a focal boost to the macroscopic intraprostatic tumor nodule(s).

Extended field radiotherapy measurements in a single shot using a BaFBr-based OSL-film.

This work evaluated the use of a class solution specific calibration for an extra-large BaFBr-based optically stimulated luminescence film (OSL; 43 × 35 cm2; Z eff = 4.55). The clinical need for such large dosimeters follows from the increased use of extended-field radiation therapy (EFRT). E.g. for prostate cancer EFRT is currently used in the first prospective trial investigating the benefit of adding elective irradiation of the para-aortic lymph nodes in pN1 prostate cancer. The full extent of these EFRT dose distributions is not covered by the well-established standard sized radiochromic film or 2D detector arrays. Here we investigate an OSL calibration methodology, that tackles BaFBr-based OSL's inherent energy dependence by a class solution specific calibration. 10 EFRT treatment plans used in the PART trial were investigated. One plan was used to build a class solution specific bilinear calibration model, that distinguishes between in-field and penumbra dose contributions. The effect of this calibration was evaluated with respect to a standard linear calibration, using standard IMRT patterns, the nine remaining patient plans, and to smaller prostate treatment plans. A single OSL-dosimeter could be reused for all measurements. The dosimeter captured the full extent of the dose distributions (maximum EFRT field size = 33.5 cm). The bilinear correction reduced the residual dose differences from above 10% to an average of 0.7% (max 3.6%) in comparison with a Monte Carlo simulation. Consequently global gamma agreement scores (3%-3 mm) of 95.5% ± 2.7% were reached. A more strict local evaluation resulted in an average gamma-agreement score of 93.3% ± 3.2%. The BaFBr-based OSL film, with reduced Z eff requires a class-solution specific correction. The current work shows that such a correction can be as simple as a bilinear residual dose correction driven by the measured signal. As far as we know this is the first 2D dosimeter combining reusability, a sub-mm resolution, and a size covering the typical EFRT treatment plans.

Validation of a normal tissue complication probability model for late unfavourable aesthetic outcome after breast-conserving therapy.

PURPOSE: To validate a normal tissue complication probability (NTCP) model for late unfavourable aesthetic outcome (AO) after breast-conserving therapy. MATERIALS/METHODS: The BCCT.core software evaluated the AO using standardized photographs of patients treated at the University Hospitals Leuven between April 2015 and April 2016. Dose maps in 2 Gy equivalents were calculated assuming α/ß = 3.6 Gy. The discriminating ability of the model was described by the AUC of the receiver operating characteristic curve. A 95% confidence interval (CI) of AUC was calculated using 10,000 bootstrap replications. Calibration was evaluated with the calibration plot and Nagelkerke R2. Patients with unfavourable AO at baseline were excluded. Patient, tumour and treatment characteristics were compared between the development and the validation cohort. The prognostic value of the characteristics in the validation cohort was further evaluated in univariable and multivariable analysis. RESULTS: Out of 175 included patients, 166 were evaluated two years after RT and 44 (26.51%) had unfavourable AO. AUC was 0.66 (95% CI 0.56; 0.76). Calibration was moderate with small overestimations at higher risk. When applying all of the univariable significant clinicopathological and dosimetrical variables from the validation cohort in a multivariable model, the presence of a seroma and V45 were selected as significant risk factors for unfavourable AO (Odds Ratio 4.40 (95% CI 1.96; 9.86) and 1.14 (95% CI 1.03; 1.27), p-value <.001 and .01, respectively). CONCLUSIONS: The NTCP model for unfavourable AO shows a moderate discrimination and calibration in the present prospective validation cohort with a small overestimation in the high risk patients.

Planning feasibility of extremely hypofractionated prostate radiotherapy on a 1.5 T magnetic resonance imaging guided linear accelerator.

BACKGROUND AND PURPOSE: Recently, intermediate and high-risk prostate cancer patients have been treated in a multicenter phase II trial with extremely hypofractionated prostate radiotherapy (hypo-FLAME trial). The purpose of the current study was to investigate whether a 1.5 T magnetic resonance imaging guided linear accelerator (MRI-linac) could achieve complex dose distributions of a quality similar to conventional linac state-of-the-art prostate treatments. MATERIALS AND METHODS: The clinically delivered treatment plans of 20 hypo-FLAME patients (volumetric modulated arc therapy, 10 MV, 5 mm leaf width) were included. Prescribed dose to the prostate was 5 × 7 Gy, with a focal tumor boost up to 5 × 10 Gy. MRI-linac treatment plans (intensity modulated radiotherapy, 7 MV, 7 mm leaf width, fixed collimator angle and 1.5 T magnetic field) were calculated. Dose distributions were compared. RESULTS: In both conventional and MRI-linac treatment plans, the V35Gy to the whole prostate was >99% in all patients. Mean dose to the gross tumor volume was 45 Gy for conventional and 44 Gy for MRI-linac plans, respectively. Organ at risk doses were met in the majority of plans, except for a rectal V35Gy constraint, which was exceeded in one patient, by 1 cc, for both modalities. The bladder V32Gy and V28Gy constraints were exceeded in two and one patient respectively, for both modalities. CONCLUSION: Planning of stereotactic radiotherapy with focal ablative boosting in prostate cancer on a high field MRI-linac is feasible with the current MRI-linac properties, without deterioration of plan quality compared to conventional treatments.