Double-strand breaks measured along a 160 MeV proton Bragg curve using a novel FIESTA-DNA probe in a cell-free environment.

Proton radiotherapy treatment planning systems use a constant relative biological effectiveness (RBE) = 1.1 to convert proton absorbed dose into biologically equivalent high-energy photon dose. This method ignores linear energy transfer (LET) distributions, and RBE is known to change as a function of LET. Variable RBE approaches have been proposed for proton planning optimization. Experimental validation of models underlying these approaches is a pre-requisite for their clinical implementation. This validation has to probe every level in the evolution of radiation-induced biological damage leading to cell death, starting from DNA double-strand breaks (DSB). Using a novel FIESTA-DNA probe, we measured the probability of double-strand break (P DSB) along a 160 MeV proton Bragg curve at two dose levels (30 and 60 Gy (RBE)) and compared it to measurements in a 6 MV photon beam. A machined setup that held an Advanced Markus parallel plate chamber for proton dose verification alongside the probes was fabricated. Each sample set consisted of five 10 µl probes suspended inside plastic microcapillary tubes. These were irradiated with protons to 30 Gy (RBE) at depths of 5-17.5 cm and 60 Gy (RBE) at depths of 10-17.2 cm with 1 mm resolution around Bragg peak. Sample sets were also irradiated using 6MV photons to 20, 40, 60, and 80 Gy. For the 30 Gy (RBE) measurements, increases in P DSB/Gy were observed at 17.0 cm followed by decreases at larger depth. For the 60 Gy (RBE) measurements, no increase in P DSB/Gy was observed, but there was a decrease after 17.0 cm. Dose-response for P DSB between 30 and 60 Gy (RBE) showed less than doubling of P DSB when dose was doubled. Proton RBE effect from DSB, RBEP,DSB, was <1 except at the Bragg peak. The experiment showed that the novel probe can be used to perform DNA DSB measurements in a proton beam. To establish relevance to clinical environment, further investigation of the probe's chemical scavenging needs to be performed.

A review of patient questions from physicist-patient consults.

PURPOSE: To provide insight into the types of questions asked to medical physicists by patients during one-on-one physicist-patient consults at one institution. MATERIALS AND METHODS: Medical physicists trained in patient communication techniques met with patients to provide an overview of the treatment planning and delivery processes, discuss the patient's treatment plan, and answer any technical questions. From August 2016 to December 2019, 152 physicist-patient consults were conducted. In the initial months of the study (August 2016-December 2017), following each physicist-patient consult, all patient questions were documented by the physicists. For the remaining time period (January 2018-December 2019), any newly encountered questions were periodically added to the list. The questions were compiled into a comprehensive list and organized into categories. RESULTS: There were a total of 88 unique patient questions. These questions fit into four topical categories. Fifty-four questions (61.4%) were in the "Treatment Planning and Delivery Questions" category, 15 questions (17.1%) were in the "General Radiation Questions or Concerns" category, 13 questions (14.8%) were in the "Safety and Quality Assurance Questions" category, and 6 questions (6.8%) were in the "Medical Questions" category. Overall, patients were primarily concerned about how radiation works, the treatment planning and delivery processes, and what is being done to keep them safe throughout their treatment. CONCLUSION: Physicist-patient consults provided an opportunity to address the technical aspects of radiation therapy with patients in greater detail. The fact that patient questions could be conveniently grouped into only four topical categories indicates that it may be straightforward for other medical physicists to prepare for effectively addressing technical questions during physicist-patient consults.

Incorporating biological modeling into patient-specific plan verification.

PURPOSE: Dose-volume histogram (DVH) measurements have been integrated into commercially available quality assurance systems to provide a metric for evaluating accuracy of delivery in addition to gamma analysis. We hypothesize that tumor control probability and normal tissue complication probability calculations can provide additional insight beyond conventional dose delivery verification methods. METHODS: A commercial quality assurance system was used to generate DVHs of treatment plan using the planning CT images and patient-specific QA measurements on a phantom. Biological modeling was performed on the DVHs produced by both the treatment planning system and the quality assurance system. RESULTS: The complication-free tumor control probability, P+ , has been calculated for previously treated intensity modulated radiotherapy (IMRT) patients with diseases in the following sites: brain (-3.9% ± 5.8%), head-neck (+4.8% ± 8.5%), lung (+7.8% ± 1.3%), pelvis (+7.1% ± 12.1%), and prostate (+0.5% ± 3.6%). CONCLUSION: Dose measurements on a phantom can be used for pretreatment estimation of tumor control and normal tissue complication probabilities. Results in this study show how biological modeling can be used to provide additional insight about accuracy of delivery during pretreatment verification.

Quantification of DNA double-strand breaks using Geant4-DNA.

PURPOSE: This study aims to standardize the simulation procedure in measuring DNA double-strand breaks (DSBs), by using advanced Monte Carlo toolkits, and newly introduced experimental methods for DNA DSB measurement. METHODS: For the experimental quantification of DNA DSB, an innovative DNA dosimeter was used to produce experimental data. GATE in combination with Geant4-DNA toolkit were exploited to simulate the experimental environment. The PDB4DNA example of Geant4-DNA was upgraded and investigated. Parameters of the simulation such energy threshold (ET) for a strand break and base pair threshold (BPT) for a DSB were evaluated, depending on the dose. RESULTS: Simulations resulted to minimum differentiation in comparison to experimental data for ET = 19 ± 1 eV and BPT = 10 bp, and high differentiation for ET<17.5 eV or ET>22.5 eV and BPT = 10 bp. There was also small differentiation for ET = 17.5 eV and BPT = 6 bp. Uncertainty has been kept lower than 3%. CONCLUSIONS: This study includes first results on the quantification of DNA double-strand breaks. The energy spectrum of a LINAC was simulated and used for the first time to irradiate DNA molecules. Simulation outcome was validated on experimental data that were produced by a prototype DNA dosimeter.

Longitudinal Growth Outcomes Following First-line Treatment for Pediatric Patients With Eosinophilic Esophagitis.

OBJECTIVES: No formal comparative effectiveness studies have been conducted to evaluate the effect of eosinophilic esophagitis (EoE) treatment choice on long-term growth in pediatric patients. Long-term studies of inhaled corticoid steroids in asthma, however, suggest possible effects on linear growth. The aim of this study was to compare longitudinal, anthropometric growth in children with EoE according to treatment approach. METHODS: We conducted a retrospective, multicenter cohort study of anthropometric growth (height and body mass index [BMI] z scores) in pediatric (<18 years of age) patients newly diagnosed with EoE across 5 clinical sites between 2005 and 2014. We compared differences in growth according to treatment approach over a 12-month period. Modification by sex and age was examined and sensitivity analyses were conducted to assess robustness of results given study assumptions. RESULTS: In the 409 patients identified, the mean age and proportion male differed by treatment (P =  < 0.01 and P = 0.04, respectively). Baseline growth measures were associated with slight impairment of height at diagnosis (median baseline height z score of -0.1 [interquartile range -0.9, 0.8]). In general, treatment approach was not associated with any significant increase or decrease in expected growth over a 12-month period. Subtle decrease in linear growth was observed with treatment using a combined elemental and topical steroid (Δ height z score [adjusted]: -0.04; 95% confidence interval [CI]: -0.08, -0.01). Differences in linear growth differed by sex (P for interaction <0.01). For elemental formula in combination with topical steroids, only girls exhibited a significant decline in linear growth (Δ height z score [adjusted]: -0.24; 95% CI: -0.32, -0.17). A slight reduction in BMI was observed for patients treated with a combination of elemental diet and dietary elimination (Δ BMI z score [adjusted]: -0.07; 95% CI: -0.13, -0.01). CONCLUSIONS: Treatment of EoE, in general, is not associated with major anthropometric growth changes in most pediatric patients. Slight linear growth impairment was observed for topical steroid treatment, and sex differences in growth by treatment approach were observed. Future prospective studies should evaluate the effect of treatment on optimal growth and development and over a longer period of follow-up.

Dosimetric Evaluation of Pinnacle's Automated Treatment Planning Software to Manually Planned Treatments.

INTRODUCTION: With the advent of complex treatment techniques like volumetric modulated arc therapy, there has been increasing interest in treatment planning technologies aimed at reducing planning time. One of these such technologies is auto-planning, which is an automated planning module within Pinnacle3. This study seeks to retrospectively evaluate the dosimetric quality of auto-planning-derived treatment plans as they compare to manual plans for intact prostate, prostate and lymph nodes, and brain treatment sites. MATERIALS AND METHODS: Previous clinical plans were used to generate site-specific auto-planning templates. These templates were used to compare the 3 evaluated treatment sites. Plans were replanned using auto-planning and compared to the clinically delivered plans. For the planning target volume, the following metrics were evaluated: homogeneity index, conformity index, D2cc, Dmean, D2%, D98%, and multiple dose fall-off parameters. For the organs at risk, D2cc, Dmean, and organ-specific clinical metrics were evaluated. Statistical differences were evaluated using a Wilcoxon paired signed-rank test with a significance level of 0.05. Statistically significant ( P < 0.05) differences were noted in organs at risk sparing. RESULTS: For the prostate, there was as much as 6.8% reduction in bladder Dmean and 23.5% reduction in penile bulb Dmean. For the prostate + lymph nodes, decreases in Dmean values ranging from 4.1% in the small bowel to 22.3% in the right femoral head were observed. For brain, significant improvements were observed in Dmax and Dmean to most organs at risk. CONCLUSION: Our study showed improved organs at risk sparing in most organs while maintaining planning target volume coverage. Overall, auto-planning can generate plans that delivered the same target coverage as the clinical plans but offered significant reductions in mean dose to organs at risk.

Practice Pattern Variation in Pediatric Eosinophilic Esophagitis in the Carolinas EoE Collaborative: A Research Model in Community and Academic Practices.

OBJECTIVES: Differences in the initial management of pediatric eosinophilic esophagitis (EoE) by practice setting have not been well characterized. We aimed to characterize these differences for sites in the Carolinas EoE Collaborative (CEoEC), a multicenter network of academic and community practices. METHODS: We performed a retrospective cohort study of pediatric EoE patients at five CEoEC sites: University of North Carolina (UNC) Hospital, Charlotte Asthma and Allergy Specialists, Greenville Health Systems, Wake Forest Baptist Medical Center, and the Medical University of South Carolina Hospital. Cases of EoE were defined by consensus guidelines. Data were extracted from electronic medical records. We tested for differences among sites and used a multinomial model (polytomous regression) to assess associations between treatment and site, adjusting on patient factors. RESULTS: We identified 464 children with EoE across the CEoEC sites. The median age was highest at Wake Forest (11.4 years), the median eosinophil count was highest at UNC (69 eos/hpf), and UNC had the most male patients (82%). UNC used topical steroids for initial treatment in 86% of cases, compared with <1% in Greenville (P < 0.01). Greenville used dietary elimination more frequently than UNC (81% vs 2%, P < 0.01). Differences in treatment approach held after adjusting for potential baseline confounders. There was no significant association between patient factors and initial treatment approach. CONCLUSIONS: Significant differences in EoE patient factors and treatment approaches were identified across CEoEC sites and were not explained by patient or practice factors. This suggests that institutional or provider preferences drive initial treatment approaches, and that more data are needed to drive best practice decisions.

Comparative performance evaluation of a new a-Si EPID that exceeds quad high-definition resolution.

PURPOSE: Electronic portal imaging devices (EPIDs) are an integral part of the radiation oncology workflow for treatment setup verification. Several commercial EPID implementations are currently available, each with varying capabilities. To standardize performance evaluation, Task Group Report 58 (TG-58) and TG-142 outline specific image quality metrics to be measured. A LinaTech Image Viewing System (IVS), with the highest commercially available pixel matrix (2688x2688 pixels), was independently evaluated and compared to an Elekta iViewGT (1024x1024 pixels) and a Varian aSi-1000 (1024x768 pixels) using a PTW EPID QC Phantom. METHODS: The IVS, iViewGT, and aSi-1000 were each used to acquire 20 images of the PTW QC Phantom. The QC phantom was placed on the couch and aligned at isocenter. The images were exported and analyzed using the epidSoft image quality assurance (QA) software. The reported metrics were signal linearity, isotropy of signal linearity, signal-tonoise ratio (SNR), low contrast resolution, and high-contrast resolution. These values were compared between the three EPID solutions. RESULTS: Computed metrics demonstrated comparable results between the EPID solutions with the IVS outperforming the aSi-1000 and iViewGT in the low and high-contrast resolution analysis. CONCLUSION: The performance of three commercial EPID solutions have been quantified, evaluated, and compared using results from the PTW QC Phantom. The IVS outperformed the other panels in low and high-contrast resolution, but to fully realize the benefits of the IVS, the selection of the monitor on which to view the high-resolution images is important to prevent down sampling and visual of resolution.

DNA double-strand breaks as a method of radiation measurements for therapeutic beams.

PURPOSE: Many types of dosimeters are used to measure radiation dose and calibrate radiotherapy equipment, but none directly measure the biological effect of this dose. The purpose here is to create a dosimeter that can measure the probability of double-strand breaks (DSB) for DNA, which is directly related to the biological effect of radiation. METHODS: A DNA dosimeter, consisting of magnetic streptavidin beads attached to four kilobase pair DNA strands labeled with biotin and fluorescein amidite (FAM) on opposing ends, was suspended in phosphate-buffered saline (PBS). Fifty microliter samples were placed in plastic tubes inside a water tank setup and irradiated at the dose levels of 25, 50, 100, 150, and 200 Gy. After irradiation, the dosimeters were mechanically separated into beads (intact DNA) and supernatant (broken DNA/FAM) using a magnet. The fluorescence was read and the probability of DSB was calculated. This DNA dosimeter response was benchmarked against a Southern blot analysis technique for the measurement of DSB probability. RESULTS: For the DNA dosimeter, the probabilities of DSB at the dose levels of 25, 50, 100, 150, and 200 Gy were 0.043, 0.081, 0.149, 0.196, and 0.242, respectively, and the standard errors of the mean were 0.002, 0.003, 0.006, 0.005, and 0.011, respectively. For the Southern blot method, the probabilities of DSB at the dose levels of 25, 50, 100, 150, and 200 Gy were 0.053, 0.105, 0.198, 0.235, and 0.264, respectively, and the standard errors of the mean were 0.013, 0.024, 0.040, 0.044, and 0.063, respectively. CONCLUSIONS: A DNA dosimeter can accurately determine the probability of DNA double-strand break (DSB), one of the most toxic effects of radiotherapy, for absorbed radiation doses from 25 to 200 Gy. This is an important step in demonstrating the viability of DNA dosimeters as a measurement technique for radiation.

Comparison of initial patient setup accuracy between surface imaging and three point localization: A retrospective analysis.

PURPOSE: Historically, the process of positioning a patient prior to imaging verification used a set of permanent patient marks, or tattoos, placed subcutaneously. After aligning to these tattoos, plan specific shifts are applied and the position is verified with imaging, such as cone-beam computed tomography (CBCT). Due to a variety of factors, these marks may deviate from the desired position or it may be hard to align the patient to these marks. Surface-based imaging systems are an alternative method of verifying initial positioning with the entire skin surface instead of tattoos. The aim of this study was to retrospectively compare the CBCT-based 3D corrections of patients initially positioned with tattoos against those positioned with the C-RAD CatalystHD surface imager system. METHODS: A total of 6000 individual fractions (600-900 per site per method) were randomly selected and the post-CBCT 3D corrections were calculated and recorded. For both positioning methods, four common treatment site combinations were evaluated: pelvis/lower extremities, abdomen, chest/upper extremities, and breast. Statistical differences were evaluated using a paired sample Wilcoxon signed-rank test with significance level of <0.01. RESULTS: The average magnitudes of the 3D shift vectors for tattoos were 0.9 ± 0.4 cm, 1.0 ± 0.5 cm, 0.9 ± 0.6 cm and 1.4 ± 0.7 cm for the pelvis/lower extremities, abdomen, chest/upper extremities and breast, respectively. For the CatalystHD, the average magnitude of the 3D shifts for the pelvis/lower extremities, abdomen, chest/upper extremities and breast were 0.6 ± 0.3 cm, 0.5 ± 0.3 cm, 0.5 ± 0.3 cm and 0.6 ± 0.2 cm, respectively. Statistically significant differences (P < 0.01) in the 3D shift vectors were found for all four sites. CONCLUSION: This study shows that the overall 3D shift corrections for patients initially aligned with the C-RAD CatalystHD were significantly smaller than those aligned with subcutaneous tattoos. Surface imaging systems can be considered a viable option for initial patient setup and may be preferable to permanent marks for specific clinics and patients.