Foote, Robert L.

Background: Particle therapy is a noninvasive, catheter-free modality for cardiac ablation. We previously demonstrated the efficacy for creating ablation lesions in the porcine heart. Despite several earlier studies, the exact mechanism of early biophysical effects of proton and photon beam delivery on the myocardium remain incompletely resolved. Methods: Ten normal and 9 infarcted in situ porcine hearts received proton beam irradiation (40 Gy) delivered to the left ventricular myocardium with follow-up for 8 weeks. High-resolution electroanatomical mapping of the left ventricular was performed at baseline and follow-up. Bipolar voltage amplitude, conduction velocity, and connexin-43 were determined within the irradiated and nonirradiated areas. Results: The irradiated area in normal hearts showed a significant reduction of bipolar voltage amplitude (10.1±4.9 mV versus 5.7±3.2, P <0.0001) and conduction velocity (85±26 versus 55±13 cm/s, P =0.03) beginning at 4 weeks after irradiation. In infarcted myocardium after irradiation, bipolar voltage amplitude of the infarct scar (2.0±2.9 versus 0.8±0.7 mV, P =0.008) was significantly reduced as well as the conduction velocity in the infarcted heart (43.7±15.7 versus 26.3±11.4 cm/s, P =0.02). There were no significant changes in bipolar voltage amplitude and conduction velocity in nonirradiated myocardium. Myocytolysis, capillary hyperplasia, and dilation were seen in the irradiated myocardium 8 weeks after irradiation. Active caspase-3 and reduction of connexin-43 expression began in irradiated myocardium 1 week after irradiation and decreased over 8 weeks. Conclusions: Irradiation of the myocardium with proton beams reduce connexin-43 expression, conduction velocity, and bipolar conducted electrogram amplitude in a large porcine model. The changes in biomarkers preceded electrophysiological changes after proton beam therapy.

Purpose: This study evaluates beam angles used to generate highly individualized proton therapy treatment plans for patients eligible for carbon ion radiotherapy (CIRT). Methods and Materials: We retrospectively evaluated patients treated with pencil beam scanning intensity modulated proton therapy from 2015 to 2020 who had indications for CIRT. Patients were treated with a 190° rotating gantry with a robotic patient positioning system. Treatment plans were individualized to provide maximal prescription dose delivery to the tumor target volume while sparing organs at risk. The utilized beam angles were grouped, and anatomic sites with at least 10 different beam angles were sorted into histograms. Results: A total of 467 patients with 484 plans and 1196 unique beam angles were evaluated and characterized by anatomic treatment site and the number of beam angles utilized. The most common beam angles used were 0° and 180°. A wide range of beam angles were used in treating almost all anatomic sites. Only esophageal cancers had a predominantly unimodal grouping of beam angles. Pancreas cancers showed a modest grouping of beam angles. Conclusions: The wide distribution of beam angles used to treat CIRT-eligible patients suggests that a rotating gantry is optimal to provide highly individualized beam arrangements.

AbstractPurposeProton treatment plan perturbation by common dental fixtures such as amalgams (Am) and porcelain‐fused‐to‐metal (PFM) crowns has, to date, been uncharacterized. Previous studies have been conducted to determine the physical effect of these materials within the beam path for single spots, but their effects on complex treatment plans and clinical anatomy have not yet been quantified. The present manuscript aims to study the effect of Am and PFM fixtures on proton treatment planning in a clinical setting.MethodsAn anthropomorphic phantom with removable tongue, maxilla, and mandible modules was simulated on a clinical computed tomography (CT) scanner. Spare maxilla modules were modified to include either a 1.5 mm depth central groove occlusal amalgam (Am) or a porcelain‐fused‐to‐metal (PFM) crown, implanted on the first right molar. Modified tongue modules were 3D printed to accommodate several axial or sagittal oriented pieces of EBT‐3 film. Clinically representative spot‐scanning proton plans were generated in Eclipse v.15.6 using the proton convolution superposition (PCS) algorithm v.15.6.06 using a multi‐field optimization (MFO) technique with the goal of delivering a uniform 54 Gy dose to a clinical target volume (CTV) typical of a base‐of‐tongue (BoT) treatment. A typical geometric beam arrangement of two anterior oblique (AO) beams and a posterior beam was employed. Plans optimized without any material overrides were delivered to the phantom A) without implants; B) with Am fixture; or C) with PFM crown. Plans were also reoptimized and delivered with inclusion of material overrides to equate relative stopping power of the fixture with that of a previously measured result.ResultsPlans exhibit slightly greater dose weight towards AO beams. The optimizer accounted for inclusion of fixture overrides by increasing beam weights to the beam closest to the implant. Film measurements exhibited cold spots directly within the beam path through the fixture in plans with and without overridden materials. Cold spots were somewhat mitigated in plans including overridden materials in the structure set but were not entirely eliminated. Cold spots associated with Am and PFM fixtures were quantified at 17% and 14% for plans without overrides, respectively, and 11% and 9% with using Monte Carlo simulation. Compared with film measurements and Monte Carlo simulation, the treatment planning system underestimates the dose shadowing effect in plans including material overrides.ConclusionsDental fixtures create a dose shadowing effect directly in line with the beam path through the material. This cold spot is partially mitigated by overriding the material to measured relative stopping powers. Due to uncertainties in modeling perturbation through the fixture, the magnitude of the cold spot is underestimated using the institutional TPS when compared to measurement and MC simulation.

Surgical treatment of pelvic sarcoma involving the bone is the standard of care but is associated with several sequelae and reduced functional quality of life (QOL). Treatment with photon and proton radiotherapy is associated with relapse. Carbon ion radiotherapy (CIRT) may reduce both relapse rates and treatment sequelae. The PROSPER study is a tricontinental, nonrandomized, prospective, three-arm, pragmatic trial evaluating treatments of pelvic sarcoma involving the bone. Patients aged at least 15 years are eligible for inclusion. Participants must have an Eastern Cooperative Oncology Group Performance Status score of two or less, newly diagnosed disease, and histopathologic confirmation of pelvic chordoma, chondrosarcoma, osteosarcoma, Ewing sarcoma with bone involvement, rhabdomyosarcoma (RMS) with bone involvement, or non-RMS soft tissue sarcoma with bone involvement. Treatment arms include (1) CIRT (n = 30) delivered in Europe and Asia, (2) surgical treatment with or without adjuvant radiotherapy (n = 30), and (3) proton therapy (n = 30). Arms two and three will be conducted at Mayo Clinic campuses in Arizona, Florida, and Minnesota. The primary end point is to compare the 1-year change in functional QOL between CIRT and surgical treatment. Additional comparisons among the three arms will be made between treatment sequelae, local control, and other QOL measures.

AbstractBackgroundWe seek to inform radiotherapy (RT) delivery for adenoid cystic carcinoma of the head and neck (ACC) by evaluating RT techniques and recurrence patterns.MethodsWe identified patients with ACC treated with curative‐intent RT from 2005 to 2021. Imaging was reviewed to determine local recurrence (LR).ResultsNinety‐one patients were included. The 5‐year LR risk was 12.2% (6.6–22.7). One patient each experienced a marginal and out‐of‐field recurrence. Patients receiving >60 Gy postoperatively had a 5‐year LR risk of 0% compared to 10.7% (4.2–27.2) with ≤60 Gy. Those receiving 70 and <70 Gy definitively had a 5‐year LR risk of 15.2% (2.5–91.6) and 33.3% (6.7–100.0), respectively. No patients had regional nodal failure.ConclusionsModern, conformal RT for ACC results in low rates of LR. Doses >60 and 70 Gy may improve control in the postoperative and definitive settings, respectively. Elective nodal treatment can be omitted in well‐selected patients.

AbstractBackgroundWe aim to explore the prognostic role of absolute lymphocyte count (ALC) before, during, and after treatment on oncologic outcomes in human papillomavirus associated oropharyngeal cancer (HPV(+)OPSCC).MethodsRetrospective cohort at a tertiary center, 2006–2018. Multivariable Cox regressions were used to determine the effect of ALC on risk of progression. Univariate linear regression was performed to determine clinical factors associated with lower ALC.ResultsAll 197 patients underwent primary surgery. Mean (SD) ALC nadirs (×109 cells/L) were: baseline (N = 149): 1.69 (0.56); postoperative (N = 126): 1.58 (0.59); post‐RT (N = 141): 0.68 (0.35) and long‐term (N = 105): 0.88 (0.37). Lower baseline ALC nadir was associated with worse overall survival (HR 3.85, 95%CI: 1.03–14.29, p = 0.04). Lower postoperative ALC nadir was associated with higher risk of progression (HR 2.63, 95%CI: 1.04–6.67, p = 0.04).ConclusionsLower baseline ALC is associated with worse survival, whereas lower postoperative ALC is associated with increased risk of progression in surgically treated HPV(+)OPSCC.Level of Evidence3

AbstractBackgroundIn proton therapy dose calculation, Monte Carlo (MC) simulations are superior in accuracy but more time consuming, compared to analytical calculations. Graphic processing units (GPUs) are effective in accelerating MC simulations but may suffer thread divergence and racing condition in GPU threads that degrades the computing performance due to the generation of secondary particles during nuclear reactions.PurposeA novel concept of virtual particle (VP) MC (VPMC) is proposed to avoid simulating secondary particles in GPU‐accelerated proton MC dose calculation and take full advantage of the computing power of GPU.MethodsNeutrons and gamma rays were ignored as escaping from the human body; doses of electrons, heavy ions, and nuclear fragments were locally deposited; the tracks of deuterons were converted into tracks of protons. These particles, together with primary and secondary protons, are considered to be the realistic particles. Histories of primary and secondary protons were replaced by histories of multiple VPs. Each VP corresponded to one proton (either primary or secondary). A continuous‐slowing‐down‐approximation model, an ionization model, and a large angle scattering event model corresponding to nuclear interactions were developed for VPs by generating probability distribution functions (PDFs) based on simulation results of realistic particles using MCsquare. For efficient calculations, these PDFs were stored in the Compute Unified Device Architecture textures. VPMC was benchmarked with TOPAS and MCsquare in phantoms and with MCsquare in 13 representative patient geometries. Comparisons between the VPMC calculated dose and dose measured in water during patient‐specific quality assurance (PSQA) of the selected 13 patients were also carried out. Gamma analysis was used to compare the doses derived from different methods and calculation efficiencies were also compared.ResultsIntegrated depth dose and lateral dose profiles in both homogeneous and inhomogeneous phantoms all matched well among VPMC, TOPAS, and MCsquare calculations. The 3D–3D gamma passing rates with a criterion of 2%/2 mm and a threshold of 10% was 98.49% between MCsquare and TOPAS and 98.31% between VPMC and TOPAS in homogeneous phantoms, and 99.18% between MCsquare and TOPAS and 98.49% between VPMC and TOPAS in inhomogeneous phantoms, respectively. In patient geometries, the 3D–3D gamma passing rates with 2%/2 mm/10% between dose distributions from VPMC and MCsquare were 98.56 ± 1.09% in patient geometries. The 2D–3D gamma analysis with 3%/2 mm/10% between the VPMC calculated dose distributions and the 2D measured planar dose distributions during PSQA was 98.91 ± 0.88%. VPMC calculation was highly efficient and took 2.84 ± 2.44 s to finish for the selected 13 patients running on four NVIDIA Ampere GPUs in patient geometries.ConclusionVPMC was found to achieve high accuracy and efficiency in proton therapy dose calculation.

AbstractBackgroundBoth dose and linear energy transfer (LET) could play a substantial role in adverse event (AE) initialization of cancer patients treated with pencil‐beam‐scanning (PBS) proton therapy. However, not all the voxels within the AE regions are directly induced from the dose and LET effect. It is important to study the synergistic effect of dose and LET in AE initialization by only including a subset of voxels that are dosimetrically important.PurposeTo perform exploratory investigation of the dose and LET effects upon AE initialization in PBS using seed spots analysis.MethodsA total of 113 head‐and‐neck (H&N) cancer patients receiving curative PBS were included. Among them, 20 patients experienced unanticipated CTCAEv4.0 grade ≥3 AEs (AE group) and 93 patients did not (control group). Within the AE group, 13 AE patients were included in the seed spot analysis to derive the descriptive features of AE initialization and the remaining 7 mandible osteoradionecrosis patients and 93 control patients were used to derive the feature‐based volume constraint of mandible osteoradionecrosis. The AE regions were contoured and the corresponding dose–LET volume histograms of AE regions were generated for all patients in the AE group. We selected high LET voxels (the highest 5% of each dose bin) with a range of moderate‐to‐high dose (≥∼40‐Gy relative biological effectiveness) as critical voxels. Critical voxels that were contiguous with each other were grouped into clusters. Each cluster was considered a potential independent seed spot for AE initialization. Seed spots were displayed in a 2D dose–LET plane based on their mean dose and LET to derive the descriptive features of AE initialization. A volume constraint of mandible osteoradionecrosis was then established based on the extracted features using a receiver operating characteristic curve.ResultsThe product of dose and LET (xBD) was found to be a descriptive feature of seed spots leading to AE initialization in this preliminary study. The derived xBD volume constraint for mandible osteoradionecrosis showed good performance with an area under curve of 0.87 (sensitivity of 0.714 and specificity of 0.807 in the leave‐one‐out cross‐validation) for the very limited patient data included in this study.ConclusionOur exploratory study showed that both dose and LET were observed to be important in AE initializations. The derived xBD volume constraint could predict mandible osteoradionecrosis reasonably well in the very limited H&N cancer patient data treated with PBS included in this study.

AbstractPurposeFor total skin electron (TSE) beam radiation therapy, the anterior eye and conjunctiva can be protected with eye shields to prevent keratitis, xerophthalmia, and cataractogenesis. Conventional metal eye shields can reduce patient balance by obscuring vision and thus increasing the risk for falls. We report on the design, fabrication, and clinical use of transparent acrylic eye shields for TSE.MethodsThe primary design goals were a seven‐fold reduction in the dose to the anterior eye and conjunctiva to meet published dose‐recommendations, preservation of vision for the wearer, and biocompatibility for external use. Resembling thick swim goggles, the design features 23 mm thick acrylic lenses that are mounted in a 3‐D printed support structure that conforms to the eye socket and can be worn with a strap. Dose measurements were performed in a simulated Stanford‐technique treatment with an anthropomorphic phantom using Gafchromic EBT filmResultsThe transparent eye shields were manufactured using a 3D‐printer and CNC‐machine. Based on measurements from the simulated treatments for each of the eye shields, the eye shields provided a 12‐fold reduction in dose to the lens. After use in more than 200 fractions, the shields were well tolerated by patients, and there were no reports of any incidents or adverse events.ConclusionTransparent TSE eye shields are able to reduce the dose to the eyes while maintaining vision during treatment at a reasonable cost.

AbstractBackgroundMerkel cell carcinoma (MCC) is a rare, aggressive cutaneous malignancy that usually occurs in the head/neck or extremities. However, there are reports of MCC developing in the lymph nodes or parotid gland without evidence of a primary cutaneous lesion.MethodsWe reviewed 415 patients with biopsy‐proven MCC. Patients with MCC of unknown primary (n = 37, 9%, MCCUP) made up the study cohort. The primary endpoints of the study were rate of recurrence, disease‐free survival, and overall survival.ResultsPatients with MCCUP presented with tumors in lymph nodes (n = 34) or parotid gland (n = 3). Nodal disease was most commonly detected in the inguinal/external iliac (n = 15) or axillary (n = 14) regions. The mean age at diagnosis was 70 years and 24% were female. Patients presented with distant metastases in 24.3% of cases. Patients with stage IIIA disease treated with regional lymph node dissection (RLND) had a lower risk of disease recurrence (hazard ratio 0.26, p = 0.046). Recurrence‐free survival was 59.3% at 5 years. Disease‐specific survival was 63.3% at 5 years.ConclusionPatients with MCCUP have a high risk of recurrence and mortality. The optimal treatment for MCCUP has yet to be elucidated, although therapeutic RLND appears beneficial for these patients.