A method to implement inter-track interactions in Monte Carlo simulations with TOPAS-nBio and their influence on simulated radical yields following water radiolysis.

Objective.In FLASH radiotherapy (dose rates ≥40 Gy s-1), a reduced normal tissue toxicity has been observed, while maintaining the same tumor control compared to conventional radiotherapy (dose rates ≤0.03 Gy s-1). This protecting effect could not be fully explained yet. One assumption is that interactions between the chemicals of different primary ionizing particles, so-called inter-track interactions, trigger this outcome. In this work, we included inter-track interactions in Monte Carlo track structure simulations and investigated the yield of chemicals (G-value) produced by ionizing particles.Approach.For the simulations, we used the Monte Carlo toolkit TOPAS, in which inter-track interactions cannot be implemented without further effort. Thus, we developed a method enabling the simultaneous simulation ofNoriginal histories in one event allowing chemical species to interact with each other. To investigate the effect of inter-track interactions we analyzed theG-value of different chemicals using various radiation sources. We used electrons with an energy of 60 eV in different spatial arrangements as well as a 10 MeV and 100 MeV proton source. For electrons we setNbetween 1 and 60, for protons between 1 and 100.Main results.In all simulations, the totalG-value decreases with increasingN. In detail, theG-value for•OH , H3O and eaqdecreases with increasingN, whereas theG-value of OH-, H2O2and H2increases slightly. The reason is that with increasingN, the concentration of chemical radicals increases allowing for more chemical reactions between the radicals resulting in a change of the dynamics of the chemical stage.Significance.Inter-track interactions resulting in a variation of the yield of chemical species, may be a factor explaining the FLASH effect. To verify this hypothesis, further simulations are necessary in order to evaluate the impact of varyingG-values on the yield of DNA damages.

Anti-Proliferative Effect of Radiotherapy and Implication of Immunotherapy in Anaplastic Thyroid Cancer Cells.

Radiotherapy and immunotherapy have shown promising efficacy for the treatment of solid malignancies. Here, we aim to clarify the potential of a combined application of radiotherapy and programmed cell death-ligand 1 (PD-L1) monoclonal antibody atezolizumab in primary anaplastic thyroid cancer (ATC) cells. The radiation caused a significant reduction in cell proliferation, measured by luminescence, and of the number of colonies. The addition of atezolizumab caused a further reduction in cell proliferation of the irradiated ATC cells. However, the combined treatment did not cause either the exposure of the phosphatidylserine or the necrosis, assessed by luminescence/fluorescence. Additionally, a reduction in both uncleaved and cleaved forms of caspases 8 and 3 proteins was detectable in radiated cells. The DNA damage evidenced the over-expression of TP53, CDKN1A and CDKN1B transcripts detected by RT-qPCR and the increase in the protein level of P-γH2AX and the DNA repair deputed kinases. PD-L1 protein level increased in ATC cells after radiation. Radiotherapy caused the reduction in cell viability and an increase of PD-L1-expression, but not apoptotic cell death in ATC cells. The further combination with the immunotherapeutic atezolizumab could increase the efficacy of radiotherapy in terms of reduction in cell proliferation. Further analysis of the involvement of alternative cell death mechanisms is necessary to clarify their cell demise mechanism of action. Their efficacy represents a promising therapy for patients affected by ATC.

Efficiency analysis of rapid antigen test based SARS-CoV-2 in hospital contact tracing and screening regime: test characteristics and cost effectiveness.

In the context of the current SARS-CoV-2 pandemic, reliable and cost-efficient screening and testing strategies are crucial to prevent disease transmission and reduce socioeconomic losses. To assess the efficiency of a rapid antigen test (RAT)-based SARS-CoV-2 contact-tracing and screening regime, we conducted a retrospective analysis of RAT and polymerase chain reaction (PCR) test data over a 1-year period, assessed test characteristics and estimated cost-effectiveness. The RAT had a sensitivity of 70.2% overall and 89.3% for people with a high risk of infectivity. We estimated inpatient treatment and quarantined healthcare worker costs of over € 5860.83, whereas the cost of identifying one SARS-CoV-2 positive person by RAT for our patient cohort was € 1210.75. In contrast, the estimated respective PCR cost was € 5043.32. Therefore, a RAT-based contract tracing and screening regime may be an efficient and cost-effective way to contribute to the early identification and prevention of SARS-CoV-2 transmission.

Radiation doses to mediastinal organs at risk in early-stage unfavorable Hodgkin lymphoma- a risk stratified analysis of the GHSG HD17 trial.

Introduction: The German Hodgkin Study Group (GHSG) HD17 trial established the omission of radiotherapy (RT) for patients with early-stage unfavorable Hodgkin lymphoma being PET-negative after 2 cycles of BEACOPP escalated plus 2 cycles of ABVD. This patient group reveals heterogeneity in characteristics and disease extent which prompted us to perform a decisive dosimetric analysis according to GHSG risk factors. This may help to tailor RT individually balancing risks and benefits. Methods: For quality assurance, RT-plans were requested from the treating facilities (n= 141) and analyzed centrally. Dose-volume histograms were scanned either paper-based or digitally to obtain doses to mediastinal organs. These were registered and compared according to GHSG risk factors. Results: Overall, RT plans of 176 patients were requested, 139 of which had dosimetric information on target volumes within the mediastinum. Most of these patients were stage II (92.8%), had no B-symptoms (79.1%) and were aged < 50 years (89.9%). Risk factors were present in 8.6% (extranodal involvement), 31.7% (bulky disease), 46.0% (elevated erythrocyte sedimentation rate) and 64.0% (three involved areas), respectively. The presence of bulky disease significantly affected the mean RT doses to the heart (p=0.005) and to the left lung (median: 11.3 Gy vs. 9.9 Gy; p=0.042) as well as V5 of the right and left lung, respectively (median right lung: 67.4% vs. 51.0%; p=0.011; median left lung: 65.9% vs. 54.2%; p=0.008). Significant differences in similar organs at risk parameters could be found between the sub-cohorts with the presence or absence of extranodal involvement, respectively. In contrast, an elevated erythrocyte sedimentation rate did not deteriorate dosimetry significantly. No association of any risk factor with radiation doses to the female breast was found. Conclusion: Pre-chemotherapy risk factors may help to predict potential RT exposure to normal organs and to critically review treatment indication. Individualized risk-benefit evaluations for patients with HL in early-stage unfavorable disease are mandatory.

Radiation Therapy in the German Hodgkin Study Group HD 16 and HD 17 Trials: Quality Assurance and Dosimetric Analysis for Hodgkin Lymphoma in the Modern Era.

Purpose: Radiation therapy (RT) is an integral part of treatment concepts for early-stage Hodgkin lymphoma. This analysis reports on RT quality in the recent HD16 and 17 trials of the German Hodgkin Study Group (GHSG). Methods and Materials: All RT plans of involved-node radiation therapy (INRT) in HD 17 were requested for analysis, along with 100 and 50 involved-field radiation therapy (IFRT) plans in HD 16 and 17, respectively. A structured assessment regarding field design and protocol adherence was performed by the reference radiation oncology panel of the GHSG. Results: Overall, 100 (HD 16) and 176 (HD 17) patients were eligible for analysis. In HD 16, 84% of RT series were evaluated as correct, with significant improvement compared with the predecessor studies (P < .001). In HD 17, 76.1% of INRT cases revealed a correct RT design compared with 69.0% of IFRT-cases, which was superior to previous studies (P < .001). Comparing INRT and IFRT, we found no significant differences in the percentage of any deviation (P = .418) or major deviations (P = .466). Regarding dosimetry, INRT was accompanied by an improvement in thyroid doses. Comparing different RT techniques, we found that intensity-modulated RT showed a reduction of high doses in the lung at the expense of an increased low-dose exposure in HD 17. Conclusions: The latest study generation of the GHSG demonstrates an improved quality in RT. A modern INRT design could be established without deterioration in quality. On a conceptual level, an individual consideration of the appropriate RT technique has to be performed.

The Majority of United States Citizens With Cancer do not Have Access to Carbon Ion Radiotherapy.

As of December 31, 2020, there were 12 facilities located in Asia and Europe which were treating cancer patients with carbon ion radiotherapy (CIRT). Between June 1994 and December 2020, 37,548 patients were treated with CIRT worldwide. Fifteen of these patients were United States (U.S.) citizens. Using the Surveillance, Epidemiology, and End Results cancer statistics database, the Mayo Clinic in Rochester, MN has conservatively estimated that there are approximately 44,340 people diagnosed each year in the U.S. with malignancies that would benefit from treatment with CIRT. The absence of CIRT facilities in the U.S. not only limits access to CIRT for cancer care but also prevents inclusion of U.S. citizens in phase III clinical trials that will determine the comparative effectiveness and cost effectiveness of CIRT for a variety of malignancies for FDA approval and insurance coverage. Past and present phase III clinical trials have not been able to enroll U.S. citizens due to their unwillingness or inability to travel abroad for CIRT for an extended period. These barriers could be overcome with a limited number of CIRT facilities in the U.S.

The fast calibration model for dosimetry with an electronic portal imaging device.

PURPOSE: The aim of this study was to develop an algorithm that corrects the image of an electronic portal imaging device (EPID) of a linear accelerator so that it can be used for dosimetric purposes, such as in vivo dosimetry or quality assurance for photon radiotherapy. For that purpose, the impact of the field size, phantom thickness, and the varying spectral photon distribution within the irradiation field on the EPID image was investigated. METHODS: The EPID measurements were verified using reference measurements with ionization chambers. Therefore, absolute dose measurements with an ionization chamber and relative dose measurements with a detector array were performed. An EPID calibration and correction algorithm was developed to convert the EPID image to a dose distribution. The algorithm was validated by irradiating inhomogeneous phantoms using square fields as well as irregular IMRT fields. RESULTS: It was possible to correct the influence of the field size, phantom thickness on the EPID signal as well as the homogenization of the image profile by several correction factors within 0.6%. A gamma index analysis (3%, 3 mm) of IMRT fields showed a pass rate of above 99%, when comparing to the planning system. CONCLUSION: The developed algorithm enables an online dose measurement with the EPID during the radiation treatment. The algorithm is characterized by a robust, non-iterative, and thus real-time capable procedure with little measuring effort and does not depend on system-specific parameters. The EPID image is corrected by multiplying three independent correction factors. Therefore, it can easily be extent by further correction factors for other influencing variables, so it can be transferred to other linear accelerators and EPID configurations.

Dual PI3K/mTOR Inhibitor NVP-BEZ235 Leads to a Synergistic Enhancement of Cisplatin and Radiation in Both HPV-Negative and -Positive HNSCC Cell Lines.

The standard of care for advanced head and neck cancers (HNSCCs) is radiochemotherapy, including cisplatin. This treatment results in a cure rate of approximately 85% for oropharyngeal HPV-positive HNSCCs, in contrast to only 50% for HPV-negative HNSCCs, and is accompanied by severe side effects for both entities. Therefore, innovative treatment modalities are required, resulting in a better outcome for HPV-negative HNSCCs, and lowering the adverse effects for both entities. The effect of the dual PI3K/mTOR inhibitor NVP-BEZ235 on a combined treatment with cisplatin and radiation was studied in six HPV-negative and six HPV-positive HNSCC cell lines. Cisplatin alone was slightly more effective in HPV-positive cells. This could be attributed to a defect in homologous recombination, as demonstrated by depleting RAD51. Solely for HPV-positive cells, pretreatment with BEZ235 resulted in enhanced cisplatin sensitivity. For the combination of cisplatin and radiation, additive effects were observed. However, when pretreated with BEZ235, this combination changed into a synergistic interaction, with a slightly stronger enhancement for HPV-positive cells. This increase could be attributed to a diminished degree of DSB repair in G1, as visualized via the detection of γH2AX/53BP1 foci. BEZ235 can be used to enhance the effect of combined treatment with cisplatin and radiation in both HPV-negative and -positive HNSCCs.

IL1 Pathway in HPV-Negative HNSCC Cells Is an Indicator of Radioresistance After Photon and Carbon Ion Irradiation Without Functional Involvement.

Background: Treatment of locally advanced HPV-negative head and neck squamous cell carcinoma (HNSCC) with photon radiation is the standard of care but shows only moderate success. Alterations in response toward DNA DSB repair, apoptosis, and senescence are underlying determinants of radioresistance in the tumor cells. Recently, senescence and the associated secretory phenotype (SASP) came into the focus of research and raised the need to identify the tumor-promoting molecular mechanisms of the SASP. The aim of this project was to unravel more of this process and to understand the impact of the IL1 pathway, which plays a major role in SASP. The studies were performed for photon and 12C-ion irradiation, which strongly vary in their effect on radioresistance. Materials and Methods: A panel of five HPV-negative HNSCC cell lines was treated with photon and 12C-ion irradiation and examined for clonogenic survival, DNA DSB repair, and senescence. SASP and IL1 gene expressions were determined by RNA sequencing and activation of the IL1 pathway by ELISA. A functional impact of IL1A and IL1B was examined by specific siRNA knockdown. Results: Cell killing and residual DSBs were higher after 12C-ion than after photon irradiation. 12C-ion induced more senescence with a significant correlation with cell survival. The impact on radioresistance appears to be less than after photon irradiation. The expression of SASP-related genes and the IL1 pathway are strongly induced by both types of irradiation and correlate with radioresistance and senescence, especially IL1A and IL1B which exhibit excellent associations. Surprisingly, knockdown of IL1A and IL1B revealed that the IL1 pathway is functionally not involved in radioresistance, DSB repair, or induction of senescence. Conclusions: IL1A and IL1B are excellent indicators of cellular radioresistance and senescence in HNSCC cells without functional involvement in these processes. Clearly more research is needed to understand the molecular mechanisms of senescence and SASP and its impact on radioresistance.

Carbon Ion Beam Boost Irradiation in Malignant Tumors of the Nasal Vestibule and the Anterior Nasal Cavity as an Organ-Preserving Therapy.

BACKGROUND: Surgery and radiotherapy are current therapeutic options for malignant tumors involving the nasal vestibule. Depending on the location, organ-preserving resection is not always possible, even for small tumors. Definitive radiotherapy is an alternative as an organ-preserving procedure. Carbon ion beam radiotherapy offers highly conformal dose distributions and more complex biological radiation effects eventually resulting in optimized normal tissue sparing and improved outcome. The aim of the current study was to analyze toxicity, local control (LC), and organ preserving survival (OPS) after irradiation of carcinoma of the nasal vestibule with raster-scanned carbon ion radiotherapy boost (CIRT-B) combined with volumetric intensity modulated arc therapy (VMAT) with photons. METHODS: Between 12/2015 and 05/2021, 21 patients with malignant tumors involving the nasal vestibule were irradiated with CIRT-B combined with VMAT and retrospectively analyzed. Diagnosis was based on histologic findings. A total of 17 patients had squamous cell carcinoma (SCC) and 4 had other histologies. In this series, 10%, 67%, and 24% of patients had Wang stages 1, 2, and 3 tumors, respectively. Three patients had pathologic cervical nodes on MRI. The median CIRT-B dose was 24 Gy(RBE), while the median VMAT dose was 50 Gy. All patients with pathologic cervical nodes received simultaneously integrated boost with photons (SIB) up to a median dose of 62.5 Gy to the pathological lymph nodes. Eight patients received cisplatin chemotherapy. All patients received regular follow-up imaging after irradiation. Kaplan-Meier estimation was used for statistical assessment. RESULTS: The median follow-up after irradiation was 18.9 months. There were no common toxicity criteria grade 5 or 4 adverse events. A total of 20 patients showed grade 3 adverse events mainly on skin and mucosa. All patients were alive at the end of follow-up. The median OPS after treatment was 56.5 months. The 6- and 24-month OPS were 100% and 83.3%, respectively. All local recurrences occurred within 12 months after radiotherapy. The median progression free survival (PFS) after treatment was 52.4 months. The 6-, 12-, and 24-month PFS rates were 95%, 83.6%, and 74.3%, respectively. CONCLUSION: CIRT-B combined with VMAT in malignant tumors of the nasal vestibule is safe and feasible, results in high local control rates, and thus is a good option as organ-preserving therapy. No radiation-associated grade 4 or 5 acute or late AE was documented.

Development, Monte Carlo simulations and experimental evaluation of a 3D range-modulator for a complex target in scanned proton therapy.

The purpose of this work was to develop and manufacture a 3D range-modulator (3D RM) for a complex target contour for scanned proton therapy. The 3D RM is considered to be a viable technique for the very fast dose application in patient-specific tumors with only one fixed energy. The RM was developed based on a tumor from a patient CT and manufactured with high-quality 3D printing techniques with both polymer resin and aluminum. Monte Carlo simulations were utilized to investigate its modulating properties and the resulting dose distribution. Additionally, the simulation results were validated with measurements at the Marburg Ion-Beam Therapy Centre. For this purpose, a previously developed water phantom was used to conduct fast, automated high-resolution dose measurements. The results show a very good agreement between simulations and measurements and indicate that highly homogeneous dose distributions are possible. The delivered dose is conformed to the distal as well as to the proximal edge of the target. The 3D range-modulator concept combines a high degree of dose homogeneity and conformity, comparable to standard IMPT with very short irradiation times, promising clinically applicable dose distributions for lung and/or FLASH treatment, comparable and competitive to those from conventional irradiation techniques.

Students' learning behavior in digital education for radiation oncology.

PURPOSE: Digitalization of medical education is an important trend in terms of reforming and modernizing the global education environment. It has been long requested by students and politicians. The goal of this study was to assess the student perception of a newly developed digital educational program in radiation oncology (RO) using an interactive e­book combined with short learnings clips on a YouTube channel combined with periodic videoconferences and a forum for queries. METHODS: We performed five evaluations during and at the end of two terms with multiple-choice and free-text answers. We evaluated student perception of our new digital learning scenario in three semesters: one pre-clinical and two clinical semesters. In addition, we analyzed all comments from the kMED forum, the YouTube channel, or the e­mail contacts. We analyzed the learning behavior of the students based on access to the videos and the number and quality of the reflective questions answered as well as the results of the final examinations. RESULTS: The students accepted the offer for asynchronous teaching and mainly learned on weekdays (74% of the videos), but also on weekends (23%) and less on public holidays (4%). The answer quality of the reflective questions was good with over 50% correct answers on the first attempt. Learning to be on one's own authority was very difficult for the students, even in the last clinical semesters of the medical study. Without direct intervention by the teacher, access to the learning material by the students was limited and delayed. Therefore, voluntary interim tests were performed during the first analysis term, which led to an increased number of student accesses to the videos and higher number of answers. Nevertheless, in the first analysis term, the average results in the final exam of the students who did not perform the interim test were below average at 59.1%, and the students who performed the test had better results at 69.5% but this was also not satisfactory. In the second analysis term, we taught with the same digital teaching model but with an additional scheme for learning over the term, 2­week compulsory intermediate tests, and frequent videoconferences to answer any questions. In this term, we measured a success rate of 93% in the final exam. All annotations were very positive regarding the new educational project. The evaluations showed high acceptance of the new education program. The students stated they would prefer the new education course to be continued in future. CONCLUSION: Digital teaching methods make not only the type and quality of teaching transparent, but also the learning behavior of the students. Our analysis has shown that, in addition to the quality of the teaching, the clear structure and specification of the learning content per learning week as well as regular monitoring of what has been learned are of decisive importance for the learning success of the students.

Experimental determination of modulation power of lung tissue for particle therapy.

In particle therapy of lung tumors, modulating effects on the particle beam may occur due to the microscopic structure of the lung tissue. These effects are caused by the heterogeneous nature of the lung tissue and cannot be completely taken into account during treatment planning, because these micro structures are too small to be fully resolved in the planning CT. In several publications, a new material parameter called modulation power (Pmod) was introduced to characterize the effect. For various artificial lung surrogates, this parameter was measured and published by other groups and ranges up to approximately 1000µm. Studies investigating the influence of the modulation power on the dose distribution during irradiation are using this parameter in the rang of 100-800µm. More precise measurements forPmodon real lung tissue have not yet been published. In this work, the modulation power of real lung tissue was measured using porcine lungs in order to produce more reliable data ofPmodfor real lung tissue. For this purpose,ex-vivoporcine lungs were frozen in a ventilated state and measurements in a carbon ion-beam were performed. Due to the way the lungs were prepared and transferred to a solid state, the lung structures that modulate the beam could also be examined in detail using micro CT imaging. An optimization of the established methods of measuring the modulation power, which takes better account of the typical structures within lung tissue, was developed as well.

Investigating the feasibility of TOPAS-nBio for Monte Carlo track structure simulations by adapting GEANT4-DNA examples application.

Purpose.The purpose of this work is to investigate the feasibility of TOPAS-nBio for track structure simulations using tuple scoring and ROOT/Python-based post-processing.Materials and methods.There are several example applications implemented in GEANT4-DNA demonstrating track structure simulations. These examples are not implemented by default in TOPAS-nBio. In this study, the tuple scorer was used to re-simulate these examples. The simulations contained investigations of different physics lists, calculation of energy-dependent range, stopping power, mean free path andW-value. Additionally, further applications of the TOPAS-nBio tool were investigated, focusing on physical interactions and deposited energies of electrons with initial energies in the range of 10-60 eV, not covered in the recently published GEANT4-DNA simulations. Low-energetic electrons are currently of great interest in the radiobiology research community due to their high effectiveness towards the induction of biological damage.Results.The quantities calculated with TOPAS-nBio show a good agreement with the simulations of GEANT4-DNA with deviations of 5% at maximum. Thus, we have presented a feasible way to implement the example applications included in GEANT4-DNA in TOPAS-nBio. With the extended simulations, an insight could be given, which further tracking information can be gained with the track structure code and how cross sections and physics models influence a particle's fate.Conclusion.With our results, we could show the potentials of applying the tuple scorer in TOPAS-nBio Monte Carlo track structure simulations. Using this scorer, a large amount of information about the track structure can be accessed, which can be analyzed as preferred after the simulation.

Monte Carlo calculation of beam quality correction factors in proton beams using FLUKA.

Purpose.To provide Monte Carlo calculated beam quality correction factors (kQ) for monoenergetic proton beams using the Monte Carlo codefluka.Materials and methods.The Monte Carlo codeflukawas used to calculate the dose absorbed in a water-filled reference volume and the air-filled cavities of six plane-parallel and four cylindrical ionization chambers. The chambers were positioned at the entrance region of monoenergetic proton beams with energies between 60 and 250 MeV. Based on these dose values,fQas well askQfactors were calculated whilefQ0factors were taken from Andreoet al(2020Phys. Med. Biol.65095011).Results. kQfactors calculated in this work were found to agree with experimentally determinedkQfactors on the 1%-level, with only two exceptions with deviations of 1.4% and 1.9%. The comparison offQfactors calculated usingflukawithfQfactors calculated using the Monte Carlo codesgeant4 andpenhshowed a general good agreement for low energies, while differences for higher energies were pronounced. For high energies, in most cases the Monte Carlo codesflukaandgeant4 lead to comparable results while thefQfactors calculated withpenhare larger.Conclusion.flukacan be used to calculatekQfactors in clinical proton beams. The divergence of Monte Carlo calculatedkQfactors for high energies suggests that the role of nuclear interaction models implemented in the different Monte Carlo codes needs to be investigated in more detail.

Estimating the modulating effect of lung tissue in particle therapy using a clinical CT voxel histogram analysis.

To treat lung tumours with particle therapy, different additional tasks and challenges in treatment planning and application have to be addressed thoroughly. One of these tasks is the quantification and consideration of the Bragg peak (BP) degradation due to lung tissue: as lung is an heterogeneous tissue, the BP is broadened when particles traverse the microscopic alveoli. These are not fully resolved in clinical CT images and thus, the effect is not considered in the dose calculation. In this work, a correlation between the CT histograms of heterogeneous material and the impact on the BP curve is presented. Different inorganic materials were scanned with a conventional CT scanner and additionally, the BP degradation was measured in a proton beam and was then quantified. A model is proposed that allows an estimation of the modulation power by performing a histogram analysis on the CT scan. To validate the model for organic samples, a second measurement series was performed with frozen porcine lunge samples. This allows to investigate the possible limits of the proposed model in a set-up closer to clinical conditions. For lung substitutes, the agreement between model and measurement is within ±0.05 mm and for the organic lung samples, within ±0.15 mm. This work presents a novel, simple and efficient method to estimate if and how much a material or a distinct region (within the lung) is degrading the BP on the basis of a common clinical CT image. Up until now, only a direct in-beam measurement of the region or material of interest could answer this question.

Pediatric classical Hodgkin lymphoma.

Over the past century, classical Hodgkin lymphoma (HL) has been transformed from a uniformly fatal disease to one of the most curable cancers. Given the high cure rate, a major focus of classical HL management is reducing the use of radiation therapy (RT) and chemotherapy agents such as procarbazine and doxorubicin to minimize long-term toxicities. In both North America and Europe, an important philosophy in the management of classical HL is to guide the intensity of treatment according to the risk category of the disease. The main factors used for risk classification are tumor stage, bulk of disease, and the presence of B symptoms. Response to chemotherapy is an important factor guiding the utilization of RT in ongoing Children's Oncology Group (COG) and European Network Pediatric Hodgkin Lymphoma (EuroNet-PHL) trials. Both trial groups have transitioned to reduced RT volumes that target the highest risk sites using highly conformal techniques, along with standard or intensified chemotherapy regimens to improve outcomes in higher risk patients. However, given the potential acute toxicities of intensified chemotherapy, immunoregulatory drugs are being investigated in upcoming trials. The purpose of this review is to summarize current approaches to treating pediatric classical HL according to the COG and EuroNet-PHL.

Monte Carlo calculation of perturbation correction factors for air-filled ionization chambers in clinical proton beams using TOPAS/GEANT.

INTRODUCTION: Current dosimetry protocols for clinical protons using air-filled ionization chambers assume that the perturbation correction factor is equal to unity for all ionization chambers and proton energies. Since previous Monte Carlo based studies suggest that perturbation correction factors might be significantly different from unity this study aims to determine perturbation correction factors for six plane-parallel and four cylindrical ionization chambers in proton beams at clinical energies. MATERIALS AND METHODS: The dose deposited in the air cavity of the ionization chambers was calculated with the help of the Monte Carlo code TOPAS/Geant4 while specific constructive details of the chambers were removed step by step. By comparing these dose values the individual perturbation correction factors pcel, pstem, psleeve, pwall, pcav⋅pdis as well as the total perturbation correction factor pQ were derived for typical clinical proton energies between 80 and 250MeV. RESULTS: The total perturbation correction factor pQ was smaller than unity for almost every ionization chamber and proton energy and in some cases significantly different from unity (deviation larger than 1%). The maximum deviation from unity was 2.0% for cylindrical and 1.5% for plane-parallel ionization chambers. Especially the factor pwall was found to differ significantly from unity. It was shown that this is due to the fact that secondary particles, especially alpha particles and fragments, are scattered from the chamber wall into the air cavity resulting in an overresponse of the chamber. CONCLUSION: Perturbation correction factors for ionization chambers in proton beams were calculated using Monte Carlo simulations. In contrast to the assumption of current dosimetry protocols the total perturbation correction factor pQ can be significantly different from unity. Hence, beam quality correction factors [Formula: see text] that are calculated with the help of perturbation correction factors that are assumed to be unity come with a corresponding additional uncertainty.

Monte Carlo simulations and dose measurements of 2D range-modulators for scanned particle therapy.

This paper introduces the concept of a 2D range-modulator as a static device for generating spread-out Bragg peaks at very small distances to the target. The 2D range-modulator has some distinct advantages that can be highly useful for different research projects in particle therapy facilities. Most importantly, it creates an instantaneous, quasi-static irradiation field with only one energy, thus decreasing irradiation time tremendously. In addition, it can be manufactured fast and cost efficiently and its SOBP width and shape can be adjusted easily for the specific purpose/experiment. As the modulator is a static element, there is no need for rotation (e.g. like in a modulation wheel) or lateral oscillation and due to the small base structure period it can be positioned close to the target. Two different rapid prototyping manufacturing techniques were utilized. The modulation properties of one polymer and one steel modulator were investigated with both simulations and measurements. For this purpose, a sophisticated water phantom system (WERNER), that can perform fast, completely automated and high resolution dose measurements, was developed. Using WERNER, the dose distribution of a modulator can be verified quickly and reliably, both during experiments, as well as in a time constrained clinical environment. The maximum deviation between the Monte Carlo simulations and dose measurements in the spread-out Bragg peak region was 1.4% and 4% for the polymer and steel modulator respectively. They were able to create spread-out Bragg peaks with a high degree of dose homogeneity, thus validating the whole process chain, from the mathematical optimization and modulator development, to manufacturing, MC simulations and dose measurements. Combining the convenience, flexibility and cost-effectiveness of rapid prototyping with the advantages of highly customizable modulators, that can be adapted for different experiments, the 2D range-modulator is considered a very useful tool for a variety of research objectives. Moreover, we have successfully shown that the manufacturing of 2D modulators with high quality and high degree of homogeneity is possible, paving the way for the further development of the more complex 3D range-modulators, which are considered a viable option for the very fast treatment of moving targets and/or FLASH irradiation.

Establishment of a Transformation Coupled in vitro End Joining Assay to Estimate Radiosensitivity in Tumor Cells.

Here, we present a modified in vitro end-joining (EJ) assay to quantify EJ capacity, accuracy as well as pathway switch to alternative end-joining (Alt-EJ) or single strand annealing (SSA). A novel transformation assay was established to specifically measure circular repair products, which correlate with classical EJ efficiency. The EJ assay was validated using EJ-deficient mammalian cell lines (Ku80, DNA-PKcs, LigIV, or XRCC4 mutants). A pathway switch to Alt-EJ and SSA was seen exclusively in Ku-deficient cells. Circular EJ product formation correlated with cell survival and DSB repair capacity after X-irradiation. Investigation of 14 HNSCC cell lines revealed differences in the total EJ capacity but a broader variation in the amount of circular repair products. Sequencing of repair junctions in HNSCC cells demonstrated a predominance of high-fidelity EJ and an avoidance of both Alt-EJ and SSA. A significant correlation was observed between the amount of circular repair products, repair of IR-induced DSB and radiosensitivity. Collectively, these data indicate that the presented in vitro-EJ-assay can not only estimate the repair capacity of cancer cells to enable the stratification into radiosensitive or radioresistant, but can also identify repair pathway deregulation such as a switch to Alt-EJ or SSA, which enables tumor targeting.