Integrate range shifter in immobilization for proton therapy: 3D printed materials characterization

3D printing is investigated for application in patient immobilization during proton therapy (PT). It potentially enables a merge of immobilization, range shifting and other functionality into one patient-specific structure. Beside minimizing the lateral beam spread due to the removal of air gap it could also reduce the collision risk and the treatment time compared to movable nozzle snouts. In this first study, 9 different 3D printed materials were characterized in detail. The resulting data (Table 1) will serve as input for the design of a printed immobilization structure. The printed test objects showed reduced geometric printing accuracy for 3 materials. Compression testing yielded Young’s moduli from 0.6 MPa to 3445 MPa, without deterioration after exposure to 100 Gy in a MV photon beam. Dual-energy CT methods were used to estimate the effective atomic number Zeff, the relative electron density e and the stopping power ratio SPR. Zeff ranged from 5.91 to 10.43. The SPR and e both ranged from 0.6 to 1.22. The measured photon attenuation coefficients at therapeutic energies scaled linearly with e. In a 62 MeV proton beam, good agreement was seen between the DECT estimated SPR and the measured range shift, except for the higher Zeff. As opposed to the photon attenuation, the proton range shifting was printing orientation dependent for certain materials. In conclusion printed materials exhibit a wide variation in structural and radiological properties. The quantification of these characteristics enables optimal material selection for the design of a multifunctional 3D printed immobilization structure for PT

Strigolactones spatially influence lateral root development through the cytokinin signaling network

Strigolactones are important rhizosphere signals that act as phytohormones and have multiple functions, including modulation of lateral root (LR) development. Here, we show that treatment with the strigolactone analog GR24 did not affect LR initiation, but negatively influenced LR priming and emergence, the latter especially near the root-shoot junction. The cytokinin module ARABIDOPSIS HISTIDINE KINASE3 (AHK3)/ARABIDOPSIS RESPONSE REGULATOR1 (ARR1)/ARR12 was found to interact with the GR24-dependent reduction in LR development, because mutants in this pathway rendered LR development insensitive to GR24. Additionally, pharmacological analyses, mutant analyses, and gene expression analyses indicated that the affected polar auxin transport stream in mutants of the AHK3/ARR1/ARR12 module could be the underlying cause. Altogether, the data reveal that the GR24 effect on LR development depends on the hormonal landscape that results from the intimate connection with auxins and cytokinins, two main players in LR development

Analysis of chromosomal radiosensitivity of healthy BRCA2 mutation carriers and non-carriers in BRCA families with the G2 micronucleus assay

Breast cancer risk drastically increases in individuals with a heterozygous germline BRCA1 or BRCA2 mutation, while it is estimated to equal the population risk for relatives without the familial mutation (non-carriers). The aim of the present study was to use a G2 phase-specific micronucleus assay to investigate whether lymphocytes of healthy BRCA2 mutation carriers are characterized by increased radiosensitivity compared to controls without a family history of breast/ovarian cancer and how this relates to healthy non-carrier relatives. BRCA2 is active in homologous recombination, a DNA damage repair pathway, specifically active in the late S/G2 phase of the cell cycle. We found a significantly increased radiosensitivity in a cohort of healthy BRCA2 mutation carriers compared to individuals without a familial history of breast cancer (P=0.046; Mann-Whitney U test). At the individual level, 50% of healthy BRCA2 mutation carriers showed a radiosensitive phenotype (radiosensitivity score of 1 or 2), whereas 83% of the controls showed no radiosensitivity (P=0.038; one-tailed Fisher's exact test). An odds ratio of 5 (95% CI, 1.07-23.47) indicated an association between the BRCA2 mutation and radiosensitivity in healthy mutation carriers. These results indicate the need for the gentle use of ionizing radiation for either diagnostic or therapeutic use in BRCA2 mutation carriers. We detected no increased radiosensitivity in the non-carrier relatives

Hypofractionated intensity modulated irradiation for localized prostate cancer, results from a phase I/II feasibility study

<p>Abstract</p> <p>Background</p> <p>To assess acute (primary endpoint) and late toxicity, quality of life (QOL), biochemical or clinical failure (secondary endpoints) of a hypofractionated IMRT schedule for prostate cancer (PC).</p> <p>Methods</p> <p>38 men with localized PC received 66 Gy (2.64 Gy) to prostate,2 Gy to seminal vesicles (50 Gy total) using IMRT.</p> <p>Acute toxicity was evaluated weekly during radiotherapy (RT), at 1–3 months afterwards using RTOG acute scoring system. Late side effects were scored at 6, 9, 12, 16, 20, 24 and 36 months after RT using RTOG/EORTC criteria.</p> <p>Quality of life was assessed by EORTC-C30 questionnaire and PR25 prostate module. Biochemical failure was defined using ASTRO consensus and nadir+2 definition, clinical failure as local, regional or distant relapse.</p> <p>Results</p> <p>None experienced grade III-IV toxicity. 10% had no acute genito-urinary (GU) toxicity, 63% grade I; 26% grade II. Maximum acute gastrointestinal (GI) scores 0, I, II were 37%, 47% and 16%. Maximal acute toxicity was reached weeks 4–5 and resolved within 4 weeks after RT in 82%.</p> <p>Grade II rectal bleeding needing coagulation had a peak incidence of 18% at 16 months after RT but is 0% at 24–36 months. One developed a urethral stricture at 2 years (grade II late GU toxicity) successfully dilated until now. QOL urinary symptom scores reached a peak incidence 1 month after RT but normalized 6 months later. Bowel symptom scores before, at 1–6 months showed similar values but rose slowly 2–3 years after RT. Nadir of sexual symptom scores was reached 1–6 months after RT but improved 2–3 years later as well as physical, cognitive and role functional scales.</p> <p>Emotional, social functional scales were lowest before RT when diagnosis was given but improved later. Two years after RT global health status normalized.</p> <p>Conclusion</p> <p>This hypofractionated IMRT schedule for PC using 25 fractions of 2.64 Gy did not result in severe acute side effects. Until now late urethral, rectal toxicities seemed acceptable as well as failure rates. Detailed analysis of QOL questionnaires resulted in the same conclusion.</p

IGRT/ART phantom with programmable independent rib cage and tumor motion

Abstract PURPOSE: This paper describes the design and experimental evaluation of the Methods and Advanced Equipment for Simulation and Treatment in Radiation Oncology (MAESTRO) thorax phantom, a new anthropomorphic moving ribcage combined with a 3D tumor positioning system to move target inserts within static lungs. METHODS: The new rib cage design is described and its motion is evaluated using Vicon Nexus, a commercial 3D motion tracking system. CT studies at inhale and exhale position are used to study the effect of rib motion and tissue equivalence. RESULTS: The 3D target positioning system and the rib cage have millimetre accuracy. Each axis of motion can reproduce given trajectories from files or individually programmed sinusoidal motion in terms of amplitude, period, and phase shift. The maximum rib motion ranges from 7 to 20 mm SI and from 0.3 to 3.7 mm AP with LR motion less than 1 mm. The repeatability between cycles is within 0.16 mm root mean square error. The agreement between CT electron and mass density for skin, ribcage, spine hard and inner bone as well as cartilage is within 3%. CONCLUSIONS: The MAESTRO phantom is a useful research tool that produces programmable 3D rib motions which can be synchronized with 3D internal target motion. The easily accessible static lungs enable the use of a wide range of inserts or can be filled with lung tissue equivalent and deformed using the target motion system.status: publishe

Towards 3D printed multifunctional immobilization for proton therapy: initial materials characterization

Purpose: 3D printing technology is investigated for the purpose of patient immobilization during proton therapy. It potentially enables a merge of patient immobilization, bolus range shifting, and other functions into one single patient-speci c structure. In this rst step, a set of 3D printed materials is characterized in detail, in terms of structural and radiological properties, elemental composition, directional dependence, and structural changes induced by radiation damage. These data will serve as inputs for the design of 3D printed immobilization structure prototypes. Methods: Using four di erent 3D printing techniques, in total eight materials were subjected to testing. Samples with a nominal dimension of 20×20×80 mm3 were 3D printed. The geometrical printing accuracy of each test sample was measured with a dial gage. To assess the mechanical response of the samples, standardized compression tests were performed to determine the Young’s modulus. To investigate the e ect of radiation on the mechanical response, the mechanical tests were performed both prior and after the administration of clinically relevant dose levels (70 Gy), multiplied with a safety factor of 1.4. Dual energy computed tomography (DECT) methods were used to calculate the relative electron density to water ρe, the e ective atomic number Ze , and the proton stopping power ratio (SPR) to water SPR. In order to validate the DECT based calculation of radiological properties, beam measurements were performed on the 3D printed samples as well. Photon irradiations were performed to measure the photon linear attenuation coe cients, while proton irradiations were performed to measure the proton range shift of the samples. The direc- tional dependence of these properties was investigated by performing the irradiations for di erent orientations of the samples. Results: The printed test objects showed reduced geometric printing accuracy for 2 materials (deviation > 0.25 mm). Compression tests yielded Young’s moduli ranging from 0.6 to 2940 MPa. No deterioration in the mechanical response was observed after exposure of the samples to 100 Gy in a therapeutic MV photon beam. The DECT-based characterization yielded Ze ranging from 5.91 to 10.43. The SPR and ρe both ranged from 0.6 to 1.22. The measured photon attenuation coe cients at clinical energies scaled linearly with ρe. Good agreement was seen between the DECT estimated SPR and the measured range shift, except for the higher Ze . As opposed to the photon attenuation, the proton range shifting appeared to be printing orientation dependent for certain materials. Conclusions: In this study, the rst step toward 3D printed, multifunctional immobilization was performed, by going through a candidate clinical work ow for the rst time: from the material printing to DECT characterization with a veri cation through beam measurements. Besides a proof of concept for beam modi cation, the mechanical response of printed materials was also investigated to assess their capabilities for positioning functionality. For the studied set of printing techniques and materials, a wide variety of mechanical and radiological properties can be selected from for the intended purpose. Moreover the elaborated hybrid DECT methods aid in performing in-house quality assurance of 3D printed components, as these methods enable the estimation of the radiological properties relevant for use in radiation therapy

Increased chromosomal radiosensitivity in asymptomatic carriers of a heterozygous BRCA1 mutation

Background: Breast cancer risk increases drastically in individuals carrying a germline BRCA1 mutation. The exposure to ionizing radiation for diagnostic or therapeutic purposes of BRCA1 mutation carriers is counterintuitive, since BRCA1 is active in the DNA damage response pathway. The aim of this study was to investigate whether healthy BRCA1 mutations carriers demonstrate an increased radiosensitivity compared with healthy individuals. Methods: We defined a novel radiosensitivity indicator (RIND) based on two endpoints measured by the G2 micronucleus assay, reflecting defects in DNA repair and G2 arrest capacity after exposure to doses of 2 or 4 Gy. We investigated if a correlation between the RIND score and nonsense-mediated decay (NMD) could be established. Results: We found significantly increased radiosensitivity in the cohort of healthy BRCA1 mutation carriers compared with healthy controls. In addition, our analysis showed a significantly different distribution over the RIND scores (p = 0.034, Fisher’s exact test) for healthy BRCA1 mutation carriers compared with non-carriers: 72 % of mutation carriers showed a radiosensitive phenotype (RIND score 1–4), whereas 72 % of the healthy volunteers showed no radiosensitivity (RIND score 0). Furthermore, 28 % of BRCA1 mutation carriers had a RIND score of 3 or 4 (not observed in control subjects). The radiosensitive phenotype was similar for relatives within several families, but not for unrelated individuals carrying the same mutation. The median RIND score was higher in patients with a mutation leading to a premature termination codon (PTC) located in the central part of the gene than in patients with a germline mutation in the 5′ end of the gene. Conclusions: We show that BRCA1 mutations are associated with a radiosensitive phenotype related to a compromised DNA repair and G2 arrest capacity after exposure to either 2 or 4 Gy. Our study confirms that haploinsufficiency is the mechanism involved in radiosensitivity in patients with a PTC allele, but it suggests that further research is needed to evaluate alternative mechanisms for mutations not subjected to NMD

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