Mutations in the adenosine deaminase ADAR1 that prevent endogenous Z-RNA binding induce Aicardi-Goutières-syndrome-like encephalopathy.

Mutations in the adenosine-to-inosine RNA-editing enzyme ADAR1 p150, including point mutations in the Z-RNA recognition domain Zα, are associated with Aicardi-Goutières syndrome (AGS). Here, we examined the in vivo relevance of ADAR1 binding of Z-RNA. Mutation of W197 in Zα, which abolished Z-RNA binding, reduced RNA editing. Adar1W197A/W197A mice displayed severe growth retardation after birth, broad expression of interferon-stimulated genes (ISGs), and abnormal development of multiple organs. Notably, malformation of the brain was accompanied by white matter vacuolation and gliosis, reminiscent of AGS-associated encephalopathy. Concurrent deletion of the double-stranded RNA sensor MDA5 ameliorated these abnormalities. ADAR1 (W197A) expression increased in a feedback manner downstream of type I interferons, resulting in increased RNA editing at a subset of, but not all, ADAR1 target sites. This increased expression did not ameliorate inflammation in Adar1W197A/W197A mice. Thus, editing of select endogenous RNAs by ADAR1 is essential for preventing inappropriate MDA5-mediated inflammation, with relevance to the pathogenesis of AGS.

RNA editing of AZIN1 coding sites is catalyzed by ADAR1 p150 after splicing.

Adenosine-to-inosine RNA editing is catalyzed by nuclear adenosine deaminase acting on RNA 1 (ADAR1) p110 and ADAR2, and cytoplasmic ADAR1 p150 in mammals, all of which recognize dsRNAs as targets. RNA editing occurs in some coding regions, which alters protein functions by exchanging amino acid sequences, and is therefore physiologically significant. In general, such coding sites are edited by ADAR1 p110 and ADAR2 before splicing, given that the corresponding exon forms a dsRNA structure with an adjacent intron. We previously found that RNA editing at two coding sites of antizyme inhibitor 1 (AZIN1) is sustained in Adar1 p110/Aadr2 double KO mice. However, the molecular mechanisms underlying RNA editing of AZIN1 remain unknown. Here, we showed that Azin1 editing levels were increased upon type I interferon treatment, which activated Adar1 p150 transcription, in mouse Raw 264.7 cells. Azin1 RNA editing was observed in mature mRNA but not precursor mRNA. Furthermore, we revealed that the two coding sites were editable only by ADAR1 p150 in both mouse Raw 264.7 and human embryonic kidney 293T cells. This unique editing was achieved by forming a dsRNA structure with a downstream exon after splicing, and the intervening intron suppressed RNA editing. Therefore, deletion of a nuclear export signal from ADAR1 p150, shifting its localization to the nucleus, decreased Azin1 editing levels. Finally, we demonstrated that Azin1 RNA editing was completely absent in Adar1 p150 KO mice. Thus, these findings indicate that RNA editing of AZIN1 coding sites is exceptionally catalyzed by ADAR1 p150 after splicing.

Assessment and validation of glottic motion using cone-beam CT and real-time cine MRI.

PURPOSE: This study aimed to assess the margin for the planning target volume (PTV) using the Van Herk formula. We then validated the proposed margin by real-time magnetic resonance imaging (MRI). METHODS: An analysis of cone-beam computed tomography (CBCT) data from early glottic cancer patients was performed to evaluate organ motion. Deformed clinical target volumes (CTV) after rigid registration were acquired using the Velocity program (Varian Medical Systems, Palo Alto, CA, USA). Systematic (Σ) and random errors (σ) were evaluated. The margin for the PTV was defined as 2.5 Σ + 0.7 σ according to the Van Herk formula. To validate this margin, we accrued healthy volunteers. Sagittal real-time cine MRI was conducted using the ViewRay system (ViewRay Inc., Oakwood Village, OH, USA). Within the obtained sagittal images, the vocal cord was delineated. The movement of the vocal cord was summed up and considered as the internal target volume (ITV). We then assessed the degree of overlap between the ITV and the PTV (vocal cord plus margins) by calculating the volume overlap ratio, represented as (ITV∩PTV)/ITV. RESULTS: CBCTs of 17 early glottic patients were analyzed. Σ and σ were 0.55 and 0.57 for left-right (LR), 0.70 and 0.60 for anterior-posterior (AP), and 1.84 and 1.04 for superior-inferior (SI), respectively. The calculated margin was 1.8 mm (LR), 2.2 mm (AP), and 5.3 mm (SI). Four healthy volunteers participated for validation. A margin of 3 mm (AP) and 5 mm (SI) was applied to the vocal cord as the PTV. The average volume overlap ratio between ITV and PTV was 0.92 (range 0.85-0.99) without swallowing and 0.77 (range 0.70-0.88) with swallowing. CONCLUSION: By evaluating organ motion by using CBCT, the margin was 1.8 (LR), 2.2 (AP), and 5.3 mm (SI). The margin acquired using CBCT fitted well in real-time cine MRI. Given that swallowing during radiotherapy can result in a substantial displacement, it is crucial to consider strategies aimed at minimizing swallowing and related motion.

RNA editing at a limited number of sites is sufficient to prevent MDA5 activation in the mouse brain.

Adenosine deaminase acting on RNA 1 (ADAR1), an enzyme responsible for adenosine-to-inosine RNA editing, is composed of two isoforms: nuclear p110 and cytoplasmic p150. Deletion of Adar1 or Adar1 p150 genes in mice results in embryonic lethality with overexpression of interferon-stimulating genes (ISGs), caused by the aberrant recognition of unedited endogenous transcripts by melanoma differentiation-associated protein 5 (MDA5). However, among numerous RNA editing sites, how many RNA sites require editing, especially by ADAR1 p150, to avoid MDA5 activation and whether ADAR1 p110 contributes to this function remains elusive. In particular, ADAR1 p110 is abundant in the mouse brain where a subtle amount of ADAR1 p150 is expressed, whereas ADAR1 mutations cause Aicardi-Goutières syndrome, in which the brain is one of the most affected organs accompanied by the elevated expression of ISGs. Therefore, understanding RNA editing-mediated prevention of MDA5 activation in the brain is especially important. Here, we established Adar1 p110-specific knockout mice, in which the upregulated expression of ISGs was not observed. This result suggests that ADAR1 p150-mediated RNA editing is enough to suppress MDA5 activation. Therefore, we further created Adar1 p110/Adar2 double knockout mice to identify ADAR1 p150-mediated editing sites. This analysis demonstrated that although the elevated expression of ISGs was not observed, only less than 2% of editing sites were preserved in the brains of Adar1 p110/Adar2 double knockout mice. Of note, we found that some sites were highly edited, which was comparable to those found in wild-type mice, indicating the presence of ADAR1 p150-specific sites. These data suggest that RNA editing at a very limited sites, which is mediated by a subtle amount of ADAR1 p150, is sufficient to prevents MDA5 activation, at least in the mouse brain.

An Aicardi-Goutières Syndrome-Causative Point Mutation in Adar1 Gene Invokes Multiorgan Inflammation and Late-Onset Encephalopathy in Mice.

Aicardi-Goutières syndrome (AGS) is a congenital inflammatory disorder accompanied by overactivated type I IFN signaling and encephalopathy with leukodystrophy and intracranial calcification. To date, none of the mouse models carrying an AGS-causative mutation has mimicked such brain pathology. Here, we established a mutant mouse model carrying a K948N point mutation, corresponding to an AGS-causative K999N mutation, located in a deaminase domain of the Adar1 gene that encodes an RNA editing enzyme. Adar1K948N/K948N mice displayed postnatal growth retardation. Hyperplasia of splenic white pulps with germinal centers and hepatic focal inflammation were observed from 2 mo of age. Inflammation developed in the lungs and heart with lymphocyte infiltration in an age-dependent manner. Furthermore, white matter abnormalities with astrocytosis and microgliosis were detected at 1 y of age. The increased expression of IFN-stimulated genes was detected in multiple organs, including the brain, from birth. In addition, single-nucleus RNA sequencing revealed that this elevated expression of IFN-stimulated genes was commonly observed in all neuronal subtypes, including neurons, oligodendrocytes, and astrocytes. We further showed that a K948N point mutation reduced the RNA editing activity of ADAR1 in vivo. The pathological abnormalities found in Adar1K948N/K948N mice were ameliorated by either the concurrent deletion of MDA5, a cytosolic sensor of unedited transcripts, or the sole expression of active ADAR1 p150, an isoform of ADAR1. Collectively, such data suggest that although the degree is mild, Adar1K948N/K948N mice mimic multiple AGS phenotypes, including encephalopathy, which is caused by reduced RNA editing activity of the ADAR1 p150 isoform.

Genome-Wide Identification and Comprehensive Analysis of the GASA Gene Family in Peanuts (Arachis hypogaea L.) under Abiotic Stress.

Peanut (Arachis hypogaea L.) is a globally cultivated crop of significant economic and nutritional importance. The role of gibberellic-acid-stimulated Arabidopsis (GASA) family genes is well established in plant growth, development, and biotic and abiotic stress responses. However, there is a gap in understanding the function of GASA proteins in cultivated peanuts, particularly in response to abiotic stresses such as drought and salinity. Thus, we conducted comprehensive in silico analyses to identify and verify the existence of 40 GASA genes (termed AhGASA) in cultivated peanuts. Subsequently, we conducted biological experiments and performed expression analyses of selected AhGASA genes to elucidate their potential regulatory roles in response to drought and salinity. Phylogenetic analysis revealed that AhGASA genes could be categorized into four distinct subfamilies. Under normal growth conditions, selected AhGASA genes exhibited varying expressions in young peanut seedling leaves, stems, and roots tissues. Notably, our findings indicate that certain AhGASA genes were downregulated under drought stress but upregulated under salt stress. These results suggest that specific AhGASA genes are involved in the regulation of salt or drought stress. Further functional characterization of the upregulated genes under both drought and salt stress will be essential to confirm their regulatory roles in this context. Overall, our findings provide compelling evidence of the involvement of AhGASA genes in the mechanisms of stress tolerance in cultivated peanuts. This study enhances our understanding of the functions of AhGASA genes in response to abiotic stress and lays the groundwork for future investigations into the molecular characterization of AhGASA genes.

Accounting for Preinvasive Conditions in Analysis of Invasive Cancer Risk: Application to Breast Cancer.

BACKGROUND: Preinvasive cancer conditions are often actively treated to minimize progression to life-threatening invasive cancers, but this creates challenges for analysis of invasive cancer risk. Conventional methods of treating preinvasive conditions as censoring events or targeting at the composite outcome could both lead to bias. METHODS: We propose two solutions: one that provides exact estimates of risk based on distributional assumptions about progression, and one that provides risk bounds corresponding to extreme cases of no or complete progression. We compare these approaches through simulations and an analysis of the Sister Study data in the context of ductal carcinoma in situ (DCIS) and invasive breast cancer. RESULTS: Simulations suggested important biases with conventional approaches, whereas the proposed estimate is consistent when progression parameters are correctly specified, and the risk bounds are robust in all scenarios. With Sister Study, the estimated lifetime risks for invasive breast cancer are 0.220 and 0.269 with DCIS censored or combined. Without detailed progression information, a sensitivity analysis suggested lifetime risk falls between the bounds of 0.214 and 0.269 across assumptions of 10%-95% of DCIS patients progressing to invasive cancer in an average of 1-10 years. CONCLUSIONS: When estimating invasive cancer risk while preinvasive conditions are actively treated, it is important to consider the implied assumptions and potential biases of conventional approaches. Although still not perfect, we proposed two practical solutions that provide improved understanding of the underlying mechanism of invasive cancer.

3D star shot analysis using MAGAT gel dosimeter for integrated imaging and radiation isocenter verification of MR-Linac system.

PURPOSE: This study aims to investigate a star shot analysis using a three-dimensional (3D) gel dosimeter for the imaging and radiation isocenter verification of a magnetic resonance linear accelerator (MR-Linac). METHODS: A mixture of methacrylic acid, gelatin, and tetrakis (hydroxymethyl) phosphonium chloride, called MAGAT gel, was fabricated. One MAGAT gel for each Linac and MR-Linac was irradiated under six gantry angles. A 6 MV photon beam of Linac and a 6 MV flattening filter free beam of MR-Linac were delivered to two MAGAT gels and EBT3 films. MR images were acquired by MR-Linac with a clinical sequence (i.e., TrueFISP). The 3D star shot analysis for seven consecutive slices of the MR images with TrueFISP was performed. The 2D star shot analysis for the central plane of the gel was compared to the results from the EBT3 films. The radius of isocircle (ICr ) and the distance between the center of the circle and the center marked on the image (ICd ) were evaluated. RESULTS: For MR-Linac with MAGAT gel measurements, ICd at the central plane was 0.46 mm for TrueFISP. Compared to EBT3 film measurements, the differences in ICd and ICr for both Linac and MR-Linac were within 0.11 and 0.13 mm, respectively. For the 3D analysis, seven consecutive slices of TrueFISP images were analyzed and the maximum radii of isocircles (ICr_max ) were 0.18 mm for Linac and 0.73 mm for MR-Linac. The tilting angles of radiation axis were 0.31° for Linac and 0.10° for MR-Linac. CONCLUSION: The accuracy of 3D star shot analysis using MAGAT gel was comparable to that of EBT3 film, having a capability for integrated analysis for imaging isocenter and radiation isocenter. 3D star shot analysis using MAGAT gel can provide 3D information of radiation isocenter, suggesting a quantitative extent of gantry-tilting.

Development of an anthropomorphic multimodality pelvic phantom for quantitative evaluation of a deep-learning-based synthetic computed tomography generation technique.

PURPOSE: The objective of this study was to fabricate an anthropomorphic multimodality pelvic phantom to evaluate a deep-learning-based synthetic computed tomography (CT) algorithm for magnetic resonance (MR)-only radiotherapy. METHODS: Polyurethane-based and silicone-based materials with various silicone oil concentrations were scanned using 0.35 T MR and CT scanner to determine the tissue surrogate. Five tissue surrogates were determined by comparing the organ intensity with patient CT and MR images. Patient-specific organ modeling for three-dimensional printing was performed by manually delineating the structures of interest. The phantom was finally fabricated by casting materials for each structure. For the quantitative evaluation, the mean and standard deviations were measured within the regions of interest on the MR, simulation CT (CTsim ), and synthetic CT (CTsyn ) images. Intensity-modulated radiation therapy plans were generated to assess the impact of different electron density assignments on plan quality using CTsim and CTsyn . The dose calculation accuracy was investigated in terms of gamma analysis and dose-volume histogram parameters. RESULTS: For the prostate site, the mean MR intensities for the patient and phantom were 78.1 ± 13.8 and 86.5 ± 19.3, respectively. The mean intensity of the synthetic image was 30.9 Hounsfield unit (HU), which was comparable to that of the real CT phantom image. The original and synthetic CT intensities of the fat tissue in the phantom were -105.8 ± 4.9 HU and -107.8 ± 7.8 HU, respectively. For the target volume, the difference in D95% was 0.32 Gy using CTsyn with respect to CTsim values. The V65Gy values for the bladder in the plans using CTsim and CTsyn were 0.31% and 0.15%, respectively. CONCLUSION: This work demonstrated that the anthropomorphic phantom was physiologically and geometrically similar to the patient organs and was employed to quantitatively evaluate the deep-learning-based synthetic CT algorithm.

Prospective Study of Plant-Based Dietary Patterns and Diabetes in Puerto Rican Adults.

BACKGROUND: Vegetarian-type dietary patterns have been associated with reducing the risk of developing diabetes and may function as an effective strategy for diabetes management. OBJECTIVES: We aimed to examine the associations between adherence to plant-based diet indices and the risk of developing diabetes in the Boston Puerto Rican Health Study. METHODS: Puerto Rican adults (n = 646), aged 45-75 y and free of diabetes at baseline, were included. Dietary intake was assessed via a validated FFQ. Three plant-based dietary indices were calculated: an overall plant-based diet index (PDI), a healthful plant-based diet index (hPDI), and an unhealthful plant-based diet index (uPDI). Incident diabetes was defined as fasting plasma glucose ≥ 126 mg/dL (7.0 mmol/L), glycated hemoglobin ≥ 6.5% (48 mmol/mol), or use of hypoglycemic agents during follow-up. Cox proportional hazards were used to evaluate associations between the dietary patterns and incidence of diabetes, adjusting for potential confounders, such as age, sex, socioeconomic status, lifestyle factors, obesity, total energy intake, depressive symptomatology, and plasma concentrations of lipids. RESULTS: During a mean of 4.2 y of follow-up, we identified 134 diabetes cases. After adjustment for covariates, higher hPDI was associated with lower risk of developing diabetes (adjusted HR for the highest compared with the lowest tertile: 0.54; 95% CI: 0.31, 0.94; P-trend = 0.03). In contrast, the PDI and uPDI were not significantly associated with the risk of diabetes (P-trend > 0.3 for both). CONCLUSIONS: The healthful plant-based dietary index, but not the total plant-based dietary index, was inversely associated with diabetes risk. These findings suggest that the quality of plant-based diets must be considered when recommending plant-based diets for the prevention of diabetes.This trial was registered at clinicaltrials.gov as NCT01231958.

Correlation between 3D scanner image and MRI for tracking volume changes in head and neck cancer patients.

INTRODUCTION: We investigated the correlation between optical surface imaging using a three-dimensional (3D) scanner and magnetic resonance imaging (MRI) for suggesting feasibility in the clinical process of tracking volume changes in head and neck patients during radiation treatment. METHODS: Ten patients were divided into two groups depending on the location of their tumor (i.e., right or left side). With weekly imaging data, the change in volume based on MRI was evaluated during the treatment course. Four volumes of interest (VOIs) were calculated on the 3D surface image of the facial and cervical areas using an optical 3D scanner, and the correlation between volumetric parameters were analyzed. RESULTS: The target volume changed significantly overall for both groups. The changes parotid volume reduced by up to 3.8% and 28.0% for groups A (right side) and B (left side), respectively. In Group A, VOI 1 on the facial area and VOI 3 on the cervical area decreased gradually during the treatment course by up to 3.3% and 10.7%, respectively. In Group B, only VOI 4 decreased gradually during the treatment course and reduced by up to 9.2%. In group A, the change in target volume correlated strongly with right-side parotid, VOI 1, and VOI 3, respectively. The parotid also showed strong correlations with VOIs (P < 0.01). The weight loss was strongly correlated with either PTV or parotid without statistical significance (P > 0.05). In group B (left side), the change in target volume correlated strongly with each volumetric parameter, including weight loss. For individual patient, PTV showed more correlation with VOIs on the cervical area than VOIs on the facial area. CONCLUSIONS: An optical 3D scanner can be applied to track changes in volume without radiation exposure during treatment and the optical surface image correlated with MRI.

Causal Proportional Hazards Estimation with a Binary Instrumental Variable.

Instrumental variables (IV) are a useful tool for estimating causal effects in the presence of unmeasured confounding. IV methods are well developed for uncensored outcomes, particularly for structural linear equation models, where simple two-stage estimation schemes are available. The extension of these methods to survival settings is challenging, partly because of the nonlinearity of the popular survival regression models and partly because of the complications associated with right censoring or other survival features. Motivated by the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer screening trial, we develop a simple causal hazard ratio estimator in a proportional hazards model with right censored data. The method exploits a special characterization of IV which enables the use of an intuitive inverse weighting scheme that is generally applicable to more complex survival settings with left truncation, competing risks, or recurrent events. We rigorously establish the asymptotic properties of the estimators, and provide plug-in variance estimators. The proposed method can be implemented in standard software, and is evaluated through extensive simulation studies. We apply the proposed IV method to a data set from the Prostate, Lung, Colorectal and Ovarian cancer screening trial to delineate the causal effect of flexible sigmoidoscopy screening on colorectal cancer survival which may be confounded by informative noncompliance with the assigned screening regimen.

ADAR1-mediated RNA editing is required for thymic self-tolerance and inhibition of autoimmunity.

T cells play a crucial role in the adaptive immune system, and their maturation process is tightly regulated. Adenosine deaminase acting on RNA 1 (ADAR1) is the enzyme responsible for adenosine-to-inosine RNA editing in dsRNAs, and loss of ADAR1 activates the innate immune sensing response via melanoma differentiation-associated protein 5 (MDA5), which interprets unedited dsRNA as non-self. Although ADAR1 is highly expressed in the thymus, its role in the adaptive immune system, especially in T cells, remains elusive. Here, we demonstrate that T cell-specific deletion of Adar1 in mice causes abnormal thymic T cell maturation including impaired negative selection and autoimmunity such as spontaneous colitis. This is caused by excessive expression of interferon-stimulated genes, which reduces T cell receptor (TCR) signal transduction, due to a failure of RNA editing in ADAR1-deficient thymocytes. Intriguingly, concurrent deletion of MDA5 restores thymocyte maturation and prevents colitis. These findings suggest that prevention of MDA5 sensing of endogenous dsRNA by ADAR1-mediated RNA editing is required for preventing both innate immune responses and T cell-mediated autoimmunity.

On the self-triggering Cox model for recurrent event data.

Recurrent event data frequently occur in longitudinal studies when subjects experience more than one event during the observation period. Often, the occurrence of subsequent events is associated with the experience of previous events. Such dependence is commonly ignored in the application of standard recurrent event methodology. In this paper, we utilize a Cox-type regression model with time-varying triggering effect depending on the number and timing of previous events to enhance both model fit and prediction. Parameter estimation and statistical inference is achieved via the partial likelihood. A statistical test procedure is provided to assess the existence of the triggering effects. We demonstrate our approach via comprehensive simulation studies and a real data analysis on chronic pseudomonas infections in young cystic fibrosis patients. Our model provides significantly better predictions than standard recurrent event models.

Modulation indices and plan delivery accuracy of volumetric modulated arc therapy.

PURPOSE: We evaluated the performance of various modulation indices (MI) for volumetric modulated arc therapy (VMAT) to predict plan delivery accuracy. METHODS: The specific indices evaluated were MI quantifying the mechanical uncertainty (MIt ), MI quantifying the mechanical and dose calculation uncertainties (MIc ), MI for station parameter optimized radiation therapy (MISPORT ), modulation complexity score for VMAT (MCSv ), leaf travel modulation complexity score (LTMCS), plan averaged beam area (PA), plan averaged beam irregularity (PI), plan averaged beam modulation (PM), and plan normalized monitor unit (PMU) to predict VMAT delivery accuracy. By utilizing 240 VMAT plans generated with the Trilogy and TrueBeam STx, Spearman's rank correlation coefficients (r) were calculated between the MIs and measures of conventional methods. RESULTS: For the Trilogy system, MIc showed the highest r values with gamma passing rates (GPRs) (r = -0.624 with P < 0.001 for MapCHECK2 and r = -0.655 with P < 0.001 for ArcCHECK). For TrueBeam STx, MIc also showed the highest r values with GPRs (r = -0.625 with P < 0.001 for the MapCHECK2 and r = -0.561 with P < 0.001 for the ArcCHECK). The MIt and MIc showed the highest r values to the MLC position errors for the Trilogy and TrueBeam STx systems (r = 0.770 with P < 0.001 and r = 0.712 with P < 0.001, respectively). The PA showed the highest percent of r values (P < 0.05) to differences in the dose-volume parameters between original VMAT plans and actual deliveries for the Trilogy systems (30.9%). Both the MIt and MIc showed the highest percent of r values (P < 0.05) to differences in the dose-volume parameters between original VMAT plans and actual deliveries for the TrueBeam STx systems (31.8%). CONCLUSION: To comprehensively review the results, the MIc showed the best performance to predict the VMAT delivery accuracy.

Characteristics of the Exradin W1 scintillator in the magnetic field.

To investigate the angular dependency of the W1 scintillator with and without a magnetic field, the beam incidence angles to the detector varied from 0° to 360° at intervals of 30° when the detector was pointed in both the craniocaudal and right-to-left directions. The beam incidence angles also varied from 0° to 360° at intervals of 45° when the W1 scintillator was in the anterior-to-posterior direction. To investigate the field size dependency of the W1 scintillator with and without a magnetic field, the doses by an identical beam-on time were measured at various square field sizes and the measured doses were normalized to the dose at the field of 10.5 cm × 10.5 cm (FS10.5). With and without a magnetic field, the deviations of the doses to the dose at the beam incident angle of 0° were always less than 1% regardless of the dosimeter positioning relative to the magnetic field direction. When the field sizes were equal to or less than FS10.5, the differences in the output factors with and without a magnetic field were less than 0.7%. However, those were larger than 1% at fields larger than FS10.5, and up to 3.1%. The W1 scintillator showed no angular dependency to the magnetic field. Differences larger than 1% in the output factors with and without a magnetic field were observed at field sizes larger than 10.5 cm × 10.5 cm.

Development of a Geant4-based independent patient dose validation system with an elaborate multileaf collimator simulation model.

Despite the improvements in the dose calculation models of the commercial treatment planning systems (TPS), their ability to accurately predict patient dose is still limited. One of the limitations is caused by the simplified model of the multileaf collimator (MLC). The aim of this study was to develop a Monte Carlo (MC) method-based independent patient dose validation system with an elaborate MLC model for more accurate dose evaluation. Varian Clinac 2300 IX was simulated using Geant4 toolkits, after which MC commissioning with measurements was performed to validate the simulation model. A DICOM-RT interface was developed to obtain the beam delivery conditions including the hundreds of MLC motions. Finally, the TPS dose distributions were compared with the MC dose distributions for water phantom cases and a patient case. Our results show that the TPS overestimated the absolute abutting leakage dose in the closed MLC field, with about 20% more of the maximum dose than that of the MC calculation. For water phantom cases, the dose distributions inside the target region were almost identical with the dose difference of less than 2%, while the dose near the edge of the target shows difference about 10% between Geant4 and TPS due to geometrical differences in MLC model. For the patient analysis, the Geant4 and TPS doses of all organs were matched well within 1.4% of the prescribed dose. However, for organs located in areas with high ratio of leaf pairs with distances less than 10 mm leaf pair (LP(<10mm) ), the maximum dose of TPS was overestimated by about 3% of the prescribed dose. These dose comparison results demonstrate that our system for calculating the patient dose is quite accurate. Furthermore, if the MLC sequences in treatment plan have a large ratio of LP(short) , more than 3% dose difference in normal tissue could be seen.

Air-electron stream interactions during magnetic resonance IGRT : Skin irradiation outside the treatment field during accelerated partial breast irradiation.

PURPOSE: To investigate and to prevent irradiation outside the treatment field caused by an electron stream in the air generated by the magnetic field during magnetic resonance image-guided accelerated partial breast irradiation (APBI). MATERIALS AND METHODS: In all, 20 patients who received APBI with a magnetic resonance image-guided radiation therapy (MR-IGRT) system were prospectively studied. The prescription dose was 38.5 Gy in 10 fractions of 3.85 Gy and delivered with a tri-cobalt system (the ViewRay system). For each patient, primary plans were delivered for the first five fractions and modified plans with different gantry angles from those of the primary plan (in-treatment plans) were delivered for the remaining five fractions to reduce the skin dose. A 1 cm thick bolus was placed in front of the patient's jaw, ipsilateral shoulder, and arm to shield them from the electron stream. Radiochromic EBT3 films were attached to the front (towards the breast) and back (towards the head) of the bolus during treatment. Correlations between the measured values and the tumor locations, treatment times, and tumor sizes were investigated. RESULTS: For a single fraction delivery, the average areas of the measured isodoses of 14% (0.54 Gy), 12% (0.46 Gy), and 10% (0.39 Gy) at the front of the boluses were as large as 3, 10.4, and 21.4 cm2, respectively, whereas no significant dose could be measured at the back of the boluses. Statistically significant but weak correlations were observed between the measured values and the treatment times. CONCLUSION: During radiotherapy for breast cancer with an MR-IGRT system, the patient must be shielded from electron streams in the air generated by the interaction of the magnetic field with the beams of the three-cobalt treatment unit to avoid unwanted irradiation of the skin outside the treatment field.

Intensity-modulated radiotherapy versus three-dimensional conformal radiotherapy in rectal cancer treated with neoadjuvant concurrent chemoradiation: a meta-analysis and pooled-analysis of acute toxicity.

BACKGROUND: To compare the acute gastrointestinal (GI) and genitourinary (GU) toxicity profiles between intensity-modulated radiotherapy (IMRT) and three-dimensional conformal radiotherapy (3DCRT) in rectal cancer patients treated with neoadjuvant chemoradiation (NCRT) using meta-analysis and pooled-analysis from published articles. METHODS: Literature search was performed in PubMed and EMBASE from inception to March 2017. The odd ratios (ORs) were calculated and random effects model was used for meta-analysis. Chi-square or Fisher's exact test was performed for the pooled-analysis. RESULTS: Six studies including a total of 859 patients met the inclusion criteria. Most patients (98.7%) received NCRT. In the meta-analysis, IMRT reduced grade ≥ 2 acute overall GI toxicity, diarrhea and proctitis with ORs of 0.38, 0.32 and 0.60, respectively (all P < 0.05), compared to 3DCRT. IMRT also reduced acute grade ≥ 3 proctitis compared to 3D-CRT (OR, 0.24; P = 0.03). No significant heterogeneity or publication bias was detected. In the pooled-analysis, IMRT reduced the incidence of grade ≥ 2 acute overall GI toxicity, diarrhea, proctitis and GU toxicity (all P < 0.05). Moreover, lower incidence of grade ≥ 3 acute overall GI toxicity, diarrhea and proctitis were observed in the patients treated with IMRT (all P < 0.05). CONCLUSIONS: IMRT significantly reduced acute toxicity in locally advanced rectal cancer patients treated with NCRT compared to 3DCRT.

Early oral immunotherapy in peanut-allergic preschool children is safe and highly effective.

BACKGROUND: Oral immunotherapy (OIT) is an effective experimental food allergy treatment that is limited by treatment withdrawal and the frequent reversibility of desensitization if interrupted. Newly diagnosed preschool children may have clinical and immunological characteristics more amenable to treatment. OBJECTIVE: We sought to test the safety, effectiveness, and feasibility of early OIT (E-OIT) in the treatment of peanut allergy. METHODS: We enrolled 40 children aged 9 to 36 months with suspected or known peanut allergy. Qualifying subjects reacted to peanut during an entry food challenge and were block-randomized 1:1 to receive E-OIT at goal maintenance doses of 300 or 3000 mg/d in a double-blinded fashion. The primary end point, sustained unresponsiveness at 4 weeks after stopping early intervention oral immunotherapy (4-SU), was assessed by double-blinded, placebo-controlled food challenge either upon achieving 4 prespecified criteria, or after 3 maintenance years. Peanut-specific immune responses were serially analyzed. Outcomes were compared with 154 matched standard-care controls. RESULTS: Of 40 consented subjects, 3 (7.5%) did not qualify. Overall, 29 of 37 (78%) in the intent-to-treat analysis achieved 4-SU (300-mg arm, 17 of 20 [85%]; 3000 mg, 12 of 17 [71%], P = .43) over a median of 29 months. Per-protocol, the overall proportion achieving 4-SU was 29 of 32 (91%). Peanut-specific IgE levels significantly declined in E-OIT-treated children, who were 19 times more likely to successfully consume dietary peanut than matched standard-care controls, in whom peanut-specific IgE levels significantly increased (relative risk, 19.42; 95% CI, 8.7-43.7; P < .001). Allergic side effects during E-OIT were common but all were mild to moderate. CONCLUSIONS: At both doses tested, E-OIT had an acceptable safety profile and was highly successful in rapidly suppressing allergic immune responses and achieving safe dietary reintroduction.