Impact of a contouring atlas on radiographer inter-observer variation in male pelvis radiotherapy.

PURPOSE/OBJECTIVE: To determine the impact of a MR-based contouring atlas for male pelvis radiotherapy delineation on inter-observer variation to support radiographer led real-time magnetic resonance image guided adaptive radiotherapy (MRgART). MATERIAL/METHODS: Eight RTTs contoured 25 MR images in the Monaco treatment planning system (Monaco 5.40.01), from 5 patients. The prostate, seminal vesicles, bladder, and rectum were delineated before and after the introduction of an atlas developed through multi-disciplinary consensus. Inter-observer contour variations (volume), time to contour and observer contouring confidence were determined at both time-points using a 5-point Likert scale. Descriptive statistics were used to analyse both continuous and categorical variables. Dice similarity coefficient (DSC), Dice-Jaccard coefficient (DJC) and Hausdorff distance were used to calculate similarity between observers. RESULTS: Although variation in volume definition decreased for all structures among all observers post intervention, the change was not statistically significant. DSC and DJC measurements remained consistent following the introduction of the atlas for all observers. The highest similarity was found in the bladder and prostate whilst the lowest was the seminal vesicles. The mean contouring time for all observers was reduced by 50% following the introduction of the atlas (53 to 27 minutes, p=0.01). For all structures across all observers, the mean contouring confidence increased significantly from 2.3 to 3.5 out of 5 (p=0.02). CONCLUSION: Although no significant improvements were observed in contour variation amongst observers, the introduction of the consensus-based contouring atlas improved contouring confidence and speed; key factors for a real-time RTT-led MRgART.

To see or not to see: Evaluation of magnetic resonance imaging sequences for use in MR Linac-based radiotherapy treatment.

BACKGROUND/PURPOSE: This work evaluated the suitability of MR derived sequences for use in online adaptive RT workflows on a 1.5 Tesla (T) MR-Linear Accelerator (MR Linac). MATERIALS/METHODS: Non-patient volunteers were recruited to an ethics approved MR Linac imaging study. Participants attended 1-3 imaging sessions in which a combination of DIXON, 2D and 3D volumetric T1 and T2 weighted images were acquired axially, with volunteers positioned using immobilisation devices typical for radiotherapy to the anatomical region being scanned. Images from each session were appraised by three independent reviewers to determine optimal sequences over six anatomical regions: head and neck, female and male pelvis, thorax (lung), thorax (breast/chest wall) and abdomen. Site specific anatomical structures were graded by the perceived ability to accurately contour a typical organ at risk. Each structure was independently graded on a 4-point Likert scale as 'Very Clear', 'Clear', 'Unclear' or 'Not visible' by observers, consisting of radiographers (therapeutic and diagnostic) and clinicians. RESULTS: From July 2019 to September 2019, 18 non-patient volunteers underwent 24 imaging sessions in the following anatomical regions: head and neck (n=3), male pelvis (n=4), female pelvis (n=5), lung/oesophagus (n=5) abdomen (n=4) and chest wall/breast (n=3). T2 sequences were the most preferred for perceived ability to contour anatomy in both male and female pelvis. For all other sites T1 weighted DIXON sequences were most favourable. CONCLUSION: This study has determined the preferential sequence selection for organ visualisation, as a pre-requisite to our institution adopting MR-guided radiotherapy for a more diverse range of disease sites.

The impact of gadolinium-based MR contrast on radiotherapy planning for oropharyngeal treatment on the MR Linac.

PURPOSE: Gadolinium-based contrast agents (GBCAs) may add value to magnetic resonance (MR)-only radiotherapy (RT) workflows including on hybrid machines such as the MR Linac. The impact of GBCAs on RT dose distributions however have not been well studied. This work used retrospective GBCA-enhanced datasets to assess the dosimetric effect of GBCAs on head and neck plans. METHODS: Ten patients with oropharyngeal squamous cell carcinoma receiving RT from November 2018 to April 2020 were included in this study. RT planning included contrast-enhanced computed tomography (CT) and MR scans. A contrast agent "contour" was defined by delineating GBCA-enhanced regions using an agreed window/level threshold, transferred to the planning CT and given a standardized electron density (ED) of 1.149 in the Monaco treatment planning system (Elekta AB). Four plans were per patient calculated and compared using two methods: (1) optimized without contrast (Plan A) then recalculated with ED (Plan B), and (2) optimized with contrast ED (Plan C) then without (Plan D). For target parameters minimum and maximum doses to 1cc of PTVs, D95 values, and percent dose differences were calculated. Dose differences for organs-at-risk (OARs) were calculated as a percentage of the clinical tolerance value. For the purposes of this study, ±2% over the whole treatment course was considered to be a clinically acceptable dose deviation. Wilcoxon-signed rank tests were used to determine any dose differences within and between the two methods of optimization and recalculation (p < 0.05). Pearson's correlations were used to establish the relationship between gadolinium uptake volume in a structure (i.e., proportion of structure covered by a density override) and the resulting dose difference. RESULTS: The median percent dose differences for key reportable dosimetric parameters between non-contrast and simulated contrast plans were <1.2% over all fractions over all patients for reportable target parameters (mean 0.34%, range 0.22%-1.02%). The percent dose differences for maximum dose to 1cc of both PTV1 and PTV2 were significantly different after application of density override (p < 0.05) but only in method 2 (Plan C vs. Plan D). For D95 PTV1, there was a statistically significant effect of density override (p < 0.01), however only in method 1 (Plan A vs. Plan B). There were no significant differences between calculation methods of the impact of contrast in most target parameters with the exception of D95 PTV1 (p < 0.01) and for D95 PTV2 (p < 0.05). The median percent dose differences for reportable OAR parameters as a percentage of clinical planning tolerances were <2.0% over a full treatment course (mean 0.65%, range 0.27%-1.62%). There were no significant differences in dose to OARs within or between methods for contrast impact assessment. CONCLUSIONS: Dose differences to targets and OARs in oropharyngeal cancer treatment due to the presence of GBCA were minimal, and this work suggests that prospective in vivo evaluations of impact may not be necessary in this clinical site. Accounting for GBCAs may not be needed in daily adaptive workflows on the MR Linac.

Developing electronic learning to deliver MR safety training in a radiotherapy department.

INTRODUCTION/BACKGROUND: Magnetic Resonance Imaging (MRI) is used in radiotherapy planning, and increasingly in on-treatment guidance. The potential for the MR environment to be hazardous, without stringent safe working practices, is real. Guidance suggests all workers in MRI undergo annual safety training. To facilitate a tangible MR safety program, an electronic learning module was created and evaluated. METHODS: An existing presentation, normally delivered face-to-face, was modified and questions added to test knowledge. The module was delivered and feedback collected, together with answers to the questions, over three phases to ensure deliverability, clarity, and robustness. These comprised an initial pilot phase for non-MR personnel, an evaluation phase for staff renewing annual MR safety training, and finally for new therapeutic radiographer graduates, a test-retest methodology. RESULTS: Seven participants took part in the initial pilot phase, followed by thirty-one in the evaluation phase. Participants included radiographers (therapeutic and diagnostic), play specialists, clinical oncologists and anaesthetists, physicists and nursing staff. Within the evaluation group, 74.2% achieved a score >80%. Incorrect responses were principally related to questions regarding expected levels of responsibility and working practices, rather than the physics of high magnetic field strengths. The test-retest phase (n = 5) followed. Mean scores prior to learning were 59%, improving to 79% following learning, with the weakest sections mirroring those highlighted within the evaluation phase. DISCUSSION: Transferring MR safety training into an electronic format has provided a standardised, tangible tool that provides evidence of compliance with recommended guidance. CONCLUSIONS: This work illustrates the transition of MR safety learning for radiotherapy staff from passive presentation, to an interactive teaching methodology. The e-learning module has now been implemented within the department.

Right, left and cilia: How asymmetry is established.

The initial breaking of left-right (L-R) symmetry in the embryo is controlled by a motile-cilia-driven leftward fluid flow in the left-right organiser (LRO), resulting in L-R asymmetric gene expression flanking the LRO. Ultimately this results in left- but not right-sided activation of the Nodal-Pitx2 pathway in more lateral tissues. While aspects of the initial breaking event clearly vary between vertebrates, events in the Lateral Plate Mesoderm (LPM) are conserved through the vertebrate lineage. Evidence from model systems and humans highlights the role of cilia both in the initial symmetry breaking and in the ability of more lateral tissues to exhibit asymmetric gene expression. In this review we concentrate on the process of L-R determination in mouse and humans.

Therapeutic Radiographers at the Helm: Moving Towards Radiographer-Led MR-Guided Radiotherapy.

INTRODUCTION: Magnetic resonance-guided adaptive radiotherapy (MRgART) has the potential to improve treatment processes and outcomes for a variety of tumour sites; however, it requires significant clinical resources. Magnetic resonance linear accelerator (MR-linac) treatments require a daily multidisciplinary presence for delivery. To facilitate sustainable MRgART models, agreed protocols facilitating therapeutic radiographer (RTT)-led delivery must be developed to establish a service similar to conventional image-guided radiotherapy (IGRT). This work provides a clinical perspective on the implementation of a protocol-driven 'clinician-lite' MRgART workflow at one institution. METHODS: To identify knowledge, skills, and competence required at each step in the MRgART workflow, an interdisciplinary informal survey and needs assessment were undertaken to identify additional or enhanced skills required for MRgART, over and above those required for conventional cone-beam computed tomography-based IGRT. The MRgART pathway was critically evaluated by relevant professionals to encourage multidisciplinary input and discussion, allowing an iterative development of the RTT-led workflow. Starting with the simplest online adaptation strategy, consisting of a virtual couch shift and online replanning, clear guidelines were established for the delivery of radical prostate radiotherapy with a reduction in staff numbers present. RESULTS: The MRgART-specific skills identified included MRI safety and screening, MR image acquisition, MRI-based anatomy, multimodality image interpretation and registration, and treatment plan evaluation. These skills were developed in RTTs via tutorials, workshops, focussed self-directed reading, teaching of colleagues, and end-to-end workflow testing. After initial treatments and discussions, roles and responsibilities of the three professional groups (clinicians, RTTs, and physicists) have evolved to achieve a 'clinician-lite' workflow for simple radical prostate treatments. DISCUSSION: Through applying a definitive framework and establishing agreed threshold and action levels for action within anticipated treatment scenarios similar to those in cone-beam computed tomography-based IGRT, we have implemented a 'clinician-lite' workflow for simple adaptive treatments on the MR-linac. The responsibility for online plan evaluation and approval now rests with physicists and RTTs to streamline MRgART. Early evaluation of the framework after treatment of 10 patients has required minimal online clinician input (1.5% of 200 fractions delivered). CONCLUSION: A 'clinician-lite' prostate treatment workflow has been successfully introduced on the MR-linac at our institution and will serve as a model for other tumour sites, using more complex adaptive strategies. Early indications are that this framework has the potential to improve patient throughput and efficiency. Further identification and validation of roles and responsibilities such as online contouring, and more interactive online planning, will facilitate RTTs to fully lead in the online workflow as adaptive radiotherapy becomes ever more complex.

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.

Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

Isomerization in the CDR2 of a monoclonal antibody: Binding analysis and factors that influence the isomerization rate.

Isomerization of a monoclonal antibody is one of the common routes of protein degradation. An isomerization in the complementarity-determining region (CDR) was found previously and is investigated in depth in this work. Affinity analysis proves that the antibody with one isomerized heavy chain has lower binding. Binding constants were determined, and exhibited a slower on-rate in conjunction with a faster off-rate for this isomerization. To determine the role of the buffer on the rate of isomerization, this antibody was incubated in various matrices and the amount of isomerized antibody was determined by hydrophobic interaction chromatography (HIC). The rate was found to be dependent on the pH as well as the net negative charge of the buffer components that can act as proton acceptors. An Arrhenius plot was performed to predict the levels of isomerization and a comparison of real samples proved the model was correct. This work affirms that isomerization in the CDR of a therapeutic antibody is important to monitor and the formulation buffer plays a significant role in the rate of the isomerization.

A quantitative human monoclonal antibody immunoassay using anti-idiotypic antibody as a membrane antigen surrogate with surface-plasmon-resonance detection.

Biologically active membrane proteins are difficult to isolate. Very often the isolated membrane proteins have low binding affinity or no biological integrity at all. Despite some success in isolation, one has to overcome the hurdles of obtaining sufficient quantity of the proteins and maintaining biological activity upon coating them on surfaces for developing an ELISA. Thus an alternative approach may be useful. The present study describes a quantification assay method for a therapeutic hmAb-1 (human monoclonal antibody-1) that recognizes a cell-surface protein employing an anti-ID (anti-idiotypic antibody) to hmAb-1 as a surrogate antigen in an immunoassay format using surface- plasmon-resonance technology. This assay is applicable for quantification of hmAb-1 in process streams, final drug-product quality control, as well as low-concentration drug substances in intravenous-solution bags. The surrogate nature of the anti-ID was confirmed by demonstrating that the anti-ID displaced the interaction between the hmAb-1 and its membrane antigen in a FACS titration test. The assay format involves first capturing hmAb-1 on the flow-cell surface, which then binds quantitatively to anti-ID in a mixture of increasing quantity of hmAb-1 in solution. An inverse dose-response relation between this anti-ID bound signal (or resonance units) and hmAb-1 concentration was established. The dose-response range of the calibration curve for hmAb-1 was between 20 and 300 ng/ml. The precision, accuracy and specificity of the assay are reported in the present paper.

Adjustment difficulties of adolescents with sickle cell disease.

TOPIC: The psychosocialfactors that affect adolescents with sickle cell disease (SCD). PURPOSE: To explore whether specific psychosocial factors can provide clues to the future adjustment of this population. SOURCES: Ovid Web, Medline, Psychinfo, and CINAHL databases for the years 1997 to 2001. CONCLUSIONS: Promoting effective psychosocial functioning is as important as managing the medical aspects of SCD, yet this is an area of care that is commonly overlooked. Nurses, therefore, have an opportunity to have a significant impact on the lives of adolescents with SCD if they intervene in ways to promote both biological and psychosocial adjustment.

Haptens and monoclonal antibodies for immunoassay of imidazolinone herbicides.

A set of haptens structurally resembling the herbicide imazethapyr (PURSUIT) was synthesized and used to derive monoclonal antibodies (MAbs) and direct and indirect competition enzyme immunoassays (EIAs) which could detect imazethapyr, imazaquin (SCEPTER), imazapic (CADRE), and imazamox (RAPTOR) in the 3-30 ng/mL (parts per billion) range, and imazapyr (ARSENAL) and imazamethabenz-methyl (ASSERT) in the 300-500 ppb range. Two MAbs, 3A2 and 3A5, had affinities of 10-75 nM for imazethapyr. MAbs 1A5, 1D2, and 3A5 were specific for the S isomers of the herbicides. Some MAbs were stable in solutions containing up to 15% methanol and 5% acetonitrile in indirect EIAs. Plates coated with hapten conjugates for indirect EIA could be stored frozen. Selectivity for the imidazolinones by some MAbs varied with different coating conjugates. These MAbs and haptens should prove useful in immunochemical analysis and residue recovery methods for imazethapyr and other imidazolinone herbicides.