Artificial Intelligence for Radiotherapy Auto-Contouring: Current Use, Perceptions of and Barriers to Implementation.

AIMS: Artificial intelligence has the potential to transform the radiotherapy workflow, resulting in improved quality, safety, accuracy and timeliness of radiotherapy delivery. Several commercially available artificial intelligence-based auto-contouring tools have emerged in recent years. Their clinical deployment raises important considerations for clinical oncologists, including quality assurance and validation, education, training and job planning. Despite this, there is little in the literature capturing the views of clinical oncologists with respect to these factors. MATERIALS AND METHODS: The Royal College of Radiologists realises the transformational impact artificial intelligence is set to have on our specialty and has appointed the Artificial Intelligence for Clinical Oncology working group. The aim of this work was to survey clinical oncologists with regards to perceptions, current use of and barriers to using artificial intelligence-based auto-contouring for radiotherapy. Here we share our findings with the wider clinical and radiation oncology communities. We hope to use these insights in developing support, guidance and educational resources for the deployment of auto-contouring for clinical use, to help develop the case for wider access to artificial intelligence-based auto-contouring across the UK and to share practice from early-adopters. RESULTS: In total, 78% of clinical oncologists surveyed felt that artificial intelligence would have a positive impact on radiotherapy. Attitudes to risk were more varied, but 49% felt that artificial intelligence will decrease risk for patients. There is a marked appetite for urgent guidance, education and training on the safe use of such tools in clinical practice. Furthermore, there is a concern that the adoption and implementation of such tools is not equitable, which risks exacerbating existing inequalities across the country. CONCLUSION: Careful coordination is required to ensure that all radiotherapy departments, and the patients they serve, may enjoy the benefits of artificial intelligence in radiotherapy. Professional organisations, such as the Royal College of Radiologists, have a key role to play in delivering this.

Distinct genome-wide DNA methylation and gene expression signatures in classical monocytes from African American patients with systemic sclerosis.

BACKGROUND: Systemic sclerosis (SSc) is a multisystem autoimmune disorder that has an unclear etiology and disproportionately affects women and African Americans. Despite this, African Americans are dramatically underrepresented in SSc research. Additionally, monocytes show heightened activation in SSc and in African Americans relative to European Americans. In this study, we sought to investigate DNA methylation and gene expression patterns in classical monocytes in a health disparity population. METHODS: Classical monocytes (CD14+ + CD16-) were FACS-isolated from 34 self-reported African American women. Samples from 12 SSc patients and 12 healthy controls were hybridized on MethylationEPIC BeadChip array, while RNA-seq was performed on 16 SSc patients and 18 healthy controls. Analyses were computed to identify differentially methylated CpGs (DMCs), differentially expressed genes (DEGs), and CpGs associated with changes in gene expression (eQTM analysis). RESULTS: We observed modest DNA methylation and gene expression differences between cases and controls. The genes harboring the top DMCs, the top DEGs, as well as the top eQTM loci were enriched for metabolic processes. Genes involved in immune processes and pathways showed a weak upregulation in the transcriptomic analysis. While many genes were newly identified, several other have been previously reported as differentially methylated or expressed in different blood cells from patients with SSc, supporting for their potential dysregulation in SSc. CONCLUSIONS: While contrasting with results found in other blood cell types in largely European-descent groups, the results of this study support that variation in DNA methylation and gene expression exists among different cell types and individuals of different genetic, clinical, social, and environmental backgrounds. This finding supports the importance of including diverse, well-characterized patients to understand the different roles of DNA methylation and gene expression variability in the dysregulation of classical monocytes in diverse populations, which might help explaining the health disparities.

An Update to the Malthus Model for Radiotherapy Utilisation in England.

AIMS: The Malthus Programme predicts national and local radiotherapy demand by combining cancer incidence data with decision trees detailing the indications, and appropriate dose fractionation, for radiotherapy. Since the last model update in 2017, technological advancements and the COVID-19 pandemic have led to increasing hypofractionation of radiotherapy schedules. Indications for radiotherapy have also evolved, particularly in the context of oligometastatic disease. Here we present a brief update on the model for 2021. We have updated the decision trees for breast, prostate, lung and head and neck cancers, and incorporated recent cancer incidence data into our model, generating a current estimate of fraction demand for these four cancer sites across England. MATERIALS AND METHODS: The decision tree update was based on evidence from practice-changing randomised controlled trials, published guidelines, audit data and expert opinion. Site- and stage-specific incidence data were taken from the National Disease Registration Service. We used the updated model to estimate the proportion of patients who would receive radiotherapy (appropriate rate of radiotherapy) and the fraction demand per million population at a national and Clinical Commissioning Group level in 2021. RESULTS: The total predicted fraction demand has decreased by 11.4% across all four cancer sites in our new model, compared with the 2017 version. This reduction can be explained primarily by greater use of hypofractionated treatments (including stereotactic ablative radiotherapy) and a shift towards earlier stage presentation. The only large change in appropriate rate of radiotherapy was an absolute decrease of 3% for lung cancer. CONCLUSIONS: Compared with our previous model, the current version predicts a reduction in fraction demand across England. This is driven principally by hypofractionation of radiotherapy regimens, using technology that requires increasingly complex planning. Treatment complexity and local service factors need to be taken into account when translating fraction burden into linear accelerator demand or throughput.

Conditional knockout of oestrogen receptor alpha in CD11c+ cells impacts female survival and inflammatory cytokine profile in murine lupus.

Oestrogen and oestrogen receptor alpha (ERα) have been implicated in systemic lupus erythematosus pathogenesis. ERα signalling influences dendritic cell (DC) development and function, as well as inflammation and downstream immune responses. We previously reported that ERα modulates multiple Toll-like receptor-stimulated pathways in both conventional and plasmacytoid DCs in lupus-prone mice. For example, CD11chi MHCII+ cell numbers are reduced in mice with global ERα deficiency or when expressing a short variant of ERα. Herein, RNA-seq analysis of CD11chi cells from bone marrow of NZM2410 mice expressing WT ERα versus ERα short versus ERα null revealed differentially expressed complement genes, interferon-related genes and cytokine signalling (e.g., IL-17 and Th17 pathways). To better understand the role of ERα in CD11c+ cells, lupus prone NZM2410 mice with selective deletion of the Esr1 gene in CD11c+ cells were generated. Phenotype and survival of these mice were similar with the exception of Cre positive (CrePos) female mice. CrePos females, but not males, all died unexpectedly prior to 35 weeks. DC subsets were not significantly different between groups. Since ERα is necessary for robust development of DCs, this result suggests that DC fate was determined prior to CD11c expression and subsequent ERα deletion (i.e., proximally in DC ontogeny). Overall, findings point to a clear functional role for ERα in regulating cytokine signalling and inflammation, suggesting that further study into ERα-mediated regulatory mechanisms in DCs and other immune cell types is warranted.

Machine Learning for Auto-Segmentation in Radiotherapy Planning.

Manual segmentation of target structures and organs at risk is a crucial step in the radiotherapy workflow. It has the disadvantages that it can require several hours of clinician time per patient and is prone to inter- and intra-observer variability. Automatic segmentation (auto-segmentation), using computer algorithms, seeks to address these issues. Advances in machine learning and computer vision have led to the development of methods for accurate and efficient auto-segmentation. This review surveys auto-segmentation techniques and applications in radiotherapy planning. It provides an overview of traditional approaches to auto-segmentation, including intensity analysis, shape modelling and atlas-based methods. The focus, though, is on uses of machine learning and deep learning, including convolutional neural networks. Finally, the future of machine-learning-driven auto-segmentation in clinical settings is considered, and the barriers that must be overcome for it to be widely accepted into routine practice are highlighted.

Variations in Demand across England for the Magnetic Resonance-Linac Technology, Simulated Utilising Local-level Demographic and Cancer Data in the Malthus Project.

AIMS: Cancer incidence varies across England, which affects the local-level demand for treatments. The magnetic resonance-linac (MR-linac) is a new radiotherapy technology that combines imaging and treatment. Here we model the demand and demand variations for the MR-linac across England. MATERIALS AND METHODS: Initial clinical indications were provided by the MR-linac consortium and introduced into the Malthus radiotherapy clinical decision trees. The Malthus model contains Clinical Commissioning Group (CCG) population, cancer incidence and stage presentation data (for lung and prostate) and simulated the demand for the MR-linac for all CCGs and Radiotherapy Operational Delivery Networks (RODN) across England. RESULTS: Based on the initial target clinical indications, the MR-linac could service 16% of England's fraction burden. The simulated fractions/million population demand/annum varies between 3000 and 10 600 fractions/million at the CCG level. Focussing only on the cancer population, the simulated fractions/1000 cancer cases demand/annum ranges from 1028 to 1195 fractions/1000 cases. If a national average for fractions/million demand was then used, at the RODN level, the variation from actual annual demand ranges from an overestimation of 8400 fractions to an underestimation of 5800 fractions. When using the national average fractions/1000 cases, the RODN demand varies from an overestimation of 3200 fractions to an underestimation of 3000 fractions. CONCLUSIONS: Planning cancer services is complex due to regional variations in cancer burden. The variations in simulated demand of the MR-linac highlight the requirement to use local-level data when planning to introduce a new technology.

Drama at Dunder Mifflin: Workplace Bullying Discourses on The Office.

This study examines the portrayal and affective framing of workplace bullying behaviors on the popular American television show The Office. Quantitative and qualitative content analyses were conducted on 54 episodes spanning the show's nine seasons. Results revealed 331 instances of workplace bullying, for an average of 6.13 bullying behaviors per episode. Workplace bullying behavior on The Office was grouped into five categories: sexual jokes, public humiliation, practical jokes, belittlement, and misuse of authority. In general, instances of workplace bully were scripted as humorous and lacking significant consequences, which could further contribute to social discourses that perpetuate the problem of bullying in real-life workplaces.

Enhanced magnetic and room temperature intrinsic magnetodielectric effect in Mn modified Ba2Mg2Fe12O22 Y-type hexaferrite.

We have reported a systematic investigation on structural, magnetic, magnetodielectric and magnetoimpedance characteristics of Y-type Ba2Mg2(Fe1-x Mn x )12O22 (0 ⩽ x ⩽ 0.12) hexaferrite synthesized by solid-state reaction route. Rietveld refinement of x-ray diffraction pattern confirms the phase purity of all the samples with rhombohedral crystal structure. The Mn dopant modulates not only superexchange angle near to the boundary of magnetic blocks but also magnetic transition temperature. Temperature-dependent magnetization data suggests that due to Mn doping at Fe sites, ferrimagnetic to proper screw transition temperature (T II) increases from 190 K to 208 K, while there is a decrease in proper screw to longitudinal conical spin transition temperature (T I) from 35 K to 25 K. We observe remarkable decrease in the magnetic field from 20 kOe to 12 kOe to produce intermediate spin ordering from ferrimagnetic ordering which can be understood because of modification of superexchange angle due to Mn doping. The value of loss tangent decreases with increasing doping concentration at 300K, i.e. ~60% and 180% in BMFM4 (x = 0.04) and BMFM8 (x = 0.08) respectively as compared to BMF, suggesting the evolution of intrinsic feature in the doped samples. Magnetodielectric (MD) effect shows that in the low-frequency regime, the robust MD effect is because of Maxwell-Wagner interfacial polarization, whereas in the high-frequency regime intrinsic effect dominates. Further, magnetoimpedance measurement confirms the presence of substantial intrinsic MD% (~6%) at 1.3 T applied field at 300 K for 4% Mn-doped sample. Finally, the nature and strength of magnetoelectric coupling in BMFM4 and BMFM8 samples at 300 K is found to be biquadratic (P 2 M 2) and maximum strength of coupling is 3.09 × 10-4 emu2 g-2 and 2.34 × 10-4 emu2 g-2, respectively.

Autosegmentation of the rectum on megavoltage image guidance scans.

Autosegmentation of image guidance (IG) scans is crucial for streamlining and optimising delivered dose calculation in radiotherapy. By accounting for interfraction motion, daily delivered dose can be accumulated and incorporated into automated systems for adaptive radiotherapy. Autosegmentation of IG scans is challenging due to poorer image quality than typical planning kilovoltage computed tomography (kVCT) systems, and the resulting reduction of soft tissue contrast in regions such as the pelvis makes organ boundaries less distinguishable. Current autosegmentation solutions generally involve propagation of planning contours to the IG scan by deformable image registration (DIR). Here, we present a novel approach for primary autosegmentation of the rectum on megavoltage IG scans acquired during prostate radiotherapy, based on the Chan-Vese algorithm. Pre-processing steps such as Hounsfield unit/intensity scaling, identifying search regions, dealing with air, and handling the prostate, are detailed. Post-processing features include identification of implausible contours (nominally those affected by muscle or air), 3D self-checking, smoothing, and interpolation. In cases where the algorithm struggles, the best estimate on a given slice may revert to the propagated kVCT rectal contour. Algorithm parameters were optimised systematically for a training cohort of 26 scans, and tested on a validation cohort of 30 scans, from 10 patients. Manual intervention was not required. Comparing Chan-Vese autocontours with contours manually segmented by an experienced clinical oncologist achieved a mean Dice Similarity Coefficient of 0.78 (SE < 0.011). This was comparable with DIR methods for kVCT and CBCT published in the literature. The autosegmentation system was developed within the VoxTox Research Programme for accumulation of delivered dose to the rectum in prostate radiotherapy, but may have applicability to further anatomical sites and imaging modalities.

TLR7 Agonism Accelerates Disease and Causes a Fatal Myeloproliferative Disorder in NZM 2410 Lupus Mice.

Murine models of lupus, both spontaneous and inducible, are valuable instruments to study SLE pathogenesis. Accelerants such as Type I IFN are often used to trigger earlier disease onset. We used a topical TLR7 agonist, previously reported to induce lupus-like disease in WT mice within weeks, to validate this data in C57BL/6j mice, and to test TLR7 agonism as an accelerant in lupus-prone NZM2410 mice. We found that TLR7-stimulated B6 and NZM2410 mice had significantly reduced survival and exhibited profound splenomegaly with significantly reduced B cells (4 vs. 40%), and T cells (8 vs. 31%). Spleen pathology and IHC revealed massive expansion of F4/80+ cells in TLR7-treated mice consistent with histiocytosis. While resiqimod treatment caused mild autoimmunity in B6 mice and accelerated autoimmunity in NZM2410 mice, it did not cause significant nephritis or proteinuria in either strain (renal function intact at death). Given the macrophage expansion, cytopenias, and disruption of normal splenic lymphoid follicle architecture, histiocytic sarcoma is favored as the cause of death. An alternative etiology is a macrophage activation syndrome (MAS)-like syndrome, since the mice also had a transaminitis and histologic hemophagocytosis in the setting of their rapid mortality. For investigators who are focused on murine models of lupus nephritis, this model is not ideal when utilizing B6 mice, however topical resiqimod may prove useful to accelerate autoimmunity and nephritis in NZM2410 mice, or potentially to investigate secondary complications of lupus such as histiocytic diseases or macrophage activation like syndromes.

Novel mechanism for estrogen receptor alpha modulation of murine lupus.

Female sex is a risk factor for lupus. Sex hormones, sex chromosomes and hormone receptors are implicated in the pathogenic pathways in lupus. Estrogen receptor alpha (ERα) knockout (KO) mice are used for defining hormone receptor effects in lupus. Prior studies of ERα KO in lupus have conflicting results, likely due to sex hormone levels, different lupus strains and different ERα KO constructs. Our objective was to compare a complete KO of ERα vs. the original functional KO of ERα (expressing a short ERα) on disease expression and immune phenotype, while controlling sex hormone levels. We studied female lupus prone NZM2410 WT and ERα mutant mice. All mice (n = 44) were ovariectomized (OVX) for hormonal control. Groups of each genotype were estrogen (E2)-repleted after OVX. We found that OVXed NZM mice expressing the truncated ERα (ERα short) had significantly reduced nephritis and prolonged survival compared to both wildtype and the complete ERαKO (ERα null) mice, but surprisingly only if E2-repleted. ERα null mice were not protected regardless of E2 status. We observed significant differences in splenic B cells and dendritic cells and a decrease in cDC2 (CD11b+CD8-) dendritic cells, without a concomitant decrease in cDC1 (CD11b-CD8a+) cells comparing ERα short to ERα null or WT mice. Our data support a protective role for the ERα short protein. ERα short is similar to an endogenously expressed ERα variant (ERα46). Modulating its expression/activity represents a potential approach for treating female-predominant autoimmune diseases.

A new mark-recapture approach for abundance estimation of social species.

Accurate estimates of population abundance are a critical component of species conservation efforts in order to monitor the potential recovery of populations. Capture-mark-recapture (CMR) is a widely used approach to estimate population abundance, yet social species moving in groups violate the assumption of CMR approaches that all individuals in the population are detected independently. We developed a closed CMR model that addresses an important characteristic of group-living species-that individual-detection probability typically is conditional on group detection. Henceforth termed the Two-Step model, this approach first estimates group-detection probability and then-conditional on group detection-estimates individual-detection probability for individuals within detected groups. Overall abundance is estimated assuming that undetected groups have the same average group size as detected groups. We compared the performance of this Two-Step CMR model to a conventional (One-Step) closed CMR model that ignored group structure. We assessed model sensitivity to variation in both group- and individual-detection probability. Both models returned overall unbiased estimates of abundance, but the One-Step model returned deceptively narrow Bayesian confidence intervals (BCI) that failed to encompass the correct population abundance an average 52% of the time. Contrary, under the Two-Step model, CI coverage was on average 96%. Both models had similar root mean squared errors (RMSE), except for scenarios with low group detection probability, where the Two-Step model had much lower RMSE. For illustration with a real data set, we applied the Two-Step and regular model to non-invasive genetic capture-recapture data of mountain gorillas (Gorilla beringei beringei). As with simulations, abundance estimates under both models were similar, but the Two-Step model estimate had a wider confidence interval. Results support using the Two-Step model for species living in constant groups, particularly when group detection probability is low, to reduce risk of bias and adequately portray uncertainty in abundance estimates. Important sources of variation in detection need to be incorporated into the Two-Step model when applying it to field data.

Older Age, Early Symptoms and Physical Function are Associated with the Severity of Late Symptom Clusters for Men Undergoing Radiotherapy for Prostate Cancer.

AIMS: To identify symptom clusters and predisposing factors associated with long-term symptoms and health-related quality of life after radiotherapy in men with prostate cancer. MATERIALS AND METHODS: Patient-reported outcomes (PROs) data from the Medical Research Council RT01 radiotherapy with neoadjuvant androgen deprivation therapy trial of 843 patients were used. PROs were collected over 5 years with the University of California, Los Angeles Prostate Cancer Index (UCLA-PCI) and the 36 item Short-Form Health Survey (SF-36). Symptom clusters were explored using hierarchical cluster analysis. The association of treatment dose, baseline patient characteristics and early symptom clusters with the change in severity of PROs over 3 years was investigated with multivariate linear mixed effects models. RESULTS: Seven symptom clusters of three or more symptoms were identified. The clusters were stable over time. The longitudinal profiles of symptom clusters showed the onset of acute symptoms during treatment for all symptom clusters and significant recovery by 6 months. Some clusters, such as physical health and sexual function, were adversely affected more than others by androgen deprivation therapy, and were less likely to return to pretreatment levels over time. Older age was significantly associated with decreased long-term physical function, physical health and sexual function (P < 0.001). Both baseline and acute symptom clusters were significant antecedents for impaired function and health-related quality of life at 3 years. CONCLUSIONS: Men with poorer physical function and health before or during treatment were more likely to report poorer PROs at year 3. Early assessment using PROs and lifestyle interventions should be used to identify those with higher needs and provide targeted rehabilitation and symptom management.

Re-irradiation in the Brain: Primary Gliomas.

Recurrence of gliomas is a challenging clinical scenario to treat. There has historically been reluctance among neuro-oncologists to consider re-irradiation owing to concerns regarding toxicity, including the risk of radionecrosis. This overview examines the evidence behind re-irradiation, which is predominately from single institution case series. The development, validation and modification of the Combs prognostic score are outlined. Published data on both fractionated radiotherapy and stereotactic radiosurgery suggest that it has an acceptable safety profile as long as the cumulative total dose normalised to 2 Gy/fraction (NTDcumulative) is limited to 100 Gy. There is limited evidence on combining systemic therapy with re-irradiation, but bevacizumab seems to be well tolerated and may reduce the radionecrosis risk. We conclude with three key recommendations: use of the Combs prognostic score to select appropriate patients; increased adoption of re-irradiation in the era of modern precision radiotherapy; use of either fractionated radiotherapy or stereotactic radiosurgery depending on tumour size and location to a maximum NTDcumulative of 100 Gy.