Mepolizumab decreases tissue eosinophils while increasing type-2 cytokines in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis is an often treatment-resistant inflammatory disease mediated by type-2 cytokines, including interleukin (IL)-5. Mepolizumab, a monoclonal antibody drug targeting IL-5, has demonstrated efficacy and safety in inflammatory airway disease, but there is negligible evidence on direct tissue response. The study's aim was to determine the local effect of mepolizumab on inflammatory biomarkers in sinonasal tissue of eosinophilic chronic rhinosinusitis patients. METHODS: Adult patients with eosinophilic chronic rhinosinusitis received 100mg mepolizumab subcutaneously at four-weekly intervals for 24 weeks in this prospective phase 2 clinical trial. Tissue eosinophil counts, eosinophil degranulation (assessed as submucosal eosinophil peroxidase deposition by immunohistochemistry) and cytokine levels (measured in homogenates by immunoassay) were evaluated in ethmoid sinus tissue biopsies collected at baseline and at weeks 4, 8, 16 and 24. RESULTS: Twenty patients (47.7 ± 11.7 years, 50% female) were included. Sinonasal tissue eosinophil counts decreased after 24 weeks of treatment with mepolizumab (101.64 ± 93.80 vs 41.74 ± 53.76 cells per 0.1 mm2 ; p = .035), eosinophil degranulation remained unchanged (5.79 ± 2.08 vs 6.07 ± 1.20, p = .662), and type-2 cytokine levels increased in sinonasal tissue for IL-5 (10.84 ± 18.65 vs 63.98 ± 50.66, p = .001), IL-4 (4.48 ± 3.77 vs 9.38 ± 7.56, p = .004), IL-13 (4.02 ± 2.57 vs 6.46 ± 3.99, p = .024) and GM-CSF (1.51 ± 1.74 vs 4.50 ± 2.97, p = .001). CONCLUSION: Mepolizumab reduced eosinophils in sinonasal tissue, demonstrating that antagonism of IL-5 suppresses eosinophil trafficking. With reduced tissue eosinophils, a local type-2 inflammatory feedback loop may occur. The study exposes mechanistic factors which may explain incomplete treatment response.

Harnessing the disruption on medical trainee education due to COVID-19 in New South Wales, Australia.

The coronavirus disease (COVID-19) pandemic has caused disruption and uncertainty for junior medical doctor training and education. This has compounded the existing stress experienced by this cohort. However, by choosing appropriate educational models, as well as using novel educational approaches and advancing our online technology capabilities, we may be able to provide acceptable and even, superior solutions for educational training moving forward, as well as promote trainee wellbeing during these uncertain times.

Digital pathology: semper ad meliora.

This review is an evidence-based summary of digital pathology: past, present and future. It discusses digital surgical pathology and the cytopathology digitisation challenge as well as the performance of digital histopathology and cytopathology as a diagnostic tool, particularly in contrast to user perceptions. Time and cost efficiency of digital pathology, learning curves, education and quality assurance, with the importance of validation of systems, is emphasised. The review concludes with a discussion of digital pathology as a source of 'big data' and where this might lead pathologists in the digital pathology future.

Constant Quest for Quality: Digital Cytopathology.

BACKGROUND: Special consideration should be given when creating and selecting cytopathology specimens for digitization to maximize quality. Advances in scanning and viewing technology can also improve whole-slide imaging (WSI) output quality. METHODS: Accumulated laboratory experience with digitization of glass cytopathology slides was collected. RESULTS: This paper describes characteristics of a cytopathology glass slide that can reduce quality on resulting WSI. Important points in the glass cytopathology slide selection process, preparation, scanning, and WSI-editing process that will maximize the quality of the resulting acquired digital image are covered. The paper outlines scanning solutions which have potential to predict issues with a glass cytopathology slide before image acquisition, allowing for adjustment of the scanning approach. WSI viewing solutions that better simulate the traditional microscope experience are also discussed. CONCLUSION: In addition to taking advantage of technical advances, practical steps can taken to maximize quality of cytopathology WSI.

Cytopathology whole slide images and adaptive tutorials for senior medical students: a randomized crossover trial.

BACKGROUND: Diagnostic cytopathology is an essential part of clinical decision-making. However, due to a combination of factors including curriculum reform and shortage of pathologists to teach introductory cytopathology, this area of pathology receives little or no formal attention in most medical school curricula. We have previously described the successful use of efficient and effective digital learning resources, including whole slide images (WSI) and virtual microscopy adaptive tutorials (VMATs), to teach cytopathology to pathology specialist trainees - a group that had prior exposure to cytopathology in their day to day practice. Consequently, in the current study we attempted to demonstrate the efficiency and efficacy of this eLearning resource in a cohort of senior medical students that was completely naïve to the subject matter (cytopathology). METHODS: We evaluated both the quantitative and qualitative impact of these digital educational materials for learning cytopathology compared with existing resources (e-textbooks and online atlases). The senior medical students were recruited from The University of New South Wales Australia for a randomized cross-over trial. Online assessments, administered after each arm of the trial, contained questions which related directly to a whole slide image. Two categories of questions in the assessments (focusing on either diagnosis or identification of cellular features) were utilized to determine efficacy. User experience and perceptions of efficiency were evaluated using online questionnaires containing Likert scale items and open-ended questions. RESULTS: For this cohort of senior medical students, virtual microscopy adaptive tutorials (VMATs) proved to be at least as effective as existing digital resources for learning cytopathology. Importantly, virtual microscopy adaptive tutorials had superior efficacy in facilitating accurate diagnosis on whole slide images. Student perceptions of VMATs were positive, particularly regarding the immediate feedback, interactivity and equity of learning which this learning resource provides. CONCLUSIONS: Virtual microscopy adaptive tutorials have the potential to improve the efficacy of learning microscopic pathology for medical students. The enhanced learning experience provided by these eLearning tools merits further investigation of their utility for other cohorts, including specialist trainees.

Cytopathology whole slide images and virtual microscopy adaptive tutorials: A software pilot.

BACKGROUND: The constant growth in the body of knowledge in medicine requires pathologists and pathology trainees to engage in continuing education. Providing them with equitable access to efficient and effective forms of education in pathology (especially in remote and rural settings) is important, but challenging. METHODS: We developed three pilot cytopathology virtual microscopy adaptive tutorials (VMATs) to explore a novel adaptive E-learning platform (AeLP) which can incorporate whole slide images for pathology education. We collected user feedback to further develop this educational material and to subsequently deploy randomized trials in both pathology specialist trainee and also medical student cohorts. Cytopathology whole slide images were first acquired then novel VMATs teaching cytopathology were created using the AeLP, an intelligent tutoring system developed by Smart Sparrow. The pilot was run for Australian pathologists and trainees through the education section of Royal College of Pathologists of Australasia website over a period of 9 months. Feedback on the usability, impact on learning and any technical issues was obtained using 5-point Likert scale items and open-ended feedback in online questionnaires. RESULTS: A total of 181 pathologists and pathology trainees anonymously attempted the three adaptive tutorials, a smaller proportion of whom went on to provide feedback at the end of each tutorial. VMATs were perceived as effective and efficient E-learning tools for pathology education. User feedback was positive. There were no significant technical issues. CONCLUSION: During this pilot, the user feedback on the educational content and interface and the lack of technical issues were helpful. Large scale trials of similar online cytopathology adaptive tutorials were planned for the future.

Cytopathology whole slide images and adaptive tutorials for postgraduate pathology trainees: a randomized crossover trial.

To determine whether cytopathology whole slide images and virtual microscopy adaptive tutorials aid learning by postgraduate trainees, we designed a randomized crossover trial to evaluate the quantitative and qualitative impact of whole slide images and virtual microscopy adaptive tutorials compared with traditional glass slide and textbook methods of learning cytopathology. Forty-three anatomical pathology registrars were recruited from Australia, New Zealand, and Malaysia. Online assessments were used to determine efficacy, whereas user experience and perceptions of efficiency were evaluated using online Likert scales and open-ended questions. Outcomes of online assessments indicated that, with respect to performance, learning with whole slide images and virtual microscopy adaptive tutorials was equivalent to using traditional methods. High-impact learning, efficiency, and equity of learning from virtual microscopy adaptive tutorials were strong themes identified in open-ended responses. Participants raised concern about the lack of z-axis capability in the cytopathology whole slide images, suggesting that delivery of z-stacked whole slide images online may be important for future educational development. In this trial, learning cytopathology with whole slide images and virtual microscopy adaptive tutorials was found to be as effective as and perceived as more efficient than learning from glass slides and textbooks. The use of whole slide images and virtual microscopy adaptive tutorials has the potential to provide equitable access to effective learning from teaching material of consistently high quality. It also has broader implications for continuing professional development and maintenance of competence and quality assurance in specialist practice.

Angiotropism is an independent predictor of local recurrence and in-transit metastasis in primary cutaneous melanoma.

The migration of melanoma cells along the external surface of blood vessels (angiotropism) has recently been proposed as a mechanism for melanoma metastasis (termed extravascular migratory metastasis). To determine whether the presence of angiotropism, as seen in the routine hematoxylin and eosin sections of primary cutaneous melanomas (PCMs), predicts the development of local or in-transit melanoma recurrence, 32 patients with a PCM who developed local or in-transit recurrence were matched for Breslow thickness with 59 "control" patients with a PCM who did not. The slides from both groups of patients were analyzed in a "blinded" manner for evidence of angiotropism. Other histologic and clinical variables were also assessed. Angiotropism was found more often in patients who developed local or in-transit recurrence (cases) compared with those patients who did not (controls) (P=0.02). Variables that showed a statistically significant association with angiotropism on univariate analysis were: increasing Breslow thickness (P<0.0001), greater Clark level (P<0.001), increasing mitotic index (P<0.0001), presence of ulceration (P<0.01), and absence of regression (P<0.05). The median disease-free survival was 72 months for patients with angiotropism and 104 months for those without (P=0.02). On multivariate analysis the presence of angiotropism was an independent predictor of decreased disease-free survival (P=0.02). This is the first reported study to identify a statistically significant association between the development of local or in-transit recurrence of PCM and the histologic presence of angiotropism and that angiotropism is an independent predictor of decreased disease-free survival, as far as we are aware. Our findings support the hypothesis that angiotropism represents a pathogenic mechanism for metastasis in patients with PCM.