PRAME Immunohistochemistry for Distinguishing Vulvar and Vaginal Melanoma From Benign Melanocytic Nevi.

Vulvovaginal melanoma (VVM) is a rare but deadly disease, accounting for 5% of all vulvar malignancies, with a 5-yr survival rate of only 47% for all stages of the disease. VVM is a distinct subset of melanoma, with a unique genomic profile and underlying pathogenesis unassociated with sun exposure. Distinguishing these rare malignancies from very common pigmented lesions of the vulva and vagina is challenging as histologic features often overlap between entities. PReferentially expressed Antigen in MElanoma (PRAME) is a melanoma-associated protein, and immunohistochemistry (IHC) for PRAME distinguishes cutaneous, oral mucosal, and retinal melanoma from atypical nevi. Given the biological differences between VVM and cutaneous melanoma, the utility of PRAME IHC for the diagnosis of VVM is unknown. We accrued a cohort of 20 VVM and 21 benign vulvar melanocytic nevi. We found that nuclear PRAME IHC staining with 4+ intensity was present in 85% of the VVM and 0% of the nevi. With the assistance of PRAME IHC, we found evidence of close or positive margin involvement in 3 of 10 cases where margins were originally diagnosed as negative for melanoma in situ. Our study is the first to assess PRAME IHC in a cohort of VVM cases and provides confidence for using PRAME IHC to assist with diagnosis and margin assessment in this rare disease.

Practical Application of Deep Learning in Diagnostic Neuropathology-Reimagining a Histological Asset in the Era of Precision Medicine.

In the past few decades, neuropathology has experienced several paradigm shifts with the introduction of new technologies. Deep learning, a rapidly progressing subfield of machine learning, seems to be the next innovation to alter the diagnostic workflow. In this review, we will explore the recent changes in the field of neuropathology and how this has led to an increased focus on molecular features in diagnosis and prognosis. Then, we will examine the work carried out to train deep learning models for various diagnostic tasks in neuropathology, as well as the machine learning frameworks they used. Focus will be given to both the challenges and successes highlighted therein, as well as what these trends may tell us about future roadblocks in the widespread adoption of this new technology. Finally, we will touch on recent trends in deep learning, as applied to digital pathology more generally, and what this may tell us about the future of deep learning applications in neuropathology.

Preoperative Corticosteroids Reduce Diagnostic Accuracy of Stereotactic Biopsies in Primary Central Nervous System Lymphoma: A Systematic Review and Meta-Analysis.

BACKGROUND AND OBJECTIVES: Despite general acceptance that corticosteroid therapy (CST) should be withheld before biopsy for suspected primary central nervous system lymphoma (PCNSL), there remains conflicting evidence surrounding the precise impact of preoperative CST on the histopathological diagnosis. The objective of this systematic review and meta-analysis was to describe and quantify the effects of preoperative CST on the diagnostic accuracy of biopsies for PCNSL. METHODS: Primary articles were screened from Ovid MEDLINE, Embase, Web of Science, and Scopus databases. Meta-analysis was performed for immunocompetent patients with histologically confirmed PCNSL. Subgroup and regression analyses were performed to assess the effects of biopsy type, CST duration, dose, and preoperative taper on the diagnostic accuracy. In addition, the sensitivity of cerebrospinal fluid (CSF) analyses for PCNSL was assessed. RESULTS: Nineteen studies, comprising 1226 patients (45% female; mean age: 60.3 years), were included. Preoperative CST increased the risk of nondiagnostic biopsy with a relative risk (RR) of 2.1 (95% CI: 1.1-4.1). In the stereotactic biopsy subgroup, the RR for nondiagnostic biopsy was 3.0 (95% CI: 1.2-7.5). CST taper, duration, and dose did not significantly influence diagnostic biopsy rates. The sensitivity of CSF cytology, including flow cytometry, for PCNSL was 8.0% (95% CI: 6.0%-10.7%). CONCLUSION: Our results suggest that preoperative CST reduces the diagnostic yield of stereotactic biopsies for PCNSL. We found no evidence that tapering CST before biopsy improves diagnostic rates. CSF analysis currently has a poor sensitivity for the diagnosis of PCNSL.

Molecular prognostication in grade 3 meningiomas and p16/MTAP immunohistochemistry for predicting CDKN2A/B status.

Background: The World Health Organization 2021 classification introduces molecular grading criteria for anaplastic meningiomas, including TERT promoter (TERTp) mutations and CDKN2A/B homozygous deletion. Additional adverse prognostic factors include H3K27me3 and BAP1 loss. The aim of this study was to explore whether these molecular alterations stratified clinical outcomes in a single-center cohort of grade 3 meningiomas. Additionally, we examined whether p16 and MTAP immunohistochemistry can predict CDKN2A/B status. Methods: Clinical and histopathological information was obtained from the electronic medical records of grade 3 meningiomas resected at a tertiary center between 2007 and 2020. Molecular testing for TERTp mutations and CDKN2A/B copy-number status, methylation profiling, and immunohistochemistry for H3K27me3, BAP1, p16, and methylthioadenosine phosphorylase (MTAP) were performed. Predictors of survival were identified by Cox regression. Results: Eight of 15 cases demonstrated elevated mitotic index (≥20 mitoses per 10 consecutive high-power fields), 1 tumor exhibited BAP1 loss, 4 harbored TERTp mutations, and 3 demonstrated CDKN2A/B homozygous deletion. Meningiomas with TERTp mutations and/or CDKN2A/B homozygous deletion showed significantly reduced survival compared to anaplastic meningiomas with elevated mitotic index alone. Immunohistochemical loss of p16 and MTAP demonstrated high sensitivity (67% and 100%, respectively) and specificity (100% and 100%, respectively) for predicting CDKN2A/B status. Conclusions: Molecular alterations of grade 3 meningiomas stratify clinical outcomes more so than histologic features alone. Immunohistochemical loss of p16 and MTAP show promise in predicting CDKN2A/B status.

Tryptic peptide reference data sets for MALDI imaging mass spectrometry on formalin-fixed ovarian cancer tissues.

MALDI imaging mass spectrometry is a powerful tool for morphology-based proteomic tissue analysis. However, peptide identification is still a major challenge due to low S/N ratios, low mass accuracy and difficulties in correlating observed m/z species with peptide identities. To address this, we have analyzed tryptic digests of formalin-fixed paraffin-embedded tissue microarray cores, from 31 ovarian cancer patients, by LC-MS/MS. The sample preparation closely resembled the MALDI imaging workflow in order to create representative reference data sets containing peptides also observable in MALDI imaging experiments. This resulted in 3844 distinct peptide sequences, at a false discovery rate of 1%, for the entire cohort and an average of 982 distinct peptide sequences per sample. From this, a total of 840 proteins and, on average, 297 proteins per sample could be inferred. To support the efforts of the Chromosome-centric Human Proteome Project Consortium, we have annotated these proteins with their respective chromosome location. In the presented work, the benefit of using a large cohort of data sets was exemplified by correct identification of several m/z species observed in a MALDI imaging experiment. The tryptic peptide data sets generated will facilitate peptide identification in future MALDI imaging studies on ovarian cancer.

From Theory to Practice: Implementing the WHO 2021 Classification of Adult Diffuse Gliomas in Neuropathology Diagnosis.

Diffuse gliomas are the most common type of primary central nervous system (CNS) neoplasm to affect the adult population. The diagnosis of adult diffuse gliomas is dependent upon the integration of morphological features of the tumour with its underlying molecular alterations, and the integrative diagnosis has become of increased importance in the fifth edition of the WHO classification of CNS neoplasms (WHO CNS5). The three major diagnostic entities of adult diffuse gliomas are as follows: (1) astrocytoma, IDH-mutant; (2) oligodendroglioma, IDH-mutant and 1p/19q-codeleted; and (3) glioblastoma, IDH-wildtype. The aim of this review is to summarize the pathophysiology, pathology, molecular characteristics, and major diagnostic updates encountered in WHO CNS5 of adult diffuse gliomas. Finally, the application of implementing the necessary molecular tests for diagnostic workup of these entities in the pathology laboratory setting is discussed.

A Research Translation, Implementation and Impact Strategy for the Australian Healthy Environments and Lives (HEAL) Research Network.

Healthy Environments And Lives (HEAL) is the Australian national research network established to support improvements to health, the Australian health system, and the environment in response to the unfolding climate crisis. The HEAL Network comprises researchers, community members and organisations, policymakers, practitioners, service providers, and other stakeholders from diverse backgrounds and sectors. HEAL seeks to protect and improve public health, reduce health inequities and inequalities, and strengthen health system sustainability and resilience in the face of environmental and climate change, all with a commitment to building on the strengths, knowledge, wisdom, and experience of Aboriginal and Torres Strait Islander people, culture, and communities. Supporting applied research that can inform policy and practice, and effective research translation, implementation, and impact are important goals across the HEAL Network and essential to achieve its intended outcomes. To aid translation approaches, a research translation, implementation, and impact strategy for the HEAL Network was developed. The strategy has been created to inform and guide research translation across HEAL, emphasising communication, trust, partnerships, and co-design with communities and community organisations as well as the decision-makers responsible for public policies and programs. Development of the strategy was guided by research translation theory and practice and the Health in All Policies and Environment in All Policies frameworks. As described in this paper, the strategy is underpinned by a set of principles and outlines preliminary actions which will be further expanded over the course of the HEAL Network's activities. Through these actions, the HEAL Network is well-positioned to ensure successful research translation and implementation across its program of work.

Deciphering the molecular nature of ovarian cancer biomarker CA125.

The ovarian cancer biomarker CA125 has been extensively investigated over the last 30 years. The knowledge about the exact molecular nature of this protein, however, remains fragmented. This review provides an overview of the structural research regarding CA125, and presents an orthogonal verification method to confirm the identity of this molecule. The need for independent identification of CA125 is exemplified by several reports where mutually exclusive data concerning the existence of isoforms and the glycan moieties is presented. Mass spectrometry can overcome the pitfalls of a single detection/identification method such as antibody probing. Independent verification of CA125 identity in characterization studies will help establish a refined model of its molecular structure that will promote the development of new approaches for diagnosis, prognosis and therapy of ovarian cancer.

Exploring the immunoproteome for ovarian cancer biomarker discovery.

Most scientific efforts towards early detection of ovarian cancer are commonly focused on the discovery of tumour-associated antigens (TAA). Autologous antibodies against TAA, however, may serve as more sensitive diagnostic markers. They circulate in the blood before TAA and are usually more abundant than the TAAs themselves as a result of amplification through the humoral immune response. Accumulating evidence also suggests that a humoral response already exists during malignant transformation when aberrant gene expression is translated into premalignant cellular changes. This article reviews the current knowledge about autoantibodies against TAA in ovarian cancer and presents current immunoproteomic approaches for their detection.

Fatores associados a condição física ativa em pacientes com hipertensão arterial sistêmica: Um estudo transversal / Factors associated with active physical condition in hypertensive patients: A cross sectional study

O exercício físico é uma intervenção não farmacológica que pode colaborar para o controle dos valores pressóricos em pacientes hipertensos, sendo este recomendado por diretrizes internacionais e nacionais. Entretanto, a adesão de pacientes hipertensos a programas de exercício físico ainda está longe do ideal. Assim, o objetivo do presente estudo foi determinar os fatores que podem influenciar um estilo de vida ativo em pacientes hipertensos. Participaram do estudo oitenta e sete (87) indivíduos diagnosticados clinicamente com hipertensão arterial sistêmica que aceitaram participar de forma voluntária. Os pacientes foram submetidos a dois questionários que abordavam as características socioeconômicas, demográficas, tempo de diagnóstico da doença, conhecimento sobre a ação benéfica do exercício físico na hipertensão arterial sistêmica; bem como caracterizavam o nível de atividade física dos pacientes (IPAq). A partir dos resultados do IPAq, os pacientes foram dicotomizados em ativos ou sedentários. O teste de qui-quadrado demonstrou associação significante entre a condição física e o fator idade, sexo, tempo de diagnóstico de hipertensão arterial sistêmica e ser estimulado a praticar exercícios físicos por um profissional da área da saúde. Após a inserção dos fatores significantes na regressão logística binária univariada, os resultados demonstraram que os fatores: idade maior que 55 anos (OR bruta=2,27), ser estimulado por um profissional da área da saúde, (OR bruta=0,169) e ser homem (OR bruta=2,95) eram preditores da condição física ativa do paciente hipertenso. Por sua vez, a análise multivariada demonstrou que apenas os fatores idade (OR ajustada=12,43) e ser estimulado por um profissional da área da saúde a praticar exercício físico (OR ajustada=-2,21) continuavam preditores da condição hipertensa ativa. Os dados do presente estudo apresentam indícios que pacientes hipertensos com mais de 55 anos que são estimulados por profissionais da área da saúde a praticar exercícios físicos apresentam mais chance de serem fisicamente ativos.(AU)

Physical exercise is a non-pharmacological approach recommended by national and international guidelines from health care associations, to collaborate with blood pressure control in hypertensive people. However, hypertensive patients adherence to physical exercise programs is far from the ideal. Thus, the aim of the present study is determine the factors associated with active physical condition in hypertensive patients. Eighty-seven (87) clinically diagnosed patients with hypertension were recruited to participate in this study. Patients were underwent to two questionnaires. The first-one recorded socio economic and demographic characteristics, time since diagnosis and knowledge about the beneficial effects of physical exercise in hypertension; The second questionnaire dichotomized hypertensive people to active or sedentary state (IPAq). Since the classification of physical state, the chi-square test showed significantly association between physical condition and age, gender, time since diagnosis and be encouraged to practice physical exercises by a health professional. Univariate binary logistic regression showed that be older than 55 year (unadjusted OR =2.27), be encouraged to practice physical exercises by a health professional, (unadjusted OR =0,169) and be a man (unadjusted OR =2.95) were predictor factors of the active physical condition in hypertensive patients. In turn, multivariate binary logistic regression showed age (adjusted OR =12, 43) and be encouraged to practice physical exercises by a health professional (adjusted OR =-2.21) as the significantly predictor factor in active hypertensive state. Data of the present study evidenced that hypertensive patients older than 55 years, which are encouraged to practice physical exercises by a health professional, present higher odds ratio to be active physically.(AU)