Late stillbirth due to listeriosis

Listeriosis is a sporadic infectious disease, which affects high-risk populations, such as the elderly, pregnant women, newborns, and immunocompromised patients. During pregnancy, listeriosis usually presents like a mild non-specific infection, but it may be responsible for fetal loss, preterm labor, early onset neonatal sepsis, and neonatal death. We report the case of a late stillbirth secondary to maternal chorioamnionitis. Listeria monocytogenes was isolated from the amniotic fluid and the fetal pleural fluid. The fetal autopsy revealed a disseminated inflammatory response with multi-organ involvement. This case illustrates the importance of the prevention and the diagnosis of listeriosis during gestation and may help us to understand the physiopathology of fetal loss due to listeriosis

Prognostic Role of the Expression of Latent-Membrane Protein 1 of Epstein-Barr Virus in Classical Hodgkin Lymphoma

The prognostic impact of the presence of Epstein-Barr virus (EBV) in classical Hodgkin lymphoma (cHL) is controversial. Previous studies reported heterogeneous results, rendering difficult the clinical validation of EBV as a prognostic biomarker in this lymphoma. The objective of this study was to evaluate the survival impact of the expression of EBV Latent-Membrane Protein 1 (EBV-LMP1) in tumoral Hodgkin-Reed-Sternberg (HRS) cells of primary diagnostic samples of cHL. Formalin-Fixed Paraffin-Embedded (FFPE) lymph node samples from 88 patients with cHL were analyzed. Patients were treated with the standard first-line chemotherapy (CT) with Adriamycin, Bleomycin, Vinblastine and Dacarbazine (ABVD) followed by radiotherapy. The Kaplan-Meier method and the Cox proportional hazards model were used for carrying out the survival analysis. In order to investigate whether the influence of EBV was age-dependent, analyses were performed both for patients of all ages and for age-stratified subgroups. In bivariate analysis, the expression of EBV was associated with older age (p = 0.011), mixed cellularity subtype cHL (p < 0.001) and high risk International Prognostic Score (IPS) (p = 0.023). Overall survival (OS) and progression-free survival (PFS) were associated with the presence of bulky disease (p = 0.009) and advanced disease at diagnosis (p = 0.016). EBV-positive cases did not present a significantly lower OS and PFS in comparison with EBV-negative cases, for all ages and when stratifying for age. When adjusted for covariates, absence of bulky disease at diagnosis (HR: 0.102, 95% CI: 0.02-0.48, p = 0.004) and limited disease stages (I-II) (HR: 0.074, 95% CI: 0.01-0.47, p = 0.006) were associated with a significant better OS. For PFS, limited-disease stages also retained prognostic impact in the multivariate Cox regression (HR: 0.145, 95% CI: 0.04-0.57, p = 0.006). These results are of importance as the early identification of prognostic biomarkers in cHL is critical for guiding and personalizing therapeutic decisions. The prognostic role of EBV in cHL could be modulated by the type of CT protocol employed and interact with the rest of presenting features

Assessment of a New ROS1 Immunohistochemistry Clone (SP384) for the Identification of ROS1 Rearrangements in Patients with Non–Small Cell Lung Carcinoma: the ROSING Study

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm

New European union regulations related to whole slide image scanners and image analysis software

Whole slide imaging (WSI) scanners and automatic image analysis algorithms, in order to be used for clinical applications, including primary diagnosis in pathology, are subject to specific regulatory frameworks in each country. Until May 25, 2018, in the European Union (EU), in vitro diagnostic (IVD) medical devices were regulated by directive 98/79/EC (in vitro diagnostic medical device directive [IVDD]). Main scanner vendors have obtained a Conformité Européenne mark of their products that in Europe were classified as General Class IVDD, so that conformity is only based on a self-declaration of the manufacturer. This contrasts with the initial classification of the US Food and Drug Administration (FDA) of WSI system as Class III medical devices, although the first digital pathology WSI system to be cleared by FDA was classified as Class II, with special controls. Other digital pathology solutions (automated cervical cytology slide reader) are considered of higher risk by US and European regulations. There is also some disparity in the classification of image analysis solutions between Europe and the United States. All IVD-MDs must be approved under the new European regulation (in vitro diagnostic medical device regulation) 2017/746 after May 26, 2024. This means the need of a performance evaluation, including a scientific validity report, an analytical performance report, and a clinical performance report. According to its clinical use (e.g., screening, diagnosis, or staging of cancer), a WSI slide scanner can be now classified as Class C device. A special regulation is applied to companion diagnostics. The new EU regulation 2017/746 contemplates the use of standard unique identifiers for medical devices and the creation of a European database on medical devices (Eudamed). Existing validation studies and clinical guidelines already available in the literature are a sound basis to avoid that this new regulation becomes a barrier for digital pathology development in Europe

Whole-slide image analysis identifies a high content of Hodgkin Reed-Sternberg cells and a low content of T lymphocytes in tumor microenvironment as predictors of adverse outcome in patients with classic Hodgkin lymphoma treated with ABVD.

Classic Hodgkin lymphoma (cHL) constitutes the most frequent lymphoma in young adults. Its histopathology is unique as a scattered tumor population, termed Hodgkin Reed-Sternberg (HRS) cells is diluted in a prominent tumor microenvironment (TME) composed of T lymphocytes, B lymphocytes, macrophages, neutrophils, eosinophils and histiocytes. Traditionally, the identification of prognostic biomarkers in the cHL TME has required visual inspection and manual counting by pathologists. The advent of whole-slide imaging (WSI) and digital image analysis methods could significantly contribute to improve this essential objective in cHL research, as a 10-20% of patients are still refractory or relapsed after conventional chemotherapy. In this work, we have digitized a total of 255 diagnostic cHL slides and quantified the proportion of HRS cells (CD30), B cells (CD20) and T cells (CD3) by digital image analysis. Data obtained where then correlated with the overall survival (OS) and progression free survival (PFS) of cHL patients. Quantification of HRS cells, B cells and T cells reflects the biological heterogeneity of the different cHL histological subtypes analyzed. A percentage of 2.00% of HRS cells statistically significantly discriminated between patients achieving a complete metabolic response (CMR) and refractory or relapsed (R/R) patients both for the OS (P=0.001) and PFS (P=0.005). Furthermore, patients with a percentage of T cells below the 26.70% in the TME showed a statistically significantly shorter OS (P=0.019) and PFS (P=0.041) in comparison with patients above this threshold. A subgroup of patients with a low content of T cells and high content of HRS cells exhibited a special aggressive clinical course. Currently, there is the need to implement quantitative and easy scalable methods to enhance clinical translation, as the cHL TME plays a central role in the clinical course of the disease. The results of this study could contribute to the identification of prognostic biomarkers specifically looking at the cHL TME and their inclusion in future clinical trials

Pathogenic Variants Associated with Epigenetic Control and the NOTCH Pathway Are Frequent in Classic Hodgkin Lymphoma

Classic Hodgkin lymphoma (cHL) constitutes a B-cell neoplasm derived from germinal center lymphocytes. Despite high cure rates (80–90%) obtained with the current multiagent protocols, a significant proportion of cHL patients experience recurrences, characterized by a lower sensitivity to second-line treatments. The genomic background of chemorefractory cHL is still poorly understood, limiting personalized treatment strategies based on molecular features. In this study, using a targeted next-generation sequencing (NGS) panel specifically designed for cHL research, we compared chemosensitive and chemorefractory diagnostic tissue samples of cHL patients. Furthermore, we longitudinally examined paired diagnosis–relapsesamples of chemorefractory cHL in order to define patterns of dynamic evolution and clonal selection. Pathogenic variants in NOTCH1 and NOTCH2 genes frequently arise in cHL. Mutations in genes associated with epigenetic regulation (CREBBP and EP300) are particularly frequent in relapsed/refractory cHL. The appearance of novel clones characterized by mutations previously not identified at diagnosis is a common feature in cHL cases showing chemoresistance to frontline treatments. Our results expand current molecular and pathogenic knowledge of cHL and support the performance of molecular studies in cHL prior to the initiation of first-line therapies

The Need for Standardization in Next-Generation Sequencing Studies for Classic Hodgkin Lymphoma: A Systematic Review.

Classic Hodgkin lymphoma (cHL) constitutes a B cell-derived neoplasm defined by a scarce tumoral population, termed Hodgkin and Reed-Sternberg (HRS) cells, submerged into a histologically heterogeneous microenvironment. The paucity of HRS cells has historically hampered genetic studies, rendering the identification of the recurrent genetic lesions and molecular pathways deregulated in this lymphoma difficult. The advent of high-throughput sequencing methods such as next-generation sequencing (NGS) could sensibly optimize the identification of the mutational landscape of cHL. However, there is no current consensus either in the design of panels for targeted NGS or in its most relevant clinical applications. In this work, we systematically review the current state of NGS studies of cHL, stressing the need for standardization both in the candidate genes to be analyzed and the bioinformatic pipelines. As different institutions have developed and implemented their own customized NGS-based protocols, to compare and systematically review the major findings of this ongoing research area could be of added value for centers that routinely perform diagnostic, monitoring and genotyping strategies in cHL samples. The results of this systematic review should contribute to the interdepartmental harmonization and achievement of a consensus in the current clinical applications of NGS studies of cHL

La mejora de la competencia emocional en Educación Primaria y Secundaria dentro de las clases de Educación Física

Resumen basado en el de la publicación.El objetivo principal del proyecto es la mejora de la competencia emocional en Educación Física, basándose en las habilidades sociales y empatía como representantes de la competencia emocional interpersonal. Los resultados obtenidos, en general, son satisfactorios en referencia a los objetivos establecidos. Debido a que tras la aplicación del programa de intervención, las puntuaciones medias obtenidas en la mayoría de los factores estudiados son superiores en relación con la toma inicial, tanto en función de sexo como en función de la etapa educativa al que fue dirigido, a excepción del factor Asertividad.Consejería de Educación, Cultura y Deportes de Castilla-La ManchaCastilla La ManchaES

Assessment of a new ROS1 immunohistochemistry clone (SP384) for the identification of ROS1 rearrangements in patients with non-small cell lung carcinoma: the ROSING study

Introduction: The ROS1 gene rearrangement has become an important biomarker in NSCLC. The College of American Pathologists/International Association for the Study of Lung Cancer/Association for Molecular Pathology testing guidelines support the use of ROS1 immunohistochemistry (IHC) as a screening test, followed by confirmation with fluorescence in situ hybridization (FISH) or a molecular test in all positive results. We have evaluated a novel anti-ROS1 IHC antibody (SP384) in a large multicenter series to obtain real-world data. Methods: A total of 43 ROS1 FISH-positive and 193 ROS1 FISH-negative NSCLC samples were studied. All specimens were screened by using two antibodies (clone D4D6 from Cell Signaling Technology and clone SP384 from Ventana Medical Systems), and the different interpretation criteria were compared with break-apart FISH (Vysis). FISH-positive samples were also analyzed with next-generation sequencing (Oncomine Dx Target Test Panel, Thermo Fisher Scientific). Results: An H-score of 150 or higher or the presence of at least 70% of tumor cells with an intensity of staining of 2+ or higher by the SP384 clone was the optimal cutoff value (both with 93% sensitivity and 100% specificity). The D4D6 clone showed similar results, with an H-score of at least 100 (91% sensitivity and 100% specificity). ROS1 expression in normal lung was more frequent with use of the SP384 clone (p < 0.0001). The ezrin gene (EZR)-ROS1 variant was associated with membranous staining and an isolated green signal FISH pattern (p = 0.001 and p = 0.017, respectively). Conclusions: The new SP384 ROS1 IHC clone showed excellent sensitivity without compromising specificity, so it is another excellent analytical option for the proposed testing algorithm