The Grey Zones of Classic Hodgkin Lymphoma

Simple Summary Classic Hodgkin lymphoma (CHL) is a well-defined lymphoid neoplasm with a minority of characteristic neoplastic cells of B cell origin, namely Hodgkin and Reed-Sternberg cells immersed in a rich reactive inflammatory infiltrate in the background. Although CHL has always been set apart from non-Hodgkin lymphomas, cases with morphological and phenotypic features intermediate between CHL and other lymphomas have been described. Whereas some of these lymphomas only represent morphological mimics, others exhibit mutational and gene expression profiles which overlap with CHL, indicating that these cases, frequently termed grey zone lymphomas, reside on the biological boundary between CHL and large B-cell lymphomas. In the present review, we aim to describe the current knowledge of these rare lymphomas, address diagnostic issues and summarize today's concepts on the classification of grey zone lymphomas and related tumors. Classic Hodgkin lymphoma (CHL) is a well-defined neoplasm characterized by the presence of a minority of pathognomonic Hodgkin and Reed-Sternberg (HRS) cells in a reactive inflammatory background. Although genotypically of B cell origin, HRS cells exhibit a downregulated B cell program and therefore are set apart from other B cell lymphomas in the current WHO classification. However, cases with morphological and phenotypic features overlapping with CHL have been recognized, and the category of B cell lymphoma-unclassifiable-with features intermediate between diffuse large B cell lymphoma (DLBCL) and CHL, also termed grey zone lymphoma, was first introduced into the WHO classification in 2008 as provisional entity. These cases, as well as others raising a differential diagnosis of CHL can present diagnostic problems, as well as therapeutic challenges. Whereas some of these lymphomas only represent biologically unrelated morphological mimics, others, especially mediastinal grey zone lymphoma, exhibit genetic and gene expression profiles which overlap with CHL, indicating a true biological relationship. In this review, we address areas of diagnostic difficulties between CHL and other lymphoma subtypes, discuss the biological basis of true grey zone lymphoma based on recent molecular studies and delineate current concepts for the classification of these rare tumors

Between Participatory Approaches and Politics, Promoting Social Innovation in Smart Cities: Building a Hum–Animal Smart City in Lucca

In recent decades, the interest in social innovation and nature-based solutions has spread in scientific articles, and they are increasingly deployed for cities’ strategic planning. In this scenario, participatory approaches become pivotal to engaging the population and stakeholders in the decision- making process. In this paper, we reflect on the first year’s results and the strengths and weaknesses— of the participatory activities realized in Lucca to co-design and co-deploy a smart city based on human–animal relationships in the framework of the European project Horizon 2020 (IN-HABIT). Human–animal bonds, as nature-based solutions, are scientifically and practically underestimated. Data were collected on the activities organized to implement a public–private–people partnership in co-designing infrastructural solutions (so-called Animal Lines) and soft nature-based solutions to be implemented in the city. Stakeholders actively engaged in mutual discussions with great enthusiasm, and the emergent ideas (the need to improve people’s knowledge of animals and develop a map showing pet-friendly services and places and the need for integration to create innovative pet services) were copious and different while showing many connections among the various points of view. At the same time, a deeper reflection on the relationships among the participatory activities and institutionally integrated arrangements also emerged

IGHV mutational status of nodal marginal zone lymphoma by NGS reveals distinct pathogenic pathways with different prognostic implications

The precise B cell of origin and molecular pathogenesis of nodal marginal zone lymphoma (NMZL) remain poorly defined. To date, due to the rarity of NMZL, the vast majority of already-published studies have been conducted on a limited number of samples and the technical approach to analyze the immunoglobulin genes was of amplifying rearranged variable region genes with the classical direct sequencing of the PCR products followed by cloning. Here, we studied the B cell Ig heavy-chain repertoires by next-generation sequencing (NGS) in 30 NMZL cases. Most of the cases were mutated (20/28; 71.5%) with homologies to the respective germ line genes ranging from 85 to 97, 83%, whereas 8/28 (28.5%) were unmutated. In addition, our results show that NMZL cases have a biased usage of specific immunoglobulin heavy-chain variable (IGHV) region genes. Moreover, we documented intraclonal diversity in all (100%) of the mutated cases and ongoing somatic hypermutations (SHM) have been confirmed by hundreds of reads. We analyzed the mutational pattern to detect and quantify antigen selection pressure and we found a positive selection in 4 cases, whereas in the remaining cases there was an unspecific stimulation. Finally, the disease-specific survival and the progression-free survival were significantly different between cases with mutated and unmutated IGHV genes, pointing out mutational status as a possible new biomarker in NMZL

p66Shc deficiency in the Eμ-TCL1 mouse model of chronic lymphocytic leukemia enhances leukemogenesis by altering the chemokine receptor landscape

The Shc family adaptor p66Shc acts as a negative regulator of proliferative and survival signals triggered by the B Cell Receptor and, by enhancing the production of reactive oxygen species, promotes oxidative stress-dependent apoptosis. Additionally, p66Shc controls the expression and function of chemokine receptors that regulate lymphocyte traffic. Chronic lymphocytic leukemia cells have a p66Shc expression defect which contributes to their extended survival and correlates with poor prognosis. We have analyzed the impact of p66Shc ablation on disease severity and progression in the mouse model of chronic lymphocytic leukemia Eμ-TCL1. We show that Eμ-TCL1/p66Shc-/- mice develop an aggressive disease that has an earlier onset, a higher incidence and leads to earlier death compared to Eμ-TCL1 mice. Eμ-TCL1/p66Shc-/- mice display substantial leukemic cell accumulation in both nodal and extranodal sites. The target organ selectivity correlates with an upregulation of chemokine receptors whose ligands are expressed therein. This also applies to chronic lymphocytic leukemia cells, where chemokine receptor expression and extent of organ infiltration were found to inversely correlate with their p66Shc expression levels. p66Shc expression declined with disease progression in Eμ-TCL1 mice and could be restored by treatment with the Bruton tyrosine kinase inhibitor Ibrutinib. Our results highlight p66Shc deficiency as an important factor in chronic lymphocytic leukemia progression and severity and underscore p66Shc expression as a relevant therapeutic target

How future surgery will benefit from SARS-COV-2-related measures: a SPIGC survey conveying the perspective of Italian surgeons

COVID-19 negatively affected surgical activity, but the potential benefits resulting from adopted measures remain unclear. The aim of this study was to evaluate the change in surgical activity and potential benefit from COVID-19 measures in perspective of Italian surgeons on behalf of SPIGC. A nationwide online survey on surgical practice before, during, and after COVID-19 pandemic was conducted in March-April 2022 (NCT:05323851). Effects of COVID-19 hospital-related measures on surgical patients' management and personal professional development across surgical specialties were explored. Data on demographics, pre-operative/peri-operative/post-operative management, and professional development were collected. Outcomes were matched with the corresponding volume. Four hundred and seventy-three respondents were included in final analysis across 14 surgical specialties. Since SARS-CoV-2 pandemic, application of telematic consultations (4.1% vs. 21.6%; p < 0.0001) and diagnostic evaluations (16.4% vs. 42.2%; p < 0.0001) increased. Elective surgical activities significantly reduced and surgeons opted more frequently for conservative management with a possible indication for elective (26.3% vs. 35.7%; p < 0.0001) or urgent (20.4% vs. 38.5%; p < 0.0001) surgery. All new COVID-related measures are perceived to be maintained in the future. Surgeons' personal education online increased from 12.6% (pre-COVID) to 86.6% (post-COVID; p < 0.0001). Online educational activities are considered a beneficial effect from COVID pandemic (56.4%). COVID-19 had a great impact on surgical specialties, with significant reduction of operation volume. However, some forced changes turned out to be benefits. Isolation measures pushed the use of telemedicine and telemetric devices for outpatient practice and favored communication for educational purposes and surgeon-patient/family communication. From the Italian surgeons' perspective, COVID-related measures will continue to influence future surgical clinical practice

Genetic and Viral landscape in B-Cell Lymphomas : Insights on the EBV Role and Associated Shifts in The Tumour Microenviroment.

The cellular milieau in which lymphoma cells thrive has solely recently become a relevant focus of investigation. The functions of what was belived to be passive bystanders are rapidly becoming elucidated in order to explore potential targets for immunotherapy. Albeit our comprehension of cytogenetic abnormalities and molecular pathways in lymphoma are in advance of solid organ tumors, the same cannot be asserted of the tumor microenvironment. Viruses, being obligate parasites, are under continuous burden in order to survive in front of strong host immune responses. To preserve a replicative advantage , they employ manifold tricks to turn themselves immunologically undetectable. Indeed , EBV may actively reshape lymphoma microenvironment, which is coming into view as a pivotal constituent of the tumor. This talent is at least to some extent due to the elegant strategy evolved by this herpes virus to establish a latent infection in memory B lymphocytes. In point of fact , EBV orchestrates a variety of complex mechanisms facilitating the escape of lymphoma cells from anti-tumor immune responses while sustaining the creation of niches in which tumor cells may survive and prosper. Enlightenment of the contribution of tumor microenvironment in lymphomagenesis is providing the fabric for detecting and validating new therapies that aim both lymphoma cells and crucial microenvironmental components

Genetic and Viral landscape in B-Cell Lymphomas : Insights on the EBV Role and Associated Shifts in The Tumour Microenviroment.

The cellular milieau in which lymphoma cells thrive has solely recently become a relevant focus of investigation. The functions of what was belived to be passive bystanders are rapidly becoming elucidated in order to explore potential targets for immunotherapy. Albeit our comprehension of cytogenetic abnormalities and molecular pathways in lymphoma are in advance of solid organ tumors, the same cannot be asserted of the tumor microenvironment. Viruses, being obligate parasites, are under continuous burden in order to survive in front of strong host immune responses. To preserve a replicative advantage , they employ manifold tricks to turn themselves immunologically undetectable. Indeed , EBV may actively reshape lymphoma microenvironment, which is coming into view as a pivotal constituent of the tumor. This talent is at least to some extent due to the elegant strategy evolved by this herpes virus to establish a latent infection in memory B lymphocytes. In point of fact , EBV orchestrates a variety of complex mechanisms facilitating the escape of lymphoma cells from anti-tumor immune responses while sustaining the creation of niches in which tumor cells may survive and prosper. Enlightenment of the contribution of tumor microenvironment in lymphomagenesis is providing the fabric for detecting and validating new therapies that aim both lymphoma cells and crucial microenvironmental components