Management of Extranodal Marginal Zone Lymphoma: Present and Upcoming Perspectives

Extranodal marginal zone lymphoma (EMZL) encompasses a subgroup of non-Hodgkin lymphomas that often present with localized involvement and may manifest in a diversity of organs and tissues. EMZL pathogenesis is in some cases linked to chronic inflammation/infection, which may impose additional diagnostic and clinical challenges. The most studied and established connection is the presence of Helicobacter pylori in gastric EMZL. Due to its heterogeneity of presentation and intricate pathological features, treatment can be complex, and staging systems are decisive for the choice of therapy. Nevertheless, there is no consensus regarding the most suitable staging system, and recommendations vary among different countries. As a rule of thumb, in limited stages, a local therapy with surgery or radiation is the preferred option, and it is potentially curative. Of note, eradicating the causal agent may be an important step of treatment, especially in gastric EMZL, in which Helicobacter pylori eradication remains the first-line therapy for the majority of patients. In patients with more advanced stages, watch-and-wait is a valuable option, especially amongst those without clear indications for systemic therapy, and it may be carried on for several years. If watch-and-wait is not an option, systemic therapy may be needed. Even though several agents have been tested as monotherapy or in combination in recent years, there is no consensus regarding the first-line therapy, and decisions can vary depending on individual factors, such as age, clinical performance and stage. This review aims to discuss the several aspects of EMZL, including genetic milieu, pathogenesis and staging systems, that may influence the choice of therapy. In addition, we present a summary of evidence of several systemic therapies, compare different recommendations worldwide and discuss future perspectives and novelties in its therapy

Advances in Lymphoma Molecular Diagnostics

Lymphomas encompass a diverse group of malignant lymphoid neoplasms. Over recent years much scientific effort has been undertaken to identify and understand molecular changes in lymphomas, resulting in a wide range of genetic alterations that have been reported across all types of lymphomas. As many of these changes are now incorporated into the World Health Organization’s defined criteria for the diagnostic evaluation of patients with lymphoid neoplasms, their accurate identification is crucial. Even if many alterations are not routinely evaluated in daily clinical practice, they may still have implications in risk stratification, treatment, prognosis or disease monitoring. Moreover, some alterations can be used for targeted treatment. Therefore, these advances in lymphoma molecular diagnostics in some cases have led to changes in treatment algorithms. Here, we give an overview of and discuss advances in molecular techniques in current clinical practice, as well as highlight some of them in a clinical context

Vitamin D Enhances Immune Effector Pathways of NK Cells Thus Providing a Mechanistic Explanation for the Increased Effectiveness of Therapeutic Monoclonal Antibodies

Patients with diffuse large cell lymphoma who have an adequate vitamin D supply derive significantly more benefit from immuno-chemotherapy with rituximab than patients with vitamin D deficiency; this is especially true for female patients. We have already been able to show that vitamin D increases the antibody-dependent cytotoxicity (ADCC) of NK cells in a sex-dependent manner, but it is unclear how vitamin D makes NK cells more efficient. Methods: Healthy individuals with vitamin D deficiency were supplemented with vitamin D to sufficient levels. NK cells were isolated from blood samples before and after vitamin D saturation. For transcriptome analysis, we used the Affymetrix Gene-Chip 2.0™. Gene expression analysis as well as supervised and unsupervised pathway analysis were performed. Results: Among others the “NK cell-associated cytotoxicity pathway” increased after vitamin D substitution. Five IFN-α subtypes (2, 4, 6, 7 and 10) and IFN-κ were more highly expressed and are mainly responsible in these pathways. In contrast, the pathway “interferon-gamma response”, as well as other sets in cytokine production and chemotaxis showed a reduction. Toll-like receptor genes (TLR-8, TLR-7, TLR-2) were downregulated and, therefore, are responsible for the decline of these pathways. The same could be shown for the “ubiquitin-ligase” pathway. Conclusions: Increased expression of several IFN-α subtypes may explain the increased ADCC of NK cells in vitamin D-replenished and otherwise healthy subjects. Other regulators of interferon production and ADCC are compensatory upregulated in compensation, such as Toll-like receptors and those of the ubiquitin ligase, and normalize after vitamin D substitution

B-cell receptor reactivity against Rothia mucilaginosa in nodular lymphocyte-predominant Hodgkin lymphoma

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a Hodgkin lymphoma expressing functional B-cell receptors (BCR). Recently, we described a dual stimulation model of IgD+ lymphocyte-predominant cells by Moraxella catarrhalis antigen RpoC and its superantigen MID/hag, associated with extralong CDR3 and HLA-DRB1*04 or HLADRB1*07 haplotype. The aim of the present study was to extend the antigen screening to further bacteria and viruses. The fragment antibody-binding (Fab) regions of seven new and 15 previously reported cases were analyzed. The reactivity of non-Moraxella spp.-reactive Fab regions against lysates of Rothia mucilaginosa was observed in 5/22 (22.7%) cases. Galactofuranosyl transferase (Gltf) and 2,3-butanediol dehydrogenase (Bdh) of R. mucilaginosa were identified by comparative silver- and immuno-staining in two-dimensional gels, with subsequent mass spectrometry and validation by western blots and enzyme-linked immunosorbent assay. Both R. mucilaginosa Gltf and Bdh induced BCR pathway activation and proliferation in vitro. Apoptosis was induced by recombinant Gltf/ETA’-immunotoxin conjugates in DEV cells expressing recombinant R. mucilaginosa-reactive BCR. Reactivity against M. catarrhalis RpoC was confirmed in 3/7 newly expressed BCR (total 10/22 reactive to Moraxella spp.), resulting in 15/22 (68.2%) cases with BCR reactivity against defined bacterial antigens. These findings strengthen the hypothesis of bacterial trigger contributing to subsets of NLPHL

Humorale und Zelluläre Immunantwort von Patienten mit COVID-19

Die von SARS-CoV-2 ausgelöste Erkrankung COVID-19 führte seit dem erstmaligen Auftreten in Wuhan 2019 zu einer anhaltenden Pandemie und bisher mehreren Millionen Toten. Frühzeitig gab es Hinweise auf schwere Dysregulationen des Immunsystems in Folge der Infektion. Die Pathogenese der durch SARS-CoV2 ausgelösten Komplikationen ist noch nicht vollständig geklärt. In dieser Arbeit berichten wir über die Analyse des zellulären Immunstatus, der Verhältnisse der Immunzell-Populationen zueinander, Monozyten Subpopulationen, Immunglobuline und klinische Charakteristika von Patienten mit COVID-19, die von April 2020 bis Juli 2020 auf einer Intensivstation (ICU) (N = 23) und einer Normalstation (NCU) (n = 10) behandelt wurden, im Vergleich zu zwei Kontrollgruppen: Diese bestanden ersten aus Patienten, die aus nicht-infektiösen Gründen auf der ICU behandelt wurden (n = 30) und zweiten aus Patienten, die wegen anderer Infektionen als COVID-19 auf der NCU behandelt wurden (n = 21). Patienten mit COVID-19 auf ICU wiesen im Vergleich zu den anderen Kohorten signifikante Unterschiede auf, darunter eine niedrigere Zahl an Lymphozyten, eine geringere Anzahl von CD8+ T-Zellen, einen geringeren Prozentsatz aktivierter und intermediärer Monozyten und ein erhöhtes B/T8-Zellverhältnis. Die verstorbenen Patienten mit COVID-19 auf der ICU wiesen eine geringere Anzahl von B-, T-, CD4+ T-, CD8+ T-Lymphozyten, NK-Zellen und aktivierten Monozyten auf. Das B/T8-Verhältnis zeigte sich in der Gruppe der Patienten, die COVID-19 überlebten signifikant erniedrigt. In Patienten mit COVID-19 auf ICU wurden signifikant höhere IgG1 und IgG3 Werte festgestellt, während Patienten mit COVID-19 auf NCU im Vergleich zu Patienten, die wegen anderen Infektionen als mit SARS-CoV2 auf einer NCU behandelt wurden, erhöhte Werte von IgG3 aufwies. Zusammenfassend neben vielen anderen Veränderungen des Immunsystems wurden ein erhöhtes B/T8-Zell-Verhältnis und eine geringere Anzahl aktivierter Monozyten vor allem bei Patienten mit schwerem COVID-19 beobachtet. Beide Parameter waren in Patienten mit COVID-19 auf ICU mit einem erhöhten Sterberisiko assoziiert.Cellular and humoral immune response in patients with COVID-19 The disease caused by SARS-CoV-2 – COVID-19 – initiated a persistent pandemic since its first case in Wuhan in 2019, being responsible for millions of deaths. Already in the earlier phases of the pandemics there were signs of a severe immune dysregulation following the infection. The pathogenesis of complications caused by SARS-CoV2 has not been fully elucidated. In this work, we report of the analysis of cellular immune status, ratios of immune cell populations, monocyte subpopulations, immunoglobulins and clinical characteristics of patients with COVID-19 treated in an intensive care unit (ICU) (cohort 1, N = 23) and a normal care unit (NCU) (cohort 2, n = 10) compared with control groups: patients treated in the ICU for non-infectious reasons (cohort 3, n = 30) and patients treated in the NCU for infections other than COVID-19 (cohort 4, n = 21). Patients in cohort 1 had significant differences compared to the other cohorts, including lower lymphocyte counts, lower CD8+ T cell counts, lower percentages of activated and intermediate monocytes, and increased B/T8 cell ratios. The deceased patients in cohort 1 had lower numbers of B, T, CD4+ T lymphocytes, CD8+ T lymphocytes, NK cells, and activated monocytes. The B/T8 ratio was found to be significantly decreased in the group of patients who survived COVID-19. Cohort 1 showed significantly higher IgG1 and IgG3 levels, while cohort 2 showed increased levels of IgG3 compared with patients treated for infections other than SARS-CoV2 in an NCU. Among many other immune system changes, an increased B/T8 cell ratio and a lower number of activated monocytes were observed in patients with severe COVID-19. Both parameters were associated with an increased risk of death in cohort 1

Advances in Lymphoma Molecular Diagnostics

Lymphomas encompass a diverse group of malignant lymphoid neoplasms. Over recent years much scientific effort has been undertaken to identify and understand molecular changes in lymphomas, resulting in a wide range of genetic alterations that have been reported across all types of lymphomas. As many of these changes are now incorporated into the World Health Organization’s defined criteria for the diagnostic evaluation of patients with lymphoid neoplasms, their accurate identification is crucial. Even if many alterations are not routinely evaluated in daily clinical practice, they may still have implications in risk stratification, treatment, prognosis or disease monitoring. Moreover, some alterations can be used for targeted treatment. Therefore, these advances in lymphoma molecular diagnostics in some cases have led to changes in treatment algorithms. Here, we give an overview of and discuss advances in molecular techniques in current clinical practice, as well as highlight some of them in a clinical context

New monoclonal antibody biosimilars approved in 2015 in Latin America: Position statement of the Latin American Forum on Biosimilars in biosimilarity, interchangeability and extrapolation of indications

Introduction: The Latin American Forum on Biosimilars (FLAB) is an annual meeting that brings together various stakeholders, including key opinion leaders, the pharmaceutical industry, academics, patients, lawyers and other healthcare professionals, to present and discuss recent findings regarding biosimilars. In 2015, the meeting theme was interchangeability and automatic substitution. Regarding biosimilarity, interchangeability and extrapolation of indications, the discussion centred on two products in Brazil and Argentina: CT-P13, an infliximab biosimilar; and RTXM83, a rituximab biosimilar. Here, we conduct a critical analysis of the available scientific and medical information on these products to establish a FLAB position statement in the context of the current regulations in Brazil and Argentina. Biosimilarity, interchangeability and extrapolation of indications: RTXM83 is still not approved in Brazil and is currently under a technology transfer agreement. In Argentina, the drug was approved for commercialization under the name Novex, with extrapolation of indications for rheumatoid arthritis, which according to the Argentinian Society of Rheumatology, lacks the necessary clinical data for such an approval. CT-P13 is already approved in Brazil, and is on the market. The approval was based on the data presented in the PLANETAS and PLANETRA studies. Interchangeability will not be considered for this product until further studies are presented. Discussion: Based on the available evidence, CT-P13 is the only biological molecule marketed in Latin America that can be considered a true biosimilar. Extrapolation is only acceptable when the diseases for which the reference product is intended to treat are entirely similar. Extrapolation based on only preclinical studies is not acceptable. Conversely, although the proposed rituximab biosimilar (RTXM83) was approved by ANMAT (National Administration for Medicines, Food and Medical Technology) in Argentina, clinical data demonstrating its equivalence with the reference rituximab, is necessary before RTXM83 can be considered a true biosimilar.Fil: Feijó Azevedo, Valderilio. Universidade Federal do Paraná; Brasil. Health Research and Educational Center; BrasilFil: Babini, Alejandra. Hospital Italiano Córdoba; Argentina. Sociedad Argentina de Reumatología; ArgentinaFil: Vieira Teixeira, Fabio. Clínica Gastrosaude de Marilia; Brasil. Grupo de Estudos de Doença Inflamatória Intestinal; BrasilFil: Age Kos, Igor. Universidade Federal do Paraná; Brasil. Health Research and Educational Center; BrasilFil: Matar, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario; Argentin

The biosimilars journey: current status and ongoing challenges

Biosimilar products are already approved and marketed in several countries. The Food and Drug Administration has approved ten different biosimilars, and the European Medicines Agency has approved 40. Even though this scenario has provided important experience with biosimilar products, there are still challenges and unanswered questions. Up to now, a good amount of knowledge has been gathered in order to support the importance of the totality of evidence and the construction of a biosimilarity exercise for regulatory approval. In addition, the extrapolation of indications has been proved viable when a careful analysis is performed. The models for clinical trials and the use of the most sensible populations have been extensively discussed, and there is apparent homogeneity in manufacturer choices for study designs. However, some challenges remain. The lack of regulatory harmony, especially concerning naming, the marketed intended copies, the interchangeability, and the biosimilars in orphan diseases are some of those and are the focus of discussion in this review

Autoantibodies against SUMO1-DHX35 in long-COVID

Long COVID is a collection of symptoms as a late sequelae of SARS-CoV-2 infection. It often includes mental symptoms such as cognitive symptoms, persisting loss of smell and taste, in addition to exertional dyspnea. A role of various autoantibodies (autoAbs) has been postulated in long-COVID and is being further investigated. With the goal of identifying potentially unknown autoAbs, we screened plasma of patients with long COVID on in-house post-translationally modified protein macroarrays including citrullinated, SUMOylated and acetylated membranes. SUMO1ylated isoform DEAD/H (Asp-Glu-Ala-Asp/His) box helicase 35 (SUMO1-DHX35) was identified as only candidate antigen. In adult patients with long COVID, IgG autoAbs against SUMO1-DHX35 of IgG class were found in seven of 71 (9.8%) plasma samples, of IgM and IgG class in one of 69 (1.4%) samples, not in 200 healthy adult controls, not in 442 healthy children, and 146 children after SARS-CoV-2 infection. All autoAb-positive seven patients were female. AutoAb titers ranged between 200 to up to 400 By point mutagenesis and expression of FLAG-tagged mutants of DHX35 in HEK293 cells, and subsequent SUMOylation of purified constructs, lysine 53 was identified as a unique, never yet identified, SUMOylation site. The autoAbs had no reactivity against the non-SUMO1ylated mutant (K53R) of DHX35. To summarize, autoAbs against SUMO1-DHX35 were identified in adult female patients with long-COVID. Further studies are needed to verify the frequency of occurrence. The function of DHX35 has not yet been determined and there is no available information in relation to disease implication. The molecular mechanism causing the SUMOylation, the potential functional consequences of this post-translational modification on DHX35, and a potential pathogenicity of the autoAbs against SUMO1-DHX35 in COVID-19 and other possible contexts remain to be elucidated