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.

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.

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.

Objective: Brazil was strongly affected by the COVID-19 pandemic. Its continental dimension and socio-demographic characteristics pose challenges to distribution and accessibility, making vaccination programs challenging. The objectives of the study were to describe the clinical and demographic characteristics of the general population vaccinated against COVID-19 by October 2021 and analyze the strategies implemented during the vaccination program. Study design and setting: A retrospective nationwide study that analyzed data from the OpenDataSUS platform of the Informatics Department of the Brazilian Ministry of Health (DataSUS), which contains information from all individuals in Brazil who have received at least one dose of any vaccine against COVID-19 approved by the National Health Agency (ANVISA) from 17 January to 3 October 2021. Results: Until 3 October, a total of 146,254,578 persons (68.6 per 100 inhabitants) received at least one dose of a vaccine in Brazil. The north and northeast regions had the lowest vaccination rates compared with the remaining regions (North: 56.8, Northeast: 62.0, South: 74.4, and Southeast: 73.2 per 100 inhabitants). Elderly individuals had the highest vaccination rates, particularly those above 70 years old. Heterologous dosing regimens were administered to 1,063,079 individuals (0.7% of those receiving the first dose). Conclusions: The COVID-19 vaccination program reached more than two-thirds of the population in Brazil by 9 months after its start, but the vaccination coverage was heterogeneous, reflecting the country’s geographic and socio-demographic characteristics. Establishing priority groups for vaccination was a main characteristic of the vaccination strategy. In addition, technology transfer agreements have played an important role in increasing vaccine accessibility.

Cytomegalovirus (CMV) reactivation after stem cell or solid organ transplantation remains a major cause of morbidity and mortality in this setting. T-cell receptor (TCR)-like antibodies bind to intracellular peptides presented in major histocompatibility complex (MHC) molecules on the cell surface and may have the potential to replace T-cell function in immunocompromised patients. Three previously selected CMV-specific, human leukocyte antigen (HLA)-restricted (HLA-A*0101, HLA-A*0201 and HLA-B*0702) Fab-antibodies (A6, C1 and C7) were produced as IgG antibodies with Fc optimization. All antibodies showed specific binding to CMV peptide-loaded tumor cell lines and primary fibroblasts expressing the corresponding MHC-I molecules, leading to specific target cell lysis after the addition of natural killer (NK) cells. When deployed in combination as an antibody pool against target cells expressing more than one matching HLA allele, cytotoxic effects were amplified accordingly. CMV-specific TCR-like antibodies were also able to mediate their cytotoxic effects through neutrophils, which is important considering the delayed recovery of NK cells after stem cell transplantation. When tested on patient blood obtained during CMV reactivation, CMV-specific antibodies were able to bind to and induce cytotoxic effects in lymphocytes. CMV-specific TCR-like antibodies may find application in patients with CMV reactivation or at risk of CMV reactivation. In contrast to previous HLA/peptide-directed therapeutic approaches, the concept of a TCR-like antibody repertoire covering more than one HLA allele would make this therapeutic format available to a much larger group of patients.

While novel cellular and immune-based therapies have fundamentally reshaped oncology, they have also introduced a complex new spectrum of immune-mediated adverse events. 1,2 Management of these toxicities frequently relies on corticosteroidbased regimens, which can be effective and lead to symptom control. 1,2 However, this strategy has important drawbacks: steroids may dampen the anti-tumour efficacy of immune-based therapies, and steroid-induced immunosuppression increases the infection risk and may adversely affect non-relapse morbidity and mortality. 3 These challenges underscore the need for rigorous post-marketing surveillance of advanced therapeutic medicinal products, as well as focused clinical and translational efforts to describe rare and unexpected adverse events and develop tools for early recognition, risk stratification, and optimal management of recurrent and clinically significant toxicities.Immunotherapies and Cell Therapies: A Deeper Evaluation of Advanced Therapeutic Medicinal Products", these issues are addressed from complementary perspectives.Immune checkpoint inhibitors (ICIs) have improved survival across a broad spectrum of malignancies and are nowadays currently standard of care in multiple therapeutic settings. At the same time, they have introduced new immune-mediated toxicities. 4 Cutaneous adverse events are among the most frequent and usually manageable, but in rare cases, severe, life-threatening reactions such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) can occur. 2 In their systematic review, Zhou et al. describe 50 patients reported in 47 publications. They report a mortality of 20%, with infections and tumour progression as leading causes of death, likely reflecting treatment-related immunosuppression. 5 Events typically occurred early (median 23 days after ICI initiation), and death followed a median of 28 days after onset. Poor outcome was associated with TEN phenotype and larger body surface area involvement, while dual ICI therapy correlated with a higher rate of TEN than monotherapy. 5 Corticosteroids and intravenous immunoglobulins were the most frequently used treatments, but in this small cohort, no regimen showed clear superiority. These findings underscore the need for vigilant early monitoring and better therapeutic strategies for suspected ICI-related SJS/TEN. 5 Bispecific antibodies (BsAbs) have rapidly expanded the therapeutic armamentarium options for relapsed or refractory B-cell lymphomas, offering potent T-cell-redirecting activity. 6,7 As their use becomes routine, a systematic understanding of their toxicity spectrum has become essential to optimizing outcomes. The review by Doig and Yannakou provides a comprehensive synthesis of the acute and delayed adverse events (AEs)AEs associated with currently approved BsAbs. Cytokine release syndrome (CRS) remains the most common AE, typically manifesting early and predominantly in low-grade, yet requiring vigilant risk-adapted mitigation strategies. 8 The manuscript underscores how step-up dosing, premedication, and standardized intervention algorithms have improved the safety without compromising efficacy. 8 Neurotoxicity, including immune-effector cell-associated neurotoxicity syndrome (ICANS), although ocurringoccurring less frequently than with CAR -T cell therapy, remains present. 8 The authors reinforce the importance of early recognition and The CRS Map, published on the MINERVA platform, encompasses 24 cell types, 425 entities and 430 interactions, and can be interactively explored and used for data visualization and network analyses, including the overlay of clinical cytokine datasets. 9 This explorable resource supports hypothesis generation, biomarker discovery, and future in silico modelingmodelling that may inform CRS management, prediction, and prevention.Persistent cytopenias following CAR -T cell therapy pose a challenge to clinicians and patients, as it becomes especially important to manage its their consequences: infection, bleeding, and anaemia. Predictive tools can help identify patients at higher risk of developing cytopenias. The CAR-HEMATOTOX is a simple bedside score composed of biomarkers representing a poor haematopoietic reserve (haemoglobin, platelet-and neutrophil count) and inflammatory stressors on marrow function (ferritin and C-reactive protein, CRP). 10 This score has been shown to predict the depth and length of neutropenia, infectious complications 11 and even progression-free survival (PFS) and overall survival (OS). 12 In this issue, Lesan and colleagues further validate this score in an independent German cohort, across multiple CAR -T products. 13 Despite being a small study, the authors identify key predictors of cytopenias following CAR -T cell therapy. In particular, early thrombocytopenia and neutropenia at the time of CRS were strongly associated with CAR-HEMATOTOX, especially pre-existing thrombocytopenia. 13 This is important as this is the timepoint when patients receive immunosuppression for CRS but would equally be at risk of developing infections. In the later phase, high CAR-HEMATOTOX was associated with anaemia. Although the study did not confirm an association between CAR-HEMATOTOX and PFS or OS, the message findings supports using the CAR-HEMATOTOX score prior to infusion and referencing it in post-infusion clinical decision-making.Taken together, this issue brings together essential insights on immune-related adverse events across multiple domains, including real-world evidence, integrative systems approaches, and systematic literature review. As treatments become more complex, pharmacovigilance and high-quality reporting remain crucial to improve our understanding of the safety profiles of novel mechanisms of action, with the potential to ultimately influence patient outcomes. In parallel, a deeper understanding of the underlying mechanisms of these toxicities can inform clinical decision-making and...