Zanubrutinib, Obinutuzumab, and Venetoclax for First-Line Treatment of Mantle Cell Lymphoma with a TP53 Mutation.

BACKGROUND: TP53-mutant mantle cell lymphoma (MCL) is associated with poor survival outcomes with standard chemoimmunotherapy. Dual BTK and BCL2-inhibition with or without anti-CD20 monoclonal antibody therapy has shown promising activity in TP53-mutant MCL. We conducted a multi-center phase 2 study of zanubrutinib, obinutuzumab, and venetoclax (BOVen) in untreated MCL patients with TP53 mutation. Patients initially received zanubrutinib 160mg twice daily and obinutuzumab. Obinutuzumab 1000mg was given on cycle 1 day 1, 8, 15 and day 1 of cycles 2-8. After 2 cycles, venetoclax was added with weekly dose-ramp up to 400mg daily. After 24 cycles, if patients were in complete remission with undetectable minimal residual disease using an immunosequencing assay, treatment was discontinued. The primary endpoint was met if ³11 patients were progression free at 2 years. The study included 25 patients with untreated MCL with TP53 mutation. The best overall response rate was 96% (24/25) and the complete response rate was 88% (22/25). Frequency of uMRD5 and uMRD6 at cycle 13 was 95% (18/19) and 84% (16/19). With median follow up of 28.2 months, the primary endpoint was met with a 2-year progression-free survival of 72%, and the 2-year disease-specific and overall survival were 91% and 76%, respectively. Common side effects were generally low grade and included diarrhea (64%), neutropenia (32%), and infusion-related reactions (24%). BOVen was well tolerated and met its primary efficacy endpoint in TP53-mutant mantle cell lymphoma. These data support its use and further evaluation of the BOVen regimen in this high-risk population. NCT03824483.

Hand Hygiene Compliance and Its Associated Factors Among Health Care Workers at Mogadishu Somali Turkiye Recep Tayyip Erdogan Training and Research in a Tertiary Care Hospital.

Background: Hand hygiene is a critical preventive measure for controlling infections, particularly in underdeveloped nations. Materials and Methods: A cross-sectional study was conducted in a hospital in Mogadishu, Somalia, from January to March 2024. This study aimed to assess compliance with hand hygiene practices and related factors among healthcare professionals. Results: The study population comprised 52% men and 47.3% women. Most participants held bachelor's degrees, with the majority being nurses or midwives. A significant proportion had over five years of work experience. Almost all participants were knowledgeable about hand hygiene. Most reported cleaning and drying their hands before, during, and after contact with bodily fluids during aseptic procedures. Age, gender, educational status, marriage, working experience, type of occupation, receiving hand hygiene training and knowledge, and having the availability of water, soap, alcohol, and gloves significantly affected the overall uptake of infection control measures in Mogadishu (p<0.05). Conclusion: The findings highlight an urgent need for targeted interventions to enhance hand hygiene practices in Somalia. Addressing training gaps and resource shortages is crucial for reducing infection rates and safeguarding patient health in this high-risk setting.

Challenges in defining the immune microenvironment in T-cell lymphoma.

Not available.

Lack of SMARCB1 expression characterizes a subset of human and murine peripheral T-cell lymphomas.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous group of malignancies with poor outcome. Here, we identify a subgroup, PTCL-NOSSMARCB1-, which is characterized by the lack of the SMARCB1 protein and occurs more frequently in young patients. Human and murine PTCL-NOSSMARCB1- show similar DNA methylation profiles, with hypermethylation of T-cell-related genes and hypomethylation of genes involved in myeloid development. Single-cell analyses of human and murine tumors revealed a rich and complex network of interactions between tumor cells and an immunosuppressive and exhausted tumor microenvironment (TME). In a drug screen, we identified histone deacetylase inhibitors (HDACi) as a class of drugs effective against PTCL-NOSSmarcb1-. In vivo treatment of mouse tumors with SAHA, a pan-HDACi, triggered remodeling of the TME, promoting replenishment of lymphoid compartments and reversal of the exhaustion phenotype. These results provide a rationale for further exploration of HDACi combination therapies targeting PTCL-NOSSMARCB1- within the TME.

SETD1B mutations confer apoptosis resistance and BCL2 independence in B cell lymphoma.

The translocation t(14;18) activates BCL2 and is considered the initiating genetic lesion in most follicular lymphomas (FL). Surprisingly, FL patients fail to respond to the BCL2 inhibitor, Venetoclax. We show that mutations and deletions affecting the histone lysine methyltransferase SETD1B (KMT2G) occur in 7% of FLs and 16% of diffuse large B cell lymphomas (DLBCL). Deficiency in SETD1B confers striking resistance to Venetoclax and an experimental MCL-1 inhibitor. SETD1B also acts as a tumor suppressor and cooperates with the loss of KMT2D in lymphoma development in vivo. Consistently, loss of SETD1B in human lymphomas typically coincides with loss of KMT2D. Mechanistically, SETD1B is required for the expression of several proapoptotic BCL2 family proteins. Conversely, inhibitors of the KDM5 histone H3K4 demethylases restore BIM and BIK expression and synergize with Venetoclax in SETD1B-deficient lymphomas. These results establish SETD1B as an epigenetic regulator of cell death and reveal a pharmacological strategy to augment Venetoclax sensitivity in lymphoma.

Seroprevalence of hepatitis C, hepatitis B, hiv and syphilis among blood donors at a tertiary care hospital in Mogadishu-Somalia in 2020-2022: a retrospective study.

BACKGROUND: The safety of blood donation requires screening for transfusion-transmitted infections, including human immunodeficiency virus (HIV), syphilis, hepatitis B virus (HBV) and hepatitis C virus (HCV). This study aimed to determine the seroprevalence of HIV, HBV, HCV and syphilis in blood donors of Mogadishu Tertiary Care Hospital, Somalia from 2020 to 2022. METHODS: The records of 109,385 blood donors who attended our blood center in Mogadishu-Somalia between 2020 and 2022 were examined retrospectively. Serum samples of donors; HBsAg, anti-HCV, anti-HIV and syphilisscreening tests were studied using the microparticleEnzyme-Linked ImmunoSorbent Assay (ELISA)(Vitros, Ortho-Clinical Diagnostics, U.S) method.The distribution of HBsAg, anti-HCV, anti-HIV and syphilis positivity rates of 109,385 blood donors according to years, gender and age were examined. Kolmogorov Smirnov, Skewness, Kurtosis tests and histogram were used for normality analysis. Chi-squared test (χ2) and Fisher Exact test were used to analyze categorical data. Categorical variables were expressed as frequency (percentage). Analysis of continuous data was performed with the Mann Whitney U test. P < 0.05 value was considered statistically significant. RESULTS: HBsAg positivity was found in 0.6% of the donors, anti-HCV positivity in 0.01%, anti-HIV positivity in 0.03% and syphilispositivity in 0.3%. The results showed that among the blood donors, the prevalence of syphilis, HIV, Hepatitis B, and Hepatitis Cwas notably low. CONCLUSION: The prevalence of HBV, HCV, HIV, and syphilis among blood donors in Somalia was found to be quite low. Even if our found seroprevalence rates are low, to guarantee the safety of blood for recipients, strict selection of blood donors and thorough screening of donors' blood using accepted procedures are strongly advised.

Temporal Genomic Dynamics Shape Clinical Trajectory in Multiple Myeloma.

To comprehensively unravel the temporal relationship between initiating and driver events and its impact on clinical outcomes, we analyzed 421 whole-genome sequencing profiles from 382 patients. Using clock-like mutational signatures, we estimated a time lag of 2-4 decades between initiating events and diagnosis. In patients with hyperdiploidy, we demonstrate that trisomies of odd-numbered chromosomes can be acquired simultaneously with other chromosomal gains, such as 1q gain. We provide evidence that hyperdiploidy is acquired after canonical IGH translocation when both events are present. Finally, patients with early 1q gain had adverse outcomes similar to those with 1q amplification (>1 extra-copies), but faring worse than those with late 1q gain. This underscores that the prognostic impact of 1q gain/amp depends more on the timing of acquisition than on the number of extra copies gained. Overall, this study contributes to a better understanding of the life history of MM and may have prognostic implications.

Cultural Use and the Knowledge of Ethnomedicinal Plants in the Pülümür (Dersim-Tunceli) Region.

Pülümür has been a refuge place for internal and external exiles several times throughout history, and today it is a district of the province of Tunceli (known as Dersim in the region), which differs significantly from many settlements around it in terms of biodiversity and social aspects. The aim of this study is to identify, catalog, and report the traditional medicinal uses of plants in this province, where every living thing and many natural objects around it are regarded as sacred, with a scientific ethnobotanical approach. The field study was completed between May 2016 and July 2023. The collection of plant excursion and plant usage information was implemented in two stages; in the first stage, a survey about the collection and the uses of medicinal plants was conducted. At this stage, plant samples were collected by visiting 49 villages of the district and performing face-to-face interviews with 112 participants (51 female and 61 male). In the second stage, the usage statistics related to the data obtained from the field studies were determined. For this reason, every informant was interviewed at least twice, people who were previously interviewed were included too. In the course of this study, interviews from 211 participants (95 female and 116 male) were analyzed. As a result of analysis, the traditional medicinal uses of 120 plants belonging to 48 families were identified. The most taxa are identified from the Asteraceae (15), Rosaceae (13), Fabaceae (8), Lamiaceae (8), and Apiaceae (6) families. In Pülümür, these medicinal plants are mostly used for the treatment of wounds, abdominal pain, constipation, and diabetes.

Multiplexed Spatial Profiling of Hodgkin Reed-Sternberg Cell Neighborhoods in Classic Hodgkin Lymphoma.

PURPOSE: Classic Hodgkin lymphoma (cHL) is a B-cell lymphoma that occurs primarily in young adults and, less frequently, in elderly individuals. A hallmark of cHL is the exceptional scarcity (1%-5%) of the malignant Hodgkin Reed-Sternberg (HRS) cells within a network of nonmalignant immune cells. Molecular determinants governing the relationship between HRS cells and their proximal microenvironment remain largely unknown. EXPERIMENTAL DESIGN: We performed spatially resolved multiplexed protein imaging and transcriptomic sequencing to characterize HRS cell states, cellular neighborhoods, and gene expression signatures of 23.6 million cells from 36 newly diagnosed Epstein-Barr virus (EBV)-positive and EBV-negative cHL tumors. RESULTS: We show that MHC-I expression on HRS cells is associated with immune-inflamed neighborhoods containing CD8+ T cells, MHC-II+ macrophages, and immune checkpoint expression (i.e., PD1 and VISTA). We identified spatial clustering of HRS cells, consistent with the syncytial variant of cHL, and its association with T-cell-excluded neighborhoods in a subset of EBV-negative tumors. Finally, a subset of both EBV-positive and EBV-negative tumors contained regulatory T-cell-high neighborhoods harboring HRS cells with augmented proliferative capacity. CONCLUSIONS: Our study links HRS cell properties with distinct immunophenotypes and potential immune escape mechanisms in cHL.

Polytypic B cells, monotypic/monoclonal B-cell proliferations, and neoplastic T cells diverge from TET2-/DNMT3A-mutant clonal hematopoiesis in follicular helper T-cell lymphomas.

Not available.

Intratumoral T-cell composition predicts epcoritamab-based treatment efficacy in B-cell non-Hodgkin lymphomas.

Leveraging endogenous tumor-resident T-cells for immunotherapy using bispecific antibodies (BsAb) targeting CD20 and CD3 has emerged as a promising therapeutic strategy for patients with B-cell non-Hodgkin lymphomas. However, features associated with treatment response or resistance are unknown. To this end, we analyzed data from patients treated with epcoritamab-containing regimens in the EPCORE NHL-2 trial (NCT04663347). We observed downregulation of CD20 expression on B-cells following treatment initiation both in progressing patients and in patients achieving durable complete responses (CR), suggesting that CD20 downregulation does not universally predict resistance to BsAb-based therapy. Single-cell immune profiling of tumor biopsies obtained following one cycle of therapy revealed substantial clonal expansion of cytotoxic CD4+ and CD8+ T-cells in patients achieving CR, and an expansion of follicular helper and regulatory CD4+ T-cells in patients whose disease progressed. These results identify distinct tumor-resident T-cell profiles associated with response or resistance to BsAb therapy.

The biological and clinical impact of deletions before and after large chromosomal gains in multiple myeloma.

ABSTRACT: Acquisition of a hyperdiploid (HY) karyotype or immunoglobulin heavy chain (IgH) translocations are considered key initiating events in multiple myeloma (MM). To explore if other genomic events can precede these events, we analyzed whole-genome sequencing data from 1173 MM samples. By integrating molecular time and structural variants within early chromosomal duplications, we indeed identified pregain deletions in 9.4% of patients with an HY karyotype without IgH translocations, challenging acquisition of an HY karyotype as the earliest somatic event. Remarkably, these deletions affected tumor suppressor genes (TSGs) and/or oncogenes in 2.4% of patients with an HY karyotype without IgH translocations, supporting their role in MM pathogenesis. Furthermore, our study points to postgain deletions as novel driver mechanisms in MM. Using multiomics approaches to investigate their biologic impact, we found associations with poor clinical outcome in newly diagnosed patients and profound effects on both the oncogene and TSG activity despite the diploid gene status. Overall, this study provides novel insights into the temporal dynamics of genomic alterations in MM.

A practical approach to the modern diagnosis and classification of T- and NK-cell lymphomas.

ABSTRACT: T- and natural killer (NK)-cell lymphomas are neoplasms derived from immature T cells (lymphoblastic lymphomas), or more commonly, from mature T and NK cells (peripheral T-cell lymphomas, PTCLs). PTCLs are rare but show marked biological and clinical diversity. They are usually aggressive and may present in lymph nodes, blood, bone marrow, or other organs. More than 30 T/NK-cell-derived neoplastic entities are recognized in the International Consensus Classification and the classification of the World Health Organization (fifth edition), both published in 2022, which integrate the most recent knowledge in hematology, immunology, pathology, and genetics. In both proposals, disease definition aims to integrate clinical features, etiology, implied cell of origin, morphology, phenotype, and genetic features into biologically and clinically relevant clinicopathologic entities. Cell derivation from innate immune cells or specific functional subsets of CD4+ T cells such as follicular helper T cells is a major determinant delineating entities. Accurate diagnosis of T/NK-cell lymphoma is essential for clinical management and mostly relies on tissue biopsies. Because the histological presentation may be heterogeneous and overlaps with that of many benign lymphoid proliferations and B-cell lymphomas, the diagnosis is often challenging. Disease location, morphology, and immunophenotyping remain the main features guiding the diagnosis, often complemented by genetic analysis including clonality and high-throughput sequencing mutational studies. This review provides a comprehensive overview of the classification and diagnosis of T-cell lymphoma in the context of current concepts and scientific knowledge.

Somatic mutations in FAS pathway increase hemophagocytic lymphohistiocytosis risk in patients with T- and/or NK-cell lymphoma.

ABSTRACT: Although significant progress has been made in understanding the genetic basis of primary hemophagocytic lymphohistiocytosis (HLH), the pathogenesis of secondary HLH, the more prevalent form, remains unclear. Among the various conditions giving rise to secondary HLH, HLH in patients with lymphoma (HLH-L) accounts for a substantial proportion. In this study, we investigated the role of somatic mutations in the pathogenesis of HLH-L in a cohort of patients with T- and/or natural killer-cell lymphoma. We identified a 3-time higher frequency of mutations in FAS pathway in patients with HLH-L. Patients harboring these mutations had a 5-time increased HLH-L risk. These mutations were independently associated with inferior outcome. Hence, our study demonstrates the association between somatic mutations in FAS pathway and HLH-L. Further studies are warranted on the mechanistic role of these mutations in HLH-L.

Mixed histiocytic neoplasms: A multicentre series revealing diverse somatic mutations and responses to targeted therapy.

Histiocytic neoplasms are diverse clonal haematopoietic disorders, and clinical disease is mediated by tumorous infiltration as well as uncontrolled systemic inflammation. Individual subtypes include Langerhans cell histiocytosis (LCH), Rosai-Dorfman-Destombes disease (RDD) and Erdheim-Chester disease (ECD), and these have been characterized with respect to clinical phenotypes, driver mutations and treatment paradigms. Less is known about patients with mixed histiocytic neoplasms (MXH), that is two or more coexisting disorders. This international collaboration examined patients with biopsy-proven MXH with respect to component disease subtypes, oncogenic driver mutations and responses to conventional (chemotherapeutic or immunosuppressive) versus targeted (BRAF or MEK inhibitor) therapies. Twenty-seven patients were studied with ECD/LCH (19/27), ECD/RDD (6/27), RDD/LCH (1/27) and ECD/RDD/LCH (1/27). Mutations previously undescribed in MXH were identified, including KRAS, MAP2K2, MAPK3, non-V600-BRAF, RAF1 and a BICD2-BRAF fusion. A repeated-measure generalized estimating equation demonstrated that targeted treatment was statistically significantly (1) more likely to result in a complete response (CR), partial response (PR) or stable disease (SD) (odds ratio [OR]: 17.34, 95% CI: 2.19-137.00, p = 0.007), and (2) less likely to result in progression (OR: 0.08, 95% CI: 0.03-0.23, p < 0.0001). Histiocytic neoplasms represent an entity with underappreciated clinical and molecular diversity, poor responsiveness to conventional therapy and exquisite sensitivity to targeted therapy.