Search Results (306)

Background: Richter transformation (RT) is defined as the histologic transformation of Chronic Lymphocytic Leukemia (CLL) to either diffuse large B-cell lymphoma or Hodgkin lymphoma. Transformation into lymphoproliferative neoplasms with plasmablastic differentiation is exceptionally rare and poorly characterized. Case Presentation: We present the first case of a patient with CLL evolving into plasmablastic myeloma (PBM). A 62-year-old man with previously treated CLL developed thrombocytopenia and rapidly progressive acute kidney injury. Serum electrophoresis showed new IgA-λ protein (2.2 g/L) with λ and κ light chains at 3445.4 and 7.3 mg/L. Bone marrow examination showed extensive infiltration (>95%) by plasmablasts and mature plasma cells, with a consistent immunophenotype (CD38+, CD138+, MUM1+, CD19−, CD20−). In situ hybridization with EBER was negative. Mutation assessment by NGS demonstrated a TP53 mutation and FISH prob panel revealed a new del17p. Clonal relatedness was confirmed by shared IGHV somatic hypermutation using NGS. The patient was primary refractory to frontline myeloma therapy with Dara-VRd and succumbed rapidly to his disease. Discussion: This case illustrates an exceptionally rare form of RT. Recognition and incorporation in new classifications of plasmablastic RT as a distinct entity is critical, as its biology and resistance profile differ from classical RT. Full article

Therapy resistance is a major obstacle to cancer treatment, and transforming growth factor-beta (TGF-β) signaling has emerged as a major instigator across many cancer types and therapeutic regimens. Solid tumors overexpress TGF-β ligands, and canonical and non-canonical TGF-β signaling pathways drive molecular changes in most cell types within the tumor to hijack therapeutic responses. Cancer therapies further stimulate TGF-β release to potentiate this problem. Molecular mechanisms of TGF-β action supporting resistance include upregulation of drug efflux pumps, enhanced DNA Damage Repair, elaboration of stiffened extracellular matrix, and decreased neoantigen presentation. TGF-β also activates pro-survival pathways, such as epidermal growth factor receptor, B-cell lymphoma-2 expression, and AKT-mTOR signaling. TGF-β-induced epithelial-to-mesenchymal transformation leads to tumor heterogeneity and acquisition of stem-like states. In the tumor microenvironment, TGF-β induces extracellular matrix production, contractility, and secretion of immunosuppressive cytokines by cancer-associated fibroblasts that contribute to drug resistance. TGF-β also blunts cytotoxic T and NK cell activities and stimulates recruitment and differentiation of immunosuppressive cells, including T-regulatory cells, M2 macrophages, and myeloid-derived suppressor cells. The importance of TGF-β signaling in development of drug resistance cannot be understated and should be further explored mechanistically to identify novel molecular approaches and combinatorial drug dosing strategies to prevent drug-resistance. Full article

Background/Objectives: Fluorescence in situ hybridization (FISH) is a standard diagnostic tool for detecting gene fusions and rearrangements in lymphomas but is limited by incomplete genomic coverage, dependence on predefined probes, and difficulty identifying atypical or noncanonical fusion partners. These constraints often result in inconclusive diagnoses in complex lymphoma cases. This study evaluates a novel Hi-C-based sequencing assay from formalin-fixed paraffin-embedded (FFPE) samples to detect clinically significant gene fusions and rearrangements in cases where conventional FISH was inconclusive or expected biomarkers were not detected. Methods: Five diffuse large B-cell lymphoma cases with previously atypical gene fusions or rearrangements by FISH were analyzed using both standard FISH and a Hi-C-based lymphoma assay. Standard FISH was performed using break-apart probes targeting MYC, BCL2, and BCL6, and dual-fusion probes targeting IGH::MYC and IGH::BCL2. The Hi-C assay utilized high-resolution sequencing of FFPE tissue to map chromatin interactions and identify structural variations across the genome and assessment of their clinical relevance. Results: In this series of five lymphoma cases, Hi-C detected additional structural variants beyond those identified by FISH. It identified typical and atypical translocation partners of key oncogenes (MYC, BCL2, BCL6), cryptic breakpoints, and novel genomic events, including TP53 loss, KMT2A amplification, and complex rearrangements, which were undetectable by FISH. The Hi-C assay’s whole-genome coverage enabled comprehensive profiling. Conclusions: The Hi-C-based lymphoma assay offers a transformative diagnostic tool, overcoming FISH limitations by providing unbiased, high-resolution detection of structural variations. This approach enhances diagnostic accuracy and supports personalized therapeutic strategies in lymphoma management, warranting further validation for clinical adoption. Full article

Background/Objectives: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are low-grade B-cell lymphomas (LGBCLs) with indolent clinical courses but a lifelong risk of histologic transformation (HT) to aggressive lymphomas, particularly diffuse large B-cell lymphoma. Predicting HT can be challenging due to class imbalances and the inherent complexity of time-dependent events. While there are current prognostic indices for survival, they do not specifically address HT risk. This study aimed to develop and validate survival-based and traditional classification machine-learning models to predict HT in cohorts. Methods: Using a multicenter retrospective dataset (n = 1068), survival models (Cox proportional hazards, Lasso-Cox, Random Survival Forest, Gradient-boosted Cox [GBM-Cox], eXtreme Gradient Boosting [XGBoost]-Cox), and classification models (Logistic regression, Lasso logistic, Random Forest, Gradient Boosting, XGBoost) were compared. The best-performing survival models—XGBoost-Cox, Lasso-Cox, and GBM-Cox—were assessed on an independent test set (n = 92). Model sensitivity was maximized using optimal binary risk cutoff points based on Youden’s index. Results: Survival models showed superior predictive performance than classical classifiers, with XGBoost-Cox exhibiting the highest mean accuracy (85.3%), time-dependent area under the curve (0.795), sensitivity (98%), specificity (83.9%), and concordance index (0.836). Incorporating next-generation sequencing (NGS) data improved model accuracy and specificity, indicating that genetic factors improve HT prediction. Principal component analysis revealed distinct gene mutation patterns associated with HT risk, highlighting DNA-repair genes such as TP53, BLM, and RAD50. Conclusions: This study highlights the clinical value of survival-based machine-learning methods integrated with NGS data to personalize HT risk stratification for patients with FL and MZL. Full article

Richter transformation (RT) affects 2–10% of chronic lymphocytic leukemia (CLL) patients, evolving into an aggressive lymphoma—most often diffuse large B-cell lymphoma—with poor prognosis, especially when clonally related to CLL. Key risk factors include unmutated IGHV, TP53 and NOTCH1 mutations, stereotyped B-cell receptors, and complex cytogenetics. This review summarizes RT biology, clinical predictors, and treatment outcomes. Traditional chemoimmunotherapy (e.g., R-CHOP) yields complete response rates around 20–30% and median overall survival of 6–12 months; intensified regimens (R-EPOCH, hyper-CVAD) offer only modest gains. Allogeneic hematopoietic stem cell transplantation is potentially curative but limited to fit patients due to high treatment-related mortality. Emerging therapies now include Bruton’s tyrosine kinase and BCL-2 inhibitors, which achieve partial responses but short progression-free survival. CD19-directed chimeric antigen receptor T-cell therapies produce overall response rates of 60–65%, though relapses remain frequent. Bispecific antibodies (e.g., CD3×CD20 agents epcoritamab and mosunetuzumab) show promising activity and tolerable toxicity in relapsed/refractory RT. Ongoing trials are exploring combinations with checkpoint inhibitors, triplet regimens, and novel targets such as ROR1, CD47, and CDK9. Continued research into optimized induction, consolidation, and innovative immunotherapies is essential to improve outcomes in this biologically distinct, high-risk CLL-related lymphoma. Full article

This narrative review consolidates existing evidence about the interaction between Epstein-Barr virus (EBV) and SARS-CoV-2 in cancer development. EBV is a recognized oncogenic driver, whereas COVID-19 may heighten cancer risk by immunological dysregulation, persistent inflammation, and reactivation of latent viruses. We underscore molecular similarities (e.g., NF-κB activation, T-cell exhaustion) and clinical ramifications for high-risk individuals, stressing the necessity for interdisciplinary research to alleviate dual viral risks. EBV, a well-known oncogenic virus, has been linked to numerous malignancies, including lymphomas, nasopharyngeal carcinoma, and gastric cancer. Through the production of viral proteins that interfere with immune evasion, cellular signaling, and genomic integrity, it encourages malignant transformation and ultimately results in unchecked cell proliferation. Because of its capacity to induce tissue damage, immunological dysregulation, and chronic inflammation, COVID-19, which is brought on by the SARS-CoV-2 virus, has become a possible carcinogen. The virus’s influence on cellular pathways and its long-term effects on the immune system may raise the chance of malignancy, particularly in people with pre-existing vulnerabilities, even if direct correlations to cancer are still being investigated. When two viruses co-infect a host, the review highlights the possibility of synergistic effects that could hasten the development of cancer. It describes how overlapping mechanisms like inflammation, immune suppression, and viral reactivation may be used by a combined EBV and COVID-19 infection to exacerbate carcinogenic processes. Gaining an understanding of these relationships is essential for creating tailored treatment plans and enhancing cancer prevention in high-risk groups. Full article

Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed the therapeutic landscape for relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Our study aims to describe the clinical outcomes of CAR T-cell therapy in patients with R/R DLBCL treated at a single regional center in Italy, with the goal of comparing these outcomes to those reported by high-volume academic centers. Methods: Data were retrospectively collected from a cohort of consecutive 41 patients who underwent to CD19 CAR-T infusion from June 2020 until September 2024 at CAR-T center of Reggio Calabria (Italy). Results: The median age was 66 years, 60.9% were refractory to their most recent regimen, and 24.4% had previously failed autologous stem cell transplant. Bridging therapy was administered in 82.9% of cases. A total of 27 patients (65.8%) received Axi-cel, and 14 (34.2%) received Tisa-cel. At median follow-up of 6.9 months, the best ORR and CR rate were 63.4% and 51.2%, respectively. Median PFS was 3 months, and median OS was 8.4 months. A total of 81.4% of patients developed a CRS, grade 1 in most cases (78.4%); 26.8% developed ICANS: two (5.4%) and three (8.1%) had grade 2 and 3, respectively. In univariate analyses, early response predicted longer survival, whereas high tumor burden and more than one extranodal site were associated with worse outcomes. Conclusions: Our retrospective cohort study reports similar data in terms of clinical response as compared to pivotal trials and other reports, confirming that CAR-T may offer more durable response rates and longer progression-free intervals in R/R DLBCL in our real-world context. Full article

Hodgkin’s Lymphoma (HL) affects approximately 8500 individuals annually in the United States. The 5-year relative survival rate has improved to 88.5%, driven by transformative advances in immunotherapy and precision oncology. The integration of Brentuximab vedotin (BV) and immune checkpoint inhibitors (ICIs) has redefined treatment paradigms. The phase III SWOG S1826 trial established nivolumab plus doxorubicin, vinblastine, and dacarbazine (N + AVD) as an emerging new standard for advanced-stage HL, achieving a 2-year progression-free survival (PFS) of 92% compared to 83% for BV plus AVD (HR 0.48, 95% CI: 0.33–0.70), with superior safety, particularly in patients over 60. In relapsed/refractory HL, pembrolizumab outperforms BV, with a median PFS of 13.2 versus 8.3 months (HR 0.65, 95% CI: 0.48–0.88), as demonstrated in the KEYNOTE-204 trial. Emerging strategies, including novel ICI combinations, minimal residual disease (MRD) monitoring via circulating tumor DNA (ctDNA), and artificial intelligence (AI)-driven diagnostics, promise to further personalize therapy. This review synthesizes HL’s epidemiology, pathogenesis, diagnostic innovations, and therapeutic advances, highlighting the role of precision medicine in addressing unmet needs and disparities in HL care. Full article

To deliver the most effective cancer treatment, clinicians require rapid and accurate diagnoses that delineate tumor type, stage, and prognosis. Consequently, minimizing the need for repetitive and invasive procedures like biopsies and myelograms, along with their associated risks, is a critical challenge. Non-invasive monitoring offers a promising avenue for tumor detection, screening, and prognostication. While the identification of oncogenes and biomarkers from circulating tumor cells or tissue biopsies is currently standard practice for cancer diagnosis and classification, accumulating evidence underscores the significant role of epigenetics in regulating stem cell fate, including proliferation, self-renewal, and malignant transformation. This highlights the importance of analyzing the methylome, exosomes, and circulating RNA for detecting cellular transformation. The development of diagnostic assays that integrate liquid biopsies with epigenetic analysis holds immense potential for revolutionizing tumor management by enabling rapid, non-invasive diagnosis, real-time monitoring, and personalized treatment decisions. This review covers current studies exploring the use of epigenetic regulation, specifically the methylome and circulating RNA, as diagnostic tools derived from liquid biopsies. This approach shows promise in facilitating the differentiation between primary central nervous system lymphoma and other central nervous system tumors and may enable the detection and monitoring of acute myeloid/lymphoid leukemia. We also discuss the current limitations hindering the rapid clinical translation of these technologies. Full article

Background/Objectives: Diffuse Large B-Cell Lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma and demands precise segmentation and classification of nuclei for effective diagnosis and disease severity assessment. This study aims to evaluate the performance of HoVerNet, a deep learning model, for nuclei segmentation and classification in CMYC-stained whole slide images and to assess its integration into a user-friendly diagnostic tool. Methods: A dataset of 122 CMYC-stained whole slide images (WSIs) was used. Pre-processing steps, including stain normalization and patch extraction, were applied to improve input consistency. HoVerNet, a multi-branch neural network, was used for both nuclei segmentation and classification, particularly focusing on its ability to manage overlapping nuclei and complex morphological variations. Model performance was validated using metrics such as accuracy, precision, recall, and F1 score. Additionally, a graphic user interface (GUI) was developed to incorporate automated segmentation, cell counting, and severity assessment functionalities. Results: HoVerNet achieved a validation accuracy of 82.5%, with a precision of 85.3%, recall of 82.6%, and an F1 score of 83.9%. The model showed powerful performance in differentiating overlapping and morphologically complex nuclei. The developed GUI enabled real-time visualization and diagnostic support, enhancing the efficiency and usability of DLBCL histopathological analysis. Conclusions: HoVerNet, combined with an integrated GUI, presents a promising approach for streamlining DLBCL diagnostics through accurate segmentation and real-time visualization. Future work will focus on incorporating Vision Transformers and additional staining protocols to improve generalizability and clinical utility. Full article

The B-cell lymphoma 2 (Bcl-2)-related ovarian killer (BOK), a member of the Bcl-2 protein family, shares a similar domain structure and amino acid sequence homology with the pro-apoptotic family members BAX and BAK. Although BOK is involved in the development of various types of cancer, its mechanism of action in breast cancer remains unclear. This study found that BOK was involved in the process of MG132, inhibiting the migration and epithelial–mesenchymal transition (EMT) of breast cancer cells induced by transforming growth factor-β. Furthermore, interfering BOK reversed the inhibition of breast cancer cell migration and the EMT process by MG132. Additional studies revealed that BOK silencing promoted the expression of EMT-related markers in breast cancer cells, while BOK overexpression inhibited EMT and migration. Using RNA-seq sequencing and Western blotting, we confirmed that the Wnt signaling pathway is involved in BOK regulating the EMT process in breast cancer cells. Therefore, we conclude that low BOK expression promotes breast cancer EMT and migration by activating the Wnt signaling pathway. This study enhances our understanding of breast cancer pathogenesis and suggests that BOK may serve as a potential prognostic marker and therapeutic target for breast cancer. Full article

Background: Mycosis fungoides (MF), the most prevalent cutaneous T cell lymphoma, features clonal CD4⁺ T cell proliferation within a Th2-dominant microenvironment. Interleukin-4 (IL-4) promotes disease progression while Brentuximab Vedotin (BV), an anti-CD30 antibody–drug conjugate, shows efficacy but faces resistance challenges. Methods: We conducted a narrative literature review (2010–2024) synthesizing evidence on IL-4 signaling and BV’s efficacy in MF to develop a theoretical framework for combination therapy. Results: IL-4 may modulate CD30 expression and compromise BV’s effectiveness through immunosuppressive microenvironment remodeling. Theoretical mechanisms suggest that IL-4 pathway inhibition could reprogram the microenvironment toward Th1 dominance and restore BV sensitivity. However, no direct experimental evidence validates this combination, and safety concerns including potential disease acceleration require careful evaluation. Conclusions: The proposed IL-4/BV combination represents a biologically compelling but unproven hypothesis requiring systematic preclinical validation and biomarker-driven clinical trials. This framework could guide future research toward transforming treatment approaches for CD30-positive MF by targeting both malignant cells and their immunologically permissive microenvironment. Full article

Follicular lymphoma (FL) is one of the most common types of non-Hodgkin’s lymphomas. The tumor is characterized by a wide range of clinical manifestations, ranging from indolent forms to early transformation and progression with a poor prognosis. The search for clinically significant genetic changes is essential for personalized risk assessment and treatment selection. The CREBBP gene is frequently mutated in this type of lymphoma, with changes occurring at the level of the earliest tumor precursor cells. However, the prognostic and diagnostic significance of the CREBBP gene mutation status in FL has not been fully established. In this study, we analyzed sequencing data of exons 22–30 of the CREBBP gene in 86 samples from patients with different grades of FL (1–3B), including those in the 3A–3B subgroup without the t(14;18) translocation. We also investigated the prognostic significance of CREBBP gene mutations in relation to the treatment options, namely high-dose chemotherapy with autologous hematopoietic stem cell transplantation (HDCT/auto-HSCT) and conventional chemotherapy programs (CCT). It was found that FL patients with a single missense mutation in the KAT domain of the CREBBP gene experienced an extremely low number of early adverse events related to lymphoma and had better long-term survival rates, regardless of treatment option. In contrast, when comparing patients with FL without a missense mutation in the KAT domain or those with multiple mutations in the CREBBP gene, overall and progression free survival were worse, and early progression and histological transformation were more common. Compared to standard therapy, patients who underwent HDCT/auto-HSCT in the FL 1–3B (14;18)-positive group without a single missense mutation in the KAT domain had better survival rates and lower rates of transformation and early progression. In addition, among patients with FL 3A–3B (14;18)-negative, we found that there were no cases of a missense mutation in the KAT domain of the CREBBP gene. This suggests that a single missense mutation in the CREBBP gene may be a feature that discriminates 14;18-positive FL with a favorable prognosis from a high-risk disease. FL 3A–3B (14;18)-negative may represent a distinct variant with different biology and underlying mechanisms of development compared to classical FL. Full article

There has been extensive research on the KSHV/HHV8 virus, which has led to a better understanding of viral transmission, pathogenesis, viral-driven lymphoid proliferation, neoplastic transformation, and how we might combat these processes clinically. On an extensive review of the literature, only two true KSHV/HHV8-positive lymphoid neoplasms are described: primary effusion lymphoma (PEL), which can also present as solid or extracavitary primary effusion lymphoma (EC-PEL) and diffuse large B-cell lymphoma (DLBCL). Two lymphoproliferative disorders have also been described, and while they are not true monotypic neoplasms, these lesions can transform into neoplasms: KSHV/HHV8-positive germinotropic lymphoproliferative disorder (GLPD) and multicentric Castleman disease (MCD). This review provides a somewhat concise overview of information related to KSHV/HHV8-positive lymphoid neoplasms and pertinent associated lymphoproliferative lesions. Full article

Precision medicine is transforming hematologic cancer care by tailoring treatments to individual patient profiles and moving beyond the traditional “one-size-fits-all” model. This review outlines foundational technologies, disease-specific advances, and emerging directions in precision hematology. The field is enabled by molecular profiling techniques, including next-generation sequencing (NGS), whole-exome sequencing (WES), and RNA sequencing (RNA-seq), as well as epigenomic and proteomic analyses. Complementary tools such as liquid biopsy and minimal residual disease (MRD) monitoring have improved diagnosis, risk stratification, and therapeutic decision making. We discuss major molecular targets and personalized strategies across hematologic malignancies: FLT3 and IDH1/2 in acute myeloid leukemia (AML); Philadelphia chromosome–positive and Ph-like subtypes in acute lymphoblastic leukemia (ALL); BCR-ABL1 in chronic myeloid leukemia (CML); TP53 and IGHV mutations in chronic lymphocytic leukemia (CLL); molecular subtypes and immune targets in diffuse large B-cell lymphoma (DLBCL) and other lymphomas; and B-cell maturation antigen (BCMA) in multiple myeloma. Despite significant progress, challenges remain, including high costs, disparities in access, a lack of standardization, and integration barriers in clinical practice. However, advances in single-cell sequencing, spatial transcriptomics, drug repurposing, immunotherapies, pan-cancer trials, precision prevention, and AI-guided algorithms offer promising avenues to refine treatment and improve outcomes. Overcoming these barriers will be critical for ensuring the equitable and widespread implementation of precision medicine in routine hematologic oncology care. Full article