Search Results (480)

Background: Diffuse large B-cell lymphoma (DLBCL) is one of the most frequent lymphomas. To date, it is not possible to identify which DLBCL patients will have an aggressive clinical evolution only by using hematoxylin and eosin (H&E) histological images. Methods: This study predicted the prognosis of DLBCL using H&E images, computer vision and deep learning. The series included 114 DLBCL cases, split into 2 prognostic groups according to overall survival, and 44 cases of reactive lymphoid tissue. Results: The curve fitting and slope analysis showed a point of inflection at 2 years (24 months), which differentiated patients with aggressive clinical evolution (“Dead < 2 years”, b1 = −0.024) from the rest with moderate clinical evolution (“Others”, b1 = −0.003). Twenty different convolutional neural networks (CNNs) were used, and explainable artificial intelligence (XAI) was also applied. The final model based on DarkNet-19 predicted prognosis groups with high performance (test set accuracy = 96.3%). The other performance parameters were precision (94.5%), recall (95.0%), false positive rate (3.1%), specificity (96.9%), and F1 score (94.7%). XAI, including grad-CAM, occlusion sensitivity, and image-LIME, confirmed that the CNN focused on the correct areas. Hybrid partitioning to prevent information leakage with patient-based analysis, image classification between DLBCL and 44 cases of reactive lymphoid tissue, and hyperparameter tuning were also successfully performed. Correlation with the clinicopathological characteristics found that the Dead < 2 years group was correlated with stage III–IV, International Prognostic Index (IPI) High + High/intermediate, progressive disease, non-GCB cell-of-origin, CD10−, BCL2+, and Epstein–Barr virus (EBER)+. Analysis of the microenvironment, immune checkpoint, cell cycle, and germinal center markers showed that Dead < 2 years had higher IL10, PD-L1, and CD163 levels and lower E2F1 protein expression. No differences were found for Ki67, CSF1R, CASP8, TNFAIP8, LMO2, MYC, MDM2, CDK6, and TP53 markers at a quantitative level. Conclusions: The DLBCL overall survival can be predicted using H&E histological images and deep learning using the 2-year (24 months) point (similar to POD24). This trained CNN can be used as a pretrained model for transfer learning in the future. Full article

Objectives: The genetic architecture of B-cell lymphomas is not fully characterized. We aimed to identify novel candidate variants associated with four common B-cell lymphoma subtypes—diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL), and marginal zone lymphoma (MZL)—through cross-trait analyses with correlated idiopathic inflammatory myopathies subtypes, dermatomyositis (DM) and polymyositis (PM). Methods: Leveraging shared genetic susceptibility with DM and PM, we applied a pleiotropy-informed conditional false discovery rate (condFDR) method to recompute nominal single nucleotide polymorphism association p-values for each B-cell lymphoma subtype. Associations were considered significant at condFDR <0.01. Functional annotation was performed using FUMA (Functional Mapping and Annotation of Genome-Wide Association Studies), followed by Gene Ontology (GO) enrichment analysis via clusterProfiler, with similar GO terms clustered for interpretation and visualization. Results: We identified 4, 2, 13, and 6 novel candidate loci for DLBCL, FL, CLL, and MZL, respectively. Most loci exhibited regulatory effects on genes involved in adaptive immune responses and cell death pathways. Notably, for DLBCL locus 1q23.3 affects SLAMF genes implicated in natural killer and lymphocyte activation. A trans-eQTL at 2q13 for FL was associated with BCL11A, a multifunctional oncogene. For CLL, a novel locus at 16q24.1 regulates IRF8, a known CLL risk gene. Functional mapping of previously reported CLL risk loci revealed RIPK1 (6p25.2), linked to necroptosis. No enriched biological pathways were detected for MZL risk-associated genes. Conclusions: These findings advance our understanding of the genetic architecture of four B-cell lymphoma subtypes and aim to inform future genetic and functional studies. Full article

Background: Testicular irradiation presents technical challenges due to the temperature-dependent cremasteric reflex causing positional variability, yet detailed immobilization protocols addressing this issue and cone-beam computed tomography (CBCT)-based setup data remain lacking. This formative and preliminary single-patient descriptive technical report describes a temperature-controlled immobilization technique and reports preliminary setup observations from its clinical application. Methods: A 74-year-old male with primary testicular diffuse large B-cell lymphoma (DLBCL) received prophylactic contralateral testicular irradiation. The immobilization protocol combined a custom thermoplastic device with infrared warming to maintain the scrotal surface temperature at 36–36.5 °C, intended to facilitate a relaxed scrotal position prior to and during each fraction under temperature-controlled conditions. Treatment was delivered using a three-field three-dimensional conformal radiotherapy (3D-CRT) technique (30.6 Gy in 17 fractions), and seven CBCT scans were used to document interfraction setup measurements. Results: The treatment was completed as planned with adequate target coverage (clinical target volume [CTV] D97% = 100%) and minimal organ-at-risk (OAR) doses. Setup measurements showed a CTV root-mean-square displacement (RMS) of 3.8 mm and a mean Dice similarity coefficient (DSC) of 0.85, while the testis alone showed an RMS of 5.2 mm and a mean DSC of 0.73. Conclusions: The temperature-controlled immobilization technique was feasibly implemented, and the setup measurements observed during its application showed a CTV RMS of 3.8 mm and a mean DSC of 0.85. These findings may provide a practical reference for institutions encountering this rare clinical scenario. Full article

CD20 × CD3 bispecific antibodies (BsAbs) have emerged as a meaningful therapeutic option for relapsed or refractory diffuse large B-cell lymphoma (DLBCL), redirecting endogenous T cells against malignant B cells independently of major histocompatibility complex-mediated antigen presentation, and have received regulatory approval after at least two prior lines of therapy. However, a substantial proportion of patients experience primary resistance or early relapse, underscoring the need to characterize the underlying biological mechanisms, which are the focus of this review. Several tumor-intrinsic determinants of resistance have been identified, including CD20 loss driven by MS4A1 mutations, alternative splicing, and gene deletion, as well as genomic reprogramming involving TP53, MYC, and NOTCH1 alterations. T-cell dysfunction represents another critical resistance domain, encompassing inadequate intratumoral cytotoxic CD8+ T-cell infiltration, expansion of immunosuppressive regulatory and follicular helper T cells, progressive exhaustion with upregulation of PD-1, LAG-3, TIM-3, and TIGIT, and impaired T-cell fitness from prior treatment exposure. Microenvironmental barriers, including checkpoint ligand upregulation, PD-L1-enriched extracellular vesicles, spatial exclusion of effector cells from immune-cold germinal center-like niches, hypoxia, and metabolic competition, further reinforce immune escape. Emerging strategies to overcome resistance include epigenetic priming, checkpoint inhibitor combinations, 4-1BB costimulatory approaches, and next-generation multispecific antibody designs. Full article

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma, constituting an important public health problem. Although curable, it presents a widely variable prognosis. The main tool used for prognostic stratification in DLBCL is the International Prognostic Index (IPI), which does not consider crucial biological variables for understanding its prognostic heterogeneity. Cell adhesion molecules (CAMs) play a central role in cancer biology and can be evaluated in affected tissues or in plasma, in soluble forms (sCAMs). CAMs promote proliferation, survival, and dissemination of malignant cells. Although extensively studied in solid tumors, their role remains unclear in hematological malignancies, particularly in DLBCL. Methods: This is a prospective and longitudinal study involving 87 newly diagnosed DLBCL (ND-DLBCL) patients aiming to quantify plasma levels of sCAMs (sICAM-1, sVCAM-1, sP-selectin, and sE-cadherin) at diagnosis and assessing its potential prognostic impact, as well as establishing clinical-biological associations. Results: Plasma quantification of sICAM-1, sVCAM-1, and sP-selectin did not present prognostic impact in DLBCL. However, continuous increases in sE-cadherin levels, as well as sE-cadherin ≥ 126.55 ng/mL were associated with lower response rates to R-CHOP regimen, higher frequency of recurrence following first-line therapy, and shortened survival. Additionally, sE-cadherin concentration ≥ 126.55 ng/mL was an independent predictor related to decreased overall survival. Conclusion: sE-cadherin measured at diagnosis has emerged as a new prognostic biomarker able to predict response, relapse and survival in ND-DLBCL. Full article

Background: Intraventricular central nervous system (CNS) lymphoma is an atypical presentation of extranodal lymphoma, whether primary or secondary. The most commonly diagnosed subtype of lymphoma is diffuse large B-cell lymphoma (DLBCL). There is a documented relation of HIV, EBV and KSHV infections with lymphomagenesis. AIDS-related lymphomas (ARLs) are described as a defining illness of the acquired immunodeficiency syndrome (AIDS). This study presents a novel case and systematic review of clinical, radiographic and histopathological features of intraventricular lymphomas. Methods: We report on a 27-year-old woman with a left lateral ventricle DLBCL with surrounding edema treated with steroids. A systematic review of 147 additional cases (1977–2025) was conducted, analyzing patient demographics, tumor characteristics, clinical features, imaging, treatment, and outcomes. The tumor locations were divided into three groups depending on the extent of ventricular involvement. Descriptive statistics summarized findings. Findings: 147 cases (mean age, 54.2 years; range, 3–87; 63.3% male) were analyzed. Immunodeficiency in patients was unusual (6.1%). Fully intraventricular lesions were the most common presentation (52.4%), with systemic involvement solely in 10 cases (6.8%). The lesions were predominantly located in the lateral ventricles or fourth ventricles (46 times each), and bilateral involvement was noted 37 additional times. DLBCL was diagnosed in 101 cases (78.9%). Interpretation: Intraventricular involvement in central nervous system lymphoma poses a diagnostic and therapeutic challenge due to non-specific symptoms and atypical locations. Adding to the diagnostic difficulty of intraventricular masses in young patients, we wish to highlight that immunocompromised patients are a notably insignificant subgroup of patients in our study. Full article

Objective: Primary extranodal lymphomas of the head and neck region are relatively rare and represent a biologically distinct subset. The diagnosis and differential diagnosis of head and neck lymphomas are important and deserve special attention. The aim of the present study was to retrospectively evaluate patients diagnosed with primary head and neck lymphomas at the Department of Pathology between January 2020 and January 2026. Histopathological subtypes, localization, relative frequencies, and overall survival were analyzed. Materials and Methods: This retrospective study included 31 cases diagnosed with lymphoma involving the head and neck region. Medical records were reviewed. Histopathological slides were re-evaluated under light microscopy by experienced pathologists. All cases were classified according to the current World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues. An extensive immunohistochemical panel was applied. Statistical analysis was performed using SPSS statistical software (version 27.0; IBM Corp., Armonk, NY, USA). Results: The study group included 31 patients with head and neck lymphoma. The most common histological type was diffuse large B-cell lymphoma (DLBCL) (54.8%). Other histological subtypes included follicular lymphoma (FL), mantle cell lymphoma (MCL), extranodal NK/T-cell lymphoma (NKTCL), anaplastic large cell lymphoma (ALCL), and Hodgkin lymphoma (HL). The most common location was the tonsil (38.7%). Other locations included the nasopharynx, oral cavity, nasal cavity, salivary glands, and thyroid. Epstein–Barr virus (EBV) positivity was detected in two patients (6.5%), and human immunodeficiency virus (HIV) infection was identified in two patients (6.5%). At the time of the last follow-up, 27 patients (87.1%) were alive, whereas four patients (12.9%) had died. The mortality rate was 12.9%. The median overall survival was 28 months (95% CI: 10–45). Conclusions: Malignant lymphoma should be considered when evaluating head and neck masses, and histopathological assessment of the affected tissue remains the cornerstone of diagnosis. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is molecularly heterogeneous, and approximately 30-50% of patients fail to achieve cure with standard R-CHOP. Genotype-directed first-line therapy may improve outcomes by targeting subtype-specific oncogenic pathways. This study evaluated the feasibility, efficacy, and safety of a molecularly adapted R-CHOP-X strategy with two-year follow-up. Methods: In this single-center, prospective, non-randomized study conducted between September 2023 and the data cut-off (16 September 2025), 43 adults with newly diagnosed DLBCL (excluding high-grade B-cell lymphoma, primary immune-privileged, and primary mediastinal large B-cell lymphomas) underwent tumor genotyping using the LymphGen classification after targeted sequencing: a 19-gene Sanger panel (Cohort 1, n = 35) or an expanded 60-gene panel (Cohort 2, n = 8; proof-of-concept). All patients received one initial cycle of R-CHOP as bridge therapy pending molecular profiling results, followed by five cycles of R-CHOP-X, with the additional agent (vorinostat, acalabrutinib, decitabine, or lenalidomide) selected according to molecular subtype. Response was assessed by PET/CT per Lugano criteria; adverse events were graded per NCI CTCAE v5.0. Results: The overall study population was predominantly high-risk: 72% had an IPI of 3–5, 58% had stage III–IV disease, and 67% exhibited a non-GCB immunophenotype. Expansion from the 19-gene to the 60-gene panel reduced unclassifiable (NOS) cases from 34% to 12%. The overall response rate was 100% (43/43); complete response among patients completing therapy was 100% (35/35). At two years, overall survival was 92% (95% CI 83–100%) and progression-free survival was 94% (95% CI 86–100%). Two early relapses occurred (NOS and N1 subtypes), both resulting in death. Grade 3–4 neutropenia, thrombocytopenia, and anemia occurred in 26%, 12%, and 7% of patients, respectively; no dose reductions or treatment discontinuations were recorded. Conclusions: Molecularly adapted R-CHOP-X is feasible and associated with high response rates and favorable two-year survival in newly diagnosed DLBCL, comparing favorably with historical R-CHOP outcomes in high-risk populations. Expanded genomic panels substantially improve molecular classifiability. These findings warrant validation in larger, multicenter, randomized clinical trials. Full article

Background/Objectives: Central Nervous System (CNS) relapse represents a severe and often fatal complication of Diffuse Large B-Cell Lymphoma (DLBCL). This study aimed to evaluate clinical, biological, and treatment-related factors associated with progression-free survival (PFS) until CNS relapse in patients with DLBCL. Methods: A retrospective cohort study was conducted using clinical data from adult DLBCL patients evaluated and treated at the Regional Institute of Oncology, Iași, Romania, between 2015 and 2023. Associations between clinical, biological, and treatment-related variables and CNS relapse were evaluated using univariate and multivariable Cox proportional hazards models, Fine–Gray competing-risk analyses, and propensity score-based methods to address confounding by indication for CNS prophylaxis. Results: Twenty-six CNS relapse events (6.3%) and 72 deaths without prior CNS relapse occurred over a median follow-up of 12 months. In the prespecified reduced multivariable Cox model, non-R-CHOP regimens (HR 4.57, 95% CI 1.67–12.52; p = 0.003) and high CNS-IPI scores (HR 4.70, 95% CI 1.14–19.46; p = 0.033) were independently associated with CNS relapse. The 20-month cumulative incidence of CNS relapse was 7.0% in the R-CHOP-like group versus 35.2% in the non-R-CHOP group (Gray’s test p < 0.001). Fine–Gray modeling confirmed the association for non-R-CHOP regimens (SHR 3.38, 95% CI 1.21–9.45; p = 0.02). Cell-of-origin subtype, double-expressor phenotype, and Ki-67 were not significantly associated with CNS relapse. Conclusions: High CNS-IPI and treatment with non-R-CHOP regimens independently predicted earlier CNS relapse. Future multicenter studies with molecular profiling are needed to refine CNS risk stratification. Full article

The high incidence of thrombosis in lymphoma is largely due to chronic inflammation and endothelial dysfunction. To elucidate the mechanisms underlying thrombus formation and fibrinolysis, we investigated interactions between circulating endothelial cells and peripheral blood mononuclear cells (MNCs), along with inflammatory signaling pathways, in patients with follicular lymphoma (FL), Hodgkin lymphoma (HL), and diffuse large B-cell lymphoma (DLBCL), independent of the presence of thrombosis, compared to healthy controls by flow cytometry, immunoblotting, and fluorometric assays. We observed increased tissue factor (TF) expression on CD31+ endothelial cells in DLBCL and FL. In DLBCL, inducible nitric oxide synthase expression was elevated in MNCs, while reduced nitrite levels correlated with an advanced clinical stage in patients with thrombosis. In lymphoma, nuclear factor kappa B (NFκB) signaling was activated in MNCs, while signal transducer and activator of transcription 3 (STAT3) activation was increased in DLBCL with thrombosis. Trans-endothelial migration of MNC was enhanced in HL, FL and DLBCL with thrombosis and reduced by inflammatory cytokine tumor necrosis factor alpha (TNF-α) that promoted platelet aggregation like interleukin-6 (IL-6) in HL and FL. Fibrinolytic analyses showed reduced tissue type plasminogen activator in lymphoma, whereas increased urokinase-type plasminogen activator (uPA) was linked to poorer total survival in DLBCL with thrombosis, suggesting a compensatory role in early thrombus resolution. These findings indicate that chronic inflammation promotes endothelial activation, dysregulated fibrinolysis, and increased vascular permeability, contributing to heightened thrombotic risk. This study provides mechanistic insight into lymphoma-associated thrombosis and identifies TF, uPA, and the inflammatory signaling pathways as potential biomarkers and therapeutic targets. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) and high-grade follicular lymphoma (FL) are aggressive B-cell malignancies predominantly affecting older adults. R-CHOP remains the frontline standard of care, with frail and elderly patients requiring attenuated regimens such as R-mini-CHOP. Real-world comparative data in elderly and Hispanic populations remain limited. We aimed to evaluate outcomes of R-mini-CHOP versus R-CHOP in elderly patients and to explore potential differences by ethnicity. Methods: Single-center retrospective analysis of adult patients older than 70 years with DLBCL and high-grade FL, treated between January 2014 and June 2025. Clinical characteristics, treatment responses, and survival outcomes were analyzed. The overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan–Meier method. Results: A total of 136 patients were included (72 R-mini-CHOP; 64 R-CHOP). Patients receiving R-mini-CHOP were older (median 82 vs. 74 years) and had higher-risk features. Overall response rates were 88.7% and 92.6% in the R-mini-CHOP and R-CHOP groups, respectively. Two-year OS was 79.3% for R-mini-CHOP and 76.7% for R-CHOP. Median OS and PFS were not reached in either group. Elevated lactate dehydrogenase (LDH) was associated with an inferior response. We identified a trend toward better response with R-CHOP in Hispanic patients, although this was not statistically significant. Conclusions: In this real-world cohort, R-mini-CHOP achieved response and survival outcomes comparable to R-CHOP despite worse baseline characteristics. These findings support the use of dose-attenuated therapy in frail and elderly patients and suggest that equitable access to care may mitigate ethnic disparities in outcomes. Full article

Background: Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) exhibit substantial heterogeneity, reflecting the diversity of the germinal center (GC). Histologic transformation of FL to DLBCL is associated with poor prognosis, yet robust biomarkers predicting transformation remain limited. Methods: We integrated single-cell DNA sequencing, single-cell RNA sequencing, and spatial transcriptomics in diagnostic lymph-node biopsies from non-transformed FL (ntFL), transformed FL (tFL), and DLBCL to characterize clonal states and immune niches in GC lymphomas. T-cell signatures associated with transformation were evaluated in an independently published single-cell FL dataset. Results: Transcriptional profiling revealed similarities between tFL and DLBCL, consistent with a GC-related malignant program. The tFL microenvironment showed enrichment of exhausted CD4⁺ regulatory and CD8⁺ effector T cells, together with CD4⁺ follicular helper T cells (Tfh) displaying an adhesion-related phenotype. Spatial analysis suggested increased proximity of exhausted/immunosuppressive T cells and enhanced Tfh-B-cell interactions in tFL compared with ntFL. These immune signatures were also observed in an external cohort and were associated with early transformation. In addition, clonal hematopoiesis-associated mutations were detected in microenvironmental cells across samples, suggesting a potential contribution to the lymphoma microenvironment. Conclusions: This work demonstrates the feasibility of integrating single-cell and spatial analyses in GC lymphomas and provides a framework for investigating tumor heterogeneity and immune organization. These findings may inform future studies on biomarker development and the rational design of immunotherapies. Full article

Extracellular vesicles (EVs), as key mediators of intercellular communication, play multifaceted roles in the pathogenesis, treatment, drug resistance, and monitoring of B-cell non-Hodgkin lymphomas (B-NHLs), including diffuse large B-cell lymphoma (DLBCL), Burkitt lymphoma (BL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). EVs derived from lymphoma cells or tumor microenvironment cells carry diverse cargoes such as proteins, microRNAs (miRNAs), and viral oncoproteins, which regulate tumor progression by modulating signaling pathways related to cell proliferation, invasion, apoptosis, autophagy, and immune suppression. In terms of treatment, accumulating evidence suggests that EVs may be associated with the efficacy of classical regimens such as R-CHOP, and they also hold potential as therapeutic targets and drug delivery vehicles for B-NHL. They contribute to drug resistance by altering the expression of key molecules or reshaping the tumor niche. Additionally, EV-derived biomarkers enable non-invasive diagnosis and monitoring of treatment response and prognosis. This review summarizes the latest research progress on the roles of EVs in major B-NHL subtypes, aiming to provide new insights for the development of innovative diagnostic and therapeutic strategies for B-NHL. Full article

Background and Clinical Significance: Diffuse Large B-Cell Lymphoma (DLBCL) is a morphologically and molecularly heterogeneous lymphoproliferative disorder that originates from a clonal B-cell ancestor. Patients usually present with rapidly enlarging lymph nodes or mass(es) at single or multiple sites. Generally, 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography with computed tomography (PET-CT) is performed post-treatment to evaluate remission status, especially in radiologically residual tumors. Myofibroblastoma (MFB) is a benign mesenchymal tumor of the mammary stroma composed of fibroblasts and myofibroblasts. These entities do not often present concurrently. Case presentation: The patient was an 80-year-old man with a history of stage IV-BS Diffuse Large B-Cell Lymphoma (DLBCL) with a high-risk International Prognostic Index (IPI). The patient underwent treatment with a six-cycle R-CHOP regimen. Immediately after the last cycle, an 18F-Fluorodeoxyglucose (18F-FDG) positron emission tomography with computed tomography (PET-CT) scan revealed a nodular solid lesion with a faintly increased metabolic standardized uptake value (SUVmax) of 3 in the upper outer quadrant of his left breast. A biopsy of the breast lesion was performed, and it revealed a benign mesenchymal tumor, specifically a Myofibroblastoma. The patient has not presented any symptoms or complications since surgery (12 months) and remains in complete remission (CR). Conclusions: Given the potential diagnostic pitfalls and therapeutic implications of residual tumors in the context of DLBCL, a conscientious evaluation by a multidisciplinary team (MDT) is highly recommended. Full article

Background: Glofitamab is a bispecific antibody engaging CD3 on T-cells and CD20 on B-cells. Glofitamab is approved for the treatment of relapsed, refractory diffuse large B-cell lymphoma (R/R DLBCL). Lymphocyte-activation gene 3 (LAG3) and T-lymphocyte-associated protein 4 (CTLA4) are immune checkpoint receptors with inhibitory effects on T-cell activity. There are several common germline variants of both receptor genes. Methods: Here, we evaluate clinical outcomes in R/R DLBCL patients treated with glofitamab according to the single-nucleotide polymorphisms LAG3 rs870849 and CTLA4 rs231775. Results: While there was no apparent association of CTLA4 genotype with glofitamab treatment outcomes, significant differences emerged in LAG3 rs870849 carriers with extended progression-free and overall survival in homozygous LAG3 T455, intermediate PFS and OS in heterozygous LAG3 I455T, and short PFS and OS in homozygous LAG3 I455 carriers. Conclusions: LAG3 rs870849 may be a prognostic response marker in R/R DLBCL treated with glofitamab. Full article