Search Results (695)

Background: Trichosporon japonicum is a rare but highly lethal pathogen causing fungemia in immunocompromised patients. With the expanding use of chimeric antigen receptor T (CAR-T) cell therapy, the spectrum of opportunistic fungal infections is changing, yet data on T. japonicum infections in this setting remain scarce. Case Presentation: A 69-year-old man with diffuse large B-cell lymphoma developed catheter-associated fungemia after CAR-T cell reinfusion. He initially presented with neck pain and white oral mucosal patches, followed by fever four days later. T. japonicum was isolated from both peripheral blood and central venous catheter tip cultures, identified by microscopic examination, mass spectrometry, and molecular sequencing. Antifungal prophylaxis was initiated before fever onset based on close monitoring of white blood cell count, procalcitonin, interleukin-6, and C-reactive protein; treatment was subsequently adjusted according to species identification and antifungal susceptibility results. Infection was controlled within two weeks after catheter removal and immune recovery. The patient remained well at six-month follow-up. Conclusion: This case adds to the limited literature on T. japonicum fungemia in patients receiving CAR-T therapy. Our experience, together with a review of the literature, underscores that successful management requires prompt catheter removal, immune restoration, and combination therapy with voriconazole and amphotericin B, as echinocandin monotherapy should be avoided. Awareness of this pathogen in immunocompromised patients is critical. 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/Objectives: CD19-directed chimeric antigen receptor T (CAR-T) cell therapy induces profound immune remodeling. Nonetheless, biomarkers predicting complete remission (CR) remain poorly defined. We characterized longitudinal cytokine and immune-cell dynamics after CAR-T infusion and identified early immunological features associated with CR. Methods: Longitudinal immune profiling was performed in 18 patients with non-Hodgkin lymphoma, including 14 with relapsed/refractory diffuse large B-cell lymphoma treated with anti-CD19 CAR-T cells. Peripheral blood was collected at the baseline and days 7, 14, 21, 28, and 60 post-infusion. Multiparameter flow cytometry quantified lymphoid and myeloid subsets and Toll-like receptor (TLR)2 and TLR4 expression. Serum cytokines were measured by multiplex assays. Machine-learning-based feature selection identified variables associated with CR. Results: Two inflammatory waves were observed. The first, at day 7, featured elevated IL-6, IL-10, IFN-α, IFN-γ, and TNF-α, accompanied by increased CD4⁺ T cells, HLA-DR^high classical monocytes, and non-classical monocytes. The second, at days 21–28, showed increased IL-5, IL-6, IL-12, IFN-γ, and GM-CSF, with expansion of CD4⁺ and CD8⁺ T cells, regulatory T cells, NK-T cells, and non-classical monocytes. TLR2 expression was significantly upregulated at day 7 on T-cell subsets and on classical and intermediate monocytes. An exploratory feature-selection analysis identified baseline and day-7 TLR2 and TLR4 expression on lymphoid and myeloid cells, early IFN-γ levels, and monocyte frequencies as variables associated with CR. Conclusions: Together, these data show that anti-CD19 CAR-T therapy induces two coordinated waves of cytokine release and immune-cell activation. Moreover, the findings suggest that early modulation of innate immune features, particularly TLR2 expression, is associated with complete remission, although these biomarker relationships remain exploratory and require validation in larger cohorts. 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

Epstein–Barr virus (EBV)-positive primary central nervous system lymphoma (PCNSL) is a rare entity typically associated with profound immunosuppression, most commonly in transplant recipients or individuals with HIV. We report a case of EBV-positive PCNSL arising in a 75-year-old male with myasthenia gravis receiving chronic mycophenolate mofetil (MMF) therapy outside the transplant setting. The patient presented with progressive neurological deficits, and brain magnetic resonance imaging demonstrated multiple enhancing lesions. Stereotactic biopsy revealed diffuse large B-cell lymphoma of non–germinal center subtype with immunoblastic features and EBV-encoded RNA (EBER) positivity, confirming EBV-positive PCNSL. MMF was discontinued, and the patient was treated with rituximab and high-dose methotrexate, resulting in stable disease. This case highlights that prolonged MMF therapy may confer sufficient immunosuppression to permit EBV-driven lymphoproliferative disease even in non-transplant patients. Early recognition, withdrawal of immunosuppression, and initiation of methotrexate-based chemotherapy can lead to favorable outcomes. 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

Skin diseases frequently coexist with other disorders, such as metabolic syndrome, diabetes mellitus, depression, psoriatic arthritis, and cardiovascular disease. Altered levels of distinct chemokines, like CCL5/RANTES, CXCL12/SDF-1a, CCL7/MCP-3, CCL2/MCP-1, CXCL1/GROa, and the eotaxin family, contribute to the development and/or exacerbation of inflammation, which is a common feature of numerous skin diseases as well as metabolic syndrome. The pathological and molecular connections between chronic inflammatory skin diseases and metabolic syndrome are increasingly recognized as being driven by shared inflammatory pathways, oxidative stress, and adipokine dysregulation. While systemic inflammation acts as a common thread, the precise mechanisms for some conditions remain partially understood. Nevertheless, the exact pathological and molecular connections between skin diseases (i.e., psoriasis, atopic dermatitis, pemphigus vulgaris, acute and chronic spontaneous urticaria, bullous pemphigoid, squamous cell carcinoma, alopecia areata, systemic sclerosis, discoid lupus erythematosus, diffuse large B-cell lymphoma) and metabolic syndrome are not yet fully understood. This narrative review summarizes the robust association between various chronic inflammatory skin diseases and metabolic syndrome in the context of pro-inflammatory chemokines. 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: Malignant lymphoma is the most common hematological malignancy; however, primary central nervous system lymphoma accounts for only a small percentage of non-Hodgkin lymphoma (NHL). Among these, primary cauda equina lymphoma (CEL) is extremely uncommon. Its rarity and atypical clinical presentation often make diagnosis challenging. Case Presentation: An 80-year-old man presented with progressive gait disturbance, lower-extremity weakness, and numbness. MRI revealed diffuse swelling and homogeneous gadolinium enhancement of the cauda equina at T12–L1; additionally, CSF cytology identified malignant lymphocytes. Open biopsy confirmed a diagnosis of diffuse large B-cell lymphoma. At diagnosis, the patient was classified as Ann Arbor stage IV, and the clinical parameters corresponded to a high-risk International Prognostic Index (IPI) category. The patient received five courses of immunochemotherapy with rituximab, methotrexate, vincristine, and procarbazine (R-MPV), resulting in marked radiological improvement and functional recovery, achieving a complete response. However, consolidation therapy was discontinued as the patient did not wish to continue. Unfortunately, intracranial relapse occurred four months later, and the patient ultimately succumbed to infectious complications. Only 29 cases of primary CEL have been reported. For all cases, a biopsy with histopathological examination is required for a definitive diagnosis. Currently, combined chemotherapy and radiotherapy are considered the standard treatment. This case was diagnosed through nerve biopsy with cauda equina at T12 to L1 levels, and immunochemotherapy successfully reduced the lesion while improving lower extremity function. Conclusions: Despite the considerable burden on patients, nerve biopsy is necessary for primary CEL to obtain a diagnosis and an early therapeutic approach for both neurological and vital prognoses. 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