Search Results (610)

TP53 genetic alterations represent a critical molecular feature in diffuse large B-cell lymphoma (DLBCL), with well-established associations with aggressive disease behavior and therapeutic resistance. However, significant controversy persists regarding the clinical utility of p53 immunohistochemical (IHC) expression as a surrogate marker. This study presents a thorough investigation of TP53 genetic alterations and their correlation with p53 protein expression in 664 cases of DLBCL. Using targeted next-generation sequencing (tNGS), we identified TP53 alterations (mutations and/or copy number losses (CNLs)) in 170 cases (25.6%). Among them, 161 cases had mutations. Concurrent analysis of copy number variations (CNVs) in 109 cases revealed TP53 CNLs in 17.4% (19/109), with 68.4% (13/19) of these showing coexisting mutations. Immunohistochemical evaluation of p53 expression in 371 cases demonstrated strong positivity (≥65% cells) in 21% (78/371), complete negativity (<1%) in 5.7% (21/371), and wild-type pattern (1–65%) in 73.3% (272/371) of cases. The p53 IHC laboratory-developed test (LDT) showed 79.2% sensitivity and 91.6% specificity for detecting TP53 alterations overall, though sensitivity varied significantly by mutation type: 86.2% for missense mutations but only 14.3% for nonsense mutations. Clinically, cases with TP53 alterations exhibited more aggressive disease characteristics, including higher ECOG performance scores, increased frequency of B symptoms, and poorer initial treatment responses (complete response rate 68.3% vs. 82.5% in wild-type cases). Most importantly, TP53 genetic alterations, but not p53 protein expression patterns, emerged as an independent prognostic factor for progression-free survival. Our findings demonstrate that tNGS effectively identifies most TP53 alterations and complementary CNV analysis enhances detection of copy number losses. The p53 IHC LDT serves as a useful but imperfect screening tool, with high specificity but variable sensitivity depending on mutation types. These results have important implications for molecular diagnostics in DLBCL, supporting the necessity for comprehensive genetic testing rather than reliance on protein expression analysis alone for accurate risk stratification and treatment planning. Full article

Drug resistance remains a major obstacle in cancer treatment despite advances in therapeutic regimens. To address this, we explored the potential of Doxorubicin (Dox) delivery in poly (lactide-co-glycolic acid) (PLGA) nanoparticles to enhance Diffuse large B-cell lymphoma (DLBCL) cell death. This research investigates the potential of Doxorubicin and advanced delivery methods. We used PLGA nanoparticles with Oleyl cysteineamide (OCA); its amphiphilic nature enables interfacial anchoring and thiol surface functionalization of PLGA NPs. Compared to PLGA-NPs, PLGA-OCA-NPs enhance immunity and induce tumor cell death. They also show significant apoptotic cell death and induced immune responses in DLBCL mouse models. Dox-conjugated PLGA-OCA-NPs (DOX-OCA) exhibit significant in vitro and in vivo anticancer activity compared to free DOX, showing remarkable antitumor effects with reduced systemic toxicity in mouse models. Our findings underscore the promising potential of PLGA-OCA-NPs in DLBCL treatment, offering a hopeful future in cancer therapy. This innovative delivery system offers enhanced immune responses and effectively addresses toxicity concerns, marking a significant step forward in cancer therapy. 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

Background: Primary lymphoma of peripheral nerves (PLPN) is a rare extranodal non-Hodgkin lymphoma that mimics benign nerve conditions, leading to diagnostic delays. This systematic review evaluates the clinical, radiological, and pathological features of PLPN, alongside diagnostic and therapeutic strategies. Materials and Methods: A systematic search was conducted across PubMed, Scopus, and Web of Science, and identified 23 studies reporting 27 cases of PLPN. Data on demographics, clinical presentation, diagnostics, treatment, and outcomes were extracted and synthesized qualitatively due to study heterogeneity. Results: The sciatic nerve was most involved (48.15%), followed by the ulnar (18.5%) and radial nerves (18.5%). The median age at diagnosis was 58 years, with symptoms including motor deficits (88.9%), sensory disturbances (74.1%), and pain (70.4%). B-cell lymphomas accounted for 81.5% of cases, predominantly diffuse large B-cell lymphoma. MRI findings were non-specific; however, diffusion-weighted imaging (DWI) showed diagnostic potential. Treatments included combination therapies (51.9%), chemotherapy (25.9%), and surgery. Complete remission was achieved in 70.8%, with a 2-year survival rate of 83.3%. Conclusions: PLPN is rare but likely underdiagnosed. Early recognition requires multidisciplinary collaboration, advanced imaging, and standardized protocols. Future research should focus on molecular characterization, diagnostic criteria, and treatment optimization to improve outcomes for this challenging condition. Full article

Epigenetic regulation is critical to B cell development, guiding gene expression via DNA methylation, histone modifications, chromatin remodeling, and noncoding RNAs. In mature B cell neoplasms, particularly diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), and chronic lymphocytic leukemia (CLL), these mechanisms are frequently disrupted. Recurrent mutations in key epigenetic regulators such as EZH2, KMT2D, CREBBP, and TET2 lead to altered chromatin states, repression of tumor suppressor genes, and enhanced oncogenic signaling. Dysregulation of specific microRNAs (e.g., miR-155, miR-21) further contributes to pathogenesis and therapeutic resistance. In DLBCL, hypermethylation of SMAD1 and CREBBP mutations are associated with immune evasion and chemoresistance. In FL, EZH2 gain-of-function and KMT2D loss-of-function mutations alter germinal center B cell programming, while in CLL, DNA hypomethylation patterns reflect the cell of origin and correlate with clinical outcome. Targeted therapies such as the EZH2 inhibitor tazemetostat have demonstrated efficacy in EZH2-mutant FL, while HDAC and BET inhibitors show variable responses across B cell malignancies. The limitations of current epigenetic therapies reflect the complexity of targeting epigenetic dysregulation rather than therapeutic futility. These challenges nonetheless highlight the relevance of epigenetic alterations as biomarkers and therapeutic targets, with potential to improve the management of mature B cell neoplasms. Full article

Primary cutaneous lymphomas (PCLs), including cutaneous T-cell lymphomas (CTCL) and primary cutaneous B-cell lymphomas (PCBCL), are a diverse group of non-Hodgkin lymphomas that primarily affect the skin. Radiotherapy (RT) plays a pivotal role in the treatment of these lymphomas, particularly for localized disease, due to its ability to deliver precise, skin-directed treatment. Mycosis fungoides (MF) and Sézary syndrome (SS), the most common subtypes of CTCL, often require skin-directed therapies such as electron beam therapy and superficial brachytherapy to manage localized lesions. Electron beam therapy, including total skin electron beam therapy (TSEBT), has been utilized for decades, offering high response rates but with the risk of cumulative skin toxicity. Recently, low-dose radiotherapy (LDRT) has gained attention as an effective alternative that reduces toxicity while maintaining durable responses. Superficial brachytherapy is another modality that delivers radiation through custom molds, allowing for homogeneous dosing over complex anatomical areas like the face. Both teleradiotherapy and brachytherapy have demonstrated high complete response rates, with low recurrence rates observed when higher doses are used. In the context of primary cutaneous B-cell lymphomas, such as primary cutaneous marginal zone lymphoma (PCMZL) and primary cutaneous follicle center lymphoma (PCFCL), radiotherapy also offers excellent local control, particularly for indolent subtypes. However, more aggressive subtypes, such as diffuse large B-cell lymphoma, leg type (PCDLBCL-LT), may require systemic therapies in addition to radiation. Overall, teleradiotherapy and brachytherapy are essential components of the therapeutic arsenal for primary cutaneous lymphomas, offering effective disease control with manageable toxicity, while ongoing research focuses on optimizing treatment strategies and exploring novel combinations with systemic therapies. Full article

(1) Background: Bispecific antibodies (BsAbs) for the treatment of relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) can be delivered in ambulatory healthcare settings; however, the safe and effective management of potential side effects, such as cytokine release syndrome (CRS), requires protocolized monitoring and management. (2) Methods: An Expert Working Group (EWG) of nine hematologists from across Canada, with experience in leading BsAb program implementation, combined a review of published literature, a comparison of national/provincial/regional guidance documents and protocols, and their professional experiences to produce an informed framework for BsAb program implementation in various healthcare settings. (3) Results: The EWG supports and recommends the progression of BsAb provision from predominantly inpatient hospital settings to community/ambulatory care settings closer to the patient’s home. A seven-step implementation process is outlined to support the safe and effective establishment of such programs, from establishing leadership, through customization of protocols, to education and execution. Strategies and considerations are offered to overcome potential barriers and empower healthcare professionals who are working to establish or improve BsAb programs across Canada. (4) Conclusions: For patients with R/R DLBCL, the safe and effective provision of BsAbs closer to home is both feasible and preferred. This guidance is intended to support the efficient and effective setup or enhancement of BsAb programs in lymphoma. Full article

CD20-negative aggressive B-cell lymphomas are a rare and heterogeneous group of lymphomas representing a diagnostic challenge for pathologists and a therapeutic issue for clinicians, because the outcome of these patients is poor with the current therapeutic approaches. CD20-negative aggressive lymphomas include plasmablastic lymphoma, primary effusion lymphoma, ALK-positive large B-cell lymphoma and HHV8-positive diffuse large B-cell lymphoma. Conditions of immunosuppression and viral infections, such as Epstein–Barr virus and Human Herpes virus 8, are associated with all of these lymphomas with the exclusion of ALK-positive large B-cell lymphoma, which occurs in immunocompetent hosts and is not associated with viral infections. Common features of these aggressive tumors are high-grade histology with immunoblastic or plasmablastic differentiation, the absence or weak expression of mature B-cell markers such as CD20 and the frequent expression of plasma cell-associated markers. The aim of this review is to highlight the diagnostic challenges associated with the group of CD20-negative aggressive B-cell lymphomas, emphasizing key morphologic and molecular features, which are critical in the diagnosis of the different entities belonging to this rare group of diseases. Full article

Objectives: Evaluation of the predictive potential of pre-CAR-T [¹⁸F]FDG PET/CT in Diffuse Large B-Cell Lymphoma (DLBCL) patients concerning Cytokine Release Syndrome (CRS) and Immune Effector Cell-associated Neurotoxicity Syndrome (ICANS). Methods: Eighteen DLBCL patients (mean age: 60 ± 12 years) who underwent pre-therapeutic [¹⁸F]FDG-PET/CT and CAR-T cell therapy were retrospectively included. Median follow-up time was ten months (IQR6-16) after CAR-T cell infusion. Age, sex, serum lactate dehydrogenase (LDH), interleukin-6 (IL-6), C-reactive protein (CRP), and modified Endothelial Activation and Stress Index (mEASIX) were obtained. Potential occurrence of CRS/ICANS and the SUV_max were evaluated. Pearson and Spearman correlations, group comparisons (Mann–Whitney U-test) and the odds ratio (OR) were calculated. P values below 0.05 were defined as statistically significant and 95%-confidence intervals (CI) were calculated. Results: Pre-therapeutic SUV_max correlated positively with LDH (r = 0.5; p = 0.02), with the grade of CRS (r = 0.5; p = 0.03) and with the grade of ICANS (r = 0.6; p = 0.01). Appearance of ICANS was significantly correlated with pre-therapeutic SUV_max (p = 0.03; U = 7.0; Z = −2.2). Using ROC analysis and Youden’s index, an SUV_max threshold of 17 (AUC: 0.865; p < 0.01) was defined. Patients exceeding a pre-therapeutic SUV_max of 17 had a significantly higher risk of CRS grade > 1 (OR = 22; CI 2, 314; p = 0.03) and ICANS grade > 1 (OR = 18; CI 1, 271; p = 0.04). Conclusions: Pre-therapeutic SUV_max may be a useful marker for identifying DLBCL patients at risk for CRS and ICANS. Full article

We aimed to establish non-invasive diagnostic models comparable to pathology testing and explore reliable digital imaging biomarkers to classify diffuse large B-cell lymphoma (DLBCL) and invasive ductal carcinoma (IDC). Our study enrolled 386 breast nodules from 279 patients with DLBCL and IDC, which were pathologically confirmed and underwent ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) examination. Patients from two centers were separated into internal and external cohorts. Notably, we introduced 2.5D deep learning and machine learning to extract features, develop models, and discover biomarkers. Performances were assessed using the area under curve (AUC) and confusion matrix. Additionally, the Shapley additive explanation (SHAP) and local interpretable model-agnostic explanations (LIME) techniques were employed to interpret the model. On the internal cohort, the optimal model PT_TDC_SVM achieved an accuracy of 0.980 (95% confidence interval (CI): 0.957–0.991) and an AUC of 0.992 (95% CI: 0.946–0.998), surpassing the other models. On the external cohort, the accuracy was 0.975 (95% CI: 0.913–0.993) and the AUC was 0.996 (95% CI: 0.972–0.999). The optimal imaging biomarker PET_LBP-2D_gldm_DependenceEntropy demonstrated an average accuracy of 0.923/0.937 on internal/external testing. Our study presented an innovative automated model for DLBCL and IDC, identifying reliable digital imaging biomarkers with significant potential. Full article

B-cell lymphomas, including Burkitt lymphoma (BL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL), evade CD4+ T-cell immunity through novel HLA class II-associated immunosuppressive mechanisms. Despite expressing surface HLA-DR, these tumors fail to activate antigen-specific CD4+ T cells, independent of co-stimulation or PD-L1 checkpoint inhibition. We identified lymphoma-secreted factors that broadly disrupt HLA class II-mediated antigen presentation in both malignant B cells and dendritic cells (DCs), silencing T-cell responses. This inhibition is allele-independent (affecting DR1, DR4, DR7) but spares HLA class I-mediated CD8+ T-cell recognition, indicating a targeted immune evasion strategy. Biochemical and mass spectrometry (MALDI-MS) analyses revealed unique low-molecular-weight peptides (693–790 Da) in BL cells, absent in normal B cells, which may mediate this suppression. Functional fractionation confirmed bioactive inhibitory fractions in lymphoma lysates, further implicating tumor-intrinsic molecules in immune escape. These findings highlight a previously unrecognized axis of B-cell lymphoma immune evasion, where secreted factors disable HLA class II function across antigen-presenting cells. Therapeutically, neutralizing these immunosuppressive molecules could restore CD4+ T-cell surveillance and enhance immunotherapies in B-cell malignancies. This work underscores the importance of HLA class II dysfunction in lymphoma progression and identifies candidate targets for reversing immune suppression. Full article

T-cell-engaging antibodies are a promising new type of treatment for patients with refractory or relapsed (R/R) diffuse large B-cell lymphoma, which has changed the prognosis and evolution of these patients in clinical trials. Bispecific antibodies (BsAbs) bind to two different targets (B and T lymphocytes) at the same time and in this way mimic the action of CAR (chimeric antigen receptor) T-cells. They are the T-cell-engaging antibodies most used in practice and are a solution for patients who do not respond to second- or later-line therapies, including chemoimmunotherapy, followed by salvage chemotherapy and hematopoietic stem cell transplantation. They are a therapeutic option for patients who are ineligible for CAR T-cell therapy and are also active in those with prior exposure to CAR T-cell treatment. A remarkable advantage of BsAbs is their rapid availability, even if the disease progresses rapidly, unlike CAR T-cell treatment, and they avoid the practical and financial challenges raised by autologous CAR T-cell therapies. CAR-T has been proven to have better efficacy compared to BsAbs, but cytokine release syndrome and neurotoxicity have appeared significantly more frequently in patients treated with CAR T-cells. The possibility of combining BsAbs with chemotherapy and their administration for relapses or as a frontline therapy is being studied to increase their efficacy. BsAbs are a life-saving therapy for many patients with diffuse large B-cell malignant non-Hodgkin’s lymphoma (NHL) who have a poor prognosis with classical therapies, but are not without adverse effects and require careful monitoring. 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

Background and aim: Advanced Therapy Medicinal Products (ATMPs) are innovative drugs based on genes, tissues, or cells that target rare and severe diseases. ATMPs have shown promising clinical outcomes but are associated with high costs, raising questions about cost-effectiveness. Hence, this systematic review aims to analyze the cost-effectiveness and cost-utility profiles of the European Medicines Agency-authorized ATMPs for treating rare diseases. Methods: A systematic review was conducted following PRISMA guidelines. Studies were identified by searching PubMed, Embase, Web of Science, and ProQuest scientific databases. Economic evaluations reporting incremental cost-effectiveness/utility ratios (ICERs/ICURs) for ATMPs were included. Costs were standardized to 2023 Euros, and a cost-effectiveness plane was constructed to evaluate the results against willingness-to-pay (WTP) thresholds of EUR 50,000, EUR 100,000, and EUR 150,000 per QALY, as part of a sensitivity analysis. Results: A total of 61 studies met the inclusion criteria. ATMPs for rare blood diseases, such as tisagenlecleucel and axicabtagene ciloleucel, were found to be cost-effective in a majority of studies, with incremental QALYs ranging from 1.5 to 10 per patient over lifetime horizon. Tisagenlecleucel demonstrated a positive cost-effectiveness profile in the treatment of acute lymphoblastic leukemia (58%), while axicabtagene ciloleucel showed a positive profile in the treatment of diffuse large B-cell lymphoma (85%). Onasemnogene abeparvovec for spinal muscular atrophy (SMA) showed uncertain cost-effectiveness results, and voretigene neparvovec for retinal diseases was not cost-effective in 40% of studies, with incremental QALYs around 1.3 and high costs exceeding the WTP threshold set. Conclusions: ATMPs in treating rare diseases show promising economic potential, but cost-effectiveness varies across indications. Policymakers must balance innovation with system sustainability, using refined models and the long-term impact on patient outcomes. Full article