Search Results (447)

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

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

Breast-conserving surgery followed by external beam Radiotherapy (RT) is a standard approach for early-stage Breast Cancer (BC). This retrospective study aims to determine the risk of RT-induced lung cancer for both standard and hypofractionated treatments. Fifty-eight Sicilian women treated at Humanitas Istituto Clinico Catanese (Misterbianco, Italy) between 2015 and 2021 with standard fractionated 3D-CRT (50 Gy in 2 Gy/fraction) were included. All treatment plans were designed using a hypofractionated schedule (42.56 Gy in 2.66 Gy/fraction). An Eclipse™ plug-in script was developed using the Eclipse Scripting Application Programming Interface (ESAPI) to extract patient and treatment data from the Treatment Planning System and compute Organ At Risk (OAR) volume, Organ Equivalent Dose (OED), Excess Absolute Risk (EAR), and Lifetime Attributable Risk (LAR) using the Schneider Mechanistic Model and reference data from regional populations, A-bomb survivors, and patients with Hodgkin’s Disease (HD). The OED distributions exhibited a statistically significant shift toward higher values in standard fractionated plans (p < 0.01, one-tailed paired Student’s t-test), leading to increased EAR and LAR. These results indicate that hypofractionated treatment may lower the risk of radiation-induced lung cancer. The feasibility of a priori risk estimation was evaluated by integrating the script into the TPS, allowing rapid comparison of SF and HF plans during planning. Full article

Hodgkin lymphoma (HL) is a common neoplasm in adolescents and young adults, primarily treated with doxorubicin (DOX) and bleomycin (BLM), which may cause severe adverse effects. The cure rate decreases to 75% in advanced-stage disease, highlighting the need for improved treatment strategies. Pentoxifylline (PTX), an NF-κB pathway inhibitor, enhances chemotherapy-induced apoptosis in cancer cells, making it a promising candidate for HL therapy. This study assessed the effects of PTX, DOX, and BLM on apoptosis, proliferation, and senescence in Hs-445 HL cells. Cell viability and clonogenicity were measured by spectrophotometry and spectrofluorimetry, while apoptosis, caspase activity, cell cycle, mitochondrial membrane potential (ΔΨm), proliferation, and senescence were analyzed via flow cytometry. Gene expression was assessed by qPCR. PTX significantly induced apoptosis, especially when combined with BLM or BLM+DOX (triple therapy), and modulated gene expression by upregulating proapoptotic and downregulating antiapoptotic markers. PTX increased caspase-3, -8, and -9 activity and disrupted the ΔΨm, particularly with BLM or triple therapy. Furthermore, PTX abolished DOX-induced G2 cell cycle arrest, reduced proliferation, and clonogenicity, and reversed DOX- and BLM-induced senescence. In conclusion, PTX induces apoptosis in HL cells, enhances DOX and BLM cytotoxicity synergistically, and reverses senescence, suggesting its potential as an adjunct therapy for HL. Full article

The Epstein–Barr virus (EBV) is a prevalent virus linked to various diseases, including infectious mononucleosis (IM), nasopharyngeal carcinoma, and Hodgkin’s lymphoma. Over the past few decades, EBV diagnostic strategies have evolved significantly—progressing from traditional serological assays and histopathology to more sensitive and specific molecular techniques such as nucleic acid amplification and high-throughput sequencing (HTS). While conventional methods remain valuable for their accessibility and established clinical use, they are often limited by sensitivity, speed, and multiplexing capability. In contrast, emerging technologies, including isothermal amplification, Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-based diagnostics, multi-omics integration, and AI-assisted analysis, have demonstrated great promise in improving diagnostic accuracy, speed, and applicability in diverse clinical settings, including point-of-care testing (POCT). This review systematically explores the historical development of EBV diagnostic technologies, highlighting key milestones and future trends in precision medicine and global health readiness. 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

Polatuzumab vedotin (PoV) is a novel antibody-drug conjugate that targets CD79B for the treatment of Non-Hodgkin Lymphoma (NHL). This meta-analysis aimed to evaluate the efficacy and safety of PoV in patients with NHL. A systematic review and meta-analysis of clinical trials evaluating PoV in NHL were conducted. The primary outcomes were complete response (CR) rates, progression-free survival (PFS), and overall survival (OS). Safety outcomes were also assessed. Random-effects models were used for the pooled analyses. Thirteen studies with 1533 patients with NHL were included. PoV significantly improved CR rates compared to control treatments (OR 1.50, 95% CI 1.01–2.21, p = 0.04) and PFS (MD 4.17 months, 95% CI 2.18–6.15, p < 0.0001). OS was not significantly different (OR 0.97, 95% CI 0.47–2.01, p = 0.93). Adverse events were more common with PoV (RR 1.38, 95% CI 0.98–1.94, p < 0.0001). PoV improves CR rates and PFS in patients with NHL, particularly those with relapsed/refractory disease, but is associated with increased adverse events. Further research is needed on long-term survival outcomes and optimal patient selection. PoV appears to be a promising targeted therapy option for NHL, which warrants further investigation. Full article

Intravascular lymphoma (IVL) is a rare, aggressive subtype of non-Hodgkin lymphoma (NHL) characterized by the selective proliferation of neoplastic lymphoid cells within small and medium-sized blood vessels, most frequently of B-cell origin (IVLBCL). Its protean clinical presentation, lack of pathognomonic findings, and absence of tumor masses or lymphadenopathies often lead to diagnostic delays and poor outcomes. IVLBCL can manifest in classic, hemophagocytic syndrome-associated (HPS), or cutaneous variants, with extremely variable organ involvement including the central nervous system (CNS), skin, lungs, and endocrine system. Diagnosis requires histopathologic identification of neoplastic intravascular lymphoid cells via targeted or random tissue biopsies. Tumor cells are highly atypical and display a non-GCB B-cell phenotype, often expressing CD20, MUM1, BCL2, and MYC; molecularly, they frequently harbor mutations in MYD88 and CD79B, defining a molecular profile shared with ABC-type DLBCL of immune-privileged sites. Therapeutic approaches are based on rituximab-containing chemotherapy regimens (R-CHOP), often supplemented with CNS-directed therapy due to the disease’s marked neurotropism. Emerging strategies include autologous stem cell transplantation (ASCT) and novel immunotherapeutic approaches, potentially exploiting the frequent expression of PD-L1 by tumor cells. A distinct but related entity, intravascular NK/T-cell lymphoma (IVNKTCL), is an exceedingly rare EBV-associated lymphoma, showing unique own histologic, immunophenotypic, and molecular features and an even poorer outcome. This review provides a comprehensive overview of the current understandings about clinicopathological, molecular, and therapeutic landscape of IVL, emphasizing the need for increased clinical awareness, standardized diagnostic protocols, and individualized treatment strategies for this aggressive yet intriguing malignancy. Full article

Background/Objectives: Neuronal oscillations play a key role in the symptoms of Parkinson’s disease (PD). This study investigates the effects of random synaptic inputs, their correlations, and the interaction with synaptic dynamics and spike timing-dependent plasticity (STDP) on the membrane potential and firing patterns of subthalamic nucleus (STN) neurons, both in healthy and PD-affected states. Methods: We used a modified Hodgkin–Huxley model with a Langevin stochastic framework to study how synaptic conductance, random input fluctuations, and STDP affect STN neuron firing and membrane potential, including sensitivity to refractory period and synaptic depression variability. Results: Our results show that random inputs significantly affect the firing patterns of STN neurons, both in healthy cells and those with PD under DBS treatment. STDP, along with random refractory periods and fluctuating input currents, increases the irregularity of inter-spike intervals (ISIs) in output neuron spike trains. Sensitivity analyses highlight the key role of synaptic depression and refractory period variability in shaping firing patterns. Combining random inputs with STDP boosts the correlation between neuron activities. Furthermore, at fixed input noise levels, the model’s output closely matches experimental firing rate and ISI variability data from PD patients and animals, with statistical tests confirming significant effects of STDP on firing regularity. Conclusions: The findings suggest that the stochastic dynamics of STN neurons, combined with STDP, are crucial for shaping neuronal firing patterns in both healthy and PD-affected states. These insights improve our understanding of how noise and plasticity contribute to neural function and dysfunction, with implications for PD symptom management. Full article

Angioimmunoblastic T-cell lymphoma (AITL) is a rare and aggressive subtype of non-Hodgkin lymphoma, the monitoring of which is largely restricted to radiological methods. Diagnosis relies on identifying characteristic clinicopathological features, supported by the detection of recurrent somatic mutations in RHOA, TET2, IDH2 and DNMT3A. The characteristic molecular profile of AITL and the high levels of circulating tumour DNA (ctDNA) measurable in AITL before treatment makes this an attractive lymphoma subtype in which to further investigate the role of ctDNA monitoring. The detection of somatic mutations in pre-treatment AITL-containing tissue samples was compared to those detected in pre-treatment ctDNA samples in a cohort of 12 patients. Changes in ctDNA somatic mutation burden over time were then correlated with radiological response. All six paired pre-treatment ctDNA and tissue samples had variants in common. All (8/8) previously ctDNA-detectable IDH2 and RHOA variants were undetectable in ctDNA samples at the time of end-of-treatment complete metabolic response (CMR). In comparison, the majority of both previously ctDNA-detectable DNMT3A variants (3/4) and TET2 variants (6/11) were detectable in ctDNA samples at the time of end-of-treatment CMR. These observations suggest that IDH2/RHOA variants may be more reliable markers of measurable residual disease in AITL than DNMT3A/TET2 variants. Full article

The Epstein–Barr virus (EBV) is the first human herpesvirus identified as an oncogenic agent, with approximately 95% of adults worldwide being latently infected. EBV infection is associated with multiple diseases, including nasopharyngeal carcinoma, Hodgkin’s lymphoma, infectious mononucleosis, and multiple sclerosis. Given significant EBV-associated disease burden, developing effective vaccines against EBV remains a priority. In this review, we first presented the current understanding of EBV biology and pathogenesis, focusing on its biological structure and immune evasion mechanisms, and discussed key viral antigens—including gp350, gp42, gH/gL, and latency proteins—as potential targets for EBV vaccine development. We also summarized recent advances in various EBV vaccine platforms, including subunit, viral vector-based, nanoparticle-based, and mRNA vaccines, and discussed the related preclinical and clinical evidence, although no effective EBV vaccine has been approved for clinical use yet. In summary, this review provides an overview of the current landscape in EBV vaccine research, and sheds new light on developing new therapeutic approaches against EBV-associated diseases. Full article

Background and Clinical Significance: Methotrexate is widely used as a disease-modifying antirheumatic drug for rheumatoid arthritis (RA), yet prolonged immunosuppression may lead to rare complications, including Epstein–Barr virus (EBV)-positive lymphoproliferative disorders (LPDs). Case Presentation: We present the case of a 70-year-old woman with RA on chronic immunosuppressive therapy who developed symptoms resembling recurrent tonsillitis. CT imaging revealed bilateral necrotic palatine tonsils and extensive necrotic lymphadenopathy involving the cervical, mediastinal, and axillary regions. Bilateral tonsillectomy was performed due to concerns about malignancy or infection, and histopathology confirmed a polymorphic EBV-positive LPD with Hodgkin-like features, consistent with iatrogenic immunodeficiency-associated LPD. Methotrexate was subsequently discontinued, and the patient was managed conservatively without systemic chemotherapy. Clinical recovery was observed during follow-up. Conclusions: This case highlights the importance of considering methotrexate-associated LPDs in the differential diagnosis of atypical tonsillar infections in immunosuppressed patients, particularly when necrotic features or systemic lymphadenopathy are present. The pathogenesis may involve EBV reactivation under impaired immune surveillance due to methotrexate, leading to abnormal B-cell proliferation and clonal expansion. This case is contextualized through a comparative analysis of published reports, highlighting clinical features and treatment responses of methotrexate-associated EBV-positive LPDs in the form of a focused literature review. Full article

Programmed death-ligand 1 (PD-L1) on tumor cells, including Hodgkin and Reed–Sternberg (HRS) cells in classical Hodgkin’s lymphoma (cHL), suppresses immune responses in the tumor immune microenvironment (TME). We analyzed PD-L1 expression in macrophages and HRS cells of 98 cHL cases and correlated the findings with clinicopathological features, overall survival (OS), and progression-free survival (PFS). Epstein–Barr virus (EBV) was detected by in situ hybridization for EBV-encoded RNA. Ten high-power fields were evaluated to count the total number of macrophages and PD-L1+ macrophages, and to calculate PD-L1 histoscore (H-score) in HRS cells. EBV-positive cHL was found in 22.5% of patients. The median H-score was 80 (range 0–300). Bulky disease was associated with a lower number of PD-L1+ macrophages, and extranodal disease with a higher number (p = 0.05). EBV-positive cHL showed a higher PD-L1 H-score in HRS cells and a greater number of PD-L1⁺ macrophages (p = 0.005); both of these features, along with the proportion of PD-L1⁺ macrophages, were associated with shorter PFS and OS (p < 0.001). High PD-L1 expression in HRS and macrophages may be linked to worse clinical outcomes. Full article