Search Results (891)

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma in adults and is characterized by aggressive progression and substantial molecular and clinical heterogeneity. Despite advances in immunochemotherapy, a considerable proportion of patients develop relapsed or refractory disease, highlighting the need to better understand the molecular mechanisms underlying DLBCL. Nei-Xiao-Luo-Li-San (NXLLS), a traditional herbal formulation historically used for nodules and tumor-like masses, provides a pharmacological model for investigating molecular responses and candidate regulatory mechanisms in DLBCL. Methods: NXLLS was chemically characterized to assess its compositional profile and compositional similarity among batches. Its biological effects were evaluated by assessing cell viability, migration, invasion, and cell-cycle progression in Toledo DLBCL cells. Molecular responses to NXLLS were investigated through an integrated approach combining transcriptomic analysis, network pharmacology, and molecular assays. The functional role of ATF5 was further evaluated using lentiviral overexpression and knockdown. Results: Chromatographic profiling provided an exploratory assessment of compositional similarity among NXLLS samples and supported the selection of eight representative compounds using liquid chromatography–mass spectrometry (LC–MS) annotation and high-performance liquid chromatography (HPLC) authentic-standard confirmation. NXLLS reduced cell viability, migration, and invasion in Toledo DLBCL cells within the tested concentration range. At the molecular level, NXLLS was associated with altered cell-cycle distribution and potential G1-phase accumulation at later time points, reduced vascular endothelial growth factor (VEGF)-associated enzyme-linked immunosorbent assay (ELISA) signal, and modulated stress-response genes. RNA sequencing (RNA-seq) revealed transcriptional changes involving stress-response and histone deacetylase (HDAC)-associated epigenetic pathways. Correspondingly, HDAC expression was reduced, whereas acetylated histone H3 lysine 9 (Ac-H3K9) and acetylated histone H3 lysine 27 (Ac-H3K27) levels were increased. ATF5 knockdown recapitulated several cellular and epigenetic changes observed following NXLLS treatment, supporting ATF5 as a potential downstream mediator of the NXLLS response. Conclusions: This study identified potential molecular targets associated with the response to NXLLS in Toledo DLBCL cells, with ATF5 further investigated as a potential downstream mediator. The findings also suggest an association between the NXLLS response and HDAC-related epigenetic changes, providing a basis for further investigation of their mechanistic relationships. Full article

Cutaneous T-cell lymphoma (CTCL) is a chronic, generally incurable group of non-Hodgkin lymphomas associated with substantial symptom burden, yet receipt of palliative-intent treatment in this population remains uncharacterized. We conducted a cross-sectional retrospective study of 13,215 patients with CTCL using the National Cancer Database (2004–2023) to evaluate receipt of palliative-intent treatment by sociodemographic and disease characteristics using χ² tests, Wilcoxon rank sum tests, Fisher’s exact tests, and multivariable logistic regression. Only 355 patients (2.7%) received palliative-intent treatment. In multivariable analysis, the strongest factors associated with palliative-intent treatment receipt were regional stage (OR, 3.19; 95% CI, 2.43–4.17) and distant stage (OR, 2.49; 95% CI, 1.86–3.31). Treatment at academic facilities was associated with significantly lower odds of NCDB-defined palliative care receipt (OR, 0.59; 95% CI, 0.47–0.76). Medicare insurance, primary cutaneous CD30+ histology, higher comorbidity burden, head and neck primary site, and more recent diagnosis were also independently associated with receipt of palliative-intent treatment. Sex, race, income, and distance to the facility were not significant. Palliative-intent treatment receipt is markedly low in CTCL despite guideline recommendations supporting early integration. Systematic screening for palliative care needs is warranted, particularly for patients with advanced-stage disease or high symptom burden. Full article

Background/Objectives: CD20×CD3 bispecific antibodies (BsAbs) have changed the management of relapsed/refractory (R/R) B-cell non-Hodgkin lymphoma. Whether and how radiotherapy (RT) can be safely and usefully combined with BsAb therapy remains undefined. This Perspective reviews the biological rationale and the available clinical evidence, distinguishing the established findings from the hypotheses. Methods: We conducted a targeted, non-systematic review of RT combined with CD20×CD3 BsAbs in B-cell lymphoma, searching PubMed/MEDLINE, the Cochrane Library, and ClinicalTrials.gov, supplemented by conference abstracts and a post hoc verification search. Given the immaturity and heterogeneity of the field, we used a narrative synthesis rather than a systematic search. Sources were classified as direct evidence, mixed/indirect (non-disaggregable) evidence, or registered trials without results; only the first category was used to support clinical claims. Results: Direct evidence comprises three case reports, a 7-patient lymphoma subgroup, and a 29-patient cohort with disaggregated CRS/neurotoxicity data. Additional mixed/indirect evidence comes from a 12-patient series. Three registered trials have not yet reported results. Five partially overlapping rationales are proposed: cytoreduction, the modulation of the tumour microenvironment, the management of tumour flare, the consolidation of residual disease, and urgent local control during BsAb step-up dosing. The potential antagonistic effects, including CD20 loss and T-cell depletion, have received comparatively little study. Whether RT-induced lymphopenia could blunt BsAb efficacy remains a key open question. Conclusions: The available evidence indicates only that RT has occasionally been delivered around BsAb therapy in small, non-comparative series, without a consistent toxicity signal. It does not establish the benefit, synergy, or optimal sequencing. Prospective studies are needed to define the role of RT in this setting. Full article

Background/Objectives: Hodgkin lymphoma (HL) and primary mediastinal B-cell lymphoma (PMBCL) affect young women, with cure rates exceeding 80%. Treatment-related gonadal insufficiency is recognized for its impact on fertility, yet fertility preservation remains underutilized, and prospective data are limited. The aim of this study is to prospectively evaluate gonadal function in women ≤40 years old with lymphoma undergoing chemotherapy. Methods: Ovarian reserve and endocrine ovarian function were evaluated by sequential measurements of follicle-stimulating hormone (FSH), luteinizing hormone (LH), anti-Müllerian hormone (AMH), progesterone, and estradiol at diagnosis, during, and after chemotherapy. Results: 81 female patients ≤40 years old were enrolled, including 53 with HL and 28 with NHL (16 with PMBCL). HL patients had significantly lower AMH values for their respective age group compared to all other diagnoses (p = 0.05), which was more striking for patients ≤30 years old (p = 0.039), indicating pre-existing reduced ovarian reserve in HL. In HL, both FSH and AMH levels indicate gonadal dysfunction for at least six months post-chemotherapy, with AMH serving as a more sensitive biomarker than FSH. For PMBCL patients treated with R-DA-EPOCH, AMH suppression was noticed, with no evidence of recovery up to 18 months post-treatment. At all time points, the PMBCL patients had significantly lower AMH values compared to the HL patients (AMH6: p = 0.03, AMH12 and AMH18: p = 0.05). AMH emerged as the most sensitive marker of ovarian damage, with pretreatment levels <7 pmol/L predicting impaired ovarian reserve in HL patients. Conclusions: For HL, the pretreatment cut-off of 7 pmol/L could discriminate patients with ovarian insufficiency post-treatment, whereas no statistically significant predictive association was identified in PMBCL. These findings require validation in larger cohorts. Full article

Background/Objectives: Cutaneous T-cell lymphomas (CTCL), most commonly mycosis fungoides and Sézary syndrome, are rare non-Hodgkin lymphomas. Advanced disease responds poorly to current treatments, highlighting the need for new molecularly targeted therapies. WEE1 is a central regulator of the G2/M checkpoint and S-phase progression and has emerged as a therapeutic target in several malignancies, yet it has not been systematically explored in CTCL. Methods: We screened a library of more than 2200 kinase inhibitors in CTCL cell lines and selected adavosertib for further study. Its effects were tested in four CTCL lines; primary keratinocytes and fibroblasts; patient-derived malignant CD4⁺ T cells and healthy donor CD4⁺ T cells; and a MyLa xenograft model, using viability, apoptosis, cell-cycle, Western blot, and phospho-protein array assays. Results: Adavosertib reduced viability at submicromolar IC₅₀ values (0.26–0.56 µM) across all four CTCL lines while largely sparing primary skin cells and was more active in malignant than in healthy donor CD4⁺ T cells. It induced apoptosis and cell-line-specific S-phase and/or G2/M accumulation, lowered WEE1 and phospho-CDK1 (Tyr15), and increased phospho-H2A.X. A phospho-protein array showed activation of checkpoint and stress signalling. In a preliminary xenograft experiment, adavosertib slowed MyLa tumour growth. Conclusions: These preclinical data identify WEE1 as a therapeutic target in CTCL and support further preclinical and early-phase clinical evaluation of adavosertib in this disease. Full article

Background: Immunotherapy and targeted therapy have gained ground over conventional chemotherapy in treating various cancers. While pulmonary toxicity associated with these agents is rare, it represents a significant factor in both mortality and morbidity and may influence the overall success of cancer treatment. This case series report adds to the emerging evidence of cancer therapy-induced pneumonitis features and corticotherapy outcomes. Patients and methods: This single-center, retrospective case series analyzed 12 consecutive cases of patients undergoing immunotherapy (four receiving nivolumab, four receiving pembrolizumab) or targeted therapy (three receiving obinutuzumab, one receiving abemaciclib) for cancer (seven with lung cancer, three with non-Hodgkin lymphoma, one with breast cancer, one with renal cancer) who developed pneumonitis during their follow-up. Results: The interval from oncological treatment initiation to pneumonitis onset ranged from 6 to 48 months (median = 18.5), and in four patients it occurred after discontinuation of oncologic therapy. In most patients, the diagnosis was established with high probability based only on the clinical presentation, radiologic pattern, and concomitant oncologic therapy. Bronchoscopy with bronchoalveolar lavage analysis was performed in eight of the 12 patients, particularly when onset followed treatment discontinuation. The main symptom was dyspnea (10/12 cases), and three of 12 patients had respiratory failure (SpO₂ ≤ 88%). The CTCAE severity grades were: one mild, seven moderate, three severe, and one life-threatening. The CT scan showed different patterns (7 OP, 4 NSIP-like, and 1 HP). Eleven patients received oral methylprednisolone (0.40 to 0.82 mg/kg) for 5 to 16 weeks. Two patients continued oncologic treatment, and six discontinued. Pneumonitis improved or resolved in 11 of the 12 patients; one patient deteriorated after reintroduction of immunotherapy and subsequently died from cancer-related complications. Conclusions: Immunotherapy- and targeted therapy-induced pneumonitis can express various features and severities, and prompt recognition and diagnosis based on clinical, radiologic and contextual elements are mandatory. In this small, heterogeneous series the individualized corticosteroid regimens used were followed by favorable outcomes. Our observations suggest that, in selected clinically improving patients, follow-up may rely only on clinical assessment and chest X-ray, and extensive tests may be reserved for non-responsive cases. Full article

Diffuse large B-cell lymphoma (DLBCL), the most prevalent subtype of non-Hodgkin lymphoma (NHL), is an aggressive and fairly heterogeneous group with diverse clinical, pathological, and molecular features. Despite the success of first-line immunochemotherapy, relapsed or treatment-resistant forms remain a clinical challenge. Consequently, minimally invasive markers are needed to predict refractoriness. Recently, circulating microRNAs (miRNAs) have emerged as highly stable, promising biomarkers. MiRNAs such as miR-21, miR-155, miR-222-3p, and the miR-17~92 cluster act as oncogenes that promote tumor survival, while others, such as miR-34, miR-181a, miR-144, miR-101, miR-10a, and miR-320, act as tumor suppressors. Despite multiple recent publications that have correlated dysregulated miRNAs with diagnostic and prognostic importance, the clinical translation has not been fully addressed. Overall, this review provides an updated perspective on the potential of miRNAs in DLBCL and outlines key challenges and future directions for their integration into precision oncology, as miRNAs can remodel the clinical management of DLBCL by enabling earlier diagnosis, improved prognostication, and personalized treatment approaches. Full article

Chronic hepatitis C virus (HCV) infection is an established risk factor for B-cell lymphoproliferative disorders and represents a paradigmatic model of infection-driven lymphomagenesis. Although direct-acting antivirals have markedly reduced the burden of HCV-related disease, HCV-associated lymphomas continue to occur. Moreover, HCV screening remains incomplete in some geographical areas and healthcare settings, leaving a substantial proportion of infected individuals unaware of their status. This narrative review integrates current evidence on the mechanisms linking chronic HCV infection to mixed cryoglobulinemia and overt B-cell non-Hodgkin lymphoma. HCV lymphotropism and persistent antigenic stimulation could initially promote the selection and expansion of autoreactive B-cell clones, while mixed cryoglobulinemia represents the most informative pre-lymphomatous risk condition. Cytokine-mediated survival signals, particularly those involving B-cell activating factor, reinforce clonal persistence and cooperate with host genetic susceptibility, impaired apoptotic control, and activation-induced cytidine deaminase-mediated genomic instability. The progressive acquisition of somatic driver mutations, copy-number alterations, and epigenetic and transcriptomic changes may enable selected clones to escape functional anergy and become increasingly independent of the original viral stimulus that, in turn, represents an initial trigger of the lymphoproliferative process. Recurrent abnormalities converge on NF-κB, NOTCH, chromatin-regulatory, apoptotic, and cell-cycle pathways, although HCV-associated lymphomas remain molecularly heterogeneous. Emerging microRNA profiles further contribute to the molecular characterization of the transition from chronic infection and cryoglobulinemia to lymphoma. Despite the availability of highly effective antiviral therapies, HCV-associated lymphomagenesis remains clinically relevant and continues to provide an especially informative model for understanding how chronic viral infection can drive human cancer development. Full article

Background/Objectives: Lymphomas are the third most common pediatric malignancy, with non-Hodgkin lymphoma (NHL) comprising around 7% of childhood cancers. Environmental exposures have been linked to its etiology. Particulate matter (PM) prenatal exposure is increasingly scrutinized for potential effects on early-life carcinogenesis. We investigated whether exposure during pregnancy to PM_2.5 and PM₁₀ was associated with childhood NHL incidence. Methods: A population-based case–control study was conducted in Spain (2009–2016), including 3,682,038 children < 15 years. Incident NHL cases (n = 289) were identified through the Spanish Childhood Tumor Registry. Prenatal PM_2.5 and PM₁₀ exposures were estimated using a random forest model. Logistic regression estimated odds ratios (ORs) and 95% confidence intervals (CIs). Exposures were modeled continuously and categorically by tertiles (low, medium, or high exposure) to assess nonlinearity; trimester-specific analyses were also explored. Results: In the analysis with the continuous exposure, higher prenatal PM_2.5 was associated with increased odds of NHL, and PM₁₀ showed smaller associations. With categorical variables, medium and high-level exposure to PM_2.5 showed an association with higher NHL incidence, especially in the third trimester. High-level exposure to PM₁₀ during the first and second trimesters was linked to a higher NHL incidence in children under five years. Conclusions: Maternal PM_2.5 and PM₁₀ exposure during pregnancy could be associated with childhood NHL incidence, with stronger associations among children diagnosed before age 5. These findings warrant replication and mechanistic investigation. Full article

Background: Late-onset neutropenia (LON) and hypogammaglobulinemia are recognized sequelae of rituximab therapy in B-cell non-Hodgkin lymphoma, and both may leave patients vulnerable to infection once treatment has ended. Methods: Fifty-three patients with newly diagnosed, unfavorable diffuse large B-cell lymphoma (DLBCL) who entered remission on dose-adjusted (DA) R-EPOCH immunochemotherapy were retrospectively evaluated. Neutropenia (absolute neutrophil count < 1.5 × 10⁹/L, CTCAE-graded), hypogammaglobulinemia and infections were registered at treatment completion and 6 and 12 months later. Results: All laboratory parameters changed significantly over time. Most reached their nadir at the end of treatment, whereas the absolute neutrophil count alone reached its lowest value later, at 6 months. Neutropenia, largely mild to moderate, affected 17.6% of patients at treatment completion, 22.4% at 6 months and 7.9% at 12 months. Neutropenia at 6 months was a new event, with no overlap with end-of-treatment neutropenia, and was mostly transient. Hypogammaglobulinemia (IgG < 5 g/L) occurred in 33.3%, 16.7% and 20.0%, respectively; median IgG declined to a nadir at the end of treatment and recovered thereafter, although the deficit tended to persist in the same patients. Post-treatment infections were recorded in 73.6% of patients (mostly respiratory); neutropenia was not associated with infection at any time point, whereas end-of-treatment hypogammaglobulinemia was associated with respiratory infection (p = 0.040). The independent predictors of 6-month neutropenia were a greater number of dose-escalated cycles, lower baseline leukocyte count and the absence of on-treatment infection, whereas 6-month hypogammaglobulinemia was predicted by autologous transplantation and the absence of B symptoms. In exploratory body composition analyses, lower baseline psoas muscle mass was associated with end-of-treatment neutropenia (p = 0.042) and greater muscle loss with other site (skin and gastrointestinal) infection (p = 0.004). Conclusions: After DA-R-EPOCH, LON is a delayed and largely transient event separate from end-of-treatment neutropenia, whereas hypogammaglobulinemia is more persistent and clinically relevant for respiratory infections. Full article

Radiation-free treatment for early-stage classic Hodgkin lymphoma (eHL) has been shown to be less effective than standard combined-modality treatment (CMT; chemotherapy plus involved-node radiotherapy (INRT)), which achieves long-term disease control of 94–95%. Approximately 70% of patients can be cured with chemotherapy alone, whereas about 5% fail CMT. Identifying patients who can safely receive chemotherapy alone and those requiring intensified CMT could enable a risk-adapted treatment strategy. The RAFTING trial (NCT04866654; EudraCT 2020-002382-33) is an international, prospective, phase 2, non-inferiority study enrolling patients 18–70 years, stage I–IIA eHL without bulky disease, B symptoms, or extranodal involvement. Low-risk (LR) patients are defined by total metabolic tumor volume (TMTV) <84 mL and negative PET-2. Those with at least one modified EORTC (mEORTC) risk factor, in which bulky disease is replaced by a large nodal mass (5–10 cm), receive four ABVD cycles, while those without risk factors receive two ABVD cycles alone. High-risk (HR) patients, defined by TMTV ≥84 mL and/or positive PET-2, receive “triple therapy”: 4 ABVD cycles, INRT (20/30 Gy), and nivolumab (240 mg q2w, ≤doses). LR patients are monitored using cfDNA. Limited relapse is treated with INRT (36 Gy) and nivolumab. The RAFTING trial is the first prospective eHL study to personalize treatment using TMTV and PET-2. It aims to omit radiotherapy in LR patients, intensify treatment in HR patients, and spare relapsed LR patients high-dose chemotherapy and autologous transplantation. CfDNA is being evaluated as a relapse marker. Despite the protocol’s complexity, this study exemplifies personalized medicine and could transform treatment practices. Full article

Background: Perinatal and early-life factors may influence non-Hodgkin lymphoma (NHL) risk, but study results have been mixed and exposure data for childhood ages are limited. Herein, we investigated associations of these exposures with risk of NHL and common subtypes. Methods: This case–control study included 2280 NHL cases and 2253 controls, enrolled from 2002 to 2014 at the Mayo Clinic Rochester. Self-reported perinatal and early-life exposures included maternal age at birth, birth order, birthweight, time breastfed, height and weight at ages 7, 12, and 18 years relative to peers, and age and weight when growth ceased. We used logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs), adjusting for design variables and potential confounders. Linear trend tests were performed for ordinal variables, and heterogeneity tests were performed to evaluate whether associations varied across four NHL subtypes. Results: After multivariable adjustment, greater birth weight (OR = 1.15 for quartile 4 vs. 1; p-trend = 0.04), weight at age 7 relative to peers (compared to average, OR = 1.05 for heavy and OR = 0.87 for thin; p-trend = 0.002), and weight when growth ceased (OR = 1.30 for quartile 4 vs. 1; p-trend < 0.001) were associated with increased NHL risk. An inverse association was observed for breastfeeding duration with NHL risk (OR = 0.77 for >6 months vs. never; 95% CI 0.61–0.97). Associations did not significantly vary by major NHL subtype (p-heterogeneity > 0.05). Other perinatal and early-life exposures were not associated with NHL risk. Conclusions: Greater body weight at birth and through childhood may be associated with increased NHL risk, potentially extending the life-course perspective on adiposity and lymphomagenesis, with implications for prevention. Full article

Diffuse large B-cell lymphoma (DLBCL) represents the most frequent subtype of non-Hodgkin lymphoma; however, conventional 2D cultures and murine models fail to fully recapitulate the complexity of the human tumor microenvironment (TME). To address these limitations, we developed and characterized three chitosan-based hydrogels with distinct physicochemical and mechanical properties as tunable three-dimensional (3D) platforms for DLBCL culture. U2932 lymphoma cells were encapsulated either alone or in co-culture with WPMY-1 stromal cells to investigate the effects of matrix stiffness and stromal support on lymphoma growth. Furthermore, co-culture with stromal cells promoted rapid spheroid formation and generated larger cellular aggregates than mono-cultures, with the most pronounced effect observed in the 2% chitosan hydrogel. Live/dead assays demonstrated high cell viability within the selected culture condition. Overall, the 2% chitosan formulation provided the most suitable microenvironment for supporting DLBCL growth and organization, highlighting its potential as a physiologically relevant 3D in vitro model for investigating lymphoma biology and evaluating novel therapeutic strategies. Full article

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of clinically aggressive mature T-cell and natural killer (NK)-cell neoplasms that account for approximately 10–15% of all non-Hodgkin lymphomas in Western countries . The most common subtypes include extranodal NK/T-cell lymphoma (ENKTL), nodal T-follicular helper cell lymphomas, peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS), anaplastic large cell lymphoma (ALK-positive and ALK-negative), and T-cell lymphoblastic lymphoma. Non-coding RNAs (ncRNAs) constitute the majority of the human transcriptome and play critical roles in regulating gene expression, cellular proliferation, differentiation, migration, and apoptosis. Among these, long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as key regulators of lymphomagenesis and disease progression in PTCLs. These molecules modulate diverse oncogenic pathways through chromatin remodeling, transcriptional regulation, competing endogenous RNA activity, and interactions with RNA-binding proteins, thereby influencing proliferation, immune evasion, treatment resistance, and clinical outcomes. Representative examples include the lncRNA TCLlnc1, which promotes PTCL progression through activation of transforming growth factor-β (TGF-β) signaling, and the circRNAs circKIF4A, circADARB1, and circ-LAMP1, which regulate miRNA-dependent signaling networks involving PDK1/BCL11A, STAT3, and DDR2, respectively. In this review, we summarize the current understanding of the biological and clinical roles of lncRNAs and circRNAs in PTCL and related T-cell and NK-cell neoplasms and highlight their potential as diagnostic and prognostic biomarkers as well as therapeutic targets. We also discuss recent advances and future directions for integrating ncRNA-based approaches into precision medicine for T-cell lymphoma. Full article

Lymphomas are broadly categorized into Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Despite treatment advances, they remain a major cause of cancer-related morbidity and mortality in Canada. This study examined temporal trends in socioeconomic inequalities in lymphoma mortality in Canada from 2000 to 2019. Using a unique census division level dataset (n = 280) constructed by pooling information from the Canadian Vital Statistics Death Database, the Canadian Census of Population and the National Household Survey, we measured mortality in HL and NHL in Canada. The age-standardized Concentration index (C) was used to quantify income and education inequalities in lymphoma. Time trend analyses were conducted to examine the changes in the observed socioeconomic inequalities. Crude HL mortality declined significantly over the study period. Crude NHL mortality remained largely unchanged in Canada overall, although modest declines were observed in the Prairies. The age-standardized C indicated persistent income and education inequalities for both lymphoma types. For NHL, mortality became increasingly concentrated among lower-income and lower-education populations over time. The persistent and widening socioeconomic inequalities observed in HL and NHL mortality, respectively, in Canada underscore the need for targeted public health interventions and more equitable distribution of resources to address systematic and avoidable differences in cancer outcomes associated with socioeconomic disadvantage. Full article