Search Results (357)

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) exhibits pronounced racial disparities in incidence and outcomes, yet the molecular basis remains poorly understood. Here, we examined racial differences in gene rearrangements (MYC, BCL2, BCL6), fusions (IGH::MYC, IGH::BCL2), and their interactions among White, Black, Asian, and Other-race groups in patients with DLBCL to uncover genetic drivers of disparities. Methods: We analyzed 919 DLBCL cases (2006–2023) from Johns Hopkins Hospital using fluorescence in situ hybridization to detect gene abnormalities. We used logistic regression and proportional odds models, adjusted for age and sex, to evaluate racial differences in five gene abnormalities and 10 gene–gene interaction pairs. Pearson’s Chi-squared and Goodman–Kruskal’s gamma tests assessed prevalence and interaction severity across racial groups. Results: MYC rearrangements and the MYC*IGH::MYC interaction were marginally more frequent in the White group than in Black and Other groups (p = 0.092, p = 0.098, respectively). IGH::BCL2 fusions were more prevalent in the Asian group than in the White group (p = 0.095), and the BCL2*IGH::BCL2 interaction was significantly higher in the Asian group (p = 0.049) than in the White group. Although high-grade B-cell lymphoma (HGBCL) prevalence showed no significant racial differences (p = 0.16), the Asian group exhibited a higher proportion of aggressive HGBCL with concurrent IGH::MYC and IGH::BCL2 fusions compared with the White group (p = 0.076). Age significantly influenced all gene abnormalities and interactions (p < 0.001–0.052), except for MYC rearrangements and specific pairs. Sex and sex–race interactions showed no significant effects. Conclusions: This study highlights molecular contributions to the racial differences in DLBCL disease. Further research collecting ancestry-specific biomarkers, treatment regimens, and clinical variables and outcomes is needed to advance personalized treatment strategies. Full article

Perioperative anesthesia might directly alter cancer cell biology. We investigated the effects of levobupivacaine treatment on lung adenocarcinoma cells. A549 cells were treated with levobupivacaine at concentrations of 0.1 mM and 0.5 mM for 2 h. Transfection with angiotensin-converting enzyme 2 (ACE2) small interfering RNA (siRNA) was performed 6 h before the levobupivacaine treatment. Cell proliferation was assessed using a cell counting kit 8 (CCK-8), and ATP synthesis was evaluated with the CellTiter-Glo^® 2.0 assay at 0 and 24 h after anesthesia exposure. RT-PCR was performed to examine various biomarkers. The levobupivacaine treatment suppressed ATP synthesis without affecting cell proliferation. This was associated with the upregulation of ACE2 and the downregulation of pro-cancer biomarkers, including HIF-1α, MMP-9, and β-catenin. The anticancer effect of levobupivacaine was negated when ACE2 siRNA was introduced, and it was further suppressed when combined with levobupivacaine. The RT-PCR results indicated that the expressions of B-cell/CLL lymphoma 2 (BCL2) and wingless/integrated 1 (WNT1) were reduced after levobupivacaine treatment, but these effects were reversed with ACE2 siRNA induction. The administration of levobupivacaine suppressed A549 cell metabolism and downregulated HIF-1α, MMP-9, WNT1, EGFR, and BCL2 in an ACE2-dependent manner. Full article

Background/Objectives: Diffuse large B-cell lymphoma (DLBCL) is a molecularly and pathogenically heterogenous disease with varying clinical outcomes, as reflected by the significant number of patients who develop relapse/refractory disease (rrDLBCL) following standard treatment with the combined R-CHOP regimen. The molecular background of rrDLBCL is not yet fully understood, and prognostic and/or companion diagnostic biomarkers for identification and treatment stratification of these patients are in high demand. Methods: This exploratory study used comprehensive proteomic data to identify proteins associated with treatment response. Proteome profiles of DLBCL cells were analyzed through groupwise comparison between cell lines with a resistant or sensitive response to rituximab, cyclophosphamide, doxorubicin, and vincristine. Their responses were determined using subsequent drug response screens, mimicking the conditions of diagnostic samples prior to treatment. Results: A total of 98 differentially abundant proteins, including NSFL1C, GET4, PCNA, and SMC5, were found between resistant and sensitive cells. These same 98 proteins were examined in two cohorts of DLBCL patients, leading to the identification of 16 proteins whose expression was consistently associated with treatment response both in vitro and in patient tissue samples. Among these, GET4 and NSFL1C showed the highest enrichment in R-CHOP resistant patients compared to sensitive responders. In the cell line study, GET4 was enriched in cyclophosphamide-resistant cell lines and NSFL1C enriched in vincristine-resistant cell lines, associating GET4 and NSFL1C enrichment in patient samples to responsiveness to cyclophosphamide and vincristine, respectively. Enrichment of DNA damage repair proteins was observed within the differential proteins, highlighting the need to investigate DNA damage repair involvement in treatment responses. Conclusions: This study identifies 16 proteins with concordant treatment response specificity in DLBCL cell lines and lymphoma tissue patient samples, suggesting their potential as prognostic markers for DLBCL. Full article

Objectives: The potential use of electron density (ED) and effective atomic number (Zeff) derived from dual-energy computed tomography (DECT) as novel quantitative imaging biomarkers for differentiating malignant brain tumors was investigated. Methods: Data pertaining to 136 patients with a pathological diagnosis of brain metastasis (BM), glioblastoma, and primary central nervous system lymphoma (PCNSL) were retrospectively reviewed. The 10th percentile, mean and 90th percentile values of conventional 120-kVp CT value (CTconv), ED, Zeff, and relative apparent diffusion coefficient derived from diffusion-weighted magnetic resonance imaging (rADC: ADC of lesion divided by ADC of normal-appearing white matter) within the contrast-enhanced tumor region were compared across the three groups. Furthermore, machine learning (ML)-based diagnostic models were developed to maximize diagnostic performance for each tumor classification using the indices of DECT parameters and rADC. Machine learning models were developed using the AutoGluon-Tabular framework with rigorous patient-level data splitting into training (60%), validation (20%), and independent test sets (20%). Results: The 10th percentile of Zeff was significantly higher in glioblastomas than in BMs (p = 0.02), and it was the only index with a significant difference between BMs and glioblastomas. In the comparisons including PCNSLs, all indices of CTconv, Zeff, and rADC exhibited significant differences (p < 0.001–0.02). DECT-based ML models exhibited high area under the receiver operating characteristic curves (AUC) for all pairwise differentiations (BMs vs. Glioblastomas: AUC = 0.83; BMs vs. PCNSLs: AUC = 0.91; Glioblastomas vs. PCNSLs: AUC = 0.82). Combined models of DECT and rADC demonstrated excellent diagnostic performance between BMs and PCNSLs (AUC = 1) and between Glioblastomas and PCNSLs (AUC = 0.93). Conclusion: This study suggested the potential of DECT-derived ED and Zeff as novel quantitative imaging biomarkers for differentiating malignant brain tumors. Full article

Follicular lymphoma management is rapidly evolving with advanced cellular therapies. This review examines the optimal sequencing of autologous stem cell transplantation (autoSCT), allogeneic stem cell transplantation (alloSCT), and CAR T-cell therapy. AutoSCT is a crucial intervention for chemosensitive relapsed FL, prolonging progression-free survival, though not typically curative. AlloSCT, offering a potential cure via a graft-versus-lymphoma effect, carries significant risks like graft-versus-host disease and non-relapse mortality, thus primarily serving as a salvage option for high-risk or treatment-refractory cases after other modalities, including autoSCT. CAR T-cell therapy, utilizing genetically modified T cells targeting CD19, has revolutionized relapsed/refractory FL. Products like axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel have demonstrated high response rates and durable remissions even in heavily pretreated patients with high-risk features. This potent therapy is increasingly considered a bridge between autoSCT and alloSCT, expanding treatment options. Additionally, bispecific antibodies such as mosunetuzumab, epcoritamab and odrenextamab provide convenient off-the-shelf options, exhibiting strong efficacy and favorable safety. However, their impact on subsequent CAR-T outcomes, especially with CD19-targeting bispecifics, remains an area of ongoing investigation and uncertainty. The complex interplay of these therapies necessitates individualized decisions, emphasizing patient characteristics and disease-specific factors to optimize outcomes in FL. Further research into predictive biomarkers and refined treatment algorithms is crucial for future management. Full article

Background: Cancer treatments can damage the ovaries, with implications for fertility and reproductive lifespan. Therefore, a useful biomarker for fertility preservation counseling is needed, and anti-Müllerian hormone (AMH) measurement provides an index of the treatment gonadotoxicity. The debate is currently open as to whether the ovarian reserve may already be reduced before exposure to anticancer therapy. Therefore, our aim was to evaluate the influence of cancer on AMH levels. Methods: The present retrospective, cross-sectional study was carried out at the Centre for Reproductive Medicine and IVF Unit in Conversano, ASL Bari (Bari, Italy). All data were collected between 2019 and 2023. The serum AMH levels of 175 female patients with cancer were compared with those of non-cancer patients of reproductive age, just before starting chemotherapy. Results: AMH levels in women with breast cancer did not differ significantly from those in women without breast cancer (2.83 [0.81–9.15] ng/mL vs. 2.58 [0.7–9.2] ng/mL; p-value = 0.23). The AMH levels of the non-Hodgkin or Hodgkin lymphoma group were significantly lower than those of the non-cancer group (1.9 [0.7–7.0] vs. 3.2 [0.9–10.00] ng/mL; p-value < 0.05). Conclusions: AMH levels of non-Hodgkin or Hodgkin lymphoma patients were already reduced before cancer therapy compared to those of non-cancer patients. These results may be related to the systemic effect of the lymphoma, compared with other types of cancer. Full article

People with HIV (PWH) are at an increased risk for AIDS-associated non-Hodgkin lymphoma (AIDS-NHL); however, the immune signatures underlying this risk are not well understood. In this study, we utilized mass cytometry by time-of-flight (CyTOF) to analyze T-cells and monocytes in the PBMCs of treatment-naïve PWH, including those 3 to 36 months before an AIDS-NHL diagnosis (HIV-positive pre-NHL), as well as people without HIV (PWoH). Mass cytometry is an advanced single-cell analysis platform that combines flow cytometry principles with mass spectrometry. Unlike conventional flow cytometry, this technology employs antibodies conjugated to unique metal isotopes instead of fluorescent markers, enabling simultaneous measurement of over 40 distinct cellular markers per individual cell without spectral overlap limitations. Participants were enrolled at the Los Angeles site of the MACS/WIHS Combined Cohort Study (MWCCS). Unsupervised clustering and Uniform Manifold Approximation and Projection (UMAP) analysis identified CD3⁺ T-cell and CD14⁺ monocyte metaclusters, and Spearman’s rank correlation assessed their relationships with B-cell subsets exhibiting aberrant phenotypes. We observed elevated levels of CD8⁺CD20⁺ T-cells, CD8⁺CD14⁺ T-cells, and M2-like CD14⁺CD163⁺ monocytes in HIV-positive pre-NHL individuals compared to HIV-negative controls. Positive correlations were found between CD19⁺ AICDA⁺ cMYC⁺ B-cells and M1-like CD14⁺cMYC⁺ monocytes (metacluster, MC02), and between metaclusters of CD8⁺PD-1⁺CD27⁺CXCR4⁻ T-cells (MC05) and CD4⁺FoxP3⁺PD-1⁺CD27⁺CD28⁺CXCR4⁻ ICOS⁺ T-cells (MC08). In addition, a different CD19⁺ B-cell metacluster (FoxP3⁺AICDA⁺cMYC⁺) was positively associated with a metacluster of CD8⁺PD-1⁺CD27⁺CD28⁺CXCR4⁺ T-cells (MC03). Moreover, the metacluster of CD8⁺PD-1⁺CD27⁺CXCR4⁻ T-cells (MC05) negatively correlated with M2-like CD14⁺CD163⁺ monocytes (MC06), while CD8⁺CD14⁺ T-cells positively correlated with AICDA⁺ Bregs and IL-10⁺ B-regs in HIV-positive pre-NHL individuals. Unsupervised analysis revealed increased frequencies of CD8⁺CD20⁺ T-cells in HIV-positive individuals compared to HIV-negative controls. These immune alterations provide valuable insights into potential biomarkers for early detection, monitoring, and therapeutic strategies for AIDS-NHL. Full article

Background: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of relapsed/refractory large B-cell lymphoma (LBCL), but its administration is often complicated by cytokine release syndrome (CRS). Interleukin-6 (IL-6) is widely used to monitor CRS, though its clinical value diminishes after tocilizumab administration. We aimed to evaluate serum amyloid A (SAA), a dynamic acute-phase reactant, as a treatment-independent biomarker of inflammation and toxicity in CAR-T recipients. Methods: This retrospective study included 43 adults with LBCL treated with axicabtagene ciloleucel. SAA and other inflammatory markers were assessed from lymphodepletion through day +11 post-infusion. CRS and ICANS were graded per ASTCT criteria. Statistical analyses included Mann–Whitney U tests, Spearman’s correlation, and ROC curve analysis to evaluate predictive performance. Results: SAA levels peaked at day +4 and normalized by day +11, displaying wave-like kinetics. Levels were significantly higher in patients with any-grade CRS at early timepoints but showed no association with ICANS. SAA correlated strongly with CRP, suPAR, sST2, fibrinogen, ferritin, procalcitonin, and IL-6. Compared to IL-6, SAA was more predictive of CRS at day +2 and +4, and unaffected by tocilizumab. Baseline SAA also correlated with the mEASIX score, suggesting linkage to endothelial stress. Non-responders at 3-month PET had higher baseline SAA than responders (196.0 vs. 17.7 mg/L, p = 0.036), with ROC analysis yielding an AUC of 0.74 and an optimal threshold of 79.8 mg/L. Conclusions: SAA is a robust and dynamic marker of systemic inflammation, with potential utility in both toxicity monitoring and response prediction in the CAR-T setting. Its independence from IL-6 modulation positions it as a promising biomarker for future integration into clinical algorithms. Full article

Aldehyde dehydrogenase 1A1 (ALDH1A1) has emerged as a significant biomarker associated with tumor progression, chemoresistance, and poor prognosis in various cancers, including breast, lung, prostate, and lymphoma. Current diagnostic methods for ALDH1A1, such as flow cytometry and ELISA, are limited by long detection times, the need for labeling, and a reduced sensitivity in complex biological matrices. This study presents a novel optical fiber biosensor based on magnesium silicate nanoparticle-doped fibers for the label-free detection of ALDH1A1. The biosensor design incorporated protein G for enhanced antibody orientation and binding efficiency and anti-ALDH1A1 antibodies for specific recognition. Several sensor configurations were fabricated using a semi-distributed interferometer (SDI) format, and their performances were evaluated across a wide concentration range (10 fM–100 nM) in both phosphate-buffered saline (PBS) and fetal bovine serum (FBS). Our findings demonstrated that the inclusion of protein G significantly improved sensor sensitivity and reproducibility, achieving a limit of detection (LoD) of 172 fM in PBS. The sensor also maintained a positive response trend in FBS, indicating its potential applicability in clinically relevant samples. This work introduces the first reported optical fiber biosensor for soluble ALDH1A1 detection, offering a rapid, label-free, and highly sensitive approach suitable for future use in cancer diagnostics. Full article

Diffuse large B-cell lymphoma (DLBCL) is a molecular and clinical heterogenous entity, and, over the past 30 years, many efforts have been made in trying to dissect this diverseness and identify biomarkers capable of efficiently stratifying DLBCL patients and spotting the ones showing a worse clinical outcome. Despite the achievement in this research field, only a few biomarkers have been validated and introduced in a clinical setting. Among those, approximately 5–15% of DLBCL cases harbor MYC gene translocations, often involving immunoglobulin genes as a translocation partner, and concomitant point mutations, correlating with a poor response to standard therapies. However, given the difficulty in detecting these abnormalities requiring specialized techniques and high-quality specimens, the use of metabolomics (i.e., the study of small metabolites in body fluids and tissues) can offer a useful alternative for the identification of high-risk DLBCL patients. Amino acids (AAs) are metabolites essential in the process of tumorigenesis and can increase immune escape and drug resistance. Therefore, we review the use of metabolomics to improve the diagnosis and prognosis in DLBCL patients in relation to the MYC role in the regulation of amino acid metabolism, as these metabolites may be used as potential biomarkers in a clinical environment. Full article

Background/Objectives: Fluorescence in situ hybridization (FISH) is a standard diagnostic tool for detecting gene fusions and rearrangements in lymphomas but is limited by incomplete genomic coverage, dependence on predefined probes, and difficulty identifying atypical or noncanonical fusion partners. These constraints often result in inconclusive diagnoses in complex lymphoma cases. This study evaluates a novel Hi-C-based sequencing assay from formalin-fixed paraffin-embedded (FFPE) samples to detect clinically significant gene fusions and rearrangements in cases where conventional FISH was inconclusive or expected biomarkers were not detected. Methods: Five diffuse large B-cell lymphoma cases with previously atypical gene fusions or rearrangements by FISH were analyzed using both standard FISH and a Hi-C-based lymphoma assay. Standard FISH was performed using break-apart probes targeting MYC, BCL2, and BCL6, and dual-fusion probes targeting IGH::MYC and IGH::BCL2. The Hi-C assay utilized high-resolution sequencing of FFPE tissue to map chromatin interactions and identify structural variations across the genome and assessment of their clinical relevance. Results: In this series of five lymphoma cases, Hi-C detected additional structural variants beyond those identified by FISH. It identified typical and atypical translocation partners of key oncogenes (MYC, BCL2, BCL6), cryptic breakpoints, and novel genomic events, including TP53 loss, KMT2A amplification, and complex rearrangements, which were undetectable by FISH. The Hi-C assay’s whole-genome coverage enabled comprehensive profiling. Conclusions: The Hi-C-based lymphoma assay offers a transformative diagnostic tool, overcoming FISH limitations by providing unbiased, high-resolution detection of structural variations. This approach enhances diagnostic accuracy and supports personalized therapeutic strategies in lymphoma management, warranting further validation for clinical adoption. Full article

Backgrounds: Epstein–Barr virus (EBV) is implicated in the pathogenesis of different B-cell lymphomas and lymphoproliferative disorders, including diffuse large B-cell lymphoma (DLBCL) arising in immunodeficiency settings. Despite its clinical significance, the mechanisms of EBV-mediated lymphomagenesis across different disease subtypes remain poorly understood. Global DNA methylation profiling can provide insight into tumor heterogeneity and disease mechanisms. Methods: To further characterize the underlying biology of EBV(+) DLBCL, we performed a global methylome analysis of a cohort of EBV(+)/(−) DLBCL. Illumina MethylationEPIC array data were generated from a curated set of DLBCL tissue samples (n = 43) from a rural patient population with defined EBV status and immunodeficiency background. Differential methylation analyses were conducted using linear mixed models to identify significant methylation changes associated with EBV status. Results: Principle component analysis (PCA) and probe-level comparisons revealed a distinct, globally hypermethylated DNA methylome in EBV(+) DLBCL compared to EBV(−) cases, and an overall hypomethylated profile in all DLBCL relative to control tissues. We identified a total of 117,334 differentially methylated probes mapping to 1557 cancer-associated genes in EBV(+) versus EBV(−) DLBCL, and 330,872 probes mapping to 4230 cancer-associated genes in all DLBCL versus controls. Pathway enrichment analysis highlighted distinct biological processes in EBV(+) DLBCL, including P53 feedback loops (hypermethylated genes) and MAPK signaling (hypomethylated genes). Conclusions: These findings demonstrate that EBV(+) DLBCL is epigenetically distinct from EBV(−) disease, with alterations that may contribute to clinical heterogeneity and potentially serve as biomarkers for disease classification and therapeutic targeting. Full article

The current classification of Hodgkin lymphoma (HL) is the result of an integrated approach that combines the evaluation of morphological patterns, immunophenotypic characteristics, molecular features, and clinical presentation. Evolving from its origins based solely on histological observation to the latest updates in the WHO 5th Edition, this system has become an essential tool for accurate diagnosis and personalized therapeutic strategies. Each subtype of classic HL (cHL)—nodular sclerosis, mixed cellularity, lymphocyte-rich, and lymphocyte-depleted—exhibits distinctive pathological and clinical features, now better understood through multidisciplinary studies and international collaborations. HL also includes nodular lymphocyte-predominant HL (NLPHL), a distinct entity with unique morphologic, immunophenotypic, and clinical features. A hallmark morphological feature of cHL is the presence of Hodgkin and Reed-Sternberg (HRS) cells, large and often multinucleated cells derived from B lymphocytes that have lost their typical B-cell phenotype. Identifying these cells is critical for diagnosis and for differentiating HL from other hematologic malignancies. HL is characterized by the rarity of malignant cells, a high curability rate, and a rich immune cell microenvironment that is both shaped and exploited by the tumor. Understanding these core aspects paves the way for exploring the role of immunologic and genetic biomarkers in refining classification, enhancing diagnosis, improving prognostic assessment, and guiding therapy for patients with cHL. Full article

Cutaneous T-cell Lymphomas (CTCLs) are a heterogeneous group of non-Hodgkin lymphomas that currently have an incompletely understood pathophysiology and several challenges in both diagnosis and management. Single-cell RNA sequencing (scRNA-seq) is a powerful tool that enables the analysis of gene expression at the individual-cell level, revealing cellular heterogeneity and a complex tumor microenvironment. As single-cell RNA sequencing has become increasingly utilized, we aimed to provide an update on recent notable applications of single-cell RNA sequencing in CTCL and their findings. The included studies highlight the intricate network of interactions in the tumor microenvironment that contributes to tumorigenesis. While CTCL is notoriously heterogeneous, our results identify key markers that prove promising for diagnosis, prognostication, and therapeutic targets. Full article

Primary central nervous system lymphoma (PCNSL) is a rare extra-nodal non-Hodgkin lymphoma confined to the central nervous system. The cancer biology of PCNSL remains incomplete and is often associated with genetic aberrations with abnormal signaling pathways, cell differentiation, regulation of epigenetic modification, and the tumor microenvironment. Stereotactic brain biopsy remains the gold standard for the diagnosis of PCNSL. For patients ill-suited for biopsy, MYD88 and IL-10 may be important biomarkers to diagnose PCNSL. High-dose methotrexate-based polychemotherapy is currently the standard induction treatment for PCNSL, followed by consolidation treatments including autologous stem cell transplant and whole-brain radiotherapy. Some studies suggest that low-dose lenalidomide is recommended as a maintenance therapy for PCNSL. Currently, relapse rates of PCNSL range from 25 to 50% with poor prognosis. Insight research is necessary to identify novel targeted treatments to improve outcomes in relapsed/refractory disease, such as immunomodulatory drugs, immune checkpoint inhibitors, signaling pathway inhibitors, and chimeric antigen receptor T-cell therapy. Full article