Diffuse Large B-cell Lymphoma Research Articles

A patient with concurrent EBV-negative diffuse large B-cell lymphoma and angioimmunoblastic T-cell lymphoma: a case report

IntroductionDiffuse large B-cell lymphoma (DLBCL) is an aggressive form of non-Hodgkin lymphoma that accounts for approximately a quarter of all lymphomas in the United States. It is rare to have co-occurring T cell lymphoma with DLBCL as they often develop following treatment of DLBCL rather than concomitantly.Case presentationWe report a 71-year-old male patient diagnosed with Epstein–Barr virus (EBV) -negative DLBCL with concurrent angioimmunoblastic T-cell lymphoma (AITL). A right inguinal lymph node biopsy demonstrated aggressive B-cell lymphoma consistent with DLBCL with the non-germinal center immunophenotype that was EBV-negative. Furthermore, abnormal T-cells with irregular nuclear contours were found in T cell receptor sequencing with monoclonal gamma and beta T cells. A bone marrow biopsy demonstrated occasional large atypical CD3+PD1+ T cells with corresponding identical T-cell receptor clones in the lymph node biopsy. Next-generation sequencing from the lymph node biopsy demonstrated dual inactivating TET2 mutations.ConclusionComposite DLBCL and AITL is a rare occurrence and the absence of EBV is even more so. Given the rare nature of having these two hematologic malignancies simultaneously, no standard of care exists. However, R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) is a regimen commonly used in both malignancies individually, and therefore this patient was treated using this approach achieving a partial remission after four cycles of therapy. Unfortunately, he developed refractory disease 1 month after completion of six cycles of R-CHOP.

Arterial effects of anthracycline: structural & inflammatory assessments in non-human primates and lymphoma patients.

Anthracyclines, such as doxorubicin, are important anti-cancer therapies but are associated with arterial injury. Histopathological insights have been limited to small animal models and the role of inflammation in the arterial toxic effects of anthracycline is unclear in humans. Our aims were: 1) To evaluate aortic media fibrosis and injury in non-human primates treated with anthracyclines; 2) To assess the effect of anthracycline on aortic inflammation in patients treated for lymphoma. &#160;Methods1) African Green monkeys (AGM) received doxorubicin (30-60 mg/m2/biweekly intravenously, cumulative dose: 240 mg/m2). Blinded histopathologic analyses of the ascending aorta were performed 15 weeks after the last doxorubicin dose and compared to 5 age- and gender-matched healthy, untreated AGMs. 2) Analysis of the thoracic aorta of patients with diffuse large B-cell lymphoma (DLBCL), at baseline and after doxorubicin exposure, was performed using 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in this observational study by maximal tissue-to-background ratio (TBRmax).</p> &#160;Results: In AGMs, doxorubicin exposure was associated with greater aortic fibrosis (collagen deposition: doxorubicin 6.23±0.88% vs. controls 4.67±0.54%; p=0.01) and intracellular vacuolization (doxorubicin 66.3±10.1 vs controls 11.5±4.2 vacuoles/field, p<0.0001) than untreated controls. In 101 patients with DLBCL, there was no change in aortic TBRmax after anthracycline exposure (TBRmax 1.46 ± 0.16 vs 1.44 ± 0.14 respectively, p=0.14). Univariate analyses yielded similar results.</p> &#160;Conclusions: In a large animal model, anthracycline exposure was associated with aortic fibrosis. In patients with lymphoma, anthracycline exposure was not associated with aortic inflammation. Further research is required to elucidate the mechanisms of anthracycline-related vascular harm.

A clinical challenge of cardiomyopathies: Beyond the heart

Introduction: The relation between the cancer and the heart is diverse. It can be affected all parts of the heart directly or indirectly caused by the systemic manifestation of the cancer or by cancer therapy. Paraneoplastic dermatomyositis and tumor lysis syndrome (TLS) are two examples of systemic manifestations of cancer. Being systemic, the cardiovascular system can be affected. Heart failure and arrhythmias are the main cardiac manifestations. Case Report: A 68-year-old man with a recent diagnosis of diffuse large B-cell lymphoma waiting to begin chemotherapy, and paraneoplastic dermatomyositis, presented at the emergency department (ED) with palpitations and dyspnea with a week of evolution. At the physical examination, he presented with pulmonary edema and the novo rapid atrial fibrillation. Also, an Nt-pro BNP of 8957 pg/mL, and echocardiography with severe dilated left ventricle, with a severe reduced ejection fraction. Already in the ward, the patient developed a spontaneous TLS. The etiological interpretation was that paraneoplastic dermatomyositis and TLS were the triggers of atrial fibrillation (AF). Then, the combination of them was responsible for development of the dilated cardiomyopathy (tachymyocardiopathy). The chemotherapy regimen was changed to R-CEOP (Rituximab, cyclophosphamide, etoposide, vincristine sulfate, and prednisone). Conclusion: This clinical case perfectly shows how the world of cardiomyopathies can be challenging and hard to understand all the complexity of the patients.

Lisocabtagene Maraleucel (Breyanzi)

CDA-AMC recommends that Breyanzi be reimbursed by public drug plans for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS), primary mediastinal large B-cell lymphoma (PMBCL), high-grade B-cell lymphoma (HGBCL), and DLBCL arising from follicular lymphoma, who have disease that is refractory to first-line chemoimmunotherapy or who experience relapse within 12 months of first-line chemoimmunotherapy, and who are candidates for autologous hematopoietic stem cell transplant (HSCT), if certain conditions are met. Breyanzi should only be covered to treat adults with DLBCL not otherwise specified, PMBCL, HGBCL, or DLBCL arising from follicular lymphoma who do not experience a response to first-line therapy or who experience relapse within 12 months of first-line therapy; who are eligible for autologous HSCT; and who are in relatively good health (as measured by performance status). Breyanzi should only be reimbursed for patients who have not yet been treated with chimeric antigen receptor (CAR) T-cell therapy, if it is prescribed and administered by clinicians with expertise in lymphomas and CAR T-cell therapy in a hospital setting with adequate resources, and if the cost of Breyanzi is not more than that of axicabtagene ciloleucel (axi-cel). It must also be feasible to administer Breyanzi.

About a Case: Orbital Plasmablastic Lymphoma in an Immunocompetent Patient

Plasmablastic lymphoma (PBL) is considered as an aggressive rare variant of diffuse large B-cell lymphoma (DLBCL) that has a predilection to develop in immunodeficient patients, particularly HIV-positive individuals. It is a rare CD20-negative aggressive lymphoma with a poor prognosis and a therapeutic challenge for pathologists. This report highlights the development of orbital PBL in a 45-year-old immunocompetent male. It includes the clinical presentation, radiological characteristics, histological appearances, immuno-histochemical particularities, and therapeutic response criteria of plasmablastic lymphoma.

Primary Thyroid Diffuse Large B-Cell Lymphoma: A Case Report.

Primary thyroid lymphoma is rare. Hashimoto's disease is usually found as a risk factor. Among thyroid lymphoma, diffuse large B-cell lymphoma (DLBCL) is the most aggressive and frequent one. A 56-year-old man with a medical history of Hashimoto's disease presented with a neck mass and dysphonia. A computed tomography scan revealed a large thyroid mass. Fine-needle aspiration cytology (FNAC) was consistent with lymphoma, confirmed by a core needle as a DLBCL. The patient was transferred to the Department of Hematology and Oncology for chemotherapy with good results. Primary thyroid lymphoma accounts for less than 5% of all thyroid gland malignancies and less than 2% of extranodal lymphomas. It frequently affects women in the sixth or seventh decade. Hashimoto's disease is a major risk factor. DLBCL is the most common histological subtype with aggressive evolution. Radiology and FNAC are not usually very precise and a biopsy is needed. Treatment includes surgery, radiotherapy, chemotherapy, and targeted therapy.

Efficacy and Safety of Polatuzumab Vedotin Plus Rituximab, Cyclophosphamide, Doxorubicin and Prednisone for Previously Untreated Diffuse Large B-Cell Lymphoma: A Real-World, Multi-Center, Retrospective Cohort Study.

Polatuzumab vedotin plus R-CHP (Pola-R-CHP) is approved as a new standard first-line therapy for diffuse large B-cell lymphoma (DLBCL) based on the POLARIX trial. However, real-world data on its efficacy and safety in unselected patients is lacking. We conducted a retrospective cohort study to evaluate Pola-R-CHP versus R-CHOP outcomes in routine clinical practice in China. This is a multi-institutional retrospective cohort study and included all consecutive patients that received at least one dose of polatuzumab vedotin up until February 2024. A total of 600 eligible patients from 6 centers were identified, 131 receiving Pola-R-CHP and 469 R-CHOP. After 1:2 propensity score matching, 128 pairs were obtained for further survival and prognosis analysis. With a median follow-up of 12.8months, 12-month progression-free survival (PFS) was numerically higher with Pola-R-CHP versus R-CHOP (90.3% vs. 84.1%, p=0.18). Benefits were consistently observed across molecular subgroups, especially advanced stage, ECOG ≥ 2, extranodal involvement ≥ 2 and non-GCB group. The complete response rate of the Pola-R-CHP group was higher than that of the RCHOP group (86.8% vs. 79.7%; p=0.09), but there was no statistical difference. Safety profiles were comparable, with no new concerns. Among 128 patients treated with Pola-R-CHP, 96 underwent gene sequencing analysis: MCD (25.0%), EZB (13.5%), combined subtype (12.5%), ST2 (9.4%), and other/unclassifiable subtype (30.2%). The most common mutations (> 25% of cases) were PIM1, TP53, BCL-6, KMT2D, SOCS1, BCL-2. Genetic testing results show the correlation between genotyping, gene mutations in PIM1/TP53 and therapeutic efficacy. This large real-world study supports Pola-R-CHP as an effective frontline option for DLBCL, with sustained efficacy versus R-CHOP observed in unselected populations. While 12-month PFS failed to reach statistical significance, subgroup analyses favor Pola-R-CHP. Further research with a wider population, longer follow-up, and screening of advantageous groups are warranted.

Integrative analysis of a novel immunogenic PANoptosis‑related gene signature in diffuse large B-cell lymphoma for prognostication and therapeutic decision-making

This study aimed to develop a PANoptosis-related gene prognostic index (PANGPI) to explore its potential value in predicting the prognosis and immunotherapy response of diffuse large B-cell lymphoma (DLBCL). Differentially expressed genes of DLBCL from GEO databases were analyzed and mapped to the PANoptosis gene set. The independent prognostic value of the PANGPI signature was evaluated using LASSO Cox regression and multivariate Cox regression. Additionally, the tumor infiltrating lymphocyte (TIL) characteristics and mutation landscape of both subgroups were evaluated, and drug sensitivity was predicted using the GDSC database. Furthermore, in silico docking and molecular dynamic simulation studies were presented to elucidate the mode of interaction of these predicted drugs. The PANGPI risk score was an independent risk factor for the prognosis of patients with DLBCL and exhibited good prognostic predictive performance. Furthermore, the cytolytic activity of the TILs was positively correlated with the PANGPI scores. Additionally, the PANGPI enabled the identification of 3 chemotherapeutic agents, including BMS-536924, Gefitinib, Navitoclax for DLBCL patients in the high-risk group. We established a novel PANoptosis-related gene subtyping system in DLBCL, which could shed a novel light on the development of new biomarkers for DLBCL.

The Prevalence of Diffuse Large B-Cell Lymphoma Varies Substantially by Methods Applied: Results From a Population-Based Study.

Accurate prevalence estimates of diffuse large B-cell lymphoma (DLBCL) are important for numerous purposes including orphan drug designation. A key criterion for orphan drug designation is a disease prevalence of less than 5/10,000 persons. The objective is to apply and compare different methods of prevalence assessment. In the present nationwide Danish cohort study, the prevalence of DLBCL was assessed using different methodologies, including register-based and formula-based approaches. The prevalence calculations were based on 9,492 patients diagnosed with DLBCL since year 2000. Incidence increased and survival improved in the period, resulting in higher prevalence of DLBCL. In year 2023, the 2-,3-,5-,10-, and 20-year prevalences were 1.53, 2.19, 3.45, 6.08, and 8.80 per 10,000 adults using the register-based approach. The formula-based approach was generally accurate when using restricted mean survival. However, when using median survival, the total prevalence was estimated at 8.1 per 10,000 adults. Furthermore, when extrapolating the median survival from the 5-year survival under constant hazard assumption as done in some orphan drug designation reports, the prevalence was estimated at 6.6 per 10,000 adults. In conclusion, the estimated DLBCL prevalences are sensitive to the applied method. DLBCL would disqualify from orphan drug designation in some of the mentioned scenarios.

A case of gastric/duodenal diffuse large B cell lymphoma observed during the administration of tacrolimus/azathioprine for dermatomyositis.

The patient was diagnosed with amyopathic dermatomyositis complicated with interstitial pneumonia (IP) at age 35. She had been treated with prednisolone and maintained on tacrolimus (TAC) + azathioprine (AZA). Eight years later, she experienced epigastric pain, and esophagogastroduodenoscopy (EGD) led to a diagnosis of duodenal ulcer. The pain did not improve, so she visited our hospital, where she presented with malaise, anemia, and weight loss. An EGD revealed submucosal tumor-like protrusions in the anterior and posterior walls of the gastric antrum and punched-out ulcers with auricle-like marginal swelling on the inside of the protrusions. Irregular-shaped punched-out ulcers were also observed in the duodenal bulb. Lymphoma was suspected, and biopsy was performed. Histopathology showed diffuse large, atypical lymphocytes with enlarged nuclei, and immunohistochemical staining revealed CD20-positive cells. Diffuse large B cell lymphoma (DLBCL) was diagnosed, which was considered as lymphomas arising in immune deficiency/dysregulation. After discontinuing TAC + AZA for three months, the gastrointestinal symptoms improved, and on EGD, the duodenal lesions had disappeared, with only a shallow depression covered with regenerated epithelium remaining in the posterior wall of the gastric antrum. Seven months later, the patient underwent follow-up EGD, and the disappearance of lymphoma cells was confirmed histopathologically by biopsy. Repeated and detailed endoscopic examination should be considered in an immunosuppressed patient with treatment-resistant gastric or duodenal ulcers.

A multi-view prognostic model for diffuse large B-cell lymphoma based on kernel canonical correlation analysis and support vector machine

Background and objectivePositron emission tomography/computed tomography (PET/CT) is recommended as the standard imaging modality for diffuse large B-cell lymphoma (DLBCL) staging. However, many studies have neglected the role of patients' prognostic factors with respect to imaging PET/CT of quantitative features. In this paper, a multi-view learning (MVL) model is established to make full use of both clinical and imaging data to predict the prognosis of DLBCL patients and thereby assist doctors in decision-making.MethodsFeature engineering, including feature extraction, feature screening by recursive feature elimination, and dimensionality reduction by principal component analysis, are successively performed on the clinical data and imaging data of the research subjects to obtain the study data. After dividing the data into training and test sets, an instance weighting method is applied to the training data. Subsequently, kernel mapping is performed on the imaging features and clinical features separately, and this kernel mapping is processed in the new kernel feature space using kernel canonical correlation analysis (KCCA). Lastly, model training is performed on the obtained common kernel subspace using a support vector machine (SVM). The final overall model, named SVM-2view-KCCA (SVM-2 K), was compared with three other multi-view models (Ensemble-SVM, Multi-view maximum entropy discrimination, and canonical correlation analysis). The performance of the model was evaluated on the test data with respect to several dichotomous metrics: accuracy, sensitivity, F1 score, the area under the curve (AUC), and G-mean.ResultsThe SVM model improved AUC by 10.5%, sensitivity by 11.9%, accuracy by 9.8%, F1 score by 9.2%, and G-mean by 7.8% for the DLBCL test data after feature engineering based on dimensionality reduction and instance weighting. In the performance comparison of single-view learning models, the SVM-based integration of clinical and imaging features achieved the best overall performance (AUC = 86.3%, accuracy = 91.6%, sensitivity = 83.2%, F1 = 85.7%, and G-mean = 86.1%). In the comparison of MVL models, SVM-2 K achieved the best overall performance (AUC = 92.1%, accuracy = 96.9%, sensitivity = 90.9%, F1 = 92.8%, and G-mean = 91.4%), and the performance of each MVL model was better than that of the best single-view learning model.ConclusionsMVL models outperformed single-view learning models. Of the MVL models, the proposed SVM-2 K achieved the best overall performance and could accurately predict patient prognosis.

Survival of HIV associated diffuse large B-cell lymphoma and Burkitt lymphoma in China

Combination antiretroviral therapy (ART) has improved outcomes for human immunodeficiency virus (HIV) associated non-Hodgkin lymphoma. This is an analysis of 127 patients with HIV with Burkitt lymphoma (HIV-BL) and diffuse large B-cell lymphoma (HIV-DLBCL) treated at the Zhongnan Hospital of Wuhan University over a 17-year period during the ART and rituximab era. The median CD4 count for the cohorts was 0.141 × 109/L (range, 0.001-0.861 × 109/L). DA-EPOCH ± R (54%) were most commonly used in HIV-BL. CHOP± R (42%) was most commonly used to treat HIV-DLBCL. The complete response rate after first-line curative therapy was 10/28 (36%) in HIV-BL and 25/57 (44%) in HIV-DLBCL. The 2-year progression-free survival (PFS) and overall survival (OS) for the HIV-BL cohort was 50% and 41% respectively. The 2-year PFS and OS for the HIV-DLBCL cohort was 55% and 47% respectively. Current China practice favours the treatment of HIV-BL and HIV-DLBCL similarly to the HIV-negative population with the use of concurrent ART. However, due to the extremely low percentage of patients receiving ART prior to the lymphoma diagnosis, the high percentage of patients with poor performance status, and the advanced stage at diagnosis, the treatment of HIV-related lymphoma remains the major challenge in China.

Do Pre-Treatment Biopsy Characteristics Predict Early Tumour Progression in Feline Diffuse Large B Cell Nasal Lymphoma Treated With Radiotherapy?

The standard of care treatment for localised feline nasal lymphoma (FeNL) is radiation therapy (RT). Early local or systemic failure occurs in 17%-45% of cats treated with RT with or without chemotherapy. The aim of this study was to determine if pre-treatment biopsy characteristics could predict early tumour progression in FeNL. Inclusion criteria consisted of histologically confirmed FeNL, available paraffin blocks of diagnostic quality, localised to the sinonasal cavity on staging pre-RT, treated with IMRT/IGRT (10 × 4.2 Gy) without chemotherapy and at least 1 year follow-up. All pre-RT biopsies were reviewed and evaluated with CD3, CD20, CD79a, pan-CK and Ki-67 immunohistochemistry and the mitotic activity index was determined. The primary endpoint was progression-free survival (PFS) at 1 year and hazard-ratios (HR) with confidence interval (CI) were calculated. Twenty-eight cats fit the inclusion criteria, and all had diffuse large B-cell lymphoma. Seventeen cats (61%) were progression free at 1 year. Of the 11 cats that progressed in the first year, two had local progression, two had both local and systemic progression and seven had systemic progression. The mitotic index (HR: 1.03, CI 0.9-1.19, p = 0.645), Ki-67 (HR: 1.00, CI 0.98-1.02, p = 0.845) and > 30% of tumour-infiltrating T cells (HR: 0.38, CI 0.09-1.56, p = 0.175) were not significantly associated with PFS. In this uniformly RT treated population of FeNL, none of the evaluated pre-RT histologic parameters could predict early treatment failure.

Recurrent primary cutaneous marginal zone lymphoma: acomparative study of initial tumours, recurrences, andoutcomes in 61 patients.

Primary cutaneous marginal zone lymphoma (PCMZL) is considered a lymphoproliferative disorder (International Consensus Classification, ICC) or an overt lymphoma (WHO-HAEM5). Seeking evidence for a reactive process or true lymphoma, we retrieved recurrent PCMZLs from the French Study Group of Cutaneous Lymphoma (GFELC) database. Histology, phenotype (light-chain restriction, immunoglobulin, and immune-receptor translocation-associated protein-1 [IRTA1] expression) and B-cell clonality at diagnosis and recurrence were compared according to recurrence site (local, locoregional, or distant) and outcomes. Initial lesions of the 61 patients (mean age 52) were mostly isolated on the trunk (48%) and classified T1 (70%). Times to first recurrence for local, locoregional, and distant recurrences, were 20, 29, and 37 months, respectively. Light-chain restriction type did not differ significantly between local/locoregional recurrences and distal recurrences (P = 0.06; n = 60). The same B-cell clones were identified for 23/42 local/locoregional recurrences, while 5/19 distant recurrences showed different clonal profiles (P = 0.0003). No tumour expressed IRTA1. Fifty-eight tumours were heavy-chain (IgG/IgG4) class-switched PCMZLs and 3 IgM+/IgD- PCMZLs. All IgM+ tumours underwent either transformation (skin or brain) into diffuse large B-cell lymphomas (DLBCLs) and extracutaneous spreading. As suggested by WHO-HAEM5, immunoglobulin phenotype assessment (IgM alongside IgD) appears to be a possible valuable tool in the initial diagnosis of PCMZL to differentiate between the indolent class-switched PCMZL (IgM-negative) and IgM+ (IgD-) PCMZL, which has an uncertain prognosis. The variation in B-cell rearrangements and light chain restriction observed in distant recurrences of PCMZL may suggest different antigen-driven stimulation processes.

The Role of CD-19 Targeting Chimeric Antigen Receptor (CAR) T-cell Therapy in Non-Hodgkin Lymphoma

Chimeric Antigen Receptor (CAR) T-cell therapy has improved outcomes in multiple hematological malignancies, such as multiple myeloma and non-Hodgkin lymphoma. CD-19 targeting CAR T-cells have improved outcomes in both aggressive and indolent types of non-Hodgkin lymphoma. Four CAR T-cell products have been approved by the United States (U.S.) Food and Drug Administration (FDA) for the management of non-Hodgkin lymphoma. This article reviews the currently available commercial CAR T-cells products' role in managing diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. We summarize pivotal clinical trials and real-world data on their efficacy and safety.

Depletion of Tregs from CD4+ CAR-Tcells enhances the tumoricidal effect of CD8+ CAR-Tcells in anti-CD19 CAR-T therapy.

Chimeric antigen receptor T (CAR-T) cell therapy, which targets CD19 for hematological malignancies, represents a breakthrough in cancer immunotherapy. However, some patients may develop resistance to CAR-T treatment, underscoring the importance of optimizing CAR-T design to enhance responsiveness. Here, we investigated the impact of different subpopulations in anti-CD19 CAR-T cells on the tumoricidal effect. Different populations of anti-CD19 CAR-T cells were isolated by magnetic-activated cell sorting (MACS). Their lytic activities on the acute lymphocytic leukemia cell line SUP-B15 and diffuse large B-cell lymphoma EB-3 cell line were examined in a co-culture system. The anti-tumorigenic outcome of different CAR-T cell compositions was evaluated in a xenograft mouse model of EB-3 cells. CD8+CAR-T cells exhibited the most potent tumoricidal activity against SUP-B15 and EB-3 cells. Additionally, CD4+ T helper cells enhanced the lytic effects of CD8+ CAR-T cells by increasing the availability of interleukin-2 (IL-2). Depleting CD25+Treg (T regulatory) cells from CD4+CAR-T population further augmented the tumoricidal activity of CD8+CAR-T cells by preventing IL-2 deprivation. Consistently, in vivo experiments demonstrated that the CD4+CD25+ Treg population dampened the antitumor activity of CD8+CAR-T cells, while depletion of Tregs from CD4+CAR-T cells enhanced the tumoricidal effect. These findings emphasize the potential role of CAR Treg cells in therapeutic resistance, suggesting that the depletion of Tregs in the anti-CD19 CAR-T population may serve as a strategy to augment the anticancer effect of CD8+CAR-T cells.

High expression of RHOF is an effective diagnostic marker and a potential prognostic indicator for primary mediastinal large B-cell lymphoma.

Due to the overlap of histological and molecular features of primary mediastinal large B-cell lymphoma (PMBL) with other lymphomas and its low incidence, the diagnosis and prognostic assessment of PMBL pose certain challenges. This study included 51 PMBL and 375 diffuse large B-cell lymphoma, not otherwise specified (DLBCL-NOS) from the GEO database and 65 PMBL and 117 DLBCL-NOS from a single center. At the transcriptional and protein levels, RHOF expression in PMBL was significantly higher than in DLBCL-NOS (P < 0.001). ROC curve analysis suggested that high RHOF expression had a high discriminative diagnostic ability for PMBL and DLBCL-NOS (transcriptional level, AUC = 0.913-0.940; protein level, AUC = 0.878). Comparing RHOF with commonly used PMBL diagnostic markers CD23, CD30, and PD-L1, it was found that high RHOF expression is a more useful diagnostic marker for PMBL (AUC (RHOF) = 0.878 > AUC (CD23) = 0.818 > AUC (CD30) = 0.756 > AUC (PD-L1) = 0.590). The diagnostic model based on CD23, CD30, and RHOF exhibits higher sensitivity for the diagnosis of PMBL than any of the individual markers mentioned above. Concerning prognosis, high RHOF transcriptional expression was significantly associated with poorer overall survival (OS) in PMBL (P = 0.00037), while high RHOF protein expression was significantly associated with poorer OS and progression-free survival (PFS) in PMBL (P = 0.034; P = 0.034). This study indicates that high RHOF expression in PMBL is closely associated with the diagnosis, prognosis, and clinical pathological features of the disease. High RHOF expression demonstrates a superior diagnostic ability in distinguishing PMBL from DLBCL-NOS compared to existing markers. Furthermore, research on RHOF expression in PMBL holds promise for providing new targets and insights for prognosis assessment and treatment of PMBL.

Inhibition of CDGSH iron‑sulfur domain 2 exhibits tumor-suppressing effects on diffuse large B-cell lymphoma (DLBCL) by inducing ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 pathway

CDGSH iron‑sulfur domain 2 (CISD2) is recognized as a ferroptosis-related gene that has potential as a target for cancer treatment. However, it is still uncertain whether targeting CISD2 can modulate ferroptosis in diffuse large B-cell lymphoma (DLBCL) cells and exhibit cancer-suppressing effects. The present study thoroughly investigated the role of CISD2 in DLBCL. CISD2 was found to be overexpressed in DLBCL, and its inhibition resulted in substantial growth inhibition in DLBCL cells. The growth inhibition effect resulting from CISD2 silencing could be reversed by a ferroptosis inhibitor, whereas inhibitors of apoptosis and necrosis did not yield the same reversal. CISD2-silenced DLBCL cells exhibited increased sensitivity to growth inhibition induced by ferroptosis suppressors. The inhibition of CISD2 induced ferroptotic cell death in DLBCL cells, which was supported by the overproduction of lipid peroxides, depletion of glutathione, accumulation of iron, and increased presence of shrunken mitochondria. Further investigation revealed reduced levels of NRF2, GPX4, and SLC7A11 in CISD2-silenced DLBCL cells. The overexpression of NRF2 significantly reduced the occurrence of ferroptotic cell death in DLBCL cells in which CISD2 was silenced. Furthermore, CISD2 inhibition exhibited tumor-suppressing effects in vivo associated with the induction of ferroptotic cell death in xenografts. These findings suggest that CISD2inhibition has tumor-suppressing effects on DLBCL by promoting ferroptotic cell death via the NRF2/SLC7A11/GPX4 pathway. Therefore, CISD2 holds promise as a viable candidate target for treating DLBCL.

BCL11A expression worsens the prognosis of DLBCL and its co-expression with C-MYC predicts poor survival

Non-Hodgkin's lymphoma (NHL) is a significant global malignancy, with diffuse large B cell lymphoma (DLBCL) being the most prevalent subtype, accounting for 25-50% of newly diagnosed cases in China. Despite a 60% survival rate achieved with R-CHOP regiment for DLBCL, approximately 40% of patients experience relapse or develop resistance to treatment. While the oncogenic transcription factor B-cell chronic lymphocytic leukaemia/lymphoma 11A (BCL11A) has been implicated in various tumors, its specific role in DLBCL remains unclear. In this study, we conducted retrospective histomorphological and immunophenotypic analyses on paraffin sample tissues and collected fresh tissue samples for protein and mRNA analyses to investigate the relationship between BCL11A and DLBCL. Additionally, we classified DLBCL into subtypes based on cells of origin (COO) and examined the expressions of BCL11A, C-MYC, P53 and other protein expressions to better understand the factors contributing to poor clinical outcomes in DLBCL. Our findings revealed elevated BCL11A expression in DLBCL, with increased expression associated with worse prognosis and higher C-MYC expression. Patients exhibiting co-expression of C-MYC and BCL11A had significantly lower survival rates compared to those with singular expression. Furthermore, BCL11A protein expression levels demonstrated significant associations with P53 and C-MYC protein expression levels in the Germinal Center B-cell-like (GCB) subtype. These findings suggest that BCL11A may serve as a potential prognostic marker and therapeutic target for DLBCL.

Machine Learning Algorithms Identify Target Genes and the Molecular Mechanism of Matrine against Diffuse Large B-cell Lymphoma.

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin's lymphoma worldwide. Novel treatment strategies are still needed for this disease. The present study aimed to systematically explore the potential targets and molecular mechanisms of matrine in the treatment of DLBCL. Potential matrine targets were collected from multiple platforms. Microarray data and clinical characteristics of DLBCL were downloaded from publicly available database. Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were applied to identify the hub genes of DLBCL using R software. Then, the shared target genes between matrine and DLBCL were identified as the potential targets of matrine against DLBCL. The least absolute shrinkage and selection operator (LASSO) algorithm was used to determine the final core target genes, which were further verified by molecular docking simulation and receiver operating characteristic (ROC) curve analysis. Functional analysis was also performed to elucidate the potential mechanisms. A total of 222 matrine target genes and 1269 DLBCL hub genes were obtained through multiple databases and machine learning algorithms. From the nine shared target genes of matrine and DLBCL, five final core target genes, including CTSL, NR1H2, PDPK1, MDM2, and JAK3, were identified. Molecular docking showed that the binding of matrine to the core genes was stable. ROC curves also suggested close associations between the core genes and DLBCL. Additionally, functional analysis showed that the therapeutic effect of matrine against DLBCL may be related to the PI3K-Akt signaling pathway. Matrine may target five genes and the PI3K-Akt signaling pathway in DLBCL treatment.