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Monitoring quality of healthcare is vital to ensure that changes made to clinical practice achieve the intended goals. Assessing temporal trends due to the accumulated effect of all changes in clinical practice in a given period is essential in quality monitoring. However, this assesment is compplicated by the fact that numerous of changes might occour over time unrelated to the clinical practice. Furthermore, the methods used to assess temporal trends in patient outcomes in the medical literature are heterogeneous, making it difficult to compare results between studies. In this paper, we describe methods that enable researchers to investigate temporal trends in survival data and we discuss their pros and cons. Numerous unrelated changes may occur over time which must be taken into account and disentangled when assessing the improvement in clinical management. The methods and interpretation thereof are exemplified on patients with diffuse large B-cell lymphoma from the Danish lymphoma registry. [ABSTRACT FROM AUTHOR]

Background: This investigation assessed the therapeutic potential of combining linperlisib, a targeted inhibitor of phosphatidylinositol 3-kinase delta (PI3Kδ), with gemcitabine and oxaliplatin (GEMOX) for patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Methods: This was a multicenter, phase Ib/II clinical study conducted across six sites in China, enrolling 39 individuals with histologically confirmed R/R DLBCL. The treatment protocol included oral linperlisib alongside GEMOX administered intravenously every three weeks for up to six cycles. The primary efficacy endpoint was the objective response rate (ORR). Results: The ORR observed in the full study population was 53.8% (95% confidence interval [CI]: 37.2–69.9). The median duration of response was 5.7 months (95% CI: 4.3–9.1), and the median progression-free survival was 5.4 months (95% CI: 1.8–6.7). The 1-year OS rate was 65.5% (95% CI: 48.1–78.3). Frequently observed adverse events included decreases in neutrophil counts (74.4%), white blood cell counts (64.1%) and platelet counts (64.1%). Conclusions: This study highlights the potential of linperlisib plus GEMOX as a treatment for R/R DLBCL, demonstrating a tolerable safety profile and encouraging efficacy results. Trial registration: NCT04500561. [ABSTRACT FROM AUTHOR]

Background: The significance of the controlling nutritional status (CONUT) score in predicting the prognostic outcomes of diffuse large B-cell lymphoma (DLBCL) has been widely explored, with conflicting results. Therefore, the present meta-analysis aimed to identify the prognostic significance of the CONUT in DLBCL by aggregating current evidence. Methods: The Web of Science, PubMed, Embase, CNKI and Cochrane Library databases were searched for articles from inception to October 15, 2024. The prognostic value of CONUT for DLBCL was analyzed by determining the pooled hazard ratios (HRs) with 95% confidence intervals (CIs). The Newcastle–Ottawa Scale (NOS) was used to analyze study quality. Results: Eight studies including 2687 cases were included in this work. The NOS scores of these studies were 7–9 (median, 8), demonstrating high quality. Our analyses revealed that an elevated CONUT score significantly predicted poor overall survival (OS) (HR = 1.63, 95%CI = 1.29–2.05, p < 0.001) and inferior progression-free survival (PFS) (HR=1.22, 95%CI = 1.12–1.33, p < 0.001) in patients with DLBCL. Further, the elevated CONUT score showed a significant correlation with the following clinicopathological factors in DLBCL: Ann Arbor stage III-IV, Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 2–4, presence of extranodal disease, ≥high intermediate National Comprehensive Cancer Network International Prognostic Index (NCCN IPI), presence of B symptoms, elevated lactose dehydrogenase (LDH) levels, and presence of bone marrow infiltration. Conclusions: An increased CONUT score was dramatically associated with poor OS and PFS in patients with DLBCL, as well as with clinicopathological characteristics representing DLBCL tumor development. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma in adult, characterized by uncontrolled cell proliferation and strong aggressiveness. Previous studies have found that cyclin-dependent kinase 1(CDK1) are related to tumor growth and metastasis. However, the role of CDK1 in DLBCL is exclusive. This study investigated the clinical implications and expression of CDK1 in DLBCL. Methods: Gene expression data for healthy subjects were sourced from the Genotype-Tissue Expression repository. Clinical details and survival statistics of patients with DLBCL were obtained from the Gene Expression Omnibus archive (GSE10846). Patients were categorized based on CDK1 expression levels, and differences in clinical outcomes between the groups were examined. Univariate and multivariate Cox regression analyses were used to ascertain whether CDK1 expression independently predicted DLBCL prognosis. The protein expression of CDK1 was gauged by immunohistochemistry. Additionally, we investigated the effect of CDK1 inhibition on DLBCL cell growth and death using the Cell Counting Kit-8 and flow cytometry. Results: In the control group, CDK1 expression was predominantly observed in the hematopoietic and reproductive systems. CDK1 levels in patients with DLBCL were notably elevated compared with those in controls. Significant differences were noted in the lactate dehydrogenase ratio and overall survival based on CDK1 expression. Statistical analyses confirmed that CDK1 was an independent predictor of DLBCL outcomes. Elevated CDK1 protein levels were observed in a significant number of DLBCL samples, in contrast to normal lymph node samples from individuals without lymphoma. The inhibitor Ro-3306 curtails DLBCL cell growth and enhances cell death in vitro. Conclusions: Elevated CDK1 levels are correlated with poor prognosis in patients with DLBCL. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL), the most common B-cell non-Hodgkin lymphoma rarely presents with circulating lymphoma cells (CL) at diagnosis. Previous studies were limited by small sample size precluding robust analysis. Hence, we evaluated the prognostic relevance of CL cells in newly diagnosed DLBCL patients. Based on peripheral blood (PB) immunophenotyping, patients were grouped into CL + and CL−. CL was defined as detectable clonally restricted B-cells that matched the actual or expected B-cell immunophenotype of DLBCL. The primary endpoint was progression-free survival (PFS), and secondary endpoints included overall survival (OS) and diagnosis-to-treatment interval (DTI). Among the 1266 patients with DLBCL, 621 had PB flow at diagnosis, and after excluding patients not meeting eligibility criteria, 588 cases remained. Among these, 85 (15%) were CL + and 503 were CL- (85%). Patients in CL + group were younger (67 vs. 70 years, p = 0.03) with a higher proportion of non-bulky disease (85% vs. 56%, p < 0.0001), normal albumin (79% vs. 54%, p < 0.0001), and MYC/BCL2 and/or BCL6 rearrangements (18% vs. 7%, p = 0.003) compared to the CL − group. Patients with CL at diagnosis had significantly inferior PFS and OS compared with those without CL. After adjusting for factors associated with inferior PFS and OS in univariable analysis, presence of CL remained significantly associated with inferior PFS (HR = 2.04, 95%CI = 1.47–2.84, p < 0.0001) and OS (HR = 1.61, 95%CI = 1.1–2.36, p = 0.01), respectively. There was no significant difference in DTI between the two groups. Given the prognostic relevance associated with presence of CL, clinicians should consider checking PB flow at diagnosis in all newly diagnosed DLBCL patients. [ABSTRACT FROM AUTHOR]

Background: Infections are common complications and causes of death during immunochemotherapy in diffuse large B-cell lymphoma (DLBCL). The gut microbiota plays a significant role in bacterial infection, but its relationship and predictive capacity with infectious complications in DLBCL are unknown. Methods: We performed 16S rRNA gene sequencing of fecal samples collected from 41 patients with newly diagnosed DLBCL at baseline, after every two cycles of standard immunochemotherapy, during infection, and after infection recovery. Analysis of the diversity and species composition of these samples was used to evaluate the relationship between gut microbiota and bacterial infection. Results: Our findings demonstrate the dynamic changes of Enterobacteriaceae in patients with DLBCL during immunochemotherapy. The abundance of Enterobacteriaceae was markedly higher at baseline in patients who subsequently developed bacterial infection during immunochemotherapy than in those who did not (P < 0.0001), and showed a further increase during infection (P < 0.01), after recovery from the infection, the Enterobacteriaceae was significantly decreased (P < 0.001). While there was no significant change in patients who did not develop bacterial infection. The univariate and multivariate analysis showed that baseline abundance of Enterobacteriaceae > 4.5% was independently associated with post-immunochemotherapy bacterial infection. Conclusions: Our findings suggest that the gut microbiota signatures differ between patients with DLBCL who do and do not develop bacterial infection. The baseline abundance of Enterobacteriaceae is associated with the post-immunochemotherapy bacterial infection, and it has certain predictive value. Detecting the changes of gut microbiota can help predict the risk of bacterial infection after immunochemotherapy. [ABSTRACT FROM AUTHOR]

Introduction: Primary bone marrow diffuse large B-cell lymphoma is a rare clinical entity, and the "bone marrow–liver–spleen" type of diffuse large B-cell lymphoma is rarer, with only a few published cases in literature. Though bone marrow–liver–spleen-type diffuse large B-cell lymphoma has unique presentations such as fever, cytopenias, and hemophagocytic lymphohistiocytosis, no cases with cold autoimmune hemolytic anemia have been reported. Case presentation: A 39-year-old Sri Lankan woman, previously healthy, presented with shortness of breath, productive cough, and fever for 4 days. Examination revealed pallor, icterus, and massive hepatosplenomegaly with no peripheral lymphadenopathy. Further investigation revealed pancytopenia (hemoglobin 58 g/L, white blood cell count 1.73 × 109/L, platelets 23 × 109/L, a reticulocyte index of 4.43%, and lactate dehydrogenase levels of 1690 U/L). Blood picture analysis was suggestive of hemolytic anemia, which was confirmed by a positive direct antiglobulin test with anti-C3d. The bone marrow biopsy revealed markedly hypercellular marrow with polymorphic infiltrate of mononuclear cells accounting for about 80–85% of nucleated cells. These cells were predominantly medium to large cells in size with scanty cytoplasm, irregular nuclear margins, prominent nucleoli, and many mitotic figures. These mononuclear cells were positive for immunohistochemical markers of CD20, BCL2, and CD10. The Ki-67 index was 24%. In addition, this patient had cold autoimmune hemolytic anemia. Contrast-enhanced computed tomography of the chest, abdomen, and pelvis revealed homogeneously enlarged liver and spleen with no significant lymphadenopathy. These findings were compatible with the diagnosis of bone marrow–liver–spleen-type diffuse large B-cell lymphoma. The patient was referred for specialized oncological management. Conclusion: Though there are reported cases of primary bone marrow diffuse large B-cell lymphoma presenting with cold autoimmune hemolytic anemia, no such cases of bone marrow–liver–spleen-type diffuse large B-cell lymphoma have been reported. As this unique entity has a rather grim prognosis, it is of utmost importance to identify it early and treat aggressively. Owing to the limited availability of published accounts of this uncommon disease, we believe it is important to document our case to add to the understanding of this rare condition and its various presentations, which can easily be misinterpreted. [ABSTRACT FROM AUTHOR]

Background and objective: Positron 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. Methods: Feature 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. Results: The 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. Conclusions: MVL 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. [ABSTRACT FROM AUTHOR]

The phosphatidylinositol 3‑kinase/protein kinase B (PI3K/AKT) signaling pathway is critically active in many cell types, both normal and neoplastic. Many small-molecule inhibitors targeting different levels of the PI3K/AKT pathway have been developed for cancer therapy, but their efficacy is reduced by compensatory pathway re-activation mechanisms, and their tolerability by toxic side effects. We studied this problem using cell lines representing diffuse large B-cell lymphoma (SUDHL-4 and OCI-Ly7), a genetically-encoded live-cell reporter of AKT activity, and 3 small-molecule inhibitors targeting different levels of the pathway: idelalisib (PI3Kδ), GSK2334470 (PDPK1), and ipatasertib (AKT). Half-maximal (IC50) concentrations of these inhibitors for AKT activity inhibition at 1 h, when used individually, were much lower than their IC50 values for reduction of viable cell number after 4 days. Time-course studies explained this discrepancy: AKT activity in the continuous presence of the inhibitors returned to normal after 24 h, and was supranormal after inhibitor removal. Combining all 3 inhibitors produced sustained inhibition of AKT activity, was broadly synergistic at reducing viable cell number, enabled substantially lower doses of each inhibitor to be used, and was enhanced further by the mTOR inhibitor rapamycin. Moreover, combined PDPK1 and AKT inhibition showed synergy with multiple different PI3K inhibitors. In a syngeneic mouse cell line model of lymphoma (A20), the triple combination showed antitumor activity and no evidence of toxicity. Our findings provide proof of concept suggesting further study of the safety and efficacy of low-dose multilevel PI3K/AKT pathway inhibition, for lymphoma and perhaps other cancers. [ABSTRACT FROM AUTHOR]

Background: This study evaluates the health-related quality of life (HRQoL) of persons with diffuse large B-cell lymphoma (DLBCL) by using EQ-5D-5L and SF-6Dv2 and compares the measurement properties of the two instruments. Method: DLBCL patients were identified via a patient group and were surveyed using web-based questionnaires. Demographic information, socioeconomic status (SES), clinical characteristics, and EQ-5D-5L and SF-6Dv2 responses were collected and statistically described. The association between the EQ-5D-5L and SF-6Dv2 dimensions were analyzed using the Spearman's correlation coefficient, whereas the correlation of the utility scores was evaluated using Pearson's correlation coefficient. The agreement between the responses of the two instruments were examined using a Bland–Altman (B-A) plot. A one-way analysis of variance (ANOVA) was performed to compare the utility scores across subgroups in different clinical states (a t-test was used if there were two subgroups). In addition, the graded response model (GRM) was used to describe the discrimination ability and difficulty characteristics of the dimensions in the two instruments. Results: In total, 582 valid responses were collected, among which 477 respondents were associated with initial-treatment and 105 respondents were relapsed/refractory (RR) patients. The mean (standard deviation [SD]) EQ-5D-5L and SF-6Dv2 utility scores of the DLBCL patients were 0.828 (0.222) and 0.641 (0.220), respectively. The correlation between the EQ-5D-5L and SF-6Dv2 dimensions ranged from 0.299 to 0.680, and the correlation between their utility scores was 0.787. The B-A plot demonstrated an acceptable but not strong agreement between EQ-5D-5L and SF-6Dv2 utility scores. The GRM model results indicated that all dimensions of each instrument were highly discriminating overall, but EQ-5D-5L had suboptimal discriminative power among patients with good health. Conclusion: Both the EQ-5D-5L and SF-6Dv2 showed valid properties to assess the HRQoL of DLBCL patients. However, utility scores derived from the two instruments had substantial difference, thereby prohibiting the interchangeable use of utilities from the two instruments. [ABSTRACT FROM AUTHOR]

Many therapies are available for the treatment of relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after ≥ 2 lines of therapy, albeit with scant evidence on the comparative effectiveness of these therapies. This study used inverse probability of treatment weighting to indirectly compare treatment outcomes of epcoritamab from the EPCORE NHL-1 trial with individual patient data from clinical practice cohorts treated with chemoimmunotherapy (CIT) and novel therapies (polatuzumab-based regimens, tafasitamab-based regimens, and chimeric antigen receptor T-cell [CAR T] therapies) for third-line or later R/R large B-cell lymphoma (LBCL) and DLBCL. In this analysis, epcoritamab demonstrated significantly better response rates and overall survival rates than CIT, polatuzumab-based regimens, and tafasitamab-based regimens. No statistically significant differences in response rates or survival were found for epcoritamab compared with CAR T in R/R LBCL. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is a malignant tumour. Although some standard therapies have been established to improve the cure rate, they remain ineffective for specific individuals. Therefore, it is meaningful to find more novel therapeutic approaches. Macrophage polarisation is extensively involved in the process of tumour development. Recombinant hirudin (rH) affects macrophages and has been researched frequently in clinical trials lately. Our article validated the regulatory role of rH in macrophage polarisation and the mechanism of PAR-1 by collecting clinical samples and subsequently establishing a cellular model to provide a scientifically supported perspective for discovering new therapeutic approaches. Method: We assessed the expression of macrophage polarisation markers, cytokines and PAR-1 in clinical samples. We established a cell model by co-culture with THP-1 and OCI-Ly10 cell. We determined the degree of cell polarisation and expression of validation cytokines by flow cytometry, ELISA, and RT-qPCR to confirm the success of the cell model. Subsequently, different doses of rH were added to discover the function of rH on cell polarisation. We confirmed the mechanism of PAR-1 in macrophage polarisation by transfecting si-PAR-1 and pcDNA3.1-PAR-1. Results: We found higher expression of M2 macrophage markers (CD163 + CMAF+) and PAR-1 in 32 DLBCL samples. After inducing monocyte differentiation into M0 macrophages and co-culturing with OCI-Ly10 lymphoma cells, we found a trend of these expressions in the cell model consistent with the clinical samples. Subsequently, we discovered that rH promotes the polarisation of M1 macrophages but inhibits the polarisation of M2 macrophages. We also found that PAR-1 regulates macrophage polarisation, inhibiting cell proliferation, migration, invasion and angiogenic capacity. Conclusion: rH inhibits macrophage polarisation towards the M2 type and PAR-1 regulates polarisation, proliferation, migration, invasion, and angiogenesis of DLBCL-associated macrophages. [ABSTRACT FROM AUTHOR]

Background: The metabolic tumour area (MTA) was found to be a promising predictor of prostate cancer. However, the role of MTA based on 18F-FDG PET/CT in diffuse large B-cell lymphoma (DLBCL) prognosis remains unclear. This study aimed to elucidate the prognostic significance of MTA and evaluate its incremental value to the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI) for DLBCL patients treated with first-line R-CHOP regimens. Methods: A total of 280 consecutive patients with newly diagnosed DLBCL and baseline 18F-FDG PET/CT data were retrospectively evaluated. Lesions were delineated via a semiautomated segmentation method based on a 41% SUVmax threshold to estimate semiquantitative metabolic parameters such as total metabolic tumour volume (TMTV) and MTA. Receiver operating characteristic (ROC) curve analysis was used to determine the optimal cut-off values. Progression-free survival (PFS) and overall survival (OS) were the endpoints that were used to evaluate the prognosis. PFS and OS were estimated via Kaplan‒Meier curves and compared via the log-rank test. Results: Univariate analysis revealed that patients with high MTA, high TMTV and NCCN-IPI ≥ 4 were associated with inferior PFS and OS (P < 0.0001 for all). Multivariate analysis indicated that MTA remained an independent predictor of PFS and OS [hazard ratio (HR), 2.506; 95% confidence interval (CI), 1.337–4.696; P = 0.004; and HR, 1.823; 95% CI, 1.005–3.310; P = 0.048], whereas TMTV was not. Further analysis using the NCCN-IPI model as a covariate revealed that MTA and NCCN-IPI were still independent predictors of PFS (HR, 2.617; 95% CI, 1.494–4.586; P = 0.001; and HR, 2.633; 95% CI, 1.650–4.203; P < 0.0001) and OS (HR, 2.021; 95% CI, 1.201–3.401; P = 0.008; and HR, 3.869; 95% CI, 1.959–7.640; P < 0.0001; respectively). Furthermore, MTA was used to separate patients with high NCCN-IPI risk scores into two groups with significantly different outcomes. Conclusions: Pre-treatment MTA based on 18F-FDG PET/CT and NCCN-IPI were independent predictor of PFS and OS in DLBCL patients treated with R-CHOP. MTA has additional predictive value for the prognosis of patients with DLBCL, especially in high-risk patients with NCCN-IPI ≥ 4. In addition, the combination of MTA and NCCN-IPI may be helpful in further improving risk stratification and guiding individualised treatment options. Trial registration: This research was retrospectively registered with the Ethics Committee of the Third Affiliated Hospital of Soochow University, and the registration number was approval No. 155 (approved date: 31 May 2022). [ABSTRACT FROM AUTHOR]

Background: Lymphoid neoplasm is a common disease, arising from lymphoid cells. It is divided into Hodgkin lymphoma and non-Hodgkin lymphoma. Non-Hodgkin lymphoma can be intranodular or extranodular, which happens in 25% of primary cases. The most common locations of extranodular non-Hodgkin lymphoma are the skin and gastrointestinal tract. The genital tract is a rare location; most lymphomas arise from the cervix and vagina, while the uterine corpus is an extremely rare location. In our case, the patient was diagnosed with primary extranodular non-Hodgkin lymphoma in different locations of her genital tract. Case presentation: A 48-year-old nonparous Syrian woman complained of diffuse abdominal pain, fatigue, debility, high fever, vomiting, and urinary retention for a week. The last menstrual period of the patient was 5 years previously. The physical examination showed periodic abdominal pain with severe fatigue and increased abdominal size. The laboratory investigations were within normal limits except for a low level of hemoglobin and a high level of cancer antigen 125. The radiological investigations showed a uterine sizable lobulated mass with irregular borders and high and heterogeneous density, extending to the right and left ovaries, enlargement lymph nodes around the abdominal aortic and right iliac vessels, and severe right pleural effusion with right inferior lobe atelectasis. A total hysterectomy and oophorectomy were done. The histopathological examination showed that the patient had non-Hodgkin lymphoma (primary tumor). Conclusion: Primary non-Hodgkin lymphoma in the female genital tract is an extremely rare disease. Fast diagnosis and treatment can improve the outcomes, so this differential diagnosis should be in our minds even in the absence of systematic manifestations of lymphoma. More studies are needed to explain the pathology of this disease and to put guidelines that determine the perfect methods for diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) represents a prevalent malignant tumor, with approximately 40% of patients encountering treatment challenges or relapse attributed to rituximab resistance, primarily due to diminished or absent CD20 expression. Our prior research identified PDK4 as a key driver of rituximab resistance through its negative regulation of CD20 expression. Further investigation into PDK4's resistance mechanism and the development of advanced exosome nanoparticle complexes may unveil novel resistance targets and pave the way for innovative, effective treatment modalities for DLBCL. Methods: We utilized a DLBCL-resistant cell line with high PDK4 expression (SU-DHL-2/R). We infected it with short hairpin RNA (shRNA) lentivirus for RNA sequencing, aiming to identify significantly downregulated mRNA in resistant cells. Techniques including immunofluorescence, immunohistochemistry, and Western blotting were employed to determine PDK4's localization and expression in resistant cells and its regulatory role in phosphorylation of Histone deacetylase 8 (HDAC8). Furthermore, we engineered advanced exosome nanoparticle complexes, aCD20@ExoCTX/siPDK4, through cellular, genetic, and chemical engineering methods. These nanoparticles underwent characterization via Dynamic Light Scattering (DLS) and Transmission Electron Microscopy (TEM), and their cellular uptake was assessed through flow cytometry. We evaluated the nanoparticles' effects on apoptosis in DLBCL-resistant cells and immune cells using CCK-8 assays and flow cytometry. Additionally, their capacity to counteract resistance and exert anti-tumor effects was tested in a resistant DLBCL mouse model. Results: We found that PDK4 initiates HDAC8 activation by phosphorylating the Ser-39 site, suppressing CD20 protein expression through deacetylation. The aCD20@ExoCTX/siPDK4 nanoparticles served as effective intracellular delivery mechanisms for gene therapy and monoclonal antibodies, simultaneously inducing apoptosis in resistant DLBCL cells and triggering immunogenic cell death in tumor cells. This dual action effectively reversed the immunosuppressive tumor microenvironment, showcasing a synergistic therapeutic effect in a subcutaneous mouse tumor resistance model. Conclusions: This study demonstrates that PDK4 contributes to rituximab resistance in DLBCL by modulating CD20 expression via HDAC8 phosphorylation. The designed exosome nanoparticles effectively overcome this resistance by targeting the PDK4/HDAC8/CD20 pathway, representing a promising approach for drug delivery and treating patients with Rituximab-resistant DLBCL. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous malignancy characterized by varied responses to treatment and prognoses. Understanding the metabolic characteristics driving DLBCL progression is crucial for developing personalized therapies. Methods: This study utilized multiple omics technologies including single-cell transcriptomics (n = 5), bulk transcriptomics (n = 966), spatial transcriptomics (n = 10), immunohistochemistry (n = 34), multiple immunofluorescence (n = 20) and to elucidate the metabolic features of highly malignant DLBCL cells and tumor-associated macrophages (TAMs), along with their associated tumor microenvironment. Metabolic pathway analysis facilitated by scMetabolism, and integrated analysis via hdWGCNA, identified glycolysis genes correlating with malignancy, and the prognostic value of glycolysis genes (STMN1, ENO1, PKM, and CDK1) and TAMs were verified. Results: High-glycolysis malignant DLBCL tissues exhibited an immunosuppressive microenvironment characterized by abundant IFN_TAMs (CD68+CXCL10+PD-L1+) and diminished CD8+ T cell infiltration. Glycolysis genes were positively correlated with malignancy degree. IFN_TAMs exhibited high glycolysis activity and closely communicating with high-malignancy DLBCL cells identified within datasets. The glycolysis score, evaluated by seven genes, emerged as an independent prognostic factor (HR = 1.796, 95% CI: 1.077–2.995, p = 0.025 and HR = 2.631, 95% CI: 1.207–5.735, p = 0.015) along with IFN_TAMs were positively correlated with poor survival (p < 0.05) in DLBCL. Immunohistochemical validation of glycolysis markers (STMN1, ENO1, PKM, and CDK1) and multiple immunofluorescence validation of IFN_TAMs underscored their prognostic value (p < 0.05) in DLBCL. Conclusions: This study underscores the significance of glycolysis in tumor progression and modulation of the immune microenvironment. The identified glycolysis genes and IFN_TAMs represent potential prognostic markers and therapeutic targets in DLBCL. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphomas (DLBCLs) display high molecular heterogeneity, but the International Prognostic Index (IPI) considers only clinical indicators and has not been updated to include molecular data. Therefore, we developed a widely applicable novel scoring system with molecular indicators screened by artificial intelligence (AI) that achieves accurate prognostic stratification and promotes individualized treatments. Methods: We retrospectively enrolled a cohort of 401 patients with DLBCL from our hospital, covering the period from January 2015 to January 2019. We included 22 variables in our analysis and assigned them weights using the random survival forest method to establish a new predictive model combining bidirectional long-short term memory (Bi-LSTM) and logistic hazard techniques. We compared the predictive performance of our "molecular-contained prognostic model" (McPM) and the IPI. In addition, we developed a simplified version of the McPM (sMcPM) to enhance its practical applicability in clinical settings. We also demonstrated the improved risk stratification capabilities of the sMcPM. Results: Our McPM showed superior predictive accuracy, as indicated by its high C-index and low integrated Brier score (IBS), for both overall survival (OS) and progression-free survival (PFS). The overall performance of the McPM was also better than that of the IPI based on receiver operating characteristic (ROC) curve fitting. We selected five key indicators, including extranodal involvement sites, lactate dehydrogenase (LDH), MYC gene status, absolute monocyte count (AMC), and platelet count (PLT) to establish the sMcPM, which is more suitable for clinical applications. The sMcPM showed similar OS results (P < 0.0001 for both) to the IPI and significantly better PFS stratification results (P < 0.0001 for sMcPM vs. P = 0.44 for IPI). Conclusions: Our new McPM, including both clinical and molecular variables, showed superior overall stratification performance to the IPI, rendering it more suitable for the molecular era. Moreover, our sMcPM may become a widely used and effective stratification tool to guide individual precision treatments and drive new drug development. [ABSTRACT FROM AUTHOR]

Background: The full potential of competing risk modeling approaches in the context of diffuse large B-cell lymphoma (DLBCL) patients has yet to be fully harnessed. This study aims to address this gap by developing a sophisticated competing risk model specifically designed to predict specific mortality in DLBCL patients. Methods: We extracted DLBCL patients' data from the SEER (Surveillance, Epidemiology, and End Results) database. To identify relevant variables, we conducted a two-step screening process using univariate and multivariate Fine and Gray regression analyses. Subsequently, a nomogram was constructed based on the results. The model's consistency index (C-index) was calculated to assess its performance. Additionally, calibration curves and receiver operator characteristic (ROC) curves were generated to validate the model's effectiveness. Results: This study enrolled a total of 24,402 patients. The feature selection analysis identified 13 variables that were statistically significant and therefore included in the model. The model validation results demonstrated that the area under the receiver operating characteristic (ROC) curve (AUC) for predicting 6-month, 1-year, and 3-year DLBCL-specific mortality was 0.748, 0.718, and 0.698, respectively, in the training cohort. In the validation cohort, the AUC values were 0.747, 0.721, and 0.697. The calibration curves indicated good consistency between the training and validation cohorts. Conclusion: The most significant predictor of DLBCL-specific mortality is the age of the patient, followed by the Ann Arbor stage and the administration of chemotherapy. This predictive model has the potential to facilitate the identification of high-risk DLBCL patients by clinicians, ultimately leading to improved prognosis. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL), an aggressive and heterogenic malignant entity, is still a challenging clinical problem, since around one-third of patients are not cured with primary treatment. Next-generation sequencing (NGS) technologies have revealed common genetic mutations in DLBCL. We devised an NGS multi-gene panel to discover genetic features of Chinese nodal DLBCL patients and provide reference information for panel-based NGS detection in clinical laboratories. Methods: A panel of 116 DLBCL genes was designed based on the literature and related databases. We analyzed 96 Chinese nodal DLBCL biopsy specimens through targeted sequencing. Results: The most frequently mutated genes were KMT2D (30%), PIM1 (26%), SOCS1 (24%), MYD88 (21%), BTG1 (20%), HIST1H1E (18%), CD79B (18%), SPEN (17%), and KMT2C (16%). SPEN (17%) and DDX3X (6%) mutations were highly prevalent in our study than in Western studies. Thirty-three patients (34%) were assigned as genetic classification by the LymphGen algorithm, including 12 cases MCD, five BN2, seven EZB, seven ST2, and two EZB/ST2 complex. MYD88 L265P mutation, TP53 and BCL2 pathogenic mutations were unfavorable prognostic biomarkers in DLBCL. Conclusions: This study presents the mutation landscape in Chinese nodal DLBCL, highlights the genetic heterogeneity of DLBCL and shows the role of panel-based NGS to prediction of prognosis and potential molecular targeted therapy in DLBCL. More precise genetic classification needs further investigations. [ABSTRACT FROM AUTHOR]

Background: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. Methods: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. Results: eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. Conclusions: We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL. [ABSTRACT FROM AUTHOR]

Background: Papillary carcinoma is the most frequent type of thyroid carcinoma, while primary thyroid lymphoma is uncommon disease. The coexistence of these entities has already been described, and the common risk factor is considered Hashimoto thyroiditis. The two most frequent histotypes of primary thyroid lymphoma are diffuse large B-cell and mucosa-associated lymphoid tissue lymphoma, but the coexistence of both with papillary carcinoma is rarely reported. Methods: We present a case of a previously healthy 57-years old male with rapidly growing lump on the right side of the neck. Ultrasonography revealed nodules in both thyroid lobes. Fine needle aspiration cytology and pertechnetate scintigraphy were performed. Due to the Bethesda T-5 in the "cold" nodule of the right lobe, surgery with histopathological and immunohistochemistry analysis was indicated. Results: Histopathological and immunohistochemistry methods confirmed concomitant malignancies in the thyroid gland: diffuse large B-cell lymphoma and papillary carcinoma in the right, and mucosa-associated lymphoid tissue lymphoma in the left lobe with Hashimoto thyroiditis in the remaining tissue. Patient underwent therapy procedures and was without signs of local recurrence or metastatic spread on subsequent follow-up. Conclusions: Sudden appearance of the neck mass in patients with Hashimoto thyroiditis should raise suspicion on primary thyroid lymphoma and be promptly taken in the diagnostic workup, including fine needle aspiration cytology. Pathology with immunohistochemistry is crucial for further clinical decision making. Since the standardized protocol in management of these complex patients is missing, personal approach and close collaboration between cytologist, pathologist, surgeon, haematologist and nuclear medicine specialist is essential. [ABSTRACT FROM AUTHOR]

Background: Overexpression of T-cell immunoglobulin and mucin domain-containing protein 3 (TIM3) is related to the exhaustion of CD8+ tumor-infiltrating lymphocytes (TILs) in diffuse large B-cell lymphoma (DLBCL). However, the mechanism of TIM3-mediated CD8+TILs exhaustion in DLBCL remains poorly understood. Therefore, we aimed to clarify the potential pathway involved in TIM3-mediated CD8+TILs exhaustion and its significance in DLBCL. Methods: The expression of TIM3 and its correlation with CD8+TILs exhaustion, the key ligand of TIM3, and the potential pathway of TIM3-mediated CD8+TILs exhaustion in DLBCL were analyzed using single-cell RNA sequencing and validated by RNA sequencing. The biological significance of TIM3-related pathway in DLBCL was investigated based on RNA sequencing, immunohistochemistry, and reverse transcription-quantitative polymerase chain reaction data. Finally, the possible regulatory mechanism of TIM3-related pathway in DLBCL was explored using single-cell RNA sequencing and RNA sequencing. Results: Our results demonstrated that CD8+TILs, especially the terminally exhausted state, were the major clusters that expressed TIM3 in DLBCL. Galectin-9, mainly expressed in M2 macrophages, is the key ligand of TIM3 and can induce the exhaustion of CD8+TILs through TIM3/Galectin-9 pathway. Meanwhile, high TIM3/Galectin-9 enrichment is related to immunosuppressive tumor microenvironment, severe clinical manifestations, inferior prognosis, and poor response to CHOP-based chemotherapy, and can predict the clinical efficacy of immune checkpoint blockade therapy in DLBCL. Furthermore, the TIM3/Galectin-9 enrichment in DLBCL may be regulated by the IFN-γ signaling pathway. Conclusions: Our study highlights that TIM3/Galectin-9 pathway plays a crucial role in CD8+TILs exhaustion and the immune escape of DLBCL, which facilitates further functional studies and could provide a theoretical basis for the development of novel immunotherapy in DLBCL. [ABSTRACT FROM AUTHOR]

Background: The molecular diversity exhibited by diffuse large B-cell lymphoma (DLBCL) is a significant obstacle facing current precision therapies. However, scoring using the International Prognostic Index (IPI) is inadequate when fully predicting the development of DLBCL. Reprogramming lipid metabolism is crucial for DLBCL carcinogenesis and expansion, while a predictive approach derived from lipid metabolism-associated genes (LMAGs) has not yet been recognized for DLBCL. Methods: Gene expression profiles of DLBCL were generated using the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. The LASSO Cox regression was used to construct an effective predictive risk-scoring model for DLBCL patients. The Kaplan-Meier survival assessment was employed to compare a given risk score with the IPI score and its impact on the survival of DLBCL patients. Functional enrichment examination was performed utilizing the KEGG pathway. After identifying hub genes via single-sample GSEA (ssGSEA), immunohistochemical staining and immunofluorescence were performed on lymph node samples from control and DLBCL patients to confirm these identified genes. Results: Sixteen lipid metabolism- and survival-associated genes were identified to construct a prognostic risk-scoring approach. This model demonstrated robust performance over various datasets and emerged as an autonomous risk factor for predicting the development of DLBCL patients. The risk score could significantly distinguish the development of DLBCL patients from the low-risk and elevated-risk IPI classes. Results from the inhibitory immune-related pathways and lower immune scores suggested an immunosuppressive phenotype within the elevated-risk group. Three hub genes, MECR, ARSK, and RAN, were identified to be negatively correlated with activated CD8 T cells and natural killer T cells in the elevated-risk score class. Ultimately, it was determined that these three genes were expressed by lymphoma cells but not by T cells in clinical samples from DLBCL patients. Conclusion: The risk level model derived from 16 lipid metabolism-associated genes represents a prognostic biomarker for DLBCL that is novel, robust, and may have an immunosuppressive role. It can compensate for the limitations of the IPI score in predicting overall survival and has potential clinical application value. [ABSTRACT FROM AUTHOR]

Background: c-MYC and BCL2 positivity are important prognostic factors for diffuse large B-cell lymphoma. However, manual quantification is subject to significant intra- and inter-observer variability. We developed an automated method for quantification in whole-slide images of tissue sections where manual quantification requires evaluating large areas of tissue with possibly heterogeneous staining. We train this method using annotations of tumor positivity in smaller tissue microarray cores where expression and staining are more homogeneous and then translate this model to whole-slide images. Methods: Our method applies a technique called attention-based multiple instance learning to regress the proportion of c-MYC-positive and BCL2-positive tumor cells from pathologist-scored tissue microarray cores. This technique does not require annotation of individual cell nuclei and is trained instead on core-level annotations of percent tumor positivity. We translate this model to scoring of whole-slide images by tessellating the slide into smaller core-sized tissue regions and calculating an aggregate score. Our method was trained on a public tissue microarray dataset from Stanford and applied to whole-slide images from a geographically diverse multi-center cohort produced by the Lymphoma Epidemiology of Outcomes study. Results: In tissue microarrays, the automated method had Pearson correlations of 0.843 and 0.919 with pathologist scores for c-MYC and BCL2, respectively. When utilizing standard clinical thresholds, the sensitivity/specificity of our method was 0.743 / 0.963 for c-MYC and 0.938 / 0.951 for BCL2. For double-expressors, sensitivity and specificity were 0.720 and 0.974. When translated to the external WSI dataset scored by two pathologists, Pearson correlation was 0.753 & 0.883 for c-MYC and 0.749 & 0.765 for BCL2, and sensitivity/specificity was 0.857/0.991 & 0.706/0.930 for c-MYC, 0.856/0.719 & 0.855/0.690 for BCL2, and 0.890/1.00 & 0.598/0.952 for double-expressors. Survival analysis demonstrates that for progression-free survival, model-predicted TMA scores significantly stratify double-expressors and non double-expressors (p = 0.0345), whereas pathologist scores do not (p = 0.128). Conclusions: We conclude that proportion of positive stains can be regressed using attention-based multiple instance learning, that these models generalize well to whole slide images, and that our models can provide non-inferior stratification of progression-free survival outcomes. [ABSTRACT FROM AUTHOR]

The use of central nervous system (CNS) prophylaxis for patients with diffuse large B-cell lymphoma (DLBCL) remains controversial. Although uncommon, CNS relapses are invariably fatal in this otherwise curable disease. Accurate identification of patients at risk and the optimal approach to CNS prophylaxis therefore remains an area of unmet need. The existing literature, largely retrospective in nature, provides mixed conclusions regarding the efficacy of CNS prophylaxis. The utility of CNS prophylaxis has itself been challenged. In this review, we dissect the issues which render the value of CNS prophylaxis uncertain. We first compare international clinical guidelines for CNS prophylaxis. We then interrogate the factors that should be used to identify high-risk patients accurately. We also explore how clinical patterns of CNS relapse have changed in the pre-rituximab and rituximab era. We then discuss the efficacy of CNS-directed approaches, intensification of systemic treatment and other novel approaches in CNS prophylaxis. Improved diagnostics for early detection of CNS relapses and newer therapeutics for CNS prophylaxis are areas of active investigation. In an area where prospective, randomized studies are impracticable and lacking, guidance for the use of CNS prophylaxis will depend on rigorous statistical review of retrospective data. [ABSTRACT FROM AUTHOR]

Background: The abnormality of chromosomal karyotype is one factor causing poor prognosis of lymphoma. In the analysis of abnormal karyotype of lymphoma patients, three smallest overlap regions were found, in which MYCT1 was located. MYCT1 is the first tumor suppressor gene cloned by our research team, but its studies relating to the occurrence and development of lymphoma have not been reported. Methods: R banding analyses were employed to screen the abnormality of chromosomal karyotype in clinical specimen and MYCT1 over-expression cell lines. FISH was to monitor MYCT1 copy number aberration. RT-PCR and Western blot were to detect the mRNA and protein levels of the MYCT1 and RUNX1 genes, respectively. The MYCT1 and RUNX1 protein levels in clinical specimen were evaluated by immunohistochemical DAB staining. The interaction between MYCT1 and MAX proteins was identified via Co-IP and IF. The binding of MAX on the promoter of the RUNX1 gene was detected by ChIP and Dual-luciferase reporter assay, respectively. Flow cytometry and CCK-8 assay were to explore the effects of MYCT1 and RUNX1 on the cell cycle and proliferation, respectively. Results: MYCT1 was located in one of three smallest overlap regions of diffuse large B-cell lymphoma, it altered chromosomal instability of diffuse large B-cell lymphoma cells. MYCT1 negatively correlated with RUNX1 in lymphoma tissues of the patients. MAX directly promoted the RUNX1 gene transcription by binding to its promoter region. MYCT1 may represses RUNX1 transcription by binding MAX in diffuse large B-cell lymphoma cells. MYCT1 binding to MAX probably suppressed RUNX1 transcription, leading to the inhibition of proliferation and cell cycle of the diffuse large B-cell lymphoma cells. Conclusion: This study finds that there is a MYCT1-MAX-RUNX1 signaling pathway in diffuse large B-cell lymphoma. And the study provides clues and basis for the in-depth studies of MYCT1 in the diagnosis, treatment and prognosis of lymphoma. [ABSTRACT FROM AUTHOR]

Background: 18F-FDG PET/CT provides precise information about dissemination of lymphoma lesions. Dmax, defined as distance between the two lesions that were farthest apart by PET/CT, was found to be a promising predictor of Diffuse large B-cell lymphoma (DLBCL) outcome in a small size of clinical trial data. We analyzed the impact of Dmax on the outcome of a large real-world DLBCL cohort. Methods: Data of newly diagnosed DLBCL at the Third Affiliated Hospital of Soochow University were retrospectively collected. Baseline Dmax, clinical data and survival information were recorded. A metabolic parameter, metabolic bulk volume (MBV), was also measured to verify the independent impact of Dmax. Results: Optimal cut-off values for Dmax and MBV were 45.34 cm and 21.65 cm3. With a median follow-up of 32 months, Dmax significantly impacted progression-free survival (PFS) and overall survival (OS) in 253 DLBCL patients. For Dmaxlow and Dmaxhigh groups, estimated 3-year OS were 87.0% and 53.8% (p < 0.001), while 3-year PFS were 77.3% and 37.3% (p < 0.001). And for MBVlow and MBVhighgroups, 3-year OS were 84.5% and 58.8% (p < 0.001), and 3-year PFS were 68.7% and 50.4% (p = 0.003). Multivariate analysis identified Dmax and Eastern Cooperative Oncology Group performance status (ECOG PS) independently associated with PFS and OS, while MBV only independently associated with OS. A Dmax revised prognostic index (DRPI) combining Dmax and ECOG PS identified an ultra-risk DLBCL population with 3-year PFS of 31.7% and 3-year OS of 38.5%. The area under the curve (AUC) showed that this model performed better than International prognostic Index (IPI). Conclusion: Dmax is a new and promising indicator to investigate dissemination of lymphoma lesions associated with the outcome of DLBCL. It significantly contributes to stratification of patients with disparate outcomes. Trial registration: This research has been retrospectively registered in the Ethics Committee institutional of the Third Affiliated Hospital of Soochow University, and the registration number was approval No. 155 (approved date: 31 May 2022). [ABSTRACT FROM AUTHOR]

Purpose: To investigate the prognosis value of a combined model based on 18F-fluoro-deoxyglucose positron emission tomography-computed tomography (18F-FDG PET-CT) baseline and interim parameters in patients with diffuse large B-cell lymphoma (DLBCL). Methods: We retrospectively analyzed the PET metabolic parameters and clinical data of 154 DLBCL patients between December 2015 and October 2020. All of these patients underwent 18F-FDG PET/CT scan before treatment and after three or four courses of chemotherapy. The optimal cut-off values for quantitative variables were determined by the receiver operating characteristic (ROC) curve. The baseline and interim PET/CT parameters, which respectively included maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax) and total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), and clinical characteristics were analyzed by chi-squared test, Kaplan-Meier survival curve, and Cox regression analysis. Results: Of 154 patients, 35 exhibited disease progression or recurrence. ROC analysis revealed that baseline 18F-FDG PET/CT metabolic parameters, including maximum standardized uptake value (SUVmax0), total metabolic tumor volume (TMTV0), standardized total metabolic tumor volume (STMTV0), and the distance between the two furthest lesions (Dmax), along with interim 18F-FDG PET/CT metabolic parameters such as total tumor lesion glycolysis (TTLG1), SUVmax1, TMTV1, and the rate of change of SUVmax (%ΔSUVmax), were predictive of relapse or progression in DLBCL patients (P < 0.05). The chi-squared test showed that TMTV0, STMTV0, Dmax, SUVmax1, TMTV1, TTLG1, %ΔSUVmax, Deauville score, IPI, Ann Arbor stage, and LDH were associated with patient prognosis (P < 0.05). Multivariate Cox regression analysis showed that Dmax (P = 0.021) and %ΔSUVmax (P = 0.030) were independent predictors of prognosis in DLBCL patients. There were statistically significant differences in PFS among the three groups with high, intermediate, and low risk according to the combination model (P < 0.001). The combination model presented higher predictive efficacy than single indicators. Conclusion: The combined model of baseline parameter Dmax and intermediate parameter %ΔSUVmax of 18F-FDG PET/CT improved the predictive efficacy of PFS and contributed to the risk stratification of patients, providing a reference for clinical individualization and precision treatment. [ABSTRACT FROM AUTHOR]

Background: Tumor-derived extracellular vesicles (EVs) have been proposed as the essential mediator between host immunity and cancer development. These EVs conduct cellular communication to facilitate tumor growth, enable invasion and metastasis, and shape the favorable tumor microenvironment. Lymphoma is one of the most common hematological malignancies in humans and dogs. Effective T-cell responses are required for the control of these malignancies. However, the immune crosstalk between CD8 + T-cells, which dominates anti-tumor responses, and canine lymphoma has rarely been described. Methods: This study investigates the immune manipulating effects of EVs, produced from the clinical cases and cell line of canine B cell lymphoma, on CD8 + T-cells isolated from canine donors. Results: Lymphoma-derived EVs lead to the apoptosis of CD8 + T-cells. Furthermore, EVs trigger the overexpression of CTLA-4 on CD8 + T-cells, which indicates that EV blockade could serve as a potential therapeutic strategy for lymphoma patients. Notably, EVs transform the CD8 + T-cells into regulatory phenotypes by upregulating their PD-1, PD-L1, and FoxP3 mRNA expression. The regulatory CD8 + T-cells secret the panel of inhibitory cytokines and angiogenic factors and thus create a pro-tumorigenic microenvironment. Conclusion: In summary, the current study demonstrated that the EVs derived from canine B cell lymphoma impaired the anti-tumor activity of CD8 + T-cells and manipulated the possible induction of regulatory CD8 + T-cells to fail the activation of host cellular immunity. [ABSTRACT FROM AUTHOR]

Population-based data comparing the outcomes of patients with transformed follicular lymphoma (t-FL) and de novo diffuse large B-cell lymphoma (DLBCL) are lacking. The objective of this study was to compare the survival of patients with t-FL and de novo DLBCL diagnosed in the United States between 2010–2018. We hypothesized that patients with t-FL would have an inferior survival compared to patients with de novo DLBCL. The study outcomes were relative survival (RS), overall survival (OS), and lymphoma-specific survival (LSS) compared between t-FL and de novo DLBCL. Flexible parametric survival models were used to estimate the study outcomes. There were 569 cases of t-FL and 44,706 cases of de novo DLBCL. Patients with t-FL had an estimated 5-year RS of 54% [95% confidence interval (CI), 49–59%) compared to 67% (95% CI, 66–67%) for those with de novo DLBCL (adjusted hazard ratio, 1.29; 95% CI, 1.11–1.50; P = 0.001). The corresponding 5-year OS estimates were 49% (95% CI, 44–53%) and 57% (95% CI, 57–58%), respectively (adjusted hazard ratio, 1.23; 95% CI, 1.07–1.42; P = 0.004). The corresponding 5-year LSS estimates were 54% (95% CI, 50–59%) and 66% (95% CI, 65–66%), respectively (adjusted hazard ratio, 1.34; 95% CI, 1.15–1.56; P < 0.001). This population-based registry analysis shows that patients with t-FL continue to have an inferior survival in the modern era and should be prioritized for enrollment in clinical trials. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy. Neutrophil extracellular traps (NETs) are pathogen-trapping structures in the tumor microenvironment that affect DLBCL progression. However, the predictive function of NET-related genes (NRGs) in DLBCL has received little attention. This study aimed to investigate the interaction between NRGs and the prognosis of DLBCL as well as their possible association with the immunological microenvironment. Methods: The gene expression and clinical data of patients with DLBCL were downloaded from the Gene Expression Omnibus database. We identified 148 NRGs through the manual collection of literature. GSE10846 (n = 400, GPL570) was used as the training dataset and divided into training and testing sets in a 7:3 ratio. Univariate Cox regression analysis was used to identify overall survival (OS)-related NETs, and the least absolute shrinkage and selection operator was used to evaluate the predictive efficacy of the NRGs. Kaplan–Meier plots were used to visualize survival functions. Receiver operating characteristic (ROC) curves were used to assess the prognostic predictive ability of NRG-based features. A nomogram containing the clinical information and prognostic scores of the patients was constructed using multivariate logistic regression and Cox proportional risk regression models. Results: We identified 36 NRGs that significantly affected patient overall survival (OS). Eight NRGs (PARVB, LYZ, PPARGC1A, HIF1A, SPP1, CDH1, S100A9, and CXCL2) were found to have excellent predictive potential for patient survival. For the 1-, 3-, and 5-year survival rates, the obtained areas under the receiver operating characteristic curve values were 0.8, 0.82, and 0.79, respectively. In the training set, patients in the high NRG risk group presented a poorer prognosis (p < 0.0001), which was validated using two external datasets (GSE11318 and GSE34171). The calibration curves of the nomogram showed that it had excellent predictive ability. Moreover, in vitro quantitative real-time PCR (qPCR) results showed that the mRNA expression levels of CXCL2, LYZ, and PARVB were significantly higher in the DLBCL group. Conclusions: We developed a genetic risk model based on NRGs to predict the prognosis of patients with DLBCL, which may assist in the selection of treatment drugs for these patients. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) can be cured with standard front-line immunochemotherapy, whereas nearly 30–40% of patients experience refractory or relapse. For several decades, the standard treatment strategy for fit relapsed/refractory (R/R) DLBCL patients has been high-dose chemotherapy followed by autologous hematopoietic stem cell transplant (auto-SCT). However, the patients who failed in salvage treatment or those ineligible for subsequent auto-SCT have dismal outcomes. Several immune-based therapies have been developed, including monoclonal antibodies, antibody–drug conjugates, bispecific T-cell engaging antibodies, chimeric antigen receptor T-cells, immune checkpoint inhibitors, and novel small molecules. Meanwhile, allogeneic SCT and radiotherapy are still necessary for disease control for fit patients with certain conditions. In this review, to expand clinical treatment options, we summarize the recent progress of immune-related therapies and prospect the future indirections in patients with R/R DLBCL. [ABSTRACT FROM AUTHOR]

Recent evidence suggests that bispecific antibodies (BsAbs) exhibit promising efficacy and low toxicity even in heavily treated non-Hodgkin B-cell lymphoma (B-NHL). However, the role of BsAbs in previously untreated NHL and the efficacy and safety of BsAbs used in combination remain uncertain. We summarized data published at the 64th American Society of Hematology (ASH) Annual Meeting on BsAb monotherapy or combination therapy for first-line or relapsed/refractory B-NHL. BsAb monotherapy in elderly/unfit newly diagnosed (ND) DLBCL patients achieved ORR and CR rates of 56% and 43%, respectively. In addition, BsAbs combined with chemotherapy or other novel agents raised the ORR higher than 50% without increasing the incidence of grade ≥ 3 CRS. We conclude that BsAb monotherapy or combination therapy for first-line or relapsed/refractory B-NHL has high efficacy and satisfactory safety. [ABSTRACT FROM AUTHOR]

Background: N6-methyladenosine (m6A) has been shown to participate in various essential biological processes by regulating the level of target genes. However, the function of m6A modification mediated by KIAA1429 [alias virus-like m6A methyltransferase-associated protein (VIRMA)] during the progression of diffuse large B-cell lymphoma (DLBCL) remains undefined. Methods: The expression and clinical significance of KIAA1429 were verified by our clinical data. CRISPR/Cas9 mediated KIAA1429 deletion, and CRISPR/dCas9-VP64 for activating endogenous KIAA1429 was used to evaluate its biological function. RNA sequencing (RNA-seq), methylated RNA immunoprecipitation sequencing (MeRIP-seq), RNA immunoprecipitation (RIP) assays, luciferase activity assay, RNA stability experiments, and co-immunoprecipitation were performed to investigate the regulatory mechanism of KIAA1429 in DLBCL. Tumor xenograft models were established for in vivo experiments. Results: Dysregulated expression of m6A regulators was observed, and a novel predictive model based on m6A score was established in DLBCL. Additionally, elevated KIAA1429 expression was associated with poor prognosis of patients with DLBCL. Knockout of KIAA1429 repressed DLBCL cell proliferation, facilitated cell cycle arrest in the G2/M phase, induced apoptosis in vitro, and inhibited tumor growth in vivo. Furthermore, carbohydrate sulfotransferase 11 (CHST11) was identified as a downstream target of KIAA1429, which mediated m6A modification of CHST11 mRNA and then recruited YTHDF2 for reducing CHST11 stability and expression. Inhibition of CHST11 diminished MOB1B expression, resulting in inactivation of Hippo–YAP signaling, reprogramming the expression of Hippo target genes. Conclusions: Our results revealed a new mechanism by which the Hippo–YAP pathway in DLBCL is inactivated by KIAA1429/YTHDF2-coupled epitranscriptional repression of CHST11, highlighting the potential of KIAA1429 as a novel predictive biomarker and therapeutic target for DLBCL progression. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) with signet ring cell components is extremely rare. Here, we present a case of DLBCL with signet ring cell components involving the breast, which can be easily confused with invasive lobular carcinoma of the breast or metastatic signet ring cell carcinoma of gastrointestinal origin. Case presentation: A 66-year-old woman presented with a painless mass in her left breast. Enhanced magnetic resonance imaging (MRI) of the breast revealed a 42 × 29 × 28 mm mass in the left breast. Histological examination revealed a diffuse or scattered arrangement of round cells mixed with signet ring-like cells. Immunohistochemically, the neoplastic cells were positive for PAX-5, CD79a, CD20, Bcl-6, and MUM-1 but and negative for cytokeratin, ER, PR, E-cadherin, and P120. The Ki-67 proliferation index was approximately 70%. Fluorescence in situ hybridisation (FISH) demonstrated non-rearrangement of Bcl-2, Bcl-6, and c-MYC genes. Immunohistochemistry and FISH examination confirmed the diagnosis of DLBCL. Subsequently, immunofluorescence showed both IgM and IgG deposits in the signet ring-like lymphocytes. After confirming the diagnosis, the patient received four courses of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) chemotherapy in a specialist hospital and achieved partial remission; however, she unfortunately died of secondary pneumocystis pneumonia infection 3 months later. Conclusion: Malignant lymphoma with signet ring cell morphology is quite uncommon, and this variant can be a diagnostic pitfall. We emphasise that pathologists should consider lymphoma in the differential diagnosis of malignant breast tumours. [ABSTRACT FROM AUTHOR]

Background: Dexrazoxane has been studied for its ability to prevent anthracycline-induced cardiac dysfunction (AICD) in several trials but its use in clinical practice remains limited. This is related to the low to moderate quality of the generated evidence, safety concerns and restricted prescribing indications. Additional randomized trials are needed before this drug can be routinely integrated into cardio-oncology clinical practice., Objectives: To describe the rationale and design of the HOVON 170 DLBCL - ANTICIPATE trial. This trial aims to establish the efficacy and safety of dexrazoxane for the primary prevention of AICD in patients diagnosed with Diffuse Large B-Cell Lymphoma (DLBCL) treated with six cycles R-CHOP 21 chemo-immunotherapy., Methods: This is a multicenter, parallel-group, open-label, phase III trial, randomizing 324 patients between either no cardioprotective treatment or dexrazoxane from the first R-CHOP cycle. The primary and co-primary endpoints are the incidence of AICD within 12 months of registration and the percentage of patients with complete metabolic remission at the end-of-treatment PET-CT respectively. The trial is registered at the EU Clinical Trials Register (EU-CT number 2023-505377-32) and ClinicalTrials.gov (NCT06220032)., Results: The medical research ethics committee approved the trial in May 2024. Recruitment has started in September 2024 and is expected to last for three years., Conclusions: This trial is poised to contribute crucial evidence concerning the efficacy and safety on the use of dexrazoxane in the primary prevention of AICD. The trial is anticipated to address critical knowledge gaps and offer important insights into the value of dexrazoxane in cardio-oncology practice., Competing Interests: Declarations. Ethics approval and consent to participat: Ethical approval for the conduct of this trial has been obtained from the Medical Research Ethics Committee NedMec (reference number: D-24-500268). Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Background: CD20-negative diffuse large B-cell lymphoma is a very rare and heterogeneous invasive cancer characterized by chemical resistance and poor prognosis. Primary CD20-negative diffuse large B-cell lymphoma of the central nervous system is even rarer, presenting great challenges in pathological diagnosis and clinical treatment. Case presentation: We report a case of primary CD20-negative diffuse large B-cell lymphoma of the CNS in a 54-year-old woman admitted to the hospital with a headache lasting more than 10 days. CT and MRI scans showed right temporal lobe lymphoma. Microscopically, large infiltrating lymphoid cells that induced brain tissue damage were observed. Immunohistochemistry showed that the tumor cells were CD79a+, PAX-5+, MUM1+, and CD20-. The patient was diagnosed with lymphoma and transferred to an oncology hospital for chemotherapy. However, because the disease progressed rapidly, the patient died only after two rounds of chemotherapy. Conclusions: To the best of our knowledge, this is one of the first reported cases of unclassifiable CD20-negative diffuse large B-cell lymphoma located in the CNS. This case report aims to deepen the understanding of clinicopathological features of this type of lymphoma and expand the scope of this disease. [ABSTRACT FROM AUTHOR]

Background: Anthracycline-induced cardiotoxicity is an irreversible cardiac cell injury. Therefore, it's very important to identify influencing factors of anthracycline-induced subclinical cardiotoxicity (AISC). This study was designed to analyze the influencing factors of AISC in patients with diffuse large B-cell lymphoma (DLBCL) treated with the (R)-CHOP chemotherapy regimen.Methods: This is an ongoing observational prospective clinical trial. All patients underwent conventional echocardiography and speckle tracking echocardiography at the time of enrollment and during treatment. Changes of global longitudinal peak systolic strain were assessed after 3 cycles of (R)-CHOP chemotherapy, and patients were divided into the AISC and No-AISC groups. Demographic data, clinical variables, and biochemical variables were measured. Regression models, receiver operating characteristic curve analysis, and difference values were used to explore the relationships between variables and AISC.Results: Among 70 patients who completed 3 cycles of (R)-CHOP chemotherapy, 26 developed AISC. In multiple logistic regression, HDL-C (P = 0.047), ApoA1 (P = 0.022), TG (P = 0.029) and e' (P = 0.008) were associated with AISC. The combination of HDL-C and NT-proBNP had the highest area under curves (AUC) for the diagnosis of AISC than HDL-C and NT-proBNP alone (AUC = 0.752, 95%CI: 0.63-0.87, P = 0.001). Between the No-AISC and AISC groups, there was no significant difference in HDL-C, ApoA1, and e' at baseline and after 3 cycles of chemotherapy, respectively. The dynamic changes of HDL-C, ApoA1, and e' from baseline to the end of the 3rd cycle of chemotherapy showed statistically significant differences.Conclusions: HDL-C, ApoA1, TG, and e' are independent predictive factors in DLBCL cases treated with the (R)-CHOP chemotherapy regimen. The combination of HDL-C and NT-proBNP may improve the predictive ability for AISC in patients with DLBCL administered 3 cycles of (R)-CHOP chemotherapy. Dynamic changes of HDL-C, ApoA1, and e' may be meaningful for predicting AISC.Trial Registration: Our study was registered in the Chinese Clinical Trial Registry (Approval ID. ChiCTR2100054721 http://www.chictr.org.cn/showproj.aspx?proj=145082 ). [ABSTRACT FROM AUTHOR]

Background: Regulatory T cells (Tregs) induce immune responses and may contribute to immune escape in tumors. Accumulation of Tregs in tumors represents a critical barrier to anti-tumor immunity and immunotherapy. However, conflicting results describing the role of Tregs in lymphoma warrant further investigation. The precise features and mechanisms underlying the alteration in Tregs in diffuse large B-cell lymphoma (DLBCL) are not well understood yet. In this study, we analyzed the mechanism underlying the observed alterations in Tregs in DLBCL and examined the effect of Lkb1 expression on the immunosuppressive function of human Tregs.Methods: Flow cytometry and immunofluorescence were used to analyze the proportion of Tregs and effector Tregs in the peripheral blood and lymph nodes of patients with DLBCL and control group. In vitro culture assays were used to analyze the immunosuppressive function of Tregs in the two groups. Transcriptome sequencing was performed to analyze the differentially expressed genes in the two groups, and the transcription level and protein expression of Lkb1 in the two groups were detected using RT-PCR and WES microprotein technology. Lentiviral vectors were constructed to explore the functional changes of Tregs with stable upregulation and downregulation of Lkb1. Finally, a humanized murine lymphoma model was established to study the function of Lkb1 in Tregs in the pathogenesis of DLBCL.Results: The number of Tregs was found to be dramatically increased in peripheral blood and tumor tissue in DLBCL patients compared with that in healthy controls, and decreased after treatment. Tregs from DLBCL patients exhibited multiple enhanced functions, including increased inhibition of CD8+cytotoxic T cells (CTL) against tumor cells, enhanced suppression of CD8+CTL secretion of granular enzyme, and suppression of CD8+CTL degranulation. Lkb1 was found to be upregulated in Tregs of DLBCL patients. Furthermore, Lkb1 contributes to Treg immunosuppressive function in DLBCL by regulating the mevalonate pathway. Finally, deletion of Lkb1 in Tregs suppressed tumor growth and promoted anti-tumor immunity in a DLBCL murine model.Conclusions: These findings confirmed that Lkb1-regulated Tregs are critical for immune escape in DLBCL, which emphasizes that Lkb1 is a potential target for the immunotherapy of DLBCL. [ABSTRACT FROM AUTHOR]

Background: The B-cell lymphoma 6 (BCL6) oncogene is required for the survival of diffuse large B-cell lymphoma (DLBCL), which is incurable using conventional chemotherapy. Thus, it is imperative to improve the survival of patients with DLBCL. Disulfide (DSF) has been shown to have anticancer effects, but its effect on DLBCL remains unclear. Methods: Four DLBCL cell lines (OCI-LY1, OCI-LY7, OCI-LY10 and U2932) and primary DLBCL cells from eight newly diagnosed DLBCL patients were pretreated with DSF alone or in combination with Cu. Cell morphology was observed under microscope. Flow cytometry was performed to evaluate the cell apoptosis, cell cycle, the mitochondrial membrane potential and the intracellular accumulation of reactive oxygen species (ROS). The protein expression was respectively measured by flow cytometry and western blotting. Results: DSF or DSF/Cu exhibited a marked inhibitory effect on the growth of DLBCL cells, accompanied by cell cycle arrest at the G0/G1 phase. Meanwhile, DSF or DSF/Cu significantly induced DLBCL cells apoptosis. Further study revealed that DSF or DSF/Cu promoted apoptosis by inhibiting NF-κB signaling pathway. Interestingly, DSF/Cu significantly reduced BCL6 and AIP levels. In addition, DSF significantly up-regulate p53 protein in OCI-LY7 and OCI-LY10 while down-regulate p53 protein in OCI-LY1 and U2932. Conclusion: These results provided evidence for the anti-lymphoma effects of DSF on DLBCL and suggested that DSF has therapeutic potential to DLBCL. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with variable clinical outcomes and prediction of prognosis remains important for long-term remission. We performed serial serum soluble interleukin-2 receptor (sIL-2R) measurement pretreatment and before each cycle of the treatment in 599 patients with de novo DLBCL. Genomic and transcriptomic features were analyzed by 223 DNA- and 227 RNA-sequencing, respectively. Applying the cut-off value to sIL-2R pretreatment and cycle 2 (C2) level, patients were classified into FINE subtype (pretreatment low level) with good prognosis, RES subtype (pretreatment high level and C2 low level) with intermediate prognosis, and RET subtype (pretreatment high level and C2 high level) with poor prognosis, independent of International Prognostic Index. In "others" genetic subtype, dynamic change of sIL-2R showed prognostic significance and genetic features. Compared with FINE subtype, RES subtype had increased ARID1A and MYD88 mutations, and RET subtype had increased KMT2D, LYN and SOCS1 mutations. RES and RET subtypes showed significant enrichment in oncogenic pathways, such as ERK, NF-κB, JAK-STAT, and immune-associated pathways. As for tumor microenvironment, RES subtype exhibited increased recruiting activity of CD8 + T, T helper 1, and natural killer cells, and RET subtype with increased recruiting activity of CD4 + T and regulatory T cells in silico. There was a positive correlation between transcripts of IL-2R and immune checkpoint expressions including PD-1 and CTLA-4. Our findings identified that dynamic change of sIL-2R, with this simple and easy detection method in peripheral blood, had long-term prognostic effect and specific relation to microenvironment alterations in DLBCL. [ABSTRACT FROM AUTHOR]

Background: This study aimed to propose a new user-friendly, cost effective and robust risk model to facilitate risk stratification for diffuse large B-cell lymphoma (DLBCL) treated with frontline R-CHOP regimens.Methods: Data on 998 patients with de novo DLBCL diagnosed between Jan 1st, 2005 and Dec 31st, 2018 at our center, who received frontline R-CHOP or R-CHOP-like regimens, were retrospectively collected. Patients were randomly divided into the training cohort (n = 701) and the validation cohort (n = 297). A new prognostic model for overall survival (OS) was built based on the training cohort. The performance of the new model was compared with International prognostic index (IPI), revised IPI (R-IPI) and National Comprehensive Cancer Network (NCCN)-IPI (NCCN-IPI). The new model was validated in the validation cohort.Results: The multivariate analysis of the training cohort showed that the IPI, β2-microglobulin, platelet count and red blood cell distribution width were independent factors for OS, which were incorporated into the new prognostic model. Patients were stratified into low risk, low-intermediate risk, high-intermediate risk, high risk and very high risk groups, with distinct survival outcomes. The new model achieved good C-indexes for 5-year OS prediction of 0.750 (95%CI 0.719-0.781) and 0.733 (95%CI 0.682-0.784) in the training and validation cohorts, respectively, and displayed well-fitted calibration curves. The C-index and the time-dependent ROC analysis demonstrated better performance of the new model than the IPI, R-IPI and NCCN-IPI in both training and validation cohorts. The integrated Brier score for predicting 5-year OS of the new model was lower than that of the IPI, R-IPI and NCCN-IPI in both cohorts, and decision curve analysis also showed a higher net benefit, indicating the superiority of the new model over the conventional models.Conclusion: The new prognostic model might be a useful predictive tool for DLBCL treated with R-CHOP regimens. Further external validation is warranted. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma in adults. Metabolic reprogramming in tumors is closely related to the immune microenvironment. This study aimed to explore the interactions between metabolism-associated genes (MAGs) and DLBCL prognosis and their potential associations with the immune microenvironment.Methods: Gene expression and clinical data on DLBCL patients were obtained from the GEO database. Metabolism-associated molecular subtypes were identified by consensus clustering. A prognostic risk model containing 14 MAGs was established using Lasso-Cox regression in the GEO training cohort. It was then validated in the GEO internal testing cohort and TCGA external validation cohort. GO, KEGG and GSVA were used to explore the differences in enriched pathways between high- and low-risk groups. ESTIMATE, CIBERSORT, and ssGSEA analyses were used to assess the immune microenvironment. Finally, WGCNA analysis was used to identify two hub genes among the 14 model MAGs, and they were preliminarily verified in our tissue microarray (TMA) using multiple fluorescence immunohistochemistry (mIHC).Results: Consensus clustering divided DLBCL patients into two metabolic subtypes with significant differences in prognosis and the immune microenvironment. Poor prognosis was associated with an immunosuppressive microenvironment. A prognostic risk model was constructed based on 14 MAGs and it was used to classify the patients into two risk groups; the high-risk group had poorer prognosis and an immunosuppressive microenvironment characterized by low immune score, low immune status, high abundance of immunosuppressive cells, and high expression of immune checkpoints. Cox regression, ROC curve analysis, and a nomogram indicated that the risk model was an independent prognostic factor and had a better prognostic value than the International Prognostic Index (IPI) score. The risk model underwent multiple validations and the verification of the two hub genes in TMA indicated consistent results with the bioinformatics analyses.Conclusions: The molecular subtypes and a risk model based on MAGs proposed in our study are both promising prognostic classifications in DLBCL, which may provide novel insights for developing accurate targeted cancer therapies. [ABSTRACT FROM AUTHOR]

Background: Primary ovarian lymphoma has been difficult to diagnose clinically and pathologically due to its rare incidence and non-specific clinical symptoms. Case presentation: A 75-year-old female patient was reported in this study. The patient had a six-month history of changes in bowel habits, with occasional black feces and paroxysmal pain in the abdomen. The computed tomography scan of the pelvic cavity illustrated that rectal cancer and sigmoid colon adenocarcinoma invaded the lower part of the right-side ureter. The patient was once treated with excision of part of small intestine, fallopian tube and ovary, and uterus. The pathological examination of these excised tissues, combined with the immunohistochemistry, confirmed that the female patient suffered from primary ovarian diffuse large B-cell lymphoma (DLBCL), and the lymphoma had invaded the entire right-side ovary tissues, serous membranes on the posterior surface of the uterus, and the wall of small intestine. Conclusion: Few reports were available regarding the primary ovarian DLBCL. The initial symptom of the patient was the changes in bowel habits, which had not been reported beforehand. Hopefully, this case could helpfully render the early diagnosis possible, and increase clinical understanding of primary ovarian DLBCL, which would thereby reduce the chance of misdiagnosis. [ABSTRACT FROM AUTHOR]

High-grade B-cell lymphoma with translocations involving MYC and BCL2 or BCL6, usually referred to as double hit lymphoma (DHL), is an aggressive hematological malignance with distinct genetic features and poor clinical prognosis. Current standard chemoimmunotherapy fails to confer satisfying outcomes and few targeted therapeutics are available for the treatment against DHL. Recently, the delineating of the genetic landscape in tumors has provided insight into both biology and targeted therapies. Therefore, it is essential to understand the altered signaling pathways of DHL to develop treatment strategies with better clinical benefits. Herein, we summarized the genetic alterations in the two DHL subtypes (DHL-BCL2 and DHL-BCL6). We further elucidate their implications on cellular processes, including anti-apoptosis, epigenetic regulations, B-cell receptor signaling, and immune escape. Ongoing and potential therapeutic strategies and targeted drugs steered by these alterations were reviewed accordingly. Based on these findings, we also discuss the therapeutic vulnerabilities that coincide with these genetic changes. We believe that the understanding of the DHL studies will provide insight into this disease and capacitate the finding of more effective treatment strategies. [ABSTRACT FROM AUTHOR]

Background: Intrapulmonary arteriovenous shunts is rare seen in a patient without lung involvement.Case Presentation: This is the first report of reversible intrapulmonary arteriovenous shunts secondary to extrapulmonary lymphoma as one initial symptom. The patient presented as fever of unknown origin and dyspnea, and examinations of infection were negative. Diagnosis of DLBCL was finally confirmed through bone marrow and splenic biopsies. Intrapulmonary arteriovenous shunts were diagnosed through 100% oxygen inhalation test and transthoracic contrast echocardiography (TTCE). After the treatment of lymphoma, his respiratory failure was relieved. We rechecked the 100% oxygen inhalation test and TTCE, which both indicated that his intrapulmonary arteriovenous shunts had resolved.Conclusions: We speculated the prominent inflammation from active DLBCL was the most possible mechanism associated with the reversible intrapulmonary shunt in this patient. These findings will assist us to better understand the mechanism of intrapulmonary shunts. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease defined using a number of well-established molecular subsets. Application of non-negative matrix factorization (NMF) to whole exome sequence data has previously been used to identify six distinct molecular clusters in DLBCL with potential clinical relevance. In this study, we applied NMF-clustering to targeted sequencing data utilizing the FoundationOne Heme® panel from the Phase III GOYA (NCT01287741) and Phase Ib/II CAVALLI studies (NCT02055820) in de novo DLBCL. Biopsy samples, survival outcomes, RNA-Seq and targeted exome-sequencing data were available for 423 patients in GOYA (obinutuzumab [G]-cyclophosphamide, doxorubicin, vincristine, and prednisone [CHOP] vs rituximab [R]-CHOP) and 86 patients in CAVALLI (venetoclax+[G/R]-CHOP).Results: When the NMF algorithm was applied to samples from the GOYA study analyzed using a comprehensive genomic profiling platform, four of the six groups previously reported were observed: MYD88/CD79B, BCL2/EZH2, NOTCH2/TNFAIP3, and no mutations. Mutation profiles, cell-of-origin subset distributions and clinical associations of MYD88/CD79B and BCL2/EZH2 groups were similar to those described in previous NMF studies. In contrast, application of NMF to the CAVALLI study yielded only three; MYD88/CD79B-, BCL2/EZH2-like clusters, and a no mutations group, and there was a trend towards improved outcomes for BCL2/EZH2 over MYD88/CD79B.Conclusions: This analysis supports the utility of NMF used in conjunction with targeted sequencing platforms for identifying patients with different prognostic subsets. The observed trend for improved overall survival in the BCL2/EZH2 group is consistent with the mechanism of action of venetoclax, suggesting that targeting sequencing and NMF has potential for identifying patients who are more likely to gain benefit from venetoclax therapy. [ABSTRACT FROM AUTHOR]

Background: Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphatic tumor; however, extranodal DLBCLs that exhibit initial symptoms in the maxilla and mandible are rare. Moreover, DLBCL is clinically classified as a moderate to highly malignant lymphatic tumor that can progress rapidly; therefore, early diagnosis is crucial. However, diagnosis is difficult as the disease causes a diverse range of clinical symptoms with no characteristic imaging findings. We conducted a clinical investigation to clarify the clinical characteristics of DLBCL that exhibits initial manifestation in the maxilla and mandible. Methods: Of the 2748 patients with malignant tumors of the oral and maxillofacial region examined at our hospital during a period of 11 years between January 2006 and December 2016, 27 primary cases diagnosed with DLBCL based on the chief complaint of symptoms in the gingiva and bone of the maxilla and mandible were enrolled in this study. Evaluations were based on sex, age, whether treatment was provided by a previous physician, symptoms, duration of disease until treatment was sought, clinical diagnosis, laboratory findings, and imaging results. Results: There were 15 cases that involved the maxilla and 12 that involved the mandible. The median duration of disease until treatment was sought was 60 d (3–450 d). All cases exhibited a tumor or a mass, and hypoesthesia of the chin was confirmed in eight cases wherein the mandible was involved. The clinical stages were stage I in eight cases, stage II in ten cases, and stage IV in nine cases. Serum lactate dehydrogenase (LDH) levels were elevated in 13 of 22 patients. The overall survival rate was 63%. Conclusions: Symptoms associated with nontender swelling and numbness of the lip or chin in the absence of other findings such as dental infections should raise suspicions about DLBCL. Patients should be provided appropriate imaging and accurate biopsy assessments to improve prognosis. [ABSTRACT FROM AUTHOR]

Background: Cervical thymoma is a rare thymic epithelial neoplasm. Evidence supports an increased risk of second primary malignancies in patients with thymoma. We report a rare case of a patient with synchronous cervical thymoma and diffuse large B-cell lymphoma.Case Presentation: An 81-year-old Thai woman was referred for further treatment of diffuse large B-cell lymphoma at Siriraj Hospital, Bangkok, Thailand. While waiting for a review of the original pathological examination of a mass in the left neck and a mass in the left arm, the attending physician noticed ptosis of the upper eyelids, which was proven to be caused by myasthenia gravis. The final pathology review confirmed that the arm mass was diffuse large B-cell lymphoma, but the neck mass was cervical thymoma, type B1, not diffuse large B-cell lymphoma. Interestingly, the patient reported that the arm mass had been present for 2 years, while the neck mass had grown rapidly in the past month. A diagnostic challenge had arisen when the initial morphological evaluation was not performed with care, causing the first pathologist to misinterpret that the neoplastic cells in both masses were the same.Conclusion: Concurrent cervical thymoma and diffuse large B-cell lymphoma were proven after a careful pathology review, leading to better clinical management. [ABSTRACT FROM AUTHOR]