Prognosis Of Diffuse Large B-cell Lymphoma Research Articles

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

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

Identification of oxidative stress-related hub genes for predicting prognosis in diffuse large B-cell lymphoma

BackgroundOxidative stress is a cellular characteristic that might induce the proliferation and differentiation of tumor cells and promote tumor progression in diffuse large B-cell lymphoma (DLBCL). MethodsThe DLBCL gene sequencing dataset, tumor mutation burden data, copy number variation data of Somatic cell mutation data in TCGA were downloaded for data training analysis, along with four DLBCL datasets in GEO for validation analysis. The known oxidative stress related genes (OSRGs) were collected from websites. The weighted gene co-expression network analysis (WGCNA) was conducted on the TCGA DLBCL dataset to obtain gene modules related to oxidative stress and intersected with the known OSRGs to obtain the hub genes, which were used to perform consensus clustering on the samples to obtain new phenotypes. Next, the prognosis related OSRGs were selected through regression analysis algorithms and key genes were identified. These genes were used to establish the prognostic risk model and predictive model, and to compare functional and pathway differences among different risk groups. ResultsThrough website search, we obtained 297 known OSRGs, and after intersecting with WGCNA results, we obtained 26 OSRGs. The TCGA-DLBC samples were clustered into 2 subtypes with these genes and there were significant differences in immune infiltration between subtypes. After regression analysis, we obtained a total of four key genes, BMI1, CDKN1A, NOX1, and SESN1. The risk prediction model established with these four genes as variables has accurate prognostic prediction ability. The key genes interact with 65 miRNAs, 57 TFs, 47 RBPs, and 62 drugs, respectively, and are closely related to immune infiltration of the disease. Among them, CDKN1A and SESN1 had the highest variability. ConclusionsThe key genes involved in oxidative stress could predict the prognosis of DLBCL and potentially become therapeutic targets.

Expression Profile and Prognostic Significance of Pivotal Regulators for N7-Methylguanosine Methylation in Diffuse Large B-Cell Lymphoma.

N7-methylguanosine (m7G) occurs by adding a methyl group to the N7 atom of the RNA guanine. Emerging evidence suggests that m7G modification has emerged as a crucial regulator of tumorigenesis, progression, invasion, and metastasis in multiple cancers. Nevertheless, the utility of m7G modification in diffuse large B-cell lymphoma (DLBCL) remains undefined, notably the interaction with the tumor microenvironment (TME). Here, we aimed to identify the expression profile of m7G regulators in DLBCL, construct a novel risk model, and explore their connection with TME. We initially investigated the difference and correlation in m7G regulators' expression in normal and tumor groups, classified patients by consistent clustering analysis, investigated the functional and prognostic significance of the resulting subtypes, and identified prognosis-associated genes by one-way Cox and least absolute shrinkage and selection operator (LASSO)regression calculations, and constructed a risk model. Further analysis showed that correlation among immune cell infiltration with m7G risk score and determined that it impacts the prognosis of DLBCL patients. Our research demonstrated the relevance of m7G regulators to DLBCL prognosis, providing theoretical support for precise prognostic stratification and immunotherapeutic assessment in DLBCL.

Prognostic Impact of MYD88 and TP53 Mutations in Diffuse Large B Cell Lymphoma

Abstract Background Diffuse large B cell lymphoma (DLBCL) is the most common subtype of lymphoma, It is a highly heterogeneous lymphoid neoplasm, with variations in gene expression profiles and genetic alterations, MYD88 and TP53 genes are common to be expressed and mutated in DLBCL patients with controversy regarding their role in prognosis and survival. This study aims to determine the predictive and prognostic role of MYD88 and TP53 genes mutation in DLBCL. Methods A prospective cohort study was conducted on patients who were diagnosed with DLBCL in Ain Shams university hospital, the primary objective was to detect the sensitivity and the specificity of MYD88 and TP53 genes expression for prognosis and detection of DLBCL patients. Secondary objectives were to measure ORR, 2 year PFS, and OS in relation to MYD88 and TP53 genes expression profile by detection of their expression profile using real time PCR approach. Results A total 50 DLBCL patients and 30 healthy individuals were included to assess sensitivity and specificity of MYD88 and TP53 genetic mutations in DLBCL prognosis. MYD88 and TP53 gene mutations were more sensitive, specific and accurate in predicting overall mortality (MYD88 sensitivity 95.1%, specificity 87.5%, prognostic accuracy 93.9%, P value <0.001, AUCROC 0.91, while TP53 sensitivity 82.9%, specificity 87.5%, prognostic accuracy 83.7%, P value 0.002, AUCROC 0.85) and disease progression (MYD88 sensitivity 92.5%, specificity 88.9%, prognostic accuracy 90.7%, P value <0.001, AUCROC 0.85, while TP53 sensitivity 94.3%, specificity 64.3%, prognostic accuracy 85.7%, P value 0.001, AUCROC 0.84) in comparison with international prognostic index(OS Sensitivity 70.7%, and specificity 75%, prognostic accuracy 71.4%, P value 0.011, AUCROC 0.79, while for progression, sensitivity is 79.2%, and specificity is 100%, prognostic accuracy 79.6%, P value 0.021, AUCROC 0.73). Mutant MYD88 and TP53 showed their prognostic importance for worse objective response rates and survival outcomes. Both mutant MYD88 and TP53 were associated with worse ORR (p- value=0.001). There was a significant statistical difference for both MYD88 and TP53 as regard 2 year PFS rate (Mutant 25% Vs 100% wild MYD88 P < 0.001, and Mutant TP53 62% Vs 97% wild TP53 P < 0.001), 2 year OS rate (Mutant MYD88 33% Vs wild MYD88 100% P < 0.001,and MutantTP53 70% Vs wild TP53 96% P < 0.001). Conclusion Both mutant MYD88 and TP53 can be used in predicting disease progression, and overall mortality. They showed their prognostic importance for inferior survival outcomes. mutations were associated with a significant worse 2 year OS and PFS rates and also they were correlated with poor objective response rate to treatment. The current study shows that the incorporation of the mutational status of MYD88 and TP53 (especially MYD88) into a clinical-biochemical risk score as the IPI is feasible. This encourages for more studies to test the utility of these gene mutations in prognosis of DLBCL.

Exploring the Potential of Enhanced Prognostic Performance of NCCN-IPI in Diffuse Large B-Cell Lymphoma by Integrating Tumor Microenvironment Markers: Stromal FOXC1 and Tumor pERK1/2 Expression.

FOXC1 and ERK1-2 are proteins implicated in aggressive biological behavior of various malignancies including lymphomas. We investigate the additive prognostic value of stromal FOXC1 expression and tumor phosphorylated ERK1-2 (pERK1-2) expression to the established National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), in 92 diffuse large B-cell lymphoma (DLBCL) cases. Multidimensional analysis using statistics and machine learning (ML) models assessed prognostic value of established clinicopathologic variables with stromal FOXC1 and tumor pERK1-2 expressions. Both high FOXC1 stroma group and high pERK1-2 tumor group were significantly associated with shorter progression-free survival (PFS) and overall survival (OS) compared with low group (p = 0.015, 0.034 and p = 0.025, 0.025 each respectively). In multivariable analysis, high FOXC1 stromal expression was an independent prognostic factor of OS (p = 0.037). The addition of stromal FOXC1 and tumor pERK1-2 to the NCCN-IPI score significantly improved prediction of time to death compared with NCCN-IPI score alone (Harrell's C-index = 0.801 vs. 0.764; p = 0.030). ML models reconfirmed the addition of stromal FOXC1 expression and tumor pERK1-2 to NCCN-IPI score had the highest C-index (0.952) among combinations. Stromal FOXC1 and tumor pERK1-2 were determinants of DLBCL prognosis, whose addition significantly improved prognostic performance of the NCCN-IPI.

Prognostic impact of concordant and discordant bone marrow involvement on diffuse large B-cell lymphoma.

In diffuse large B-cell lymphoma (DLBCL), bone marrow (BM) involvement includes two types that are concordant involvement and discordant involvement. It has been reported that concordant BM involvement has a worse prognosis than discordant involvement in previous studies. However, the prognostic effects of concordant or discordant BM involvement on DLBCL still need further research. In this work, DLBCL cases with BM involvement were collected and analyzed to better reflect the prognostic implications of concordant and discordant BM involvement. We reviewed the cases with newly diagnosed DLBCL and BM involvement from April 2018 to April 2022 in Northern Jiangsu People's Hospital. Overall survival (OS) and progression-free survival (PFS) were accessed by the Kaplan-Meier method and compared between groups by the log-rank test. A multivariate regression analysis based on Cox proportional hazard model was used to test the independent effect of each variable on survival. In total, 32 patients were included and 15 (46.9%) patients had concordant BM involvement and 17 (53.1%) patients had discordant BM involvement. Compared with the discordant group, the concordant group tended to be older and had elevated lactate dehydrogenase level. The outcome of patients with concordant BM involvement was worse than the discordant subset, including OS (P=0.04) and PFS (P=0.03). Furthermore, the discordant BM involvement was excluded to acquire a BM-adjusted International Prognostic Index (IPI) score. The significance of BM-adjusted IPI scores to predict OS was improved greatly compared with the previous IPI scores (P=0.053 vs. P=0.16). Multivariate analysis showed that the BM-adjusted IPI was an independent predictor for OS [hazard ratio =3.406; 95% confidence interval (CI): 1.145-10.127; P=0.03]. These results highlight the requirement for identifying BM infiltration type accurately and then adjusting the IPI score by excluding discordant BM involvement since concordant involvement can partly predict a poor prognosis of DLBCL with BM involvement other than discordant involvement.

Gene regulatory mechanisms of T cell exhaustion in diffuse large B cell lymphoma based on single-cell transcriptome data

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous and aggressive B cell malignancy that accounts for about 30 % of non-Hodgkin lymphomas. The current standard treatment for DLBCL is rituximab plus chemotherapy, but many patients are refractory or relapse, indicating the need for improved understanding of its molecular pathology. T cell exhaustion is a state of dysfunction or impairment that occurs in chronic infections or cancers, and is associated with poor prognosis in DLBCL. However, the molecular mechanisms of T cell exhaustion in DLBCL are poorly understood. In this study, we performed a comprehensive analysis of T cell exhaustion in DLBCL using public single-cell transcriptome data. We identified different subtypes of T cells and characterized their gene expression features. We found that DLBCL had a significantly higher proportion of exhausted T cells than normal tonsil, and that exhausted T cells had distinct gene expression signatures from non-exhausted T cells. These signatures included genes related to inhibitory receptors, cytokines, transcription factors and metabolic enzymes. We also found that ID3 gene was significantly upregulated in exhausted T cells in DLBCL, which may play a key role in T cell exhaustion. We constructed a protein-protein interaction network, identifying major hub proteins involved in T cell exhaustion or migration. We also performed KEGG and GO enrichment analysis for the differentially expressed genes between exhausted and non-exhausted T cells, and found important signaling pathways related to T cell exhaustion in DLBCL. Our results provide new insights into the molecular mechanisms underlying T cell exhaustion and offer novel therapeutic targets for this complex disease.

MicroRNAs implicated in canine diffuse large B-cell lymphoma prognosis.

Diffuse large B-cell lymphoma (DLBCL) is the most prevalent subtype of non-Hodgkin lymphoma (NHL) in domestic dogs, with many similarities to its human counterpart. The progression of the disease is rapid, and treatment must be initiated early to achieve cancer remission and extend life. This study examined the relationship between progression-free survival (PFS) and microRNA (miRNA) expression in dogs with DLBCL. miRNAs are small non-coding RNA molecules that typically regulate gene expression post-transcriptionally. They are involved in several pathophysiological processes, including the growth and progression of cancer. Based on the analysis of small RNA sequencing (sRNA-seq) data, we validated a group of miRNAs in lymph nodes from 44 DLBCL-affected dogs with known outcomes. We used quantitative PCR to quantify their expression and report a specific subset of miRNAs is associated with decreased PFS in dogs with DLBCL. The miR-192-5p and miR-16-5p expression were significantly downregulated in dogs with increased PFS. These results indicate that miRNA profiling may potentially identify dogs with DLBCL that will experience poor outcomes following treatment. Identifying specific miRNAs that correlate with the progression of canine DLBCL could aid the development of individualized treatment regimens for dogs.

Predicting lymphoma prognosis using machine learning-based genes associated with lactylation

BackgroundLactylation, a newly discovered PTM involving lactic acid, is linked to solid tumor proliferation and metastasis. Lymphoma patients exhibit high lactic acid levels, yet lactylation's role in lymphoma is underexplored. This study aimed to identify lactylation-related genes in lymphoma using tumor databases and assess their predictive value in patient prognosis through cell experiments and clinical specimens. MethodsUsing TCGA and GEO datasets, we analyzed the expression levels of lactylation-related genes in diffuse large B-cell lymphoma patients. We also evaluated the prognostic significance of lactylation gene risk scores, exploring their impact on drug sensitivity and tumor immune function. Key lactylation-affecting genes were identified and functionally validated through cell experiments and mouse in vivo experiments. Additionally, the relationship between lactylation and lymphoma prognosis was examined in clinical specimens. ResultsWe identified 70 genes linked to diffuse large B-cell lymphoma prognosis from the lactylation-related gene set. Using clinical data and a COX regression algorithm, we developed an optimized lactylation Riskscore model. This model significantly correlated with prognosis and showed differences in immune cell infiltration, particularly macrophages. High-risk patients showed resistance to chemotherapy drugs but responded well to immunotherapy. HNRNPH1, a lactylation-related gene, influenced patient prognosis, apoptosis, cell cycle distribution in lymphoma cells, and tumor volume in mice. In lymphoma specimens, lactylation levels correlated with Bcl-2, C-myc, and P53 levels. ConclusionsLactylation impacts diffuse large B-cell lymphoma prognosis, tumor immune function, and drug resistance. Our lactylation-based Riskscore model aids in patient stratification and treatment selection. HNRNPH1 regulates lactylation, thereby affecting patient prognosis.

Effect of Vitamin D and Skeletal Muscle Mass on Prognosis of Patients with Diffuse Large B-Cell Lymphoma.

This study investigated the prognostic impact of vitamin D deficiency and reduced skeletal muscle mass in diffuse large B-cell lymphoma (DLBCL) patients. A retrospective analysis of 186 newly diagnosed DLBCL patients from 2012 to 2022 was conducted, measuring serum 25-hydroxyvitamin D [25(OH)D] levels and the skeletal muscle index (SMI). Decreased vitamin D levels were linked to more severe DLBCL disease, with a median 25(OH)D concentration of 13 (4.0-27) ng/mL. Males in the group with a low SMI had a considerably lower 25(OH)D concentration. The optimal threshold of 25(OH)D levels for overall survival (OS) was 9.6 ng/mL, with lower values associated with a higher likelihood of recurrence and mortality. Multivariable analysis showed hazard ratios for OS of 1.4 [95% CI 0.77-2.5] for a low SMI and 3.2 [95% CI 1.8-5.8] for low 25(OH)D concentration. The combination of a low SMI and low vitamin D concentration resulted in the worst prognosis. Thus, low levels of vitamin D associated with disease progression significantly impact DLBCL prognosis, which can be further stratified by the SMI, providing valuable insights for patient management and potential therapeutic interventions.

Low NDRG2, regulated by the MYC/MIZ-1 complex and methylation, predicts poor outcomes in DLBCL patients.

Diffuse large B-cell lymphoma (DLBCL) represents the most common tumor in non-Hodgkin's lymphoma. N-Myc downstream-regulated gene 2 (NDRG2) is a tumor suppressor highly expressed in healthy tissues but downregulated in many cancers. Although cell proliferation-related metabolism rewiring has been well characterized, less is known about the mechanism of metabolic changes with DLBCL. Herein, we investigated the expressions of NDRG2, MYC and Myc-interacting zinc finger protein 1 (MIZ-1) in seven human lymphoma (mostly DLBCLs) cell lines. NDRG2 expression was inversely correlated with the expressions of MYC and MIZ-1. Further, we explored the regulatory mechanism and biological functions underlying the lymphomagenesis involving NDRG2, MYC and MIZ-1. MYC and MIZ-1 promoted DLBCL cell proliferation, while NDRG2 induced apoptosis in LY8 cells. Moreover, NDRG2 methylation was reversed by the 5-Aza-2'-deoxycytidine (5-Aza-CDR) treatment, triggering the downregulation of MYC and inhibiting DLBCL cell survival. MYC interacts with NDRG2 to regulate energy metabolism associated with mTOR. Remarkably, supporting the biological significance, the converse correlation between NDRG2 and MYC was observed in human DLBCL tumor tissues (R = -0.557). Bioinformatics analysis further validated the association among NDRG2, MYC, MIZ-1, mTOR, and related metabolism genes. Additionally, NDRG2 (P = 0.001) and MYC (P < 0.001) were identified as promising prognostic biomarkers in DLBCL patients through survival analysis. Together, our data demonstrate that the MYC/MIZ-1 complex interplays with NDRG2 to influence the proliferation and apoptosis of DLBCL cells and show the characterizations of NDRG2, MYC and MIZ-1 for metabolism features and prediction prognosis in DLBCL.

Primary Extranodal Diffuse Large B-Cell Lymphoma in the Rituximab Era: a Single-Center Retrospective Analysis

To investigate the clinical features and prognostic factors of patients with primary extranodal diffuse large B-cell lymphoma (DLBCL) in the rituximab era. The continuous data of newly diagnosed DLBCL patients with complete case data and first-line treated with rituximab, cyclophosphamide, epirubicin, vincristine, prednisone (R-CHOP) or R-CHOP treatment admitted to the Affiliated Hospital of Inner Mongolia Medical University from January 2013 to November 2023 were retrospectively analyzed. The clinical and molecular immunological features and prognosis of extranodal DLBCL were analyzed, Logistics regression model was used to analyzed the influencing factors of patients prognosis. A total of 237 patients were enrolled, of which 54.4% (129 cases) were primary extranodal sources of DLBCL, and the most common extranodal sites were as follows: stomach (19.4%), colon (14.7%), tonsils (12.4%), skin/muscle (9.3%), central (7.7%), nasal/nasopharynx (6.2%), bone marrow (5.4%), testes (4.7%). The 3-year PFS and OS of DLBCL patients with extranodal involvement of bone marrow, central, liver, gastrointestinal or pulmonary origin were significantly lower than those of other patients with extranodal DLBCL of non-special site origin, and the difference was statistically significant (PFS: 65.2% vs 76.7%, P =0.008; OS: 82.6% vs 88.3%, P =0.04). Multivariate analysis showed that the prognostic factors affecting OS included NCCN-IPI score >3 (OR : 0.142, 95%CI : 0.041-0.495, P =0.002), non-germinal center source (OR : 2.675，95%CI :1.069-6.694，P =0.036), and DEL patients (OR : 0.327, 95%CI : 0.129-0.830, P =0.019). An NCCN-IPI score >3 was the only independent adverse prognostic factor for PFS (OR : 0.235, 95%CI : 0.116-0.474, P < 0.001). Patients with primary extranodal source DLBCL are more common in gastrointestinal involvement, and the overall prognosis is worse than that of patients with lymph node origin. NCCN-IPI score is an important independent adverse prognostic factor for predicting overall survival and progression-free survival in patients with primary extranodal diffuse large B-cell lymphoma.

Baseline 18F-FDG PET/CT radiomics for prognosis prediction in diffuse large B cell lymphoma with extranodal involvement.

The objective of this investigation is to explore the capability of baseline 18F-FDG PET/CT radiomics to predict the prognosis of diffuse large B-cell lymphoma (DLBCL) with extranodal involvement (ENI). 126 patients diagnosed with DLBCL with ENI were included in the cohort. The least absolute shrinkage and selection operator (LASSO) Cox regression was utilized to refine the optimum subset from the 1328 features. Cox regression analyses were employed to discern significant clinical variables and conventional PET parameters, which were then employed with radiomics score to develop combined model for predicting both progression-free survival (PFS) and overall survival (OS). The fitness and the predictive capability of the models were assessed via the Akaike information criterion (AIC) and concordance index (C-index). 62 patients experienced disease recurrence or progression and 28 patients ultimately died. The combined model exhibited a lower AIC value compared to the radiomics model and SDmax/clinical variables for both PFS (507.101 vs. 510.658 vs. 525.506) and OS (215.667 vs. 230.556 vs. 219.313), respectively. The C-indices of the combined model, radiomics model, and SDmax/clinical variables were 0.724, 0.704, and 0.615 for PFS, and 0.842, 0.744, and 0.792 for OS, respectively. Kaplan--Meier curves showed significantly higher rates of relapse and mortality among patients classified as high-risk compared to those classified as low-risk (all P < 0.05). The combined model of clinical variables, conventional PET parameters, and baseline PET/CT radiomics features demonstrates a higher accuracy in predicting the prognosis of DLBCL with ENI.

Tumor purity-related genes for predicting the prognosis and drug sensitivity of DLBCL patients

Background:Diffuse large B-cell lymphoma (DLBCL) is the predominant type of malignant B-cell lymphoma. Although various treatments have been developed, the limited efficacy calls for more and further exploration of its characteristics.Methods:Datasets from the Gene Expression Omnibus (GEO) database were used for identifying the tumor purity of DLBCL. Survival analysis was employed for analyzing the prognosis of DLBCL patients. Immunohistochemistry was conducted to detect the important factors that influenced the prognosis. Drug-sensitive prediction was performed to evaluate the value of the model.Results:VCAN, CD3G, and C1QB were identified as three key genes that impacted the outcome of DLBCL patients both in GEO datasets and samples from our center. Among them, VCAN and CD3G+ T cells were correlated with favorable prognosis, and C1QB was correlated with worse prognosis. The ratio of CD68 + macrophages and CD8 + T cells was associated with better prognosis. In addition, CD3G+T cells ratio was significantly correlated with CD68 + macrophages, CD4 + T cells, and CD8 +T cells ratio, indicating it could play an important role in the anti-tumor immunity in DLBCL. The riskScore model constructed based on the RNASeq data of VCAN, C1QB, and CD3G work well in predicting the prognosis and drug sensitivity.Conclusions:VCAN, CD3G, and C1QB were three key genes that influenced the tumor purity of DLBCL, and could also exert certain impact on drug sensitivity and prognosis of DLBCL patients.Funding:This work is supported by the Shenzhen High-level Hospital Construction Fund and CAMS Innovation Fund for Medical Sciences (CIFMS) (2022-I2M-C&amp;T-B-062).

Comparison of Cox regression and generalized Cox regression models to machine learning in predicting survival of children with diffuse large B-cell lymphoma.

The incidence of diffuse large B-cell lymphoma (DLBCL) in children is increasing globally. Due to the immature immune system in children, the prognosis of DLBCL is quite different from that of adults. We aim to use the multicenter large retrospective analysis for prognosis study of the disease. For our retrospective analysis, we retrieved data from the Surveillance, Epidemiology and End Results (SEER) database that included 836 DLBCL patients under 18 years old who were treated at 22 central institutions between 2000 and 2019. The patients were randomly divided into a modeling group and a validation group based on the ratio of 7:3. Cox stepwise regression, generalized Cox regression and eXtreme Gradient Boosting (XGBoost) were used to screen all variables. The selected prognostic variables were used to construct a nomogram through Cox stepwise regression. The importance of variables was ranked using XGBoost. The predictive performance of the model was assessed by using C-index, area under the curve (AUC) of receiver operating characteristic (ROC) curve, sensitivity and specificity. The consistency of the model was evaluated by using a calibration curve. The clinical practicality of the model was verified through decision curve analysis (DCA). ROC curve demonstrated that all models except the non-proportional hazards and non-log linearity (NPHNLL) model, achieved AUC values above 0.7, indicating high accuracy. The calibration curve and DCA further confirmed strong predictive performance and clinical practicability. In this study, we successfully constructed a machine learning model by combining XGBoost with Cox and generalized Cox regression models. This integrated approach accurately predicts the prognosis of children with DLBCL from multiple dimensions. These findings provide a scientific basis for accurate clinical prognosis prediction.

Prognostic Significance of Double-Expresser Status in Diffuse Large B-cell lymphoma: Experience from a Tertiary Care Cancer Centre in India

Background: Diffuse large B-cell lymphoma (DLBCL) is a neoplasm of medium or large B lymphoid cells with a diffuse histopathologic growth pattern. Co-expression of MYC and BCL2 proteins in DLBCL by immunohistochemistry (IHC) is referred to as the double-expresser (DE) phenotype and is associated with inferior survival. Objectives of this study were to assess the DE status in DLBCL and to assess its utility in predicting the prognosis in DLBCL. Methods: This was a retrospective study conducted in a tertiary care cancer centre. Study population included all the cases of DLBCL, NOS diagnosed in the centre in 2012. MYC and BCL2 protein expression were analysed by immunohistochemistry. The prognostic significance of double-expressers was analysed by comparing progression free survival (PFS) and overall survival (OS) of double-expressers and non-double expressers using appropriate statistical methods. All the data were analysed using SPSS 11 software. Kaplan-Meier method was used to estimate the survival probability. A significant difference in survival between various prognostic factors was tested using the log-rank test. Prognostic factors were assessed using univariate and multivariate Cox-regression model. A P- value &lt; 0.05 was considered to be statistically significant. Results: Double-Expresser lymphoma (DEL) constituted 22.2% (n=18) of all cases of DLBCL, NOS. DE status was associated with shorter PFS (P-value = 0.049) and OS (P-value = 0.015). Conclusion: DE status is associated with poor prognosis in DLBCL, NOS. Assessment of MYC and BCL2 by IHC represents a rapid and inexpensive approach to risk-stratify patients with DLBCL at the time of diagnosis.

HLA variations in patients with diffuse large B-cell lymphoma and association with disease risk and prognosis: a case-control study.

Human leukocyte antigen (HLA) polymorphisms have been associated with the development of various autoimmune diseases, as well as malignant neoplasms. Non-Hodgkin lymphomas (NHLs) are a heterogenous group of lymphoid malignancies in which a genetic substrate has been established and is deemed to play a crucial role in disease pathogenesis. This study aimed to identify whether variations in the HLA gene region were associated with diffuse large B-cell lymphoma (DLBCL) risk and prognosis. We defined HLA class I (HLA-A, HLA-B, HLA-C) and class II (HLA-DRB1, HLA-DQB1) alleles in 60 patients with DLBCL and compared the results to those found by 236 healthy adult donors from the bone marrow bank of Northern Greece. HLA typing was performed by two molecular methods, Sequence - Specific Oligonucleotide HLA typing (SSO) and Sequence - Specific Primer HLA typing (SSP), from white blood cells recovered from peripheral blood. The phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1 and HLA-DQB1 between patients and controls were compared with the 2-sided Fisher's exact test. Results with p-value <0.05 were considered statistically significant. Odds Ratios with 95% Confidence Intervals were calculated to further strengthen the results. The 2-sided Fisher's exact test was also applied to alleles found only in one of the two groups, while the odds ratios together with the confidence intervals were corrected with Haldane-Anscombe method. Among the studied HLA polymorphisms, the frequency HLA-C*12 allele was significantly lower in patients with DLBCL compared with control subjects (6.7% vs. 34.7%, OR = 0.16, 95% CI: 0.04-0.44). Frequency of HLA-B*39 was significantly lower in patients with DLBCL compared with controls, but due to the low frequency of this polymorphism in the studied population and small sample size, determinations regarding the significance of this findings were limited. Survival analysis revealed that the presence of HLA-C*12 was not associated with improved or worsened overall and progression-free survival. No statistically significant associations were observed in the phenotypic frequencies of HLA-A, HLA-DQB1, HLA-DRB1 and the rest of HLA-B alleles between the control and DLBCL groups. Collectively, our results provide valuable insight regarding the role of HLA variations on DLBCL risk. Further studies are required to consolidate our findings and ascertain the clinical implications of these genetic variations on DLBCL management and prognosis.

The Value of Baseline PET/CT Imaging of Bone Marrow 18F-FDG Uptake Pattern in Predicting Prognosis of DLBCL

To investigate the prognostic value of bone marrow uptake pattern in 18F-deoxyglucose (18F-FDG) PET/CT imaging before diffuse large B-cell lymphoma (DLBCL) treatment. The clinical data of 156 patients with DLBCL were retrospectively analyzed. All patients underwent bone marrow biopsy, bone marrow smear, flow cytometry and 18F-FDG PET/CT scan before treatment. Taking normal liver 18F-FDG uptake as the standard, the bone marrow uptake patterns of patients were divided into three types: focal increased bone marrow uptake (fPET+), diffusely increased bone marrow uptake (dPET+), and normal bone marrow uptake (nPET). Survival analysis was performed using the Kaplan-Meier method, log-rank test was used for comparison of differences between groups, and multivariate Cox regression analysis was used to identify risk factors associated with prognosis. Among the 156 patients, 17 cases were fPET+, 28 cases were dPET+, and 111 cases were nPET. Clinical diagnosis of bone marrow infiltration (BMI) was positive in 21 cases and negative in 135 cases. There were 62 cases of recurrence and progression, and 18 cases of death. Univariate analysis showed that Ann Arbor stage III/IV, B symptoms, NCCN-IPI score, lactate dehydrogenase (LDH), BMI+ and fPET+ were associated with progression-free survival (PFS) (all P < 0.05), while Ann Arbor stage III/IV, NCCN-IPI score, LDH, BMI+ and fPET+ were associated with overall survival (OS) (all P < 0.05). Multivariate analysis showed that Ann Arbor stage III/IV, LDH and fPET+ were independent predictors of PFS (all P < 0.05). There were no independent predictors of OS in multivariate analysis. The bone marrow uptake pattern of 18F-FDG imaging in DLBCL patients before treatment has a predictive value for DLBCL, while fPET+ is an independent risk factor for PFS.

The effect of metabolic syndrome on prognosis of diffuse large B-cell lymphoma

PurposeMetabolic syndrome (MetS), characterized by insulin resistance, is closely associated with the prognosis of various cancer types, but has not been reported in diffuse large B-cell lymphoma (DLBCL). The aim of this study is to examine how other clinicopathological variables and the MetS influence the prognosis of DLBCL.MethodsClinical and pathological data were collected from 319 patients with DLBCL who were admitted to our hospital between January 2012 and December 2020. The data accessible with SPSS 27.0 enables the utilization of various statistical methods for clinical data analysis, including independent sample t test and univariate and multivariate COX regression.ResultsThe presence of MetS was linked to both overall survival (OS) and progression-free survival (PFS), in addition to other clinicopathological characteristics as age, IPI score, rituximab usage, and Ki-67 expression level. This link with OS and PFS indicated a poor prognosis, as shown by survival analysis. Subsequent univariate analysis identified IPI score, Ki-67 expression level, tumor staging, rituximab usage, lactate dehydrogenase expression level, and the presence or absence of MetS as factors linked with OS and PFS. Furthermore, multivariate Cox regression analysis confirmed the independent risk factor status of IPI score, Ki-67 expression level, rituximab usage, and the presence of MetS in evaluating the prognosis of patients with DLBCL.ConclusionThis study’s findings indicate that patients with pre-treatment MetS had a poor prognosis, with relatively shorter OS and PFS compared to those without pre-treatment MetS. Furthermore, the presence of MetS, IPI score, Ki-67 expression level, and rituximab usage were identified as independent risk factors significantly affecting the prognosis of DLBCL.

Abstract 3648: The spatial organization of cells expressing MYC and BCL2 affects immune microenvironment composition and prognosis in DLBCL

Abstract Point process analyses are widely used in ecology and geography to understand the impact and relevance of spatial distribution of points in a complex system. To date, only few studies have explored point process analyses in the context of tumor heterogeneity. Malignancies often show variable patterns of cellular distribution, and the relationship of these topographic variables with underlying biological processes and clinical outcomes is not well understood. Here, we performed spatial point process analyses in diffuse large B-cell lymphoma (DLBCL), leveraging advances in multiplexed immunohistochemistry and cellular phenotyping, with downstream multi-omic and clinicopathological analyses. We have demonstrated that survival in DLBCL is strongly associated with the fraction of malignant cells showing co-expression of the oncogenes MYC and BCL2 in the absence of BCL6 (M+2+6-). These cells display non-random spatial organization within tumor infiltrates, deviating from a poisson distribution. We therefore modeled the spatial organization of M+2+6- cells within DLBCL, using x-y coordinate information from multiplexed fluorescent immunohistochemistry (mfIHC) in four independent cohorts (N=449 patients). We derived spatial point patterns, upon which Geyers point process models were applied. We observed that patients could be divided into two groups based on these: one group showed “clustered” spatial organization, while the other displayed a “dispersed” M+2+6- cell distribution. Cases with predominantly “dispersed” M+2+6- cells showed shorter overall survival in all analyzed cohorts (P &amp;lt; 0.05 in 4/4 cohorts). We performed multi-omic analyses to identify potential biological explanations for this association between topography and clinical outcome. Using digital spatial profiling of the transcriptome from CD20, CD3 and CD68 compartments in 47 DLBCL samples, we observed that lymphomas with an M+2+6- ‘dispersed’ phenotype had an immunologically cold microenvironment enriched in Tregs and exhausted CD4+ and CD8+ T cells. Through an integration with single-cell transcriptomic analyses (N=22 samples) we observed that malignant B-cells from cases with M+2+6- ‘dispersed’ phenotype expressed genes implicated in cell migration and adhesion, but also in potentially targetable immune checkpoints such as LAG3. In summary, by integrating multiplexed immunophenotyping and point process analysis with molecular profiling in the setting of DLBCL, we show that a dispersed pattern of distribution of the M+2+6- subclonal fraction uniquely confers poor prognosis, and associates with a potentially reversible immune cold microenvironment composition. This represents the first demonstration that the spatial distribution of malignant cell subpopulations in lymphoma can embody biological and clinical significance. Citation Format: Shruti Shridar, Michal Marek Hoppe, Patrick Jaynes, Gayatri Kumar, Siddham Jasoria, Ziwei Meng, Vaibhav Rajan, Kasthuri Kannan, Claudio Tripodo, Anand Devaprasath Jeyasekharan. The spatial organization of cells expressing MYC and BCL2 affects immune microenvironment composition and prognosis in DLBCL [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3648.