OBJECTIVE: To explore the expression and clinical significance of XPO1 in newly diagnosed adult diffuse large B-cell lymphoma (DLBCL), and further investigate its functional mechanism. METHODS: Immunohistochemical testing was conducted for XPO1 expression in 93 cases of DLBCL and 30 cases of reactive lymphoid hyperplasia. A risk model was construed to find survival related genes in DLBCL patients. Cell proliferation, apoptosis, and cell cycle assays were performed to explore the effect of XPO1 inhibitor (KPT-8602) and XPO1 knockdown. Differential expression gene (DEG) was examined based on the transcriptomes. RESULTS The expression of XPO1 in DLBCL patients was higher than that of the controls. Compared with XPO1 low-expression group, XPO1 high-expression group had a worse prognosis. The constructed risk model indicated that XPO1 and 14 genes in nucleocytoplasmic transport pathway (NTP) might be potential prediction marker of adverse outcome in DLBCL. Moreover, KPT-8602 as well as the XPO1 knockdown could inhibit cell proliferation, promote apoptosis, and induce cell cycle arrest in two DLBCL cell lines, Farage and SU-DHL-4. Based on the gene expression profiling in the datasets of DLBCL, patients were classified into XPO1 high and XPO1 low expression groups, and the MYBL1 was identified as the down-stream effector of XPO1. Inhibiting the function of XPO1 or reducing its expression can significantly decrease the expression of MYBL1 Conclusion: XPO1 is highly expressed in DLBCL, which is associated with poor prognosis. The oncogenic roles of the new XPO1/MYBL1 signaling are identified in DLBCL and XPO1 inhibitor may be a potential option for newly-diagnosed DLBCL patients.
Humans ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Exportin 1 Protein ; Karyopherins/metabolism* ; Receptors, Cytoplasmic and Nuclear/metabolism* ; Cell Proliferation ; Apoptosis ; Prognosis ; Cell Line, Tumor ; Clinical Relevance

OBJECTIVE: To investigate the effect of TBL1XR1 mutation on cell biological characteristics of diffuse large B-cell lymphoma (DLBCL). METHODS: The TBL1XR1 overexpression vector was constructed and DNA sequencing was performed to determine the mutation status. The effect of TBL1XR1 mutation on apoptosis of DLBCL cell line was detected by flow cytometry and TUNEL fluorescence assay; CCK-8 assay was used to detect the effect of TBL1XR1 mutation on cell proliferation; Transwell assay was used to detect the effect of TBL1XR1 mutation on cell migration and invasion; Western blot was used to detect the effect of TBL1XR1 mutation on the expression level of epithelial-mesenchymal transition (EMT) related proteins. RESULTS: The TBL1XR1 overexpression plasmid was successfully constructed. The in vitro experimental results showed that TBL1XR1 mutation had no significant effect on apoptosis of DLBCL cells. Compared with the control group, TBL1XR1 mutation enhanced cell proliferation, migration and invasion of DLBCL cells. TBL1XR1 gene mutation significantly increased the expression of N-cadherin protein, while the expression of E-cadherin protein decreased. CONCLUSION TBL1XR1 mutation plays a role in promoting tumor cell proliferation, migration and invasion in DLBCL. TBL1XR1 could be considered as a potential target for DLBCL therapy in future research.
Humans ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Cell Proliferation ; Mutation ; Receptors, Cytoplasmic and Nuclear/genetics* ; Apoptosis ; Cell Line, Tumor ; Epithelial-Mesenchymal Transition ; Cell Movement ; Repressor Proteins/genetics* ; Nuclear Proteins/genetics* ; Cadherins/metabolism*

OBJECTIVE: To investigate the predictive value of circulating free DNA (cfDNA) combined with interleukin 10 (IL-10) in predicting central nervous system infiltration (CNSI) in diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 63 patients with DLBCL in our hospital from May 2021 to April 2023 were retrospectively analyzed. The 63 patients were divided into CNSI group (15 cases) and non-CNSI group (48 cases) base on whether CNSI occurred. The age, sex, Ann Arbor stage, ECOG score, IPI risk, CNS-IPI risk, number of extranodal sites involved, bone marrow involvement, hypertrophic disease, B symptoms, source cells, glucose quantification, Pandy test, cerebrospinal fluid (CSF) chlorine, CSF nucleated cell count, CSF protein, peripheral blood cfDNA, and IL-10 status were compared between the two groups. The correlation between cfDNA, IL-10 in peripheral blood and CSF protein was analyzed by Pearson correlation analysis. Receiver operating characteristic (ROC) curve was used to analyze the predictive value of peripheral blood cfDNA and IL-10 on secondary CNSI in DLBCL patients. The last follow-up was on November 30, 2023. Kaplan-Meier method was used to calculate the time of secondary CNSI in the non-CNSI group. RESULTS: The IPI risk, CNS-IPI risk, number of extranodal sites involved, and CSF protein in the CNSI group were significantly higher than those in the non-CNSI group (all P <0.05). The levels of cfDNA and IL-10 in peripheral blood of CNSI group were significantly higher than those of non-CNSI group (both P <0.01). cfDNA and IL-10 in peripheral blood were both positively correlated with CSF protein (r =0.402 4, 0.315 1). ROC curve analysis showed that peripheral blood cfDNA and IL-10 had certain predictive value for CNSI, and the area under the curve (AUC) was 0.829 and 0.742, respectively. The AUC of the combined detection was 0.910, with a sensitivity of 80.00% and a specificity of 93.70%. The diagnostic efficacy was significantly higher than that of the two prediction values alone. The median follow-up time was 20 (6-31) months. Non-CNSI patients were grouped based on peripheral blood cfDNA combined with IL-10 positive or negative pairs. The time of secondary CNSI in positive group was significantly shorter than that in negative group (P <0.05). CONCLUSION cfDNA and IL-10 in peripheral blood of DLBCL patients with CNSI are significantly increased, and the combined detection of cfDNA and IL-10 has good predictive value for CNSI.
Humans ; Interleukin-10/blood* ; Lymphoma, Large B-Cell, Diffuse/blood* ; Retrospective Studies ; Female ; Male ; Cell-Free Nucleic Acids/blood* ; Middle Aged ; ROC Curve ; Prognosis ; Central Nervous System Neoplasms ; Central Nervous System/pathology* ; Adult ; Predictive Value of Tests

OBJECTIVE: To investigate the biological behavior, differentiation ability, and differential gene expression of lymph node mesenchymal stem cells (MSCs) in patients with diffuse large B-cell lymphoma (DLBCL) and reactive lymphoid hyperplasia (RLH), providing a theoretical basis for clinical chemotherapy resistance. METHODS: Lymph node MSCs from patients with DLBCL and RLH were separated, passaged and cultured. The cell morphology and growth status were observed. Flow cytometry was performed to detect the immune phenotype of MSCs. The in vitro directed differentiation ability of the two types of MSCs was observed. High-throughput sequencing was used to analyze the differential gene expression and enrichment of two groups of MSCs. RESULTS: The lymph node MSCs of patients with DLBCL and RLH had similar cell morphology and growth characteristics, and both groups of MSCs expressed CD90, CD105, and CD73 on the cell surface. Compared with lymph node MSCs derived from patients with RLH, lymph node MSCs derived from DLBCL patients showed stronger osteogenic and adipogenic differentiation abilities. High-throughput sequencing results displayed that lymph node MSCs derived from DLBCL patients significantly upregulated some genes such as TOP2A, LFNG, GRIA3, SEC14L2, SPON2, AURKA, LRRC15, FOXD1, HOXC9, CDC20 and remarkably downregulated some genes such as TBC1D8, LDLR, PCDHAC2, POLH, PKP2, ANKRD37, DMKN, HSD11B1, ARHGAP20, PTGS1,etc. CONCLUSION Lymph node MSCs in DLBCL patients exhibit unique biological behavior and gene expression profiles, which may be closely related to clinical chemotherapy resistance.
Humans ; Mesenchymal Stem Cells/cytology* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Cell Differentiation ; Lymph Nodes/pathology* ; Pseudolymphoma/pathology*

<b>Objective:b>To compare the clinical characteristics of nasal NK/T-cell lymphoma（NKTL） and diffuse large B-cell lymphoma（DLBCL） to improve the diagnosis and differential diagnosis of nasal lymphomas. <b>Methods:b>A retrospective analysis of cases of nasal NKTL and DLBCL was conducted. The clinical symptoms, signs, and imaging features of both groups were compared and statistically analyzed. Results: The DLBCL group showed more symptoms like exophthalmos/diplopia and epiphora compared to the NKTL group （both P=0.040）. NKTL cases were more likely to be misdiagnosed as sinusitis（P=0.007）. In NKTL cases, nasal mucosal swelling（P<0.01）, destruction of nasal structures（P=0.002）, and external nasal structural abnormalities（P=0.003） were more prevalent. In imaging, the DLBCL group more commonly demonstrated worm-eaten destruction of sinus bones （P=0.004）, sinus masses （P=0.018）, and invasion of adjacent structures including the pterygopalatine fossa, infratemporal fossa （P<0.01）, orbit （P=0.039）, and skull base （P=0.011）. NKTL involved the turbinates（P=0.001）, nasal cavity and septum（P=0.016）, nasopharynx（P<0.01）, and "skip" infiltration of external nasal tissues（P=0.042） more frequently. No statistically significant differences were found in other clinical features between the two groups. <b>Conclusion:b>For patients with nasal obstruction and discharge, it is essential to inquire about systemic B symptoms, such as fever, and eye symptoms, such as periorbital swelling, diplopia, and lacrimation. Lymphoma should be suspected if local examination reveals diffuse nasal swelling, destruction of turbinates or septum, and external nasal structural abnormalities. Worm-eaten bone destruction and "cast-like" changes of the turbinates, septum, and nasal cavity, as well as "skip" infiltration of the external nose, are more common in NKTL. Sinus masses with invasion of the pterygopalatine fossa, infratemporal fossa, skull base, and orbit are more typical of DLBCL.
Humans ; Retrospective Studies ; Lymphoma, Extranodal NK-T-Cell/diagnosis* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Nasal Cavity/pathology* ; Male ; Diagnosis, Differential ; Female ; Middle Aged ; Nose Neoplasms/diagnosis* ; Adult ; Aged

OBJECTIVE: To explore the diagnostic value of ¹⁸F-FDG PET/CT in bone marrow infiltration (BMI) of newly diagnosed diffuse large B-cell lymphoma (DLBCL), compared with the results of bone marrow biopsy (BMB) and investigate whether the BMI diagnosed by ¹⁸F-FDG PET/CT and other factors have independent prognostic values. METHODS: Ninety-four newly diagnosed DLBCL patients who underwent PET/CT in Clinical Medical College of Shanghai General Hospital of Nanjing Medical University were included. BMB was performed within 2 weeks before or after PET/CT, and standardized treatment was performed after PET/CT. The manifestations of bone marrow (BM) FDG uptake were recorded. The diagnostic criteria of BMI were BMB positive or focal BM FDG uptake confirmed by imaging follow-up. The relationship between clinical features and BM FDG uptake and the values of PET/CT and BMB in the diagnosis of BMI was analyzed. The progression-free survival (PFS) was analyzed by Kaplan-Meier survival curves, log-rank test was used to compare PFS rate, and Cox regression model was used to analyze the independent risk factors affecting PFS. RESULTS: Among 94 DLBCL patients, 34 patients showed focal BM uptake (fPET), 7 patients showed super BM uptake (sBMU), 11 patients showed diffuse homogenous uptake higher than liver (dPET), and the other 42 patients had normal BM uptake (nPET) (lower than liver). BMB positive was found in all sBMU patients, in 20.6%(7/34) of fPET patients, and in 27.3% (3/11) of dPET patients. All nPET patients had negative BMB results. dPET patients were associated with lower hemoglobin level and leukocyte count compared with nPET group (P < 0.001, P =0.026). Compared with fPET patients, sBMU patients were more likely to have B symptoms and elevated lactate dehydrogenase (LDH). A total of 44 patients were diagnosed BMI, including 17 cases with BMB⁺. The sensitivity and specificity of BMB in the diagnosis of BMI was 38.6% (17/44) and 100% (50/50), respectively. Using fPET and sBMU as criteria of PET BMI, the diagnostic sensitivity and specificity of PET/CT was 93.2% (41/44) and 100% (50/50), respectively. Kaplan-Meier analysis showed that there was no significant difference in 2-year PFS rate between nPET and dPET patients (P >0.05), while sBMU patients had lower 2-year PFS rate compared with fPET patients (P < 0.001). Multivariate analysis showed that higher Ann Arbor stage (HR=9.010, P =0.04) and sBMU (HR=3.964, P =0.002) were independent risk factors affecting PFS. CONCLUSIONS Increased BM FDG uptake of DLBCL can be manifested as dPET, fPET and sBMU. fPET and sBMU can replace BMB to diagnose BMI. Although dPET cannot completely exclude the possibility of BMI, it does not affect the prognosis, so it can be diagnosed as PET BMI negative. sBMU is an independent prognostic risk factor.
Humans ; Positron Emission Tomography Computed Tomography/methods* ; Fluorodeoxyglucose F18 ; Prognosis ; Bone Marrow/pathology* ; Retrospective Studies ; China ; Positron-Emission Tomography/methods* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Biopsy

OBJECTIVE: To explore the effects of prognostic nutritional index (PNI) combined with D-dimer on the prognosis of patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). METHODS: The clinical data of 73 DLBCL patients at initial diagnosis were retrospectively evaluated, and the optimal cut-off point of PNI and D-dimer were determined by ROC curve. The overall survival (OS) rate and progression-free survival (PFS) rate in different subgroups were compared using Kaplan-Meier survival curves. Univariate and multivariate Cox regression analysis was performed to identify the factors associated with OS. RESULTS: Compared with the low PNI group (PNI<44.775), the high PNI group (PNI≥44.775) had better OS (P =0.022) and PFS (P =0.029), the 2-year OS rates of the two groups were 55.6% and 78.3% respectively (P =0.041). Compared with the high D-dimer group (D-dimer≥0.835), the low D-dimer group (D-dimer<0.835) had better OS (P <0.001) and PFS (P <0.001), the 2-year OS rates of the two groups were 51.4% and 86.8% respectively (P =0.001). Meanwhile, patients in the high PNI+ low D-dimer group had better OS (P =0.003) and PFS (P <0.001) than the other three groups, the 2-year OS rate was statistically different from the other three groups (P <0.05). The multivariate analysis revealed that NCCN-IPI (HR =2.083, 95%CI : 1.034-4.196, P =0.040), PNI (HR =0.267, 95%CI : 0.076-0.940, P =0.040) and PNI+D-dimer (HR =9.082, 95%CI : 1.329-62.079, P =0.024) were the independent risk factors affecting OS in patients with DLBCL. Subgroup analysis showed that PNI, D-dimer, and PNI combined with D-dimer could improve the prognostic stratification in low and low-intermediate risk DLBCL patients. CONCLUSION High PNI, low D-dimer and combination of high PNI and low D-dimer at initial diagnosis suggest a better prognosis in DLBCL patients.
Humans ; Prognosis ; Nutrition Assessment ; Retrospective Studies ; Lymphoma, Large B-Cell, Diffuse/pathology*

OBJECTIVE: To explore the expression of Exosome Component 4（EXOSC4） in the tissues of newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL) and its clinical significance. METHODS: The expression of EXOSC4 protein in the tissues of 181 newly diagnosed DLBCL patients was analyzed by immunohistochemical staining. Clinical data were collected. The correlation between EXOSC4 protein expression in the tissues of newly diagnosed DLBCL patients and clinical features were analyzed and its prognostic significance. RESULTS: The positive rate of EXOSC4 protein expression was 68.51% in the tissues of 181 newly diagnosed DLBCL patients. These patients were divided into two groups, with 44 cases in high expression group and 137 cases in low expression group. There were no significant differences in age, gender, B symptoms, serum lactate dehydrogenase (LDH) level, Eastern Cooperative Oncology Group (ECOG) score, Ann Arbor stage, extranodal disease, International Prognostic Index (IPI) score, National Comprehensive Cancer Network IPI (NCCN-IPI) score, and cell origin between the two groups (P>0.05). Cox multivariate regression analysis showed that high EXOSC4 protein expression in tissues was an independent poor prognostic factor for OS and PFS in newly diagnosed DLBCL patients (all P<0.05). K-M survival analysis showed that newly diagnosed DLBCL patients with high EXOSC4 protein expression had significantly shorter overall survival (OS) and progression free survival (PFS) than those patients with low EXOSC4 protein expression (all P<0.05). CONCLUSION High EXOSC4 protein expression in tissues of newly diagnosed DLBCL patients is an independent poor prognostic factor for survival.
Humans ; Clinical Relevance ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Prognosis ; Retrospective Studies ; Exosome Multienzyme Ribonuclease Complex/genetics*

Composite lymphoma (CL) involving B-cell lymphoma and T-cell lymphoma is extremely rare. Herein, we report three such cases using immunohistochemistry, flow cytometry, and the next-generation sequencing (NGS) to identify the pathological and molecular characteristics of CL. In the first case, the patient was admitted to hospital for generalized pruritic maculopapular rash over the whole body. An excisional biopsy of the skin lesions showed T-cell lymphoma. At the same time, the staging bone marrow (BM) biopsy revealed a diffuse large B-cell lymphoma (DLBCL). After R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapies, the patient produced a good response with substantial dissipation of the rashes and relief of skin. The other two patients were admitted to hospital due to lymphadenopathy and were diagnosed with DLBCL and follicular lymphoma (FL) after core needle biopsy of lymph nodes, BM biopsy, BM aspiration, and flow cytometry. Following R-CHOP and R-COP (rituximab, cyclophosphamide, vincristine, and prednisone) therapies, they achieved complete remission unconfirmed (CRu) and complete remission (CR). However, one or two years later, they suffered a relapse of lymphadenopathy. The shocking fact was that re-biopsy of lymphadenopathy revealed peripheral T-cell lymphoma (PTCL) and angioimmunoblastic T-cell lymphoma (AITL). NGS findings identified DNA methyltransferase 3a (DNMT3a), isocitrate dehydrogenase 2 (IDH2), Ras homolog gene family, member A (RHOA), splicing factor 3B subunit 1 (SF3B1), and tumor protein p53 (TP53) mutations. After immunochemotherapy, these patients achieved CRu and CR again. Nevertheless, they suffered a second relapse of T-cell lymphoma. Finally, they died due to progression of disease. We found that the occurrence of CL is associated with Epstein-Barr virus infection and DNMT3a, IDH2, and TP53 mutations, and the prognosis of the disease is closely related to the T-cell lymphoma components.
Humans ; Rituximab/therapeutic use* ; Vincristine/therapeutic use* ; Prednisone/therapeutic use* ; Epstein-Barr Virus Infections/drug therapy* ; Herpesvirus 4, Human ; Neoplasm Recurrence, Local ; Lymphoma, T-Cell/drug therapy* ; Cyclophosphamide/therapeutic use* ; Lymphoma, Large B-Cell, Diffuse/pathology* ; Doxorubicin/therapeutic use* ; Lymphadenopathy/drug therapy* ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use*

Humans ; Leg/pathology* ; Skin Neoplasms/pathology* ; Lymphoma, Large B-Cell, Diffuse/pathology*