Clinicopathological features of intravascular large B-cell lymphoma and collision tumors of five cases / 中华病理学杂志

Objective: To investigate the clinicopathological characteristics, diagnosis and differential diagnosis of intravascular large B-cell lymphoma (IVLBCL) and its collision tumors. Methods: Five cases of IVLBCL were collected, including 2 cases of collision tumors, and 1 case complicated with liver cirrhosis. The morphology and immunophenotype were analyzed. The related literature was reviewed. Results: There were 2 females and 3 males, aged from 53 to 73 years, with a median age of 65 years. The tumors were located in the lower extremities, right cerebellar hemisphere, left kidney, bilateral nasal cavity, and liver, respectively. Cases 2 and 3 were incidentally found in meningioma and renal cell carcinoma tissues, respectively. Case 5 had a background of liver cirrhosis. Morphologically, atypical large lymphoid cells were located in small blood vessels and capillary lumen, with little cytoplasm, hyperchromasia, prominent nucleoli, and obvious mitotic figures. Immunohistochemically, the IVLBCL tumor cells expressed CD20 and PAX5; 2 cases were CD5 positive. One of the 5 cases was GCB phenotype, and 4 cases were non-GCB phenotype. All cases expressed C-MYC (positive rate was 10%-40%). PD-L1 was positive in 4 cases (positive rate was 60%-90%). Ki-67 proliferation index was 70%-90%. CKpan, CD3, TDT, and CD34 were negative. In case 2, meningioma cells were positive for PR, EMA, and vimentin, but negative for CKpan and PD-L1. In case 3, renal carcinoma cells were positive for CKpan, PAX8, EMA, vimentin, CAⅨ and CD10, while PD-L1 was negative. No EBER expression (by in situ hybridization) or C-MYC gene translocation (FISH, break-apart probe) was detected in any of the 5 cases. Three patients were followed up, and all died within 1-13 months. Conclusions: IVLBCL is a highly aggressive lymphoma, with occult clinical manifestations and poor prognosis. Collision tumors of IVLBCL are extremely rare. A better understanding of IVLBCL would help pathologists avoid misdiagnoses.

Rara presentación de un linfoma espinal: informe de caso y diagnóstico mediante resonancia magnética / Rare presentation of a spinal lymphoma: case report and diagnosis by magnetic resonance imaging

El linfoma primario del sistema nervioso central es una forma de enfermedad extraganglionar originada en el cerebro, la leptomeninges, la médula espinal o los ojos. Los tumores espinales son neoplasias de baja prevalencia y pueden causar una morbimortalidad neurológica considerable. El linfoma aislado que surge dentro del conducto dural es la forma menos común de linfoma primario del sistema nervioso central: representa aproximadamente el 1% de los casos y se observa más a menudo en el contexto de diseminación secundaria que como el sitio primario de origen. Los síntomas son inespecíficos y dependen del nivel espinal involucrado. La presentación es insidiosa e incluye dorsalgia, debilidad y dificultad progresiva para la deambulación. La resonancia magnética es la modalidad de elección para búsqueda de lesiones dentro del conducto espinal/raquídeo, en pacientes que presentan síntomas neurológicos. El tratamiento quirúrgico no resulta útil, y el objetivo principal de la cirugía es conocer el diagnóstico histológico. (AU)

A primary central nervous system lymphoma is a form of extranodal disease originating in the brain, leptomeninges, spinal cord, or eyes. Spinal tumors are low-prevalence neoplasms and can cause considerable neurological morbidity and mortality. An isolated lymphoma emerging within the dural canal is the rarest form of primary central nervous system lymphoma: it accounts for approximately 1% of cases occurring more often in the context of secondary dissemination than as the primary site of origin. Symptoms are nonspecific and depend on the spinal level involved. The presentation is insidious and includes dorsalgia, weakness, and progressive difficulty in ambulatory function. MRI is the modality of choice to search for lesions within the spinal/rachial canal in patients presenting with neurological symptoms. Surgical treatment is not helpful, and the main objective of surgery is to know the histological diagnosis. (AU)

Expression and Clinical Significance of Exosome Component 4 in Newly Diagnosed Patients with Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

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.

Composite B-cell and T-cell lymphomas: clinical, pathological, and molecular features of three cases and literature review / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

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.

Diagnostic Efficacy of 18F-FDG PET/CT in Detecting Bone Marrow Infiltration in Patients with Newly Diagnosed Diffuse Large B-Cell Lymphoma / 生物医学与环境科学（英文）

OBJECTIVE@#Diffuse large B-cell lymphoma (DLBCL) is often associated with bone marrow infiltration, and 2-deoxy-2-(18F) fluorodeoxyglucose positron emission tomography/computed tomography ( 18F-FDG PET/CT) has potential diagnostic significance for bone marrow infiltration in DLBCL.@*METHODS@#A total of 102 patients diagnosed with DLBCL between September 2019 and August 2022 were included. Bone marrow biopsy and 18F-FDG PET/CT examinations were performed at the time of initial diagnosis. Kappa tests were used to evaluate the agreement of 18F-FDG PET/CT with the gold standard, and the imaging features of DLBCL bone marrow infiltration on PET/CT were described.@*RESULTS@#The total detection rate of bone marrow infiltration was not significantly different between PET/CT and primary bone marrow biopsy ( P = 0.302) or between the two bone marrow biopsies ( P = 0.826). The sensitivity, specificity, and Youden index of PET/CT for the diagnosis of DLBCL bone marrow infiltration were 0.923 (95% CI, 0.759-0.979), 0.934 (95% CI, 0.855-0.972), and 0.857, respectively.@*CONCLUSION@#18F-FDG PET/CT has a comparable efficiency in the diagnosis of DLBCL bone marrow infiltration. PET/CT-guided bone marrow biopsy can reduce the misdiagnosis of DLBCL bone marrow infiltration.

Reverse effect of Semaphorin-3F on rituximab resistance in diffuse large B-cell lymphoma via the Hippo pathway / 中华医学杂志(英文版)

BACKGROUND@#Exploring the underlying mechanism of rituximab resistance is critical to improve the outcomes of patients with diffuse large B-cell lymphoma (DLBCL). Here, we tried to identify the effects of the axon guidance factor semaphorin-3F (SEMA3F) on rituximab resistance as well as its therapeutic value in DLBCL.@*METHODS@#The effects of SEMA3F on the treatment response to rituximab were investigated by gain- or loss-of-function experiments. The role of the Hippo pathway in SEMA3F-mediated activity was explored. A xenograft mouse model generated by SEMA3F knockdown in cells was used to evaluate rituximab sensitivity and combined therapeutic effects. The prognostic value of SEMA3F and TAZ (WW domain-containing transcription regulator protein 1) was examined in the Gene Expression Omnibus (GEO) database and human DLBCL specimens.@*RESULTS@#We found that loss of SEMA3F was related to a poor prognosis in patients who received rituximab-based immunochemotherapy instead of chemotherapy regimen. Knockdown of SEMA3F significantly repressed the expression of CD20 and reduced the proapoptotic activity and complement-dependent cytotoxicity (CDC) activity induced by rituximab. We further demonstrated that the Hippo pathway was involved in the SEMA3F-mediated regulation of CD20. Knockdown of SEMA3F expression induced the nuclear accumulation of TAZ and inhibited CD20 transcriptional levels via direct binding of the transcription factor TEAD2 and the CD20 promoter. Moreover, in patients with DLBCL, SEMA3F expression was negatively correlated with TAZ, and patients with SEMA3F low TAZ high had a limited benefit from a rituximab-based strategy. Specifically, treatment of DLBCL cells with rituximab and a YAP/TAZ inhibitor showed promising therapeutic effects in vitro and in vivo .@*CONCLUSION@#Our study thus defined a previously unknown mechanism of SEMA3F-mediated rituximab resistance through TAZ activation in DLBCL and identified potential therapeutic targets in patients.

Clinical Analysis of Pulmonary Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To study the clinical, imaging, and pathological features of pulmonary lymphoma.@*METHODS@#Patients with pulmonary lymphoma diagnosed by lung biopsy in Zhongda Hospital Affiliated to Southeast University from November 2013 to December 2020 were collected and divided into secondary pulmonary lymphoma (SPL) group and primary pulmonary lymphoma (PPL) group according to the primary site of lymphoma. The clinical characteristics, stages, imaging features, diagnostic methods and pathological types of the two groups were analyzed.@*RESULTS@#A total of 22 patients were included, 10 cases were PPL and 12 cases were SPL. The main symptoms of the two groups were cough, dyspnea and chest pain. The proportion of stage III/IV patients and international prognostic index (IPI) in SPL group were significantly higher than those in PPL group (P<0.05). Chest high-resolution computed tomography (HRCT) mainly showed masses, nodules and consolidation in both groups. The proportions of single mass and air bronchial sign in PPL group were significantly higher than those in SPL group, while the proportions of multiple nodules, mediastinal/hilar lymphadenopathy and pleural effusion were significantly lower (P<0.05). The max standardized uptake value (SUVmax), peak standardized uptake value (SUVpeak), total lesion glycolysis (TLG) and metabolic tumor volume (MTV) of 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) in PPL group were lower than those in SPL group, but the differences were not statistically significant (P>0.05). In PPL group, 8 cases were diagnosed by transbronchial lung biopsy (TBLB) and 2 cases by percutaneous lung puncture. In SPL group, 4 cases were diagnosed by TBLB, 7 cases by percutaneous lung puncture, and 1 case by surgery. 95.5% patients were diagnosed by non-surgical methods. The main pathological type of PPL was mucosa-associated lymphoid tissue (MALT) lymphoma, while that of SPL was diffuse large B-cell lymphoma (P<0.05).@*CONCLUSION@#The clinical symptoms of pulmonary lymphoma are nonspecific, but the chest HRCT has characteristic manifestations, which can also help to distinguish between SPL and PPL. 18F-FDG PET/CT is also a potential method to distinguish between SPL and PPL. TBLB and percutaneous lung puncture biopsy are reliable methods for the diagnosis of lung lymphoma. The main pathological type of PPL is MALT lymphoma, while that of SPL is diffuse large B-cell lymphoma.

Effect of MiR-424-5p on the Drug Resistance of Diffuse Large B-Cell Lymphoma Cells by Regulating PD-1/PD-L1 Signaling Pathway / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of microRNA-424-5p (miR-424-5p) on the drug resistance of diffuse large B-cell lymphoma (DLBCL) cells by regulating the programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) signaling pathway.@*METHODS@#Human DLBCL cell line CRL2631 cells were induced to construct CRL2631-CHOP resistant cell line. RT-qPCR and Western blot were used to detect the expression levels of MiR-424-5p, PD-L1 mRNA and protein, and multidrug resistance gene-1 (MDR-1) protein in CRL2631 cells and CRL2631-CHOP cells, respectively. The target genes of MiR-424-5p was verified by dual luciferase reporter assay. The miRNA simulation/interference technology and thiazole blue (MTT) method were used to detect the resistance of CRL2631 cells and CRL2631-CHOP cells to CHOP.@*RESULTS@#Compared with CRL2631 cells, the drug resistance of CRL2631-CHOP cells to CHOP and the levels of MDR-1 protein (P<0.05), PD-L1 mRNA and protein in the cells were significantly increased (both P<0.001), while the relative level of MiR-424-5p was significantly reduced (P<0.001). The result of the dual luciferase reporter assay showed that PD-L1 was the direct downstream target gene of MiR-424-5p (P<0.001). After transfection of MiR-424-5p inhibitor, the resistance of CRL2631 cells to CHOP drugs increased, and the expression level of MDR-1 protein (P<0.01), PD-L1 mRNA and protein also increased significantly (both P<0.01). After transfection of MiR-424-5p mimics, the resistance of CRL2631-CHOP cells to CHOP drugs decreased, and the expression level of MDR-1 protein (P<0.001), PD-L1 mRNA and protein also decreased significantly (both P<0.001). Overexpression of PD-L1 could reverse the inhibitory effect of upregulating MiR-424-5p on PD-L1 (P<0.001).@*CONCLUSION@#Down-regulation of MiR-424-5p enhances the drug resistance of DLBCL cells by regulating the PD-1/PD-L1 signaling pathway.

Effect of MELK Inhibitor OTSSP167 on Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the effect of MELK inhibitor OTSSP167 against diffuse large B-cell lymphoma (DLBCL).@*METHODS@#The effect of OTSSP167 on activity, proliferation, and apoptosis of DLBCL cell line (SUDHL2 and HBL1) was detected by CCK-8 assay, 5-ethynyl-2'-deoxyuridine (EdU) staining, and Annexin V-FITC/PI double staining, respectively. DLBCL cells were inoculated into nude mice, after 4 weeks of OTSSP167 treatment, the effect of OTSSP167 on DLBCL growth in vivo was detected. Caspase-GloTM 3/7 enzyme activity assay kit was used to detect the effect of OTSSP167 on Caspase 3/7 enzyme activity of DLBCL cells. The expression levels of apoptosis and cycle-related proteins were detected by Western blot.@*RESULTS@#OTSSP167 significantly inhibited the activity of SUDHL2 and HBL1 cells in a dose-dependent manner (r =-0.61, r =-0.52). EdU staining showed that OTSSP167 could significantly inhibit the proliferation of SUDHL2 and HBL1 cells. Annexin V-FITC/PI result showed that OTSSP167 could significantly promote the apoptosis of SUDHL2 and HBL1 cells (P <0.001). The result of in vivo experiment showed that OTSSP167 could inhibit the growth of SUDHL2 cells in nude mice. The result of TUNEL staining of tumor further confirmed that OTSSP167 could promote the apoptosis of SUDHL2 cells. Caspase 3/7 enzyme activity test demonstrated that OTSSP167 could significantly increase caspase activity in SUDHL2 and HBL1 cells (r =0.98, r =0.87). Western blot showed that OTSSP167 could dose-dependently inhibit the expression of PARP, Bcl-xL, and Bcl-2 in apoptosis signaling pathway (r =-0.93, r =-0.66, r =-0.87), while p53 protein was significantly up-regulated (r =0.82). The expression of cell cycle-related proteins cdc2, Cyclin E1, Cyclin A2, and Cyclin B1 also showed a dose-dependent down-regulation (r =-0.89, r =-0.83, r =-0.61, r =-0.93).@*CONCLUSION@#The MELK inhibitor OTSSP167 can inhibit the proliferation and promote the apoptosis of DLBCL cells by inhibiting the expression of cycle-related proteins and anti-apoptosis-related proteins.

Expressions and Clinical Significance of Notch1 and Hes1 in Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the expressions of Notch1 and Hes1 in diffuse large B-cell lymphoma (DLBCL), and their correlations with clinical features.@*METHODS@#Immunohistochemistry (IHC) was performed on DLBCL samples (54 cases) and lymphadenitis tissues (20 cases) to evaluate the expressions of Notch1 and Hes1, and analyze their correlations with clinical characteristics of patients. Based on Oncomine database, the expressions of Notch1 and Hes1 mRNA and DNA were also explored.@*RESULTS@#IHC result showed that the positive expression rates of Notch1 and Hes1 in DLBCL patients were significantly higher than those in the control group (P <0.05). In DLBCL patients, the expression of Notch1 was closely associated with B symptoms, Ann Arbor stage, lymphocyte count and the level of lactate dehydrogenase (P <0.05), while the expression level of Hes1 was significantly higher in patients with B symptoms (P <0.05). Notch+/Hes1+ expression was found in 21 DLBCL tissues (38.9%), and there was a correlation between Notch1 and Hes1 expression (r =0.296, P <0.05). Bioinformatics analysis (Oncomine database) showed that the mRNA expressions of Notch1 and Hes1 in the Brune dataset were significantly higher than those in the control tissues (P <0.05).@*CONCLUSION@#The expressions of Notch1 and Hes1 in DLBCL are significantly higher than those in lymphadenitis, and correlated with B symptoms and Ann Arbor stage, suggesting that Notch1 and Hes1 play important roles in the occurrence and development of DLBCL.

Clinicopathological features of fibrin-associated diffuse large B-cell lymphoma: a report of six cases / 中华病理学杂志

Objective: To investigate the clinical, pathological and immunophenotypic features, molecular biology and prognosis of fibrin-associated large B-cell lymphoma (LBCL-FA) in various sites. Methods: Six cases of LBCL-FA diagnosed from April 2016 to November 2021 at the Beijing Friendship Hospital, Capital Medical University, Beijing, China and the First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China were collected. The cases were divided into atrial myxoma and cyst-related groups. Clinical characteristics, pathological morphology, immunophenotype, Epstein Barr virus infection status, B-cell gene rearrangement and fluorescence in situ hybridization of MYC, bcl-2, bcl-6 were summarized. Results: The patients' mean age was 60 years. All of them were male. Three cases occurred in atrial myxoma background, while the others were in cyst-related background, including adrenal gland, abdominal cavity and subdura. All cases showed tumor cells located in pink fibrin clot. However, three cyst-related cases showed the cyst wall with obviously fibrosis and inflammatory cells. All cases tested were non germinal center B cell origin, positive for PD-L1, EBER and EBNA2, and were negative for MYC, bcl-2 and bcl-6 rearrangements, except one case with MYC, bcl-2 and bcl-6 amplification. All of the 5 cases showed monoclonal rearrangement of the Ig gene using PCR based analysis. The patients had detailed follow-ups of 9-120 months, were treated surgically without radiotherapy or chemotherapy, and had long-term disease-free survivals. Conclusions: LBCL-FA is a group of rare diseases occurring in various sites, with predilection in the context of atrial myxoma and cyst-related lesions. Cyst-related lesions with obvious chronic inflammatory background show more scarcity of lymphoid cells and obvious degeneration, which are easy to be missed or misdiagnosed. LBCL-FA overall has a good prognosis with the potential for cure by surgery alone and postoperative chemotherapy may not be necessary.

The Prognostic Value of Prognostic Nutritional Index Combined with D-dimer in Patients with Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

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.

Diagnostic and Prognostic Value of 18F-FDG PET/CT in Bone Marrow Infiltration of Newly Diagnosed Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

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.

Mechanism of circZNF609 targeting miR-153 to regulate the proliferation and apoptosis of diffuse large B-cell lymphoma / 中华肿瘤杂志

Objective: To investigate the molecular mechanism of circZNF609 targeting miR-153 to regulate the proliferation and apoptosis of diffuse large B-cell lymphoma. Methods: Fifty cases of lymphoma tissue from patients with diffuse large B-cell lymphoma who were diagnosed and treated in the First Affiliated Hospital of Zhengzhou University from July 2018 to December 2019 were collected. Thirty cases of normal lymph node tissues that were confirmed to be reactive hyperplasia by pathological diagnosis during the same period were selected as controls. Real time quantitative polymerase chain reaction (PCR) was used to detect the expression of circZNF609 in diffuse large B-cell lymphoma tissues and control hyperplasia lymph nodes. Diffuse large B-cell lymphoma OCI-LY19 cells were divided into control group (blank control), si-con group (transfected with siRNA control), si-ZNF609 group (transfected with circZNF609 siRNA), and si-ZNF609+ Anti-NC group (co-transfected with circZNF609 siRNA and inhibitor control) and si-ZNF609+ Anti-miR-153 group (co-transfected with circZNF609 siRNA and miR-153 inhibitor). Cell counting kit-8 (CCK-8) was used to detected proliferation, flow cytometry was used to detect cell cycle and apoptosis. Western blot was used to detect the protein expressions of C-caspase-3, cyclin D1, p21. The luciferase reporter system was used to identifie the relationship between circZNF609 and miR-153. Results: The expression level of circZNF609 in diffuse large B-cell lymphoma tissue was (1.44±0.22), higher than (0.37±0.14) in the control tissues (P<0.001). The cell survival rate of the si-ZNF609 group was (51.74±6.39)%, lower than (100.00±10.23)% of the control group and the (99.64±11.67)% of the si-con group (P<0.001). The proportion of cells in the G(0)/G(1) phase was (63.25±4.11)%, higher than (48.62±4.32)% of the control group and (47.12±3.20)% of the si-con group (P<0.001), the apoptosis rate was (13.36±1.42)%, higher than (3.65±0.47)% of the control group and (3.84±0.62)% of the si-con group (P<0.05). The expression levels of C-caspase-3 and p21 protein were (0.85±0.09) and (0.90±0.08), higher than (0.38±0.04) and (0.65±0.07) in the control group and (0.39±0.05) and (0.66±0.05) in the si-con group (P<0.001). The expression level of cyclin D1 protein was (0.40±0.03), lower than (0.52±0.06) of the control group and (0.53±0.04) of the si-con group (all P<0.001). CircZNF609 and miR-153 are mutually targeted. The cell survival rate of the si-ZNF609+ Anti-miR-153 group was (169.92±13.25)%, higher than (100.00±9.68)% of the si-ZNF609+ Anti-NC group (P<0.001), the ratio of cells in G(0)/G(1) phase and apoptosis rate were (52.01±3.62)% and (8.20±0.87)%, respectively, lower than (64.51±5.17)% and (14.03±1.17)% in the si-ZNF609+ Anti-NC group (P<0.001). The protein expression levels of C-caspase-3 and p21 were (0.42±0.06) and (0.52±0.06), lower than (0.80±0.07) and (0.92±0.10) of the si-ZNF609+ Anti-NC group (P<0.001). The protein expression level of cyclin D1 was (0.68±0.07), higher than (0.39±0.04) in the si-ZNF609+ Anti-NC group (P<0.001). Conclusion: Down-regulation of circZNF609 inhibits the proliferation of diffuse large B-cell lymphoma OCI-LY19 cells and induces apoptosis by targeting miR-153.

Expression of PD-L1 and PD-1 in Pathological Tissue of Patients Newly Diagnosed with Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the expression of PD-L1 and PD-1 in pathological tissue of patients newly diagnosed with diffuse large B-cell lymphoma (DLBCL).@*METHODS@#Data of DLBCL patients who visited the Department of Hematology, Peking University Third Hospital from May 2014 to March 2017 were collected, and a total of 21 patients with pathological tissue sections which were still available at the initial treatment were selected. The patients were divided into complete remission (CR) group and refractory relapse (RR) group according to clinical outcome. The expression and proportion of PD-1 and PD-L1 in pathological tissue sections were detected by multiplex fluorescence immunohistochemical staining, and the differences in the expression of different molecular markers in different clinical characteristics and different prognosis were compared using non-parametric test.@*RESULTS@#The ratio of PD-L1+ cells to PD-1+ cells (PD-L1+ : PD-1+) was 5.14±3.825 in increased lactate dehydrogenase (LDH) group, which was significantly higher than 0.76±0.563 in non-increased LDH group (P=0.001). The ratio of PD-L1+ : PD-1+ in increased Treg cells group was 1.41±1.454, which was lower than 6.42±4.426 in decreased Treg cells group (P=0.023).@*CONCLUSION@#The increased expression ratio of PD-L1 to PD-1 in pathological tissue sections of newly diagnosed DLBCL patients is associated with poor prognostic clinical characteristics.

Influence of the Ratio of Peripheral Hemoglobin-to-Red Cell Distribution width on the Prognosis of Patients with Diffuse Large B-cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To investigate the influence of peripheral hemoglobin (Hb)-to-red cell distribution width (RDW) ratio (HRR) on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).@*METHODS@#Data of 265 patients with diffuse large B-cell lymphoma (DLBCL) at the Affiliated Hospital of Xuzhou Medical University from January 2014 to December 2019 were retrospectively analyzed. 132 healthy people in the same period were used as normal control group. The best cut-off points of HRR was determined by receiver operating characteristics (ROC) curve; the chi-square test was used to analyze the correlation of clinical characteristics with HRR; the Kaplan-Meier method was used to compare the overall survival (OS) and progression-free survival (PFS) of HRR patients in different groups; the Cox proportional risk model was used for univariate and multivariate analysis.@*RESULTS@#The best cut-off value of HRR was 0.936, which was divided into low HRR group and high HRR group. The low HRR group had a higher ECOG score, higher incidence of advanced Ann Arbor stage, higher NCCN-IPI score, and elevated LDH level. K-M survival analysis showed that OS (P<0.001) and PFS (P<0.001) in the low HRR group were significantly shorter than that in the higher HRR group. The multivariate analysis revealed that HRR was an independent predictor of OS（HR＝0.379，95％CI：0.237-0.605，P<0.001） and PFS （HR＝0.384，95％CI：0.241－0.614，P<0.001） in DLBCL patients.@*CONCLUSION@#Low HRR（<0.936） in patients with DLBCL indicates a poor prognosis, which is an independent prognosis risk factor.

Rituximab-Based Regimens for Treatment of Primary Gastric Diffuse Large B-Cell Lymphoma / 中国实验血液学杂志

OBJECTIVE@#To analyze clinical response of the Rituximab-based chemotherapy and prognostic features in patients with primary gastric diffuse large B-cell lymphoma (PGDLBCL).@*METHODS@#From June 2008 to December 2020, the data of 53 PGDLBCL patients were analyzed retrospectively.@*RESULTS@#The median age was 46(25-77) years old in 53 patients including 35 males and 18 females. Stomachache is the most common symptom. The diagnosis were confirmed in 47 patients by endoscopic biopsy and 6 patients by surgery. Twenty-six patients had Ⅰ/Ⅱ1 stage (Lugano staging system) disease and 27 cases had II2/IV stage disease. All patients were treated with chemotherapy, including RCHOP (25/53) and R-DA-EPOCH (28/53). Complete remission rate was 79.2%（42/53）. The 3-year and 5-year overall survival (OS) rates were 77.4% and 69.8%. Univariate analysis showed that lactate dehydrogenase(LDH), Lugano stage and lesion size affected OS. Multivariate Cox regression analysis revealed that IPI score and Lugano stage were independent prognosis risk factors affecting OS. The patients in the R-DA-EPOCH group presented better survival outcomes than those in the RCHOP group with late stage (P5-year OS=0.035).@*CONCLUSION@#Rituximab in combination with chemotherapy is the backbone of therapy for PGDLBCL. IPI score and Lugano stage are independent prognosis risk factors affecting OS of PGDLBCL. R-DA-EPOCH can be superior to R-CHOP as a first-line regimen in PGDLBCL patients with late stage.

Intravascular large B-cell lymphoma presenting with fever and refractory acidosis

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse large B-cell lymphoma, characterized by malignant B-cells primarily localized to the lumina of small- and medium-sized blood vessels without lymphadenopathy. Two patients initially presented with fever of unknown origin and persistent lactic acidosis without evidence of tissue hypoxia. Neither patient had an identifiable source of infection and both underwent peripheral blood smear demonstrating leukocytosis with a neutrophilic predominance and thrombocytopenia without evidence of hematologic malignancy. One had previously had a bone marrow biopsy which was unremarkable. Both patients' condition deteriorated rapidly, progressing to multiorgan failure requiring pressors and mechanical ventilation, which ultimately resulted in cardiopulmonary arrest. At autopsy, each patient demonstrated malignant lymphocytoid cells, staining positive for CD20, localized to the lumina of small- and medium-sized vessels in multiple organs, including the lungs, liver, spleen, and kidneys, among others, allowing for the diagnosis of IVLBCL. IVLBCL is exceedingly rare, which in combination with significant variability in presentation, can make identification and diagnosis challenging. Diagnosis requires biopsy, therefore a high index of suspicion is needed to obtain an adequate tissue sample, whether pre- or postmortem. In the presented cases, both patients exhibited type B lactic acidosis with an unknown etiology that was ultimately determined at autopsy.

Membrana de circulación extracorpórea en shock obstructivo secundario a enfermedad linfoproliferativa / Oxygenation with extracorporeal membrane in obstructive shock secondary to lymphoproliferative disease

La membrana de oxigenación extracorpórea arteriovenosa se utiliza cuando ocurre falla hemodinámica y respiratoria refractaria al tratamiento convencional; brinda soporte hemodinamico transitorio, oxigenacion y remocion de CO2, y permite reposo pulmonar. Asimismo ofrece la posibilidad de realizar ventilación ultraprotectiva y evitar la generación de VILI (Ventilation-Induced Lung Injury). No ha sido demostrada su utilización como una terapia frecuente en los casos con insuficiencia hemodinámica secundaria a shock obstructivo por afectación mediastínica. Presentamos el caso de un paciente con shock obstructivo por una masa mediastínica de origen linfoproliferativo tratada con membrana de circulación arteriovenosa extracorpórea.

The arteriovenous extracorporeal membrane is used in patients with hemodynamic and respiratory failure, unresponsive to conventional treatment. It provides transitory hemodynamic support, oxygenation and removal of CO2, allowing pulmonary rest. Moreover it offers the possibility of ultraprotective ventilation and avoids generation of VILI (Ventilation-Induced Lung Injury). It is not frequently used in patients with hemodynamic failure secondary to obstructive shock due to mediastinal compromise. We present the case of a patient with obstructive shock, mediastinal mass of lymphoproliferative origin that was treated with extracorporeal arteriovenous circulation membrane.

Clinical characteristics of primary extranodal versus nodal diffuse large B-Cell Lymphoma: A retrospective cohort study in a cancer center

Background The outcome of patients with primary extranodal diffuse large B-cell lymphoma (PE-DLBCL) varies according to the primary site involved. Primary gastrointestinal, breast, bone, craniofacial, and testicular DLBCL are rare extranodal manifestations of DLBCL. Objective The objective of the study was to describe the clinical course of patients with PE-DLBCL disease in a referral cancer center. Results From 637 patients, 51 (8.77%) were considered as having PE-DLBCL (25 gastrointestinal, 12 craniofacial, 6 breast, 5 bone, and 3 with primary testicular DLBCL). Complete remission was higher in all PE-DLBCL sites (100% in testicular, 92.6% craniofacial, 83.3% breast, 80% bone, and 80% gastrointestinal) compared with 73.3% in nodal DLBCL. Although 2 cases with breast PE-DLBC relapsed, they achieved a complete response with chemotherapy. The overall survival at 5 years was 100%, 80%, 78%, 58%, 58%, and 62% for patients with primary breast, primary bone, gastrointestinal, primary craniofacial, primary testicular, and nodal DLBCL, respectively. Conclusions PE-DLBCLs constitute rare, primary sites of lymphoproliferative disorders in most cases, with localized disease and good prognosis. They require a combined chemoimmunotherapy with radiotherapy in most cases to improve local and systemic disease.