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Objective:To investigate the clinical characteristics, efficacy and prognostic influencing factors of IgD multiple myeloma (MM) in the new immunotherapy era.Methods:The clinical data of 29 patients diagnosed with IgD MM in the Affiliated Hospital of Xuzhou Medical University from March 2014 to February 2021 were retrospectively collected. The clinical characteristics, treatment regimens and efficacy, especially the efficacy of new drugs and immunotherapy for the disease were analyzed. Kaplan-Meier method was used to analyze the overall survival (OS) and progression-free survival (PFS). Multivariate Cox proportional risk model was used for analysis of prognostic influencing factors.Results:The median age of patients was 58 years. There were 20 cases (69.0%) below 65 years, 12 cases (41.4%) of complicated with stomach function damage, 6 cases (20.7%) of extramedullary invasion. All patients were treated with combined therapy containing proteasome inhibitor bortezomib in the first-line therapy, and the overall response rate was 82.8% (24/29). Among 21 relapsed/refractory patients, 12 patients were treated with the second-line or above treatment regimen chimeric antigen receptor T cell (CAR-T) immunotherapy, including 9 cases achieving very good partial remission (VGPR) or above; 5 patients were treated with the new drug daratozumab, including 1 case achieving complete remission (CR). The median OS time of 29 patients was 48 months (95% CI 17-79 months), the median PFS time after the first-line treatment was 9 months (95% CI 3-15 months), and the median PFS time after the second-line treatment was 11 months (95% CI 1-21 months). Multivariate Cox regression results showed that CAR-T therapy is an independent influencing factor of the prognosis of relapsed/ refractory IgD MM patients ( HR = 0.094, 95% CI 0.019-0.473, P = 0.004). Conclusions:IgD MM patients are characterized with lower onset age, more renal function damage and a high incidence of extramedullary invasion. The first-line therapy containing proteasome inhibitor has a better short-term efficacy, and CAR-T therapy can improve the remission rate and survival rate of relapsed/refractory IgD MM to a certain extent.
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Objective:To explore the prognostic value of lymphocyte subsets in adult hemophagocytic syndrome (HPS).Methods:A total of 172 adult HPS patients diagnosed in 8 medical centers from January 2013 to August 2020 were selected for the study, of whom 87 were male (50.6%, 87/172), and 85 were female (49.4%, 85/172), with 68 survivors and 104 deaths. The clinical data were summarized, and variables such as lymphocyte subsets, immunoglobulin characteristics and fibrinogen were retrospectively analyzed, and the correlation between the mentioned variables and patient prognosis was analyzed. The optimal cut-off values of continuous variables were calculated by MaxStat, and the prognostic factors of HPS patients were screened based on the Cox proportional hazard regression model.Results:The median age of HPS patients was 56 (42, 66) years old, and the 5-year cumulative survival rate was 37.4% (37.4/100). The median age, platelet and albumin were 48 (27, 63) years, 84×10 9/L and 32.3 g/L in the survival group, and 59 years, 45.5×10 9/L, and 27.3 g/L in the death group, respectively. The differences between the two groups was statistically significant ( Z=?3.368, P=0.001; Z=?3.156, P=0.002; Z=?3.431, P=0.001). Patients with differentiated cluster 8+(CD8+)<11.1%, CD3+<64.9%, CD4+>51%, and CD4/CD8 ratio>2.18 had poor prognosis (χ 2=7.498, P=0.023; χ 2=4.169, P=0.041; χ 2=4.316, P=0.038; χ 2=9.372, P=0.002). Multivariable analysis showed that CD4/CD8 ratio, age, fibrinogen and hemoglobin were independent prognostic factors in HPS patients ( HR=2.435, P=0.027; HR=5.790, P<0.001; HR=0.432, P=0.018; HR=0.427, P=0.018). Conclusion:Peripheral blood lymphocyte subsets can be used to evaluate the prognosis of patients with HPS; CD4/CD8 ratio, age, fibrinogen, and hemoglobin are independent prognostic factors in HPS patients.
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Histological transformation is a special histological variation in the progression of indolent lymphoma, and is often accompanied by an aggressive enhanced clinical process. Its poor conventional treatment effect, short survival time and poor prognosis have brought great challenges to the clinical treatment. Except for aggressive clinical manifestations and clear histopathological changes, this transformed type of lymphoma is often accompanied by specific imaging, biological metabolism and molecular genetics variations. This paper reviews the progress of histopathology, clinical characteristics, molecular characteristics and treatment strategy of the histological transformation of indolent lymphoma.
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Objective:To investigate the effect of prognostic nutrition index (PNI) and clinical characteristics on the prognosis of patients with diffuse large B-cell lymphoma (DLBCL).Methods:The clinical data of 236 patients with DLBCL treated in the Affiliated Hospital of Xuzhou Medical University from November 2014 to December 2018 were retrospectively analyzed. X-Tile software and restricted cubic spline (RCS) were used to determine the best cut-off values of PNI, age and hemoglobin; Cox proportional hazard regression model was used for univariate and multivariate analyses; Kaplan-Meier method was used to analyze the overall survival (OS) of patients, and log-rank test was also performed.Results:One-hundred and fifteen of the 236 patients (48.7%) died, with a median OS time of 32 months. The 3-year OS rate was 46%, and the 5-year OS rate was 36%. The best cut-off value of PNI was 49. There was a significant non-linear relationship between PNI and the risk of poor prognosis of DLBCL ( χ2=34.64, P < 0.01); the analysis of the dose-response relationship showed that with the change of PNI, the correlation strength of the risk of poor prognosis declined non-linearly. The best cut-off value of age was 63 years old, and the correlation strength between age and the risk of poor prognosis of DLBCL showed a non-linear upward trend ( χ2=14.86, P=0.022). The best cut-off values of hemoglobin calculated by X-Tile software were 93 g/L and 129 g/L. Multivariate analysis showed that PNI, central nervous system involvement, liver involvement, age, hemoglobin, international prognostic index (IPI) score, and bulky disease were independent influencing factors of OS in DLBCL patients (all P < 0.05). In patients with germinal center B-cell-like (GCB) subtype, bcl-2-positive and bcl-6-positive, there were statistical differences in the 3-year OS rate of patients with PNI < 49 and PNI ≥ 49 (all P < 0.05). Conclusion:PNI has a certain value in the prognosis assessment of DLBCL patients, and PNI ≥ 49 indicates that the patient has a good prognosis.
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The complement system is a protein response system with a precise regulation mechanism, and an important part of the body's innate and adaptive immunity. Abnormal complement components, excessive activation and other functional disorders are closely related to the development and progression of lymphoma and immune escape. In addition, the complement system has a certain relevance to clinical treatment, especially immunotherapy. This paper reviews the role of complement system in the occurrence and treatment of lymphoma.
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Objective:To investigate the correlation of red blood cell distribution width-to-platelet ratio (RPR) with clinical features and prognosis of patients with multiple myeloma (MM).Methods:The clinical data of 137 patients with MM who were admitted to the Affiliated Hospital of Xuzhou Medical University from April 2013 to July 2019 were collected. The receiver operating characteristic (ROC) curve was used to determine the best cut-off value of RPR. According to the best cut-off value of RPR, the patients were divided into high RPR group and low RPR group, and the differences in clinical characteristics and prognosis between the two groups were analyzed.Results:The best cut-off value of RPR was 0.10, and according to the best cut-off value, the patients were divided into high RPR group (RPR ≥ 0.10, 52 cases) and low RPR group (RPR < 0.10, 85 cases). There were statistical differences between the high RPR group and low RPR group in the proportion of patients between different stratification of Durie-Salmon (DS) staging ( χ2 = 17.110, P < 0.01), International Staging System (ISS) staging ( χ2 = 10.817, P = 0.001), red blood cell distribution width standard deviation(RDW-SD) ( χ2 = 26.937, P < 0.01), hemoglobin ( χ2 = 17.140, P < 0.01), lactate dehydrogenase (LDH) ( χ2 = 7.926, P = 0.005), erythrocyte sedimentation rate (ESR) ( χ2 = 9.513, P = 0.002), β 2-microglobulin (β 2-MG) ( χ2 = 7.726, P = 0.005), and bone marrow plasma cell ratio (BMPC) ( χ2 = 6.621, P = 0.010). The overall response rate (ORR) in the low RPR group was higher than that in the high RPR group [82.4% (70/85) vs. 71.2% (37/52)], but the difference was not statistically significant ( χ2 = 2.366, P = 0.124). The deep remission rate in the low RPR group was higher than that in the high RPR group [56.5% (48/85) vs. 19.2% (10/52)], and the difference was statistically significant ( χ2 = 18.327, P < 0.01). The results of multivariate analysis showed that the albumin, RPR and degree of remission were independent influencing factors for the overall survival (OS) of newly treated MM patients (all P < 0.05). Conclusion:MM patients with elevated peripheral blood RPR have shorter OS time, and RPR may be one of the indicators for evaluating the prognosis of MM.
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As a transmembrane protein, CD47 is widely distributed in a variety of cells. It can bind to signal regulatory protein alpha (SIRPα) on macrophages and release inhibitory signals, thus avoiding phagocytosis of macrophages. In lymphoma cells, the expression of up-regulation of CD47 expression in lymphoma cells is one of the important mechanisms for inducing immune escape, and it is also a potential therapeutic target. This article reviews the research progress of CD47-induced immune escape, monoclonal antibodies targeting CD47 and cellular immunotherapy in the treatment of lymphoma.
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The microenvironment of lymphoma is an important factor affecting the development of lymphoma, which is involved in regulating the recognition and immune response of lymphoma cells by the immune system. In the era of immunotherapy of lymphoma, the state of microenvironment also affects the effect of monoclonal antibodies, small molecular compounds and other immune targeting drugs on lymphoma cells. Among them, microenvironment-related immune escape is one of the key factors leading to the failure of lymphoma treatment. This article reviews some microenvironment factors such as stromal immune cell subsets, vascular proliferation, hypoxia, immune checkpoint and the recent research progress of immune escape.
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Coupling of ubiquitin conjugation to estrogen receptor degradation (CUE) domain containing protein, a newly discovered ubiquitin binding protein that contains CUE domain, plays an important role in the tumor formation, metastasis and drug resistance. Some researches have showed that CUE domain-containing protein 1 (CUEDC1) is associated with tumor lymphatic metastasis, and CUE domain-containing protein 2 (CUEDC2) is involved in the occurrence and development of solid tumors and leukemia by regulating cell cycle and signaling pathway activity. This review summarizes the CUE domain containing protein structure and the functions in the occurrence, progression, metastasis and drug-resistance of solid tumors and leukemia.
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Coupling of ubiquitin conjugation to estrogen receptor degradation (CUE) domain containing protein, a newly discovered ubiquitin binding protein that contains CUE domain, plays an important role in the tumor formation, metastasis and drug resistance. Some researches have showed that CUE domain-containing protein 1 (CUEDC1) is associated with tumor lymphatic metastasis, and CUE domain-containing protein 2 (CUEDC2) is involved in the occurrence and development of solid tumors and leukemia by regulating cell cycle and signaling pathway activity. This review summarizes the CUE domain containing protein structure and the functions in the occurrence, progression, metastasis and drug-resistance of solid tumors and leukemia.
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CD5-positive diffuse large B-cell lymphoma (CD5+DLBCL) is a special type of DLBCL, which is characterized with later clinical staging, high-risk of relapse in extranodular tissues like bone marrow and central nervous system (CNS).Combined chemotherapy including rituximab and salvage autotransplantation/ allotransplantation can not significantly improve the prognosis. This article reviews the clinicopathological features, the possible pathogenesis, treatment status and dilemma in order to get the better understanding of CD5+DLBCL and avail the early diagnosis and individualized treatment.
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Epstein-Barr virus (EBV) is one of the most common human herpesviruses, presenting a latent infection in more than 95% of healthy adults. EBV can regulate the differentiation, proliferation and colony formation of infected lymphocytes by coding viral proteins, and it is associated with Burkitt lymphoma, NK/T cell lymphoma, Hodgkin lymphoma, and vascular immunoblastic lymphoma. This article reviews the research progress of EBV in lymphoma transformation.
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OX40 is a member of the tumor necrosis factor receptor (TNFR) superfamily. In the immune response of the body, OX40 and the OX40 ligand (OX40/OX40L) on the antigen-presenting cell membrane are important co-stimulatory molecules, which can promote the proliferation of T cells. And OX40 also has the dual role of activating and enhancing the T cell immune response. OX40/OX40L is an important target for tumor immunotherapy, and clinical studies of several OX40 agonists are currently underway. This article reviews the immunoregulatory mechanisms of OX40/OX40L and its research progress in lymphoma immunotherapy.
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Polycythemia vera (PV) is a clonal myeloproliferative neoplasms (MPN) deriving from hematopoietic stem cells (HSC), with a median survival of about 14 years. Thrombosis is the major complication affecting the survival of PV patients as well as the most common cause of death in PV patients. For PV patients, thrombosis is the result of the combined effects of various factors, and its pathogenesis is very complicated. There are many factors affecting the incidence of thrombosis in PV patients, including age, history of thrombosis, count of blood cells, platelet activity, treatment modality, JAK2 V617F burden. This paper reviews the factors affecting thrombosis in PV patients.
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Objective@#To explore the levels of IL-22 in thymus damaged by γ-ray total body irradiation (TBI), and to study the role of IL-22 in T cell reconstitution after thymic injury induced by TBI.@*Methods@#To induce thymic injury, mice were treated by sub-lethal TBI. Levels of intra-thymic and circulatory IL-22 were detected by using ELISA assay. Untreated mice were used as control. After receiving sub-lethal TBI, mice were intraperitoneally injected with PBS or recombinant mouse IL-22, which were marked as TBI+PBS or TBI+IL-22, respectively. Mice were monitored for counts of total thymic cells and circulatory white blood cells. Flow cytometry was applied to analyze percentages of thymic epithelial cells (TEC), thymocyte subsets and circulatory T cells. Real-time PCR assay was applied to analyze the mRNA expression levels of Foxn1, Ccl25, Aire and Dll4 in thymus.@*Results@#①Sub-lethal TBI treated mice expressed higher levels of intra-thymic and circulatory IL-22, compared with untreated ones (all P<0.05). ②After injection of recombinant IL-22, TBI+IL-22 mice had higher levels of intra-thymic IL-22 than TBI+PBS mice (all P<0.05). ③On day 14 after irradiation, real-time PCR assay showed that TBI+IL-22 mice had higher mRNA levels of Foxn1, Ccl25, Aire and Dll4 in thymus compared with TBI+PBS ones. Meanwhile, the TBI+IL-22 mice had higher counts of total thymic cells[(5.93±3.19)×106/ml vs (1.42±0.46)×106/ml, t=3.128, P=0.033] and circulatory white blood cells[(3.08±0.94)×106/ml vs (1.43±0.30)×106/ml, t=3.730, P=0.015] than those of TBI+PBS mice. Flow cytometry analysis indicated that TBI+IL-22 mice had higher counts of TEC and thymocytes than TBI+PBS mice on day 14 after irradiation (all P<0.05). On days 7 and 14 after irradiation, TBI+IL-22 mice had higher counts of circulatory white blood cells and T cells than TBI+PBS mice (all P<0.05).@*Conclusion@#Sub-lethal TBI induces upregulation of intra-thymic IL-22, and injecting of recombinant IL-22 increases level of IL-22 in thymus. Injecting of recombinant IL-22 improves recovery of TEC and increases numbers of thymocyte subsets and circulatory T cell after thymic injury.
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Objective@#To construct humanized anti-CD19 chimeric antigen receptor T cells and investigate its ability to kill leukemia cells in vitro and in vivo. @*Methods@#Humanized anti-human CD19 antibody with a high affinity was obtained based on mouse anti-human CD19 antibody (FMC63). Humanized CD19 CAR-T cells (hCART19) were constructed through transfection of lentivirus carrying a CAR sequence of humanized anti-CD19 scFv into human peripheral CD3+ T cells. The ability of hCART19 to kill leukemia cells and secrete cytokines was detected by LDH release assay and ELISA. The in vivo tumor-killing effect of hCART19 was evaluated in a leukemia mouse model. @*Results@#Several different humanized CD19 single-chain antibodies which were constructed by IMGT database were expressed in the eukaryotic expression vector and purified followed by acquiring humanized CD19 antibody (Clone H3L2) with similar binding ability to FMC63. Humanized CD19 CAR lentivirus vector was constructed and transfected into T cells to obtain hCART19 cells. The LDH release experiment confirmed that the killing rate of target cells was increased gradually along with the increased E/T ratio. When the ratio of E/T was 10∶1, the killing rate of target cells by hCART19 reached a maximum. When Raji cells were used as target cells, the hCART19 cells group had a significantly higher kill rate [(87.56±1.99)%] than the untransduced T cells group [(19.31±1.16)%] and the control virus transduced T cells group [(21.35±1.19)%](P<0.001). ELISA analysis showed that the secretion of IL-2 [ (10.56±0.88) pg/ml] and IFN-γ [ (199.02±12.66) pg/ml] in the hCART19 cells group were significantly higher than those in the untransduced T cells group [IL-2: (3.55±0.26) pg/ml; IFN-γ: (37.63±0.85) pg/ml] and the control virus transduced T cells group [IL-2: (2.92±0.32) pg/ml; IFN-γ: (52.07±3.33) pg/ml](P<0.001). The above experiments also showed similar results when CHO-K1-CD19 cells were used as target cells. Moreover, in a human leukemia xenograft animal model, the results showed that mice in the untransduced T cells group and the control virus transduced T cells group all died within 20 to 30 days, and the hCART19 cell group survived >40 days, which was more than the survival time of the other two groups of mice. The difference was statistically significant (χ2=11.73, P=0.008). @*Conclusion@#Humanized CD19 CAR-T cells with anti-leukemic activity have been successfully constructed, which will lay a foundation for clinical studies in the future.
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Overexpression of CCND1 and t (11;14) (q13;q32) chromosomal translocation are important markers in mantle cell lymphoma (MCL). However, part of MCL lacks the expression of CCND1. SOX11 can be used as a biomarker for its overexpression in CCND1-negative MCL. SOX11 is a neurogenic transcription factor, and its overexpression is closely related to histone modification and DNA methylation. Differential expression of SOX11 in MCL is closely related with the plasma cell differentiation, and there is a relationship between the prognosis and survival time of MCL. SOX11 cDNA is more sensitive than conventional methods for the detection of minimal residual disease (MRD). With further research of SOX11, it will become an important basis of diagnosis and prognosis in MCL, and can provide a new method for targeted therapy of MCL.
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Objective@#To explore effects of histone deacetylase inhibitor Belinostat on the immunologic function of dendritic cells (DC) and its possible mechanism.@*Methods@#Cultured mouse bone marrow-derived DC from C57BL/6 mouse in vitro. The experiments were divided into 0, 50, 100 nmol/L Belinostat + immature DC (imDC) group, and 0, 50, 100 nmol/L Belinostat mature DC (mDC). The changes of the ultrastructure of DC were observed by transmission electron microscope (TEM). Immunophenotype and CCR7 expression rate were detected by FCM, and the migration rate was observed by chemotaxis assay. The proliferation of lymphocytes stimulated by different DC was detected by mixed lymphocyte culture reaction. The cytokines in the culture supernatant, including TNF-α, IL-12 and IL-10, were examined by ELISA. RQ-PCR was used to examine the relative expression of mRNA in RelB.@*Results@#Successful cultured and identified the qualified imDC and mDC. Belinostat decreased the expression of CCR7 on imDC [(25.82±7.25)% vs (50.44±5.61)% and (18.71±2.00)% vs (50.44±5.61)%], meanwhile increased the rate on mDC [(71.14±1.96)% vs (64.90±1.47)%]. Chemotaxis assay showed that the migration rate of Belinostat+imDC and Belinostat+mDC group were both decreased, but the difference in imDC was not significant. T lymphocyte proliferation rate stimulated by 100 nmol/L Belinostat+imDC group was lower than imDC group in condition irritation cell∶reaction cell=1∶2 [(227.09±13.49)% vs (309.49±53.69)%]. Belinostat significantly suppressed the secretion of cytokines TNF-α, IL-12 and IL-10 (all P<0.01). The relative expression of mRNA in RelB was slightly decreased in Belinostat+imDC and Belinostat+mDC group (all P<0.05).@*Conclusion@#Belinostat could effectly suppress DC maturation and regulate immune tolerance of DC, which may be due to the down-regulation of mRNA level of RelB in DC.
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Multiple myeloma (MM) is a kind of common hematologic neoplasms. The application of new drugs and autologous hemopoietic stem cell transplantation can significantly improve the response rate of MM. However, as it is impossible to eradicate the minimal residual disease, recurrence is unavoidable. Maintenance therapy has the potential to increase remission degree, thus lengthening the progression-free survival and overall survival time of MM patients.
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Objective To investigate the CD47 expression in de novo acute myelogenous leukemia (AML) patients with normal karyotype and its clinical significance. Methods One hundred thirty-seven cases of de novo AML with normal karyotype and 3 healthy volunteers were selected. Relative CD47 expressions in normal bone marrow hematopoietic stem cells (HSC) and multipotent progenitor (MPP) from healthy volunteers, as well as bone marrow mononuclear cells (MNC) and leukemia stem cells (LSC, Lin-CD34+CD38-CD90-) from AML patients were determined by flow cytometry. CD47 expression on the Lin-CD34+CD38-LSC-enriched fraction of specimen was determined by flow cytometry. The FMS-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) was detected by using the Genome Analyzer platform. CD34+CD38-CD47hi and CD34+CD38-CD47lo expressing cells were identified and purified using FACS. Two groups of cells were inoculated with MethoCult H4445 medium on agarose-containing methylcellulose plates. After 12 days, MPP colony forming units (CFU) were counted, and 1×105 CD34+ CD38- CD47lo and CD34+ CD38-CD47hi cells were transplanted into NSG (NOD-SCID IL-2R γ null) mice irradiated by 280 cGy, and mice were sacrificed after 8 weeks. The ratio of human CD45+cells was detected by flow cytometry. Results The expression of CD47 in AML patients was higher than that in the healthy control. CD47 was expressed in all FAB (French-American-British) subtypes of AML. No significant difference in CD47 expression among different FAB subtypes was found (F=0.545, P>0.05). Among the 37 patients with CD34+CD38-CD47hi, 17 (46 %) were FLT3-ITD negative, and 20 (54 %) were FLT3-ITD positive. Among the 100 patients with CD34+CD38-CD47hi, 63 (63%) cases were FLT3-ITD negative, 37 (37%) cases were FLT3-ITD positive. The rate of FLT3-ITD positive in patients with CD34+ CD38- CD47lo had no statistical difference compared with patients with CD34+CD38-CD47hi (χ2= 3.79, P> 3.79). The CD34+CD38-CD47lo or CD34+CD38-CD47hi which was selected by FACS, was inoculated with the methylcellulose plate containing agarose for 12 days, and CD34+CD38-CD47lo cells could form CFU. The NSG mouse transplantation experiment showed that CD34+CD38-CD47lo cells could be reconstructed hematopoiesis, and CD34+CD38-CD47hi implantation failed. Conclusion CD34+CD38-CD47hi could enrich LSC, which may be a potential marker to detect minimal residual disease.