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Adolescent and young adult (AYA) non-Hodgkin lymphoma (NHL) is different from children and older adults in patients' clinical characteristics, pathological subtypes and genetic characteristics. The standard treatment regimen is still unclear currently. This article briefly describes the epidemiology, molecular biological features and prognostic factors of AYA-NHL, and highlights the curative effects of different treatment options in various subtypes of AYA-NHL, aiming to provide a basis for making clinical standard treatment plans.
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Objective@#To compare the efficacy of induction chemotherapy with or without autologous hematopoietic stem cell transplantation (auto-HSCT) for newly diagnosed young diffuse large B cell lymphoma (DLBCL) patients.@*Methods@#The retrospective study was performed in 90 cases of young patients (≤60 years) with newly diagnosed DLBCL and an age-adjusted International Prognostic Index (aa-IPI) score of 2 or 3. All of them were treated with R-CHOP (32 cases, rituximab combined with CHOP), dose-intensive regimens (DA-EPOCH, Hyper CVAD/MA or ESHAP) combined with or without rituximab (25 cases), and consolidated with up-front auto-HSCT (33 cases), respectively. The efficacy and the potential predictors were evaluated.@*Results@#①The median age of 90 patients was 43 (18-60) years old. The median follow-up time was 42 (3-110) months. ②The 5-year progression-free survival (PFS) for R-CHOP group, dose-intensive chemotherapy group and auto-HSCT group were (33.5±10.7) %, (55.3±10.1) % and (65.8±13.6) % (P=0.012), the 5-year overall survival (OS) were (49.7±9.0) %, (61.6±10.2) % and (78.6±7.8) % (P=0.035), respectively. There was no significant difference in 5-years PFS and OS between the R-CHOP group and dose-intensive chemotherapy group (P=0.519, P=0.437) compared with that of the dose-intensive chemotherapy group, auto-HSCT group has higher 5-year PFS (P=0.042). ③ When stratified with IPI score, the high-risk group treated with auto-HSCT (26 cases) showed similar 5-years PFS and 5-years OS to those in the low-risk group with chemotherapy alone (12 cases were in R-CHOP group and 8 cases were in dose-intensive chemotherapy group) [5-years PFS were (62.3 ±14.3)%, (58.3 ±18.6)% and (51.4±18.7)%, respectively, P=0.686; 5-years OS were (69.2±13.9)%, (62.5±15.5)% and (58.3±18.6)%, respectively, P=0.592]. ④However, the high-risk group treated with auto-HSCT (26 cases) showed superior 5-years PFS (P=0.002) and 5-years OS (P=0.019) compared to the high-risk group with chemotherapy alone (20 cases were in R-CHOP group and 17 cases were in dose-intensive chemotherapy group) [5-years PFS were (62.3±14.3)%, (41.1±13.5)% and (21.9±11.6)%, respectively; 5-years OS were (69.2±13.9)%, (51.5%±14.0)% and (35.4±13.6)%, respectively]. ⑤In the univariate analysis, as a whole, patients diagnosed with GCB subtype had higher 3-years PFS (P=0.022) and 3-years OS (P=0.037) compared to non-GCB subtype patients; in subgroup analysis, patients diagnosed with GCB subtype had higher 3-years PFS and 3-years OS compared to non-GCB subtype both in R-CHOP group (P=0.030, P=0.041) and dose-intensive chemotherapy group (P=0.044, P=0.047), but not in auto-HSCT group (P=0.199, P=0.093). ⑥In the multivariate analysis, different molecular classification (GCB/non-GCB) was an independent predictor for PFS and OS both in R-CHOP group [HR=0.274 (95% CI 0.094-0.800), P=0.018; HR=0.408 (95% CI 0.164-1.015), P=0.045] and dose-intensive chemotherapy group [HR=0.423 (95% CI 0.043-1.152), P=0.048; HR=5.758 (95% CI 0.882-6.592), P=0.035]. However, there was no significant difference in PFS and OS for auto-HSCT group between GCB/non-GCB patients.@*Conclusion@#Induction chemotherapy followed by up-front auto-HSCT has significant effect on efficacy for young and untreated patients with high risk DLBCL. Combined with induction chemotherapy followed by up-front auto-HSCT could improve the prognosis of non-GCB patients.
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Objective To explore the relevance between 18F-FDG PET-CT imaging features and laboratory parameters of multiple myeloma (MM) and its prognostic value. Methods The clinical data of 75 MM patients who received 18F-FDG PET-CT examination at the time of initial diagnosis in Tianjin Medical University Cancer Institute & Hospital from September 2008 to August 2016 were retrospectively analyzed, including their clinical features, survival time, PET-CT imaging and laboratory results. The correlation between imaging changes and laboratory results was analyzed. Kaplan-Meier method and log-rank test were used to make survival analysis. Results Of 75 patients, there were 48 patients (64.0%) who had lytic bone lesions everywhere of the bodies, especially in axial skeleton. Twenty-six patients (34.7%) had pathological fracture, which were either rib or spinal pathologic fracture. PET-CT at initial diagnosis showed that the osteolytic lesions were associated with anemia (χ2＝ 0.455, P ＝ 0.032), while pathological fractures were associated with C-reactive protein levels (χ 2 ＝ 0.976, P ＝ 0.007). The existence of pathologic fracture or lytic bone lesions showed no relevance to abnormal cytogenetics, extramedullary lesion, lactic dehydrogenase, albumin or β2-macroglobulin (β2-MG) levels as well as the survival time (all P＞0.05). Twenty-eight patients (37.3%) with
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Objective To analyze the infection rate of hepatitis B virus (HBV) in aggressive B-cell non-Hodgkin lymphoma (B-NHL), indolent B-NHL and multiple myeloma (MM) and its relationship with clinicopathological features. Methods The clinical data of 293 aggressive B-NHL, 181 indolent B-NHL and 261 MM patients in Tianjin Medical University Cancer Institute and Hospital from January 2009 to April 2017 were retrospectively analyzed. The difference of HBV infection was compared among three groups. Serum samples from all patients were tested for HBV markers, including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (HBsAb), hepatitis B e antigen (HBeAg), hepatitis B e antibody (HBeAb) and hepatitis B core antibody (HBcAb) by using chemiluminescence immunoassay. Results The positive rate of HBsAg was 9.2% (27/293), 5.5% (10/181) and 3.8% (10/261), respectively in the aggressive B-NHL group, indolent B-NHL group and MM group. The positive rate of HBsAg in the aggressive B-NHL group was higher than that in the indolent B-NHL group and MM group (χ2＝6.987, P＝0.030), and there was no statistical difference of HBsAg positive rate between the indolent B-NHL group and MM group (P ＞ 0.05). The positive rate of HBsAg, HBeAg, HBcAb in the aggressive B-NHL group was higher than that in the indolent B-NHL group and MM group [4.1% (12/293), 0, 0.8% (2/261); χ2＝ 14.976, P＝ 0.001], and there was no significant difference in the positive rate of HBsAg, HBeAg and HBcAb between the indolent B-NHL group and MM group (P ＞ 0.05). Compared with HBsAg negative aggressive B-NHL patients, HBsAg positive aggressive B-NHL patients showed, higher ratio of stage Ⅲ-Ⅳ [70.4% (19/27) vs. 49.2% (131/266), χ 2 ＝ 4.377, P＝0.036], more frequent involvement of spleen [51.9% (14/27) vs. 23.7% (63/266), χ 2＝ 10.039, P＝ 0.002], more frequent of B symptom [55.6% (15/27) vs. 32.0% (85/266), χ 2 ＝ 6.073, P＝ 0.014], more frequent of elevated total bilirubin [29.6% (8/27) vs. 14.3% (38/266), χ 2 ＝ 4.360, P ＝ 0.037] and more frequent of reduced albumin [55.6% (15/27) vs. 35.7% (95/266), χ 2＝ 4.115, P＝ 0.042]. Conclusions The infection rate of HBV in aggressive B-NHL patients is higher than that in the indolent B-NHL and MM patients. HBsAg positive aggressive B-NHL patients are associated with adverse clinical characteristics.
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Objective@#To elucidate the expression levels of key immune biomarkers, phosphate and tension homology deleted on chromosome ten (PTEN) and programmed cell death protein1(PD-1),of different immune tolerance pathway in classic Hodgkin’s lymphoma (CHL) to further determine their clinical role and prognostic significance.@*Methods@#The clinical features and prognostic factors of 56 CHL patients, who were admitted to the TianJin Medical University Cancer Institute from February 2003 to August 2013, were retrospectively analyzed. PTEN and PD-1 protein expression levels were analyzed by immunohistochemistry, Epstein-Barr virus encoded RNA (EBER) was performed by in situ hybridization assay. Correlations between the expression of biomarkers and clinicopathologic parameters were examined and survival analyses were performed.@*Results@#This cohort of 56 CHL patients included 34 males and 22 females with a median age of 25 years (ranged from 7 to 71 years). In a univariate analysis, age≥45, IPS score >2, EBER positive, high expression of PTEN protein conferred inferior 5-year OS and 5-year PFS; In a multivariate model, age≥45, IPS score >2, EBER positive, high expression of PTEN protein were identified as the independent adverse prognostic factors for CHL.@*Conclusions@#This study suggested for the first time that PTEN was independent prognostic immune biomarkers in CHL, which provided the novel therapeutic strategy of immune therapy for CHL.
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Objective@#To investigate the clinicopathologic features of patients with high-grade B-cell lymphomas (HGBL) that have rearrangements of MYC, bcl-6 and bcl-2.@*Methods@#One hundred and fifty-eight B-cell lymphomas patients from Institute of Hematology and Blood Diseases Hospital from January 2016 to April 2017 were detected by fluorescence in situ hybridization (FISH) with double color split-apart probes.@*Results@#Among 158 B-cell lymphomas, 3 cases with MYC, bcl-2 and bcl-6 rearrangements were identified, 1 of which also had CCND1/IgH translocation. All three patients were of older age, with poor prognostic parameters, multiple organs involvements, elevated LDH and advanced-tumor stage. Two of the three patients were treated with high-intensity chemotherapy and had no remission with an overall survival of 9 months and 11 months respectively. One patient had follow-up with no treatment. Histologically, all three cases showed a spectrum of morphologic features. Although initially categorized as lymphoblastic lymphoma, diffuse large lymphoma and mantle cell lymphoma respectively, two cases were associated with germinal center B-cell (GCB) immunophenotype and 1 case with non-GCB immunophenotype. They had a high proliferation index as assessed by immunostaining for Ki-67 (60%-90%).@*Conclusions@#MYC+ bcl-2+ bcl-6+ HGBL is an aggressive disease with multiple organ involvement, high serum LDH levels, advanced stage disease, poor prognosis and shorter patient survival. The diagnosis should be made by histopathology combined with FISH analysis. Its separation from other types of B cell large cell lymphoma is of clinical importance.
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Objective: To compare the efficacy between chemotherapy plus granulocyte colony-stimulating factor (G-CSF) and chemotherapy plus G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) for the mobilization of peripheral blood stem cells (PBSC) and hematopoietic recovery after transplantation in patients with multiple myeloma (MM). Methods: A retrospective study of autologous PBSC (APBSC) mobilization data of 56 MM patients who were treated with chemotherapy plus G-CSF or chemotherapy plus G-CSF and GM-CSF from May 2008 to July 2016 in Tianjin Medical University Cancer Institute and Hospital was conducted. The mobilization efficacy and hematopoietic recovery were analyzed. Results: In the univariate analysis, the successful collection rate of a single harvest in women and in patients with ISS stage Ⅲ and R-ISS stage Ⅱ/Ⅲ and treated with chemotherapy plus G-CSF was lower (P<0.05). However, age (≤60 years vs.>60 years), subtype, D-S staging (Ⅰ+Ⅱvs.Ⅲ), number of cycles of chemotherapy before mobilization (≤6 cycles vs.>6 cycles), disease phase before mobilization (PR vs. CR), and interval between diagnosis and mobilization (≤18 months vs.>18 months) were not correlated with CD34+ cell collection and successful mobilization rates (P>0.05). In the multivariate model, the successful mobilization rate in patients who received the chemotherapy plus G-CSF and GM-CSF mobilization regimen was higher (OR=12.009, 95% CI=1.961-73.537). The effect of mobilization regimens remained significant (P=0.007). Hematopoietic recovery without transplantation-related mortality occurred successfully in all patients. Conclusions: Chemotherapy plus G-CSF and GM-CSF mobilization regimens can significantly increase the effect of APBSC mobilization and ensure the recovery of hematopoietic function after transplantation. Chemotherapy plus G-CSF and GM-CSF mobilization regimens are safe and effective for mobilizing APBSCs.
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The efficacy of multiple myeloma (MM) treatments, particularly novel medicines and transplantation, has improved rapidly in the last ten years, with increasing rates of progression-free survival (PFS) and overall survival (OS). However, complete response (CR) is not enough as prognostic indicator guidance. Therefore, methods have been developed to monitor minimal residual disease (MRD), such as serum free light chain (sFLC), flow cytometry, polymerase chain reaction (PCR), next generation sequencing (NGS), and PET-CT. This article reviewed the current situation of the application of those methods in MM patients after stem cell transplantation.
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Background and purpose: Natural killer/T-cell lymphoma (NKTCL) is a scarce subtype of malignant lymphoma, and it has heterogeneous clinical manifestation and treatment effect. Currently, no precise risk stratification is used to guide prognosis. This study aimed to evaluate the prognostic impact of pre-treatment peripheral blood absolute monocyte count (AMC) and platelet-lymphocyte ratio (PLR) in patients with primary nasal NKTCL, and provide more precise information for better risk stratification to select appropriate treatment and improve survival. Methods: Clinical data of 132 patients newly diagnosed with primary nasal NKTCL was collected in the Tianjin Medical University Cancer Institute and Hospital from Jan. 2008 to Dec. 2013. The relationship between AMC and PLR in pre-treatment peripheral blood and 5-year overall survival (OS) and progression-free survival (PFS) of patients was analyzed retrospectively. Independent prognostic factors of patients were determined by univariate analysis and Cox regression analysis. Results: Pre-treatment peripheral blood AMC and PLR play important roles in the prognosis stratification of patients with primary nasal NKTCL. The prognosis in patients of AMC<0.5×109/L were higher than those of AMC≥0.5×109/L, The prognosis in patients of PLR<150 were higher than those of PLR≥150 (P<0.05). Based on the four independent risk factors of staging, ECOG scoring, AMC and PLR, we tried to establish a new prognostic model, dividing all patients into three different risk groups and found that the 5-year OS and PFS of three groups had significant statistical differences. Conclusion: Peripheral blood AMC and PLR were significantly correlated with the prognosis of patients with primary nasal NKTCL. The new prognostic patterns based on the four independent risk factors, such as staging, ECOG scoring, AMC and PLR may be more convenient and more economical than IPI (International Prognostic Index, IPI) and KPI (Korean Prognostic Index, KPI).
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Objective@#To explore the mechanism of ibrutinib on drug resistance diffuse large B-cell lymphoma (DLBCL) cells.@*Methods@#DLBCL cell line was cultured with mesenchymal stem cells (MSC) , and DLBCL cells which migrated and adhered to MSC under microscope was counted. The secretion of CXCL12 by MSC were measured by ELISA. The expression of CXCR4 on DLBCL cells were measured by flow cytometry, HBL-1 cells were transfected with a CXCR4-lentivector. An Annexin Ⅴ-binding assay was used to detect the induction of apoptosis. Clonogenic growth of DLBCL cells was evaluated on MethoCult media. Ibrutinib was injected into NOD/SCID mice, tumor growth was assessed via caliper measurements every 3 days.@*Results@#MSC promoted migration and adhesion of DLBCL cells to MSC. Ibrutinib inhibited migration and adhesion of DLBCL cells to MSC in a dose-dependent manner (P<0.05) . CXCL12 secreted by MSC and CXCR4 expressed on DLBCL cells could induce each other, which upgraded the levels of secretion and expression. Ibrutinib could inhibit the secretion of CXCL12 (SUDHL10: 660 pg/ml vs 1 400 pg/ml, P=0.004; HBL-1: 720 pg/ml vs 1 490 pg/ml, P=0.018; DLBCL:850 pg/ml vs 1 450 pg/ml, P=0.004) and expression of CXCR4 (P<0.05) . When co-cultured with MSC, the ratio of HBL-1 cells apoptosis in the group of control, mitoxantrone, ibrutinib, mitoxantrone+ibrutinib were respectively 15.1%, 17.5%, 23.5%, 58.7%. After transfected with a CXCR4-lentivector and overexpressed CXCR4, the ratios of HBL-1 cells apoptosis were 14.2%, 16.1%, 22.5%, 38.3% respectively. The ratio of DLBCL cells apoptosis induced by mitoxantrone was lower when co-cultured with MSC (P<0.05) . But with the addition of ibrutinib, the ratio of apoptosis was increaed and it was similar to cultivation without MSC, which suggested ibrutinib could inhibit drug-resistance induced by MSC. But after transfected with a CXCR4-lentivector, the overexpression of CXCR4 was detected and the ratio of apoptosis was significantly lower when co-cultured with MSC which demonstrated that ibrutinib inhibited drug-resistance by inhibiting the expression of CXCR4. MSC enhanced lymphoma clonogenicity in vitro and lymphoma cell growth in vivo. The number of colonies of control, MSC, Ibrutinib, MSC+Ibrutinib were 113±5, 205±4, 62±9, 123±3 (2.5×103/well, ±s) , respectively. The tumor volume of NOD/SCID mice were respectively 6 500, 17 000, 4 000, 10 000 mm3. Ibrutinib inhibited lymphoma clonogenicity in vitro and lymphoma cell growth in vitro.@*Conclusion@#Ibrutinib targeted the CXCL12/CXCR4 axis, inhibited the expression of CXCR4 and inhibited MSC-mediated drug resistance. Ibrutinib also inhibited lymphoma clonogenicity in vitro and lymphoma cell growth in vivo. These results provided a scientific rationality for relapsed/refractory DLBCL treatment with ibrutinib.
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Objective:To compare the efficacy between chemotherapy with granulocyte colony-stimulating factor (G-CSF) and chemo-therapy with G-CSF and granulocyte-macrophage colony-stimulating factor (GM-CSF) for the mobilization of peripheral blood hemato-poietic stem cells and hematological recovery post-transplantation in patients with malignant lymphoma. Methods:Autologous pe-ripheral blood hematopoietic stem cell mobilization data of 61 malignant lymphoma patients who were treated with chemotherapy plus G-CSF or chemotherapy plus G-CSF and GM-CSF from May 2008 to October 2016 were included in this study. The mobilization effi-cacy and hematopoietic recovery were analyzed. Results:During mobilization, White blood cells (WBC) of all patients decreased to 1.0×109/L and platelets (PLT) dropped to 40×109/L. The successful mobilization rates of CD34+cell are 52.5%in chemotherapy plus G-CSF group and 90.5%in chemotherapy plus G-CSF+GM-CSF group (P=0.003). All patients successfully underwent hematopoietic recon-struction without transplantation-related mortality. Conclusion: Although chemotherapy with G-CSF+GM-CSF can significantly in-crease the effect of autologous peripheral blood hematopoietic stem cell mobilization, the reconstruction of hematopoietic function after transplantation and side reaction between the two groups are the same. Thus, chemotherapy with G-CSF+GM-CSF is not superior to chemotherapy with G-CSF in mobilizing autologous peripheral blood hematopoietic stem cells.
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A 54-year-old man diagnosed with chronic lymphocytic leukemia (CLL) was admitted in our department in June 2014. After one cycle of FC chemotherapy, a bone marrow examination revealed normalized lymphocyte count and another acute myeloid leuke-mia (AML)-M5 clone. The patient refused sequential treatment and only received follow-up examination. He had continuous hemato-logically stable disease and died of pulmonary infection on July 2015. After a multidisciplinary team discussion, we confirmed the si-multaneous diagnosis of CLL and AML-M5. Through this discussion,tumor second hit model,tumor evolution model,andtumor heterogeneitywere further defined.
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<p><b>OBJECTIVE</b>To explore the role of CXCR4/STAT3 in mesenchymal stromal cell (MSC)-mediated drug resistance of AML cells.</p><p><b>METHODS</b>AML cell lines U937 and KG1a and primary AML cells were co-cultured with MSC from bone marrow of healthy donors. The AML cell lines cultured alone were used as control. Apoptosis induced by mitoxantrone was measured by flow cytometry. Expression of CXCR4 and STAT3 protein were detected by Western blot. After incubated with STAT3 inhibitor Cucurbitacin I or CXCR4 antagonist AMD3100, the apoptosis of AML cells induced by mitoxantrone was evaluated.</p><p><b>RESULTS</b>Apoptosis of AML cells (U937 and KG1a) and primary AML cells induced by mitoxantrone significantly decreased in cocultured group than that of control group [U937 cells: (20.08±1.53)% vs (45.33 ± 1.03)% , P=0.004; KG1a cells: (25.60 ± 1.82)% vs (40.33 ± 3.29)% , P=0.020]. Expression of phosphorylated STAT3 and CXCR4 protein in AML cells were upregulated in cocultured group. After addition of Cucurbitacin I into the co-culture system, the apoptosis rate of primary AML cells significantly increased. Similar results of the apoptosis rates were also detected when the inhibitor of CXCR4 AMD3100 was added to overcome the stromal cell-mediated drug resistance. Besides, the expression of p-STAT3 in AML cells after incubated with AMD3100 decreased significantly.</p><p><b>CONCLUSIONS</b>AML cells cocultured with MSC leads to the up-regulation of phosphorylated STAT3 and CXCR4 proteins, which resulted in AML cells resistance to chemotherapeutic drugs. Therefore targeting STAT3 or CXCR4 could be a new therapeutic strategy of AML.</p>
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Humans , Acute Disease , Apoptosis , Coculture Techniques , Drug Resistance, Neoplasm , Flow Cytometry , Gene Expression Regulation, Leukemic , Heterocyclic Compounds , Leukemia , Metabolism , Mesenchymal Stem Cells , Cell Biology , Receptors, CXCR4 , Metabolism , STAT3 Transcription Factor , Metabolism , Signal Transduction , U937 Cells , Up-RegulationABSTRACT
<p><b>OBJECTIVE</b>To investigate the effect of CAL-101, a selective inhibitor of PI3Kδ, in combination with bortezomib on the proliferation and apoptosis in human mantle cell lymphoma cell lines Z138, HBL-2 and Jeko-1 in vitro, to explore its mechanisms and provide the foundation for effective treatment strategies against mantle cell lymphoma.</p><p><b>METHODS</b>MTT assay was applied to detect the inhibitory effects of CAL-101 and bortezomib either alone or combined on Z138, HBL-2 and Jeko-1 cells. Calcusyn software was used to analyze the synergistic cytotoxicity. Western blot was used to detect the expression of PI3K-p110σ and p-Akt, Akt, p-ERK and ERK proteins after the cells were exposed to different concentrations of CAL-101. Flow cytometry was employed to assess the apoptosis rate. NF-κB kit was used to determine the changes of location of NF-κB P65, and Western blot was applied to detect the level of caswpase-3 and the phosphorylation of Akt in different groups.</p><p><b>RESULTS</b>CAL-101 and BTZ inhibited the proliferation of Z138, HBL-2 and Jeko-1 cells in a dose- and time-dependent manner. CAL-101/BTZ combination induced significantly synergistic cytotoxicity in the MCL cells. The results of Western blot assay showed that CAL-101 significantly blocked the phosphorylation of Akt and ERK in the MCL cell lines. In addition, CAL-101 combined with BTZ induced pronounced apoptosis (P < 0.01). For example, after the Z138 cells exposed to the drugs for 48 h, the apoptosis rates of the control, CAL-101, BTZ and CAL-101 + BTZ groups were: (2.6 ± 1.8)%, (40.0 ± 3.0)%, (34.0 ± 1.0)%, and (67.4 ± 1.0)%, respectively; and when drug treatment was given to HBL-2 cells over 96 h, the apoptosis rates of these four cell groups were (7.4 ± 0.6)%, (30.7 ± 5.7)%, (12.0 ± 1.0)%, and (85.0 ± 4.0)%, respectively. The combination therapy contributed to the enhanced inactivity of nuclear factor-κB (NF-κB) and Akt inactivation in the MCL cell lines (P < 0.05), however, the casepase-3 activity was up-regulated.</p><p><b>CONCLUSIONS</b>The combination of CAL-101 and bortezomib is muchmore effective in inhibiting proliferation and promoting apoptosis of mantle cell lymphoma cell lines (Z138, HBL-2 and Jeko-1), which may be mediated through inhibiting PI3K/Akt signaling pathway and the transcription of NF-κB.</p>
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Humans , Antineoplastic Agents , Pharmacology , Antineoplastic Combined Chemotherapy Protocols , Pharmacology , Apoptosis , Blotting, Western , Boronic Acids , Bortezomib , Pharmacology , Caspase 3 , Metabolism , Cell Line, Tumor , Cell Proliferation , Class Ia Phosphatidylinositol 3-Kinase , Dose-Response Relationship, Drug , Drug Synergism , Formazans , Lymphoma, Mantle-Cell , Drug Therapy , Pathology , MAP Kinase Signaling System , NF-kappa B , Metabolism , Neoplasm Proteins , Metabolism , Phosphatidylinositol 3-Kinases , Metabolism , Phosphorylation , Proto-Oncogene Proteins c-akt , Metabolism , Purines , Pharmacology , Pyrazines , Quinazolinones , Pharmacology , Signal Transduction , Software , Tetrazolium SaltsABSTRACT
Objective:To detect the inhibitory effects of CAL-101, a selective inhibitor of phosphoinostitide-3'-kinase delta (PI3Kδ), on Burkitt's lymphoma cell line Raji and diffused large B-cell lymphoma cell line SUDHL-10 and elucidate its relative mechanism. Methods:Raji and SUDHL-10 cells were treated with various concentrations of CAL-101. Methyl thiazolyl tetrazolium (MTT) assay was performed to determine the inhibitory effect of CAL-101 on lymphoma cells, and cell apoptosis was measured by Annexin V/PI and DAPI staining. Migration assays were performed with transwell to detect the migration of lymphoma cells derived from the stromal cell line HK. Western blot was used to detect the phosphorylation status of the ERK pathway. MTT and CalcuSyn software analyses were preformed to detect whether or not combining CAL-101 with bortezomib induces synergistic cytoxicity. Results:CAL-101 at con-centrations of 5, 10, 15, and 20μmol/L inhibited cell proliferation in a dose-dependent manner. The proliferation rates of the Raji cells treated with 5, 10, 15, and 20μmol/L for 48 h were 29.17%± 1.23%, 38.15%± 1.51%, 46.46%± 1.78%, and 55.8%± 2.01%, respec-tively, which were significantly higher (P<0.05) than that of the control group (1.15% ± 0.02%). Similar results were found in the SUDHL-10 cells after treatment with CAL-101 (P<0.05). CAL-101 also exerted an apoptotic effect on the lymphoma cells. The apop-totic rates of the Raji cells treated with CAL-101 for 21 h were 22.69%± 3.83%and 49.96%± 7.36%, respectively, which were signifi-cantly higher (P<0.05) than that of the control group (5.23%± 2.04%). Similar results were found in the SUDHL-10 cells (P<0.05). Treatment with 5 and 10 μmol/L CAL-101 dose-dependently inhibited the migration activity of lymphoma cells to stromal cells (P<0.05). Western blot analysis showed that the expression level of ERK phosphorylation protein was significantly downregulated in the cells treated with CAL-101. A synergistic effect between CAL-101 and bortezomib was verified. That is, these two drugs can signifi-cantly inhibit the proliferation of lymphoma cells with CI values less than 1. Conclusion:The PI3Kδ-specific inhibitor CAL-101 sup-pressed the proliferation of Raji and SUDHL-10 cells, induced apoptosis, and inhibited stromal cell-derived migration. This inhibitory effect may be induced by blocking the ERK pathway. Overall, our study indicated that CAL-101 is a novel and potential agent in the therapeutic strategy against aggressive B-cell lymphoma.
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Objective:To investigate the etiology, clinical characteristics, and treatment of myelodysplastic syndrome/acute my-eloid leukemia (t-MDS/AML) secondary to malignant tumors. Methods: We retrospectively analyzed 11 patients with t-MDS/AML and investigated the treatment of primary tumors, clinical manifestations, treatment, and survival of t-MDS/AML patients. Results:A total of 11 patients were exposed to cytotoxic chemotherapeutic agents or radiation therapy for their primary tumors. The median laten-cy was 36 months. Common symptoms were fatigue, dyspnea, bleeding, and infection, all of which were related to deficits in hemato-poiesis. Therapeutic regimen included support therapy, immunomodulatory therapy, and chemotherapy. The median overall survival and disease-free survival periods were 28 months and 19 months, respectively, and the overall survival rate for 3 years was 44.4%. Conclu-sion:t-MDS/AML is a serious complication of chemotherapy or radiotherapy for a malignant or nonmalignant condition. The curative effect is limited, and prognosis is poor. Therefore, we should take t-MDS/AML into consideration when making treatment plans for can-cer patients to evaluate treatment benefits and to avoid treatment-related complications.
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Objective:To investigate the clinical features, treatment strategies, and relative prognostic factors in 66 patients with solitary plasmacytoma (SP). Methods:The data of 644 patients, who were diagnosed with pathologically proven plasmacytoma in Tianjin Medical University Cancer Institute and Hospital between June 2000 and October 2012, were collected. Sixty-six of these patients (10.25%) were evaluated as SP, including 45 solitary bone plasmacytoma (SBP) and 21 extramedullary plasmacytoma (EMP). Results:SBP and EMP were the two clinical subsets of SP revealing the location of the lesion. SBP mostly occurred in the axial skeleton, whereas EMP was most frequently observed in the upper respiratory tract. The differences among tumor size, serum M-protein, and serumβ2-microglobulin exhibited statistical significance. Conclusion:Large tumor size (≥5 cm), positive serum M-protein, and serumβ2-microglobulin were the factors that affected the prognosis of SBP patients. Radiotherapy and serumβ2-microglobulin>3.5 mg/L were the favorable prognostic factors for EMP patients.
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<p><b>OBJECTIVE</b>To elucidate the impact of Hes1 on the proliferation and apoptosis of acute myeloid leukemia (AML) cells.</p><p><b>METHODS</b>The expression levels of Hes1 and p21 in AML patient samples and myeloid leukemia cell lines were analyzed by real-time PCR. Hes1 was up-regulated by retrovirus transfection in AML cell lines and the proliferation capacity were assayed by MTT, cell cycle by Hoechst/PY, apoptosis by AnnexinV.</p><p><b>RESULTS</b>The expression of Hes1 in primary AML cells and HL-60, U937, KG1a cell lines were 0.67 ± 0.24, 0.59 ± 0.43, 0.42 ± 0.03, and 0.32 ± 0.26, respectively, and p21 were 0.54 ± 0.01, 0.44 ± 0.12, 0.36 ± 0.12, and 0.59 ± 0.43, respectively. Hes1 expression levels after transduction in HL-60, U937, KG1a were 4.9 ± 0.2, 5.2 ± 0.4, 5.8 ± 0.5, respectively. Induced activation of Hes1 led to AML cells growth arrest and apoptosis, which was associated with an enhanced p21 expression. Besides, activated Hes1 led to AML cells growth inhibition in vivo.</p><p><b>CONCLUSION</b>Hes1 could mediate growth arrest and apoptosis in AML cells, which may be a novel target for AML.</p>
Subject(s)
Humans , Apoptosis , Basic Helix-Loop-Helix Transcription Factors , Cell Cycle , Cell Line, Tumor , Homeodomain Proteins , Leukemia, Myeloid, Acute , Transcription Factor HES-1 , Up-RegulationABSTRACT
<p><b>OBJECTIVE</b>To probe the clinical and pathological characteristics of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL).</p><p><b>METHODS</b>The pathologically confirmed 14 cases of NLPHL patients (since January 2001 to December 2012) were collected from Tianjin Medical University Cancer Hospital. The laboratory examinations' results, clinical manifestations, short-term and long-term outcomes of these cases were analyzed in this study.</p><p><b>RESULTS</b>The immunohistochemistry of all cases showed CD20 (+)/weak (+) and CD30 (-), most of them CD15 (-). The morbidity of NLPHL during the same period of Hodgkin's lymphoma (HL) was around 6.3%. The median age was 38 (13-54) years old, 92.9% of the patients sought medical advice according to self-feeling of superficial lymph nodes. All patients' disease progressed slowly and the sizes of lymph nodes were within 3 cm. Of the 14 patients, 7 patients were treated with chemotherapy and 7 patients chemoradiotherapy. The treatment results showed CR+CRu rate as 85.7% and ORR 100.0%. The rates of 5-year event-free survival (EFS) and overall survival (OS) were 85.7% and 100.0% respectively. Short and long term efficacies between chemotherapy and chemoradiotherapy had no significant differences. Meanwhile, varieties chemotherapy regimens showed no significant effects on short- and long-term efficacies (P>0.05).</p><p><b>CONCLUSION</b>The pathologically confirmed 14 cases of NLPHL had the classical and tumorous maxi cell, which showed CD20 (+)/weak (+) and CD30 (-), very few cases showed weak CD15 (+). The incidence of NLPHL was low. The majority of the NLPHL patients were middle-aged and youth. Moreover, the better short- and long-term outcomes over classical HL ones were observed regardless of patients' stage.</p>
Subject(s)
Adolescent , Adult , Humans , Middle Aged , Young Adult , Disease-Free Survival , Hodgkin Disease , Immunohistochemistry , Incidence , Lymph Nodes , Treatment OutcomeABSTRACT
<p><b>OBJECTIVE</b>To explore the expression of Bcl-2 mRNA and its effect on prognosis of patients with primary gastrointestinal diffuse large B-cell lymphoma (PGI-DLBCL).</p><p><b>METHODS</b>Real time quantitative PCR was used to determine the expression of Bcl-2 mRNA in 40 PGI-DLBCL patients and 17 healthy controls. The association of Bcl-2 expression with clinicopathological features and prognosis of the patients was analyzed.</p><p><b>RESULTS</b>The expression level of Bcl-2 mRNA in PGI-DLBCL patients was 1.03 ± 0.93, significantly higher than that of the controls (0.41 ± 0.21) (P < 0.05). The expression of Bcl-2 mRNA in stage IIE-IV patients (1.28 ± 1.01) was significantly higher than that in the stage I-II2 patients (0.62 ± 0.61) (P < 0.05). The expression of Bcl-2 mRNA in patients with international prognostic index (IPI) score >2 (1.95 ± 1.27) was significantly higher than those with IPI score ≤ 2 (0.86 ± 0.75)(P < 0.05). The expression of Bcl-2 mRNA in patients with complete remission (CR) (0.71 ± 0.58) was significantly lower vs. 2.42 ± 0.91 in patients with no CR (P < 0.05). Univariate analysis indicated that β2-MG, IPI score>2, the Lugano staging, and Bcl-2 mRNA expression were associated with overall survival (OS) and progression-free survival (PFS) (P < 0.05). Multivariate analysis indicated that IPI score>2 was independently associated with OS (P < 0.05), and both IPI score >2 and Bcl-2 mRNA expression were independently associated with PFS (P < 0.05).</p><p><b>CONCLUSIONS</b>The expression of Bcl-2 mRNA in the tumor tissue of PGI-DLBCL patients is significantly higher than that in controls. PGI-DLBCL patients with higher expression of Bcl-2 have a poor chemotherapy response and inferior prognosis. IPI score >2 and higher expression of Bcl-2 mRNA are independent poor prognostic factors for PFS in PGI-DLBCL patients.</p>