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In multiple myeloma, abnormal plasma cells accumulate and proliferate in the bone marrow. Recently, we observed that Runx2, a bone-specific transcription factor, is highly expressed in multiple myeloma cells and is a major driver of multiple myeloma progression in bone. The primary goal of the present study was to identify Runx2-targeting miRNAs that can reduce tumor growth. Expression analysis of a panel of miRNAs in multiple myeloma patient specimens, compared with healthy control specimens, revealed that metastatic multiple myeloma cells express low levels of miR-342 and miR-363 but high levels of Runx2. Reconstituting multiple myeloma cells (CAG) with miR-342 and miR-363 reduced the abundance of Runx2 and the expression of metastasis-promoting Runx2 target genes RANKL and DKK1, and suppressed Runx2 downstream signaling pathways Akt/β-catenin/survivin, which are required for multiple myeloma tumor progression. Intravenous injection of multiple myeloma cells (5TGM1), stably overexpressing miR-342 and miR-363 alone or together, into syngeneic C57Bl/KaLwRij mice resulted in a significant suppression of 5TGM1 cell growth, decreased osteoclasts and increased osteoblasts, and increased antitumor immunity in the bone marrow, compared with mice injected with 5TGM1 cells expressing a miR-Scramble control. In summary, these results demonstrate that enhanced expression of miR-342 and miR-363 in multiple myeloma cells inhibits Runx2 expression and multiple myeloma growth, decreases osteolysis, and enhances antitumor immunity. Thus, restoring the function of Runx2-targeting by miR-342 and miR-363 in multiple myeloma cells may afford a therapeutic benefit by preventing multiple myeloma progression. Implications: miR-342 and miR-363–mediated downregulation of Runx2 expression in multiple myeloma cells prevents multiple myeloma progression. Mol Cancer Res; 16(7); 1138–48. ©2018 AACR.

The international staging system (ISS), based on serum beta-2 microglobulin and albumin, is used to predict survival in multiple myeloma, but its prognostic significance in diffuse large B-cell lymphoma (DLBCL) remains unknown. Herein, we retrospectively analyzed 215 de novo DLBCL patients. According to ISS, there were 90 of 215 (41.9%) patients in stage I, 98 of 215 (45.6%) in stage II and 27 of 215 (12.6%) in stage III group. Patients with ISS stage II/III showed shorter overall survival (OS) and event free survival (EFS) than those with stage I treated with R-CHOP (p = 0.012 and p = 0.043, respectively), but not those treated with CHOP regimen (p > 0.05). Multivariable analysis revealed that ISS, independent of IPI, indicated different survival in both OS (HR, 5.690; 95% CI, 1.270–25.495, p = 0.023) and EFS (HR, 2.116; 95% CI, 1.005–4.455, p = 0.049) in DLBCL patients treated with R-CHOP. ISS could identify patients with better outcome in intermediate-high/high IPI risk patients (p

// Xiaoxiao Hao 1, * , Yongqiang Wei 1, * , Xiaolei Wei 1 , Lizhi Zhou 2 , Qi Wei 1 , Yuankun Zhang 1 , Weimin Huang 1 and Ru Feng 1 1 Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China 2 Department of Biostatistics, School of Public Health, Southern Medical University, Guangzhou, China * These authors contributed equally to this work Correspondence to: Ru Feng, email: ruth1626@hotmail.com Keywords: diffuse large B-cell lymphoma, glasgow prognostic score, inflammation-based prognostic score Received: March 16, 2017 Accepted: August 26, 2017 Published: September 11, 2017 ABSTRACT Inflammation-based prognostic scores, such as the glasgow prognostic score (GPS), prognostic index (PI), prognostic nutritional index (PNI), neutrophil lymphocyte ratio (NLR) and platelet lymphocyte ratio (PLR) were related to survival in many solid tumors. Recent study showed that GPS can be used to predict outcome in diffuse large B-cell lymphoma (DLBCL). However, other inflammation related scores had not been reported and it also remained unknown which of them was the most useful to evaluate the survival in DLBCLs. In this retrospective study, a number of 252 newly diagnosed and histologically proven DLBCLs from January 2003 to December 2014 were included. The high GPS, high PI, high NLR, high PLR and low PNI were all associated with poor overall survival ( p < 0.05) and event-free survival ( p < 0.05) in univariate analysis. Multivariate analysis indicated that GPS (HR = 1.781, 95% CI = 1.065–2.979, p = 0.028) remained an independent prognostic predictor in DLBCL. The c-index of GPS (0.735, 95% CI = 0.645–0.824) was greater than that of PI (0.710, 95% CI = 0.621–0.799, p = 0.602), PNI (0.600, 95% CI = 0.517–0.683, p = 0.001), PLR (0.599, 95% CI = 0.510–0.689, p = 0.029) and NLR (0.572, 95% CI = 0.503–0.642, p = 0.005) by Harrell’s concordance index. Especially in DLBCLs treated with R-CHOP, GPS still remained the most powerful prognostic score when comparing with others ( p = 0.001 and p < 0.001, respectively for OS and EFS). In conclusion, it is indicated that inflammation-based prognostic scores such as GPS, PI, NLR, PNI and PLR all could be used to predict the outcome of DLBCLs. Among them, GPS is the most powerful indicator in predicting survival in DLBCLs, even in the rituximab era.

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The prognostic value of CD30 expression in diffuse large B-cell lymphoma (DLBCL)remains controversial. Herein, we performed this retrospective study to investigate the clinical and prognostic significance of CD30 expression in patients with DLBCL.Among all the 146 patients, the expression of CD30 was observed in 23 cases (15.7%).The DLBCL patients with CD30 expression showed more likely to present B symptoms, bone marrow involvement, non-germinal centre B-cell-like (Non-GCB) DLBCL, BCL-2 and Ki-67 overexpression (p

The peripheral blood lymphocyte to monocyte ratio (LMR) at diagnosis has been used to predict survival in diffuse large B-cell lymphoma (DLBCL) patients, but its prognostic significance with respect to different cell-of-origin (COO) subtypes remains unknown. We retrospectively analyzed 168 de novo DLBCL patients in this study and found that a low LMR (≤2.6) correlates with B symptoms, elevated LDH, advanced Ann Arbor stage and higher international prognostic index (IPI) score (p

Objective International prognostic index (IPI) has been widely used for predicting outcome in diffuse large B cell lymphoma. Although the introduction of rituximab to chemotherapy has dramatically improved the outcome of DLBCL, it also changed the prognostic value of IPI. The National Comprehensive Cancer Network IPI (NCCN-IPI) and age-adjusted IPI (aaIPI) were used to evaluate the prognosis for DLBCL in the rituximab era. However which one of them is more powerful in predicting survival remains unknown in Chinese patients. Patients and Methods A total of 334 patients with de novo diffuse large B-cell lymphoma diagnosed from 2003 to 2012 were included. All patients were treated with CHOP with or without rituximab. They were divided into CHOP and R-CHOP groups. IPI, NCCN-IPI and aaIPI score were recorded. Survival was performed according to the Kaplan-Meier (K-M) curves using the log-rank test. The predictive abilities of PI, NCCN-IPI and aaIPI were investigated by Harrell's C-statistics. Result Compared with the IPI, the NCCN-IPI and the aaIPI had better discrimination in different scores in all patients treated with or without rituximab. Both the NCCN-IPI and aaIPI had power in discriminating low, low-intermediate and high-intermediate risk groups. In comparison, the NCCN-IPI discriminated low-intermediate and high-intermediate risk groups (5-year overall survival [OS]: 74% vs 50%) better than the aaIPI (5-year OS: 80% vs 62%) in all patients and in the R-CHOP group with the NCCN-IPI 5-year OS: 85% vs 67% while the aaIPI: 87% vs 77%. In the CHOP group, the aaIPI discriminated low-intermediate and high-intermediate risk groups better (5-year OS: 70% vs 25%) than the NCCN-IPI (5-year OS: 60% vs 24%). According to the Harrel C statistic, the NCCN-IPI showed higher discrimination of the different scores (C_index: 0.669 ) than the aaIPI (C_index: 0.663 ) in all the patients (C_index: 0.669 vs. 0.663), especially in the R-CHOP group (C_index: 0.681 vs. 0.636). In the CHOP group, the aaIPI had stronger power (C_index: 0.711 ) than the NCCN-IPI (C_index: 0.683 ) in discriminating different scores. Conclusion The NCCN-IPI is more powerful than the IPI for predicting survival in the rituximab era. In patients aged 60 or younger and treated with CHOP without rituximab, aaIPI is a preferable tool for evaluating prognosis. Disclosures No relevant conflicts of interest to declare.

Inflammation-based prognostic scores, such as the glasgow prognostic score (GPS), prognostic index(PI), prognostic nutritional index(PNI), neutrophil lymphocyte ratio(NLR), platelet lymphocyte ratio(PLR) was related to survival in many solid tumors. Recent study showed that GPS can be used to predict outcome in diffuse large B-cell lymphoma(DLBCL). However other inflammation related scores had not been reported in DLBCL, and it also remained unknown which of them was more useful to evaluate the survival in DLBCL. In this retrospective study, a number of 252 newly diagnosed and histologically proven DLBCL patients from January 2003 to December 2014 were included. An elevated GPS, PI, NLR, PNI and PLR were all associated with decreased overall survival(p=0.000, p=0.000, p=0.006, p=0.001 and p=0.001, respectively) and event-free survival (p=0.000, p=0.000, p=0.011, p=0.001 and p=0.009, respectively) in univariate analysis. Multivariate analysis indicated that GPS(RR=1.768, 95%CI=1.043-3.000, p =0.034) remained an independent prognostic predictor in DLBCL. The area under the curve of GPS (0.735, 95%CI=0.645-0.824) was greater than that of PI(0.710, 95%CI=0.621-0.799), PNI(0.600, 95%CI=0.517-0.683), NLR(0.572, 95%CI=0.503-0.642), and PLR(0.599, 95%CI=0.510-0.689) by Harrell's C-statistics. Especially in the DLBCL patients treated with R-CHOP, GPS also remained the most powerful inflammation-based prognostic score when comparing with PI, NLR, PNI and PLR (p=0.004, p=0.000, respectively for OS and EFS). In conclusion, these results indicate that Inflammation-based prognostic scores such as GPS, PI, NLR, PNI and PLR can be used to evaluate the outcome in DLBCL patients. Among them, GPS is the most powerful tool in predicting survival in DLBCL patients, even in the rituximab era. Disclosures No relevant conflicts of interest to declare.

Tumor-associated macrophages (TAMs), as the major component in tumor microenvironment, have been reported to correlate with the prognosis in diffuse large B-cell lymphoma (DLBCL). However due to the different subtypes of TAMs and the given therapy regimen, the prognostic value of TAMs in DLBCL patients remains controversial. To explore the prognostic significance of different TAMs subtypes in DLBCL patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone), we retrospectively analyzed 77 de novo DLBCL patients in present study. TAM markers including CD68 and CD163 were evaluated by immunohistochemistry. The cutoff value of CD68, CD163 and CD163/CD68 ratio was determined by receiver operating characteristic curve. In a total of 77 patients, CD68 high expression was found in71.4 %( 55/77) DLBCL patients and CD163 high expression in 51.4 %( 40/77 patients. Patients with high CD163 expression were more present with extranodal sites (P =0.049). However other clinical parameters including age, gender, Ann Arbor stage, performance stage, B symptoms, LDH and international prognostic index (IPI) showed no difference in patients with high and low CD68 or CD163 expression (P >0.05). CD68 expression has less effect on overall survival (OS) and event-free survival (EFS) (P =0.852, 0.782). However, high CD163 expression showed poor OS and EFS in DLBCL patients (P =0.006, 0.004) and also high CD163/CD68 ratio (P Disclosures No relevant conflicts of interest to declare.

Background Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL). Although international prognostic index (IPI) has been widely used in DLBCL to evaluate the prognosis, there is need to find new biomarkers to predict outcome. Tumor microenvironment has been reported to be associated with both metastatic spread and diminished in some tumors. Tumor-associated macrophages (TAMs) and nature-killer (NK) cells play an important role in the tumor microenvironment. Therefore, we performed this study to investigate the prognostic implications of TAMs including M1 as well as M2 and NK cells in DLBCLs. Materials and Methods We reviewed 77 cases of DLBCL diagnosed between June 2004 and October 2012, who treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP). Patients were divided into GCB and non-GCB subgroups by Hans’ algorithm. We performed immunohistochemical stains using CD68, CD163 and CD57 to mark M1 macrophages, M2 macrophages and NK cells on paraffin tissue section. The percentage of TAMs was recorded and graded as: 0 if less than 5%, 1 if 5-25%, and 2 if greater than 25% of the total cells present in tumor cells rich nodules were positive for CD68 or CD163. And counting the mean number of the CD57+ cells in 5 fields under high-power magnification (400 times): 0 if less than 5 positive cellsG1 if more than 5 positive cells. Results Of the 77 DLBCL patients treated with R-CHOP, there were 51 males (66.2%), 26 females (33.8%). The median age was 52 years (range, 16-81 years). The median follow-up was 38.1 months. The median percentage for CD68 was 12.8 %( range, 2.4–50.84), for CD163 was 12.3 %( range, 1.0–39.2). The median counts of CD57 cells were 5 (range, 1.0-78) per unit area. In univariate analysis, an increase in CD68-positive cells was related to improved EFS (grade 0 vs. grade 2, p = 0.036). By contrast, an increased number of CD163-positive cells were significantly poor associated with OS, (grade0 vs grade2, p = 0.033). Patients with elevated NK cells tended to have no effect on prognosis. In multivariate analysis, an increased CD68 -positive cells was an independent predictors of EFS (HR 0.467, 95%CI 0.236-0.922, P=0.028), an decreased CD163-positive cells and lower LDH were independent predictors for OS (HR 2.287, 95%CI 1.043-5.013, P=0.039). Conclusion These results suggest that M1 macrophages might predict favorable clinical outcome and M2 macrophages predict poor clinical outcome. However, the NK cells have no prognostic significance in DLBCL patients treated with RCHOP. Disclosures No relevant conflicts of interest to declare.

Background: CD44 variants have been implicated in metastasis and as an unfavorable prognosis factor in many types of cancers. Our previous study had showed that CD44v6 expression implied a poor clinical outcome in diffuse large B cell lymphoma (DLBCL) patients treated with CHOP. However, it is remains unknown the prognostic value in DLBCL patients treated with R-CHOP due to our sample sizes. Therefore, to examine the prognostic value of CD44v6 expression in DLBCL patients, we performed this retrospective study. Methods: All 141 patients diagnosed as de novo DLBCL according to WHO classification were further confirmed. All patients treated with R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone). The expression of CD44v6 was analyzed by immunohistochemistry (IHC). IHC was performed by an automated immunostainer complying with the instructions of the protocols. Results: Among all the 141 patients, the expression of CD44v6 was observed in 41 cases (29.1%). CD44v6 is expressed predominantly in non-germinal center type DLBCL. There was no significant difference in gender, age, B symptoms, performance status, LDH, stage and IPI score between patients with and without CD44v6 expression. Patients with CD44v6 expression showed significant inferior overall survival, but not event-free survival compared with CD44v6-negative patients. (p=0.022 and p=0.142, respectively).Multivariate analysis showed that the expression of CD44v6, independent of the international prognostic index and cell of origin, implied a poor overall survival (HR=2.223; 95% CI= 1.007-4.906, p=0.048), but not event-free survival (HR=1.457; 95% CI=0.773-2.745, p=0.245). Conclusions: These data suggest that the expression of CD44v6 implied poor outcome in DLBCL patients treated with R-CHOP. Disclosures No relevant conflicts of interest to declare.

Purpose To establish a method for detecting minimal residual disease (MRD) by eight color flow cytometry which is stable, repeatable and accurate quantitation. Method According to the ratio of 10%, 1%, 0.1%, 0.01% and 0.001%,to analyze sensitivity of the method by successively mixing the cell lines (Kasumi, KG-1a) and primary acute leukemic bone marrow cell were mixed with normal bone marrow cells. In order to ensure the specificity of the test results, we increased antibody number to eight color combinations of antibodies to adjust fluorescence compensation value after labeling antibody separately in each channel. To verify the feasibility of standardization, standardized test were in 25 bone marrow samples of acute leukemia. Result In standard conditions of detection and sensitivity of 10-5could be detected by eight color flow cytometry. In our study there were 25 cases of acute leukemia, including 14 patients with acute myeloid leukemia and 11 patients with acute B-lymphoblastic leukemia. 23 of 25 cases were detected specific leukemia associated immunophenotypes (LAIP) at diagnosis. 20 patients could be detected the original LAIP, and LAIP of 3 patients changed after remission induction therapy. To analyze the relationship between the clinical data and MRD level, the result showed that the type of LAIP had significant influence on level of MRD. After remission the level of MRD in patients who expressed cross lineage and non-synchronous antigens at diagnosis was significantly higher than those who did not express (P=0.003, P=0.006). Conclusion We established the standardized conditions of minimal residual disease detected by multiparametric flow cytometry to ensure the accuracy and specificity of the test results. It has important significance to confirm that manifestations of LAIP were consistent with the outcome in patients with acute leukemia. Disclosures No relevant conflicts of interest to declare.