Efficacy and safety of stem cell mobilization with etoposide +cytarabine plus G-CSF in poor mobilizers with relapsed or refractory lymphoma.

Background: Autologous stem cell transplantation (ASCT) is a potentially curative strategy for relapse or refractory(r/r) aggressive lymphoma. However, a proportion of lymphoma patients who are at high risk of mobilization failure fail to mobilize stem cells and cannot proceed to ASCT. The aim of this study is to explore the efficacy and safety of Etoposide combined with Cytarabine (EA) plus G-CSF mobilization in poor mobilizers (PMs) with r/r aggressive lymphoma. Methods: This retrospective study analyzed the outcomes of chemo-mobilization based on EA (Etoposide 0.1 g/m2, qd d1~3; AraC 0.5 g/m2, q12h d1~3) in 98 patients with r/r aggressive lymphoma. Of these, 39 patients met the criteria for predicted PMs as proposed by the Gruppo Italiano Trapianto di Midollo Osseo working group. Results: Of the 39 PMs, 38(97.4%) patents harvested adequate mobilization (≥2×106 CD34+ cells/kg), while 31(79.5%) patients achieved optimal mobilization (≥5×106 CD34+ cells/kg). Overall, the mean number of CD34+ cells/kg collected was 17.99(range: 1.08~83.07) ×106 with an average of 1.4 apheresis sessions, and the number was 15.86(range: 0.37~83.07) ×106 for the first apheresis, respectively. A single apheresis procedure was sufficient to reach the target yield of adequate mobilization in 35(89.7%) PMs, while 76.9% of PMs achieved optimal collection within two apheresis sessions. We observed acceptable hematological toxicity and antibiotic usage exposure in 26 patients with a mean duration of 3.6 days. No grade 4 infection or mobilization-related mortality was recorded. Most patients underwent ASCT and achieved successful hematopoietic recovery with prompt engraftment duration, except for one NK/T-cell lymphoma patient who succumbed to severe septicemia after receiving conditioning chemotherapy. Conclusion: Our findings indicate that EA plus G-CSF is an effective and tolerable CD34+ stem cell mobilization strategy for patients with r/r lymphoma, including those predicted to be PMs. This regimen could be an option for patients with r/r lymphoma, particularly those undergoing mobilization for salvage ASCT therapy.

LncRNA LINC00173 inhibits the development of endometrial cancer by interacting with HNRNPC.

BACKGROUND: Previous research has elaborated on the role of long non-coding RNA LINC00173 in the pathogenesis of various cancers; however, our knowledge of its clinical consequences and mechanisms in endometrial cancer (EC) is limited. Our current work is aimed at investigating the effect of LINC00173 in combination with its upstream gene HNRNPC on EC progression. METHODS: LINC00173 and HNRNPC levels were investigated by qRT-PCR or western blotting in EC tissues. The functional roles of HNRNPC and LINC00173 were assessed using transwell, colony formation and CCK-8 assays. A xenograft was used to verify the phenotype of LINC00173 after its overexpression. The regulatory role between HNRNPC and LINC00173 was investigated using RIP and RNA pull-down analysis. RESULTS: In EC tissues, LINC00173 expression was down-regulated. We observed that increased LINC00173 inhibited EC cell growth and migration. LINC00173 was a downstream target of HNRNPC, and its expression level was elevated by HNRNPC silencing. LINC00173 overexpression shifted part of HNRNPC into the cytoplasm from the nucleus of EC cells. Furthermore, HNRNPC expression was upregulated in EC and its silencing inhibited EC cell malignancy in vitro. CONCLUSION: LINC00173 can impair the malignancy of EC cell by interacting with HNRNPC. This finding may contribute to the understanding of the tumorigenic effects of HNRNPC and LINC00173 on EC.

High Efficacy of Stem Cell Mobilization With Etoposide+Cytarabine Plus G-CSF in Patients With Multiple Myeloma.

BACKGROUND: Efficient mobilization of CD34+ hematopoietic stem cells plays a vital role in successful autologous stem cell transplantation (ASCT) in patients with multiple myeloma (MM), especially in cases with high-risk cytogenetic recommended for tandem ASCT. However, the optimal mobilization strategy remains a matter of debate in the era of lenalidomide. The combination of etoposide with Cytarabine plus G-CSF as a novel mobilization regimen in MM has not been reported previously. METHODS: This research retrospectively studied mobilization efficacy and safety using etoposide combined with Cytarabine (etoposide 50-100 mg/m2, qd d1-3; AraC 0.5 g/m2, q12h d1~3) plus G-CSF (5 µg/kg/day, from d5 until the day of apheresis) in 128 patients with MM. 70(54.7%) patients received lenalidomide-based induction regimens treatment. RESULTS: A median of 27.75×106 CD34+ cells/kg was collected in the first apheresis, and 28.23×106 CD34+ cells/kg were collected overall. Of the 128 patients, all achieved adequate collection (≥2×106 CD34+ cells/kg), 121(94.5%) achieved optimal collection for single ASCT (≥5×106 CD34+ cells/kg), and 114(89.1%) harvested optimal collection for tandem ASCT (≥10×106 CD34+ cells/kg). In particular, the target yield of optimal collection for tandem ASCT was reached in 82.8% (106/128) by a single apheresis procedure. 14 patients obtained deeper response post mobilization. In multivariate analysis, cycles of prior chemotherapy independently affected the optimal achievement of CD34+ cells (p=0.004, OR 0.695, 95% CI 0.544~0.888). Previous lenalidomide exposure did not significantly impair CD34+ cells collection. Although 68% episodes of antibiotic usage were observed, no severe infection or treatment-related mortality occurred. CONCLUSION: Stem cell mobilization with Etoposide + Cytarabine plus G-CSF was highly efficient and safe in patients with MM, which could be considered in high-risk MM patients who were referred for tandem ASCT.

Sequential Transplantation of Haploidentical Stem Cell and Unrelated Cord Blood With Using ATG/PTCY Increases Survival of Relapsed/Refractory Hematologic Malignancies.

Allogeneic haploidentical HSCT (haplo-HSCT) and unrelated umbilical cord blood transplantation(UCBT)are used in patients lacking HLA-identical sibling or unrelated donors. With myeloablative condition and GVHD prophylaxis of using low-dose ATG and post-transplantation cyclophosphamide (PTCY), we conducted a prospective clinical trial. Of eligible 122 patients from February 2015 to December 2019 in the study, 113 patients were involved. Forty-eight patients were in the group of sequential haplo-cord transplantation (haplo-cord HSCT), and 65 patients were in the group of single UCBT. The primary endpoint of 2-year disease-free survival (DFS) was no statistical difference between groups (64.1 vs. 56.5%), p>0.05. The analysis of subgroup patients with relapsed/refractory showed haplo-cord HSCT was associated with better OS (HR 0.348, 95% CI, 0.175-0.691; p=0.0025), DFS (HR 0.402, 95% CI, 0.208-0.779; p=0.0069), and GRFS (HR 0.235, 95% CI, 0.120-0.457, p<0.0001) compared to the single cord group. The 2-year's probability in OS, DFS, and GRFS was 64.9 vs. 31.6%, 64.5 vs. 31.6%, and 60.8 vs. 15.0% in the haplo-cord group and single cord group, respectively. III-IV acute GVHD 8.3 vs. 6.2%, chronic GVHD 25.8 vs. 13.7%, and extensive chronic GVHD 5.3 vs. 1.8% were shown in corresponding group, p>0.05. The patients engrafted persistently with UCB showed better survival outcomes. Our sequential Haplo-cord HSCT with ATG/PTCY improved the survival of patients and might be an alternative transplantation approach for patients with relapsed/refractory hematologic malignancies.

Cold starting temperature time-related compensation model of inertial sensors based on particle swarm optimization algorithm.

With the miniaturization of inertial instruments, sensors mounted inside are vulnerable to interference. In a complex thermal transmission environment, temperature drift is the main factor restricting the precision of high-performance inertial sensors. To solve this problem, a new method for compensating the time-related cold starting temperature drift of the inertial sensors is introduced in this paper. Based on the perspective that temperature drift can be regarded as the response curve of the sensor system to temperature and temperature gradient, temperature compensation models of first-order, second-order, and higher-order are proposed. Meanwhile, the particle swarm optimization algorithm is used to solve the model parameters. Under various practical circumstances, the method can be used to flexibly compensate the temperature drift and reduce the standard deviation of the output signal by about four times. Compared to other models or algorithms, the simulation and experimental results indicate that the proposed model is superior in adaptability, stability, and reliability.

Improved long-term survival in all Sanz risk patients of newly diagnosed acute promyelocytic leukemia treated with a combination of retinoic acid and arsenic trioxide-based front-line therapy.

Limited data was available for long-term follow-up in newly diagnosed acute promyelocytic leukemia (APL) patients treated with all-trans-retinoic acid (ATRA) plus intravenously arsenic trioxide (ATO)-based front-line therapy. The aim of this work was to retrospectively analyze the long-term survival rate and frequency of therapy-related myeloid neoplasia (t-MN) occurring in a large cohort of APL patients. A total of 760 newly diagnosed patients with APL between January 1999 and May 2016 were evaluated. The early death rate was 9.2% (70/760). Of the remaining 690 patients with complete remission, patients were grouped according to front-line regimens: ATRA plus ATO with or without chemotherapy (ATO group) and ATRA with chemotherapy (non-ATO group). The median duration of follow-up was 7.5 years (1.0-18.3 years). ATO group showed significant superior 10-year estimated relapse-free survival (RFS) up to 90.3% comparing with 65.5% in the non-ATO group (P < 0.0001). In addition, the 10-year estimated overall survival (OS) was 93.9% for patients in the ATO group and 89.1% for those in the non-ATO group (P = 0.03). In the subgroup analysis, the RFS rate was also higher in ATO group comparing with non-ATO group in both low-to-intermediate-risk (94.2% vs 64.6%, P < 0.0001) and high-risk subgroup (89.6% vs 74.7%, P = 0.04). Notably, the 3-year RFS and OS rates in the chemotherapy-free subgroup of the low-to-intermediate-risk patients (n = 88) were 100% and 100%, respectively. In the entire cohort, a total of 10 patients developed secondary malignant neoplasms, including 7 patients with therapy-related myeloid neoplasms (t-MN). The estimated 5-year cumulative incidence risk of t-MN in the ATO and non-ATO groups was 1.0% and 0.4%, respectively (P = 0.34). Thus, our data revealed that the long-term outcome of patients treated with ATRA plus ATO-based regimens was associated with continuing high efficacy in all Sanz risk patients with newly diagnosed APL.

Prognostic impact of MYH9 expression on patients with acute myeloid leukemia.

MYH9 expression has previously been demonstrated as an independent predictor of clinical outcome in solid tumors. However, the prognostic relevance of MYH9 expression in acute myeloid leukemia is still unclear. Here, we found high MYH9 expressers were seen more frequently in females and more frequently in M4 morphology. We also found high MYH9 expressers had lower percentage of bone marrow blasts. In addition, overexpression of MYH9 was associated with an inferior overall survival. Notably, distinct microRNA signatures were seen in high MYH9 expressers. These results were also validated in an independent cohort of AML patients using the published data. In conclusion, gene of MYH9 expression might serve as a reliable predictor for overall survival in AML patients.

Homoharringtonine binds to and increases myosin-9 in myeloid leukaemia.

BACKGROUND AND PURPOSE: Homoharringtonine (HHT) is a natural alkaloid isolated from various Cephalotaxus species. HHT has been used to treat acute myeloid leukaemia (AML), chronic myeloid leukaemia (CML), chronic lymphocyte leukaemia and myelodysplastic syndromes. Although HHT inhibits protein synthesis and promotes apoptosis of leukaemia cells in preclinical studies, its molecular target proteins remain unknown. The aim of this study was to identify target proteins of HHT. EXPERIMENTAL APPROACH: We have synthesized a biotinylated affinity column and used it to identify targets of HHT and confirmed the results by MS and Western blots. We also examined the effects of HHT on the target protein and determined roles of the target protein in anti-leukaemia activities of HHT through Western blots, flow cytometry and retrovirus transfection. KEY RESULTS: Myosin-9, a member of the myosin super-family, was identified as a direct interactor of HHT. Furthermore, HHT up-regulated the expression level of myosin-9 in both AML and CML cell lines in a time-dependent manner. Thus, HHT-induced apoptosis of leukaemia cells begins in 6 h and continues to increase for 24 h. There is a positive correlation between up-regulated myosin-9 expression level and increased percentage of apoptotic cells mediated by HHT. Overexpression of myosin-9 could increase the sensitivity of the leukaemia cells to the cytotoxicity of HHT and arrest cells in S and G2/M phases. CONCLUSIONS AND IMPLICATIONS: Our results indicated that myosin-9 was the target protein of HHT and played an important role in the HHT-induced apoptosis of leukaemia cells.

High IDH1 expression is associated with a poor prognosis in cytogenetically normal acute myeloid leukemia.

The prognostic value of IDH1 mutations has been systematically evaluated in acute myeloid leukemia (AML) patients recently. However, the role of IDH1 expression in AML is still under exploration. To investigate the clinical significance, we analyzed the IDH1/2 expression in 320 patients with cytogenetically normal AML (CN-AML) by quantitative real-time reverse-transcription polymerase chain reaction. High expression of IDH1 was predominant in patients with FLT3-ITD and DNMT3A mutations and less prevalent in cases with CEBPA double allele mutations. Strong association was observed between high IDH1 expression and low expression of microRNA 181 family. Prognosis was adversely affected by high IDH1 expression, with shorter overall survival and event-free survival in the context of clinical characteristics, including age, WBC count, and gene mutations of NPM1, FLT3-ITD, CEBPA, IDH1, IDH2 and DNMT3A in CN-AML. Moreover, the clinical outcome of IDH1 expression in terms of overall survival, event-free survival and complete remission rate still remained in multivariate models in CN-AML. Importantly, the prognostic value was validated using the published microarray data from 79 adult patients treated according to the German AMLCG-1999 protocol. Our results demonstrated that high IDH1 expression is associated with a poor prognosis of CN-AML.

The risk of hepatitis B virus reactivation and the role of antiviral prophylaxis in hepatitis B surface antigen negative/hepatitis B core antibody positive patients with diffuse large B-cell lymphoma receiving rituximab-based chemotherapy.

The risk factors and the role of prophylactic antiviral therapy of hepatitis B virus (HBV) reactivation in patients with hepatitis B surface antigen (HBsAg) negative/hepatitis B core antibody (HBcAb) positive disease remain controversial. We reviewed 629 patients with diffuse large B-cell lymphoma (DLBCL). Among 629 patients, 150 of 246 patients with resolved HBV (HBsAg negative and HBcAb positive) were treated with rituximab-combined therapy. Among these 150 patients, none of 104 patients (0.0%) who were hepatitis B surface antibody (HBsAb) positive experienced HBV reactivation versus four of 46 patients (8.7%) who were HBsAb negative (p = 0.008). One of 113 patients (0.9%) with International Prognostic Index (IPI) 0-2 suffered HBV reactivation versus three of the remaining 37 patients (8.1%) with IPI 3-5 (p = 0.047). HBsAb and IPI are potential risk factors for HBV reactivation. The use of prophylactic agents may not be recommended for these patients until the occurrence of HBV reactivation.

[Clinical significance of TET2 gene expression in 157 adult acute myeloid leukemia patients with normal cytogenetics].

OBJECTIVE: To explore the clinical significance of ten-eleven-translocation methylcytosine dioxygenase 2 (TET2) mRNA expression levels in adult acute myeloid leukemia patients with normal cytogenetics (CN-AML). METHODS: Expression levels of TET2 mRNA were measured by real-time PCR in 157 adult CN-AML, and its clinical impact in CN-AML was evaluated as well. RESULTS: TET2 gene expression levels from bone marrow mononuclear cells (BMMNCs) [7.29(3.41-9.99)] and CD34+ cells [6.02(5.64-6.54)] in CN-AML were significantly lower than those [BMMNCs: 8.13(6.68-9.04), P=0.026; CD34+ cells: 6.48(5.97-7.12), P=0.034] in healthy control. And TET2 mRNA level at diagnosis [7.32(6.11-8.41)] was obviously lower than that at complete remission [8.39(7.76-8.79), P<0.01]. CN-AML patients with lower levels of TET2 mRNA showed worse survival rate [(32.7±5.9)%] at 18-month than those with higher levels [(48.6±6.9)%, P=0.041]. In multivariate analysis, lower level of TET2 mRNA was an independent prognostic factor for OS [hazard ratio(HR)2.032, 95% confidence interval (CI)1.272-3.247, P=0.003] and event-free survival [HR 1.532, 95% CI 1.014-2.314, P=0.043]. CONCLUSION: The level of TET2 mRNA is significantly lower in patients with CN-AML and it is an independent negative prognostic factor. TET2 could be an important factor for the molecular-based risk stratification in CN-AML.