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Diffuse large B-cell lymphoma (DLBCL) is the most common invasive type of non-Hodgkin lymphoma. Cell-of-origin (COO) classification is related to patients’ prognoses. Primary drug resistance in treatment for DLBCL has been observed. The specific serum biomarkers in these patients who suffer from relapsed and refractory (R/R)-DLBCL remains unclear. In the current study, using single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF), we determined and verified immune cell biomarkers at the mRNA and protein levels in single-cell resolution from 18 diagnostic PBMC specimens collected from patients with R/R DLBCL. As controls, 5 PBMC specimens from healthy volunteers were obtained. We identified a panel of 35 surface marker genes for the features of R/R DLBCL unique cell cluster by scRNA-seq of 8 R/R DLBCL patient samples and validated its efficiency in an external cohort consisting of 10 R/R DLBCL patients by CyTOF. The cell clustering and dimension reduction were compared among R/R DLBCL samples in CyTOF Space with COO as well as the C-MYC expression designation. Immune cells from each patient occupied unique regions in the 32-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Significant heterogeneity observed in subgroups was mainly attributed to individual differences among samples and not to expression differences in a single, homogeneous immune cell subpopulation. The marker panel showed reliability in labeling R/R DLBCL without any influence from COO stratification and C-MYC expression designation. Furthermore, we compared all the markers between R/R DLBCL and normal samples. A total of 12 biomarkers were significantly overexpressed in R/R DLBCL relative to the normal samples. Therefore, we further optimized the diagnostic biomarker panel of R/R DLBCL comprising CD82, CD55, CD36, CD63, CD59, IKZF1, CD69, CD163, CD14, CD226, CD84, and CD31. In summary, we developed a novel set of biomarkers for the diagnoses of patients with R/R DLBCL. Detections procedures at single-cell resolution provide precise biomarkers, which may substantially overcome intertumoral and intratumoral heterogeneity among primary samples. The findings confirmed that each case was unique and may comprise multiple, genetically distinct subclones.

De novo CD5 + diffuse large B-cell lymphoma (DLBCL) has poor survival in the era of immunochemotherapy. Accurate gene-based typing and prognostic stratification can enhance the development of effective individualized treatments. Therefore, we conducted a multicenter retrospective study to evaluate the clinicopathologic characteristics, genomic profiles, and prognostic parameters of 61 patients with CD5 + DLBCL and 60 patients with CD5 - DLBCL, with the goal of facilitating accurate prognostic stratification and potential individualized treatment strategies. Compared with patients with CD5 - DLBCL, older age, advanced stage, higher incidence of central nervous system involvement, and MYC/BCL-2 and p53 overexpression were more prevalent in CD5 + DLBCL. Most patients with CD5 + DLBCL had lymph nodes with non-germinal center B-cell-like or activated B-cell-like subtype according to immunohistochemistry or Lymph2Cx assay. Next-generation sequencing showed that the proportion of MCD subtype (based on the co-occurrence of MYD88 and CD79B mutations) in the CD5 + DLBCL cohort was higher than that in the CD5 - DLBCL cohort (54.2% vs. 13.0%, P =0.005). Compared with the CD5 - cohort, CD5 + DLBCL patients showed poor 5-year overall survival (70.9% vs. 39.0%, P0.001). Kaplan-Meier survival analysis indicated that cell of origin, MYC/BCL-2, p53, and BCL-6 expression did not have a prognostic impact on patients with CD5 + DLBCL. Multivariate analysis showed that age above 76 years, advanced stage, higher incidence of central nervous system involvement, and hypoalbuminemia were independent factors for poor prognosis in CD5 + DLBCL patients. In summary, CD5 + DLBCL displays poor prognosis, distinctive clinicopathologic characteristics and predominant genetic features of activated B-cell-like and MCD subtypes with worse survival outcome.

Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with Epstein-Barr encoding region (EBER) status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cutoff points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV DNA in natural killer T-cell lymphoma (NKTL) patients was higher than that in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and peripheral T-cell lymphoma, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the combination of EBV and EBER status could differentiate the prognosis of HL.

Introduction SCT800 is a recombinant human B-domain-deleted coagulation factor VIII (BDDrFVIII) developed in China. Aim To evaluate the repeat pharmacokinetics (PKs), efficacy, and safety of SCT800 in previously treated Chinese adolescent and adult patients with severe haemophilia A. Methods A phase III, multicentre, prospective, open-label, single-arm trial was conducted at 12 medical centres. Subjects received treatment for 24 weeks. PKs were assessed at the initial and repeated dosing 24 weeks later. The primary endpoint was annualized bleeding rate (ABR). Breakthrough bleeding episodes and inhibitor development were assessed. Results A total of 71 of 73 patients completed the study, and 18 were enrolled for the repeat PK investigation. Total exposure was 5643 exposure days. Overall, SCT800 showed comparable repeat PK profiles. The total ABR was 2.82 (95% confidence interval 2.01-3.96). During prophylaxis, 43.8% of patients had no bleeding episodes. The majority (89.4%) of bleeding episodes were controlled with 1-2 injections of SCT800, the success rate (defined as 'excellent' or 'good' haemostatic response) for the treatment of bleeding episodes was 92.6%. The incidence of treatment-related adverse events was 53.4%. Drug-related AE incidence was 4.1%. The observed AEs were similar to those of other coagulation factor VIII, but lower in frequency. No subject developed an inhibitor, and no other safety concerns were identified. Conclusions SCT800 has robust PK characteristics, and is safe and efficacious for the prophylaxis and treatment of bleeding episodes in previously treated adolescent and adult patients with severe haemophilia A.

CD5-positive diffuse large B-cell lymphoma (DLBCL) is a clinically rare subtype of DLBCL with aggressive clinical manifestations and a poor prognosis. It has been demonstrated that the prognostic nutritional index (PNI), an indicator of nutritional status and systemic inflammation, is a significant prognostic factor for several types of lymphoma. The objective of this multicenter retrospective study was to explore the prognostic value of the PNI in patients with CD5-positive DLBCL.In total, 207 patients with CD5-positive DLBCL were recruited from 11 centers of the Huaihai Lymphoma Working Group. Maximally selected rank statistics analysis was used to identify optimal cutoff points for the PNI. A Cox proportional hazards model was used for univariable and multivariable analyses. Kaplan-Meier curves were used to calculate survival rates and draw survival curves, and the log-rank test was used to compare differences between groups.The median age at diagnosis was 61 years, and the 5-year overall survival rate was 47.5%. According to the maximally selected rank statistics analysis, a score of 49.7 was the optimal cutoff point for the PNI. Subgroup analysis showed that the PNI could re-stratify patients in BCL-2-negative, MYC-negative, high-intermediate-risk and high-risk International Prognostic Index, BCL-6-positive and BCL-6-negative, high Ki-67 score (≥0.9), Ann Arbor stage III/IV, Eastern Cooperative Oncology Group performance status ≥2, and germinal center B subgroups. Multivariable analysis revealed that PNI, age, Eastern Cooperative Oncology Group performance status, albumin level, and red blood cell count were independent prognostic factors for CD5-positive DLBCL.The PNI was a significant prognostic indicator for CD5-positive DLBCL and was able to re-stratify the prognosis for clinicopathologic subgroups of patients with CD5-positive DLBCL.

PURPOSE A combination of anti–B-cell maturation antigen (BCMA) and anti-CD19 chimeric antigen receptor (CAR) T cells induced high response rates in patients with relapsed or refractory (R/R) multiple myeloma (MM), but long-term outcomes have not been assessed yet. PATIENTS AND METHODS In this single-arm, phase II trial, patients with R/R MM received a combination of anti-BCMA CAR T cells and anti-CD19 CAR T cells at a dose of 1 × 106 cells/kg, after receiving a conditioning chemotherapy consisting of cyclophosphamide and fludarabine. The overall response, long-term outcomes, and safety were assessed, as were their associations with clinical and disease characteristics. RESULTS Of 69 enrolled patients, 62 received the combined infusion of anti-BCMA and anti-CD19 CAR T cells with a median follow-up of 21.3 months. The overall response rate was 92% (57/62), and complete response or better was observed in 37 patients (60%). Minimal residual disease–negativity was confirmed in 77% (43/56) of the patients with available minimal residual disease detection. The estimated median duration of response was 20.3 months (95% CI, 9.1 to 31.5). The median progression-free survival was 18.3 months (95% CI, 9.9 to 26.7), and the median overall survival was not reached. Patients with extramedullary disease had significantly inferior survival. Fifty-nine patients (95%) had cytokine release syndrome, with 10% grade 3 or higher. Neurotoxic events occurred in seven patients (11%), including 3% grade 3 or higher. Late adverse effects were rare, except for B-cell aplasia, hypogammaglobulinemia, and infections. CONCLUSION The combination of anti-BCMA and anti-CD19 CAR T cells induced durable response in patients with R/R MM, with a median progression-free survival of 18.3 months and a manageable long-term safety profile.

Multiple myeloma (MM) remains an incurable hematologic malignancy due to its frequent drug resistance and relapse. Cluster of Differentiation 47 (CD47) is reported to be highly expressed on MM cells, suggesting that the blockade of CD47 signaling pathway could be a potential therapeutic candidate for MM. In this study, we developed a bortezomib-resistant myeloma patient-derived xenograft (PDX) from an extramedullary pleural effusion myeloma patient sample. Notably, anti-CD47 antibody treatments significantly inhibited tumor growth not only in MM cell line-derived models, including MM.1S and NCI-H929, but also in the bortezomib-resistant MM PDX model. Flow cytometric data showed that anti-CD47 therapy promoted the polarization of tumor-associated macrophages from an M2- to an M1-like phenotype. In addition, anti-CD47 therapy decreased the expression of pro-angiogenic factors, increased the expression of anti-angiogenic factors, and improved tumor vascular function, suggesting that anti-CD47 therapy induces tumor vascular normalization. Taken together, these data show that anti-CD47 antibody therapy reconditions the tumor immune microenvironment and inhibits the tumor growth of bortezomib-resistant myeloma PDX. Our findings suggest that CD47 is a potential new target to treat bortezomib-resistant MM.

Hemophagocytic lymphohistiocytosis (HLH) is an immune disorder with rapid progression and poor survival. Individual treatment strategy is restricted, due to the absence of precise stratification criteria. In this multicenter retrospective study, we aimed to develop a feasible prognostic model for adult HLH in China. A total of 270 newly diagnosed patients of adult HLH were retrieved from the Huaihai Lymphoma Working Group (HHLWG), of whom 184 from 5 medical centers served as derivation cohort, and 86 cases from 3 other centers served as validation cohort. X-Tile program and Maxstat analysis were used to identify optimal cutoff points of continuous variables; univariate and multivariate Cox analyses were used for variable selection, and the Kaplan–Meier curve was used to analyze the value of variables on prognosis. The C-index, Brier Score, and calibration curve were used for model validation. Multivariate analysis showed that age, creatinine, albumin, platelet, lymphocyte ratio, and alanine aminotransferase were independent prognostic factors. By rounding up the hazard ratios from 6 significant variables, a maximum of 9 points was assigned. The final scoring model of HHLWG-HPI was identified with four risk groups: low risk (≤3 pts), low-intermediate risk (4 pts), high-intermediate risk (5-6 pts), and high risk (≥7 pts), with 5-year overall survival rates of 68.5%, 35.2%, 21.3%, and 10.8%, respectively. The C-indexes were 0.796 and 0.758 in the derivation and validation cohorts by using a bootstrap resampling program. In conclusion, the HHLWG-HPI model provides a feasible and accurate stratification system for individualized treatment strategy in adult HLH.

Background The clinical significance of miR-17 in patients with acute myeloid leukemia (AML) remains unknown. Methods Real-time quantitative reverse transcription-polymerase chain reaction (qPCR) was performed to detect the miR-17 expression in 115 de novo AML patients, 31 patients at complete remission (CR) time, 8 patients at relapse time and 30 normal controls. Results MiR-17 was upregulated in de novo AML compared with normal controls. Patients with high expression of miR-17 had less CEBPA double mutation, less favorable ELN-risk and lower CR rate. The level of miR-17 was significantly decreased at CR phase and was returned to primary level even higher when in relapse phase. In addition, Cox regression analysis revealed that miR-17 expression retained independent prognostic significance for overall survival (OS). Moreover, the gene-expression profile analysis of miR-17 in AML obtained from TCGA database was involved in multiple biological functions and signal pathways. Among the differential expressed genes (DEGs), we identified FGL2, PLAUR, SLC2A3, GPR65, CTSS, TLR7, S1PR3, OGFRL1, LILRB1, IL17RA, SIGLEC10, SLAMF7, PLXDC2, HPSE, TCF7 and MYCL as potential direct targets of miR-17 according to in silico analysis. Conclusions High expression of miR-17 in de novo AML patients pointed to dismal clinical outcome and disease recurrence, which could serve as novel prognostic biomarker for AML patients.

Background CircPVT1's effects and mechanisms of acute lymphoblastic leukemia were explored in this research. Methods Real-time fluorescent quantitative PCR was utilized to test circPVT1 and miR-125b in ALL samples and ALL cell systems. Dual luciferase reporter assay verified the combination of circPVT1 and miR-125b. We utilized circPVAT1 as well as miR-125b's over-expression and low-expression to prove their influence on cell proliferation and invading. Results We found that more expression of circPVT1 occurred in ALL samples and ALL cell systems. CircPVT1 over-expression promoted ALL cell proliferation and migration besides invading. CircPVT1 low expression inhibited ALL cell proliferation and migration besides invading. MiR-125b was a target combination of circPVT1. CircPVT1 was able to enhance NF-κB signal pathway's expression through reducing miR-125b. Conclusions CircPVT2 can promote ALL cell proliferation and invading through miR-125b modulation of NF-κB, which would be one new potential target for ALL therapy.

BackgroundCD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is a rare subtype of DLBCL with invasive clinical features and poor prognosis. Current clinical variables based on prognostic systems for DLBCL are inadequate to accurately stratify the prognosis of CD5+ DLBCL.MethodsA total of 195 CD5+ DLBCL patients were retrospectively recruited from nine centers in Huaihai Lymphoma Working Group. MaxStat analysis was used to identify optimal cutoff points for continuous variables; univariable and multivariable Cox analyses were used for variable selection; Kaplan–Meier curve was used to analyze the value of variables on prognosis; and C-index, Brier score, and decision curve analysis were measured for predicting model performance.ResultsThe derivation and validation cohorts consisted of 131 and 64 patients. Of the whole cohort, median age at diagnosis was 61 years, of whom 100 (51.28%) were males and the 5‐year overall survival rate was 42.1%. MYC, BCL-2, and the coexpression of MYC/BCL-2 could distinguish the survival of CD5+ DLBCL. Multivariable analysis showed that age, IPI, red blood cell count, neutrophil count, MYC expression, and hepatosplenomegaly were independent predictors, and the prognostic nomogram was developed. The C‐index of the nomogram was 0.809 in the derivation and 0.770 in the validation cohort. Decision curve analysis proved that compared with IPI, the specific nomogram showed a better identification in CD5+ DLBCL.ConclusionThe proposed nomogram provided a valuable tool for prognosis prediction in patients with CD5+ DLBCL.

Multiple myeloma (MM) is a plasma cells malignant proliferative disease, especially in aged people. LncRNAs have been considered as important regulators in MM. This research was to study the effect of LncRNA MALAT1 on the proliferation and adhesion of myeloma cells and whether Long non-coding RNAs MALAT1(LncRNA MALAT1) plays its regulative role through Hippo-YAP signaling pathway by targeting miR-181a-5p. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis was used to detect the LncRNA MALAT1/miR-181a-5p expression and improve the transfection efficiency. Western blot analysis was used to analyze the expression of proliferation and apoptosis related proteins and Hippo-Yes-associated protein (YAP) signaling pathway related proteins. Cell proliferative ability and cell apoptosis were respectively determined by Cell Counting Kit-8 (CCK-8) assay and flow cytometry analysis. ELISA assay was for the determination of adherence factors. Immunohistochemistry was to detect the expression of proliferation and adhesion related proteins. LncRNA MALAT1 targeting gene was determined by Dual-luciferase reporter assay. LncRNA MALAT1 was increased in MM cells and LncRNA MALAT1 interference could inhibit cell proliferation and promote cell apoptosis with the changes in the related proteins. Also, LncRNA MALAT1 interference could inhibit cell adhesion through Hippo-YAP signaling pathway. MiR-181a-5p was demonstrated to be a target of LncRNA MALAT1 and miR-181a-5p overexpression could also regulate the changes in cellular behavior in accordance with the LncRNA MALAT1 interference. In addition, LncRNA MALAT1 interference could decrease the expression of miR-181a-5p and inhibit the growth of tumor. In conclusion, this study showed that LncRNA MALAT1 interference inhibited the proliferation and adhesion of myeloma cells by the up-regulation of miR-181a-5p through activating the Hippo-YAP signaling pathway.

Ziyuan Shen,1,&ast; Fei Wang,2,&ast; Chenlu He,1,&ast; Dashan Li,3 Shanlin Nie,3 Zhenzhen Bian,3 Mingkang Yao,4 Yuhao Xue,5 Ying Wang,6 Weiying Gu,2 Taigang Zhu,7 Yuye Shi,5 Hao Zhang,4 Shuiping Huang,1,8 Yuqing Miao,9 Wei Sang3 On behalf of the Huaihai Lymphoma Working Group1Department of Epidemiology and Biostatistics, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Department of Hematology, The First People’s Hospital of Changzhou, Changzhou, Jiangsu, People’s Republic of China; 3Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 4Department of Hematology, Affiliated Hospital of Jining Medical University, Jining, Shandong, People’s Republic of China; 5Department of Hematology, The First People’s Hospital of Huaian, Huaian, Jiangsu, People’s Republic of China; 6Department of Personnel, Suqian First Hospital, Suqian, Jiangsu, People’s Republic of China; 7Department of Hematology, The General Hospital of Wanbei Coal-Electric Group, Suzhou, People’s Republic of China; 8Center for Medical Statistics and Data Analysis, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 9Department of Hematology, Yancheng First People’s Hospital, Yancheng, Jiangsu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei SangDepartment of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of ChinaTel +8613645207648Email xyfylbl515@xzhmu.edu.cnYuqing MiaoDepartment of Hematology, Yancheng First People’s Hospital, Yancheng, Jiangsu, People’s Republic of ChinaTel +8613851342032Email miaomiaomyq@163.comIntroduction: Immunonutritional status is associated with the survival of DLBCL. This multicenter retrospective study aimed to explore the prognostic value of Prognostic Nutrition Index (PNI) in DLBCL patients by using propensity score matched analysis (PSM).Methods: A total of 990 DLBCL cases were recruited from 5 centers of Huaihai Lymphoma Working Group (HHLWG). A 1:1 PSM analysis was performed using the nearest-neighbor method, with a caliper size of 0.02. Cox regression analysis was used to examine factors associated with survival.Results: The median age at diagnosis was 62 years and 52.5% were males, with the 3-y overall survival of 65.1%. According to the MaxStat analysis, 44 was the optimal cut-off point of PNI. After PSM analysis, a total of 282 patients in PNI < 44 group could be propensity matched to PNI ≥ 44 patients, creating a group of 564 patients. Multivariable analysis revealed that PNI, age, central nervous system involvement and International Prognostic Index (IPI) were independent prognostic factors for DLBCL. Kaplan–Meier analysis indicated that patients with low PNI in Ann Arbor Stage (III/VI), ECOG (< 2), IPI (LR+LIR), GCB, and BCL-2 negative groups had a poor prognosis.Discussion: PNI could accurately stratify the prognosis of DLBCL after PSM analysis.Keywords: diffuse large B-cell lymphoma, prognostic nutrition index, propensity score matched, prognosis

Elevated Epstein-Barr virus (EBV) DNA load is common in lymphomas. However, it remains unclear whether the disparity in viral load and its prognostic value in lymphomas are correlated with Epstein-Barr encoding region (EBER) status. In this retrospective multicenter study, we collected the data of pretreatment whole blood EBV DNA (pre-EBV DNA) and EBER status and evaluated their disparity and prognostic values in lymphomas. A total of 454 lymphoma patients from December 2014 to August 2020 were retrospectively retrieved. Mann-Whitney U test, Kruskal-Wallis test and Bonferroni's adjustment were used to explore the disparity of EBV DNA and EBER status in lymphomas. Time-dependent receiver operating characteristic analysis and MaxStat analysis were used to determine optimal cutoff points of pre-EBV DNA load. Univariable and multivariable Cox proportional hazards models were established for the estimation of prognostic factors. The positive rate of EBV DNA in natural killer T-cell lymphoma (NKTL) patients was higher than that in diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL) and Hodgkin lymphoma (HL) patients, and the median positive pre-EBV copy number of NKTL was also higher than that of FL and DLBCL. EBV DNA could clearly distinguish the prognosis of DLBCL, NKTL, HL and peripheral T-cell lymphoma, and the integration of EBER status and EBV DNA could differentiate the prognosis of HL patients. Multivariable results revealed that pre-EBV DNA load had an effect on the prognosis of NKTL, FL and DLBCL. The status of pre-EBV DNA and EBER were disparate. Whole blood pre-EBV DNA predicted the prognosis of lymphomas, and the combination of EBV and EBER status could differentiate the prognosis of HL.

Despite the significant advances in the treatment of multiple myeloma (MM), this disease is still considered incurable because of relapse and chemotherapy resistance, underscoring the need to seek novel therapies with different mechanisms. Anlotinib, a novel multi-targeted tyrosine kinase inhibitor (TKI), has exhibited encouraging antitumor activity in several preclinical and clinical trials, but its effect on MM has not been studied yet. In this study, we found that anlotinib exhibits encouraging cytotoxicity in MM cells, overcomes the protective effect of the bone marrow microenvironment and suppresses tumor growth in the MM mouse xenograft model. We further examined the underlying molecular mechanism and found that anlotinib provokes cell cycle arrest, induces apoptosis and inhibits multiple signaling pathways. Importantly, we identify c-Myc as a novel direct target of anlotinib. The enhanced ubiquitin proteasomal degradation of c-Myc contributes to the cell apoptosis induced by anlotinib. In addition, anlotinib also displays strong cytotoxicity against bortezomib-resistant MM cells. Our study demonstrates the extraordinary anti-MM effect of anlotinib both in vitro and in vivo, which provides solid evidence and a promising rationale for future clinical application of anlotinib in the treatment of human MM.

T cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer with dismal prognosis. Recent studies disclosed that circPVT1 played an oncogene role in various cancers. But its role in T-ALL is still unclear. In this study, we found the expression levels of circPVT1 in bone marrows and cell lines of T-ALL were significantly up regulated and knock-down of circPVT1 in T-ALL cell lines could inhibit the cell proliferation and increase the cell apoptosis. Further analysis showed that circPVT1 could bind directly to miR-30e and contributed to the activate the Notch signaling by regulating miR-30e/DLL4 pathway. The levels of circPVT1 were obviously related to cumulative relapse rate and 5-year survival rate. In conclusion, our study reveals that circPVT1 participates in the progression of T-ALL through the miR-30e/DLL4 pathway and might represent a potential therapeutic target for T-ALL treatment.

The diagnostic hallmark of acute promyelocytic leukemia (APL) is the reciprocal translocation t(15;17), resulting in the characteristic PML-RARA fusion; however, patients occasionally have masked PML-RARArearrangements. We report an APL case with no evidence of t(15;17) or PML-RARA rearrangement by karyotype or commercial reverse transcription polymerase chain reaction analyses. Fluorescence in situ hybridization detected a small RARA insertion signal within PML. mRNA sequencing identified a novel PML-RARA transcript generated from the juxtaposition of PMLIIa (exons 1–4, 6, and 7ab) and RARA exons (3–9), with novel breakpoints in PML exon 7b and RARA exon 3. The patient achieved molecular remission after the second consolidation chemotherapy and remains in complete remission 22 months after initial presentation. This is the first report of an APL case presenting with submicroscopic ins(15;17) and simultaneous novel breakpoints in both PML and RARA. This case highlights the importance of sequence analysis to confirm APL diagnosis and for subsequent monitoring of minimal residual disease.

Anthracycline chemotherapy is commonly used in the treatment of diffuse large B-cell lymphoma (DLBCL). Treatment-related cardiotoxicity (TRC) is defined as when the patient is identified to have one of the following clinical manifestations: Symptomatic heart failure, cardiac death, arrhythmia, infarction, a decrease in left ventricular ejection fraction (LVEF) of >15% from baseline or a decrease in LVEF of >10 to 1 for predicting TRC after anthracycline chemotherapy (P

Patient: Female, 50-year-old Final Diagnosis: Chronic myeloid leukaemia Symptoms: Dizziness • weakness Medication: — Clinical Procedure: — Specialty: Hematology Objective: Unusual clinical course Background: Although the V617F mutation in the Janus kinase 2 (JAK2) gene and the breakpoint cluster region-abl1 (BCRABL1) oncogene fusion have been considered mutually exclusive in most myeloproliferative neoplasms (MPNs), many recent studies have described patients with both. This report describes a patient with chronic myelogenous leukemia (CML) and the unusual JAK2 R795S mutation and reviews 23 additional patients with JAK2 gene mutations coexisting with myelofibrosis (MF) and CML. Case Report: A 50-year-old woman with MF experienced rapid disease progression 3 weeks later, accompanied by severe abdominal pain and a white blood cell count of 257.45×109/l. Karyotype analysis indicated that she was 46, XY, Philadelphia (Ph) (+) and BCR-ABL1 positive. Bone marrow aspiration after 1 cycle of chemotherapy and treatment with dasatinib showed that her marrow was hypercellular, with an increased number of megakaryocytes and 48.5% myeloblasts expressing the myeloid antigens CD33, CD13, CD34, CD117, and CD71. Next-generation sequencing identified a rare JAK2 R795S mutation. She was diagnosed with CML in blast phase, and was successfully treated with allogeneic hematopoietic stem cell transplantation (allo-HSCT). Conclusions: JAK2 gene mutations, including the rare JAK2 R795S mutation, can coexist with BCR-ABL1 in patients with MPNs. The clinical course of MPN in patients with both BCR-ABL1 and JAK2 mutations may be different from that in patients with classical MPNs.

Background: Anthracycline chemotherapy is commonly used in the treatment of diffuse large B-cell lymphoma (DLBCL) patients. Treatment-related cardiotoxicity (TRC) may be observed during treatment and may induce severe cardiac failure or cardiac arrhythmia as the main cause of death, even several years after chemotherapy implementation. Herein, we performed a study to investigate the prognostic value of gated myocardial perfusion imaging (G-MPI) summed rest score (SRS) for the early detection of TRC caused by anthracycline chemotherapy in DLBCL patients.Methods: A total of 36 DLBCL patients were enrolled, and a series of parameters from the same individual patient were compared between baseline and after the end of the 6th R-CHOP chemotherapeutic regimen. According to whether TRC occurred during the observation period, the patients were divided into two groups, and parameters related to cardiac function were compared.Results: SRS in G-MPI and QTc interval in electrocardiogram were significantly different before and after chemotherapy (P = 0.012 and P = 0.015, respectively).By comparing parameters related to cardiac function between the TRC group (n = 22) and the no-TRC group (n = 14), only SRS was significantly different (P = 0.012). Multivariate logistic regression analysis showed that the SRS level was the only independent predicator for TRC (P = 0.018, HR = 6.053, 95% CI: 1.364-26.869). Receiver operating characteristic curve analysis identified an optimal SRS cutoff of >1for predicting TRC after anthracycline chemotherapy (P＜ 0.001).Conclusion: The G-MPI SRS level was an early indicator for TRC surveillance in DLBCL patients after anthracycline chemotherapy, thus contributing to early treatment and a subsequent decrease in mortality caused by such cardiovascular complications.

Objective: In this study, we aimed to investigate the genomic differences between Chinese patients with myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), as well as the difference between Asian and Western patients. Methods: We systematically analyzed somatic alterations of fresh bone marrow aspirate or peripheral blood specimens from 58 patients with AML and 26 patients with MDS with a hybridization capture-based next-generation sequencing (NGS) panel, including 196 genes known to be somatically altered in human hematological malignancies. Results: At least one non-synonymous gene mutation was detected in 54 AML patients (93.1%) and 23 MDS patients (95.83%). Compared with AML patients aged Conclusions: In this study, we elucidated the landscape of gene mutations in Chinese AML/MDS, and we further identified significant genomic differences between Asian and Western patients, which should improve our understanding of pathogenesis and/or lead to a better selection of targeted therapies.

This study aimed to investigate clinical characteristics and prognostic significance of activation-induced cytidine deaminase (AID) gene, miR-181b and miR-155 expression in de novo adult B-cell acute lymphoblastic leukemia (B-ALL) patients. Results showed that AID and miR-155 expression were higher in B-ALL patients than healthy controls, while miR-181b expression was lower in B-ALL patients. In addition, Ph+ B-ALLs had higher AID expression than Ph- B-ALLs, and its high expression was associated with BCR-ABL. Moreover, B-ALL patients with AIDhigh or miR-181blow expression had a shorter overall survival (OS). AIDhigh with miR-181blow, AIDhigh with miR-155low, miR-181blow, miR-155low, AIDhigh with miR-181blow and miR-155low expression were associated with shorter OS. Combination of the three molecules are more accurate predictors for unfavorable OS compared with univariate group. Therefore, AID, miR-181b and miR-155 provide clinical prognosis of adult de novo B-ALL patients and may refine their molecular risk classification.