Outcome of CARE: a 6-year national registry of acquired haemophilia A in China.

Acquired haemophilia A (AHA) is a rare haemorrhagic disorder caused by autoantibodies directed against the functional epitopes of coagulation factor VIII (FVIII). Its management relies on prompt diagnosis, control of bleeding and eradication of the inhibitor by immunosuppression. China Acquired Hemophilia Registry (CARE), a nationwide multicentre registry, was intended to survey the status of AHA and standardize its diagnosis and therapy in China. One hundred and eighty-seven registered patients had an average age of 52 years. Diagnosis was delayed in 46·5% patients. There was a significant delay from diagnosis to immunosuppressive therapy in 68·3% patients. Bleeding control was significantly higher in patients treated with prothrombin complex concentrate (PCC) versus FVIII replacement therapy (84·6% vs. 34·4%; P < 0·001). Inhibitor eradication with a combination of steroids and cyclophosphamide showed a higher partial remission (PR) rate (92·2% vs. 70·3%) and stable complete remission (CR) rate (82·8% vs. 48·6%) than with steroids alone. Logistic regression model showed age and malignancy were significantly related to survival at final follow-up. The mean age for the survivors [51 years (IQR, 35-65 years)] was significantly lower than that of the non-survivors [79 years (IQR, 67-86 years)] (P < 0·001). Overall survival was higher in non-malignancy group than malignancy group (94·9% vs. 70%) (OR = 1·313; 95% CI, 0·913-1·889, P = 0·015).

Better outcomes of modified myeloablative conditioning without antithymocyte globulin versus myeloablative conditioning in cord blood transplantation for hematological malignancies: A retrospective (development) and a prospective (validation) study.

Cord blood transplantation (CBT) is an effective option for treating hematological malignancies, but graft failure (GF) remains the primary cause of therapy failure. Thus, based on myeloablative conditioning (MAC) of busulfan with cyclophosphamide (Bu/Cy) or total body irradiation with Cy (TBI/Cy), fludarabine (Flu) was added to Bu/Cy and cytarabine (CA) to TBI/Cy for a modified myeloablative conditioning (MMAC). To compare the prognosis of MMAC with MAC, we conducted a retrospective study including 58 patients who underwent CBT with MAC or MMAC from 2000 to 2011. Neutrophil and platelet engraftment rate, overall survival (OS) and disease free survival (DFS) were significantly higher in the MMAC group (adjusted hazard ratio [HR], 2.58, 2.43, 0.36 and 0.37; p < 0.01, p = 0.01, p = 0.02 and p = 0.02, separately). Nonrelapse mortality (NRM) was comparable (p = 0.183). To validate the outcomes noted in the MMAC group, we conducted a prospective single-arm clinical trial including 188 patients who underwent CBT with MMAC from 2011 to 2015. Engraftment rate, survival and NRM of the MMAC group in the prospective trail (MMAC-P) were similar to the MMAC group in the retrospective study (MMAC-R). This study is the first to demonstrate the superiority of MMAC to MAC in CBT for hematological malignancies.

All-trans retinoic acid modulates the balance of ADAMTS13 and VWF in human microvascular endothelial cells.

PURPOSE: To better understand the antithrombotic property of All-trans retinoic acid (ATRA), we investigated whether ATRA may affect the balance between ADAMTS13 and von Willebrand factor (VWF) in human microvascular endothelial cell. METHODS: Compared to tumor necrosis factor-alpha (TNF-α), we observed the effects of ATRA on the expression of ADAMTS13 and VWF. ADAMTS13mRNA in human microvascular endothelial cell (HMEC-1 cell line) were detected by real-time polymerase chain reaction amplification (RT-PCR). The levels of ADAMTS13 and VWF antigen were detected by western blot or enzyme-linked immunosorbent assay (ELISA), and the proteolytic activity of ADAMTS13 was also determined by using GST-VWF73-His peptide as a specific substrate. RESULTS: ATRA significantly upregulated the expression of ADAMTS13mRNA in HMEC-1, while TNF-α inhibited ADAMTS13mRNA expression. ATRA could reverse the inhibition expression of ADAMTS13 by TNF-α. The results were confirmed from the levels of ADAMTS13 protein and its activity, while ATRA had no significant affection on triggering release of VWF. CONCLUSIONS: This study provides the evidence that ATRA modulates the balance of ADAMTS13 and VWF in human microvascular endothelial cell, which might be a very relevant compartment for the antithrombotic property of ATRA.

[The clinical value of F-18 FDG PET/CT in patients with secondary hemophagocytic syndrome].

The aim of this study was to investigate the role of F-18 fluoro-2-deoxyglucose positron emission tomography/computed tomography (F-18 FDG PET/CT) in diagnosis and prognostic evaluation of secondary hemophagocytic syndrome (HPS). A total of 11 secondary HPS patients examined with 18F-FDG-PET/CT were retrospectively analyzed. The diagnostic value of F-18 FDG PET/CT for malignancy detection was assessed. The values of maximum standardized uptake value (SUV(max)) in spleen (SUVS(p)) and in bone marrow (SUVBM) were measured to analyze their relationship with various laboratorial parameters and clinical outcome of secondary HPS patients. The results showed that 4 out of the 11 patients had malignancies, the sensitivity, specificity and diagnostic accuracy of F-18 FDG PET/CT for malignancy detection were 100%, 66.7% and 75% respectively, the SUV(max) of spleen and bone marrow showed no significant correlation with laboratorial parameters, a maximum SUVS(p) of 3.10 and a maximum SUVBM of 3.47 were the optimal cutoffs for predicting patients' outcome, the increased uptake of F-18 FDG in the BM and spleen were significantly associated with shorter survival time according to univariate analysis. It is concluded that 18F-FDG PET/CT may especially play an important role in diagnosis and predicting outcome of secondary HPS for the small sample size.

Tailored central nervous system-directed treatment strategy for isolated CNS recurrence of adult acute myeloid leukemia.

OBJECTIVES: The aim of this report was to investigate the tailored treatment strategies for isolated central nervous system (CNS) recurrence in adult patients with acute myeloid leukemia (AML). METHODS: Isolated CNS recurrence was documented in 34 patients: there were 18, 6, and 10 patients with meningeal involvement type (type A), cranial nerve palsy type (type B), and myeloid sarcoma type (type C), respectively. For patients with type A, intrathecal chemotherapy was the predominant strategy. For type B, systemic HD-Ara-C with four cycles was the main treatment. For type C, cranial irradiation or craniospinal irradiation was adopted and two cycles of HD-Ara-C were given after the irradiation. RESULTS: The 5-year cumulative incidence of CNS recurrence was 12.8%. There was a significantly higher WBC count (32.6∼60.8 × 10(9)/l) in patients at first diagnosis who developed CNS recurrence (all of the three types) compared with patients with no CNS recurrence (10.1 × 10(9)/l) (P = 0.005). We found that a significantly more patients with AML-M5 and 11q23 abnormalities developed CNS recurrence in type A (P < 0.001, 0.005). Twenty-four out of 34 patients (70.6%) with CNS recurrence achieved CNS complete remission at a median of 58 days (range, 30-120). The 3-year disease-free survival and overall survival estimates for all CNS recurrence patients were 21.6 and 25.3%, respectively. DISCUSSION: This report indicates that the tailored CNS-directed strategy is an effective modality to treat CNS recurrence in adult AML, but further studies are needed to improve the long-term survival.

Lack of association between COMT Val158Met polymorphism and prostate cancer susceptibility.

BACKGROUND: The relationship of prostate cancer (PCa) with the presence of catechol-O-methyltransferase (COMT) genetic polymorphism Val158Met (158G/A) has been reported with inconsistent results. The objective of this study was to quantitatively evaluate the association between Val158Met polymorphism and PCa susceptibility. METHODS: Two investigators independently searched Medline and the Cochrane Library up to July 18, 2012. Pooled odds ratio and 95% confidence interval were calculated using a fixed or random-effects model. Statistical analysis was performed with Review Manage 5.0 and Stata 11. RESULTS: Of the 7 case-control studies selected for this meta-analysis, a total of 2,292 PCa cases and 2,485 controls were included. The combined results based on all studies suggested that Val158Met was not associated with PCa risk under all genetic models. When stratifying for race, no noteworthy associations were observed in Asians or Caucasians. CONCLUSION: This meta-analysis suggests that COMT Val158Met polymorphism might not be a risk factor for PCa risk. However, further well-designed studies are required to confirm our findings.

(Bortezomib plus lenalidomide/thalidomide)- vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma: a meta-analysis of randomized controlled trials.

The aim of the study was to perform a meta-analysis of the efficacy and safety of (bortezomib plus lenalidomide/thalidomide)- vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma. We searched electronic and printed sources for relevant articles published. Inclusion criteria was as follows: randomized controlled trials (RCT) of (bortezomib plus lenalidomide/thalidomide) vs. (bortezomib or lenalidomide/thalidomide)-containing regimens as induction therapy in newly diagnosed multiple myeloma. Two reviewers independently assessed potentially eligible studies and extracted relevant data. We retrieved five RCT studies including a total of 1,200 patients. Using the random-effects model to pool the five RCT with a statistically significant heterogeneity (P = 0.03; X² = 10.69; df = 4; I² = 63%), the weighted risk ratios of a complete response (CR) for (bortezomib plus lenalidomide/thalidomide)-containing regimens was 1.81 (P = 0.005; 95% CI: 1.20-2.73). When we excluded the study by Cavo et al. (Lancet 376:2075-2085, 2010), the pooled risk ratio for CR was 1.59 (P < 0.0001, 95% CI: 1.29-1.96) with no statistically significant heterogeneity (P = 0.54; X² = 2.14; df = 3; I² = 0%) among four RCT under the fixed effects mode. The pooled odds ratio for the main grade III/IV adverse events (the peripheral neuropathy, thrombotic events, and infections) were 1.76 (P = 0.32; 95% CI: 0.58-5.31), 0.92 (P = 0.76, 95% CI: 0.52-1.61), and 1.05 (P = 0.82, 95% CI: 0.70-1.57), respectively. Our analysis showed (bortezomib plus lenalidomide/thalidomide)-containing regimens as induction treatment in newly diagnosed multiple myeloma improved CR but did not increase the risk of major adverse events (the peripheral neuropathy, thrombotic events, and infections).

[Expression of c/ebpα gene in MDS and its clinical significance].

This study was aimed to investigate the expression of CCAAT/enhancer binding protein alpha gene (c/ebpα) in patients with myelodysplastic syndromes (MDS) and to explore the significance of c/ebpα in pathogenesis and progression of MDS. Real time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) method was used to detect the expression level of c/ebpα mRNA in bone marrow mononuclear cells (BMMNC) of 33 patients with MDS and 14 normal controls. The results showed that the expression level of c/ebpα mRNA in low-risk and high-risk MDS was significantly lower than that of normal controls (p < 0.01, p < 0.001, respectively), moreover, high-risk MDS showed lower c/ebpα mRNA expression compared with low-risk MDS (p < 0.05). c/ebpα mRNA expression level in MDS was not correlated with sex, age and peripheral blood cell amount, while the ratio of blast cells in bone marrow was in the c/ebpα mRNA low expression group significantly higher than that in the high expression group (p < 0.01). It is concluded that down-regulation of c/ebpα mRNA expression level has closely associated with the pathogenesis of MDS, the c/ebpα may be an important molecular biological marker of MDS; the degree of down-regulated c/ebpα has closely related to the progression of MDS.

[Correlative study between JAK2 mutation and thrombosis in patients with myeloproliferative neoplasm].

OBJECTIVE: To investigate the frequency and clinical implication of JAK2 mutation in patients with myeloproliferative neoplasm(MPN)and the correlation between the mutation and thrombosis. METHODS: The clinical and laboratory data of 107 MPN patients was retrospectively analyzed. JAK2 mutation were detected with allele-specific polymerase chain reaction (AS-PCR) and sequencing. The significance of the mutation in disease diagnosis and molecular pathogenesis and the correlation between the mutation and thrombosis was analysed. RESULTS: JAK2 mutation was detected in 71 (66.4%) and thrombosis in 34 (31.8%) of the 107 MPN patients. Thrombosis occurred in 34.8% (16/46) of polycythemia vera (PV), 32.6% (14/43) of essential thrombocythemia (ET), and 22.2% (4/18) of primany myelofibrosis (PMF) patients. The difference among the 3 groups was not significant (χ(2) = 0.96, P > 0.05). The frequency of thrombosis in JAK2(+) MPN patients (82.4%, 28/34) was higher than that in JAK2(-) MPN patients (17.6%, 6/34) (χ(2) = 5.71, P < 0.05). The frequency of thrombosis in MPN patients > 60 years was higher (41.5%, 27/65) than that in patients < 60 years (16.7%, 7/42) (χ(2) = 7.28, P < 0.01). CONCLUSION: JAK2 V617F mutation occurs in significant percentage of Chinese patients with MPN. Patients with JAK2 mutation and older age are more succeptible to thrombosis. JAK2 mutation screening in patients with unknown thrombosis is helpful to reveal the underlying latent-MPN.

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia?

Corticosteroids are essential and one of the mainstays in the treatment of acute lymphoblastic leukemia (ALL). In vitro assays show that dexamethasone(DXM) is five to six times more cytotoxic to leukemic lymphoblasts than prednisolone (PDN) [1], and the use of DXM as an alternative drug for PDN is an important issue in the treatment of childhood ALL. The current randomized comparisons in childhood ALL indicated a statistically significant and clinically important decrease in rate of isolated central nervous system (CNS) relapses and an increase in event-free survival (EFS) with DXM. However, the data were limited in adult ALL. Recently, Labar et al. [2] reported their first investigation in comparison of the antileukemic activity and toxicity between DXM and PDN for adult patients with ALL and lymphoblastic lymphoma (LBL) through a randomized clinical trial (the ALL-4 trial of the EORTC Leukemia Group), and the author concluded that DXM as a steroid therapy for adult patients with ALL/LBL did not show any benefit compared with PDN, which did not support the experience from several other pediatric studies. In Labar's observation, about 70% of adult patients were high risk (HR) ALL. Most of the patients in pediatric trials were standard risk (SR) ALL. In our study, we also evaluate the role of DXM compared with PDN during induction or subsequent phases of therapy in adult ALL with emphasis on SR group.

[Effects of soluble secreted by acute myeloid leukemia cells on differentiation, maturation, apoptosis, and functions of dendritic cells].

BACKGROUND & OBJECTIVE: Dendritic cells (DCs) play an important role in the immunosurveillance against cancer. It has been shown that the function of DCs is impaired and their population decreases in cancer-bearing hosts. Recent observations suggest that the inability of DCs could be a result of the immunosuppression mediated by soluble factors secreted by tumor cells. This study was to investigate the effects of soluble factors secreted by acute myeloid leukemia (AML) cells on the differentiation, maturation, apoptosis, and functions of DCs derived from normal mononuclear cells. METHODS: Mononuclear cells were cultured with interleukin-4 (IL-4) and granulocyte-macrophage colony-stimulating factor (GM-CSF), in the presence or absence of 24-hour culture supernatants from fresh primary AML cells, to generate immature DCs. The maturation of DCs was induced by cytokines IL-1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha), and prostaglandin-2 (PGE-2). The phenotypic and apoptotic alterations of DCs were evaluated using flow cytometry. Precursor frequency (PF) was calculated to monitor the allostimulatory effects of DCs on CD4+ and CD8+ T cells. RESULTS: AML cell supernatant-treated DCs showed significantly lower expression of co-stimulatory molecules CD80 and CD86, and reduced response to cytokines IL-1beta, IL-6, TNF-alpha, and PGE-2. The apoptosis rate was significantly lower in AML cell supernatant-treated DCs than in control DCs [(29.4+/-9.5)% vs. (15.1+/-4.2)%, P<0.01]. The allostimulatory effects of AML cell supernatant-treated DCs on CD4+ and CD8+ T cells were significantly lower than those of normal mature DCs [PF: (1.8+/-0.5)% vs. (5.2+/-1.6)% for CD4+ T cells, (2.1+/-0.6)% vs. (6.5+/-2.0)% for CD8+ T cells, P<0.01]. CONCLUSION: Soluble factors derived from AML cells could inhibit development and functions of DCs.

[Treatment of two case childhood acute lymphoblastic leukemia by HLA-mismatched unrelated umbilical cord blood transplantation].

OBJECTIVE: To explore the hematopoietic and immunologic reconstitution and transplantation-related complications of HLA one locus mismatched unrelated umbilical cord blood transplantation for the treatment of hematological malignancies. METHODS: Two children with acute lymphoblastic leukemia received HLA-mismatched unrelated umbilical cord blood transplantation. The conditioning regimens were BU-CTX (case 1) and BU-CTX plus BCNU (case 2). GVHD prophylaxis regimen consisted of cyclosporine (CsA) and mycophenolate mofetil (MMF). The patients received 14.6 x 10(7) nucleated cells/kg with 7.24 x 10(5) CD(34)(+) cells/kg and 16.24 x 10(7) nucleated cells/kg with 21.11 x 10(5) CD(34)(+) cells/kg, respectively. RESULTS: The two recipients, ANC > 0.5 x 10(9)/L occurred at day 27 and day 17, BPC > 50 x 10(9)/L at day 53 and day 46, the peripheral blood counts normalization at day 60 and day 52, the immune function normalization at day 134 and day 122 and the DNA fingerprinting showing engraftment at day 19 and day 17, respectively. The donor-recipient pair of case 1 was male to female, and the chromosome karyotype of recipients bone marrow and peripheral blood cells showed 100%, 46, XY cells at day 49. Grade II acute graft versus host disease (aGVHD) occurred at day 26 (case 1) and day 21 (case 2). The two recipients have survived for 353 days and 256 days. CONCLUSION: The hematopoietic and immunologic reconstitution in umbilical cord blood transplantation were earlier and more durable. The transplantation-related complications were less and aGVHD were milder.