Efficacy, safety and cost of emicizumab prophylaxis in haemophilia A patients with inhibitors: A nationwide observational study in Taiwan.

INTRODUCTION: Emicizumab mimicking the cofactor function of activated factor VIII (FVIII) restores haemostasis. METHODS: This nationwide observational study aimed to retrospectively investigate efficacy, safety, and cost in 1 year before and up to 3 years after emicizumab prophylaxis for haemophilia A (HA) patients with FVIII inhibitors. RESULTS AND DISCUSSION: A total of 39 severe HA patients with a median age of 23.0 years were enrolled. The median historical peak FVIII inhibitor titre was 174.2 BU/mL with an interquartile range of 56.5-578.8 BU/mL. The median annualized bleeding rate reduced from 24 to 0 events in the first year after emicizumab prophylaxis (p < .01) and sustained in the second and third years. The median annualized joint bleeding rate reduced to 0 and maintained up to 3 years (p < .01). Twenty-seven patients (69.2%) had target joints before emicizumab prophylaxis and only seven patients (17.9%) of them had target joints after prophylaxis. Medical costs, including cost of haemostatic therapy, frequency of outpatient department visits, emergency room visits and hospital admission, were significantly reduced after emicizumab prophylaxis (p < .01). FVIII inhibitor titre decreased after emicizumab prophylaxis. Overall, three (7.7%) patients experienced 202 grade 1 drug-related adverse events after emicizumab prophylaxis. No serious adverse events were reported during emicizumab prophylaxis period. The adherence to emicizumab prophylaxis was 100% up to 3 years. CONCLUSIONS: HA patients with FVIII inhibitors treated with emicizumab prophylaxis resulted in a significant reduction in treated bleeds and associated costs. No new safety events were observed.

Characteristics and outcomes of second cancers in patients with childhood cancer: A report from the Taiwan Pediatric Oncology Group.

BACKGROUND: Patients with childhood cancer are at increased risk for the development of second cancers. METHODS: A national multicenter survey of second cancers conducted by the Taiwan Pediatric Oncology Group retrieved retrospective data from the database at the Children Cancer Foundation in Taiwan beginning in 1995. The characteristics of second cancers and associations of patient demographic and clinical characteristics with time to death due to a second cancer were analyzed. RESULTS: We examined the records of 8782 patients with a primary cancer diagnosed between January 1, 1995 and December 31, 2013, and a total of 99 patients with a second cancer were identified. The most common type of second cancer was acute myeloid leukemia (n = 35), followed by acute lymphoblastic leukemia (n = 15), central nervous system (CNS) tumors (n = 15), and sarcomas (n = 10). Secondary hematological malignancies occurred earlier than other secondary cancers. The frequencies of second CNS tumors and second bone cancers and sarcomas were notably increased when prior radiation doses increased from zero, low dose to high dose. The overall 5-year survival of patients with a second cancer was poor (33.7%). Multivariate survival analysis revealed that the year of primary diagnosis ≤2002, secondary hematological malignancies, and age at second cancer diagnosis ≤9.3 years or >26.8 years increased the risk of death following second cancer. CONCLUSION: Children who develop a second cancer have an unfavorable outcome. Early detection and improved treatment for second cancers are needed.

Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG-ALL-2002 study.

BACKGROUND: To eliminate cranial irradiation (CrRT)-related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)-directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL). METHODS: This study compared the treatment outcomes of patients overall and patients with a non-CNS-1 status (CNS-2, CNS-3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG-ALL-2002 protocol by the introduction of the modification (era 1 [2002-2008] with CrRT and era 2 [2009-2012] with delayed first TIT and no CrRT). RESULTS: There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5-year event-free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non-CNS-1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5-year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2. CONCLUSIONS: The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non-CNS-1 status.

Increased apoptosis and peripheral blood mononuclear cell suppression of bone marrow mesenchymal stem cells in severe aplastic anemia.

BACKGROUND: Although immune-mediated pathogenesis is considered an important aspect of severe aplastic anemia (SAA), its underlying mechanisms remain unclear. Mesenchymal stem cells (MSCs) are essential to the formation of specialized microenvironments in the bone marrow (BM), and MSC insufficiency can trigger the development of SAA. METHODS: To find MSC alterations in the SAA BM, we compared BM MSCs from five children with SAA and five controls. Peripheral blood mononuclear cells (PBMCs) were cocultured with MSCs to evaluate the supportive effects of MSCs on hematopoiesis. Cytometric bead array immunoassay was used to determine cytokine excretion by MSCs. The immune functions of MSCs and their conditioned medium (CM) were evaluated by PBMC proliferation assays. RESULTS: SAA MSCs were characterized by a high percentage of cells in the abnormal sub-G1 phase of the cell cycle, which suggests an increased rate of apoptosis in SAA MSCs. In comparison with control MSCs, PBMCs cocultured with SAA MSCs displayed significantly reduced PBMC proliferation (P = 0.009). Aberrant cytokine profiles were secreted by SAA MSCs, with increased concentrations of interleukin-6, interferon-γ, tumor necrosis factor-α, and interleukin-1ß in the CM. PBMC proliferation assays demonstrated additional immunosuppressive effects of SAA MSCs (P = 0.016) and their CM (P = 0.013). CONCLUSIONS: Our data revealed increased apoptosis and PBMC suppression of SAA MSCs. The alterations of MSCs may contribute to the formation of functionally abnormal microenvironments in SAA BM.

Effectiveness of Parenteral Glutamine on Methotrexate-induced Oral Mucositis in Children with Acute Lymphoblastic Leukemia.

High-dose methotrexate (HDMTX) is important for children with acute lymphoblastic leukemia (ALL). There is no effective treatment for patients with oral mucositis, which is a major side effect associated with HDMTX. Here, we reviewed the medical records of patients younger than 18 yr with newly diagnosed ALL in our hospitals from 2002 to 2013. According to the nationwide protocol (TPOG-ALL-2002), each patient received four courses of HDMTX (2.5 or 5 g/m2) during consolidation therapy. HDMTX courses with glutamine therapy were as the glutamine group, and intravenous glutamine (0.4 g/kg/day) was started within 48 h after the initiation of HDMTX for 3 consecutive days. HDMTX courses without glutamine were as the control group. A total of 347 HDMTX courses were administrated in the 96 children with ALL during the study period. The incidence of oral mucositis was significantly lower in the glutamine group than in the control group (3.8% vs. 17.6%; P = 0.004). In the glutamine group, no patients suffered from severe oral mucositis. No severe adverse effects associated with glutamine administration were noted. Accordingly, parenteral glutamine appears to be feasible and safe to prevent oral mucositis in patients receiving HDMTX.

Survival and complication rates in patients with thalassemia major in Taiwan.

BACKGROUND: While transfusion and iron chelation therapy for thalassemia major (TM) has improved dramatically in recent years, the consequences of this improvement (current rates of survival and TM-related complications) remain unknown. METHODS: This nationwide population-based cohort study analyzed 2007-2011 data obtained from the Taiwanese National Health Insurance Research Database. RESULTS: After excluding those patients receiving hematopoietic stem cell transplantation, we enrolled 454 patients with TM who received transfusion and chelation therapy (median age, 17.2 years). Among these patients, the mortality rate was 2.9% in 2007, 2.3% in 2008, 2.9% in 2009, 2.6% in 2010, and 0.7% in 2011. Heart was the most common target organ of TM-related complications. There were 80 patients (17.6%) with arrhythmia and 86 patients (18.9%) with congestive heart failure. Dysfunction of endocrine organs was common, and the most common endocrinopathy was hypogonadism (23.1%), followed by diabetes (21.2%). There were 75 patients (16.5%) with liver cirrhosis and 79 patients (17.4%) with osteoporosis. CONCLUSIONS: Adequate red blood cell transfusion and iron chelation is available to all patients with TM in Taiwan under the universal health insurance system, and has resulted in reduction of TM-related mortality to very low levels. As these patients get older, early detection of complications and adequate intervention are important to quality-of-life improvement.

Pediatric acute lymphoblastic leukemia with t(1;19)/TCF3-PBX1 in Taiwan.

BACKGROUND: In childhood acute lymphoblastic leukemia (ALL), t(1;19)(q23;p13.3) with TCF3-PBX1 fusion is one of the most frequent translocations. Historically, it has been associated with poor prognosis. Intensive treatment, however, has improved its outcome. We determined the outcome of children with this genotype treated with contemporary intensive chemotherapy in Taiwan. PROCEDURE: In Taiwan Pediatric Oncology Group 2002 ALL studies, genotypes were determined by cytogenetic analysis and/or reverse transcriptase polymerase chain reaction assay. Based on presenting features, immunophenotype and genotype, patients were assigned to one of the three risk groups: standard risk (SR), high risk (HR), or very high risk (VHR). The patients with t(1;19)/TCF3-PBX1 were treated in the HR arm receiving more intensive chemotherapy. The outcomes of patients with t(1;19)/TCF3-PBX1 were compared to that of patients with other subtypes of B-precursor ALL (B-ALL). RESULTS: Of the 1,129 patients with B-ALL, 64 (5.7%) had t(1;19)/TCF3-PBX1; 51 of whom were treated in the HR arm, but 11 were treated in the VHR and 2 in the SR arm because of physician's preference. As a group, 64 patients with t(1;19)/TCF3-PBX1 had similar 5-year event-free survival (83.3 ± 4.8%) as those with TEL-AML1 (85.2 ± 3.4%, P = 0.984) or those with hyperdiploidy >50 (84.0 ± 3.1%, P = 0.748). The cumulative risk of any (isolated plus combined) central nervous system relapse among patients with t(1;19)/TCF3-PBX1 (8.7 ± 3.8%) tended to be higher than that of patients with TEL-AML1 (5.8 ± 2.3%, P = 0.749) or those with hyperdiploidy (4.1 ± 1.8%, P = 0.135), albeit the differences did not reach statistical significance. CONCLUSIONS: With contemporary intensive chemotherapy, children with t(1;19)/TCF3-PBX1 fared as well as those with favorable genotypes (TEL-AML1 or hyperdiploidy).

Treatment for childhood acute lymphoblastic leukemia in Taiwan: Taiwan Pediatric Oncology Group ALL-2002 study emphasizing optimal reinduction therapy and central nervous system preventive therapy without cranial radiation.

BACKGROUND: Reinduction therapy has improved the outcomes in children with acute lymphoblastic leukemia (ALL). We sought to determine the optimal course(s) of reinduction therapy for standard-risk (SR, or "low-risk" in other groups) patients. Also, we evaluated outcomes using triple intrathecal therapy without cranial radiation (CrRT) for central nervous system (CNS) preventive therapy. PROCEDURE: From 2002 to 2012, all newly diagnosed children with ALL in Taiwan were enrolled in Taiwan Pediatric Oncology Group ALL-2002 protocol. SR patients were randomized to receive single or double reinduction courses. The patients enrolled before 2009 received CrRT, while those enrolled later did not. The Kaplan-Meier method was used to estimate survival rates and the difference between two groups was compared by the two-sided log-rank test. RESULTS: In 1,366 eligible patients, the 5-year overall survival (OS) was 81.6 ± 1.1% (standard error) and 5-year event-free survival (EFS) was 74.3 ± 1.2%. In SR patients, the 5-year OS for one and two reinduction courses was 91.6 ± 2.1% and 93.7 ± 1.8%, respectively, and the 5-year EFS was 85.2 ± 2.7% and 89.8 ± 2.3%, respectively. There were no significant differences in survival between these two groups. Patients with MLL or BCR-ABL1 had the worst outcomes: 5-year EFS was 23.4 and 31.8% and 5-year OS was 28.6 and 44.7%, respectively. There was no significant difference in CNS relapse or survival between the era with or without CrRT. CONCLUSIONS: For SR patients, one-course reinduction was adequate. Triple intrathecal therapy alone successfully prevented CNS relapse.

Outcomes Following Discontinuation of E. coli l-Asparaginase Upon Severe Allergic Reactions in Children With Acute Lymphoblastic Leukemia.

BACKGROUND: Discontinuation of E. coli l-asparaginase in patients with acute lymphoblastic leukemia (ALL) is unavoidable upon severe allergic reaction. We sought to examine outcomes following E. coli l-asparaginase discontinuation due to severe allergic reactions. PROCEDURE: We evaluated the outcome of children enrolled in Taiwan Pediatric Oncology Group-2002-ALL protocol between 2002 and 2012, who had E. coli l-asparaginase discontinued due to severe allergic reactions, and compared the outcomes of those who continued with Erwinia l-asparaginase (Erwinase) with those who did not. RESULTS: Among 700 patients enrolled in this study, 33 patients had E. coli l-asparaginase treatment discontinued due to severe allergic reactions. Five-year overall survival did not differ significantly among the 648 patients without discontinuation (81 ± 1.6%, mean ± SE), compared to 17 patients with allergic reactions and treated with Erwinase (88 ± 7.8%) and 16 patients with allergic reactions but not treated with Erwinase (87 ± 8.6%). Among 16 patients who did not receive Erwinase, all 10 who received ≥50% of the scheduled doses of E. coli l-asparaginase before discontinuation survived without events. CONCLUSIONS: Erwinase treatment may not be needed for some ALL patients with severe allergy to E. coli l-asparaginase if ≥50% of prescribed doses were received and/or therapy is augmented with other agents.

Validating the Sensitivity of High-Resolution Melting Analysis for JAK2 V617F Mutation in the Clinical Setting.

BACKGROUND: Janus kinase 2 (JAK2) plays an important role in normal hematopoietic growth factor signaling. The detection of the JAK2 V617F mutation (c.1849GNT, GTC → TTC) is crucial for the diagnosis of myeloproliferative neoplasm (MPN) and has become the essential criteria for diagnosis of MPN by the WHO. High-resolution melt (HRM) curve analysis is a nongel-based, closed-tube method, in which PCR amplification and subsequent analysis are sequentially performed in the well, making it more convenient than other scanning methodologies. METHODS: We evaluated JAK2 V617F mutation by HRM. Twenty-nine patients diagnosed with MPN were examined. We studied the analytical sensitivity of the HRM analysis using real-time polymerase chain reaction (PCR) for identifying the JAK2 V617F mutation. Additionally, the sensitivity of HRM analysis and allele-specific PCR (AS-PCR) assay was compared. RESULTS: The JAK2 V617F mutation was successfully discriminated at an abundance of 6% or above in HRM analysis. Both HRM analysis and AS-PCR showed 100% accuracy with detection limits of 6% and 2.5%, respectively. CONCLUSION: HRM analysis is a fast, simple, reliable, and nonexpensive method for the detection of the JAK2 V617F mutation. However, more validation of the detection limits of HRM analysis should be performed before declaration of the analytic sensitivity of the method.

Safe needling depths of upper back acupoints in children: a retrospective study.

BACKGROUND: Acupuncture is applied for treating numerous conditions in children, but few studies have examined the safe needling depth of acupoints in the pediatric population. In this study, we investigated the depths to which acupuncture needles can be inserted safely in the upper back acupoints of children and the variations in safe depth according to sex, age, weight, and body mass index (BMI). METHODS: We retrospectively studied computed tomography (CT) images of patients aged 4 to 18 years who underwent chest CT at China Medical University Hospital between December 2004 and May 2013. The safe depths of 23 upper back acupoints in the Governor Vessel (GV), Bladder Meridian (BL), Small Intestine Meridian (SI), Gallbladder Meridian (GB) and Spleen Meridian (SP) were measured directly from the CT images. The relationships between the safe depths of these acupoints and sex, age, body weight, and BMI were analyzed. RESULTS: The results indicated significant differences in safe needling depth between boys and girls in most upper back acupoints, except at BL42, BL44, BL45, BL46, GB21 and SP21. Safe depths differed significantly depending on age (p < 0.001), weight (p ≤ 0.01), and BMI (p < 0.05). Multiple regression analysis revealed that weight was the most crucial factor in determining the safe depth. CONCLUSIONS: Sex, age, weight, and BMI are relevant factors in determining the safe needling depths of upper back acupoints in children. Physicians should pay attention to wide variations in needle depth when performing acupuncture.

Tet oncogene family member 2 gene alterations in childhood acute myeloid leukemia.

BACKGROUND/PURPOSE: Mutations in the tet oncogene family member 2 gene (TET2) are frequently found in adult patients with acute myeloid leukemia (AML). Reports of TET2 mutations in children are limited. We assessed the prevalence of TET2 mutations in Taiwanese children with AML and analyzed their prognosis. METHODS: Between 1997 and 2010, a total of 69 consecutive children with AML were enrolled at the National Taiwan University Hospital. The analysis for TET2 mutations was performed using direct sequencing. Clinical characteristics and overall survival (OS) were compared between patients with and without TET2 alterations. RESULTS: Intronic and missense mutations were identified. No nonsense or frameshift mutations were observed. Two putative disease-causing missense mutations (S609C and A1865G) were identified in one patient. We estimated the prevalence of TET2 mutations in the current patient population to be 1.4%. The most common polymorphism was I1762V (45%), followed by V218M (12%), P29R (6%), and F868L (6%). Patients with polymorphism I1762V had an increased 10-year survival rate compared with patients without I1762V (48.4% vs. 25.7%, p = 0.049) by Chi-square test; OS was not different when examined using the Kaplan-Meier method (p = 0.104). CONCLUSION: The prevalence of TET2 mutations in children with AML compared with adults with AML was lower and less complex. Patient prognosis associated with TET2 mutations in children requires further investigation.

Downregulated CXCL12 expression in mesenchymal stem cells associated with severe aplastic anemia in children.

The mechanisms of idiopathic severe aplastic anemia (SAA) in children are not completely understood. Insufficiency of the bone marrow microenvironment, in which mesenchymal stem cells (MSCs) are an important element, can be a potential factor associated with hematopoietic impairment. In the current study, we studied whether aberrant gene expression could be found in MSCs from children with SAA. Using microarray analysis, two different patterns of global gene expression were detected in the SAA MSCs. Fourteen genes (POLE2, HGF, KIF20A, TK1, IL18R1, KITLG, FGF18, RRM2, TTK, CXCL12, DLG7, TOP2A, NUF2, and TYMS), which are related to DNA synthesis, cytokines, or growth factors, were significantly downregulated. Further, knockdown of gene expression was performed using the small hairpin RNA (shRNA)-containing lentivirus method. We found that knockdown of CXCL12, HGF, IL-18R1, FGF18, or RRM2 expression compelled MSCs from the controls to behave like those from the SAA children, with decreased survival and differentiation potential. Among them, inhibition of CXCL12 gene expression had the most profound effects on the behavior of MSCs. Further experiments regarding re-introduction of the CXCL12 gene could largely recover the survival and differentiation potential in MSCs with inhibition of CXCL12 expression. Our findings suggest that MSCs from children with SAA exhibit aberrant gene expression profiles and downregulation of CXCL12 gene may be associated with alterations in the bone marrow microenvironment.

Association Between Genetic Polymorphism of the MIF Gene and Colorectal Cancer in Taiwan.

BACKGROUND: Colorectal cancer (CRC) is the highest leading cause of cancer-related mortality in Taiwan. Macrophage migration inhibitory factor (MIF) has recently been defined as a novel protumorigenic factor that promotes cell proliferation, migration, and invasion. The aim of the present study is to identify the association between MIF gene polymorphism and CRC. METHODS: A case-control study was designed to test the hypothesis. A total of 192 biopsy-diagnosed CRC patients (CRC) and 256 healthy subjects (control) were recruited. Genotyping of four single nucleotide polymorphism (SNPs; rs755662, rs11548059, rs1049829, rs1803976) at chromosome positions 755662 (5' UTR), 11548059 (exon2), 1049829 (exon2), 1803976 (exon3) was performed using a Taqman SNP genotyping assay. RESULTS: There is a significant difference in genotype frequency distribution of rs755662 polymorphism between CRC patients and controls (P = 0.011). No significant difference was found in the frequency distribution of rs11548059, rs1049829, rs1803976 polymorphism in CRC patients and controls (P = 0.660, P = 0.700, and P = 0.959, respectively). Moreover, the MIF-173 SNP was also significantly associated with young patients (age < 50 years, P = 0.026) late stage (Stage IV, P = 0.038) and poor differentiation group (P = 0.040). Compared to the control group, the MIF-173 SNP also significantly associated with patients with stages III and IV (P = 0.034 and 0.003, respectively). CONCLUSION: The presence of MIF-173 (G/C) gene polymorphism (rs755662) was associated with susceptibility, patient age, and stages of CRC in Taiwanese.

High-resolution melting analyses for genetic variants in ARID5B and IKZF1 with childhood acute lymphoblastic leukemia susceptibility loci in Taiwan.

BACKGROUND: Childhood acute lymphoblastic leukemia (ALL), a heterogeneous disease that includes multiple subtypes is defined by cell lineage and chromosome anomalies. Previous genome-wide association studies have reported several ARID5B and IKZF1 single nucleotide polymorphisms (SNPs) associated with the incidence of ALL. High-resolution melting (HRM) analysis is a rapid and convenient technique to detect SNPs; we thereby detected SNPs in ARID5B and IKZF1 genes. METHODS: We enrolled 79 pediatric ALL patients and 80 healthy controls. Polymorphic variants of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs7073837, rs10740055, and rs7089424) were detected by HRM, and SNPs were analyzed for association with childhood ALL. RESULTS: The distribution of genotype rs7073837 in ARID5B significantly differed between ALL and controls (P=0.046), while those of IKZF1 (rs6964823, rs4132601, and rs6944602) and ARID5B (rs10740055 and rs7089424) did not. We analyzed the association for SNPs with B lineage ALL to find rs7073837 in ARID5B, conferring a higher risk for B lineage ALL (odds ratio, OR=1.70, 95% confidence interval, CI=1.01-2.87, P=0.049). CONCLUSION: HRM is a practical method to detect SNPs in ARID5B and IKZF1 genes. We found that rs7073837 in ARID5B correlated with a risk for childhood B lineage ALL.

Hospice shared-care saved medical expenditure and reduced the likelihood of intensive medical utilization among advanced cancer patients in Taiwan--a nationwide survey.

PURPOSE: Hospice shared care (HSC) is a new care model that has been adopted to treat inpatient advanced cancer patients in Taiwan since 2005. Our aim was to assess the effect of HSC on medical expenditure and the likelihood of intensive medical utilization by advanced cancer patients. METHODS: This is a nationwide retrospective study. HSC was defined as using "Hospice palliative care (HPC) teams to provide consultation and service to advanced cancer patients admitted in the nonhospice care ward." There were 120,481 deaths due to cancer between 2006 and 2008 in Taiwan. Patients receiving HSC were matched by propensity score to patients receiving usual care. Of the 120,481 cancer deaths, 12,137 paired subjects were matched. Medical expenditures for 1 year before death were assessed between groups using a database from the Bureau of National Health Insurance. Paired t and McNemar's tests were applied for comparing the medical expenditure and intensive medical utilization before death between paired groups. RESULTS: Compared to the non-HSC group, subjects receiving HSC had a lower average medical expenditure per person (US$3,939 vs. US$4,664; p<0.001). The HSC group had an adjusted net savings of US$557 (13.3%; p<0.001) in inpatient medical expenditure per person compared with the non-HSC group. Subjects that received different types of HPC had 15.4-44.9% less average medical expenditure per person and significantly lower likelihood of intensive medical utilization than those that did not receive HPC. CONCLUSIONS: HSC is associated with significant medical expenditure savings and reduced likelihood of intensive medical utilization. All types of HPC are associated with medical expenditure savings.

MicroRNA-146a decreases high glucose/thrombin-induced endothelial inflammation by inhibiting NAPDH oxidase 4 expression.

Diabetes is associated with hyperglycemia and increased thrombin production. However, it is unknown whether a combination of high glucose and thrombin can modulate the expression of NAPDH oxidase (Nox) subtypes in human aortic endothelial cells (HAECs). Moreover, we investigated the role of a diabetes-associated microRNA (miR-146a) in a diabetic atherothrombosis model. We showed that high glucose (HG) exerted a synergistic effect with thrombin to induce a 10.69-fold increase in Nox4 mRNA level in HAECs. Increased Nox4 mRNA expression was associated with increased Nox4 protein expression and ROS production. Inflammatory cytokine kit identified that the treatment increased IL-8 and IL-6 levels. Moreover, HG/thrombin treatment caused an 11.43-fold increase of THP-1 adhesion to HAECs. In silico analysis identified the homology between miR-146a and the 3'-untranslated region of the Nox4 mRNA, and a luciferase reporter assay confirmed that the miR-146a mimic bound to this Nox4 regulatory region. Additionally, miR-146a expression was decreased to 58% of that in the control, indicating impaired feedback restraint of HG/thrombin-induced endothelial inflammation. In contrast, miR-146a mimic transfection attenuated HG/thrombin-induced upregulation of Nox4 expression, ROS generation, and inflammatory phenotypes. In conclusion, miR-146a is involved in the regulation of endothelial inflammation via modulation of Nox4 expression in a diabetic atherothrombosis model.

Immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate: a phase III randomized controlled trial in children.

BACKGROUND: Mismatch between circulating influenza B viruses (Yamagata and Victoria lineages) and vaccine strains occurs frequently. METHODS: In a randomized controlled trial, immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate (QIV) versus trivalent inactivated influenza vaccine (TIV)-Victoria(Vic) and TIV-Yamagata(Yam) in children 3-17 years of age was evaluated. In an open-label study arm, QIV only was assessed in children 6-35 months of age. RESULTS: A total of 3094 children (932 QIV, 929 TIV-Vic, 932 TIV-Yam, and 301 QIV only) were vaccinated. QIV was noninferior to the TIVs for shared strains (A/H3N2 and A/H1N1) based on hemagglutination-inhibition (HI) antibodies 28 days after last vaccination, and superior for the unique B strains Victoria and Yamagata (geometric mean titer ratios 2.61, 3.78; seroconversion rate differences 33.96%, 44.63%). Among children in the randomized trial, adverse event rates were similar except for injection site pain (dose 1: 65.4% QIV, 54.6% TIV-Vic, 55.7% TIV-Yam). CONCLUSION: QIV elicited superior HI responses to the added B strains compared to TIV controls, potentially improving its effectiveness against influenza B. HI responses were similar between QIV and TIV controls for the shared strains. QIV had an acceptable safety profile relative to TIVs. CLINICAL TRIALS REGISTRATION: NCT01198756.

Distribution of thalassemias and associated hemoglobinopathies identified by prenatal diagnosis in Taiwan.

BACKGROUND: Hemoglobin (Hb) gene disorders are common hereditary disorders in Taiwan, and α- and ß-thalassemias are among the well-known Hb disorders here. Our study provides a primary reference for designing a locally relevant antenatal diagnostic test to control the spread of thalassemia. METHODS: Between 1998 and 2011, prenatal diagnoses for identifying thalassemia and hemoglobinopathies were performed on 1240 fetuses at risk for α-hydrops and ß-thalassemia major. RESULTS: Of 1240 specimens analyzed, 1082 (87%) were obtained by amniocentesis; 125 (10%), by chorionic villus sampling; and 33 (3%), by cordocentesis. Prenatal diagnoses revealed that 21.5% of these fetuses as thalassemia major (including α-thalassemia hydrops, ß-thalassemia major, and Hb E/ß-thalassemia); 50.2%, for thalassemia minor (include α-thalassemia carrier, ß-thalassemia carrier, and α-thalassemia combined ß-thalassemia carrier); and 28.3% for normal type (include non-α, ß-thalassemia). The most common α-hydrops were SEA (Southeast Asian) and Philippine type (frequencies of 74.91 and 5.24%, respectively). The frequency of the IVS-II-654 combined codons 41/42 mutation, the most common ß-thalassemia major mutation in this region, was 5.24%. Two fetuses were found with E/ß-thalassemia (HbE/IVS-II-654 and HbE/codons 41/42, respectively). Since 1993, Taiwan's Department of Health adopted a national program for screening pregnancies to control spread of thalassemia. In the last 10years, less than 3 such cases have occurred per year. After 2003, this number was 0 for a total of 4years (2003, 2004, 2007, and 2008). CONCLUSION: In Taiwan, incidence and frequency of thalassemia genotypes were similar to those previously reported. The national program for screening pregnancies to control spread of thalassemia that resulted in a marked decline in the number of newborns with thalassemia major. Interestingly, prenatal diagnoses revealed 21.5% for thalassemia major, 50.2% for thalassemia minor, 28.3% normal comparison of thalassemia type distribution showed normal type increasing by 13.2% and major type decreasing by 14%. This unique and significant finding needs further clinical studies and discussion to explain such a phenomenon.