Safety and Efficacy of B-domain Deleted Third Generation Recombinant Factor VIII (GreenGene F™) in Korean Patients with Hemophilia A: Data from a Post-marketing Surveillance Study.

BACKGROUND: New B-domain deleted third generation recombinant factor VIII (FVIII; GreenGene F™, beroctocog alfa) was launched in 2010. We determined safety and efficacy of GreenGene F™ during routine clinical practice in patients with hemophilia A over a period of 12 months. METHODS: From July 2010 to July 2014, a total of 136 hemophilia A patients were enrolled in a post-marketing surveillance (PMS) study. Among them, 134 patients were assessed for drug safety and 114 patients were analyzed for drug efficacy. Patients with differing hemophilia A severities and medical histories were monitored during 12 months of prophylactic and/or on-demand therapy. RESULTS: Among 134 patients evaluated, 85 (63.4%) had severe hemophilia. Ninety-two received a total of 1,266,077 units for prophylaxis, and 42 received 516,491 units for bleeding episodes. Three patients developed inhibitors. In 112 previously treated patients, one patient (0.9%) developed inhibitor after intensive FVIII treatment for surgery. Among 22 previously untreated patients, inhibitors were observed in 2 infants (9.1%). Overall, there were a total of 47 adverse events (other than inhibitors) of all types in 30 patients (22.4%), 11 in 10 patients (7.5%) of which were considered showing serious adverse events (SAEs); most of which were hemorrhages at different sites. None of the SAEs were judged as product related. An excellent/good efficacy rate of 91.3% for hemostasis and 89.4% for hemorrhage prevention was recorded. CONCLUSION: The results of this PMS study support the use of GreenGene F™ as safe and efficacious in hemorrhage prevention and treatment of hemophilia A. These results are consistent with the findings from previously published GreenGene F™ studies.

Treatment outcome of pediatric acute lymphoblastic leukemia in Yeungnam region: Multicenter retrospective study of Study Alliance of Yeungnam Pediatric Hematology-Oncology (SAYPH).

OBJECTIVES: We aimed to evaluate treatment outcomes of pediatric acute lymphoblastic leukemia (ALL) subgroups by risk-stratification, in the Yeungnam region of Korea. METHODS: We reviewed the courses of 409 newly diagnosed ALL patients from January 2004 to December 2013 in the Yeungnam region. RESULTS: All patients were classified into three risk groups: standard risk (SR, n=212), high risk (HR, n=153) and very high risk (VHR, n=44). The mean follow-up time was 73.6 ± 39.4 months. The 7-year event-free survival (EFS) and overall survival (OS) rates were 78.7 ± 2.1% and 86.8 ± 1.8%, respectively. Significant 7-year EFS and OS rates for SR (84.0 ± 2.7%, 93.7 ± 1.8%), HR (76.5 ± 3.5%, 82.1 ± 3.3%), and VHR (60.6 ± 7.5%, 69.9 ± 7.5%) were observed (P<0.001), respectively. Relapse occurred in 52 patients, and the cumulative 7-year incidence of relapse differed according to risk groups (SR vs. HR vs. VHR=12.6% vs. 14.0% vs. 29.6%, P=0.003).For the 46 relapsed patients who were treated, the 3-year EFS and OS were 42.3 ± 8.3%and 46.4± 8.4%. Among the 44 VHR patients, EFS was not significantly different between the chemotherapy-treated patients and those received hematopoietic stem cell transplantation (P=0.533). The 7-year EFS of the hyperleukocytosis subgroup (24 cases, 14 under 10 years of age)showed a tendency for better prognosis than that of the other VHR subgroups (P=0.178). CONCLUSION: Our results revealed improved outcomes in pediatric ALL patients with risk-stratified therapy. The hyperleukocytosis subgroup without any combined chromosomal abnormalities may respond favorably to chemotherapy alone after first complete remission.

Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party.

A nationwide survey was conducted to clarify the clinical features and outcomes of Korean children with Langerhans cell histiocytosis (LCH). Korea Histiocytosis Working Party analyzed the data of 603 patients who were diagnosed with LCH between 1986 and 2010 from 28 institutions in Korea. Median age at diagnosis was 65 months (range, 0 to 276 mo). Bone was the most frequently affected organ (79.6%) followed by skin (19.2%). Initially, 419 patients (69.5%) had single-system involvement (SS), 85 (14.1%) with multisystem (MS) disease without risk organ involvement (MS-RO), and 99 (16.4%) multisystem disease with risk organ involvement (MS-RO). The 5-year overall survival (OS) rates in the SS, MS-RO, and MS-RO groups were 99.8%, 98.4%, and 77.0%, respectively (P<0.001), and the 5-year reactivation rates were 17.9%, 33.5%, and 34.3%, respectively (P<0.001). The OS rate was lower in patients with RO involvement (P=0.025) and lack of response to initial treatment (P=0.001). MS involvement (P=0.036) was an independent risk factor for reactivation. Permanent consequences were documented in 99 patients (16.4%). Reactivation of disease, MS involvement, and age at diagnosis ≤ 2 years were associated with higher incidence of permanent consequences. This study emphasized that further efforts are required to improve survival of MS-RO patients and reduce reactivation in younger patients with MS involvement.

Quantitative comparison of CDKN2B methylation in pediatric and adult myelodysplastic syndromes.

BACKGROUND/AIMS: Transcriptional repression of tumor suppressor genes is determined by the quantity of promoter hypermethylation. We analyzed the methylation quantity of CDKN2B in pediatric myelodysplastic syndromes (MDS). METHODS: Quantitative measurement of CDKN2B methylation was performed in 25 pediatric MDS patients and 12 controls using pyrosequencing, and the result was compared with those from 74 adult MDS cases and 31 adult controls. The association between CDKN2B methylation quantity and factors related to prognosis including bone marrow blast percentage and karyotype was analyzed. RESULTS: Pediatric MDS patients showed a higher methylation level (MtL) of CDKN2B than pediatric controls (2.94 vs. 1.62; p = 0.031) but a lower level than adult MDS patients (8.76; p < 0.001). MtL was higher in pediatric MDS cases with >5% blasts than in pediatric controls (3.78 vs. 1.62; p = 0.052). Pediatric MDS cases with abnormal karyotype showed a higher MtL than pediatric controls (5.95 vs. 1.62; p = 0.045). CONCLUSIONS: We confirmed that methylation of CDKN2B is associated with the pathogenesis and prognosis in pediatric MDS. The difference in MtLs between pediatric and adult MDS might be related to the physiological hypermethylation of tumor suppressor genes in aging.

Prevalence of primary immunodeficiency in Korea.

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Epidemiology and clinical long-term outcome of childhood aplastic anemia in Korea for 15 years: retrospective study of the Korean Society of Pediatric Hematology Oncology (KSPHO).

PURPOSE: Aplastic anemia (AA) is a rare hematologic disease characterized by pancytopenia and hypocellular marrow. The Korean Society of Pediatric Hematology Oncology investigated retrospectively the incidence, survival, and transfusion independency according to treatment strategies in AA. METHODS: All the questionnaires were sent to members for medical records. We collected and analyzed 702 available data. RESULTS: The male and female ratio was 1.2, and the median age at diagnosis was 9.3 years. The annual incidence of Korean children with AA was 5.16 per million per year. Constitutional anemia was diagnosed in 44 children. In acquired AA, causes were identified in 39 children. Severe AA (SAA) at initial diagnosis was more common than nonsevere AA. The overall survival was 47.8% with supportive care, 68.1% with immunosuppressive therapy (IST), and 81.8% with hematopoietic stem cell transplantation. In IST, response rate was 65.7%, and relapse rate after response was 54.4% within a median of 23.0 months. The factors with overall survival were severity of disease in supportive care, severity and response in IST, donor type, graft failure, and posttransplant events in hematopoietic stem cell transplantation. CONCLUSIONS: Long-term outcome in AA was dependent on treatment strategies. These Korean results may help research and prospective international clinical trials for childhood AA.

Novel ELANE gene mutation in a Korean girl with severe congenital neutropenia.

Severe congenital neutropenia is a heterozygous group of bone marrow failure syndromes that cause lifelong infections. Mutation of the ELANE gene encoding human neutrophil elastase is the most common genetic alteration. A Korean female pediatric patient was admitted because of recurrent cervical lymphadenitis without abscess formation. She had a past history of omphalitis and isolated neutropenia at birth. The peripheral blood showed a markedly decreased absolute neutrophil count, and the bone marrow findings revealed maturation arrest of myeloid precursors at the promyelocyte to myelocyte stage. Her direct DNA sequencing analysis demonstrated an ELANE gene mutation (c.607G > C; p.Gly203Arg), but her parents were negative for it. She showed only transient response after subcutaneous 15 µg/kg/day of granulocyte colony stimulating factor administration for six consecutive days. During the follow-up observation period, she suffered from subsequent seven febrile illnesses including urinary tract infection, septicemia, and cellulitis.

Treatment Outcomes of Pediatric Acute Myeloid Leukemia in the Yeungnam Region: A Multicenter Retrospective Study of the Study Alliance of Yeungnam Pediatric Hematology-Oncology (SAYPH).

Acute myeloid leukemia (AML) is the second most common pediatric leukemia, with a survival rate of 70%. In this retrospective study, we evaluated the treatment outcomes of pediatric AML among 144 patients diagnosed between 2000 and 2013. After induction, 80.6% of patients achieved complete remission (CR). The 5-year overall survival (OS) and event-free survival (EFS) rates were 58.8 ± 4.2% and 49.8 ± 4.2%, respectively. Based on the response to induction therapy, the 5-year OS was 66.9 ± 5.7% in patients with CR (p < 0.001). Ninety-nine patients with CR after induction therapy were examined, and their 5-year OS and EFS were 66.4 ± 4.9% and 56.3 ± 5.1%, respectively. The 5-year OS rates according to treatment were 59.9 ± 7.4% in the chemotherapy group and 72.3 ± 6.3% in the hematopoietic stem cell transplantation (HSCT) group (p = 0.089). The EFS was 50.1 ± 7.4% in the chemotherapy group and 61.7 ± 6.9% in the HSCT group (p = 0.098). OS and EFS according to cytogenetics were insignificant. Our findings confirmed that the response to induction treatment was important for survival and HSCT had no significant survival benefits compared with those of chemotherapy. Moreover, many early induction deaths under the age of 2 years were observed.

Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma: the Korean Society of Pediatric Hematology-Oncology experience over 6 years (2000-2005).

The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival+/-95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2+/-12.4% vs. 31.3+/-11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients.

Health-related quality of life of moderate and severe haemophilia patients: Results of the haemophilia-specific quality of life index in Korea.

The assessment of health-related quality of life (HRQoL) as a patient-reported outcome provides information about the patients' general well-being as well as the effects of the disease and its treatment. This study aimed to investigate HRQoL using both generic and haemophilia-specific QoL instruments and to assess the clinical factors associated with HRQoL among haemophilia patients in Korea. In this cross-sectional, multicenter, observational study, moderate-to-severe haemophilia patients aged 8-64 years were recruited between November 2012 and September 2013. The EQ-5D Questionnaire, EQ Visual Analogue Scale, and Haemophilia-Specific QoL (Haemo-QoL) Questionnaire (Haemo-QoL for 8-16 years and Haemo-A-QoL for ≥17 years) were used to assess HRQoL. A total of 605 participants with a mean age of 29.32 ± 12.62 years were enrolled. The mean Haemo-QoL scores revealed significant differences by age group (children vs. adolescent vs. adult, 26.44 ± 11.3 vs. 28.88 ± 11.1 vs. 38.43 ± 17.7, respectively, p < 0.001). "Sports and leisure," "family planning," and "view" in adults and "perceived support," "friends," and "dealing" in children and adolescents were identified as the domains with the greatest HRQoL impairments. HRQoL was significantly impaired in patients with the following clinical factors: hepatitis, haemophilia-induced disability, bleeding experiences within the last 6 months, joint bleedings within the last 6 months, and haemophilic arthropathy. According to the multivariate regression analysis, HRQoL showed a negative association with the presence of haemophilia-induced disability (ß = 0.222, p < 0.0001), bleeding experiences within the last 6 months (ß = 0.098, p = 0.010), and haemophilic arthropathy (ß = 0.212, p < 0.0001). HRQoL decreased in patients with older age and impaired clinical conditions among moderate-to-severe haemophilia patients in Korea. These study findings may provide significant insights into the adequate haemophilia management using patient-reported measurements.

Mobilization effects of G-CSF, GM-CSF, and darbepoetin-alpha for allogeneic peripheral blood stem cell transplantation.

The effects of GM-/G-CSF and darbepoetin-alpha on stem cell mobilization were investigated. From February 2005 to March 2007, 30 allogeneic sibling donors were randomly assigned to a G-CSF group (5 microg/kg/day for 5-7 days) or triple group (GM-CSF 10 microg/kg/day on 1st and 2nd day, G-CSF 5 microg/kg/day for 5-7 days, and darbepoetin-alpha 40 mg on 1st day). The MNCs and CD34(+) cells were not different between the two groups, although the doses (x10(8)/kg of recipient body weight) of CD3(+) cells (3.64 +/- 1.75 vs. 2.63 +/- 1.36, P = 0.089) and CD8(+) cells (1.07 +/- 0.53 vs. 0.60 +/- 0.30, P = 0.006) were lower in the triple group. The engraftments, frequency of RBC transfusions, and hemoglobin recovery were not different between the two groups. The cumulative incidence of overall and Grades II-IV aGVHD was 64.3% vs. 61.1% and 25.9% vs. 27.1% in the G-CSF and triple regimen group, respectively, whereas the cumulative incidence of cGVHD was 20.8 +/- 1.3% and 24.4 +/- 1.7%, respectively. In conclusion, the triple regimen did not seem to be superior to G-CSF alone in terms of the CD34+ cell dose, hemoglobin recovery, and GVHD. However, the CD8+ cell count was significantly lower in the triple regimen group. The role of a lower CD8+ cell count in the graft may need to be elucidated in the future.

Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: matching with osmotic fragility test and presence of spherocyte.

BACKGROUND: Current diagnostic tests for hereditary spherocytosis (HS) focus on the detection of hemolysis or indirectly assessing defects of membrane protein, whereas direct methods to detect protein defects are complicated and difficult to implement. In the present study, we investigated the patterns of genetic variation associated with HS among patients clinically diagnosed with HS. METHODS: Multi-gene targeted sequencing of 43 genes (17 RBC membrane protein-encoding genes, 20 RBC enzyme-encoding genes, and six additional genes for the differential diagnosis) was performed using the Illumina HiSeq platform. RESULTS: Among 59 patients with HS, 50 (84.7%) had one or more significant variants in a RBC membrane protein-encoding genes. A total of 54 significant variants including 46 novel mutations were detected in six RBC membrane protein-encoding genes, with the highest number of variants found in SPTB (n = 28), and followed by ANK1 (n = 19), SLC4A1 (n = 3), SPTA1 (n = 2), EPB41 (n = 1), and EPB42 (n = 1). Concurrent mutations of genes encoding RBC enzymes (ALDOB, GAPDH, and GSR) were detected in three patients. UGT1A1 mutations were present in 24 patients (40.7%). Positive rate of osmotic fragility test was 86.8% among patients harboring HS-related gene mutations. CONCLUSIONS: This constitutes the first large-scaled genetic study of Korean patients with HS. We demonstrated that multi-gene target sequencing is sensitive and feasible that can be used as a powerful tool for diagnosing HS. Considering the discrepancies of clinical and molecular diagnoses of HS, our findings suggest that molecular genetic analysis is required for accurate diagnosis of HS.

Causes of early rebleeding after coil embolization of ruptured cerebral aneurysms.

OBJECTIVE: Early rebleeding after coil embolization of a ruptured cerebral aneurysm is rare but may cause severe disability or death. We present a case series of early rebleeding after coil embolization of ruptured cerebral aneurysms and investigate the incidence, clinical outcome and possible mechanism through retrospective analysis of angiographic and surgical findings. PATIENTS AND METHODS: This study included 347 consecutive patients who had undergone successful coil embolization of 347 ruptured cerebral saccular aneurysms. Clinical and angiographic data and findings from emergent surgery were analyzed retrospectively. RESULTS: Early rebleeding occurred in eight aneurysms (2.3%) and was especially frequent among anterior communicating artery lesions (6 out of 122, 4.9%). The other two events involved posterior communication artery lesions. The maximum diameter of the aneurysms that developed early rebleeding was 4.89 ± 0.65 mm, ranging from 3.9 to 5.7 mm. In seven out of eight patients, the immediate radiologically determined occlusion status was a residual neck, and the remaining patient had a residual sac. The coil packing density was between 21% and 34%. Six cases of rebleeding were detected within 48 h, 1 case was detected on the 5th day, and 1 case was detected on the 10th day. Coil compaction was not detected by follow-up angiography after early rebleeding. We performed surgical clipping as a rescue procedure in 5 cases and additional coil embolization in 1 case. During follow-up angiography and rescue clipping, inflow of blood to the aneurysm was detected in 6 cases. Three patients died, and the other 3 patients were severely disabled. The mechanisms of early rebleeding were divided into two types. First, blood may flow into the rupture site through a gap between the coil mesh and the aneurysm neck. Second, blood may enter the rupture site through the coil mesh due to insufficient thrombus formation. CONCLUSIONS: The early rebleeding rate after coil embolization of ruptured cerebral aneurysms in our study was 2.3%. The ruptured aneurysms were small in size (<6 mm), and rupture frequently occurred in the anterior communicating artery. In most cases, inflow of blood to the aneurysm was detected by follow-up angiography or during rescue surgery.

Clinical characteristics and treatment courses for cytomegalovirus-associated thrombocytopenia in immunocompetent children after neonatal period.

BACKGROUND: Cytomegalovirus (CMV) causes severe diseases in premature infants and immunocompromised hosts, and antiviral therapy is often required for disease control. However, the clinical manifestations and treatment courses for CMV-associated thrombocytopenia in immunocompetent children are unclear. METHODS: Medical records of the children who suffered from thrombocytopenia, and showed positive CMV polymerase chain reaction and CMV-like symptoms were retrospectively analyzed at three university hospitals in Daegu from January 2000 to March 2017. Patients suffering from leukemia, immunodeficiency, and other infections were excluded. RESULTS: Among 1,065 children with thrombocytopenia, 29 (2.7%) displayed CMV-associated thrombocytopenia. The median age at diagnosis was 15 months and the median platelet count was 26,000/µL. They were classified into the CMV-induced thrombocytopenia (23/29) and CMV-related secondary immune thrombocytopenia (ITP, 6/29) groups. Fourteen subjects had hepatic dysfunction, four had Evans syndrome, two had pneumonitis, and one had gastritis. IVIG was used for 21 patients, and six patients among them showed recurrence, for whom IVIG or antiviral therapy was used. All, except one, recurrent or chronic cases belonged to the CMV-induced thrombocytopenia group. Antiviral therapy was used more frequently for the CMV-induced thrombocytopenia group (8/23, 34.8%) than for the CMV-related secondary ITP group (0/6); however, the results were not statistically significant (P=0.148). CONCLUSION: CMV is a rare but unique etiology of thrombocytopenia, and observed even in healthy children after the neonatal period. About one-third patients need antiviral therapy for disease control. Further, CMV-induced thrombocytopenia is more complex than CMV-related secondary ITP.

Long-term therapeutic efficacy of lamivudine compared with interferon-alpha in children with chronic hepatitis B: the younger the better.

OBJECTIVES: To assess and compare the long-term therapeutic response to lamivudine compared with interferon-alpha (IFN-alpha) in children with chronic hepatitis B. METHODS: A total of 40 children (27 male; age, 1.3-18 y, mean, 7.7 y) with chronic hepatitis B who received lamivudine for at least 12 months were followed for a mean period of 39 (24-76) months. Their treatment efficacy was historically compared with that of 19 children (14 male; age, 2.1-17 y; mean, 10 y) who had been treated with IFN-alpha and were followed for a mean period of 39 (24-104) months. Therapeutic responses were compared at 2 y after the initiation of either of the treatment methods. RESULTS: Two years after the initiation of treatment, the results for children treated with lamivudine versus IFN-alpha were as follows: hepatitis B e antigen (HBeAg) seroconversion occurred in 26 (65%) of the 40 children versus 7 (37%) of the 19 children, P < 0.05. In the lamivudine-treated group, the results for children treated before the age of 7 versus age >7 were as follows: HBeAg seroconversion occurred in 17 (89%) of the 19 children versus 9 (43%) of the 21 children, P < 0.01, and loss of hepatitis B surface antigen (HBsAg) occurred in 8 (42%) versus 0%, P < 0.001. CONCLUSIONS: Long-term treatment of lamivudine led to significant improvement in the seroconversion rate of HBeAg in children with chronic hepatitis B compared with IFN-alpha therapy. Furthermore, in preschool-age children, it led to significant improvement in the seroconversion rate of HBeAg and HBsAg compared with school-age children.

Prognostic scoring model based on multi-drug resistance status and cytogenetics in adult patients with acute myeloid leukemia.

Clinical heterogenicity exists within an acute myeloid leukemia (AML) patient group with the same cytogenetic risk. Multi-drug resistance (MDR) is also regarded as one of the potential prognostic factors for AML. Accordingly, the prognostic scoring model can be generated based on both consideration of cytogenetic risk and the MDR status for AML. The CR rate, event-free (EFS) and overall survival (OS) were analysed according to cytogenetic risk, MDR status and clinical factors. Prognostic score was calculated by the sum of MDR status (0 for negative, 1 for positive) and dichotomized scoring for cytogenetic risk (0 for favorable/intermediate and 1 for unfavorable cytogenetics). MDR expression was noted in 36.6% of the patients and associated with a lower CR rate (p = 0.037). MDR, cytogenetics and the use of SCT were identified as independent prognostic factors for EFS and OS. The CR rate of the group scored with 0, 1 and 2 was 81.4, 66.7, and 44.4%, respectively (p = 0.050). The prognostic scoring model depicted a discriminating role in terms of EFS (p < 0.0001) and OS (p = 0.0001). The prognostic scoring model based on cytogenetic risk and MDR provided an improved method for evaluating the prognosis in AML and helped to stratify the risk of patients with the same cytogenetic risk.

Efficacy, Safety, and Pharmacokinetics of Beroctocog Alfa in Patients Previously Treated for Hemophilia A.

PURPOSE: Beroctocog alfa is a second generation recombinant factor VIII manufactured by removing the B-domain from factor VIII. This prospective clinical trial was conducted to evaluate the efficacy, safety, and pharmacokinetics of beroctocog alfa in patients of ages ≥12 years previously treated for severe hemophilia A. MATERIALS AND METHODS: Seventy subjects received beroctocog alfa as an on-demand treatment for acute hemorrhage. RESULTS: The final hemostatic effect was excellent in 35 subjects (50%) and good in 26 subjects (37.1%). The drug showed an overall efficacy rate of 87.1%. The majority of acute hemorrhages was treated by administering the study drug once (86.2%) or twice (10.0%), and the mean dose administered per single infusion was 28.55±6.53 IU/kg. Ten subjects underwent 12 surgical procedures, and hemostatic efficacy was excellent in seven cases (58.3%) and good in five cases (41.7%), showing a 100% efficacy rate. A total of 52 of 88 subjects (59.0%) experienced 168 adverse events. There were 18 serious adverse events (10.7%) in 11 subjects, and two (mild dyspnea and facial edema) in one subject were related to the study drug. Only one subject formed a de novo factor VIII inhibitor, for an occurrence rate of 1.4% (one-sided 95% upper confidence limit: 3.85%). The final elimination half-life was 13.3 h and 12.6 h at baseline and 6 months after administration, respectively. CONCLUSION: Our results suggest that beroctocog alfa is safe and efficacious as either an on-demand treatment for acute hemorrhage or a surgical prophylaxis in patients with hemophilia A.

Natural course of childhood chronic immune thrombocytopenia using the revised terminology and definitions of the international working group: a single center experience.

BACKGROUND: The immune thrombocytopenia (ITP) criteria were newly standardized by the International Working Group. Thus, we analyzed the natural course of childhood chronic ITP to predict the prognosis based on the revised criteria. METHODS: The medical records of children with chronic ITP from May 2000 to February 2013 in our institute were reviewed. RESULTS: Forty-seven children with chronic ITP who were not undergoing corticosteroid therapy were included. Their initial platelet count was 23±25×10(9)/L, and age at diagnosis was 6.3±4.1 years. The follow-up period was 5.4±3.7 years. Among them, 44.7% (21/47) showed spontaneous remission and maintained a platelet count ≥100×10(9)/L. And 66.0% (31/47) maintained a platelet count ≥50×10(9)/L until the last follow-up date. The time periods required for the platelet count to be maintained ≥50×10(9)/L and ≥100 ×10(9)/L were 3.1±2.7 and 3.6±2.7 years. Age at diagnosis in the ≥50×10(9)/L group (5.7±4.4 years) was significantly lower than the age at diagnosis in the <50×10(9)/L group (7.4±3.3 years) (P=0.040). And follow-up period was the factor influencing prognosis between the ≥100×10(9)/L group and <50×10(9)/L group (P=0.022). CONCLUSION: Approximately 45% of children with chronic ITP recovered spontaneously about 3-4 years after the diagnosis and 2/3 of patients maintained a platelet count ≥50×10(9)/L, relatively safe state. Age at diagnosis of ITP and follow-up period were the factors influencing prognosis in this study.

Usefulness of Intraoperative Monitoring during Microsurgical Decompression of Cervicomedullary Compression Caused by an Anomalous Vertebral Artery.

We report a case of cervicomedullary compression by an anomalous vertebral artery treated using microsurgical decompression with intraoperative monitoring. A 68-year-old woman presented with posterior neck pain and gait disturbance. MRI revealed multiple abnormalities, including an anomalous vertebral artery that compressed the spinal cord at the cervicomedullary junction. Suboccipital craniectomy with C1 laminectomy was performed. The spinal cord was found to be compressed by the vertebral arteries, which were retracted dorsolaterally. At that time, the somatosensory evoked potential (SSEP) changed. After release of the vertebral artery, the SSEP signal normalized instantly. The vertebral artery was then lifted gently and anchored to the dura. There was no other procedural complication. The patient's symptoms improved. This case demonstrates that intraoperative monitoring may be useful for preventing procedural complications during spinal cord microsurgical decompression.

Progress of in vitro factor VIII coagulant activity from 0 to 8 hours after reconstitution.

BACKGROUND: Continuous infusion of factor VIII (FVIII) is a more cost-effective method for treating hemophilia A than intermittent bolus injection. However, there is currently no specific data in Korea about the progress of in vitro FVIII coagulant activity (FVIII:C) after reconstitution from its lyophilized form. METHODS: Three commercial FVIII concentrate products (two recombinant FVIII and one plasma-derived) were used. In vitro FVIII:C was measured at 0, 2, 4, 6, and 8 hours following reconstitution in both the indoor light-exposed and light-shielded groups. RESULTS: For the three drugs, in vitro FVIII:C decreased over the 8 hours following reconstitution (P<0.001). The decline of FVIII:C was linear (P<0.001). In vitro FVIII:C for the indoor light-exposed groups was 95.3±1.9% and 90.6±2.5% after 4 and 8 hours following reconstitution, respectively, compared to baseline activity. In the light-shielded group, FVIII:C was 95.4±1.1% and 90.9±1.7% of the baseline activity after 4 and 8 hours, respectively. There was no statistical difference between FVIII:C in the indoor light-exposed and light-shielded groups (P=0.849). CONCLUSION: In vitro FVIII:C decreased after reconstitution, but activity was maintained at over 90% of the baseline value during 8 hours. Exposure to indoor light did not accelerate the loss of FVIII:C over the experimental time. This result indicates that CI with FVIII is available in 8-hour intervals, with no indoor light-exposure precautions needed.