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.

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.

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 > or =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.

Elevated cerebrospinal fluid IgG index in acute cerebellitis presenting with sudden onset headache

Acute cerebellitis is a rare inflammatory syndrome and is one of the important causes of acute cerebellar dysfunction in children. The cerebrospinal fluid (CSF) IgG index is most often tested clinically in the diagnosis of multiple sclerosis. However, it is not specific to multiple sclerosis, and can be elevated in a variety of neurologic diseases. A 7-year-old boy with acute cerebellitis presenting with sudden onset headache and subtle cerebellar dysfunction demonstrated an elevated CSF IgG index (1.1) and an absence of oligoclonal bands. On the seventeenth day, the follow-up CSF IgG index was 0.71. Two-month and one-year follow-up magnetic resonance imaging revealed cerebellar atrophy, although the patient showed no neurologic deficit. To the best of our knowledge, this case report is the first to describe acute cerebellitis accompanied by an elevated CSF IgG index and an absence of CSF oligoclonal IgG bands. These findings suggest that a breach in the blood-brain-barrier might occur in acute cerebellitis.

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.

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+/-25x10(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 > or =100x10(9)/L. And 66.0% (31/47) maintained a platelet count > or =50x10(9)/L until the last follow-up date. The time periods required for the platelet count to be maintained > or =50x10(9)/L and > or =100 x10(9)/L were 3.1+/-2.7 and 3.6+/-2.7 years. Age at diagnosis in the > or =50x10(9)/L group (5.7+/-4.4 years) was significantly lower than the age at diagnosis in the or =100x10(9)/L group and or =50x10(9)/L, relatively safe state. Age at diagnosis of ITP and follow-up period were the factors influencing prognosis in this study.

Second case of postpartum acquired hemophilia A in a Korean female

No abstract available.

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.

Various endocrine disorders in children with t(13;14)(q10;q10) Robertsonian translocation

PURPOSE: 45,XY,t(13;14)(q10;q10) karyotype can suggest infertility associated with more or less severe oligospermia in male adults. In addition, 45,XX,t(13;14)(q10;q10) karyotype carries reproductive risks such as miscarriage or infertility in female adults. However, reports on the phenotype of this karyotype in children are very rare. This study was done to observe various phenotypes of this karyotype in children. METHODS: Between January 2007 and December 2012, children diagnosed with 45,XY,t(13;14)(q10;q10) or 45,XX,t(13;14)(q10;q10) karyotype by chromosome analysis were analyzed retrospectively. RESULTS: Eight children (5 boys and 3 girls) were diagnosed with 45,XY,t(13;14)(q10;q10) or 45,XX,t(13;14)(q10;q10) karyotype. They ranged in age from 5 years and 6 months to 12 years and 4 months. The phenotypes of the study patients consisted of 1 hypogonadotrophic hypogonadism, 1 precocious puberty, 3 early puberty, 2 growth hormone deficiency (GHD) (partial) and 1 idiopathic short stature. As shown here t(13;14)(q10;q10) Robertsonian translocation shows a wide range of phenotypes. CONCLUSION: It can be said that t(13;14)(q10;q10) Robertsonian translocation shows various phenotypes from GHD to precocious puberty in children. Further large-scale studies are necessary.

Asymptomatic moyamoya syndrome, atlantoaxial subluxation and basal ganglia calcification in a child with Down syndrome / 소아과

Down syndrome, the most common chromosomal abnormality, may be associated with various neurologic complications such as moyamoya syndrome, cervical spinal cord compression due to atlantoaxial subluxation, and basal ganglia damage, as well as epileptic seizures and stroke. Many cases of Down syndrome accompanied by isolated neurologic manifestations have been reported in children; however, Down syndrome with multiple neurologic conditions is rare. Here, we have reported a case of Down syndrome in a 10-year-old girl who presented with asymptomatic moyamoya syndrome, atlantoaxial subluxation with spinal cord compression, and basal ganglia calcification. To the best of our knowledge, this is the first report of Down syndrome, in a child, which was accompanied by these 3 neurologic complications simultaneously. As seen in this case, patients with Down syndrome may have neurologic conditions without any obvious neurologic symptoms; hence, patients with Down syndrome should be carefully examined for the presence of neurologic conditions.

An Efficient Microvascular Anastomosis Training Model Based on Chicken Wings and Simple Instruments

OBJECTIVE: The aim of this study is to introduce a microvascular training model based on use of materials that can be easily obtained from the daily surroundings. METHODS: Simple microinstruments and a medical school laboratory microscope were used for anastomosis training. Chicken blood vessels were used as a material for this study. A long segment of blood vessel from the proximal brachial artery to the distal radial artery was used for training. End-to-side anastomosis was practiced first, and the training continued with end-to-end anastomosis of the appropriate segments. RESULTS: The instruments used for setting up this model were simple and easy to use; therefore, the time required for preparation of the materials and dissection of the chicken wings was only approximately five to ten minutes. The characteristics of 20 chicken wings were analyzed. The length of the brachial artery to the radial artery was 8 - 10 cm. The average diameter of the brachial artery was 1.3 mm +/- 0.2 mm and that of the radial artery was 1.0 mm +/- 0.2 mm. Taking advantage of these characteristics, the proximal brachial artery was grafted to the radial artery for practice of end-to-side anastomosis. CONCLUSIONS: This study suggests an effective and feasible method for microvascular anastomosis training using chicken wing arteries and simple microinstruments. This model may simulate the conditions of a superficial temporal artery to middle cerebral artery anastomosis surgery.

Early Prediction of Chronic Childhood Immune Thrombocytopenic Purpura According to the Response of Immunoglobulin Treatment / 임상소아혈액종양

BACKGROUND: Immune thrombocytopenic purpura (ITP) is a frequently observed bleeding disorder in children. High dose intravenous immunoglobulin G (IVIG) has been used for the treatment of ITP since 1981, and now several methods of IVIG infusion are used. Since 1983, we have treated ITP patients with short-term and low-dose IVIG according to the individual patient's daily response. This study aimed to evaluate individual patient's response after IVIG for the prediction of chronic ITP. METHODS: We evaluated 259 childhood ITP patients retrospectively who were newly diagnosed at the Department of Pediatrics, Kyungpook National University Hospital from 1983 to 2012. We analyzed the individual response to treatment and current state of disease. We evaluated the time to reach desired platelet counts after treatment of IVIG, relapse rate and diagnosis of chronic ITP. The patients were classified into 2 groups according to the time to reach desired platelet counts (50,000/microL) after daily treatment of IVIG, rapid (1 or 2 doses) and slow responder (more than 3 doses). RESULTS: Among 182 patients followed up over 6 months, 41 patients (22.5%) were eventually diagnosed with chronic ITP. Hundred and two patients (56.7%) belonged to rapid response group, and 17 of them (16.7%) were diagnosed with chronic ITP. Eighty patients (44.4%) belonged to the slow response group, and 24 of them (30%) were diagnosed with chronic ITP, which were higher than the early response group (P=0.033). CONCLUSION: Individual response rate of IVIG treatment could be a useful predictor of chronic ITP, but this finding needs support from further studies.

Early Prediction of Chronic Childhood Immune Thrombocytopenic Purpura According to the Response of Immunoglobulin Treatment / 임상소아혈액종양

BACKGROUND: Immune thrombocytopenic purpura (ITP) is a frequently observed bleeding disorder in children. High dose intravenous immunoglobulin G (IVIG) has been used for the treatment of ITP since 1981, and now several methods of IVIG infusion are used. Since 1983, we have treated ITP patients with short-term and low-dose IVIG according to the individual patient's daily response. This study aimed to evaluate individual patient's response after IVIG for the prediction of chronic ITP. METHODS: We evaluated 259 childhood ITP patients retrospectively who were newly diagnosed at the Department of Pediatrics, Kyungpook National University Hospital from 1983 to 2012. We analyzed the individual response to treatment and current state of disease. We evaluated the time to reach desired platelet counts after treatment of IVIG, relapse rate and diagnosis of chronic ITP. The patients were classified into 2 groups according to the time to reach desired platelet counts (50,000/microL) after daily treatment of IVIG, rapid (1 or 2 doses) and slow responder (more than 3 doses). RESULTS: Among 182 patients followed up over 6 months, 41 patients (22.5%) were eventually diagnosed with chronic ITP. Hundred and two patients (56.7%) belonged to rapid response group, and 17 of them (16.7%) were diagnosed with chronic ITP. Eighty patients (44.4%) belonged to the slow response group, and 24 of them (30%) were diagnosed with chronic ITP, which were higher than the early response group (P=0.033). CONCLUSION: Individual response rate of IVIG treatment could be a useful predictor of chronic ITP, but this finding needs support from further studies.

Early Prediction of Chronic Childhood Immune Thrombocytopenic Purpura According to the Response of Immunoglobulin Treatment / 임상소아혈액종양

BACKGROUND: Immune thrombocytopenic purpura (ITP) is a frequently observed bleeding disorder in children. High dose intravenous immunoglobulin G (IVIG) has been used for the treatment of ITP since 1981, and now several methods of IVIG infusion are used. Since 1983, we have treated ITP patients with short-term and low-dose IVIG according to the individual patient's daily response. This study aimed to evaluate individual patient's response after IVIG for the prediction of chronic ITP.METHODS: We evaluated 259 childhood ITP patients retrospectively who were newly diagnosed at the Department of Pediatrics, Kyungpook National University Hospital from 1983 to 2012. We analyzed the individual response to treatment and current state of disease. We evaluated the time to reach desired platelet counts after treatment of IVIG, relapse rate and diagnosis of chronic ITP. The patients were classified into 2 groups according to the time to reach desired platelet counts (50,000/microL) after daily treatment of IVIG, rapid (1 or 2 doses) and slow responder (more than 3 doses).RESULTS: Among 182 patients followed up over 6 months, 41 patients (22.5%) were eventually diagnosed with chronic ITP. Hundred and two patients (56.7%) belonged to rapid response group, and 17 of them (16.7%) were diagnosed with chronic ITP. Eighty patients (44.4%) belonged to the slow response group, and 24 of them (30%) were diagnosed with chronic ITP, which were higher than the early response group (P=0.033).CONCLUSION: Individual response rate of IVIG treatment could be a useful predictor of chronic ITP, but this finding needs support from further studies.

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.

A Case Report of Botryoid Wilms Tumor: Has Different Clinical Manifestations / 임상소아혈액종양

A previously healthy, 16-month-old boy was admitted to hospital due to fever, vomiting, and persistent gross hematuria for 2 weeks. His imaging studies showed an inhomogeneous mass, in a left dilated renal pelvis and proximal ureter, which was suggestive of a kidney neoplasm. A stage I Wilms tumor limited to the nephrectomised kidney was diagnosed by histology. The margin of ureter and renal vessels were clear. There was no evidence of anaplasia, angiolymphatic invasion, or skeletal muscle differentiation. In addition, there were polypoid protrusions of tumor into the pelvicaliceal system, resulting in such a 'botryoid' appearance. The patient had been treated with adjuvant chemotherapy using 7 cycles of intravenous actinomycin-D and vincristine (NWTS regimen EE4A) for 5 months. During a 22-month follow-up period, there has been no evidence of tumor recurrence.

A Case Report of Botryoid Wilms Tumor: Has Different Clinical Manifestations / 임상소아혈액종양

A previously healthy, 16-month-old boy was admitted to hospital due to fever, vomiting, and persistent gross hematuria for 2 weeks. His imaging studies showed an inhomogeneous mass, in a left dilated renal pelvis and proximal ureter, which was suggestive of a kidney neoplasm. A stage I Wilms tumor limited to the nephrectomised kidney was diagnosed by histology. The margin of ureter and renal vessels were clear. There was no evidence of anaplasia, angiolymphatic invasion, or skeletal muscle differentiation. In addition, there were polypoid protrusions of tumor into the pelvicaliceal system, resulting in such a 'botryoid' appearance. The patient had been treated with adjuvant chemotherapy using 7 cycles of intravenous actinomycin-D and vincristine (NWTS regimen EE4A) for 5 months. During a 22-month follow-up period, there has been no evidence of tumor recurrence.

Novel influenza A (H1N1) 2009 infection in the pediatric patients with hematologic and oncologic diseases in the Yeungnam region / 소아과

PURPOSE: Natural history and consequences of the novel 2009 influenza A H1N1 (2009 H1N1) infection in immunocompromised pediatric patients are not yet fully understood. In this study, we investigated the clinical features and outcomes of the 2009 H1N1 infection in pediatric patients with hematological and oncological diseases. METHODS: We retrospectively reviewed the medical records of 528 patients who had hematological and oncological diseases and who were treated at 7 referral centers located in the Yeungnam region. Among the 528 patients, 27 with definite diagnosis of 2009 H1N1 infection were the subjects of this study. All patients were divided into the following 3 groups: patients who were receiving chemotherapy (group 1), patients who were immunosuppressed due to a non-malignant hematological disease (group 2), and patients who were off chemotherapy and had undergone their last chemotherapy course within 2 years from the influenza A pandemic (group 3). RESULTS: All 28 episodes of 2009 H1N1 infection were treated with the antiviral agent oseltamivir (Tamiflu(R)), and 20 episodes were treated after hospitalization. Group 1 patients had higher frequencies of lower respiratory tract infection and longer durations of fever and hospitalization as compared to those in group 2. Ultimately, all episodes resolved completely with no complications. CONCLUSION: These results suggest that early antiviral therapy did not influence the morbidity or mortality of pediatric patients with hematological and oncological diseases in the Yeungnam region of Korea after the 2009 H1N1 infection. However, no definite conclusions can be drawn because of the small sample size.

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 microg/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.

A Case of Pediatric Solid Pseudopapillary Tumor of the Pancreas Treated with Gemcitabine / 임상소아혈액종양

Solid pseudopapillary tumors of the pancreas (SPTPs) are rare tumors with limited malignant potential; they are mainly diagnosed in young women. Complete surgical resection of the tumor is usually possible and patients have an excellent prognosis. However, local invasion and distant metastases have been reported in about 10-20% of patients with SPTPs; these patients require supplementary management for long-term survival. Here, we report a pediatric patient with inoperable SPTP unresponsive to neoadjuvant chemotherapy using cisplatin, ifosfamide, and etoposide which had spread to other organs. Subtotal resection of the primary tumor, radiofrequency ablation, radiotherapy, and adjuvant chemotherapy using gemcitabine were done to control this progressive SPTP.