Clinical Characteristics and Treatment Outcomes of Childhood Acute Promyelocytic Leukemia in Korea: A Nationwide Multicenter Retrospective Study by Korean Pediatric Oncology Study Group / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Acute promyelocytic leukemia (APL) is a rare disease in children and there are some different characteristics between children and adult. We aimed to evaluate incidence, clinical characteristics and treatment outcomes of pediatric APL in Korea. @*Materials and Methods@#Seventy-nine pediatric APL patients diagnosed from January 2009 to December 2016 in 16 tertiary medical centers in Korea were reviewed retrospectively. @*Results@#Of 801 acute myeloid leukemia children, 79 (9.9%) were diagnosed with APL. The median age at diagnosis was 10.6 years (range, 1.3 to 18.0). Male and female ratio was 1:0.93. Thirty patients (38.0%) had white blood cell (WBC) count greater than 10×109/L at diagnosis. All patients received induction therapy consisting of all-trans retinoic acid and chemotherapy. Five patients (6.6%) died during induction chemotherapy and 66 patients (86.8%) achieved complete remission (CR) after induction chemotherapy. The causes of death were three intracranial hemorrhage, one cerebral infarction, and one sepsis. Five patients (7.1%) suffered a relapse during or after maintenance chemotherapy. The estimated 4-year event-free survival and overall survival (OS) rates were 82.1%±4.4%, 89.7%±5.1%, respectively. The 4-year OS was significantly higher in patients with initial WBC < 10×109/L than in those with initial WBC ≥ 10×109/L (p=0.020). @*Conclusion@#This study showed that the CR rates and survival outcomes in Korean pediatric APL patients were relatively good. The initial WBC count was the most important prognostic factor and most causes of death were related to serious bleeding in the early stage of treatment.

Seroprevalence of Hepatitis A Virus in Pediatric Patients with Hematologic Malignancies after Chemotherapy and Hematopoietic Cell Transplantation

This retrospective study was performed to determine the seroprevalence of hepatitis A virus (HAV) in children and adolescents with hematologic malignancies after the completion of chemotherapy and hematopoietic cell transplantation (HCT). Of 97 enrolled patients, 60 (61.9%) were seropositive for HAV. The seroprevalences in patients undergoing chemotherapy and HCT were 60.3% (41/68) and 65.5% (19/29), respectively (P = 0.628). No significant factors associated with seropositivity for HAV after chemotherapy and HCT were identified. Anti-HAV tests and HAV re-vaccinations can be considered in children and adolescents with underlying hematologic malignancies after chemotherapy and HCT based on the anti-HAV results.

Treatment and response of autoimmune cytopenia occurring after allogeneic hematopoietic cell transplantation in children

BACKGROUND: Autoimmune cytopenia (AIC) is a rare complication of allogeneic hematopoietic cell transplantation (HCT). In this study, we reviewed the diagnosis, treatment and response to therapy for pediatric patients with post-HCT AIC at our institution. METHODS: Of the 292 allogeneic HCTs performed from January, 2011 to December, 2015 at the Department of Pediatrics, The Catholic University of Korea, seven were complicated by post-HCT AIC, resulting in an incidence of 2.4%. RESULTS: All seven patients with post-HCT AIC had received unrelated donor transplant. Six of seven patients had a major donor-recipient blood type mismatch. The subtypes of AIC were as follows: immune thrombocytopenia (ITP) 2, autoimmune hemolytic anemia (AIHA) 2, Evans syndrome 3. Median time from HCT to AIC diagnosis was 3.6 months. All but one patient responded to first line therapy of steroid±intravenous immunoglobulin (IVIG), but none achieved complete response (CR) with this treatment. After a median duration of treatment of 15.3 months, two patients with ITP achieved CR and five had partial response (PR) of AIC. Five patients were treated with rituximab, resulting in the following response: 2 CR, 2 PR, 1 no response (NR). Median time to response to rituximab was 26 days from first infusion. All patients are alive without event. CONCLUSION: Post-HCT AIC is a rare complication that may not resolve despite prolonged therapy. Rapid initiation of second line agents including but not limited to B cell depleting treatment should be considered for those that fail to achieve CR with first line therapy.

Outcome and Prognostic Factors for ETV6/RUNX1 Positive Pediatric Acute Lymphoblastic Leukemia Treated at a Single Institution in Korea / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: ETV6/RUNX1 (+) acute lymphoblastic leukemia (ALL), which is the most common genetic subtype of pediatric ALL, has a favorable prognosis. In this study, we analyzed the outcome of ETV6/RUNX1 (+) ALL patients treated at our institution with the aim of identifying significant prognostic variables. MATERIALS AND METHODS: Sixty-three patients were diagnosed with ETV6/RUNX1 (+) ALL from 2005 to 2011. Prognostic variables studied included minimal residual disease (MRD) as detected by ETV6/RUNX1 (+) fusion, and the presence of additional cytogenetic abnormalities. RESULTS: The 5-year event-free survival was 84.1±4.6%, with 10 patients relapsing at a median of 28.3 months from diagnosis for a 5-year cumulative incidence of relapse of 15.9±4.6%. Multivariate analysis revealed that the presence MRD, as detected by real-time quantitative-polymerase chain reaction or fluorescence in situ hybridization for ETV6/RUNX1 fusion at end of remission induction, and the presence of additional structural abnormalities of 12p (translocations or inversions) negatively affected outcome. Despite treatment such as allogeneic hematopoietic cell transplantation, eight of the 10 relapsed patients died from disease progression for overall survival of 82.5±6.9%. CONCLUSION: ETV6/RUNX1 (+) ALL may be heterogeneous in terms of prognosis, and variables such as MRD at end ofremission induction or additional structural abnormalities of 12p could define a subset of patients who are likely to have poor outcome.

A Novel Syntaxin 11 Gene (STX11) Mutation c.650T>C, p.Leu217Pro, in a Korean Child With Familial Hemophagocytic Lymphohistiocytosis

We report the first Far Eastern case of a Korean child with familial hemophagocytic lymphohistiocytosis (HLH) caused by a novel syntaxin 11 (STX11) mutation. A 33-month-old boy born to non-consanguineous Korean parents was admitted for intermittent fever lasting one week, pancytopenia, hepatosplenomegaly, and HLH in the bone marrow. Under the impression of HLH, genetic study revealed a novel homozygous missense mutation of STX11: c.650T>C, p.Leu217Pro. Although no large deletion or allele drop was identified, genotype analysis demonstrated that the homozygous c.650T>C may have resulted from the duplication of a maternal (unimaternal) chromosomal region and concurrent loss of the other paternal allele, likely caused by meiotic errors such as two crossover events. A cumulative study of such novel mutations and their effects on specific protein interactions may deepen the understanding of how abnormal STX1 expression results in deficient cytotoxic function.

Subclinical left ventricular dysfunction in children after hematopoietic stem cell transplantation for severe aplastic anemia: a case control study using speckle tracking echocardiography / 소아과

PURPOSE: Severe aplastic anemia (SAA), a fatal disease, requires multiple transfusion, immunosuppressive therapy, and finally, hematopoietic stem cell transplantation (HSCT) as the definitive treatment. We hypothesized that iron overloading associated with multiple transfusions and HSCTrelated complications may adversely affect cardiac function. Left ventricular (LV) function was assessed in children after HSCT for SAA. METHODS: Forty-six consecutive patients with a median age of 9.8 years (range, 1.5-18 years), who received HSCT for SAA and who underwent comprehensive echocardiography before and after HSCT, were included in this study. The data of LV functional parameters obtained using conventional echocardiography, tissue Doppler imaging (TDI), and speckle-tracking echocardiography (STE) were collected from pre- and post-HSCT echocardiography. These data were compared to those of 40 age-matched normal controls. RESULTS: In patients, the LV ejection fraction, shortening fraction, end-diastolic dimension, mitral early diastolic E velocity, TDI mitral septal E' velocity, and STE LV longitudinal systolic strain rate (SSR) decreased significantly after HSCT. Compared to normal controls, patients had significantly lower post-HSCT early diastolic E velocity and E/A ratio. On STE, patients had significantly decreased LV deformational parameters including LV longitudinal systolic strain (SS), SSR, and diastolic SR (DSR), and circumferential SS and DSR. Serum ferritin levels showed weak but significant correlations (P<0.05) with LV longitudinal SS and SSR and circumferential SS and DSR. CONCLUSION: Subclinical LV dysfunction is evident in patients after HSCT for SAA, and was associated with increased iron load. Serial monitoring of cardiac function is mandatory in this population.

Increase in Antibiotic-Resistant Gram-Negative Bacterial Infections in Febrile Neutropenic Children

BACKGROUND: The incidence of bacteremia caused by Gram-negative bacteria has increased recently in febrile neutropenic patients with the increase of antibiotic-resistant Gram-negative bacterial infections. This study aimed to identify the distribution of causative bacteria and the proportion of antibiotic-resistant bacteria in bacteremia diagnosed in febrile neutropenic children. MATERIALS AND METHODS: The medical records of febrile neutropenic children diagnosed with bacteremia between 2010 and 2014 were retrospectively reviewed. The causative bacteria and proportion of antibiotic-resistant bacteria were investigated and compared yearly during the study period. The clinical impact of antibiotic-resistant bacterial infections was also determined. RESULTS: A total of 336 bacteremia episodes were identified. During the entire study period, 181 (53.9%) and 155 (46.1%) episodes were caused by Gram-negative and Gram-positive bacteria, respectively. Viridans streptococci (25.9%), Klebsiella spp. (16.7%), and Escherichia coli (16.4%) were the most frequent causative bacteria. The overall distribution of causative bacteria was not significantly different annually. Antibiotic-resistant bacteria were identified in 85 (25.3%) episodes, and the proportion of antibiotic-resistant bacteria was not significantly different annually. Extended-spectrum β-lactamase-producing E. coli and Klebsiella spp. were most common among antibiotic-resistant Gram-negative bacteria, and they accounted for 30.6% (n = 34) of the identified E. coli and K. pneumoniae. Methicillin-resistant coagulase-negative staphylococci were most common among antibiotic-resistant Gram-positive bacteria, and it accounted for 88.5% (n = 23) of the identified coagulase-negative staphylococci. Antibiotic-resistant bacterial infections, especially antibiotic-resistant Gram-negative bacterial infections, caused significantly higher mortality due to bacteremia compared with non-antibiotic-resistant bacterial infections (P <0.001). CONCLUSION: Recently, Gram-negative bacteria caused more bacteremia cases than Gram-positive bacteria in febrile neutropenic children, and antibiotic-resistant Gram-negative bacterial infections increased. Antibiotic-resistant bacterial infections caused poorer prognosis compared with non-antibiotic-resistant bacterial infections, and therefore, continuous surveillance for changing epidemiology of antibiotic-resistant bacterial infections and their clinical impact is necessary.

Clinical characteristics and outcomes of varicella zoster virus infection in children with hematologic malignancies in the acyclovir era

BACKGROUND: Although intravenous acyclovir therapy is recommended for varicella zoster virus (VZV) infection in immunocompromised children, the clinical characteristics and outcomes of VZV infection in the acyclovir era have rarely been reported. METHODS: The medical records of children diagnosed with varicella or herpes zoster virus, who had underlying hematologic malignancies, were retrospectively reviewed, and the clinical characteristics and outcomes of VZV infection were evaluated. RESULTS: Seventy-six episodes of VZV infection (herpes zoster in 57 and varicella in 19) were identified in 73 children. The median age of children with VZV infection was 11 years (range, 1-17), and 35 (46.1%) episodes occurred in boys. Acute lymphoblastic leukemia was the most common underlying malignancy (57.9%), and 90.8% of the episodes occurred during complete remission of the underlying malignancy. Acyclovir was administered for a median of 10 days (range, 4-97). Severe VZV infection occurred in 16 (21.1%) episodes. Although the finding was not statistically significant, a previous history of hematopoietic cell transplantation (HCT) appeared to be associated with the development of more severe episodes of herpes zoster (P=0.075). CONCLUSION: Clinical characteristics of VZV infection in immunocompromised children were not significantly different from those without it, and clinical outcomes improved after the introduction of acyclovir therapy. However, risk factors for severe VZV infection require further investigation in a larger population and a prospective setting.

Clinical Features and Prognosis of Invasive Pulmonary Aspergillosis in Korean Children with Hematologic/Oncologic Diseases

Invasive pulmonary aspergillosis (IPA) is the most frequent form of invasive fungal diseases in immunocompromised patients. However, there are only a few studies on IPA in immunocompromised children in Korea. This study was designed to characterize IPA in Korean children with hematologic/oncologic diseases. Medical records of children with hematologic/oncologic diseases receiving antifungal therapy were reviewed. The enrolled children were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups. During the study period, 265 courses of antifungal therapy were administered to 166 children. Among them, two (0.8%) episodes of proven IPA, 35 (13.2%) of probable IPA, and 52 (19.6%) of possible IPA were diagnosed. More children in the IPA group suffered from neutropenia lasting for more than two weeks (51.4% vs. 21.9%, P<0.001) and showed halo signs on the chest computed tomography (78.4% vs. 40.7%, P<0.001) than in the non-IPA group. No other clinical factors showed significant differences between the two groups. Amphotericin B deoxycholate was administered as a first line antifungal agent in 33 (89.2%) IPA group episodes, and eventually voriconazole was administered in 27 (73.0%) episodes. Ten (27.0%) children in the IPA group died within 12 weeks of antifungal therapy. In conclusion, early use of chest computed tomography to identify halo signs in immunocompromised children who are expected to have prolonged neutropenia can be helpful for early diagnosis of IPA and improving prognosis of children with IPA.

Invasive Pulmonary Aspergillosis after Recent Influenza in a Child with Acute Myeloid Leukemia / 임상소아혈액종양

Respiratory viral infection has been reported as a risk factor for invasive pulmonary aspergillosis (IPA) in hematopoietic cell transplantation (HCT) recipients, and IPA following influenza has been reported. We report a 13-year-old boy diagnosed with IPA following influenza. He received allogeneic HCT and then received glucocorticoids for chronic graft-versus-host disease. On admission, he complained of non-neutropenic fever and dyspnea. He was diagnosed with influenza A via a polymerase chain reaction (PCR) test from nasopharyngeal swab, and oseltamivir was administered. Fever re-emerged nine days later and repeat PCR was positive for influenza A. His fever did not resolve despite triple antiviral and empirical antibiotic therapy. On hospital day 22, IPA was diagnosed based on chest computed tomography and positive serum galactomannan results, and his symptoms improved with voriconazole therapy. However, he died of uncontrolled bronchiolitis obliterans on hospital day 128. IPA should be considered a complication of influenza in immunocompromised children.

Invasive Pulmonary Aspergillosis after Recent Influenza in a Child with Acute Myeloid Leukemia / 임상소아혈액종양

Respiratory viral infection has been reported as a risk factor for invasive pulmonary aspergillosis (IPA) in hematopoietic cell transplantation (HCT) recipients, and IPA following influenza has been reported. We report a 13-year-old boy diagnosed with IPA following influenza. He received allogeneic HCT and then received glucocorticoids for chronic graft-versus-host disease. On admission, he complained of non-neutropenic fever and dyspnea. He was diagnosed with influenza A via a polymerase chain reaction (PCR) test from nasopharyngeal swab, and oseltamivir was administered. Fever re-emerged nine days later and repeat PCR was positive for influenza A. His fever did not resolve despite triple antiviral and empirical antibiotic therapy. On hospital day 22, IPA was diagnosed based on chest computed tomography and positive serum galactomannan results, and his symptoms improved with voriconazole therapy. However, he died of uncontrolled bronchiolitis obliterans on hospital day 128. IPA should be considered a complication of influenza in immunocompromised children.

Limitation of Prediction on Intravenous Immunoglobulin Responsiveness in Kawasaki Disease / 소아감염

PURPOSE: We aimed to evaluate predictive parameters for non-response to intravenous immunoglobulin (IVIG) in patients with Kawasaki disease (KD) before IVIG use using two controls. METHODS: We evaluated 229 consecutive KD patients who were treated with 2 g/kg of IVIG at a single center. Those who had persistent fever >24 hours after IVIG infusion made up the 23 IVIG non-responders; the first control included a total 206 defervesced cases and the second control included 46 cases that were matched for age and pre-treatment fever duration to non-responders. RESULTS: Demographic and clinical characteristics were similar in IVIG non-responders and responders at presentation. As for laboratory findings, the neutrophil differential, CRP, AST, ALT, and LDH were higher, and lymphocyte differential, total protein, albumin, platelet count, and total cholesterol were significantly lower in IVIG non-responders compared to responders by univariate analysis in both study designs. However in multivariate analysis, non-responders showed a significantly higher neutrophil differential (cutoff value, >77%, sensitivity 68.4% and specificity 79.5%) and lower cholesterol (<124 mg/dL, sensitivity 79% and specificity 70.5%). Whereas plasma albumin (<3.6 g/dL, sensitivity 73.7% and specificity 60%) was the sole laboratory parameter of non-responders in the second study design. CONCLUSION: Severity of inflammation in KD was reflected by higher or lower laboratory values at presentation. Because the multivariate analysis for these indices may be influenced by some confounding factors, including the numbers of patients of different ages and fever duration, other assessment modalities are needed for KD patients with the greatest risk of coronary artery lesions.

A Case of Walker-Warburg Syndrome Presented with Seizures

Walker-Warburg syndrome (WWS) is a rare autosomal recessive disorder characterized by congenital muscular dystrophy, brain (lissencephaly, hydrocephalus, cerebellar malformations) and retinal abnormalities, and is associated with mental retardation and seizures. In 1942, Walker was the first to report a case of WWS. As Fukuyama congenital muscular dystrophy or muscle-eye-brain disorder, it has been demonstrated that the glycosylation defects of alpha-dystroglycan which take a great role in muscle and neuron regeneration are at the root of these disorders. We report a five months old male patient who was presented with seizures as the chief complaint and was diagnosed with WWS, based on clinical criteria, MRI, muscular biopsy, ocular examination, and laboratory findings.

Subacute Necrotizing Lymphadenitis in a 3 Year-Old Male Child

Subacute necrotizing lymphadenitis is a benign form of lymphadenitis that was first described in Japan by Kikuchi in 1972. It mainly affects young women and usually manifests as fever and lymphadenopathy. Although it is a benign self-limited lymphadenitis, it has been misdiagnosed as malignant lymphoma. Histologically, involved lymph nodes contain a necrotizing process characterized by patch, well-circumscribed area with eosinophilic fibrinoid material. There is a striking degree of karyorrhexis and an absence of granulocyte with paucity of plasma cell. We expereinced a case of subacute necrotizing lymphadenitis in a 3 year old boy. There was spontaneous resolution of fever and lymphadenopathy, and now he keeps doing well.