June Dong Park

Amniotic fluid cytokines (interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-8) and the risk for the development of bronchopulmonary dysplasia

Abstract OBJECTIVE: Our purpose was to test the hypothesis that neonates who develop bronchopulmonary dysplasia have higher amniotic fluid concentrations of proinflammatory cytokines than those who do not develop bronchopulmonary dysplasia. STUDY DESIGN: The relationship between amniotic fluid concentrations of interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-8 and the occurrence of bronchopulmonary dysplasia in the neonate was examined in 69 patients who were delivered of preterm neonates (≤33 weeks) within 5 days of amniocentesis. Cytokines were measured by specific immunoassays. RESULTS: Bronchopulmonary dysplasia was diagnosed in 19% (13/69) of newborns. Median amniotic fluid concentrations of interleukin-6, tumor necrosis factor-α, interleukin-1β, and interleukin-8 concentrations were significantly higher in mothers whose infants had bronchopulmonary dysplasia than in mothers whose infants did not have bronchopulmonary dysplasia ( p p CONCLUSIONS: (1) Antenatal exposure to proinflammatory cytokines is a risk factor for the development of bronchopulmonary dysplasia; (2) the injury responsible for bronchopulmonary dysplasia in a subset of neonates may begin before birth. (Am J Obstet Gynecol 1997;177:825-30.)

Increase of interleukin-6 in tracheal aspirate at birth: a predictor of subsequent bronchopulmonary dysplasia in preterm infants.

Aim: We tested whether interleukin-6 (IL-6) in tracheal aspirate (TA) at birth, as a marker of fetal pulmonary inflammation, can be a predictor of bronchopulmonary dysplasia (BPD) in preterm infants. Methods: A total of 75 preterm (≤32 wk) infants who were intubated in the delivery room were prospectively enrolled. Multivariate logistic regression analysis was done to determine whether IL-6 in TA at birth is an independent risk factor for BPD, and a receiver-operating characteristic curve was constructed to determine the accuracy of IL-6 in TA for predicting the risk of BPD. Results: IL-6 in TA at birth was an independent risk factor for BPD. Fetal pulmonary inflammation defined as IL-6 in TA at birth ≥316 pg/ml together with patent ductus arteriosus (PDA) additively predicted the risk of BPD. The sensitivity, specificity, and positive and negative predictive values of fetal pulmonary inflammation for the identification of BPD were 73%, 71%, 58% and 83%, respectively. Conclusion: IL-6 in TA at birth can be used as a predictor of BPD in combination with the presence of PDA.

Humidifier Disinfectant–associated Children’s Interstitial Lung Disease

RATIONALE Beginning in 2006, epidemics of a fatal lung injury of unknown cause in children were observed in Korea every spring. A recent study demonstrated that this type of childrens interstitial lung disease (chILD) is associated with humidifier disinfectant use. OBJECTIVES To determine the clinical characteristics of this type of chILD and to assess whether the nationwide suspension of humidifier disinfectant sales in the autumn of 2011 affected its incidence. METHODS The clinical characteristics of suspected cases between 2006 and 2011 were determined by a nationwide retrospective study. The potential causal relationship with humidifier disinfectants was examined by a prospective surveillance study after humidifier disinfectant sales were suspended. MEASUREMENTS AND MAIN RESULTS In total, 138 children were diagnosed with this type of chILD, which was characterized by rapid progression, high mortality, predominance in the spring season, and a familial tendency. The annual incidence increased in 2011 and then dropped to zero in 2012. The children were on average 30.4 months old. The most frequent symptoms at admission were cough and dyspnea. As the disease progressed, the typical complication was spontaneous air leak. Eighty children (58%) died. Two years after humidifier disinfectant-sale suspension, no more new cases were found. CONCLUSIONS This study suggests that humidifier disinfectant inhalation causes an idiopathic type of chILD that is characterized by spontaneous air leak, rapid progression, lack of response to treatment, and high mortality. Further safety studies must be performed on common environmental compounds, particularly those that enter the human body by an unusual route.

Risk factors for the different types of chronic lung diseases of prematurity according to the preceding respiratory distress syndrome

Background : Recently, atypical chronic lung disease (CLD) of prematurity that develops in the absence of preceding respiratory distress syndrome (RDS) have been observed frequently. The specific risk factors for atypical CLD that are presumed to be different from those for classical CLD that develops following RDS were assessed.

Successful Treatment of Primary Central Nervous System Lymphoma without Irradiation in Children: Single Center Experience

Primary CNS lymphoma (PCNSL) is a very uncommon disease in children, and usually treated by chemotherapy, combined with focal or craniospinal radiotherapy (RT). However, adverse effects of RT are a concern. We evaluated the outcomes of childhood PCNSL, treated with systemic and intrathecal chemotherapy, but without RT. For fifteen years, six patients among 175 of non-Hodgkin lymphoma were diagnosed as PCNSL in Seoul National University Childrens Hospital and we analyzed their medical records retrospectively. Their male:female ratio was 5:1, and median age was 10.1 yr. The primary sites were the sellar area in three patients, parietal area in one, cerebellum in one, and multiple areas in one. Their pathologic diagnoses were diffuse large B-cell lymphoma in three patients, Burkitt lymphoma in two, and undifferentiated B-cell lymphoma in one. Five were treated with the LMB96 treatment protocol, and one was treated with the CCG-106B protocol. None had RT as a first-line treatment. One patient had a local relapse and received RT and salvage chemotherapy, without success. No patient had treatment-related mortality. Their estimated 5-yr event-free and overall survival rates were both 83.3%. In conclusion, PCNSL is a rare disease in childhood, but successfully treated by chemotherapy without RT.

Pharmacogenetic Study of Deferasirox, an Iron Chelating Agent

Transfusion-associated iron overload induces systemic toxicity. Deferasirox, a convenient long acting oral agent, has recently been introduced in clinical practice with a promising efficacy. But there are some patients who experience drug-related toxicities and cannot tolerate it. To investigate effect of genetic variations on the toxicities and find optimal target population, we analyzed the genetic polymorphisms of UDP-glucuronosyltransferase 1A (UGT1A) subfamily, multi-drug resistance-associated protein 2 (MRP2) and breast cancer resistance protein (BCRP). A total of 20 functional genetic polymorphisms were analyzed in 98 patients who received deferasirox to reduce transfusion-induced iron overload. We retrospectively reviewed the medical records to find out the drug-related toxicities. Fifteen (15.3%) patients developed hepatotoxicity. Patients without wild-type allele carrying two MRP2 haplotypes containing −1774 del and/or −24T were at increased risk of developing hepatotoxicity compared to patients with the wild-type allele on multivariate analysis (OR = 7.17, 95% CI = 1.79–28.67, P = 0.005). Creatinine elevation was observed in 9 patients (9.2%). Body weight ≥40 kg and homozygosity for UGT1A1*6 were risk factors of creatinine elevation (OR = 8.48, 95% CI = 1.7–43.57, P = 0.010 and OR = 14.17, 95% CI = 1.34–150.35, P = 0.028). Our results indicate that functional genetic variants of enzymes to metabolize and transport deferasirox are associated with drug-related toxicities. Further studies are warranted to confirm the results as the pharmacogenetic biomarkers of deferasirox.

The Effect of Enalapril and Carvedilol on Left Ventricular Dysfunction in Middle Childhood and Adolescent Patients With Muscular Dystrophy

Background and Objectives In Duchenne and Becker muscular dystrophies, cardiac function deteriorates with time resulting in heart failure which is often fatal. We prospectively evaluated the effect of enalapril and carvedilol on left ventricular (LV) dysfunction in middle childhood and adolescent patients with muscular dystrophy. Subjects and Methods Twenty-three patients with LV dysfunction (22 with Duchenne muscular dystrophy, 1 with Becker muscular dystrophy) were enrolled. We prescribed enalapril (13 patients) or carvedilol (10 patients) randomly from July 2008 to August 2010 and followed up the patients until September 2011. The changes in LV function parameters before and after the treatment were evaluated by echocardiography. Results The mean age at the start of treatment with enalapril or carvedilol was 12.6±3.7 years (median 13 years), and mean follow-up duration was 20.1±8.9 months. In the enalapril group, LV fractional shortening (FS) increased from 25.8±2.1 to 26.6±3.0 (p=0.241). In the carvedilol group, LV FS increased from 26.4±1.1 to 28.6±4.2 (p=0.110). In all 23 patients, LV FS significantly increased from 26.1±1.7 (before) to 27.6±3.7 (after treatment) (p<0.046). Indexed LV dimension at end diastole and LV end-diastolic volume decreased slightly, but without statistical significance by tri-plane volumetry. LV diastolic functional parameters were maintained during follow-up period. Conclusion Enalapril or carvedilol could improve LV systolic function in middle childhood and adolescent patients with muscular dystrophy without significant adverse effects.

Cerebellum Can Be a Possible Generator of Progressive Myoclonus

A 19-month-old girl presented with progressive myoclonic jerking of both proximal lower extremities. On her brain magnetic resonance imaging (MRI), the authors found an ill-defined mass involving cerebellar vermis and the right middle cerebellar peduncle. 11C-methionine positron emission tomography (PET) showed no abnormalities, but 18F-fluorodeoxyglucose (18F-FDG) PET revealed a well-defined hypermetabolic focus. Depth electrodes were inserted deep into the mass, which recorded focal slow waves associated with the clinical myoclonus. Following the removal of the tumor, the myoclonus was completely resolved with no neurological deficit. Here, the authors present a case showing progressive myoclonus associated with a cerebellar ganglioglioma with the electrophysiological data, which provides strong supportive evidence that the cerebellum can be a myoclonus generator.

Decreased Expression of Transforming Growth Factor-beta1 in Bronchoalveolar Lavage Cells of Preterm Infants with Maternal Chorioamnionitis

Maternal chorioamnionitis has been associated with abnormal lung development. We examined the effect of maternal chorioamnionitis on the expression of transforming growth factor-beta1 (TGF-β1) in the lungs of preterm infants. A total of 63 preterm (≤34 weeks) infants who were intubated in the delivery room were prospectively enrolled. Their placentas were examined for the presence of chorioamnionitis. Bronchoalveolar lavage (BAL) fluid and cells were obtained shortly after birth. TGF-β1 was measured in BAL fluid and TGF-β1 mRNA expression was determined by reverse transcription polymerase chain reaction (RT-PCR) in BAL cells. TGF-β1 mRNA expression in BAL cells showed a positive correlation with gestational age (r=0.414, p=0.002). TGF-β1 mRNA expression was significantly decreased in the presence of maternal chorioamnionitis (0.70±0.12 vs. 0.81±0.15, p=0.007). Adjustment for gestational age, birth weight, and delivery mode did not nullify the significance. TGF-β1 mRNA expression was marginally significantly decreased in preterm infants who developed bronchopulmonary dysplasia (BPD) later (0.75±0.11 vs. 0.82±0.15, p=0.055). However, adjustment for gestational age, patent ductus arteriosus (PDA), and maternal chorioamnionitis nullified the significance. These results might be an indirect evidence that maternal chorioamnionitis may inhibit normal lung development of fetus.

Favorable Outcome of Hematopoietic Stem Cell Transplantation Using a Targeted Once-Daily Intravenous Busulfan–Fludarabine–Etoposide Regimen in Pediatric and Infant Acute Lymphoblastic Leukemia Patients

Conditioning regimens for pediatric acute lymphoblastic leukemia (ALL) usually include total body irradiation (TBI), but TBI may result in serious sequelae. Busulfan and cyclophosphamide have been used as an alternative to TBI. Etoposide also has been widely used to enhance antileukemic effect. However, toxicities have been reported in some studies using busulfan, cyclophosphamide, and etoposide regimen. A reduced toxicity myeloablative regimen using busulfan and fludarabine showed promising results. Also, therapeutic drug monitoring (TDM) and administration of targeted doses of busulfan have been recommended to improve the outcome of hematopoietic stem cell transplantation (HSCT). In this study, we evaluated the outcome of HSCT using a targeted once-daily i.v. busulfan-fludarabine-etoposide (BuFluVP) regimen in pediatric and infant ALL. Busulfan (age ≥ 1 year, 120 mg/m(2); age < 1 year, 80 mg/m(2)) was administered once daily as the first dose on day -8, and a targeted dose of busulfan was used according to the TDM results on days -7 to -5. Forty-four patients were evaluated. Donor-type neutrophil engraftment was achieved in all patients. Veno-occlusive disease occurred in 7 patients (15.9%), but all patients were successfully treated. Cumulative incidence of treatment-related mortality and relapse were 9.1% and 9.9%, respectively. One-year overall survival and event-free survival rates of all patients were 86.2% and 83.8%, respectively. Twelve patients (27.3%) were infants at diagnosis, and their 1-year overall survival rate was 83.3%. Our study demonstrated that HSCT using a targeted once-daily i.v. BuFluVP regimen showed favorable outcomes and could be an option for HSCT in pediatric and infant ALL.