Byong Sop Lee

Ifosfamide nephrotoxicity in pediatric cancer patients.

Abstract. The renal functions in pediatric cancer patients who received ifosfamide (IFO) treatment were evaluated and the risk factors related to IFO nephrotoxicity were determined. The medical records of all children treated with IFO were reviewed, and 62 with normal renal function before IFO treatment were selected. Nephrotoxicity was diagnosed by measuring urine β2-microglobulin and glucose, and serum phosphate, bicarbonate, and creatinine. Forty-eight (77.4%) had a history of previous cisplatin treatment. Nephrotoxicity was detected in 20 patients (32.3%). β2-Microglobulinuria was observed in all 20, hypophosphatemia in 10 (16.1%), hypocarbia in 2 (3.2%), glucosuria in 5 (8.1%), and decreased creatinine clearance in 7 (11.3%). The cumulative dose of IFO and a history of previous cisplatin therapy were related to nephrotoxicity. Among the 20 patients with nephrotoxicity, the median cumulative dose of IFO in patients with a low (<500 mg/m2) and high (>500 mg/m2) cumulative dose of previous cisplatin was 80 g/m2 (73–102 g/m2) and 45 g/m2 (11–76 g/m2), respectively. Most of the nephrotoxicity persisted after cessation of IFO treatment. In conclusion, close monitoring of IFO nephrotoxicity should be started earlier in patients with high-dose cisplatin pretreatment. Tubular proteinuria, as indicated by β2-microglobulinuria, was the most-sensitive marker for IFO nephrotoxicity. Long-term follow-up study for reversibility of IFO nephrotoxicity is in progress.

Embolization versus surgical resection of pulmonary sequestration: clinical experiences with a thoracoscopic approach.

PURPOSE The goal of this study was to compare the safety and efficacy of treatment for pulmonary sequestration (PS) by transcatheter arterial embolization (TAE) versus surgical resection and to consider the role of a thoracoscopic approach. METHODS A retrospective review involving 73 children (≤ 15 years of age) with PS between 2002 and 2011 was performed. RESULTS Forty-two patients were managed with TAE, and 31 underwent surgery alone. Their presenting symptoms were pneumonia (n=11), pneumothorax (n=2), pneumomediastinum (n=1) and respiratory distress (n=6).Fifty-three (72.6%) were asymptomatic. The average age at treatment was 17.0 ± 44.4 and 31.3 ± 41.7 months for the TAE and surgery groups, respectively. In the TAE group, complete regression was observed in only 3 patients, 4 showed no regression, and 35 (83.3%) had residual lesions. Four patients developed sepsis or other blood vessel complications after TAE. The results of resection via thoracotomy versus a thoracoscopic approach were evaluated in 34 patients, including 3 who underwent the operation after TAE. Twenty-seven patients underwent thoracotomy, and 7 underwent thoracoscopic resection. There were no significant differences between the groups except time to chest tube removal, which was shorter in the thoracoscopic group (p=0.046). Complications included a wound infection in 1 patient after thoracotomy. CONCLUSIONS We believe that even in asymptomatic patients, all PSs should be resected because of the risk of infection, the low rate of natural regression, complications after TAE, and to exclude other pathology. Our experience also shows that thoracoscopic resection of PS is feasible, efficacious, and safe in newborns and infants.

Hydrothorax in a patient with Denys-Drash syndrome associated with a diaphragmatic defect

The Wilms tumor suppressor gene, WT1, plays an important role in the development of the urogenital system and the gonads, and clinical syndromes associated with WT1 mutations, such as WAGR syndrome, Denys-Drash syndrome and Frasier syndrome, typically manifest as renal and genitourinary abnormalities. WT1 may also play an important role in the development of the diaphragm, and recently several papers have reported an association between WT1 mutations and diaphragmatic hernias. In addition, WT1 mutations were also detected in some patients with Meacham syndrome, a rare malformation syndrome comprising congenital diaphragmatic hernia, double vagina, sex reversal, and cardiac malformations. Here, we report a case of an infant with typical clinical features of Deny-Drash syndrome and a heterozygous missense mutation, Arg366His, in the WT1 gene, in whom a diaphragm defect was detected after starting peritoneal dialysis. Diaphragmatic defects are rare but may be considered as clinical manifestations of WT1 mutation syndromes. In addition, we suggest that WT1 abnormalities should be suspected in patients with chronic renal failure who develop hydrothorax after peritoneal dialysis, especially in those with genitourinary abnormalities.

Neonatal pulmonary sequestration: clinical experience with transumbilical arterial embolization.

Pulmonary sequestration (PS) is a rare congenital malformation of the lower respiratory tract. The exact natural course of PS is not well understood and there are no well‐established treatment guidelines for antenatally diagnosed PS. The aim of this study was to describe clinical outcomes in neonates with PS and to evaluate the efficacy of transumbilical arterial embolization (TUE). From 1998 to 2006, total 30 neonatal cases were included. Serial antenatal ultrasound in 26 cases found 6 (23%) regressed lesions, all of which were demonstrated on postnatal chest CT. Six (20%) cases were classified as mixed‐type (combined cystic) lesions. Surgery was performed early (during initial hospitalization) in two cases and lately (after the neonatal period) in four cases. TUE was performed for 17 (57%) cases of intrapulmonary PS. Follow‐up images obtained a median of 19 months (range, 4–51) after TUE demonstrated complete (9, 53%), partial (5, 29%), and no (3, 18%) regression. The regression rate was significantly higher in solid‐type lesions (13/13, 100%) than in mixed‐type (1/4, 25%) (P = 0.006). Complications included transient hypertension (two cases, 12%), post‐embolization fever (two cases, 12%) and migration of a microcoil (one case, 6%), without long‐term morbidities. Natural courses could be observed in 10 cases of extralobar PS and regression was observed in 2 cases (20%) during a median follow‐up of 12 months (range, 6–45). A well‐designed comparative study is warranted to evaluate the long‐term efficacy and safety of TUE. Pediatr Pulmonol. 2008; 43:404–413.

Effect of Furosemide on Ductal Closure and Renal Function in Indomethacin-Treated Preterm Infants during the Early Neonatal Period

Background: Furosemide is known to increase renal prostaglandin synthesis. However, its influence on ductal closure and renal toxicities of indomethacin in preterm infants has not been conclusive, especially during the early neonatal period. Objectives: To identify the effects of furosemide after indomethacin administration on the rate of patent ductus arteriosus (PDA) closure and renal function in preterm infants. Methods: 68 infants (gestational age <34 weeks and birth weight <2,000 g) receiving indomethacin therapy (one course: 0.2–0.1–0.1 mg/kg q 12 h, mostly started <48 h after birth) were randomly assigned to the furosemide (n = 35) or control (n = 33) group. Each indomethacin dose was followed by furosemide (1.0 mg/kg) or placebo. The primary (PDA closure) and secondary (acute renal failure (ARF) and others) outcomes were assessed. Renal parameters before and 0–12 and 24–36 h after the first course of indomethacin were also investigated. Results: In an intention-to-treat analysis, there were no differences in the PDA closure rate between the furosemide (29/34) and the control (27/29) group (p = 0.437). The incidence of ARF (serum creatinine >1.6 mg/dl) was greater in the furosemide group (20/34) than in the control group (3/29) (p < 0.001). Compared with the control group, serum creatinine and cystatin C levels and fractional excretion of sodium were significantly increased in the furosemide group for 24–36 h after indomethacin therapy (p < 0.01). There were no between-group differences in mortality and other neonatal morbidity rates. Conclusions: Use of furosemide in combination with indomethacin increased the incidence of ARF but did not affect the PDA closure rate in preterm infants.

Impact of fetal echocardiography on trends in disease patterns and outcomes of congenital heart disease in a neonatal intensive care unit.

Background: Congenital heart disease (CHD) is the most common developmental malformation and the leading cause of neonatal mortality and morbidity. The introduction of fetal echocardiography has made prenatal diagnosis of CHD possible. Objective: This study was conducted to investigate the impact of fetal echocardiography on the changing disease patterns and outcomes of CHD. Methods: A retrospective analysis of data from infants with CHD admitted to the neonatal intensive care unit (NICU) of the Asan Medical Center during the time periods was performed. Period I (1994–1996) was considered representative of a period before the introduction of fetal echocardiography, while period II (2004–2006) represented a period of more extensive application of fetal echocardiography. Results: A total of 164 patients were admitted to the NICU during period I and 320 during period II. The number of infants prenatally diagnosed with CHD was 5 of 164 (3.0%) in period I and 219 of 320 (68.4%) in period II (p < 0.05). The overall accuracy of fetal diagnosis was approximately 92%. Of the 3 CHD categories, there was a greater proportion of infants with ‘significant’ heart disease in period II than I (47 vs. 32%; p < 0.05). In contrast, there was a smaller proportion of infants with ‘simple’ heart defects in period II than I (22 vs. 40%; p < 0.05). The proportion of infants with ‘complex’ heart disease was similar in both periods (28% in period I and 31% in period II). The 1-year survival rate of patients with CHD has improved remarkably with time (70.1% in period I to 88.8% in period II). Multivariate analysis showed prenatal diagnosis and planned delivery in a tertiary NICU are factors affecting CHD outcomes, especially when defects are ‘complex’ (p < 0.01). Conclusion: Fetal echocardiography has resulted in an increased frequency of prenatal CHD diagnosis, has altered the disease patterns observed in the NICU, and has resulted in better 1-year outcomes.

Epidemiology of respiratory syncytial virus infection in infants born at less than thirty-five weeks of gestational age.

Background: The aims of this study were to observe the respiratory syncytial virus (RSV) hospitalization rate and to identify the risk factors for hospitalization for RSV infection among infants in Korea born at <35 weeks of gestational age and who had not previously received palivizumab. Methods: We conducted a study over a 2.5-year period (between April 2007 and September 2009) that included premature infants (<35 weeks of gestational age) who underwent follow-up during 1 year after discharge from the neonatal intensive care unit. Demographic information was collected for each subject at baseline, and the reasons for hospitalization were obtained during the 1-year follow-up period. Results: The study population included 1022 subjects who completed follow-up interviews. Eight hundred seventeen infants were included in analysis for RSV hospitalization. Excluded from the study were 167 subjects with chronic lung disease who had received palivizumab prophylaxis and 38 subjects who were not tested for RSV. The overall incidence of RSV hospitalization in the group that did not receive palivizumab was 4.5% (37 of 817 patients). Independent risk factors associated with RSV hospitalization were multiple gestation (P = 0.022) and longer duration of mechanical ventilation in the neonatal intensive care unit (P = 0.039). Conclusion: This study showed the epidemiology and risk factors of RSV hospitalization in preterm infants in Korea. RSV infection was one of the main causes of hospitalization after discharge from the neonatal intensive care unit in patients born at <35 weeks of gestational age.

Long-term neuroprotective effect of postischemic hypothermia in a neonatal rat model of severe hypoxic ischemic encephalopathy: a comparative study on the duration and depth of hypothermia.

It is not known whether deeper or longer hypothermia (HT) can achieve better neuroprotection against hypoxic ischemic encephalopathy (HIE) in neonates. To compare the neuroprotective effects of different durations and temperatures of postischemic HT in neonatal rats with severe HIE, 7-d-old rats were subjected to the Rice-Vannucci model for 150 min hypoxia. Only the rats with identified brain lesions in diffusion-weighted MRI were assigned to normothermia (NT, 36°C/48 h) or four HT (HT-30°C/48 h; HT-30°C/24 h; HT-33°C/48 h; and HT-33°C/24 h) groups. 1H-magnetic resonance spectroscopy (1H-MRS) and T2-weighted MRI were obtained serially, and functional studies were performed. HT groups showed significantly greater residual hemispheric volume and better rotarod and cylinder tests than did the NT group at 5 wk postischemia. HT groups also showed lower lactate-plus-lipid level in 1H-MRS than did the NT group at 7 d postischemia. All of these outcome variables, however, did not differ among the 4 HT subgroups, despite a trend toward greater residual brain volume in the 48-h HT versus 24-h HT subgroups. In conclusion, neither reducing the target temperature from 33 to 30°C nor prolonging the duration from 24 to 48 h produced further improvements in neurologic outcomes in neonatal rat with HIE.

Correlation between lactate and neuronal cell damage in the rat brain after focal ischemia: An in vivo 1H magnetic resonance spectroscopic (1H-MRS) study

Background: Increased levels of lactate are observed by 1H magnetic resonance spectroscopy (1H-MRS) in rat brains after stroke. However, it is not known whether the changes in lactate levels are predictive of the degree of neuronal damage. Purpose: To investigate the correlation between changes in lactate and lipid levels measured by 1H-MRS and neuronal cell damage in the rat brain. Material and Methods: A middle cerebral artery occlusion (MCAO) model was used to evaluate focal ischemia in rats (n=36). After MCAO for 90 min T2-weighted images (T2WIs), diffusion-weighted images (DWIs), and 1H-MRS data were obtained from brains immediately, 6 hours, 9 hours, 12 hours, 18 hours, 24 hours, 3 days, and 7 days after reperfusion. Infarct volumes were measured in T2WIs obtained 4 weeks after reperfusion. The degree of neuronal damage was measured by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining in three rats from each group at the same time as brain images were collected. Results: Creatine (Cr)-normalized lactate + lipid levels ([Lac+Lip]/Cr) were negatively correlated with Cr-normalized N-acetyl-L-aspartate levels (NAA/Cr) and positively correlated with TUNEL-positive cell numbers up to 24 hours after reperfusion. (Lac+Lip)/Cr at 6 hours and 9 hours was significantly correlated with NAA/Cr at 7 days, but there was no significant correlation between (Lac+Lip)/Cr during the first 24 hours and infarct volume at 4 weeks. Conclusion: Up to 24 hours after reperfusion, (Lac+Lip)/Cr was strongly negatively correlated with NAA/Cr, and was a good predictor of neuronal damage at 7 days; however, it was not predictive of final infarct volume at 4 weeks.

A Simplified Formula Using Early Blood Gas Analysis Can Predict Survival Outcomes and the Requirements for Extracorporeal Membrane Oxygenation in Congenital Diaphragmatic Hernia

The aims of this study were to investigate whether early arterial blood gas analysis (ABGA) could define the severity of disease in infants with congenital diaphragmatic hernia (CDH). We conducted a retrospective study over a 21-yr period of infants diagnosed with CDH. Outcomes were defined as death before discharge, and extracorporeal membrane oxygenation requirements (ECMO) or death. A total 114 infants were included in this study. We investigated whether simplified prediction formula [PO2-PCO2] values at 0, 4, 8, and 12 hr after birth were associated with mortality, and ECMO or death. The area under curve (AUC) of receiver operating characteristic curve was used to determine the optimum ABGA values for predicting outcomes. The value of [PO2-PCO2] at birth was the best predictor of mortality (AUC 0.803, P < 0.001) and at 4 hr after birth was the most reliable predictor of ECMO or death (AUC 0.777, P < 0.001). The value of [PO2-PCO2] from ABGA early period after birth can reliably predict outcomes in infants with CDH.