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We successfully treated a 4-year-old girl with short bowel syndrome and eosinophilic enterocolitis with teduglutide, a glucagon-like peptide-2 analog. Her eosinophilic enterocolitis was cured without relapse, and we were able to increase enteral nutrition. We found that teduglutide had an anti-inflammatory effect in this patient with eosinophilic gastrointestinal disease associated with short bowel syndrome. This report is the first to describe use of teduglutide in the treatment of eosinophilic gastrointestinal disease., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Ogawa, Konishi, Tanaka, Takayasu, Uematsu, Ito, Takahashi and Kumamoto.)

Background: Persistent pulmonary hypertension remains a major cause of mortality and morbidity in congenital diaphragmatic hernia (CDH). The secreted glycoprotein thrombospondin-1 (TSP1), a ligand for receptor CD47, is widely expressed on both systemic and pulmonary vascular cells. TSP1-CD47 signaling has been reported to be one of the pathogeneses of pulmonary hypertension (PH)., Methods: After creating a nitrofen-induced CDH rat model, fetuses were sacrificed on D17, D19 and D21 and divided into a control group and a CDH group. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression of TSP1, CD47 and Runx3 (a regulator of TSP1). An immunofluorescence study was performed to evaluate the expression and localization of TSP1, CD47 and Runx3., Results: The relative mRNA expression of pulmonary TSP1, CD47 and Runx3 on D21 was significantly increased in the CDH group (p = 0.005, p = 0.001, p = 0.046, and p = 0.002, respectively). The immunofluorescence study also confirmed the overexpression of TSP1, CD47 and Runx3 in the CDH group., Conclusion: Our results provide evidence that TSP1-CD47 signaling is involved in the pathogenesis of PH in a nitrofen-induced CDH model. Our data suggest that anti-CD47 antibodies can be novel therapeutic targets for the treatment of PH in CDH., (© 2022 Japan Pediatric Society.)

Purpose: Consensus is lacking regarding the optimal antibiotic treatment for pediatric complicated appendicitis. This study determined the optimal first-line antibiotic treatment for pediatric patients with complicated appendicitis based on peritoneal fluid cultures., Methods: This retrospective study examined the cases of pediatric patients who underwent appendectomy for complicated appendicitis at our institution between 2013 and 2019. Peritoneal fluid specimens obtained during appendectomy were cultured for the presence of bacteria., Results: Eighty-six pediatric patients were diagnosed with complicated appendicitis. Of them, bacteria were identified in 54 peritoneal fluid samples. The major identified bacteria were Escherichia coli (n=36 [66.7%]), Bacteroides fragilis (n=28 [51.9%]), α-Streptococcus (n=25 [46.3%]), Pseudomonas aeruginosa (n=10 [18.5%]), Enterococcus avium (n=9 [16.7%]), γ-Streptococcus (n=9 [16.7%]), and Klebsiella oxytoca (n=6 [11.1%]). An antibiotic susceptibility analysis showed E. coli was inhibited by sulbactam/ampicillin in 43.8% of cases versus cefmetazole in 100% of cases. Tazobactam/piperacillin and meropenem inhibited the growth of 96.9-100% of the major identified bacteria. E. coli (100% vs. 84.6%) and P. aeruginosa (100% vs. 80.0%) were more susceptible to amikacin than gentamicin., Conclusion: Tazobactam/piperacillin or meropenem is a reasonable first-line antibiotic treatment for pediatric complicated appendicitis. In the case of aminoglycoside use, amikacin is recommended., Competing Interests: Conflict of Interest: The authors have no financial conflicts of interest., (Copyright © 2021 by The Korean Society of Pediatric Gastroenterology, Hepatology and Nutrition.)

Background: To assess the actual experiences of long-term follow-up and discuss ways to improve care during the period from childhood to adulthood in newborns who have undergone surgery., Methods: A total of 306 patients with congenital anomalies requiring newborn surgery who survived to discharge from 1994 to 2013 were eligible for inclusion. Survivors with severe chromosomal and cardiac anomalies were excluded. Patients with myelomenigocele, urogenital anomalies and miscellaneous diagnoses were also excluded. Patients with Hirschsprung's disease were excluded since many of them underwent surgery after the neonatal period. Patients with hypertrophic pyloric stenosis were also excluded since their duration of follow-up was too short for this study., Results: According to the follow-up status, survivors were categorized into 4 groups: under follow-up as an outpatient (UF, n = 67), moved (MV, n = 60), follow-up suspended by doctor (Sus, n = 87), and lost to follow-up (LF, n = 92). The incidence of active medical problems was high, and the duration of follow-up was significantly longer in the survivors with esophageal atresia, congenital diaphragmatic hernia and high-type anorectal malformations than in those with other anomalies. Survivors followed by pediatric surgeons alone, free from active medical problems or free from adverse events during the initial hospitalization were at risk of being LF., Conclusions: More than 30% of the surgical newborn cases were LF. Disease-specific and standardized multidisciplinary follow-up programs that increase both children's and parents' satisfaction and compliance are needed. (230/250 words)., (Copyright © 2020. Published by Elsevier Taiwan LLC.)

Purpose: To determine the features which predict torsion and the pre-operative indicators of malignancy in cases of ovarian torsion in ovarian tumors (OTs) in children., Methods: The medical records of 35 pediatric patients who underwent surgery for OT, except for neonate cases, from 1997 to 2018 at our institution were reviewed retrospectively., Results: The pathological diagnosis was mature teratoma in 17, immature teratoma in 9, yolk sac tumor in 3, and others in 6. The preoperative diagnosis, which was made based on the imaging findings and the serum tumor marker values, matched with the pathological diagnosis in 29/35 (83%). Ovarian torsion occurred in 14/35 (40%). All but one case that presented with torsion had intermittent abdominal pain as the primary symptom. The preoperative white blood cell count was significantly higher in cases where ovary preservation was impossible than where it was possible (p = 0.01) among the cases presenting with torsion., Conclusion: Preoperative imaging findings and the serum tumor marker values enabled us to make an accurate preoperative diagnosis. Patients with intermittent abdominal primary symptoms were more likely to have ovarian torsion than those without such symptoms, and leukocytosis may indicate irreversible ischemic changes in the affected ovary.

Background: Ovarian immature teratomas (ITs) are relatively rare among all pediatric ovarian tumors. The histological grading for ovarian ITs, which ranges from 1 to 3, is based on the proportion of immature neuroepithelial component. Higher-grade ITs in adults are treated as malignant neoplasms and require adjuvant chemotherapy. However, there is no consensus on the therapeutic management of pediatric ovarian ITs. The aim of our study was to analyze the histological grades and clinical characteristics of ovarian ITs in pediatric patients., Methods: This retrospective chart review consisted of seven patients, including one, three, and three patients with histological grade 1, 2, and 3 pediatric ovarian ITs, respectively, who were treated at our institute between 2000 and 2016. Collected data comprised age, alpha-fetoprotein (AFP) level, clinical stage, tumor size, treatment, and prognosis., Results: The median age and AFP levels of patients with grade 1, 2, and 3 ovarian ITs were 8, 7, and 10 years and 37, 112, and 221 ng/ml, respectively. All cases were Children Oncology Group (COG) stage I and International Federation of Gynecology and Obstetrics (FIGO) stage IA. All patients had unilateral tumors in the right ovary. The median tumor sizes of the grade 1, 2, and 3 IT patients were 104, 160, and 100 cm 2 , respectively. All patients underwent primary open surgery alone. Two patients, including one patient each with grade 2 and 3 ITs, underwent tumor enucleation as ovary-sparing surgery, whereas the remaining five patients underwent unilateral salpingo-oophorectomy. The median follow-up was seven years, and all cases achieved event-free survival., Conclusions: Clinical characteristics of patients with grade 3 ovarian ITs were relatively older and had higher AFP levels than those with lower-grade ITs. According to our patient's clinical course and prognosis, COG stage I pediatric ITs should be treated by surgery alone and that postoperative chemotherapy is unnecessary even for those with grade 3 ITs as well as patients with rather low AFP levels., Level of Evidence: IV., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The aim of this study was to evaluate the outcome of an early discharge protocol for pediatric acute appendicitis., Methods: The present new early discharge protocol for appendicitis consisted of both postoperative early feeding and reduced-port laparoscopic surgery, to reduce surgical stress. The outcome was studied in patients with acute appendicitis treated at the present institution from 2012 to 2013., Results: Data on 36 acute appendicitis patients (mean age, 10.3 years) were collected. Operation time was 95 ± 27 min. Preoperatively, mean white blood cell (WBC) count was 13 850 ± 3644/μL; mean C-reactive protein (CRP), 2.7 ± 2.9 mg/dL; and mean procalcitonin, 0.25 ± 0.37 ng/mL. After surgery there was a significant decrease in WBC count, which fell to within the normal range; CRP peaked at 4.9 ± 3.2 mg/dL on postoperative day (POD) 1. On POD 7, all of the hematological markers were within the normal range. There were no postoperative complications. Mean hospital stay was 2.1 ± 1.1 days. Mean frequency of oral painkiller use was 3.2 ± 3.3 times per person., Conclusions: The present early discharge protocol is safe and effective for the management of acute non-perforated appendicitis., (© 2017 Japan Pediatric Society.)

Background: Erythropoietin (EPO), an essential stimulator of erythropoiesis produced by the fetal liver, is important both in vascular remodeling and modulation of the endothelial response in the pulmonary vasculature. In addition, EPO guides alveolar development, along with retinoic acid (RA). EPO is a direct target of RA, and the retinoid pathway is altered in the nitrofen-induced congenital diaphragmatic hernia (CDH) model. In the present study, we tested the hypothesis that the synthesis of EPO is suppressed in a rat model of CDH., Materials and Methods: Pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetuses were sacrificed on D19 and D21 and divided into control and CDH groups. Immunohistochemistry and quantitative real-time polymerase chain reaction (RT-PCR) were performed to determine the expression of EPO in the fetal liver and kidney. We also estimated the expression of EPO receptor in the fetal lung., Results: The relative EPO mRNA expression in the liver on D19 and in the kidney on D21 were significantly lower in the CDH group than in the controls (P = 0.0008 and P = 0.0064, respectively). In addition, the results of immunohistochemistry supported the findings from the RT-PCR analysis. No significant changes were noted in the expression pattern or EPO receptor levels in the fetal lungs of the CDH group compared to the controls., Conclusions: Our results reveal the suppressed EPO synthesis in the CDH fetus, which may contribute to the pathogenesis of lung hypoplasia and modification of pulmonary vasculature in the CDH rat model. Pediatr Pulmonol. 2017;52:606-615. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Objective: To establish better management practices to reduce morbidities in survivors with congenital diaphragmatic hernia (CDH)., Methods: Of 60 patients treated for CDH at our institution between 1991 and 2011, 49 patients without severe anomalies were retrospectively reviewed., Results: Since 2004, gentle ventilation (GV) has been the main treatment for CDH. Patients were divided into the following two groups: the non-GV group (n = 29) who were treated before GV treatment was implemented, and the GV group (n = 20). The overall survival rate was 62.1% (18/29) and 95% (19/20) in the non-GV and GV groups, respectively (p = 0.016). Despite the high survival rate, the incidence of long-term complications in survivors was still high (14/19, 73.7%) in the GV group. In the GV group, liver-up (p = 0.106) and the need for patch repair (p = 0.257) tended to be associated with the development of long-term complications, but did not reach statistical significance. The presence of perioperative complications was associated with the development of long-term complications (p = 0.045) in the GV group., Conclusion: Patients who developed short-term complications seemed to be at risk of long-term complications. Therefore, to minimize long-term morbidities in CDH survivors, the prevention of short-term complications might be important., (Copyright © 2015. Published by Elsevier Taiwan.)

Background/purpose: The purpose of this study was to investigate echocardiographic parameters in relation to the outcomes of isolated left-sided congenital diaphragmatic hernia (CDH)., Methods: This multicenter, retrospective, observational study was conducted among patients with CDH born between 2006 and 2010. Patients in this study did not have severe cardiac malformations or chromosomal aberrations. Patients with incomplete echocardiographic examinations were excluded. In total, 84 patients with left-sided isolated CDH were included in this study. The prognostic parameters were obtained from postnatal echocardiographic images within 24h after birth., Results: Eight patients died before 90days of birth. Univariate analysis showed that the presence of continuous right to left shunt at the ductus, left pulmonary artery diameter of <2.7mm, right pulmonary artery diameter of <3.3mm, and left ventricular diastolic diameter of <10.8mm, were the predictors of poor prognosis. Multivariate logistic regression analysis showed that right pulmonary artery diameter of <3.3mm (adjusted OR 10.28, 95% C.I.: 1.15-249.19) and left ventricular diastolic diameter of <10.8mm (adjusted OR 7.86, 95% C.I.: 1.01-82.82) were predictors of poor prognosis., Conclusions: This study revealed that the predictors of poor prognosis associated with CDH include smaller right pulmonary artery and left ventricular diastolic diameters. Retrospective Study-Level II., (Copyright © 2016. Published by Elsevier Inc.)

Recurrent tracheoesophageal fistula (TEF) is still difficult to diagnose and repair. In almost all cases, recurrence appears relatively soon after the primary surgery. We herein describe a case of recurrent TEF that appeared 10 years after the primary repair. At 2 years of age, the patient suffered from mental retardation due to encephalitis and developed a hiatus hernia with gastro-esophageal reflux. He underwent the repair of a hiatus hernia and fundoplication at 3 years of age. However, the hiatus hernia recurred 6 months after the operation. The patient suffered from recurrent pneumonia for 6 years after the appearance of the recurrent hiatus hernia. At 9 years of age, he was hospitalized frequently due to recurrent severe pneumonia. After admission at 9 years of age, an endoscopic study under general anesthesia was performed and revealed subglottic stenosis and a dilated esophagus with a recurrent hiatus hernia. Tracheotomy or laryngotracheal separation was first planned in order to improve his upper airway and facilitate the safer repair of the recurrent hiatus hernia. After laryngotracheal separation, the patient still suffered from severe pneumonia. In addition, a small volume of nutritional supplement was aspirated from the tracheostomy. Thus, recurrent TEF was suspected. Tests using dye under both esophagoscopy and bronchoscopy confirmed recurrent TEF. The fistula recurred in the cervical area because of the elevation of the esophagus due to the recurrent hiatus hernia. The fistula was surgically closed, with a sternothyroid muscle flap to prevent re-recurrence. At 4 months after this operation, the recurrent hiatus hernia was repaired. Thereafter, the patient's respiratory symptoms showed a dramatic improvement. The patient is now doing well and free from further recurrences of TEF and hiatus hernia at 2 years after the final operation.

Background: Hypergastrinemia and the resultant peptic ulcer related to an enteric duplication has been quite rarely reported in the literature., Case Presentation: We herein report the case of a 4-year-old girl who presented with hypergastrinemia and a duodenal ulcer at 2 years of age. She had been followed up with a proton pump inhibitor, which resulted in resolution of the ulcer; however, unexplained hypergastrinemia had continued. A cystic lesion at the antrum was discovered at 4 years of age, which we suspected to be a gastric duplication. After we resected the lesion, the hypergastrinemia resolved without recurrence of the duodenal ulcer. The histology was compatible with a gastric duplication, and the lumen was lined with antral mucosa that strongly stained positive for gastrin. We presumed that the antral mucosa inside the duplication in our case had no hydrogen ion feedback inhibition of gastrin release from gastrin cells and increased release of gastrin from the mucosa inside the duplication led to the duodenal ulcer. Only two cases have been reported in the literature that had hypergastrinemia related to enteric duplication., Conclusion: Gastric duplication should be included in the differential diagnosis of sustained hypergastrinemia in children.

Background: The aim of this study was to investigate the natural history and associated predictors of musculoskeletal deformities in congenital diaphragmatic hernia (CDH) survivors., Methods: A multicenter retrospective survey was conducted among CDH patients between January 2006 and December 2010 in Japan, and a follow-up survey was performed between September 2013 and October 2013. One hundred and eighty-two (79.8%) of the 228 patients were alive. An orthopedic survey of 159 survivors without severe coexisting congenital anomalies was subsequently carried out, and the rates of pectus excavatum (PE), scoliosis and chest asymmetry were evaluated., Results: Scoliosis, PE and chest asymmetry were found in 20 (12.6%), 19 (11.9%) and 12 (7.5%) patients, respectively. In total, 44 patients (27.7%) developed orthopedic abnormalities. Reduction in the oxygenation index within 24 h after birth (P = 0.044), large diaphragmatic defects (P = 0.047) and patch repair (P = 0.014) were predictive for scoliosis. In addition, Apgar score at 5 min was significantly lower in the patients who developed PE (P = 0.034); and stomach herniation (P = 0.004) and liver herniation (P = 0.013) at prenatal diagnosis and large diaphragmatic defects (P = 0.036) were predictive of chest asymmetry., Conclusions: Approximately one-quarter of the survivors developed musculoskeletal abnormalities in the present survey of CDH patients. These data suggest that each musculoskeletal abnormality has its own specific predictors., (© 2016 Japan Pediatric Society.)

Introduction: Little information exists about the physical growth of patients with congenital diaphragmatic hernia (CDH). This study aimed to assess the growth of patients with CDH during long follow-up periods, and to identify growth retardation (GR) risk factors., Patients and Methods: A multicenter retrospective observational study was conducted in 2013. Of the 228 patients with CDH born between 2006 and 2010, 182 (79.8%) survived to discharge, and 174 cases were included in the study. Body weights and heights were measured at 1.5, 3, and 6 years of age. GR was defined as a Z-score relating to the weight or height of < - 2.0. Cases with GR at 1.5, 3, or 6 years of age comprised the GR group. The clinical variables of the GR and non-GR groups were compared using univariate analysis. Multiple logistic regression analyses were conducted successively on the factors that were significant at p < 0.01 in the univariate analysis and had low correlations with other factors (r < 0.7). The numerical data were divided into two groups based on a cutoff value that was calculated from a receiver operating characteristic curve., Results: The GR group comprised 35 cases (22.7%). The rates of GR at 1.5, 3, and 6 years of age were 19.5 (26/133), 14.4 (16/111), and 13.5% (5/37), respectively. The body weight Z-scores improved in cases with GR between the ages of 1.5 and 3 years (p = 0.036). As the patients aged, the wasting type of GR decreased in frequency (31, 0, and 0% at 1.5, 3, and 6 years of age, respectively) and the stunting type of GR increased in frequency (27, 31, and 100% at 1.5, 3, and 6 years of age, respectively). The univariate analysis showed that birth weight and height, liver-up, large defect size of the diaphragm, use of nitric oxide, patch repair, long hospital stay, home oxygen treatment (HOT), and vasodilator administration at discharge were significant risk factors of GR. The multivariate analysis determined that a birth weight of < 2,698 g (odds ratio [OR] = 5.5, 95% confidence interval [CI] = 2.1-16.8, p < 0.001) and HOT (OR = 5.8, 95%CI = 1.6-23.8, p = 0.007) were significant risk factors for GR., Conclusion: GR was observed in 22.7% of the CDH survivors. Body weight improved between 1.5 and 3 years of age in the GR cases, but some patients developed chronic malnutrition via acute malnutrition. Low birth weight and the need for HOT were GR risk factors. Aggressive management of acute malnutrition may improve the growth of patients with CDH., (Georg Thieme Verlag KG Stuttgart · New York.)

Purpose: Persistent pulmonary hypertension remains a major cause of mortality and morbidity in cases of congenital diaphragmatic hernia (CDH). Recently, RhoA/Rho-kinase-mediated vasoconstriction has been reported to be important in the pathogenesis of pulmonary hypertension (PH). Several recent reports have described that fasudil, a potent Rho-kinase inhibitor and vasodilator, could represent a potential therapeutic option for PH. We designed this study to investigate the hypothesis that the expression level of RhoA is increased in the nitrofen-induced CDH rat model. The expression level of Wnt11, an activator of RhoA, was also evaluated., Methods: Pregnant rats were treated with or without nitrofen on gestational day 9 (D9). Fetuses were sacrificed on D17, D19 and D21 and were divided into control and CDH groups. Quantitative real-time polymerase chain reaction was performed to determine the pulmonary gene expression levels of both Wnt11 and RhoA. An immunofluorescence study was also performed to evaluate the expression and localization of RhoA., Results: The relative mRNA expression levels of pulmonary Wnt11 and RhoA on D21 were significantly increased in the CDH group compared with the control group (p=0.016 and p=0.008, respectively). The immunofluorescence study confirmed the overexpression of RhoA in the pulmonary vessels of CDH rats on D21., Conclusions: Our results provide evidence that the RhoA/Rho-kinase-mediated pathway is involved in the pathogenesis of PH in the nitrofen-induced CDH rat model. Our data also suggest that the fasudil, a Rho-kinase inhibitor, could represent a therapeutic option for the treatment of PH in CDH., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Aim of the Study: Few follow-up studies focused on the recurrence regarding the postoperative course of congenital diaphragmatic hernia (CDH) survivors. The aim of this study was to report on risk factor for CDH patients who had the recurrence during the follow-up., Materials and Methods: A multicenter retrospective survey was conducted on neonates diagnosed to have CDH between January 2006 and December 2010. Follow-up survey was conducted between September 2013 and October 2013 (ethical approval: No. 25-222). Nine institutions agreed to participate in this survey. Out of 228, 182 (79.8%) patients were alive and 180 patients were included in this study. Two patients were excluded because the defect had not repaired at the primary operation. The patients were divided into the recurrence group (n=21) and the nonrecurrence group (n=159). Postnatal and postoperative variables were compared between these two groups. Baseline variables which showed significance in univariate analysis were entered into multiple logistic regression analysis for analyzing the recurrence. A value of p<0.05 was considered to be statistically significant by using the JMP software program (version 9; SAS Institute, Inc, Cary, North Carolina, United States)., Main Results: Out of 180, 21 (11.7%) CDH neonates had the recurrence during the course of the follow-up. Five (2.8%) patients had the recurrence before primary discharge and 16 (8.9%) patients had the recurrence after discharge. Univariate analysis showed that liver herniation (crude odds ratio [OR], 7.4; 95% confidence interval [CI], 2.73-23.68), defect size C and D, proposed by the CDH Study Group (crude OR, 7.09; 95% CI, 2.73-19.99) and patch repair (crude OR, 5.00; 95% CI, 1.91-14.70) were risk factors. Multivariate logistic regression analysis showed liver herniation (adjusted OR, 3.96; 95% CI, 1.01-16.92) was the risk factor for the recurrence., Conclusion: A wide spectrum of the disease severity and the rarity of the disease mask the risk of the recurrence for CDH patients. This study showed the only factor to predict the recurrence was the liver herniation. These data will be helpful for providing information for the long-term follow-up of the CDH patients., (Georg Thieme Verlag KG Stuttgart · New York.)

An 8-month-old boy with a left-sided incarcerated inguinal hernia involving the appendix, cecum, and terminal ileum was successfully managed via an inguinal approach during an emergency operation. A mobile cecum seemed to have contributed to the left-sided incarceration. Only 13 similar cases with the left-sided Amyand's hernia have been reported in the literature.

Purpose: Gastroesophageal reflux disease (GERD) is one of the concomitant problems in infants with congenital diaphragmatic hernia (CDH). We assessed risk factors of GERD in CDH patients., Methods: The retrospective observational study for CDH infants was conducted. Cases of CDH who were born between January 2006 and December 2010, were operated in the 9 participating institutions, and survived to discharge were included. Completion of medical therapy for GERD and incidence of surgery were primary outcomes. Kaplan-Meier survival analysis and Cox proportional hazards regression were used., Results: In 182 cases of CDH, the medical therapies for GERD were performed in 23.8% (40/168), and were completed in 60.0% (24/40). Prenatal detection of CDH (HR 5.87, CI 1.6-18.8, p = 0.012) and tube feeding at discharge (HR 5.04, 95% CI 1.3-33.1, p = 0.016) were significantly correlated with unsuccessful weaning from medical therapy. Surgery for GERD was performed in 10.7% (18/169). Gestational age (HR 4.78, 95% CI 1.5-21.1, p = 0.006) and diaphragmatic defect of more than 75% (HR 4.3, 95% CI 1.6-12.9, p = 0.005) were significantly correlated with need for antireflux surgery., Conclusion: Diaphragmatic defect of more than 75% was risk factor of future need for antireflux surgery.

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by basal cell carcinoma, skeletal abnormalities, benign tumors including ovarian fibroma, and various other phenotypic expressions. Ovarian fibromas in NBCCS before puberty are very rare. We report a 6-year-old prepubescent girl with NBCCS showing skeletal abnormalities, medulloblastoma, and ovarian fibromas. The patient was referred to our hospital owing to abdominal distension. On admission, a huge elastic hard tumor was palpable and computed tomography showed a huge tumor of the left ovary. We performed a left salpingo-oophorectomy and diagnosed the tumor as a benign fibroma. Further examination of the computed tomography images showed skeletal abnormalities. In addition, the patient had a history of medulloblastoma at the age of 4 years. Therefore, we diagnosed NBCCS. A genetic examination indicated a novel 1 bp deletion in exon 18 (c.3055delG). Sequence analysis of exon 18 using DNA from the ovarian tumor revealed a mutant allele (c.3055delG) dominant to the wild-type allele, thus suggesting loss of heterozygosity in the PTCH1 gene, which is known to be associated with NBCCS. Conclusion On the basis of our experience, physicians treating pediatric ovarian tumors should be aware that such huge benign ovarian tumors may be a phenotype of NBCCS, as shown in our patient. In addition, genetic examination focusing on the PTCH1 gene might be important for diagnosis of NBCCS in pediatric patients.

We describe a new technique to prevent spillage of cyst fluid in patients undergoing surgery for cystic ovarian tumors. The cyst is first covered with a sterilized surgical sheet applied with quick-drying glue and is then punctured. This technique completely prevents spillage of cyst fluid into abdominal cavity.

Purpose: Meconium peritonitis is caused by an intestinal perforation that may occur in the fetus, followed by severe chemical peritonitis, resulting in high morbidity., Methods: We have experienced six patients with meconium peritonitis. Cystic drainage was performed soon after birth for all patients. We investigated the concentrations of several cytokines and a chemokine (interleukin 8) in the ascites from the six patients with meconium peritonitis. In two patients we also measured the serum cytokines and chemokine level just after birth., Results: Interleukin 6 and interleukin 8 concentrations were very high in the cyst or ascites just after birth. In the serum taken from two patients, the levels of interleukin 6 and interleukin 8 were also high. In five patients who underwent drainage of cysts after birth, systemic inflammation could not be completely suppressed before curative surgery., Conclusions: Interleukin 6 and interleukin 8 play important roles in the inflammatory response syndrome associated with meconium peritonitis, and drainage of cystic fluid did not completely suppress this inflammation. To lessen the high morbidity of meconium peritonitis, efforts should be made to suppress the inflammatory response using new treatment strategies, such as administration of steroids or anti-cytokine therapy to supplement cystic drainage.

Background/purpose: The aim of this study was to establish a prenatal prognostic classification system for risk-stratified management in fetuses with isolated congenital diaphragmatic hernia (CDH)., Methods: A multi-institutional retrospective cohort study of isolated CDH, diagnosed prenatally in fetuses delivered during the 2002 to 2007 period at 5 participating institutions in Japan, was conducted. The risk stratification system was formulated based on the odds ratios of prenatal parameters for mortality at 90 days. The clinical severity in CDH infants were compared among the stratified risk groups., Results: Patients were classified into the 3 risk groups: group A (n = 48) consisted of infants showing liver-down with contralateral lung-to-thorax transverse area ratio (L/T) ratio ≥0.08; group B of infants showing liver-down with L/T ratio <0.08 or liver-up with L/T ratio ≥0.08 (n = 35), and group C of infants showing liver-up with L/T ratio <0.08 (n = 20). The mortality at 90 days in groups A, B, and C were 0.0%, 20.0%, and 65.0%, respectively. The intact discharge rates were 95.8%, 60.0%, and 5.0%, respectively. This system also accurately reflected the clinical severity in CDH infants., Conclusions: Our prenatal risk stratification system, which demonstrated a significant difference in postnatal status and final outcome, would allow for accurate estimation of the severity of disease in fetuses with isolated CDH, although it needs prospective validation in a different population., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Introduction: Both the Bianchi and the serial transverse enteroplasty (STEP) procedure have been reported to be successful in short bowel syndrome, but both have their limitations. The Bianchi technique is surgically challenging and can only tailor the diameter to half and double the length. The STEP procedure is easy, adjustable, but it changes the orientation of the muscle fibres making the circular; longitudinal and the longitudinal; circular. We have created a model to test our idea of Spiral Intestinal Lengthening and Tailoring (SILT)., Material and Methods: A double layer intestinal simulator was used as the bowel model. The orientation of the circular muscle fibres was marked. The simulator was cut spirally at a 45° and 60° angle, stretched longitudinally and retubularised. The procedure was adapted to porcine small bowel ex vivo and mucosal microcirculation was observed in three separate points by intravital videomicroscopy in vivo., Results: The simulator was lengthened by 60% and the diameter was tailored by 33% using the 45° spiral cut, 73% lengthening and 44% tailoring was achieved at 60°. The circular muscle fibres showed oblique orientation. The porcine bowel was lengthened by 136 ± 21% and the diameter was tailored by 56 ± 8%. The linear regression analysis of variants showed significant linear regression R = 0.9689 (R(2) = 0.9388), p = 0.0014. The angle of the spiral cut (α) showed the relation: α ≥ 90-arc sin R(2)/R(1). (R(1) is the radius of the original segment and R(2) the desired radius of the tailored and lengthened bowel). The bowel remained viable macroscopically 90 min after the procedure. The median red blood cell velocity reduced from 570 (control) to 558 μm s(-1) in point 1, to 382 μm s(-1) in point 2, and to 482 μm s(-1) in point 3. Oscillation of the capillary flow has not been observed., Conclusion: The SILT may be an easy, more physiological and adjustable alternative to the existing techniques.

Purpose: To review the recent Japanese experience with prenatally diagnosed congenital diaphragmatic hernia (CDH) based on a multi-institutional survey., Methods: A multicenter, retrospective cohort study was conducted on 117 patients born between 2002 and 2007 with isolated prenatally diagnosed CDH. All patients were managed by maternal transport, planned delivery, immediate resuscitation and gentle ventilation. The primary outcome measurements were the 90-day survival and intact discharge. The examined prenatal factors included gestational age (GA) at diagnosis, lung-to-head ratio (LHR), lung-to-thorax transverse area ratio (L/T) and liver position. Physical growth and motor/speech development were evaluated at 1.5 and 3 years of age. Data were expressed as the median (range)., Results: The mean GA at diagnosis was 29 (17-40) weeks. The LHR and L/T were 1.56 (0.37-4.23) and 0.11 (0.04-0.25), respectively. There were 48 patients with liver up. The mean GA at birth was 38 (28-42) weeks. The 90-day survival rate and intact discharge rate were 79 and 63%, respectively. Twelve patients had major morbidity at discharge, and 71% of these patients had physical growth or developmental retardation at 3 years of age., Conclusion: This multicenter study demonstrated that the 90-day survival rate of isolated prenatally diagnosed CDH was 79%, and that subsequent morbidity remained high. A new treatment strategy is needed to reduce the mortality and morbidity of severe CDH.

Purpose: An accurate prenatal assessment of the patients' severity is essential for the optimal treatment of individuals with congenital diaphragmatic hernia (CDH). The purpose of this study was to clarify the reliability of the lung to thorax transverse area ratio (L/T) as a prenatal predictive parameter., Methods: A multicenter retrospective cohort study was conducted on 114 isolated CDH fetuses with a prenatal diagnosis during the period between 2002 and 2007 at five participating centers in Japan. The relationship between the gestational age and the L/T was analyzed. The most powerful measurement point and accurate cutoff value of the L/T was determined by an analysis of a receiver operating characteristic curve, which was verified by comparing the patients' severity., Results: There was a negative correlation between the gestational age and the L/T in the non-survivors, and no correlation in the survivors. There were significant differences in the parameters which represented the patients' severity including the respiratory and circulatory status, the surgical findings, and the final outcomes between the groups divided at 0.080 in the minimum value of the L/T during gestation., Conclusion: The L/T was not strongly influenced by the gestational age, and it was found to be a reliable prenatal predictive parameter in fetuses with isolated CDH.

This report describes a case of fetal mediastinal teratoma complicated by hydrops fetalis managed successfully by aspiration of the tumor cyst fluid. Fetal mediastinal teratomas are rare tumors that cause hydrops fetalis or fetal demise in the prenatal period and respiratory distress in the neonatal period. The patient presented with a large cystic mass in the thoracic cavity complicated by hydrops fetalis. The hydrops resolved after fetal aspiration of the tumor cyst fluid. The infant was born without respiratory distress, and tumor resection was performed at the age of 30 days. The postoperative course was uneventful, and the patient was in good health 6 months postoperatively., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Purpose: Wnts have been reported to play a key role in the lung morphogenesis. We have previously reported that pulmonary gene expression of Wnt2 and Wnt7b is downregulated on day 15 of gestation in the nitrofen-induced congenital diaphragmatic hernia (CDH) model. However, the distribution pattern of gene expression of Wnts in the very early lung development remains unclear. Optical projection tomography (OPT) is a new technique for 3-dimensional imaging of small developing organs and gene distribution combined with whole-mount in situ hybridization. We designed this study to investigate the distribution pattern of Wnts gene expression in lung buds of nitrofen-induced CDH model using OPT., Methods: Embryos from normal and nitrofen-treated dams were harvested on embryonic day 10 (E10), and divided into controls and nitrofen group, respectively. Whole-mount in situ hybridization to detect transcripts of Wnt2 and Wnt7b was performed, analyzed, and reconstructed using OPT., Results: The expression of Wnt2 transcripts was detected in the lung bud mesenchyme and markedly diminished in nitrofen group compared to controls, whereas Wnt7b transcripts were expressed in the mesoderm of bronchi and the lung bud with no detectable difference between 2 groups., Conclusion: We provide evidence for the first time that Wnt2 expression is downregulated at lung bud stage in the nitrofen model. Optical projection tomography is potentially a useful approach to visualize both gene expression and morphology during very early stages of lung development., (Copyright © 2010 Elsevier Inc. All rights reserved.)

The serial transverse enteroplasty (STEP) procedure is a safe and successful way to lengthen the small bowel in patients with short bowel syndrome. However, postoperative dilatation of the intestine may occur, which induces bacterial overgrowth and malabsorption leading to liver failure. We describe the case of an infant boy with short bowel syndrome caused by jejunal atresia requiring the STEP procedure twice. The first STEP improved the liver function, and the second STEP allowed 80% of the total calorie intake to be tolerated enterally. One should not hesitate to perform a second STEP if after the initial bowel lengthening procedure the patient develops small bowel dilatation that interferes with enteral nutrition.

Background: The pathogenesis of congenital diaphragmatic hernia (CDH) is unknown. The sonic hedgehog (Shh) cascade is crucial for the patterning of the early respiratory system in mice. Optical Projection Tomography (OPT) is a new tool for 3D imaging small biological specimens that enables us to visualise both the anatomy of developing organs and gene expression localised in the context of normal or abnormal anatomy. We visualised Shh gene expression patterns in the nitrofen treated and control mouse lung buds at early stages of lung development., Materials and Methods: Time-mated CD1 female mice (n = 5) received oral administration of 100 mg of the herbicide 2,4-dichlorophenyl-p-nitrophenylether (nitrofen) (WAKO Chemical, Osaka, Japan) in 1 ml of olive oil or olive oil alone at 7 days of gestation. Embryos were harvested on gestation days 9-12, and stained following whole mount in situ hybridisation with labelled RNA probes to detect Shh transcripts at each stage. Embryos were scanned by OPT to obtain 3D representations of gene expression domains in the context of the changing morphology of the embryo., Results: OPT analysis of Shh transcript distribution clearly revealed gene expression in both groups. In treated embryos, there were no significant changes in Shh transcript distribution in lung buds in comparison with control embryos., Conclusion: Although altered Shh expression in the hypoplastic lung has been reported in late gestation, the present study did not reveal any significant alterations in pulmonary Shh spatial transcript distribution or gene expression level during the early gestation in nitrofen CDH model. It would be of great interest in future studies to use OPT approach to investigate pulmonary expression of Shh and other regulatory genes both during early and late stages of lung development in order to provide new insights into the pathogenesis of pulmonary hypoplasia.

We describe two female neonates who suffered from four gastrointestinal anomalies, including duodenal stenosis or atresia, malrotation, segmental dilatation of the colon, and anorectal malformation. Each patient was managed by two or three operations, resulting in good bowel movements. Since this is the first report of four gastrointestinal anomalies, these cases may provide clues to elucidate the etiology of gastrointestinal tract developmental abnormalities.

Background/purpose: Although the prognosis of congenital diaphragmatic hernia (CDH) is determined by the degree of pulmonary hypoplasia, there may be an occult contribution of infection to outcomes. The purpose of this study is to evaluate the effects of our new supportive therapy to prevent infectious complications on mortality and morbidity of CDH., Methods: Among 57 cases with CDH treated between 2002 and 2007, 43 prenatally diagnosed isolated cases were enrolled in this study. All patients were managed by a lung-protective strategy and delayed surgery. Since January 2006, we have optimized our perioperative care to reduce infectious complications by using peripherally inserted central catheters and restriction of invasive procedures including extracorporeal membranous oxygenation (ECMO). The survival rate, intubation period, maximum serum C-reactive protein (CRP) level, and complications were compared before and after the introduction of refined supportive therapy., Results: There were 25 cases (12 liver-up, 13 liver-down) treated before 2006 and 18 cases (8 liver-up, 10 liver-down) after 2006. ECMO was required for stabilization in five cases before 2006. The survival rates of total, liver-up, and liver-down cases improved from 60, 42, 77, to 83, 63, 100% after 2006, respectively. The intubation period was shortened from 37.8 +/- 24.3 to 22.2 +/- 10.8 days, and the maximum serum CRP level declined from 12.8 +/- 11.5 to 2.2 +/- 1.6 mg/dl after 2006. Nine cases developed sepsis before 2006 whereas no patients suffered from sepsis or pneumonia after 2006., Conclusion: The new supportive therapy with strict infection control improved survival rate of prenatally diagnosed CDH without using ECMO.

One of the most serious problems in patients with long-gap esophageal atresia or corrosive esophagitis is esophageal stricture, which may require esophageal resection and replacement. We describe two cases with persistent esophageal stricture successfully managed by high dose intravenous methylprednisolone following balloon dilatation. High-dose methylprednisolone with gradual tapering (daily 25, 15, 10, 5, 2 mg/kg for 4 days each) plus cimetidine and ampicillin for 1 week was intravenously administrated immediately after balloon dilatation of the esophageal stenosis. This was followed by oral prednisolone (daily 2, 1, 0.5 mg/kg for 1 week each) for persistent esophageal stricture. High dose intravenous methylprednisolone therapy was given to two patients. One patient was a 5-year-old boy with long-gap esophageal atresia who had undergone repair of the esophagus resulting in severe anastomotic stenosis of 3 cm in length. The other case was a 10-year-old boy with corrosive stenosis caused by alkali ingestion. Both patients had been requiring balloon dilatation of the esophagus with intralesional injection of dexamethasone every 3 weeks for more than 1 year to tolerate oral feeding. After the high-dose methylprednisolone protocol was initiated, the symptoms of dysphagia or choking dramatically improved in both patients, and they remained symptom-free for 8 and 7 months. There were complications of moon faces that resolved concomitantly with the withdrawal of oral prednisolone in both cases. High dose intravenous methylprednisolone in addition to intralesional injection of dexamethasone following balloon dilation is an effective therapeutic strategy for persistent esophageal strictures.

Purpose: The high incidence of cardiac malformations in humans and animal models with congenital diaphragmatic hernia (CDH) is well known. The precise molecular mechanisms underlying cardiac maldevelopment in CDH are still unclear. It has been reported that GATA4 and GATA6, members of the GATA transcription factor family, act cooperatively to regulate cardiovascular development, and the levels of cardiac GATA4 and GATA6 are important regulators of cardiomyocyte proliferation, cardiac morphogenesis, and embryo survival. In addition, the GATA4/GATA6 double heterozygous mutant embryo model displayed a spectrum of cardiovascular malformations similar to those seen in human CDH and nitrofen-induced animal models, including ventricular and aortopulmonary septal defects and thin ventricular myocardium. To test the hypothesis that expression of GATA4 and GATA6 is reduced in early stages of gestation in a CDH hypoplastic heart, we investigated the expression of GATA4 and GATA6 in the hearts of nitrofen-treated rats in early gestation. Wnt2, bone morphogenetic protein 4 (BMP4), and myocyte enhancer factor 2C (MEF2C) were also investigated as GATA4/6 target genes involved in cardiogenesis., Materials and Methods: Fetal rat hearts of normal (n = 7) and nitrofen-treated (n = 7) dams were harvested on embryonic day 13. The expression of GATA4, GATA6, Wnt2, BMP4, and MEF2C was analyzed in each heart by real-time reverse transcription-polymerase reaction., Results: The gene expression of GATA4, GATA6, Wnt2, BMP4, and MEF2C on embryonic day 13 were significantly reduced (P < .05) in the hearts of nitrofen-treated animals compared with normal hearts of equivalent age., Conclusion: Decreased expression of GATA4 and GATA6 and their target genes in the developing fetal heart may perturb the delicate regulation of cardiovascular development, resulting in cardiovascular malformations in the nitrofen rat model.

Purpose: Retinoids play an important role in lung development. A recent study has demonstrated that prenatal treatment with retinoic acid (RA) stimulates alveologenesis in hypoplastic lungs in the nitrofen model of congenital diaphragmatic hernia (CDH). Furthermore, it has also been demonstrated that the differentiation from alveolar epithelial cells type II (AECs-II) into alveolar epithelial cells type I (AECs-I), which is the key process in lung development, is disturbed in this model. We hypothesized that retinoids promote alveologenesis by stimulating differentiation of AECs-II to AECs-I at the end of gestation; and therefore, we investigated the effect of RA on the pulmonary expression of intercellular adhesion molecule 1 (ICAM-1), a marker for AECs-I, and thyroid transcription factor 1 (Ttf-1), a marker for AECs-II, in nitrofen-induced hypoplastic lungs., Materials and Methods: Pregnant rats were exposed to either olive oil or 100 mg nitrofen on day of gestation (D) 9. Five milligrams per kilogram of RA was given intraperitoneally on D18, D19, and D20; and fetuses were recovered on D21. We had 4 study groups: control (n = 7), control + RA (n = 7), CDH (n = 6), and CDH + RA (n = 6). The expression of ICAM-1 and Ttf-1 was analysed in each lung by real-time reverse transcription polymerase chain reaction and immunohistochemistry. One-way analysis of variance test was used for statistical analysis., Results: Expression levels of ICAM-1 were significantly reduced in CDH lungs compared with normal controls, whereas levels increased significantly in CDH group after the addition of RA (P < .05). Expression levels of Ttf-1 were significantly decreased in lungs from RA-treated CDH animals compared with CDH without RA (P < .05). The ICAM-1 and Ttf-1 immunoreactivity demonstrated similar pattern of expression in various groups., Conclusions: Our results demonstrate that prenatal treatment with RA accelerates AEC-I proliferation in the hypoplastic lung in CDH.

Congenital malformations of the foregut are common in humans. The respiratory and digestive tubes are both derived by division of the foregut primordium. Sonic hedgehog (Shh) and Fork head box F1 (Foxf1) genes encode regulatory molecules that play a pivotal role in gut and lung morphogenesis and are therefore important candidate genes to be examined in models of foregut developmental disruption. Optical projection tomography (OPT) is a new, rapid and non-invasive technique for three-dimensional (3D) imaging of small biological tissue specimens that allows visualization of the tissue distribution of RNA in developing organs while also recording morphology. To explore the application of OPT in this context, we visualized Shh and Foxf1 gene expression patterns in the mouse foregut and lung buds at several stages of development. Time-mated CBA/Ca mice were harvested on embryonic days 9-12. The embryos were stained following whole mount in situ hybridization with labelled RNA probes to detect Shh and Foxf1 transcripts at each stage. The embryos were scanned by OPT to obtain 3D representations of gene expression domains in the context of the changing morphology of the embryo. OPT analysis of Shh and Foxf1 expression in the foregut and lung buds revealed extra details of the patterns not previously reported, particularly in the case of Foxf1 where gene expression was revealed in a changing pattern in the mesenchyme around the developing lung. Shh expression was also revealed in the epithelium of the lung bud itself. Both genes were detected in complementary patterns in the developing bronchi as late as E12, showing successful penetration of molecular probes and imaging at later stages. OPT is a valuable tool for revealing gene expression in an anatomical context even in internal tissues like the foregut and lung buds across stages of development, at least until E12. This provides the possibility of visualizing altered gene expression in an in vivo context in genetic or teratogenic models of congenital malformations.

Retinoids are a group of molecules derived from vitamin A, which play an important role in lung development. Within the cell, retinol can either be oxidized to retinal or esterified to retinyl esters by lecithin : retinol acyltransferase (LRAT) for storage. Retinal is then oxidized to an active metabolite of vitamin A, retinoic acid (RA) by retinal dehydrogenase (RALDH). RA is the active metabolite of vitamin A. Cyp26 (a1,b1, and c1), which is a member of the cytochrome P450 family, acts by reducing the activity of RA. Cyp26 type b1 is the predominant subtype expressed in the murine lung. Several studies have suggested that nitrofen may interfere with the retinoid pathway resulting in congenital diaphragmatic hernia (CDH) and pulmonary hypoplasia. Recently, it was reported that nitrofen may act by inhibiting RALDH2. The aim of this study was to examine the pulmonary expression of Cyp26b1, LRAT, and RALDH2, the key enzymes involved in the synthesis of RA, in order to understand the mechanisms underlying pulmonary hypoplasia in the nitrofen CDH model. Pregnant rats were exposed to either olive oil or 100 mg of nitrofen on day 9 of gestation (D9). Fetal lungs were harvested at D15, D17, D19, and D21. D17, D19, and D21 lungs were divided into three groups: control, nitrofen without CDH and nitrofen with CDH, whereas D15 lungs were divided into only two groups; control and nitrofen as the diaphragm is not fully formed yet at this stage. Real- time PCR was performed to evaluate the relative level of Cyp26b1, LRAT, and RALDH2 expression in the lung. Relative levels of Cyp26b1 mRNA were significantly decreased in the lungs of nitrofen with CDH (D17;0.19 +/- 0.09, D19;0.70 +/- 0.20, D21;0.40 +/- 0.36) and nitrofen without CDH (D17;0.14 +/- 0.06, D19;0.54 +/- 0.42, D21;0.51 +/- 0.56) compared to controls (D17;0.35 +/- 0.16, D19;1.15 +/- 0.48, D21;1.28 +/- 0.78) (P < 0.05). LRAT expression was also significantly decreased in nitrofen with CDH (D17; 19.3 +/- 7.8, D19; 4.3 +/- 1.1, D21; 3.3 +/- 1.6) and nitrofen without CDH (D17; 21.2 +/- 11.1, D19; 4.5 +/- 3.6, D21; 4.1 +/- 1.6) compared to controls (D17; 153.7 +/- 29.8, D19; 26.8 +/- 16.8 D21; 10.1 +/- 3.8) (P < 0.05). There was no significant difference in the relative levels of Cyp26b1 and LRAT between nitrofen with CDH and nitrofen without CDH. There were no significant differences in RALDH2 expression among the groups at any stages. Down-regulation of Cryp26b1 and LRAT demonstrates that RA content is decreased in nitrofen induced hypoplastic lungs compared to controls. The finding that RALDH2 expression in the hypoplastic lung is not altered suggests that nitrofen may act by interfering with the retinoid metabolism during the early stage of the retinoid signaling pathway.

Pulmonary hypoplasia is the principal cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). Still, relatively little is known about the mechanisms causing lung hypoplasia associated with CDH. The differentiation from alveolar epithelial cells type II (AECs-II) into alveolar epithelial cells type I (AECs-I) is one of the key processes in lung development in late gestation. It is well known that increased lung expansion promotes differentiation into AECs-I phenotype, whereas reduced lung expansion promotes AECs-II phenotype. The recent availability of cell-specific molecule markers for AECs-I and AECs-II has provided an opportunity to study the various characteristics of these two cell types. To test the hypothesis that the differentiation of AECs-II to AECs-I is impaired in the CDH hypoplastic lung, we investigated molecular markers for AECs-I [ICAM-1, T1alpha, aquaporin 5 (AQP5)] and molecular markers for AECs-II [thyroid transcription factor-1 (Ttf-1), surfactant protein (SP)-B and C] in the nitrofen-induced CDH lung. Fetal rat lungs of normal (n = 7) and nitrofen-treated (n = 14) dams were harvested on embryonic day 21. The expression of the ICAM1, T1alpha, AQP5, SP-B, C and Ttf-1 was analyzed in each lung by real-time reverse transcription polymerase chain reaction. Immunohistochemical studies were performed to evaluate the protein expression level of ICAM1 and Ttf1. Expression levels of ICAM-1, T1alpha and AQP5 were significantly reduced (P < 0.05) in the lungs from nitrofen-treated CDH animals compared to normal controls. ICAM-1 and AQP5 immunohistochemistry showed a diffuse pattern of expression in the alveolar cells in normal lungs. By contrast, the ICAM-1 and AQP5 positive cells were markedly reduced in hypoplastic lungs with CDH. On the other hand, the expression levels of Ttf-1, SP-B and C were significantly (P < 0.05) increased in the lungs from nitrofen-treated CDH animals compared to normal controls. The population of Ttf-1 positive cells was slightly increased in the lungs from nitrofen-treated animals in immunohistochemical study. Our results demonstrate that there is significant reduction in the proportion of AECs-I and increase in the proportion of AECs-II in the hypoplastic lung in the nitrofen-induced CDH. This data provides the first evidence to support the hypothesis that AEC differentiation is impaired in CDH hypoplastic lung.

Purpose: The pathogenesis of pulmonary hypoplasia associated with congenital diaphragmatic hernia is poorly understood. Recently, it has been reported that Wnt signaling pathway plays a critical role in branching lung morphogenesis. Mice lacking Wnt7b gene die soon after birth because of respiratory failure and display severe lung hypoplasia. Wnt2 gene is expressed in the distal airway during development. To test the hypothesis that Wnt-mediated signaling is altered in nitrofen-induced hypoplastic lungs, we examined the expression of Wnt genes and Wnt target gene, BMP4 in normal and nitrofen-treated lungs., Materials and Methods: Fetal rat lungs of normal (n = 24) and nitrofen-treated (n = 24) dams were harvested on embryonic day (E)15, E17, E19, and E21. The expression of GATA6, the Wnt genes (Wnt7b, Wnt2), and BMP4 was analyzed in each lung by real-time reverse transcription polymerase chain reaction., Results: The gene expression of Wnt7b, Wnt2, and BMP4 on E15 was significantly reduced (P < .05) in lungs from nitrofen-treated animals compared with normal lungs. The expression level of GATA6, which has been reported to transactivate Wnt7b expression, was also significantly reduced (P < .05) in lungs from the nitrofen group., Conclusion: Our results provide evidence for the first time that the Wnt signaling pathway is down-regulated in nitrofen-induced hypoplastic lungs in the early stages of lung development. Decreased expression of GATA6 may account for the down-regulation of Wnt signal pathway. These data suggest that the down-regulation of Wnt signaling pathway may disrupt branching lung morphogenesis, resulting in pulmonary hypoplasia in the nitrofen rat model of congenital diaphragmatic hernia.

We report a case of ruptured giant omphalocele in whom herniated organs were successfully covered by an absorbable mesh and a subsequent skin graft. A 2,200 g male baby was born at 35 weeks of gestation. An abdominal wall abnormality was detected by prenatal ultrasound at 21 weeks of gestation. At birth, the entire liver, stomach, and small and large bowel had herniated from the defect of the abdominal wall. The thorax and abdomen were highly underdeveloped, and attempts to reduce the organs into the abdomen were unsuccessful due to the extremely small abdominal cavity and associated pulmonary hypoplasia. To protect the herniated organs and prevent abdominal infections, the organs were covered by a polyglycan mesh and subsequently a meshed split-thickness skin graft. Ten weeks later, it was confirmed that the organs were completely covered by epithelialized tissue. However, the patient suffered from frequent respiratory infections and finally died of respiratory insufficiency. Based on the experience of the patient, we conclude that coverage of the herniated organs with an absorbable mesh and a skin graft is a recommendable treatment in ruptured giant omphalocele.

Purpose: Pulmonary hypoplasia remains the principal cause of high morbidity and mortality in patients with congenital diaphragmatic hernia (CDH). The precise mechanisms causing lung hypoplasia remains unclear. Aquaporins (AQPs) are reported to constitute a family of water channels that facilitate membrane water permeability in various tissues of animals. Aquaporin 5 has been reported to be an important marker expressed in type I alveolar epithelial cells in late gestation and mediates water transport across the human airway epithelium. We hypothesized that AQP5 is reduced in hypoplastic lungs and therefore designed this study to determine AQP5 expression in normal and hypoplastic lungs., Methods: Fetal rat lungs of control (n=23) and nitrofen-treated (n=37) dams were harvested on embryonic day (E) 15, E17, E19, and E21. The expression of the AQP5 was analyzed in each lung by real-time reverse transcriptase-polymerase chain reaction. Immunohistochemical studies were performed to evaluate the protein expression level of AQP5., Results: Aquaporin 5 messenger RNA levels on E21 were significantly reduced in lungs from the nitrofen with CDH group (11.8 +/- 2.3) compared with normal controls (23.5 +/- 11.8) and nitrofen without CDH group (26.9 +/- 13.0) (P < .05). Aquaporin 5 immunohistochemistry demonstrated AQP5 strongly expressed at the apical membrane of type I alveolar epithelial cells in the normal and nitrofen without CDH groups. By contrast, the AQP5-positive cells were markedly reduced in hypoplastic lungs in the nitrofen with CDH group., Conclusion: Our results show that the expression of AQP5 is down-regulated in hypoplastic lungs with CDH. Down-regulation of AQP5 may result in abnormal pulmonary fluid metabolism in perinatal period and may be one of the mechanisms disturbing the pulmonary development in late stage in the CDH model.

Purpose: Retinoids play a key role in lung development. Recent studies suggest that retinoid signalling pathway may be disrupted in the nitrofen model of congenital diaphragmatic hernia (CDH), but the exact mechanism is not clearly understood. We hypothesized that nitrofen interferes with cellular uptake of retinol during lung morphogenesis and therefore designed this study to examine total retinol levels in lung, liver, and serum, and the gene expression of main components of the retinoid pathway in the nitrofen model of CDH., Methods: Pregnant rats were exposed to vehicle or 100 mg of nitrofen on day 9 of gestation. Term fetuses were divided in control and nitrofen with CDH and without CDH groups. Retinol levels in serum, lungs, and liver were measured using high-performance liquid chromatography. Reverse transcriptase-polymerase chain reaction was performed to evaluate the relative amount of cellular retinol-biding protein I, retinal dehydrogenase 1a2 and 1a3 (Aldh1a2 and Aldh1a3), retinoic acid receptors alpha and beta (RARalpha, RARbeta), and retinoid X receptor alpha (RXRalpha) expression in the lung., Results: Total retinol levels in the lungs were significantly lower in both nitrofen with CDH (1.78 +/- 0.37 microg/g) and nitrofen without CDH (1.61 +/- 0.24 microg/g) groups compared with controls (2.43 +/- 0.31 microg/g) (P < .001), whereas serum retinol levels were significantly higher in nitrofen with and without CDH groups (0.77 +/- 0.13 and 0.75 +/- 0.11 microg/g, respectively) compared with controls (0.58 +/- 0.12 microg/g) (P < .001). There was no significant difference in liver retinol levels between the 3 groups. Relative expression of cellular retinol-biding protein I, Aldh1a3, RARalpha, RARbeta, and RXRalpha were significantly up-regulated in the lungs of the nitrofen with CDH group (0.70 +/- 0.15, 3.94 +/- 0.91, 2.15 +/- 0.47, 3.49 +/- 1.00, 1.88 +/- 0.42, respectively) and the nitrofen without CDH group (0.61 +/- 0.14, 3.72 +/- 0.31, 1.66 +/- 0.20, 3.28 +/- 1.02, 1.38 +/- 0.24, respectively) compared with controls (0.43 +/- 0.11, 2.71 +/- 0.47, 0.79 +/- 0.42, 1.85 +/- 0.69, 0.57 +/- 0.22, respectively) (P < .05)., Conclusion: Our data clearly show that lung retinol storage is decreased in the nitrofen model of CDH. The associated increase in gene expressions of most downstream components of the retinoid signalling pathway may be a feedback reaction to the deficiency of lung retinol. These results suggest that nitrofen acts by interfering with the cellular uptake of retinol during lung morphogenesis resulting in pulmonary hypoplasia in this model.

Body stalk anomaly is characterized by severe scoliosis, severe pulmonary hypoplasia, and giant omphalocele. The prognosis of the disease is poor and most obstetricians consider it fatal. Very few patients with body stalk anomaly survive. We report the case of a baby diagnosed with body stalk anomaly in fetal life, who was saved by intensive care after birth. We closed the giant omphalocele successfully by placing karaya gum sheets over it, which created a humidified environment and promoted natural skin epithelization over the skin defect.

Objectives: Granulocyte apheresis (GCAP), involving the removal of granulocytes from the blood, may improve clinical symptoms and facilitate a reduction in the dose of steroids in adult patients with ulcerative colitis. As a preliminary trial, GCAP was used to taper the dose of steroids in 4 pediatric patients with ulcerative colitis., Methods: Three males and 1 female ranging from 11 to 17 years old were treated with GCAP once per week for 5 consecutive weeks/course. The ages of patients at clinical onset ranged from 8 to 12 years and the length of time from the clinical onset to GCAP treatment ranged from 28 to 58 months (median, 38.5 months)., Results: In 2 patients, symptoms and signs indicating disease activity improved after 2 courses of GCAP. Laboratory data and endoscopic findings also improved after treatment and the clinical efficacy was judged to be excellent in these patients. In 1 patient, GCAP improved laboratory and endoscopic hallmarks, but bloody stools persisted. Finally, the treatment was ineffective in the fourth patient who eventually underwent surgery., Conclusions: GCAP is effective in improving clinical symptoms and may play an important role in converting steroid therapy to other treatments in children with steroid-refractory or steroid-dependent ulcerative colitis.

Rhabdomyosarcomas of the perianal and perineal regions are uncommon. This study was performed to clarify the clinical characteristics and guidelines of surgical treatment of patients with perianal and perineal rhabdomyosarcomas younger than 20 years of age. Twenty-nine patients, 26 patients identified in the Japanese literature and three of our own, were analyzed and the results were compared with the data reported from the Intergroup Rhabdomyosarcoma Study Group (IRSG). Female predominance and a twin-peak age distribution in infancy and adolescence were characteristic findings of the Japanese patients that were not observed in the IRSG studies. The demographic differences between the two groups were attributed to the differences in demographics of patients younger than 10 years of age. Of the 29 patients, 17 were categorized into clinical groups III/IV and 21 patients into stages 3/4. Alveolar histology was diagnosed in 18 patients. In patients more than 10 years of age, the female predominance was more prominent and the incidences of advanced clinical groups/stages and alveolar histology were significantly higher than those in patients younger than 10 years of age. Inguinal lymph nodes were always involved in patients with lymph node metastases and three patients developed metastases to the breast. Information regarding the survival time was available for 18 patients and the 5-year overall survival was 20%. Two patients with a group I/stage 2 tumor and one with a group II/stage 3 tumor survived for more than 2 years with no evidence of the disease. In these patients, the tumors were excised by primary surgery or primary reexcision and they were not accompanied by lymph node metastasis. Based on these data, complete tumor resection prior to chemotherapy should be pursued and the inguinal lymph nodes should be at least sampled because nodal involvement is closely associated with the patient's prognosis.

In children with diseases of the spleen, every effort should be made to preserve the organ, to prevent severe infections postsplenectomy. We report the case of a 7-year-old girl with torsion of a wandering spleen who we treated by autotransplantation of splenic tissues following splenectomy, when fixation of the enlarged spleen seemed impossible. Spleen scintigraphy showed uptake in the regenerating splenic tissues 9 months after surgery, and evidence of an increase in the size of the tissues 23 months after surgery. Howell-Jolly bodies had disappeared by 16 months after surgery. These findings suggested that the transplanted splenic tissues were resuming splenic functions. Based on our experience with this case, we conclude that autotransplantation after splenectomy is a treatment option for wandering spleen with torsion when fixation seems difficult because of splenic congestion and enlargement.

Solitary nonparasitic cyst of the liver (SNPCL) is rare in children. Although there are several hypotheses regarding the pathogenesis, the true origin of SNPCL remains unknown. The authors present an infant with a huge SNPCL in whom the epithelial markers, CA19-9, DU-PAN-2, and SPan-1, were elevated in the serum and cystic fluid. The presence of CA19-9 and DU-PAN-2 was shown by immunohistochemistry in the cystic epithelia. These indicate that the classical idea of biliary origin of SNPCL is supported.

Xanthogranulomatous pyelonephritis (XGP), a morphological and clinical variant of chronic pyelonephritis, is an uncommon disease in children. It is characterized by the destruction of the renal parenchyma and replacement by granulomatous tissue containing foamy lipid-laden macrophages and is classified into diffuse and focal XGP. We present a case of diffuse XGP in a child with myotonic dystrophy complicated by cerebral palsy and discuss the importance of correct diagnosis and preoperative management to reduce inflammation and improve malnutrition associated with the disease.

Purpose: To address whether laparoscopic appendectomy could be an alternative to conventional open appendectomy in children with complicated appendicitis as well as uncomplicated appendicitis, a retrospective study comparing laparoscopic and open appendectomies was performed., Methods: One hundred patients who were treated by immediate appendectomy, either laparoscopically or by the open method, between May 2000 and August 2003 were included in the study. There were 53 patients in the laparoscopic appendectomy group and 47 patients in the open appendectomy group., Results: The operating time was significantly longer for laparoscopic appendectomy than for open appendectomy (P < .001). The length of hospital stay was significantly shorter in laparoscopic appendectomy in patients with uncomplicated appendicitis (P = .001). Thirteen of the 100 patients (13.0%) had 15 postoperative complications including wound infection (n = 8), intraabdominal abscess (n = 4), stitch abscess (n = 2), and small bowel obstruction (n = 1). In both uncomplicated and complicated appendicitis, there was no significant difference between laparoscopic and open appendectomies in the complication rates, and the incidences of each complication did not differ between the procedures. Among the 14 patients with generalized peritonitis, postoperative complications were seen in 5 patients (35.7%). Although the presence of generalized peritonitis was associated significantly with postoperative complications (P = .017), there was no significant association between the procedure and complications. Overall treatment costs were increased by 26.0% in laparoscopic appendectomy., Conclusions: Laparoscopic appendectomy should remain an option in children with uncomplicated and complicated appendicitis, and when laparoscopy is selected, consideration of the advantages and disadvantages of the procedure is essential.

Hepatoblastoma is one of the most common malignant liver tumors in young children. Recent evidences have suggested that the abnormalities in Wnt signaling pathway, as seen in frequent mutation of the beta-catenin gene, may play a role in the genesis of hepatoblastoma. However, the precise mechanism to cause the tumor has been elusive. To identify novel hepatoblastoma-related genes for unveiling the molecular mechanism of the tumorigenesis, a large-scale cloning of cDNAs and differential screening of their expression between hepatoblastomas and the corresponding normal livers were performed. We constructed four full-length-enriched cDNA libraries using an oligo-capping method from the primary tissues which included two hepatoblastomas with high levels of alpha-fetoprotein (AFP), a hepatoblastoma without production of AFP, and a normal liver tissue corresponded to the tumor. Among the 10,431 cDNAs randomly picked up and successfully sequenced, 847 (8.1%) were the genes with unknown function. Of interest, the expression profile among the two subsets of hepatoblastoma and a normal liver was extremely different. A semiquantitative RT-PCR analysis showed that 86 out of 1188 genes tested were differentially expressed between hepatoblastomas and the corresponding normal livers, but that only 11 of those were expressed at high levels in the tumors. Notably, PLK1 oncogene was expressed at very high levels in hepatoblastomas as compared to the normal infant's livers. Quantitative real-time RT-PCR analysis for the PLK1 mRNA levels in 74 primary hepatoblastomas and 29 corresponding nontumorous livers indicated that the patients with hepatoblastoma with high expression of PLK1 represented significantly poorer outcome than those with its low expression (5-year survival rate: 55.9 vs 87.0%, respectively, p=0.042), suggesting that the level of PLK1 expression is a novel marker to predict the prognosis of hepatoblastoma. Thus, the differentially expressed genes we have identified may become a useful tool to develop new diagnostic as well as therapeutic strategies of hepatoblastoma.