Neuroblastoma is one of the most frequent, yet distinctive and challenging childhood tumors. The uniqueness of this tumor depends on its biological markers, which classify neuroblastomas into ...favorable and unfavorable, with 5-year survival rates ranging from almost 100–30%. In this review, we focus on some biological factors that play major roles in neuroblastoma: MYCN, Trk, and ALK. The MYCN and Trk family genes have been studied for decades and are known to be crucial for the tumorigenesis and progression of neuroblastoma. ALK gene mutations have been recognized recently to be responsible for familial neuroblastomas. Each factor plays an important role in normal neural development, regulating cell proliferation or differentiation by activating several signaling pathways, and interacting with each other. These factors have been studied not only as prognostic factors, but also as targets of neuroblastoma therapy, and some clinical trials are ongoing. We review the basic aspects of MYCN, Trk, and ALK in both neural development and in neuroblastoma.
Purpose
We compared the efficacy of thoracoscopic repair (TR) with that of open repair (OR) for neonatal congenital diaphragmatic hernia (CDH).
Methods
The subjects of this multicenter retrospective ...cohort study were 524 infants with left-sided isolated CDH, diagnosed prenatally, and treated at one of 15 participating hospitals in Japan between 2006 and 2018. The outcomes of infants who underwent TR and those who underwent OR were compared, applying propensity score matching.
Results
During the study period, 57 infants underwent TR and 467 underwent OR. Ten of the infants who underwent TR required conversion to OR for technical difficulties and these patients were excluded from the analysis. The survival rate at 180 days was similar in both groups (TR 98%; OR 93%). Recurrence developed after TR in 3 patients and after OR in 15 patients (TR 7%, OR 3%,
p
= 0.40). The propensity score was calculated using the following factors related to relevance of the surgical procedure: prematurity (
p
= 0.1), liver up (
p
< 0.01), stomach position (
p
< 0.01), and RL shunt (
p
= 0.045). After propensity score matching, the multivariate analysis adjusted for severity classification and age at surgical treatment revealed a significantly shorter hospital stay (odds ratio 0.50) and a lower incidence of chronic lung disease (odds ratio 0.39) in the TR group than in the OR group.
Conclusions
TR can be performed safely for selected CDH neonates with potentially better outcomes than OR.
One of the most frequent complications after repair of esophageal atresia (EA) is gastroesophageal reflux disease (GERD). Although GERD-associated EA is known to often require anti-reflux surgery, ...the predicting factors remain unclear. We retrospectively analyzed EA in our institution.
Of 65 children with EA treated in our hospital from 1995 to 2018, 45 with Gross C type EA, followed for over 1 year, were enrolled in this study. The patients were divided into fundoplication and non-fundoplication groups and compared in terms of their clinical features.
The fundoplication and non-fundoplication groups included 13 and 32 cases, respectively. On univariate analysis, gestational age, body weight, prenatal diagnosis, polyhydramnios, re-do surgery, and gap length of the esophagus differed significantly between the groups (P < 0.05).
Early delivery, low body weight, and a long gap length are, are considered to be risk factors for fundoplication. However, the present study further showed that prenatal diagnosis and polyhydramnios were also significant contributing factors. The presence of a prenatal diagnosis and polyhydramnios may induce preterm delivery, therefore, cases of polyhydramnios due to suspected EA should be managed to prevent early delivery. Better understanding of the postnatal course after surgery is required, especially for prenatal diagnosis cases.
Background
The leading pathology of biliary atresia (BA) is inflammatory and fibrous obstruction of extrahepatic bile duct, but the pathogenesis remains unclear. IL13 is a cytokine associated with ...allergies and inflammatory fibrosis, and periostin induces fibrogenesis by stimulation with IL13. We analyzed the involvement of IL13 and periostin in inflammatory fibrosis in the extrahepatic bile duct of BA patients.
Materials and methods
Surgically resected tissues from the hepatic hilar area of BA patients were immunostained with CD45,
α
-SMA, IL13 and periostin and statistically analyzed. Fibroblasts from the resected tissue were cultured with recombinant IL13, and periostin production was analyzed by quantitative polymerase chain reaction and Western blotting.
Results
IL13 was stained in 93% of large and micro bile ducts, and 92.1% matched with the CD45 location (
p
= 0.006) around the large bile ducts. Periostin staining correlated with the localization of IL13 and
α
SMA (
p
< 0.001) around the large bile ducts. Periostin mRNA and protein were upregulated by IL13 stimulation in cultured fibroblasts.
Conclusion
IL13 was associated with induced periostin expression by fibroblasts, playing a vital role in the pathogenesis of fibrogenesis around the extrahepatic bile duct in BA.
Purpose
We aimed to evaluate the effect of human mesenchymal stem cells (hMSCs) on congenital diaphragmatic hernia (CDH) by intra-amniotic injection in a rat CDH model.
Methods
Nitrofen (100 mg) was ...administered to pregnant rats at E9.5. hMSCs (1.0 × 10
6
) or PBS was injected into each amniotic cavity at E18, and fetuses were harvested at E21. The fetal lungs were classified into normal, CDH, and CDH-hMSCs groups. To determine the lung maturity, we assessed the alveolar histological structure by H&E and Weigert staining and the alveolar arteries by Elastica Van Gieson (EVG) staining. TTF-1, a marker of type II alveolar epithelial cells, was also evaluated by immunohistochemical staining and real-time reverse transcription polymerase chain reaction.
Results
The survival rate after intra-amniotic injection was 72.1%. The CDH-hMSCs group had significantly more alveoli and secondary septa than the CDH group (
p
< 0.05). The CDH-hMSCs group had larger air spaces and thinner alveolar walls than the CDH group (
p
< 0.05). The medial and adventitial thickness of the pulmonary artery in the CDH-hMSCs group were significantly better (
p
< 0.001), and there were significantly fewer TTF-1-positive cells than in the CDH group (
p
< 0.001).
Conclusion
These results suggest that intra-amniotic injection of hMSCs has therapeutic potential for CDH.
Purpose
The prenatal diagnosis of the stomach position in congenital diaphragmatic hernia (CDH) has been a reliable prognostic factor, but few studies have focused on the postnatal position. We ...therefore evaluated the significance of the nasogastric (NG) tube position just after birth.
Methods
The Japanese CDH Study Group database enrolled 1037 CDH neonates over 15 years. In our multicenter retrospective study, 464 cases of left-sided isolated CDH with prenatal diagnoses were divided into two groups: NG tube below the diaphragm (BD;
n
= 190) or above the diaphragm (AD;
n
= 274). The primary outcome was the 90-day survival rate, and the secondary outcomes were mechanical ventilation duration, hospitalization duration, and recurrence rate.
Results
The BD group had a significantly higher 90-day survival rate (98.4 vs. 89.4%,
p
< 0.001), shorter mechanical ventilation (11 vs. 19 days,
p
< 0.001), shorter hospitalization (38 vs. 59 days,
p
< 0.001), and lower recurrence rate (
p
= 0.002) than the AD group. A multivariate analysis showed that BD (adjusted odds ratio, 3.68; 95% confidence interval 1.02–13.30) was a favorable prognostic factor for the 90-day survival.
Conclusion
The assessment of the NG tube position revealed it to be a reliable prognostic factor of left-sided isolated CDH. Therefore, it should be included as a routine assessment.
Biliary atresia (BA) is characterized by the inflammation and obstruction of the extrahepatic bile ducts (EHBDs) in newborn infants. SOX17 is a master regulator of fetal EHBD formation. In mouse
BA ...models, SOX17 reduction causes cell-autonomous epithelial shedding together with the ectopic appearance of SOX9-positive cystic duct-like epithelia in the gallbladder walls, resulting in BA-like symptoms during the perinatal period. However, the similarities with human BA gallbladders are still unclear. In the present study, we conducted phenotypic analysis of
BA neonate mice, in order to compare with the gallbladder wall phenotype of human BA infants. The most characteristic phenotype of the
BA gallbladders is the ectopic appearance of SOX9-positive peribiliary glands (PBGs), so-called pseudopyloric glands (PPGs). Next, we examined SOX17/SOX9 expression profiles of human gallbladders in 13 BA infants. Among them, five BA cases showed a loss or drastic reduction of SOX17-positive signals throughout the whole region of gallbladder epithelia (SOX17-low group). Even in the remaining eight gallbladders (SOX17-high group), the epithelial cells near the decidual sites were frequently reduced in the SOX17-positive signal intensity. Most interestingly, the most characteristic phenotype of human BA gallbladders is the increased density of PBG/PPG-like glands in the gallbladder body, especially near the epithelial decidual site, indicating that PBG/PPG formation is a common phenotype between human BA and mouse
BA gallbladders. These findings provide the first evidence of the potential contribution of SOX17 reduction and PBG/PPG formation to the early pathogenesis of human BA gallbladders.This article has an associated First Person interview with the joint first authors of the paper.
Background
Pulmonary hypoplasia is an important cause of morbidity and mortality in infants with congenital diaphragmatic hernia (CDH). This study aimed to verify our hypothesis that the abnormal ...development of bronchial cartilage as well as alveolar immaturity, might play a central role in hypoplasia of the lung in human CDH.
Method
We retrospectively analyzed autopsied lungs from 10 CDH cases and compared with nine age‐matched controls to assess the bronchial cartilage and alveolar maturity using morphological techniques.
Result
Ki‐67 and thyroid transcription factor‐1 (TTF‐1) expression in the alveoli significantly increased in bilateral lungs with CDH. The shortest distance from the bronchial cartilage to the pleura was significantly shorter in ipsilateral (left) lungs with CDH, showing a positive correlation with the radial alveolar count (RAC). Regarding the small bronchial cartilages less than 20 000 μm2, the average cartilage area significantly decreased in left lungs with CDH, and tended to decrease in right lungs with CDH. In addition, cartilage around the bronchi less than 200 μm in diameter tended to be smaller in left lungs with CDH. In contrast, regarding the cartilage around the bronchi 200 to 400 μm in diameter, the ratio of the total cartilage area relative to the bronchial diameter tended to be higher in left lungs with CDH, although there was a large variation.
Conclusions
These opposite directional cartilage abnormalities around the distal and more proximal bronchi support our hypothesis that abnormal development of bronchial cartilage might play an important role in the hypoplastic lung in CDH.
To evaluate the optimal timing of neonates with prenatally diagnosed congenital diaphragmatic hernia (CDH).
Data from a retrospective cohort study conducted by the Japanese CDH Study Group between ...2011 and 2018 were divided into two groups according to delivery timing: 36-37 and 38-41 weeks of gestation (wg). Death before 90 days as the primary outcome and the duration of hospitalization, oxygen therapy and tube feeding at discharge as the secondary outcomes were analyzed with generalized linear model applying inverse probability of treatment weighting method. We also performed layered analysis according to stomach position.
Among 493 neonates with prenatally diagnosed, isolated and left CDH, 237 were born at 38-41wg. The duration of hospitalization was significantly shorter in those born at 38-41wg, especially among those with stomach malposition, and the other outcomes showed no difference.
Delivery at 38-41wg could be beneficial for those with high grade stomach position.
Purpose
Predicting lethal pulmonary hypoplasia in infants with congenital diaphragmatic hernia (CDH) before extracorporeal membrane oxygenation (ECMO) initiation is difficult. This study aimed to ...predict lethal pulmonary hypoplasia in patients with CDH prior to ECMO.
Methods
This was a multicenter cohort study involving neonates prenatally diagnosed with isolated unilateral CDH (born 2006–2020). Patients who required ECMO due to respiratory insufficiency were included in this study. Patients who underwent ECMO due to transient disorders were excluded from analysis. Blood gas analysis data within 24 h of birth were compared between survivors and non-survivors. Predictive abilities were assessed for factors with significant differences.
Results
Overall, 34 patients were included (18 survivors and 16 non-survivors). The best pre-ductal PaO
2
was significantly lower in non-survivors than in survivors (50.4 IQR 30.3–64.5 vs. 67.5 IQR 52.4–103.2 mmHg, respectively;
p
= 0.047). A cutoff PaO
2
of 42.9 mmHg had a sensitivity, specificity, and positive predictive value of 50.0%, 94.4%, and 88.9%, respectively, to predict mortality.
Conclusion
The best PaO
2
within 24 h after birth predicted mortality following ECMO initiation. This should be shared to families and caregivers to optimize the best interests of the infants with CDH.
PDF
