照井 慶太

症例は12歳、女児。腹痛を主訴に近医を受診し、先天性胆道拡張症・急性膵炎の診断で当科紹介となった。MRCP上、拡張した肝外胆管は頭側で左右肝管に分岐し、尾側では膵管に合流した。さらに別の肝外胆管も認められ、胆嚢管を分岐し尾側で十二指腸に連なった。ERCP上、両者は左右肝管合流部直下で交通し、拡張胆管は膵管と合流して長い共通管を形成しており、膵・胆管合流異常を伴う重複胆管と診断した。近位胆管は両胆管交通部直上の総肝管で切離し、遠位胆管は膵内で2本の肝外胆管を別個に処理し、肝管空腸吻合術を施行した。重複胆管は非常に稀な病態で、本邦では97例(うち小児11例)を数えるにすぎない。小児例では膵・胆管合流異常を併存することが多く、成人例では悪性腫瘍の合併も散見され、複雑な胆道形態から種々の病態を生じうる。胆管の走行と併存疾患を正確に評価し、適切な治療戦略を立てることが肝要である。(著者抄録)

Purpose: The optimal timing of surgery for congenital diaphragmatic hernia (CDH) is controversial. We aimed to validate our protocol for the timing of CDH repair using the quantified patent ductus arteriosus (PDA) flow pattern. Methods: This retrospective comparative study analyzed patients with a prenatal diagnosis of isolated CDH between 2007 and 2020. We defined the “LR ratio” as the percentage of velocity–time integral (VTI) of the left-to-right flow of PDA against overall VTI on echocardiography. Since 2010, we followed the decision criterion of performing surgery when LR ratio of > 50% has been achieved in the patients (protocol group). The protocol group (2010–2020) was compared with the historical control group (2007–2009). Results: The average age at surgery was 104.1 ± 175.9 and 37.3 ± 30.6 h in the control and protocol groups, respectively (p = 0.11). Survival rate (88.9% vs. 95.0%, p = 0.53) and the rate of worsening of pulmonary hypertension within 24 h after surgery (22.2% vs. 10.0%, p = 0.57) were not different between the groups. The protocol group had a significantly shorter duration of tracheal intubation (26.9 ± 21.1 vs. 13.3 ± 9.5 days, p = 0.03). Conclusion: Our decision criterion might have the advantage of facilitating early and safe surgery for patients with CDH.

PURPOSE: The optimal timing of surgery for congenital diaphragmatic hernia (CDH) is controversial. We aimed to validate our protocol for the timing of CDH repair using the quantified patent ductus arteriosus (PDA) flow pattern. METHODS: This retrospective comparative study analyzed patients with a prenatal diagnosis of isolated CDH between 2007 and 2020. We defined the "LR ratio" as the percentage of velocity-time integral (VTI) of the left-to-right flow of PDA against overall VTI on echocardiography. Since 2010, we followed the decision criterion of performing surgery when LR ratio of > 50% has been achieved in the patients (protocol group). The protocol group (2010-2020) was compared with the historical control group (2007-2009). RESULTS: The average age at surgery was 104.1 ± 175.9 and 37.3 ± 30.6 h in the control and protocol groups, respectively (p = 0.11). Survival rate (88.9% vs. 95.0%, p = 0.53) and the rate of worsening of pulmonary hypertension within 24 h after surgery (22.2% vs. 10.0%, p = 0.57) were not different between the groups. The protocol group had a significantly shorter duration of tracheal intubation (26.9 ± 21.1 vs. 13.3 ± 9.5 days, p = 0.03). CONCLUSION: Our decision criterion might have the advantage of facilitating early and safe surgery for patients with CDH.

胚細胞腫瘍は胎生期の原始胚細胞が胚細胞になるまでの間に発生してくる腫瘍と考えられており,その種類や悪性度は様々である.しかし,本邦における小児頭蓋外胚細胞腫瘍に関するまとまった報告は少ない.我々は,2003年から2017年までの間に当院で治療した頭蓋外胚細胞腫瘍63例について,後方視的に臨床学的特徴と治療経過を検討した.診断時年齢の中央値は6.6歳(日齢10-14歳),原発部位は卵巣40例,精巣9例,仙尾部7例,縦隔7例であった.組織学的分類では成熟奇形腫41例,未熟奇形腫6例,卵黄嚢腫瘍11例,複合組織型3例,絨毛癌1例,組織型不明1例(脳転移・頭蓋内出血により生検未施行)であった.成熟奇形腫摘出後の再発例を含めた13例の悪性胚細胞腫瘍に対して白金製剤をベースにした化学療法を施行し,11例(85%)で寛解が得られた.悪性胚細胞腫瘍は化学療法に対する感受性が高く,再発例に対しても化学療法が奏功する.また,術前化学療法により腫瘍縮小が得られることが多く,自験例においても術前化学療法により腫瘍の完全切除を達成できた症例を経験した.巨大な腫瘍や腹膜播種を伴い初回手術時に完全切除が困難と考えられる症例に対しては,「化学療法+遅延手術」を選択肢の一つとして考えるべきである.(著者抄録)

OBJECTIVE: The aim of the study was to investigate the effect of abdominal drainage at appendectomy for complicated appendicitis in children. SUMMARY OF BACKGROUND DATA: Although an abdominal drain placement at appendectomy is an option for reducing or preventing postoperative infectious complication, there is controversy regarding its effect for complicated appendicitis. METHOD: The study used the data on appendectomies for complicated appendicitis in children (≤15 years old) that were operated in 2015 and registered in the National Clinical Database, a nationwide surgical database in Japan. One-to-two propensity score matching was performed to compare postoperative outcomes between patients with and without drainage at appendectomy. RESULT: The study included 1762 pediatric appendectomies for complicated appendicitis, 458 of which underwent abdominal drainage at appendectomy. In the propensity-matched analysis, the drainage group showed a significant increase in wound dehiscence [drain (-) vs drain (+); 0.3% vs 2.4%, P = 0.001], and postoperative hospital stay (median: 7 days vs 9 days, P < 0.001). There were no significant differences in the incidence of any complications, organ space surgical site infection, re-admission, and reoperation.Subgroup analyses in perforated appendicitis and perforated appendicitis with abscess, and open and laparoscopic appendectomy all demonstrated that drain placement was not associated with a reduction in any complication or organ space surgical site infection. However, it was significantly associated with longer hospital stays. CONCLUSION: This study suggested that an abdominal drain placement at appendectomy for complicated appendicitis among children has no advantage and can be harmful for preventing postoperative complications.

PURPOSE: Growth retardation is a severe morbidity in infants with congenital diaphragmatic hernia (CDH). This study aimed to determine when catch-up growth starts in infants with CDH and to determine the adequate amount of nutrition required during catch-up growth. METHODS: This was a multicenter retrospective cohort study involving neonates with isolated CDH (born 2006-2010; n = 98). Weight gain velocity (WGV) was calculated using body weight Z-scores. The minimum required weight gain was defined as WGV ≥ 0. Patients were dichotomized into severe and non-severe cases according to diaphragmatic defects. RESULTS: Average monthly WGV changed from < 0 to ≥ 0 at 2 months of age. Total caloric intake at 2 months of age was lower when the WGV between 1 and 3 months was < 0 in both severe cases [122 (95% confidence interval (CI) 116-128) vs. 97 (95% CI 84-110) kcal/kg/day, p = 0.02] and non-severe cases [115 (95% CI 110-120) vs. 99 (95% CI 87-111) kcal/kg/day, p < 0.001)]. CONCLUSION: Catch-up growth started at approximately 2 months of age. During this period, total caloric intake of > 122 kcal/kg/day was needed to avoid decreases in the body weight Z-score in severe cases.

A 2-month-old boy who had undergone radical surgery for esophageal atresia at 10 h after birth started to present intermittent choking and coughing during suckling and sleep. Upper gastrointestinal series revealed recurrent tracheoesophageal fistula at the Th3 level. Enteral feeding via trans-jejunal tube was started and reoperation was performed at 10 months old, when he weighed 9.6 kg (+0.56SD). Thoracotomy was performed after inserting the guidewire into the fistula under both bronchoscopy and gastroscopy. The fistula was resected and both esophageal and tracheal ends were sutured. Part of the thymus was obtained and the free thymic fat pad (FTFP) was interposed between sutured sites along with the application of fibrin-glue to the affected area to prevent re-recurrence. Postoperative course was uneventful and computed tomography (CT) at 1 month following the operation demonstrated the residual FTFP. FTFP can be a feasible, useful, and effective option for interposition in recurrent TEF surgery, compared to conventional pedicled or free tissue.

PURPOSE: To date, there is no compelling evidence of the optimal timing of surgery for congenital diaphragmatic hernia (CDH). This study aimed to establish the optimal timing of surgery in neonates with isolated left-sided CDH. METHODS: This multicenter cohort study enrolled 276 patients with isolated left-sided CDH at 15 institutions. Based on the timing of surgery, the patients were classified into four groups [< 24 h (G1), 24-47 h (G2), 48-71 h (G3), and ≥ 72 h (G4)]. The clinical outcomes were compared among the groups using a logistic regression model, after adjusting for potential confounders, such as disease severity. RESULTS: Multivariate analyses showed that G2 also had a lower mortality rate than the other groups. In mild and severe cases, there were no significant differences in mortality across the four groups. In moderate cases, G2 resulted in significantly increased survival rates, compared with G1. CONCLUSION: The study results suggest that surgery within 24 h of birth is not recommended for patients with moderate severity CDH, that there is no benefit in the delay of surgery for more than 72 h in mild severity CDH patients, and that there is no definite optimal time to perform surgery in severe cases of CDH.

Background: Esophageal leiomyomatosis (EL) is a rare benign tumor defined as a diffuse form of marked hypertrophy in the muscular layer of the esophagus. Relapses have been reported as a result of misdiagnoses of other tumors or achalasia, followed by inappropriate surgical intervention. The endoscopic approach is preferred because of its lesser degree of invasiveness and better cosmesis; however, its effectiveness for treatment of EL is unclear because these tumors are bulkier and more extensive than those in other esophageal diseases. Case presentation: We treated an 11-year-old girl who had been experiencing progressive dysphagia, vomiting, and coughing during sleep since the age of 4 years and was correctly diagnosed with EL using computed tomography and endoscopic ultrasonography. She was successfully treated with total minimally invasive esophagectomy (MIE), combining thoracoscopy and laparoscopy, in the prone position, without any complications or recurrence of symptoms. To our knowledge, this is the first case report of MIE for EL. A review of 84 EL cases (including the present case) revealed a rate of accurate preoperative diagnosis of only 23.8%. Esophagectomy should be employed because the recurrence rate of the non-esophagectomy cases, involving myotomy and tumorectomy, was significantly higher than that of the esophagectomy cases (57.9% vs. 7.7%, p = 0.002). Among 11 relapse cases in the non-esophagectomy cases, esophagectomy was performed in eight. Among the four relapse cases in the esophagectomy group, additional esophagectomy was necessary in three because of insufficient resection of the tumors at the primary esophagectomy. Conclusions: Multimodal imaging contributes to accurate diagnosis and assessment of the extent of the tumors, thus leading to the selection of the appropriate surgical intervention, i.e., radical esophagectomy. Total MIE in the prone position provides excellent exposure of the operative fields; our experience suggests that total MIE is beneficial for EL, as it is for other esophageal tumors.

PURPOSE: Oncolytic viral therapy for neuroblastoma (NB) cells with Sindbis virus (SINV) is a promising strategy for treating high-risk NB. Here, we evaluated the possibility of using SINV structural proteins as therapeutic agents for NB since UV-inactivated SINV could induce cytopathogenic effects. METHODS: The cytotoxicity of UV-inactivated SINV toward human NB cell lines NB69, NGP, GOTO, NLF, SK-N-SH, SH-SY5Y, CHP134, NB-1, IMR32, and RT-BM-1 were analyzed. Apoptosis was confirmed by TUNEL assays. To determine the components of SINV responsible for the cytotoxicity of UV-inactivated SINV, expression vectors encoding the structural proteins, namely capsid, E2, and E1, were transfected in NB cells. Cytotoxicity was evaluated by MTT assays. RESULTS: UV-inactivated SINV elicited more significant cytotoxicity in NB69, NGP, and RT-BM-1 than in normal human fibroblasts. Results of the transfection experiments showed that all NB cell lines susceptible to UV-inactivated SINV were highly susceptible to the E1 protein, whereas fibroblasts transfected with vectors harboring capsid, E1, or E2 were not. CONCLUSIONS: We demonstrated that the cytotoxicity of the UV-inactivated SINV is due to apoptosis induced by the E1 structural protein of SINV, which can be used selectively as a therapeutic agent for NB.

OBJECTIVE: To determine the appropriate initial ventilatory mode for neonatal congenital diaphragmatic hernia (CDH) by comparing patient prognosis following conventional mechanical ventilation (CMV) versus high-frequency oscillatory ventilation (HFO). STUDY DESIGN: This multicenter retrospective cohort study was performed at 15 participating hospitals in Japan between 2011 and 2016. The 328 eligible CDH infants were classified into CMV (n = 78) and HFO groups (n = 250) to compare mortality and incidence of bronchopulmonary dysplasia (BPD). Propensity score matching was applied to reduce confounding by indication. RESULT: While crude mortality was significantly higher in the HFO than the CMV group, adjusted odds ratio (OR) did not show significant difference in mortality between groups (OR of HFO group: 0.98, 95% confidence interval (CI): 0.57-1.67). Adjusted OR of BPD incidence showed no significant difference between groups (OR of HFO group: 1.66, 95%CI: 0.50-5.49). CONCLUSION: Initial ventilatory mode in CDH patients, whether CMV or HFO, does not affect prognosis.

PURPOSE: To establish and validate risk models of mortality and morbidity associated with 12 major pediatric surgical procedures using the National Clinical Database-Pediatric (NCD-P) data. METHODS: We used the NCD-P data for the development and validation datasets. By using multivariate logistic regression to analyze the development dataset, we created a prediction model for 30-day mortality and morbidity in 12 major pediatric surgical procedures, including tracheoplasty, pneumonectomy, fundoplication, total/subtotal excision of malignant tumor, and surgeries for Hirschsprung disease, anorectal malformation, biliary atresia, choledocal cyst, midgut volvulus, funnel chest, gastrointestinal perforation, and intestinal obstruction. We selected variables that were almost identical to those used in the American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P). The primary outcomes were 30-day mortality and composite morbidity. We assessed the obtained models using the C-indices of the development and validation datasets. RESULTS: Overall, 10 and 21 variables were identified for mortality and morbidity, respectively. C-indices of mortality were 0.940 and 0.924 in the development and validation datasets, respectively. C-indices of morbidity were 0.832 and 0.830 in the development and validation datasets, respectively. CONCLUSIONS: Based on the NCD-P data, we developed satisfactory risk models for mortality and morbidity prediction in major pediatric surgeries. LEVEL OF EVIDENCE: Level I (Prognosis Study).

PURPOSE: This study aimed to elucidate the clinical characteristics of neonates with congenital diaphragmatic hernia (CDH) associated with pneumothorax and evaluate the risk factors for the development of pneumothorax. METHODS: A retrospective cohort study was conducted in the 15 institutions participating in the Japanese CDH Study Group. A total of 495 neonates with isolated CDH who were born between 2011 and 2018 were analyzed in this study. RESULTS: Among the 495 neonates with isolated CDH, 52 (10.5%) developed pneumothorax. Eighteen (34.6%) patients developed pneumothorax before surgery, while 34 (65.4%) developed pneumothorax after surgery. The log-rank test showed that the cumulative survival rate was significantly lower in patients with pneumothorax than in those without pneumothorax. Univariate analysis revealed significant differences between patients with pneumothorax and those without pneumothorax with regard to the best oxygenation index within 24 h after birth, mean airway pressure (MAP) higher than 16 cmH2O, diaphragmatic defect size, and need for patch closure. Multiple logistic regression analysis indicated that only the MAP was associated with an increased risk of pneumothorax. CONCLUSIONS: The cumulative survival rate was significantly lower in isolated CDH patients with pneumothorax than in those without pneumothorax. A higher MAP was a risk factor for pneumothorax in CDH patients.

INTRODUCTION:  We aimed to establish and validate a risk score for fetuses with congenital diaphragmatic hernia (CDH) using only prenatal ultrasound findings. MATERIAL AND METHODS:  Derivation (2011-2016, n = 350) and validation (2006-2010, n = 270) cohorts were obtained from a Japanese CDH study group database. Using a logistic regression analysis, we created a prediction model and weighted scoring system from the derivation dataset and calculated the odds ratio of an unsatisfactory prognosis (death within 90 days of life or hospitalization duration exceeding 180 days). Five adverse prognostic factors obtained using prenatal ultrasound, including an observed/expected lung area-to-head circumference ratio (o/eLHR) <25%, liver herniation occupying more than one-third of the thoracic space, thoracic stomach, right-side CDH, and severe malformations, were used as predictors. The obtained model was validated using the validation cohort. RESULTS:  The unsatisfactory prognosis prediction model was obtained based on the adjusted odds ratios. The C statistics of the model were 0.83 and 0.80 in the derivation and validation datasets, respectively. The five variables were weighted proportionally to their adjusted odds ratios for an unsatisfactory prognosis (o/eLHR <25%, 1 point; liver herniation occupying more than one-third of the thoracic space, 1 point; thoracic stomach, 1 point; right-side CDH, 2 points; and severe malformations, 3 points). Unsatisfactory prognosis rates for the low- (0-2 points), intermediate- (3-5 points), and high-risk (6-8 points) groups were 17, 46, and 100%, respectively (p < 0.001), in the validation cohort. CONCLUSION:  Our simple risk score effectively predicted the prognosis of fetuses with CDH.

PURPOSE: Our aim was to compare postoperative outcomes of laparoscopic and open appendectomies for acute appendicitis in children under the circumstance of widespread use of laparoscopic surgery. METHOD: This study included data on laparoscopic and open appendectomies in children with acute appendicitis from the National Clinical Database, which is a Japanese nationwide surgical database, in 2015. The occurrence rates of complications within 30 days after the surgery and postoperative hospital stay were compared by univariate and multivariate analyses. p < 0.05 was considered statistically significant. RESULTS: This study included 4489 appendectomies, of which 3166 surgeries (70.5%) were performed laparoscopically. Appendectomy was performed for complicated and uncomplicated appendicitis in 1765 (39.3%) and 2724 cases (60.7%), respectively. Postoperative complications within 30 days were observed in 246 operations (5.5%). Organ-space surgical site infection (SSI), deep wound SSIs, and superficial wound SSIs were observed in 2.3%, 1.0%, and 2.4% of operations, respectively. On multivariate analysis, the incidence of postoperative complications (odds ratio 1.21, 95% CI 0.90-1.64, p = 0.207) and the length of hospital stay (median 4 days in both groups, p = 0.835) were not significantly different between patients who underwent laparoscopic or open appendectomy. Subgroup analysis in complicated and uncomplicated appendicitis cases also demonstrated no significant differences in the incidence of postoperative complications between those who underwent laparoscopic or open appendectomy. CONCLUSION: This study suggested that the occurrence of postoperative complication and the length of hospital stay in pediatric patients who underwent laparoscopic appendectomy are similar with those in pediatric patients who underwent open appendectomy for acute appendicitis.

PURPOSE: The relationship between reflux index (RI) and bolus exposure parameters in multichannel intraluminal impedance (MII) has not been examined sufficiently among children. The significance of acid and bolus exposure in evaluating pediatric reflux disease (RD) was explored by focusing on mucosal lesions. METHODS: We conducted MII-pH on 28 patients (median age 8 years) with suspected RD. We assessed relationships between RI and bolus exposure indices, and also compared acid and bolus exposures across patients grouped by endoscopic esophageal mucosal lesions. RESULTS: RI correlated significantly with distal acid reflux events (r = 0.60), acid bolus exposure time (BET) (0.55), and bolus clearance time (BCT) (0.48). Significant differences were observed among the control, non-erosive RD (NERD), and erosive RD (ERD) groups in all acid and several bolus exposure indices (distal and proximal frequencies, and BCT), while no significant difference was apparent between NERD and ERD. Acid exposure tended to be more severe in high-grade than in low-grade ERD, while no similar tendency was found in any bolus parameters other than BCT. CONCLUSIONS: MII-pH showed great potential for investigating the pathophysiology of pediatric RD, with RI revealing different correlations with variable bolus exposure indices. However, no specific parameters allowing precise discrimination between RDs or mucosal severities were identified.

Neuroblastoma, an embryonal tumor arising from the sympathetic ganglia and adrenal medulla, is among the most intractable pediatric cancers. Although a variety of genetic changes have been identified in neuroblastoma, how they contribute to its pathogenesis remains largely unclear. Recent studies have identified alterations of the anaplastic lymphoma kinase (ALK) gene in neuroblastoma; ALK F1174L (a phenylalanine-to-leucine substitution at codon 1174) represents one of the most frequent of these somatic mutations, and is associated with amplification of the MYCN gene, the most reliable marker for the poor survival. We engineered the mouse Alk locus so that ALK F1174L is expressed by its endogenous promoter and can be induced in a spatiotemporally controlled fashion using Cre-loxP system. Although expression of ALK F1174L resulted in enhanced proliferation of sympathetic ganglion progenitors and increased the size of the sympathetic ganglia, it was insufficient to cause neuroblastoma. However, lethal neuroblastoma frequently developed in mice co-expressing ALK F1174L and MYCN, even in a genetic background where MYCN alone does not cause overt tumors. These data reveal that physiological expression of ALK F1174L significantly potentiates the oncogenic ability of MYCN in vivo. Our conditional mutant mice provide a valuable platform for investigating the pathogenesis of neuroblastoma.

BACKGROUND: I.v. atropine (IA) for infantile hypertrophic pyloric stenosis (IHPS) is a good alternative to pyloromyotomy but has not been broadly accepted. The lower success rate is one of the greatest disadvantages of IA. We investigated the risk factors for unsuccessful results following IA for IHPS. METHODS: Medical records of patients with IHPS who were admitted to Kimitsu Chuo Hospital between 2002 and 2016 and were initially given atropine sulfate were retrospectively reviewed. Atropine was given i.v. (0.1 mg/kg/day in eight divided doses). Oral feeding of milk was started with a small amount and increased in a stepwise fashion to full feed. IA therapy was defined as unsuccessful in the presence of projectile vomiting more than three times a day or intolerance to a predetermined amount of milk. RESULTS: Of the 48 patients with IHPS, 33 patients were successfully treated with IA and 15 patients needed surgical intervention. On univariate analysis the risk factors for unsuccessful IA therapy were younger age, lower bodyweight, and shorter duration of symptoms before diagnosis. On multivariate analysis age at diagnosis < 30 days was the only significant risk factor for unsuccessful IA therapy (OR, 5.7 l P = 0.03). CONCLUSIONS: Age at diagnosis < 30 days is a risk factor for unsuccessful IA therapy in IHPS. This might be considered when IA therapy is used for neonates with IHPS.

Dendritic cells (DC) play a key role in the initiation of both antitumor immunity and immunological tolerance. It has been demonstrated that exposure to soluble factors produced by tumor cells modulates DC functions and induces tolerogenic DC differentiation. In this study, we investigated the effects of neuroblastoma cell line-derived soluble factors on DC differentiation. Monocytes isolated from healthy volunteers were incubated with interleukin (IL)-4 and granulocyte-macrophage colony-stimulating factor in the presence of culture supernatants from neuroblastoma cell lines. The culture supernatants from neuroblastoma cell lines, such as NLF and GOTO, partially blocked both downregulation of CD14 and upregulation of CD1a, and dramatically decreased IL-12 and tumor necrosis factor (TNF)-α production from mature DC, while no effect of SH-SY5Y cell supernatant was noted. In addition, IL-6 and IL-10 production from monocytes was increased by the supernatants of NLF and GOTO cells at 24 hours after incubation. Furthermore, we evaluated DC functions through stimulation of invariant natural killer T (iNKT) cells. α-Galactosylceramide-pulsed DC co-cultured with supernatants of NLF cells were unable to sufficiently stimulate iNKT cells. The decreased ability of iNKT cells to produce interferon (IFN)-γ after stimulation with neuroblastoma cell line supernatant-cultured DC was reversed by addition of IL-12. CD40 expression and IL-12 production in NLF-sup-treated DC were increased by addition of exogenous IFN-γ. These results indicate that tolerogenic DC are induced in the neuroblastoma tumor microenvironment and attenuate the antitumor effects of iNKT cells. Interactions between iNKT cells and αGalCer-pulsed DC have the potential to restore the immunosuppression of tolerogenic DC through IFN-γ production.

BACKGROUND: The optimum enteral (EN) and parenteral nutrition (PN) regimens during acute management of congenital diaphragmatic hernia (CDH) remain unclear. We examined the effects of EN and PN on weight gain in CDH patients. METHODS: A multicenter retrospective cohort study of neonates with CDH (born 2006-2010; n = 105) who survived to discharge was conducted. Patients were divided as receiving PN ≥ or <50 kcal/kg/day at 1 week of age, and EN ≥ or <60 kcal/kg/day at 2 weeks of age. Changes in bodyweight at 30, 60, and 90 days of age were compared. RESULTS: The higher EN group (n = 39) had greater mean weight gain than the lower EN group (n = 66; 90 days: 2,501 g, 95% CI: 2,294-2,710 g vs 1,706 g, 95% CI: 1,553-1,861 g; P <0.001). When patients received lower EN, the higher PN group (n = 24) had greater mean weight gain than the lower PN group (n = 42; 90 days: 1,768 g, 95% CI: 1,574-1,961 g vs 1,411 g, 95% CI: 1,264-1,558 g; P = 0.004). CONCLUSION: The amount of EN in the acute phase of CDH management is essential for weight gain during infancy. When patients are intolerant to adequate EN, supportive PN is also essential.

BACKGROUND: Invariant natural killer T (iNKT) cells play an important role in tumor immunity, enhancing both innate and acquired immunity. We have previously shown the enhancement of antibody-dependent cellular cytotoxicity against neuroblastoma by activated iNKT cells. As a first step towards clinical application, we studied the frequency and proliferative response of circulating iNKT cells in children with and without cancer. METHODS: Blood samples were collected from 10 patients with pediatric malignant solid tumors and 11 patients with non-neoplastic diseases (control). The frequency of circulating iNKT cells was quantified by flow cytometry. Whole peripheral blood mononuclear cells were then stimulated with α-galactosylceramide (α-GalCer) for 7 days, and the expansion rate of the iNKT-cell fraction was assessed. RESULTS: The frequency of iNKT cells in the patients of the cancer and control group did not differ to a statistically significant extent. The iNKT-cell population increased after α-GalCer stimulation in all cases. The iNKT cells of patients who had undergone intensive chemotherapy also had the potential to expand in vitro. CONCLUSIONS: Unlike adult cancer patients, the numbers of circulating iNKT cells were not decreased in pediatric cancer patients. α-GalCer stimulation induced a proliferative response in all of the patients.

The outcome of multimodal therapy for localized bladder rhabdomyosarcoma is quite good in terms of morbidity, and conservative surgery is generally recommended. However, in cases originating in the bladder neck, tumorectomy or partial cystectomy has adverse effects on bladder function. A 2-year-old girl underwent transurethral resection of a bladder tumor (TUR-BT), chemotherapy consisting of vincristine, actinomycin-D, and cyclophosphamide, and radiotherapy. She was in remission for 3 years when frequent urination became evident. Her bladder capacity and compliance were low however, her urinary symptom was controlled using anticholinergic medication. Accordingly, TUR-BT could be an optional approach for bladder rhabdomyosarcoma.

BACKGROUND: Among biliary atresia (BA) patients undergoing revision following failed portoenterostomy, long-term native liver survival (NLS), physical condition, and indications for revision were explored. METHODS: From 1977-2015, 33 of 95 BA patients (35%) at our institution underwent revision. Ten- and 20-year NLS rates (NLSRs) and biochemical statuses of 20-year-old native liver survivors were compared between post-portoenterostomy BA patients with and without history of revision. Factors associated with 10-year NLS following revision and optimal cut-offs for potential predictors were analyzed. RESULTS: Overall 10- and 20-year NLSRs were 57% and 54%, respectively. Ten- and 20-year NLSRs were 49% and 45% in the revision group and 63% and 61% in the non-revision group, respectively. Among 20-year-old native liver survivors, differences in admission rates between ages 10-20 years were not significant for cholangitis (revision, 46%; non-revision, 40%; P = 0.30) or portal hypertension (revision, 38%; non-revision, 15%; P = 0.21). Differences in hepatobiliary function-associated blood tests between these groups at 20 years old were only significant for aspartate aminotransferase (P = 0.02) and gamma-glutamyl transpeptidase (P = 0.047). Among potential predictors of 10-year NLS that we investigated, rate of change in total bilirubin (TB) over the first month post-portoenterostomy was best (P = 0.0019), and the receiver operating characteristic curve revealed an optimal cut-off for this first-month change in TB of -3.7 mg/dl (area under the curve, 0.85; sensitivity, 0.79; specificity, 0.83). CONCLUSIONS: In approximately half of the patients, revision provided 10- and 20-year NLS, and biochemical status at 20 years old was comparable across revision and non-revision patients. Rate of change in TB during the first month post-portoenterostomy offers a sensitive predictor of revision.

PURPOSE: Fatality resulting from respiratory collapse (RC) during general anesthesia (GA) induction in children with mediastinal tumors has been reported. We explored potentially useful parameters for predicting the risk of RC based on objective imaging results. METHODS: We retrospectively reviewed the records of 31 patients (median age: 4years; range: 4months-15years) with mediastinal tumors treated between 2000 and 2015. Comparing those with RC under GA induction to those without (RC group vs. non-RC group), we analyzed a variety of factors that might predict respiratory obstruction during GA induction, including our new parameter, the standardized tumor volume (STV), which is adapted from the formula for the volume of an ellipsoid. RESULTS: All eight patients in the RC group had large tumors in the anterior mediastinum, including lymphoma, teratoma, and germ cell tumor. The mean STV value of the RC group was significantly larger than that of the non-RC group (3.6±1.4 vs. 1.4±1.0, p=0.006). Using an STV cut-off value of 2.5, the sensitivity and specificity for predicting RC under GA induction were both 0.86, making STV more useful than previously reported risk factors. CONCLUSION: Anterior mediastinal tumors in children can often cause airway obstruction under GA induction. Measuring STV can help predict the respiratory risk during GA among pediatric patients with anterior mediastinal tumors. LEVEL OF EVIDENCE: III.

BACKGROUND: Tumor immunity has been suggested to play a key role in clinical and biological behavior of neuroblastomas. Given that CD1-restricted invariant natural killer T (iNKT) cells enhance both innate and acquired tumor immunity, we investigated the expression of the iNKT-cell-specific T-cell receptor Vα24-Jα18 in neuroblastoma tissues and its correlation with clinical and biological characteristics. METHODS: Using real- time quantitative PCR, we quantified the expression of Vα24-Jα18 in untreated tumor samples from 107 neuroblastoma cases followed in our institution and analyzed the correlation between the presence of infiltrated iNKT cells and clinical characteristics or patients' outcome. RESULTS: Vα24-Jα18 receptor was detected in 62 untreated cases (57.9%). The expression was significantly higher in stages 1, 2, 3, or 4S (P = 0.0099), in tumors with low or intermediate risk (P = 0.0050), with high TrkA expression (P = 0.0229), with favorable histology (P = 0.0026), with aneuploidy (P = 0.0348), and in younger patients (P = 0.0036). The overall survival rate was significantly higher in patients with iNKT-cell infiltration (log-rank; P = 0.0089). CONCLUSIONS: Since tumor-infiltrating iNKT cells were predominantly observed in neuroblastomas undergoing spontaneous differentiation and/or regression, we suggest that iNKT cells might play a key role in these processes.

OBJECTIVE: To establish a simple risk stratification system for patients with congenital diaphragmatic hernia (CDH) based on postnatal information within 24 h after birth. STUDY DESIGN: A multi-institutional retrospective cohort study was conducted including 348 neonates who had isolated CDH born between 2006 and 2010. Based on the two most powerful variables for 90-day survival selected by multivariate analyses, a risk stratification system was established. RESULTS: Multiple logistic regression analysis identified two adverse prognostic factors: an Apgar score at 1 min (Ap1) of 0-4 (odds ratio (OR) 3.3, P = 0.004), and a best oxygenation index (OI) &gt;= 8.0 (OR 11.4, P &lt; 0.001). Based on a combinations of these two factors, patients were classified into three risk categories. The 90-day survival rates in categories 1-3 were 100, 88 and 52%, respectively (P &lt; 0.001). CONCLUSION: Our simple risk stratification system based on Ap1 and best OI was capable of predicting mortality well.

OBJECTIVE: Roles of magnetic resonance cholangiopancreatography (MRCP), endoscopic retrograde cholangiopancreatography (ERCP), drip infusion cholangiography with computed tomography (DIC-CT), and intraoperative cholangiopancreatography (IOCP) in visualizing pancreaticobiliary anatomy for pediatric choledocal cyst (CC) operations were examined. METHODS: From 1980-2013, 117 pediatric CC patients (median age, 3 years) underwent hepaticojejunostomy at our institution, with imaging modalities of ERCP (n = 81 over 34 years), MRCP, DIC-CT, and IOCP (n = 45, 20, and 45 cases over the last 12 years). First, visualization rates for pancreaticobiliary maljunction (PBM), common bile duct (CBD), pancreatic duct (PD), and intrahepatic bile duct (IHBD) were investigated. Sensitivity, specificity, and accuracy for detecting hepatic duct stricture were then compared between MRCP and IOCP. RESULT: Visualization rates of PBM, CBD, PD, and IHBD were 57%, 100%, 64%, and 100% for MRCP; 82%, 77%, 95%, and 32% for ERCP; 25%, 75%, 21%, and 85% for DIC-CT; and 87%, 100%, 87%, and 100% for IOCP, respectively. Combination of MRCP and IOCP achieved rates of 89%, 100%, 91%, and 100%, respectively. Sensitivity, specificity, and accuracy for detecting stenosis were 86%, 68%, and 71% for MRCP, and 100%, 89%, and 91% for IOCP, respectively. CONCLUSIONS: Combining MRCP and IOCP can provide satisfactory pancreaticobiliary anatomical information for surgical planning for pediatric CC, with hepatic duct strictures evaluated more accurately by IOCP.

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.

Anti-ganglioside GD2 antibodies mainly work through antibody-dependent cellular cytotoxicity (ADCC) and have demonstrated clinical benefit for children with neuroblastoma. However, high-risk neuroblastoma still has a high recurrence rate. For further improvement in patient outcomes, ways to maximize the cytotoxic effects of anti-GD2 therapies with minimal toxicity are required. Activated invariant natural killer T (iNKT) cells enhance both innate and type I acquired anti-tumor immunity by producing several kinds of cytokines. In this report, we investigated the feasibility of combination therapy using iNKT cells and an anti-GD2 antibody. Although some of the expanded iNKT cells expressed natural killer (NK) cell markers, including FcγR, iNKT cells were not directly associated with ADCC. When co-cultured with activated iNKT cells, granzyme A, granzyme B and interferon gamma (IFNγ) production from NK cells were upregulated, and the cytotoxicity of NK cells treated with anti-GD2 antibodies was increased. Not only cytokines produced by activated iNKT cells, but also NK-NKT cell contact or NK cell-dendritic cell contact contributed to the increase in NK cell cytotoxicity and further IFNγ production by iNKT cells and NK cells. In conclusion, iNKT cell-based immunotherapy could be an appropriate candidate for anti-GD2 antibody therapy for neuroblastoma.

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.