Safety, efficacy and pharmacokinetics of palivizumab in off-label neonates, infants, and young children at risk for serious respiratory syncytial virus infection: a multicenter phase II clinical trial.

Background: Pediatric patients with certain rare diseases are at increased risk of severe respiratory syncytial virus (RSV) infection. However, the prophylactic use of anti-RSV antibody (palivizumab) in these patients is not indicated at present in Japan. Methods: This first-in-the-world multicenter, uncontrolled, open-label, phase II clinical trial was carried out between 28 July 2019 and 24 September 2021 at seven medical institutions in Japan to investigate the efficacy, safety, and pharmacokinetics of palivizumab in 23 subjects recruited from among neonates, infants, or children aged 24 months or younger who had any of the following conditions: pulmonary hypoplasia, airway stenosis, congenital esophageal atresia, inherited metabolic disease, or neuromuscular disease. At least four continuous doses of palivizumab were administered intramuscularly at 15 mg/kg at intervals of 30 days. Findings: Twenty-three enrolled subjects completed the study. No subject required hospitalization for RSV. Adverse events (AE) did not notably differ from the event terms described in the latest interview form. Five severe AEs required unplanned hospitalization, but resolved without RSV infection. Therapeutically effective concentrations of palivizumab were maintained throughout the study period. Interpretation: Palivizumab might be well tolerated and effective in preventing serious respiratory symptoms and hospitalization due to severe RSV infection, indicating the prophylactic use in the pediatric patients included in this study. Funding: Japan Agency for Medical Research and Development (AMED), grant numbers 19lk0201097h0001 (to MM), 20lk0201097h0002 (to MM), 21lk0201097h0003 (to MM), and 22lk0201097h0004 (to MM). AMED did not have any role in the execution of this study, analysis and interpretation of the data, or the decision to submit the results.

Novel Causative RET Mutation in a Japanese Family with Hirschsprung's Disease: Case Report and Factors Impacting Disease Severity.

RET gene variances confer susceptibility to Hirschsprung's disease (HSCR) with pathogenetic mutations being identified in half of familial cases. This investigation of familial HSCR was aimed to clarify the relationship between genetic mutations and clinical phenotype using next-generation sequencing. A novel c2313C > G(D771E) RET mutation was identified in all three affected family members. The mutation involved the kinase domain, which is believe to impair RET activity and intestinal function. A second RET mutation, c1465G > A(D489N), was found only in the extensive aganglionosis case. We conclude that the novel c2313C > A(D771E) mutation in RET may be pathogenic for HSCR, while the c1465C > G(D489N) mutation may be related to phenotype severity.

A strategy to prevent tracheo-innominate artery fistula in the course of laryngotracheal separation: 9-year experience in a children's hospital.

AIM OF THE STUDY: Laryngotracheal separation (LTS) is known to be the definitive solution for intractable aspiration pneumonia in neurologically impaired children. Postoperatively, a tracheostomy cannula is usually required. However, there are fatal cannula related complications such as a tracheo-innominate artery fistula (TIAF). We present our methods of preventing TIAF. METHODS: A retrospective review in a single center from 2011 to 2019 identified 57 cases treated with LTS. We divided them into three groups: no pre-existing tracheostomy (n = 26), pre-existing tracheostomy with preservation of the pre-existing fistula (n = 20), and pre-existing tracheostomy without preservation of the pre-existing fistula (n = 11). The first group underwent traditional modified Lindeman's procedure. The second received transection of the trachea above the tracheostomy site, while the third had transection of the trachea at the tracheostomy site and creation of a distal end tracheostomy. Proper length and the angle of the cannula were selected to prevent damaging the innominate artery by the tip of the cannula. If the innominate artery compressed the trachea anteriorly, prophylactic arterial transection was considered. RESULTS: Three patients (5.3%) died from causes unrelated to the surgical treatment. Only one patient had a postoperative TIAF followed by LTS (1.8%). Other postoperative complications were: wound infection (8.8%), intratracheal granuloma (12.3%), intratracheal minor bleeding (10.5%), wound granuloma (43.9%), leakage (1.8%). No one required revision of LTS. CONCLUSION: Success rates of LTS were high without major complications in all three groups and implies a safe operation and a definitive solution to intractable aspiration.

Preoperative sonographic evaluation of the defect size and the diaphragm rim in congenital diaphragmatic hernia - preliminary experience.

BACKGROUND: Sonographic assessment before congenital diaphragmatic hernia repair has rarely been studied. OBJECTIVE: To evaluate the accuracy of preoperative ultrasound in measuring the defect size and in anticipating the presence of a rim and thereby to determine ultrasound's usefulness in informing the surgical approach for definitive repair of congenital diaphragmatic hernia. MATERIALS AND METHODS: We performed a retrospective review of the medical records of seven children with left congenital diaphragmatic hernia who had undergone ultrasound and definitive repair between 2014 and 2017 at our institution. RESULTS: The estimated defect size by ultrasound to the actual defect size measured intraoperatively for each case were as follows: 23 × 25 mm to 20 × 26 mm (case 1); 23 × 30 mm to 20 × 30 mm (case 2); 43 × 25 mm to 30 × 30 mm (case 3); 21 × 23 mm to 20 × 25 mm (case 4); 19 × 24 mm to 10 × 30 mm (case 5); 32 × 33 mm to 30 × 50 mm (case 6); and almost total absence to 40 × 50 mm (case 7). Presence or absence of each part of the diaphragm rim evaluated by ultrasound was almost identical with the actual intraoperative findings. According to the ultrasound findings, we performed a successful thoracoscopic repair in cases 1-5 with relatively small defects and presence of all parts of the rim or absence of only posterolateral rim. CONCLUSION: There was good concordance between ultrasound findings and operative findings regarding the size of the defect and presence or absence of the diaphragm rim.

Safety and efficacy of noncardiac surgical procedures in the management of patients with trisomy 13: A single institution-based detailed clinical observation.

Intensive treatment including surgery for patients with trisomy 13 (T13) remains controversial. This study aimed to evaluate the safety and efficacy of noncardiac surgical intervention for T13 patients. Medical records of patients with karyotypically confirmed T13 treated in the neonatal intensive care unit in Nagano Children's Hospital from January 2000 to October 2016 were retrospectively reviewed, and data from patients who underwent noncardiac surgery were analyzed. Of the 20 patients with T13, 15 (75%) underwent a total of 31 surgical procedures comprising 15 types, including tracheostomy in 10 patients and gastrostomy in 4. Operative time, anesthesia time, and amount of bleeding are described for the first time in a group of children with T13. All the procedures were completed safely with no anesthetic complications or surgery-related death. The overall rate of postoperative complications was 19.3%. Patients receiving tracheostomy had stable or improved respiratory condition. Six of them were discharged home and were alive at the time of this study. These results suggest at least short-term safety and efficacy of major noncardiac surgical procedures, and long-term efficacy of tracheostomy on survival or respiratory stabilization for home medical care of children with T13. Noncardiac surgical intervention is a reasonable choice for patients with T13.

Discordant clinical phenotype in monozygotic twins with Alagille syndrome: Possible influence of non-genetic factors.

Alagille syndrome is a multisystem developmental disorder characterized by bile duct paucity, congenital heart disease, vertebral anomalies, posterior embryotoxon, and characteristic facial features. Alagille syndrome is typically the result of germline mutations in JAG1 or NOTCH2 and is one of several human diseases caused by Notch signaling abnormalities. A wide phenotypic spectrum has been well documented in Alagille syndrome. Therefore, monozygotic twins with Alagille syndrome provide a unique opportunity to evaluate potential phenotypic modifiers such as environmental factors or stochastic effects of gene expression. In this report, we describe an Alagille syndrome monozygotic twin pair with discordant placental and clinical findings. We propose that environmental factors such as prenatal hypoxia may have played a role in determining the phenotypic severity.

Extraosseous Ewing sarcoma in the mesentery: the first report of cases in children.

Extraosseous ewing sarcoma (EES) is a rare soft-tissue tumor usually found in the extremities or paraspinal region. We describe the case of a 4-year-old boy with a large cystic mass in the mesentery diagnosed as mesenteric lymphangioma preoperatively and as EES after partial resection and histopathological examination. EES in the mesentery is extremely rare, with only 2 reports described in the English literature. This represents the first report of EES in a child.

Surgical intervention for esophageal atresia in patients with trisomy 18.

Trisomy 18 is a common chromosomal aberration syndrome involving growth impairment, various malformations, poor prognosis, and severe developmental delay in survivors. Although esophageal atresia (EA) with tracheoesophageal fistula (TEF) is a potentially fatal complication that can only be rescued through surgical correction, no reports have addressed the efficacy of surgical intervention for EA in patients with trisomy 18. We reviewed detailed clinical information of 24 patients with trisomy 18 and EA who were admitted to two neonatal intensive care units in Japan and underwent intensive treatment including surgical interventions from 1982 to 2009. Nine patients underwent only palliative surgery, including six who underwent only gastrostomy or both gastrostomy and jejunostomy (Group 1) and three who underwent gastrostomy and TEF division (Group 2). The other 15 patients underwent radical surgery, including 10 who underwent single-stage esophago-esophagostomy with TEF division (Group 3) and five who underwent two-stage operation (gastrostomy followed by esophago-esophagostomy with TEF division) (Group 4). No intraoperative death or anesthetic complications were noted. Enteral feeding was accomplished in 17 patients, three of whom were fed orally. Three patients could be discharged home. The 1-year survival rate was 17%: 27% in those receiving radical surgery (Groups 3 and 4); 0% in those receiving palliative surgery (Groups 1 and 2). Most causes of death were related to cardiac complications. EA is not an absolute poor prognostic factor in patients with trisomy 18 undergoing radical surgery for EA and intensive cardiac management.

Inhibition of nuclear factor-κB activity by small interfering RNA in esophageal squamous cell carcinoma cell lines.

Chemotherapy with 5-fluorouracil (5-FU) is commonly used in combination therapy for esophageal squamous cell carcinoma (ESCC), but its efficacy is limited in certain patients. Recent studies suggest that constitutive activation of nuclear factor-κB (NF-κB) has a critical role in tumorigenesis and is associated with poor prognosis and resistance to chemoradiation therapy in many types of human cancers. In the present study, we evaluated the effect of small interfering RNA targeting NF-κB (NF-κB siRNA) combined with 5-FU on the proliferation of two cell lines of cultured ESSCs. Immunofluorescence and immunoblot analyses revealed that the NF-κB protein was localized mostly in the cytoplasm of ESCCs. When cultured ESCCs were exposed to tumor necrosis factor-α, NF-κB was transferred to the nucleus and activated. ESCCs with activated NF-κB had poor sensitivity to 5-FU. When cells were transfected with NF-κB siRNA, the levels of NF-κB protein were significantly decreased in the cytoplasm and the nucleus. Transcriptional activity of NF-κB was significantly suppressed in cells treated with 5-FU and NF-κB siRNA compared to cells treated with 5-FU alone. 5-FU consistently suppressed proliferation of ESCCs in a dose-dependent manner, and this effect was significantly enhanced when combined with NF-κB siRNA. These results suggest that combination therapy of 5-FU with NF-κB siRNA may provide a new therapeutic option for ESCC.

[A case of complete response of gemcitabine (GEM) monotherapy-refractive liver metastatic pancreatic cancer treated with GEM+S-1 combined chemotherapy].

A 75-year-old man with pancreatic body cancer underwent distal pancreatectomy and was treated with gemcitabine (GEM) as an adjuvant therapy. Multiple liver metastases appeared three months after the surgery. With GEM+S-1 combined chemotherapy, liver metastatic lesions became unidentifiable upon imaging 7 months later. Complete response status had continued as long as 13 months. Though grade 3 neutropenia appeared after 2 courses of the combined therapy, the patient well tolerated it after controlling the dosing schedule. The GEM+S-1 combined chemotherapy was expected to have synergistic effects for GEM monotherapy-refractive pancreatic cancer.

Nutritional assessment of patients after pylorus-preserving gastrectomy for early gastric cancer.

UNLABELLED: The aim of this study was to evaluate the nutritional advantages of pylorus-preserving gastrectomy (PPG) in comparison with distal gastrectomy with Billroth I anastomosis (DG) in early gastric cancer (EGC). Between 2005 and 2007, 24 patients underwent PPG and 30 underwent DG. Subjective global assessment, objective data assessment, and endoscopic findings of the remnant stomach were compared between the two groups. Two years after surgery, the patients' body weights recovered to 97% in PPG, but they continued to decrease in DG. Postoperative blood lymphocyte counts remained low in DG, but recovered to preoperative levels 6 months after surgery in PPG. Food residue in the gastric remnant was frequently observed in PPG (71.4%) than in DG (15.8%, P = 0.001). In nutritional aspect, PPG may be a more ideal operation than DG. However, food residue in the gastric remnant should be considered in PPG. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12262-010-0167-4) contains supplementary material, which is available to authorized users.

Long-term outcome of children with biliary atresia who were not transplanted after the Kasai operation: >20-year experience at a children's hospital.

OBJECTIVE: Sequential strategies combining the Kasai operation as a first-line treatment and liver transplantation as a second-line option, if necessary, have been accepted for patients with biliary atresia (BA). To understand the role of the Kasai operation in the treatment of BA, it is necessary to analyze the long-term outcome of the operation alone and to evaluate the present status of survivors retaining their native livers. MATERIALS AND METHODS: A retrospective chart review was carried out for a group of 80 patients who had undergone the Kasai operation between 1970 and 1986 at the Kanagawa Children's Medical Center. RESULTS: The 5-, 10-, and 20-year survival rates of patients with their native livers were 63%, 54%, and 44%, respectively. The survival rates varied significantly depending on the type of BA, age at initial Kasai operation, era of surgery, and surgical method. By age 20, nearly half of the adult survivors had already developed liver cirrhosis and its sequelae. Episodes of cholangitis and gastrointestinal bleeding occurred after 20 years of age in 37% and 17% of the adult patients, respectively, and 20% of the adult patients died of liver failure or underwent living-related partial liver transplantation in their 20s. Five female patients gave birth to a total of 9 children, and 1 male patient fathered a child. CONCLUSIONS: Although increasing numbers of patients with BA survive 20 years or more after the Kasai operation, meticulous lifelong postoperative care should be continued for the survivors because of the possibility of hepatic deterioration.