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The aim of this study was to elucidate the prevalence of urachal remnants in children in relation to patient age as well as to identify their anatomic variants, using a laparoscopic view.The medical records of 394 pediatric patients who underwent laparoscopic inguinal hernia repair were reviewed. Patients were divided into four groups based on their age at surgery. Using laparoscopic visualization, the presence and anatomic variants of urachal remnants were analyzed.A urachal remnant was confirmed in 140 children (35.5%). Although the prevalence was significantly higher in the group of children aged 1 year (63.2%) than in any other group, no significant difference in the prevalence was observed between the groups aged ≥ 1 year. In 42 cases (10.7%), the urachal remnant merged into the lateral umbilical ligament.Our results suggest a recommendation of nonoperative management of asymptomatic urachal remnants, especially in patients less than 1 year of age due to its probable spontaneous resolution. Knowledge of the anatomic variants could improve the accuracy of diagnosis of urachal remnants and the comprehension of its structure and localization for the achievement of accurate and complete excision.

Introduction: This study aimed to assess the preventive or therapeutic effects of blenderized food (BF) on selenium deficiency in pediatric patients with severe motor and intellectual disabilities (SMID). Methods: The medical records of all 40 consecutive pediatric patients with SMID who underwent nutritional assessment were retrospectively reviewed and compared between two groups: the enteral formula (EF) group and the BF group fed with BF providing more than 10% of total caloric intake. Next, for the selenium-deficient patients who were newly started on blenderized tube feeds after the first nutritional assessment, improvement of selenium deficiency and change of dietary contents were assessed. Results: The BF group patients had a significantly lower prevalence of selenium deficiency and higher serum selenium levels than the EF group patients. In all 7 selenium-deficient patients who started blenderized tube feeds after the first nutritional assessment, serum selenium levels were significantly increased at the second nutritional assessment, even though total selenium intake, selenium intake by EF, and total caloric intake did not differ significantly, and, in fact, caloric intake was significantly decreased by EF. Conclusion: Combined feeding of BFs can be useful for prevention and therapy of selenium deficiency in pediatric SMID patients.

Introduction: Laparoscopic resection has gradually been adopted for neuroblastoma patients; however, some authors reported that, due to its technically demanding procedures, this operation should be performed only by highly experienced surgeons. The aim of this study was to evaluate the safety and feasibility of laparoscopic resection of abdominal neuroblastoma by pediatric surgical trainees. Subjects and Methods: In this multicenter, retrospective study, including 18 children with abdominal neuroblastoma indicated for 19 laparoscopic resections (1 with bilateral neuroblastomas) from 1999 to 2018, the clinical data were retrospectively reviewed and compared between trainee and attending surgeons. Results: None of the cases had image-defined risk factors (IDRFs) at surgery. All patients successfully underwent complete laparoscopic resection without blood transfusion, open conversion, or intraoperative or postoperative complications. Of the 19 cases, 6 were performed by pediatric surgical trainees under the guidance of attending surgeons, and 13 were performed by attending surgeons. With comparable tumor, largest diameter, operative time, and bleeding amount were not significantly different between the two groups. In the trainee surgeon group, one local recurrence occurred at a secondary resection site in the bilateral neuroblastoma patient with Stage L2. Conclusions: Laparoscopic resection of neuroblastoma could be safe and feasible when limited to absent IDRFs at surgery by pediatric surgical trainees under the guidance of experienced attending surgeons, as well as by attending surgeons.

Purpose The aim of this study was to elucidate the incidence of urachal remnants in children in relation to patient age as well as to identify their anatomic variants, using a laparoscopic view.Methods The medical records of 394 pediatric patients who underwent laparoscopic inguinal hernia repair were reviewed. Patients were divided into four groups based on their age at surgery. Using laparoscopic visualization, the presence and anatomic variants of urachal remnants were analyzed.Results A urachal remnant was confirmed in 140 children (35.5%). Although the incidence was significantly higher in the group of children aged < 1 year (63.2%) than in any other group, no significant difference in the incidence was observed between the groups aged ≥ 1 year. In 42 cases (10.7%), the urachal remnant merged into the lateral umbilical ligament.Conclusions Our results suggest a recommendation of nonoperative management of asymptomatic urachal remnants, especially in patients less than 1 year of age due to its probable spontaneous resolution. Knowledge of the anatomic variants could improve the accuracy of diagnosis of urachal remnants and the comprehension of its structure and localization for the achievement of accurate and complete excision.

A high-frequency radio wave (HFRW) scalpel has been reported to achieve a fine smooth incision with good hemostasis and minimizes the surrounding tissue destruction. Since an umbilicoplasty was performed for cosmetic purposes, we introduced the HFRW scalpel for umbilical hernia repair in July 2016. This retrospective study aimed to investigate the safety and efficacy of an HFRW scalpel for umbilical hernia repair in children, compared to a surgical scalpel with electrocautery. We reviewed the medical records of 139 patients who underwent umbilical hernia repair using a surgical scalpel with electrocautery or an HFRW scalpel between January 2013 and November 2018. Patients were divided into two groups: the surgical scalpel with electrocautery (SE) group (n = 62) and the HFRW scalpel (HFRW) group (n = 77), for comparison of surgical outcomes. Umbilical hernia repair using the HFRW scalpel was successful without intraoperative complications in all 77 patients. Although the HFRW scalpel was directly used for skin incision, no burn injury was observed. Procedure duration was significantly shorter in the HFRW group than the SE group (P

INTRODUCTION Laparoscopy-assisted percutaneous endoscopic gastrostomy (LAPEG) can reduce the risk of percutaneous endoscopic gastrostomy-related complications, such as intra-abdominal organ injury, and determine the optimal position for placement of the gastrostomy tube. We first employed LAPEG 10 years ago but limited its application to elderly patients. Indications for LAPEG have now expanded to small children. This retrospective study aimed to determine the feasibility of LAPEG in children weighing

Ghrelin was recently reported to promote recovery from hepatic injury. We hypothesized that it could also be associated with clinical recovery of the transplanted liver from ischemia and reperfusion injury. Our aims were to investigate perioperative ghrelin changes following pediatric living donor liver transplantation (LDLT) and to analyze the association of these changes with postoperative hepatic function. We measured plasma acyl ghrelin (AG) concentrations before surgery, at the end of surgery and on postoperative days (PODs) 1, 3 and 7 in 12 children who underwent LDLTs, and, as controls, pre- and post-operatively and on POD1 in 7 children who underwent benign abdominal mass resection. The correlations between the participants’ ghrelin profiles and hepatic function-related data were evaluated. AG levels significantly declined to 15.6% of preoperative levels after LDLT and almost returned to baseline on POD3. Post-operative AG levels were significantly reduced to a greater extent following LDLT than benign abdominal mass resection. AG levels on POD1 inversely correlated with aspartate aminotransferase levels and cold/total ischemia time (P

Background/Purpose We examined the effects and mechanisms of rikkunshito (RKT) and hangeshashinto (HST) on cisplatin-induced mucosal injuries in the rat small bowel. Methods Juvenile rats were divided into 6 groups: sham control, cisplatin injection without kampo medicines, and cisplatin injection with oral administration of low and high doses of RKT (1000 mg/kg and 2000 mg/kg) and HST (500 mg/kg and 1000 mg/kg). Fecal condition, intestinal morphological changes, enterocyte proliferation, and enterocyte apoptosis were assessed. Results Diarrhea and atrophy of ileal villi observed in the cisplatin group were significantly improved in all kampo groups. Injury scores of the jejunum were significantly lower with RKT (2000 mg/kg) and HST (500 and 1000 mg/kg) than with cisplatin, and those of the ileum were significantly lower with HST (500 and 1000 mg/kg) than with cisplatin. Enterocyte proliferation of the jejunum was significantly increased with RKT (2000 mg/kg) and HST (500 mg/kg) compared with cisplatin, and those of the ileum were significantly increased in all kampo groups compared with the cisplatin group. Jejunal and ileal apoptosis following cisplatin administration was significantly inhibited by HST. Conclusions RKT and HST prevented cisplatin-induced intestinal mucosal injury with increasing proliferation of intestinal epithelial cells. HST also attenuated cisplatin-induced crypt cell apoptosis.

Summary Background & aims Nutritional metabolism is complex in pediatric patients with severe motor and intellectual disability (SMID), and therefore, appropriate estimation of the energy requirements is difficult. Focusing on ghrelin's role in energy metabolism regulation, we investigated plasma ghrelin levels in pediatric SMID patients and analyzed its nutritional significance as a regulatory marker of energy reserve. Methods Fasting plasma total, acyl, and des-acyl ghrelin levels in 40 patients with SMID, including cerebral palsy (CP) (n = 20) and muscular disease (MD) (n = 8), and healthy controls (n = 13) were investigated. The correlations of plasma ghrelin levels with anthropometry, blood nutritional markers, energy intake, and resting energy expenditure (REE) measured with indirect calorimetry were analyzed. A p value Results SMID patients had significantly higher acyl ghrelin, and lower body mass index (BMI), z-scores of body weight (BW), body height and BMI, and albumin than controls. CP patients had significantly higher total and acyl ghrelin, z-score of the mid-upper arm circumference (MUAC), retinol-binding protein, transthyretin, creatinine, and glucose than MD patients. Total and acyl ghrelin in CP patients and des-acyl ghrelin in MD patients had significant negative correlations with MUAC and upper arm fat area. In CP patients, total and acyl ghrelin had significant positive correlations with REE/BW (kcal/kg), and total ghrelin was predictive of REE/BW (r2 = 0.625, p Conclusions An increase in acyl ghrelin observed in SMID patients possibly indicates energy reserve deficiency. In CP patients, total and acyl ghrelin inversely reflected total body fat mass, resulting in strongly positive correlations with REE/BW. The measurement of plasma ghrelin may be useful to assess nutritional metabolism and energy reserve in pediatric SMID patients, such as CP and MD patients.

INTRODUCTION This study aimed to compare the safety and efficacy of laparoscopic percutaneous extraperitoneal closure (LPEC) and conventional open repair (OR) for inguinal hernia in infants younger than 6 months. METHODS The medical records of 202 patients who had undergone LPEC or OR at an age younger than 6 months between 2010 and 2016 were reviewed. Patient characteristics and surgical outcomes were compared between LPEC and OR. RESULTS In total, there were 120 LPEC (76 males, 44 females) and 83 OR (76 males, 7 females) cases. There were no differences in median age, median bodyweight, and presence of incarceration between the two groups (LPEC group: 3 months (range, 0-5 months), 5.7 kg (range, 2.3-9.6 kg), and 13.3%; OR group: 3 months (range, 1-5 months), 5.5 kg (range, 2.1-9.0 kg), and 12.0%). LPEC was completed in all cases without any intraoperative complications or open conversions. In the LPEC group, 60.0% of unilateral hernia patients had a contralateral patent processus vaginalis and underwent prophylactic closure. The incidence of metachronous contralateral hernia was significantly lower in the LPEC group than in the OR group (0% vs 10.0%, P

The standard treatment for Wilms tumor (WT) is primary resection. However, in cases with unresectable tumor or tumor spillage, which are considered to have high surgical risks, more intensive chemotherapy and radiotherapy are required. In the present study, we retrospectively analyzed preoperative image parameters to identify factors associated with surgical risks. Twenty-nine patients with WT were enrolled in this study. Data on various preoperative image parameters, such as tumor size, tumor volume, displacement of great vessels, and contralateral extension of the tumor were collected, and their relationship with surgical factors, including operative time, hemorrhage, tumor spillage, and unresectability were analyzed. Patients with unresectable tumor or with tumor spillage (surgical high-risk group) more frequently demonstrated displacement of great vessels and contralateral tumor extension. Operative time and blood loss were also significantly related to tumor size, area, volume, displacement of great vessels and contralateral extension. Besides tumor size, displacement of great vessels and contralateral extension were significantly associated with surgical risks. These factors are easily determined using CT images and are, therefore, useful to decide whether preoperative chemotherapy should be started instead of primary tumor resection for large localized WTs.

Atrial natriuretic peptide (ANP) is a cardiac hormone released by the atrium in response to stretching forces. Via its receptor, guanylyl cyclase-A (GC-A), ANP maintains cardiovascular homeostasis by exerting diuretic, natriuretic, and hypotensive effects mediated, in part, by endothelial cells. Both in vivo and in vitro, ANP enhances endothelial barrier function by reducing RhoA activity and reorganizing the actin cytoskeleton. We established mouse endothelial cells that stably express GC-A and used them to analyze the molecular mechanisms responsible for actin reorganization. Stimulation by ANP resulted in phosphorylation of myosin light chain (MLC) and promotion of cell spreading. p21-activated kinase 4 (PAK4) and cerebral cavernous malformations 2 (CCM2), a scaffold protein involved in a cerebrovascular disease, were required for the phosphorylation of MLC and promotion of cell spreading by ANP. Finally, in addition to the GC domain, the kinase homology domain of GC-A was also required for ANP/GC-A signaling. Our results indicate that CCM2 and PAK4 are important downstream mediators of ANP/GC-A signaling involved in cell spreading, an important initial step in the enhancement of endothelial barrier function.

A mature teratoma of the pancreas has rarely been reported, and postoperative superior mesenteric artery syndrome (SMAS) is extremely rare in pediatric pancreatic surgery. A 12-year-old girl underwent an enucleation of the large mature teratoma located at the pancreas uncus. Although her postoperative recovery was fair, the bile-stained gastric juice continued draining at a rate of>1.5 l per day for 2 weeks. An upper gastrointestinal series revealed an abrupt disruption with to-and-fro peristalsis at the third portion of the duodenum. Endoscopy revealed an extrinsic pulsatile compression of this third portion. The aortomesenteric angle measured 12° on ultrasonography, which met the criteria for SMAS. The patient underwent a modified transposition procedure, “switching jejunojejunostomy,” on postoperative day 18. The gastrointestinal passage gradually improved, and complete oral intake was established 1 month after the first surgery. It was considered that the clinical symptoms of SMAS were caused by an anatomical deformation after the pancreatic tumor resection. Switching jejunojejunostomy was found to be an acceptable therapeutic option for this condition.

CT-guided localization followed by video-assisted thoracoscopic surgery was performed in three children with pulmonary nodules less than 5 mm in diameter. The patients' respective primary diagnoses were Wilms tumor, hepatoblastoma, and osteosarcoma of the femur. The pulmonary nodules were marked preoperatively by a percutaneously placed hook-wire or dye under CT guidance. Although none of the nodules was grossly detected during the operation, they were correctly resected under the guidance of the hook-wire wound or dye. A histological assessment revealed viable metastatic lesions in the case of hepatoblastoma, completely necrotic lesions in the case of Wilms tumor, and inflammatory nodules in the case of osteosarcoma. CT-guided localization followed by video-assisted thoracoscopic surgery appears to be a beneficial procedure in children with tiny pulmonary nodules.

Pediatric living donor liver transplant (LDLT) patients sometimes develop graft fibrosis after non-recurrent diseases such as biliary atresia (BA). Donor-specific antibodies (DSA) have recently been shown to play a possible role in graft damage after liver transplantation. We report the impact of DSA on pediatric LDLT for BA patients.Patients under age 18 years who received LDLT for BA at our institution and who had at least 5 years' follow-up were identified, and 23 were eventually enrolled in this study. Pathological findings were assessed with the use of the last available biopsy. Patients were divided into 2 groups, DSA-positive and DSA-negative. Graft fibrosis after LDLT was assessed according to DSA groups.The mean patient age at transplant was 2.6 years. The mean time to the last available biopsy after LDLT was 8.2 years (4.8-15.6 years); 6 patients (26%) showed no fibrosis, whereas fibrosis was graded as F1, F2, or F3 in 8 patients (35%), 8 patients (35%), and 1 patient, respectively. DSA were observed in 12 patients (52%). Moderate graft fibrosis (F2 and F3) was found in 7 (58%) of the DSA-positive group, but only 2 (18%) of the DSA-negative group, showing a statistically significant difference (P .05). Pre-transplant cross-matching was performed in 17 patients. The 2 patients with a positive cross-match were DSA-positive. Six cross-match-negative patients developed de novo DSA after LDLT.Graft fibrosis was observed after LDLT for BA during long-term follow-up, more commonly in DSA-positive patients. DSA may play a role in fibrosis formation.

BACKGROUND We have introduced and performed percutaneous sclerotherapy on pediatric patients, and information regarding the mid- and long-term results after percutaneous treatment of peripheral venous malformations is necessary to counsel patients and their parents about the outcome of the therapy. This study was designed to retrospectively evaluate the long-term satisfaction of pediatric patients following percutaneous sclerotherapy for venous malformations (VMs). METHODS A total of 53 children younger than 16 years of age with VMs who underwent sclerotherapy were included in this study. Self-assessment questionnaires regarding the treatment effectiveness and patients' satisfaction were sent to 50 of 53 patients. Sclerotherapy was performed using 3% polidocanol, absolute ethanol, or 5% ethanolamine oleate (EO). RESULTS The median numbers of sessions per patient was 2.0 (range, 1-12), and the median follow-up time was 1.8 years (range, 6months-8.3years). Forty-two patients (84%) returned the questionnaire. The most frequent symptom was swelling (95%, 40/42) before sclerotherapy. After treatment, patients felt less pain (82%, 23/28), functional limitation (78%, 14/18), swelling (70%, 28/40), and cosmetic disfigurement (59%, 13/22). None of the patients responded "worse" for any symptoms, and 30 patients (71%) reported being "very satisfied" or "satisfied" with the treatment. CONCLUSION Percutaneous sclerotherapy of VMs was safe and effective for relieving symptoms in our pediatric patients, and many of them were satisfied with the outcomes.

Rhabdomyosarcoma (RMS) is a malignant mesenchymal tumor and the most common soft tissue sarcoma in children. Because of several complications associated with intensive multimodal therapies, including growth disturbance and secondary cancer, novel therapies with less toxicity are urgently needed. C‐type natriuretic peptide (CNP), an endogenous peptide secreted by endothelial cells, exerts antiproliferative effects in multiple types of mesenchymal cells. Therefore, we investigated whether CNP attenuates proliferation of RMS cells. We examined RMS patient samples and RMS cell lines. All RMS clinical samples expressed higher levels of guanylyl cyclase B (GC‐B), the specific receptor for CNP, than RMS cell lines. GC‐B expression in RMS cells decreased with the number of passages in vitro. Therefore, GC‐B stable expression lines were established to mimic clinical samples. CNP increased cyclic guanosine monophosphate (cGMP) levels in RMS cells in a dose‐dependent manner, demonstrating the biological activity of CNP. However, because cGMP is quickly degraded by phosphodiesterases (PDEs), the selective PDE5 inhibitor sildenafil was added to inhibit its degradation. In vitro, CNP, and sildenafil synergistically inhibited proliferation of RMS cells stably expressing GC‐B and decreased Raf‐1, Mitogen‐activated protein kinase kinase (MEK), and extracellular signal‐regulated kinase (ERK) phosphorylation. These results suggested that CNP in combination with sildenafil exerts antiproliferative effects on RMS cells by inhibiting the Raf/MEK/ERK pathway. This regimen exerted synergistic effects on tumor growth inhibition without severe adverse effects in vivo such as body weight loss. Thus, CNP in combination with sildenafil represents a promising new therapeutic approach against RMS.

We herein report the rare case of a 4-year-5-month-old boy who presented with primary renal neuroblastoma. The patient developed repeated lung and liver metastatic recurrences, but, following a combination of chemotherapy, radiation therapy and aggressive surgical resection, the patient is now in remission. To investigate the pathogenesis of lung metastasis, immunohistochemistry was performed for matrix metalloproteinase-9 and -14 (MMP-9 and MMP-14), molecular markers of invasion, metastasis and angiogenesis in neuroblastoma. In the present case, MMP-9 expression was not observed, but MMP-14 expression was detected in the primary lesion and was more highly expressed in the metastatic lesion compared with the primary one. Given the MMP-14 staining in other cases, expression of MMP-14 may be associated with the aggressiveness of the tumor. This suggests that selected clones with high MMP-14 expression in the primary tumor might metastasize and form MMP-14-rich lesions.

Background We attempted to knock out the expression of Hanganutziu-Deicher (H-D) antigens through the use of a CRISPR (clustered regulatory interspaced short palindromic repeat)/Cas9 system for pig cytidine monophospho- N -acetylneuraminic acid hydroxylase (CMAH). Methods Plasmids expressing hCas9 and sgRNA for pCMAH were prepared by ligating oligos into the BbsI site of pX330. The N-terminal and C-terminal EGFP coding regions overlapping 482 bp were PCR-amplified and placed under a ubiquitous CAG promoter. The approximately 400-bp genomic fragments containing the sgRNA target sequence of pCMAH were placed into the multi-cloning sites flanked by the EGFP fragments. The pCAG-EGxxFP-target was mixed with pX330 with/without the sgRNA sequences and then introduced into HEK293T cells. Results Four oligos and primers, gSO1, gSO3, gSO4, and gSO8, were nominated from 8 candidates. Among them, gSO1 showed the best efficiency. Pig endothelial cells (PECs) from an α-Gal knockout pig were then used to examine the changes in the expression of the H-D antigen by the knockout of the CMAH genome by the pX330-gS01. Conclusions Changes in the expression of the H-D antigen in the PECs with the CRISPR (gS01) were clear in comparison with those in the parental cells, on the basis of FACS analysis data. The expression of the H-D antigen can be knocked out by use of the CRISPR system for pCMAH, thus confirming that this system is a very convenient system for producing knockout pigs.

Background/purpose We evaluated the long-term umbilical appearance and patient/parent satisfaction at follow-up after umbilical hernia repair (UHR). Methods In a retrospective review of 128 children who underwent UHR and were followed up for over 5 years, satisfaction was assessed using e-mailed questionnaires and attached photographs of the umbilicus. Results The survey response rate was 80.3% by parents, 79.5% by patients, and 72.1% using photographs. The median follow-up period was 7.6 (range, 5.3–10.1) years. The satisfaction rate was 78.9% among parents and 91.5% among patients; however, eight patients (8.5%) reported dissatisfaction with the results. The main reason for dissatisfaction was the shallow depth of the umbilicus (parents, 10/20; patients, 5/8). During the follow-up period, satisfaction increased in 14 cases (14.7%) and decreased in 10 cases (10.5%). Superior hooding was considered an ideal shape for the umbilicus. Concomitant laparoscopic surgery and higher age at surgery were significantly associated with dissatisfaction in parents ( P = 0.045) and patients ( P = 0.046), respectively. Large defect size was significantly associated with decreased satisfaction during the follow-up period ( P = 0.030). Conclusion E-mail surveys are useful for long-term follow-up after UHR. Patients with these above risk factors should receive long-term follow-up with careful attention to patient satisfaction. Level of evidence Type of study: prognosis study, level II.

Background Some chemotherapeutic agents have been reported to promote lung metastasis. However, there have been no reports regarding chemotherapy-induced liver metastasis. We hypothesized that chemotherapy might also enhance liver metastasis. The present study aimed to create a chemotherapy-enhanced liver metastasis mouse model and investigate its mechanism. Materials and methods Mice were pretreated with cisplatin, vincristine, or saline by intraperitoneal injection. Next, B16F10 mouse melanoma cells and BE(2)-C human neuroblastoma cells were injected into the spleens of C57BL/6 and BALB/c nu/nu mice, respectively, to induce experimental liver metastasis, and the number of liver nodules was determined. We also analyzed the effect of chemotherapy on changes of the liver tissue regarding representative metastasis-promoting factors using real-time quantitative polymerase chain reaction and immunohistochemical and histological analysis. Results Cisplatin increased the number of nodules by 4.7-fold in the B16F10 liver metastasis model. Vincristine increased the number of nodules by 3.8-fold in the BE(2)-C liver metastasis model. Cisplatin increased mRNA levels of matrix-metalloproteinase (MMP)-2 and periostin, while vincristine increased MMP-9 and S100A8/9 levels in liver tissues. Cisplatin induced fibrosis, whereas vincristine induced neutrophil recruitment in liver tissues according to histological and immunohistochemical analysis. Conclusions We concluded that cisplatin or vincristine could enhance liver metastasis of mouse melanoma cells or human neuroblastoma cells, respectively. In addition, the mRNA expression of MMP-2 and periostin, or MMP-9 and S100A8/9 is increased by cisplatin or vincristine pretreatment, possibly resulting in fibrosis or neutrophil recruitment, respectively. These niche factors might be associated with increased liver metastasis.

Background Patients with intestinal failure (IF) are candidates for intestinal transplantation (ITx). In Japan, these patients have few opportunities to undergo cadaveric ITx because of low rates of organ donation. The donor criteria and recipient priority for ITx are still unknown. We reviewed our cases of IF to investigate which patients should be prioritized for ITx. Methods Patients with IF who were registered as candidates for cadaveric ITx between January 2010 and November 2015 in our institute were included in this retrospective study. Their data were gathered from their charts and analyzed. Results Five patients were included. Their primary diseases included total colon aganglionosis (n = 1), chronic idiopathic intestinal pseudo-obstruction syndrome (n = 2), superior mesenteric vein embolization (n = 1), and graft loss after ITx (n = 1). Two patients died of liver failure (LF) during the waiting period. The remaining three are now alive and waiting for transplantation. The lengths of the remaining intestine were more than 20 cm in living cases but less than 20 cm in fatal cases. In the fatal cases, they had several episodes of catheter-related blood stream infection, which caused LF and acute renal failure. Conclusions We identified two patients with less than 20 cm residual small bowel who died after acute deterioration of liver function. Patients with ultra-short bowel could have a higher risk of LF. Therefore, they should be referred as soon as possible to a specialized hospital where ITx is a choice of treatment for IF.

Cisplatin is an effective chemotherapeutic agent used to treat a variety of malignant tumors. The major toxicity associated with cisplatin treatment is granulocytopenia. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, protects against toxicity in many organs, including the heart, blood vessels, lung, and kidney. The objective of this study was to investigate the myeloprotective effects of CNP in a mouse model of cisplatin-induced granulocytopenia. The mice were divided into two groups: cisplatin with vehicle and cisplatin with CNP. CNP (2.5 μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started two day before cisplatin injection, and continued until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), we counted total and living cells and granulocyte/macrophage colony-forming units (CFU-GM) in bone marrow. In addition, at 0, 1, 2, and 4 days after cisplatin injection, we measured mRNA levels of CXC chemokine receptor 4 (CXCR4) and chemokine CXC ligand 12 (CXCL12) in bone marrow. CNP significantly attenuated the reduction in bone marrow nucleated cell count and CFU-GM in bone marrow at 4 days after cisplatin injection. Four days after cisplatin injection, CNP significantly decreased the CXCR4 mRNA level in bone marrow, but had no effect on the level of CXCL12 mRNA. CNP exerts myeloprotective effects in cisplatin-induced granulocytopenia and decreases CXCR4 expression.

Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts.C57BL/6 mice were divided into two groups, CNP-treated (2.5 μg/kg/min) and vehicle, to evaluate BLM-induced (1 mg/kg) pulmonary fibrosis and inflammation. A periostin-CNP transgenic mouse model exhibiting CNP overexpression in fibroblasts was generated and examined for the anti-inflammatory and anti-fibrotic effects of CNP via fibroblasts in vivo. Additionally, we assessed CNP attenuation of TGF-β-induced differentiation into myofibroblasts by using immortalized human lung fibroblasts stably expressing GC-B receptors. Furthermore, to investigate whether CNP acts on human lung fibroblasts in a clinical setting, we obtained primary-cultured fibroblasts from surgically resected lungs of patients with lung cancer and analyzed levels of GC-B mRNA transcription.CNP reduced mRNA levels of the profibrotic cytokines interleukin (IL)-1β and IL-6, as well as collagen deposition and the fibrotic area in lungs of mice with bleomycin-induced pulmonary fibrosis. Furthermore, similar CNP effects were observed in transgenic mice exhibiting fibroblast-specific CNP overexpression. In cultured-lung fibroblasts, CNP treatment attenuated TGF-β-induced phosphorylation of Smad2 and increased mRNA and protein expression of α-smooth muscle actin and SM22α, indicating that CNP suppresses fibroblast differentiation into myofibroblasts. Furthermore, human lung fibroblasts from patients with or without interstitial lung disease substantially expressed GC-B receptor mRNA.These data suggest that CNP ameliorates bleomycin-induced pulmonary fibrosis by suppressing TGF-β signaling and myofibroblastic differentiation in lung fibroblasts. Therefore, we propose consideration of CNP for clinical application to pulmonary fibrosis treatment.

Purpose The aim of the present study was to compare the efficacy, complications and outcomes of the following two different surgical strategies, in patients receiving delayed local treatment for INSS 4 neuroblastoma (NB): complete resection (CR; period A), and gross total resection (GTR)/subtotal resection (STR) with local irradiation (period B). Methods We retrospectively analyzed 17 patients with INSS 4 neuroblastoma (NB) who received delayed local treatment (period A, n=11; period B, n=6). Results Eleven patients in period A received CR. Two patients underwent GTR and 4 patients underwent STR in period B. The amount of blood loss in period A was significantly greater than that seen in period B. Postoperative complications were observed in 8 patients in period A (73%), but only 1 patient in period B had postoperative complications (17%) (p

Percutaneous endoscopic gastrostomy (PEG) is a widely used minimally invasive procedure. However, PEG is difficult in neurologically impaired patients due to scoliosis with a high-riding stomach and intestinal dilatation. Fluoroscopy-guided PEG (F-PEG) is expected to avoid PEG-related complications such as intestinal injury and malpositioned tube placement. The aim of this retrospective study is to evaluate the feasibility and safety of F-PEG in children. Twenty-one handicapped pediatric patients underwent F-PEG from January 2012 to December 2014 at our hospital. Among them, 6 had scoliosis, 7 had a high-riding stomach, and 3 had gastric volvulus. F-PEG was performed in all 21 patients without any major complications. The median procedure duration was 22 minutes. In 1 patient with severe scoliosis (Cobb angle, 118 degrees) and a high-riding stomach, F-PEG was safely performed. In conclusion, F-PEG is a simple and feasible technique, and can reduce the risk of PEG-related complications in handicapped pediatric patients.

Granulocytopenia is the major toxicity associated with cisplatin treatment. Atrial natriuretic peptide (ANP) is a cardiac hormone used clinically for the treatment of acute heart failure in Japan. ANP exerts a wide range of protective effects on various organs, including the heart, blood vessels, lungs, and kidneys. This study’s objective was to investigate the protective effects of ANP on cisplatin-induced granulocytopenia in mice. The mice were divided into two groups: cisplatin with vehicle and cisplatin with ANP. ANP (1.5 μg/kg/min via osmotic pump, subcutaneously) or vehicle administration was started 1 day before cisplatin injection until the mice were killed. At 0, 2, 4, 8, and 14 days after cisplatin injection (16 mg/kg, intraperitoneally as a single dose), the white blood cell, red blood cell, and platelet counts were measured in the peripheral blood in both groups. The numbers of total and live cells and colony-forming unit-granulocyte–macrophage (CFU-GM) colonies in the bone marrow of the mice were also examined. In addition, at 0, 0.5, 1, and 2 days after cisplatin injection, serum granulocyte colony-stimulating factor (G-CSF) levels were measured. ANP significantly attenuated the white blood cell count decrease in the peripheral blood 2 and 4 days after cisplatin injection. ANP also attenuated the decrease in the number of live cells and CFU-GM colonies in bone marrow 2, 4, and 8 days after cisplatin injection. ANP significantly increased serum G-CSF levels 1 day after cisplatin injection. ANP has protective effects in cisplatin-induced granulocytopenia, with increased G-CSF production.

In pediatric LDLT, graft reduction is sometimes required because of the graft size mismatch. Dividing the portal triad and hepatic veins with a linear stapler is a rapid and safe method of reduction. We herein present a case with a left lateral segment reduction achieved using a linear stapler after reperfusion in pediatric LDLT. The patient was a male who had previously undergone Kasai procedure for biliary atresia. We performed the LDLT with his father's lateral segment. According to the pre-operative volumetry, the GV/SLV ratio was 102.5%. As the patient's PV was narrow, sclerotic and thick, we decided to put an interposition with the IMV graft of the donor between the confluence and the graft PV. The graft PV was anastomosed to the IMV graft. The warm ischemic time was 34 min, and the cold ischemic time was 82 min. The ratio of the graft size to the recipient weight (G/R ratio) was 4.2%. After reperfusion, we found that the graft had poor perfusion and decided to reduce the graft size. We noted good perfusion in the residual area after the lateral edge was clamped with an intestinal clamp. The liver tissue was sufficiently fractured with an intestinal clamp and then was divided with a linear stapler. The final G/R ratio was 3.6%. The total length of the operation was 12 h and 20 min. The amount of blood lost was 430 mL. No surgical complications, including post-operative hemorrhage and bile leakage, were encountered. We believe that using the linear stapler decreased the duration of the operation and was an acceptable technique for reducing the graft after reperfusion.

Background In our previous study, we reported on the development of substituting S147C for HLA-E as a useful gene tool for xenotransplantation. In this study we exchanged the codon of HLA-Ev (147), checked its function, and established a line of transgenic mice. Methods A new construct, a codon exchanging human HLA-Ev (147) + IRES + human beta 2-microgloblin, was established. The construct was subcloned into pCXN2 (the chick beta-actin promoter and cytomegalovirus enhancer) vector. Natural killer cell− and macrophage-mediated cytotoxicities were performed using the established the pig endothelial cell (PEC) line with the new gene. Transgenic mice with it were next produced using a micro-injection method. Results The expression of the molecule on PECs was confirmed by the transfection of the plasmid. The established molecules on PECs functioned well in regulating natural killer cell−mediated cytotoxicity and macrophage-mediated cytotoxicity. We have also successfully generated several lines of transgenic mice with this plasmid. The expression of HLA-Ev (147) in each mouse organ was confirmed by assessing the mRNA. The chick beta-actin promoter and cytomegalovirus enhancer resulted in a relatively broad expression of the gene in each organ, and a strong expression in the cases of the heart and lung. Conclusion A synthetic HLA-Ev (147) gene with a codon usage optimized to a mammalian system represents a critical factor in the development of transgenic animals for xenotransplantation.

Background The purpose of this study was to produce molecules that can precisely regulate the complement and coagulation system and to assess the expression of such molecules in transgenic animals. Methods The CTDM gene, which is composed of the delta-1-99 amino acid (aa) C1-INH, EGF domain 4-6 of thrombomoduline (TM), short consensus repeat (SCR) 2-4 of DAF(CD55), and SCR 2-4 of MCP(CD46) was established. The codon usage for expression in mammals was adopted. The cDNA of CTDM was subcloned into the pCPI site (the human insulin promoter and a cytomegalovirus enhancer). pCPI-CTDM was transfected into pig endothelial cells (PEC). The expression of the molecule was clearly assessed by means of flow cytometry. Results BD3F1 female mice were induced to superovulate and were then crossed with BD3F1 males. Micro-injection and embryo transfer were performed by standard methods, thus generating transgenic mice that express CTDM. The mice carried the CTDM plasmid, as verified by PCR. Tissue expression levels in transgenic mouse lines generated with the constructs were follows: pancreas, 1.0; brain, 5.4; thymus, 0.3; heart, 0.2; lung, 1.2; liver, 0.1; kidney, 0.1; intestine, 0.4; and spleen, 1.6. A naive control mouse was also analyzed in the exact manner as for the transgenic mice. Conclusions A synthetic CTDM gene with codon usage optimized to the mammalian system represents a critical factor in the development of transgenic animals.

Background/purpose Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children. Since patients with high-risk RMS have limited treatment options and a poor prognosis, and late complications including growth disturbance and secondary cancer induced by chemotherapy or radiation therapy are essential problems, novel therapies are urgently needed. C-type natriuretic peptide (CNP) has physiological activity mainly for mesenchymal cells to inhibit cell proliferation. We hypothesized that CNP attenuates proliferation of human RMS, a malignant mesenchymal tumor and provide rationale for using CNP to treat RMS.

We have introduced and performed percutaneous sclerotherapy on pediatric patients, and information regarding the mid- and long-term results after percutaneous treatment of peripheral venous malformations is necessary to counsel patients and their parents about the outcome of the therapy. This study was designed to retrospectively evaluate the long-term satisfaction of pediatric patients following percutaneous sclerotherapy for venous malformations (VMs).A total of 53 children younger than 16 years of age with VMs who underwent sclerotherapy were included in this study. Self-assessment questionnaires regarding the treatment effectiveness and patients' satisfaction were sent to 50 of 53 patients. Sclerotherapy was performed using 3% polidocanol, absolute ethanol, or 5% ethanolamine oleate (EO).The median numbers of sessions per patient was 2.0 (range, 1-12), and the median follow-up time was 1.8 years (range, 6months-8.3years). Forty-two patients (84%) returned the questionnaire. The most frequent symptom was swelling (95%, 40/42) before sclerotherapy. After treatment, patients felt less pain (82%, 23/28), functional limitation (78%, 14/18), swelling (70%, 28/40), and cosmetic disfigurement (59%, 13/22). None of the patients responded "worse" for any symptoms, and 30 patients (71%) reported being "very satisfied" or "satisfied" with the treatment.Percutaneous sclerotherapy of VMs was safe and effective for relieving symptoms in our pediatric patients, and many of them were satisfied with the outcomes.

We herein report the rare case of a 4-year-5-month-old boy who presented with primary renal neuroblastoma. The patient developed repeated lung and liver metastatic recurrences, but, following a combination of chemotherapy, radiation therapy and aggressive surgical resection, the patient is now in remission. To investigate the pathogenesis of lung metastasis, immunohistochemistry was performed for matrix metalloproteinase-9 and -14 (MMP-9 and MMP-14), molecular markers of invasion, metastasis and angiogenesis in neuroblastoma. In the present case, MMP-9 expression was not observed, but MMP-14 expression was detected in the primary lesion and was more highly expressed in the metastatic lesion compared with the primary one. Given the MMP-14 staining in other cases, expression of MMP-14 may be associated with the aggressiveness of the tumor. This suggests that selected clones with high MMP-14 expression in the primary tumor might metastasize and form MMP-14-rich lesions.

Cancer stem cells (CSCs) are defined as a small population of cancer cells with the properties of high self-renewal, differentiation, and tumor-initiating functions. Recent studies have demonstrated that aldehyde dehydrogenase 1 (ALDH1) is a marker for CSCs in adult cancers. Although CSCs have been identified in some different types of pediatric solid tumors, there have been no studies regarding the efficacy of ALDH1 as a marker for CSCs. Therefore, in order to elucidate whether ALDH1 can be used as a marker for CSCs of pediatric sarcoma, we examined the characteristics of a population of cells with a high ALDH1 activity (ALDH1high cells) in rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children. We used the human embryonal RMS (eRMS) cell lines RD and KYM-1, and sorted the cells into two subpopulations of ALDH1high cells and cells with a low ALDH1 activity (ALDH1low cells). Consequently, we found that the ALDH1high cells comprised 3.9% and 8.2% of the total cell population, respectively, and showed a higher capacity for self-renewal and tumor formation than the ALDH1low cells. With regard to chemoresistance, the survival rate of the ALDH1high cells was found to be higher than that of the ALDH1low cells following treatment with chemotherapeutic agents for RMS. Furthermore, the ALDH1high cells exhibited a higher degree of pluripotency and gene expression of Sox2, which is one of the stem cell markers. Taken together, the ALDH1high cells possessed characteristics of CSCs, including colony formation, chemoresistance, differentiation and tumor initiation abilities. These results suggest that ALDH1 is a potentially useful marker of CSCs in eRMS.

Currarino syndrome with Hirschsprung disease (CS-HD) is extremely rare. We present the first family with CS-HD. Case 1: A 28-year-old woman was admitted with severe abdominal distension and dyspnea. She was diagnosed with anal stenosis, hemisacrum, anterior sacral meningocele (ASM), tethered cord (TC), and short-segment aganglionosis. She underwent the modified Duhamel operation after meningocele repair and cord detethering. A bicornuate uterus, bilateral ovarian dermoid cysts, and small rectal duplication were also noted intraoperatively. Case 2: The daughter of case 1 was admitted for abdominal distension and anal stenosis at the age of 17 days. Studies revealed a hemisacrum, ASM, TC, presacral mass, atrial septal defect, polyp in the right nasal cavity, right vesicoureteral reflux, and short-segment aganglionosis. She underwent the modified Soave operation at the age of 1 year and 4 months after meningocele repair, cord detethering, and resection of the presacral mass (epidermoid cyst). In both cases, the aganglionic segments were confirmed by preoperative rectal suction biopsy and postoperative pathological examination on full-thickness rectal specimens. Some causal genes for Currarino syndrome (CS) and Hirschsprung disease (HD) are currently investigated. Thus far, 10 CS-HD cases have been reported, including 6 cases of familial CS. However, all the patients had sporadic HD. Recent reports suggest that anomalies of the enteric nerve system contribute to postoperative constipation in CS cases.

Primary liver cancer with lymph node metastasis was recognized as poor prognosis. We herein report a case of post operative lymph node recurrence treated with UFT. A 74-year-old man with a huge mass lesion in the right liver with para Aortic lymph node metastasis admitted our hospital in April 2007. Extended right lobe hepatectomy and lymph node dissection were performed in May. A histological examination of the resected specimen showed a combined hepatocellular-cholangiocarcinoma with three lymph node metastasis. Computed tomography(CT)revealed intra hepatic metastasis (S3) and right adrenal grand metastasis 5 months after surgery. Transarterial embolization (TAE) and right adrenalectomy were performed for each metastasis. CT revealed a lymph node metastasis at the right side of infra vena cava 1 year after surgery. He was treated by oral administration of UFT (200 mg/day). The AFP and PIVKA-II value gradually decreased after administration of UFT. The size of lymph node metastasis became small confirmed by CT. But the AFP and PIVKA-II value increased 1 year and 7 months after surgery. TAE was performed against lymph node metastasis 1 year and 9 months after surgery. This case suggests UFT is useful for suppressing the growth of the lymph node metastasis.

Background Pulmonary fibrosis has high rates of mortality and morbidity; however, no effective pharmacological therapy has been established. C-type natriuretic peptide (CNP), a member of the natriuretic peptide family, selectively binds to the transmembrane guanylyl cyclase (GC)-B receptor and exerts anti-inflammatory and anti-fibrotic effects in various organs through vascular endothelial cells and fibroblasts that have a cell-surface GC-B receptor. Given the pathophysiological importance of fibroblast activation in pulmonary fibrosis, we hypothesized that the anti-fibrotic and anti-inflammatory effects of exogenous CNP against bleomycin (BLM)-induced pulmonary fibrosis were exerted in part by the effect of CNP on pulmonary fibroblasts. Methods C57BL/6 mice were divided into two groups, CNP-treated (2.5 μg/kg/min) and vehicle, to evaluate BLM-induced (1 mg/kg) pulmonary fibrosis and inflammation. A periostin-CNP transgenic mouse model exhibiting CNP overexpression in fibroblasts was generated and examined for the anti-inflammatory and anti-fibrotic effects of CNP via fibroblasts in vivo. Additionally, we assessed CNP attenuation of TGF-β-induced differentiation into myofibroblasts by using immortalized human lung fibroblasts stably expressing GC-B receptors. Furthermore, to investigate whether CNP acts on human lung fibroblasts in a clinical setting, we obtained primary-cultured fibroblasts from surgically resected lungs of patients with lung cancer and analyzed levels of GC-B mRNA transcription. Results CNP reduced mRNA levels of the profibrotic cytokines interleukin (IL)-1β and IL-6, as well as collagen deposition and the fibrotic area in lungs of mice with bleomycin-induced pulmonary fibrosis. Furthermore, similar CNP effects were observed in transgenic mice exhibiting fibroblast-specific CNP overexpression. In cultured-lung fibroblasts, CNP treatment attenuated TGF-β–induced phosphorylation of Smad2 and increased mRNA and protein expression of α-smooth muscle actin and SM22α, indicating that CNP suppresses fibroblast differentiation into myofibroblasts. Furthermore, human lung fibroblasts from patients with or without interstitial lung disease substantially expressed GC-B receptor mRNA. Conclusions These data suggest that CNP ameliorates bleomycin-induced pulmonary fibrosis by suppressing TGF-β signaling and myofibroblastic differentiation in lung fibroblasts. Therefore, we propose consideration of CNP for clinical application to pulmonary fibrosis treatment.