Tetsuya Mitsunaga

Toxoplasma gondii–derived heat shock protein 70 stimulates maturation of murine bone marrow–derived dendritic cells via Toll-like receptor 4

Abstract Toxoplasma gondii –derived heat shock protein 70 (T.g.HSP70) induced maturation of bone marrow–derived dendritic cells (DCs) of wild-type (WT) C57BL/6 mice as evidenced by an increase in surface expression of MHC class I and II molecules and costimulatory molecules such as CD40, CD80, and CD86. Functionally, decreased phagocytic ability and increased alloreactive T cell stimulatory ability were observed in T.g.HSP70-stimulated DCs. These phenotypic and functional changes of T.g.HSP70-stimulated DCs were demonstrated in Toll-like receptor (TLR) 2- and myeloid differentiation factor 88 (MyD88)-deficient but not TLR4-deficient C57BL/6 mice. DCs from WT and TLR2-deficient but not TLR4-deficient mice produced IL-12 after T.g.HSP70 stimulation. T.g.HSP70-stimulated DCs from WT, TLR2-deficient, and MyD88-deficient, but not TLR4-deficient mice expressed IFN-β mRNA. Thus, T.g.HSP70 stimulates murine DC maturation via TLR4 through the MyD88-independent signal transduction cascade.

Role of pediatric endoscopic retrograde cholangiopancreatography in an era stressing less-invasive imaging modalities.

Background:The significance of pediatric endoscopic retrograde cholangiopancreatography (ERCP) according to age or disease variation is inconclusive. This study aimed to evaluate the usefulness of pediatric ERCP in diagnosing or treating small children with pancreaticobiliary disorders, including choledochal cyst (CC) and biliary atresia (BA). Methods:From 1980 to 2011, 235 ERCPs were performed in 220 pediatric patients (median age, 2 years) at our institution. Underlying pathology was CC in 92 patients (3 years), BA in 62 patients (55 days), and others in 66 patients. Success and complication rates, and ERCP findings were retrospectively analyzed. Results:The overall success rate was 96%. Rates for individual pathologies were 99% for CC, 92% for BA, and 96% for others. The success rate was 100% among children >3 years, but 92% when limited to infants. Post-ERCP hyperamylasemia and duodenal perforation occurred in 9% and 0.4% of cases, respectively. Regarding preoperative evaluation of the pancreaticobiliary system in CC, ERCP clearly delineated pancreaticobiliary maljunction (79%) and the pancreatic duct (94%), whereas it visualized the common bile duct and intrahepatic bile duct at relatively low rates (77% and 33%, respectively). ERCP successfully identified 16 cases (18%) with non-BA of 90 patients with suspected BA. Moreover, ERCP demonstrated only pancreatic duct in 70% of all BA. Conclusions:ERCP among children including infants with CC and BA can be performed with fairly satisfactory results. Although pediatric ERCP can also help describe the pancreaticobiliary system in detail, its indication should be deliberately considered when anatomical information from less-invasive imaging modalities is insufficient.

Endoscopic sphincterotomy is a useful preoperative management for refractory pancreatitis associated with pancreaticobiliary maljunction.

BACKGROUND Pancreatitis associated with pancreaticobiliary maljunction (PBM) is commonly treated nonoperatively before surgery. It is, however, sometimes uncontrollable, and little has been reported about the management. METHODS Focusing on the preoperative management, we reviewed clinical courses of 4 PBM cases (ages 1 to 7 years old). Each had pancreatitis that was totally resistant to medical treatment and was applied endoscopic sphincterotomy (ES). RESULTS The first case underwent percutaneous transhepatic catheter drainage (PTCD) primarily. In spite of daily lavage using the drainage tube for a week, plugs located in the common channel were not removed, and clinical findings were not improved. Therefore, ES followed by removal of protein plugs was performed to improve pancreatitis dramatically. Through this experience, 3 subsequent cases with refractory pancreatitis all underwent successful ES primarily soon after the medical treatments turned out to be ineffective. In all 4 cases, protein plugs were impacted in common channels, and ES could successfully remove the plugs that were impossible to remove by using PTCD. Improved preoperative pancreaticobiliary decompression by ES shortens the duration of recalcitrant acute pancreatitis associated with PBM allowing for a subsequent safe operation. CONCLUSIONS Endoscopic sphincterotomy is one of the useful preoperative managements for refractory pancreatitis associated with PBM.

Endoscopic management for congenital esophageal stenosis: A systematic review

Congenital esophageal stenosis (CES) is an extremely rare malformation, and standard treatment have not been completely established. By years of clinical research, evidence has been accumulated. We conducted systematic review to assess outcomes of the treatment for CES, especially the role of endoscopic modalities. A total of 144 literatures were screened and reviewed. CES was categorized in fibromuscular thickening, tracheobronchial remnants (TBR) and membranous web, and the frequency was 54%, 30% and 16%, respectively. Therapeutic option includes surgery and dilatation, and surgery tends to be reserved for ineffective dilatation. An essential point is that dilatation for TBR type of CES has low success rate and high rate of perforation. TBR can be distinguished by using endoscopic ultrasonography (EUS). Overall success rate of dilatation for CES with or without case selection by using EUS was 90% and 29%, respectively. Overall rate of perforation with or without case selection was 7% and 24%, respectively. By case selection using EUS, high success rate with low rate of perforation could be achieved. In conclusion, endoscopic dilatation has been established as a primary therapy for CES except TBR type. Repetitive dilatation with gradual step-up might be one of safe ways to minimize the risk of perforation.

Use of preoperative, 3-dimensional magnetic resonance cholangiopancreatography in pediatric choledochal cysts

BACKGROUND Standard choledochal cyst (CC) operations involve dilated extrahepatic bile duct excision followed by biloenterostomy. However, biliary variants and associated intrahepatic bile duct (IHBD) stenoses or dilatations triggering postoperative sequelae require additional procedures. The usefulness of preoperative 3-dimensional magnetic resonance cholangiopancreatography (3D MRCP) and virtual cholangioscopy (VES) for observing biliary morphology and pancreaticobiliary maljunction (PBM) was evaluated. METHODS In 16 pediatric CC patients (age range, 4 months to 9 years; median, 3 years), visualization of PBM and aberrant bile duct anatomy and IHBD morphology at the hepatic hilum (HH), umbilical portion (UP), and posterior branch (POST) were compared between 3D-MRCP and intraoperative cholangiography (IOC). VES and intraoperative cholangioscopy (IOS) findings were compared. RESULTS HH, UP, and POST visualization rates were 100%, 94%, and 94%, respectively, by 3D-MRCP, and 100%, 69%, and 69%, respectively, by IOC. IHBD stenosis detection rates at each region were 38%, 13%, and 13%, respectively, by 3D-MRCP, and 25%, 0%, and 9%, respectively, by IOC. IHBD dilatation detection rates at each part were 75%, 47%, and 60%, respectively, by 3D-MRCP, and 88%, 82%, and 91%, respectively, by IOC. PBM was confirmed in 56% and 93% of cases on 3D-MRCP and IOC, respectively. Both 3D-MRCP and IOC showed biliary variants in 5 cases (31%). VES showed membranous strictures at HH, UP, and POST in 6, 2, and 2 cases, respectively, whereas IOS did so at HH in 4 cases and POST in 2. CONCLUSION Preoperative 3D-MRCP and VES accurately depict biliary morphology, allowing concrete operative planning in pediatric CC patients, complementing IOC and IOS.

Toll-like receptor mRNA expression in liver tissue from patients with biliary atresia.

Background and Aim: Inappropriate host immunological reactions against unknown ligands via the Toll-like receptor (TLR) cascades may trigger progressive inflammatory biliary destruction that manifests as biliary atresia (BA) in newborns or infants. The aim of the study was to clarify the role of the innate immune system in the development of BA. Patients and Methods: Liver tissue was obtained from 49 patients with pediatric hepatobiliary diseases: 19 with BA, 21 with choledochal cysts, and 9 with other hepatobiliary diseases. BA samples obtained during the initial portoenterostomy and reoperation or liver transplantation (LT) were classified as early and late BA groups, respectively. Of the early BA group, those requiring LT were designated as the LT group, and the others were designated as the non-LT group. The mRNA expression levels of TLRs 2, 3, 4, 7, and 8 were determined by real-time quantitative reverse transcription-polymerase chain reaction and were compared between groups. The correlation between TLR mRNA expression level and age at sampling was examined for each TLR in the patients with BA. Results: TLR8 mRNA, encoding the receptor for single-stranded RNA, was significantly higher in the early BA group, compared with non-BA groups (P = 0.008). Within the BA group, mRNA levels of TLRs 2 and 8 were significantly higher in the early group than in the late group (P = 0.02 and 0.006, respectively), despite there being no significant correlation between TLR mRNA expression and age at sampling, except for TLR7 (r = 0.77, P = 0.001). Compared with the non-LT group, the LT group demonstrated significantly higher mRNA expression of TLRs 3 and 7 (P = 0.02 and 0.01, respectively). Conclusions: Innate immune responses may contribute to the initiation and progression of BA. Severe inflammation characteristic of BA around the time of the first operation may abate postoperatively, but determination of selected TLR mRNA expression levels in the liver at the time of Kasai portoenterostomy may assist in predicting the prognosis of patients with BA.

Intralobar bronchopulmonary sequestration evaluated by contrast-enhanced three-dimensional MR angiography.

Abstract Bronchopulmonary sequestration (PS) is characterized by non-functioning lung tissue fed from one or several aberrant systemic arteries. The condition is diagnosed by visualizing the feeding arteries using non-invasive CT, MRI, colour Doppler sonography or conventional angiography. We present a 5-year-old boy in whom intralobar sequestration was diagnosed using contrast-enhanced 3D MR angiography, which visualised fine blood vessels in the thoraco-abdominal region without arterial puncture. This technique is useful for diagnosing PS.

A rare presentation in a case of gastric duplication cyst communicating to the pancreatic duct: coincidental detection during pyloromyotomy for hypertrophic pyloric stenosis

A rare case of gastric duplication of childhood is reported. A 1-month-old boy underwent pyloromyotomy for infantile hypertrophic pyloric stenosis. At laparotomy, a protruding lesion was identified in the anterior wall of the pylorus. The pylorus was hypertrophic as indicated preoperatively, and a normal pyloromyotomy was performed. Wedge biopsy of the protruding lesion revealed an intestinal structure, and gastric duplication was diagnosed. The child remained asymptomatic thereafter, but considering the risk of the duplication becoming symptomatic, a second laparotomy was performed at 1 year of age. The duplication cyst shared part of the wall with the pylorus, and the cyst was removed by cystectomy, leaving the pyloric muscle intact. The cyst was found to be communicating with the pancreatic duct. The child is doing well without any symptoms as of 18 months after second laparotomy. To the best of our knowledge, this is the youngest case of gastroduodenal duplication with pancreatic duct communication yet reported.

Antibody-dependent cellular cytotoxicity toward neuroblastoma enhanced by activated invariant natural killer T cells

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.

Significance of imaging modalities for preoperative evaluation of the pancreaticobiliary system in surgery for pediatric choledochal cyst

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.