Kiyohiko Ohshiro

Complications after cyst excision with hepaticoenterostomy for choledochal cysts and their surgical management in children versus adults

The aim of this study was to review the cases 200 children and 40 adults who had cyst excision combined with hepaticoenterostomy (CEHE) for choledochal cyst, with particular emphasis on post-CEHE complications and their surgical management. Patients who had CEHE at the age of 15 years or less were defined as children, and those aged 16 years or older were defined as adults. The mean age when patients became initially symptomatic was 3 years in children and 26 years in adults. Eleven adults became symptomatic as children (< or = 15 years of age). The mean age of CEHE in children and adults was 4.2 years and 35 years, respectively. The time interval between the onset of initial symptoms and CEHE was significantly less in children than in adults (P < .0001). Of the 200 children, 176 had primary CEHE, and 24 had secondary CEHE converted from cystoenterostomy or other biliary surgery. Seventy children had intraoperative cyst endoscopy, which enabled us to examine the proximal intrahepatic bile ducts for stenosis and debris, and to wash out debris, protein plugs, and stones from the intrapancreatic ducts. Of the 40 adults, 22 had primary CEHE, 18 had secondary CEHE. The mean follow-up period was 10.9 years in children and 10.7 years in adults. The number of patients with post-CEHE complications in children and adults was 18 (9.0%) and 17 (42.5%), respectively. The post-CEHE complication rate in children was significantly lower than in adults (P < .0001). The 18 children had 25 post-CEHE complications such as cholangitis, intrahepatic bile duct stones, pancreatitis, stone formation in the intrapancreatic terminal choledochus or pancreatic duct, and bowel obstruction. Twenty-seven post-CEHE complications developed in the 17 adults including 2 cases of cholangiocarcinoma. There were no post-CEHE complications in the 70 children who had intraoperative cyst endoscopy. No stone formation was seen in the 145 children who had CEHE at the age of 5 years or less. Eight stone formations were seen in seven (12.7%) of the remaining 55 children aged over 5 years. Stones developed in seven (17.5%) adults. The incidence of post-CEHE stone formation in children aged 5 years or less was significantly lower than in other children and adults (P < .0001). Reoperation was required in 15 children: revision of hepaticoenterostomy in 4, percutaneous transhepatic cholangioscopic lithotomy (PTCSL) in 1, excision of intrapancreatic terminal choledochus in 2, endoscopic sphincterotomy of the papilla of Vater in 1, pancreaticojejunostomy in 1, and laparotomy for bowel obstruction in 6. Ten adults required reoperations: revision of hepaticoenterostomy in 2, PTCSL in 2, left hepatic lobectomy in 1, endoscopic sphincterotomy in 2, exploratory laparotomy in 2, and adhesiolysis in 1. The authors conclude that early diagnosis followed by CEHE is the treatment of choice for choledochal cyst, and intraoperative cyst endoscopy is recommended as a valuable adjunct to CEHE.

Abnormal distribution of intestinal pacemaker (C-KIT-positive) cells in an infant with chronic idiopathic intestinal pseudoobstruction

BACKGROUND Chronic idiopathic intestinal pseudoobstruction (CIIPO) is a rare syndrome with an obscure pathogenesis. The proto-oncogene c-kit encodes a transmembrane tyrosine kinase receptor C-KIT that is critical for the development of the interstitial cells of Cajal, cells that are regarded as being the pacemaker cells of the gut. Thus, C-KIT immunopositive (C-KIT-) cells in the muscle layers of the bowel are considered to be intestinal pacemaker cells. METHODS In this study, the distribution of intestinal pacemaker cells was examined for the first time using C-KIT immunohistochemistry in an infant with CIIPO. RESULTS C-KIT+ cells were found lying on either side of the border between the two muscle layers (longitudinal and circular) of the bowel and dispersed unevenly throughout both muscle layers. Myenteric plexuses were not demarcated by C-KIT+ cells. In contrast, in controls, C-KIT+ cells were located distinctly between the two muscle layers of the small bowel and dispersed evenly throughout the muscle layers of the colon. Myenteric plexuses were clearly demarcated by C-KIT+ cells. CONCLUSIONS This case demonstrates for the first time that there is abnormal distribution of intestinal pacemaker cells in CIIPO and provides new evidence that abnormal c-kit gene expression may be responsible for autonomic gut dysmotility. C-KIT immunohistochemistry may be an indispensable tool for diagnosing CIIPO.

Administration of antenatal glucocorticoids prevents pulmonary artery structural changes in nitrofen-induced congenital diaphragmatic hernia in rats☆

BACKGROUND/PURPOSE The aim of this study was to investigate whether maternal administration of dexamethasone has any effect on pulmonary vasculature in nitrofen-induced experimental congenital diaphragmatic hernia (CDH) in a rat model. METHODS A CDH model was induced in pregnant rats after administration of 100 mg nitrofen on day 9.5 of gestation. Antenatal dexamethasone, 0.25 mg/kg was given intraperitoneally on day 18.5 and 19.5 of gestation. The fetuses were divided into three groups: group I (n = 10), normal controls; group II (n = 10), nitrofen-induced CDH; group III (n = 10), nitrofen-induced CDH with maternal antenatal dexamethasone treatment. The fetuses were killed by cesarean section at term. Victorian blue van Gieson staining and immunostaining with antialpha smooth muscle actin (ASMA) were performed on lung tissue. The degree of adventitial thickness and area, and medial thickness and area were measured in pulmonary arteries by image analyzer and analyzed statistically. RESULTS There was a significant increase in adventitial thickness and area in group II compared with group I and III (P < .01). There was also a significant increase in medial thickness in group II compared with group I and III (P < .01). The degree of adventitial thickness and area and degree of medial thickness and area were similar in controls and maternal dexamethasone-treated CDH group. CONCLUSION This study demonstrates that antenatal maternal dexamethasone treatment prevents pulmonary artery structural changes in nitrofen-induced CDH in rats.

Intestinal pacemaker C-KIT+ cells and synapses in allied Hirschsprung's disorders.

The cause of bowel dysmotility in allied Hirschsprungs disorders (AHDs) such as hypoganglionosis (HYPG), immature ganglia (IMG) and neuronal intestinal dysplasia (NID) remains unexplained. Recent experimental studies in mice have shown that c-kit gene product positive (C-KIT+) cells are responsible for intestinal pacemaker activity and that c-kit is also closely involved in synapse formation. To further understand the pathophysiology of AHDs, the authors used immunohistochemistry to study the distribution of C-KIT+ cells and synapses in the muscle layers of normal bowel from controls (12 cases) and bowel from patients with AHDs (10 patients; mean age, 3.0 years; 5 HYPG, 3 NID, 2 IMG). Anti-human C-KIT serum and monoclonal antibody 171B5 (a novel marker of synapses) were used for visualization of C-KIT+ cells and 171B5+ synapses, respectively. In normal bowel from controls and patients with AHDs, moderate to many C-KIT immunoreactive (C-KIT-IR+) cells were observed in the muscle layers. Myenteric plexuses were clearly demarcated by C-KIT-IR+ cells. 171B5 immunoreactive (171B5-IR+) synapses were abundant in the muscle layers and within the myenteric plexuses. In contrast, the number of C-KIT-IR+ cells or 171 B5-IR+ synapses was reduced in the muscle layers of bowel affected by AHDs, except within the myenteric plexuses, where there was a moderate to large number of 171B5-IR+ synapses identified. A lack of intestinal pacemaker C-KIT+ cells may be of great significance with respect to the bowel dysmotility associated with AHDs and also to the abnormal synapse formation seen in the muscle layers of bowel affected by these disorders.

Active collagen synthesis in infantile hypertrophic pyloric stenosis

Abstract M-57 antibody, which is capable of distinguishing newly-synthesized type I procollagen from fully-processed, mature collagen, was used to examine the expression of collagen synthesis in hypertrophic pyloric muscle from patients with infantile hypertrophic pyloric stenosis (IHPS). Seven specimens from IHPS patients were removed at the time of operation; age-matched normal pyloric tissue of 5 post-mortem cases was obtained as controls. Immunohistochemistry was performed using antibody of the amino-terminal end of the procollagen type I propeptide (M-57). Newly-synthesized procollagen (M-57) was strongly detected in both the connective tissue septa between circular muscle bundles, and among the circular-muscle fibers in patients with IHPS. No M-57 staining was observed among the circular-muscle fibers in controls. Our findings show that the hypertrophic circular muscle in IHPS is actively synthesizing collagen, and this may be responsible for the characteristic “firm” nature of the pyloric tumor.

Altered insulin-like growth factor I mRNA expression in human hypoplastic lung in congenital diaphragmatic hernia

BACKGROUND/PURPOSE Insulin-like growth factor I (IGF-I) is a peptide growth factor that is synthesized in many organs during human development and plays a role in the growth and differentiation of tissue. IGF-I has been shown to be produced in rat and human fetal lung and to be an important mitogen involved in lung growth and development. The cells responsible for the synthesis of IGF-I in lung in vivo have been demonstrated to be type II pneumocytes, alveolar macrophages, and mesenchymal cells. Recent studies have shown that IGF-I mRNA expression in the lung is predominant during fetal life and decreases before birth, becoming barely detectable in the neonatal lung. The aim of this study was to investigate IGF-I mRNA expression in CDH lung to understand the basis of pulmonary hypoplasia in newborns with CDH. METHODS Lung tissue samples were obtained during autopsy from 13 patients with CDH. Nine were full-term newborns (mean age, 3.8 days), and four were stillborns. Normal lung tissue from eight sudden infant death syndrome infants (mean age, 15.3 days) acted as controls. In situ hybridization was performed on frozen sections using IGF-I-specific and digoxigenin-labeled oligonucleotide probe and visualized by nitro blue tetrazolium staining. RESULTS In control lung, IGF-I mRNA expression was absent or weak in type II pneumocytes and alveolar macrophages. In contrast, there was strong IGF-I mRNA expression in type II pneumocytes and alveolar macrophages in hypoplastic CDH lung in newborns as well as stillborns. CONCLUSION The findings of strong IGF-I mRNA expression in the hypoplastic lung suggest that lung hypoplasia in CDH is a persistence of fetal stage of lung development.

Increased insulin-like growth factor and platelet-derived growth factor system in the pyloric muscle in infantile hypertrophic pyloric stenosis

BACKGROUND Infantile hypertrophic pyloric stenosis (IHPS) is characterized by hypertrophy of the pyloric muscle. The etiology of IHPS is unknown. The growth of smooth muscle cells (SMC) is regulated by several growth factors. Insulin-like growth factor (IGF) and platelet-derived growth factor (PDGF) act synergistically to stimulate SMC proliferation. The effects of IGF-I and PDGF are mediated via their receptors. METHODS Full-thickness muscle biopsy specimens were obtained from eight IHPS patients (age range, 14 to 46 days) at pyloromyotomy and from eight age-matched controls without gastrointestinal disease at autopsy performed within 4 hours after death. Indirect three-step immunohistochemistry was performed using anti-IGF-I, IGF-I receptor alpha (IGF-IR alpha), IGF-IR beta, PDGF-BB and PDGF receptor (PDGF-R) antibodies and visualized by peroxidase staining. RESULTS The most striking difference between tissues from IHPS patients and controls was the marked increase in IGF-I, IGF-IR alpha, IGF-IR beta and PDGF-R in the hypertrophic circular muscle layer, and, to a lesser degree, in the longitudinal muscle in pyloric stenosis. CONCLUSION The findings suggest that the upregulated local IGF and PDGF systems may play a role in the development of pyloric muscle hypertrophy in IHPS.

Antenatal Dexamethasone Suppresses Tumor Necrosis Factor-α Expression in Hypoplastic Lung in Nitrofen-Induced Diaphragmatic Hernia in Rats

The hypoplastic lung in congenital diaphragmatic hernia (CDH) has both a quantitative and qualitative reduction in surfactant. Tumor necrosis factor-α (TNF-α) drastically decreases surfactant phospholipids synthesis by isolated human type II pneumocytes. Recently, it was shown that TNF-α mRNA expression is increased in human hypoplastic CDH lung. Antenatal glucocorticoid therapy demonstrates improved surfactant biochemical immaturity in an animal CDH model. The aim of this study was to investigate the effect of antenatal dexamethasone (Dex) on TNF-α protein and gene expression in nitrofen-induced CDH hypoplastic lung in rats. A CDH model was induced in pregnant rats after the administration of nitrofen on d 9.5 of gestation. Dex was given intraperitoneally on d 18.5 and 19.5. Cesarean section was performed on d 21. In situ hybridization was performed with a rat TNF-α-specific and digoxigenin-labeled oligonucleotide probe. TNF-α level was measured in solubilized lung tissue extracts by ELISA. In control lung, TNF-α mRNA expression was weak or absent. In contrast, strong TNF-α mRNA expression was demonstrated in type II pneumocytes and bronchiolar epithelium in CDH lung. In Dex-treated CDH lung, TNF-α mRNA expression was weak in both type II pneumocytes and the bronchiolar epithelium. The level of TNF-α was elevated significantly in CDH lung compared with levels in control lung extracts (p< 0.01). In Dex-treated CDH lung, TNF-α protein was significantly decreased compared with CDH lung (p< 0.05). Our findings suggest that the reduction in the local production of TNF-α may be one contributing mechanism by which antenatal glucocorticoid therapy improves pulmonary parenchymal immaturity, including surfactant.

Primary Mucinous Cystadenoma Arising from Behind the Posterior Peritoneum of the Descending Colon in a Child: A Case Report

This is the first report of a primary mucinous cystadenoma (MCA) arising from behind the posterior peritoneum of the descending colon in a paediatric patient. A large intra-abdominal cystic lesion was found incidentally during renal ultrasonography in a 14-year-old girl. Imaging studies showed a 13 x 9 x 15 cm homogeneous cystic lesion with mild contrast enhancement of the wall. The cyst appeared to originate from the retroperitoneum, but was separated from the left kidney, ovary, and pancreas. At laparotomy, there was a cyst behind the posterior peritoneum of the descending colon. The cyst was successfully excised, and histopathology showed MCA. Although primary MCA in the retroperitoneum is extremely rare in children, it should be considered in the differential diagnosis of an intra-abdominal cyst, since it needs to be excised to eliminate the risk of infection, recurrence, and malignancy.

Increased Local Synthesis of Epidermal Growth Factors in Infantile Hypertrophic Pyloric Stenosis

Infantile hypertrophic pyloric stenosis (IHPS) is characterized by hypertrophy of the pyloric muscle. The growth of smooth muscle cells is regulated by several growth factors. Epidermal growth factor (EGF) and heparin-binding EGF-like growth factor are potent mitogens for smooth muscle cells. In the present study, we investigated immunohistochemical localization of EGF and EGF-related peptides and EGF mRNA expression in pyloric smooth muscle cells to determine whether the EGF family is involved in the process of pyloric muscle hypertrophy in IHPS. Pyloric muscle biopsy specimens were obtained at the time of pyloromyotomy from 10 patients with IHPS. Control material included 10 pyloric muscle specimens taken at autopsy from age-matched cases without evidence of gastrointestinal disease. Indirect immunohistochemistry was performed using the avidin-biotin-peroxidase complex method with anti-EGF, anti-EGF receptor, and anti–heparin-binding EGF-like growth factor antibody. In situ hybridization was performed using digoxigenin-labeled EGF-specific oligonucleotide probe. The pattern of immunoreactivity in pyloric muscle with EGF, EGF receptor, and heparin-binding EGF-like growth factor was similar in all specimens. There was a marked increase in EGF, EGF receptor, and heparin-binding EGF-like growth factor immunoreactivity and EGF mRNA expression in smooth muscle cells in pyloric circular and longitudinal muscle from patients with IHPS compared with control specimens. These data suggest that the up-regulated local synthesis of EGF and EGF-related peptides in pyloric muscle may play a critical role in the development of pyloric muscle hypertrophy in IHPS.