Kazuaki Tokiwa

OK-432 therapy for lymphangioma in children: why and how does it work?

Intralesional injection of OK-432 (lyophilized incubation mixture of group A Streptococcus pyogenes of human origin) is safe and effective therapy for lymphangioma. The authors evaluated the mechanism of this therapy in 6 patients who had cystic lymphangioma. The intracystic fluid of the cystic lymphangioma was aspirated before and after (on days 1 and 4) the OK-432 therapy. Changes in cell populations and cytokine productions in each aspirated fluid were analyzed. White blood cells in the intracystic fluid increased markedly in number. Before OK-432 therapy, 96% of the intracystic white blood cells were lymphocytes, and the remaining were neutrophils and macrophages. On day 1, the percentages of neutrophils and macrophages increased to 72% and 21%, respectively. On day 4, the percentage of lymphocytes increased to 72%. Flow cytometry analysis using monoclonal antibodies showed that the number of natural killer cells (CD56+) and T cells (CD3+) had increased. The activity of cytotoxic tumor necrosis factor (TNF) and interleukin-6 increased immediately after OK-432 injection and remained high in titer until day 4. These findings suggest that the white blood cells induced and activated by OK-432, and the cytokines (including TNF) produced by these cells increased the endothelial permeability, and thus the accelerated lymph drainage and increased lymph flow let to shrinkage of the cystic spaces.

OK-432 therapy for unresectable lymphangiomas in children

To avoid surgery-related complications, intralesional OK-432 therapy was used in 23 patients with unresectable lymphangiomas (1986 through 1989). Total or near total shrinkage of the lesions, without serious complication, was noted in 10, marked shrinkage in 8, slight shrinkage in 3, and no response was noted in the remaining 2. Recurrence of the lesions has not been observed during follow-up (4 to 35 months). The side effects of OK-432 therapy were a fever for 2 to 3 days and a local inflammatory reaction lasting 3 to 5 days. The local inflammation did not cause any damage to the overlying skin and did not lead to scar formation. The results suggest that intralesional OK-432 therapy is effective for most unresectable lymphangiomas.

Congenital choledochal dilatation with emphasis on pathophysiology of the biliary tract

Of 37 patients with congenital choledochal dilatation, aged 8 days to 12 years, who had undergone excision with Roux-en-Y hepaticojejunostomy, 26 patients could be analyzed for morphologic abnormalities and pathophysiology of the biliary tract. Of the 26 patients with congenital choledochal dilatation, 25 (96.2%) had an abnormal choledochopancreaticoductal junction. Of the 12 patients with cystic-type choledochal dilatation, 10 had the C-P type of abnormal choledochopancreaticoductal junction, and of the 13 patients with fusiform-type choledochal dilatation, nine had the P-C type. The amylase levels in the choledochal cyst and the gallbladder were elevated regardless of the form of choledochal dilatation. An adenocarcinoma in a cystic choledochal dilatation was found in one child. Therefore, longstanding inflammation of the biliary tract caused by the reflux of pancreatic juice might be one of the factors in carcinogenesis in the biliary tract. This free reflux of pancreatic juice was demonstrated not only by amylase levels in the biliary tract but also by intraoperative biliary manometry. This reflux might be explained by the lack of sphincter function at the junction of the common bile and pancreatic ducts.

Successful treatment of congenital systemic juvenile xanthogranuloma with Langerhans cell histiocytosis-based chemotherapy.

Abstract: Juvenile xanthogranuloma (JXG), one of the most common forms of non-Langerhans cell histiocytosis (LCH), usually presents in young children as spontaneously regressing cutaneous lesions. However, the systemic type of JXG is difficult to treat in newborn infants, and fatal cases have been reported. In the patient described here, solid masses were discovered by fetal sonography during the 38th gestational week. At birth she had multiple tumors on the back, cheek, and hip as well as marked hepatosplenomegaly accompanied by respiratory failure. Laboratory results indicated pancytopenia, obstructive liver dysfunction, and coagulopathy. Brain magnetic resonance imaging revealed a tumor at the left pontine angle, and dysmorphic histiocytes were present in her spinal fluid. She was diagnosed with systemic JXG by histopathologic findings of the hip mass. The LCH-based multiagent chemotherapy including cytarabine, vincristine, methotrexate, and prednisolone ameliorated the symptoms rapidly. She was treated for 12 months and is currently doing well as a normally developing 2-year-old.

Intraarterial chemotherapy with lipid contrast medium for hepatic malignancies in infants

Antitumor drugs dispersed in a lipid lymphographic medium (Lipiodol, Laboratorie Guerbert, Rue Jean‐Chaptal, France) were intraarterially administered in two infants with unresectable hepatoblastoma. The Lipiodol and antitumor drug complex was found to selectively accumulate in the tumor and was associated with a marked reduction in the tumor size and a 50% decrease in the alpha‐fetoprotein (AFP) level after 4 days in one patient and 16 days in the other. The tumor was successfully resected by right trisegmentectomy in one patient, but surgery was not performed on the other because of evidence of pulmonary metastasis. The patients had moderate fever for 2 to 3 days after the intraarterial chemotherapy. It is believed that intraarterial chemotherapy with Lipiodol may be a useful preoperative chemotherapy for initially unresectable hepatoblastoma.

Biliary manometry in choledochal cyst with abnormal choledochopancreatico ductal junction

Intraoperative manometry of the biliary tract and measurement of amylase levels in choledochal cysts were performed in seven patients, aged 14 months to 5 years, with choledochal cysts, in an investigation of the pathophysiology of the biliary tract. An abnormal choledochopancreatico ductal junction was observed in these seven patients by preoperative endoscopic retrograde cholangiopancreaticography (ERCP) or intraoperative cholangiograms. All six patients examined showed a high amylase level in the choledochal cyst (5,450 to 46,500 Somogyi Units). The intraoperative manometry of the biliary tract showed that a remarkable high pressure zone as was found in the area of sphincter of Oddi was not found in the area of abnormal choledochopancreatico ductal junction. The pressure recordings also demonstrated that the sphincter of Oddi pressure in the patient with choledochal cyst was increased by gastrin stimulation. On the contrary, no pressure reaction to gastrin or secretin was found in the area of abnormal choledochopancreatic ductal junction. From these results it seems that free reflux of pancreatic juice into the biliary system occurs, and the reflux stream depends upon the pressure gradient between pancreatic ductal pressure and common bile duct pressure because of the lack of a sphincter function at the choledochopancreatico ductal junction.

Results of surgical correction of anorectal malformations. A 10-30 year follow-up.

Of 119 patients with surgical correction of anorectal malformations, 47 who were 10-30 years of age were interviewed personally and had manometric studies to evaluate postoperative continence. This clinical study included not only long-term anorectal function but also sexual function. Patients with low type anomalies or with intermediate type anomalies were more likely to be continent, whereas patients with high type lesions had some problems with continence. However, only two of the 16 patients (12%) with high type anomalies were classified as having poor results. This rate is perhaps lower than might be expected. Thus, incontinent patients may become continent even if they were classified as having fecal incontinence before 6 years of age. Most patients who were 15-30 years of age had normal sexual function except for two females with irregular menstruation. These results indicate that achievement of fecal continence and sexual function in patients with high type anomalies treated by abdominoperineal rectoplasty depends on careful dissection as close as possible to the rectal wall and bringing the terminal bowel down exactly within the sling of the puborectal muscle.

Cellular activity in the gallbladder of children with anomalous arrangement of the pancreaticobiliary duct

BACKGROUND/PURPOSE Anomalous arrangement of the pancreaticobiliary duct (AAPBD) is closely related to congenital biliary dilatation and frequently associated with biliary tract malignancy. To examine the mechanism of biliary tract carcinogenesis in patients with AAPBD, we investigated histologically the early changes in cell proliferative kinetics of the gallbladder mucosa of children with AAPBD. METHODS Twenty-three specimens of gallbladder were obtained from 23 children with AAPBD, and six control specimens were obtained from pediatric patients. All specimens were fixed routinely and paraffin embedded and examined histologically with H&E staining and immunohistochemically with monoclonal antibody Ki-67(MIB-1), which reacts with a human nuclear antigen associated with cell proliferation. Ki-67 labeling index (Ki-67 LI) was obtained by counting the numbers of Ki-67-positive cells per 1,000 gallbladder epithelial cells. RESULTS Significant differences in Ki-67 LI were noted between children with and without AAPBD. Furthermore, Ki-67 LI and the incidence of epithelial hyperplasia of gallbladder were significantly higher in children with AAPBD in whom the major pancreatic duct joined the common bile duct (P-C type) than in those in whom the common bile duct joined the major pancreatic duct (C-P type). CONCLUSIONS Cellular proliferative activity was increased in children with AAPBD, especially those with the P-C-type anomaly. These results suggest that the early mucosal changes of the gallbladder occurred in early childhood of patients with AAPBD and might be associated with gallbladder cancer. Early diagnosis and early surgical division of the biliary tract and pancreatic duct is recommended for children with AAPBD.

Mutational analysis of the RET proto-oncogene in a kindred with multiple endocrine neoplasia type 2A and Hirschsprung's disease

BACKGROUND/PURPOSE Germline mutations of the RET proto-oncogene (RET; 10q11.2) have been reported in multiple endocrine neoplasia type 2A (MEN 2A) and Hirschsprungs disease. The authors investigated a Japanese kindred in which MEN 2A and Hirschsprungs disease frequently have been found. METHODS The pedigree consisted of 28 members (11 boys and 17 girls) spanning 4 generations, of whom, 8 were affected with MEN 2A or Hirschsprungs disease. RESULTS Direct sequence DNA analysis of the RET proto-oncogene showed a heterozygosity for a G to C transition at the second nucleotide of codon 620 (exon 10) in the patients, resulting in the replacement of cysteine by a serine residue in the affected Ret protein. This family added a novel RET missense mutation (C620S) predisposing to the association of MEN 2A and Hirschsprungs disease. CONCLUSION Detection of the mutated RET gene carriers may be used for genetic counseling of potential risk for Hirschsprungs disease as well as MEN 2A in the affected families.

Myoepithelial hamartoma of the ileum causing intussusception in an infant

Intussusception is a relatively common pediatric gastrointestinal emergency, although the etiology in most cases remains unknown. In a small number of cases the lead point is a tumor or tumor-like lesion of the small bowel. We report an unusual case of a myoepithelial hamartoma of the ileum causing an intussusception in a 4-month-old boy. This is the second such report in the literature.