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Many patients with biliary atresia (BA) have impaired metabolism of copper (Cu) and zinc (Zn) because of the obstruction of bile ducts. An excessive Cu accumulation is cytotoxic and results in fibrosis in hepatic tissues. Since Zn works antagonistically to Cu, lower Zn concentrations may deteriorate liver damage. In the 1980's, we performed a series of surgeries on BA patients for the construction and alteration of the bile flow route, which is the major excretion route for Cu. We obtained liver and serum samples at each surgery, and measured Cu and Zn concentrations by inductively coupled plasma atomic emission spectrometry. Hepatic Cu concentration decreased with the improvement of cholestasis after the establishment of bile excretion. Conversely, when cholestasis persisted or recurred, increases in hepatic and serum Cu concentrations were noted. Hepatic Zn concentration was lower than previously reported normal values. High hepatic and serum Cu concentrations due to persistent or recurrent cholestasis and low hepatic Zn concentration may deteriorate hepatic fibrosis and liver cirrhosis.

In the hospitals of the Tohoku Neuroblastoma Study Group (TNBSG), treatment for children with advanced neuroblastoma (NB) was intensified in the mid-1990's with the introduction of myeloablative therapy (MT) with stem cell transplantation (SCT) including the use of autologous peripheral blood stem cells (PBSC) and bone marrow transplantation (BMT). In this report, we examined whether the intensified therapy improved the outcome of children with advanced NB (age> 12 months) who were diagnosed between 1991 and 1997. Patients were 36 children (23 boys and 13 girls) with an average age of 3.4 years (range; 1 to 14 years). Six of them had stage III disease, and the other 30 had stage IV. They were treated initially with induction chemotherapy, surgery, and post-operative chemoradiotherapy, after which 17 of them continued further chemotherapy and the other 19 received MT/SCT (18 with PBSCT and 1 with BMT). Progression-free survival (PFS) rate at seven years from diagnosis was 43.5% for all patients, 66.7% for stage III patients and 38.2% for stage IV patients. The difference between stage III and IV patients was not significant. Among the 30 patients with stage IV disease, PFS at seven years was significantly higher in the 19 patients who received MT/SCT (55.6%) than in the 11 patients who did not receive it (12.5%). There was no difference in clinical and biological risk factors between these two groups, except for the proportion of patients with favorable response to initial therapy (36% and 80% for patients without and with MT/SCT, respectively). Furthermore, the proportion of patients with N-myc amplification was significantly higher in patients with progressive disease (PD) after MT/SCT than in those in CR after MT/SCT. The results of this retrospective study of children with advanced NB suggest that therapy intensification involving MT/SCT might result in lengthened survival time for patients with stage IV disease, and that post-transplant PD remains a risk for patients with high levels of N-myc amplification.

Gastric peristaltic contractions are controlled by an intrinsic electrical pacemaker located in the mid-body along the greater curve. This study was undertaken to investigate gastric motility in long-term survivors of neonatal gastric rupture who were surgically deprived of their original pacemaker. Four patients, 1 boy and 3 girls, aged between 6 and 12 years were studied. Physiological activity of the gastric remnant was assessed in terms of electrical as well as peristaltic functions by means of electrogastrography and video-recorded barium swallow study. Electrical and mechanical pacing activities were classified into normogastria or dysrhythmia (brady- or tachygastria) according to their frequencies. In these patients, ectopic pacemakers were found to be arising just distal to the site of resection along the greater curve. Electrophysiologically, one patient was diagnosed as having normogastria, and other 3 patients were found to have dysrhythmia (2, bradygastria; 1, tachygastria) on the basis of electrogastrographic analyses. In two of three patients studied further by fluoroscopy, electrical activity agreed well with peristaltic activity. In one patient, however, electrical tachygastria was associated with peristaltic bradygastria. In conclusion, an ectopic pacemaker arises in the stomach that does not remain silent after neonatal surgical loss of its own pacemaker. Noninvasive electrogastrography seems useful in assessing electrical potentials generated by the ectopic pacemaker.

Hepatic and serum bile acids in five patients with biliary atresia were preoperatively determined by microanalysis using gas chromatography-mass spectrometry with negative ion chemical ionization detection. The hepatic content of total bile acids was markedly elevated (3079+/-711 nmol/g protein), most of which were primary bile acids. Accumulation of unconjugated bile acids (2.93% to 4.62% of the total) was observed in the liver tissue of these patients, although only trace amounts were detected in their sera. The ratio of glycine-conjugated to taurine-conjugated bile acids was 0.44+/-0.18 in liver tissue and 0.79+/-0.52 in serum and these values were significantly lower than those of controls. This study has shown that the composition of bile acids in serum does not reflect that in liver tissue faithfully. The accumulation of these hydrophobic bile acids may contribute to initiating or exacerbating liver injury in infants with cholestatic liver diseases.

The "touchdown" polymerase chain reaction (PCR) technique has been applied to analyze expression of the neuron-specific protein, PGP9.5, and tyrosine hydroxylase (TH) genes for detection of minimal residual neuroblastoma cells in bone marrow and peripheral blood. PGP9.5 and TH gene products were not detected in any normal samples (n = 72) examined. However, in patients more than 1 year of age with stage III and IV neuroblastoma PGP9.5 mRNA was detected in six of seven bone marrow samples and in four of eight peripheral blood samples, and TH mRNA in four of seven and three of eight, respectively. The detection sensitivity was up to 10(-6) to 10(-7) micrograms of total cellular RNA for PGP9.5 and 10(-4) micrograms for TH. Among forty bone marrow specimens from nineteen patients with neuroblastoma both PGP9.5 and TH mRNAs were detected in six, and only PGP9.5 mRNA was detected in ten. Since detection of PGP9.5 and TH gene transcripts by the "touchdown" PCR was highly specific and sensitive, it might be most informative at present to carry out both PGP9.5 and TH mRNA assays for minimal residual neuroblastoma cells in blood and bone marrow.

We report a nine-month-old boy with stage III B hepatoblastoma of caudate lobe origin. Surgical resection was attempted following six courses of chemotherapy, but viable tumor cells remained microscopically at resection margins. Subsequently, he received peripheral blood stem cell transplantation (PBSCT), whose preparative regimen being consisted of carboplatin, etoposide, tetrahydropyranyl adriamycin, and melphalan. Since then, the patient shows no relevance of local relapse or distant metastasis without any chemotherapy. PBSCT for patients with post-operative residue may improve the outcome of advanced hepatoblastoma and worth of a further clinical investigation.

We investigated changes in the pattern of hepatic innervation in liver specimens from 15 infants with biliary atresia and 4 age-matched controls by immunohistochemical methods. In the control, nerve fibers identified by immunoreactivity for neural cell adhesion molecule (NCAM) and S100 protein were present around the branches of hepatic arteries, portal veins and bile ducts in the portal areas and the hepatic lobules. In biliary atresia, NCAM and S100 positive nerve fibers were increased in the vicinity of the hepatic arteries and the portal veins in the enlarged portal areas, while no nerve fibers were observed around bile ducts and periportal ductules which became NCAM positive. No innervation in the lobules was seen in any cases regardless of the histological alteration. These findings may suggest that the abnormal innervation in the liver with biliary atresia does not occur as a result of structural changes in liver architecture caused by portal fibrosis and inflammation, but is associated with immaturity or malformation of hepatic innervation in the patients.

Some patients of biliary atresia (BA) suffer from chronic hepatic dysfunction and/or persistent jaundice. The adverse effects of chronic liver disease on nutrition and growth should be considered on BA patients. We studied 45 BA patients ranging in age from 0.5 to 38 years and divided them into 2 groups. Group A contains the patients whose total bilirubin > or = 2 mg/100 ml, and Group B contains the patients whose total bilirubin < 2 mg/100 ml. We measured height, weight, triceps skin fold (TSF), midarm circumference (MAC) and midarm muscle area (MAMA). Visceral protein kinetics was evaluated on the basis of serum albumin and prealbumin levels. Caloric and protein intake was calculated by collecting intake data for 3 days. The results of this study were; 1) The mean TSF in Group A (47th percentile) was not significantly different from that in Group B (53th percentile). 2) The mean MAMA was significantly lower (p < 0.01) in Group A (16.4th percentile) than in Group B (36.7th percentile) 3) The prealbumin level was significantly lower (p < 0.001) in Group A (mean 9.9 mg/100 ml) than in Group B (mean 18.8 mg/100 ml). The authors conclude that the evaluation of MAMA and prealbumin were very useful to characterize the low metabolic status of protein in the damaged liver. And repeated nutritional assessment was necessary to evaluate liver function and provide adequate nutrition in BA patients.

The scintigram using 99mTechnetium-DTPA galactosyl human serum albumin (99mTc-GSA) which binds to asialoglycoprotein receptors on hepatocytes is a good index of hepatocyte function in various liver diseases in adult patients. In 43 patients (4 months to 30 years old) who had undergone Kasai procedure, we performed 53 series of 99mTc-GSA scintigrams and checked the laboratory data of blood draw and the clinical status. The indices for blood clearance and liver accumulation were evaluated on the basis of the dynamic data after 99mTc-GSA injection. HH15 as an index of the blood clearance, and LHL15 as an index of the accumulation of the hepatocytes were calculated and the HH15/LHL15 ratio (H/L15) was examined. 99mTc-GSA scintigram correlated with liver function and clinical status. Our results revealed that 1) The deterioration of the liver functions and clinical status correlates proportionally with H/L15, 2) The results of 99m Technetium-GSA scintigram correlate with several liver function tests, especially direct bilirubin, albumin and choline esterase, 3) This scintigram is an useful index of clinical status and hepatic function as well as the change of the hepatic parenchymal reserve in BA patients, especially for the evaluation of liver transplantation.

Between 1953 and 1995, 300 patients with biliary atresia underwent surgery at Tohoku University Hospital. The 10-year survival of patients who were operated on in or before 1965 was 9%. But the survival rate went up to 61% in patients operated on between 1976 and 1985. Eighty-five patients including 2 who developed liver failure after Kasai operation and underwent liver transplantation have survived more than 10 years. Eleven of them (13%) have recurrent or persistent jaundice. Of the 30 patients who have survived more than 20 years (10 males and 20 females, age range; 20 to 41 years), 20 underwent hepatic portoenterostomy, 8 underwent hepaticoenterostomy and the remaining 2 underwent hepatic portocholecystostomy. None of these patients has undergone liver transplantation. Twenty-two patients have led near-normal lives. The remaining 8 patients have experienced some troubles due to cholangitis, portal hypertension, intrahepatic gallstones and so on. Two of them are considered as candidates for liver transplantation. While the majority of long-term survivors of biliary atresia have good quality of life, close long-term follow-up is essential even in patients with biliary atresia aged 20 years or more.

Eleven children, 4 males and 7 females, with biliary atresia receiving living related liver graft were studied. The mean age was 1.8 years and the mean body weight was 10.3 kg. The donors were 4 fathers and 7 mothers. The graft was the lateral segment or left lobe. ABO blood group matching was compatible in 9 and incompatible in 2. All patients except one were crossmatch negative. Immunosuppression at induction was triple therapy (cyclosporine, azathioprine and steroid) or FK506 plus steroid. Acute rejection episodes were treated with pulse steroids. When the signs of rejection persisted despite steroid pulse therapy, 15-deoxyspergualin (DSG) was added. The survival rate of the patients was 73%. Three patients died of portal vein thrombosis, hepatic artery thrombosis and sepsis respectively. Other major complications included hyperbilirubinemia, bile duct stenosis, bile leakage and portal vein anastomosis narrowing. Complications of the donor were sepsis in one, and liver dysfunction in two. Although there are some complications related to graft size mismatch and operative procedure, living related partial liver transplantation is an effective therapy in countries where donor source is restricted.

The Japanese Biliary Atresia Society founded in 1980 for the aim of investigations of all aspects of biliary atresia (BA), started a nationwide registry of BA patients in 1989. A total of 626 cases were registered from 1989 to 1994. The male to female ratio was 0.58. Corrective surgery was performed in 603 patients. Regarding the type of obstruction, 63 cases were Type I, atresia of the common bile duct, 9 were Type II, atresia of the hepatic ducts, and 543 were Type III, atresia of the porta hepatis. As initial corrective procedures, original Roux-en Y, Suruga II and Roux-en Y with intestinal valve were mainly employed. Jaundice cleared in 346 patients (57%) and decreased in 131, while it persisted in 120. The 5-year-follow-up showed that 34 patients, 49% of the patients who were followed up, were alive without jaundice, while 28 (41%) are dead. Thirty five, 33% of the patients who were entered to the Registry, were lost to follow-up.

This study discusses four children of hepatocellular carcinoma (HCC) who were asymptomatic HBsAg carriers or had HBsAg-positive chronic hepatitis for 3 to 11 years before the occurrence of the carcinoma. Three of these four patients were positive for anti-HBe at 3 to 5 years before the diagnosis of hepatocellular carcinoma. Autopsy findings disclosed liver cirrhosis in all the four patients. To the best of our knowledge few reports have documented children in HBsAg carrier status or with HBsAg-positive hepatitis prior to the development of hepatocellular carcinoma. It is emphasized that HBsAg-positive children, with or without detectable hepatic lesions in routine examinations, have a possibility of developing HCC, and should be carefully monitored for long periods.

During the past 9 years, we have treated 23 patients with gastrointestinal hemorrhage following corrective surgery for biliary atresia. Ulcers or erosions of the stomach, duodenum or intestinal wall were observed endoscopically in 20 cases. In other 3 cases, bleeding point was not determined endoscopically, but massive bleeding was recognized frequently. Ten patients bled within 6 months of surgery, and the incidence of bleeding was also seen even after the age of 10 years. A history of cholangitis, the presence of jaundice and the use of cholagogues were related to the postoperative gastrointestinal bleeding. Serum concentrations of gastrin and gastric inhibitory polypeptide showed high values after surgery in almost half the biliary atresia patients examined, however, no clear relationship between the concentration of these factors and gastrointestinal hemorrhage was established.

In biliary atresia, one-fourth of the patients showed prolonged jaundice in spite of a good excretion of bile after surgery. To investigate the cause of jaundice, factors related to the serum bilirubin level were examined in 28 recent cases. Furthermore, clinical analysis was performed in 86 cases of good excretion of bile after surgery. The following results were obtained: The daily amount of bilirubin excretion in bile and bilirubin concentration play an important role in decreasing the serum bilirubin level. The most important factor for prolonged jaundice is ascending cholangitis. Shortening of the life span of the red blood cells is one of the causes of prolonged jaundice.

Eighteen patients with biliary atresia who showed persistent jaundice after hepatic porto-jejunostomy were studied clinically. It was revealed that: 1) Patients who had abnormally high preoperative values of laboratory data showed persistent jaundice; 2) high portal pressure occurred frequently in patients with persistent jaundice; 3) most patients of persistent jaundice had a history of postoperative cholangitis; 4) in contrast to jaundice-free patients, those with persistent jaundice tended to show elevation in gamma-globulin, TTT and gamma-GTP in the early postoperative period. These results suggest that for patients showing an upward tendency in these laboratory data after surgery, carefully management should be taken, even if the serum bilirubin level continue to decrease.