Outcome of hepatoblastoma treated with the JPLT-1 (Japanese Study Group for Pediatric Liver Tumor) Protocol-1: A report from the Japanese Study Group for Pediatric Liver Tumor.

PURPOSE: Hepatoblastoma is the most common malignant liver tumor in childhood. Multicenter studies elucidate the optimal pre- or postoperative chemotherapeutic regimens. This report reviews the results of the Japanese Study Group for Pediatric Liver Tumor Protocol-1 (JPLT-1) and compares its outcomes with published reports of other studies. METHODS: From March 1991 to December 1999, 154 patients with malignant liver tumor including 145 cases of hepatoblastomas were enrolled in the JPLT study. Data from 134 cases were analyzed in this study. JPLT-1 protocol 91A was used for patients with stage I or II hepatoblastoma. The chemotherapy regimen consisted of repeated courses of cisplatin (CDDP), 40 mg/m(2), and tetrahydropyranyl (THP)-Adriamycin, 30 mg/m(2). JPLT-1 protocol 91B was administered to patients with stage IIIA, IIIB, or IV hepatoblastoma. The chemotherapy regimen consisted of repeated courses of CDDP, 80 mg/m(2), and THP-Adriamycin, 30 mg/m(2)/day for 2 days. Courses were repeated every 4 weeks as tolerated. RESULTS: Seven patients died of chemotherapy-related side effects. Six of them died of sepsis caused by leukopenia and 1 case of liver failure. Overall survival rate (3-year/6-year) was 100%/100% for stage I (n = 9), 100%/95.7% for stage II (n = 32), 76.6%/73.8% for stage IIIA (n = 48), 50.3%/50.3% for stage IIIB (n = 25), 64.8%/38.9% for stage IV (n = 20), and 77.8%/73.4% overall. For stage IIIA and B disease, intravenous chemotherapy was better than intraarterial chemotherapy (66.4% v 38.1% for event-free survival and 69.3% v. 57.1% for overall survival). Patients less than 1 year of age had a better prognosis than older patients, but age was not a significant prognostic factor by multivariate analysis. CONCLUSIONS: The overall and event-free survival rates of the JPLT-1 study of hepatoblastoma were comparable with the results of other multicenter studies in Europe and the United States. The event-free survival rate at 3 years for stage IIIB and IV disease was under 50%. New treatment strategies are needed for patients with advanced hepatoblastoma.

Supercharged gastric tube pull-up procedure for total esophageal reconstruction.

Total esophageal reconstruction using a gastric tube is complicated because it sometimes causes postoperative complications such as anastomotic leakage, stenosis, or fistula formation resulting from insufficient blood flow at the distal end. To overcome this problem, during the past 5 years the authors performed seven additional microvascular anastomoses using the short gastric vessels of the gastric tube. No postoperative complications occurred except partial tracheal necrosis in 1 patient. Postoperative radiographic examination showed no reflux or stasis in all patients, and no evidence of necrosis at the anastomotic site of the pulled-up gastric tube was observed by postoperative endoscopy. This technique reduces risk and may contribute to the successful reconstruction of the digestive tract after total esophagectomy.

Expression of the intermediate filament nestin in gastrointestinal stromal tumors and interstitial cells of Cajal.

It has recently been proposed that gastrointestinal stromal tumors (GISTs) originate from stem cells that differentiate toward a phenotype of interstitial cells of Cajal (ICCs). Nestin is a newly identified intermediate filament protein, and is predominantly expressed in immature cells, such as neuroectodermal stem cells and skeletal muscle progenitor cells, and tumors originating from these cells. In this study, we examined, using immunohistochemistry, the nestin expression in GISTs and ICCs to clarify the origin of GISTs. Strong immunoreactivity for nestin was observed in all 18 GISTs, and its expression was confirmed by Western blot and Northern blot analyses. In contrast, three leiomyomas and a schwannoma that developed in the gastrointestinal tract showed no apparent immunoreactivity for nestin. Among 17 mesenchymal tumors (seven leiomyosarcomas, five malignant peripheral nerve sheath tumors, and five fibrosarcomas) that occurred in sites other than the gastrointestinal tract, only two malignant peripheral nerve sheath tumors were moderately immunoreactive for nestin. Furthermore, with fluorescence double immunostaining of the normal small intestine, nestin expression was demonstrated in ICCs. These results show that nestin may be a useful marker for diagnosis of GISTs, and support the current hypothesis that GISTs are tumors of stem cells that differentiate toward an ICC phenotype.

Inhibition by an angiogenesis inhibitor, TNP-470, of the growth of a human hepatoblastoma heterotransplanted into nude mice.

BACKGROUND/PURPOSE: The effect of TNP-470, an angiogenesis inhibitor, on the growth of a hepatoblastoma transplanted into nude mice was examined. METHODS: A hepatoblastoma obtained from a 3-year-old girl was serially transplanted into nude mice subcutaneously, and the transplant tumors of the seventh and eighth generations were used for experiments. Expression of various markers in the tumors was examined immunohistochemically. TNP-470 was injected subcutaneously every other day into tumor-bearing mice from 3 weeks after tumor transplantation. The proliferation of tumor cells and endothelial cells was estimated by means of the bromodeoxyuridine labeling index. RESULTS: The original hepatoblastoma showed the histology of the epithelial type, consisting of both the fetal and embryonal subtypes and was positively stained with anti-alpha-fetoprotein (AFP), anti-cytokeratin-19 and polyclonal anticarcinoembryonic antigen antibodies, and an antihuman hepatocyte antibody (hepatocyte paraffin 1). The transplant tumors consisted of solid nests of tumor cells with numerous vascular lakes of various sizes, and showed positive staining with all antibodies that reacted positively with the original hepatoblastoma. Injections of TNP-470 at the doses of 15 mg and 30 mg/kg body weight suppressed the tumor growth and the increase in the serum level of AFP dose dependently. Injections of TNP-470 also suppressed the proliferation of tumor cells and endothelial cells in the tumors. CONCLUSIONS: Hepatoblastomas maintained in nude mice retained the immunohistochemical characteristics of the original hepatoblastoma, and TNP-470 suppressed the growth of hepatoblastomas transplanted into nude mice. TNP-470 may be worth investigating further as to its usefulness as a therapy for hepatoblastomas.

The role of oval cells in rat hepatocyte transplantation.

BACKGROUND: Oval cells are liver cells capable of differentiating into either hepatocytes or biliary epithelial cells. We compared growth of hepatocytes and biliary epithelial cells between spleens transplanted with oval cell-free and oval cell-enriched rat liver cells. METHODS: Oval cell-enriched liver cells were obtained from livers of adult rats that had undergone treatment with acetylaminofluorene and partial hepatectomy, although oval cell-free liver cells were obtained from livers of untreated rats. Hepatocyte and biliary epithelial cell growth in the spleen was evaluated by counting periodic acid-Schiff-positive cells and cytokeratin 19-positive cells respectively in sections from transplanted spleens. RESULTS: Spleens transplanted with oval cell-free liver cells and spleens transplanted with oval cell-enriched liver cells contained similar numbers of hepatocytes after 2 weeks. Numbers of hepatocytes in spleens transplanted with oval cell-free liver cells decreased markedly at 4 and 8 weeks, then increasing slightly until 32 weeks. In spleens transplanted with oval cell-enriched liver cells, numbers of hepatocytes decreased only slightly at 4 weeks and then increased markedly. At 4, 8, 12, 16, 24, and 32 weeks, numbers of hepatocytes in spleens transplanted with oval cell-enriched liver cells respectively were 2.3, 3.5, 4.5, 6.7, 6.3, and 15.1 times hepatocyte numbers in spleens transplanted with oval cell-free liver cells. Numbers of biliary epithelial cells in spleens receiving oval cell-enriched liver cells showed changes similar to those in spleens transplanted with oval cell-free liver cells, increasing markedly at 4 weeks and then markedly and rapidly decreasing. CONCLUSIONS: Intrasplenic transplantation of oval cell-enriched liver cells enhanced growth of hepatocytes compared with transplantation of oval cell-free liver cells; this was not true for biliary epithelial cells.

The evaluation of meconium disease by distribution of cathepsin D in intestinal ganglion cells.

Meconium disease (MD) results in intestinal obstruction in the neonate where tenacious meconium is found in the distal ileum and proximal colon. The obstructive symptoms improve at several days of age after some of the meconium is passed. We observed premature infants with MD who underwent ileostomy for intestinal obstruction due to tenacious meconium. Afterward, meconium was passed well and the clinical symptoms improved. After closing the ileostomy, growth and defecation became normal. The MD in our cases was documented by histologic changes in the maturation of ganglion cells observed at the time of ileostomy creation and closure. For an objective evaluation of the maturation of intestinal ganglion cells (IGC), we attempted to distinguish immature from mature cells by the expression of cathepsin D. We examined the distribution of cathepsin D in IGC in patients with MD to test the hypothesis that ganglion-cell immaturity might be related to MD. In ganglion cells at the time of ileostomy, cathepsin D was detected in the perinuclear cytoplasm (immature staining pattern), while at the time of ileostomy closure it was detected in intense granules throughout the cytoplasm (mature staining pattern). We propose that it would be possible to evaluate the maturation of IGC by the intracellular distribution of cathepsin D in MD and suggest that immaturity of IGC might be the cause of MD.

Role of c-kit receptor tyrosine kinase in development of oval cells in the rat 2-acetylaminofluorene/partial hepatectomy model.

Oval cells that develop in the rat 2-acetylaminofluorene/partial hepatectomy (AAF/PH) model express the c-kit receptor tyrosine kinase (KIT) and its ligand, stem cell factor (SCF). We investigated the role of the SCF/KIT system in the development of oval cells using Ws/Ws rats, whose c-kit kinase activity was severely impaired owing to a small deletion in the kinase domain. On days 7, 9, and 13 after PH in the AAF/PH model, the development of oval cells was remarkably suppressed in Ws/Ws rats when compared with that of the control normal (+/+) rats. However, oval cells that developed in Ws/Ws rats expressed marker proteins of oval cells, such as alpha-fetoprotein (AFP), cytokeratin-19 (CK-19), and flt-3 receptor tyrosine kinase, similar to those of +/+ rats. Furthermore, labeling with [3H]-thymidine and immunostaining of Ki-67 showed that the proliferative activity of oval cells that developed in Ws/Ws rats was comparable with that of +/+ rats. The present results indicate that the signal transduction of the SCF/KIT system plays a crucial role in the development of oval cells, at least, in the rat AAF/PH model, and suggest that KIT-mediated signal transduction plays only a small role in determining the phenotype and in the proliferative activity of oval cells.

Synovial sarcoma of the esophagus: report of a case.

Synovial sarcomas are exceedingly rare neoplasms of the digestive tract. We herein report a case of a synovial sarcoma occurring in the esophagus of a 20-year-old man. He had a history of acute lymphocytic leukemia and had undergone aggressive chemotherapy between the ages of 4 and 8 years. The tumor, which was large and extended into the upper mediastinum, was successfully resected without an esophagectomy via the cervical approach. After postoperative radiation and chemotherapy, the patient remained healthy, without any evidence of disease 20 months after the operation.

[TNM classification--pediatric tumors].

The clinical and postsurgical TNM classifications (cTNM and pTNM) for neuroblastoma (NB), nephroblastoma (WT) and soft tissue sarcomas were presented in 1982 by the TNM Committee in UICC in collaboration with SIOP. The Japanese TNM Committee proposed new pTNM systems (J-pTNM) for NB and WT, and new cTNM and pTNM system for primary liver carcinoma in infants and children (HT). These pTNMs were based on the staging systems developed by the Malignant Tumor Committee of the Japanese Society of Pediatric Surgeons. The proposal of subdivision of M category in NB was presented for testing the new telescopic ramifications of TNM. The TNM for HT was added as a new classification recommended for testing. The effectiveness of these TNM systems was assessed using NB, WT and hepatoblastoma (HB) cases which were registered in collaborating institutes. The analyses suggested that pTNM, especially the J-pTNM system in NB, WT and HT were effective for the assessment of prognoses, although cTNM systems were not enough to assess the extent of the disease.

Intrahepatic metastases in hepatocellular carcinoma: the role of the portal vein as an efferent vessel.

The mechanism and pathogenesis of the high frequency of intrahepatic metastasis in hepatocellular carcinoma (HCC) has not yet been elucidated. Two hundred and thirty one tumors (< or = 5 cm in diameter) of resected specimens of HCC were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens selected at random from the 231 tumors. The most frequent site for tumor spread in HCC was capsular invasion followed by extracapsular invasion, vascular invasion, and finally intrahepatic metastasis. There was a strong statistical correlation between the presence of intrahepatic metastasis and the frequency of vascular invasion (correlation coefficient = 0.998). Radiopaque material injected directly into 23 resected tumors entered only the portal vein in 17 tumors and into both the portal and hepatic veins in six tumors. In all eight patients with unresectable lesions, radiopaque media injected percutaneously into tumor nodules flowed only into the portal vein. These findings suggest that tumor spread in HCC progresses from capsular invasion to intrahepatic invasion and that the portal vein may act as an efferent tumor vessel.

Rhabdoid tumor of the kidney: a report of two cases with respective tumor markers and a specific chromosomal abnormality, del(11p13).

Malignant rhabdoid tumor is a rare, aggressive, invariably lethal tumor that is resistant to multimodal treatment. In this report, two patients with malignant rhabdoid tumor of the kidney (RTK) are described. The first patient is the first case of RKT with hyperreninemia, and the second case is also the first case with a specific chromosomal abnormality, del 11p13. The first patient presented with hematuria and a mass in the left kidney. Plasma renin, angiotensin, and aldosterone levels were elevated and paralleled the tumor progression. The karyotype of the tumor cells was normal (46,XX). In the second patient, who presented with a mass in the right kidney, the concentration of plasma tissue polypeptide antigen was elevated and paralleled the tumor progression. The karyotype of the tumor cells was 46,XX, del(11)(pter-p13::p12-qter). RTK with a cytogenetic abnormality of del(11p13), which is usually found in aniridia-Wilms' tumor syndrome, has not been known. Both patients died of metastatic disease within 7 months of diagnosis in spite of the multimodal therapy. The clinicopathology of RTK and the differences between Wilms' tumor and RTK raise compelling questions which should be the subject of future studies.

Intrahepatic metastases in hepatocellular carcinoma: evidence for spread via the portal vein as an efferent vessel.

BACKGROUND: The mechanism and pathogenesis of the high frequency of intrahepatic metastasis in hepatocellular carcinoma (HCC) has not yet been elucidated. METHODS: Two hundred thirty-one tumors ( < or = 5 cm in diameter) of resected specimens of HCC were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens selected from the 231 tumors. RESULTS: The most frequent site for tumor spread in HCC was capsular invasion followed by extracapsular invasion, vascular invasion, and finally intrahepatic metastasis. Radiopaque material injected directly into 23 resected tumors entered the portal vein in only 17 tumors and entered into both the portal and hepatic veins in six tumors. CONCLUSIONS: These findings suggest that tumor spread in HCC progresses from capsular invasion to intrahepatic invasion and that the portal vein may act as an efferent tumor vessel.

Pathologic and radiographic studies of intrahepatic metastasis in hepatocellular carcinoma; the role of efferent vessels.

The efferent vessel of hepatocellular carcinoma (HCC) and the mechanism and pathogenesis of the high frequency of intrahepatic metastasis in HCC has not yet been clarified. Three hundred ninety-three resected specimens of HCC were examined for tumor thrombosis in the portal vein and the hepatic vein: 231 tumors < or = 5 cm in diameter were examined for the relationship between mode of tumor spread and tumor size. Efferent vessels in HCC were identified by direct injection of radiopaque material into the tumor in 23 resected liver specimens and by percutaneous infusion of radiopaque media into tumor nodules in 8 patients. The mode of tumor spread in HCC progressed from capsular invasion to extracapsular invasion, then to vascular invasion, and finally to intrahepatic metastasis. There was a strong statistical correlation between the presence of intrahepatic metastasis and portal vein thrombosis (p < 0.05, R = 0.998). Radiopaque material injected directly into 23 resected tumors entered only the portal vein in 17 tumors and into both the portal and hepatic veins in 6 tumors. In all 8 patients with unresectable lesions, radiopaque media injected percutaneously into tumor nodules flowed only into the portal vein. These findings suggest that intrahepatic invasion by HCC may occur through the portal vein as an efferent tumor vessel.

Sporadic visceral neuropathy.

We encountered three cases of chronic functional colonic obstruction caused by intramural ganglion cell death. Morphologic and pharmacological studies were performed using resected specimens. The patients included a 59-year-old man, a 72-year-old woman, and a 28-year-old man. Barium enema studies revealed segmental stenosis in their left colon. A mecholyl test was positive in all three cases and was useful in diagnosing this disorder. Histopathologic and cytometric examinations disclosed both degeneration and the disappearance of intramural ganglion cells. The number of muscarinic acetylcholine receptors was observed to increase in the muscle layers of the stenotic portion. In addition, the muscle of the affected region showed hypersensitivity to the muscarinic agonist (oxotremorine). These results seem to suggest that this disease is caused by a noncongenital injury to the intramural ganglion cells while the resulting stenosis is considered to reflect the degeneration of the ganglion cells. The etiology of ganglion cell death still remains to be clarified; however, we propose that patients with this disorder may represent a subset of patients with sporadic visceral neuropathy.

Immaturity of the myenteric plexus is the aetiology of meconium ileus without mucoviscidosis: a histopathologic study.

The most common aetiology of meconium ileus is a deficiency in trypsin activity caused by cystic fibrosis. The pathogenesis of meconium ileus without mucoviscidosis is less well understood, although a number of causative factors have been suggested. The symptoms and clinical course of nine patients with meconium ileus without mucoviscidosis were reviewed, and the myenteric plexus of a surgical specimen of intestine was examined histologically and cytometrically. The nuclei of the intramural ganglion cells were much smaller than were seen in normal newborn infants. The nuclear areas resembled those seen in fetuses of 5-6 months gestational age, but the number of ganglion cells approached normal. This immaturity of the ganglia was observed both in the contracted distal ileum and dilated proximal ileum. Patients with an ileostomy passed solid faeces for about 1 to 2 months postoperatively, after which time the faeces became watery. The intramural ganglia were mature at the time of ileostomy closure. We conclude that immaturity of the myenteric plexus in the ileum and colon seems to be the main aetiologic factor in meconium ileus without mucoviscidosis.

Extensive dissection at the porta hepatis for biliary atresia.

Dissection at the porta hepatis is the crucial step in surgery for biliary atresia. The authors describe their procedure for extensively dissecting the porta hepatis. The technique is based on an anatomic cast corrosion of the human liver, and the portal vein serves as the landmark for dissection. Lateral dissection at the hepatic hilus is critical to the procedure. On the right side, the anterior portal branches are dissected to the bifurcation of the S5 and S7 segmental portal branches, over the bifurcation of the anterior and posterior portal branches. On the left side, the liver parenchyma, which bridges the umbilical point, is sectioned, and the left portal branch is dissected to the umbilical point over the pars transversalis and taped. The fibrous mass that lies within the confines of the portal branches, including the dorsal aspect, is transected completely. This procedure was performed in 16 infants; the jaundice cleared in 93.7%.

Successful Kasai operation for biliary atresia in a 9 month old.

A rare case of a successful Kasai operation for biliary atresia in a 9 month old is described. For infants over 6 months of age, there had been no reports of long-term survival after this procedure.

Outcome of 21 patients with biliary atresia living more than 10 years.

The outcome of 21 survivors (8 males, 13 females; age range, 11 to 29 years) followed for > 10 years after surgery for biliary atresia are discussed. Of the 21 patients, 18 with type III disease had hepatic portoenterostomy (Kasai operation), and 3 with type I disease had hepaticoenterostomy. Twenty patients are alive leading almost normal lives; however, 13 (61.9%) patients did have a history of complications, including hemorrhage from esophageal varices in 10, from a gastric ulcer or erosion in 3, and from a duodenal ulcer in 2; biliary reobstruction in 3; and multiple pulmonary arteriovenous fistulae in 2. Of those with complications, 7 required surgery. One died suddenly at the age of 19 years of a bleeding gastric ulcer. Liver function is normal in 9 (45.0%) of the 20 alive patients, 2 (10.0%) have slight hepatic dysfunction, and 9 (45.0%) have mild-to-moderate hepatic dysfunction. Liver function is almost normal in 3 patients who had a history of variceal hemorrhage.

Clinical, laboratory and prognostic features of congenital large intestinal motor dysfunction (pseudo-Hirschsprung's disease).

One hundred and forty-eight cases of congenital large intestinal motor dysfunction (pseudo-Hirschsprung's disease) were reported by members of the Japanese Society of Pediatric Surgeons during the past 20 years. The disorder was defined as a congenital, non-mechanical obstruction of the intestine with the presence of intramural ganglia in the terminal rectum. Intramural ganglia were abnormal in 77 cases, normal in 42, and could not be determined in 29. Of those with abnormal intramural ganglia, 54 had immature ganglia or hypoganglionosis (oligoganglionosis), 15 had neuronal intestinal dysplasia, and eight had a segmental anomaly. Of those with a normal myenteric plexus, 22 had chronic and twelve had suspected idiopathic intestinal pseudo-obstruction syndrome; eight had megacystis-microcolon-intestinal hypoperistalsis syndrome. While cases with both hypoganglionosis and normal intramural ganglia had normal acetylcholine esterase activity, a significantly greater number of patients with hypoganglionosis lacked normal rectoanal reflexes. Patients with hypoganglionosis, chronic idiopathic intestinal pseudo-obstruction syndrome, and megalocystis-microcolon-intestinal hypoperistalsis syndrome had poor prognoses with an overall mortality of 36.9%. These findings indicate that congenital large intestinal motor dysfunction remains a serious disease of childhood.