Long-term survivors of advanced neuroblastoma with MYCN amplification: A report of 19 patients surviving disease-free for more than 66 months.

PURPOSE: According to initial reports, stage 4 neuroblastoma patients with amplification of the MYCN proto-oncogene developed progressive disease within 8 months. The prognosis for such patients, however, should now be reevaluated in light of recent results achieved with up-to-date combination chemotherapy. PATIENTS AND METHODS: Patients with stage 3, 4, and 4S neuroblastoma and more than 10 copies of MYCN received induction chemotherapy, which from January 1985 to February 1991 consisted of regimen A(1 )(cyclophosphamide 1,200 mg/m(2) on day 1, vincristine 1.5 mg/m(2) on day 1, pirarubicin 40 mg/m(2) on day 3, and cisplatin 90 mg/m(2) on day 5) and from March 1991 to September 1993 consisted of regimen A(3 )(cyclophosphamide 1,200 mg/m(2) on days 1 and 2, pirarubicin 40 mg/m(2) on day 3, etoposide 100 mg/m(2) on days 1 through 5, and continuous infusion cisplatin 25 mg/m(2) on days 1 through 5). Most of these patients underwent radical surgery to remove the original tumor and local metastases, irradiation, and supralethal preconditioning regimens, followed by blood stem-cell transplantation (SCT). Data on the patients were collected in December 1998, and the factors contributing to disease-free survival were analyzed. RESULTS: During the study period, 66 patients with more than 10 copies of MYCN were treated. Five of nine patients with stage 3 disease, 13 of 55 with stage 4, and one of two with stage 4S survived for at least 66 months. It is interesting that all but one patient who survived for more than 66 months underwent SCT, in contrast with only five of 45 patients who died. CONCLUSION: Not all patients with advanced neuroblastoma who have more than 10 copies of MYCN will die. The requisites for survival in such patients seem to be intensive induction chemotherapy, effective surgery, irradiation, and the use of SCT.

Combined fibrolamellar carcinoma and cholangiocarcinoma exhibiting biphenotypic antigen expression: a case report.

Fibrolamellar carcinoma (FLC), a variant of hepatocellular carcinoma (HCC), very rarely occurs in association with cholangiocarcinoma (CC). This report describes the first case of FLC coexisting with CC (FLC-CC) from Japan. Although the major part of the tumour located in the right lobe of the liver showed the typical features of FLC, CC was admixed with the FLC, not only in the primary hepatic tumour, but also in the lymph node metastases. Immunohistochemical analysis revealed that, although carcinoembryonic antigen (CEA), which can be detected with monoclonal antibodies in the cytoplasm and the cell surface of CC cells but not HCC cells, was expressed in only the CC cells in the primary tumour, it was expressed extensively in the cytoplasm of both CC and FLC cells in the metastatic and recurrent tumours. Furthermore, Hep Par 1, a hepatocyte specific antigen, was also expressed in both the FLC and CC cells. These findings suggest that, in this case, both FLC and CC were possibly derived from the same cancer stem cell with the capacity to differentiate into both hepatocytes and bile duct epithelium, and that both the cellular components, therefore, exhibited biphenotypic antigen expression.

Differentiation-associated expression and intracellular localization of cyclin-dependent kinase inhibitor p27KIP1 and c-Jun co-activator JAB1 in neuroblastoma.

Neuroblastoma is a unique pediatric cancer, which spontaneously regress in some infants and undergo maturation in older children. The cyclin-dependent kinase inhibitor p27KIP1 negatively control cell cycle progression and its expression is reported to be associated with differentiation and prognosis of some human cancers. To examine whether p27KIP1 is involved in differentiation of neuroblastomas, expression and localization of p27KIP1 in 30 cases of neuroblastic tumors were determined with immunohistochemistry. p27KIP1 was expressed in all cases, but staining intensity and intracellular localization varied in association with tumor differentiation. Primitive small round neuroblasts showed negative or only weak nuclear staining, while differentiating tumor cells displayed a novel, intense cytoplasmic positivity besides the nuclear staining, and mature ganglion cells showed intense positive reaction confined to the nucleus. A neuroblastoma cell line TGW was also immunostained positively for p27KIP1 in the cytoplasm after differentiation induction, and western blot analysis revealed an increase of p27KIP1 in these cells, corroborating the in vivo observations. JAB1, which is thought to bind p27KIP1 and transport it from the nucleus to the cytoplasm for proteasome/ubiquitin-mediated degradation, was found to be localized both in the cytoplasm and the nucleus in undifferentiated and differentiating tumors whereas located predominantly in the nucleus of differentiated tumor cells. These data indicate that the cytoplasmic localization of p27KIP1 in the process of differentiation is due to upregulation of p27KIP1 synthesis and subsequent degradation and suggest a role of p27KIP1 in differentiation of neuroblastoma.

Effects of granisetron in children undergoing high-dose chemotherapy: a multi-institutional, cross-over study.

The efficacy of granisetron hydrochloride 20 microg/kg and 40 microg/kg were compared using a cross-over method to determine the optimal dose in children with solid tumors receiving high-dose chemotherapy. Granisetron controlled the onset of vomiting in 17 of 23 patients (73.9%) who were given 40 microg/kg of granisetron, while 8 of 21 patients (38.1%) were free of vomiting in the 20 microg/kg group. The average frequency of vomiting was 7.22 times in the 20 microg/kg dose versus 4.44 times in the 40 microg/kg dose. No safety problems were associated with either dose. The 40 microg/kg dose of granisetron appears to be more optimal.

Development of intrahepatic cholelithiasis long after primary excision of choledochal cysts.

BACKGROUND: Biliary stricture with dilatation is a putative cause of intrahepatic bile duct stones. However, this hypothesis has never been proved. STUDY DESIGN: Fifty-six patients had operative cholangiography, underwent standard excision of a choledochal cyst, and were reviewed at follow-up clinics at a mean follow-up time of 13 years and 6 months. The incidence of complications such as intrahepatic cholelithiasis was analyzed according to the morphologic types of the intrahepatic bile ducts as observed at the initial operation. RESULTS: Group 1 patients (29 cases) did not show any dilatation of the intrahepatic bile ducts. Intrahepatic cholelithiasis developed in only one case (3 percent). In group 2 (24 cases), the intrahepatic bile ducts were dilated but not associated with any downstream stenosis. One patient (4 percent) suffered from intrahepatic cholelithiasis. Group 3 patients (3 cases) had dilatation of the intrahepatic bile ducts associated with downstream stenosis, and none of them was free from the development of intrahepatic biliary stones (3 cases). CONCLUSIONS: Patients with biliary dilatation with stricture of the intrahepatic bile ducts are most likely to develop intrahepatic cholelithiasis after surgical excision of a choledochal cyst, and their stenosis should be relieved by whatever means feasible at initial operation.

Idiopathic gastric volvulus in infancy and childhood.

Gastric volvulus is a rare condition in childhood. Most of the reported cases have been acute and secondary in type with predisposing factors. Between 1965 and 1988, 49 patients were treated at this institution for chronic idiopathic gastric volvulus. Patients were divided further into two groups according to age at admission. The main symptom was vomiting in the neonatal and infantile group, whereas it was abdominal distension, vomiting, weight loss, or constipation in the older age group. This clinical feature was different from that of acute gastric volvulus in which the symptoms resulted from gastric obstruction. Plain film of the abdomen showed no characteristic findings. Contrast study of upper gastrointestinal series showed findings similar to those of the acute volvulus, but the extent or degree was less significant. Conservative treatment was successfully undertaken for the patients in the neonatal and infantile group just by keeping them in prone position. The rationale for this method was demonstrated by the clinical and radiological improvement. Fundic gastropexy was performed in all of 18 patients of the older age group and in one of 31 patients of the neonatal and infantile group. The operative results were satisfactory except for one patient with mental retardation. In Japan, neonates or infants are customarily nursed in the supine position. This is presumed to be a reason why the chronic idiopathic gastric volvulus is frequently noticed.

Cystic dilatation of the intrahepatic biliary system in biliary atresia after hepatic portoenterostomy.

Five cases of intrahepatic biliary cyst or cystic dilatation and one suspicious case were found (6.4%) among 93 survivors of biliary atresia. The age at manifestation of such cysts ranged from 6 months to 12 years. These cysts or cystic dilatations were treated surgically in two cases, by percutaneous transhepatic cholangiodrainage (PTCD) in two, and not treated in one. Four patients are alive; one died of biliary atresia. Twenty-nine well-documented cases of intrahepatic biliary cyst were found in the literature, including five treated by the authors. The modes of dilatation were as follows: type A, noncommunicating cyst; type B, cyst with tiny communication with the intestinal loop; and type C, cystic dilatation. Clinical symptoms were fever, jaundice, acholic stool, and "cholangitis." Nineteen patients (66%) had symptoms within 4 years after the Kasai operation (first group); the modes of dilatation were mostly types A and B. However, in five of six patients with type C dilatation, symptoms developed after 10 years of age (second group). The prognosis for the second group appears poor because the condition of the liver worsens once cystic dilatation develops.

Sacroperineal anorectoplasty using intraoperative ultrasonography: a preliminary report.

Intraoperative ultrasonography (US) was applied to sacroperineal anorectoplasty for the purpose of making a pull-through tunnel under visual guidance. Intraoperative US images the horizontal plane of the muscle complex and the tip of the forceps, which is placed at the entrance of the tunnel (ie, the space anterior to the puborectalis sling), ready to penetrate the muscle complex. A surgeon can thus penetrate the center of the muscle by confirming the relation between the muscle and forceps on the US screen. Postoperative computed tomography of four patients on whom this technique was applied demonstrated that the rectum was pulled through the exact center of the puborectalis and external sphincter muscles.

Left hepatic trisegmentectomy for interlobar hepatoblastoma located close to the hepatic hilum.

A 10-month-old boy was noted to have hepatomegaly, and hepatic angiography showed a huge tumor of the medial segment of the left lobe, located close to the hepatic hilum and involving the anterior segment of the right lobe in contiguity. We considered at first that resection would not be possible, but at operation the anterior segmental branch of the right hepatic artery was successfully ligated and divided, which made left trisegmentectomy possible in this case. Postoperatively, the patient was treated with cisplatin and tetrahydropyranyl Adriamycin he was doing well without any evidence of disease 24 months after the hepatectomy.

Spontaneous regression of patient omphalomesenteric duct: from a fistula to Meckel's diverticulum.

A newborn with a patent omphalomesenteric duct is described in this report. This anomaly is a very rare one. Regression of the omphalomesenteric duct occurs as a normal embryonic event in the intrauterine life between the fifth and ninth week of gestation; however, in this case regression occurred spontaneously in the neonatal period and resulted in a Meckel's diverticulum with no connection with the umbilicus. This is the first case to be reported.

Further experience with the antireflux valve to prevent ascending cholangitis in biliary atresia.

BACKGROUND/PURPOSE: The intussusception-type antireflux valve is a mechanism introduced by Nakajo, who reported the results of his initial 17 cases in 1990. This report summarizes our further experience with new patients, together with follow-up results of the cases previously reported by Nakajo. METHODS: In total, 46 new patients who had biliary atresia underwent portoenterostomy at the authors' two units. The authors hoped to construct the intussuscepted antireflux valve in the Roux-en-Y loop, whenever possible, at the time of hepatic portoenterostomy. RESULTS: Among the 46 patients, one case each was found to be too young or too old to have the valve constructed during the surgery. In another case, the Roux-en-Y loop became too short after repeated revisions of the portoenterostomy. In another patient, the valve was first constructed but later removed because of jejunal perforation near the valve. In the last patient, the valve was not constructed for unspecified reasons. The authors constructed the antireflux valve in 42 patients, but it was maintained in 41. In one case, the valve truly prevented reflux of the intestinal juice during an episode of intestinal obstruction. The valve was found to be incompetent in one patient 5 years after the initial surgery. CONCLUSION: The incidence of cholangitis was high in patients with postoperative cystic dilatation of the intrahepatic bile ducts, and low in those without it.

Treatment of disseminated hepatoblastoma involving bilateral lobes.

A 30-month-old boy was investigated because of a huge abdominal mass in the right upper abdomen. A computed tomography scan and celiac angiography showed that the tumor involved bilateral lobes of the liver. At first, for this disseminated and "unresectable" tumor we did liver biopsy and hepatic arterial catheterization. Through this catheter we started chemotherapy using THP-Adriamycin and cis-platinum. After three courses of chemotherapy, a second-look operation was performed and trisegmentectomy was done to remove the main tumor and metastases, including the left lobe and the right anterior segment. The trisegmentectomy was performed with success, and the boy's serum alpha-fetoprotein (AFP) remains normal 37 months after the start of treatment, indicating a probable permanent cure. Such cases have rarely been reported in the literature. Our experience in treating this patient would seem to encourage aggressive management of advanced hepatoblastoma in other patients.

The role of subfractionation of alpha-fetoprotein in the treatment of pediatric surgical patients.

Subfractionation of serum alpha-fetoprotein (AFP) is a useful method to discriminate between yolk sac tumors, hepatic malignancies, and benign liver diseases in adults but has not been validated in infants and children. AFP subfractionation was performed on AFP-positive sera from 73 infants and children. AFP subfraction profiles were classified into three common types: (1) yolk sac type, (2) hepatoblastoma type, and (3) benign hepatic type, according to the reactivity of individual AFP samples to lectins. In 68 of 73 samples (93.2%), AFP subfraction profiles were accurately classified into these three types, and an atypical AFP subfraction profile resembling the hepatoblastoma type was found in sera from five infants (6.8%). Differentiation between hepatoblastoma and hepatitis when patients are very young can be difficult. Subfractionation is more accurate when patients are older. This technique was found to be useful in the diagnosis of neonatal ovarian tumors, in recurrent hepatoblastoma/ yolk sac tumor with low serum AFP, and in the differential diagnosis of hepatic mass (malignancy versus hyperplastic nodule) in the liver with long-standing cholestasis. Estimation of serum AFP subfraction profiles facilitates the differential diagnosis of various AFP-positive pediatric diseases, such as hepatoblastoma, hepatoma, hepatitis or germ cell tumors. This test is inexpensive, can be carried out within 48 hours, and should be performed for the differential diagnosis of pediatric liver disease.

Familial multiple mesothelial cysts of the spleen.

A 5-month-old boy who was diagnosed as having hydrops fetalis at 25 weeks' gestation had severe ascites of unknown origin. At the age 12 months, ultrasonography and computed tomography showed multiple cysts in the spleen that were increasing in size rapidly. Splenectomy resulted in complete disappearance of the ascites. These cysts were diagnosed as mesothelial cysts because the cell lining of the splenic cysts stained positively with alcian blue and cytokeratin. The boy's mother had undergone splenectomy for splenic and retroperitoneal lymphangiomas at 4 years of age. Histological reevaluation showed that the lining of her splenic cysts had the same mesothelial components as her son's. Their chromosomal assay showed normal karyotypes. Mesothelial cyst of the spleen appears similar to splenic lymphangioma morphologically; however, bleomycin and OK-432 were not effective. Familial splenic mesothelial (epidermoid) cysts have been reported in three sets of siblings, but this is the first report of their occurrence in mother and son.

Double termination of the alimentary tract in females: a report of 12 cases and a literature review.

Twelve female infants with double termination of the alimentary tract were reported. One patient had a high rectovaginal fistula, but in the other 11 cases the tract opened into the bowel uniformly at the level of the levator ani (anorectal-vestibular fistula). In these patients, diagnosis of the anatomical level of the fistula was made definitely with our radiological technique. Excision of not only the fistulous tract but also the anterior half of the rectum below the fistula is essential to achieve a cure without recurrence. The pathogenesis of this condition is discussed and the pertinent literature reviewed.

Determination of plasma total renin level by RIA with a monoclonal antibody: value as a marker for nephroblastoma.

Plasma total renin is a new, useful marker for nephroblastoma, but the conventional method for determining its level is sophisticated and requires large blood samples. To develop a simpler technique, a monoclonal antibody specific for both inactive and active renin (inactive + active = total) was raised, and a radioimmunoassay (RIA) system was established. This monoclonal antibody stains only the juxtaglomerular apparatus; values determined by this RIA did not change before and after activation. So far, the RIA system has been applied to 136 samples from 92 patients. Plasma total renin levels were also determined with the conventional method: samples were activated, then renin activity was assayed by measuring angiotensin I. The coefficient of the data obtained by these two different techniques was 0.921 (P less than .01). Plasma total renin levels in patients with nephroblastoma were significantly increased (546.5 +/- 297.8 pg/mL) over those in patients with neuroblastoma (218.6 +/- 46.5 pg/mL) and in controls (165.8 +/- 67.5 pg/mL, P less than .01). After removal of Wilms' tumors, the levels decreased to normal when sampled every 2 weeks. It was concluded that a newly developed RIA system is more useful in determining plasma total renin levels in patients with nephroblastoma.

Piston-pump-type high frequency oscillatory ventilation for neonates with congenital diaphragmatic hernia: a new protocol.

High frequency ventilation and extracorporeal membrane oxygenation (ECMO) are devices that are expected to save the lives of newborn infants whose pulmonary conditions have deteriorated. A piston-pump-type high-frequency oscillator (HFO), developed by Bryan and Miyasaka called "Hummingbird," is considered to be superior to high frequency "jet" ventilators or those of the flow-interrupter type, and was used successfully in two neonates with congenital diaphragmatic hernia (CDH) in a high-risk group. The first baby was on a conventional ventilator with pharmacologic support for the first 54 hours and then operated on. Postoperative deterioration necessitated the use of HFO for the next eight days. The infant then recovered uneventfully. For the second baby, HFO was necessary both preoperatively and postoperatively. This baby had a major diaphragmatic defect and her case was complicated with pneumothorax. There was a long stormy course on HFO (total, 70 days), but the patient was successfully extubated on the 75th day postoperatively and is now doing well. We believe active long preoperative stabilization with pharmacologic support and preoperative and postoperative hyperventilation with a piston-pump-type HFO may be a new innovative strategy for the management of severe CDH patients.

Serial determination of serum neuron-specific enolase in patients with neuroblastoma and other pediatric tumors.

The importance of determination of serum neuron-specific enolase (NSE) in patients with neuroblastoma has been emphasized by several authors. However, the specificity and sensitivity of NSE have not yet been well studied in tumors of infancy and childhood, nor is the role of serial determination of NSE in monitoring these patients fully understood. Concentrations of serum NSE were determined by a newly developed radioimmunoassay technique in 241 samples from 111 patients. NSE was also assayed in sera of nude mice bearing human pediatric tumors (16 samples), as well as in 30 tumor specimens. Eighty-two serum samples from 19 patients with neuroblastoma all showed NSE values (mean 120.2 ng/mL, range 16.2 to 722.0 ng/mL) elevated beyond the upper border of the normal range (14.6 ng/mL), even though four of the 19 patients had normal urinary excretion of 3-methoxy-4-hydroxymandelic acid (VMA) and 3-methoxy-4-hydroxy-phenylacetic acid (HVA). Twelve of these patients were monitored with serial NSE determinations, and their serum NSE were found to correlate well with the tumor burden, but were transiently modified by chemotherapeutically induced cell death. All 68 samples from nine patients, free of neuroblastoma at assessment, showed NSE values within the normal range. Thirteen of 25 patients with tumors other than neuroblastoma, however, showed serum NSE values mildly elevated beyond the upper border of the normal range (mean of the 25 patients 36.7 ng/mL, range 5.0 to 234.0 ng/mL). Results from our nude mouse study and from NSE analysis of the tumor extracts paralleled the clinical results.(ABSTRACT TRUNCATED AT 250 WORDS)

Primary chemotherapy for children with rhabdomyosarcoma of the 'special pelvic' sites: is preservation of the bladder possible?

Twenty-one children with rhabdomyosarcoma involving the "special pelvic" sites, defined as such occurring in the bladder, prostate, vagina and uterus, were treated with primary surgery between 1969 and 1977, and with primary chemotherapy beginning in 1978. Among 11 patients in the latter group who were placed in Clinical Group III (according to the classification of the US Intergroup Rhabdomyosarcoma Study (IRS), six showed partial response (PR) and underwent tumorectomy by radical surgery an average of 6 months after the start of treatment, and three showed complete response (CR) and were treated with further chemotherapy in the hope that cystectomy could be avoided. However, in the latter group, the tumor recurred (39 months, 35 months, and 27 months later), and all eventually underwent total cystectomy. Seven of the nine long-term survivors underwent total cystectomy and have premanent urinary-cutaneous stomas. Two had tumor-free bladders, but function was impaired in one because of the effect of irradiation. Normal function was preserved in only one patient in the series, whose tumor was located at the dome of the bladder. To preserve bladder function in children with rhabdomyosarcoma in these sites, more effective forms of chemotherapy will be required.

Histopathologic findings of advanced neuroblastoma after intensive induction chemotherapy.

BACKGROUND: Histopathologic findings of advanced neuroblastoma after intensive induction chemotherapy have not been studied well. METHODS: In the present study, all of the surgical specimens from 19 patients who had advanced abdominal neuroblastoma and were pretreated intensively with the protocol of the Study Group of Japan were reviewed. The authors found that dissection of the contralateral lymph nodes is mandatory in advanced neuroblastoma when the goal is the complete dissection of the abdominal disease. Effects of chemotherapy were graded histologically according to the ratio of viable residual neuroblastoma tissue to total areas of the tumor, including neuroblastoma, ganglioneuroblastoma, ganglioneuroma, hemorrhage, necrosis and fibrosis, in five ranks from ( ) to (-). CONCLUSIONS: The newly introduced, highly cytotoxic regimen of the Japanese protocol, designated "A3," appears to be more effective histologically than the conventional regimen, designated "A1" or "new A1." Effects designated ( ) or (++) were prerequisites for survival in stage IV disease, but some stage III patients with the (+) effect survived.