Shiro Matsuyama

Treatment of advanced neuroblastoma with emphasis on intensive induction chemotherapy. A report from the study group of Japan

One hundred nine newly treated patients with advanced neuroblastoma were entered in this study between January 1985 and May 1989. The eligible patients included infants younger than 12 months of age with Stage IVA disease (bone cortex, distant lymph node, and/or remote organ metastases) and patients aged 12 months or older with Stage III or IV disease (IVA plus IVB with tumor crossing the mid‐line and with metastases confined to bone marrow, liver, and skin). The patients first received six cyclic course of intensive chemotherapy (regimen A1), consisting of cyclophosphamide (1200 mg/m2), vincristine (1.5 mg/m2), tetrahydropyranyl adriamycin (pyrarubicin; 40 mg/m2), and cisplatin (90 mg/m2). Original tumors and the regional lymph node metastases were removed some time during these first six cycles of chemotherapy. The patients were further divided into three groups. Patients in course 1 received alternating treatment by regimen B (cyclophosphamide and ACNU) and intensified regimen A1, and those in course 2 were treated with alternating administration of regimen C (cyclophosphamide and DTIC) and intensified A1. Patients in course 3 were treated with bone marrow transplantation (BMT) preceded by high‐dose preconditioning chemotherapy. Survival rates were 77% in Stage III and 54% in Stage IV at 2 years, and 70% in Stage III and 45% in Stage IV at 3 years. The major toxicities encountered were bone marrow suppression with leukocyte counts down to 100/mm3, mild cystitis, and hearing impairment. The 2‐year survival rate was 78% in 21 patients who underwent BMT when complete remission was achieved. We concluded that our intensive induction chemotherapy is of significant value in increasing the rate of complete response, and in widening the indications for and achieving improved results of treatment with BMT.

Therapeutic significance of surgery in advanced neuroblastoma: A report from the study group of Japan

The role of surgery was evaluated in 19 stage III and 102 stage IV neuroblastoma patients, all of whom were treated with intensive induction chemotherapy by the Study Group of Japan between January 1985 and March 1990. For stage III neuroblastoma, surgical intervention at the primary site was performed in 18 of the 19 patients, 9 during and 9 after the first three cycles of A1 regimen, consisting of high-dose cyclophosphamide, vincristine, THP-adriamycin, and cis-platinum. Gross complete resection of primary tumor and regional lymph nodes was feasible in 17 of the 19 patients (89%), and the survival rate for the 17 patients were 79%, 70%, and 70% at 2 years, 3 years, and 4 years, respectively. For stage IV, surgical intervention at the primary site was performed in 92 of the 102 patients (90%): 30 cases during the first 3 cycles of A1 chemotherapy and 62 cases after that, with gross complete resection accomplished in 81 of the 102 patients (79%). The 81 patients with gross complete resection achieved had a better prognosis than those 11 patients with partial resection (P less than .05). Overall survival rate was 62% at 2 years for 27 patients who underwent complete resection after 3 cycles of A1 when resolution of all metastases was obtained, whereas the survival was 52% at 2 years for 31 patients who similarly underwent complete resection but when evidence of persistent metastases was present. Patients in whom the ipsilateral kidney was preserved at surgery had an outcome superior to that of those with associated nephrectomy (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Bcl-2 oncoprotein expression and apoptosis in neuroblastoma

Bcl-2 protooncogene, originally discovered at the chromosomal breakpoint of the t(14;18) in follicular lymphoma, is known to regulate the process of programmed cell death or apoptosis. The inhibition of apoptosis is thought to be one of the mechanisms involved in the development of tumors. To investigate the possible association of bcl-2 protooncogene with the tumorigenesis of neuroblastomas, the authors examined bcl-2 expression by immunohistochemistry in 49 neuroblastomas and 7 ganglioneuromas. The distribution of apoptotic cells was also examined by the TUNEL method (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling). Bcl-2 oncoprotein was detected in the cytoplasm in 40 of 49 neuroblastomas (81.6%). There was no correlation between bcl-2 oncoprotein expression and the clinical features of neuroblastoma. The incidence of bcl-2-positive tumors in ganglioneuroma was significantly lower than that in neuroblastoma (28.6%) (P < .01). TUNEL stained the nuclei of tumor cells in 11 of 34 (32.4%) neuroblastomas. TUNEL-positive cells tended to be located around calcifications in neuroblastomas in patients less than 1 year old. Examination of serial sections showed that apoptotic cells were distributed in the area where bcl-2 oncoprotein was not expressed. What we have observed indicates that apoptosis of neuroblastoma cells may be regulated by bcl-2 expression. Our observations suggest that the survival of neuroblastoma cells might be promoted by bcl-2 expression and that bcl-2 might be associated with the tumorigenesis of neuroblastomas.

Rupture of the Spleen in the Newborn: Treatment Without Splenectomy

In the newborn, traumatic rupture of the spleen is rare. Only 24 survivors have been reported in the world literatures, including four cases which have appeared in the Japanese literature. All were treated by splenectomy.‘-3 In view of the danger of overwhelming infection following splenectomy in early childhood,4 preserving whatever splenic tissue remains vascularized is indicated. SeraS reported two infants in whom pneumococcal meningitis occurred after splenectomy in the neonatal period for splenic rupture. The first survivor of a ruptured spleen treated by repair of the organ is reviewed.

Massive apoptosis detected by in situ DNA nick end labeling in neuroblastoma.

To seek evidence that tumor regression in neuroblastoma might result from massive apoptosis, we investigated tumor cell death in 39 neuroblastomas. Characteristic histologic features of apoptosis, condensed nuclear fragments and eosinophilic cytoplasm, were observed in all specimens. A ladder of DNA fragments induced by apoptosis was demonstrated by means of DNA agarose gel electrophoresis in 18 of the 19 tumors examined. In situ DNA nick end labeling (TUNEL) stained the nuclei with DNA fragmentation in 16 of 39 neuroblastomas. The TUNEL -positive cells were distributed in a scattered fashion in 10 tumors. In the remaining six tumors, they were densely located around nonviable areas of calcifications, where karyorrhectic or pyknotic cells were frequently observed. Five of six patients with such tumors were under 12 months of age, but there was no significant difference between the two groups in the patient age, origin of the primary lesion, or tumor stage. Biological features, including histology. DNA ploidy, and N-myc amplification, were not significantly different . Double fluorescent staining for bcl-2 oncoprotein and TUNEL showed that bcl-2 oncoprotein was expressed in the cytoplasm of tumor cells that were negative for TUNEL staining. This accumulated evidence suggests that massive apoptosis of tumor cells occurs in some neuroblastomas and may be related to tumor regression, whereas inhibition of apoptosis by bcl-2 oncoprotein expression might be associated with the tumorigenesis of neuroblastomas, as reported in our previous study.

Surgical treatment of neuroblastomas in infants under 12 months of age

BACKGROUND Surgical treatment of neuroblastomas, both those detected by screening and those detected clinically, in infants less than 12 months of age, is controversial, because some tumors in this age group potentially have the ability to regress spontaneously. METHODS From January 1985 to March 1997, the authors treated 50 infants (under 1 year of age) with neuroblastoma: 23 boys and 27 girls. Forty-one cases were detected preclinically by screening when the patients were 6 to 11 months of age (median, 7 months), and nine patients were discovered to have clinical manifestations at the age of 1 to 10 months (median, 4 months). RESULTS The tumor was INSS stage 3 or 4 in 10 patients (24%) with screening-detected tumor and in five (56%) with clinically detected tumor, although the difference was not statistically significant. Four screening-positive patients had multifocal primary tumors, and three of them were synchronous bilateral adrenal neuroblastomas. There was no statistically significant difference between the screening-detected tumors and the clinically detected tumors in biological characteristics such as Shimadas histology, DNA ploidy, and N-myc amplification. Complete resection of the primary lesion was accomplished by either primary surgery or second look (delayed primary) surgery in 46 patients (92%), and the resection was incomplete in the remaining four. In patients with bilateral adrenal tumors, the larger one was primarily resected, and the smaller contralateral tumor was enucleated or resected by partial adrenalectomy. Surgical complications included postoperative adhesive ileus (n=2), Horners syndrome (n=2), renal atrophy (n=1), renal failure (n=1), phrenic nerve injury (n=1), chylous ascites (n=1), chylothorax (n=1) and intussusception (n=1). One patient died of respiratory failure caused by a complication, but 49 patients (98%) were alive at the time of evaluation. CONCLUSION When considering surgical treatment of infants with biologically favorable neuroblastoma, the risk involved in treatment should be weighed against the risk inherent in a tumor capable of spontaneous regression, and aggressive surgery is unacceptable.

The relationship between disturbed transit and dilated bowel, and manometric findings of dilated bowel in patients with duodenal atresia and stenosis

To determine whether dilated bowel proximal to obstruction associated with duodenal atresia and stenosis is related to feeding problems after a surgical correction of obstruction, the authors reviewed retrospectively the degree of bowel dilatation and disturbed transit as well as other clinical features in 18 duodenal atresia and 12 duodenal stenosis patients. A multivariate analysis was conducted to determine the possible correlation among them. The authors also evaluated the physiological function of the dilated bowel in duodenal atresia and stenosis patients (n = 8) by manometry of dilated bowel. The results were as follows. (1) In multivariate analysis, using the degree of disturbed transit as a dependent variable and using other clinical features as independent variables, the presence of postoperative complication and the existence of bowel dilatation 2 weeks after the operation were risk factors for disturbed transit. (2) One or two episodes of phase 3 were found in six of eight measured patients during the recorded period. The most distinctive manometric finding was the low contraction amplitude of both phase 2 and phase 3. These results indicate that dilated bowel was related to disturbed transit during the postoperative period, and that the low contraction amplitude of the dilated bowel was the main pathophysiological feature. The tapering or plication of dilated bowel might be indicated in patients with a markedly dilated bowel.

A peculiar form of multiple cystic dilatation of the intrahepatic biliary system found in a patient with biliary atresia

The authors report a peculiar form of intrahepatic multiple cysts of the biliary system in a patient with biliary atresia (BA). An 11-year-old girl was admitted to our institution to be investigated for repeated cholangitis occurring after the age of 10 years. She underwent a hepaticojejunostomy, caused by Type I (cyst-type) BA, in the neonatal period. The radiological examination results showed multiple cystic dilatation of the intrahepatic biliary system with a vascular structure protruding into the cyst lumen. Such cystic dilatation with a protruding vascular structure has been noted in patients with Carolis disease and congenital hepatic fibrosis, and ductal plate malformation is shown to be responsible for the cyst formation. The authors postulate that such malformation of the intrahepatic biliary system is related to the cyst formation in our case.

Evaluation of patients with advanced neuroblastoma surviving more than 5 years after initiation of an intensive Japanese protocol: A report from the study group of Japan for treatment of advanced neuroblastoma

In January 1985, a single protocol consisting of cyclophosphamide, vincristine, tetrahydropyranyl adriamycin, and cis-platinum for the treatment of advanced neuroblastoma was begun nationwide in Japan and was found to improve clinical results significantly in terms of 2- or 3-year survival rate. Between January 1985 and December 1988, 113 eligible patients (7 infants younger than 12 months of age with stage IVA disease and 106 patients aged 12 months or older with stage III or IV disease) were enrolled and followed up for 5 years or more after initiation of treatment, as of March 1994. In this study, the usefulness of the protocol for the treatment of advanced neuroblastoma was evaluated with survival rates in relation to age, tumor site, stage, and N-myc amplification for patients surviving more than 5 years after initiation of the protocol. Fifty of the 113 patients were alive 5 years or more after initiation of the treatment, 39 without any episodes of disease recurrence. Fourteen (70%) of 20 patients with stage III, 6 (50%) of 12 with stage IVB, and 24 (30%) of 81 with stage IVA disease were alive and disease-free 5 years after initiation of the protocol. Twenty (56%) of 36 patients without N-myc amplification were alive at 5 years after initiation of the protocol. Only one patient who was alive without evidence of the disease at 5 years had recurrence afterward.

Primary volvulus of the small intestine in infants.

Primary small bowel volvulus which no definite cause can be detected surgically is rare. In this paper, we present five cases of primary small bowel volvulus and discuss the clinical features including etiology.