Thomas J. Moss

Delayed surgery and bone marrow transplantation for widespread neuroblastoma.

From 1983 to 1986, 21 patients with poor prognosis neuroblastoma were treated with bone marrow transplantation. This regimen included induction chemotherapy, delayed surgical resection, local irradiation, and intensive chemoradiotherapy followed by infusion of allogeneic or autologous marrow. This therapeutic approach resulted in a 57% long-term survival rate (follow-up: 14–48 months), which appears to be approximately three times superior to conventional chemotherapy in a comparable group of children. In addition, complete resection was possible in 11 of 17 patients operated on after induction therapy. Recurrence in the primary site after bone marrow transplantation occurred in only one of 18 evaluable patients. Thus, this approach almost always eradicates primary tumor in patients with neuroblastoma with advanced disease.

Expression of a developmental stage-specific antigen by neuronal precursor cells of human fetal cerebellum

A monoclonal antibody that was prepared against human neuroblastoma cells was shown to react strongly with fetal brain and moderately with adult brain by quantitative absorption testing. Immunoperoxidase staining demonstrated expression of the antigen by neuronal precursor cells in the cerebellar external granular layer of a 24- to 26-week fetus but not by their mature derivatives in the granular and molecular layers of adult cerebellum. The antigen was also present on subventricular cells of fetal cerebral cortex, as well as adult and fetal astrocytes. The expression of this antigen by neuronal precursor cells in the external granular layer but not their mature derivatives suggests that it is a stage-specific marker for cerebellar neuronal development.

Serial immunocytologic analysis of blood for tumor cells in two patients with neuroblastoma.

Tumor surveillance tests are used to determine whether malignant cells are responsive or resistant to therapeutic regimens. For patients with neuroblastoma, conventional methods of surveillance are not sensitive enough. Because tumor cells are shed into the circulation, immunocytologic analysis of blood may function as a sensitive monitoring system. In this study, five blood samples were obtained from two patients with disseminated neuroblastoma at diagnosis and during therapy. These samples were analyzed with monoclonal antibodies and immunoperoxidase staining to determine whether circulating neuroblasts were present. In both patients, the presence or absence of circulating neuroblasts yielded information that was more sensitive than that from conventional tests. The authors conclude that immunocytologic analysis of blood should be included with conventional monitoring methods for surveillance of patients with disseminated neuroblastoma.

Preatherosclerotic aortic lesions in cystic fibrosis

Patients with cystic fibrosis have fat malabsorption, providing an experimental model for evaluation of the hypothesis that a low-fat intake may prevent atherosclerosis. We studied the frequency and extent of aortic precursor lesions (fatty streaks, early fibromusculoelastic lesions, late fibromusculoelastic lesions) found at autopsy in this disease as well as in other patients with debilitating disorders but with no apparent impairment of fat absorption. Fatty streaks were less common in the cystic fibrosis group, as were the late fibromusculoelastic lesions. There was no significant difference in the frequency, length, or thickness of the early fibromusculoelastic lesions. The findings suggest that fat may be responsible for progression but not initiation of the fibromusculoelastic precursor lesions, and support the concept that early restriction of dietary fat may prevent, delay, or otherwise modify atherosclerosis in the adult.

FOUR DRUG CHEMOTHERAPY, TOTAL BODY IRRADIATION |[lpar]|TBI|[rpar]| AND ALLOGENEIC OR AUTOLOGOUS BONE MARROW TRANSPLANTATION |[lpar]|EMT|[rpar]| FOR METASTATIC NEUROBLASTOMA

Intensive chemotherapy, TBI, and BMT may improve the outcome for children with metastatic neuroblastoma (August, et al, 1982). We are testing a new four drug chemotherapy and TBI pretransplant regimen for its toxicity and efficacy. Five patients received cis-platinum, VM26, doxorubicin, melphalan, and TBI (VAMP-TBI); and 3 received melphalan and TBI (M-TBI) because they could not tolerate the other agents or because their tumor was judged resistent. Allogeneic (allo) marrow was given to 5 and autologous (auto) marrow to 3 patients. They were 1 1/2 to 7 yrs old when transplanted (median 5 yrs) and were transplanted 5-13 mos after diagnosis (median 10 mos). Auto marrow had no neuroblastoma cells by immunoperoxidase staining for neuron specific enolase and cell surface antigens, which detects 1 tumor cell/105 normal cells. The most consistent acute toxicity from VAMP-TBI was severe mucositis, vomiting, and diarrhea; M-TBI also caused these complications but to a lesser extent. One acute toxic death occurred with each regimen. Of the 5 patients receiving VAMP-TBI, 3 have no evidence of disease (NED) at 60 (auto), 195 (allo), and 317 (allo) days; and 1 (auto) is 7 days post transplantation. One of 3 receiving M-TBI is NED at 45 days (auto), and another has progressive disease at 189 days (allo). We conclude that VAMP-TBI is a tolerable conditioning regimen. The survival of 3 of 4 evaluable patients receiving VAMP-TBI with NED suggests that this regimen should continue to be investigated.

EXPRESSION OF A COMMON ANTIGEN BY FETAL CEREBELLAR NEURONS AND ASTROCYTES

Nervous system markers can provide information on maturation, differentiation,and intercellular interactions. Monoclonal anti-body 459 (ab 459),was previously found to react strongly with fetal brain,and moderately with adult brain. The objective of this study was to determine which neural cells express the antigen (ag 459) defined by ab 459. Brains obtained within 12 hours postmortem from adults and a 22 week fetus were frozen and sectioned with a cryostat. They were fixed with acetone, incubated with ab 459, followed by biotinylated anti-mouse immunoglobulin, and then avidin-biotin-peroxidase complexes. Ag 459 is expressed by fetal neurons in the external granular layer of cerebellum; these same cells were negative for glial fibrillary acidicprotein and neuron specific enolase (NSE). Ab 459 also labelled morphologically mature fetal neurons, which were NSE positive,in a cerebellar nucleus. Adult cerebellar neurons of the granular layer, which are derived from fetal external granular layer, and all adult cortical neurons did not display ag 459. Both adult and fetal astrocytes expressed ag 459.Ag 459 is the first anti-genic determinant to be defined on human fetal neuronsin the external granularlayer of the cerebellum. The expression of this determinant on these cells,but not their maturederivatives, suggests that ag 459 is a stage specific marker for cerebellarneuron development. Astrocytes assist in migration of cerebellarfetal neurons in vivo, and the presence of ag 459 on fetalastrocytes and fetal neurons raise the possibility that this marker may be involved in the migration process.

141 PRE-ATHEROSCLEROTIC AORTIC LESIONS IN CYSTIC FIBROSIS

The purpose of this study was to evaluate the frequency and extent of aortic precursor lesions (fatty streaks, early fibro-musculoelastic lesions, late fibromusculoelastic lesions) found at autopsy in cystic fibrosis. Patients with this disease suffer from fat malabsorption and thus provide a unique experimental model for evaluation of the hypothesis that low fat intake may prevent atherosclerosis. Other patients with debilitating disorders but with no apparent impairment of fat absorption served as controls. Autopsy material from 35 patients, 9 with cystic fibrosis and 26 with leukemia and other malignancies were studied.Fatty streaks were less common in the cystic fibrosis group (p. < .001) as were the late fibromusculoelastic lesions (p. = .007). There was no significant difference in the frequency, length, or thickness of the early fibromusculoelastic lesions. The findings suggest that fat is responsible for progression but not initiation of the fibromusculoelastic precursor lesions.The results support the concept that early restriction of dietary fat may prevent, delay, or otherwise modify atherosclerosis in the adult.