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Biomedical subjects

R C Seeger

Publications and source records attributed to R C Seeger.

At least 91 records · Page 5Linked to original sources
PubMed1991

Aggressive surgery combined with intensive chemotherapy improves survival in poor-risk neuroblastoma.

One hundred eighteen children with metastatic (Childrens Cancer Study Group [CCSG] stage IV), extensive regional (stage III), or stage II neuroblastoma with N-myc amplification received an intensive chemotherapeutic regimen of cis-platinum, etoposide, doxorubicin, and cyclophosphamide combined with persistent aggressive attempts at complete primary tumor resection. Fourteen patients were unevaluable and 42 left the study to be placed on bone marrow transplant protocols. The remaining 62 children were evaluated in detail. Complete excision was eventually accomplished in 39 patients (63%), 23 of whom are disease-free survivors after 8 to 47 months (median, 20 months). Twenty-three patients underwent partial excision or biopsy of their lesion and only 6 are alive without evidence of disease (P = .0011). Timing of surgery or site of tumor did not influence surgical outcome. N-myc oncogene expression could not predict which lesions would be completely resectable. Surgical complications occurred 21% of the time but the impact on the clinical course and chemotherapy administration was minimal. The ipsilateral kidney was removed with the tumor in 18 cases, 14 of which were during complete resection. Twelve of these children are disease-free survivors. With new intensive chemotherapy capable of eliciting an effective response from primary and metastatic neuroblastoma, aggressive surgical approaches for complete tumor resection are warranted and can be expected to improve patient outcome.

Adolescent↗
PubMed1991

Treatment of high-risk solid tumors of childhood with intensive therapy and autologous bone marrow transplantation.

Autologous bone marrow transplantation (ABMT) allows delivery of intensive, marrow-ablative chemotherapy or chemoradiotherapy to children with high-risk solid tumors. Results from several studies of neuroblastoma suggest that outcome is improved by ABMT; however, relapses can occur months to years after complete clinical remission. Other high-risk tumors including peripheral neuroepithelioma, Ewing's sarcoma, rhabdomyosarcoma, Wilms' tumor, and brain tumors also appear to be responsive to intensive marrow-ablative therapy, although few studies have been reported. For tumors that can metastasize to marrow, a sensitive method is necessary for detecting tumor cell contamination. Immunocytologic analysis with monoclonal antibodies can identify one neuroblastoma cell per 10(5) normal marrow cells; this method also is applicable to other tumors with appropriate antibodies. Ex vivo removal (purging) of tumor cells decreases the probability of infusing tumorigenic cells with the ABMT. There is considerable experience in tumor detection and purging for neuroblastoma, but little has been done for other childhood solid tumors. Future investigations of ABMT will aim to further increase disease-free survival by intensifying induction and marrow-ablative regimens and by developing therapies to be given after ABMT that are directed at minimal residual disease. As pilot investigations mature, the efficacy of ABMT and conventional chemotherapy will be compared in multi-institution randomized studies.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

High levels of p19/nm23 protein in neuroblastoma are associated with advanced stage disease and with N-myc gene amplification.

The gene encoding a novel protein designated nm23-H1, which was recently identified as identical to the A subunit of nucleotide diphosphate kinase from human erythrocytes, has been proposed to play a role in tumor metastasis suppression. We report that untreated neuroblastoma tumors contain a cellular polypeptide (Mr = 19,000) designated p19, identified in two-dimensional electrophoretic gels, which occurs at significantly higher levels (P = 0.0001) in primary tumors containing amplified N-myc gene. The partial amino acid sequence obtained for p19 is identical to the sequence of the human nm23-H1 protein. An antibody to the A subunit of erythrocyte nucleotide diphosphate kinase reacted exclusively with p19. In this study, significantly higher levels of p19/nm23 occurred in primary neuroblastoma tumors from patients with advanced stages (III and IV) relative to tumors from patients with limited stages (I and II) of the disease. Even among patients with a single copy of the N-myc gene, tumors from patients with stages III and IV had statistically significantly higher levels of p19/nm23 than tumors from patients with stages I and II. Our findings indicate that, in contrast to a proposed role for nm23-H1 as a tumor metastasis suppressor, increased p19/nm23 protein in neuroblastoma is correlated with features of the disease that are associated with aggressive tumors. Therefore, nm23-H1 may have distinct if not opposite roles in different tumors.

Amino Acid Sequence↗
PubMed1991

Loss of heterozygosity for alleles on chromosomes 11q and 14q in neuroblastoma.

Partial monosomy for the short arm of chromosome 1 is a frequent cytogenetic abnormality in neuroblastomas. Molecular genetic analysis of tumor samples using chromosome specific polymorphic DNA markers has identified somatic loss of heterozygosity for alleles on chromosomes 1p (1p36.1-1p36.3) and 14q. In order to determine if other chromosomal losses occur and to further investigate chromosome 14, we used polymorphic DNA markers localized to chromosome 11 and 14 to analyze fifteen neuroblastomas and corresponding constitutional cells. Somatic loss of heterozygosity was observed in 5 of 12 informative cases (42%) for chromosome 11q (11q13-11q23) and 4 of 12 cases (33%) for chromosome 14q specific alleles. Two of the five tumors that had lost 11q alleles retained heterozygous alleles for sequences on 14q. The other three samples had lost both the 11q and 14q allelic sequences. These results suggest that in addition to chromosomes 1p and 14q, sequences localized to 11q may also play an important role in the development and/or progression of neuroblastomas.

Alleles↗
PubMed1990

Neuropeptide Y expression in the developing adrenal gland and in childhood neuroblastoma tumors.

Neuropeptide Y (NPY) expression is limited to tissues of the central and peripheral nervous system. In the adrenal gland, NPY is found in a subset of cells of the adrenal medulla. Using in situ hybridization analysis, NPY mRNA expression was characterized during human fetal adrenal medullary development. We found a biphasic pattern of NPY mRNA expression during the development of the human adrenal medulla. NPY mRNA is detectable at the earliest evaluable time point (7.5 weeks of gestational age) through 18 weeks of gestational age, and is then not detectable until 8 months after birth. We also analyzed NPY mRNA expression in neuroblastoma tumors, which often arise in the adrenal medulla. Thirty-eight neuroblastoma tumors were analyzed for NPY mRNA expression using in situ hybridization. We found NPY mRNA expression in 30 of 38 tumors; 15 of 15 Stage IVS tumors from children under 1 year of age at diagnosis expressed NPY mRNA, whereas 0 of 4 Stage IV tumors from children less than 1 year of age at diagnosis expressed NPY mRNA. These data suggest that in children under 1 year of age at diagnosis, Stage IVS and Stage IV neuroblastoma may be marked by the presence or absence, respectively, of NPY mRNA expression. Moreover, since NPY is expressed for only a short period of time during embryogenesis, these tumors may arise from different neuroblast populations occurring during the course of adrenal medullary development.

Adrenal Glands↗
PubMed1990

Chromogranin A in children with neuroblastoma. Serum concentration parallels disease stage and predicts survival.

Chromogranin A is an acidic protein costored and coreleased with catecholamines from storage vesicles. Its serum concentration is elevated in patients with peptide-producing endocrine neoplasia. We measured serum chromogranin A at the time of diagnosis in 34 children with all stages of neuroblastoma. With a sensitivity of 91% and specificity of 100%, serum chromogranin A emerged as a useful diagnostic tool for neuroblastoma, comparable to or better than other measurements such as neuron-specific enolase, ferritin, or dopamine-beta-hydroxylase. Mean serum chromogranin A correlated with disease stage (r = 0.76, P less than 0.01). The relationship of prognosis (progression-free survival) to baseline serum chromogranin A, age, and disease stage was determined in 34 patients at risk for relapse, with a median followup period of 18 mo (range, 1-48 mo). The survival rate for patients with lower serum chromogranin A levels (less than 190 ng/ml at the time of diagnosis) was 69%, whereas it was 30% for those with higher chromogranin A levels (P less than 0.05). Furthermore, when subjects were additionally stratified by either age or stage, chromogranin A was an effective prognostic tool in patients who either were older than 1 yr (P less than 0.005) or had more advanced disease (stage III or IV; P less than 0.05). We conclude that serum chromogranin A in neuroblastoma is (a) a valuable (sensitive and specific) diagnostic tool, (b) a correlate of tumor burden, and (c) a useful predictor of survival.

Biomarkers, Tumor↗
PubMed1990

N-myc gene amplification in neuroblastoma is associated with altered phosphorylation of a proliferation related polypeptide (Op18).

We have recently identified and cloned the gene for a cytosolic polypeptide, designated oncoprotein 18 (Op18), which is expressed in acute lymphocytic leukemia and some solid tumors including neuroblastoma. Op18 is phosphorylated upon treatment of lymphoid cells with phorbol myristate acetate. We have proposed that unphosphorylated Op18 plays a role in cellular proliferation, and that its phosphorylated forms, namely Op18a and Op18b, are associated with diminished cell proliferation. In this study, we report that in neuroblastoma tumors, the phosphorylation of Op18 was substantially diminished with increasing N-myc gene copy number. Treatment of the neuroblastoma cell line SMS-KCNR, which contains 75 copies of the N-myc gene, with retinoic acid for ten days resulted in an increase in Op18 phosphorylation. Our findings provide evidence for distinct patterns of Op18 phosphorylation in neuroblastoma tumors with and without N-myc gene amplification.

Cell Division↗
PubMed1989

A surgical perspective on the current staging in neuroblastoma--the International Neuroblastoma Staging System proposal.

In the three most widely used neuroblastoma staging systems--Evans, Pediatric Oncology Group (POG), and TNM-Union Internationale Contre le Cancer (UICC)--few staging problems are presented by the completely resected tumor or with the patient who has metastatic disease. Difficulties arise with the localized tumor when there is extension across the midline and with the demonstration of lymph node involvement. A new International Staging System for Neuroblastoma (INSS) is proposed that incorporates both lymph node invasion and extension across the midline into surgical staging. Clear criteria for diagnosis are established and clinical responses are defined. New prognostic factors may be added. The surgical role remains significant in staging, diagnosis, and therapy. Use of a common system throughout the world would facilitate the evaluation of clinical trials and help achieve the goal of developing optimum therapy for the biologically different types of neuroblastoma.

General Surgery↗
PubMed1989

Excellent outcome of stage II neuroblastoma is independent of residual disease and radiation therapy.

The optimal management for patients with stage II neuroblastoma has not yet been established. In order to determine the impact of adding chemotherapy and/or radiation therapy to surgery, we reviewed by questionnaire 156 patients with stage II neuroblastoma treated by 28 Childrens Cancer Study Group (CCSG) institutions from 1978 to 1985. Survival and progression-free survival (PFS) were analyzed by life-table methods with respect to age at diagnosis, site and size of primary tumor, spinal cord involvement, extent of initial resection, and treatment in addition to surgery. The overall 5-year survival was 96%; the PFS was 90%, similar to previous CCSG studies. Age at diagnosis had a small impact on PFS, with 92% PFS for patients less than 2 years of age at diagnosis, and 84% for those greater than 2 (P = .10). The only site with an adverse outcome was the head and neck (n = 11), with a PFS of 68% compared with 93% for the remaining sites (P = .02). Size of primary and intraspinal extension of primary did not affect PFS. The extent of resection and subsequent treatment with radiation therapy and/or chemotherapy did not affect the PFS. The outcome for 75 patients treated with surgery alone (6-year PFS, 89%) was not significantly different from that of 66 patients receiving radiation therapy (6-year PFS, 94%). There was no significant difference between 40 patients with gross or microscopic residual disease treated with surgery alone (PFS, 92%) and 59 patients with residual disease who also received radiation (PFS, 90%). Five of seven patients who progressed after surgery alone have been salvaged with further therapy and are now free of disease. One survives with disease, so that the 6-year survival is 98% for those treated initially with surgery alone, compared with 95% for those receiving radiation therapy and/or chemotherapy. These data suggest that surgery alone, even if complete resection is not achieved, is sufficient initial therapy for stage II neuroblastoma. The data also identify another stage of neuroblastoma, in addition to stage IV-S, for which almost all patients have a favorable prognosis because their tumor may be biologically limited in growth.

Abdominal Neoplasms↗
PubMed1988

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.

Adult↗
PubMed1988

International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma.

Neuroblastoma is one of the most common tumors in childhood. However, it often has been difficult to compare clinical and laboratory studies of this disease due to a lack of uniform criteria for diagnosis, staging, and response. An international group of conferees addressed each of these issues and reached a consensus. Specific criteria for making a diagnosis of neuroblastoma are defined. A new neuroblastoma staging system is proposed that takes into account the most important elements of current but incompatible systems. Finally, criteria for response to treatment are standardized. The criteria proposed herein represent an international consensus of essentially every major pediatric oncology group or organization in the United States, Europe, and Japan. The staging system should be referred to as the International Neuroblastoma Staging System, and the response criteria as the International Neuroblastoma Response Criteria. Implementation of these criteria will greatly facilitate the comparison of clinical and laboratory studies by different groups and countries. Furthermore, these criteria should serve as a foundation on which future modifications or improvements can be based.

Humans↗
PubMed1988

Detection of N-myc gene expression in neuroblastoma tumors by in situ hybridization.

The presence of N-myc DNA amplification in human neuroblastoma tumors has been shown to be an independent prognostic factor predicting rapid progression of disease. Southern blot analysis has been used previously to detect N-myc amplification in these tumors. The authors report an analysis of N-myc gene expression by in situ hybridization in 28 human neuroblastoma tumors previously studied by Southern blot analysis. In the LA-N-5 human neuroblastoma cell line known to be amplified for N-myc, reaction conditions favoring RNA-RNA hybridization yielded an optimal signal. Using these hybridization conditions, in situ hybridization analysis of N-myc expression in 28 human neuroblastoma tissues correlated perfectly with N-myc DNA amplification in these tumors as detected by Southern blot analysis. In particular, there were no tumors in which N-myc RNA expression was found by in situ hybridization analysis in the absence of DNA amplification detectable by Southern blot, nor were there tumors that had DNA amplification in the absence of RNA expression. Heterogeneity of N-myc RNA expression was observed both among cells in any given tumor area, as well as within different areas of a single tumor. N-myc expression by in situ hybridization analysis was not observed in those tumors with more neuronally differentiated, ganglioneuroma histology. It is concluded that in situ hybridization of tissue sections is as effective as Southern blot analysis of tumor cell DNA in identifying human neuroblastoma tumors in which the N-myc gene is of prognostic significance.

Humans↗
PubMed1988

Bone marrow transplantation for poor prognosis neuroblastoma.

These studies suggest that intensive chemoradiotherapy (eg., VAMP-TBI), if given relatively soon after diagnosis and before development of progressive disease, improves long-term survival for patients with advanced neuroblastoma. Although this particular therapy is not useful for those who already have developed progressive disease, other intensive regimens may warrant testing in this latter group of patients. Our current study is testing aggressive induction chemotherapy, ex vivo purging of autologous marrow, and VAMP-TBI followed by BMT. Because of the increasing risk of progressive disease with time after diagnosis, we recommend beginning the BMT phase by 20 weeks after diagnosis. This should result in 85% of newly diagnosed patients entering the BMT phase without progressive disease; and, with fewer toxic deaths, 90% should survive the BMT phase. Thus, approximately 70% of patients could be disease-free survivors 8-9 months after diagnosis. Because a significant number of patients still develop progressive disease during induction or after BMT, efforts are being made to improve induction and pretransplant therapies and to identify prognostic factors. If modifications of the current regimens do not decrease the rate of progressive disease, it may be necessary to develop additional or different therapy for patients identified to be at high risk. Hopefully, new strategies will further increase the percentage of patients with tumor-free survival.

Bone Marrow Transplantation↗