Biomedical subjects

M Tsokos

Publications and source records attributed to M Tsokos.

At least 127 records · Page 7Linked to original sources

PubMed1993

Malignant schwannoma with melanocytic and neuroepithelial differentiation in an infant with congenital giant melanocytic nevus: a complex neurocristopathy.

We describe an infant girl, born with a pigmented giant nevus, who developed a malignant schwannoma in the retroperitoneum at 16 months of age. At birth the nevus covered over 50% of her body and histologically was a compound nevus with extension into the deep dermis surrounding dermal appendages. The malignant schwannoma was biphasic with areas composed of spindle and round cells. Ultrastructurally, the majority of the tumor cells exhibited a Schwann cell phenotype, but neuroepithelial and melanocytic cells were identified as well. We believe that this constellation of findings represents a form of neurocristopathy. Neurocristopathy, as defined by Bolande (Hum Pathol 5:409-429, 1974), is a disease that results from aberrations in the migration, growth, or cytodifferentiation of neural crest tissues. These diseases may be simple (a singular pathologic process, usually localized) or complex (multiple neuroectodermal lesions). We report this case because the occurrence of retroperitoneal malignant schwannoma arising in a 16-month-old infant born with a pigmented giant nevus is unique, and may represent a previously undescribed form of a complex neurocristopathy.

Female↗

PubMed1993

Characterization of a new IL-6-dependent human B-lymphoma cell line in long term culture.

We have established a cell line (DS-1) of B-cell lineage in long-term culture. It was derived from an immunodeficient patient with intestinal lymphangiectasia and lymphoma by culturing malignant pleural effusion cells with IL-6 in vitro. The cell surface phenotype was; PCA-1, HLA Class II(+); CD25, CD19, CD20, CD30, CD38(-). Cell proliferation was poor in medium and exhibited an eight-fold, dose-dependent increase of proliferation in response to rIL-6 of human but not murine origin. The secretion of IgG into culture supernatants by DS-1 was not enhanced by rIL-6. While constitutive production of IL-6 was not detected by bioassay using murine B9 hybridoma cells or by ELISA, the presence of IL-6 message was detected in polyA+ selected mRNA by Northern analysis. Spontaneous proliferation of DS-1 cells was inhibited by neutralizing polyclonal antibodies to IL-6 (37%) and mAb to IL-6 (54%) and IL-6R (53%). DS-1 expressed both high and low affinity IL-6 receptors (Kd 1.2 x 10(-11) and 6.7 x 10(-10), respectively) by radiolabelled binding and Scatchard analysis. Thus, DS-1 represents an autocrine IL-6-producing cell line of B-cell lineage which resembles lymphoid malignancies arising in patients with AIDS and other immunodeficiency diseases. Despite constitutive IL-6 production, the in vitro growth of DS-1 is dependent upon exogenous IL-6. DS-1 may thus be useful as a model of IL-6 dependency. This cell line may also facilitate development of strategies for diagnosis and treatment of B-cell lymphomas in immunocompromised patients.

Adult↗

PubMed1993

Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma.

PURPOSE: In an effort to improve outcome in patients with metastatic or high-risk localized Ewing's sarcoma family of tumors (ESF) and rhabdomyosarcoma (RMS), we explored the role of consolidation therapy with total-body irradiation (TBI) plus autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Ninety-one patients were entered onto one of three consecutive protocols from 1981 to 1986. Induction therapy consisted of four or five cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC); in the earlier series, patients received one or two cycles with dactinomycin instead of doxorubicin. Irradiation of the primary site was used for local control. Patients who attained a complete response (CR) to induction therapy were eligible for consolidation with 8 Gy TBI plus VAdriaC and ABMT. RESULTS: Nineteen patients were ineligible for consolidation after failing to achieve or maintain a CR following induction therapy; all 19 are dead of disease. Seven eligible patients elected to forgo consolidation; three of seven are long-term event-free survivors. Sixty-five patients received consolidation therapy; 20 of 65 are long-term event-free survivors. A local control rate of 83% was achieved using radiation therapy as the primary modality of local control. Patients with metastatic disease at diagnosis fared substantially worse than did patients with localized tumors (6-year event-free survival [EFS] rate, 14% v 38%; two-sided P [P2] = .008). CONCLUSIONS: Consolidation of patients with metastatic or high-risk localized pediatric sarcomas with 8 Gy TBI plus ABMT has failed to improve the outcome of this group of patients. Metastatic disease at diagnosis continues to confer the poorest prognosis. New therapeutic strategies are needed to consolidate more effectively the remissions that can be achieved in the majority of these patients.

Adolescent↗

PubMed1993

dbl oncogene expression in childhood tumors and tumor cell lines.

We studied the expression of the dbl oncogene in the total RNA obtained from a wide spectrum of childhood tumors, including Ewing's sarcomas, peripheral neuroectodermal tumors (PNET), esthesioneuroblastomas, neuroblastomas, retinoblastomas, rhabdomyosarcomas, osteosarcomas, and synovial sarcomas. Material was obtained from primary tumors, nude mice xenografts, and tumor cell lines. Following the Northern blot technique, a single band of 2.8 kb was found in each analyzed case. Induction of neural differentiation in Ewing's sarcoma, peripheral PNET, and neuroblastoma cell lines with dibutyryl cyclic AMP did not change the expression of the dbl oncogene. We conclude that the wide expression of the dbl oncogene in these childhood tumors reduces its value as a molecular marker for their differential diagnosis; on the other hand, the dbl oncogene does not appear to be an essential molecular factor in the process of neuroectodermal differentiation of small round cell tumors of childhood.

Animals↗

PubMed1993

Expression of transforming growth factor-beta isoforms in small round cell tumors of childhood. An immunohistochemical study.

The transforming growth factor (TGF)-betas are a highly conserved group of potent multifunctional cell regulatory proteins with variable effects on cell growth and differentiation. Most of the small round cell group of childhood tumors are thought to arise from either primitive mesenchyme or neuroectoderm and show evidence of skeletal muscle or neural differentiation, and rarely both. To investigate the possibility that the TGF-betas have a role in the growth or differentiation of these neoplasms, we used antibodies specific for peptide sequences of the three known mammalian TGF-beta isoforms (TGF-betas 1, 2, and 3) to probe for TGF-beta protein expression in a total of 49 cases. TGF-beta 1 immunoreactivity was present in 16/17 (94%) of rhabdomyosarcomas, and the staining intensity was usually strong. TGF-beta 1 was also present in three of three ectomesenchymomas. In contrast, TGF-beta 1 was absent in all but one out of nine poorly differentiated neuroblastomas. Differentiating neuronal cells of ganglioneuroblastomas, however, were strongly positive for TGF-beta 1. Ewing's sarcomas and peripheral primitive neuroectodermal tumors had a less consistent, but usually positive, staining pattern. TGF-beta 3 staining patterns were very similar to those of TGF-beta 1. TGF-beta 2 immunoreactivity was only rarely detected in this group of tumors. The results suggest different roles for TGF-betas 1 and 3 in neuroblastoma and rhabdomyosarcoma. Expression of TGF-betas 1 and 3 is associated with neuronal differentiation of neuroblastoma. In contrast, these proteins may promote the growth of rhabdomyosarcoma by suppressing differentiation.

Adolescent↗

PubMed1993

A novel germline p53 splicing mutation in a pediatric patient with a second malignant neoplasm.

A novel germline p53 splicing mutation was identified in a pediatric patient with two metachronous primary cancers that are constituent tumors of the Li-Fraumeni syndrome. Genomic DNA from the second tumor showed the same mutation and loss of heterozygosity at the p53 locus. The mutant mRNA and protein were present in the tumor tissue. In contrast, in the normal tissues bearing the germline mutation in the heterozygous state, predominantly normal mRNA was expressed and the mutant p53 protein was not detectable. The functional silence and relative lack of mutant p53 mRNA expression in the normal tissues of this patient may be caused by decreased stability or decreased production. If this proves a more general pattern of expression of mutant p53 in individuals with germline mutations, these findings may explain the paucity of tumors in individuals affected with the Li-Fraumeni syndrome.

Adult↗

PubMed1992

Frequency and diversity of p53 mutations in childhood rhabdomyosarcoma.

The p53 gene was examined in primary or metastatic tumors from six patients with rhabdomyosarcoma (RMS) and in five RMS cell lines by screening methods including single-strand conformation polymorphism analysis, the RNase protection assay, sequencing of complementary DNA subclones, and Southern blotting. Six original tumors were of embryonal histology, four alveolar, and one mixed. p53 mutations were identified in four of the six tumors or cell lines derived from tumors with embryonal histology and in one of the four with alveolar histology. Consistent with p53 allele loss, each mutation was found in the homo- or hemizygous state. One tumor showed a G to C transversion at p53 codon 213 (arginine to proline), and another showed deletion of the entire gene. The p53 mutations in cell lines included a codon 248 C to T transition (arginine to tryptophan) in RD and a codon 280 A to T transversion (arginine to serine) in RH30. The cell line CTR contained a 4-base pair deletion at codons 219/220 in exon 6 with resultant frame shift and premature termination in exon 7. These data support the role of diverse types of p53 mutations in the pathogenesis and/or progression of a significant proportion of cases of childhood RMS.

Adolescent↗

PubMed1992

Clinical, pathologic, and biochemical features of a cholesterol lipidosis accompanied by hyperlipidemia and xanthomas.

We describe the unique clinical and histopathologic features of a child with biochemical and immunocytochemical features of Niemann-Pick disease type C (NPC). Clinically, she was found to have multiple xanthomas of the upper aerodigestive tract with dysphagia and expressive language delay, splenomegaly, bony infarcts, and type IIb hyperlipidemia. Neurologic examination was otherwise normal. Microscopy revealed foam cells in her bone marrow, liver, tongue, tonsils, glottis, and in normal-appearing peritonsillar mucosa. Lipid analysis of a liver biopsy specimen showed a small increase in phospholipids, a twofold increase in sphingomyelin, a fivefold increase in cholesterol, and a marked (25-fold) increase in bis(monoacylglycerol) phosphate. Lysosomal acid hydrolase activities in cultured skin fibroblasts were nondiagnostic. Biochemical and immunocytochemical studies of cultured fibroblasts demonstrated lysosomal accumulation of unesterified LDL-derived cholesterol as well as delayed induction of homeostatic responses to endogenous cholesterol consistent with a diagnosis of NPC. Based upon these observations, we speculate that this patient could have a new phenotypic expression of NPC or represents a new cholesterol lipidosis biochemically resembling NPC. The chance occurrence of two separate lipid disorders seems less likely.

Biopsy↗

PubMed1992

Dynamic model of differentiation in Ewing's sarcoma cells. Comparative analysis of morphologic, immunocytochemical, and oncogene expression parameters.

We report the establishment of a model of neural differentiation in four well-characterized Ewing's sarcoma cell lines. This process was induced by serum-depleted medium (1% fetal bovine serum) and agents such as dibutyryl cyclic AMP and retinoic acid. The morphologic changes were characterized predominantly by the presence of neurite-like elongated processes showing varicosities and branching along their course with numerous internal filaments and electron-dense granules. Immunocytochemically, differentiation was accompanied by a considerable increase in reactivity for neural markers of several types: neuroblastic, neuroepithelial, neuroendocrine, Schwannian and even glial. In contrast, the tumor promoter, phorbol 12-myristate 13-acetate inhibited differentiation. Several morphologic changes were observed in phorbol 12-myristate 13-acetate-treated cells: the cells became smaller and rounder, were poorly adherent to substrate, by electron microscopy lacked cytoplasmic organelles, electron-dense granules or neural processes, and showed decreased expression of neural markers. Northern blot analysis was performed to establish whether there was any relationship between neural differentiation and degree of N-myc, c-myc and dbl oncogene expression. There was no N-myc oncogene expression in the mRNA of Ewing's sarcoma cells, even after neural induced differentiation. The degree of c-myc and dbl oncogene expression appeared heterogeneous, and varied with the culture condition. Based on these results, it may be inferred that Ewing's sarcoma cells in vitro display a variable neural phenotype, there being a variety of biologic responses to diverse culture media and various differentiation agents, but with no consistent effect on N-myc, c-myc and dbl oncogene expression.

Bucladesine↗

PubMed1992

Peripheral primitive neuroectodermal tumors. Diagnosis, classification, and prognosis.

In conclusion, the group of peripheral primitive neuroectodermal tumors has been redefined in recent years on the basis of cytogenetic, molecular genetic and more precisely defined histopathologic characteristics. Although in the past, many tumors has been called Ewing's sarcoma, currently this diagnosis is limited to tumors which cannot be more specifically classified on the basis of their ultrastructural and immunophenotypic characteristics. Most small round cell tumors previously classified as Ewing's sarcoma are now classified as peripheral PNET. The consistent cytogenetic abnormality in Ewing's sarcoma and peripheral PNET and patterns of neurotransmitter enzymes have supported a common neuroectodermal origin. The precise characterization of soft tissue Ewing's sarcoma is further complicated by the several primitive rhabdomyosarcomas that may exhibit a similar light microscopic appearance. The importance of histopathologic distinction among these various round cell tumors of childhood is well recognized. Furthermore, primitive tumors with overlapping neural and mesenchymal features, known as malignant ectomesenchymoma, are now identified more often than previously. Finally, molecular biologic and cytogenetic differences between peripheral PNET and neuroblastoma have confirmed their clinical and biologic differences, in spite of their morphologic similarities. Molecular genetic and flow cytometric evaluation have contributed to the distinction of groups with prognostic significance and offer possibilities for new clinical trials.

Adolescent↗

PubMed1992

Enzymatic treatments on paraffin blocks for DNA flow cytometry.

The Hedley method for DNA ploidy analysis on paraffin-embedded tissue allows retrospective studies of large numbers of common and rare tumors for which treatment, progression, and outcome are known. However, the technique is cumbersome and has many variables, only some of which can be controlled at the time of laboratory analysis. We performed DNA ploidy analyses on two blocks from two islet cell tumors and on five blocks from two colon carcinomas. Sections of 50-microns thickness were deparaffinized in xylene, rehydrated in graded alcohols and in distilled water, and disaggregated with various enzymatic treatments: 0.05% pepsin (30 and 90 min), 0.5% pepsin (30 and 90 min), 0.05% protease (60 min), and 0.1% protease (60 min). The cell suspensions obtained were filtered, washed in PBS, and visually evaluated in a hemocytometer. Nuclei were treated with RNAse (0.1%) and stained with 50 micrograms/ml propidium iodide. Results were evaluated with the following criteria: (a) recovery of DNA aneuploid and/or G2M cells (cell-cycle analysis and visual evaluation); (b) coefficient of variation of the major peak (DNA diploid or DNA aneuploid depending on the case); (c) amount of debris (background events and visual evaluation); (d) mean channel for the G0G1 peak; (e) event rate; and (f) G2M/G0G1 ratio. The best results were observed with 0.05% protease when there was tissue necrosis and hence cell fragility, with 0.1% protease when there was significant tissue fibrosis, and with 0.05% pepsin (90 min) when there were intact cellular specimens without fibrous entrapment. The original procedure using 0.5% pepsin for 30 min produced less cell recovery, and histogram quality similar to or worse than these modifications in all cases studied.(ABSTRACT TRUNCATED AT 250 WORDS)

DNA, Neoplasm↗

PubMed1992

Rhabdomyosarcoma. A new classification scheme related to prognosis.

We classified 159 cases of rhabdomyosarcoma (RMS) according to the conventional scheme adopted by the World Health Organization and a modified conventional scheme established at the National Cancer Institute (NCI), Bethesda, Md. The major modification in the NCI scheme was the inclusion of compact round-cell RMS with scant myogenesis in the group of alveolar RMS despite lack of an alveolar architecture. These tumors were previously considered to be embryonal RMS, but their cytologic features are quite different from those seen in embryonal RMS and are indistinguishable from those encountered in alveolar RMS. These tumors are referred to as "solid alveolar RMS." Survival curves were constructed with the method of Kaplan-Meier and compared with the unstratified and stratified methods of Mantel-Haenszel (with stratification factors being stage, site, and age) and with the Cox regression analysis. Both histologic schemes showed a statistically significant prognostic value in unstratified analyses, but the NCI scheme demonstrated prognostic value even in stratified analyses and in the Cox regression analysis in our series of cases. The data indicate that the NCI scheme can serve as a highly predictive, independent prognostic factor in RMS and that the alveolar category should be expanded to include the solid round-cell RMS, even in the absence of a classic alveolar architecture.

Adolescent↗

PubMed1991

Expression of mdr-1/P-glycoprotein in human neuroblastoma.

Increased expression of the mdr-1 gene encoding the drug efflux pump P-glycoprotein is a well-established mediator of acquired drug resistance in vitro, and a similar role has been hypothesized in vivo in human malignancy. Because expression of mdr-1 is increased in neuroblastoma cell lines by differentiating agents, the authors hypothesized a similar correlation with differentiation in vivo in neuroblastomas. In 12 tumors from 11 patients, total RNA analysis demonstrated no correlation with differentiation, but a correlation could be detected in the cell-based methods of analysis. The very primitive 'stroma'-poor, poorly differentiated neuroblastomas had low levels of mdr-1/P-glycoprotein. The intermediate grades had higher levels of expression and although heterogeneity of differentiation appeared within these tumors, both primitive and more differentiated cells expressed the gene at comparable levels within the tumor. One very well-differentiated neuroblastoma, a ganglioneuroma, had no detectable expression in the neurofibrillary material, but demonstrated expression in adjacent large ganglionic cells. Thus mdr-1/P-glycoprotein expression increased with increasing differentiation among tumors, and was present in ganglionic cells in the most well-differentiated tumor. The three tumors with the highest levels of expression were obtained from patients who received preoperative chemotherapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1990

Modulation of EGF receptor expression by differentiating agents in human colon carcinoma cell lines.

The existence of an autocrine loop for self-stimulation of growth in malignant cells has been proposed for transforming growth factor-alpha (TGF alpha) and its receptor, the epidermal growth factor (EGF) receptor, in a variety of malignant cell types. Expression of both has been described in colon carcinoma. In order to investigate whether there is a correlation between TGF alpha and EGF receptor mRNA expression and differentiation, we studied the effects of differentiating agents on seven human colon carcinoma cell lines. All of the lines responded to the differentiating agents. In four of the seven lines there was increased EGF receptor mRNA two to five days after treatment with 2 mM sodium butyrate. In three of these lines TGF alpha mRNA and protein were also increased. In the one cell line treated with the differentiating agents DMF and DMSO, EGF receptor mRNA was also increased. [125I]-EGF binding to the cells was measured before and after treatment with butyrate. In two of three cell lines, increased EGF receptor mRNA was accompanied by a 2.4-fold increase in the number of binding sites per cell. In SW620 cells, no EGF receptor binding was detected before or after butyrate treatment. In the two cell lines in which butyrate increased EGF receptor binding, simultaneous treatment with EGF did not enhance growth. These data demonstrate increased expression of the TGF alpha/EGF receptor system after differentiation of colon carcinoma cell lines and suggest that their expression may be characteristic of a differentiated phenotype.

Alkaline Phosphatase↗

PubMed1990

Adenomatoid tumor of the adrenal gland with ultrastructural and immunohistochemical demonstration of a mesothelial origin.

We describe an adenomatoid tumor arising in the left adrenal gland of a patient who underwent bilateral adrenalectomy for the ectopic adrenocorticotropic hormone syndrome. The mesothelial origin of the tumor was confirmed by electron microscopy and positive immunohistochemical staining for keratin. The tumor had a prominent cystic component raising the question whether adrenal cysts are derived from mesothelial inclusions. It is proposed that consideration be given to adding a new category of "mesothelial cysts" to the classification of adrenal gland cysts.

Adrenal Gland Neoplasms↗

PubMed1989

Intensive combined modality therapy of small round cell and undifferentiated sarcomas in children and young adults: local control and patterns of failure.

Seventy-five patients (ages 4-35 years) with the following small round cell tumors and undifferentiated sarcoma were treated at the National Cancer Institute: Ewing's sarcoma (n = 32), peripheral neuroepithelioma (n = 14), rhabdomyosarcoma (n = 24), undifferentiated sarcoma (n = 5). Most patients had poor prognostic features including 36 (48%) with metastatic disease, and 42 (56%) with central (truncal) tumors (22 in the pelvis). Treatment included 5 cycles of intensive induction chemotherapy with vincristine, cyclophosphamide and adriamycin, plus aggressive local radiation therapy using simulation and computerized treatment planning for all patients. Thereafter, complete clinical responses were consolidated with intensive chemotherapy, total body irradiation and autologous bone marrow transplantation. There were three local only failures, 10 local plus distant failures, 36 distant only failures, 3 treatment-related deaths, and one intercurrent death. Overall actuarial survival and event-free survival at 4 years are 49 and 29%, respectively. Actuarial freedom from local progression was seen in 74% of patients at 4 years, quite remarkable considering the bulk and location of most of these tumors. Without aggressive surgery, many of these high risk patients had satisfactory outcomes, but better systemic treatments are still needed.

Adolescent↗

PubMed1989

Multifocal verruciform xanthoma of the upper aerodigestive tract in a child with a systemic lipid storage disease.

We report the clinical, light-microscopic, and ultrastructural features of a case of multifocal verruciform xanthoma in the upper aerodigestive tract of a child with a systemic lipid disorder. Lipid storage cells were found in liver, bone marrow, and as a component of verruciform xanthomas. To our knowledge this represents the first case of verruciform xanthoma reported in (a) a child, (b) as a multifocal lesion in the upper aerodigestive tract, (c) associated with a systemic lipid disorder, and (d) with ultrastructural evidence of lipid accumulation within endothelial cells. Although this patient presented with lesions involving the tongue and larnyx, subsequently lesions were found in the bone marrow and liver. Two months later more lesions were discovered on the epiglottis, posteior tongue, right glottis, and in grossly normal peritonsillar mucosa. Six months later a new oral lesion developed. Based upon these observations, we speculate that the pathogenesis of verruciform xanthoma involves accumulation of excess lipid in subepithelial sites which is scavenged by macrophages. Lipid-laden macrophages release epithelial growth factors that lead to epithelial hyperplasia. Depending on the degree of epithelial hyperplasia, the gross appearance of verruciform xanthomas may be flat, sessile, papillary, or verrucous.

Child, Preschool↗

PubMed1989

Primary pigmented nodular adrenocortical disease. A light and electron microscopic study of eight cases.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare cause of Cushing's syndrome, which is adrenocorticotropic hormone-independent and involves both adrenal glands. The characteristic pathological features include multiple pigmented cortical nodules and atrophy of the internodular cortex. The adrenal size ranges from small to normal or slightly enlarged. Review of the gross, light microscopic, and ultrastructural features of eight cases seen at the National Institutes of Health revealed several very unusual findings. We observed the following in our patients: macronodules up to 3.0 cm; microscopic foci of necrosis; mitoses; cortical hyperplasia rather than internodular atrophy; focal confluence of nodules giving a diffuse pattern of cortical involvement, and a focal trabecular growth pattern. The nodules were composed primarily of eosinophilic, lipid-poor cells similar to those of the zona reticularis. However, lipid-rich cells similar to those of the zona fasciculata were also demonstrated in the nodules by both light and electron microscopy. This suggests that the adrenal cortical nodules of PPNAD may be derived from not only the zona reticularis, but also the zona fasciculata.

Adolescent↗