Monoclonal antibody ONS-M21 recognizes integrin α3 in gliomas and medulloblastomas

The monoclonal antibody ONS-M21 recognizes an antigen found on the surface of glioma and medulloblastoma cells but does not react with the antigens of normal brain tissue. We purified and identified the 140-kDa protein by means of an antibody-binding affinity column. This 140-kDa antigen has sequences homologous to the amino-terminal region and five parts of the internal domain of integrin α3. When the integrin α3-related sequences was amplified and used to analyse the mRNA of glioma and medulloblastoma surgical specimens, the transcription level of integrin α3 mRNA appeared to be quantitatively correlated with the grade of malignancy. These findings suggest that the ONS-M21 antibody, which reacts with integrin α3, might be useful in the diagnosis of gliomas and medulloblastomas. © 1999 Cancer Research Campaig

Recombinant humanised anti-HER2/neu antibody (Herceptin®) induces cellular death of glioblastomas

Glioblastoma multiforme (GBM) remains the most devastating primary tumour in neuro-oncology. Targeting of the human epithelial receptor type 2 (HER2)-neu receptor by specific antibodies is a recent well-established therapy for breast tumours. Human epithelial receptor type 2/neu is a transmembrane tyrosine/kinase receptor that appears to be important for the regulation of cancer growth. Human epithelial receptor type 2/neu is not expressed in the adult central nervous system, but its expression increases with the degree of astrocytoma anaplasia. The specificity of HER2/neu for tumoral astrocytomas leads us to study in vitro treatment of GBM with anti-HER2/neu antibody. We used human GBM cell lines expressing HER2/neu (A172 express HER2/neu more than U251MG) or not (U87MG) and monoclonal humanised antibody against HER2/neu (Herceptin®). Human epithelial receptor type 2/neu expression was measured by immunohistochemistry and flow cytometry. Direct antibody effect, complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity were evaluated by different cytometric assays. We have shown, for the first time, the ability of anti-HER2/neu antibodies to induce apoptosis and cellular-dependent cytotoxicity of HER2/neu-expressing GBM cell lines. The results decreased from A172 to U251 and were negative for U87MG, in accordance with the decreasing density of HER2/neu receptors

In vivo visualization of GL261-luc2 mouse glioma cells by use of Alexa Fluor–labeled TRP-2 antibodies

OBJECT: For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies. METHODS: GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope. RESULTS: Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes. CONCLUSIONS: Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors

Genetic landscape of sporadic unilateral adrenocortical adenomas without <em>PRKACA</em> p.Leu206Arg mutation.

CONTEXT: adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/PKA signaling pathway are common in cortisol-producing ACAs, while activating mutations in the gene encoding &beta;-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear. OBJECTIVE: aim of the study was to define the genetic landscape of sporadic unilateral ACAs. DESIGN AND SETTING: next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples. PATIENTS: 99 patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation. MAIN OUTCOME MEASURES: identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation. RESULTS: 706 somatic protein-altering mutations were detected in 88/99 tumors (median: 6 per tumor). We identified several mutations in genes of the cAMP/PKA pathway, including three novel mutations in PRKACA, associated with female sex and Cushing&#39;s syndrome. We also found genetic alterations in different genes involved in the Wnt/&beta;-catenin pathway, associated with larger tumors and endocrine inactivity, and, notably, in many genes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs. CONCLUSIONS: This study provides the largest sequencing effort on ACAs up to now. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis

Genetic landscape of sporadic unilateral adrenocortical adenomas without <em>PRKACA</em> p.Leu206Arg mutation.

CONTEXT: adrenocortical adenomas (ACAs) are among the most frequent human neoplasias. Genetic alterations affecting the cAMP/PKA signaling pathway are common in cortisol-producing ACAs, while activating mutations in the gene encoding &beta;-catenin (CTNNB1) have been reported in a subset of both benign and malignant adrenocortical tumors. However, the molecular pathogenesis of most ACAs is still largely unclear. OBJECTIVE: aim of the study was to define the genetic landscape of sporadic unilateral ACAs. DESIGN AND SETTING: next-generation whole-exome sequencing was performed on fresh-frozen tumor samples and corresponding normal tissue samples. PATIENTS: 99 patients with ACAs (74 cortisol-producing and 25 endocrine inactive) negative for p.Leu206Arg PRKACA mutation. MAIN OUTCOME MEASURES: identification of known and/or new genetic alterations potentially involved in adrenocortical tumorigenesis and autonomous hormone secretion, genotype-phenotype correlation. RESULTS: 706 somatic protein-altering mutations were detected in 88/99 tumors (median: 6 per tumor). We identified several mutations in genes of the cAMP/PKA pathway, including three novel mutations in PRKACA, associated with female sex and Cushing&#39;s syndrome. We also found genetic alterations in different genes involved in the Wnt/&beta;-catenin pathway, associated with larger tumors and endocrine inactivity, and, notably, in many genes of the Ca2+-signaling pathway. Finally, by comparison of our genetic data with those available in the literature, we describe a comprehensive genetic landscape of unilateral ACAs. CONCLUSIONS: This study provides the largest sequencing effort on ACAs up to now. We thereby identified somatic alterations affecting known and novel pathways potentially involved in adrenal tumorigenesis

Long-term results of carmustine wafers implantation for newly-diagnosed glioblastomas in France: Controlled propensity matched multicenter cohort study

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