Angiogenesis inhibitors and hypoxia.
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Angiogenesis Inhibitors↗
Biomedical subjects
Mark W Kieran
Publications and source records attributed to Mark W Kieran.
Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (STI-571, Gleevec): a case report and laboratory investigation.
Pilocytic astrocytomas are the most common childhood glioma. Most children with pilocytic astrocytomas survive many years with their tumor, but alternative treatment approaches are needed for those with refractory or metastatic disease. Signaling by the platelet-derived growth factor tyrosine kinase receptor pathways have been postulated to contribute to the development of gliomas. The authors treated a single patient with refractory, metastatic pilocytic astrocytoma with the tyrosine kinase inhibitor imatinib mesylate and observed marked, transient regression of tumor during treatment. Immunohistochemistry was used to assess expression of reported target genes of imatinib mesylate in this patient's tumor tissue and of the PDGFR in pilocytic astrocytomas from 19 other patients. Immunohistochemistry showed that the patient's tumor cells did not express any of the reported target molecules inhibited by imatinib mesylate. PDGFR expression was detected in tumor vasculative in the panel of 20 tumors, and not in the tumor cells. The authors suggest that the PDGFR-signaling pathway postulated to contribute to the development of gliomas in adults might not contribute to pilocytic astrocytomas in children, and that treatment with imatinib mesylate should be considered in patients with refractory pilocytic astrocytoma.
Astrocytoma↗
Neuropsychological functioning after surgery in children treated for brain tumor.
OBJECTIVE: To describe the neuropsychological functioning of children treated with surgery only for localized brain tumors in Dana-Farber Cancer Institute Protocol 92-077. Subsequent reports will describe the neuropsychological functioning of children treated with surgery and stereotactic radiation therapy on Dana-Farber Cancer Institute 92-077. METHODS: The intellectual functioning of 106 patients was evaluated within 3 months after surgery. An in-depth assessment of the neuropsychological functioning, including an impairment index, was conducted for a subset of 77 school-age children (6-16 yr old) across six functional domains. Descriptive statistics were generated; binomial distribution analyses were performed to assess whether the proportion of individuals with impaired performance on each measure exceeded normative expectations. The impairment index assessed whether poor performance was attributable to a few children or reflected the performance of the cohort as a whole. RESULTS: Although the Full Scale IQ was within normative expectations, the Verbal IQ was higher than the Performance IQ with 45% of individuals showing a significant discrepancy (P < 0.01) between these scales. There was an increased prevalence of poor performance for measures of motor output, verbal memory, and visuospatial organization. The distribution of the impairment index indicated moderate impairment across the school-age cohort rather than severe impairment in a few patients. CONCLUSION: The results document a moderate level of neuropsychological morbidity among children with brain tumors before stereotactic radiation therapy, presumably referable to the tumor itself and the surgery. The extent to which stereotactic radiation therapy may increase this burden will be assessed in follow-up studies evaluating the longitudinal neuropsychological data.
Adolescent↗
Therapeutic potential of thiazolidinediones as anticancer agents.
Thiazolidinediones (TZDs) are synthetic ligands that activate the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma). These compounds are widely used in the treatment of Type 2 diabetes. TZDs have antitumour activity in a wide variety of experimental cancer models, in vitro and in vivo, by affecting the cell cycle, induction of cell differentiation and apoptosis as well as by inhibiting tumour angiogenesis. These effects are mediated through both PPAR-gamma-dependent and -independent pathways depending on concentration and tumour cell type. Angiogenesis inhibition mechanisms of TZDs include directly inhibiting endothelial cell proliferation and migration as well as decreasing tumour cell vascular endothelial growth factor production. Further studies suggest that TZDs may be effective in prevention of certain cancers and in the treatment of cancer as adjuvant therapy.
Angiogenesis Inhibitors↗
Psychological adjustment of 'surgery-only' pediatric neuro-oncology patients: a retrospective analysis.
A recent increase in diagnoses of pediatric neuro-oncology tumors combined with recent advancements in medical treatment of such tumors has resulted in a growing cohort of pediatric brain tumor survivors. These survivors are at risk for short and long-term psychological adjustment problems. Most studies regarding these survivors have focused on children who have received combinations of surgery, radiation, and chemotherapy as medical treatment. The sub-group of pediatric neuro-oncology patients who receive surgery as the only form of medical treatment has not been closely followed for adjustment problems. In this study, data were retrospectively collected from semi-structured clinical interviews with 34 'surgery-only' pediatric neuro-oncology patients who were 2 weeks to 5 years off medical treatment for their tumor. These data suggest that these survivors may be experiencing significant short and long-term mood, behavioral, and academic adjustment problems in comparison to national averages for children regarding these issues. Additional research examining the psychological adjustment process for surgery-only pediatric neuro-oncology patients is needed to validate these preliminary findings and facilitate the development of targeted interventions to address the identified adjustment problems.
Adaptation, Psychological↗
Pulmonary vein stenosis: expression of receptor tyrosine kinases by lesional cells.
BACKGROUND: Primary pulmonary vein stenosis (PVS) is a progressive disorder of infants. Although catheter based intervention and chemotherapy are used to manage the disorder, the benefit of these approaches is reduced considerably by restenosis. The nature of the intimal cells causing the occlusive lesions in PVS is poorly understood. METHODS: Seven PVS cases were studied with antibodies for smooth muscle actin (SMA), muscle-specific actin (MSA), monoclonal desmin, S100 protein, CD31, CD34, CD45RO, CD68, CD99, Ki-67 (MIB-I), and with antibodies directed against several receptor tyrosine kinases (RTK), including platelet-derived growth factor alpha and beta receptor (PDGFR-alpha and -beta), epidermal growth factor receptor (EGFR), fibroblast growth factor receptor (FGFR), vascular endothelial growth factor 1 and 2 receptor (VEGFR), and stem cell factor receptor (c-kit). RESULTS: Lesional cells stained strongly and diffusely with SMA and MSA, but not for macrophage, lymphocyte, endothelial markers, or for Ki-67. RTK expression was strong and diffuse for PDGFR-alpha and -beta, FGFR, and VEGFR-2. Lesional cells stained for VEGF and PDGF beta receptor was phosphorylated. CONCLUSIONS: The histologic appearance, and the strong diffuse immunoreactivity for smooth muscle markers, indicates that the intimal lesional cells are myofibroblast-like. Expression of various receptor tyrosine kinases and some ligands suggests an autocrine or paracrine role of these proteins in the pathogenesis of the intimal occlusive lesion in PVS.
Animals↗
Chemotherapy for progressive low-grade gliomas in children older than ten years: the Dana-Farber experience.
The purpose of this retrospective study was to examine the clinical and radiographic response rates to and toxicity of chemotherapy for low-grade gliomas in children older than 10 years of age. Between June 1999 and January 2001, seven consecutive children between the ages of 10 and 18 were treated with vincristine and carboplatin +/- thioguanine, procarbazine, CCNU [lomustine], and vincristine (TPCV) for progressive low-grade gliomas. All 7 children completed a 10-week induction course of vincristine and carboplatin; 3 were switched to TPCV during the maintenance phase of therapy after developing an allergic reaction to carboplatin. Overall, 4 patients had a radiographic response to treatment with chemotherapy (3 partial responses and 1 minor response: objective response rate of 57%), and 2 more showed stable disease. One patient progressed while on treatment and 1 patient progressed off treatment, and after 31 months had elapsed. The resulting progression-free survival at the time of this report was 71%. The median duration of follow-up was 32 months (range 25-42 months). Hematologic toxicity was common, but did not result in cessation of therapy. No other significant treatment-related toxicities were observed. The results suggest that the clinical response/disease stabilization rate in children older than 10 years of age does not differ markedly from that observed in younger children. A prospective clinical trial of chemotherapy for progressive low-grade gliomas in children older than 10 years is therefore warranted.
Adolescent↗