Publications (268) View all
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Article: Clinic-pathological description of three paediatric medulloblastoma cases with MLL2/3 gene mutations.
Neuropathology and Applied Neurobiology 05/2013; · 3.80 Impact Factor -
Article: Clinicopathological characteristics and treatment of rhabdoid glioblastoma.
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ABSTRACT: Object Rhabdoid glioblastoma (GB) is an exceedingly rare tumor in which some of the tumor cells possess rhabdoid features such as eccentric nuclei, abundant eosinophilic cytoplasm, and pseudopapillary formations. These tumors are exceptionally aggressive, and leptomeningeal dissemination is common. In the 9 previously reported cases, the longest survival was only 9 months, with a median survival of 17.8 weeks. The authors report the clinicopathological characteristics of 4 cases of rhabdoid GB and demonstrate the utility of intensive temozolomide and adjuvant therapy in these tumors. The authors also review the literature to provide the most comprehensive understanding of these rare tumors to date. Methods A retrospective review was performed of patients treated for GB at the Duke University Medical Center between 2004 and 2012. One of two experienced neuropathologists identified 4 cases as being rhabdoid GBs. Immunohistochemistry and fluorescence in situ hybridization analyses were performed in all cases. Kaplan-Meier analysis was used to assess overall survival, with the log-rank test being used to evaluate differences between survival curves. An extensive review of the literature was also performed. Results The median age of patients with rhabdoid GB was 30 years. Clinical presentation varied with location, with headache being a presenting symptom in 90% of patients. All lesions were supratentorial, and 45.5% of the cases involved the temporal lobe. Leptomeningeal dissemination occurred in 63.6% of patients, with 1 patient having extracranial metastasis to the scalp and lungs. Fluorescence in situ hybridization revealed epidermal growth factor receptor gain or amplification in all study cases. The median survival in the authors' cohort was significantly higher than that of all previously reported cases (27.5 vs 4.5 months, p = 0.003). Postoperative treatment in the authors' cohort included radiotherapy with concurrent temozolomide, bevacizumab, interleukin 13, CCNU, and/or etoposide. Conclusions Enhanced survival in the authors' 4 patients suggests that the current standard of care for the treatment of GB may be beneficial in rhabdoid GB cases, with postoperative radiotherapy and concomitant temozolomide treatment followed by adjuvant therapy. Due to the rapid tumor dissemination associated with these lesions, aggressive and timely therapy is warranted, with frequent surveillance and/or continued therapy despite stable disease. Additionally, patients should undergo full craniospinal imaging to monitor the development of distant metastatic disease.Journal of Neurosurgery 05/2013; · 2.96 Impact Factor -
Article: Intraaxial dermoid cyst of the medulla.
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ABSTRACT: Intracranial dermoid cysts are rare congenital lesions that typically occur in the cisternal spaces. However, exceptionally rare cases of intraaxial involvement have been reported, with only 8 cases having been described in the literature. The authors report the first case of an intraaxial dermoid cyst located in the medulla and the first occurrence in an elderly patient. They also review the literature of the existing intraparenchymal cases and provide treatment guidelines. A 66-year-old man presented with slowly progressive dysphagia, left lower-extremity numbness, nausea, and hyperhidrosis. Neurological examination revealed decreased pinprick sensation of the left side of his face and body, and decreased vibratory sensation in his left lower extremity. Additionally, he had an unusual extraocular movement in which abduction of the eye resulted in closure of the contralateral eye. Magnetic resonance imaging revealed a nonenhancing cystic lesion centered in the medulla. The patient underwent a suboccipital craniotomy with laminectomy of C1-2 for excision of the cyst, with subtotal resection due to adherence of the cyst wall to the brainstem. At follow-up 7.5 years after surgery, the patient's neurological examination was stable. Magnetic resonance imaging did not reveal any progression or recurrence of the cyst. As the cyst wall is typically adherent to surrounding structures, resection is usually subtotal due to the risk of neurological deficits. As there have been no cases of progression after subtotal resection, gross-total resection is not warranted for the treatment of these lesions.Journal of Neurosurgery 04/2013; · 2.96 Impact Factor -
Article: Glioblastoma stem cells generate vascular pericytes to support vessel function and tumor growth.
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ABSTRACT: Glioblastomas (GBMs) are highly vascular and lethal brain tumors that display cellular hierarchies containing self-renewing tumorigenic glioma stem cells (GSCs). Because GSCs often reside in perivascular niches and may undergo mesenchymal differentiation, we interrogated GSC potential to generate vascular pericytes. Here, we show that GSCs give rise to pericytes to support vessel function and tumor growth. In vivo cell lineage tracing with constitutive and lineage-specific fluorescent reporters demonstrated that GSCs generate the majority of vascular pericytes. Selective elimination of GSC-derived pericytes disrupts the neovasculature and potently inhibits tumor growth. Analysis of human GBM specimens showed that most pericytes are derived from neoplastic cells. GSCs are recruited toward endothelial cells via the SDF-1/CXCR4 axis and are induced to become pericytes predominantly by transforming growth factor β. Thus, GSCs contribute to vascular pericytes that may actively remodel perivascular niches. Therapeutic targeting of GSC-derived pericytes may effectively block tumor progression and improve antiangiogenic therapy.Cell 03/2013; 153(1):139-52. · 32.40 Impact Factor -
Article: TERT promoter mutations occur frequently in gliomas and a subset of tumors derived from cells with low rates of self-renewal.
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ABSTRACT: Malignant cells, like all actively growing cells, must maintain their telomeres, but genetic mechanisms responsible for telomere maintenance in tumors have only recently been discovered. In particular, mutations of the telomere binding proteins alpha thalassemia/mental retardation syndrome X-linked (ATRX) or death-domain associated protein (DAXX) have been shown to underlie a telomere maintenance mechanism not involving telomerase (alternative lengthening of telomeres), and point mutations in the promoter of the telomerase reverse transcriptase (TERT) gene increase telomerase expression and have been shown to occur in melanomas and a small number of other tumors. To further define the tumor types in which this latter mechanism plays a role, we surveyed 1,230 tumors of 60 different types. We found that tumors could be divided into types with low (<15%) and high (≥15%) frequencies of TERT promoter mutations. The nine TERT-high tumor types almost always originated in tissues with relatively low rates of self renewal, including melanomas, liposarcomas, hepatocellular carcinomas, urothelial carcinomas, squamous cell carcinomas of the tongue, medulloblastomas, and subtypes of gliomas (including 83% of primary glioblastoma, the most common brain tumor type). TERT and ATRX mutations were mutually exclusive, suggesting that these two genetic mechanisms confer equivalent selective growth advantages. In addition to their implications for understanding the relationship between telomeres and tumorigenesis, TERT mutations provide a biomarker that may be useful for the early detection of urinary tract and liver tumors and aid in the classification and prognostication of brain tumors.Proceedings of the National Academy of Sciences 03/2013; · 9.68 Impact Factor
