Faculty Bibliography

The Sonic hedgehog (Shh) signaling pathway plays a critical role in normal cerebellar development and has been implicated in medulloblastomas, common malignant childhood tumors of the cerebellum. To test whether Shh mis-expression is sufficient for medulloblastoma formation, we used ultrasound biomicroscopy-guided in utero injection of a Shh-expressing retrovirus into the cerebellum of 13.5-day mouse embryos to show that direct activation of the Shh pathway can lead to tumor formation. Significantly, medulloblastomas were observed in 76% of the mice infected with Shh-expressing retrovirus. Furthermore, contrary to recent suggestions that the Shh transcriptional target Gli1 plays a critical role in Shh-induced tumorigenesis, we found that medulloblastomas form in Gli1 null mutant mice. We have developed an efficient mouse model of medulloblastoma and shown that Gli1 is not required for tumorigenesis when Shh signaling is activated upstream in the pathway

Magnetic resonance imaging (MRI) has been utilized for screening and detecting brain tumors in mice based upon their imaging characteristics appearance and their pattern of enhancement. Imaging of these tumors reveals many similarities to those observed in humans with identical pathology. Specifically, high-grade murine gliomas have histologic characteristics of glioblastoma multiforme (GBM) with contrast enhancement after intravenous administration of gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA), implying disruption of the blood-brain barrier in these tumors. In contrast, low-grade murine oligodendrogliomas do not reveal contrast enhancement, similar to human tumors. MRI can be used to identify mice with brain neoplasms as inclusion criteria in preclinical trials

Cap43 is a protein whose RNA is induced under conditions of severe hypoxia or prolonged elevations of intracellular calcium. Additionally, Ni and Co also induce Cap43 because they produce a state of hypoxia in cells. Cap43 protein is expressed at low levels in normal tissues; however, in a variety of cancers, including lung, brain, melanoma, liver, prostate, breast, and renal cancers, Cap43 protein is overexpressed in cancer cells. The low level of expression of Cap43 in some normal tissues compared with their cancerous counterparts, combined with the high stability of Cap43 protein and mRNA, makes the Cap43 gene a new, important cancer marker. We hypothesize that the mechanism of Cap43 overexpression in cancer cells involves a state of hypoxia characteristic of cancer cells where the Cap43 protein becomes a signature for this hypoxic state

The May 2002 COM. A 38-year-old man presented with new onset seizures and a 69-year-old woman presented with bilateral headaches and episodes of syncope. Both were found to have extra-axial masses that were contrast-enhancing and thought to be meningiomas. Both had complete resection. Microscopic examination revealed an inflammatory lesion composed of plasma cells, scattered lymphocytes and numerous large histocytic cells, which exhibited emperi polesis and were CD1 a negative, but positive for CD68 and S100. The diagnosis of Destombes-Rosai-Dorfman Disease (DRDD) was rendered. Both cases had good long-term outcome. The differential diagnosis of inflammatory masses in the dura (plasmacytoma, lymphomas, plasma cell fibroma, angiofollicular hyperplasia [Castleman's-disease] and Langerhan's cell histiocytosis) are discussed

Our purpose is to describe the incidence and clinical features of leptomeningeal dissemination (LM) in children with progressive low-grade neuroepithelial tumor (LGN). We have continuously tracked all patients with primary CNS tumors since 1986. Satisfactorily followed data were obtained on 427 of the 588 patients with localized LGN at diagnosis between 1986 and 1998, 177 (42%) of whom developed progressive or recurrent disease. LM was identified in 13/177 (7%). The median age at initial diagnosis was 5 years and at LM diagnosis was 8.5 years. The primary tumor sites were diencephalon (6), brainstem (3), cerebellum (2), cerebrum (1), and spinal cord (1). The histologies were pilocytic astrocytoma (4), ganglioglioma (4), fibrillary astrocytoma (3), mixed glioma (1), and glioneurofibroma (1). Management included chemotherapy (2) or radiotherapy (3) or both (7); 1 patient received only radical resections of symptomatic lesions. The 5-year progression-free survival rates for patients with localized versus LM disease at recurrence were 22% (95% confidence interval [CI], 13%-25%) versus 15% (95% CI, 0.1%-36%), respectively ( P = 0.28). The 5- and 10-year overall survival rates for patients with localized disease versus LM were 87% (95% CI, 82%-92%) and 83% (95% CI, 77%-89%) versus 68% (95% CI, 39%-91%) and 68% (95% CI, 39%-91%), respectively ( P = 0.05). The 7% incidence of LM is a low estimate because patients were not routinely staged at recurrence. Tumors arising from the diencephalon appeared to predispose to LM; no other predisposing features were identified. We strongly urge that for optimum treatment planning all patients with recurrent LGN be staged with an enhanced spine and brain MRI before adjuvant therapy is initiated. The good survival of patients with LGN and LM reflects a more indolent disease than malignant CNS tumors with LM

BACKGROUND AND PURPOSE: Tumefactive demyelinating lesions (TDLs) can simulate intracranial neoplasms in clinical presentation and MR imaging appearance, and surgical biopsy is often performed in suspected tumors. Proton MR spectroscopy has been applied in assessing various intracranial diseases and is increasingly used in diagnosis and clinical management. Our purpose was to determine if multivoxel proton MR spectroscopy can be used to differentiate TDLs and high-grade gliomas. METHODS: Conventional MR images, proton MR spectra, and medical records were retrospectively reviewed in six patients with TDLs diagnosed by means of biopsy or by documented clinical improvement, with or without supporting laboratory testing and follow-up imaging. Proton MR spectra of 10 high-grade gliomas with similar conventional MR imaging appearances were used for comparison. In contrast-enhancing, central, and perilesional areas of each lesion, peak heights of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were measured and the lactate peak noted. Cho/Cr and NAA/Cr ratios of corresponding regions in TDLs and gliomas were compared. RESULTS: No significant differences in mean Cho/Cr ratios were found in the corresponding contrast-enhancing, central, or perilesional areas of TDLs and gliomas. The mean central-region NAA/Cr ratio in gliomas was significantly lower than that of TDLs, but mean NAA/Cr ratios in other regions were not significantly different. A lactate peak was identified in four of six TDLs and three of 10 gliomas. CONCLUSION: In the cases examined, the NAA/Cr ratio in the central region of TDLs and high-grade gliomas differed significantly. However, overall metabolite profiles of both lesions were similar; this finding emphasizes the need for the cautious interpretation of spectroscopic findings

INI1/hSNF5 is a component of the ATP-dependent chromatin remodeling hSWI/SNF complex and a tumor suppressor gene of aggressive pediatric atypical teratoid and malignant rhabdoid tumors (AT/RT). To understand the molecular mechanisms underlying its tumor suppressor function, we studied the effect of reintroduction of INI1/hSNF5 into AT/RT-derived cell lines such as MON that carry biallelic deletions of the INI1/hSNF5 locus. We demonstrate that expression of INI1/hSNF5 causes G(0)-G(1) arrest and flat cell formation in these cells. In addition, INI1/hSNF5 repressed transcription of cyclin D1 gene in MON, in a histone deacetylase (HDAC)-dependent manner. Chromatin immunoprecipitation studies revealed that INI1/hSNF5 was directly recruited to the cyclin D1 promoter and that its binding correlated with recruitment of HDAC1 and deacetylation of histones at the promoter. Analysis of INI1/hSNF5 truncations indicated that cyclin D1 repression and flat cell formation are tightly correlated. Coexpression of cyclin D1 from a heterologous promoter in MON was sufficient to eliminate the INI1-mediated flat cell formation and cell cycle arrest. Furthermore, cyclin D1 was overexpressed in AT/RT tumors. Our data suggest that one of the mechanisms by which INI1/hSNF5 exerts its tumor suppressor function is by mediating the cell cycle arrest due to the direct recruitment of HDAC activity to the cyclin D1 promoter thereby causing its repression and G(0)-G(1) arrest. Repression of cyclin D1 gene expression may serve as a useful strategy to treat AT/RT

Following a car accident a 28-year-old female, complained of a sharp pain of the anterior and posterior base of the neck on expiration and with exertion. Subsequently, she noticed a feeling of discomfort in her back when lifting her arm above her head. Imaging studies revealed a tumor mass involving the third intercostal nerve on the right side of T2. The differential diagnosis included neurofibroma and neurilemmoma. This was followed annually and five years later an increase in size warranted a transthoracic, transpleural removal en bloc of this lesion. At surgery, a 3 cm soft tissue tumor engulfed the third intercostal nerve and extended into the third intervertebral foramen where the proximal part of the nerve root was enlarged. The right third intercostal nerve was dissected and removed along with the tumor, after negative nerve stimulation. Histopathological examination showed multiple enlarged coalescent lymphoid follicles with an onion skin appearance of tight concentric layering of small, uniform mature lymphocytes at the periphery, arranged in a targetoid fashion with broad mantle zones and relatively small germinal centers. The germinal centers of variable size included hyalinized blood vessels. Lollipop follicles were seen. The interfollicular stroma showed numerous hyperplastic collagenized capillaries within an inflammatory background. However, the perinodal soft tissue was replaced by numerous inflammatory cells, primarily lymphocytes. The final diagnosis was Castleman's disease, hyaline vascular type. Castleman's disease can mimic various tumors and because Castleman's disease is a rare reactive entity, its diagnosis is generally overlooked by radiologists and clinicians. It is likely that this mass arose from one of the posterior intercostal lymph nodes, situated in the paravertebral region, however the capsule was not readily seen and the sinuses were not apparent. Almost all previous cases of Castleman's disease, hyaline vascular type were described in the anterior mediastinum. Hyaline vascular Castleman's disease usually does not invade and replace neighboring structures. This case is unique because of its location and the local invasion of adjacent structures

BACKGROUND: Endometrial cancer is the most common malignancy involving the female genital tract in the United States. There is a paucity of reports of brain metastases in this disease, and most of these reports emphasize that this pattern of dissemination is rare. CASE: We present a case of a 63-year-old woman who had high-grade endometrial carcinoma treated with surgery and radiotherapy. She had three separate episodes of relapse in the lungs, the first two relapses being treated surgically. Chemotherapy was also administered following surgery for the first relapse. The third pulmonary recurrence was treated with chemotherapy and then consolidated with thoracic radiation. Four years from the date of diagnosis, and a few weeks after completion of thoracic radiotherapy, she had evidence of a solitary cerebellar metastasis. This was treated surgically and followed by whole brain irradiation. She died 6 months after this central nervous system diagnosis with systemic dissemination of her cancer. CONCLUSION: The existing literature on brain metastases from endometrial cancer is reviewed together with the patterns of spread of endometrial cancer. We call attention to the unusually long course of this patient. Partially successful treatment for metastatic disease may have predisposed eventual development of brain metastases. This occurrence reinforces reports emphasizing their increasing incidence in association with endometrial cancer

Enhanced expression of tenascin-C (TN-C) at the invasive edges of glioblastoma multiforme in close association with vascular sprouts, suggests a role for TN-C in microvascular cell migration. To test this hypothesis, we studied the migration of endothelial cells in vitro. In an aggregate migration assay, bovine retinal endothelial cells (BRECs) and human umbilical vein endothelial cells spread and migrated similarly on TN-C or fibronectin (FN). In contrast, U251 MG glioma cells migrated less on TN-C than on FN. Morphological features of U251 MG glioma cells on TN-C included poor cell spreading and short processes. In contrast, on FN, U251 MG glioma cells spread and exhibited long radial processes. Using a transmembrane migration assay, we observed that BREC adhesion was similar on TN-C or FN, whereas U251 MG glioma cells adhered better to FN than to TN-C. In addition, BRECs migrated more across the membrane toward regions coated with TN-C than FN, and conversely, U251 MG glioma cells migrated more toward FN than TN-C. Migration of endothelial and glioma cells toward TN-C or FN occurred in a dose-dependent manner and was strongly dependent on cell adhesion. In this assay, ultrastructural study revealed the migrating phenotype of the endothelial cells through the micropores of the membrane and their spread morphology on TN-C. Moreover, in situ hybridization revealed specific expression of TN-C in migrating microvascular cells in a cerebral microvascular ring assay. Finally in a phosphorylation assay, TN-C enhanced focal adhesion kinase phosphorylation of BRECs, but not of U251 MG glioma cells, and FN enhanced focal adhesion kinase phosphorylation of both BRECs and U251 MG cells. The expression of TN-C by migrating endothelial cells and the promotion of endothelial cell adhesion and migration by TN-C suggest a potential role for TN-C in pathological angiogenesis