Citations

Abstract The history of meningioma is reviewed, highlighting the personalities and events that shaped our understanding and management of this tumor. Early descriptions, nomenclature, and the history of surgical removal of meningioma are discussed and the important role of this tumor in the development of neurosurgery as a whole is stressed.

Abstract Forty-four cases of meningeal hemangiopericytoma that were treated between 1938 and 1987 are reviewed. Fifty-five percent of these tumors occurred in men. The average age of the patients at diagnosis was 42 years. The average duration of preoperative symptoms was 11 months. Symptoms were related to tumor location, which was similar to that of meningioma. The operative mortality was 9% overall, and has been zero since 1974 (18 patients). The average time before the first recurrence was 47 months, with the recurrence rates at 1, 5, and 10 years after surgery being 15, 65, and 76%, respectively. Ten patients have developed extraneural metastasis, mostly to lung and bone, at an average of 99 months after the first operation. The 10- and 15-year rates of metastasis were 33 and 64%, respectively. The average survival period has been 84 months, with survival rates at 5, 10, and 15 years after surgery of 67, 40, and 23%, respectively. The histological diagnosis of the tumor was not related to survival or recurrence and did not change with recurrence. Tentorial and posterior fossa tumors tended to be more lethal. Total tumor resection favorably affected recurrence and survival, as opposed to subtotal resection. Metastasis adversely affected survival, and was followed by death at an average of 24 months after its diagnosis. Radiation therapy after the first operation extended the average time before first recurrence from 34 to 75 months, and extended survival from 62 to 92 months.

Abstract Dendritic cells (DCs) are professional APCs that reside in peripheral tissues and survey the body for pathogens. Upon activation by inflammatory signals, DCs undergo a maturation process and migrate to lymphoid organs, where they present pathogen-derived Ags to T cells. DC migration depends on tight regulation of the actin cytoskeleton to permit rapid adaptation to environmental cues. We investigated the role of hematopoietic lineage cell-specific protein 1 (HS1), the hematopoietic homolog of cortactin, in regulating the actin cytoskeleton of murine DCs. HS1 localized to lamellipodial protrusions and podosomes, actin-rich structures associated with adhesion and migration. DCs from HS1−/− mice showed aberrant lamellipodial dynamics. Moreover, although these cells formed recognizable podosomes, their podosome arrays were loosely packed and improperly localized within the cell. HS1 interacts with Wiskott–Aldrich syndrome protein (WASp), another key actin-regulatory protein, through mutual binding to WASp-interacting protein. Comparative analysis of DCs deficient for HS1, WASp or both proteins revealed unique roles for these proteins in regulating podosomes with WASp being essential for podosome formation and with HS1 ensuring efficient array organization. WASp recruitment to podosome cores was independent of HS1, whereas HS1 recruitment required Src homology 3 domain-dependent interactions with the WASp/WASp-interacting protein heterodimer. In migration assays, the phenotypes of HS1- and WASp-deficient DCs were related, but distinct. WASp−/y DCs migrating in a chemokine gradient showed a large decrease in velocity and diminished directional persistence. In contrast, HS1−/− DCs migrated faster than wild-type cells, but directional persistence was significantly reduced. These studies show that HS1 functions in concert with WASp to fine-tune DC cytoarchitecture and direct cell migration.

Abstract Rationale: Given recent success in delivering interferon-beta (IFNβ) using replication incompetent adenovirus in patients with malignant pleural effusions, we hypothesized that vectors that could replicate (inducing oncolysis) and express IFNβ at high level would be more effective. Both vaccinia virus (VV) and vesicular stomatitis (VSV) expressing mouse IFNβ have been constructed in a manner to improve their safety and efficacy as oncolytic vectors. In this study, we evaluated these two oncolytic vectors in different murine thoracic cancer models for clinical translation. Experimental procedures: We compared the efficacy of VVIFNβ and VSVIFNβ to kill 3 mouse lung cancer and 4 mouse mesothelioma lines in vitro over a 5 day-period assessing cell viability by MTT assay. The amount of IFNβ produced by these two vectors were measured with ELISA. The viral replication in infected mice was assessed by measuring viral titers in both immunocompetent and immunodeficient mice bearing an IFN-non-responsive AB12 tumor, following intratumoral injection of either vector at 108 pfu/mouse. To assess their anti-tumor activity, the two vectors were also given at 108 pfu/mouse intratumorally in mice bearing two lung cancer tumors on their flanks. Results: The replication of VSVIFNβ and its killing ability was limited in some of the tumor lines. This appeared to be due to an intact IFN response pathway. In contrast, VVIFNβ was able to kill all of the tumor lines. In culture, VSV replicates faster than VV, which resulted in faster cell killing (in susceptible cell lines), but with less IFNβ production. The amount of IFNβ production by VVIFNβ was comparable with AdIFNβ over a 5 day period. VVIFNβ-infected immunodeficient mice showed minimal or no toxicity when given virus intravenously, while all 5 mice infected with VSVIFNβ developed neurotoxicity within a week. In the TC-1 lung cancer model, VVIFNβ caused tumor regression, while VSVIFNβ and AdIFNβ were completely ineffective. In a second model using LKRM2, all 3 viral vectors were equivalent. The anti-tumor effect of VVIFNβ was shown to be mainly CD8 dependant, as depletion of CD8 with antibody dampened the tumor growth inhibition from 48% to 20%. Conclusions: Overall, VVIFNβ appears to be a better oncolytic vector than VSVIFNβ for a number of reasons: 1) it is safer, 2) it is able to replicate in vitro and in vivo in almost every cell line tested, 3) it induces longer and larger IFNβ production, and 4) it can potentially be given intravenously. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1513.

Abstract A better understanding of the antagonistic interaction and cross-talk between the pivotal oncogenic and tumor suppressor signaling pathways, and the concerted cancer signaling networks that control tumorigenesis and metastasis should give rise to novel therapeutic interventions. Hyperactivated ERBB/RAS is known to drive neoplastic transformation, tumorigenesis and metastasis in a large percentage of human cancers, and thus finding novel measures to countervail activated EGFR/HER2/RAS signals to reverse tumorigenesis and metastasis remains an important goal in cancer biology. Instead of targeting an upstream signaling component, we targeted the most downstream signaling module in the ERBB/RAS pathway, the SIAH-dependent proteolytic machinery. SIAHs are evolutionarily conserved RING E3 ligases that are the critical downstream “gatekeeper” signaling modules in the RAS signal transduction pathway. We show that human SIAH E3 ligase is upregulated in proliferating tumor cells in human tumor specimens, and that proper SIAH function is required for RAS signal transduction. By inhibiting SIAH2 E3 ligase, we have blocked both tumorigenesis and metastasis in eleven of the most aggressive human cancer cell lines known in athymic nude mice. Our observations highlight the important roles that SIAH2 plays in RAS-dependent tumorigenesis and metastasis in human cancer. In this study, we aim to identify the molecular mechanism underlying SIAH2 deficiency-mediated growth inhibition in human cancer cells. We have found that SMAD2/3/4 - the essential downstream mediators of TGFβ signaling, are novel SIAH2 substrates in that SIAH2 physically interacts with, ubiquitinates and degrades SMAD2/3/4 (not SMAD1). The identification of SIAH2-mediated SMAD2/3/4 modulation may provide an additional molecular mechanism to explain the well documented, but less understood RAS-TGFβ antagonism described in normal development, tumorigenesis and metastasis. We propose that the tumor promoting activity of SIAH2 may be mediated through the degradation of SMAD2/3/4 proteins which enhancing the growth-promoting activity of the RAS pathway while suppressing the growth inhibitory action of the TGFβ pathway. Since the substrate specificity of ubiquitin-mediated proteolysis is primarily determined by the E3 ligase, our results provide new insights into the role of altered proteolysis in mediating the RAS-TGFβ antagonism and cross-talk observed in the genesis and progression of human cancers. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5073.

Abnormal copper metabolism has been linked with neurological disorders, such as Wilson and Menkes disease. Another disorder causing symptoms similar to copper metabolism disorder is Niemann-Pick type C. However, a definite pathophysiological connection between Niemann-Pick type C and copper metabolism disorders has never been established. The authors present an adolescent with an unusual presentation of copper deficiency—dysarthria, ataxia, and vertical gaze paresis, without significant cognitive degeneration or pathological magnetic resonance imaging (MRI). The patient was found to carry 2 mutations in the NPC1 gene. A possible link, explaining how copper deficiency might induce the Niemann-Pick phenotype might involve overproduction of cholesterol and inhibition of acid sphingomyelinase. We suggest that copper metabolism disorders be included in the differential diagnosis for ataxia and dysarthria, even in cases with unusual presentations. Moreover, should the connection between copper and Niemann-Pick be validated, screening for copper metabolism disorders may be advisable in Niemann-Pick type C patients and vice-versa.