Neuropathology in Canada: the first one hundred years.

We describe the evolution of neuropathology in Canada, beginning with William Osler who began working in Montréal in 1874 and finishing with the major period of expansion in the 1970s. Organized services began in the 1930s, in Montréal with the neurosurgeons Wilder Penfield and William Cone, and in Toronto with Eric Linell and Mary Tom, who both began their careers as neuroanatomists. Jerzy Olszewski and Gordon Mathieson, who trained in Montréal and Toronto, drove the creation of the Canadian Association of Neuropathologists in 1960. Training guided by the Royal College of Physicians and Surgeons of Canada was formalized in 1965, with the first certifying examination in 1968 and the subsequent creation of formal structured training programs. The number of neuropathologists in Canada increased rapidly through the 1960s and 1970s, with individuals coming from both clinical neuroscience and anatomic pathology backgrounds, a pattern that persists to the present day.

Pseudoglandular elements in schwannomas.

CONTEXT: Uncommon examples of schwannomas are seen in which a coexisting glandular component is present. The pseudoglandular schwannoma is a relatively recently described variant in which cystic spaces are lined by pseudocolumnar or cuboidal-like neoplastic Schwann cells exhibiting an epithelial-like appearance. OBJECTIVES: To determine the incidence of pseudoglandular elements in schwannomas, to describe the variable morphology of the schwannomas that may contain pseudoglandular elements, and to discuss the potential mechanisms of development and biological significance of these elements. DESIGN: We screened 202 schwannomas from any anatomic site for the presence of pseudoglandular elements and examined these with light microscopy, immunohistochemistry, and electron microscopy. RESULTS: Sixteen (7.9%) of the schwannomas contained pseudoglandular elements, which ranged from poorly to well organized in appearance and which were found in schwannomas exhibiting a wide range of morphologic appearances. The Schwann cell nature of the cells composing these elements was apparent both immunohistochemically and ultrastructurally. The frequency of proliferative activity within these elements was no greater than that observed throughout the remainder of the respective schwannomas. CONCLUSIONS: Our observations suggest that, rather than representing a distinct phenotypic schwannoma variant, pseudoglandular elements likely arise as a response to a degenerative phenomenon, perhaps reflecting the propensity that the Schwann cell has to palisade formation. Such elements may be found within a variety of schwannoma variants and do not appear to possess a unique growth potential.

Reovirus prolongs survival and reduces the frequency of spinal and leptomeningeal metastases from medulloblastoma.

Medulloblastoma (MB), the most common pediatric brain tumor, is a highly malignant disease with a 5-year survival rate of only 60%. Tumor cells invade surrounding tissue and disseminate through cerebral spinal fluid, making treatment difficult. Human reovirus type 3 exploits an activated Ras pathway in tumor cells to support productive infection as an oncolytic virus. Here, we examined the ability of human reovirus to kill MB cells lines and surgical specimens in vitro and inhibit tumor growth/metastases in vivo. Most human MB cell lines tested (five of seven = 71.4%), two MB cell lines derived from spontaneously arising tumors in Patched-1(+/-) mice (two of two = 100%) and three MB primary cultures derived from surgical specimens, were susceptible to reovirus infection. Reovirus was internalized and transcribed in both susceptible and resistant cell lines. However, viral protein synthesis was restricted to cell lines with higher levels of activated Ras, suggesting that Ras plays a critical role in reovirus oncolysis in MB. Using an in vivo Daoy orthotopic animal model, we found that a single i.t. injection of reovirus dramatically prolonged survival compared with controls (160 versus 70 days, respectively; P = 0.0003). Repeating this experiment with GFP-labeled Daoy cells and multiple i.t. administrations of reovirus, we again found prolonged survival and a dramatic reduction in spinal and leptomeningeal metastases (66.7% in control injections versus 0.0% in the live virus group). These data suggest that this oncolytic virus may be a potentially effective novel therapy against human MB. Its ability to reduce metastases to the spinal cord could allow a reduction in the dose/field of total neuroaxis cerebral-spinal radiotherapy currently used to treat/prevent cerebral spinal fluid dissemination.

Targeting leukocyte MMPs and transmigration: minocycline as a potential therapy for multiple sclerosis.

Multiple sclerosis is characterized by the infiltration of leukocytes into the CNS. As matrix metalloproteinases (MMPs) facilitate the passage of leukocytes across matrix barriers, we tested the hypothesis that targeting MMPs could attenuate neuro-inflammation. We report that minocycline, a widely used generic drug with a good safety record, inhibited MMP activity, reduced production of MMP-9 and decreased the transmigration of T lymphocytes across a fibronectin matrix barrier. In addition, minocycline was efficacious against both mild and severe experimental autoimmune encephalomyelitis (EAE) in mice, an animal model of multiple sclerosis. When severe EAE was produced, minocycline pre-treatment delayed the course of the disease: when maximal disease activity occurred in vehicle-treated EAE mice, minocycline animals were relatively normal and had minimal signs of inflammation and demyelination in the CNS. When tested in mice afflicted with mild EAE, minocycline attenuated the clinical severity of disease throughout the course of treatment. These results indicate that minocycline may constitute a safe and inexpensive therapy for multiple sclerosis.