Challenges in neurosurgical intraoperative consultation.

BACKGROUND: Intraoperative consultation for neurosurgical specimens can be difficult at times, despite the use of both frozen section and squash preparation. Various factors influence the diagnostic accuracy of these procedures. This study was conducted to evaluate reasons for discordant case results in neurosurgical intraoperative consultations and make a comparative analysis of these two commonly used methods to identify the possible pitfalls, errors, and limitations. MATERIALS AND METHODS: All the neurosurgical cases received in the Department of Pathology for intraoperative consultation over a period of 3 years were studied retrospectively. The slides of frozen sections and squash preparation were retrieved and the diagnosis was compared with the final diagnosis given on paraffin-embedded sections. RESULTS AND OBSERVATIONS: A total of 6% of the cases were found to be discordant; these included angiomatous meningioma, Non-Hodgkins lymphoma, metastatic renal cell carcinoma, cerebellopontine angle fibrous meningioma, and craniopharyngioma. Highly vascular lesions, unavailability of squash preparation in a few cases and technical errors like thick smears, excessively crushed specimen, freezing, and cautery induced and crushing artifacts contributed to misdiagnosis. CONCLUSION: The discrepant cases need to be reviewed regularly by pathologists to familiarize themselves with the morphological changes and artifacts. The knowledge of possible errors could minimize misinterpretation and help in providing a more conclusive opinion to the operating surgeon.

Ligand-dependent activation of the hedgehog pathway in glioma progenitor cells.

The hedgehog (Hh) signaling pathway regulates progenitor cells during embryogenesis and tumorigenesis in multiple organ systems. We have investigated the activity of this pathway in adult gliomas, and demonstrate that the Hh pathway is operational and activated within grade II and III gliomas, but not grade IV de novo glioblastoma multiforme. Furthermore, our studies reveal that pathway activity and responsiveness is confined to progenitor cells within these tumors. Additionally, we demonstrate that Hh signaling in glioma progenitor cells is ligand-dependent and provide evidence documenting the in vivo source of Sonic hedgehog protein. These findings suggest a regulatory role for the Hh pathway in progenitor cells within grade II and III gliomas, and the potential clinical utility of monitoring and targeting this pathway in these primary brain tumors.

CXCR4 expression mediates glioma cell invasiveness.

Glioblastoma multiforme is a highly invasive tumor bearing a dismal prognosis. Experimental strategies that focus on the specific biological cues governing the invasive capacity of these tumors may hold significant therapeutic promise. In this context, we describe the in vitro and in vivo association of the cell surface chemokine receptor, CXCR4, with the development of an invasive phenotype in malignant glioblastoma. We demonstrate that invasive populations of glioma cells overexpress CXCR4 at the message and protein levels, and that this expression ranges from 25- to 89-fold higher than that found in noninvasive tumor cells. Furthermore, neutralization of CXCR4 significantly impairs the in vitro invasive capacity of malignant glial cells. In addition, glioma cells secrete CXCL12 and demonstrate robust invasive capacity toward a CXCL12 gradient in vitro. These findings underscore the importance of CXCR4 as a potential therapeutic target for the treatment of invasive glioblastoma.

A herpes simplex virus type 1 mutant deleted for gamma34.5 and LAT kills glioma cells in vitro and is inhibited for in vivo reactivation.

To create an oncolytic herpes simplex virus type 1 (HSV-1) that is inhibited for reactivation, we constructed a novel herpes recombinant virus with deletions in the gamma34.5 and LAT genes. The LAT gene was replaced by the gene for green fluorescent protein, thereby allowing viral infection to be followed. This virus, designated DM33, is effective in killing primary and established human glioma cell lines in culture. DM33 is considerably less virulent following intracerebral inoculation of HSV-susceptible BALB/c mice than the wild-type HSV-1 strain McKrae. The safety of this virus is further supported by the retention of its sensitivity to ganciclovir and its relatively limited toxicity against cultured human neuronal cells, astrocytes, and endothelial cells. The ability of DM33 to spontaneously reactivate was tested in a rabbit ocular infection model that accurately depicts human herpes infection and reactivation. Following ocular infection of rabbits, spontaneous reactivation was detected in 83% (15/18) of the eyes infected with wild-type McKrae. In contrast, none of the eyes infected with DM33 had detectable reactivation. The efficacy of this virus in cultured human glioma cell lines, its safety, confirmed by its inability to reactivate, and its attenuated neurovirulence make DM33 a promising oncolytic agent for tumor therapy.

Prognostic indicators of childhood acute viral encephalitis.

OBJECTIVE: To devise a set of clinical signs and laboratory parameters that would help clinicians assess prognosis in patients and plan appropriate management. METHODS: Medical records of 147 paediatric cases (with a discharge diagnosis of acute viral encephalitis) admitted over a ten year period from 1987 to 1997 were reviewed and relevant information collected on a data extraction form. RESULTS: Of 147 patients, 24 (16.3%) died and 48 (32.7%) were left with severe neurological deficits. A GCS (Glasgow Coma Scale) score between 6-10 had an association with poor outcome (OR = 2.62, Chi-square = 5.57, p-value = 0.018) and that a GCS score of > or = 5 was even more strongly suggestive of poor outcome (OR = 5.49, Chi-square = 12.08, p-value = 0.0005). A history of having seizures, for more than 3 days, also showed a strong association with poor outcome (OR = 3.66, Chi-square = 5.46, p-value = 0.019). CONCLUSION: Patients with an increased risk of death and severe disability can be identified using a few guidelines. Of these, a history of seizures of > 3 days and/or impaired consciousness (GCS < or = 10), at the time of presentation to the hospital, constitute high risk. These cases must be identified promptly and aggressive therapy initiated in order to improve long term outcome.