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  • Author or Editor: Linda B. Thomas x
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Howard Broder, Andrea Anderson, Sylvia K. Odesa, Thomas J. Kremen and Linda M. Liau

Object

Dendritic cells (DCs) are potent antigen-presenting cells that have been shown to play a critical role in the initiation of host immune responses against tumor antigens. In this study, a recombinant adenovirus vector encoding the melanoma-associated antigen, MART-1, was used to transduce murine DCs, which were then tested for their ability to activate cytotoxic T lymphocytes (CTLs) and induce protective immunity against B16 melanoma tumor cells implanted intracranially.

Methods

Genetic modification of murine bone marrrow–derived DCs to express MART-1 was achieved through the use of an E1-deficient, recombinant adenovirus vector (AdVMART1). Sixty-two C57BL/6 mice were immunized by subcutaneous injection of AdVMART-1-transduced DCs (23 mice), untransduced DCs (17 mice), or sterile saline (22 mice). Using the B16 murine melanoma, which naturally expresses the MART-1 antigen, all the mice were then challenged intracranially with viable, unmodified syngeneic B16 tumor cells 7 days later. Splenocytes obtained from representative animals in each group were harvested for standard cytotoxicity and enzyme-linked immunospot assays. The remaining mice were followed for survival.

Immunization of C57BL/6 mice with DCs transduced with AdVMART1-DC elicited the development of antigen-specific CTL responses. As evidenced by a prolonged survival curve when compared with control-immunized mice harboring intracranial B16 tumors, AdMART1-DC vaccination was able to elicit partial protection against central nervous system (CNS) tumor challenge in vivo. However, this CNS antitumor immunity was weaker than that previously demonstrated against subcutaneous B16 tumors in which the same vaccination strategy was used.

Conclusions

These data suggest that immune responses generated against CNS tumors by DC-based vaccines may be different from those obtained against subcutaneous tumors.

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Isaac Yang, Thomas J. Kremen, Adrian J. Giovannone, Elena Paik, Sylvia K. Odesa, Robert M. Prins and Linda M. Liau

Object

Little is known about the quantitative modulation of major histocompatibility complex (MHC) Class I expression on human gliomas that is effected by interferons; even less is known about the immunogenic peptides that are accommodated in the peptide-binding motifs of MHC Class I alleles in these brain tumors. In this article the authors investigated the ability of interferon (IFN)α and IFNγ to upregulate MHC Class I expression and to modulate acid-eluted Class I—bound peptides on human glioblastoma multiforme (GBM) cells in vitro.

Methods

Early-passage primary human GBM cell cultures and U87MG GBM cells were incubated with varying doses of INFα or IFNγ ranging between 0 and 2000 U/ml. Upregulation of MHC Class I expression was assayed by immunocytochemical analysis, flow cytometry, and Western blot analysis. Modulation of acid-eluted MHC Class I—bound peptides from the IFN-treated GBM cells was examined with the aid of mass spectroscopy.

The in vitro expression of the MHC Class I molecule was upregulated by both IFNα and IFNγ in a dose-dependent manner. Interferon-γ exhibited a more potent effect on MHC Class I upregulation, peaking at 10 U/ml; whereas the effect of IFNα was less marked, reaching a plateau at 500 U/ml. In addition, a native peptide eluted from MHC Class I molecules of human GBM cells was identified and found to be consistently upregulated by IFN treatment.

Conclusions

Interferon-α and IFNγ can significantly upregulate the MHC Class I molecules that are expressed on the cell surface of human GBM cells as well as the potentially immunogenic peptides bound to the MHC. These results may help explain the molecular basis for increased immunogenicity with IFN treatment of human GBMs and might provide added insight into the design of future antitumor vaccines for human brain tumors.

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Delbert E. Evans, Philip W. Catron, James J. McDermott, Linda B. Thomas, Arthur I. Kobrine and Edward T. Flynn

✓ To investigate possible approaches to the treatment of neural damage induced by air embolism and other forms of acute cerebral ischemia, somatosensory evoked potentials (SEP's) were measured after cerebral air embolism in the anesthetized cat. Air was introduced into the carotid artery in increments of 0.08 ml until the SEP amplitude was reduced to approximately 10% or less of baseline values. Either a saline or lidocaine infusion was begun 5 minutes after inducing cerebral ischemia. In the saline-treated group, SEP amplitude was reduced to 6.7% ± 1.6% (mean ± standard error of the mean) of baseline, with a return to 32.6% ± 4.7% of baseline over a 2-hour period. In the lidocaine-treated group, SEP amplitude was reduced to 5.9% ± 1.5%, with a return to 77.3% ± 6.2% over a 2-hour period. The results suggest that lidocaine administration facilitates the return of neural function after acute cerebral ischemia induced by air embolism.

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Peter M. Grossi, Michael J. Ellis, Thomas J. Cummings, Linda L. Gray, Takanori Fukushima and John H. Sampson

✓Cholesterol granulomas (CGs) are benign lesions resulting from an inflammatory reaction to cholesterol and hemosiderin. These masses most often arise within the temporal bone or nasal sinuses; intracerebral CGs are extremely rare. In this report the authors present an unusual case of a CG arising within the lateral ventricle.

The patient presented with transient hemiparesis and numbness. Computed tomography and magnetic resonance imaging demonstrated a cystic partially enhancing midline mass within the right lateral ventricle, expanding the ventricle and displacing the septum pellucidum. The patient underwent an interhemispheric, transcallosal resection of the lesion. Microscopic examination revealed a granulomatous inflammatory lesion containing cholesterol clefts, macrophages, and hemosiderin. Embedded within the granulomatous response were foci of tiny cystlike structures lined by nonciliated flattened cuboidal epithelium, consistent with the diagnosis of CG.

To the authors' knowledge this is the first reported case of CG presenting as an intraventricular mass. The origin of this lesion is unclear, but it may relate to prior traumatic brain injury. The authors describe the presentation, imaging findings, histopathological characteristics, and surgical treatment of this rare lesion and related pathological entities.

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Harvey S. Levin, Gerri Hanten, Garland Roberson, Xiaoqi Li, Linda Ewing-Cobbs, Maureen Dennis, Sandra Chapman, Jeffrey E. Max, Jill Hunter, Russell Schachar, Thomas G. Luerssen and Paul Swank

Object

The aim of this study was to determine whether the presence of intracranial pathophysiology on computed tomography (CT) scans obtained within 24 hours of mild traumatic brain injury (MTBI) in children adversely affects neuropsychological outcome during the 1st year postinjury.

Methods

A prospective longitudinal design was used to examine the neuropsychological outcomes in children (ages 5–15 years) who had been treated for MTBI, which was defined as a loss of consciousness for up to 30 minutes and a lowest Glasgow Coma Scale (GCS) score of 13–15. Exclusion criteria included any preinjury neurological disorder. Outcome assessments were performed within 2 weeks and at 3, 6, and 12 months postinjury. Outcomes were compared between patients with MTBI whose postinjury CT scans revealed complications of brain pathophysiology (32 patients, CMTBI group) and those with MTBI but without complications (48 patients, MTBI group).

Results

Significant interactions confirmed that the pattern of recovery over 12 months after injury differed depending on the intracranial pathology, presence and severity of injuries to body regions other than the head, preinjury attention-deficit hyperactivity disorder (ADHD), and socioeconomic status. Children in the CMTBI group had significantly poorer episodic memory, slower cognitive processing, diminished recovery in managing cognitive interference, and poorer performance in calculating and reading than patients in the MTBI group. Among the patients with mild or no extracranial injury, visuomotor speed was slower in those in the CMTBI group; and among patients without preinjury ADHD, working memory was worse in those in the CMTBI group.

Conclusions

Neuropsychological recovery during the 1st year following MTBI is related to the presence of radiographically detectable intracranial pathology. Children with intracranial pathology on acute CT performed more poorly in several cognitive domains when compared with patients whose CT findings were normal or limited to a linear skull fracture. Depending on the presence of preinjury ADHD and concomitant extracranial injury, working memory and visuomotor speed were also diminished in patients whose CT findings revealed complications following MTBI. Computed tomography within 24 hours postinjury appears to be useful for identifying children with an elevated risk for residual neuropsychological changes.