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Fourth ventricle rosette-forming glioneuronal tumor

Case report

Mahlon Johnson, John Pace, and Judy F. Burroughs

✓ The authors describe a rosette-forming glioneuronal tumor of the fourth ventricle in a 29-year-old woman. She had been experiencing dizziness for 1 year and headaches for 1 month. Cranial computed tomography revealed a relatively circumscribed mass involving the inferior cerebellum and floor of the fourth ventricle with extension into the ventricle. Histologically, much of the tumor was piloid with Rosenthal fibers as well as telangiectatic blood vessels; other areas contained complete or incomplete neurocytic rosettes. This tumor type must be differentiated from pilocytic astrocytomas, other gliomas with a piloid glial component, and glioneuronal tumors arising from the floor of the fourth ventricle or inferior cerebellum. Recognition of, and long-term follow up for, this recently described pathological entity may clarify the nature of this lesion and strategies for its optimal management.

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Cystic cavernous malformation of the cerebellopontine angle

Case illustration

Charles B. Stevenson, Mahlon D. Johnson, and Reid C. Thompson

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Detection of proliferating S-phase brain tumor cells by in situ DNA replication

Robert J. Weil, Steven A. Toms, Mahlon D. Johnson, and Amanda Mealer

Object. Current methods used to describe the proliferative status of brain tumors rely on labor-intensive, potentially costly procedures. This article provides a description of a rapid, inexpensive, uncomplicated technique used to identify proliferating cells in tissue obtained at the time of resection.

Methods. Touch preparations of 16 fresh astrocytic tumors and four fresh healthy temporal neocortical tissue samples were obtained at the time of surgery. Slides were placed in hypotonic potassium chloride to permeabilize their membranes, incubated in nucleotide precursors, and labeled with bromodeoxyuridine; they were later examined with the aid of a fluorescence microscope. The percentage of tumor cells in the S phase increased in conjunction with the grade of tumor and corresponded with the findings of immunohistochemical staining for the cell-cycle marker MIB-1. These results were confirmed in cell culture by using normal human astrocytes and two glioma cell lines. Slides can be analyzed in as little as 30 minutes after removal of tissue during surgery.

Conclusions. In this study the authors describe a simple method by which cells in the S phase of the cell cycle, which are contained in fresh tumor obtained at the time of surgery, can be labeled. This method may prove a useful adjunct to frozen-section analysis and may permit discrimination of neoplastic tissues from other tissues observed in small specimen samples.

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Evidence for mitogen-associated protein kinase activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells

Mahlon D. Johnson, Ann Woodard, Paul Kim, and Maria Frexes-Steed

Object. Coexpression of platelet-derived growth factor (PDGF)—BB and activated PDGF-β receptor in meningioma cells indicates that this cytokine may act as an autocrine or paracrine stimulant of meningioma growth. The intracellular events transducing signals from PDGF-β receptor tyrosine kinases are unknown. In this study the authors evaluated whether or not mitogen-activated protein kinases (MAPKs) are expressed in meningiomas, regulate their growth, and transduce mitogenic signals of PDGF-BB.

Methods. Ten human meningioma tumors as well as cells cultured from two normal leptomeninges and 10 additional human meningiomas were evaluated using Western blot analysis to determine the presence of MAPK and phosphorylated (activated) MAPK. The effects of PD098059, a selective inhibitor of MAPK phosphorylation/activation, on proliferation of meningioma cells stimulated with 10% fetal bovine serum was also evaluated. Last, the authors evaluated whether PDGF-BB stimulation of meningioma cells was associated with activation of MAPK.

Western blots of lysates from meningiomas and from cultured leptomeningeal and meningioma cells demonstrated MAPK and phosphorylated MAPK. Treatment with PD098059 produced a 52 to 84% (x = 69.8) loss in [3H]thymidine incorporation, which was associated with a partial or complete loss of phosphorylated MAPK after 3 days of treatment. The PDGF-BB produced a significant increase in [3H]thymidine incorporation and phosphorylation of MAPK at 1 and 3 days. Coadministration of PD098059 completely blocked PDGF-BB's stimulation of [3H]thymidine incorporation and cell proliferation concomitant with reduced MAPK phosphorylation.

Conclusions. The findings indicate that MAPK is constitutively expressed in leptomeningeal and meningioma cells and transduces mitogenic signals of PDGF, contributing to the growth of human meningiomas.

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Indolent granulomatous angiitis

Case report

Mahlon D. Johnson, Robert Maciunas, Jeffrey Creasy, and Robert D. Collins

✓ Granulomatous angiitis is a rare, treatable central nervous system vasculitis. Prompt diagnosis may be thwarted by protean presenting symptoms, an indolent clinical course, and atypical neurological findings. The authors describe a case of indolent granulomatous angiitis in which the patient presented with cerebellar signs and tissue changes suggestive of an atypical cerebellar infarction. After several years of remissions and relapses, repeat evaluation and biopsy disclosed granulomatous angiitis both in remote infarctions and in new cortical lesions. The clinical course and neuroradiological and pathological findings are compared with previous reports of fulminant and indolent granulomatous angiitis.

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The role of optical spectroscopy in epilepsy surgery in children

Sanjiv Bhatia, John Ragheb, Mahlon Johnson, Sanghoon Oh, David I. Sandberg, and Wei-Chiang Lin

Object

Surgery is an important therapeutic modality for pediatric patients with intractable epilepsy. However, existing imaging and diagnostic technologies such as MR imaging and electrocochleography (ECoG) do not always effectively delineate the true resection margin of an epileptic cortical lesion because of limitations in their sensitivity. Optical spectroscopic techniques such as fluorescence and diffuse reflectance spectroscopy provide a nondestructive means of gauging the physiological features of the brain in vivo, including hemodynamics and metabolism. In this study, the authors investigate the feasibility of using combined fluorescence and diffuse reflectance spectroscopy to assist epilepsy surgery in children.

Methods

In vivo static fluorescence and diffuse reflectance spectra were acquired from the brain in children undergoing epilepsy surgery. Spectral measurements were obtained using a portable spectroscopic system in conjunction with a fiber optic probe. The optical investigations were conducted at the normal and abnormal cortex as defined by intraoperative ECoG and preoperative imaging studies. Biopsy samples were taken from the investigated sites located within the zone of resection. The optical spectra were classified into multiple subsets in accordance with the ECoG and histological study results. The authors used statistical comparisons between 2 given data subsets to identify unique spectral features. Empirical discrimination algorithms were developed using the identified spectral features to determine if the objective of the study was achieved.

Results

Fifteen pediatric patients were enrolled in this pilot study. Elevated diffuse reflectance signals between 500 and 600 nm and/or between 650 and 850 nm were observed commonly in the investigated sites with abnormal ECoG and/or histological features in 10 patients. The appearance of a fluorescent peak at 400 nm was observed in both normal and abnormal cortex of 5 patients. These spectral alterations were attributed to changes in morphological and/or biochemical characteristics of the epileptic cortex. The sensitivities and specificities of the empirical discrimination algorithms, which were constructed using the identified spectral features, were all > 90%.

Conclusions

The results of this study demonstrate the feasibility of using static fluorescence and diffuse reflectance spectroscopy to differentiate normal from abnormal cortex on the basis of intraoperative assessment of ECoG and histological features. It is therefore possible to use fluorescence and diffuse reflectance spectroscopy as an aid in epilepsy surgery.

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Ectopic brain tissue in the trigeminal nerve presenting as rapid-onset trigeminal neuralgia: case report

Jeffrey H. Zimering, Jonathan J. Stone, Audrey Paulzak, John D. Markman, Mahlon D. Johnson, and G. Edward Vates

The authors report the case of a 52-year-old man who presented with rapid-onset lancinating facial pain consistent with trigeminal neuralgia. Magnetic resonance imaging revealed a nonenhancing small lesion on the right trigeminal nerve concerning for an atypical schwannoma or neuroma. The patient underwent resection of the mass via a right retrosigmoid approach. His facial pain completely resolved immediately postoperatively and had not recurred at 6 months after surgery. The mass was consistent with normal brain tissue (neurons and glial cells) without evidence of mitoses. A final histopathological diagnosis of ectopic brain tissue with neural tissue demonstrating focal, chronic T-cell inflammation was made. The partial rhizotomy during resection was curative for the facial pain. To the authors’ knowledge, this is the first report of neuroglial ectopia causing trigeminal neuralgia.

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Fibroblast growth factor receptor–3 expression in meningiomas with stimulation of proliferation by the phosphoinositide 3 kinase–Akt pathway

Laboratory investigation

Mahlon D. Johnson, Mary J. O'Connell, Webster Pilcher, and Jay E. Reeder

Object

Fibroblast growth factor receptors (FGFRs)–1, –2, and –3 are expressed in the developing brain and may participate in CNS neoplasia. Fibroblast growth receptor–3 has not been demonstrated in the human CNS or its tumors. Nonetheless, it has been implicated in the pathogenesis of several other forms of neoplasia.

Methods

Twenty-four human meningiomas were evaluated using Western blot analysis for expression of FGFR3, its ligand acidic FGF, and concomitant phosphorylation/activation of p44/42 mitogen-activated protein kinase (MAPK), Akt, and STAT3. Mutations in exons 7 and 10 of the FGFR3 gene were analyzed by polymerase chain reaction in 10 meningiomas. Primary meningioma cells cultured from 10 human meningiomas were also treated with acidic FGF and evaluated for cell proliferation or activation/phosphorylation of p44/42 MAPK, Akt, and STAT3.

Results

Immunoblotting demonstrated the presence of FGFR3 in 12 (71%) of 17 primarily fibroblastic and transitional WHO Grade I meningiomas. The FGFR3 was detected in 4 (80%) of 5 WHO Grade II, and 2 of 2 Grade III tumors. Acidic FGF was detected in 3 (18%) of 17 Grade I, 1 (20%) of 5 Grade II, and 1 (50%) of 2 Grade III meningiomas. In WHO Grade I meningiomas, 3 of 6 tumors with no detectable FGFR3 had no detectable p-STAT3. In WHO Grades II and III meningiomas, FGFR3 expression was associated with p-STAT3, p-Akt, and p-p44/42 MAPK expression. No mutations were demonstrated in exons 7 or 10 by polymerase chain reaction in any meningioma. Treatment with acidic FGF, a ligand for FGFR3, stimulated meningioma cell proliferation and activation of Akt and STAT3 in primary meningioma cell cultures.

Conclusions

These findings suggest that FGFR3 and acidic FGF are expressed in adult human leptomeninges as well as WHO Grades I and II meningiomas. Fibroblast growth factor receptor–3 activation stimulates meningioma cell proliferation by activation of the phosphoinositide 3 kinase–Akt-PRAS40-mTOR and STAT3 pathways.

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Evidence for phosphatidylinositol 3-kinase—Akt—p70S6K pathway activation and transduction of mitogenic signals by platelet-derived growth factor in human meningioma cells

Mahlon D. Johnson, Evelyn Okediji, Ann Woodard, Steven A. Toms, and George S. Allen

Object. The intracellular events transducing mitogenic signals from platelet-derived growth factor—β (PDGFβ) receptor tyrosine kinases are not precisely known. In this study the authors evaluated whether the phosphatidylinositol 3-kinase (PI3-K)—Akt—p70S6K pathway is expressed in meningiomas, regulates their growth, and transduces mitogenic signals of PDGF-BB.

Methods. Nine meningioma tumors obtained in humans were evaluated using Western blot analysis for phosphorylated (activated) Akt and phosphorylated p70S6K. Cells cultured from seven of these meningiomas were also screened using Western blot analysis for Akt and for phosphorylated Akt and p70S6K. The authors also evaluated whether PDGF-BB stimulation of meningioma cells was associated with the phosphorylation of Akt and p70S6K known to activate these kinases. In addition, the effects of wortmannin, an inhibitor of PI3-K, on proliferation and activation of Akt and p70S6K in meningioma cells stimulated with PDGF-BB were evaluated.

Western blots of lysates from meningiomas demonstrated phosphorylated Akt and p70S6K. Treatment with PDGF-BB stimulated phosphorylation of Akt and p70S6K in each meningioma cell culture. Wortmannin (500 and 1000 nM) significantly decreased PDGF-BB stimulation of meningioma cells (p < 0.001) while it reduced Akt and p70S6K phosphorylation but not mitogen-activated protein kinase/extracellular signal—regulated kinase (MAPK/ERK) phosphorylation.

Conclusions. These findings indicate that Akt and p70S6K are constitutively expressed and activated in meningioma cells and that the PI3-K—Akt—p70S6K pathway may participate in transduction of mitogenic signals in meningiomas independent of the Raf-1—MEK-1—MAPK/ERK cascade.