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Mark A. Mittler, Beverly C. Walters, and Edward G. Stopa

✓ This study provides an objective assessment of the reliability of histological grading of astrocytoma specimens obtained using stereotactic biopsy. Pathological diagnosis of brain tumors provides an index of disease severity and guides clinical practice in their treatment. It also functions as the gold standard in assessing the validity of diagnostic tests such as magnetic resonance imaging. Often diagnoses are made from biopsy material obtained using stereotactic technique. The current study was designed to evaluate this gold standard with regard to interobserver and intraobserver variability.

Four certified neuropathologists from academic centers in the United States and Canada were asked to grade 30 brain biopsy specimens obtained stereotactically in patients with astrocytomas. Intraobserver agreement was analyzed in individual observers by comparing their first and second readings, separated by 5 to 14 weeks. Interobserver data were analyzed by comparing initial readings across all observers for individual diagnoses. Kappa analysis was used to measure agreement beyond chance.

Intraobserver agreement was 74.73% for glioblastomas multiforme, 51.43% for anaplastic astrocytomas, and 65.22% for low-grade astrocytomas. The most common disagreements were between anaplastic astrocytomas and glioblastomas multiforme, followed by disagreements between anaplastic and low-grade astrocytomas. Interobserver agreement on initial readings was 62.41% (κ 0.39) for glioblastomas, 36.04% (κ 0.06) for anaplastic astrocytomas, and 57.14% (κ 0.48) for low-grade astrocytomas.

A significantly greater degree of reliability was seen in histopathological diagnoses of low- or high-grade astrocytomas than in those of intermediate-grade astrocytomas. Therefore, the highest variability occurs at the point of clinical decision making—namely, intermediate-grade tumors that may or may not be selected to receive adjuvant therapy. This considerable variability is an issue that needs to be recognized and further addressed by analysis of current and proposed astrocytoma grading schemes.

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Sudhakar Vadivelu, Morris Edelman, Steven J. Schneider, and Mark A. Mittler

The authors describe the case of a child who presented with hydrocephalus and phenotypic features characteristic of a multiple congenital anomalies/mental retardation syndrome. Dysmorphic facies, medial plantar lipomatosis, and developmental delay were observed in this case and are identical to documented findings of Pierpont syndrome diagnosed in 3 boys. This is the fourth case reported to date and is the first documented case of an oncological process— an intraventricular atypical choroid plexus papilloma tumor—found in association with Pierpont syndrome. Syndromes associated with choroid plexus papilloma are reviewed.

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Sudhakar Vadivelu, Harold L. Rekate, Debra Esernio-Jenssen, Mark A. Mittler, and Steven J. Schneider

OBJECTIVE

The incidence of posttraumatic ventriculomegaly (PTV) and shunt-dependent hydrocephalus after nonaccidental head trauma (NAHT) is unknown. In the present study, the authors assessed the timing of PTV development, the relationship between PTV and decompressive craniectomy (DC), and whether PTV necessitated placement of a permanent shunt. Also, NAHT/PTV cases were categorized into a temporal profile of delay in admission and evaluated for association with outcomes at discharge.

METHODS

The authors retrospectively reviewed the cases of patients diagnosed with NAHT throughout a 10-year period. Cases in which sequential CT scans had been obtained (n = 28) were evaluated for Evans' index to determine the earliest time ventricular dilation was observed. Discharge outcomes were assessed using the King's Outcome Scale for Childhood Head Injury score.

RESULTS

Thirty-nine percent (11 of 28) of the patients developed PTV. A low admission Glasgow Coma Scale (GCS) score predicted early PTV presentation (within < 3 days) versus a high GCS score (> 1 week). A majority of PTV/NAHT patients presented with a subdural hematoma (both convexity and interhemispheric) and ischemic stroke, but subarachnoid hemorrhage was significantly associated with PTV/NAHT (p = 0.011). Of 6 patients undergoing a DC for intractable intracranial pressure, 4 (67%) developed PTV (p = 0.0366). These patients tended to present with lower GCS scores and develop ventriculomegaly early. Only 2 patients developed hydrocephalus requiring shunt placement.

CONCLUSIONS

PTV presents early after NAHT, particularly after a DC has been performed. However, the authors found that only a few PTV/NAHT patients developed shunt-dependent hydrocephalus.

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Salvatore Zavarella, Mitsutoshi Nakada, Shawn Belverud, Salvatore J. Coniglio, Amanda Chan, Mark A. Mittler, Steven J. Schneider, and Marc Symons

Object

Medulloblastomas are the most common malignant brain tumors in children. These tumors are highly invasive, and patients harboring these lesions are frequently diagnosed with distant spread. In this study, the authors investigated the role of Rac1, a member of the Rho family of small guanosine triphosphatases, in medulloblastoma invasion.

Methods

Three established medulloblastoma cell lines were used: DAOY, UW-228, and ONS-76. Specific depletion of Rac1 protein was accomplished by transient transfection of small interfering RNA. Cell invasion through extracellular matrix (Matrigel) was quantified using a transwell migration assay. Mitogen activated protein kinase activation was determined using phospho-MAP kinase–specific antibodies, and inhibition of MAP kinase pathways was achieved by specific small molecule inhibitors. Localization of Rac1 and its expression levels were determined by immunohistochemical analysis using a Rac1-specific antibody, and Rac1 activation was qualitatively assessed by Rac1 plasma membrane association.

Results

Small interfering RNA–mediated depletion of Rac1 strongly inhibited medulloblastoma cell invasion. Although depletion of Rac1 inhibited the proliferation of UW-228 cells, and of ONS-76 cells to a lesser extent, it stimulated the proliferation of DAOY cells. Depletion of Rac1 also inhibited the activation of the ERK and JNK MAP kinase pathways, and inhibition of either pathway diminished invasion and proliferation. Immunohistochemical analysis demonstrated that the Rac1 protein was overexpressed in all medulloblastoma tumors examined, and indicated that Rac1 was hyperactive in 6 of 25 tumors.

Conclusions

The authors' data show that Rac1 is necessary for the invasive behavior of medulloblastoma cells in vitro, and plays a variable role in medulloblastoma cell proliferation. In addition, these results indicate that Rac1 stimulates medulloblastoma invasion by activating the ERK and JNK pathways. The authors suggest that Rac1 and signaling elements controlled by this guanosine triphosphatase may serve as novel targets for therapeutic intervention in malignant medulloblastomas.