Predominant occurrence of somatic mutations of the NF2 gene in meningiomas and schwannomas

The NF2 gene is a putative tumor-suppressor gene that, when it is altered in the germline, causes neurofibromatosis type 2, a tumor-susceptibility disease that mainly predisposes to schwannomas and meningiomas. The recent isolation of the NF2 gene on chromosome 22 allows the identification of somatic mutations in human tumors. We have searched for mutations of the NF2 gene in 331 primary human tumors using a screening method based on denaturing gradient gel electrophoresis, which allows the detection of mutations in 95% of the coding sequence. Mutations were observed in 17 of 57 meningiomas and in 30 of 89 schwannomas. No mutations were observed for 17 ependymomas, 70 gliomas, 23 primary melanomas, 24 pheochromocytomas, 15 neuroblastomas, 6 medulloblastomas, 15 colon cancers, and 15 breast cancers. All meningiomas and one-half of the schwannomas with identified NF2 mutations demonstrated chromosome 22 allelic losses. We conclude that the involvement of the NF2 gene in human tumorigenesis may be restricted to schwannomas and meningiomas, where it is frequently inactivated by a two-hit process. © 1995 Wiley-Liss, Inc.     

Differential expression of extracellular matrix metalloproteinase inducer (CD147) in normal and ulcerated corneas: role in epithelio-stromal interactions and matrix metalloproteinase induction

Extracellular matrix metalloproteinase inducer (EMMPRIN) was originally identified on the tumor cell surface as an inducer of matrix metalloproteinase (MMP) production in neighboring fibroblasts. Here we demonstrate a role for EMMPRIN in MMP induction during corneal wound healing. MMP and EMMPRIN expression was analyzed in normal and ulcerated human corneas, as well as in corneal epithelial and stromal cells in culture using confocal microscopy, zymography, immunoblots, and real-time polymerase chain reaction. In normal cornea EMMPRIN was predominantly expressed in the epithelium but was markedly induced in the anterior stroma of ulcerated corneas. This coincided with MMP-2 induction that co-localized with EMMPRIN at the epithelio-stromal boundary. The role of epithelial-stromal interaction in MMP induction was investigated in an in vitro co-culture system and demonstrated an induction and co-localization of EMMPRIN and MMP-2 in the fibroblasts at the interface with epithelial cells. Direct contact of fibroblasts with EMMPRIN-containing purified epithelial cell membranes also induced MMP-1, MMP-2, and EMMPRIN and this was inhibited by a blocking anti-EMMPRIN antibody, suggesting that EMMPRIN was primarily responsible for this induction. These findings, and the up-regulation of EMMPRIN by epidermal growth factor and transforming growth factor-beta, demonstrate a role for EMMPRIN in wound healing and suggest that sustained local up-regulation of EMMPRIN and MMPs in chronic situations in which healing is delayed may lead to excessive matrix degradation and corneal melts.     

Romberg's progressive hemifacial atrophy: an association with scleral melting

We report the unusual case of a 43-year-old woman who presented with Romberg's progressive facial hemiatrophy and spontaneous scleral perforation in the ipsilateral eye, for which scleral grafting was performed. Histologic and ultrastructural examination of the scleral specimen revealed a noninflammatory lytic process. The location of the scleral loss, exactly on the line of the "en coup de sabre" atrophy, as well as the light microscopy and ultrastructural histopathologic findings suggest that the scleral destruction was a late manifestation of Romberg's disease.     

Chemotherapy alone as initial treatment for primary CNS lymphoma in patients older than 60 years: a multicenter phase II study (26952) of the European Organization for Research and Treatment of Cancer Brain Tumor Group.

PURPOSE: To assess the efficacy and toxicity of chemotherapy alone in patients older than 60 years with primary CNS lymphoma. PATIENTS AND METHODS: Fifty patients with a median age of 72 years and a median Karnofsky performance score (KPS) of 50 were eligible for this multicenter phase II study. The protocol consisted of high-dose methotrexate (MTX), lomustine, procarbazine, methylprednisolone, and intrathecal chemotherapy with MTX and cytarabine. The patients received one induction cycle; if objective response was achieved, five additional maintenance cycles were administered every 6 weeks. The median follow-up of patients was 3 years. RESULTS: Twenty four patients (48%) achieved an objective response (compete response [CR], 42%; partial response, 6%), with a median duration of CR of 27 months (range, 3 to 47+ months). Overall median survival time was 14.3 months, and 1-year progression-free survival was 40% (95% confidence interval [CI], 26% to 53%). Myelosuppression was the most frequent side effect, with grade 3 to 4 neutropenia in 19% of patients. One patient died during chemotherapy, as a result of pulmonary embolism. Most patients improved or preserved their cognitive functions (47% and 45% of the patients, respectively) and KPS (36% and 52% of the patients, respectively) until relapse, whereas cognitive and KPS decline attributed to delayed treatment neurotoxicity occurred in 8% and 12% patients, respectively. CONCLUSION: In the elderly, this chemotherapy regimen compares favorably with radiotherapy (RT) alone and reduces considerably the risk of delayed neurotoxicity associated with combined chemoradiotherapy. Chemotherapy alone is an appropriate strategy in older patients to delay or avoid RT.     

Analysis of the p21 gene in gliomas

The p21 gene encodes a cyclin dependent kinase inhibitor protein (p21) which has a tumor suppressive activity in a variety of tumor cell lines. Since, the p21 gene is up-regulated by the p53 tumor suppressor gene, which is frequently mutated in gliomas, acting therefore in the same control pathway, it constitutes a good candidate gene to be also inactivated in these tumors. To test this hypothesis, DNAs from 81 gliomas (48 glioblastomas, 11 anaplastic astrocytomas, 10 low-grade astrocytomas, 12 oligodendrogliomas and mixed gliomas), were investigated for mutations in the p21 coding sequence by denaturant gradient gel electrophoresis followed by sequencing. All these tumors have been previously screened for p53 mutations. Three different DNA variants were identified on codon 31 (17 cases), 27 (1 case) and 117 (1 case) and shown to be also present in matching constitutional DNA, suggesting they were polymorphisms. None of the tumors demonstrated a somatic mutation. No significant correlation between the presence of a p21 variant and the p53 mutation tumor status was observed. In conclusion, mutation in the p21 gene unlikely contributes to the development of gliomas.     

Sensitivity of the Montreal Cognitive Assessment in screening for cognitive impairment in patients with newly diagnosed high-grade glioma

Journal of Neuro-Oncology - Cognitive impairment is frequent in patients with high-grade glioma and requires cognitive follow-up. Cognitive screening tools such as the Montreal Cognitive Assessment...     

Determination of corneal asphericity after myopia surgery with the excimer laser: a mathematical model.

PURPOSE. To determine the theoretical change of corneal asphericity within the zone of laser ablation after a conventional myopia treatment, which conforms to Munnerlyn's paraxial formula and in which the initial corneal asphericity is not taken into consideration. METHODS. The preoperative corneal shape in cross section was modeled as a conic section of apical radius R(1) and shape factor p(1). A myopia treatment was simulated, and the equation of the postoperative corneal section within the optical zone was calculated by subtracting the ablation profile conforming to a general equation published by Munnerlyn et al. The apical radius of curvature r(2) of the postoperative profile was calculated analytically. The postoperative corneal shape was fitted by a conic section, with an apical radius equal to r(2) and a shape factor p(2) equal to the value that induced the lowest sum of horizontal residuals and the lowest sum of squared residuals. These calculations were repeated for a range of different dioptric treatments, initial shape factor values, and radii of curvature to determine the change of corneal asphericity within the optical zone of treatment. RESULTS. Analytical calculation of r(2) showed it to be independent of the initial preoperative shape factor p(1). The determination of p(2) was unambiguous, because the same value induced both the lowest sum of residuals and the lowest sum of the squared residuals. For corneas initially prolate (p(1) < 1), prolateness increased (p(2) < p(1) < 1), whereas for oblate corneas (p(1) > 1), oblateness increased (p(2) > p(1) > 1) within the treated zone after myopia treatment. This trend increased with the increasing magnitude of treatment and decreased with increasing initial apical radius of curvature R(1). CONCLUSIONS. After conventional myopic excimer laser treatment conforming to Munnerlyn's paraxial formula, the postoperative theoretical corneal asphericity can be accurately approximated by a best-fit conic section. For initially prolate corneas, there is a discrepancy between the clinically reported topographic trend to oblateness after excimer laser surgery for myopia and the results of these theoretical calculations.     

Expanded polytetrafluoroethylene episcleral implants used as encircling scleral buckling. an experimental and histopathological study

To investigate tissue changes induced by the implantation of expanded polytetrafluoroethylene (e-PTFE) used as encircling scleral buckling, an experimental and histopathological study was performed in rabbits. The eyes of 12 rabbits were implanted during 20-128 days with e-PTFE episcleral implants. Of these, 8 eyes were uncomplicated and enabled us to perform the histopathological study, 2 others were discarded for too short a time of implantation and, in 2 additional eyes, the episcleral implant was exposed with a wide conjunctival erosion. Surrounding the implant, a constant encapsulation was combined with numerous giant cells, forming a granuloma caused by irregularities of the implant outline. Its porous structure allowed a peripheral colonization by fibrovascular tissue. Scleral thinning and scleral invagination were the main scleral changes. No change of the conjunctiva made us suspect that a granuloma occurred before it was found histologically. The granulomatous changes did not seem to modify the apparently good experimental tolerance of the material after its implantation.