miR-125b controls apoptosis and temozolomide resistance by targeting TNFAIP3 and NKIRAS2 in glioblastomas.

Diffusely infiltrating gliomas are among the most prognostically discouraging neoplasia in human. Temozolomide (TMZ) in combination with radiotherapy is currently used for the treatment of glioblastoma (GBM) patients, but less than half of the patients respond to therapy and chemoresistance develops rapidly. Epigenetic silencing of the O(6)-methylguanine-DNA methyltransferase (MGMT) has been associated with longer survival in GBM patients treated with TMZ, but nuclear factor κB (NF-κB)-mediated survival signaling and TP53 mutations contribute significantly to TMZ resistance. Enhanced NF-κB is in part owing to downregulation of negative regulators of NF-κB activity, including Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and NF-κB inhibitor interacting RAS-like 2 (NKIRAS2). Here we provide a novel mechanism independent of TP53 and MGMT by which oncogenic miR-125b confers TMZ resistance by targeting TNFAIP3 and NKIRAS2. GBM cells overexpressing miR-125b showed increased NF-κB activity and upregulation of anti-apoptotic and cell cycle genes. This was significantly associated with resistance of GBM cells to TNFα- and TNF-related inducing ligand-induced apoptosis as well as resistance to TMZ. Conversely, overexpression of anti-miR-125b resulted in cell cycle arrest, increased apoptosis and increased sensitivity to TMZ, indicating that endogenous miR-125b is sufficient to control these processes. GBM cells overexpressing TNFAIP3 and NKIRAS2 were refractory to miR-125b-induced apoptosis resistance as well as TMZ resistance, indicating that both genes are relevant targets of miR-125b. In GBM tissues, high miR-125b expression was significantly correlated with nuclear NF-κB confirming that miR-125b is implicated in NF-κB signaling. Most remarkably, miR-125b overexpression was clearly associated with shorter overall survival of patients treated with TMZ, suggesting that this microRNA is an important predictor of response to therapy.

[Headache and transient aphasia in a 35-year-old female patient]. / Kopfschmerzen und passagere Aphasie bei einer 35-jährigen Patientin.

We describe the case of a 35-year-old female patient who suffered from fulminant tick-borne encephalitis and subsequently died. Remarkable about this case was that the woman was not living in an endemic area and that the disease occurred outside the usual season. Furthermore, this indicates that an increase in transmission of tick-borne encephalitis can be expected outside the classical endemic areas in higher altitudes, possibly as a consequence of climate changes.

Atypical presentation of Behçet's disease with central nervous system involvement successfully treated with infliximab.

Central nervous system involvement is a rare and serious complication of Behçet's disease (BD). Herein, we describe a patient with an atypical central lesion, who experienced progressive hypesthesia of the right arm and sensory loss of the trigeminal nerve together with intense headache. A repeated biopsy was necessary to conclusively establish the diagnosis of BD. Therapy with infusions of infliximab led to a remarkable full remission. TNFα-blocking therapy was successfully replaced by azathioprine. The present well-illustrated case demonstrates the difficulty of establishing the diagnosis of BD with central nervous system involvement, the dramatic benefit of short given TNF-α-blocking agent, and the long-term remission with azathioprin.

Morbidity in 201 patients with small sized meningioma treated by microsurgery.

BACKGROUND: The management of patients with small, often asymptomatic meningiomas is controversial and includes observation, microsurgery (MS) and stereotactic radiosurgery (SRS). The purpose of this retrospective study was to analyze the morbidity and the extent of removal after MS for small (< or =3 cm) intracranial meningiomas and compare these results to those of SRS reported in the literature. METHODS: All patients with an intracranial meningioma with a maximum diameter up to 3 cm operated on in our institution over a 10 year period (1992-2002) were included in the study and retrospectively analyzed. Patients were grouped into asymptomatic and symptomatic and according to tumor location as: group I (cranial vault, parasagittal, lateral sphenoid), group II (falx, frontobasal, medial sphenoid, parasellar and tentorial), group III (cavernous sinus, petroclival, petrosal, CPA and foramen magnum). FINDINGS: There were a total of 201 patients, of whom 102 were asymptomatic and 99 were symptomatic. The overall risk of permanent neurological morbidity was 4.9% in asymptomatic and 23.2% in symptomatic patients. The combined risk in asymptomatic and symptomatic patients was 5.4% in group I, 11.5% in group II, and 39.9% in group III lesions. Radical removal was achieved in all patients in group I, in 93.7% of group II, and 80% of group III lesions. There was no disease related mortality. CONCLUSIONS: MS provides excellent efficacy and morbidity results in groups I and II meningiomas, especially in asymptomatic patients and might therefore be considered the first choice of treatment for these patients. The results of MS in group III were worse than those of SRS reported in the literature.

[Fibro-osseous lesion of the central nervous system]. / A központi idegrendszer fibroosseosus laesiója.

The case of a 53-year-old woman with headache and progressive right sided decline of visual acuity is reported. Computed tomography scans of the brain revealed multiple circumscribed foci of mineralization located over the left frontal and parietal, as well as the right central brain parenchyma. Surgical sampling of the left frontal lesion yielded a conglomerate composed of mineralized vessels, myriad of psammoma bodies, and metaplastic lamellar bone entangled within poorly cellular collagen fibers. No evidence was found of an underlying vascular malformation or tumor, nor was there evidence of parenchymal necrosis of infectious origin. On account of the organoid association of the mesenchymal elements and the mineralized moiety, the lesion was consistent with fibro-osseous lesion of the central nervous system. Also known as "calcifying pseudotumor" of the brain, the origin of this exceedingly rare condition is, as yet, unknown. By analogy, its pathogenesis is likely to involve mechanisms underlying tumoral calcinosis of soft tissues.

Desmoplastic neuroepithelial tumor of infancy in the nevus sebaceus syndrome: report of a unique constellation and review of the literature.

The nevus sebaceus syndrome (NSS) is a neurocutaneous disorder characterized by unilateral hyperplasia of skin appendages and skeletal hemihypertrophy, hemimegalencephaly, or hemiatrophy along with disabling seizures. Despite the proneness of the dermal stigmata to eventually undergo neoplastic transformation, the malformative lesions of the central nervous system rarely evolve into frank tumors. We present the case of a 10-year-old girl with left-sided sebaceus nevi, ipsilateral enlargement of the skull, and a desmoplastic neuroepithelial tumor (DNET) in the right fronto-parietal area of the brain. The tumor was removed by surgery. Histologically, it corresponded to a mitotically active small-cell anaplastic astrocytoma with genuine desmoplasia. Investigative methods included immunohistochemical positivity for glial fibrillary acidic protein, lack of expression of neuronal markers, and ultrastructural documentation of sheaths of basal lamina and collagen around tumor cells. A survey of the literature of brain tumors associated with NSS revealed two cases of histologically verified pilocytic astrocytomas, and one each of a choroid plexus papilloma, a mixed glioma, and a meningioma, as well as a subependymal giant cell astrocytoma--the latter possibly in an overlap syndrome of NSS and tuberous sclerosis. We hypothesize that the tumor described herein, one involving both atypical differentiation and enhanced growth potential, is paradigmatic of neuropathological events to be expected in the NSS.

[Cholesterol granuloma at the sella region: a new method of the differential diagnosis of craniopharyngioma]. / A sella-tájék koleszterin-granulomája: új alternatíva a craniopharyngeoma elkülönító kórisméjében?

Cholesterol-granuloma is a pseudotumoral mass that is believed to enlarge by a self-perpetuating sequence of repeated hemorrhages and reparative tissue reaction. Albeit an almost ubiquitous phenomenon throughout the body, cholesterol-granuloma has recently been appreciated as a distinctive lesion mimicking or associated with craniopharyngiomas. Upon review of a surgical series of 15 purported craniopharyngiomas, the authors identified 3 such occurrences. All were characterized by a predominance of slit-like cholesterol clefts with multi-nucleated giant cells embedded in a fibrotic stroma permeated with lipid laden macrophages, lymphocytes, as well as organizing hemorrhage. Non-craniopharyngioma specific cuboidal epithelium was present in one case. The mean age of patients--all males--with cholesterol-granuloma was 26 years, and all but one had an intrasellar tumor component. Clinical symptoms referrable to hypopituitarism predominated. At variance with the above, patients with adamantinomatous or papillary craniopharyngiomas were 23.5 and 46 years old, respectively, and presented with neurological deficits or ones due to hypothalamic involvement by their tumors. With marginal central nervous tissue present in 53 percent of the specimens, 75 percent of adamantinomatous craniopharyngiomas, but only 12 percent of cholesterol-granulomas showed invasive growth. At present cholesterol-granulomas are conceived as a clinicopathologically distinctive lesion of uncertain origin. They most probably represent a clinically relevant entity in the ontogenesis of adamantinomatous craniopharyngiomas with predisposing factors yet to be elucidated.

[Meningeal melanocytoma]. / Meningealis melanocytoma.

The authors report on a case of melanocytoma surgically removed from the craniocervical meninges of a 59-year-old man. Although the excision had been incomplete, the patient showed a disease-free course extending well over ten years. On histology, the tumor consisted of moderately cellular arrays of spindle-shaped melanocytes with a vaguely angiocentric whorling tendency, and without evidence of infiltrative growth. Electron microscopy identified tumor cells as ones bearing dendritic processes with complex melanosomes. The latter showed histochemical properties of melanosomal melanin, as well as immunoreactivity for the melanosome-associated markers HMB-45, and MELAN-A. Hallmarks of meningial differentiation were, at the same time, absent. The MIB-1 proliferation rate of the lesion, as assessed in a simultaneous testing of a panel including primary and metastatic central nervous system melanomas, as well as a uveal melanoma remained inferior to 1.5 percent. The data presented and a critical review of the literature suggest that meningeal melanocytoma is a mostly benign nevus-like lesion of neural crest cells with a very limited, although not discountable, margin for aggressive growth.

[Rhabdoid meningioma: a potentially aggressive new variant]. / Rhabdoid meningeoma: potenciálisan agresszív új variáns.

Rhabdoid meningioma is a recently recognized clinicopathologic entity characterized histologically by cytoplasmic aggregates of intermediate filaments, and clinically by the propensity of such tumors to pursue an aggressive course. The authors report on clinical, radiologic and pathologic findings in three cases of rhabdoid meningioma identified in a retrospective surgical series of 204 meningothelial tumors. Patients included two females, aged 39 and 55 years, and a 54-year-old male. In the first two cases the tumors were located on the right and left lesser sphenoid wing, respectively; in the third case, the right cerebellopontine angle was affected. All three neoplasms evolved on a background on transitional meningioma and were conspicuous for dis-cohesive tumor cells and suppression of syncytical architecture. Immunohistochemistry and ultrastructural examination confirmed the meningothelial origin of inclusion-bearing rhabdoid cells. Although none of the tumors showed evidence of histologic anaplasia and Ki-67 labeling indices remained inferior to 2%, infiltrative growth into adjacent brain was noted in all three cases. On follow-up ranging from 8 months to 6 years, the patients remained either disease-free or alive with nonprogressive residual tumor. On account of their clinical behavior, well-differentiated rhabdoid meningiomas will be accommodated in the category of atypical meningiomas (WHO grade II). Their pathogenesis is likely to involve disrupted cytoskeletal integration of cell motility and proliferation, of which the rhabdoid phenotype may possibly represent a morphologic correlate.

[Lipomatous meningioma: report of two cases and review of the literature]. / Lipomatosus meningeoma: két eset ismertetése és irodalmi áttekintés.

Lipomatous meningioma is a benign tumor characterized either by an admixture of mature adipocytes and meningioma or the production of triglycerides by neoplastic meningothelial cells assuming a lipoblast-like appearance. The authors report on two instances of this exceedingly rare lesion occurring in the left middle cranial fossa and over the right frontal convexity of two female patients aged 79 years and 60 years, respectively. In the former, the tumor was an incidental autopsy finding, while the latter underwent surgery for symptoms of intracranial space occupation. Light microscopy showed interwoven islands of fatty tissue and transitional meningioma in the first case; whereas a monomorphous signet-ring cell phenotype prevailed in the second. Oil-Red-O staining confirmed the presence of neutral fat in both specimens. Immunohistochemical coexpression of epithelial membrane antigen, vimentin, and S100 protein supported the meningothelial origin of tumor cells. On the other hand, the CD 68 macrophage antigen was not detected. Cytoplasmic lipid droplets along with hallmarks of meningothelial differentiation were visualized ultrastructurally in part of the meningioma component of the first case and throughout the second. These findings are consistent with a metaplastic origin of the adipocytic element. Whatever its histogenesis, lipomatous meningioma may, on occasion, represent a major challenge with therapeutic implications for both preoperative imaging and histological diagnosis.

[Neuromuscular choristoma]. / Neuromuscularis choristoma.

Neuromuscular choristomas are malformative pseudotumoral masses composed of striated muscle and peripheral nerves. This rare condition almost exclusively affects large nerve trunks of infants and young children, and may cause neurologic deficits of variable severity. We report a case of neuromuscular choristoma identified in the lumbosacral lipoma of a 4-month-old boy. The lesion was characterized by an organoid association of myogenic and neurogenic elements reminiscent of neuromuscular units. Myosin immunophenotyping revealed disordered groups of type-I and type-II extrafusal myofibers. There was no immunoreactivity for smooth muscle specific alpha actin. Most participating axons were of the large myelinated type. Pathogenetic theories of neuromuscular choristoma involve aberrant migration of developing peripheral nerves, dysgenesis of muscle spindles, as well as mesenchymal differentiation of the primitive neuroectoderm. Neuromuscular choristomas arising in connection with congenital lipomas may derive from a dysembryogenic process of stem cells of the caudal neural tube.

Chordoid glioma of the third ventricle: confirmatory report of a new entity.

The term "chordoid glioma" was recently introduced to denote a circumscribed, apparently low-grade neoplasm arising in or preferentially involving the third ventricle of middle-aged women. We report biopsy and postmortem findings in a 60-year-old woman with symptoms of forgetfulness, headache, and lethargy. Neuroimaging showed a contrast-enhancing third ventricular mass with obstructive hydrocephalus. The tumor was subtotally resected. Microscopically, it consisted of clusters and strands of epithelioid cells in a mucoid matrix. Its margins were remarkably discrete and showed little tendency to infiltrate surrounding brain parenchyma. The majority of neoplastic cells were glial fibrillary acidic protein (GFAP) and vimentin positive, whereas S100 protein labeled only individual cells. Stains for epithelial membrane antigen (EMA) and cytokeratin were nonreactive. There was no evidence of neuroendocrine differentiation or expression of estrogen and progesteron receptors. Lymphoplasmacellular infiltrates were noted throughout the lesion and at the tumor-brain interface. The MIB-1 labeling index averaged 1.5%. At present, chordoid glioma is considered a glial neoplasm of uncertain histogenesis with distinct clinicopathologic features.

Signet-ring cell ependymoma: case report with implications for pathogenesis and differential diagnosis.

We describe light microscopic, immunohistochemical and ultrastructural features of a signet-ring cell ependymoma (WHO grade II) identified in a surgically resected left cerebellar cystic tumor from a 64-year-old man. Part of the tumor showed clear-cell differentiation. Immunohistochemical coexpression of glial fibrillary acidic protein and epithelial membrane antigen, characteristic of ependymoma, was detected in both components. Sinuous intermediate junctions, cytoplasmic lumina, and scant astroglial filaments were demonstrated by electron microscopy. Signet-ring cell change was shown to be induced by disproportionate cavitation of either microvillus-bearing cytoplasmic lumina or microrosettes. The staining qualities of clear cells were mainly due to paucity and degeneration of subcellular organelles. Therefore, signet-ring cell ependymomas represent a unique anomaly of intra- and extracellular compartmentalization to be distinguished from various unrelated forms of cytoplasmic volume increase, resulting in an optically similar "empty" appearance of tumor cells. As a clinically relevant consequence, signet-ring cell ependymoma must be included in the differential diagnosis of primary or metastatic neoplasms of the central nervous system, having in common a phenotype characterized by overdeveloped optically lucent cell bodies.