Chordoid glioma of the third ventricle was recently reported as a novel tumor entity of the central nervous system with characteristic clinical and histopathological features (Brat et al., J Neuropathol Exp Neurol 57: 283-290, 1998). Here, we report on a histopathological, immunohistochemical and molecular genetic analysis of five cases of this rare neoplasm. All tumors were immunohistochemically investigated for the expression of various differentiation antigens, the proliferation marker Ki-67, and a panel of selected proto-oncogene and tumor suppressor gene products. These studies revealed a strong expression of GFAP, vimentin, and CD34. In addition, most tumors contained small fractions of neoplastic cells immunoreactive for epithelial membrane antigen, S-100 protein, or cytokeratins. The percentage of Ki-67 positive cells was generally low (<5%). All tumors showed immunoreactivity for the epidermal growth factor receptor and schwannomin/merlin. There was no nuclear accumulation of the p53, p21 (Waf-1) and Mdm2 proteins. To examine genomic alterations associated with the development of chordoid gliomas, we screened 4 tumors by comparative genomic hybridization (CGH) analysis. No chromosomal imbalances were detected. More focussed molecular genetic analyses revealed neither aberrations of the TP53 and CDKN2A tumor suppressor genes nor amplification of the EGFR, CDK4, and MDM2 proto-oncogenes. Our data strongly support the hypothesis that chordoid glioma of the third ventricle constitutes a novel tumor entity characterized by distinct morphological and immunohistochemical features, as well as a lack of chromosomal and genetic alterations commonly found in other types of gliomas or in meningiomas.

✓ Meningeal melanocytomas are uncommon lesions. They are generally considered to be benign tumors that derive from leptomeningeal melanocytes. A rare case of a metastatic spinal meningeal melanocytoma is presented. All relevant cases reported in literature since 1972, when the term “meningeal melanocytoma” was first used, were reviewed. Rates of tumor recurrence from 1 to 5 years were calculated for this rare lesion, based on published data and on additional information obtained from personal contact with most of the authors. Recurrency rates of 47 patients suitable for evaluation were correlated with the different therapeutic approaches. Complete tumor resection alone and incomplete resection alone followed by irradiation appeared to be superior to incomplete resection alone in terms of disease-free survival. Statistical significance was achieved for complete tumor resection at follow up between 1 and 4 years (range p = 0.010–0.050) and for incomplete resection combined with radiotherapy after 2 years (p = 0.034). Complete tumor resection should be considered the best therapeutic option, followed by incomplete resection combined with postoperative radiotherapy.

Familial Hypertrophic Cardiomyopathy (FHC) is frequently caused by mutations in the β-cardiac myosin heavy chain (β-MyHC). To identify changes in sarcomeric function triggered by such mutations, distinguishing mutation effects from other functional alterations of the myocardium is essential. We previously identified a direct effect of mutation R723G (MyHC723) on myosin function in slow Musculus soleus fibers. Here we investigate contractile features of left ventricular cardiomyocytes of FHC-patients with the same MyHC723-mutation and compare these to the soleus data. In mechanically isolated, triton-permeabilized MyHC723-cardiomyocytes, maximum force was significantly lower but calcium-sensitivity was unchanged compared to donor. Conversely, MyHC723-soleus fibers showed significantly higher maximum force and reduced calcium-sensitivity compared to controls. Protein phosphorylation, a potential myocardium specific modifying mechanism, might account for differences compared to soleus fibers. Analysis revealed reduced phosphorylation of troponin I and T, myosin-binding-protein C, and myosin-light-chain 2 in MyHC723-myocardium compared to donor. Saturation of protein-kinaseA phospho-sites led to comparable, i.e., reduced MyHC723-calcium-sensitivity in cardiomyocytes as in M. soleus fibers, while maximum force remained reduced. Myofibrillar disarray and lower density of myofibrils, however, largely account for reduced maximum force in MyHC723-cardiomyocytes. The changes seen when phosphorylation of sarcomeric proteins in myocardium of affected patients is matched to control tissue suggest that the R723G mutation causes reduced Ca(++)-sensitivity in both cardiomyocytes and M. soleus fibers. In MyHC723-myocardium, however, hypophosphorylation can compensate for the reduced calcium-sensitivity, while maximum force generation, lowered by myofibrillar deficiency and disarray, remains impaired, and may only be compensated by hypertrophy.

The authors describe the first case of an intracranial transition of a melanocytoma into a primary malignant melanoma within a short time. A 37-year-old woman presented with progressive brainstem syndrome due to a tumor, originally diagnosed and treated 12 years earlier, that extended from the petroclival area to the anterior craniocervical junction. The histological workup following subtotal tumor resection of the initial tumor had revealed the typical features of a fibrous melanocytic meningioma without increased proliferation. Ten years after the patient had completed treatment for the melanocytic meningioma, control neuroimaging demonstrated growth of the residual tumor with compression of the brainstem. Another neurosurgical intervention revealed a dark tumor of hard consistency. At this time immunohistochemical examinations demonstrated melanocytic features (expression of vimentin, S100 protein, and melan A) of the lesion with focally increased proliferation (5% of Ki-67-positive cells) but no higher mitotic activity. Clinical signs of deterioration along with imaging-confirmed tumor progression precipitated another operation within 7 months. A neuropathological examination revealed epithelial and anaplastic changes and indicated that the MIB-1 indices were greater than 25%. Pleomorphic changes and a focal high mitotic activity led to the diagnosis of a primary cerebral malignant melanoma. The patient's later clinical course consisted of a rapid diffuse meningeal spread of the lesion throughout the entire brain and spine. Despite whole-brain and stereotactic radiation therapy as well as chemotherapy, the patient died 4 months after the last neuropathological diagnosis. Although grossly resembling a meningioma, melanocytomas lack the former's histological and immunohistochemical features. The biological behavior of a melanocytoma is variable and recurrence may happen after subtotal resection, but intracranial transition into a malignant melanoma has not been observed previously.

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) mice, we analyzed the role of MK2/3 in cross-striated muscle by transcriptome and proteome analyses and by histology. We demonstrated enhanced expression of the slow oxidative skeletal muscle myofiber gene program, including the peroxisome proliferator-activated receptor gamma (PPAR␥) coactivator 1␣ (PGC-1␣). Using reporter gene and electrophoretic gel mobility shift assays, we demonstrated that MK2 catalytic activity directly regulated the promoters of the fast fiber-specific myosin heavy-chain IId/x and the slow fiber-specific sarco/endoplasmic reticulum Ca 2؉ -ATPase 2 (SERCA2) gene. Elevated SERCA2a gene expression caused by a decreased ratio of transcription factor Egr-1 to Sp1 was associated with accelerated relaxation and enhanced contractility in MK2/3 ؊/؊ cardiomyocytes, concomitant with improved force parameters in MK2/3 ؊/؊ soleus muscle. These results link MK2/3 to the regulation of calcium dynamics and identify enzymatic activity of MK2/3 as a critical factor for modulating cross-striated muscle function by generating a unique muscle phenotype exhibiting both reduced fatigability and enhanced force in MK2/3 ؊/؊ mice. Hence, the p38-MK2/3 axis may represent a novel target for the design of therapeutic strategies for diseases related to fiber type changes or impaired SERCA2 function.

The diagnosis of dialysis-related amyloid (AB-amyloid) has been based usually on clinical and radiological criteria. Following the discovery that beta 2-microglobulin was the major protein of this amyloid, we isolated and radiolabelled uremic plasma beta 2-microglobulin. After intravenous injection, gamma-camera images of selected joint areas were obtained from 42 patients who were on regular hemodialysis therapy. Positive scans involving the shoulder, hip, knee and carpal regions were found in 13 of 14 patients treated for more than 10 years and 10 of 16 patients treated for 5 to 10 years. Patients treated for less time had negative scans. Specificity was indicated by negative scans in non-amyloid inflammatory lesions in control hemodialysis patients. Up to 48-fold tracer enrichment was detected in excised AB-amyloid containing tissue as compared to amyloid-free tissue. These findings suggest that circulating radiolabelled beta 2-microglobulin is taken up by the amyloid deposits. This method may non-invasively detect tissue infiltrates of amyloid. It may also permit prospective evaluation of the efficacy of prophylactic dialysis strategies which are designed to prevent or delay the onset of this complication of long-term dialysis.

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