Meningial perineurioma: a benign peripheral nerve sheath tumor in a previously unrecognized central nervous system location, mimicking meningioma

Perineurioma is an uncommon, mostly benign, spindle-cell tumor of peripheral nerve sheath origin with a predilection for the soft tissues. Although increasing awareness points to the sites of involvement by perineurioma possibly being as ubiquitous as those frequented by schwannian tumors, only one intracerebral example has been described to date. We report on a surgically resected perineurioma of the falx cerebri in an 86-year-old woman. Preoperative imaging showed an enhancing extraaxial mass of 6 cm × 5.7 cm × 3.7 cm. Histologically, the tumor consisted of a proliferation of spindle cells interwoven by a lattice of basal lamina. Alongside a prevailing soft tissue perineurioma pattern, sclerosing and reticular areas were seen as well. Tumor cells coexpressed EMA and GLUT-1, and a minority immunoreacted for smooth muscle actin. Pericellular basal lamina was decorated with collagen type IV. No staining for S100 protein was detected. Mitotic activity was virtually absent, and the MIB1 labeling index averaged 2%. Ultrastructural examination revealed abundant pinocytotic vesicles within and conspicuous tight junctions between slender cytoplasmic processes which, in turn, were encased by discontinuous basal lamina. FISH analysis confirmed loss of at least part of one chromosome 22q. This observation calls attention to perineurioma as a novel item in the repertoire of low-grade meningial spindle cell neoplasms, in the differential diagnostic context of which it is apt to being misconstrued as either meningioma, solitary fibrous tumor, or neurofibroma. Confusion with the latter bears the risk of overgrading innocuous features of perineurioma as criteria for malignancy.

Cancer therapy modulates VEGF signaling and viability in adult rat cardiac microvascular endothelial cells and cardiomyocytes

This work was motivated by the incomplete characterization of the role of vascular endothelial growth factor-A (VEGF-A) in the stressed heart in consideration of upcoming cancer treatment options challenging the natural VEGF balance in the myocardium. We tested, if the cytotoxic cancer therapy doxorubicin (Doxo) or the anti-angiogenic therapy sunitinib alters viability and VEGF signaling in primary cardiac microvascular endothelial cells (CMEC) and adult rat ventricular myocytes (ARVM). ARVM were isolated and cultured in serum-free medium. CMEC were isolated from the left ventricle and used in the second passage. Viability was measured by LDH-release and by MTT-assay, cellular respiration by high-resolution oxymetry. VEGF-A release was measured using a rat specific VEGF-A ELISA-kit. CMEC were characterized by marker proteins including CD31, von Willebrand factor, smooth muscle actin and desmin. Both Doxo and sunitinib led to a dose-dependent reduction of cell viability. Sunitinib treatment caused a significant reduction of complex I and II-dependent respiration in cardiomyocytes and the loss of mitochondrial membrane potential in CMEC. Endothelial cells up-regulated VEGF-A release after peroxide or Doxo treatment. Doxo induced HIF-1α stabilization and upregulation at clinically relevant concentrations of the cancer therapy. VEGF-A release was abrogated by the inhibition of the Erk1/2 or the MAPKp38 pathway. ARVM did not answer to Doxo-induced stress conditions by the release of VEGF-A as observed in CMEC. VEGF receptor 2 amounts were reduced by Doxo and by sunitinib in a dose-dependent manner in both CMEC and ARVM. In conclusion, these data suggest that cancer therapy with anthracyclines modulates VEGF-A release and its cellular receptors in CMEC and ARVM, and therefore alters paracrine signaling in the myocardium.

Paracrine effects of mesenchymal stem cells enhance vascular regeneration in ischemic murine skin

New theories on the regeneration of ischemic vasculature have emerged indicating a pivotal role of adult stem cells. The aim of this study was to investigate homing and hemodynamic effects of circulating bone marrow-derived mesenchymal stem cells (MSCs) in a critically ischemic murine skin flap model. Bone marrow-derived mesenchymal stem cells (Lin(-)CD105(+)) were harvested from GFP(+)-donor mice and transferred to wildtype C57BL/6 mice. Animals receiving GFP(+)-fibroblasts served as a control group. Laser scanning confocal microscopy and intravital fluorescence microscopy were used for morphological analysis, monitoring and quantitative assessment of the stem cell homing and microhemodynamics over two weeks. Immunohistochemical staining was performed for GFP, eNOS, iNOS, VEGF. Tissue viability was analyzed by TUNEL-assay. We were able to visualize perivascular homing of MSCs in vivo. After 4 days, MSCs aligned along the vascular wall without undergoing endothelial or smooth muscle cell differentiation during the observation period. The gradual increase in arterial vascular resistance observed in the control group was abolished after MSC administration (P<0.01). At capillary level, a strong angiogenic response was found from day 7 onwards. Functional capillary density was raised in the MSC group to 197% compared to 132% in the control group (P<0.01). Paracrine expression of VEGF and iNOS, but not eNOS could be shown in the MSC group but not in the controls. In conclusion, we demonstrated that circulating bone marrow-derived MSCs home to perivascular sites in critically ischemic tissue, exhibits paracrine function and augment microhemodynamics. These effects were mediated through arteriogenesis and angiogenesis, which contributed to vascular regeneration.