TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group "subependymoma, posterior fossa" (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas)

Intrakranielle Blutungen

$\bf Problem:$ Intrazerebrale Blutungen stellen eine häufige Erkrankung dar. In der Literatur wird über konservative und operative Therapieansätze kontrovers diskutiert. $\bf Methode:$ Es wurden die Daten von 102 Patienten mit intrazerebralen Blutungen verwendet Bei den Patienten wurden 3mg rtPA über drei Tage über eine externe Ventrikeldrainage oder eine Codman$\circledR$- Drainage nach intrazerebral appliziert. $\bf Ergebnis:$ Die prozentuale Volumenreduktion aller Patienten mit intraventrikulärer Blutung nach der dritten rtPA-Gabe betrug 68.4%, bei der Patientengruppe mit Hauptblutungsanteil im Parenchym wurde eine Volumenabnahme von insgesamt 73.05% verzeichnet. $\bf Diskussion:$ Die intrazerebrale Injektion von rtPA ist eine effektive minimalinvasive Technik zur Therapie von tiefen intrazerebralen und intraventrikulären Blutungen

Syringomyelia regression after shunting of a trapped fourth ventricle

We describe a case of progressive syringomyelia following post-infectious trapped fourth ventricle (TFV), which resolved after shunting of the fourth ventricle. A 28-year-old female who had previously undergone treatment of intracerebral hemorrhage and meningitis developed a hydrocephalus with TFV. After 3 years she developed disturbance of walking and coordination. Cranial-CT revealed an enlargement of the shunted fourth ventricle as a result of shunt dysfunction. Furthermore a cervical syringomyelia developed. The patient underwent a revision of a failed fourth ventriculo- peritoneal shunt. Postoperatively, syringomyelia resolved within 6 months and the associated neurological deficits improved significantly. An insufficiency of cerebrospinal fluid draining among patients with TFV can be associated with communicating syringomyelia. An early detection and treatment seems important on resolving syringomyelia and avoiding permanent neurological deficits. Ventriculo-peritoneal shunt in trapped fourth ventricles can resolve a secondary syringomyelia

Gradient 3D Printed PLA Scaffolds on Biomedical Titanium: Mechanical Evaluation and Biocompatibility

The goal of the present investigation was to find a solution to crucial engineering aspects related to the elaboration of multi-layered tissue-biomimicking composites. 3D printing technology was used to manufacture single-layered and gradient multi-layered 3D porous scaffolds made of poly-lactic acid (PLA). The scaffolds manufacturing process was optimized after adjusting key printing parameters. The scaffolds with 60 μm side length (square-shaped pores) showed increased stiffness values comparing to the other specimens. A silicone adhesive has been further used to join biomedical titanium plates, and the PLA scaffolds; in addition, titania nanotubes (TNTs were produced on the titanium for improved adhesion. The titanium-PLA scaffold single lap joints were evaluated in micro-tensile testing. The electrochemical processing of the titanium surface resulted in a 248% increase of the ultimate strength in the overlap area for dry specimens and 40% increase for specimens immersed in simulated body fluid. Finally, the biocompatibility of the produced scaffolds was evaluated with primary cell populations obtained after isolation from bone residual tissue. The manufactured scaffolds present promising features for applications in orthopedic implantology and are worth further

Molecular characterization of CNS paragangliomas identifies cauda equina paragangliomas as a distinct tumor entity

Paragangliomas/pheochromocytomas are rare neuroendocrine tumors that arise from the adrenal gland or ganglia at various sites throughout the body. They display a remarkable diversity of driver alterations and are associated with germline mutations in up to 40% of the cases. Comprehensive molecular profiling of abdomino-thoracic paragangliomas revealed four molecularly defined and clinically relevant subtypes. Paragangliomas of the cauda equina region are considered to belong to one of the defined molecular subtypes, but a systematic molecular analysis has not yet been performed. In this study, we analyzed genome-wide DNA methylation profiles of 57 cauda equina paragangliomas and show that these tumors are epigenetically distinct from non-spinal paragangliomas and other tumors. In contrast to paragangliomas of other sites, chromosomal imbalances are widely lacking in cauda equina paragangliomas. Furthermore, RNA and DNA exome sequencing revealed that frequent genetic alterations found in non-spinal paragangliomas—including the prognostically relevant SDH mutations—are absent in cauda equina paragangliomas. Histologically, cauda equina paragangliomas show frequently gangliocytic differentiation and strong immunoreactivity to pan-cytokeratin and cytokeratin 18, which is not common in paragangliomas of other sites. None of our cases had a familial paraganglioma syndrome. Tumors rarely recurred (9%) or presented with multiple lesions within the spinal compartment (7%), but did not metastasize outside the CNS. In summary, we show that cauda equina paragangliomas represent a distinct, sporadic tumor entity defined by a unique clinical and morpho-molecular profile

Safety and Effectiveness of Mycophenolate Mofetil in Interstitial Lung Diseases: Insights from a Machine Learning Radiographic Model

Introduction: Treatment of interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) often includes systemic corticosteroids. Use of steroid-sparing agents is amenable to avoid potential side effects. Methods: Functional indices and high-resolution computed tomography (HRCT) patterns of patients with non-IPF ILDs receiving mycophenolate mofetil (MMF) with a minimum follow-up of 1 year were analyzed. Two independent radiologists and a machine learning software system (Imbio 1.4.2.) evaluated HRCT patterns. Results: Fifty-five (n = 55) patients were included in the analysis (male: 30 [55%], median age: 65.0 [95% CI: 59.7-70.0], mean forced vital capacity %predicted [FVC %pred.] +/- standard deviation [SD]: 69.4 +/- 18.3, mean diffusing capacity of lung for carbon monoxide %pred. +/- SD: 40.8 +/- 14.3, hypersensitivity pneumonitis: 26, connective tissue disease-ILDs [CTD-ILDs]: 22, other ILDs: 7). There was no significant difference in mean FVC %pred. post-6 months (1.59 +/- 2.04) and 1 year (-0.39 +/- 2.49) of treatment compared to baseline. Radiographic evaluation showed no significant difference between baseline and post-1 year %ground glass opacities (20.0 [95% CI: 14.4-30.0] vs. 20.0 [95% CI: 14.4-25.6]) and %reticulation (5.0 [95% CI: 2.0-15.6] vs. 7.5 [95% CI: 2.0-17.5]). A similar performance between expert radiologists and Imbio software analysis was observed in assessing ground glass opacities (intraclass correlation coefficient [ICC] = 0.73) and reticulation (ICC = 0.88). Fourteen patients (25.5%) reported at least one side effect and 8 patients (14.5%) switched to antifibrotics due to disease progression. Conclusion: Our data suggest that MMF is a safe and effective steroid-sparing agent leading to disease stabilization in a proportion of patients with non-IPF ILDs. Machine learning software systems may exhibit similar performance to specialist radiologists and represent fruitful diagnostic and prognostic tools

TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group 'subependymoma, posterior fossa' (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma-subependymoma morphology. Mixed ependymoma-subependymoma tumors varied in their extent of ependymoma differentiation (2-95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p &amp;lt; 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p &amp;lt; 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas)