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Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.
An integrative correlation of myopathology, phenotype and genotype in late onset Pompe disease
(2019)
Aims: Pompe disease is caused by pathogenic mutations in the alpha 1,4‐glucosidase (GAA) gene and in patients with late onset Pome disease (LOPD), genotype–phenotype correlations are unpredictable. Skeletal muscle pathology includes glycogen accumulation and altered autophagy of various degrees. A correlation of the muscle morphology with clinical features and the genetic background in GAA may contribute to the understanding of the phenotypic variability.
Methods: Muscle biopsies taken before enzyme replacement therapy were analysed from 53 patients with LOPD. On resin sections, glycogen accumulation, fibrosis, autophagic vacuoles and the degree of muscle damage (morphology‐score) were analysed and the results were compared with clinical findings. Additional autophagy markers microtubule‐associated protein 1A/1B‐light chain 3, p62 and Bcl2‐associated athanogene 3 were analysed on cryosections from 22 LOPD biopsies.
Results: The myopathology showed a high variability with, in most patients, a moderate glycogen accumulation and a low morphology‐score. High morphology‐scores were associated with increased fibrosis and autophagy highlighting the role of autophagy in severe stages of skeletal muscle damage. The morphology‐score did not correlate with the patient's age at biopsy, disease duration, nor with the residual GAA enzyme activity or creatine‐kinase levels. In 37 patients with LOPD, genetic analysis identified the most frequent mutation, c.‐32‐13T>G, in 95%, most commonly in combination with c.525delT (19%). No significant correlation was found between the different GAA genotypes and muscle morphology type.
Conclusions: Muscle morphology in LOPD patients shows a high variability with, in most cases, moderate pathology. Increased pathology is associated with more fibrosis and autophagy.
Malignant brain tumors, including gliomas, brain metastases and anaplastic meningiomas, are associated with poor prognosis, and represent an unmet medical need. ASA404 (DMXAA), a vascular disrupting agent, has demonstrated promising results in several preclinical tumor models and early phase clinical trials. However, two phase III trials in non-small cell lung cancer reported insufficient results. The aim of the present study was to determine the effects of ASA404 on brain tumors. The effects of ASA404 were evaluated in vitro and in vivo using subcutaneous, and orthotopical models for malignant glioma (U-87, LN-229, U-251, LN-308 and Tu-2449), brain metastasis (HT-29) and malignant meningioma (IOMM-Lee). The acute effects of ASA404 on tumor tissue were analyzed using conventional and immunohistochemical staining techniques [hematoxylin and eosin, MIB-1 antibody/proliferation maker protein Ki-67, cleaved caspase-8, stimulator of interferon genes (STING), ionized calcium-binding adapter molecule 1]. Furthermore, the sizes of subcutaneous tumors were measured and the symptom-free survival rates of animals with intracranial tumors receiving ASA404 treatment were analyzed. ASA404 demonstrated low toxicity in vitro, but exhibited strong effects on subcutaneous tumors 24 h following a single dose of ASA404 (25 mg/kg). ASA404 induced necrosis, hemorrhages and inhibited the proliferation, and growth of tumors in the subcutaneous glioma models. However, ASA404 failed to demonstrate comparable effects in any of the intracranial tumor models examined and did not result in a prolongation of survival. Expression of STING, the molecular target of ASA404, and infiltration of macrophages, the cells mediating ASA404 activity, did not differ between subcutaneous and intracranial tumors. In conclusion, ASA404 demonstrates clear efficacy in subcutaneous tumor models, but has no relevant activity in orthotopic brain tumor models. The expression of STING and infiltration with macrophages were not determined to be involved in the differential activity observed among tumor models. It is possible that the low penetration of ASA-404 into the brain prevents concentrations sufficient enough reaching the tumor in order to exhibit acute effects in vivo.