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Chordomas are slow-growing rare malignant neoplasms. The aim of this study was to establish a primary model of chordoma in the lumbosacral orthotopic area, to compare the growth rate to the subcutaneous site, and to show that this new graft site optimizes tumor growth and bony invasion. Eleven chordoma samples were transplanted subcutaneously in the flank and/or in contact with the lumbosacral region and grown into nude mice. Engraftment rate was significantly more successful in the lumbosacral environment compared with the flank at P0. Two xenografts from 2 patients showed bone invasion. One tumor was maintained through multiple rounds of serial transplantation, creating a model for study. Histological and immunostaining analysis confirmed that tumor grafts recapitulated the primary tumor from which they were derived, consisting of a myxoid chordoma expressing brachyury, cytokeratin AE1, EMA, and VEGF. Clear destruction of the bone by the tumor cells could be demonstrated. Molecular studies revealed PIK3CA and PTEN mutations involved in PI3K signaling pathway and most of the frequently reported chromosomal alterations. We present a novel orthotopic primary xenograft model of chordoma implanted for the first time in the lumbosacral area showing bone invasion, PIK3CA, and PTEN mutations that will facilitate preclinical studies.

Pediatric chordomas are rare malignant neoplasms, and few data are available for optimizing therapeutic strategies and outcome. This study aimed at evaluating how best to manage them and to identify prognostic factors. This multicentric retrospective study included 40 children diagnosed with chordomas between 1966 and 2012. Clinical, radiological, and histopathological data, treatment modalities, and outcomes were reviewed. The median age was 12 years old. Most chordomas were histologically classical forms (45.5%) and were mostly located at the skull base (72.5%). The overall survival (OS) was 66.6% and 58.6%, and progression-free survival (PFS) was 55.7% and 52% at 5 and 10 years, respectively. Total resection was correlated with a better outcome (p = 0.04 for OS and PFS, log-rank). A histopathological/immunohistochemical grading system recently crafted for adults was applied. In a multivariate analysis, it significantly correlated with outcome (PFS and OS, p = 0.004), and the loss of BAF47 immunoexpression appeared to be a significant independent prognostic factor (PFS, p = 0.033). We also identified clinical and histopathological parameters that correlated with prognosis. A new grading system combined with the quality of surgical resection could help classify patients to postpone radiotherapy in case of low risk. Targeted therapy and reirradiation at recurrence may be considered as potential therapeutic strategies.

To distinguish pyruvate dehydrogenase deficiency (PDH) from other antenatal neurometabolic disorders thereby improving prenatal diagnosis, we describe imaging findings, clinical phenotype, and brain lesions in fetuses from 3 families with molecular characterization of this condition. Neuropathological analysis was performed in 4 autopsy cases from 3 unrelated families with subsequent biochemical and molecular confirmation of PDH complex deficiency. In 2 families there were mutations in the PDHA1 gene; in the third family there was a mutation in the PDHB gene. All fetuses displayed characteristic craniofacial dysmorphism of varying severity, absence of visceral lesions, and associated encephaloclastic and developmental supra- and infratentorial lesions. Neurodevelopmental abnormalities included microcephaly, migration abnormalities (pachygyria, polymicrogyria, periventricular nodular heterotopias), and cerebellar and brainstem hypoplasia with hypoplastic dentate nuclei and pyramidal tracts. Associated clastic lesions included asymmetric leukomalacia, reactive gliosis, large pseudocysts of germinolysis, and basal ganglia calcifications. The diagnosis of PDH deficiency should be suspected antenatally with the presence of clastic and neurodevelopmental lesions and a relatively characteristic craniofacial dysmorphism. Postmortem examination is essential for excluding other closely related entities, thereby allowing for biochemical and molecular confirmation.

Chordomas are slow-growing malignant neoplasms. Determination of histopathologic prognostic factors using a large cohort study has been limited by their low incidence. In this retrospective study, we investigated the clinical, histopathologic, and immunohistochemical prognostic factors in 287 chordomas from 111 patients assessed by central pathologic review. Expression patterns of a variety of markers, including vascular endothelial growth factor (VEGF), mTOR pathway, c-kit, HER2, epidermal growth factor receptor (EGFR) and STAT3, and KRAS, BRAF, EGFR, and PIK3CA mutations were analyzed. On univariate analysis, the results confirm surgery as the best treatment, as judged by patient progression-free survival (PFS) and overall survival (OS). Proton therapy, the presence of a dedifferentiated component, mitotic figures, and Ki67 and p53 labeling indices correlated with PFS. Necrosis and apoptosis correlated with OS. Based on these findings, we propose a histopathologic grading system that correlates with PFS and OS. On multivariate analysis, extent of resection, tumor grade, and proton therapy were independent prognostic factors of PFS; extent of resection, tumor location, and grade were independent prognostic factors of OS. Based on the expression of EGFR, pSTAT3, VEGF, and mTOR pathway proteins, (in 85.9%, 79.1%, 85.7%, and 46% of chordomas, respectively), and 2 new mutations in the PIK3CA gene, we also provide evidence for potential therapeutic targets.

The mammalian target of rapamycin (mTOR) signaling pathway is a key developmental pathway involved in mechanisms underlying cellular aging and neurodegeneration. We hypothesized that its deregulation may occur during early brain development in patients with Down syndrome (DS). The expression patterns and cellular distribution of components of mTOR signaling (phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR) were investigated in developing hippocampi from controls and patients with DS and from adults with DS and Alzheimer disease–associated pathology using immunocytochemistry. In control hippocampi, only phosphorylated S6 was detected prenatally (19–41 gestational weeks); it became undetectable 2 months postnatally. Increased expression of phosphorylated S6, phosphorylated S6 kinase, phosphorylated eukaryotic initiation factor 4E binding protein 1, and phosphorylated mTOR was observed in DS hippocampus compared with controls. Phosphorylated S6 and phosphorylated S6 kinase were detected prenatally and persisted throughout postnatal development. Prominent expression of mTOR components was observed in pyramidal neurons with granulovacuolar degeneration and in neurons containing neurofibrillary tangles in the hippocampi of DS subjects with Alzheimer disease pathology. These findings suggest that a dysregulated mTOR pathway may contribute to both early hippocampal developmental abnormalities and hippocampal functional impairment developing before neurodegeneration. Moreover, the expression patterns of mTOR components in adult DS hippocampus support its association with Alzheimer disease–related histopathologic changes.

Neurologic morbidity associated with congenital cytomegalovirus (CMV) infection is a major public health concern. The pathogenesis of cerebral lesions remains unclear. We report the neuropathologic substrates, the immune response, and the cellular targets of CMV in 16 infected human fetal brains aged 23 to 28.5 gestational weeks. Nine cases were microcephalic, 10 had extensive cortical lesions, 8 had hip-pocampal abnormalities, and 5 cases showed infection of the olfactory bulb. The density of CMV-immunolabeled cells correlated with the presence of microcephaly and the extent of brain abnormalities. Innate and adaptive immune responses were present but did not react against all CMV-infected cells. Cytomegalovirus infected all cell types but showed higher tropism for stem cells/radial glial cells. The results indicate that 2 main factors influence the neuropathologic outcome at this stage: the density of CMV-positive cells and the tropism of CMV for stem/ progenitor cells. This suggests that the large spectrum of CMV-induced brain abnormalities is caused not only by tissue destraction but also by the particular vulnerability of stem cells during early brain development. Florid infection of the hippocampus and the olfactory bulb may expose these patients to the risk of neurocognitive and sensorineural handicap even in cases of infection at late stages of gestation.

Disabilities after brain injury in very preterm infants have mainly been attributed to noncystic periventricular white matter injury (PWMI). We analyzed spatiotemporal patterns of PWMI in the brains of 18 very preterm infants (25–29 postconceptional weeks [pcw]), 7 preterm infants (30–34 pcw), and 10 preterm controls without PWMI. In very preterm infants, we examined PWMI in detail in 2 axonal crossroad areas in the frontal lobe: C1 (lateral to the lateral angle of the anterior horn of the lateral ventricle, at the exit of the internal capsule radiations) and C2 (above the corpus callosum and dorsal angle of the anterior horn). These brains had greater microglia-macrophage densities and activation but lesser astroglial reaction (glial fibrillary acidic protein and monocarboxylate transporter 1 expression) than in preterm cases with PWMI. In preterm infants, scattered necrotic foci were rimmed by axonal spheroids and ionized calcium binding adaptor molecule 1–positive macrophages. Diffuse lesions near these foci consisted primarily of hypertrophic and reactive astrocytes associated with fewer microglia. No differences in Olig2-positive preoligodendrocytes between noncystic PWMI and control cases were found. These data show that the growing axonal crossroad areas are highly vulnerable to PWMI in very preterm infants and highlight differences in glial activation patterns between very preterm and preterm infants.