An HLA-G/SPAG9/STAT3 axis promotes brain metastases.

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies.

The proteomic landscape of glioblastoma recurrence reveals novel and targetable immunoregulatory drivers.

Glioblastoma (GBM) is characterized by extensive cellular and genetic heterogeneity. Its initial presentation as primary disease (pGBM) has been subject to exhaustive molecular and cellular profiling. By contrast, our understanding of how GBM evolves to evade the selective pressure of therapy is starkly limited. The proteomic landscape of recurrent GBM (rGBM), which is refractory to most treatments used for pGBM, are poorly known. We, therefore, quantified the transcriptome and proteome of 134 patient-derived pGBM and rGBM samples, including 40 matched pGBM-rGBM pairs. GBM subtypes transition from pGBM to rGBM towards a preferentially mesenchymal state at recurrence, consistent with the increasingly invasive nature of rGBM. We identified immune regulatory/suppressive genes as important drivers of rGBM and in particular 2-5-oligoadenylate synthase 2 (OAS2) as an essential gene in recurrent disease. Our data identify a new class of therapeutic targets that emerge from the adaptive response of pGBM to therapy, emerging specifically in recurrent disease and may provide new therapeutic opportunities absent at pGBM diagnosis.

Immunohistochemical Markers in the Diagnosis of Calcifying Pseudoneoplasm of the Neuraxis.

BACKGROUND: Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like lesion with unknown pathogenesis. It is likely under-reported due to diagnostic challenges including the nonspecific radiographic features, lack of diagnostic markers, and often asymptomatic nature of the lesions. METHODS: We performed detailed examination of 11 CAPNON specimens diagnosed by histopathology, with the help of electron microscopy and immunohistochemistry. RESULTS: Electron microscopy revealed the presence of fibrillary materials consistent with neurofilaments. In addition to some entrapped axons at the periphery of CAPNONs, we discovered that all specimens stained positive for neurofilament-light (NF-L) within the granular amorphous cores, but not neurofilament-phosphorylated (NF-p). CAPNONs also showed variable infiltration of CD8+ T-cells and a decreased ratio of CD4/CD8+ T-cells, suggesting an immune-mediated process in the pathogenesis of CAPNON. CONCLUSION: NF-L and CD4/CD8 immunostains may serve as diagnostic markers for CAPNON and shed light on its pathogenesis.

Hemorrhagic giant cerebral capillary telangiectasia resulting in death: Case report and literature review.

We report a rare case of death caused by hemorrhage of a giant cerebral central nervous system capillary telangiectasia (CCT). A 49-year-old female presented comatose after suffering a traumatic head injury due to an unwitnessed fall. Computed tomography of the head revealed an acute 8.1 × 5.2 cm right intraparenchymal hematoma. Postmortem pathology found thin-walled dilated capillaries consistent with a giant cerebral CCT. The radiological complexity and rarity of giant CCTs result in these malformations often going undiagnosed. We review other cases of giant intracranial CCTs reported in the English literature and confirm that this is the first case of a hemorrhagic giant cerebral CCT causing death. This report emphasizes the existence and complications of giant CCTs and stresses the importance of their investigation to ensure patients receive optimal treatment and follow-up.

Intraventricular ganglioglioma with extensive hemorrhage.

Gangliogliomas represent a rare form of neuroepithelial tumor (up to 1.3% of brain tumors [1]), which even more rarely present with hemorrhage or localize intraventricularly. To date, only two cases of ganglioglioma with both of these features have been reported. Our patient is a 23-year-old woman who presented with signs and symptoms of increased intracranial pressure (ICPI), with a post-subtotal resection diagnosis of WHO Grade I ganglioglioma localizing bilaterally to the lateral ventricles. One year following the operation, the tumor showed radiologic evidence of interval hemorrhage, which was verified histopathologically following a second subtotal resection. Greater than 95% of the lesion represented a large hematoma with organization and well-defined fibrous pseudo-capsule, with very scanty fragments of adjacent/peripheral low-grade neuroglial tumor. This case represents a very rare presentation of intraventricular ganglioglioma with extensive hemorrhage.
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Plexiform schwannoma of the thoracolumbar spine a rare clinical entity - a case report.

Plexiform schwannomas are peripheral nerve sheath tumours rarely found in the spine. We present a case of a 65-year-old male with a spinal plexiform schwannoma in order to add to the general fund of knowledge regarding the natural history, diagnosis and surgical management of this extremely rare clinical entity.

Radiologic and Histopathologic Features of Calcifying Pseudoneoplasm of the Neural Axis.

AIM: To describe the radiologic and corresponding histopathologic features of calcifying pseudoneoplasms of the neural axis. METHODS: Two cases of calcifying pseudoneoplasm of the neural axis were retrospectively reviewed. The first case was documented in a 64-year-old woman, who presented with lower back pain with radiation to her left leg. The second case was documented in a 70-year-old man, who presented with headaches. Medical records, radiologic and histologic findings, and related literature were reviewed. RESULTS: In the first case, imaging of the lumbar spine revealed a 3.8 × 2.2-cm calcified lesion at the level of vertebrae L5 and S1. A subsequent excision exposed an extradural lesion at L5. Histopathologic examination showed amorphous and granular calcifying material with occasional fibrohistiocytic and giant cell reaction, consistent with calcifying pseudoneoplasm of the neural axis. In the second case, imaging of the head revealed a 2.4 × 2.6-cm well-circumscribed, lobulated, calcified lesion within the basal frontal lobe. Subsequent resection exposed an intradural mass with a nodular arrangement of amorphous and granular calcifying material associated with fibrohistiocytic and giant cell reaction. Both patients had a favorable postoperative course and failed to show any clinical or radiologic sign of recurrence. CONCLUSION: Calcifying pseudoneoplasm of the neural axis is an uncommon condition with an excellent prognosis but is often misdiagnosed due to its nonspecific clinical presentation and varied findings on radiology.

Statin-associated Autoimmune Myopathies: A Pathophysiologic Spectrum.

BACKGROUND: Statins have recently been reported to cause a rare autoimmune inflammatory and/or necrotic myopathy that begins or persists after drug cessation. METHODS: We report on 26 patients seen at a neuromuscular centre between 2005 and 2011 who demonstrated muscle weakness/myalgias and creatine kinase elevations during or after statin treatment with continuation of signs and symptoms despite statin withdrawal. RESULTS: All patients were treated with immunosuppressive therapy with good response; all improved biochemically and 86% improved clinically. Sixty-five percent of patients who attempted to taper off immunosuppressive therapy relapsed. We report on a novel finding whereby five of the seven patients who underwent multiple biopsies throughout their disease demonstrated a transformation of their histological diagnosis, with four progressing from having myofibre necrosis with minimal or no inflammation to a diagnosis of polymyositis. CONCLUSIONS: This study offers preliminary evidence that statin-associated necrotizing myopathy and statin-associated polymyositis may not be separate entities but are part of the same pathophysiological spectrum. Both entities respond well to immunosuppression.

Spinal calcifying pseudoneoplasm of the neuraxis (CAPNON) associated with facet joint pathologies: CAPNON diagnostic and pathogenic insights.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumor-like fibro-osseous lesion that can develop anywhere in the neuraxis. Approximately a half of reported CAPNONs developed in the spinal region, mostly close to the facet joint (FJ). The diagnosis of spinal CAPNONs is challenging given the existence of mimics and associated pathologies including calcific degeneration of the FJ ligaments (DFJL) and synovial cysts (SCs). The pathogenesis of CAPNON remains elusive, although there have been a few hypotheses including degenerative, reactive, proliferative and immune-mediated processes. Our present study examined clinical, radiological and pathological features of 12 spinal CAPNONs in comparison to 9 DFJL foci, and diagnostic and pathogenic relationship between CAPNONs and FJ pathologies. On imaging, CAPNONs were all tumor-like and typically bigger than DFJL foci. All CAPNONs showed pathologically diagnostic features including characteristic cores, consistently identifiable core-surrounding/peripheral palisading of macrophages and other cells including multinucleated giant cells, variable infiltration of CD8+ T-cells, and multifocal immunopositivity of neurofilament light chain (NF-L). These features were absent or limited in the DFJL foci with statistically significant differences from CAPNONs, except calcifications. Spinal CAPNONs co-existed with DFJL foci in all cases; some had transitional foci with overlapping focal CAPNON and DFJL-like features. These findings, along with our previously reported relationship between CAPNONs and SCs, suggest that spinal CAPNONs may occur in association with or in transition from calcifying/calcified degenerative lesions of FJ ligaments and/or SCs when a reactive proliferative process is complemented by other pathogenic changes such as immune-mediated pathology and NF-L deposition/expression.

Cylindrical spirals and other concentric structures of skeletal muscle in patients with neurological diseases.

Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs.

Acute lymphoblastic leukemia in a patient with constitutional chromosome 1pter-p36.31 duplication and 1q43-qter deletion.

Chromosome 1 is the largest of all human chromosomes, containing 3141 genes. It is linked to 890 known genetic diseases including congenital hypothyroidism, hemochromatosis, and prostate cancer. Recognized deletion and duplication syndromes have been described. Deletions in the short arm (p) of the chromosome have been identified in tumors of the brain and kidneys. Duplications in the long (q) arm of the chromosome are reported in myelodysplastic syndromes. Solitary 1p36 deletion or 1q42 duplication are rarely reported entities and their associations with malignancy have not been characterized. We report a case of a child with constitutional 1pter-p36.31 duplication and 1q43-qter deletion who developed acute lymphoblastic leukemia (ALL). The patient's oncologic presentation and subsequent clinical course raise the question of the association of the underlying genetic abnormality and its malignant potential, specifically in relation to ALL. Acquired chromosome 1 deletions and duplications have been well described in other malignant diseases. Constitutional chromosome 1p duplication and 1q deletions have not been described with ALL.

ß-Catenin marks proliferating endothelial cells in glioblastoma.

BACKGROUND: Angiogenesis is a key process in the growth and maintenance of tumors. The Wnt signaling pathway is required for angiogenesis of the central nervous system though development of the blood-brain barrier and subsequent proliferation of endothelial cells during tumor growth. However, the specificity of the Wnt pathway in regulating endothelial cells of different central nervous systems remains to be investigated. MATERIALS & METHODS: Patient-derived tissue samples from 35 paraffin-embedded tumors were used to assess ß-catenin immunoexpression. Tumor samples consisted of the following pathologies: grade II diffuse astrocytoma, glioblastoma, hemangioblastoma, and metastatic adenocarcinoma (lung or breast primary). Average percent reactivity was recorded as a mean observed in ten high-power fields. The following scale was used to grade immunoreactivity: 0 = immunonegative, 1 = 1-25% reactive, 2 = 26-50% reactive, 3 = 51-75% reactive, 4 = 76-100% reactive. RESULTS: While we did not observe nuclear expression of ß-catenin in any samples, there was uniform cytoplasmic expression of ß-catenin within glial tumor cells. There was a clear distinction in tumor endothelial cells whereby diffuse staining was noted in areas of microvascular hyperplasia in GBM and a less immunoreactive profile in low-grade astrocytomas. By contrast, non-glial tumors, contained very minimal cytoplasmic ß-catenin expression in tumor and stromal cells and were devoid of immunoreactivity in endothelial cells. CONCLUSION: ß-catenin is unique marker of proliferating endothelial cells in GBM. Therapies targeting the spatial and structural heterogeneity inherent to GBM may prove to be efficacious and result in an improved survivorship.

Spinal calcifying pseudoneoplasm of the neuraxis (CAPNON) and CAPNON-like lesions: CAPNON overlapping with calcified synovial cysts.

Calcifying pseudoneoplasm of the neuraxis (CAPNON) is a rare tumour-like fibro-osseous lesion in the neuraxis including the spine. It is diagnosed by the presence of the following histological features: granular amorphous to chondromyxoid fibrillary cores with calcification/ossification, peripheral palisading of spindle to epithelioid cells, variable fibrous stroma, and foreign body reaction with multinucleated giant cells, as well as positive NF-L immunostaining. Spinal CAPNON is sometimes named as tumoural calcinosis that is tumour-like dystrophic calcification usually in the periarticular tissue and also described in calcified synovial cyst (CSC). We examined clinical, radiological and pathological features of five spinal CAPNONs and 21 spinal CSCs including three recurrent lesions. The results demonstrated some radiological and pathological overlaps between these two entities, as well as distinct features of each entity to be diagnosed. All CAPNONs showed the diagnostic histological features with NF-L positivity mainly in lesion cores and variable CD8+ T-cells. In contrast, CSCs exhibited the synovial lining and variable degenerative/reactive changes with some CAPNON-like features, but mostly no to occasionally limited NF-L positivity and less CD8+ T-cells with statistically significant differences between groups of CAPNONs and CSCs. Four CSCs contained CAPNON-like foci with the CAPNON diagnostic features including prominent NF-L positivity, and some transitional features from CSC to CAPNON. As the pathogenesis of CAPNON is likely reactive/degenerative in association with an inflammatory/immunological process involving NF-L protein deposition, our findings suggest the link between spinal CAPNON and CSC, with possible transition from CSC to CAPNON or CAPNON developing in reaction to CSC.

Evaluation of DNA Methylation Array for Glioma Tumor Profiling and Description of a Novel Epi-Signature to Distinguish IDH1/IDH2 Mutant and Wild-Type Tumors.

Molecular biomarkers, such as IDH1/IDH2 mutations and 1p19q co-deletion, are included in the histopathological and clinical criteria currently used to diagnose and classify gliomas. IDH1/IDH2 mutation is a common feature of gliomas and is associated with a glioma-CpG island methylator phenotype (CIMP). Aberrant genomic methylation patterns can also be used to extrapolate information about copy number variation in a tumor. This project's goal was to assess the feasibility of DNA methylation array for the simultaneous detection of glioma biomarkers as a more effective testing strategy compared to existing single analyte tests. METHODS: Whole-genome methylation array (WGMA) testing was performed using 48 glioma DNA samples to detect methylation aberrations and chromosomal gains and losses. The analyzed samples include 39 tumors in the discovery cohort and 9 tumors in the replication cohort. Methylation profiles for each sample were correlated with IDH1 p.R132G mutation, immunohistochemistry (IHC), and previous 1p19q clinical testing to assess the sensitivity and specificity of the WGMA assay for the detection of these variants. RESULTS: We developed a DNA methylation signature to specifically distinguish a IDH1/IDH2 mutant tumor from normal samples. This signature is composed of 11 CpG sites that were significantly hypermethylated in the IDH1/IDH2 mutant group. Copy number analysis using WGMA data was able to identify five of five positive samples for 1p19q co-deletion and was concordant for all negative samples. CONCLUSIONS: The DNA methylation signature presented here has the potential to refine the utility of WGMA to predict IDH1/IDH2 mutation status of gliomas, thus improving diagnostic yield and efficiency of laboratory testing compared to single analyte IDH1/IDH2 or 1p19q tests.

A primary DICER1-sarcoma with KRAS and TP53 mutations in a child with suspected ECCL.

A child had been followed since infancy by our multi-disciplinary neuro-oncology clinic with annual magnetic resonance imaging (MRI) under the presumed diagnosis of encephalocraniocutaneous lipomatosis (ECCL), with clinical features including nevus psiloliparus, scalp lipoma, nodular skin tag on and coloboma of the eyelid, cortical atrophy and meningeal angiomatosis. At the age of 4, she was found to have a large temporoparietal lesion causing elevated intracranial pressure requiring surgical resection. Histopathological exam of the tumor was suggestive of an intracranial sarcoma. Sequencing analysis of the tumor revealed mutations in DICER1, KRAS and TP53. Subsequent germline testing confirmed DICER1 syndrome and revealed an insignificant FGFR1 variant at a low frequency. Methylation profile of the tumor showed the tumor clustered most closely with sarcoma (rhabdomyosarcoma-like), confirming this tumor to be a primary DICER1-sarcoma. Compared to the previously reported cases, our unique case of primary DICER1-sarcoma also demonstrated neurofilament and chromogranin positivity, and genomic instability with loss of chromosome 4p, 4q, 8p, 11p, and 19p, as well as gains in chromosome 7p, 9p, 9q, 13q, and 15q on copy variant analysis. The detailed sequencing and methylation information discovered in this unique case of DICER1-sarcoma will hopefully help further our understanding of this rare and emerging entity.

Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma.

Pediatric medulloblastoma (MB) is the most common solid malignant brain neoplasm, with Group 3 (G3) MB representing the most aggressive subgroup. MYC amplification is an independent poor prognostic factor in G3 MB, however, therapeutic targeting of the MYC pathway remains limited and alternative therapies for G3 MB are urgently needed. Here we show that the RNA-binding protein, Musashi-1 (MSI1) is an essential mediator of G3 MB in both MYC-overexpressing mouse models and patient-derived xenografts. MSI1 inhibition abrogates tumor initiation and significantly prolongs survival in both models. We identify binding targets of MSI1 in normal neural and G3 MB stem cells and then cross referenced these data with unbiased large-scale screens at the transcriptomic, translatomic and proteomic levels to systematically dissect its functional role. Comparative integrative multi-omic analyses of these large datasets reveal cancer-selective MSI1-bound targets sharing multiple MYC associated pathways, providing a valuable resource for context-specific therapeutic targeting of G3 MB.

The case for blood-brain barrier dysfunction in the pathogenesis of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disease that leads to a progressive loss of integrative and memory capacities of the brain. This is the predominant form of neurodegenerative dementia, with a growing prevalence of between 1 in 50 and 1 in 100 in North America. Numerous hypotheses related to the etiology of AD have developed over the years. However, among the various published hypotheses, the predominant one is related to the progressive and prominent accumulation of central nervous system ß-amyloid peptide and the ensuing brain burden created. It is, therefore, important to consider the homeostatic mechanisms underlying ß-amyloid transport dynamics between the brain and blood vascular compartments. As well, there is a dynamic interrelationship between soluble and insoluble forms of the peptide. Factors that underlie and regulate these dynamic processes are likely relevant to the end accumulation of ß-amyloid peptide in the brain compartment and ultimately in insoluble forms, which is characteristic of, and significant for, the pathophysiology of the Alzheimer's brain. Significantly, and in particular relation to the amyloid burden theory mentioned above, it has been postulated that a dysfunctioning blood-brain barrier (BBB) may play a significant, if not critical, role in the pathogenesis of AD. By allowing the influx of injurious materials or agents into the brain or by impeding or blocking the efflux of those materials and/or agents, BBB-related neuronopathies and their associated sequelae could, and do, ensue.