A case of recurrent epilepsy-associated rosette-forming glioneuronal tumor with anaplastic transformation in the absence of therapy.

Rosette-forming glioneuronal tumor (RGNT) most commonly occurs adjacent to the fourth ventricle and therefore rarely presents with epilepsy. Recent reports describe RGNT occurrence in other anatomical locations with considerable morphologic and genetic overlap with the epilepsy-associated dysembryoplastic neuroepithelial tumor (DNET). Examples of RGNT or DNET with anaplastic change are rare, and typically occur in the setting of radiation treatment. We present the case of a 5-year-old girl with seizures, who underwent near total resection of a cystic temporal lobe lesion. Pathology showed morphologic and immunohistochemical features of RGNT, albeit with focally overlapping DNET-like patterns. Resections of residual or recurrent tumor were performed 1 year and 5 years after the initial resection, but no adjuvant radiation or chemotherapy was given. Ten years after the initial resection, surveillance imaging identified new and enhancing nodules, leading to another gross total resection. This specimen showed areas similar to the original tumor, but also high-grade foci with oligodendroglial morphology, increased cellularity, palisading necrosis, microvascular proliferation, and up to 13 mitotic figures per 10 high power fields. Ancillary studies the status by sequencing showed wild-type of the isocitrate dehydrogenase 1 (IDH1), IDH2, and human histone 3.3 (H3F3A) genes, and BRAF studies were negative for mutation or rearrangement. Fluorescence in situ hybridization (FISH) showed codeletion of 1p and 19q limited to the high-grade regions. By immunohistochemistry there was loss of nuclear alpha-thalassemia mental retardation syndrome, X-linked (ATRX) expression only in the high-grade region. Next-generation sequencing showed an fibroblast growth factor receptor receptor 1 (FGFR1) kinase domain internal tandem duplication in three resection specimens. ATRX mutation in the high-grade tumor was confirmed by sequencing which showed a frameshift mutation (p.R1427fs), while the apparent 1p/19q-codeletion by FISH was due to loss of chromosome arm 1p and only partial loss of 19q. Exceptional features of this case include the temporal lobe location, 1p/19q loss by FISH without true whole-arm codeletion, and anaplastic transformation associated with ATRX mutation without radiation or chemotherapy

Osteopontin Expression in Cardiomyocytes Is Increased in Pediatric Patients With Sepsis or Pneumonia

Sepsis and pneumonia are major causes of death in the United States, and their pathophysiology includes infection with inflammation and immune dysfunction. Both sepsis and pneumonia cause cardiovascular dysfunction. The expression of Osteopontin (OPN) in cardiomyocytes of patients with sepsis or pneumonia, and its role the induced cardiac dysfunction have not been thoroughly investigated. OPN is a matricellular protein synthesized by multiple diseased tissues and cells including cardiomyocytes. Here, we studied the expression of OPN protein using immunofluorescence in human myocardial autopsy tissues from pediatric and mid age or elderly patients with sepsis and/or pneumonia. Fourteen human myocardial tissues from six pediatric patients and eight mid-age or elderly patients were studied. Immunofluorescence was used to investigate the expression of OPN in paraffin-embedded heart sections co-stained with the myocyte markers Actin Alpha 1 (ACTA1) and Myosin Light Chain 2 (MLC2). A quantitative analysis was performed to determine the number of ACTA1 and MLC2 positive cardiomyocytes that express OPN. The results showed that OPN expression was significantly increased in cardiomyocytes in the hearts from pediatric patients with sepsis and/or pneumonia (N = 3) relative to pediatric patients without sepsis/pneumonia (N = 3), or adult to elderly patients with sepsis/pneumonia (N = 5). Among the older septic hearts, higher levels of cardiomyocyte OPN expression was seen only in conjunction with severe coronary arterial occlusion. This is the first study to document increased OPN expression in cardiomyocytes of pediatric subjects with sepsis or pneumonia. Our findings highlight a potentially important role for OPN in sepsis- or pneumonia-mediated cardiac dysfunction in pediatric patients

The Role of Muscle Biopsy in the Diagnosis of Inflammatory Myopathy

Muscle biopsies of patients with immune-mediated inflammatory myopathies are characterized by a combination of chronic inflammatory infiltrates and muscle fiber necrosis. In addition, there are typical histochemical, immunohistochemical, and ultrastructural findings of each type of inflammatory myopathy. Accurate classification of inflammatory myopathies is important because inclusion body myositis does not respond to immunosuppressive treatment, polymyositis is frequently part of an overlap syndrome, and dermatomyositis is associated with cancer in adults. Necrotizing myopathy without inflammation may be due to a partially treated inflammatory myopathy, a toxic myopathy, or a paraneoplastic myopathy. Metabolic myopathies and muscular dystrophies may clinically and rarely pathologically mimic inflammatory myopathy. Correct identification of these entities depends on better awareness of clinical similarities between metabolic myopathy and inflammatory myopathy; appropriate utilization of immunohistochemical, ultrastructural, biochemical, and genetic techniques on muscle samples in difficult cases; and maximizing communication between the clinician and the pathologist

Glioneuronal Neoplasms with Malignant Histological Features: A Study of 36 Cases

Objective: Malignant glioneuronal tumors show considerable morphological diversity. Their biological behavior and clinicopathological characteristics are incompletely understood. With the exception of anaplastic ganglioglioma, they are not assigned to a specific entity in the current WHO classification. It is also not clear whether histological features of these neoplasms influence prognosis. Material and Method: We identified 36 glioneuronal tumors with malignant histological features among the departmental archives and neuropathology consultation files of the authors. We reviewed the pathological and radiological features of these tumors to construct a preliminary histological categorization. Results: Based on their pathological features, we divided the study group into three histologically distinct categories: 1) glioneuronal tumors with a malignant glial component (anaplastic gangliogliomas); 2) glioneuronal tumors with a malignant neuronal/neuroblastic component; 3) glioneuronal tumors with both malignant neuronal and glial components. All tumors occurred in a younger age group compared to glioblastomas and appeared radiologically well-defined, cystic and solid with variable contrast enhancement. There was a high rate of local recurrence (29 of 36 patients) and 12 patients died during follow-up period. Median progression-free survival was less than 12 months, and did not differ among categories. Cerebrospinal tumor spread was seen in only one patient. Concurrent WHO grade I ganglioglioma and the presence of a malignant neuronal component did not appear to influence prognosis Conclusion: MGNTs were considered in three simple categories based on their malignant component(s). Tumors in all categories exhibited a high rate of local recurrence and aggressive behavior akin to malignant gliomas as opposed to classical PNET. Nevertheless, MGNT demonstrated clinicopathological features that distinguish them from typical glioblastoma. The exact nosology of MGNTs is unresolved and our study underscores the need for a more comprehensive classification of these neoplasms within the WHO scheme

Two new rare pathogenic variants in DES gene causing distal myofibrillar myopathy: Two cases of myofibrillar myopathy

Myofibrilar myopathy is associated with a wide spectrum of clinical phenotypes, affecting individuals between the age of 25-45 year of age with proximal, distal or generalized weakness. In addition to the skeletal muscle being involved, the heart can be affected and congestive heart failure and arrhythmias can be the predominant feature of the disease. Here, we present 2 new variants in DES causing desmin-myofibrillary myopathies. These variants are not present in population databases and they were not reported in the literature. The discovery of new pathogenic variants such as these ones, help further understanding of this disease and facilitate diagnosis in future patients

WP1066 induces cell death in a schwannomatosis patient–derived schwannoma cell line

Schwannomatosis is a rare genetic disorder that predisposes individuals to development of multiple schwannomas mainly in spinal and peripheral nerves and to debilitating chronic pain often unrelated to any schwannoma. Pathogenic variants of two genes, SMARCB1 and LZTR1 , are causal in familial cases. However, many schwannomatosis patients lack mutations in these genes. Surgery is the standard treatment for schwannomas but leaves patients with increasing neurological deficits. Pain management is a daily struggle controlled by the use of multiple analgesic and anti-inflammatory drugs. There is a need for both nonsurgical treatment to manage tumor growth and nonaddictive, nonsedative pain control. Because standard clinical trials are exceedingly difficult for patients with rare disorders, precision medicine approaches offer the possibility of bespoke therapeutic regimens to control tumor growth. As a proof of principle, we obtained a bio-specimen of paraspinal schwannoma from a schwannomatosis patient with a germline point mutation in the SMARCB1/INI gene. We created an hTERT immortalized cell line and tested the ability of targeted small molecules with efficacy in neurofibromatosis type 2–related schwannomas to reduce cell viability and induce cell death. We identified WP1066, a STAT3 inhibitor, currently in phase 2 clinical trials for pediatric and adult brain tumors as a lead compound. It reduced cell viability and STAT-3 phosphorylation and induced expression of markers for both necroptosis and caspase-dependent cell death. The results demonstrate feasibility in creating patient-derived cell lines for use in precision medicine studies

Central Nervous System Aspergillosis: An Unexpected Complication following Neurosurgery

Post-surgical aspergillosis is an uncommon complication that carries a high mortality rate in affected patients. The diagnosis is challenging given the lack of highly sensitive methods to isolate Aspergillus from surgical sites. Here, we present a case of post-surgical aspergillosis that occurred after the resection of acoustic neuroma in an immunocompetent patient. Imaging revealed leptomeningeal enhancement and a cerebellar extra-axial fluid collection adjacent to the right retrosigmoid craniotomy. The patient was taken to the operating room for debridement, where purulent fluid was obtained from subdural space. The diagnosis was achieved by histopathology and polymerase chain reaction (PCR) in brain tissue. Appropriate investigations failed to detect contamination in the operating room. The patient was successfully treated with 3 months of voriconazole. We highlight the importance of recognizing this uncommon complication and advocate for the use of molecular techniques to improve the diagnostic yield in central nervous system aspergillosis