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Histiocytic sarcoma (HS) is a rare malignant neoplasm of macrophage-dendritic cell lineage that can occur at any site. Primary base of skull involvement is exceedingly rare. We present the case of a previously healthy 56-year-old man who complained of headaches and showed localized neurologic symptoms. Magnetic resonance imaging demonstrated a hyperintense and enhancing mass involving the sphenoid bone and the clivus with an extradural component that compressed the distal pons. The differential diagnosis included chordoma or chondrosarcoma. An endoscopic trans-sphenoidal resection was performed. Microscopically, the tumor showed epithelioid and spindle morphology with atypia, mitoses, and necrosis. No osteoid, cartilaginous, or myxoid matrix was identified. By immunohistochemistry, the tumor was positive for CD68 (KP-1) and lysozyme, variably positive for CD4, CD11c, CD14, CD68 (PGM-1), CD45, and CD163, and negative for markers of epithelial, melanocytic, lymphoid, myeloid, muscle, and dendritic cell origin. Expression of PD-L1 by immunohistochemistry and

Bcl-2-associated athanogene 3 (BAG3) myopathy is a rare myofibrillar myopathy characterized by toe walking and clumsiness in the first decade with rapid progression to cardiomyopathy and restrictive lung disease in the second decade. Most patients (18 patients) have the c.626C >T (p.Pro209Leu) mutation. We describe BAG3 myopathy due to p.Pro209Leu in a 13-year-old girl with initial prominent neuropathic phenotype and no cardiac or respiratory involvement. Parents reported toe walking and clumsiness since 3 years old. Examination at the age of 13 years showed findings suggestive of Charcot-Marie-Tooth disease. Nerve conduction studies revealed demyelinating polyneuropathy. Next-generation sequencing panel for inherited neuropathies was unrevealing. Whole exome sequencing identified a de novo mutation in BAG3. Muscle biopsy confirmed myofibrillar myopathy. No cardiac involvement or symptoms of respiratory involvement at the age of 14 years. This case emphasizes the phenotypic variability of BAG3 myopathy and the importance of thorough electrophysiological examination and muscle pathology for establishing a precise diagnosis.

Brain metastases (BM) are the most common brain tumors in adults occurring in up to 40% of all cancer patients. Multi-omics approaches allow for understanding molecular mechanisms and identification of markers with prognostic significance. In this study, we profile 130 BM using genomics and transcriptomics and correlate molecular characteristics to clinical parameters. The most common tumor origins for BM were lung (40%) followed by melanoma (21%) and breast (15%). Melanoma and lung BMs contained more deleterious mutations than other subtypes (p &lt, 0.001). Mutational signatures suggested that the bulk of the mutations were gained before metastasis. A novel copy number event centered around the MCL1 gene was found in 75% of all samples, suggesting a broader role in promoting metastasis. Unsupervised hierarchical cluster analysis of transcriptional signatures available in 65 samples based on the hallmarks of cancer revealed four distinct clusters. Melanoma samples formed a distinctive cluster in comparison to other BM subtypes. Characteristics of molecular profiles did not correlate with survival. However, patients with self-identified black race or those who did not receive radiation correlated with poor survival. These data identify potential new drivers of brain metastatic progression. Our data also suggest further investigation of sociodemographic and clinical features is needed in BM cohorts.

INTRODUCTION Diffuse leptomeningeal glioneural tumor (DLGT) is a very rare central nervous tumor that has no standard of care for its treatment. This report illustrates a case of DLGT with a unique presentation and a first description of multiple systemic metastasis. Case: 19 year-old male with personal history of hereditary multiple osteochondromas and recent covid-19 infection who on investigation of headaches, progressive cranio-neuropathies, and right-sided weakness was found to have vasospasms resulting in acute infarcts in multiple vascular areas, and diffuse leptomeningeal enhancement in the thoracic spine and cauda equina. Patient underwent meningeal biopsy, after 2 months of first symptoms, which revealed DLGT per two different neuro-oncology centers. Course of disease was complicated with hydrocephalus needing shunt placement soon after diagnosis. Craniospinal radiation concurrent with temozolomide was started one month from diagnosis. Patient developed pancytopenia and chemotherapy was stop in the first weeks during radiation therapy. Metastatic disease to bone marrow was diagnosed in the second adjuvant temozolomide cycle through biopsy. One week after, on investigation of pleural effusion, lung metastasis were discovered on pleural cytology and thoracic computer tomography. Liquid biopsy showed non-actionable mutations on PIK3CA, BRAF and KRAS. Chemotherapy with carboplatin and vincristine was started with markedly improvement of pancytopenia and pleural effusions leading to cessation of frequent transfusions and auxiliary oxygen. Vincristine dose was decreased due to painful neuropathy and tinnitus. At the end of endovenous chemotherapy, worsening of disease was found with metastasis to muscles of the face and brain parenchyma. Patient was then enrolled in hospice, dying weeks after. CONCLUSION DLGT should be considered in the differential diagnosis of vasospasm. DLGT is a primary central nervous system that can metastasize to other organs. Although no standard of care is yet identified, chemotherapy with vincristine and carboplatin can be offered to systemic metastatic disease.

Background SMARCB1-deficient sinonasal carcinoma (SDSC) is an aggressive subtype of head and neck cancers that has a poor prognosis despite multimodal therapy. We present a unique case with next generation sequencing data of a patient who had SDSC with perineural invasion to the trigeminal nerve that progressed to a brain metastasis and eventually leptomeningeal spread. Case presentation A 42 year old female presented with facial pain and had resection of a tumor along the V2 division of the trigeminal nerve on the right. She underwent adjuvant stereotactic radiation. She developed further neurological symptoms and imaging demonstrated the tumor had infiltrated into the cavernous sinus as well as intradurally. She had surgical resection for removal of her brain metastasis and decompression of the cavernous sinus. Following her second surgery, she had adjuvant radiation and chemotherapy. Several months later she had quadriparesis and imaging was consistent with leptomeningeal spread. She underwent palliative radiation and ultimately transitioned quickly to comfort care and expired. Overall survival from time of diagnosis was 13 months. Next generation sequencing was carried out on her primary tumor and brain metastasis. The brain metastatic tissue had an increased tumor mutational burden in comparison to the primary. Conclusions This is the first report of SDSC with perineural invasion progressing to leptomeningeal carcinomatosis. Continued next generation sequencing of the primary and metastatic tissue by clinicians is encouraged toprovide further insights into metastatic progression of rare solid tumors. Electronic supplementary material The online version of this article (10.1186/s12885-019-6043-0) contains supplementary material, which is available to authorized users.

We report a child with hypotonia, optic atrophy, progressive encephalopathy and intractable infantile spasms who was diagnosed with PEHO syndrome. Extensive investigation was performed to diagnose an underlying etiology. Electron transport chain activities in muscle biopsies showed an isolated complex IV deficiency. Genetic examination focused on complex IV genes such as mtDNA and relevant nuclear DNA analysis was unremarkable. Whole exome sequencing with trio revealed a heterozygous de novo mutation at c.757G>A (p.E253K) in the KIF1A gene. The protein encoded by this gene functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. The relation between this genetic mutation and decreased activity of the mitochondrial respiratory chain complex is discussed in details. Our study further confirmed that the molecular basis of PEHO syndrome at least in a subset of patients is a dominant KIF1A variant affecting the motor domain of the protein. This is the first description of the decreased activity of mitochondrial respiratory chain complex in association with either PEHO syndrome or KIF1A mutation. This study emphasizes that the results of the mitochondrial enzymes should be interpreted with caution and clinicians should be actively looking for other underlying diagnoses with further comprehensive studies.

INTRODUCTION: Histologically diagnosed embryonal tumors (ET) of the central nervous system (CNS) in the pediatric population represent a group of aggressive malignancies with historically poor prognoses. Immunohistochemistry (IHC) and cytogenetics refined tumor classification and improved treatment strategies. Modern advancements in molecular methods including methylation profiling provide further delineation of distinct ET subclasses. CASE DESCRIPTION: We present two cases with initial diagnosis of a CNS embryonal tumor with EWSR1 rearrangement. Relapsed tissue in both cases displayed acquisition of INI-1 loss consistent with atypical teratoid/rhabdoid tumor (AT/RT). The first case presented at 14 months of age with vomiting and altered mental status. Imaging revealed right frontal lobe hemorrhagic mass with signs of increased intracranial pressure; pathology returned as a CNS embryonal tumor with EWSR1-PLAGL1 translocation. Patient ultimately experienced multiple relapses with tumor sample each with INI-1 loss. The second case presented at 11 months of age with new onset seizures and was found to have right frontal tumor; pathology returned as CNS embryonal tumor with EWSR1-PLAGL1 translocation. Patient experienced recurrence in original tumor bed and pathology was consistent with malignant recurrence with INI-1 loss. Methylation profiling for diagnostic samples in both patients was consistent with ET not otherwise specified, while methylation profiling of relapsed tissue in both cases was consistent with AT/RT. EWSR1 translocation was persistent from diagnostic to relapsed samples. CONCLUSION/DISCUSSION: These cases illustrate the need for ongoing analysis in patients with CNS primitive neuroectodermal tumors and EWSR1 rearrangements, and the unique role of molecular studies in relapsed tissue. The emergence of treatment resistance in a subpopulation of cells more consistent with AT/RT suggests these patients could benefit from upfront and experimental treatment approaches for AT/RT.

Neurofibromatosis type-1 is a familial genetic syndrome associated with a predisposition to develop peripheral and central nervous system neoplasms. We have previously reported on a subset of gliomas developing in these patients with morphologic features resembling subependymal giant cell astrocytoma, but the molecular features of these tumors remain undefined. A total of 14 tumors were studied and all available slides were reviewed. Immunohistochemical stains and telomere-specific FISH were performed on all cases. In addition, next-generation sequencing was performed on 11 cases using a platform targeting 644 cancer-related genes. The average age at diagnosis was 28 years (range: 4–60, 9F/5M). All tumors involved the supratentorial compartment. Tumors were predominantly low grade (n = 12), with two high-grade tumors, and displayed consistent expression of glial markers. Next-generation sequencing demonstrated inactivating NF1 mutations in 10 (of 11) cases. Concurrent TSC2 and RPTOR mutations were present in two cases (1 sporadic and 1 neurofibromatosis type-1-associated). Interestingly, alternative lengthening of telomeres was present in 4 (of 14) (29%) cases. However, an ATRX mutation associated with aberrant nuclear ATRX expression was identified in only one (of four) cases with alternative lenghtening of telomeres. Gene variants in the DNA helicase RECQL4 (n = 2) and components of the Fanconi anemia complementation group (FANCD2, FANCF, FANCG) (n = 1) were identified in two alternative lenghtening of telomere-positive/ATRX-intact cases. Other variants involved genes related to NOTCH signaling, DNA maintenance/repair pathways, and epigenetic modulators. There were no mutations identified in DAXX, PTEN, PIK3C genes, TP53, H3F3A, HIST1H3B, or in canonical hotspots of IDH1, IDH2, or BRAF. A subset of subependymal giant cell astrocytoma-like astrocytomas are alternative lenghtening of telomere-positive and occur in the absence of ATRX alterations, thereby suggesting mutations in other DNA repair/maintenance genes may also facilitate alternative lenghtening of telomeres. These findings suggest that subependymal giant cell astrocytoma-like astrocytoma represents a biologically distinct group that merits further investigation.

Astroblastomas (ABs) are rare brain tumors of unknown origin. We performed an integrative genetic and epigenetic analysis of AB-like tumors. Here, we show that tumors traceable to neural stem/progenitor cells (radial glia) that emerge during early to later brain development occur in children and young adults, respectively. Tumors with MN1-BEND2 fusion appear to present exclusively in females and exhibit overexpression of genes expressed prior to 25 post-conception weeks (pcw), including genes enriched in early ventricular zone radial glia and ependymal tumors. Other, histologically classic ABs overexpress or harbor mutations of mitogen-activated protein kinase pathway genes, outer and truncated radial glia genes, and genes expressed after 25 pcw, including neuronal and astrocyte markers. Findings support that AB-like tumors arise in the context of epigenetic and genetic changes in neural progenitors. Selective gene fusion, variable imprinting and/or chromosome X-inactivation escape resulting in biallelic overexpression may contribute to female predominance of AB molecular subtypes.

This study reports the results of the first brain tissue banking experience of Turkey in the Unit for Aging Brain and Dementia at Dokuz Eylul University, Department of Geriatric Medicine, Izmir. Here, we have briefly described our efforts on brain banking in our country, which consist of six brains from autopsies that had at least two years of clinical follow-up in the 2015-2017 period. The evaluation led to the diagnosis of two Alzheimer's disease (AD) with cerebral amyloid angiopathy, one AD with dementia with Lewy bodies, one corticobasal degeneration, one multiple system atrophy, one vascular dementia. We believe that the study is of a special importance because of its potential of becoming a brain banking center in the region and because of its contributing to the international knowledge of the neuropathological features of dementia, while characterizing the epidemiology of these diseases in the region.

High-grade diffuse large B-cell lymphoma (HG-DLBCL) refers to DLBCL with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit DLBCL) that exhibits poor prognosis. Double-expressor DLBCL (c-myc+/bcl-2+) has intermediate prognosis when compared to HG-DLBCL. Primary central nervous system lymphoma (PCNSL) has distinct pathophysiology (frequent non-germinal center-like subtype and double-expressor) and has worse prognosis than systemic DLBCL. By fluorescence in situ hybridization (FISH), 25–30% of PCNSLs harbor BCL6 abnormalities with rare alterations in MYC, BCL2, double-hit or triple-hit events. We describe the clinicopathologic features and status of MYC, BCL2 and BCL6 in 12 PCNSLs (7 women, 5 men; median age 63 years; range: 28–79). Six cases showed focal starry-sky pattern. Immunohistochemically, all (100%) were of non-germinal center-like subtype, and 8/10 (80%) cases were double-expressors. Ki-67 ranged from 70 to 100%. FISH was positive in 9/12 (75%) cases: 4 (33%) harbored a BCL6 rearrangement, 3 (25%) had a gain of BCL2, 2 (17%) cases each had a gain of BCL6 and gain of IGH, and gain of MYC and deletion of MYC were observed in 1 case each (8%). Two (16%) cases were MYC/BCL6 double-hit PCNSLs. No MYC/BCL2 or triple-hit cases were identified. Eleven (92%) patients received chemotherapy and one also received whole brain radiation. The median time of follow-up was 4.4 months (range, 0.3–40.3). Seven (58%) patients are alive, 4 (33%) have died, and 1 (8%) had no follow-up. Five alive patients are in remission, including one MYC/BCL6 double-hit PCNSL. Our results add two new cases of rare double-hit PCNSL to the literature.

Aims: Cellular schwannoma is a specific subtype of schwannoma, prone to misinterpretation as a malignant neoplasm. Involvement of the intracranial compartment by these tumours is extremely rare. We aim to characterise this clinicopathological subgroup. Methods and results: We identified a total of 20 cellular schwannomas with predominant intracranial involvement. The mean age of the patients at the time of surgery was 37years (range=16–81), with a slight female predominance (1.5:1 ratio). The most common sites were the eighth (n=8) and fifth (n=6) cranial nerves. Three tumours involved the anterior cranial fossa/olfactory groove, and a single case involved the glossopharyngeal nerve. All tumours met established criteria for cellular schwannoma, and were composed of interlacing fascicles of spindle cells lacking Verocay bodies with minimal Antoni B pattern and variable chronic inflammation and foamy histiocytes. Rare findings included haemosiderin deposition (n=6), necrosis (n=4), brisk mitotic activity (>10 mitoses per 10 high-power fields) (n=2), focal epithelioid morphology (n=2), myxoid areas (n=2), neuroblastoma-like pattern (n=1) and granular cells (n=1). Immunohistochemical stains demonstrated expression of Schwann cell markers (S100 protein, SOX10, collagen IV) and preserved H3 K27 trimethylation in all cases tested. Fourteen patients had postoperative follow-up, ranging from 2months to 21years (mean=66months). In patients with follow-up, local recurrence/persistence developed in six cases; five tumours were initially incompletely resected. No metastatic disease or deaths were reported. Conclusions: Intracranial cellular schwannomas share morphological and immunophenotypical features with cellular schwannomas at others sites may demonstrate locally aggressive growth but appear to lack metastatic potential.

Background. While pituitary tumors are well understood, little research has been done on metastasis from primary tumors into pituitary adenomas, also known as composite tumors. Because only 34 cases of composite tumors have been reported to date, we hope to better characterize these tumors by reviewing cases reported in the literature and reviewed our own documented case, which includes next-generation sequencing. Case Presentation. A 74-year-old man presented to the emergency department with left vision loss for 3 months. He had a history of colon cancer treated with colectomy and clear cell renal carcinoma treated with left nephrectomy. A preoperative MRI demonstrated growth of a peripherally enhancing, centrally necrotic mass with sellar expansion measuring 5.7×3.1×3.0 cm. Given these findings, an endoscopic endonasal transsphenoidal resection was performed. Histological assessment revealed a composite tumor: one neoplasm was a nonfunctioning pituitary adenoma, and another neoplasm was a clear cell carcinoma. Next-generation sequencing demonstrated that the tumors shared mutations in VHL and Notch2. The patient died 2 months later from systemic metastatic cancer. Conclusion. From our literature review, most metastatic lesions in these composite tumors originated from neoplasms of the lung and kidney. Approximately 63% patients presented with ophthalmoplegia as the initial symptom while 23% displayed hormonal abnormalities. Postoperative mortality had a median of 3.5 months. In our patient, the presence of VHL and Notch2 mutations in both tumors highlights the possibility of using next-generation sequencing to help identify therapeutic targets even in complex composite neoplasms.

Limb-girdle muscular dystrophy R9 (LGMD2I, LGMDR9) is an autosomal recessive disorder caused by pathogenic variants in the fukutin-related protein ( FKRP) gene. We describe a 17 year old boy with LGMDR9 whose symptoms began at age 5 years. Muscle histopathology, immunostaining, and western blotting were consistent with a dystroglycanopathy. Genetic testing identified maternal inheritance of the most common pathogenic FKRP variant c.826C>A (p.L276I). Also detected was a novel insertion and duplication on the paternally inherited FKRP allele: a single nucleotide insertion (c.948_949insC) and an eighteen nucleotide duplication (c.999_1017dup18) predicted to result in premature translation termination (p.E389*). Based on the clinical features and course of the patient, heterozygosity for the common pathogenic FKRP variant, and abnormal glycosylation of alpha-dystroglycan, we suggest that the novel FKRP insertion and duplication are pathogenic. This case expands the genetic heterogeneity of LGMDR9 and emphasize the importance of muscle biopsy for precise diagnosis.

Dysferlinopathies are a group of phenotypically heterogeneous disorders caused by pathogenic variants in the DYSF (DYStrophy-associated Fer-1-like) gene encoding dysferlin. The phenotypic spectrum includes Miyoshi muscular dystrophy (MMD), limb-girdle muscular dystrophy type R2, distal myopathy with anterior tibial onset, and isolated hyperCKemia. MMD is characterized by muscle weakness and atrophy predominantly affecting the calf muscles with symptoms onset between 14 and 40 years of age. There is no clear phenotype – genotype correlation for dysferlinopathy. We describe a 15-year-old girl who presented with a phenotype consistent with MMD. However, she was initially treated for presumed polymyositis without improvement. Subsequent genetic testing revealed two novel variants in DYSF: c.3225dup (p.Gly1076Trpfs*38) in exon 30 and c.3349-2A > G (Splice acceptor) in intron 30. No dysferlin was detected in a muscle biopsy using immunostains and western blots, a result consistent with dysferlinopathy that supports the pathogenicity of the DYSF variants.

Objectives We describe a 13-year-old girl with a past medical history of epilepsy, intellectual impairment, dysphagia with gastric tube dependence, and autism spectrum disorder who presented with focal status epilepticus. Methods Video-electroencephalography revealed left occipital pseudoperiodic epileptiform discharges and frequent seizures originating from the left hemisphere. The seizure was refractory to antiepileptic medications and pharmacologic coma. Subsequently, left occipital lobectomy was done. Extensive evaluation including whole exome sequencing, histopathologic examination of brain and muscle samples, mitochondrial DNA content analysis of tissue sample was completed to detect the etiology. Results Skeletal muscle mitochondrial DNA content (qPCR) analysis showed approximately 37% of the mean value of age and tissue matched control group consistent with a mitochondrial depletion syndrome. Microscopic examination of the brain showed cortical abnormalities that largely consisted of infarct-like pathology in a laminar manner, abnormalities of neuronal distribution, and white matter changes. Compound heterozygous mutations of the CARS2 gene were identified by whole exome sequencing; V52G variant [p.Val52Gly (GTG>GGG):c.155 T>G in exon 1] was inherited from the mother and T188M variant[p.Thr188Met (ACG>ATG): c.563 C>T in exon 5] was inherited from the father. Conclusion This is the first detailed clinicopathologic description of the Alpers-Huttenlocher syndrome phenotype from CARS mutations.

The epidural space is an uncommon site for involvement by hematolymphoid malignancies, and may present unexpectedly with neurological symptoms related to spinal cord compression. Our objective was to review the clinical and pathologic features of cases with initial presentations of cord compression, subsequently diagnosed as a hematolymphoid malignancy after pathologic examination. Review of the Department of Pathology's archives revealed 15 patients who presented with spinal cord compression due to epidural hematolymphoid malignancies between 2008-2019. These cases involved five primary epidural lymphomas, including an ALK-negative anaplastic large T-cell lymphoma previously not reported at this site, three diffuse large B cell lymphomas, one B-lymphoblastic lymphoma, four cases of myeloid sarcoma, one case with a previous history of acute myeloid leukemia, five cases with plasma cell neoplasms and epidural lesions as the initial presentation of plasma cell myeloma, one case showing aberrant T-cell marker expression, and one case being a histiocytic sarcoma that is rarely reported in the spine. A hematolymphoid malignancy was suspected clinically or radiologically in only five of these cases. These cases represent the spectrum of hematolymphoid malignancies that can involve the epidural space and present for the first time with cord compression, resulting in clinical, radiological and pathologic diagnostic challenges. Their diagnoses require a high degree of awareness, suspicion, and thorough histologic evaluation with ancillary studies for appropriate disease classification and therapeutic intervention. To our knowledge, this is one of the largest and most diverse of such series in the English language literature.

Social media use continues to grow among pathologists. Discussions of current topics, posts of educational information, and images of pathological entities are commonly found and distributed on popular sites such as Facebook and Twitter. However, little is known about the presence of neuropathology content in social media and the audience for such content. We designed and distributed a survey to assess the demographics of users viewing neuropathology content and their opinions about neuropathology in social media. User posts on the Facebook group, Surgical Neuropathology, were also analyzed. The results show that there is a demand for neuropathology content of high quality, curated by experts, and that this demand is present among both specialists and nonspecialists. These findings suggest that social media may be useful for rapid dissemination of information in the field of neuropathology. This format also offers a unique opportunity to extend the reach of information to nonneuropathologists who may not receive neuropathology journals or have access to specialty-level neuropathology training, to build networks between professionals, and potentially to influence public opinion of neuropathology on an international scale.

A 28-year-old man with a history of HIV infection (genotype 1 subtype B) who was not on antiretroviral treatment presented with 2–3 months of progressive weakness of his extremities. He had been on fluconazole therapy for 8 months for Cryptococcal meningitis. He initially noticed right followed by left lower and bilateral upper extremity weakness. Review of systems was negative for sensory symptoms or dysautonomia. His examination was notable for severe proximal (Medical Research Council [MRC] scale 1–2/5) more than distal weakness, affecting both flexor and extensor muscle groups (MRC scale 3/5), and neck flexion (MRC scale 2/5) weakness. He had left more than right brisk deep tendon reflexes throughout (+3) and sustained clonus in his ankles. He was alert and oriented. His cranial nerve and sensory examination was unremarkable. Negative inspiratory force and vital capacity were −22 cmH2O and 0.7 L, respectively.

Li Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome caused by germline mutations in TP53. TP53 is the most common mutated gene in human cancer, occurring in 30–50% of glioblastomas (GBM). Here, we highlight a precision medicine platform to identify potential targets for a GBM patient with LFS. We used a comparative transcriptomics approach to identify genes that are uniquely overexpressed in the LFS GBM patient relative to a cancer compendium of 12,747 tumor RNA sequencing data sets, including 200 GBMs. STAT1 and STAT2 were identified as being significantly overexpressed in the LFS patient, indicating ruxolitinib, a Janus kinase 1 and 2 inhibitors, as a potential therapy. The LFS patient had the highest level of STAT1 and STAT2 expression in an institutional high-grade glioma cohort of 45 patients, further supporting the cancer compendium results. To empirically validate the comparative transcriptomics pipeline, we used a combination of adherent and organoid cell culture techniques, including ex vivo patient-derived organoids (PDOs) from four patient-derived cell lines, including the LFS patient. STAT1 and STAT2 expression levels in the four patient-derived cells correlated with levels identified in the respective parent tumors. In both adherent and organoid cultures, cells from the LFS patient were among the most sensitive to ruxolitinib compared to patient-derived cells with lower STAT1 and STAT2 expression levels. A spheroid-based drug screening assay (3D-PREDICT) was performed and used to identify further therapeutic targets. Two targeted therapies were selected for the patient of interest and resulted in radiographic disease stability. This manuscript supports the use of comparative transcriptomics to identify personalized therapeutic targets in a functional precision medicine platform for malignant brain tumors.

Diffuse midline glioma, H3-K27M mutant (DMG-K27M) is a newly described, molecularly distinct infiltrative glioma that almost exclusively arises in midline CNS structures, including the brain stem, especially the pons, as well as the thalamus and spinal cord with rare examples seen in the cerebellum, third ventricle, and hypothalamus. To our knowledge, only 1 case of a molecularly confirmed DMG-K27M arising in the pineal region has been previously reported. We present the second occurrence of a tissue-confirmed DMG-K27M of the pineal region, which, to our knowledge, is the first case reported in a child and the first case with documented preoperative MRI. This case, in addition to a prior report described in an adult, defines the lower end of a broad age range of DMG-K27M onset (12-65 years) and establishes the pineal gland as a bona fide site of origin for this newly codified midline glioma.

As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its simple definition of presence of vascular proliferation and/or necrosis in a diffuse astrocytoma, the wide variety of cytohistomorphologic appearances overlap with many other neoplastic or non-neoplastic lesions. Here, after a brief review of glioblastoma is provided, the differential diagnostic possibilities with an emphasis on mimics and pitfalls are discussed. To provide an approach applicable to diagnostic practice, these discussions are grouped arbitrarily according to general malignant appearance such as pleomorphic xanthoastrocytoma and ganglioglioma, especially their anaplastic versions, and cellular features such as small cell and epithelioid glioblastoma. Some non-neoplastic lesions that can potentially be mistaken for glioblastoma under certain circumstances are also briefly mentioned. Additional studies, including immunohistochemistry and molecular markers, are included where applicable. Otherwise, exhaustive review of these individual entities, including their epidemiology and molecular biology, is outside the scope of this discussion.

Solitary fibrous tumors of the spine are rare lesions. Their description in the literature is limited to case reports and small case series. While generally benign lesions, they can recur and occasionally occur as malignancies. Here the authors present the case of a 10-year-old boy, the youngest patient and first preadolescent reported thus far, with this condition. In addition, they perform a comprehensive review of all previously published cases of spinal solitary fibrous tumors.

The presence of Alternative lengthening of telomeres (ALT) and/or ATRX loss, as well as the role of other telomere abnormalities, have not been formally studied across the spectrum of NF1-associated solid tumors. Utilizing a telomere-specific FISH assay, we classified tumors as either ALT-positive or having long (without ALT), short, or normal telomere lengths. A total of 426 tumors from 256 NF1 patients were evaluated, as well as 99 MPNST tumor samples that were sporadic or of unknown NF1 status. In the NF1-glioma dataset, ALT was present in the majority of high-grade gliomas: 14 (of 23; 60%) in contrast to only 9 (of 47; 19%) low-grade gliomas (p = 0.0009). In the subset of ALT-negative glioma cases, telomere lengths were estimated and we observed 17 (57%) cases with normal, 12 (40%) cases with abnormally long, and only 1 (3%) case with short telomeres. In the NF1-associated malignant nerve sheath tumor (NF1-MPNST) set (n = 75), ALT was present in 9 (12%). In the subset of ALT-negative NF1-MPNST cases, telomeres were short in 9 (38%), normal in 14 (58%) and long in 1 (3%). In the glioma set, overall survival was significantly decreased for patients with ALT-positive tumors (p

Severe focal motor epilepsy is considered a clinical hallmark of Rasmussen encephalitis (RE). The authors report a 6-year-old girl with progressive right sided hemiparesis, loss of language skills, left sided hemispheric atrophy, and brain pathologic features characteristic for RE. The patient did not experience seizures over a 2year period after symptom onset and for several months during follow-up. This report expands the clinical spectrum of RE and suggests that seizures are not a universal symptom of RE. Our patient's quite remarkable neurologic deficits along with active inflammation in the absence of epilepsy supports that, at least in some individuals, unilateral hemispheric progressive inflammation can occur without active seizure activity.

Patient: Male, 31 Final Diagnosis: Light chain depsotion disease Symptoms: — Medication: — Clinical Procedure: None Specialty: Hematology Objective: Rare co-existance of disease or pathology Background: Light chain deposition disease is a systemic disease characterized by deposition of immunoglobin light chains in various organs. Cardiac involvement of light chain deposition disease, also known as cardiac nonamyloidotic immunoglobin deposition disease (CIDD), is a rare clinical entity, where clinical outcome is very variable and best treatment approaches are not well known. Case Report: We present the case of a 31-year-old man with a solitary thoracic plasmacytoma and cardiac light chain deposition disease with evidence of congestive heart failure by echocardiography and cardiac markers. The patient underwent surgical resection of the plasmacytoma followed by systemic therapy with 50% VDT-PACE and then VRD with near-normalization of his heart function. A melphalan-based stem cell transplant is planned in this young patient to achieve the best possible long-term remission. Conclusions: CIDD is a very rare disease, with previous reports showing diverse manifestations with variable outcome. A high level of clinical suspicion should be maintained in such cases and early intervention, as in our patient, can restore cardiac function. There is very little literature on the optimal management of these patients. A combination of surgery and chemotherapy were pursued in our patient with very good results.

Severe recurrent proximal muscle weakness without neuroleptic malignant syndrome secondary to antidopaminergic medication has rarely been reported. We report a 29-year-old man with history of obsessive compulsive disorder and Tourette syndrome who presented with 2 months of worsening dyspnea 3 weeks after starting ziprasidone 40 mg daily that required mechanical ventilation. A year before, after an increased risperidone dose from 0.5 to 1 mg daily, he had developed proximal muscle weakness that spontaneously improved 2 months after discontinuation of risperidone. On this admission, his creatine kinase (CK) was 3318 units/L, and ziprasidone was discontinued. He fully recovered 2 months after discontinuation of ziprasidone, and his CK was 62 units/L. Genetic testing for limb-girdle muscular dystrophy was negative. This case highlights the importance of evaluating CK level in patients taking antidopaminergic medication with any suggestion of muscle weakness to prevent potentially life-threatening complication.

We report on a unique case of a giant, recurrent, supratentorial neurenteric cyst causing intractable eplipsy. Following resection, the patient developed a delayed reactive cerebritis with focal edema and worsened seizures that fully resolved with medical management. At last follow-up, over 18 months later, the patient has no evidence for cyst recurrence and remains seizure-free. we conclude that complete resection of these lesions not only requires fenestration, but also microsurgical stripping of the cyst wall. Moreover, post-operative management inclues monitoring for worsened seizures as a consequence of intracranial exposure to the cystic contents and subsequent reactive cerebritis.