Purpose Gliosarcoma is a histologic variant of glioblastoma (GBM), and like GBM carries a poor prognosis. Median survival is less than one (1) year with less than 5% of patients alive after 5 years. Although there is no cure, standard treatment includes surgery, radiation and chemotherapy. While very similar to GBM, gliosarcoma exhibits several distinct differences, morphologically and molecularly. Therefore, we report a comprehensive analysis of DNA copy number changes in gliosarcoma using a cytogenomic DNA copy number (CN) microarray (OncoScan ® ). Methods Cytogenomic DNA copy number microarray (OncoScan ® ) was performed on 18 cases of gliosarcoma. MetaCore™ enrichment was applied to the array results to detect associated molecular pathways. Results The most frequent alteration was copy number loss, comprising 57% of total copy number changes. The number of losses far exceeded the number of amplifications (***, < 0.001) and loss of heterozygosity events (***, < 0.001). Amplifications were infrequent (4.6%), particularly for EGFR . Chromosomes 9 and 10 had the highest number of losses; a large portion of which correlated to CDKN2A/B loss. Copy number gains were the second most common alteration (26.2%), with the majority occurring on chromosome 7. MetaCore™ enrichment detected notable pathways for copy number gains including: HOXA, Rho family of GTPases, and EGFR; copy number loss including: WNT, NF-kß, and CDKN2A; and copy number loss of heterozygosity including: WNT and p53. Conclusions The pathways and copy number alterations detected in this study may represent key drivers in gliosarcoma oncogenesis and may provide a starting point toward targeted oncologic analysis with therapeutic potential.

Disclosure: J.O. reports editorial consultancy for American Cancer Society. M.K.K. reports a grant from Merck Pharmaceuticals, outside the submitted work. S.S. reports advisory role for Novocure. Authors responsible for statistical analysis: Statistical analysis of patient data was conducted by co-authors Manali Rupji and Jeanne Kowalski. Data availability: Sequence data generated in this study has been deposited in GEO Bank (accession number GSE131521). The source data underlying Figs. 1a, 1b, 2, 3b, and Supplementary Fig. 1 are provided as a source data file. The source data file has been deposited in the Open Science Framework (OSF) repository (https://osf.io/5uwz7/? view_onlyZf3a998f613e543288d342d245569b81e). The authors declare that all other data supporting the findings of this study are available within the main article and its Supplementary Information file or from corresponding authors upon reasonable request.

Corticobasal degeneration (CBD) may be expressed as an atypical parkinsonism with a mean disease survival of about 7 years, 1 the shortest reported survival being 24 months. 2 We report a patient with corticobasal syndrome (CBS) and pathology-confirmed CBD whose 10-month course was manifested as a frontal alien hand evolving into agrypnia excitata.Case report. A 60-year-old man without family history of neurologic illnesses developed falls and worsening dexterity of his right arm over 4 months, followed by severe insomnia and episodes of intermittent truncal tremor triggered by limb movement. By 7 months, he had developed an asymmetric parkinsonism with marked rigidity, high-frequency jerky hand tremor, and hyperreflexia. He had right-hand ideomotor apraxia but no cortical sensory loss. He exhibited picking movements with his right hand, which he did not perceive as alien (video on the Neurology ® Web site at Neurology.org).His medical history included hepatitis C-associated liver cirrhosis, diagnosed 3 years previously, and ribavirin-induced peripheral neuropathy. Brain MRI showed only minimal atrophy of the left posterior frontal and anterotemporal lobes (figure, A). PET with fluorodeoxyglucose showed mild decreased metabolic activity in the posterior parietal lobes and the bilateral thalami (figure, B). Routine CSF studies had normal results, including 14-3-3 protein. Levodopa yielded no benefits. By 8 months, he was bedbound, was unable to fall or remain asleep, and appeared to be in a constant dream-like state (detailed observations by his daughter during this period are available online as supplemental correspondence). He also manifested paranoid ideation and hallucinations. He died within 10 months after symptom onset.Postmortem examination. The brain weighed 1,275 g. The left hemisphere showed mild frontal and parietal atrophy. There was moderate to severe neuronal cell loss and gliosis in the neocortex, basal ganglia, thalamus, and midbrain. Microvacuolization (spongiform change) was present within the superficial neocortex, most prominent in the middle frontal gyrus, cingulate gyrus, and inferior parietal lobule. No Lewy bodies were identified in the brain with hematoxylin & eosin staining. a-Synuclein staining was negative in the brainstem. 4R tau-immunoreactive neurons and astroglia, thread-like deposits, astrocytic plaques, and coiled bodies were found throughout the cerebral cortex, basal ganglia, subthalamic nucleus, cerebellar dentate nucleus, midbrain, pons, and medulla ( figure, C). Within the thalamus, there was severe neuronal and glial tau deposition within the ventral lateral and reticular nuclei, as well as the zona incerta. There was moderate involvement of the dorsomedial nucleus, but relatively sparse involvement of the anterior (anteroventral) nucleus with only a few tau-immunoreactive neurons. Swollen achromatic balloon-like neurons were also documented. There was no associated b-amyloid staining. Tissue submitted to the National Prion Disease Pathology Surveillance Center showed no e...

Melanoma brain metastases (MBM) occur in ~50% of advanced melanoma patients. It is unclear if systemic therapies synergize with radiotherapy (RT) and what the impact of RT timing has on efficacy. We find that RT followed by ICI (immune checkpoint inhibitors) (RTàICI) improves MBM patient survival compared to other combination strategies, also shown here in a murine melanoma model. RNA-seq of MBM tumors in the RTàICI group exhibit overrepresentation of genes implicated in NFKB signaling. There is also expression of GABAA receptor subunits across both treatment groups. We show that melanoma cells express functional GABAA receptors and that benzodiazepines impair tumor growth. Combination of sub-lethal RT doses with benzodiazepine results in significant ipsilateral and out of field abscopal anti-tumor activity, which is associated with enhanced tumor infiltration with poly-functional CD8 T-cells. This study provides evidence that RT enhances MBM response to ICI and synergizes with benzodiazepines to promote anti-tumor activity.

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