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PURPOSE Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship with NF2 loss. Given the predominance of NF2 mutations in meningiomas, we evaluated the efficacy of GSK2256098, a FAK inhibitor, as part of the first genomically driven phase II study in recurrent or progressive grade 1-3 meningiomas. PATIENTS AND METHODS Eligible patients whose tumors screened positively for NF2 mutations were treated with GSK2256098, 750 mg orally twice daily, until progressive disease. Efficacy was evaluated using two coprimary end points: progression-free survival at 6 months (PFS6) and response rate by Macdonald criteria, where PFS6 was evaluated separately within grade-based subgroups: grade 1 versus 2/3 meningiomas. Per study design, the FAK inhibitor would be considered promising in this patient population if either end point met the corresponding decision criteria for efficacy. RESULTS Of 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients with NF2 mutations were enrolled and treated: 12 grade 1 and 24 grade 2/3 patients. Across all grades, one patient had a partial response and 24 had stable disease as their best response to treatment. In grade 1 patients, the observed PFS6 rate was 83% (10/12 patients; 95% CI, 52 to 98). In grade 2/3 patients, the observed PFS6 rate was 33% (8/24 patients; 95% CI, 16 to 55). The study met the PFS6 efficacy end point both for the grade 1 and the grade 2/3 cohorts. Treatment was well tolerated; seven patients had a maximum grade 3 adverse event that was at least possibly related to treatment with no grade 4 or 5 events. CONCLUSION GSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive NF2-mutated meningiomas, compared with historical controls. The criteria for promising activity were met, and FAK inhibition warrants further evaluation for this patient population.

Assessing residents and clinical fellows is a high-stakes activity. Effective assessment is important throughout training so that identified areas of strength and weakness can guide educational planning to optimize outcomes. Assessment has historically been underemphasized although medical education oversight organizations have strengthened requirements in recent years. Growing acceptance of competency-based medical education and its logical extension to competency-based time-variable (CB-TV) graduate medical education (GME) further highlights the importance of implementing effective evidence-based approaches to assessment. The Clinical Competency Committee (CCC) has emerged as a key programmatic structure in graduate medical education. In the context of launching a multi-specialty pilot of CB-TV GME in our health system, we have examined several program’s CCC processes and reviewed the relevant literature to propose enhancements to CCCs. We recommend that all CCCs fulfill three core goals, regularly applied to every GME trainee: (1) discern and describe the resident’s developmental status to individualize education, (2) determine readiness for unsupervised practice, and (3) foster self-assessment ability. We integrate the literature and observations from GME program CCCs in our institutions to evaluate how current CCC processes support or undermine these goals. Obstacles and key enablers are identified. Finally, we recommend ways to achieve the stated goals, including the following: (1) assess and promote the development of competency in all trainees, not just outliers, through a shared model of assessment and competency-based advancement; (2) strengthen CCC assessment processes to determine trainee readiness for independent practice; and (3) promote trainee reflection and informed self-assessment. The importance of coaching for competency, robust workplace-based assessments, feedback, and co-production of individualized learning plans are emphasized. Individual programs and their CCCs must strengthen assessment tools and frameworks to realize the potential of competency-oriented education.

ImportanceSARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) Tissue Pathology Study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository.MethodsRECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Casual inference methods will be employed to investigate associations between risk factors and pathologic outcomes.DiscussionRECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.Clinicaltrials.govnumber:NCT05292274

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Supplementary Figure from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Supplementary Data from Microenvironmental Landscape of Human Melanoma Brain Metastases in Response to Immune Checkpoint Inhibition

Supplementary Tables 1 and 2, Figures 1-9. Supplemental Table 1. H-score analysis for SPRY2 staining in 10 EGFRvIII-negative and 10 EGFRvIII-positive tumors. Supplemental Table 2. Upregulated genes shared by human GBMs expressing EGFRvIII and 9L.EGFRvIII rat tumors compared to wild-type EGFR human GBMs or 9L.EV rat tumors. Supplemental Figure 1. SPRY2 is efficiently knocked down by shRNA expression in GBM cell lines. Supplemental Figure 2. SPRY2 knockdown by a second non-overlapping shRNA reduces cellular proliferation, and SPRY2 knockdown by transient siRNA transfection reduces colony formation in soft agar in EGFRvIII-expressing cells. Supplemental Figure 3. SPRY2 knockdown increases cellular sensitivity to EGFR and c-MET co-inhibition. Supplemental Figure 4. SPRY2 knockdown promotes response to EGFR and c-MET coinhibition in GSC cells. Supplemental Figure 5. p38 and JNK control anchorage-independent growth and response to EGFR and c-MET co-inhibition. Supplemental Figure 6. shRNA-mediated knockdown of MKP-1 or MKP-5 reduces MKP-1 or MKP-5 mRNA level. Supplemental Figure 7. SPRY2 protein expression in kidney and cerebellum sections by immunohistochemical analysis. Supplemental Figure 8. SPRY2 correlates well with ERK phosphorylation in a panel of GBM cell lines. Supplemental Figure 9. TCGA GBM dataset analysis reveals that SPRY2 expression is associated with reduced patient survival.

Leakage corrected rCBV distributions for each ROI of each subgroup (EGFRvIII+ and EGFRvIII-). We note although these rCBV results are consistent with those obtained via PHI, the separation between EGFRvIII+ and EGFRvIII- is notably weaker.

Purpose:Previous studies have shown that the PI3K/Akt/mTOR pathway is activated in up to 70% of breast cancer brain metastases, but there are no approved agents for affected patients. GDC-0084 is a brain penetrant, dual PI3K/mTOR inhibitor that has shown promising activity in a preclinical model of glioblastoma. The aim of this study was to analyze the efficacy of PI3K/mTOR blockade in breast cancer brain metastases models.Experimental Design: The efficacy of GDC-0084 was evaluated in PIK3CA-mutant and PIK3CA wild-type breast cancer cell lines and the isogenic pairs of PIK3CA wild-type and mutant (H1047R/+) MCF10A cells in vitro. In vitro studies included cell viability and apoptosis assays, cell-cycle analysis, and Western blots. In vivo, the effect of GDC-0084 was investigated in breast cancer brain metastasis xenograft mouse models and assessed by bioluminescent imaging and IHC.Results:In vitro, GDC-0084 considerably decreased cell viability, induced apoptosis, and inhibited phosphorylation of Akt and p70 S6 kinase in a dose-dependent manner in PIK3CA-mutant breast cancer brain metastatic cell lines. In contrast, GDC-0084 led only to growth inhibition in PIK3CA wild-type cell lines in vitro. In vivo, treatment with GDC-0084 markedly inhibited the growth of PIK3CA-mutant, with accompanying signaling changes, and not PIK3CA wild-type brain tumors.Conclusions:The results of this study suggest that the brain-penetrant PI3K/mTOR targeting GDC-0084 is a promising treatment option for breast cancer brain metastases with dysregulated PI3K/mTOR signaling pathway conferred by activating PIK3CA mutations. A national clinical trial is planned to further investigate the role of this compound in patients with brain metastases.

Western blot analysis of p-p44/42 MAPK (Erk1/2) (Thr202/Tyr204), p-MEK1/2 (Ser217/221), p-p90RSK (Ser380), p-MSK1 (Thr581) in JIMT-1 BR-3, MDA-MB-361, MDA-MB-231 BrM2 and BS-004 cell lines treated with GDC-0084 in increasing concentrations for a total of 6 hours

Purpose: The epidermal growth factor receptor variant III (EGFRvIII) mutation has been considered a driver mutation and therapeutic target in glioblastoma, the most common and aggressive brain cancer. Currently, detecting EGFRvIII requires postoperative tissue analyses, which are ex vivo and unable to capture the tumor's spatial heterogeneity. Considering the increasing evidence of in vivo imaging signatures capturing molecular characteristics of cancer, this study aims to detect EGFRvIII in primary glioblastoma noninvasively, using routine clinically acquired imaging.Experimental Design: We found peritumoral infiltration and vascularization patterns being related to EGFRvIII status. We therefore constructed a quantitative within-patient peritumoral heterogeneity index (PHI/ϕ-index), by contrasting perfusion patterns of immediate and distant peritumoral edema. Application of ϕ-index in preoperative perfusion scans of independent discovery (n = 64) and validation (n = 78) cohorts, revealed the generalizability of this EGFRvIII imaging signature.Results: Analysis in both cohorts demonstrated that the obtained signature is highly accurate (89.92%), specific (92.35%), and sensitive (83.77%), with significantly distinctive ability (P = 4.0033 × 10−10, AUC = 0.8869). Findings indicated a highly infiltrative-migratory phenotype for EGFRvIII+ tumors, which displayed similar perfusion patterns throughout peritumoral edema. Contrarily, EGFRvIII− tumors displayed perfusion dynamics consistent with peritumorally confined vascularization, suggesting potential benefit from extensive peritumoral resection/radiation.Conclusions: This EGFRvIII signature is potentially suitable for clinical translation, since obtained from analysis of clinically acquired images. Use of within-patient heterogeneity measures, rather than population-based associations, renders ϕ-index potentially resistant to inter-scanner variations. Overall, our findings enable noninvasive evaluation of EGFRvIII for patient selection for targeted therapy, stratification into clinical trials, personalized treatment planning, and potentially treatment-response evaluation. Clin Cancer Res; 23(16); 4724–34. ©2017 AACR.

Photomicrographs illustrating p-MEK1/2 (Ser221) and p-p44/42 MAPK (Erk1/2) (Thr202/Tyr204) expression in mouse brains harboring either JIMT-1 BR-3 or MDA-MB-231 BrM2 intracranial tumors, stratified by treatment with sham or GDC-0084.

GDC-0084-induced changes in cell cycle in the PIK3CA-mutant cell line MDA-MB-361 and in the PIK3CA-wildtype cell line BS-004

BACKGROUND: Patients with SARS-CoV-2 may present or eventually develop central nervous system and ophthalmic signs and symptoms. Varying reports have emerged regarding isolation of viral RNA from these tissue sites, as well as largely autopsy-based histopathologic descriptions of the brain and the eye in patients with CoVID-19. EVIDENCE ACQUISITION: A primary literature search was performed in literature databases such as PubMed, Google Scholar, and Cochrane Library. Keywords were used alone and in combination including the following: SARS CoV-2, CoVID-19, eye, brain, central nervous system, histopathology, autopsy, ocular pathology, aqueous, tears, vitreous, neuropathology, encephalitis. RESULTS: The reported ophthalmic pathologic and neuropathologic findings in patients with SARS-CoV-2 are varied and inconclusive regarding the role of direct viral infection versus secondary pathology. The authors own experience with autopsy neuropathology in CoVID-19 patients is also described. There is a particular paucity of data regarding the histopathology of the eye. However, it is likely that the ocular surface is a potential site for inoculation and the tears a source of spread of viral particles. CONCLUSIONS: Additional large post-mortem studies are needed to clarify the role of SARS-CoV in the ophthalmic and neuropathologic manifestations of CoVID-19.

Patients with progressive or recurrent meningiomas have limited systemic therapy options. Focal adhesion kinase (FAK) inhibition has a synthetic lethal relationship withEligible patients whose tumors screened positively forOf 322 patients screened for all mutation cohorts of the study, 36 eligible and evaluable patients withGSK2256098 was well tolerated and resulted in an improved PFS6 rate in patients with recurrent or progressive

High-grade astrocytoma with piloid features (HGAP) is a recently recognized glioma type whose classification is dependent on its global epigenetic signature. HGAP is characterized by alterations in the mitogen-activated protein kinase (MAPK) pathway, often co-occurring with CDKN2A/B homozygous deletion and/or ATRX mutation. Experience with HGAP is limited and to better understand this tumor type, we evaluated an expanded cohort of patients (n = 144) with these tumors, as defined by DNA methylation array testing, with a subset additionally evaluated by next-generation sequencing (NGS). Among evaluable cases, we confirmed the high prevalence CDKN2A/B homozygous deletion, and/or ATRX mutations/loss in this tumor type, along with a subset showing NF1 alterations. Five of 93 (5.4%) cases sequenced harbored TP53 mutations and RNA fusion analysis identified a single tumor containing an NTRK2 gene fusion, neither of which have been previously reported in HGAP. Clustering analysis revealed the presence of three distinct HGAP subtypes (or groups = g) based on whole-genome DNA methylation patterns, which we provisionally designated as gNF1 (n = 18), g1 (n = 72), and g2 (n = 54) (median ages 43.5 years, 47 years, and 32 years, respectively). Subtype gNF1 is notable for enrichment with patients with Neurofibromatosis Type 1 (33.3%, p = 0.0008), confinement to the posterior fossa, hypermethylation in the NF1 enhancer region, a trend towards decreased progression-free survival (p = 0.0579), RNA processing pathway dysregulation, and elevated non-neoplastic glia and neuron cell content (p < 0.0001 and p < 0.0001, respectively). Overall, our expanded cohort broadens the genetic, epigenetic, and clinical phenotype of HGAP and provides evidence for distinct epigenetic subtypes in this tumor type.

Rearrangements involving the neurotrophic receptor tyrosine kinase (NTRK) gene family have been reported in diverse tumor types, and NTRK‐targeted therapies have recently been approved. In this article, we report a case of a 26‐year‐old man with an NTRK2‐rearranged isocitrate dehydrogenase‐wild‐type glioblastoma who showed a robust but temporary response to the NTRK inhibitor larotrectinib. Rebiopsy after disease progression showed elimination of the NTRK2‐rearranged tumor cell clones, with secondary emergence of a PDGFRA‐amplified subclone. Retrospective examination of the initial biopsy material confirmed rare cells harboring PDGFRA amplification. Although mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma has been previously described, mosaicism involving a fusion gene driver event has not. This case highlights the potential efficacy of NTRK‐targeted treatment in glioblastoma and the implications of molecular heterogeneity in the setting of targeted therapy. Key Points This case highlights the efficacy of the NTRK inhibitor larotrectinib in treating NTRK‐rearranged glioblastoma. This is the first case to demonstrate mosaicism in glioblastoma involving both a fusion gene and amplification for receptor tyrosine kinases. Intratumoral heterogeneity in glioblastoma has significant implications for tumor resistance to targeted therapies.

Adamantinomatous craniopharyngiomas (ACP) are characterized by alterations in the CTNNB1 gene while almost all papillary craniopharyngiomas (PCP) harbor a canonical V600E mutation in the BRAF gene. Although other recurrent driver genes have not been described to date in craniopharyngiomas, the heterogeneous clinical course of these tumors might be associated with the acquisition of further genomic alterations. It is well known that telomerase reverse transcriptase (TERT) promoter (TERTp) alterations, including mutations or methylation, upregulate the expression of TERT and increase telomerase activity, promoting tumorigenesis. We investigated whether TERTp mutations or methylation are associated with tumor relapse in a subset of craniopharyngiomas. Samples from 42 patients with histologically confirmed craniopharyngioma were retrieved. We determined TERTp, BRAF, and CTNNB1 hotspot mutations in all samples using targeted sequencing and the TERTp methylation status by methylation-specific polymerase chain reaction (PCR) in 30 samples. While BRAF V600E mutations and CTNNB1 mutations were detected in 12 (28.6%) and 21 patients (50%) in the initial tumors and subsequent recurrences, respectively, none of the patients in our cohort, including those with multiple relapses, harbored a TERTp mutation. Furthermore, TERTp methylation was detected in 14 out of 24 cases (58.3%) with available primary samples; however, no correlation between TERTp methylation with the pathological subtype, genotype, or tumor aggressiveness was detected. These data suggest that elevated telomerase activity via acquisition of TERTp mutations is an infrequent pathway in the tumorigenesis of craniopharyngiomas, regardless of their clinical course.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need because central nervous system progression is frequently an end stage of the disease. Immune checkpoint inhibitors (ICI) provide a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique elements of the MBM TME and correlates of MBM response to ICI, we collected 32 fresh MBM and performed single-cell RNA sequencing of the MBM TME and T-cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity in the MBM TME, most notably multiple distinct neutrophil states, including an IL8-expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. In addition, we observed significant relationships between intracranial T-cell phenotypes and the distribution of T-cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data identify unique features of the MBM TME that may represent potential targets to improve clinical outcomes for patients with MBM.

Context.— Postmortem evaluation for neurodegenerative disease is expensive in time and materials. These challenges can be met by implementing simpler sampling protocols while preserving anatomic relations. Objective.— To determine the diagnostic effectiveness and cost-effectiveness of a simplified brain blocking protocol compared with the standard blocking protocol used in our Alzheimer's Disease Research Center (ADRC). Design.— We prospectively compared the neuropathologic diagnoses established from our standard 19-cassette/19 brain sites ADRC protocol to a simplified 6-cassette/12 brain sites protocol in 52 consecutive cases. The simplified protocol generated 14 slides for comparison to 52 slides from our standard protocol. Results.— Compared with the ADRC protocol the simplified protocol produced Alzheimer Disease Neuropathologic Changes probability scores that were the same in 50 of 52 cases (r = 0.99). Staging for Lewy pathology was equivalent in 45 of 52 (r = 0.98), scoring for cerebral amyloid angiopathy was equivalent in 48 of 52 (r = 0.97), and grading for arteriolosclerosis was the same in 45 of 52 cases (r = 0.92). Progressive supranuclear palsy (n = 4), multiple system atrophy (n = 2), and corticobasal degeneration (n = 1) could be diagnosed by either protocol independently. The estimated savings per case was 72% or $1744.89 ($2436.37 [ADRC] versus $691.48 [simplified]). Conclusions.— The diagnosis of neurodegenerative disease at autopsy can be done accurately with a less expensive, simplified protocol. Our protocol is similar to those of previously published approaches, but it has a simpler organization scheme. This method should be valuable to institutions where autopsy cost considerations may be important.

Brain metastases from lung adenocarcinoma (BM-LUAD) frequently cause patient mortality. To identify genomic alterations that promote brain metastases, we performed whole-exome sequencing of 73 BM-LUAD cases. Using case-control analyses, we discovered candidate drivers of brain metastasis by identifying genes with more frequent copy-number aberrations in BM-LUAD compared to 503 primary LUADs. We identified three regions with significantly higher amplification frequencies in BM-LUAD, including MYC (12 versus 6%), YAP1 (7 versus 0.8%) and MMP13 (10 versus 0.6%), and significantly more frequent deletions in CDKN2A/B (27 versus 13%). We confirmed that the amplification frequencies of MYC, YAP1 and MMP13 were elevated in an independent cohort of 105 patients with BM-LUAD. Functional assessment in patient-derived xenograft mouse models validated the notion that MYC, YAP1 or MMP13 overexpression increased the incidence of brain metastasis. These results demonstrate that somatic alterations contribute to brain metastases and that genomic sequencing of a sufficient number of metastatic tumors can reveal previously unknown metastatic drivers.

Mucoepidermoid carcinoma (MEC) is often seen in salivary glands and can harbor MAML2 translocations (MAML2+). The translocation status has diagnostic utility as an objective confirmation of the MEC diagnosis, for example, when distinction from the more aggressive adenosquamous carcinoma (ASC) is not straightforward. To assess the diagnostic relevance of MAML2, we examined our 5-year experience in prospective testing of 8106 solid tumors using RNA-seq panel testing in combinations with a two-round Delphi-based scenario survey. The prevalence of MAML2+ across all tumors was 0.28% (n = 23/8106) and the majority of MAML2+ cases were found in head and neck tumors (78.3%), where the overall prevalence was 5.9% (n = 18/307). The sensitivity of MAML2 for MEC was 60% and most cases (80%) were submitted for diagnostic confirmation; in 24% of cases, the MAML2 results changed the working diagnosis. An independent survey of 15 experts showed relative importance indexes of 0.8 and 0.65 for “confirmatory MAML2 testing” in suspected MEC and ASC, respectively. Real-world evidence confirmed that the added value of MAML2 is a composite of an imperfect confirmation test for MEC and a highly specific exclusion tool for the diagnosis of ASC. Real-world evidence can help move a rare molecular-genetic biomarker from an emerging tool to the clinic.

Background Precision oncology relies on molecular diagnostics, and the value-proposition of modern healthcare networks promises a higher standard of care across partner sites. We present the results of a clinical pilot to standardize precision oncology workflows. Methods Workflows are defined as the development, roll-out, and updating of disease-specific molecular order sets. We tracked the timeline, composition, and effort of consensus meetings to define the combination of molecular tests. To assess clinical impact, we examined order set adoption over a two-year period (before and after roll-out) across all gastrointestinal and hepatopancreatobiliary (GI) malignancies, and by provider location within the network. Results Development of 12 disease center-specific order sets took ~9 months, and the average number of tests per indication changed from 2.9 to 2.8 (P = .74). After roll-out, we identified significant increases in requests for GI patients (17%; P < .001), compliance with testing recommendations (9%; P < .001), and the fraction of “abnormal” results (6%; P < .001). Of 1088 GI patients, only 3 received targeted agents based on findings derived from non-recommended orders (1 before and 2 after roll-out); indicating that our practice did not negatively affect patient treatments. Preliminary analysis showed 99% compliance by providers in network sites, confirming the adoption of the order sets across the network. Conclusion Our study details the effort of establishing precision oncology workflows, the adoption pattern, and the absence of harm from the reduction of non-recommended orders. Establishing a modifiable communication tool for molecular testing is an essential component to optimize patient care via precision oncology.

Meningeal solitary fibrous tumor (SFT) is a rare tumor with high propensity to recur and metastasize, even late in the course of disease. The WHO 2021 classification of CNS tumors divides SFT in 3 grades, based on mitotic index and necrosis. We re-examined our cohort of 126 patients (57 F, 69 M; mean age 53.0 years) with SFT, confirmed by STAT6 nuclear positivity and/or NAB2::STAT6 fusion, with extended follow-up (median 7.6 years; range 4 days-26.6 years). Tumors included 76 grade 1, 36 grade 2 and 14 grade 3 according to 2021 WHO criteria, evaluated at primary resection (n=90), recurrence (n=35), or metastasis (n=1). Fifty-six patients had one or more post-surgical events, the earliest event being local recurrence (n=41) or metastasis (n=15). Forty patients died (29 of disease; 9 of other causes; 2 unknown). Overall survival (OS), and progression-free survival (PFS, recurrence and/or metastasis) from time of primary resection (n=90) were not significantly associated with grade; however, risk of metastasis differed significantly (5-year estimates: 4.1%, 15.3%, and 37.8% for grades 1, 2, and 3 SFT, respectively; p=0.005). NAB2::STAT6 fusion status was known in 101 cases (51 = ex5-7-ex16-17, 26 = ex4_ex2-3; 12 = ex2-3_exANY/other and 12 =no fusion). Disease specific 5-year survival in primary tumors with molecular data (n = 75) was 80.0% in patients whose tumors harbored ex5-7_ex16-17 compared to 93.3% in all others combined (p=0.014). Targeted TERT promoter mutation testing was performed in 98 patients, revealing patients with tumors lacking TERT promoter mutation (n = 88) were younger at time of surgery than those harboring a mutation (n=10; p = 0.022), and none with a mutation harboring concurrent ex5-7_ex16-17 fusion (p = 0.0009). In summary, WHO 2021 grade is associated with risk of metastasis. Patients whose tumors harbor ex5-7_ex16-17 fusion have a higher risk of dying from the disease.

Cerebrovascular disease is rarely reported in neurosarcoidosis and constitutes one of its least well-described forms, though recognition for it has grown in the last decade with recent studies estimating a higher frequency of occurrence than previously known.Patients with ischemic stroke were included if the mechanism was directly attributable to sarcoidosis of the CNS. Patients were excluded if an alternative stroke etiology was of equal or higher likelihood than CNS sarcoidosis.Neurologic disease was the initial presenting manifestation of sarcoidosis in 8/11 (72.7%), and ischemic stroke was an inaugural manifestation of sarcoidosis in 4/11 (36.4%). Small vessel disease was the predominant ischemia subtype (10/11, 90.9%) with pontine perforating vessels (6/11, 54.5%) and lenticulostriate arteries (3/11, 27.3%) being the vasculature most often affected. Vessels with a more rostral supratentorial distribution were uncommonly affected. Common neuroinflammatory accompaniments included leptomeningitis (10/11, 90.9%) and cranial nerve disease (3/11, 27.3%). Recurrent strokes occurred in 8/11 (72.7%), and recurrent neuroinflammation occurred in 7/11 (63.6%). Antiplatelet drugs were used in 6/11 (54.5%) patients. Most (10/11, 90.9%) required at least two lines of immunosuppression to achieve inflammatory disease remission in this context; infliximab was the most successfully employed immunosuppressant (7/8 treatment courses, 87.5%). Recurrent strokes occurred in 8/11 (72.7%) patients, and a second inflammatory attack occurred in 7/11 (63.6%) patients. The presenting median modified Rankin Scale score of 4.0 improved to 2.0 over a median period of follow-up of 52.0 months.Ischemic strokes in neurosarcoidosis occur in a caudal-to-rostral distribution, tend to affect small caliber blood vessels that lack collateral blood flow, and typically associate with inflammatory leptomeningeal disease. The risk for relapse in the forms of stroke or neuroinflammation are high in this neurosarcoidosis phenotype.

Assessing residents and clinical fellows is a high-stakes activity. Effective assessment is important throughout training so that identified areas of strength and weakness can guide educational planning to optimize outcomes. Assessment has historically been underemphasized although medical education oversight organizations have strengthened requirements in recent years. Growing acceptance of competency-based medical education and its logical extension to competency-based time-variable (CB-TV) graduate medical education (GME) further highlights the importance of implementing effective evidence-based approaches to assessment. The Clinical Competency Committee (CCC) has emerged as a key programmatic structure in graduate medical education. In the context of launching a multi-specialty pilot of CB-TV GME in our health system, we have examined several program's CCC processes and reviewed the relevant literature to propose enhancements to CCCs. We recommend that all CCCs fulfill three core goals, regularly applied to every GME trainee: (1) discern and describe the resident's developmental status to individualize education, (2) determine readiness for unsupervised practice, and (3) foster self-assessment ability. We integrate the literature and observations from GME program CCCs in our institutions to evaluate how current CCC processes support or undermine these goals. Obstacles and key enablers are identified. Finally, we recommend ways to achieve the stated goals, including the following: (1) assess and promote the development of competency in all trainees, not just outliers, through a shared model of assessment and competency-based advancement; (2) strengthen CCC assessment processes to determine trainee readiness for independent practice; and (3) promote trainee reflection and informed self-assessment. The importance of coaching for competency, robust workplace-based assessments, feedback, and co-production of individualized learning plans are emphasized. Individual programs and their CCCs must strengthen assessment tools and frameworks to realize the potential of competency-oriented education.

Cancer therapy-induced adverse effects on the brain are a major challenge in neuro-oncology. Brain tissue necrosis (treatment necrosis [TN]) as a consequence of brain directed cancer therapy remains an insufficiently characterized condition with diagnostic and therapeutic difficulties and is frequently associated with significant patient morbidity. A better understanding of the underlying mechanisms, improvement of diagnostic tools, development of preventive strategies, and implementation of evidence-based therapeutic practices are pivotal to improve patient management. In this comprehensive review, we address existing challenges associated with current TN-related clinical and research practices and highlight unanswered questions and areas in need of further research with the ultimate goal to improve management of patients affected by this important neuro-oncological condition.

Melanoma-derived brain metastases (MBM) represent an unmet clinical need due to central nervous system (CNS) progression as a frequent, end-stage site of disease. Immune checkpoint inhibition (ICI) represents a clinical opportunity against MBM; however, the MBM tumor microenvironment (TME) has not been fully elucidated in the context of ICI. To dissect unique MBM-TME elements and correlates of MBM-ICI response, we collected 32 fresh MBM and performed single cell RNA sequencing of the MBM-TME and T cell receptor clonotyping on T cells from MBM and matched blood and extracranial lesions. We observed myeloid phenotypic heterogeneity, most notably multiple distinct neutrophil states including an IL-8 expressing population that correlated with malignant cell epithelial-to-mesenchymal transition. Additionally, we observe significant relationships between intracranial T cell phenotypes and the distribution of T cell clonotypes intracranially and peripherally. We found that the phenotype, clonotype, and overall number of MBM-infiltrating T cells were associated with response to ICI, suggesting that ICI-responsive MBMs interact with peripheral blood in a manner similar to extracranial lesions. These data demonstrate unique features of the MBM-TME, which may represent potential targets to improve clinical outcomes for patients with MBM.

Expanding the US Food and Drug Administration–approved indications for immune checkpoint inhibitors in patients with cancer has resulted in therapeutic success and immune-related adverse events (irAEs). Neurologic irAEs (irAE-Ns) have an incidence of 1%–12% and a high fatality rate relative to other irAEs. Lack of standardized disease definitions and accurate phenotyping leads to syndrome misclassification and impedes development of evidence-based treatments and translational research. The objective of this study was to develop consensus guidance for an approach to irAE-Ns including disease definitions and severity grading. A working group of four neurologists drafted irAE-N consensus guidance and definitions, which were reviewed by the multidisciplinary Neuro irAE Disease Definition Panel including oncologists and irAE experts. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness and accuracy on 9-point scales in electronic surveys and provided free text comments. Aggregated survey responses were incorporated into revised definitions. Consensus was based on numeric ratings using the RAND/University of California Los Angeles (UCLA) Appropriateness Method with prespecified definitions. 27 panelists from 15 academic medical centers voted on a total of 53 rating scales (6 general guidance, 24 central and 18 peripheral nervous system disease definition components, 3 severity criteria and 2 clinical trial adjudication statements); of these, 77% (41/53) received first round consensus. After revisions, all items received second round consensus. Consensus definitions were achieved for seven core disorders: irMeningitis, irEncephalitis, irDemyelinating disease, irVasculitis, irNeuropathy, irNeuromuscular junction disorders and irMyopathy. For each disorder, six descriptors of diagnostic components are used: disease subtype, diagnostic certainty, severity, autoantibody association, exacerbation of pre-existing disease or de novo presentation, and presence or absence of concurrent irAE(s). These disease definitions standardize irAE-N classification. Diagnostic certainty is not always directly linked to certainty to treat as an irAE-N (ie, one might treat events in the probable or possible category). Given consensus on accuracy and usability from a representative panel group, we anticipate that the definitions will be used broadly across clinical and research settings.

Patients with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) may present or eventually develop central nervous system and ophthalmic signs and symptoms. Varying reports have emerged regarding isolation of viral RNA from these tissue sites, as well as largely autopsy-based histopathologic descriptions of the brain and the eye in patients with COVID-19.A primary literature search was performed in literature databases such as PubMed, Google Scholar, and Cochrane Library. Keywords were used alone and in combination including the following: SARS CoV-2, COVID-19, eye, brain, central nervous system, histopathology, autopsy, ocular pathology, aqueous, tears, vitreous, neuropathology, and encephalitis.The reported ophthalmic pathologic and neuropathologic findings in patients with SARS-CoV-2 are varied and inconclusive regarding the role of direct viral infection vs secondary pathology. The authors own experience with autopsy neuropathology in COVID-19 patients is also described. There is a particular paucity of data regarding the histopathology of the eye. However, it is likely that the ocular surface is a potential site for inoculation and the tears a source of spread of viral particles.Additional large postmortem studies are needed to clarify the role of SARS-CoV in the ophthalmic and neuropathologic manifestations of COVID-19.

BACKGROUND cIMPACT-NOW-3 recommends that IDH-wildtype diffuse astrocytic glioma Grade II or III with EGFR amplification, or combined whole chromosome 7 gain and whole chromosome 10 loss, or TERT promoter mutation should receive an integrated classification: Diffuse astrocytic glioma, IDH-wildtype with molecular features of glioblastoma, WHO grade IV. The aims of this study were: Outline the features of a cohort of patients with molecular glioblastoma according to the above criteria; Assess clinical and molecular factors that may inform prognosis; Determine if cIMPACT-NOW-3 recommendation changed clinical practice and clinical trial enrolment. METHODS 61 patients diagnosed with IDH-wildtype diffuse astrocytic glioma Grade II or III and EGFR amp or mTERT or chromosome (+7/-10) between 2011 and 2019 at MGH were included in this single center retrospective cohort study. Data collected: sex, age, extent of surgery, functional status, histological grade, molecular diagnostics and treatment. Progression was defined using RANO criteria, progression was quantified in terms of months from the initial surgery. Survival was defined in terms of months from initial surgery to date of death or last known visit. RESULTS mOS was 16 months, mPFS was 9 months. 14 patients (23%) survived > 24 months, 7 ≥ 36 months (mOS 32 months; 9 deceased). The probability of survival in patients with markedly enhancing tumors was 0.5 at 3 months versus 0.5 at 11 months in non-enhancing tumors. The probability of survival in patients who underwent biopsy only was 0.5 at 5 months compared to 0.5 at 12 months in patients with maximally resected tumors. 1 patient was enrolled in a clinical trial at diagnosis. 6 were enrolled at time of recurrence. CONCLUSIONS mOS and pFS in the deceased patients was comparable to historical data on survival in IDH wild-type glioblastomas. Inclusion criteria in clinical trials have not reflected the cIMPACT-NOW-3 recommendation so far.

The genetic alterations that define primary central nervous system lymphoma (PCNSL) are incompletely elucidated, and the genomic evolution from diagnosis to relapse is poorly understood. We performed whole-exome sequencing (WES) on 36 PCNSL patients and targeted MYD88 sequencing on a validation cohort of 27 PCNSL patients. We also performed WES and phylogenetic analysis of 3 matched newly diagnosed and relapsed tumor specimens and 1 synchronous intracranial and extracranial relapse. Immunohistochemistry (IHC) for programmed death-1 ligand (PD-L1) was performed on 43 patient specimens. Combined WES and targeted sequencing identified MYD88 mutation in 67% (42 of 63) of patients, CDKN2A biallelic loss in 44% (16 of 36), and CD79b mutation in 61% (22 of 36). Copy-number analysis demonstrated frequent regions of copy loss (ie, CDKN2A), with few areas of amplification. CD79b mutations were associated with improved progression-free and overall survival. We did not identify amplification at the PD-1/PD-L1 loci. IHC for PD-L1 revealed membranous expression in 30% (13 of 43) of specimens. Phylogenetic analysis of paired primary and relapsed specimens identified MYD88 mutation and CDKN2A loss as early clonal events. PCNSL is characterized by frequent mutations within the B-cell receptor and NF-κB pathways. The lack of PD-L1 amplifications, along with membranous PD-L1 expression in 30% of our cohort, suggests that PD-1/PD-L1 inhibitors may be useful in a subset of PCNSL. WES of PCNSL provides insight into the genomic landscape and evolution of this rare lymphoma subtype and potentially informs more rational treatment decisions.

Background Update 3 of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) recognizes amplification of epidermal growth factor receptor (EGFR) as one important aberration in diffuse gliomas (World Health Organization [WHO] grade II/III). While these recommendations endorse testing, a cost-effective, clinically relevant testing paradigm is currently lacking. Here, we use real-world clinical data to propose a financially effective diagnostic test algorithm in the context of new guidelines. Methods To determine the prevalence, distribution, neuroradiographic features (Visually Accessible REMBRANDT Images [VASARI]), and prognostic relevance of EGFR amplification in lower-grade gliomas, we assembled a consecutive series of diffuse gliomas. For validation we included publicly available data from The Cancer Genome Atlas. For a cost-utility analysis we compared combined EGFR and isocitrate dehydrogenase (IDH) testing, EGFR testing based on IDH results, and no EGFR testing. Results In n = 71 WHO grade II/III gliomas, we identified EGFR amplification in 28.2%. With one exception, all EGFR amplifications occurred in IDH-wildtype gliomas. Comparison of overall survival showed that EGFR amplification denotes a significantly more aggressive subset of tumors (P 5% tumor contrast enhancement (75%, P = 0.016), and mild (not avid) enhancement (P = 0.016). The proposed testing algorithm reserves EGFR fluorescence in situ hybridization (FISH) testing for IDH-wildtype cases. Implementation would result in ~37.9% cost reduction at our institution, or about $1.3-4 million nationally. Conclusion EGFR-amplified diffuse gliomas are "glioblastoma-like" in their behavior and may represent undersampled glioblastomas, or subsets of IDH-wildtype diffuse gliomas with inherently aggressive biology. EGFR FISH after IDH testing is a financially effective and clinically relevant test algorithm for routine clinical practice.

BACKGROUND Papillary craniopharyngiomas are characterized by BRAFV600E mutations. Targeted therapy can elicit a dramatic radiographic regression of these tumors. Therefore, prediction of BRAF mutation status before definitive surgery could enable neoadjuvant treatment strategies. OBJECTIVE To establish preoperative prediction criteria to identify patients with a BRAF mutant craniopharyngioma. METHODS Sixty-four patients with craniopharyngioma were included in this study. We determined BRAF mutation status by targeted sequencing. After scoring interobserver variability between presurgical clinical data and radiographic features, we established a diagnostic rule for BRAF mutation in our discovery cohort. We then validated the rule in an independent cohort. RESULTS The BRAFV600E mutation was detected in 12 of 42 patients in the discovery cohort. There were no patients under age 18 with BRAF mutation. Calcification was rare in tumors with BRAF mutation (P

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.