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Solitary fibrous tumor is a rare mesenchymal neoplasm arising from the serosal membranes, dura, and deep soft tissues. A solitary fibrous tumor of the CNS, head, neck, and spine can be challenging to diagnose on imaging. Preoperative consideration of a solitary fibrous tumor is critical, especially in the setting of a high-grade solitary fibrous tumor, which has a high recurrence rate and metastatic potential. This review highlights multimodal imaging features of solitary fibrous tumors, including CT, MR imaging (SWI, MRA, MRS, DWI, and perfusion), FDG PET, and catheter-directed angiography. Radiologic pathologic correlations are also provided. The management of solitary fibrous tumor is a team effort orchestrated with surgery, radiation oncology, and neurointerventional and diagnostic radiology. For high-grade solitary fibrous tumors, preoperative tumor embolization followed by surgical resection and adjuvant radiation therapy improves patient outcomes. Additional whole-body staging and follow-up MR imaging are important to evaluate recurrence or distal metastasis. Learning Objective: To recognize the multimodal imaging appearance of solitary fibrous tumor in the CNS, head and neck, and spine. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Hereditary myosin myopathies are muscle disorders caused by mutations in myosin heavy chain genes. The MYH2 gene encodes the fast 2A skeletal muscle isoform, and mutations manifest as joint contractures, muscle weakness, and external ophthalmoplegia. Muscle biopsy shows decreased type 2A fibers, and vacuoles are sometimes present in adults with progressive disease. PRESENTATION OF CASE: This case describes a full term baby boy with hypotonia, dysmorphic features, dysphagia, and aspiration. Whole genome sequencing detected a novel heterozygous variant in the MYH2 gene. Muscle biopsy showed decreased type 2A fibers and vacuoles in myofibers. DISCUSSION: Hypotonia and dysphagia are common in infants with a MYH2 myopathy. However, dysmorphic features and vacuoles on biopsy have not previous been described in infants with MYH2 myopathies. CONCLUSION: This case reports an unusual phenotype of a rare neonatal-onset congenital myopathy associated with a novel heterozygous variant in MYH2. [ABSTRACT FROM AUTHOR]

The article discusses Langerhans cell histiocytosis. Langerhans cell histiocytosis is the neoplastic proliferation of Langerhans cells. The article describes the histopathology, signs and symptoms, epidemiology, radiographic findings, etiology, prognosis, and treatment of Langerhans cell histiocytosis.

Purpose: Primary central nervous system lymphoma (PCNSL) is a rare but deadly malignancy that principally affects adults in the fifth and sixth decades of life. Despite diagnostic advances in analyses of cerebral spinal fluid and neuroimaging, definitive diagnosis of PCNSL requires primary brain tissue biopsy. While small neurosurgical biopsy volumes are pursued to minimize removal of normal brain tissue, the spatial margins to precisely biopsy pathologic tissue are narrow and can result in missed diagnoses. Furthermore, prior steroid treatment can significantly reduce tumor burden increasing the likelihood of a non-diagnostic biopsy., Methods: A retrospective case report from a tertiary referral center using a combination of neuroradiological studies, sterotactic tissue biopsy, and molecular testing for genome mutations., Results: A 72-year-old woman with strong suspicion for PCNSL clinically and radiologically, but cerebral spinal fluid and primary brain tissue biopsy were negative for tumor. However, vitreous liquid biopsy molecular testing for a MYD88 mutation as well as B-cell clonality ( IGH/IGK rearrangement) were positive, indicating the presence of secondary vitreoretinal lymphoma from PCNSL. Only after autopsy of her brain was histopathological and immunohistochemical evidence of PCNSL confirmed., Conclusion: This case illustrates the unique contribution of liquid biopsy neuropathology-oriented molecular testing in a challenging case with high clinical suspicion of PCNSL in which gold-standard diagnostic testing failed to yield a diagnosis.

Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.

Objective: The goal of the work described here was to develop the first neuronavigation-guided transcranial histotripsy (NaviTH) system and associated workflow for transcranial ablation., Methods: The NaviTH system consists of a 360-element, 700 kHz transmitter-receiver-capable transcranial histotripsy array, a clinical neuronavigation system and associated equipment for patient-to-array co-registration and therapy planning and targeting software systems. A workflow for NaviTH treatments, including pre-treatment aberration correction, was developed. Targeting errors stemming from target registration errors (TREs) during the patient-to-array co-registration process, as well as focal shifts caused by skull-induced aberrations, were investigated and characterized. The NaviTH system was used in treatments of two <96 h post-mortem human cadavers and in experiments in two excised human skullcaps., Results: The NaviTH was successfully used to create ablations in the cadaver brains as confirmed in post-treatment magnetic resonance imaging A total of three ablations were created in the cadaver brains, and targeting errors of 9, 3.4 and 4.4 mm were observed in corpus callosum, septum and thalamus targets, respectively. Errors were found to be caused primarily by TREs resulting from transducer tracking instrument design flaws and imperfections in the treatment workflow. Transducer tracking instrument design and workflow improvements reduced TREs to <2 mm, and skull-induced focal shifts, following pre-treatment aberration correction, were 0.3 mm. Total targeting errors of the NaviTH system following the noted improvements were 2.5 mm., Conclusions: The feasibility of using the first NaviTH system in a human cadaver model has been determined. Although accuracy still needs to be improved, the proposed system has the potential to allow for transcranial histotripsy therapies without requiring active magnetic resonance treatment guidance., Competing Interests: Conflict of interest T.I.G., A.S.P., Z.X. and J.R.S., and the University of Michigan have a financial interest in HistoSonics, Inc. All other authors have no financial disclosures or conflicts of interest to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Extragonadal germ cell tumors (EGCTs) are rare, representing <5% of all germ cell tumors (GCTs). Whilst EGCTs share morphological and immunohistochemical features with their gonadal counterparts, they tend to be more aggressive and are frequently associated with secondary somatic malignancies. The aim of our study was to evaluate the clinical, morphological and immunohistochemical features, and to analyze tumors for chromosomal abnormalities of 12p, in addition to any novel genetic alterations, in a series of EGCTs. Seventy-seven EGCTs were included. Anterior mediastinum was the most common anatomic site, followed by central nervous system, retroperitoneum, sacroccygeal area, and neck. Whole genome SNP array identified isochromosome 12p in 26% of tumors. Additional cytogenetic abnormalities included the presence of gain of chr 21 in 37% of tumors. Somatic-type malignancies were identified in 8% of patients. Disease progression (metastasis and/or recurrence) was documented in 8 patients, most of whom died from their relapse. Three patients who died of disease had somatic-type malignancies. Mediastinal seminomas had a significantly better overall survival when compared to mediastinal non-seminomatous GCTs. Our study demonstrates that EGCTs share similar histologic features, but diverse clinical outcomes compared to their gonadal counterparts. Outcomes vary according to anatomic location and histologic subtypes. Our data corroborate that somatic-type malignancies are frequently encountered in mediastinal EGCTs and that their presence portends a poorer prognosis., Competing Interests: Declaration of competing interest None of the authors has any conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Context.—: Although the basic principles of intraoperative diagnosis in surgical neuropathology have not changed in the last century, the last several decades have seen dramatic changes in tumor classification, terminology, molecular classification, and modalities used for intraoperative diagnosis. As many neuropathologic intraoperative diagnoses are performed by general surgical pathologists, awareness of these recent changes is important for the most accurate intraoperative diagnosis., Objective.—: To describe recent changes in the practice of intraoperative surgical neuropathology, with an emphasis on new entities, tumor classification, and anticipated ancillary tests, including molecular testing., Data Sources.—: The sources for this review include the fifth edition of the World Health Organization Classification of Tumours of the Central Nervous System, primary literature on intraoperative diagnosis and newly described tumor entities, and the authors' clinical experience., Conclusions.—: A significant majority of neuropathologic diagnoses require ancillary testing, including molecular analysis, for appropriate classification. Therefore, the primary goal for any neurosurgical intraoperative diagnosis is the identification of diagnostic tissue and the preservation of the appropriate tissue for molecular testing. The intraoperative pathologist should seek to place a tumor in the most accurate diagnostic category possible, but specific diagnosis at the time of an intraoperative diagnosis is often not possible. Many entities have seen adjustments to grading criteria, including the incorporation of molecular features into grading. Awareness of these changes can help to avoid overgrading or undergrading at the time of intraoperative evaluation., Competing Interests: The authors have no relevant financial interest in the products or companies described in this article., (© 2024 College of American Pathologists.)

Abstract: A 12-year-old boy developed acute headache and vomiting. MRI brain showed a partially cystic suprasellar mass. He underwent cyst fenestration, but the cyst regrew, so he underwent transcranial subtotal resection of the mass. The pathologic diagnosis was adamantinomatous craniopharyngioma. Residual tumor was treated with proton beam radiation therapy, and panhypopituitarism was treated with hormone replacement therapy, including growth hormone. Serial brain MRI scans over several years showed no evidence of tumor recurrence. But at four years after radiation, surveillance MRI showed a new focus of nonenhancing FLAIR hyperintensity in the left basal ganglia attributed to gliosis caused by radiotherapy. Seven months later, he developed progressive right hemiparesis, expressive aphasia, and blurred vision, prompting reevaluation. MRI brain showed new enhancing and T2/FLAIR hyperintense lesions in the midbrain, basal ganglia, thalamus, anterior temporal lobe, and optic tract. The abnormal regions showed low diffusivity and relatively high regional blood flow. Stereotactic biopsy disclosed a WHO Grade 4 astrocytoma, likely radiation-induced. A germline ataxia telangiectasia mutation was found in the tumor tissue. The risk of radiation-induced pediatric brain malignancies is low but may have been increased by the mutation., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 by North American Neuro-Ophthalmology Society.)

Objective: Transcranial histotripsy has shown promise as a non-invasive neurosurgical tool, as it has the ability to treat a wide range of locations in the brain without overheating the skull. One important effect of histotripsy in the brain is the blood-brain barrier (BBB) opening (BBBO) at the ablation site, but there is a knowledge gap concerning the extent of histotripsy-induced BBBO. Here we describe induction of BBBO by transcranial histotripsy and use of magnetic resonance imaging (MRI) and histology to quantify changes in BBBO at the periphery of the histotripsy ablation zone over time in the healthy mouse brain., Methods: An eight-element, 1 MHz histotripsy transducer with a focal distance of 32.5 mm was used to treat the brains of 23 healthy female BL6 mice. T1-gadolinium (T1-Gd) MR images were acquired immediately following histotripsy treatment and during each of the subsequent 4 wk to quantify the size and intensity of BBB leakage., Results: The T1-Gd MRI results revealed that the hyperintense BBBO volume increased over the first week and subsided gradually over the following 3 wk. Histology revealed complete loss of tight junction proteins and blood vessels in the center of the ablation region immediately after histotripsy, partial recovery in the periphery of the ablation zone 1 wk following histotripsy and near-complete recovery of tight junction complex after 4 wk., Conclusion: These results provide the first evidence of transcranial histotripsy-induced BBBO and repair at the periphery of the ablation zone., Competing Interests: Conflict of interest Z.X. and the University of Michigan have a financial interest in HistoSonics, Inc. All other authors have no financial disclosures or conflicts of interest to disclose., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Aims: Targeting tumor metabolism may improve the outcomes for patients with glioblastoma (GBM). To further preclinical efforts targeting metabolism in GBM, we tested the hypothesis that brain tumors can be stratified into distinct metabolic groups with different patient outcomes. Therefore, to determine if tumor metabolites relate to patient survival, we profiled the metabolomes of human gliomas and correlated metabolic information with clinical data. Results: We found that isocitrate dehydrogenase-wildtype (IDHwt) GBMs are metabolically distinguishable from IDH mutated (IDHmut) astrocytomas and oligodendrogliomas. Survival of patients with IDHmut gliomas was expectedly more favorable than those with IDHwt GBM, and metabolic signatures can stratify IDHwt GBMs subtypes with varying prognoses. Patients whose GBMs were enriched in amino acids had improved survival, while those whose tumors were enriched for nucleotides, redox molecules, and lipid metabolites fared more poorly. These findings were recapitulated in validation cohorts using both metabolomic and transcriptomic data. Innovation: Our results suggest the existence of metabolic subtypes of GBM with differing prognoses, and further support the concept that metabolism may drive the aggressiveness of human gliomas. Conclusions: Our data show that metabolic signatures of human gliomas can inform patient survival. These findings may be used clinically to tailor novel metabolically targeted agents for GBM patients with different metabolic phenotypes. Antioxid. Redox Signal . 39, 942-956.

Background: High-grade gliomas have a poor prognosis and do not respond well to treatment. Effective cancer immune responses depend on functional immune cells, which are typically absent from the brain. This study aimed to evaluate the safety and activity of two adenoviral vectors expressing HSV1-TK (Ad-hCMV-TK) and Flt3L (Ad-hCMV-Flt3L) in patients with high-grade glioma., Methods: In this dose-finding, first-in-human trial, treatment-naive adults aged 18-75 years with newly identified high-grade glioma that was evaluated per immunotherapy response assessment in neuro-oncology criteria, and a Karnofsky Performance Status score of 70 or more, underwent maximal safe resection followed by injections of adenoviral vectors expressing HSV1-TK and Flt3L into the tumour bed. The study was conducted at the University of Michigan Medical School, Michigan Medicine (Ann Arbor, MI, USA). The study included six escalating doses of viral particles with starting doses of 1×10 10 Ad-hCMV-TK viral particles and 1×10 9 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×10 11 Ad-hCMV-TK viral particles and 1×10 9 Ad-hCMV-Flt3L viral particles (cohort B), 1×10 10 Ad-hCMV-TK viral particles and 1×10 10 Ad-hCMV-Flt3L viral particles (cohort C), 1×10 11 Ad-hCMV-TK viral particles and 1×10 10 Ad-hCMV-Flt3L viral particles (cohort D), 1×10 10 Ad-hCMV-TK viral particles and 1×10 11 Ad-hCMV-Flt3L viral particles (cohort E), and 1×10 11 Ad-hCMV-TK viral particles and 1×10 11 Ad-hCMV-Flt3L viral particles (cohort F) following a 3+3 design. Two 1 mL tuberculin syringes were used to deliver freehand a mix of Ad-hCMV-TK and Ad-hCMV-Flt3L vectors into the walls of the resection cavity with a total injection of 2 mL distributed as 0·1 mL per site across 20 locations. Subsequently, patients received two 14-day courses of valacyclovir (2 g orally, three times per day) at 1-3 days and 10-12 weeks after vector administration and standad upfront chemoradiotherapy. The primary endpoint was the maximum tolerated dose of Ad-hCMV-Flt3L and Ad-hCMV-TK. Overall survival was a secondary endpoint. Recruitment is complete and the trial is finished. The trial is registered with ClinicalTrials.gov, NCT01811992., Findings: Between April 8, 2014, and March 13, 2019, 21 patients were assessed for eligibility and 18 patients with high-grade glioma were enrolled and included in the analysis (three patients in each of the six dose cohorts); eight patients were female and ten were male. Neuropathological examination identified 14 (78%) patients with glioblastoma, three (17%) with gliosarcoma, and one (6%) with anaplastic ependymoma. The treatment was well-tolerated, and no dose-limiting toxicity was observed. The maximum tolerated dose was not reached. The most common serious grade 3-4 adverse events across all treatment groups were wound infection (four events in two patients) and thromboembolic events (five events in four patients). One death due to an adverse event (respiratory failure) occurred but was not related to study treatment. No treatment-related deaths occurred during the study. Median overall survival was 21·3 months (95% CI 11·1-26·1)., Interpretation: The combination of two adenoviral vectors demonstrated safety and feasibility in patients with high-grade glioma and warrants further investigation in a phase 1b/2 clinical trial., Funding: Funded in part by Phase One Foundation, Los Angeles, CA, The Board of Governors at Cedars-Sinai Medical Center, Los Angeles, CA, and The Rogel Cancer Center at The University of Michigan., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: Currently, there is a knowledge gap in our understanding of the magnetic resonance imaging (MRI) characteristics of brain tumors treated with histotripsy to evaluate treatment response as well as treatment-related injuries. Our aim was to bridge this gap by investigating and correlating MRI with histological analysis after histotripsy treatment of mouse brain with and without brain tumors and evaluating the evolution of the histotripsy ablation zone on MRI over time., Methods: An eight-element, 1 MHz histotripsy transducer with a focal distance of 32.5 mm was used to treat orthotopic glioma-bearing mice and normal mice. The tumor burden at the time of treatment was ∼5 mm 3 . T2, T2*, T1 and T1-gadolinium (Gd) MR images and histology of the brain were acquired on days 0, 2 and 7 for tumor-bearing mice and days 0, 2, 7, 14, 21 and 28 post-histotripsy for normal mice., Results: T2 and T2* sequences most accurately correlated with histotripsy treatment zone. The treatment-induced blood products, T1 along with T2, revealed blood product evolution from oxygenated, de-oxygenated blood and methemoglobin to hemosiderin. And T1-Gd revealed the state of the blood-brain barrier arising from the tumor or histotripsy ablation. Histotripsy leads to minor localized bleeding, which resolves within the first 7 d as evident on hematoxylin and eosin staining. By day 14, the ablation zone could be distinguished only by the macrophage-laden hemosiderin, which resides around the ablation zone, rendering the treated zone hypo-intense on all MR sequences., Conclusion: These results provide a library of radiological features on MRI sequences correlated to histology, thus allowing for non-invasive evaluation of histotripsy treatment effects in in vivo experiments., Competing Interests: Conflict of interest Z.X., T.H. and J.S. have financial and/or other relationships with HistoSonics Inc. The University of Michigan has a financial interest in HistoSonics Inc., (Copyright © 2023 World Federation for Ultrasound in Medicine & Biology. Published by Elsevier Inc. All rights reserved.)

Introduction: Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. Access to timely molecular diagnostic testing for brain tumor patients is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment., Methods: By combining stimulated Raman histology (SRH), a rapid, label-free, non-consumptive, optical imaging method, and deep learning-based image classification, we are able to predict the molecular genetic features used by the World Health Organization (WHO) to define the adult-type diffuse glioma taxonomy, including IDH-1/2, 1p19q-codeletion, and ATRX loss. We developed a multimodal deep neural network training strategy that uses both SRH images and large-scale, public diffuse glioma genomic data (i.e. TCGA, CGGA, etc.) in order to achieve optimal molecular classification performance., Results: One institution was used for model training (University of Michigan) and four institutions (NYU, UCSF, Medical University of Vienna, and University Hospital Cologne) were included for patient enrollment in the prospective testing cohort. Using our system, called DeepGlioma, we achieved an average molecular genetic classification accuracy of 93.2% and identified the correct diffuse glioma molecular subgroup with 91.5% accuracy within 2 minutes in the operating room. DeepGlioma outperformed conventional IDH1-R132H immunohistochemistry (94.2% versus 91.4% accuracy) as a first-line molecular diagnostic screening method for diffuse gliomas and can detect canonical and non-canonical IDH mutations., Conclusions: Our results demonstrate how artificial intelligence and optical histology can be used to provide a rapid and scalable alternative to wet lab methods for the molecular diagnosis of brain tumor patients during surgery., (Copyright © Congress of Neurological Surgeons 2023. All rights reserved.)

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid (<90 seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma (n = 153) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of 93.3 ± 1.6%. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Purpose: Glioblastoma(GBM) is a lethal disease characterized by inevitable recurrence. Here we investigate the molecular pathways mediating resistance, with the goal of identifying novel therapeutic opportunities., Experimental Design: We developed a longitudinal in vivo recurrence model utilizing patient-derived explants to produce paired specimens(pre- and post-recurrence) following temozolomide(TMZ) and radiation(IR). These specimens were evaluated for treatment response and to identify gene expression pathways driving treatment resistance. Findings were clinically validated using spatial transcriptomics of human GBMs., Results: These studies reveal in replicate cohorts, a gene expression profile characterized by upregulation of mesenchymal and stem-like genes at recurrence. Analyses of clinical databases revealed significant association of this transcriptional profile with worse overall survival and upregulation at recurrence. Notably, gene expression analyses identified upregulation of TGFβ signaling, and more than one-hundred-fold increase in THY1 levels at recurrence. Furthermore, THY1-positive cells represented <10% of cells in treatment-naïve tumors, compared to 75-96% in recurrent tumors. We then isolated THY1-positive cells from treatment-naïve patient samples and determined that they were inherently resistant to chemoradiation in orthotopic models. Additionally, using image-guided biopsies from treatment-naïve human GBM, we conducted spatial transcriptomic analyses. This revealed rare THY1+ regions characterized by mesenchymal/stem-like gene expression, analogous to our recurrent mouse model, which co-localized with macrophages within the perivascular niche. We then inhibited TGFBRI activity in vivo which decreased mesenchymal/stem-like protein levels, including THY1, and restored sensitivity to TMZ/IR in recurrent tumors., Conclusions: These findings reveal that GBM recurrence may result from tumor repopulation by pre-existing, therapy-resistant, THY1-positive, mesenchymal cells within the perivascular niche., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier Inc.)

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., (© 2022. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Objective: This study investigated the effect of various histotripsy dosages on tumor cell kill and associated bleeding in two murine brain tumor models (glioma [Gl261] and lung metastasis [LL/2-Luc2])., Methods and Materials: GL261 or LL/2-Luc2 cells were cultured and implanted into the brains of C57BL/6 mice. Histotripsy (1-cycle pulses, 5 Hz PRF, 30 MPa-P) was performed using a 1 MHz transducer for five different dosages for each cell line: 5, 20 or 200 pulses per location (PPL) at a single treatment point, or 5 or 10-20 PPL at multiple treatment points. MRI, bioluminescence imaging and histology were used to assess tumor ablation and treatment effects within 4-6 h post-treatment., Results: All treatment groups resulted in a reduction of BLI intensity for the LL/2-Luc2 tumors, with significant signal reductions for the multi-point groups. The average pre-/post-treatment BLI flux (photons/s, ×10 8 ) for the different treatment groups were: 4.39/2.19 (5 PPL single-point), 5.49/1.80 (20 PPL single-point), 3.86/1.73 (200 PPL single-point), 2.44/1.11 (5 PPL multi-point) and 5.85/0.80 (10 PPL multi-point). MRI and H&E staining showed increased tumor damage and hemorrhagic effects with increasing histotripsy dose for both GL261 and LL/2-Luc2 tumors, but the increase in tumor damage was diminished beyond 10-20 PPL for single-point treatments and outweighed by increased hemorrhage. In general, hemorrhage was confined to be within 1 mm of the treatment boundary for all groups., Conclusions: Our results suggest that a lower number of histotripsy pulses at fewer focal locations can achieve substantial tumor kill while minimizing hemorrhage.

Accurate intraoperative diagnosis is essential for providing safe and effective care during brain tumor surgery. Our standard-of-care diagnostic methods are time, resource, and labor intensive, which restricts access to optimal surgical treatments. To address these limitations, we propose an alternative workflow that combines stimulated Raman histology (SRH), a rapid optical imaging method, with deep learning-based automated interpretation of SRH images for intraoperative brain tumor diagnosis and real-time surgical decision support. Here, we present OpenSRH , the first public dataset of clinical SRH images from 300+ brain tumors patients and 1300+ unique whole slide optical images. OpenSRH contains data from the most common brain tumors diagnoses, full pathologic annotations, whole slide tumor segmentations, raw and processed optical imaging data for end-to-end model development and validation. We provide a framework for patch-based whole slide SRH classification and inference using weak (i.e. patient-level) diagnostic labels. Finally, we benchmark two computer vision tasks: multiclass histologic brain tumor classification and patch-based contrastive representation learning. We hope OpenSRH will facilitate the clinical translation of rapid optical imaging and real-time ML-based surgical decision support in order to improve the access, safety, and efficacy of cancer surgery in the era of precision medicine. Dataset access, code, and benchmarks are available at https://opensrh.mlins.org., Competing Interests: Competing interests: C.W.F. is an employee and shareholder of Invenio Imaging, Inc., a company developing SRH microscopy systems. D.A.O. is an advisor and shareholder of Invenio Imaging, Inc, and T.C.H. is a shareholder of Invenio Imaging, Inc.

The World Health Organization (WHO) published the fifth edition of the WHO Classification of Tumors of the Central Nervous System (WHO CNS5) in 2021, as an update of the WHO central nervous system (CNS) classification system published in 2016. WHO CNS5 was drafted on the basis of recommendations from the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) and expounds the classification scheme of the previous edition, which emphasized the importance of genetic and molecular changes in the characteristics of CNS tumors. Multiple newly recognized tumor types, including those for which there is limited knowledge regarding neuroimaging features, are detailed in WHO CNS5. The authors describe the major changes introduced in WHO CNS5, including revisions to tumor nomenclature. For example, WHO grade IV tumors in the fourth edition are equivalent to CNS WHO grade 4 tumors in the fifth edition, and diffuse midline glioma, H3 K27M -mutant, is equivalent to midline glioma, H3 K27 -altered. With regard to tumor typing, isocitrate dehydrogenase (IDH)-mutant glioblastoma has been modified to IDH -mutant astrocytoma. In tumor grading, IDH -mutant astrocytomas are now graded according to the presence or absence of homozygous CDKN2A/B deletion. Moreover, the molecular mechanisms of tumorigenesis, as well as the clinical characteristics and imaging features of the tumor types newly recognized in WHO CNS5, are summarized. Given that WHO CNS5 has become the foundation for daily practice, radiologists need to be familiar with this new edition of the WHO CNS tumor classification system. Online supplemental material and the slide presentation from the RSNA Annual Meeting are available for this article. © RSNA, 2022.

In this inaugural clinicopathological conference, the invited experts discussed the diagnostic approach to central nervous system infections in immunocompromised hosts. The case presented involved a pancreas-kidney transplant recipient with multiple brain abscesses caused by Bartonella henselae. CSF metagenomic next-generation sequencing played a significant role in the diagnosis. Bartonella henselae is a gram-negative zoonotic pathogen that causes cat-scratch disease, which can be transmitted to humans through cat bites or scratches. Symptoms can vary in severity, correlating with the patient's immune status. Visceral organ involvement, ocular involvement, and neurological manifestations have been reported in immunocompromised patients, but brain abscesses are rare., (© 2022 Wiley Periodicals LLC.)

Background: Accurate specimen analysis of skull base tumors is essential for providing personalized surgical treatment strategies. Intraoperative specimen interpretation can be challenging because of the wide range of skull base pathologies and lack of intraoperative pathology resources., Objective: To develop an independent and parallel intraoperative workflow that can provide rapid and accurate skull base tumor specimen analysis using label-free optical imaging and artificial intelligence., Methods: We used a fiber laser-based, label-free, nonconsumptive, high-resolution microscopy method (<60 seconds per 1 × 1 mm2), called stimulated Raman histology (SRH), to image a consecutive, multicenter cohort of patients with skull base tumor. SRH images were then used to train a convolutional neural network model using 3 representation learning strategies: cross-entropy, self-supervised contrastive learning, and supervised contrastive learning. Our trained convolutional neural network models were tested on a held-out, multicenter SRH data set., Results: SRH was able to image the diagnostic features of both benign and malignant skull base tumors. Of the 3 representation learning strategies, supervised contrastive learning most effectively learned the distinctive and diagnostic SRH image features for each of the skull base tumor types. In our multicenter testing set, cross-entropy achieved an overall diagnostic accuracy of 91.5%, self-supervised contrastive learning 83.9%, and supervised contrastive learning 96.6%. Our trained model was able to segment tumor-normal margins and detect regions of microscopic tumor infiltration in meningioma SRH images., Conclusion: SRH with trained artificial intelligence models can provide rapid and accurate intraoperative analysis of skull base tumor specimens to inform surgical decision-making., (Copyright © Congress of Neurological Surgeons 2022. All rights reserved.)

Histotripsy has been previously applied to target various cranial locations in vitro through an excised human skull. Recently, a transcranial magnetic resonance (MR)-guided histotripsy (tcMRgHt) system was developed, enabling pre-clinical investigations of tcMRgHt for brain surgery. To determine the feasibility of in vivo transcranial histotripsy, tcMRgHt treatment was delivered to eight pigs using a 700-kHz, 128-element, MR-compatible phased-array transducer inside a 3-T magnetic resonance imaging (MRI) scanner. After craniotomy to open an acoustic window to the brain, histotripsy was applied through an excised human calvarium to target the inside of the pig brain based on pre-treatment MRI and fiducial markers. MR images were acquired pre-treatment, immediately post-treatment and 2-4 h post-treatment to evaluate the acute treatment outcome. Successful histotripsy ablation was observed in all pigs. The MR-evident lesions were well confined within the targeted volume, without evidence of excessive brain edema or hemorrhage outside of the target zone. Histology revealed tissue homogenization in the ablation zones with a sharp demarcation between destroyed and unaffected tissue, which correlated well with the radiographic treatment zones on MRI. These results are the first to support the in vivo feasibility of tcMRgHt in the pig brain, enabling further investigation of the use of tcMRgHt for brain surgery., Competing Interests: Conflict of interest disclosure Z.X. and T.H. have financial and/or other relationships with HistoSonics Inc. The University of Michigan has a financial interest in Histosonics Inc., (Copyright © 2021. Published by Elsevier Inc.)

Background: Neuro-oncology has grown tremendously since 2010, marked by increasing society membership, specialized clinical expertise, and new journals. Yet, modest improvement in racial/ethnic diversity amongst clinical trial participants, researchers, and clinicians led us to conduct a survey to identify opportunities to enhance diversity and inclusiveness amongst neuro-oncology professionals., Methods: In summer 2020, the Women and Diversity Committee of the Society for Neuro-Oncology (SNO) distributed an anonymous online survey to members and affiliates including the European Association of Neuro-Oncology (EANO), Asian Society for Neuro-Oncology (ASNO), Society for Neuro-Oncology Latin America (SNOLA) and Society for Neuro-Oncology Sub-Saharan Africa (SNOSSA). The survey captured personal and professional characteristics, biases, effective mentorship qualities, career service metrics, and suggested field/society changes. Results were analyzed by geography, profession, age, racial/ethnic, and sexual identity. Standard descriptive statistics characterized the study population., Results: The 386 respondents were predominantly female (58%) with a median age range of 40-49 years (31%), White (65%), and SNO members (97%). Most worked in North America (77%) in a research profession (67%). A majority of White respondents reported never experiencing biases (64%), while the majority of non-White respondents reported unconscious biases/microaggressions, followed by a lack of/limited mentorship. Qualitative assessments showcased that personal/professional success metrics were linked to needed improvements in diversity and inclusion efforts within the neuro-oncology field., Conclusions: The prevalence of racial/ethnic biases and poor mentorship rates amongst underrepresented groups in neuro-oncology is high and potentially linked to the limited diverse representation amongst members and affiliates. These findings warrant a swift implementation of equity and inclusion practices within the neuro-oncology field., (Published by Oxford University Press on behalf of the Society for Neuro-Oncology 2021.)

Importance: Use of next-generation sequencing (NGS) to identify clinically actionable genomic targets has been incorporated into routine clinical practice in the management of advanced solid tumors; however, the clinical utility of this testing remains uncertain., Objective: To determine which patients derived the greatest degree of clinical benefit from NGS profiling., Design, Setting, and Participants: Patients in this cohort study underwent fresh tumor biopsy and blood sample collection for genomic profiling of paired tumor and normal DNA (whole-exome or targeted-exome capture with analysis of 1700 genes) and tumor transcriptome (RNA) sequencing. Somatic and germline genomic alterations were annotated and classified according to degree of clinical actionability. Results were returned to treating oncologists. Data were collected from May 1, 2011, to February 28, 2018, and analyzed from May 1, 2011, to April 30, 2020., Main Outcomes and Measures: Patients' subsequent therapy and treatment response were extracted from the medical record to determine clinical benefit rate from NGS-directed therapy at 6 months and exceptional responses lasting 12 months or longer., Results: During the study period, NGS was attempted on tumors from 1138 patients and was successful in 1015 (89.2%) (MET1000 cohort) (538 men [53.0%]; mean [SD] age, 57.7 [13.3] years). Potentially clinically actionable genomic alterations were discovered in 817 patients (80.5%). Of these, 132 patients (16.2%) received sequencing-directed therapy, and 49 had clinical benefit (37.1%). Exceptional responses were observed in 26 patients (19.7% of treated patients). Pathogenic germline variants (PGVs) were identified in 160 patients (15.8% of cohort), including 49 PGVs (4.8% of cohort) with therapeutic relevance. For 55 patients with carcinoma of unknown primary origin, NGS identified the primary site in 28 (50.9%), and sequencing-directed therapy in 13 patients resulted in clinical benefit in 7 instances (53.8%), including 5 exceptional responses., Conclusions and Relevance: The high rate of therapeutically relevant PGVs identified across diverse cancer types supports a recommendation for directed germline testing in all patients with advanced cancer. The high frequency of therapeutically relevant somatic and germline findings in patients with carcinoma of unknown primary origin and other rare cancers supports the use of comprehensive NGS profiling as a component of standard of care for these disease entities.

Background: Detection of glioma recurrence remains a challenge in modern neuro-oncology. Noninvasive radiographic imaging is unable to definitively differentiate true recurrence versus pseudoprogression. Even in biopsied tissue, it can be challenging to differentiate recurrent tumor and treatment effect. We hypothesized that intraoperative stimulated Raman histology (SRH) and deep neural networks can be used to improve the intraoperative detection of glioma recurrence., Methods: We used fiber laser-based SRH, a label-free, nonconsumptive, high-resolution microscopy method (<60 sec per 1 × 1 mm2) to image a cohort of patients (n = 35) with suspected recurrent gliomas who underwent biopsy or resection. The SRH images were then used to train a convolutional neural network (CNN) and develop an inference algorithm to detect viable recurrent glioma. Following network training, the performance of the CNN was tested for diagnostic accuracy in a retrospective cohort (n = 48)., Results: Using patch-level CNN predictions, the inference algorithm returns a single Bernoulli distribution for the probability of tumor recurrence for each surgical specimen or patient. The external SRH validation dataset consisted of 48 patients (recurrent, 30; pseudoprogression, 18), and we achieved a diagnostic accuracy of 95.8%., Conclusion: SRH with CNN-based diagnosis can be used to improve the intraoperative detection of glioma recurrence in near-real time. Our results provide insight into how optical imaging and computer vision can be combined to augment conventional diagnostic methods and improve the quality of specimen sampling at glioma recurrence., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Undiagnosed significant hydrocephalus is an uncommon finding at forensic autopsy as many cases present in life with complex neurological symptoms. We present a case of a 46-year-old man with no neurological deficits or history of head trauma that was incidentally found to have a massive hydrocephalus at autopsy. This was found to be associated with an unruptured arteriovenous malformation completely confined to the choroid plexus as well as complete agenesis of the corpus callosum. The arteriovenous malformation was found to form a calcified obstruction at the foramen of Monro analogous to a mass lesion, such as a colloid cyst of the third ventricle. The association of this malformation and agenesis of the corpus callosum has never been described. Histologic examination of the brain confirmed significant loss of white matter tracts and thinning of the cortical ribbon due to pressure atrophy of the ependymal lining without significant gliosis, cortical dysplasia, or evidence of other developmental malformations. Autopsy is a vital tool in the evaluation of such rare cases, enhances epidemiologic data, and increases the understanding of these pathophysiological associations.

Differentiating pseudoprogression from true tumor progression has become a significant challenge in follow-up of diffuse infiltrating gliomas, particularly high grade, which leads to a potential treatment delay for patients with early glioma recurrence. In this study, we proposed to use a multiparametric MRI data as a sequence input for the convolutional neural network with the recurrent neural network based deep learning structure to discriminate between pseudoprogression and true tumor progression. In this study, 43 biopsy-proven patient data identified as diffuse infiltrating glioma patients whose disease progressed/recurred were used. The dataset consists of five original MRI sequences; pre-contrast T1-weighted, post-contrast T1-weighted, T2-weighted, FLAIR, and ADC images as well as two engineered sequences; T1post-T1pre and T2-FLAIR. Next, we used three CNN-LSTM models with a different set of sequences as input sequences to pass through CNN-LSTM layers. We performed threefold cross-validation in the training dataset and generated the boxplot, accuracy, and ROC curve, AUC from each trained model with the test dataset to evaluate models. The mean accuracy for VGG16 models ranged from 0.44 to 0.60 and the mean AUC ranged from 0.47 to 0.59. For CNN-LSTM model, the mean accuracy ranged from 0.62 to 0.75 and the mean AUC ranged from 0.64 to 0.81. The performance of the proposed CNN-LSTM with multiparametric sequence data was found to outperform the popular convolutional CNN with a single MRI sequence. In conclusion, incorporating all available MRI sequences into a sequence input for a CNN-LSTM model improved diagnostic performance for discriminating between pseudoprogression and true tumor progression.

BACKGROUNDOur objective was to investigate whether primary Sjögren's syndrome (pSS) is associated with multiple system atrophy (MSA).METHODSWe performed a retrospective cohort study assessing (a) rates of MSA in a cohort of patients with pSS and (b) rates of pSS in a cohort of patients with MSA. These data were compared with rates in respective control groups. We additionally reviewed the neuropathologic findings in 2 patients with pSS, cerebellar degeneration, parkinsonism, and autonomic dysfunction.RESULTSOur cohort of 308 patients with pSS had a greater incidence of MSA compared with 4 large population-based studies and had a significantly higher prevalence of at least probable MSA (1% vs. 0%, P = 0.02) compared with 776 patients in a control cohort of patients with other autoimmune disorders. Our cohort of 26 autopsy-proven patients with MSA had a significantly higher prevalence of pSS compared with a cohort of 115 patients with other autopsy-proven neurodegenerative disorders (8% vs. 0%, P = 0.03). The 2 patients we described with pSS and progressive neurodegenerative disease showed classic MSA pathology at autopsy.CONCLUSIONOur findings provide evidence for an association between MSA and pSS that is specific to both pSS, among autoimmune disorders, and MSA, among neurodegenerative disorders. The 2 cases we describe of autopsy-proven MSA support that MSA pathology can explain neurologic disease in a subset of patients with pSS. These findings together support the hypothesis that systemic autoimmune disease plays a role in neurodegeneration.FUNDINGThe Michigan Brain Bank is supported in part through NIH grant P30AG053760.

The discovery of a new mass involving the brain or spine typically prompts referral to a neurosurgeon to consider biopsy or surgical resection. Intraoperative decision-making depends significantly on the histologic diagnosis, which is often established when a small specimen is sent for immediate interpretation by a neuropathologist. Access to neuropathologists may be limited in resource-poor settings, which has prompted several groups to develop machine learning algorithms for automated interpretation. Most attempts have focused on fixed histopathology specimens, which do not apply in the intraoperative setting. The greatest potential for clinical impact probably lies in the automated diagnosis of intraoperative specimens. Successful future studies may use machine learning to automatically classify whole-slide intraoperative specimens among a wide array of potential diagnoses.

Histiocytosis syndromes (HS) are group of heterogeneous disorders characterized by abnormal accumulation and infiltration of histiocytes, cells derived from hematopoietic cells of monocyte/macrophage lineage. Overall these disorders are rare. When they do occur they involve many organ systems including the central nervous system (CNS). While imaging findings can provide important clues, diagnosis of this disorder is challenging and definitive diagnosis often necessitates pathologic examination. In this review, we describe imaging features of HS involving the CNS, with the aim to increase our understanding of these disorders. The entities discussed in this review will include: Langerhans cell histiocytosis (LCH), Rosai-Dorfman Disease (RDD), Erdheim Chester Disease (ECD), hemophagocytic lymphohistiocytosis (HLH), and crystal-storing histiocytosis (CSH)., (Copyright © 2019 Elsevier Inc. All rights reserved.)

We present a case of a 22-year-old man who died unexpectedly after a seizure due to a previously undiagnosed calcifying pseudoneoplasm of the neuraxis (CAPNON). Calcifying pseudoneoplasm of the neuraxis is a rare entity, and this is, to our knowledge, the first described case of sudden death due to CAPNON. Sudden death due to undiagnosed central nervous system mass lesions is rare, and most cases are attributable to hemorrhage, hydrocephalus, or increased intracranial pressure due to mass effect. Seizure is a rare cause of sudden death due to central nervous system mass lesions. This case highlights that mass lesions may cause sudden death due to seizure, even without other pathologic evidence of a cause of death, such as hemorrhage or edema. Furthermore, benign, reactive, and low-grade mass lesions may cause sudden death due to seizure. Seizure should remain in the autopsy differential as a cause of death, even where there is no pathologically evident mechanism by which a mass lesion caused death.

Background: Intracerebral hemorrhage (ICH) is characterized by a 30-d mortality rate of 40% and significant disability for those who survive., Objective: To investigate the initial safety concerns of histotripsy mediated clot liquefaction and aspiration in a porcine ICH model. Histotripsy is a noninvasive, focused ultrasound technique that generates cavitation to mechanically fractionate tissue. Histotripsy has the potential to liquefy clot in the brain and facilitate minimally invasive aspiration., Methods: About 1.75-mL clots were formed in the frontal lobe of the brain (n = 18; n = 6/group). The centers of the clots were liquefied with histotripsy 48 h after formation, and the content was either evacuated or left within the brain. A control group was left untreated. Pigs underwent magnetic resonance imaging (MRI) 7 to 8 d after clot formation and were subsequently euthanized. Neurological behavior was assessed throughout. Histological analysis was performed on harvested brains. A subset of pigs underwent acute analysis (≤6 h)., Results: Histotripsy was able to liquefy the center of clots without direct damage to the perihematomal brain tissue. An average volume of 0.9 ± 0.5 mL was drained after histotripsy treatment. All groups showed mild ischemia and gliosis in the perihematomal region; however, there were no deaths or signs of neurological dysfunction in any groups., Conclusion: This study presents the first analysis of histotripsy-based liquefaction of ICH in vivo. Histotripsy safely liquefies clots without significant additional damage to the perihematomal region. The liquefied content of the clot can be easily evacuated, and the undrained clot has no effect on pig survival or neurological behavior., (Copyright © 2019 by the Congress of Neurological Surgeons.)

Intraoperative diagnosis is essential for providing safe and effective care during cancer surgery 1 . The existing workflow for intraoperative diagnosis based on hematoxylin and eosin staining of processed tissue is time, resource and labor intensive 2,3 . Moreover, interpretation of intraoperative histologic images is dependent on a contracting, unevenly distributed, pathology workforce 4 . In the present study, we report a parallel workflow that combines stimulated Raman histology (SRH) 5-7 , a label-free optical imaging method and deep convolutional neural networks (CNNs) to predict diagnosis at the bedside in near real-time in an automated fashion. Specifically, our CNNs, trained on over 2.5 million SRH images, predict brain tumor diagnosis in the operating room in under 150 s, an order of magnitude faster than conventional techniques (for example, 20-30 min) 2 . In a multicenter, prospective clinical trial (n = 278), we demonstrated that CNN-based diagnosis of SRH images was noninferior to pathologist-based interpretation of conventional histologic images (overall accuracy, 94.6% versus 93.9%). Our CNNs learned a hierarchy of recognizable histologic feature representations to classify the major histopathologic classes of brain tumors. In addition, we implemented a semantic segmentation method to identify tumor-infiltrated diagnostic regions within SRH images. These results demonstrate how intraoperative cancer diagnosis can be streamlined, creating a complementary pathway for tissue diagnosis that is independent of a traditional pathology laboratory.