The BCL6 corepressor gene (BCOR) is a tumor suppressor gene located on human chromosome X that regulates cell differentiation and body structure development [2]. Alteration of BCOR has been identified in sarcomas, as well as hematopoietic and central nervous system (CNS) tumors [2]. In the case of CNS tumors, a subgroup has been identified with a distinct DNA methylation profile showing internal tandem duplication in exon 15 of the BCOR gene (BCOR-ITD) [6]. Recently, gene fusions involving BCOR and EP300 have been reported in several CNS tumors with DNA methylation profiles resembling BCOR-ITD or low-grade glioma with MYB alterations (LGG-MYB) [5, 7, 8]. A fusion involving BCORL1 has also been reported [9]. To date, only a few cases (< 10) with EP300::BCOR fusions have been described, warranting further study to understand the genomic and clinicopathologic features of these tumors relative to BCOR-ITD cases. In this study, we have profiled tumors from 21 patients that define a single DNA methylation group predominantly harboring EP300::BCOR fusions (BCOR-fusion group), and compared them to 15 BCOR-ITD cases, along with other tumors (Table S1, Fig. 1a). The BCOR alterations in tumors from the 21 patients in the BCOR-fusion group included: documented EP300::BCOR fusions (n = 11); CREBBP::BCOR fusion (n = 1); MEAF6::CXXC5 fusion (n = 1); BCOR-Stop mutations (n = 2); and BCOR gene status undetermined but suggestive of fusion based on copy number breakpoints and methylation class (n = 6). Of note, one of the 21 patients had 2 tumors analyzed: Y691 (primary) and AX30 (recurrent), both of which showed a EP300::BCOR fusion (Table S1). RNA sequencing demonstrated fusions at EP300 exon 31 and BCOR exons 4–7, and one fusion at CREBBP exon 31 and BCOR exon 6 (Fig. S1). The DKFZ v12b6 classifier gave confidence scores > 0.9 on 13 cases of these 21 tumors, with 12 cases matching to the EP300::BCOR fusion class and 1 case (with a demonstrated EP300::BCOR fusion) matching to the BCOR-ITD class. The remaining 8 cases (scores < 0.90) were suggested as EP300::BCOR, BCOR-ITD, or other classes. Copy number variation (CNV) analysis using GISTIC2.0 [4] showed that BCOR-fusion tumors are enriched for chromosome 22q12.31 deletion (FDR-adjusted p = 5.6e-5), where EP300 is located. CNV plots showed a high frequency of amplifications near the BCOR gene on chromosome X in the BCOR-fusion tumor group (Fig. 1b). CNV breakpoints (Fig. 1c) at EP300 and BCOR were present in 18 out of 21 BCOR-fusion patients, but none of BCOR-ITD.

Objective: Magnetic resonance (MR) thermography–guided laser interstitial thermal therapy, or stereotactic laser ablation (SLA), is a minimally invasive alternative to open surgery for focal epilepsy caused by cerebral cavernous malformations (CCMs). We examined the safety and effectiveness of SLA of epileptogenic CCMs. Methods: We retrospectively analyzed 19 consecutive patients who presented with focal seizures associated with a CCM. Each patient underwent SLA of the CCM and adjacent cortex followed by standard clinical and imaging follow-up. Results: All but one patient had chronic medically refractory epilepsy (median duration 8 years, range 0.5-52 years). Lesions were located in the temporal (13), frontal (five), and parietal (one) lobes. CCMs induced magnetic susceptibility artifacts during thermometry, but perilesional cortex was easily visualized. Fourteen of 17 patients (82%) with >12 months of follow-up achieved Engel class I outcomes, of which 10 (59%) were Engel class IA. Two patients who were not seizure-free from SLA alone became so following intracranial electrode-guided open resection. Delayed postsurgical imaging validated CCM involution (median 83% volume reduction) and ablation of surrounding cortex. Histopathologic examination of one previously ablated CCM following open surgery confirmed obliteration. SLA caused no detectable hemorrhages. Two symptomatic neurologic deficits (visual and motor) were predictable, and neither was permanently disabling. Significance: In a consecutive retrospective series, MR thermography–guided SLA was an effective alternative to open surgery for epileptogenic CCM. The approach was free of hemorrhagic complications, and clinically significant neurologic deficits were predictable. SLA presents no barrier to subsequent open surgery when needed.

Background: Prior studies have applied driver mutations targeting the RTK/RAS/PI3K and p53 pathways to induce the formation of high-grade gliomas in rodent models. In the present study, we report the production of a high-grade spinal cord glioma model in pigs using lentiviral gene transfer. Methods: Six Gottingen Minipigs received thoracolumbar (T14-L1) lateral white matter injections of a combination of lentiviral vectors, expressing platelet-derived growth factor beta (PDGF-B), constitutive HRAS, and shRNA-p53 respectively. All animals received injection of control vectors into the contralateral cord. Animals underwent baseline and endpoint magnetic resonance imaging (MRI) and were evaluated daily for clinical deficits. Hematoxylin and eosin (H&E) and immunohistochemical analysis was conducted. Data are presented using descriptive statistics including relative frequencies, mean, standard deviation, and range. Results: 100% of animals (n = 6/6) developed clinical motor deficits ipsilateral to the oncogenic lentiviral injections by a three-week endpoint. MRI scans at endpoint demonstrated contrast enhancing mass lesions at the site of oncogenic lentiviral injection and not at the site of control injections. Immunohistochemistry demonstrated positive staining for GFAP, Olig2, and a high Ki-67 proliferative index. Histopathologic features demonstrate consistent and reproducible growth of a high-grade glioma in all animals. Conclusions: Lentiviral gene transfer represents a feasible pathway to glioma modeling in higher order species. The present model is the first lentiviral vector induced pig model of high-grade spinal cord glioma and may potentially be used in preclinical therapeutic development programs.

Introduction: Aggressive prolactinomas (APRLs) pose a significant clinical challenge due to their high rate of regrowth and potentially life-threatening complications. In this study, we present a case of a patient with an APRL who had a trial of multiple therapeutic modalities with the aim to provide a review of molecular abnormalities and management of APRLs by corroborating our experience with previous literature. Methods: A total of 268 articles were reviewed and 46 were included. Case reports and series, and studies that investigated the molecular and/or genetic analysis of APRLs were included. Special care was taken to include studies describing prolactinomas that would fall under the APRL subtype according to the European Society of Endocrinology guidelines; however, the author did not label the tumor as “aggressive” or “atypical”. Addiontionally, we present a case report of a 56-year-old man presented with an invasive APRL that was resistant to multiple treatment modalities. Results: Literature review revealed multiple molecular abnormalities of APRLs including mutations in and/or deregulation of ADAMTS6, MMP-9, PITX1, VEGF, POU6F2, CDKN2A, and Rb genes. Mismatch repair genes, downregulation of microRNAs, and hypermethylation of specific genes including RASSF1A, p27, and MGMT were found to be directly associated with the aggressiveness of prolactinomas. APRL receptor analysis showed that low levels of estrogen receptor (ER) and an increase in somatostatin receptors (SSTR5) and epidermal growth factor receptors (EGFR) were associated with increased invasiveness and higher proliferation activity. Our patient had positive immunohistochemistry staining for PD-L1, MSH2, and MSH6, while microarray analysis revealed mutations in the CDKN2A and POU6F2 genes. Despite undergoing two surgical resections, radiotherapy, and taking dopamine agonists, the tumor continued to progress. The patient was administered pazopanib, which resulted in a positive response and the patient remained progression-free for six months. However, subsequent observations revealed tumor progression. The patient was started on PD-L1 inhibitor pembrolizumab, yet the tumor continued to progress. Conclusion: APRLs are complex tumors that require a multidisciplinary management approach. Knowledge of the molecular underpinnings of these tumors is critical for understanding their pathogenesis and identifying potential targets for precision medical therapy.

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.

Multidisciplinary tumor boards (TB) are an essential part of brain tumor care, but quantifying the impact of imaging on patient management is challenging due to treatment complexity and a lack of quantitative outcome measures. This work uses a structured reporting system for classifying brain tumor MRIs, the brain tumor reporting and data system (BT-RADS), in a TB setting to prospectively assess the impact of imaging review on patient management. Published criteria were used to prospectively assign three separate BT-RADS scores (an initial radiology report, secondary TB presenter review, and TB consensus) to brain MRIs reviewed at an adult brain TB. Clinical recommendations at TB were noted and management changes within 90 days after TB were determined by chart review. In total, 212 MRIs in 130 patients (median age = 57 years) were reviewed. Agreement was 82.2% between report and presenter, 79.0% between report and consensus, and 90.1% between presenter and consensus. Rates of management change increased with increasing BT-RADS scores (0—3.1%, 1a—0%, 1b—66.7%, 2—8.3%, 3a—38.5%, 3b—55.9, 3c—92.0%, and 4—95.6%). Of 184 (86.8%) cases with clinical follow-up within 90 days after the tumor board, 155 (84.2%) of the recommendations were implemented. Structured scoring of MRIs provides a quantitative way to assess rates of agreement interpretation alongside how often management changes are recommended and implemented in a TB setting.

The CD8 + T-cell response is prognostic for survival outcomes in several tumor types. However, whether this extends to tumors in the brain, an organ with barriers to T cell entry, remains unclear. Here, we analyzed immune infiltration in 67 brain metastasis (BrM) and found high frequencies of PD1 + TCF1 + stem-like CD8 + T-cells and TCF1- effector-like cells. Importantly, the stem-like cells aggregate with antigen presenting cells in immune niches, and niches were prognostic for local disease control. Standard of care for BrM is resection followed by stereotactic radiosurgery (SRS), so to determine SRS’s impact on the BrM immune response, we examined 76 BrM treated with pre-operative SRS (pSRS). pSRS acutely reduced CD8 + T cells at 3 days. However, CD8 + T cells rebounded by day 6, driven by increased frequency of effector-like cells. This suggests that the immune response in BrM can be regenerated rapidly, likely by the local TCF1 + stem-like population.

Purpose: Genetic analyses of gliomas have identified key molecular features that impact treatment paradigms beyond conventional histomorphology. Despite at-times lower grade histopathologic appearances, IDH-wildtype infiltrating gliomas expressing certain molecular markers behave like higher-grade tumors. For IDH-wildtype infiltrating gliomas lacking traditional features of glioblastoma, these markers form the basis for the novel diagnosis of diffuse astrocytic glioma, IDH-wildtype (wt), with molecular features of glioblastoma (GBM), WHO grade-IV (DAG-G). However, given the novelty of this approach to diagnosis, literature detailing the exact clinical, radiographic, and histopathologic findings associated with these tumors remain in development. Methods: Data for 25 patients matching the DAG-G diagnosis were obtained from our institution’s retrospective database. Information regarding patient demographics, treatment regimens, radiographic imaging, and genetic pathology were analyzed to determine association with clinical outcomes. Results: The initial radiographic findings, histopathology, and symptomatology of patients with DAG-G were similar to lower-grade astrocytomas (WHO grade 2/3). Overall survival (OS) and progression free survival (PFS) associated with our cohort, however, were similar to that of IDH-wt GBM, indicating a more severe clinical course than expected from other associated features (15.1 and 5.39 months respectively). Conclusion: Despite multiple features similar to lower-grade gliomas, patients with DAG-G experience clinical courses similar to GBM. Such findings reinforce the need for biopsy and subsequent analysis of molecular features associated with any astrocytoma regardless of presenting characteristics.

The glutamine pathway is emerging as an important marker of cancer prognosis and a target for new treatments. In gliomas, the most common type of brain tumors, metabolic reprogramming leads to abnormal consumption of glutamine as an energy source, and increased glutamine concentrations are associated with treatment resistance and proliferation. A key challenge in the development of glutamine-based biomarkers and therapies is the limited number of in vivo tools to noninvasively assess local glutamine metabolism and monitor its changes. In this review, we describe the importance of glutamine metabolism in gliomas and review the current landscape of translational and emerging imaging techniques to measure glutamine in the brain. These techniques include MRS, PET, SPECT, and preclinical methods such as fluorescence and mass spectrometry imaging. Finally, we discuss the roadblocks that must be overcome before incorporating glutamine into a personalized approach for glioma management.

Cryptococcoid Sweet syndrome is a rare histologic variant of the neutrophilic dermatosis presenting clinically with skin lesions typical of classical Sweet syndrome but with yeast-like structures suggestive of Cryptococcus on histopathology. Histochemical stains for fungus and cultures are negative whereas staining for myeloperoxidase is positive. We present 2 cases of cryptococcoid Sweet syndrome with atypical skin manifestations, including hemorrhagic bullae and plaques, and provide a brief review of the literature. Clinicians should be aware that this variant of Sweet syndrome can present with uncommon clinical findings and has histopathologic findings suggestive of Cryptococcus species.