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COVID-19 has also been linked to hypercoagulability and elevated cerebrovascular accidents rates [[3], [6], [9]]; however, little is known regarding the impact of COVID-19-associated coagulopathy on tumor biology. Here, we discuss the case of a young adult with a thalamic high-grade glioma, COVID-19-associated coagulopathy, and histopathologic evidence of extensive vascular thrombosis within the tumor microenvironment. Post-operative head CT and MRI demonstrated successful drain placement, but exhibited marked hemorrhage in the tumor and ventricles, with displacement of the septum pellucidum (Figs. [Extracted from the article]

Pediatric brain tumors are the leading cause of childhood cancer mortality. Recurring genetic abnormalities play an essential role in the diagnosis and prognosis of pediatric brain tumors. However, clinical workup has not routinely included whole genome assessment. Here, we present high resolution whole genome array results in 11 pediatric brain tumors. Array identified clinically relevant abnormalities in all samples. Copy number aberrations with targeted therapy implication, GOPC-ROS1 fusion, CDK4 amplification, and NF1 deletion, were detected in 3 cases. In addition, array detected recurring genetic abnormalities, including KIAA1549-BRAF fusion, 19q13.42 amplification, i(17q), and monosomy 6, which assisted accurate histological diagnosis in pediatric brain tumors. In conclusion, our results show that whole genome high-resolution array detects diagnostic and treatment-relevant copy number abnormalities in pediatric brain tumors. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the tolerability and efficacy of gemcitabine plus radiation therapy (RT) in this phase 1 study of patients with newly diagnosed malignant glioma (HGG).Patients and Methods: Between 2004 and 2012, 29 adults with HGG were enrolled. After any extent of resection, RT (60 Gy over 6 weeks) was given concurrent with escalating doses of weekly gemcitabine. Using a time-to-event continual reassessment method, 5 dose levels were evaluated starting at 500 mg/m(2) during the last 2 weeks of RT and advanced stepwise into earlier weeks. The primary objective was to determine the recommended phase 2 dose of gemcitabine plus RT. Secondary objectives included progression-free survival, overall survival (OS), and long-term toxicity.Results: Median follow-up was 38.1 months (range, 8.9-117.5 months); 24 patients were evaluable for toxicity. After 2005 when standard practice changed, patients with World Health Organization grade 4 tumors were no longer enrolled. Median progression-free survival for 22 patients with grade 3 tumors was 26.0 months (95% confidence interval [CI] 15.6-inestimable), and OS was 48.5 months (95% CI 26.8-inestimable). In 4 IDH mutated, 1p/19q codeleted patients, no failures occurred, with all but 1 alive at time of last follow-up. Seven with IDH mutated, non-codeleted tumors with ATRX loss had intermediate OS of 73.5 months (95% CI 32.8-inestimable). Six nonmutated, non-codeleted patients had a median OS of 26.5 months (95% CI 25.4-inestimable). The recommended phase 2 dose of gemcitabine plus RT was 750 mg/m(2)/wk given the last 4 weeks of RT. Dose reductions were most commonly due to grade 3 neutropenia; no grade 4 or 5 toxicities were seen.Conclusions: Gemcitabine concurrent with RT is well-tolerated and yields promising outcomes, including in patients with adverse molecular features. It is a candidate for further study, particularly for poor-prognosis patient subgroups with HGG. [ABSTRACT FROM AUTHOR]

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. 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 mm3. 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. 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. 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. [ABSTRACT FROM AUTHOR]

It is increasingly clear that both adult and pediatric glial tumor entities represent collections of neoplastic lesions, each with individual pathological molecular events and treatment responses. In this review, we discuss the current prognostic biomarkers validated for clin-ical use or with future clinical validity for gliomas. Accurate prognostication is crucial for managing patients as treatments may be associated with high morbidity and the benefits of high risk interventions must be judged by the treating clinicians.We also reviewbiomark-ers with predictive validity, which may become clinically relevant with the development of targeted therapies for adult and pediatric gliomas. [ABSTRACT FROM AUTHOR]

Clear cell tumors of the central nervous system (CNS) encompass a variety of tumor subtypes that are challenging to diagnose given their similar morphologic features. Here, I use a case-based approach to review the clinicopathologic and radiologic features to help guide the general pathologist in the diagnosis of clear cell tumors of the CNS. First, the reader is invited to study 6 images of different CNS tumors with clear cell morphology. Then, each case is expanded in light of clinical and radiologic data and includes a histopathologic description of the tumor. A brief discussion follows with up-to-date diagnostic tools. Finally, I propose an immunohistochemical algorithm to navigate through the complex features that characterize clear cell tumors of the CNS. This review aims to provide a comprehensive approach to diagnosing clear cell neoplasms of the CNS based on improved assessment of the clinicopathologic and radiologic features of each entity. [ABSTRACT FROM AUTHOR]

Recent work has identified novel point mutations in isocitrate dehydrogenase 1 ( IDH1) in the majority of the World Health Organization grades II and III infiltrative gliomas and secondary grade IV glioblastomas. Gangliogliomas consist of neoplastic ganglion and glial cells and, in contrast to infiltrative gliomas, are generally indolent. Yet distinguishing between a ganglioglioma and an infiltrative glioma with admixed gray matter can be difficult, perhaps accounting for some 'gangliogliomas' that ultimately show aggressive behavior. In this multi-institutional study, 98 cases originally diagnosed as ganglioglioma were analyzed for IDH1 mutations, 86 of which had follow-up data available. Eight cases (8.2%) were positive for R132H IDH1 mutations; six had silent IDH2 mutations and two had nonsense IDH2 mutations. The presence of mutant IDH1 in gangliogliomas correlated with a greater risk of recurrence ( P = 0.0007) and malignant transformation and/or death ( P < 0.0001) compared with tumors that were IDH1 wild type. Furthermore, the age of patients with IDH1-mutant gangliogliomas was higher than those without mutations (25.5 vs. 46.1 years, P = 0.0033). IDH1/2 testing of tumors suspected of being gangliogliomas may therefore be advisable, particularly in the adult population. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The AMP-activated protein kinase (AMPK) is a sensor of cellular energy status that has a dual role in cancer, i.e., pro- or anti-tumorigenic, depending on the context. In medulloblastoma, the most frequent malignant pediatric brain tumor, several in vitro studies previously showed that AMPK suppresses tumor cell growth. The role of AMPK in this disease context remains to be tested in vivo. Here, we investigate loss of AMPKα2 in a genetically engineered mouse model of sonic hedgehog (SHH)-medulloblastoma. In contrast to previous reports, our study reveals that AMPKα2 KO impairs SHH medulloblastoma tumorigenesis. Moreover, we performed complementary molecular and genomic analyses that support the hypothesis of a pro-tumorigenic SHH/AMPK/CNBP axis in medulloblastoma. In conclusion, our observations further underline the context-dependent role of AMPK in cancer, and caution is warranted for the previously proposed hypothesis that AMPK agonists may have therapeutic benefits in medulloblastoma patients. Note: an abstract describing the project was previously submitted to the American Society for Investigative Pathology PISA 2018 conference and appears in The American Journal of Pathology (Volume 188, Issue 10, October 2018, Page 2433). [ABSTRACT FROM AUTHOR]

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. 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 1×1010 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort A), and then 1×1011 Ad-hCMV-TK viral particles and 1×109 Ad-hCMV-Flt3L viral particles (cohort B), 1×1010 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort C), 1×1011 Ad-hCMV-TK viral particles and 1×1010 Ad-hCMV-Flt3L viral particles (cohort D), 1×1010 Ad-hCMV-TK viral particles and 1×1011 Ad-hCMV-Flt3L viral particles (cohort E), and 1×1011 Ad-hCMV-TK viral particles and 1×1011 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. 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). 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. 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. [ABSTRACT FROM AUTHOR]

As glioma cells infiltrate the brain they become associated with various microanatomic brain structures such as blood vessels, white matter tracts, and brain parenchyma. How these distinct invasion patterns coordinate tumor growth and influence clinical outcomes remain poorly understood. We have investigated how perivascular growth affects glioma growth patterning and response to antiangiogenic therapy within the highly vascularized brain.Orthotopically implanted rodent and human glioma cells are shown to commonly invade and proliferate within brain perivascular space. This form of brain tumor growth and invasion is also shown to characterize de novo generated endogenous mouse brain tumors, biopsies of primary human glioblastoma (GBM), and peripheral cancer metastasis to the human brain. Perivascularly invading brain tumors become vascularized by normal brain microvessels as individual glioma cells use perivascular space as a conduit for tumor invasion. Agent-based computational modeling recapitulated biological perivascular glioma growth without the need for neoangiogenesis. We tested the requirement for neoangiogenesis in perivascular glioma by treating animals with angiogenesis inhibitors bevacizumab and DC101. These inhibitors induced the expected vessel normalization, yet failed to reduce tumor growth or improve survival of mice bearing orthotopic or endogenous gliomas while exacerbating brain tumor invasion. Our results provide compelling experimental evidence in support of the recently described failure of clinically used antiangiogenics to extend the overall survival of human GBM patients. [ABSTRACT FROM AUTHOR]