Leptomeningeal metastases and dural spread in adult high-grade astrocytomas.

Leptomeningeal (LM) metastases or dural spread by adult high-grade astrocytomas are problematic; it is unclear which tumor types are predisposed to spread and at what time intervals from original diagnosis. We reviewed our recent experience with these tumor types with LM or dural spread, all of which had assessments that allowed CNS World Health Organization, 5th Edition classification. Following a database search, 2018-present, 10 patients were identified: 4 glioblastomas, IDH-wildtype, WHO grade 4; 4 astrocytomas, IDH-mutant, WHO grade 4; 1 high-grade astrocytoma with piloid features (HGAP) proven by DNA methylation, and 1 high-grade astrocytic tumor that fell closest to the HGAP category by DNA methylation. Most had LM dissemination; 2 had dural spread. Intervals from initial tumor diagnosis to LM spread for 4 astrocytomas, IDH-mutant were 1, 6, 7, and 14 years. Two glioblastomas, IDH-wildtype had dural spread at the time of diagnosis; 1 had a 6-year interval to metastasis; and 1 had a 3-month interval to LM spread. The definite HGAP showed an interval of 7 years to metastasis and the possible HGAP had LM spread recognized at the time of initial diagnosis. All adult high-grade astrocytic tumor types are capable of LM or dural spread, including HGAP.

Characterization of the Genomic and Immunologic Diversity of Malignant Brain Tumors through Multisector Analysis.

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell-intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. SIGNIFICANCE: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies.This article is highlighted in the In This Issue feature, p. 1.

TP53 Mutation and Extraneural Metastasis of Glioblastoma: Insights From an Institutional Experience and Comprehensive Literature Review.

Extraneural metastases of glioblastoma (GBM), although rare, are becoming an increasingly recognized occurrence. Currently, the biological mechanism underlying this rare occurrence is not understood. To explore the potential genomic drivers of extraneural metastasis in GBM, we present the molecular features of 4 extraneural metastatic GBMs, along with a comprehensive review and analysis of previously reported cases that had available molecular characterization. In addition to our 4 cases, 42 patients from 35 publications are reviewed. To compare the molecular profiles between GBM cases with extraneural metastasis and the general GBM population, genomic data from GBM samples in The Cancer Genome Atlas (TCGA) database were also analyzed. We found that 64.5% (20/31) of the cases with extraneural metastasis that were tested for TP53 changes had at least 1 TP53 pathogenic variant detected in either 1 or both primary and metastatic tumors. In contrast, TP53 mutation was significantly less frequent in the unselected GBM from TCGA (22.6%, 56/248) (P=0.000). In addition, O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation was more common in unselected TCGA GBM cases (48.6%, 170/350) than in cases with extraneural metastasis (31.8%, 7/22), although not statistically significant. Although isocitrate dehydrogenase (IDH) mutation is a rare occurrence in high-grade astrocytomas, IDH-mutant grade 4 astrocytomas are at least as likely to metastasize as IDH wild-type GBMs; 3 metastatic cases definitively harbored an IDH1 (p.R132H) mutation in our analysis. Our findings not only provide potential biomarkers for earlier screening of extraneural metastasis, but could also suggest clues to understanding biological mechanisms underlying GBM metastasis, and for the development of therapeutic modalities.

Blood glutamate scavengers increase pro-apoptotic signaling and reduce metastatic melanoma growth in-vivo.

Inhibition of extracellular glutamate (Glu) release decreases proliferation and invasion, induces apoptosis, and inhibits melanoma metastatic abilities. Previous studies have shown that Blood-glutamate scavenging (BGS), a novel treatment approach, has been found to be beneficial in attenuating glioblastoma progression by reducing brain Glu levels. Therefore, in this study we evaluated the ability of BGS treatment to inhibit brain metastatic melanoma progression in-vivo. RET melanoma cells were implanted in C56BL/6J mice to induce brain melanoma tumors followed by treatment with BGS or vehicle administered for fourteen days. Bioluminescent imaging was conducted to evaluate tumor growth, and plasma/CSF Glu levels were monitored throughout. Immunofluorescence staining of Ki67 and 53BP1 was used to analyze tumor cell proliferation and DNA double-strand breaks. In addition, we analyzed CD8, CD68, CD206, p-STAT1 and iNOS expression to evaluate alterations in tumor micro-environment and anti-tumor immune response due to treatment. Our results show that BGS treatment reduces CSF Glu concentration and consequently melanoma growth in-vivo by decreasing tumor cell proliferation and increasing pro-apoptotic signaling in C56BL/6J mice. Furthermore, BGS treatment supported CD8+ cell recruitment and CD68+ macrophage invasion. These findings suggest that BGS can be of potential therapeutic relevance in the treatment of metastatic melanoma.

Distinct tumor signatures using deep learning-based characterization of the peritumoral microenvironment in glioblastomas and brain metastases.

Tumor types are classically distinguished based on biopsies of the tumor itself, as well as a radiological interpretation using diverse MRI modalities. In the current study, the overarching goal is to demonstrate that primary (glioblastomas) and secondary (brain metastases) malignancies can be differentiated based on the microstructure of the peritumoral region. This is achieved by exploiting the extracellular water differences between vasogenic edema and infiltrative tissue and training a convolutional neural network (CNN) on the Diffusion Tensor Imaging (DTI)-derived free water volume fraction. We obtained 85% accuracy in discriminating extracellular water differences between local patches in the peritumoral area of 66 glioblastomas and 40 metastatic patients in a cross-validation setting. On an independent test cohort consisting of 20 glioblastomas and 10 metastases, we got 93% accuracy in discriminating metastases from glioblastomas using majority voting on patches. This level of accuracy surpasses CNNs trained on other conventional DTI-based measures such as fractional anisotropy (FA) and mean diffusivity (MD), that have been used in other studies. Additionally, the CNN captures the peritumoral heterogeneity better than conventional texture features, including Gabor and radiomic features. Our results demonstrate that the extracellular water content of the peritumoral tissue, as captured by the free water volume fraction, is best able to characterize the differences between infiltrative and vasogenic peritumoral regions, paving the way for its use in classifying and benchmarking peritumoral tissue with varying degrees of infiltration.

Long non-coding RNA HULC stimulates the epithelial-mesenchymal transition process and vasculogenic mimicry in human glioblastoma.

BACKGROUND: Long non-coding RNA (lncRNA) HULC (highly upregulated in liver cancer) is considered as an oncogenic factor for various malignant tumors. This study aimed to reveal the role of lncRNA HULC in the malignant behavior of glioblastoma (GBM) by exploring its effects on the epithelial-mesenchymal transition (EMT) and vasculogenic mimicry (VM) of human GBM. MATERIALS AND METHODS: The contents of VM in 27 GBM samples were assessed by immunohistochemistry-histology and their association with progress-free survival (PFS) was analyzed. Human GBM SHG44 and U87 cells were manipulated to establish stable lncRNA HULC overexpressing and silencing cells by lentivirus-based technology. The effects of altered lncRNA HULC on vasculogenic tubular formation, invasion, and EMT process in GBM cells were tested in vitro and the growth of implanted GBM tumors and their EMT process were examined in vivo. RESULTS: The numbers of VM were positively associated with disease progression, but negatively with PFS periods of GBM patients. Compared with the control vec cells, lncRNA HULC overexpression significantly increased the tubular formation, invasion, and EMT process of both SHG44 and U87 cells, accompanied by promoting the growth of implanted GBM tumors and EMT process in mice. LncRNA HULC silencing had opposite effects on the tubular formation, invasion, and EMT process as well as tumor growth of GBM cells. CONCLUSION: LncRNA HULC stimulates the EMT process and VM in human GBM, and may be a therapeutic target for intervention of GBM.

Single-cell chromatin accessibility profiling of glioblastoma identifies an invasive cancer stem cell population associated with lower survival.

Chromatin accessibility discriminates stem from mature cell populations, enabling the identification of primitive stem-like cells in primary tumors, such as glioblastoma (GBM) where self-renewing cells driving cancer progression and recurrence are prime targets for therapeutic intervention. We show, using single-cell chromatin accessibility, that primary human GBMs harbor a heterogeneous self-renewing population whose diversity is captured in patient-derived glioblastoma stem cells (GSCs). In-depth characterization of chromatin accessibility in GSCs identifies three GSC states: Reactive, Constructive, and Invasive, each governed by uniquely essential transcription factors and present within GBMs in varying proportions. Orthotopic xenografts reveal that GSC states associate with survival, and identify an invasive GSC signature predictive of low patient survival, in line with the higher invasive properties of Invasive state GSCs compared to Reactive and Constructive GSCs as shown by in vitro and in vivo assays. Our chromatin-driven characterization of GSC states improves prognostic precision and identifies dependencies to guide combination therapies.

A Rare Case of Glioblastoma With Extensive Liver Metastases.

Glioblastoma (GBM), the most common primary brain tumor, is a highly aggressive malignancy for which the median survival is about 13 months, and 5-year survival is well under 5%. These tumors usually occur in the brain and enlarge and infiltrate through white matter, including crossing through the corpus callosum to the opposite cerebral hemisphere. They may spread to distant parts of the central nervous system (CNS) via cerebrospinal fluid pathways. Extraneural metastases from primary brain tumors are quite rare, for 2 probable reasons: because most patients survive less than 2 years, and because of the absence of true lymphatics in the CNS. Typical sites for distant extraneural metastasis of GBM are lungs and pleura, followed by lymph nodes and bones; spread to the liver is exceptional. Most of the reported cases with liver metastases had either single or only a few such metastatic lesions. We report a probably unique case of GBM with extensive liver metastases along with a review of previous cases of liver metastasis from GBM, and we discuss the possible mechanisms of metastasis.

Extracranial Metastasis of IDH-1 Wild Type Glioblastomas.

AIM: To identify the effects of different immunohistochemical features of glioblastomas with spinal metastases based on the metastatic spread and survival rate. MATERIAL AND METHODS: A total of 214 patients who were diagnosed with and operated for brain tumor in our clinic between 2007 and 2018, and pathologically diagnosed with glioblastoma were retrospectively evaluated. Among them, 141 medical records were reviewed, and 23 of them underwent spinal magnetic resonance imaging postoperatively due to various complaints. RESULTS: All patients with glioblastoma with spinal metastases had negative isocitrate dehydrogenase 1 (IDH-1) in the immunohistochemical examination. The incidence of spinal metastasis is 1.91%. The median Ki-67 index is 30 (range, 4-90; median Ki-67 index: 30+/-18.5). IDH mutation is wild in 55%, mutant in 33%, and not otherwise specified in 12%. Four patients with spinal metastasis has wild-type IDH with mean Ki-67 index of 60, and one of them was a woman (25%) and the remaining three were men (%75), with mean age of 32 years. CONCLUSION: Gliomas with high immunohistochemical proliferation indexes and wild-type IDH with poor prognostic features based on the new classification tended to metastasize to the spine in the early disease stage; therefore, early spinal scanning and radiation therapy might extend the life expectancy. High Ki-67 index and the presence of wild-type isocitrate dehydrogenase may be the predictive factors for spinal screening.

Extracranial metastases in secondary glioblastoma multiforme: a case report.

BACKGROUND: Glioblastoma (GBM) is known for its devastating intracranial infiltration and its unfavorable prognosis, while extracranial involvement is a very rare event, more commonly attributed to IDH wild-type (primary) GBM evolution. CASE PRESENTATION: We present a case of a young woman with a World Health Organization (WHO) grade II Astrocytoma evolved to WHO grade IV IDH mutant glioblastoma, with subsequent development of lymphatic and bone metastases, despite the favorable biomolecular pattern and the stability of the primary brain lesion. CONCLUSIONS: Our case highlights that grade II Astrocytoma may evolve to a GBM and rarely lead to a secondary metastatic diffusion, which can progress quite rapidly; any symptoms referable to a possible systemic involvement should be carefully investigated.

Early Pulmonary Metastasis After a Surgical Resection of Glioblastoma Multiforme. A Case Report.

BACKGROUND Glioblastoma multiforme is one of the most aggressive types of tumors that affect the central nervous system. It has an extremely high morbidity and mortality rate despite immediate treatment and advances in chemotherapy, radiotherapy, and surgery. In the natural history of the disease, extracranial metastases of glioblastoma multiforme are a rare complication that can be localized in the lungs, bone, liver, and lymph nodes. CASE REPORT A 66-year-old male presented with pulmonary metastasis after the surgical resection of a primary glioblastoma multiforme tumor. Seventeen days after surgery while in the intensive care unit, the patient had leukocytosis with a predominance of neutrophils. An exploratory bronchoscopy evidenced a white lesion that prevented the visualization of the bronchus. Consequently, a sample was taken for pathological study that demonstrated pulmonary metastasis due to glioblastoma multiforme. CONCLUSIONS Surgical resection of the tumor can precipitate the appearance of extracranial metastases, especially pulmonary metastases.

Spinal Metastasis of Cerebral Glioblastoma with Genetic Profile: Case Report and Review of Literature.

BACKGROUND: Spinal metastasis of cerebral glioblastoma (GBM) is rare, with some reports suggesting a prevalence of 1%-2%. CASE DESCRIPTION: Herein, we present 2 unique cases of spinal metastasis of cerebral GBM, 1 of which was histologically proven to be a drop spinal GBM metastasis. The first case was a 25-year-old female who presented with a spinal intradural intramedullary spinal lesion a few months after resection of a left temporal lobe GBM (isocitrate dehydrogenase wild type). The patient underwent surgical resection of the new lesion, and subsequent histopathologic examination proved that the intramedullary spinal lesion was GBM. The patient experienced full recovery postoperatively, and then a few months later, she presented again with widespread drop metastasis of the spinal cord. The second case is a middle-aged male with right temporal GBM who developed spinal metastasis 10 months after his diagnosis. CONCLUSIONS: We are reporting these 2 cases due to the rarity of spinal metastasis in GBM. We reviewed the current literature and included genetic and molecular profiles in the discussion. Currently, there are no established treatment guidelines for GBM spinal metastasis. The Stupp protocol after initial brain surgery for GBM did not appear to have beneficial effects on prolonging survival in these patients with spinal metastasis. The goal of treatment was primarily to alleviate pain and neurologic deficits with no effect on overall outcome. Prognosis following the diagnosis of spinal metastasis is poor.

Neuronal signatures in cancer.

Despite advances in the treatment of solid tumors, the prognosis of patients with many cancers remains poor, particularly of those with primary and metastatic brain tumors. In the last years, "Cancer Neuroscience" emerged as novel field of research at the crossroads of oncology and classical neuroscience. In primary brain tumors, including glioblastoma (GB), communicating networks that render tumor cells resistant against cytotoxic therapies were identified. To build these networks, GB cells extend neurite-like protrusions called tumor microtubes (TMs). Synapses on TMs allow tumor cells to retrieve neuronal input that fosters growth. Single cell sequencing further revealed that primary brain tumors recapitulate many steps of neurodevelopment. Interestingly, neuronal characteristics, including the ability to extend neurite-like protrusions, neuronal gene expression signatures and interactions with neurons, have now been found not only in brain and neuroendocrine tumors but also in some cancers of epithelial origin. In this review, we will provide an overview about neurite-like protrusions as well as neurodevelopmental origins, hierarchies and gene expression signatures in cancer. We will also discuss how "Cancer Neuroscience" might provide a framework for the development of novel therapies.

[Factor analysis of cerebrospinal fluid spread in glioblastoma].

Objective: To analyze the prognosis factors of cerebrospinal fluid (CSF) spread after surgery in glioblastoma (GBM) patients when tumors progressed and the effect factors on prognosis. Methods: A retrospective study was conducted on 124 patients who were pathologically diagnosed as glioblastoma after surgery, and found tumor progressed during regularly follow-up at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University between January 2009 and August 2017.There were 82 males and 42 females, aged 47.9 years(range: 19 to 75 years) .Patients were divided into local recurrence group(96 cases) and CSF spread group (28 cases) .Clinical data were recorded in detail and compared by independent sample t test or χ(2) test.Kaplan-Meier survival curves was used to demonstrated the distribution of progression free survival (PFS) overall survival (OS) and post progression survival (PPS), and differences between local recurrence and CSF spread groups were assessed by Log-rank test.Cox proportion hazard regression analysis was used to identify independent prognostic factors. Results: Logistics regression analysis showed ventricle entry was the only prognosis factor of CSF spread (OR=2.667, 95% CI: 1.128 to 6.304, P=0.025).No significant distinction was observed in PFS between CSF spread group and local recurrence group(7.0 months vs.9.3 months, P=0.066).However, OS and PPS were substantially shortened in CSF spread group (13.0 months vs.23.0 months, P=0.011; 6.0 months vs.11.0 months, P=0.022, respectively).Mutations of isocitrate dehydrogenase gene, distant spread, gross-total resection, Ki-67 index>30% were independent prognostic factors of GBM patients. Conclusions: Ventricle entry is a prognosis factor for CSF spread, after which the median OS and PPS are markedly diminished.However, ventricle entry is not independent prognosis factor shortening survival.

Spinal metastasis of glioblastoma multiforme before gliosarcomatous transformation: a case report.

BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive malignant brain tumors. Intracranial GBM metastases to the spine are rarely detected clinically. Secondary gliosarcomas after treatment of primary GBM are rarely described. CASE PRESENTATION: Herein, we report the case of a 53-year-old woman who presented to our emergency room with progressive headache and weakness on the left side. Plain computed tomography and contrast magnetic resonance imaging of the brain revealed an approximately 6.8 cm × 4.5 cm right temporoparietooccipital intraaxial cystic tumor with surrounding diffuse perifocal edema that caused midline shift toward the left. Emergency craniotomy was performed to remove the tumor, and pathological examination revealed GBM. The patient received proton beam therapy, Gliadel implantation, and oral temozolomide chemotherapy as well as targeted therapy with bevacizumab. Approximately 15 months after diagnosis, she underwent surgical resection of the right temporal recurrent tumor and was newly diagnosed as having a metastatic spinal tumor. Pathologically, the right temporal and metastatic spinal tumors were gliosarcoma and GBM, respectively. CONCLUSIONS: Concurrent spinal metastasis and gliosarcomatous transformation, which are two types of GBM complications, are rare. To our knowledge, this is the first report of a case of recurrent GBM with gliosarcoma after proton bean therapy.

Molecular profiling of an osseous metastasis in glioblastoma during checkpoint inhibition: potential mechanisms of immune escape.

Peripheral metastases of glioblastoma (GBM) are very rare despite the ability of GBM cells to pass through the blood-brain barrier and be disseminated through the peripheral blood. Here, we describe a detailed genetic and immunological characterization of a GBM metastasis in the skeleton, which occurred during anti-PD-1 immune checkpoint therapy. We performed whole genome sequencing (WGS) and 850 K methylation profiling of the primary and recurrent intracranial GBM as well as one of the bone metastases. Copy number alterations (CNA) and mutational profiles were compared to known genomic alterations in the TCGA data base. In addition, immunophenotyping of the peripheral blood was performed. The patient who was primarily diagnosed with IDH-wildtype GBM. After the resection of the first recurrence, progressive intracranial re-growth was again detected, and chemotherapy was replaced by PD-1 checkpoint inhibition, which led to a complete intracranial remission. Two months later MR-imaging revealed multiple osseous lesions. Biopsy confirmed the GBM origin of the skeleton metastases. Immunophenotyping reflected the effective activation of a peripheral T-cell response, with, however, increase of regulatory T cells during disease progression. WGS sequencing demonstrated distinct genomic alterations of the GBM metastasis, with gains along chromosomes 3 and 9 and losses along chromosome 4, 10, and 11. Mutational analysis showed mutations in potentially immunologically relevant regions. Additionally, we correlated tumour-infiltrating lymphocyte and microglia presence to the occurrence of circulating tumour cells (CTCs) in a larger cohort and found a decreased infiltration of cytotoxic T cells in patients positive for CTCs. This study exemplifies that the tumour microenvironment may dictate the response to immune checkpoint therapy. In addition, our study highlights the fact that despite an effective control of intracranial GBM, certain tumour clones have the ability to evade the tumour-specific T-cell response and cause progression even outside of the CNS.

Cytomorphology of glioblastoma metastic to a cervical lymph node diagnosed by fine needle aspiration (FNA): A case report and review of literature.

Glioblastoma is an aggressive primary central nervous system tumor with a dismal prognosis. However, extracranial metastases are extremely rare. Very few cases have been reported in the literature. We present a case of a 64-year-old male with glioblastoma metastatic to a cervical lymph node in which the diagnosis was made on fine needle aspiration cytology (FNAC). The cytomorphologic features of glioblastoma are distinct, with pleomorphic cells in loosely cohesive clusters with prominent nucleoli, coarsely clumped chromatin and cellular processes. We suggest that FNAC, along with clinical history, is a cost effective, safe, and diagnostically accurate method of diagnosing glioblastoma metastases. Cell block is also helpful in establishing the diagnosis.

A case of dyskinesia after levetiracetam administration.

BACKGROUND: Antiepileptic drug (AED) induced dyskinesia is an unusual manifestation in the medical field. In the previous case reports describing first generation-AED related involuntary movements, the authors suggested that a plausible cause is pharmacokinetic interactions between two or more AEDs. To date, development of dyskinesia after levetiracetam (LEV) has not been reported. CASE PRESENTATION: A 28-year-old woman with a history of brain metastasis from spinal cord glioblastoma presented with several generalized tonic-clonic seizures without restored consciousness. LEV was administered intravenously. Thereafter no more clinical or electroencephalographic seizures were noted on video-EEG monitoring, while chorea movement was observed in her face and bilateral upper limbs. DISCUSSION AND CONCLUSIONS: To our knowledge, there is no case report of dyskinesia after administration of LEV. Considering the temporal relationship and absence of ictal video-EEG findings, we suggest that development of choreoathetosis was closely associated with the undesirable effects of LEV. We propose that dopaminergic system dysregulation and genetic susceptibility might underlie this unusual phenomenon after LEV treatment.

Glioblastoma with tumor-to-tumor metastasis from lung adenocarcinoma.

Glioblastoma is a tumor with widely variable morphology. It may rarely show pseudoepithelial components or true epithelial differentiation. Metastasis to glioblastomas have been previously reported, but were unsupported by immunohistochemical or molecular analyses. Herein we describe a glioblastoma with carcinomatous foci in a patient with no past clinical history of tumors outside the central nervous system. The carcinomatous foci expressed epithelial, but not glial markers. Therefore, whole-body imaging was carried out to verify the presence of carcinoma. A lung mass was biopsied and it resulted as primary lung adenocarcinoma. Carcinomatous foci of glioblastoma and lung adenocarcinoma had the same KRAS mutation which was absent in glial areas of the glioblastoma. Thus, glioblastoma with tumor-to-tumor metastasis was diagnosed. This case demonstrates that, albeit rare, metastases to glioblastoma may occur, and they should be considered in the differential diagnosis of glioblastoma with carcinomatous foci. Even when the past clinical history is negative, the presence of carcinoma should be investigated to rule out glioblastoma with tumor-to-tumor metastasis.