Tavakoli, Mehdi MD; Isen, Danielle R. DO; Singhal, Aparna MD; Hackney, James R. MDEditor(s): Frohman, Larry MD Author Information

Background:Intravenous (IV) methamphetamine abuse is associated with a variety of short- and long-term effects on the nervous system, some of which have yet to be fully elucidated. One known systemic complication that has not been described in nervous system tissues is the deposition of substrate crystals contained in injectable drugs.Case Description:An unusual case is presented of a 35-year-old active IV methamphetamine abuser with posterior reversible encephalopathy syndrome (PRES) who subsequently developed multifocal bilateral cerebellar enhancing lesions and leptomeningeal enhancement due to biopsy-proven crystalline deposits.Conclusion:Although large crystalline substances will not normally penetrate the blood–brain barrier (BBB), during a state of BBB compromise such as with PRES, talc deposition may occur in the central nervous system.

BACKGROUND AND IMPORTANCE:Ameloblastic carcinoma (AC) is a malignant neoplasm of epithelial origin that typically arises from the mandible or maxilla. It represents approximately 2% of all odontogenic tumors. Gross total resection is the surgical goal given AC's aggressiveness and propensity for recurrence. We present the first reported AC metastasis to the cervical spine. CLINICAL PRESENTATION:A 61-yr-old African American female with a history of AC of bilateral mandibles and lung metastases presented with neck pain and right arm weakness progressive over several months. Cervical spine imaging demonstrated a cervical 3 pathological fracture with severe anterior vertebral body compression and resultant cervical 2-3 kyphotic deformity and bony retropulsion causing severe cord compression. The patient underwent a cervical 3 corpectomy and cervical 2-4 anterior fixation followed by a cervical 3 laminectomy and cervical 2-5 dorsal internal fixation and fusion. Postoperatively, the patient's neurological exam remained stable and imaging showed improved spinal alignment and appropriate anterior and posterior instrumentation. Unfortunately, the patient thereafter suffered a decline in performance status and progression of lung metastatic disease. Her oncology team is considering chemotherapy and stereotactic radiosurgery, but her prognosis remains grim. CONCLUSION:AC is a rare and aggressive pathology with a poor prognosis despite multimodal therapy. We present the first case of AC metastatic spread to the spine. We aim to bring this pathology to the attention of our worldwide neurosurgical colleagues and share our surgical approach and multidisciplinary management to assist those who may encounter this pathology in the future.

Background Glioblastoma (GBM) has a 5-year survival rate of 3%-5%. GBM treatment includes maximal resection followed by radiotherapy with concomitant and adjuvant temozolomide (TMZ). Cytochrome C oxidase (CcO) is a mitochondrial enzyme involved in the mechanism of resistance to TMZ. In a prior retrospective trial, CcO activity in GBMs inversely correlated with clinical outcome. The current Cyto-C study was designed to prospectively evaluate and validate the prognostic value of tumor CcO activity in patients with newly diagnosed primary GBM, and compared to the known prognostic value of MGMT promoter methylation status. Methods This multi-institutional, blinded, prospective biomarker study enrolled 152 patients with newly diagnosed GBM who were to undergo surgical resection and would be candidates for standard of care. The primary end point was overall survival (OS) time, and the secondary end point was progression-free survival (PFS) time. Tumor CcO activity and MGMT promoter methylation status were assayed in a centralized laboratory. Results OS and PFS did not differ by high or low tumor CcO activity, and the prognostic validity of MGMT promoter methylation was confirmed. Notably, a planned exploratory analysis suggested that the combination of low CcO activity and MGMT promoter methylation in tumors may be predictive of long-term survival. Conclusions Tumor CcO activity alone was not confirmed as a prognostic marker in GBM patients. However, the combination of low CcO activity and methylated MGMT promoter may reveal a subgroup of GBM patients with improved long-term survival that warrants further evaluation. Our work also demonstrates the importance of performing large, multi-institutional, prospective studies to validate biomarkers. We also discuss lessons learned in assembling such studies.

A 60-year-old woman noted headaches, transient visual obscurations and pulsatile tinnitus. She had Frisén grade 4 papilloedema. Brain magnetic resonance imaging showed a large subfrontal cystic mass with ring enhancement. Tumour pathology was in-keeping with an intraparenchymal schwannoma. This uniquely rare tumour is discussed.

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas arising in individuals with NF1 with a focus on recent preclinical and clinical data. In this review, possible mechanisms of gliomagenesis are discussed, including the contribution of different signaling pathways and tumor microenvironment. Furthermore, we discuss the recent notable advances in the developing therapeutic landscape for NF1-associated gliomas including clinical trials and collaborative efforts.

Summary The rise in aging population worldwide is increasing death from cancer, including glioblastoma. Here, we explore the impact of brain aging on glioma tumorigenesis. We find that glioblastoma in older patients and older mice displayed reduced neuronal signaling, including a decline of NTRK-like family member 6 (SLITRK6), a receptor for neurotrophic factor BDNF. This reduction was linked to the systemic decline of nicotinamide adenine dinucleotide (NAD + ) with aging, as old mice exposed to young blood via parabiosis or supplemented with the NAD + precursor NMN (nicotinamide mononucleotide) reverted phenotypically to young-brain responses to glioma, with reactivated neuronal signaling and reduced death from tumor burden. Interestingly, the phenotypic reversal by NMN was largely absent in old mice undergoing parabiosis with BDNF +/- young mice and in BDNF +/- mice undergoing tumor challenge, supporting the notion that the lower NAD + -BDNF signaling in the aging brain aggravated glioma tumorigenesis. We propose that the aging-associated decline in brain NAD + worsens glioma outcomes at least in part by decreasing neuronal/synaptic activity and increasing neuroinflammation.

Receptor activator of nuclear factor kappa B ligand (RANKL) and receptor activator of nuclear factor kappa B (RANK) are essential for mammary gland development and carcinogenesis; they also drive thermoregulation and modulate inflammatory activation in the brain. RANK was variably expressed in metastatic breast cancer cells but minimally expressed in the adjacent brain parenchyma. This is in contrast to the expression of RANKL, which was minimal in metastatic breast cancer but highly variable in tumoral stroma. A significant negative correlation between RANK in metastatic tumor and RANKL in tumoral stroma was identified. Background: Receptor activator of nuclear factor kappa B (RANK) and its ligand, RANKL, are essential for mammary gland development and play a vital role in breast carcinogenesis. RANKL-RANK signaling also drives thermoregulation and modulates inflammatory activation in the brain. The expression of RANKL in primary breast cancer (BC) has been negatively associated with brain metastases, while significantly higher levels of RANK are seen in BC with brain metastases. We examined the expression of RANK and RANKL in BC metastasis to the brain. Patients and Methods: We examined the expression of RANK and RANKL in 40 cases of BC metastasis to the brain. Results: RANK was variably expressed in BC cells but minimally expressed in the adjacent brain parenchyma. In contrast, the expression of RANKL was minimal in metastatic BC but highly variable in tumoral stroma. RANKL expression in normal brain stroma obtained during autopsy was negligible. Histologic grade and BC subtypes were not significantly associated with RANK expression in metastatic BC. A significant negative correlation between RANK in metastatic BC and RANKL in tumoral stroma was identified (P < .001). Conclusion: RANK expressed by primary BC and RANKL detected in the tumor microenvironment together participate in cancer development, while the same principle may operate at distant sites. Further investigation is necessary to provide additional insight into the role of the RANKL-RANK pathway in BC progression and to investigate the potential efficacy of therapeutic strategies targeting these molecules in BC metastasis to the brain. (C) 2020 Elsevier Inc. All rights reserved.

•Intracranial neurenteric cysts are rare but can present as extra-axial lesions in the posterior fossa.•Malignant change is extremely rare and such lesions show more focal, nodular and heterogeneous enhancement.•Most common malignant pathology seen was adenocarcinoma, papillary type.

OBJECTIVE:Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism. METHODS:Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry. RESULTS:Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core. CONCLUSIONS:Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.

No clear guidelines exist for the appropriate diagnostic workup of an intracranial mass suspected to be a metastasis from unknown primary origin. Dural metastasis from prostatic origin is very rare. Patients with a known history of metastatic prostate cancer who present with a newly discovered lesion on brain imaging require neurosurgical biopsy to confirm diagnosis prior to initiating treatment. Intracranial metastasis from prostate cancer is rare, and dural metastasis is rarer than intraparenchymal metastasis. Current consensus guidelines support immunohistochemical staining with classic markers such as prostate-specific antigen (PSA) to identify prostatic origin. However, PSA detection of prostate metastases declines with higher Gleason scores and in patients undergoing androgen deprivation therapy. NKX3.1 is another stain that is highly sensitive and specific for prostate. Our patient was a 54-year-old man with a history of metastatic prostate cancer who presented with new-onset seizures. Brain imaging revealed a dural-based lesion with surrounding vasogenic edema and midline shift. The patient underwent resection of the lesion, which was stained with multiple cancer markers. Prostate-specific antigen was negative, but NKX3.1 was positive indicating a prostatic origin for the mass. He underwent a craniectomy to remove the lesion and was given steroids. However, he succumbed to his illness several months later. Here, we document the first report to our knowledge of a patient with prostate metastasis to the dura that is PSA negative, but NKX3.1 positive.

Intraventricular melanoma is a very rare and highly malignant disease. Safe resection is the mainstay of treatment, but no standard guidelines exist for adjuvant therapy. Early histologic and molecular diagnosis is key for improved survival.

BACKGROUND: Angiosarcomas are rare malignant tumors of endothelial origin. Nearly one half of all angiosarcomas occur in the head and neck. Temporal bone angiosarcomas are extremely uncommon. We present a case of temporal bone angiosarcoma and a review of the relevant data. CASE DESCRIPTION: We present the case of a 20-year-old man with a painful right postauricular mass after a closed head injury. Radiologic studies demonstrated a large right osteolytic and heterogeneously enhancing mass. The patient underwent right transpetrosal craniectomy for resection. Histologic studies confirmed high-grade sarcoma. Immunohistochemical staining demonstrated a uniformly positive ERG endothelial marker, CD31 staining with cytoplasmic and membranous patterns of immunopositivity, positive nuclear staining for FLI-1, positive cytoplasmic and membranous staining for CD99 and STATE, and negative smooth muscle actin stains in the neoplastic cells. Ki-67 staining showed similar to 94% positivity in the neoplastic cell nuclei. Postoperative follow-up imaging studies demonstrated evidence of metastatic right cervical lymphadenopathy. CONCLUSIONS: Angiosarcoma of the temporal bone is extremely uncommon. In the present case report, we explored a relationship between trauma and angiosarcoma of the temporal bone. We reviewed the reported data regarding the pathogenesis, diagnosis, treatment, radiologic findings, and histologic characteristics of angiosarcoma of the temporal bone.

Glioblastoma harbors frequent alterations in receptor tyrosine kinases, phosphatidylinositol-3 kinase (PI3K) and phosphatase and tensin homolog (PTEN) that dysregulate phospholipid signaling driven tumor proliferation and therapeutic resistance. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a 32 kDa intrinsically unstructured protein containing a polybasic (+13) effector domain (ED), which regulates its electrostatic sequestration of phospholipid phosphatidylinositol (4,5)-bisphosphate (PIP2), and its binding to phosphatidylserine, calcium/calmodulin, filamentous actin, while also serving as a nuclear localization sequence. MARCKS ED is phosphorylated by protein kinase C (PKC) and Rho-associated protein kinase (ROCK) kinases; however, the impact of MARCKS on glioblastoma growth and radiation sensitivity remains undetermined. In the present study, using a tetracycline-inducible system in PTEN-null U87 cells, we demonstrate that MARCKS overexpression suppresses growth and enhances radiation sensitivity in vivo. A new image cytometer, Xcyto10, was utilized to quantify differences in MARCKS ED phosphorylation on localization and its association with filamentous actin. The overexpression of the non-phosphorylatable ED mutant exerted growth-suppressive and radiation-sensitizing effects, while the pseudo-phosphorylated ED mutant exhibited an enhanced colony formation and clonogenic survival ability. The identification of MARCKS protein-protein interactions using co-immunoprecipitation coupled with tandem mass spectrometry revealed novel MARCKS-associated proteins, including importin-β and ku70. On the whole, the findings of this study suggest that the determination of the MARCKS ED phosphorylation status is essential to understanding the impact of MARCKS on cancer progression.

BACKGROUND:Arteriovenous malformations (AVMs) can occur in all regions of the brain and spinal cord, with clinical consequences and risks varying by location. Delayed AVM rupture despite digital subtraction angiography-confirmed obliteration post-radiation is exceedingly rare. CASE DESCRIPTION:To our knowledge, we present the first documented case of delayed hemorrhage associated with a cerebellar AVM 5 years after linear accelerator-based radiation in a man aged 31 years despite apparent angiographic obliteration. CONCLUSIONS:Intracranial hemorrhage after radiosurgery in digital subtraction angiography-confirmed obliterated AVMs is rare, with limited understanding of risk factors, appropriate preventative management, and mechanisms of occurrence. This case serves to demonstrate the need for greater awareness of this rare complication, as well as the need for appropriate surveillance and management strategies.

In this cohort of gross totally resected atypical meningioma followed with observation local recurrence occurred in 30.3% at 3 years. Ki67 index and mitotic number predict for local failure and could help stratify patients that would benefit from adjuvant therapy.