Solitary metastasis to the skull as the first sign of hepatocellular carcinoma in a patient in long-term remission.

Background: Hepatocellular carcinoma (HCC) is a common malignant tumor with a 5-year survival rate of 10%, presenting with extrahepatic metastases in 15-17% of patients. HCC-bone metastases represent approximately one-quarter of all HCC metastases, most frequently in the spine, pelvis, ribs, or femur. HCC-skull metastases, however, make up 0.4-1.6% of all HCC- bone metastases. Furthermore, solitary HCC-skull metastasis without known active primary HCC is an unusual presentation warranting further review and consideration. Case Description: Here, the authors report a unique case of a solitary HCC-skull metastasis in a patient without known active cancer but in long-term remission for HCC. The patient is a 69-year-old male with past HCC who presented with a nontender skull mass. A computed tomography scan showed a heterogeneously enhancing mass centered in the high left parietal bone with intracranial extension. There was a noted mass effect on the left posterior frontoparietal region without worrisome midline shift. Pathology ultimately revealed the mass to be metastatic HCC. To aid in the understanding and clinical management of this rare presentation, we reviewed the literature regarding clinical presentation, radiological features, pathology, and outcome. Conclusion: Ultimately, early detection of the primary source of cancer is pivotal to successful treatment and prognosis, and skull lesions such as these must include HCC in the differential diagnosis.

Pituitary Incidentalomas in the United States: A National Database Estimate.

OBJECTIVE: Increasing use of imaging is associated with increasing diagnoses of pituitary incidentalomas (PIs), which often do not require surgical or medical treatment. In this study, we evaluate U.S. incidence, epidemiology, and trends of pituitary adenomas (PAs) and PIs from 2004 to 2018. METHODS: A total of 50,220 PAs were selected from the SEER (Surveillance Epidemiology and End Results) 2020 submission. PIs that do not initially require surgical or medical treatment were filtered from PAs if they were best diagnostically confirmed by radiography, not indicated as prolactinomas in physician reports, not recommended surgery initially, and reported a correct tumor size. Age-adjusted incidence rates, patient demographics, tumor characteristics, trends over time, and differences between PAs and PIs were explored. RESULTS: Between 2004 and 2018, the incidence rates of PAs and PIs were 4.28 ± 0.04 and 1.53 ± 0.02 per 100,000 population, respectively. When observing changes from 2004 to 2018, a nearly 3-fold increase from 0.73 ± 0.05 to 2.00 ± 0.09 per 100,000 was observed for PIs. The proportion of PIs significantly increased from 24.91% of all PA diagnoses in 2004 to 42.07% in 2018 (P < 0.001). When comparing non-PI PAs with PIs, PIs were more commonly diagnosed in females (64.72% vs. 54.27%; P < 0.001) with microadenomas (61.68% vs. 13.37%; P < 0.001). CONCLUSIONS: Reports of increasing PAs in the United States are likely caused by an increase in diagnosing PIs. This result parallels findings from other countries. This national PI estimate may serve as a point of comparison for future studies investigating imaging and PI rates at individual institutions.

Trends in Academic Misrepresentation in Neurological Surgery Residency Applicants: A 2-Year Analysis.

OBJECTIVE: Academic misrepresentation is not an unknown phenomenon, with recent reports in neurosurgery detecting a 45% misrepresentation rate in prospective neurosurgical residents. The purpose of this study was to determine current rates of academic misrepresentation by prospective neurosurgical residents at a single institution across 2 distinct application cycles. METHODS: We retrospectively reviewed all Electronic Residency Application Service applications to 1 institution's neurosurgical residency program in the 2015 (n = 320) and 2020 (n = 355) application cycles. Reported academic works were verified through an extensive Web search of PubMed, Google Scholar, and the individual journal Web sites. Misrepresentation was defined in our study as listing work that does not exist, self-promotion to primary authorship, self-promotion (excluding primary authorship), incorrectly listing online-only publications, and listing non-peer-reviewed work as peer-reviewed. RESULTS: In 2015, 253 (79.1%) applicants reported a total of 2097 citations and 305 (85.9%) applicants reported a total of 3018 citations in 2020 (P < 0.05). Median peer-reviewed articles per applicant rose significantly in 2020 (3.0 vs. 4.0, P < 0.001). Misrepresentation rates decreased dramatically in 2020 to 18.4% from a previously reported misrepresentation rate of 45% in 2012 (P < 0.0001). Increased United States Medical Licensing Exam Step 2 scores were associated with a decreased likelihood of misrepresentation (odds ratio = 0.97, P < 0.001). CONCLUSIONS: Misrepresentation rates within neurosurgical residency candidates have significantly decreased despite an increase in reported citations. A variety of steps including education, modifying reporting methods, and increased screening may help even further decrease misrepresentation.

Emerging and investigational targeted chemotherapy and immunotherapy agents for metastatic brain tumors.

INTRODUCTION: Metastases to the central nervous system are the most common cause of malignant intracranial tumors in adults. Current standard of care includes surgery and radiation, but overall survival remains poor. A range of systemic therapies are emerging as promising treatment options for these patients. AREAS COVERED: This study reviews novel drug regimens that are under investigation in phase 1 and 2 clinical trials. To identify relevant therapies under clinical investigation, a search was performed on http://clinicaltrials.gov and Pubmed with the keywords brain metastasis, Phase I clinical trial, and Phase II clinical trial from 2016 to 2020. The authors detail the mechanisms of action of all trial agents, outline evidence for their utility, and summarize the current state of the field. EXPERT OPINION: Current advancements in the medical management of brain metastases can be categorized into targeted therapies, methods of overcoming treatment resistance, novel combinations of therapies, and modulation of the tumor microenvironment with a specific focus on immunotherapy. Each of these realms holds great promise for the field going forward. A more streamlined structure for enrollment into clinical trials will be a crucial step in accelerating progress in this area.

The evolving role of antiangiogenic therapies in glioblastoma multiforme: current clinical significance and future potential.

Introduction: Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults, but its prognosis remains poor despite significant advances in our understanding of its molecular biology and investigation of numerous treatment modalities. Despite conventional treatment consisting of surgical resection, radiotherapy, and temozolomide marginally prolonging survival, most GBM patients die within 2 years of initial diagnosis. Bevacizumab (Bev) is the best-studied antiangiogenic agent for GBM and currently the only FDA-approved second-line treatment. Areas covered: Areas covered in this review include the molecular pathways of angiogenesis in glioblastoma, specifically the overexpression of vascular endothelial growth factor (VEGF) and robust formation of tumor neovasculature. In addition, this review covers pharmacological targeting of this process as a longstanding attractive clinical strategy, specifically by Bev. Expert opinion: This review attempts to discuss the history of early studies of antiangiogenic treatment for GBM that eventually failed in subsequent studies and the evolving modern role of Bev in the course of treatment for a variety of indications, including symptom control, reduced glucocorticoid use, and improved quality of life.

AJAP1 expression modulates glioma cell motility and correlates with tumor growth and survival.

Glioblastoma multiforme (GBM) is one of the most common primary malignant brain tumors. Unraveling the molecular and genetic complexity that determines GBM's pronounced migratory property could provide new options for therapeutic targeting that may significantly complement current surgical and chemoradiation therapy and alter the current poor outcome. In this study, we establish stable AJAP1 overexpressing glioma cells in order to examine in vivo tumor growth. We examine AJAP1 localization by confocal microscopy and AJAP1's functional effect on migration and invasion across surfaces coated with laminin. Finally, analysis of AJAP1 expression in murine xenografts and GBM primary tumors revealed its association with tumor growth and survival. Stable overexpression of AJAP1 promotes adherence, decreases invasion of glioma cells through an extracellular-like matrix, and slows migration in the presence of laminin. These observations are reversed by gene knockdown using multiple siRNAs. Additionally, overexpression of AJAP1 decreases colony formation in glioma cells, and leads to smaller tumor growth with increased survival in glioma xenograft mice. Loss of AJAP1 protein expression predicts worse survival in GBM patients. AJAP1 overexpression decreases cell motility in the presence of laminin and decreases tumor growth in xenografts. Its loss of expression predicts worse survival in patients. This study extends our prior observations and implicates AJAP1 as a potential prognostic marker and a viable target for therapeutic intervention in GBM.

OTX2 is a therapeutic target for retinoblastoma and may function as a common factor between C-MYC, CRX, and phosphorylated RB pathways.

The homeobox transcription factor orthodenticle homeobox 2 (OTX2) plays a critical role in very early neurogenesis, but can become oncogenic when aberrantly expressed later in life. We previously discovered its novel oncogenic role in the malignant childhood brain tumor medulloblastoma and hypothesize an oncogenic role in retinoblastoma. Primary retinoblastoma tumors and cell lines were analyzed by quantitative-PCR, immunoblotting and immunohistochemistry for OTX2. The effect of modulating OTX2 expression on tumorigenesis was tested pharmacologically and by siRNA. A lentiviral shRNA-engineered vector was used for conditional knockdown studies on tumor growth in vivo. A luciferase reporter assay was used to analyze ATRA's effect on OTX2's promoter. In this study on retinoblastoma, OTX2 was frequently amplified and/or overexpressed in primary tumors and cell lines. Knockdown of OTX2 expression by siRNA or pharmacologic inhibition by all-trans retinoic acid (ATRA) repressed OTX2 expression and cell proliferation and significantly decreased tumor growth in vivo. Loss of OTX2 expression also resulted in decreased expression of C-MYC and CRX, genes previously implicated in retinoblastoma tumorigenesis. Loss of OTX2 expression increased the phosphorylation of RB, a potential mechanism of modulating cell proliferation. Aberrant expression of OTX2 may contribute to the development of retinoblastoma. OTX2 may serve as a common transcription factor that interlinks multiple tumor-driving pathways. These results also show that OTX2 can be genetically and pharmacologically targeted, providing an exciting new therapeutic option that may be less toxic and more efficacious than current treatments.

Radiation-induced malignant gliomas: a current review.

OBJECTIVE: Radiation-induced malignant gliomas (RIMGs) are known uncommon risks of brain irradiation. We describe 4 cases of RIMG that occurred at our institution and conduct the largest comprehensive review of the literature to characterize RIMGs better. METHODS: Patients were identified through the PubMed database. Pearson R linear correlation test was used to evaluate the correlation between radiotherapy (RT) dose and age and latency period. Student t test was used to evaluate differences between latency periods for original tumor lesions. A normalized biologic equivalent dose analysis was performed to indicate the minimum and maximum radiation threshold for neoplasia. A Kaplan-Meier analysis was used to illustrate the overall survival curves. RESULTS: The analysis included 172 cases from the PubMed database and 4 cases occurring at our institution. The median RT dose administered was 35.6 Gy, with the most common dosage ranges being 21-30 Gy (31%) and 41-50 Gy (21.5%). Median latency period was 9 years until diagnosis of RIMG, and RIMG occurred within 15 years in 82% of the patients. There was no correlation between the age of the patient at the time RT was administered (R(2) = 0.00081) or amount of RT (R(2) = 0.00005) and latency period for RIMG. The mean biologic equivalent dose for neoplasia of a RIMG was 63.3 Gy. The median survival of patients with RIMG improved over time (P = 0.004), with median survival of 9 months before 2007 and 11.5 months after 2007. CONCLUSIONS: The risk of RIMG appears to be the same for all age groups, histologies, and RT dosages. Although the risk is low, patients should be aware of RIMG as a possible complication of brain irradiation.

Adherens junctional associated protein-1: a novel 1p36 tumor suppressor candidate in gliomas (Review).

In a broad range of human cancers 1p36 has been a mutational hotspot which strongly suggests that the loss of tumor suppressor activity maps to this genomic region during tumorigenesis. Adherens junctional associated protein-1 (AJAP1; also known as Shrew1) was initially discovered as a novel transmembrane protein of adherent junctions in epithelial cells. Gene profiling showed AJAP1 on 1p36 is frequently lost or epigenetically silenced. AJAP1 may affect cell motility, migration, invasion and proliferation by unclear mechanisms. AJAP1 may be translocated to the nucleus, via its interaction with ß-catenin complexes, where it can regulate gene transcription, then possibly have a potent impact on cell cycling and apoptosis. Significantly, loss of AJAP1 expression predicts poor clinical outcome of patients with malignant gliomas such as GBM and it may serve as a promising tumor suppressor-related target. In this review, we summarize and discuss current knowledge that may identify AJAP1 as a tumor suppressor in gliomas.

AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization.

AIMS: Down-regulation of AJAP1 in glioblastoma multiforme (GBM) has been reported. However, the expression profiles of AJAP1 in gliomas and the underlying mechanisms of AJAP1 function on invasion are still poorly understood. METHODS: The gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 overexpression in GBM cell lines, cellular polarity, cytoskeleton distribution, and antitumor effect were investigated in vitro and in vivo. RESULTS: AJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low-grade gliomas and AJAP1-overexpressing GBM cells, but difficult to assess in high-grade gliomas due to its absence. AJAP1 overexpression altered the cytoskeleton and cellular polarity in vitro and inhibited the tumor growth in vivo. CONCLUSIONS: AJAP1 is dysregulated at an early stage of gliomagenesis and may suppress glioma cell invasion and proliferation, which suggests that AJAP1 may be a potential diagnostic and prognostic marker for gliomas.

The adherens junction-associated protein 1 is a negative transcriptional regulator of MAGEA2, which potentiates temozolomide-induced apoptosis in GBM.

Previous studies identified the frequent loss of adherens junction-associated protein 1 (AJAP1) expression in glioblastoma (GBM) and its correlation with worse survival. AJAP1 may suppress glioma cell migration, which plays an important role in tumor progression in malignant gliomas such as GBM. However, the role of AJAP1 in cell cycle arrest or apoptosis and resistance to chemotherapy remains unclear. Based on microarray screening results, quantitative PCR and luciferase plasmid reporter constructs were used to evaluate the possible regulatory role of AJAP1 on MAGEA2 expression and function. Cell death assays, TUNEL and other markers of apoptosis were utilized to detect cell apoptosis. Restoration of AJAP1 expression in glioma cells was analyzed after temozolomide exposure. AJAP1 suppressed the expression of MAGEA2 and inhibited the transcriptional activity of MAGEA2 in glioma cells. As AJAP1 expression decreased MAGEA2 protein expression apoptosis increased moderately. Consistent with increased cell death, the induced loss of MAGEA2 expression correlated with increased caspase 3/7 activity, BCL2/BAX ratio and TUNEL signal. AJAP1 expression enhanced cell death in the presence of temozolomide. This study suggests AJAP1 may also function as a pro-apoptotic factor and potentiate cell death by temozolomide in glioma cells. This effect may be partially explained by AJAP1-mediated gene regulation of MAGEA2.

Fluorescence-guided malignant glioma resections.

Gliomas are the most common primary brain tumors and result in dismal outcomes when present at high grades. Surgery is the first-line treatment, and maximum safe resection is recommended. However, the infiltrative nature of malignant gliomas makes complete resection difficult as tumor margins are unclear. The use of fluorescence to delineate tumor margins intraoperatively has emerged as a safe and effective tool for increasing the extent of resection. This review discusses several exogenous agents that have been investigated in humans. Aminolevulinic acid is the most studied fluorophore and has been used in many clinical trials, including a multi-center phase III randomized controlled trial. It has been shown to increase extent of resection, progression-free survival, and overall survival. Another fluorophore, fluorescein, has also demonstrated utility in increasing resection quality and overall survival. Developing technologies such as fluorescence spectroscopy to enhance endogenous fluorescence has fairly recently been shown to delineate tumor margins intraoperatively. This method does not require the administration of exogenous agents, but instead distinguishes tumor from normal brain by using changes in the fluorescence emission profile of the tissue. This review also discusses various agents such as nanoparticles that are currently in preclinical testing. Fluorescence-guided resections show great promise for furthering our surgical abilities, and in the foreseeable future will become the standard of care for patients diagnosed with gliomas.

Deletion or epigenetic silencing of AJAP1 on 1p36 in glioblastoma.

Glioblastoma is universally fatal because of its propensity for rapid recurrence due to highly migratory tumor cells. Unraveling the genomic complexity that underlies this migratory characteristic could provide therapeutic targets that would greatly complement current surgical therapy. Using multiple high-resolution genomic screening methods, we identified a single locus, adherens junctional associated protein 1 (AJAP1) on chromosome 1p36 that is lost or epigenetically silenced in many glioblastomas. We found AJAP1 expression absent or reduced in 86% and 100% of primary glioblastoma tumors and cell lines, respectively, and the loss of expression correlates with AJAP1 methylation. Restoration of AJAP1 gene expression by transfection or demethylation agents results in decreased tumor cell migration in glioblastoma cell lines. This work shows the significant loss of expression of AJAP1 in glioblastoma and provides evidence of its role in the highly migratory characteristic of these tumors.

Neuronal-astrocyte metabolic interactions: understanding the transition into abnormal astrocytoma metabolism.

Brain function depends on complex metabolic interactions among only a few different cell types, with astrocytes providing critical support for neurons. Astrocyte functions include buffering the extracellular space, providing substrates to neurons, interchanging glutamate and glutamine for synaptic transmission with neurons, and facilitating access to blood vessels. Whereas neurons possess highly oxidative metabolism and easily succumb to ischemia, astrocytes rely more on glycolytic metabolism and hence are less susceptible tolack of oxygen. Astrocytoma cells seem to retain basic metabolic mechanisms of astrocytes; for example, they show a high glycolytic rate, lactate extrusion, ability to flourish under hypoxia, and opportunistic use of mechanisms to enhance cell division and maintain growth. Differences in metabolism between neurons and astrocytes may also extend to astrocytoma cells, providing therapeutic opportunities against astrocytomas, including sensitivity to acetate, a high rate of glycolysis and lactate extrusion, glutamate uptake transporters, differential sensitivities of monocarboxylate transporters, presence of glycogen, high interlinking with gap junctions, use of nicotinamide adenine dinucleotide phosphate for lipid synthesis, using different isoforms of synthetic enzymes (e.g. isocitrate dehydrogenase, pyruvate carboxylase, pyruvate kinase, lactate dehydrogenase), and different glucose uptake mechanisms. These unique metabolic susceptibilities may augment conventional therapeutic attacks based on cell division differences and surface receptors alone.

Glioblastoma multiforme: a review of therapeutic targets.

Glioblastoma is the commonest primary brain tumor, as well as the deadliest. Malignant gliomas such as glioblastoma multiforme (GBM) present some of the greatest challenges in the management of cancer patients worldwide, despite notable recent achievements in oncology. Even with aggressive surgical resections using state-of-the-art preoperative and intraoperative neuroimaging, along with recent advances in radiotherapy and chemotherapy, the prognosis for GBM patients remains dismal: survival after diagnosis is about 1 year. Established prognostic factors are limited, but include age, Karnofsky performance status, mini-mental status examination score, O6-methylguanine methyltransferase promoter methylation and extent of surgery. Standard treatment includes resection of > 95% of the tumor, followed by concurrent chemotherapy and radiotherapy. Nevertheless, GBM research is being conducted worldwide at a remarkable pace, in the laboratory and at the bedside, with some of the more recent promising studies focused on identification of aberrant genetic events and signaling pathways to develop molecular-based targeted therapies, tumor stem cell identification and characterization, modulation of tumor immunological responses and understanding of the rare long-term survivors. With this universally fatal disease, any small breakthrough will have a significant impact on survival and provide hope to the thousands of patients who receive this diagnosis annually. This review describes the epidemiology, clinical presentation, pathology and tumor immunology, with a focus on understanding the molecular biology that underlies the current targeted therapeutics being tested.