Michael C. Oh

Choroid plexus papillomas: advances in molecular biology and understanding of tumorigenesis

Choroid plexus papillomas are rare, benign tumors originating from the choroid plexus. Although generally found within the ventricular system, they can arise ectopically in the brain parenchyma or disseminate throughout the neuraxis. We sought to review recent advances in our understanding of the molecular biology and oncogenic pathways associated with this disease. A comprehensive PubMed literature review was conducted to identify manuscripts discussing the clinical, molecular, and genetic features of choroid plexus papillomas. Articles concerning diagnosis, treatment, and long-term patient outcomes were also reviewed. The introduction of atypical choroid plexus papilloma as a distinct entity has increased the need for accurate histopathologic diagnosis. Advances in immunohistochemical staining have improved our ability to differentiate choroid plexus papillomas from other intracranial tumors or metastatic lesions using combinations of key markers and mitotic indices. Recent findings have implicated Notch3 signaling, the transcription factor TWIST1, platelet-derived growth factor receptor, and the tumor necrosis factor-related apoptosis-inducing ligand pathway in choroid plexus papilloma tumorigenesis. A combination of commonly occurring chromosomal duplications and deletions has also been identified. Surgical resection remains the standard of care, although chemotherapy and radiotherapy may be considered for recurrent or metastatic lesions. While generally considered benign, these tumors possess a complex biology that sheds insight into other choroid plexus tumors, particularly malignant choroid plexus carcinomas. Improving our understanding of the molecular biology, genetics, and oncogenic pathways associated with this tumor will allow for the development of targeted therapies and improved outcomes for patients with this disease.

Tuberculoma of the central nervous system

Tuberculosis is among the oldest and most devastating infectious diseases worldwide. Nearly one third of the worlds population has active or latent disease, resulting in 1.5 million deaths annually. Central nervous system involvement, while rare, is the most severe form of tuberculosis. Manifestations include tuberculoma and tuberculous meningitis, with the majority of cases occurring in children and immunocompromised patients. Despite advancements in imaging and laboratory diagnostics, tuberculomas of the central nervous system remain a diagnostic challenge due to their insidious nature and nonspecific findings. On imaging studies tuberculous meningitis is characterized by diffuse basal enhancement, but tuberculomas may be indistinguishable from neoplasms. Early diagnosis is imperative, since clinical outcomes are largely dependent on timely treatment. Stereotactic biopsy with histopathological analysis can provide a definitive diagnosis, but is only recommended when non-invasive methods are inconclusive. Standard medical treatment includes rifampicin, isoniazid, pyrazinamide, and streptomycin or ethambutol. In cases of drug resistance, revision of the treatment regimen with second-line agents is recommended over the addition of a single drug to the first-line regimen. Advances in genomics have identified virulent strains of tuberculosis and are improving our understanding of host susceptibility. Neurosurgical referral is advised for patients with elevated intracranial pressure, seizures, or brain or spinal cord compression. This review synthesizes pertinent findings in the literature surrounding central nervous system tuberculoma in an effort to highlight recent advances in pathophysiology, diagnosis, and treatment.

Prognosis by tumor location in adults with spinal ependymomas.

OBJECT Ependymomas are primary central nervous system tumors that occur more frequently in the spines of adults than they do there in children. Previous studies consist mainly of retrospective single-institutional experiences or case studies. In this study, a comprehensive literature review was performed on reported cases of spinal ependymoma treated with resection to determine whether tumor location along the spinal axis conveys important prognostic information. METHODS A PubMed search was performed to identify all papers that included data on patients with spinal ependymoma. Only cases involving adult patients who underwent ependymoma resection with a clearly reported tumor location were included for analysis. Tumor locations were separated into 6 groups: cervicomedullary, cervical, cervicothoracic, thoracic, thoracolumbar, and conus + cauda equina. Kaplan-Meier survival and Cox regression analyses were performed to determine the effect of tumor location on progression-free survival (PFS) and overall survival (OS). RESULTS A total of 447 patients who underwent resection of spinal ependymomas with clearly indicated location of tumor were identified. The most common locations of spinal ependymomas were the cervical (32.0%) and conus + cauda equina (26.8%) regions. The thoracolumbar and cervicomedullary regions had the fewest tumors (accounting for, respectively, 5.1% and 3.4% of the total number of cases). The conus + cauda equina and thoracolumbar regions had the highest percentage of WHO Grade I tumors, while tumors located above these regions consisted of mostly WHO Grade II tumors. Despite the tendency for benign grades in the lower spinal regions, PFS for patients with spinal ependymomas in the lower 3 regions (thoracic, thoracolumbar, conus + cauda equina) was significantly shorter (p < 0.001) than for those with tumors in the upper regions (cervicomedullary, cervical, cervicothoracic), but the difference in OS did not achieve statistical significance (p = 0.131). CONCLUSIONS Spinal ependymomas along different regions of spinal axis have different characteristics and clinical behaviors. Tumor grade, extent of resection, and PFS varied by tumor location (upper vs lower spinal regions), while OS did not. Recurrence rates were higher for the lower spinal cord tumors, despite a greater prevalence of lower WHO grade lesions, compared with upper spinal cord tumors, suggesting that tumor location along the spinal axis is an important prognostic factor.

Overexpression of CD97 Confers an Invasive Phenotype in Glioblastoma Cells and Is Associated with Decreased Survival of Glioblastoma Patients

Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene-expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007). CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM.

Adjuvant radiotherapy delays recurrence following subtotal resection of spinal cord ependymomas

BACKGROUND Ependymoma is the most common glial tumor of the adult spinal cord. Current consensus recommends surgical resection with gross total resection (GTR) whenever possible. We performed a comprehensive review of the literature to evaluate whether adjuvant radiotherapy after subtotal resection (STR) has any benefit. METHODS A PubMed search was performed to identify adult patients with spinal cord ependymoma who underwent surgical resection. Only patients who had clearly defined extent of resection with or without adjuvant radiotherapy were included for analysis. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine the effects of adjuvant radiotherapy on progression-free survival (PFS) and overall survival (OS). RESULTS A total of 348 patients underwent surgical resection of spinal cord ependymomas, where GTR was obtained in 77.0% (268/348) of patients. Among those who received STR, 58.8% (47/80) received adjuvant radiotherapy. PFS was significantly prolonged among those who received adjuvant radiotherapy after STR (log rank; P < .001). This prolonged PFS with adjuvant radiotherapy remained significant in multivariate Cox regression analysis (STR versus STR + RT group; hazard ratio (HR) = 2.26, P = .047). By contrast, improved OS was only associated with GTR (GTR versus STR + RT group; HR = 0.07, P = .001) and benign ependymomas (HR = 0.16, P = .001). CONCLUSIONS Surgery remains the mainstay treatment for spinal cord ependymomas, where GTR provides optimal outcomes with longest PFS and OS. Adjuvant radiotherapy prolongs PFS after STR significantly, and OS is improved by GTR and benign tumor grade only.

The prognostic implications of Hyam's subtype for patients with Kadish stage C esthesioneuroblastoma

Esthesioneuroblastoma (EN) is a rare sinonasal tumor with varied aggressiveness and potential for intracranial invasion. EN is staged anatomically with radiographic evaluation using the Kadish staging system (stages A, B, and C) and histologically by using Hyams criteria (grades 1-4). Here we show that despite radiographic evidence of aggressive features, the prognosis of patients with Kadish stage C EN is best predicted by tumor histology using Hyams criteria. We retrospectively analyzed patients with EN with Kadish stage C who were evaluated and treated at our institution between 1995 and 2009. Clinical information was collected using patient medical records, imaging, and review of pathological specimens. Twenty patients with Kadish stage C EN were identified with mean age of 51 years (31-70 years) with a median follow-up of 41.4 months (1.3-175 months). Upon pathological review, 44.4% of patients had low-grade (1/2) and 55.6% had high-grade (3/4) histology. About 37.5% of patients with low-grade EN had undergone gross total resection (GTR) and the remaining 62.5% had GTR and adjuvant radiation, whereas 50% of patients with high-grade ER had undergone GTR, 20% had undergone GTR and adjuvant radiation, and 30% had been treated with a subtotal resection (STR) and adjuvant radiation. The 5-year and 10-year survival in patients with low-grade EN was 86% in comparison to 56% and 28% with high-grade EN, respectively. In patients with low-grade EN, the 2-year progression free survival (PFS) was 86% and the 5-year PFS was 65% in comparison to 73% and 49% in patients with high-grade EN, respectively. The patients tumor histology (Hyams criteria) appeared to be the best way of predicting the prognosis and for selecting patients for adjuvant radiotherapy.

Overexpression of Calcium-Permeable Glutamate Receptors in Glioblastoma Derived Brain Tumor Initiating Cells

Glioblastoma multiforme is the most malignant type of primary brain tumor with a poor prognosis. These tumors consist of a heterogeneous population of malignant cells, including well-differentiated tumor cells and less differentiated cells with stem cell properties. These cancer stem cells, known as brain tumor initiating cells, likely contribute to glioma recurrence, as they are highly invasive, mobile, resistant to radiation and chemotherapy, and have the capacity to self-renew. Glioblastoma tumor cells release excitotoxic levels of glutamate, which may be a key process in the death of peritumoral neurons, formation of necrosis, local inflammation, and glioma-related seizures. Moreover, elevated glutamate levels in the tumor may act in paracrine and autocrine manner to activate glutamate receptors on glioblastoma tumor cells, resulting in proliferation and invasion. Using a previously described culturing condition that selectively promotes the growth of brain tumor initiating cells, which express the stem cell markers nestin and SOX-2, we characterize the expression of α-amino-3-hydroxy-5-methyl-4-isozolepropionic acid (AMPA)-type glutamate receptor subunits in brain tumor initiating cells derived from glioblastomas. Here we show for the first time that glioblastoma brain tumor initiating cells express high concentrations of functional calcium-permeable AMPA receptors, compared to the differentiated tumor cultures consisting of non-stem cells. Up-regulated calcium-permeable AMPA receptor expression was confirmed by immunoblotting, immunocytochemistry, and intracellular calcium imaging in response to specific agonists. Our findings raise the possibility that glutamate secretion in the GBM tumor microenvironment may stimulate brain tumor derived cancer stem cells.

Pathology of spinal ependymomas: an institutional experience over 25 years in 134 patients.

BACKGROUND Ependymomas constitute approximately 40% of primary intraspinal tumors. Current World Health Organization (WHO) grading may not correlate with observed progression-free survival (PFS). OBJECTIVE This retrospective study of prospectively collected data examines whether PFS is influenced by the histological grade or by the extent of resection. It also analyzes the usage and effectiveness of postoperative adjuvant radiotherapy. METHODS We reviewed 134 consecutive patients with ependymomas of all grades. Pathology slides were re-reviewed and the histological grades were confirmed by a single neuropathologist. Postoperative residual or recurrence was evaluated with follow-up magnetic resonance imaging. RESULTS There were 85 male and 49 female patients, ranging from 10 to 79 (median 41) years of age. Thirty patients had WHO grade I tumors, 101 had grade II tumors, and 3 had grade III tumors. Kaplan-Meier analysis of PFS demonstrated a mean duration of 6 years for grade I, 14.9 years for grade II, and 3.7 years for grade III (P < .001). In grade II ependymomas, mean PFS was 11.2 years with subtotal resection and 17.8 years with gross total resection (P < .01). PFS of patients who underwent subtotal resection was not significantly changed by adjuvant radiotherapy (P < .36). CONCLUSION Patients with grade II ependymoma have significantly longer PFS than patients with grade I ependymoma. The extent of resection did not affect PFS in grade I ependymoma but it did in grade II. Contrary to its higher grade, WHO grade II ependymoma carries a better prognosis than WHO grade I ependymoma.

Prognosis by tumor location in adults with intracranial ependymomas

Intracranial ependymomas are rare tumors in adults. Thus, factors affecting prognosis are poorly understood. We performed a study to investigate whether tumor location is an important prognostic factor in adults who undergo surgery for intracranial ependymomas. PubMed was searched to identify studies that reported clinical outcomes in adult patients with intracranial ependymoma. Data were extracted for patient and tumor characteristics, extent of resection, progression-free survival (PFS), and overall survival (OS). Tumors were categorized as supratentorial or infratentorial and extraventricular or intraventricular. Presenting clinical features and tumor characteristics were tabulated. Kaplan-Meier and multivariate Cox regression survival analyses were performed to determine PFS and OS by tumor location. Extent of resection was also analyzed by tumor location. A total of 183 patients were included in the meta-analysis. Patients presented at a mean of 8.2months with a myriad of clinical features. The mean tumor size was 3.38 cm, and 19.3% of tumors were cystic. Supratentorial tumors were most commonly located in the frontal and parietal lobes, and infratentorial tumors in the fourth ventricle. Supratentorial tumors demonstrated significantly poorer PFS (p<0.001) and OS (p=0.003) than infratentorial tumors, despite a higher rate of gross total resection (GTR) for the supratentorial tumors (72.6% versus 42.1%). Extraventricular ependymomas displayed significantly poorer PFS than intraventricular ependymomas (p=0.009). In summary, supratentorial ependymomas have significantly poorer PFS and OS than their infratentorial counterparts, despite being more conducive to GTR, suggesting increased clinical aggressiveness. Extraventricular location is also associated with significantly poorer PFS than intraventricular location.

CD97 is a multifunctional leukocyte receptor with distinct roles in human cancers (Review)

G-protein coupled receptors (GPCRs) represent the most diverse and biologically ubiquitous protein receptors. The epidermal growth factor seven-span transmembrane (EGF-TM7) family consists of adhesion GPCRs with a diverse functional repertoire. CD97 is the most broadly expressed member with roles in cell adhesion, migration and regulation of intercellular junctions. CD97 is also expressed in a variety of human malignancies including those of the thyroid, stomach, colon and brain. CD97 confers an invasive phenotype and has been shown to correlate with tumor grade, lymph node invasion, metastatic spread and overall prognosis. More recently, CD97 was found to signal through Gα12/13, resulting in increased RHO-GTP levels. Proven roles in tumor invasion and signaling make CD97 an exciting novel therapeutic target. In this review, we will discuss the structure and function of this receptor, with a specific focus on its mechanistic significance in neoplastic diseases.