Isaac Yang

ABSTRACT INTRODUCTION: Vestibular schwannoma (VS) is a benign tumor derived from Schwann cells. Hearing loss commonly occurs in varying degrees as a result of VS and can have a significant and lasting impact on quality of life. Treatment options include observation, surgical resection, stereotactic radiosurgery (SRS) and stereotactic radiotherapy (SRT). In this study, we assess the outcomes of patients with VS treated with either SRS or SRT. METHODS: Patients receiving SRS or SRT for VS between 1996 and 2010 were reviewed. Inclusion criteria: 1) histopathologically confirmed VS, 2) SRS or SRT performed at UCLA Ronald Reagan Medical Center, 3) functional hearing and/or tumor size assessed pre- and post-SRS or SRT. Functional hearing was defined as ability to use a phone with the affected ear. RESULTS: 66 patients met all of the inclusion criteria and had information readily available. 21 received SRS while 45 received SRT. 34 were male and 32 were female. The average age at completion of SRS or SRT was 55 years old (range: 23-83). The median dose for SRS was 1200cGy, and the average dose for SRT was 180cGy to the 90% IDL over 30 fractions. Patients had an average radiological and clinical follow-up of 41 and 35 months, respectively. 91% of patients had either stable or decreased tumor size on final radiologic follow-up; 95% had stable or improved functional hearing on final clinical follow-up. SRT was associated with a lower rate of tumor size increase following treatment relative to SRS (5% vs. 25%, respectively, p=0.067). Similarly, in patients with functional hearing prior to treatment, SRT was associated with a lower risk of functional hearing loss relative to SRS (3% vs. 40%, respectively, p=0.04). CONCLUSIONS: Patients with VS often seek SRS or SRT to control the growth of their tumor and/or preserve their hearing. Our data show good tumor control over time with SRS and SRT. Furthermore, SRT was associated with improved tumor control and functional hearing results relative to SRS. Further research is needed to determine optimal use of SRS and SRT for treatment of VS.

Central nervous system (CNS) involvement by rheumatoid arthritis (RA) in the form of rheumatoid meningitis (RM) is rare and most commonly occurs in the setting of longstanding severe RA. Due to a wide range of clinical presentations and nonspecific laboratory findings, it presents a diagnostic challenge often requiring brain biopsy. Only a few histopathologically confirmed cases have been described in the literature. Our aim is to describe two cases of RM and review the literature. The first case is of a previously healthy 37-year-old man who presented with severe headaches and focal neurologic deficits. Magnetic resonance imaging demonstrated abnormal leptomeningeal enhancement in the left frontal and parietal sulci. The second case is of a 62-year-old woman with a history of mild chronic joint pain who presented with confusion, personality changes and seizures. Both patients ultimately underwent brain biopsy which demonstrated RM on pathologic examination. Administration of cortic...

Glioblastoma multiforme, the most common lethal primary brain tumor, is comprised of a phenotypically diverse population of cells. The cancer stem cell hypothesis suggests that the bulk tumor mass may contain a subpopulation of cells with stem-like characteristics. Recently, a CD133+ stem cell-like subpopulation was identified in glioblastoma multiforme. This subpopulation of cells can recreate the heterogeneity of the original tumor when injected intracranially into immunodeficient mice. It is expected that 1 X 103 CD133+ cells injected intracranially into C57BL/6 mice will be more tumorigenic than 1 X 104 heterogeneous GL261 murine glioma cells injected intracranially into C57BL/6 mice. In order to test this hypothesis, GL261 cells were grown in vitro in tumporsphere media, collected and labeled with PE Anti-mouse CD133 antibody. Using flow cytometry, it was determined that CD133+ cells comprised 0.3% of the GL261 population. Sorting CD133+ using Fluorescence-activated Cell Sortin...

Interferon-gamma (IFNgamma) is a cytokine that acts on cell-surface receptors, activating transcription of genes that offer treatment potential by increasing tumor immunogenicity, disrupting proliferative mechanisms, and inhibiting tumor angiogenesis. However, abnormally low levels of IFNgamma are produced by tumor cells and local T cells in the glioma microenvironment. Current investigations into the immunomodulating effects of IFNgamma suggest that IFNgamma has the potential to be used clinically in the treatment of brain tumors and as a promising adjunct to other immunotherapeutic modalities. Here the authors review the published literature that highlights the potential role of IFNgamma in the treatment and immunotherapy of malignant gliomas.

Glioblastoma multiforme (GBM) is characterized as one of the most common and most deadly malignant primary brain tumors. Current treatment modalities include the use of surgical resection and adjuvant chemotherapy and radiation therapy, though survival is still limited. Because of this, new treatment strategies are needed to improve overall survival. Immunotherapy has emerged as a potential treatment, but still possesses certain limitations to have a substantial clinical effect. In addition, nanotechnology has emerged as potent treatment effectors that have been shown to augment the effects of therapies including chemotherapy, gene therapy, and more. Nanoparticles possess a novel approach due to the myriad of functional groups that can create targeted treatments, though further optimization is still required. In this review, the authors will present the current uses and abilities of nanotechnology and its implication for use with immunotherapy in the treatment of GBM.

There are few published prospective data sets specifically focusing on patients younger than 40 years old undergoing microsurgery for vestibular schwannoma. We describe functional outcomes and long-term tumor control after surgery in patients younger than 40 years old enrolled in a prospectively collected database over a 25-year period. We selected all vestibular schwannoma patients from a prospectively collected database who were younger than 40 years old at the time of surgical resection for a vestibular schwannoma. Rates of tumor control and hearing preservation were analyzed using Kaplan-Meier analysis, and risk factors for facial nerve palsy, hearing loss, and trigeminal neuropathy were analyzed using multivariate logistic regression. A total of 204 patients younger than 40 years of age met our inclusion criteria and were included in the analysis. Our data indicate that surgical resection leads to durable long-term freedom from tumor recurrence or progression in 89% of young patients at 15 years of follow-up. Consistent with other published series, hearing was preserved in 68% of patients with smaller tumors (<3 cm). Facial nerve function was preserved in 76% of patients with smaller tumors and 52% of patients with larger tumors (P<.001). On multivariate logistic regression, tumor size was a significant predictor of hearing loss, whereas gross total resection was nearly a significant predictor of hearing loss controlling for other variables (P=.06). We present the largest prospectively studied cohort of young patients undergoing microsurgical resection of vestibular schwannoma. These data suggest that surgical resection provides excellent long-term tumor control in these patients.

Analysis of extracellular vesicles (EVs) derived from plasma or cerebrospinal fluid (CSF) has emerged as a promising biomarker platform for therapeutic monitoring in glioblastoma patients. However, the contents of the various subpopulations of EVs in these clinical specimens remain poorly defined. Here we characterize the relative abundance of miRNA species in EVs derived from the serum and cerebrospinal fluid of glioblastoma patients. EVs were isolated from glioblastoma cell lines as well as the plasma and CSF of glioblastoma patients. The microvesicle subpopulation was isolated by pelleting at 10,000×g for 30 min after cellular debris was cleared by a 2000×g (20 min) spin. The exosome subpopulation was isolated by pelleting the microvesicle supernatant at 120,000×g (120 min). qRT-PCR was performed to examine the distribution of miR-21, miR-103, miR-24, and miR-125. Global miRNA profiling was performed in select glioblastoma CSF samples. In plasma and cell line derived EVs, the relative abundance of miRNAs in exosome and microvesicles were highly variable. In some specimens, the majority of the miRNA species were found in exosomes while in other, they were found in microvesicles. In contrast, CSF exosomes were enriched for miRNAs relative to CSF microvesicles. In CSF, there is an average of one molecule of miRNA per 150-25,000 EVs. Most EVs derived from clinical biofluids are devoid of miRNA content. The relative distribution of miRNA species in plasma exosomes or microvesicles is unpredictable. In contrast, CSF exosomes are the major EV compartment that harbor miRNAs.

Traditional posterior approaches to the thoracic spine are done with either costo-transversectomy, lateral extracavitary approaches, or transpedicular approaches. The transpedicular approach is the only one that preserves the rib head. However, placing an expandable cage with this rib head intact poses special challenges because of the narrow corridor defined by the rib head and the spinal cord. Instead of removing the rib head, which requires pleural dissection and carries the risks of pleural injury, we disarticulate it and push it laterally during cage placement. This avoids pleural dissection and affords expandable cage placement through a transpedicular approach.

Despite advances in surgical techniques and medical therapies, a significant proportion of pituitary adenomas remain endocrinologically active, demonstrate persistent radiographic disease, or recur when followed for long periods of time. While surgical intervention remains the first-line therapy, stereotactic radiosurgery is increasingly recognized as a viable treatment option for these often challenging tumors. In this review, we comprehensively review the literature to evaluate both endocrinologic and radiographic outcomes of radiosurgical management of pituitary adenomas. The literature clearly supports the use of radiosurgery, with endocrinologic remission rates and time to remission varying by tumor type [prolactinoma: 20-30%, growth hormone secreting adenomas: ~50%, adrenocorticotrophic hormone (ACTH)-secreting adenomas: 40-65%] and radiographic control rates almost universally greater than 90% with long-term follow-up. We stratify the outcomes by tumor type, review the importance of prognostic factors (particularly, pre-treatment endocrinologic function and tumor size), and discuss the complications of treatment (with special attention to endocrinopathy and visual complications). We conclude that the literature supports the use of radiosurgery for treatment-refractory pituitary adenomas, providing the patient with a minimally invasive, safe, and effective treatment option for an otherwise resistant tumor. As such, we provide literature-based treatment considerations, including radiosurgical dose, endocrinologic, radiographic, and medical considerations for each adenoma type.

Paragangliomas are tumors of neural crest origin that arise from the extra-adrenal paraganglia. In contrast with the often quoted 10% rule of malignancy for pheochromocytomas, the rate of malignancy as defined by local invasion or distant metastasis has been reported to be from 20% to as high as 50% in some case series with the most common sites of distant metastases being the liver, lungs, and bones. Here we present the case of a patient who presented with a rare case of intracranial metastasis from abdominal paraganglioma. Our patient was a 48-year-old male with a distant history of multiple resections of abdominal paraganglioma in 1975 who presented with left shoulder, and left occipital metastasis 35 years after his original paraganglioma operations. Intracranial metastasis of paraganglioma is rare. There are unfortunately no known criteria to assess the risk of metastatic potential and given the long possible latency period between the resection of the primary tumor and the discovery of metastatic disease, patients with paragangliomas require lifelong monitoring. The optimal interval of monitoring has not been elucidated but follow-up every 5-10 years seems warranted.

ABSTRACT : Vestibular schwannoma (VS) is a skull base tumor most commonly in the CP angle. Hearing loss commonly occurs in varying degrees as a result of VS and can have a significant and lasting impact on quality of life. In this study, we compare the long term clinical outcomes of patients with VS treated with either SRS or SRT. : A retrospective analysis of 197 patients receiving SRS or SRT for VS between 1996 and 2010 at the UCLA Medical Center was performed. The inclusion criteria: 1) diagnosis of VS without other intracranial tumors, 2) SRS or SRT performed at UCLA Ronald Reagan Medical Center. Patients without clinical follow up data and those with neurofibromatosis were excluded from this analysis. : In this analysis, 32% of the patients received SRS while 68% received SRT. The average age at completion of SRS or SRT was 55 years old (range: 23-83). The median dose for SRS was 12Gy, and the average dose for SRT was 180cGy to the 90% IDL over 30 fractions. Patients had an average radiological and clinical follow-up of greater than 3 years. SRT demonstrated a trend towards a higher rate of tumor control following treatment relative to SRS, this difference though was not statistically significant (96% vs 80%, P = 0.067). Conversely, in patients with functional hearing prior to treatment, SRT was associated with significantly improved functional hearing preservation compared to SRS (97% vs 60%, respectively, P = 0.045). : Our data indicates excellent tumor control with long term follow up for both SRS and SRT. This analysis suggests that SRT may be associated with improved rates of hearing preservation when compared to SRS. Further investigation is required to further characterize the optimal use of SRS and SRT for treatment of VS.

Cystic vestibular schwannomas (VSs) are described as being more aggressive than solid tumors. We examined 468 VS patients to evaluate whether the presence of cystic components in VSs may be an important feature for predicting postoperative outcome. We selected all VS patients from a prospectively collected database (1984-2009) who underwent microsurgical resection for VS. Hearing data were analyzed using American Association of Otolaryngology-Head and Neck Surgery. Facial nerve dysfunction was analyzed using the House-Brackmann scale. We used univariate comparisons to determine the clinical impact of cystic changes on preoperative and postsurgical hearing and facial nerve preservation. We identified 58 patients (11%) with cystic changes and 410 patients with solid VSs. In this analysis, cystic VS patients tended to have larger tumors (78% of patients with >2.0 cm extrameatal extension) compared with the solid VS group, which consisted of many smaller and medium-sized tumors (P < .0001). Univariate analyses found that tumors with cystic changes did not lead to worse rates of preoperative hearing loss (χ(2), P = not significant) compared with solid VSs. Cystic changes conferred worse postoperative hearing in patients with medium-sized tumors (P = .035). Cystic changes also did not significantly affect facial nerve outcomes (χ(2), P = not significant). Cystic tumors tend to be larger than noncystic tumors and affect outcomes by reducing the rate at which hearing preservation is attempted and by worsening hearing outcome in medium-sized tumors. Further, peripheral cysts cause lower rates of hearing preservation compared with centrally located cysts.

Spontaneous intracerebral hemorrhage (ICH) is a devastating cause of morbidity and mortality. Intraparenchymal hematomas are often surgically evacuated. This generates fragments of perihematoma brain tissue that may elucidate their etiology. The goal of this study is to analyze the value of these specimens in providing a possible etiology for spontaneous ICH as well as the utility of using immunohistochemical markers to identify amyloid angiopathy. Surgically resected hematomas from 20 individuals with spontaneous ICH were examined with light microscopy. Hemorrhage locations included 11 lobar and nine basal ganglia hemorrhages. Aβ immunohistochemistry and Congo red stains were used to confirm the presence of amyloid angiopathy, when this was suspected. Evidence of cerebral amyloid angiopathy (CAA) was observed in eight of the 20 specimens, each of which came from lobar locations. Immunohistochemistry confirmed CAA in the brain fragments from these eight individuals. Patients with immunohistochemically confirmed CAA were older than patients without CAA, and more likely to have lobar hemorrhages (OR 3.0 and 3.7, respectively). Evidence of CAA was not found in any of the basal ganglia specimens. One specimen showed evidence of CAA-associated angiitis, with formation of a microaneurysm in an inflamed segment of a CAA-affected arteriole, surrounded by acute hemorrhage. In another specimen, Aβ immunohistochemistry showed the presence of senile plaques suggesting concomitant Alzheimer's disease (AD) changes. Surgically evacuated hematomas from patients with spontaneous ICH should be carefully examined, paying special attention to any fragments of included brain parenchyma. These fragments can provide evidence of the etiology of the hemorrhage. Markers such as Aβ 1-40 can help to identify underlying CAA, and should be utilized when microangiopathy is suspected. Given the association of (Aβ) CAA with AD, careful examination of entrapped brain fragments may also provide evidence of AD in a given patient.

With limited studies available, the correlation between the extent of resection and tumor recurrence in vestibular schwannomas (VSs) has not been definitively established. In this prospective study, the authors evaluated 772 patients who underwent microsurgical resection of VSs to analyze the association between total tumor resection and the tumor recurrence rate. The authors selected all cases from a prospectively collected database of patients who underwent microsurgical resection as their initial treatment for a histopathologically confirmed VS. Recurrence-free survival was analyzed using Kaplan-Meier analysis. The authors studied the impact of possible confounders such as patient age and tumor size using stepwise Cox regression to calculate the proportional hazard ratio of recurrence while controlling for other cofounding variables. The authors analyzed data obtained in 571, 89, and 112 patients in whom gross-total, near-total, and subtotal resections, respectively, were performed. A gross-total resection was achieved in 74% of the patients, and the overall recurrence rate in these patients 8.8%. There was no significant relation between the extent of resection and the rate of tumor recurrence (p = 0.58). As expected, the extent of resection was highly correlated with patient age, tumor size, and surgical approach (p < 0.0001). Using Cox regression, the authors found that the approach used did not significantly affect tumor control when the extent of resection was controlled for. While complete tumor removal is ideal, the results presented here suggest that there is no significant relationship between the extent of resection and tumor recurrence.

Although not uncommon, dislocation of the toes, including that of the great toe, is not commonly reported in published studies. In the present report, we describe a series of 18 patients with toe dislocations managed by our department from January 2001 to December 2007. We considered the radiographic pattern of injury in our series of patients. Of the 18 patients, 10 (55.56%) had their toe dislocations treated by closed reduction with or without internal fixation. Seven patients (38.89%) with complex dislocation, defined as open dislocation or dislocation not amenable to (failed attempt) closed reduction, that required open reduction and internal fixation. One patient (5.56%) with a dislocated toe declined to undergo any form of treatment.

Vestibular schwannomas are histopathologically benign tumors arising from the Schwann cell sheath surrounding the vestibular branch of cranial nerve VIII and are related to the NF2 gene and its product merlin. Merlin acts as a tumor suppressor and as a mediator of contact inhibition. Thus, deficiencies in both NF2 genes lead to vestibular schwannoma development. Recently, there have been major advances in our knowledge of the molecular biology of vestibular schwannomas as well as the development of novel therapies for its treatment. In this article the authors comprehensively review the recent advances in the molecular biology and characterization of vestibular schwannomas as well as the development of modern treatments for vestibular schwannoma. For instance, merlin is involved with a number of receptors including the CD44 receptor, EGFR, and signaling pathways, such as the Ras/raf pathway and the canonical Wnt pathway. Recently, merlin was also shown to interact in the nucleus wit...

Modern advances in cancer immunotherapy have led to the development of active immunotherapy that utilizes tumor-associated antigens to induce a specific immune response against the tumor. Current methods of immunotherapy implementation are based on the principle that tumor-associated antigens are capable of being processed by antigen-presenting cells and inducing an activated cytotoxic T-lymphocyte-specific immune response that targets the tumor cells. Antigen internalization and processing by antigen-presenting cells, such as dendritic cells, or macrophages results in their surface association with MHC class I molecules, which can be recognized by an antigen-specific cytotoxic T-lymphocyte adaptive immune response. With the aim of augmenting current immunotherapeutic modalities, much effort has been directed towards enhancing antigen-presenting cell activation and optimizing the processing of tumor-associated antigens and major histocompatibility molecules. The goal of these immunotherapy modifications is to ultimately improve the adaptive specific immune response in killing of tumor cells while sparing normal tissues. Immunotherapy has been actively studied and applied in glioblastomas. Preclinical animal models have shown the feasibility of an active immunotherapy approach through the utilization of tumor vaccines, and recently several clinical studies have also been initiated. Recently, endogenous heat-shock proteins have been implicated in the mediation of both the adaptive and innate immune responses. They are now being investigated as a potential modality and adjuvant to immunotherapy, and they represent a promising novel treatment for human glioblastomas.

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