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Isaac Yang, Won Kim, Antonio De Salles and Marvin Bergsneider

Object

Stereotactic radiosurgery (SRS) has emerged as an adjuvant radiation-based therapy for pituitary adenomas. Here, the authors present a systematic analysis of SRS for growth hormone–secreting adenomas to characterize the efficacy of SRS in the treatment of acromegaly.

Methods

A comprehensive search of the English language literature revealed 970 patients with new, recurrent, or persistent acromegaly that had been treated using SRS along with assessable and quantifiable outcome data. Articles published between June 1998 and September 2009 were included in the analysis. Patient outcome data were aggregated and investigated based on tumor size, radiosurgery dose, and clinical outcomes both with and without medication.

Results

The overall disease control rate without medication was 48%–53%, and the overall disease control rate with or without medication was 73%. The overall mean duration of the reported follow-up was 48.5 ± 25.8 months. The mean overall tumor volume in this analysis was 2.11 ± 1.16 cm3. The Pearson product-moment correlation coefficient for tumor volume and cure rate was not significant (r = 0.0668, p = 0.8546).

Conclusions

Data from this analysis suggest that tumor size may not be a significant prognostic factor in disease control after radiosurgery for acromegaly. The overall disease control rate was approximately 48% without suppressive medications after radiosurgery for acromegaly. With the advancement of increasingly sophisticated stereotactic planning and tumor targeting, the precision of radiosurgery may continue to improve in the treatment of acromegaly.

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Isaac Yang, Seunggu J. Han, Michael E. Sughrue, Tarik Tihan and Andrew T. Parsa

Object

The tumor microenvironment in astrocytomas is composed of a variety of cell types, including infiltrative inflammatory cells that are dynamic in nature, potentially reflecting tumor biology. In this paper the authors demonstrate that characterization of the intratumoral inflammatory infiltrate can distinguish high-grade glioblastoma from low-grade pilocytic astrocytoma.

Methods

Tumor specimens from ninety-one patients with either glioblastoma or pilocytic astrocytoma were analyzed at the University of California, San Francisco. A systematic neuropathology analysis was performed. All tissue was collected at the time of the initial surgery prior to adjuvant treatment. Immune cell infiltrate not associated with necrosis or hemorrhage was analyzed on serial 4-μm sections. Analysis was performed for 10 consecutive hpfs and in 3 separate regions (total 30 × 0.237 mm2). Using immunohistochemistry for markers of infiltrating cytotoxic T cells (CD8), natural killer cells (CD56), and macrophages (CD68), the inflammatory infiltrates in these tumors were graded quantitatively and classified based on microanatomical location (perivascular vs intratumoral). Control markers included CD3, CD20, and human leukocyte antigen.

Results

Glioblastomas exhibited significantly higher perivascular (CD8) T-cell infiltration than pilocytic astrocytomas (62% vs 29%, p = 0.0005). Perivascular (49%) and intratumoral (89%; p = 0.004) CD56-positive cells were more commonly associated with glioblastoma. The CD68-positive cells also were more prevalent in the perivascular and intratumoral space in glioblastoma. In the intratumoral space, all glioblastomas exhibited CD68-positive cells compared with 86% of pilocytic astrocytomas (p = 0.0014). Perivascularly, CD68-positive infiltrate was also more prevalent in glioblastoma when compared with pilocytic astrocytoma (97% vs 86%, respectively; p = 0.0003). The CD3-positive, CD20-positive, and human leukocyte antigen-positive infiltrates did not differ between glioblastoma and pilocytic astrocytoma.

Conclusions

This analysis suggests a significantly distinct immune profile in the microenvironment of high-grade glioblastoma versus low-grade pilocytic astrocytoma. This difference in tumor microenvironment may reflect an important difference in the tumor biology of glioblastoma.

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Daniel T. Nagasawa, Zachary A. Smith, Nicole Cremer, Christina Fong, Daniel C. Lu and Isaac Yang

Spinal cord ependymomas are rare neoplasms, comprising approximately 5% of all CNS tumors and 15% of all spinal cord tumors. Although surgery was once reserved for diagnosis alone, the evolution of surgical practices has elevated resection to the treatment of choice for these lesions. While technological advances continue to improve the capacity for gross-total resections and thus decrease the risk of recurrence, ependymoma spinal surgery still contains a variety of potential complications. The presence of neurological deficits and deterioration are not uncommonly associated with spinal cord ependymoma surgery, including sensory loss, dorsal column dysfunction, dysesthetic syndrome, and bowel and bladder dysfunction, particularly in the immediate postoperative period. Surgical treatment may also lead to wound complications and CSF leaks, with increased risk when radiotherapy has been involved. Radiation therapy may also predispose patients to radiation myelopathy and ultimately result in neurological damage. Additionally, resections of spinal ependymomas have been associated with postoperative spinal instability and deformities, particularly in the pediatric population. Despite the advances in microsurgical techniques and intraoperative cord monitoring modalities, there remain a number of serious complications related to the treatment of spinal ependymoma tumors. Identification and acknowledgment of these potential problems may assist in their prevention, early detection, and increased quality of life for patients afflicted with this disease.

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Cort D. Lawton, Daniel T. Nagasawa, Isaac Yang, Richard G. Fessler and Zachary A. Smith

Glioblastoma multiforme (GBM) is one of the most common and aggressive primary brain tumors, composing 12%–20% of all intracranial tumors in adults. Average life expectancy is merely 12–14 months following initial diagnosis. Patients with this neoplasm have one of the worst 5-year survival rates among all cancers despite aggressive multimodal treatment consisting of maximal tumor resection, radiation therapy, and adjuvant chemotherapy. With recent advancements in management strategies, there has been improvement in the overall trend in patient outcomes; however, recurrence remains nearly inevitable. While most tumors recur locally, metastases to distal locations have become more common. Specifically, the last decade has seen an increased incidence of spinal metastases, representing an emerging complication in patients with intracranial GBM. However, the literature regarding prevention strategies and the presentation of spinal metastases has remained scarce. As local control of primary lesions continues to improve, more cases of spinal metastases are likely to be seen. In this review the authors present a new case of metastatic GBM to the L-5 nerve root, and they summarize previous cases of intracranial GBM with leptomeningeal spinal metastatic disease. They also characterize key features of this disease presentation and discuss areas of future investigation necessary for enhanced prevention and treatment of this complication.

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Brendan Fong, Garni Barkhoudarian, Patrick Pezeshkian, Andrew T. Parsa, Quinton Gopen and Isaac Yang

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 with E3 ubiquitin ligase CRL4DCAF1. A greater understanding of the molecular mechanisms behind vestibular schwannoma tumorigenesis has begun to yield novel therapies. Some authors have shown that Avastin induces regression of progressive schwannomas by over 40% and improves hearing. An inhibitor of VEGF synthesis, PTC299, is currently in Phase II trials as a potential agent to treat vestibular schwannoma. Furthermore, in vitro studies have shown that trastuzumab (an ERBB2 inhibitor) reduces vestibular schwannoma cell proliferation. With further research it may be possible to significantly reduce morbidity and mortality rates by decreasing tumor burden, tumor volume, hearing loss, and cranial nerve deficits seen in vestibular schwannomas.

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Andrew I. Yang, Brendan J. McShane, Frederick L. Hitti, Sukhmeet K. Sandhu, H. Isaac Chen and John Y. K. Lee

OBJECTIVE

First-line treatment for trigeminal neuralgia (TN) is pharmacological management using antiepileptic drugs (AEDs), e.g., carbamazepine (CBZ) and oxcarbazepine (OCBZ). Surgical intervention has been shown to be an effective and durable treatment for TN that is refractory to medical therapy. Despite the lack of evidence for efficacy in patients with TN, the authors hypothesized that patients with neuropathic facial pain are prescribed opioids at high rates, and that neurosurgical intervention may lead to a reduction in opioid use.

METHODS

This is a retrospective study of patients with facial pain seen by a single neurosurgeon. All patients completed a survey on pain medications, medical comorbidities, prior interventions for facial pain, and a validated pain outcome tool (the Penn Facial Pain Scale). Patients subsequently undergoing neurosurgical intervention completed a survey at the 1-month follow-up in the office, in addition to telephone interviews using a standardized script between 1 and 6 years after intervention. Univariate and multivariate logistic regression were used to predict opioid use.

RESULTS

The study cohort consisted of 309 patients (70% Burchiel type 1 TN [TN1], 18% Burchiel type 2 [TN2], 6% atypical facial pain [AFP], and 6% TN secondary to multiple sclerosis [TN-MS]). At initial presentation, 20% of patients were taking opioids. Of these patients, 55% were receiving concurrent opioid therapy with CBZ/OCBZ, and 84% were receiving concurrent therapy with at least one type of AED. Facial pain diagnosis (for diagnoses other than TN1, odds ratio [OR] 2.5, p = 0.01) and facial pain intensity at its worst (for each unit increase, OR 1.4, p = 0.005) were predictors of opioid use at baseline. Neurosurgical intervention led to a reduction in opioid use to 8% at long-term follow-up (p < 0.01, Fisher’s exact test; n = 154). Diagnosis (for diagnoses other than TN1, OR 4.7, p = 0.002) and postintervention reduction in pain at its worst (for each unit reduction, OR 0.8, p < 10−3) were predictors of opioid use at long-term follow-up. On subgroup analysis, patients with TN1 demonstrated a decrease in opioid use to 5% at long-term follow-up (p < 0.05, Fisher’s exact test), whereas patients with non-TN1 facial pain did not. In the nonsurgical group, there was no statistically significant decrease in opioid use at long-term follow-up (n = 81).

CONCLUSIONS

In spite of its high potential for abuse, opioid use, mostly as an adjunct to AEDs, is prevalent in patients with facial pain. Opportunities to curb opioid use in TN1 include earlier neurosurgical intervention.

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Winward Choy, Won Kim, Daniel Nagasawa, Stephanie Stramotas, Andrew Yew, Quinton Gopen, Andrew T. Parsa and Isaac Yang

Meningiomas are mostly benign, slow-growing tumors of the CNS that originate from arachnoidal cap cells. While monosomy 22 is the most frequent genetic abnormality found in meningiomas, a multitude of other aberrant chromosomal alterations, signaling pathways, and growth factors have been implicated in its pathogenesis. Losses on 22q12.2, a region encoding the tumor suppressor gene merlin, represent the most common genetic alterations in early meningioma formation. Malignant meningioma progression, however, is associated with more complex karyotypes and greater genetic instability. Cytogenetic studies of atypical and anaplastic meningiomas revealed gains and losses on chromosomes 9, 10, 14, and 18, with amplifications on chromosome 17. However, the specific gene targets in a majority of these chromosomal abnormalities remain elusive.

Studies have also implicated a myriad of aberrant signaling pathways involved with meningioma tumorigenesis, including those involved with proliferation, angiogenesis, and autocrine loops. Understanding these disrupted pathways will aid in deciphering the relationship between various genetic changes and their downstream effects on meningioma pathogenesis.

Despite advancements in our understanding of meningioma pathogenesis, the conventional treatments, including surgery, radiotherapy, and stereotactic radiosurgery, have remained largely stagnant. Surgery and radiation therapy are curative in the majority of lesions, yet treatment remains challenging for meningiomas that are recurrent, aggressive, or refractory to conventional treatments. Future therapies will include combinations of targeted molecular agents as a result of continued progress in the understanding of genetic and biological changes associated with meningiomas.

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Isaac Yang, Thomas J. Kremen, Adrian J. Giovannone, Elena Paik, Sylvia K. Odesa, Robert M. Prins and Linda M. Liau

Object

Little is known about the quantitative modulation of major histocompatibility complex (MHC) Class I expression on human gliomas that is effected by interferons; even less is known about the immunogenic peptides that are accommodated in the peptide-binding motifs of MHC Class I alleles in these brain tumors. In this article the authors investigated the ability of interferon (IFN)α and IFNγ to upregulate MHC Class I expression and to modulate acid-eluted Class I—bound peptides on human glioblastoma multiforme (GBM) cells in vitro.

Methods

Early-passage primary human GBM cell cultures and U87MG GBM cells were incubated with varying doses of INFα or IFNγ ranging between 0 and 2000 U/ml. Upregulation of MHC Class I expression was assayed by immunocytochemical analysis, flow cytometry, and Western blot analysis. Modulation of acid-eluted MHC Class I—bound peptides from the IFN-treated GBM cells was examined with the aid of mass spectroscopy.

The in vitro expression of the MHC Class I molecule was upregulated by both IFNα and IFNγ in a dose-dependent manner. Interferon-γ exhibited a more potent effect on MHC Class I upregulation, peaking at 10 U/ml; whereas the effect of IFNα was less marked, reaching a plateau at 500 U/ml. In addition, a native peptide eluted from MHC Class I molecules of human GBM cells was identified and found to be consistently upregulated by IFN treatment.

Conclusions

Interferon-α and IFNγ can significantly upregulate the MHC Class I molecules that are expressed on the cell surface of human GBM cells as well as the potentially immunogenic peptides bound to the MHC. These results may help explain the molecular basis for increased immunogenicity with IFN treatment of human GBMs and might provide added insight into the design of future antitumor vaccines for human brain tumors.

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Carlito Lagman, Vera Ong, Lawrance K. Chung, Lekaa Elhajjmoussa, Christina Fong, Anthony C. Wang, Quinton Gopen and Isaac Yang

OBJECTIVE

The purpose of this study is to present an illustrative case of pediatric superior semicircular canal dehiscence (SSCD) and to systematically review the current published literature in the pediatric population.

METHODS

An electronic search of the Scopus, Web of Science, PsycINFO, Cochrane, and Embase databases was performed by 2 independent authors through January 2017. Search term combinations included “pediatrics,” “children,” “canal,” and “dehiscence.” Inclusion criteria were as follows: English, full-text clinical studies, case reports, and case series describing pediatric patient(s) (younger than 18 years) with CT evidence of SSCD. Baseline patient demographic characteristics, clinical presentations, dehiscence characteristics, management strategies, and outcome data were extracted.

RESULTS

A total of 14 studies involving 122 patients were included in the quantitative synthesis. The patients’ mean age was 7.22 years. Male predominance was observed (approximate male-to-female ratio of 1.65:1). Neurodevelopmental disorders were common (n = 14, 11.5%). Auditory signs and symptoms were more common than vestibular signs and symptoms. Hearing loss (n = 62, 50.8%) was the most common auditory symptom and an indicator for imaging evaluation. Vertigo was the most common vestibular symptom (n = 8, 6.6%). Hearing aids were recommended in 8 cases (6.6%), and surgical repair was performed in 1 case (0.8%). Symptom outcomes and follow-up durations were infrequently reported.

CONCLUSIONS

The authors’ data suggest that in pediatric SSCD, males are more commonly affected than females. This is different than the adult population in which females are predominantly affected. A history of otologic and/or neurodevelopmental abnormalities was common. There was a preponderance of auditory symptoms in this age group. Conservative management was favored in the majority.

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Michael E. Sughrue, Rajwant Kaur, Martin J. Rutkowski, Ari J. Kane, Gurvinder Kaur, Isaac Yang, Lawrence H. Pitts and Andrew T. Parsa

Object

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.

Methods

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.

Results

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.

Conclusions

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.