Characteristics and overall survival in pediatric versus adult skull base chordoma: a population-based study.

PURPOSE: Less than 5% of chordomas occur in pediatric patients. While many studies have explored the treatment and outcomes of skull base chordomas, few have focused on the differences between pediatric and adult populations. The aim of this study is to analyze the epidemiological variables and clinical outcomes between pediatric and adult skull base chordomas using a large-sample, population-based cancer database. METHODS: The National Cancer Database was queried between 2004 and 2015 for skull base chordomas. We stratified patients as pediatric (<18 years) and adults (≥18 years). We compared several clinical covariates between the two groups. RESULTS: Our cohort consisted of 658 patients, 61 pediatric (9.3%), and 597 adults (90.7%). Pediatric patients were more likely to have larger tumor size (41.4 ± 15.7 mm versus 34.1 ± 15.8 mm, p < 0.01) and universally treated at academic facilities. There was no significant difference in overall survival. CONCLUSIONS: Pediatric skull base chordomas are rare tumors that are managed with aggressive surgical resection, followed by radiation. While there may be difference between tumor presentation, outcomes between pediatric and adult patients are similar.

Regulation of induced pluripotent stem (iPS) cell induction by Wnt/ß-catenin signaling.

Wnt signaling has been implicated in promoting somatic cell reprogramming. However, its molecular mechanisms remain unknown. Here we report that Wnt/ß-catenin enhances iPSCs induction at the early stage of reprogramming. The augmented reprogramming induced by ß-catenin is not due to increased total cell population or activation of c-Myc. In addition, ß-catenin interacts with reprogramming factors Klf4, Oct4, and Sox2, further enhancing expression of pluripotency circuitry genes. These studies reveal novel mechanisms underlying the regulation of reprogramming somatic cells to pluripotency by Wnt/ß-catenin signaling.

Intraoperative neuromonitoring techniques in the surgical management of acoustic neuromas.

Unfavorable outcomes such as facial paralysis and deafness were once unfortunate probable complications following resection of acoustic neuromas. However, the implementation of intraoperative neuromonitoring during acoustic neuroma surgery has demonstrated placing more emphasis on quality of life and preserving neurological function. A modern review demonstrates a great degree of recent success in this regard. In facial nerve monitoring, the use of modern electromyography along with improvements in microneurosurgery has significantly improved preservation. Recent studies have evaluated the use of video monitoring as an adjunctive tool to further improve outcomes for patients undergoing surgery. Vestibulocochlear nerve monitoring has also been extensively studied, with the most popular techniques including brainstem auditory evoked potential monitoring, electrocochleography, and direct compound nerve action potential monitoring. Among them, direct recording remains the most promising and preferred monitoring method for functional acoustic preservation. However, when compared with postoperative facial nerve function, the hearing preservation is only maintained at a lower rate. Here, the authors analyze the major intraoperative neuromonitoring techniques available for acoustic neuroma resection.

Ergonomics of Endoscopic Skull Base Surgery: A Systematic Review.

OBJECTIVE: There has been a significant expansion in endonasal endoscopic skull base surgery (EES) that has been used to address a wide range of intracranial and sinonasal pathologies. Although there exists a large amount of literature on approaches and patient outcomes, there is a paucity of data describing ergonomics in this field. Our goal was to evaluate and summarize the literature on ergonomics in EES. METHODS: We systematically reviewed all published, peer-reviewed, English language literature in the PubMed and Web of Science databases as screened by multiple reviewers describing ergonomics as related to EES. RESULTS: A total of 50 articles were found that described significant conclusions and descriptions on ergonomics in EES. We found and summarized the different technical aspects of ergonomics as pertaining to EES and provided evidence-based suggestions on operating room and surgeon setup. CONCLUSIONS: There are several improvements in EES ergonomics that can decrease fatigue, improve efficiency, and overall surgeon well-being.

Characteristics and overall survival in pediatric versus adult esthesioneuroblastoma: A population-based study.

BACKGROUND: Esthesioneuroblastoma (ENB) is an uncommon sinonasal malignancy and is even less common in the pediatric population. OBJECTIVE: The purpose of this study is to compare characteristics and outcomes of ENB between adult and pediatric patients. METHODS: The National Cancer Database was queried for patients with histologically proven ENB of the nasal cavity and paranasal sinuses, and then baseline characteristics, treatment, and survival data compared between the pediatric (age < 18 years) and adult (age ≥ 18 years) populations. RESULTS: 1411 patients were identified, with 45 in the pediatric cohort and 1366 in the adult cohort. Ten-year overall survival (OS) in the pediatric cohort was improved compared to the adult cohort, 87% and 66%, respectively (p < 0.05). Adjuvant chemotherapy was more commonly utilized in the pediatric cohort (p < 0.001). Race was associated with decreased OS in the pediatric cohort (p = 0.013). Pediatric patients had shorter length of stay (p = 0.009) and lived closer to their provider (p = 0.044) than adult ENB patients. CONCLUSION: Treatment of ENB in pediatric patients more commonly includes chemotherapy and more commonly occurs at academic medical centers. OS is improved in pediatric ENB compared to adults as well, but larger studies are necessary.

The role of regulatory T-cells in glioma immunology.

Despite recent advances in treatment, the prognosis for glioblastoma multiforme (GBM) remains poor. The lack of response to treatment in GBM patients may be attributed to the immunosuppressed microenvironment that is characteristic of invasive glioma. Regulatory T-cells (Tregs) are immunosuppressive T-cells that normally prevent autoimmunity when the human immune response is evoked; however, there have been strong correlations between glioma-induced immunosuppression and Tregs. In fact, induction of Treg activity has been correlated with glioma development in both murine models and patients. While the exact mechanisms by which regulatory T-cells function require further elucidation, various cytokines such as interleukin-10 (IL-10) and transforming growth factor-ß (TFG-ß) have been implicated in these processes and are currently under investigation. In addition, hypoxia is characteristic of tumor development and is also correlated with downstream induction of Tregs. Due to the poor prognosis associated with immunosuppression in glioma patients, Tregs remain a promising area for immunotherapeutic research.

Comparison of glioma-associated antigen peptide-loaded versus autologous tumor lysate-loaded dendritic cell vaccination in malignant glioma patients.

Dendritic cell (DC) vaccination is emerging as a promising therapeutic option for malignant glioma patients. However, the optimal antigen formulation for loading these cells has yet to be established. The objective of this study was to compare the safety, feasibility, and immune responses of malignant glioma patients on 2 different DC vaccination protocols. Twenty-eight patients were treated with autologous tumor lysate (ATL)-pulsed DC vaccination, whereas 6 patients were treated with glioma-associated antigen (GAA) peptide-pulsed DCs. Safety, toxicity, feasibility, and correlative immune monitoring assay results were compared between patients on each trial. Because of HLA subtype restrictions on the GAA-DC trial, 6/15 screened patients were eligible for treatment, whereas 28/32 patients passed eligibility screening for the ATL-DC trial. Elevated frequencies of activated natural killer cells were observed in the peripheral blood from GAA-DC patients compared with the ATL-DC patients. In addition, a significant correlation was observed between decreased regulatory T lymphocyte (Treg) ratios (postvaccination/prevaccination) and overall survival (P = 0.004) in patients on both trials. In fact, Treg ratios were independently prognostic for overall survival in these patients, whereas tumor pathology was not in multivariate analyses. In conclusion, these results suggest that ATL-DC vaccination is associated with wider patient eligibility compared with GAA-DC vaccination. Decreased postvaccination/prevaccination Treg ratios and decreased frequencies of activated natural killer cells were associated with prolonged survival in patients from both trials, suggesting that these lymphocyte subsets may be relevant immune monitoring endpoints for immunotherapy protocols in malignant glioma patients.

Hearing preservation after LINAC radiosurgery and LINAC radiotherapy for vestibular schwannoma.

Linear accelerators (LINAC) can deliver both radiosurgery and fractionated radiotherapy. In this systematic analysis, we compare hearing preservation in patients with vestibular schwannomas (VS) treated with either LINAC-based radiotherapy (SRT) or LINAC-based radiosurgery (SRS), with an emphasis on the prognostic implications of tumor size and patient age. A total of 400 patients met our criteria for LINAC SRS, with an average hearing preservation rate of 66.3%. Patients with smaller tumors (<3.0 cm(3)) treated with SRS had similar hearing preservation rates to those with larger tumors. However, younger patients (<55 years) demonstrated improved hearing preservation compared to older patients (≥55 years). When comparing LINAC SRS to LINAC SRT directly, hearing preservation was similar in patients with smaller tumors. However, patients with larger tumors (≥3.0cm(3)) who received SRT had higher hearing preservation rates than those who received SRS. A total of 629 patients met our criteria for LINAC SRT, with an average hearing preservation rate of 75.3%. Patients with larger tumors who received SRT had better hearing outcomes than those with smaller tumors, while there was no significant difference in hearing preservation in younger patients compared to older patients. When comparing LINAC SRS to LINAC SRT directly, younger patients had similar hearing preservation rates. However, older patients who received SRT had improved hearing preservation compared to those who received SRS. In a direct comparison of average hearing preservation, patients who received SRT had higher hearing preservation rates than those who underwent SRS. Prospective studies will be needed to further characterize radiation dose and other variables.

Monitoring of regulatory T cell frequencies and expression of CTLA-4 on T cells, before and after DC vaccination, can predict survival in GBM patients.

PURPOSE: Dendritic cell (DC) vaccines have recently emerged as an innovative therapeutic option for glioblastoma patients. To identify novel surrogates of anti-tumor immune responsiveness, we studied the dynamic expression of activation and inhibitory markers on peripheral blood lymphocyte (PBL) subsets in glioblastoma patients treated with DC vaccination at UCLA. EXPERIMENTAL DESIGN: Pre-treatment and post-treatment PBL from 24 patients enrolled in two Phase I clinical trials of dendritic cell immunotherapy were stained and analyzed using flow cytometry. A univariate Cox proportional hazards model was utilized to investigate the association between continuous immune monitoring variables and survival. Finally, the immune monitoring variables were dichotomized and a recursive partitioning survival tree was built to obtain cut-off values predictive of survival. RESULTS: The change in regulatory T cell (CD3(+)CD4(+)CD25(+)CD127(low)) frequency in PBL was significantly associated with survival (p = 0.0228; hazard ratio = 3.623) after DC vaccination. Furthermore, the dynamic expression of the negative co-stimulatory molecule, CTLA-4, was also significantly associated with survival on CD3(+)CD4(+) T cells (p = 0.0191; hazard ratio = 2.840) and CD3(+)CD8(+) T cells (p = 0.0273; hazard ratio = 2.690), while that of activation markers (CD25, CD69) was not. Finally, a recursive partitioning tree algorithm was utilized to dichotomize the post/pre fold change immune monitoring variables. The resultant cut-off values from these immune monitoring variables could effectively segregate these patients into groups with significantly different overall survival curves. CONCLUSIONS: Our results suggest that monitoring the change in regulatory T cell frequencies and dynamic expression of the negative co-stimulatory molecules on peripheral blood T cells, before and after DC vaccination, may predict survival. The cut-off point generated from these data can be utilized in future prospective immunotherapy trials to further evaluate its predictive validity.

The molecular biology and novel treatments of vestibular schwannomas.

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 CRL4(DCAF1). 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.

Post-transplantation primary central nervous system lymphoma: A case report and review of the literature.

BACKGROUND: Post-transplantation primary central nervous system lymphoma (PT-PCNSL) is a rare neoplasm that can develop within months to years after transplantation, and imaging often reveals multiple lesions with homogeneous or ring enhancement. The clinical and imaging presentation of PT-PCNSL can often be nonspecific and present a diagnostic challenge. CASE DESCRIPTION: A 56-year-old woman presented to a tertiary university emergency room with altered mental status 15 months after undergoing renal transplantation. On brain MRI, she was found to have three rim-enhancing mass lesions, and biopsy revealed PT-PCNSL. CONCLUSION: There has been a steady increase in the number of patients living following organ transplantation in the United States and an increasing likelihood that PT-PCNSL will increasingly be encountered in neurosurgical practice. We present here a case of PT-PCNSL and a brief review of the relevant clinical characteristics, treatment options, and prognosis of PT-PCNSL.

Clinical characteristics and diagnostic imaging of epidermoid tumors.

Epidermoid tumors are rare, benign congenital lesions which typically present between the third and fifth decades of life. They are thought to originate from ectodermal cells misplaced during neural tube formation and separation. While epidermoids may present anywhere in the cranial vault, they are characteristically located intradurally and in a paramedian position within the cerebellopontine angle and parasellar regions. Although imaging results may vary depending upon cystic content, CT scanning generally reveals a well-circumscribed, nonenhancing, lobulated, hypodense mass. They are hypointense on T1-weighted MRI, and hyperintense on T2-weighted MRI, diffusion-weighted imaging and fluid-attenuated inversion recovery sequences. The use of appropriate neuroimaging should be utilized to differentiate epidermoids from other intracranial lesions. While gross total resection of these tumors is the definitive treatment to prevent recurrence and aseptic meningitis, a subtotal resection may be necessary to preserve neurological function.

The tumor biology and molecular characteristics of medulloblastoma identifying prognostic factors associated with survival outcomes and prognosis.

Medulloblastomas (MB) are highly aggressive primitive neuroectodermal tumors (PNET) usually located in the posterior fossa. Current treatment for MBs, which includes a combination of surgery, chemotherapy and radiation, remain challenging especially in younger patients. However, advances in the understanding of regulatory pathways in cerebellar development have elucidated possible areas of dysfunction involved in tumorigenesis. Multiple studies have demonstrated the importance of the sonic hedgehog, Wnt, and Notch pathways in MB pathogenesis at the molecular level. While staging and prognosis are often based on the Chang classification system, future algorithms will involve identifying molecular markers in order to allow for more specific risk stratifications of various MB subtypes and provide improved correlation with staging and prognosis. Future development of novel therapies that target the heterogeneity of MB and are tailored to the tumor's unique molecular profile may yield improved outcomes for these patients.