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Background: Esthesioneuroblastoma (EN) of the paranasal sinus comprises less than 3% of tumors of in pediatric and adolescent patients [1]. The collective adult literature indicates a critical role for radiotherapy in attaining cure [2], yet pediatric outcome data is limited. Radiation in pediatric patients with EN can cause significant morbidity due to the proximity of critical structures. Proton radiotherapy offers a potential dosimetric benefit that may improve long-term survival and toxicity outcomes in the pediatric population [3]., Methods: We retrospectively identified eight patients treated for EN with proton radiotherapy from 2000-2013. Times to event clinical endpoints are summarized using the Kaplan-Meier methods and are from the date of radiotherapy completion. Toxicities are reviewed and graded according to CTCAE v. 4.0., Results: Median follow up was 4.6 years for survivors (range 0.8-9.4 years). The 4 year overall survival was 87.5%. Four of eight patients (one elective) had comprehensive neck radiotherapy. No local or regional failures were observed. Two patients failed distantly with diffuse leptomeningeal disease and intraparenchymal brain metastases, at 0.6 and 1.3 months respectively. Four patients developed radiation related late toxicities including endocrine dysfunction, two cases of grade 2 retinopathy and one case of grade 3 optic neuropathy., Conclusions: In a limited cohort, proton radiotherapy appears to provide excellent locoregional disease control even in those patients with locally advanced disease and intracranial extension. Distant failure determined overall survival in our cohort. Toxicities were acceptable given disease location and extent., (© 2015 Wiley Periodicals, Inc.)

Purpose: To estimate the hazard for neurologic (central nervous system, CNS) and nonneurologic (non-CNS) death associated with patient, treatment, and systemic disease status in patients receiving stereotactic radiosurgery after whole-brain radiation therapy (WBRT) failure, using a competing risk model., Patients and Methods: Of 757 patients, 293 experienced recurrence or new metastasis following WBRT. Univariate Cox proportional hazards regression identified covariates for consideration in the multivariate model. Competing risks multivariable regression was performed to estimate the adjusted hazard ratio (aHR) and 95% confidence interval (CI) for both CNS and non-CNS death after adjusting for patient, disease, and treatment factors. The resultant model was converted into an online calculator for ease of clinical use., Results: The cumulative incidence of CNS and non-CNS death at 6 and 12 months was 20.6% and 21.6%, and 34.4% and 35%, respectively. Patients with melanoma histology (relative to breast) (aHR 2.7, 95% CI 1.5-5.0), brainstem location (aHR 2.1, 95% CI 1.3-3.5), and number of metastases (aHR 1.09, 95% CI 1.04-1.2) had increased aHR for CNS death. Progressive systemic disease (aHR 0.55, 95% CI 0.4-0.8) and increasing lowest margin dose (aHR 0.97, 95% CI 0.9-0.99) were protective against CNS death. Patients with lung histology (aHR 1.3, 95% CI 1.1-1.9) and progressive systemic disease (aHR 2.14, 95% CI 1.5-3.0) had increased aHR for non-CNS death., Conclusion: Our nomogram provides individual estimates of neurologic death after salvage stereotactic radiosurgery for patients who have failed prior WBRT, based on histology, neuroanatomical location, age, lowest margin dose, and number of metastases after adjusting for their competing risk of death from other causes., (Published by Elsevier Inc.)

Gangliogliomas are rare tumors of the central nervous system that are thought to arise from a glioneuronal precursor and consist of both neuronal and glial elements. Grade III, or anaplastic ganglioglioma (AGG), most commonly affects children and young adults, generally arises in a supratentorial location, is highly epileptogenic, and often results in diffuse local and distant failure within the craniospinal axis. Pathologically, these tumors are graded by the degree of malignancy in their glial portion and radiologic diagnosis is difficult due to the wide variation in its degree of solid and cystic components, contrast uptake, and calcification patterns. This report presents three cases of AGG, with initial treatment including subtotal resection followed by conformal radiotherapy. In the case where the AGG developed in the setting of an existent low-grade astrocytoma, the patient received no chemotherapy. Both of the other de novo cases were managed with adjuvant chemoradiotherapy with temozolomide. Recurrence occurred at 6, 16, and 20 months following therapy. Two of the three patients experienced symptomatic decline at recurrence, but experienced Karnofsky performance status (KPS) improvement after salvage therapy, including the reduction of cranial neuropathy and balance. All patients had a significant reduction in presenting symptoms following salvage therapy. Patients died at 23, 20, and 22 months following initial surgical management, respectively. A review of anaplastic and malignant gangliogliomas is presented in the context of these three cases.

Prolonged survival in brain metastasis patients increases recurrence rates and places added importance on salvage therapies. Research examining carmustine polymer wafers as an adjuvant therapy for brain metastasis is limited. We present a single institution retrospective series documenting the use of BCNU wafers placed in the cavity of resected recurrent brain metastases that had failed prior stereotactic radiosurgery (SRS). Between February 2002 and April 2013, a total of 31 patients with brain metastases failed SRS and underwent resection with intracavitary placement of carmustine wafers. Clinical outcomes including local control, survival, cause of death, and toxicity were determined from electronic medical records. Kaplan-Meier analysis was performed to assess local control and survival. Imaging features were reviewed and described for patients with serial post-operative follow-up imaging examinations over time. Overall survival at 6 months and 12 months was 63% and 36%, respectively. Fourteen of 31 patients (45%) died from neurologic causes. Local control within the resection cavity was 87% and 70% at 6 and 12 months, respectively. Five patients (16%) underwent further salvage therapy following carmustine wafer placement after local failure. Resection cavities of all six patients with follow-up imaging showed linear peripheral enhancement. Pericavity and wafer enhancement was present as early as the same day as surgery and persisted in all cases to 6 months or longer. Carmustine polymer wafers are an effective salvage treatment following resection of a brain metastasis that has failed prior SRS. For patients with successful local control after wafer implantation, linear enhancement at the cavity is common., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Object: Neurofibromatosis Type 2 (NF2) is a rare autosomal dominant disorder predisposing patients to meningiomatosis. The role of stereotactic radiosurgery (SRS) is poorly defined in NF2, and although the procedure has excellent control rates in the non-NF2 population, its utility has been questioned because radiation has been hypothesized to predispose patients to malignant transformation of benign tumors. To the authors' knowledge, this is the first study to examine the use of SRS specifically for meningiomas in patients with NF2., Methods: The authors searched a tumor registry for all patients with NF2 who had undergone Gamma Knife radiosurgery (GKRS) for meningioma in the period from January 1, 1999, to September 19, 2013, at a single tertiary care cancer center. Medical records were retrospectively reviewed for patient and tumor characteristics and outcomes., Results: Among the 12 patients who met the search criteria, 125 meningiomas were identified, 87 (70%) of which were symptomatic or progressive and thus treated with GKRS. The median age at the first GKRS was 31 years (interquartile range [IQR] 27-37 years). Five patients (42%) had multiple treatments with a median of 27 months (IQR 14-50 months) until the subsequent GKRS. The median follow-up in surviving patients was 43 months (IQR 34-110 months). The 5-year local tumor control and distant treatment failure rates were 92% and 77%, respectively. Toxicities occurred in 25% of the GKRS treatments, although the majority were Grade 1 or 2. At the last follow-up, 4 patients (33%) had died a neurological death at a median age of 39 years (IQR 37-46 years), and their cases accounted for 45% of all tumors, 55% of all treated tumors, and 58% of all GKRSs. Univariate analysis revealed several predictive variables for distant failure, including male sex (HR 0.28, 95% CI 0.086-0.92, p = 0.036), age at distant failure (HR 0.92, 95% CI 0.90-0.95, p < 0.0001), and prior number of GKRS treatments (HR 1.2, 95% CI 1.1-1.4, p = 0.0049). Local failure, maximum size of the treated tumor, delivered tumor margin dose, and WHO grade were not significant. On multivariate analysis, age at distant failure (HR 0.91, 95% CI 0.88-0.95, p < 0.0001) and prior number of GKRSs (HR 1.3, 95% CI 1.1-1.5, p = 0.004) remained significant. No malignant transformation events among treated tumors were observed., Conclusions: Radiosurgery represents a feasible modality with minimal toxicity for NF2-associated meningiomas. Increasing patient age was associated with a decreased rate of distant failure, whereas an increasing number of prior GKRS treatments predicted distant failure. Further studies are necessary to determine the long-term patterns of treatment failure in these patients.

Background: Stereotactic radiosurgery for the treatment of brain metastases is commonly delivered without regard to primary cancer histology. This study sought to determine if the primary site of origin for brain metastases affected the propensity for local failure., Methods: A total of 83 patients with 200 brain metastases were examined retrospectively for predictors of infield failure. Tumor, patient, and treatment characteristics were analyzed including primary tumor histology, radiosurgical dose and age. Cox proportional hazards models, univariate and multivariate analyses were used to identify predictors of local failure., Results: Freedom from local failure for the entire population was 83% and 65% at 6 and 12 months, respectively. Multivariate analysis revealed that breast cancer brain metastases have a significantly lower risk of local failure than melanoma (HR = 0.31, p< 0.001). Additionally, multivariate analysis revealed that increasing dose lowered risk for local failure (HR = 0.87, p<0.001)., Conclusions: Melanoma histology leads to a higher rate of local failure. Higher prescription dose results in higher incidence of local control.

Objective: This study sought to assess clinical outcomes in patients receiving gamma knife radiosurgery (GK) for treatment of brain metastases from melanoma and evaluate for potential predictive factors., Methods: We reviewed 188 GK procedures in 129 consecutive patients that were treated for brain metastases from melanoma. The population consisted of 84 males and 45 females with a median age of 57 years. Fifty-five patients (43%) had a single metastasis. Seventy-one patients (55%) received chemotherapy, 58 patients (45%) received biologic agents, and 36 patients (28%) received prior whole brain radiation therapy (WBRT). The median marginal dose was 18.8 Gy (range 12 to 24 Gy)., Results: Actuarial survival was 52%, 26%, and 13% at 6, 12, and 24 months, respectively. The median survival time was 6.7 months. Local tumor control was 95%, 81% 53% at 6, 12, and 24 months, respectively. The median time to LBF was 25.2 months. Freedom from distant brain failure was 40%, 29%, and 10% at 6, 12, and 24 months, and the median time to DBF was 4.6 months. At the time of data analysis, 108 patients (84%) had died. Fifty-eight patients (52%) died from neurologic death. The median time to neurologic death from GK treatment was 7.9 months. Multivariate analysis revealed that hemorrhage of metastases prior to GK (P = .02) and LBF (P = .03) were the dominant predictors of neurologic death., Conclusions: GK achieves excellent local control and may improve outcomes as a component of a multidisciplinary treatment strategy. Distant brain failure and neurologic demise remain problematic and prospective trials are necessary., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Our objective was to explore the hypothesis that the risk of leptomeningeal dissemination (LMD) in patients who underwent stereotactic radiosurgery (SRS) for brain metastases is influenced by the site of the primary cancer, the addition of whole brain radiation therapy (WBRT), surgical resection, and control over their systemic disease. We conducted a retrospective cohort analysis of 805 patients who were treated with SRS for brain metastases between 1999 and 2012 at the Wake Forest Baptist Medical Center, and excluded all patients with evidence of LMD before SRS. The primary outcome was LMD. Forty-nine of 795 patients developed LMD with a cumulative incidence of 6.2% (95% Confidence Interval (CI), 4.7-8.0). Median time from SRS to LMD was 7.4 months (Interquartile Range (IQR), 3.3-15.4). A colorectal primary site (Hazard Ratio (HR), 4.5; 95% CI 2.5-8.0; p < 0.0001), distant brain failure (HR, 2.0; 95% CI 1.2-3.2; p = 0.007), breast primary site (HR, 1.6; 95% CI 1.0-2.7; p = 0.05), the number of intracranial metastases at time of initial SRS (HR, 1.1; 95% CI 1.0-1.2; p = 0.02), and age (by 5-year interval) (HR, 0.9; 95% CI 0.8, 0.9; p = 0.0006) were independent factors associated with LMD. There was no evidence that surgical resection before SRS altered the risk of LMD (HR, 1.1; 95 % CI 0.6-2.0, p = 0.78). In patients who underwent SRS for brain metastases, a colorectal or breast primary site, distant brain failure, younger age, and an increased number of intracranial metastases were independently associated with LMD. Given its relative rarity as an outcome, multi-institutional prospective studies will likely be necessary to validate and quantify these relationships.

Objectives: The standard concurrent radiotherapy and chemotherapy regimens for patients with oropharyngeal cancer are highly toxic. Human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) has recently emerged as a distinct biological and clinical entity with improved response to treatment and prognosis. A tailored therapeutic approach is needed to optimize patient care. The aim of our study was to investigate the impact of HPV and smoking status on early toxicities (primarily mucositis) associated with concurrent chemotherapy and radiotherapy in patients with OPSCC., Materials and Methods: We retrospectively evaluated 72 consecutive patients with OPSCC and known HPV status treated with concurrent radiotherapy and chemotherapy at our institution. Treatment-related toxicities were stratified by smoking and HPV status and compared using univariate and multivariate logistic regression., Results: HPV-positive patients had a 6.86-fold increase in the risk of having severe, grade 3-4 mucositis. This effect was preserved after adjusting for patient smoking status, nodal stage, radiotherapy technique and radiotherapy maximum dose. Additionally, HPV status had significant effect on the objective weight loss during treatment and at three months after treatment. Consistently, non-smokers had a significant 2.70-fold increase in the risk of developing severe mucositis., Conclusion: Risk factors for OPSCC modify the incidence of treatment-related early toxicities, with HPV-positive and non-smoking status correlating with increased risk of high grade mucositis and associated outcomes. Retrospective single-institution studies need to be interpreted cautiously. However, this finding is important to consider when designing therapeutic strategies for HPV-positive patients and merits further investigation in prospective clinical trials., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Purpose: Stereotactic body radiation therapy (SBRT) and accelerated hypofractionated radiation therapy (AHRT) have favorable local control (LC) relative to conventional fractionation in the treatment of stage I non-small cell lung cancer (NSCLC). We report the results of our single institution experience with the treatment of early stage NSCLC with SBRT or AHRT in cases where SBRT was felt to be suboptimal., Methods: One hundred and sixty patients with Stage 1 and node negative Stage 2 NSCLC were treated with SBRT or AHRT from 2003 to 2011. Median follow-up was 29.4 and 19 months (mo), respectively. The median dose was 54Gy in 3 fractions (fx) (SBRT) and 70.2Gy in 26 fx (AHRT). Acute and late toxicities (tox) were graded (G) per CTCAE v4. Time to local (LF), regional (RF) and distant (DF) failure were estimated using the Kaplan-Meier method. The impact of patient and tumor related factors on LF were estimated by multivariate Cox proportional hazard model., Results: Three-year LC rates were 87.7% (SBRT) and 71.7% (AHRT). The 3-year freedom from DF was 73.3% and 68.1%. Median OS was 38.4 (95% CI 29.7-51.6) and 35 (95% CI 22-48.3) mo. No G3 or 4 tox were observed. At 1 year, 30% and 50% of complications resolved, while (5-6%) had persistent chest wall pain. Multivariate analysis demonstrated that increasing dose per fraction and tumor size (>5.5 vs. 4cm) in the AHRT and SBRT group were found to be associated with a reduced (HR 0.33 95% CI 0.13-0.84, p=0.021) and increased (HR: 6.372 95% CI 1.23-32.92, p=0.027) hazard for local failure respectively., Conclusions: Our results compare favorably with other reports of treatment for early stage NSCLC. AHRT patients had comparable LC despite increased size and central disease. Toxicity was limited and overall survival, regional and distant recurrences were similar between groups., (Published by Elsevier Ireland Ltd.)

Purpose: To determine factors associated with the durability of stereotactic radiation surgery (SRS) for treatment of trigeminal neuralgia (TN)., Methods and Materials: Between 1999 and 2008, 446 of 777 patients with TN underwent SRS and had evaluable follow-up in our electronic medical records and phone interview records. The median follow-up was 21.2 months. The Barrow Neurologic Institute (BNI) pain scale was used to determine pre- and post-SRS pain. Dose-volume anatomical measurements, Burchiel pain subtype, pain quality, prior procedures, and medication usage were included in this retrospective cohort to identify factors impacting the time to BNI 4-5 pain relapse by using Cox proportional hazard regression. An internet-based nomogram was constructed based on predictive factors of durable relief pre- and posttreatment at 6-month intervals., Results: Rates of freedom from BNI 4-5 failure at 1, 3, and 5 years were 84.5%, 70.4%, and 46.9%, respectively. Pain relief was BNI 1-3 at 1, 3, and 5 years in 86.1%, 74.3%, and 51.3% of type 1 patients; 79.3%, 46.2%, and 29.3% of type 2 patients; and 62.7%, 50.2%, and 25% of atypical facial pain patients. BNI type 1 pain score was achieved at 1, 3, and 5 years in 62.9%, 43.5%, and 22.0% of patients with type 1 pain and in 47.5%, 25.2%, and 9.2% of type 2 patients, respectively. Only 13% of patients with atypical facial pain achieved BNI 1 response; 42% of patients developed post-Gamma Knife radiation surgery (GKRS) trigeminal dysfunction. Multivariate analysis revealed that post-SRS numbness (hazard ratio [HR], 0.47; P<.0001), type 1 (vs type 2) TN (HR, 0.6; P=.02), and improved post-SRS BNI score at 6 months (HR, 0.009; P<.0001) were predictive of a durable pain response., Conclusions: The durability of SRS for TN depends on the presenting Burchiel pain type, the post-SRS BNI score, and the presence of post-SRS facial numbness. The durability of pain relief can be estimated pre- and posttreatment by using our nomogram for situations when the potential of relapse may guide the decision for initial intervention., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Purpose/objective(s): Regional failures occur in up to 15% of patients treated with stereotactic body radiotherapy (SBRT) for stage I/II lung cancer. This report focuses on the management of the unique scenario of isolated regional failures., Methods: Patients treated initially with SBRT or accelerated hypofractionated radiotherapy were screened for curative intent treatment of isolated mediastinal failures (IMFs). Local control, regional control, progression-free survival, and distant control were estimated from the date of salvage treatment using the Kaplan-Meier method., Results: Among 160 patients treated from 2002 to 2012, 12 suffered IMF and were amenable to salvage treatment. The median interval between treatments was 16 months (2-57 mo). Median salvage dose was 66 Gy (60-70 Gy). With a median follow-up of 10 months, the median overall survival was 15 months (95% confidence interval, 5.8-37 mo). When estimated from original treatment, the median overall survival was 38 months (95% confidence interval, 17-71 mo). No subsequent regional failures occurred. Distant failure was the predominant mode of relapse following salvage for IMF with a 2-year distant control rate of 38%. At the time of this analysis, three patients have died without recurrence while four are alive and no evidence of disease. High-grade toxicity was uncommon., Conclusions: To our knowledge, this is first analysis of salvage mediastinal radiation after SBRT or accelerated hypofractionated radiotherapy in lung cancer. Outcomes appear similar to stage III disease at presentation. Distant failures were common, suggesting a role for concurrent or sequential chemotherapy. A standard full course of external beam radiotherapy is advisable in this unique clinical scenario.

Background: Insurers have started to deny reimbursement for routine brain surveillance with magnetic resonance imaging (MRI) after stereotactic radiosurgery (SRS) for brain metastases in favor of symptom-prompted imaging. The authors investigated the clinical and economic impact of symptomatic versus asymptomatic metastases and related these findings to the use of routine brain surveillance., Methods: Between January 2000 and December 2010, 442 patients underwent upfront SRS for brain metastases. In total, 127 asymptomatic patients and 315 symptomatic patients were included. Medical records were used to determine the presenting symptoms, distant and local brain failure, retreatment, and need for hospital and rehabilitative care. Cost-of-care estimates were based on Medicare payment rates as of January 2013., Results: Symptomatic patients had an increased hazard for all-cause mortality (hazard ratio, 1.448) and were more likely to experience neurologic death (42% vs 20%; P < .0001). Relative to asymptomatic patients, symptomatic patients required more craniotomies (43% vs 5%; P < .0001), had more prolonged hospitalization (2 vs 0 days; P < .0001), were more likely to have Radiation Therapy Oncology Group grade 3 and 4 post-treatment symptoms (24% vs 5%; P < .0001), and required $11,957 more on average to manage per patient. Accounting for all-cause mortality rates and the probability of diagnosis at each follow-up period, the authors estimated that insurers would save an average $1326 per patient by covering routine surveillance MRI after SRS to detect asymptomatic metastases., Conclusions: Patients who presented with symptomatic brain metastases had worse clinical outcomes and cost more to manage than asymptomatic patients. The current findings argue that routine brain surveillance after radiosurgery has clinical benefits and reduces the cost of care., (© 2013 American Cancer Society.)

Background: Cavernous sinus metastases represent difficult clinical scenarios because of the lack of surgical options. We investigate the use of Gamma Knife stereotactic radiosurgery (GKRS) as a treatment option of these metastases., Objectives: To determine the patterns of failure for cavernous sinus metastases and to identify factors that predict for improved outcomes., Methods: This is a retrospective review of 19 patients treated with GKRS for cavernous sinus metastases over a 9-year period between May 2002 and October 2011. The median marginal tumor dose was 18 Gy. Patients were followed with serial imaging. Kaplan Meier analysis was used to estimate local control and overall survival. Fischer exact test was used to determine any predictive factors for local control or survival., Results: Median follow-up time was 22.4 months. Kaplan Meier estimate of overall survival at 1, 2, and 4 years was 76%, 44%, and 44% survival, respectively. 11 patients experienced intracranial failure. Of these, 7 (64%) were local and 4 (36%) were distant intracranial failures. Local control was 76%, 44%, and 44% at 1, 2 and 4 years, respectively. Six of seven local failures in the series were considered to be marginal failures because they were abutting the 50% isodose volume. Head and neck primary tumors were associated with 86% of local failures (P = 0.017) and was the only factor that predicted for local failure., Conclusions: GKRS appears to be a feasible and safe modality for treatment of cavernous sinus metastases. Local failures appear to be due to a marginal miss of microscopically occult disease.

Hemophagocytic lymphohistiocytosis (HLH) is a rare systemic inflammatory syndrome that results from unrestrained immune cell activation. Despite significant advances in the understanding of the pathophysiology of HLH, interventions remain limited for this often-fatal condition. Secretory sphingomyelinase (S-SMase) is a pro-inflammatory lipid hydrolase that is upregulated in several inflammatory conditions, including HLH. S-SMase promotes the formation of ceramide, a bioactive lipid implicated in several human disease states. However, the role of the S-SMase/ceramide pathway in HLH remains unexplored. To further evaluate the role of S-SMase upregulation in HLH, we tested the serum of patients with HLH (n = 16; primary = 3, secondary = 13) and healthy control patients (n = 25) for serum S-SMase activity with tandem sphingolipid metabolomic profiling. Patients with HLH exhibited elevated levels of serum S-SMase activity, with concomitant elevations in several ceramide species and sphingosine, while levels of sphingosine-1-phosphate were significantly decreased. Importantly, the ratio of C16 -ceramide:sphingosine was uniquely elevated in HLH patients that died despite appropriate treatment, but remained low in HLH patients that survived, suggesting that this ratio may be of prognostic significance. Together, these results demonstrate upregulation of the S-SMase/ceramide pathway in HLH, and suggest that the balance of ceramide and sphingosine determine clinical outcomes in HLH. ., (Copyright © 2013 Wiley Periodicals, Inc.)

We previously reported a vascular endothelial growth factor (VEGF) autocrine loop in head and neck squamous cell carcinoma (HNSCC) cell lines, supporting a role for VEGF in HNSCC tumorigenesis. Using a phosphotyrosine proteomics approach, we screened the HNSCC cell line, squamous cell carcinoma-9 for effectors of VEGFR2 signaling. A cluster of proteins involved in cell migration and invasion, including the p130Cas paralog, human enhancer of filamentation 1 (HEF1/Cas-L/Nedd9) was identified. HEF1 silencing and overexpression studies revealed a role for VEGF in regulating cell migration, invasion and matrix metalloproteinase (MMP) expression in a HEF1-dependent manner. Moreover, cells plated on extracellular matrix-coated coverslips showed enhanced invadopodia formation in response to VEGF that was HEF1-dependent. Immunolocalization revealed that HEF1 colocalized to invadopodia with MT1-MMP. Analysis of HNSCC tissue microarrays for HEF1 immunoreactivity revealed a 6.5-fold increase in the odds of having a metastasis with a high HEF1 score compared with a low HEF1 score. These findings suggest that HEF1 may be prognostic for advanced stage HNSCC. They also show for the first time that HEF1 is required for VEGF-mediated HNSCC cell migration and invasion, consistent with HEF1's recent identification as a metastatic regulator. These results support a strategy targeting VEGF:VEGFR2 in HNSCC therapeutics.

Although significant advances have been made in treating malignant pediatric central nervous system tumors such as medulloblastoma, no effective therapy exists for diffuse pontine glioma or intramedullary spinal astrocytoma. Biology of these 2 tumors is poorly understood, in part because diffuse pontine gliomas are not treated surgically, and tumor specimens from intramedullary spinal astrocytomas are rare and minuscule. At the 2007 Neurobiology of Disease in Children Symposium, we presented evidence that malignant glioma behaviors, including antiapoptosis, invasiveness, and treatment resistance, are enhanced by hyaluronan, an extracellular glycosaminoglycan. We review the clinical course of pediatric intramedullary spinal astrocytoma and diffuse pontine glioma, and show expression of membrane proteins that interact with hyaluronan: CD44, extracellular matrix metalloproteinase inducer, and breast cancer resistance protein (BCRP/ABCG2). Furthermore, we describe novel animal models of these tumors for preclinical studies. These findings suggest that hyaluronan antagonism has potential therapeutic value in malignant central nervous system tumors.