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BACKGROUND: The extent of surgical management of regional lymph nodes in the treatment of cutaneous head and neck melanoma on and anterior to O'Brien's watershed line is controversial. By comparing patients' cohorts of two separate melanoma expert centers we investigate the effectiveness of comprehensive versus (super-) selective neck dissection approach.METHODS: Sixty patients with macroscopic (palpable) neck node metastases (N2b) from anterior scalp and face melanoma were retrospectively studied. Forty therapeutic modified radical neck dissections (MRND; levels I-V) combined with elective parotidectomy from The Netherlands Cancer Institute (NCI) were compared with 16 (super-) selective neck dissections [(S)SND; 3-4 levels] and 4 solely MRNDs from Erasmus Medical Center (EMC). Cohorts were analyzed for site of recurrence, overall survival (OS), melanoma-specific survival (MSS), and disease-free survival (DFS).RESULTS: Clinical characteristics of patients were equal in both groups. In the NCI cohort 62.5% (n = 25) of patients recurred versus 65% (n = 13) in the EMC cohort. None of the NCI recurrences affected the parotid gland in contrast to 3 patients in the EMC group. Survival characteristics were not different between the two groups: OS (p = 0.56), MSS (p = 0.98), DFS (p = 0.92).CONCLUSION: This study does not support to continue the practice of routine elective parotidectomy and MRND in melanoma patients undergoing a lymph node dissection for macroscopic (palpable) nodal disease and justifies (S)SND.

Background: Sentinel lymph node (SN) biopsy (SLNB) has proven to be a valuable tool for staging melanoma patients. Since its introduction in the early 1990s, this procedure has undergone several technological refinements, including the introduction of single photon emission computed tomography combined with computed tomography (SPECT/CT) as well as radio- and fluorescence-guidance. The purpose of the current study was to evaluate the effect of this technological evolution on SLNB in the head and neck region. Primary endpoint was the false-negative (FN) rate. Secondary endpoints were number of harvested SNs, overall operation time, operation time per harvested SN and postoperative complications. Patients and Methods: A retrospective database was queried for cutaneous head and neck melanoma patients who underwent SLNB at The Netherlands Cancer Institute between 1993 and 2016. The implementation of new detection techniques was divided in 4 groups: (1) 1993-2005, with preoperative lymphoscintigraphy and intraoperative use of both a gamma ray detection probe and patent blue (n = 30); (2) 2006-2007, with addition of preoperative roadmaps based on SPECT/CT (n = 15); (3) 2008-2009, with intraoperative use of a portable gamma camera (n = 40); and (4) 2010-2016, with the addition of near-infrared fluorescence guidance (n = 192). Results: A total of 277 patients were included. At least one SN was identified in all patients. A tumor-positive SN was found in 59 patients (21.3%), 10 in group 1 (33.3%), 3 in group 2 (20.0%), 6 in group 3 (15.0%) and 40 in group 4 (20.8%). Regional recurrences of patients with tumor-negative SNs resulted in an overall FN rate of 11.9% (FN groups 1: 16.7%; 2: 0%; 3: 14.3%; 4: 11.1%). The number of harvested nodes increased with advancing technologies (P = 0.003) whereas Breslow thickness and operation time per harvested SN decreased (P = 0.003 and P = 0.017, respectively). There was no significant difference in percentage of tumor-positive SNs, overall operation time and complication rate between the different groups. Conclusion: The use of advanced detection technologies led to a higher number of identified SNs without increase in overall operation time, which may indicate an improved surgical efficiency. Operation time per harvested SN decreased, the average FN rate remained 11.9% and unchanged over 23 years. There was no significant change in postoperative complication rate.

Background: Surgical resection is the standard of care for parotid gland tumors. Comprehensive reports on the surgical complications of parotidectomy are lacking. This study focuses on surgical wound complications of parotid gland surgery.Patients and methods: In the period 2002-2012, 390 consecutive patients (395 procedures) who underwent parotid gland surgery were selected for retrospective analysis. Based on subsequent management, the impact of surgical site complications was graded by the Clavien-Dindo Classification (CDC).Results: In 83 (21.0%) of the procedures, at least one complication was registered. In total, 118 complications were described. Rated to CDC, 61 patients (15.4%) were graded as class 2 or higher. This implies therapy was dictated. Fortyfive (11.4%) of the complications were surgical site infections (551). In 9 patients (2.3%) surgical complications required a surgical intervention under general anesthesia (CDC class 3b), and in 19 patients (4.8%) other invasive treatment (CDC class 3a) was needed.Conclusions: The Clavien-Dindo Classification proved to be very useful for retrospective registration of surgical complications. Of the 61 patients, 33 were managed by conservative therapy. No risk profile was found for patients at risk for direct surgical complications. (C) 2019 Elsevier Ltd, BASO similar to The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.

Purpose/Objective(s) Indications for postoperative radiotherapy after meningioma resection are controversial. DNA methylation profiling identifies meningiomas at risk for recurrence, but logistic and technical barriers have encumbered clinical translation of this approach. The aim of this study was to optimize and validate a clinically-tractable targeted gene expression biomarker to predict meningioma outcomes and responses to postoperative radiotherapy. Materials/Methods Targeted gene expression and Illumina 850k DNA methylation profiling were performed on a discovery cohort of 173 meningiomas (median follow-up 7.8 years) and an external validation cohort of 331 meningiomas (median follow-up 5.8 years) from patients treated with surgery (n = 504) and postoperative radiotherapy (n = 73) at independent, international institutions (70% WHO grade 1, 24% WHO grade 2, 6% WHO grade 3). RNA sequencing was performed on the discovery cohort, and 125 genes were selected for targeted gene expression profiling based on associations with meningioma recurrence. Regularized Cox regression was used to develop continuous gene expression risk score for local freedom from recurrence (LFFR). The model (34 meningioma genes and 7 housekeeping genes) and risk quartiles (low, low-intermediate, high-intermediate, and high) were locked and validated on the external cohort. Multivariate regressions (MVR) incorporating WHO grade, DNA methylation grouping, extent of resection, primary versus recurrent presentation, and postoperative radiotherapy were used to assess the risk score across clinical contexts. Results The gene expression risk score (concordance-index 0.78 ± 0.03) outperformed DNA methylation grouping (0.71 ± 0.03) and WHO grade (0.65 ± 0.03) in stratifying meningioma LFFR in the validation cohort (n = 331). The risk score classified 43% of WHO grade 1 meningiomas as high-intermediate (n = 82) or high risk (n = 34), with 5-year LFFR and overall survival (OS) of 83% and 89% for high-intermediate risk WHO grade 1 meningiomas, and 41% and 73% for high risk WHO grade 1 meningiomas, respectively. Low risk WHO grade 1 meningiomas (n = 50) had 5-year LFFR and OS of 92% and 88%, respectively. High and high-intermediate risk scores were independently prognostic for LFFR (HR 2.9, 95% CI 1.2-4.4) and OS (HR 2.7, 95% CI 1.3-5.6) on MVR. An interaction term between postoperative radiotherapy and risk score was predictive for LFFR (P = 0.046) and OS (P = 0.001) on MVR in the validation cohort, suggesting meningiomas with higher risk scores derived greater benefit from postoperative radiotherapy. Conclusion Here we use targeted gene expression profiling to develop a risk score predicting meningioma outcomes and responses to postoperative radiotherapy. This cost-effective assay outperforms DNA methylation grouping and WHO grade in discriminating meningioma outcomes, and may be useful for guiding clinical trial design.

Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1 (HSV-1), which can be administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma (EMA label). The phase 3 OPTiM registration study showed an overall response rate (ORR) of 26%. Since December 2016, 48 eligible patients started treatment at the Netherlands Cancer Institute. We included 26 patients in this study with a follow up time ≥6 months, reporting Overall Response Rate (ORR), Disease Control Rate (DCR), Adverse Events (AE), prior treatment for melanoma and baseline characteristics, documented in a prospectively maintained database. In house developed treatment protocol consists of clinical evaluation, periodic PET-CT and histological biopsies for response evaluation. Median follow-up was 12.5 months. Of 26 patients, 16 (61.5%) had a Complete Response (CR) as their best response. Seven (26.9%) patients had a Partial Response (PR) as their best response, 1 (3.8%) patient Stable Disease (SD) and 2 (7.7%) patients Progressive Disease (PD). Best ORR was 88.5%. DCR was 92.3%. Grade 1-2 AEs occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site erythema. All patients underwent prior treatment. Prior treatment did not influence response or toxicity of T-VEC. Best ORR for T-VEC monotherapy at our institute was 88.5% with 61.5% achieving a CR. This prospective study for T-VEC in early metastatic (stage IIIB/C-IVM1a) melanoma demonstrated superior results to the phase 3 OPTiM study and confirms the role of oncolytic immunotherapy for melanoma.

Background Parotidectomy in melanoma of the coronal scalp and face with clinically involved cervical lymph node metastasis is based on predicted cervical lymphatic drainage described by O'Brien. Methods In total, 40 parotidectomies with en bloc therapeutic neck dissection were retrospectively analyzed. Results Lymphatic spread of melanoma to the parotid lymph nodes was observed in 10 of 40 specimens (25%). Eight of the 10 parotid-positive patients developed a recurrence vs 17 of the 30 parotid-negative patients (P = 0.28). There were no differences in overall survival, melanoma-specific survival, and disease-free survival between the parotid-positive and parotid-negative patients. Conclusion Although in this series no survival differences were found, parotidectomy still merits a sustained role in therapeutic neck dissection procedures to improve regional control and to prevent facial nerve damage after surgery for a second relapse from occult metastases in the parotid.

Background TNM staging of melanoma has recently been altered by the introduction of the 8th edition of the AJCC Cancer Staging manual. The purpose of this study is to analyze the inter-observer variation of histopathology reports and its effect on recommended treatment policy. Methods We retrospectively analyzed 296 cases, diagnosed as primary cutaneous head and neck melanoma (2005–2016), referred to the Netherlands Cancer Institute (NCI) for treatment after prior diagnosis in another hospital (non-NCI). All reports were analyzed for patients demographics, tumor characteristics and histopathologic features. Results In 53% and 40% of the cases, the histopathologic parameters were discordant, according to AJCC 7th and 8th edition, respectively. This indicated a perfect inter-observer agreement for the measurement of Breslow thickness (Intraclass correlation coefficient (ICC) = 0.981) and a substantial agreement for subtype (kappa statistic (κ) = 0.648) and ulceration (κ = 0.802), while only moderate for dermal mitotic activity (κ = 0.472). After NCI review, recommended treatment policies were changed in 13% and 11% of the patients when applying TNM 7 and TNM 8, respectively. Scheduling sentinel lymph node biopsy (SLNB) changed in 14 (5%) and 10 (3%) cases when using TNM 7 and TNM 8, respectively. Conclusion Review by a NCI pathologist of histopathologic parameters of primary cutaneous head and neck melanoma led to significant changes in treatment decision. Introduction of the AJCC 8th edition led to slightly less discordances between NCI and non-NCI reports and consequently smaller impact on treatment planning. Expert review remains indicated when a SLNB is considered for additional staging in selected cases.

Author(s): Vasudevan, H; Magill, S; Seo, K; Villanueva-Meyer, J; Choudhury, A; Liu, SJ; Pekmezci, M; Findakly, S; Hilz, S; LaStella, S; Braunstein, SE; Oberheim, NA; Aghi, MK; Theodosopoulos, PV; Sneed, PK; Berger, MS; McDermott, MW; Lim, D; Ulian, E; Costello, J; Raleigh, D

BACKGROUND: The aim of glioblastoma surgery is to maximize the extent of resection, while preserving functional integrity. Standards are lacking for surgical decision-making and consequently surgical strategies may differ between neurosurgical teams. In this study we quantitated and compared surgical decision-making throughout the brain between neurosurgical teams for patients with a glioblastoma using probability maps. MATERIAL AND METHODS: All adults with first-time glioblastoma surgery in 2012–2013 from twelve tertiary referral centers for neuro-oncological care were included in this study. For each patient, pre- and postoperative tumor were manually segmented on MRI and aligned to standard brain space. Resection probability maps and biopsy probability maps were constructed in 1 mm resolution for each team’s cohort. Brain regions with differential biopsy and resection results between teams were identified. RESULTS: The study cohort consisted of 1085 patients of whom 305 received a biopsy and 780 a resection. Biopsy probability maps demonstrated differences between teams in biopsy rate per brain location, such as for the right caudate nucleus, indicating variation in biopsy decisions. Resection probability maps demonstrated differences between teams in residual tumor rate per brain location, such as for the left sagittal striatum and neighboring posterior corpus callosum, indicating variation in resection decisions. CONCLUSION: Biopsy and resection probability maps indicate treatment variation between teams for patients with a glioblastoma. This conveys useful objective arguments for quality of care discussions between surgical teams for these patients.

To investigate whether quantitative dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion magnetic resonance imaging (MRI) metrics are influenced by cellular and genomic expression patterns of glioblastoma angiogenesis.Twenty-five stereotactic neurosurgical tissue samples were prospectively obtained from enhancing and non-enhancing tumour regions from 10 patients with treatment-naïve glioblastoma. Using monoclonal antibodies, histopathological features of angiogenesis were examined: total microvascular density, vascular morphology, and hypoxia. Angiogenic expression patterns of tissue samples were investigated using RNA microarrays. DSC perfusion MRI metrics were measured from the tissue sampling sites. MRI and histopathological variables were compared using Pearson's correlations. Microarray analysis was performed using false discovery rate (FDR) statistics.Thirteen enhancing and 12 non-enhancing MR image-guided tissue specimens were prospectively obtained. Enhancing tumour regions demonstrated a significant difference in DSC perfusion and histopathological metrics of angiogenesis when compared to non-enhancing regions. Four angiogenic pathways (vascular endothelial growth factor [VEGF], hypoxia inducible factor [HIF], platelet-derived growth factor [PDGF], fibroblast growth factor [FGF]; 25 individual genes) were significantly up-regulated within enhancing regions when compared to non-enhancing regions (adjusted p0.05, FDR0.05). A statistically significant correlation was observed between VEGF-A expression, microvascular density, microvascular morphology, and DSC perfusion MRI metrics (p0.05).Pro-angiogenic genomic and cellular expression patterns of treatment-naïve primary glioblastoma significantly influences morphological and physiological DSC perfusion metrics suggesting that expression levels of therapeutically relevant genetic signatures can be quantified using MRI.

Introduction: Low-grade gliomas (LGG, WHO grade I-II) account for 16.9-22% of all primary brain tumors. Management of these tumors consists of surgery, sometimes followed by radiation and/or chemotherapy. Arigorous, quantitative evaluation of the literature investigating the management of LGG has never been published. Methods: We conducted an exhaustive, PRISMA-compliant systematic review of the literature from January 1966 to September 2016 comparing the association of chemotherapy, radiation, or extent of resection with survival and progression-free survival at 2, 5, and 10years in LGG. Included studies were graded for quality using AAN criteria. Pre-specified data were extracted and summary statistics were calculated using the inverse variance method and random effects model. Results: Five studies (n=567) report on LGG patients treated with chemotherapy. The relative risk (RR) and 95% confidence intervals [95% CI] for death (chemotherapy vs. no chemotherapy) at 2, 5, and 10years was 1.34 [0.85-2.12], 0.83 [0.64-1.09], and 0.77 [0.58-1.03]. RR for progression at 2, 5, and 10years was 0.92 [0.64-1.33], 0.69 [0.55-0.87, p=0.001], and 0.58 [0.39-0.87, p=0.008]. Asensitivity analysis of OS including only classIand II studies showed a RR of death (chemotherapy vs. no chemotherapy) at 2, 5, and 10years of 1.23 [0.72-2.08], 0.78 [0.58-1.05, p=0.1], and 0.69 [0.56-0.86, p=0.0006]. Among only IDH1-mutated patients, the RR of progression with chemotherapy compared to control at 2, 5, and 10years was 0.48 [0.06-4.1], 0.27 [0.08-0.84, p=0.02], and 0.21 [0.03-1.59]. Ten studies (n=1918) provide data regarding the effect of post-operative radiation vs. delayed or no radiation. RR and 95% CI for death at 2, 5, and 10years was 0.92 [0.53-1.58], 0.93 [0.60-1.43], and 0.99 [0.69-1.41]. RR for progression at 2, 5, and 10years was 0.66 [0.51-0.86, p=0.002], 0.73 [0.61-0.88, p=0.0008], and 0.74 [0.60-0.91, p=0.005]. Twenty-three studies (n=3891) compare gross total resection (GTR) vs. subtotal resection (STR) in LGG. RR and 95% CI of death at 2, 5, and 10years (GTR vs. STR) was 0.29 [0.17-0.52, p

Background Talimogene laherparepvec (T-VEC) is a modified herpes simplex virus, type 1 (HSV-1), which can be administered intralesionally in patients with stage IIIB/C-IVM1a unresectable melanoma. When surgery is not a treatment option in the head and neck region, i.e. due to the location or the size of the tumor, T-VEC therapy can be an elegant alternative to systemic immunotherapy. Methods 9 patients with melanoma in the head and neck region started treatment with T-VEC monotherapy at the Netherlands Cancer Institute, of which 4 are still currently on treatment. We collected data on response, adverse events (AE) and baseline characteristics. For response evaluation, we used clinical evaluation with photography, 3-monthly PET-CT’s and histological biopsies. Results Median age at baseline was 78.3 years. Of the 5 patients who stopped treatment, the median follow-up time was 9.1 months. Of these patients, 3 (60%) had a complete response (CR), 1 (20%) patient had a partial response (PR) and 1 (20%) patient showed progressive disease (PD) as their best response. ORR was 80%. Duration of response varies between 1.6-21.6 months. 2 patients developed distant metastases, 1 during T-VEC treatment and 1 after achieving a CR with a time to progression of 14.2 months. 4 patients are still on treatment today. Grade 1 AE’s occurred in all patients. Mostly, these consisted of fatigue, influenza-like symptoms and injection site pain. PET-CT and histological biopsies proved to be a clinically useful tool to evaluate treatment response for T-VEC monotherapy, confirming pCR or PD to stage IV disease requiring systemic treatment. Conclusions ORR for T-VEC monotherapy for melanoma in the head and neck region at our institute was 80% with 60% achieving a CR. This real world data on T-VEC monotherapy in stage IIIB/C-IVM1a unresectable melanoma of the head and neck region demonstrates interesting results and suggests T-VEC is an elegant alternative to systemic therapy in this select elderly and frail patient population. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure V. Franke: Honoraria (institution), Advisory / Consultancy, Research grant / Funding (institution): amgen. M.W.J.M. Wouters: Research grant / Funding (institution): Novartis. W.J. van Houdt: Advisory / Consultancy, Research grant / Funding (institution): amgen. A.C.J. van Akkooi: Research grant / Funding (institution): Novartis; Advisory / Consultancy, Research grant / Funding (institution): amgen; Research grant / Funding (institution): BMS; Research grant / Funding (institution): MSD-Merck; Research grant / Funding (institution): Merck-Pfizer. All other authors have declared no conflicts of interest.

BACKGROUND Nearly 80,000 new cases of primary brain tumors are expected to be diagnosed this year in the United States: 32% of CNS tumors are malignant. Anecdotally, patients who report use of cannabis, frequently describe higher quality of life scores (QOL) in standardized instruments. However, the lack of available tools that allow systematic documentation of cannabis use results in a barrier to accurately assess efficacy and potential benefits and risks. MATERIAL AND METHODS We conducted a single center, observational study: patients with primary brain tumors answered a previously validated instrument to explore cannabis use. QOL was assessed using the instruments from the European Organisation for Research and Treatment of Cancer(EORTC): QLQ-C30 and its complementary module BN-20 as well as the EuroQol group’s instrument EQ-5D-5L. Eligible participants were identified as cannabis users or non-users, completing the instruments in a self-administered fashion. RESULTS To date, 45 patients who signed informed consent were enrolled and answered the questionnaires, mean age was 51 (SD 13.5) years, 31 were male, 25 were considered active cannabis users (624% males and 36% females). At baseline, the mean Global Health score in the QLQ-C30 instrument was 68.6 (SD: 20.6) among cannabis users and 82 (SD: 18.05) among non-users. The mean difference in Global Health QOL scores between users and non-users was 13.35 (95%CI: 1.34, 25.35; p=0.03). In contrast the difference between cannabis users and non-users in QOL index in the EQ-5D-5L instrument was 0.13 (0.77 vs 0.91; p=0.002). Among cannabis users, patients perceive their symptoms as moderate before using cannabis and mild after using cannabis (p>0.001). CONCLUSION In our analysis, patients who use cannabis have, on average, lower QOL scores signaling that sicker patients resort to cannabis to improve their symptoms and ultimately their quality of life. Patients’ perception is one of improvement in the overall quality of life when using cannabis. Our findings provide background support to perform prospective studies in the impact of cannabis in quality of life of patients with central nervous system tumors.

Background Although the EORTC 18071-trial has shown a clear survival benefit for adjuvant ipilimumab, accurately selecting patients for this toxic adjuvant therapy is important. We aimed to identify prognostic factors for death and disease recurrence in AJCC stage IIIC melanoma patients. Patients and Methods Retrospective analysis of patients who underwent lymph node dissection (LND) for stage IIIC melanoma in our institution between 2000 and 2016. Baseline characteristics, melanoma-specific survival (MSS), and disease-free survival (DFS) were assessed, and prognostic factors for recurrence and survival were analyzed using uni- and multivariable analysis. Results A total of 205 patients were included. Median follow-up was 20 months (interquartile range 11-43 months), median MSS was 28 months, and median DFS was 11 months. Five-year MSS was 33% and 5-year DFS was 23%. N3 (≥4 involved lymph nodes) and extracapsular extension (ECE) carried an increased risk of disease recurrence after LND and death by melanoma. Patients with both N3 and ECE had virtually no long-term survival. Conclusions Although survival for patients with stage IIIC is poor in general, patients with both N3 disease and ECE constitute the group with the worst prognosis and should be considered for adjuvant therapy with ipilimumab or any other future effective adjuvant therapy (study).

BACKGROUND AND PURPOSE: Super-resolution track density imaging generates anatomic images with submillimeter voxel resolution by using high-angular-resolution diffusion imaging and fiber-tractography. TDI within the diseased human brain has not been previously described. The purpose of this study was to correlate TDI with histopathologic features of GBM. MATERIALS AND METHODS: A total of 43 tumor specimens (24 contrast-enhancing, 12 NE, and 7 centrally necrotic regions) were collected from 18 patients with treatment-naive GBM by use of MR imaging–guided neurosurgical techniques. Immunohistochemical stains were used to evaluate the following histopathologic features: hypoxia, architectural disruption, microvascular hyperplasia, and cellular proliferation. We reconstructed track density maps at a 0.25-mm isotropic spatial resolution by using probabilistic streamline tractography combined with constrained spheric deconvolution (model order, 8; 0.1-mm step size; 1 million seed points). Track density values were obtained from each tissue site. A P value of .05 was considered significant and was adjusted for multiple comparisons by use of the false discovery rate method. RESULTS: Track density was not significantly different between contrast-enhancing and NE regions but was more likely to be elevated within regions demonstrating aggressive histopathologic features ( P < .05). Significant correlation between relative track density and hypoxia (odds ratio, 3.52; P = .01), architectural disruption (odds ratio, 3.49; P = .03), and cellular proliferation (odds ratio, 1.70; P = .05) was observed irrespective of the presence or absence of contrast enhancement. CONCLUSIONS: Numeric values of track density correlate with GBM biologic features and may be clinically useful for identification of regions of tumor infiltration within both enhancing and NE components of GBM. CE : contrast-enhanced FA : fractional anisotropy GBM : glioblastoma multiforme NE : nonenhancing TDI : track density imaging

INTRODUCTION The aim of glioblastoma surgery is to maximize the extent of resection, while preserving functional integrity. Standards are lacking for surgical decision-making and consequently surgical strategies may differ between neurosurgical teams. In this study, we quantitated and compared surgical decision-making throughout the brain between neurosurgical teams for patients with a glioblastoma using probability maps. METHODS All adults with first-time glioblastoma surgery in 2012-2013 from 10 tertiary referral centers for neurooncological care were included in this study. For each patient, pre- and postoperative tumor were manually segmented on MRI and aligned to standard brain space. Resection probability maps and biopsy probability maps were constructed in 1 mm resolution for each team's cohort. Brain regions with differential biopsy and resection results between teams were identified. RESULTS The study cohort consisted of 931 patients of whom 293 received a biopsy and 638 a resection. Biopsy probability maps demonstrated differences between teams in biopsy rate per brain location, such as for the left precuneus and superior parietal lobule, indicating variation in biopsy decisions. Resection probability maps demonstrated differences between teams in residual tumor rate per brain location, such as for the left saggital striatum and neighboring posterior corpus callosum, indicating variation in resection decisions. CONCLUSION Biopsy and resection probability maps indicate treatment variation between teams for patients with a glioblastoma. This conveys useful objective arguments for quality of care discussions between surgical teams for these patients.

BACKGROUND AND PURPOSE: Glioblastoma multiforme (GBM) and single brain metastasis (MET) are the 2 most common malignant brain tumors that can appear similar on anatomic imaging but require vastly different treatment strategy. The purpose of our study was to determine whether the peak height and the percentage of signal intensity recovery derived from dynamic susceptibility-weighted contrast-enhanced (DSC) perfusion MR imaging could differentiate GBM and MET. MATERIALS AND METHODS: Forty-three patients with histopathologic diagnosis of GBM ( n = 27) or MET ( n = 16) underwent DSC perfusion MR imaging in addition to anatomic MR imaging before surgery. Regions of interest were drawn around the nonenhancing peritumoral T2 lesion (PTL) and the contrast-enhancing lesion (CEL). T2* signal intensity-time curves acquired during the first pass of gadolinium contrast material were converted to the changes in relaxation rate to yield T2* relaxivity (ΔR2*) curve. The peak height of maximal signal intensity drop and the percentage of signal intensity recovery at the end of first pass were measured for each voxel in the PTL and CEL regions of the tumor. RESULTS: The average peak height for the PTL was significantly higher ( P = .04) in GBM than in MET. The average percentage of signal intensity recovery was significantly reduced in PTL (78.4% versus 82.8%; P = .02) and in CEL (62.5% versus 80.9%, P < .01) regions of MET compared with those regions in the GBM group. CONCLUSIONS: The findings of our study show that the peak height and the percentage of signal intensity recovery derived from the ΔR2* curve of DSC perfusion MR imaging can differentiate GBM and MET.

The application of focal radiation therapies in the management of malignant gliomas has gone through a number of stages. Earlier efforts to improve local control of malignant gliomas involved the use of brachytherapy. Despite some early encouraging results, Phase 3 studies did not prove a significant survival benefit for the addition of brachytherapy for newly diagnosed glioblastoma. Most recently radiosurgery has been employed using the same rationale in that improved local control may improve survival. Results of the RTOG Phase 3 study are pending final publication, but early abstracted reports are negative. While radiosurgery and brachytherapy continue to be used as a form of therapy for selected patients with recurrent gliomas, new information from metabolic imaging studies suggests our problem with these techniques in part may be related to targeting. This paper reviews the recent literature and results of the use of brachytherapy and radiosurgery in the management of newly diagnosed and recurrent malignant gliomas.

INTRODUCTION The extent of resection is important to improve survival in patients with a glioblastoma. The neurosurgeon’s aim is to maximize the extent of resection, while preserving functional integrity. Standards to aid in patient counselling and guide surgical decision making are nevertheless lacking, hence quality of surgical care might differ between neuro-oncological care teams. In this study we present a novel volumetric method to quantify post-resection residual tumors throughout the brain for patient populations. This allows direct comparison of surgical results between care teams. METHODS All adults with first-time glioblastoma surgery in 2012-2013 in each of two Dutch and one United States tertiary referral centres for neuro-oncological care were included in this study. From each of these patient populations preoperative tumors and postoperative residual disease were segmented on MRI and registered to standard space. Brain maps of tumor and residual tumor locations were constructed for each country. Differences between these brain maps were analysed to explore patient selection and treatment variation. RESULTS This study cohort consisted of 403 patients (the Netherlands: 268; the United States: 135). Of these, 111 tumors were biopsied and 292 resected. Tumor localization maps illustrate established preferential sites for glioblastoma distributions for each cohort, indicating similar patient referral patterns, selection or recruitment. Resection probability maps demonstrate no differential residual tumor localization throughout the brain, indicating similar surgical decision making. Brain maps were reviewed by the care teams and arguments for future decision making were discussed. CONCLUSIONS Brain maps of tumor localization convey important information that can be used to compare neuro-oncological care teams in terms of patient selection. In addition, surgical decision making can be made explicit through resection probability maps. This novel volumetric approach can provide objective arguments for discussions between care teams on the quality of neurosurgical care for patients with a glioblastoma.

Alterations in the CDK4/6 – RB signaling pathway are common causes of dysregulation of the cell cycle in many cancers, including glioblastoma. Palbociclib is an oral, highly selective, reversible inhibitor of CDK4/6, which leads to phosphorylation of RB and cell-cycle arrest. In a two-arm study, we evaluated the efficacy and safety of palbociclib in patients with recurrent glioblastoma. Notable eligibility criteria included confirmation of RB proficiency by IHC; ≤ 3 relapses; KPS ≥ 60; secondary glioblastomas were included; there were no limitation on prior treatments including bevacizumab. Patients were administered oral palbociclib 125 mg daily for 21 consecutive days followed by a 7 day break. Arm 1 planned for 15 patients to receive palbociclib for 7 days prior to indicated surgical resection for progression, followed by palbociclib. Arm 2 planned for 15 patients to receive palbociclib without additional resection. The primary objective was PFS-6, which was hypothesized to be 30% in this heavily pretreated population, and null hypothesis of 10%. Secondary objectives of toxicity, OS, and ORR. Exploratory results included biomarker assessment and pharmacodynamic effects for the surgical Arm 1 patients. A total of 22 patients were enrolled; 6 on Arm 1 and 16 on Arm 2. Median age for all arms was 47.5 years old (range 23 – 78 years old); 54% (12 patients) were male; and the median KPS was 90 (range 60 – 100). Palbociclib was started at first recurrence in 50% (11 patients – 3 in Arm 1 and 8 in Arm 2) of patients; at second recurrence in 36% (8 patients – 3 in Arm 1 and 5 in Arm 2); and at third recurrence in 14% (3 patients, all in Arm 2). Bevacizumab had previously been used in 77% (17 patients – 4 in Arm 1 and 13 in Arm 2) of cases. The trial was stopped early secondary to futility, with 95% (18 of 19) evaluable patients progressing within 6 months of intiating treatment. Four samples were available for immunohistochemistry for Rb and Ki67. There were no consistent changes in Rb expression or cell proliferation when compared to samples from diagnosis. Median progression free survival for all patients was 5.14 weeks (range 5 days – 142 weeks) and median overall survival was 15.4 weeks (range 2 – 274 weeks). Two patients (10%) had treatment related AEs that were grade ≥3. In this trial, palbociclib did not appear to have been an effective treatment for recurrent glioblastoma. However, this was a heavily pretreated patient population and targeting the CDK4/6 pathway may deserve further exploration.

BACKGROUND: The effect of timing of initiation of radiotherapy (RT) after surgery on the outcome of patients with glioblastoma (GBM) remains controversial. Most neurosurgeons and neuro-oncologists believe that early initiation of RT may result in clinical benefits. However, certain reports suggested that delayed RT may be positively associated with survival for GBM patients. To further explore this issue, we analyzed three clinical trials for newly diagnosed GBM patients receiving temozolomide (TMZ) conducted at UCSF. METHODS: From 2004 through 2010, 207 adult patients with supratentorial GBM were enrolled into 3 clinical trials which consisted of RT plus TMZ and an experimental agent. Timing of RT was defined as the time interval between definitive surgery and commencement of RT, which was intended to be within 6 weeks per protocol eligibility. Overall survival (OS) and Progression-free survival (PFS), measured from study registration, were estimated using the Kaplan-Meier method. Analysis by classification and regression trees was used to determine the cut-off values for timing of RT at which there was a significant difference in OS and PFS. Cox proportional hazards model was used to assess the effect of RT timing (in days) on clinical outcomes, adjusting for treatment protocol, age, KPS, and extent of resection. RESULTS: The median wait time between surgery and RT was 29.5 days (range: 7-89 days). There was no significant difference in timing of RT with respect to baseline variables, except for resection extent: patients who were given RT earlier were more likely to have undergone a biopsy than more extensive surgery. Unexpectedly, a short delay in RT administration (at 30-34 days) was predictive of prolonged OS (HR = 0.58, p < 0.02) as well as prolonged PFS (HR = 0.55, p < 0.001), compared to early initiation of RT (

BACKGROUND: The purpose of this study was to use ex vivo NMR spectroscopy of image guided tissue samples in order to characterize the metabolic signatures of gliomas and to determine which in vivo parameters are likely to be of interest for directing treatment, evaluating response and predicting outcome. METHODS: A total of 254 image guided tissue samples were obtained from 126 patients with glioma who were undergoing surgical resection for either a new or recurrent lesion. Half of each sample was flash frozen for analysis using ex vivo high resolution magic angle spinning (HRMAS) 1H spectroscopy with a 500MHz NMR scanner. Metabolite levels were estimated from the ex vivo spectra using the HR-QUEST software package. The other half of each sample was fixed in paraffin for subsequent histological analysis. Confirmation of the presence of tumor, the definition of tumor grade and evaluation of histology were made by an experienced pathologist. Associations between samples with different pathologies and/or from different anatomic regions were evaluated using a proportional odds logistic regression model with repeated measures in order to take account of the multiple samples per subject. RESULTS: Significant differences in the ex vivo metabolite levels were observed between samples from groups that were separated based upon (i) primary tumor grade, (ii) IDH status, (iii) having arisen as primary vs secondary GBM, (iv) being classified as corresponding to recurrent GBM vs treatment effect and (v) coming from regions of GBM that were contrast enhancing versus non-enhancing on T1-weighted post-Gadolinium images. Key metabolites that were relevant for making distinctions between the various groupings included levels of 2-hydroxglutarate, myo-inositol, phosphocholine, glycerophosphcholine, glutathione, glycine, glutamate, creatine, N-acetylasparate and mobile lipids. CONCLUSIONS: Many of the metabolites that were highlighted as being associated with different pathologies and regional imaging characteristics can be measured using clinically available 3T whole body MR scanners in conjunction with in vivo 1H MR spectroscopic imaging. Recent advances in the methodology for acquiring and analyzing such data have made it possible to obtain maps of metabolite levels from the brain in a scan time of 5-10 minutes. Applications to patient care include assessment of tumor burden, prediction of outcome and tailoring treatment to individual patient characteristics.Supported by: NIH P50 {"type":"entrez-nucleotide","attrs":{"text":"CA097257","term_id":"34950564","term_text":"CA097257"}}CA097257, RO1 {"type":"entrez-nucleotide","attrs":{"text":"CA127612","term_id":"35007666","term_text":"CA127612"}}CA127612 and P01 CA118816. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

In recent years, advances in our understanding of the biology of low-grade gliomas (LGG) and high-grade gliomas (HGG) have driven new paradigms in molecular markers, diagnostic imaging, operative techniques and technologies, and adjuvant therapies. Taken together, these developments are collectively pushing the envelope towards improved quality of life and survival. Here, we review the recent literature to synthesize a comprehensive review of the value of extent of resection for LGGs and HGGs in the modern neurosurgical era.

We have performed a complete one-loop calculation of [gamma][gamma][r arrow][ital ZZ] in the standard model, including both gauge bosons and fermions in the loop. We confirm the large irreducible continuum background from the [ital W] boson loop found by Jikia. We have included the photon-photon luminosity, and find that the continuum background of transverse [ital Z] boson pairs prohibits finding a heavy Higgs boson with a mass [approx gt]350 GeV in this decay mode.

This paper contributes on presenting a step towards the realization of Carrier Ethernet control plane based on the next generation network (NGN). Specifically, transport MPLS (T-MPLS) is taken as the transport technology in Carrier Ethernet. It begins with providing an overview of the evolving architecture of the next generation network (NGN). As an essential candidate among the NGN transport technologies, the definition of Carrier Ethernet (CE) is also introduced here. The second part of this paper depicts the contribution on the T-MPLS based Carrier Ethernet network with control plane based on NGN architecture. The approaches to QoS mapping, label distribution and connection and admission control (CAC) are specified here. At last, a simple T-MPLS based Carrier Ethernet network model with three kinds of users (VoIP, VoD and HTTP) and a RACE based control module is simulated in OPNET. The model is aiming at illustrating the improvement of the Carrier Ethernet network with the NGN control plane.

Summary We investigated the expression of c-erbB-2 protein in two matched groups of breast cancer patients, one with and one without relapse. 37 patients with relapse were compared with 42 patients without recurrence for time of observation, adjuvant treatment, age, menopausal status and estrogen receptor content. Paraffin-embedded sections were stained with the polyclonal antibody 21N, raised against a synthetic peptide from the predicted sequence of the c-erbB-2 protein. The staining of c-erbB-2 was measured on a scale of 0 to 3+. C-erbB-2 staining was negative in 16 (38%) patients in the relapse-free group, and in 8 (22%) of the patients with metastases. Neither disease-free survival (DFS) nor overall survival (OS) were dependent upon the extent of c-erbB-2 expression. An analysis by estrogen receptor (ER) status (i.e. positive or negative) and by c-erbB-2 expression (i.e. positive or negative) revealed that patients with ER-positive primaries and negative c-erbB-2 have the longest disease-free survival (DFS) and overall survival (OS). We conclude that c-erbB-2 expression might be clinically useful only if other prognostic variables (e.g. estrogen receptor content in the tumor) are also considered.

Purpose/Objective(s): Pituitary tumors are relatively uncommon. Primary goals of treatment include normalization of hormonal level and improving visual or neurological symptoms. Surgery, medical treatment, irradiation, or combination of these modalities is used to achieve these goals. The purpose of this analysis is to determine the clinical outcome of pituitary adenoma treated with fractionated external beam radiation therapy. Materials/Methods: This is a retrospective analysis of pituitary adenoma treated at our center between 2006 and 2014. A total of 88 patients with biopsy-proven adenomas were identified. Median age at diagnosis was 38 years (18e79 years) and 49 patients (56%) were males. Majority of tumors were marcoadenoma (87%). Presenting symptoms were mainly hormonal disturbance in 43 patients (49%), visual defects in 29 patients (33%) and headache in 21 patients (23%). Prolactinomas were the most common secretory adenoma in 22 patients (51%), followed by growth hormone secreting adenomas in 15 patients (35%) and ACTH-secreting tumors in 5 patients (12%), while one patient had TSH-secreting adenoma. The cohort follow up time reached 87 months (mean; 32 months). The primary endpoints are clinical and biochemical control. Results: Thirteen patients lost to follow up, therefore 75 patients were included in the final analysis. Surgery was the primary treatment modality in 70 patients (93%).While medical treatment was used for inoperable or hormonal secreting adenoma in 30 patients (40%). Fractionated radiation therapy was delivered to 28 patients (37%), indications for radiation were symptomatic, incompletely resected tumors (16 patients) or persistent hypersecretion (12 patients). For secretory tumors the median radiation dose was 52Gy (50-54Gy), and lower dose was delivered for non-secretory adenoma; mean 50Gy (45-52Gy). For patients received radiation therapy, the tumor control rate is 75% for non-functioning adenomas, and 69% for functioning adenomas. Conclusion: Pituitary adenoma is a slow growing benign tumor; however devastating effect can result from neurological deficits or hormonal imbalance. Our results reveal that functioning adenomas carry worse prognosis. Fractionated radiation therapy, as an adjunct to surgery and medical treatment, offers good clinical and biochemical control for pituitary adenoma. More aggressive multimodal approach and incorporation of new radiation technique may help to achieve better clinical outcome. Author Disclosure: R.A. Abu-Hijlih: None. Y. Ismael: None. H. Ghatasheh: None. A. Fawzi: None. A. Alsharbaji: None. M. Elyan: None. B. Al-Haj: None. A. Almousa: None.

This paper presents a modified architecture for an input queued switch that reduces external speedup. Maximal size scheduling algorithms for input-buffered crossbars requires a speedup between port card and switch card. The speedup is typically in the range of 2, to compensate for the scheduler performance degradation. This implies, that the required bandwidth between port card and switch card is 2 times the actual port speed, adding to cost and complexity. To reduce this bandwidth, a modified architecture is proposed that introduces a small amount of input and output memory on the switch card chip. This architecture allows for internal speedup in the switch card and the external speedup between port card and switch card can be reduced significantly. A simulation study is used for buffer dimensioning and demonstrates the feasibility of the proposed architecture.

Purpose: To assess the outcome of high central dose Gamma Knife radiosurgery plus marimastat in patients with recurrent malignant glioma. Methods and Materials: Twenty-six patients with recurrent malignant glioma were enrolled in a prospective Phase II study between November 1996 and January 1999. The radiosurgery dose was prescribed at the 25–30% isodose surface to increase the dose substantially within the tumor's presumably hypoxic core. Marimastat was administered after radiosurgery to restrict regional tumor progression. Survival was compared with that of historical patients treated at our institution with standard radiosurgery. Results: The median times to progression after radiosurgery for Grade 3 and 4 patients was 31 and 15 weeks, respectively. The corresponding median survival time after radiosurgery was 68 and 38 weeks. The median survival time after radiosurgery in the historical patients was 59 and 44 weeks. Conclusion: The dual strategies of using high central dose radiosurgery to overcome tumor hypoxia together with marimastat to inhibit local tumor invasion may offer a small survival advantage for recurrent Grade 3 tumors; they do not offer an advantage for recurrent Grade 4 tumors.

previously reported improvement in PFS (10.4 vs. 4.0 years, p Z 0.002; HR Z 0.50). Treatment arm was identified as a prognostic variable in favor of RT + PCV for both OS (p Z 0.003; HR Z 0.59) and PFS (p < 0.001; HR Z 0.49). Histology was prognostic for OS (p < 0.001; HR Z 2.16) and PFS (p < 0.001; HR Z 1.85) in favor of O compared to A. Male gender was prognostic for inferior OS (p Z 0.02; HR Z 1.51). Molecular markers were not pre-specified; post-hoc analysis of these is ongoing. Conclusions: For “high-risk” LGG, defined as age < 40 years with subtotal resection/biopsy or 40 years with any degree of resection, RT followed by 6 cycles of PCV prolongs both OS and PFS, and RT plus chemotherapy should therefore be considered a new standard of care for such patients. Astrocytic histology and male gender predict for poorer survival. Acknowledgment: This project was supported by RTOG grant U10 CA21661, and CCOP grant U10 CA37422 from the National Cancer Institute (NCI). Author Disclosure: M.P. Mehta: E. Research Grant; Novocure. F. Honoraria; Research to Excellence, Soreno Foundation. G. Consultant; Abbvie, BMS, Elekta, Merck, Novocure, Novelos, Phillips. I. Travel Expenses; Abbvie, Celldex, Elekta, Phillips, Roche. K. Advisory Board; Celldex, Roche. N. Stock Options; Pharmacyclics, Accuray. P. Royalty; Demos. S. Leadership; RTOG. M. Won: None. E.G. Shaw: None. J. Buckner: None. M. Gilbert: E. Research Grant; Merck, Genentech, GSK. F. Honoraria; Genentech, Merck. K. Advisory Board; Merck, Genentech, BMS, Abbvie, EMD Serono. G. Barger: None. S. Coons: None. P. Ricci: None. D. Bullard: None. P.D. Brown: None. K. Stelzer: None. D.G. Brachman: None. J.H. Suh: G. Consultant; Varian. C. Schultz: None. J. Bahary: None. B.J. Fisher: None. H. Kim: None. A.D. Murtha: None. W.J. Curran: S. Leadership; RTOG.

Object. The goal of this study was to perform a critical review of literature pertinent to low-grade gliomas of the cerebral hemisphere in adults and, on the basis of this review, to evaluate systematically the prognostic effect of extent of resection on survival and to determine if treatment-related guidelines could be established for patients in whom these tumors have been newly diagnosed. Quality of evidence for current treatment options, guidelines, and standards as well as methodological limitations were evaluated. Methods. Several prognostic factors thought to affect outcome in patients with low-grade gliomas include the patient's age and neurological status, tumor volume and histological characteristics, and treatment-related variables such as timing of surgical intervention, extent of resection, postoperative tumor volume, and radiation therapy. Patient age and the histological characteristics of the lesion are generally accepted prognostic factors. Among treatment-related factors, timing and extent of resection are controversial because of the lack of randomized controlled trials addressing these issues and the difficulty in obtaining information from available studies that have methodological limitations. All English-language studies on low-grade gliomas published between January 1970 and April 2000 were reviewed. Thirty studies that included statistical analyses were further evaluated with regard to the prognostic effect of extent of resection. Of these 30 studies, those that included pediatric patients, unless adults were analyzed separately, were excluded from further study because of the favorable outcome associated with the pediatric age group. Also excluded were studies including pilocytic and gemistocytic astrocytomas, because the natural histories of these histological subtypes are significantly different from that of low-grade gliomas. Series in which there were small numbers of patients (< 75) were also excluded. Results for oligodendrogliomas are reported separately. Currently, for patients with low-grade glial tumors located in the cerebral hemisphere, the only management standard based on high-quality evidence is tissue diagnosis. All other treatment methods are practice options supported by evidence that is inconclusive or conflicting. The majority of published series that the authors identified had design-related limitations including a small study size, a small number of events (that is, deaths for survival studies), inclusion of pediatric patients, and/or inclusion of various histological types of tumors with different natural histories. Of the 30 series addressing the issue of timing and extent of surgery, almost all had additional design limitations. Methods used to determine the extent of resection were subjective and qualitative in almost all studies. Only five of the 30 series met the authors' criteria, and these studies are discussed in detail. Conclusions. Management of low-grade gliomas is controversial and practice parameters are ill defined. This is caused by limited knowledge regarding the natural history of these tumors and the lack of high-quality evidence supporting various treatment options. Although a prospective randomized study seems unlikely, both retrospective matched studies and prospective observational trials will improve the clinician's ability to understand the importance of various prognostic factors.

PURPOSE To assess the efficacy and toxicity of paclitaxel administered as a 3-hour infusion to patients with recurrent malignant glioma. PATIENTS AND METHODS Adult patients with recurrent malignant glioma following radiation therapy, who had received no more than one prior chemotherapy regimen and who had a Karnofsky performance status (KPS) > or = 60, were treated with a 3-hour infusion of paclitaxel every 3 weeks. The initial dose was 210 mg/m2; dose escalation to 240 mg/m2 was allowed. Tumor response was assessed at 6-week intervals using radiographic and clinical criteria. Treatment was continued until documented tumor progression or a total of 12 paclitaxel infusions. RESULTS Of 41 eligible patients, all were assessable for treatment toxicity and 40 (98%) were assessable for response. The response rate (disease stabilization or better) was 35%. Twenty-nine patients (71%) underwent dose escalation to 240 mg/m2 without the use of growth factors. Toxicities included alopecia (98%), nausea (22%), arthralgias (32%), CNS toxicity (24%), peripheral neuropathy (15%), cardiac toxicity (7%), and myelosuppression (10% grade 3 or 4 hematologic toxicity). No patient developed febrile neutropenia. There was one allergic reaction (2%). CONCLUSION Paclitaxel is well tolerated at this dose schedule in patients with recurrent malignant glioma, and affords a modest response rate. Because minimal myelotoxicity was encountered in our patients, a dose-escalating phase I/II study of paclitaxel is planned to determine the maximal-tolerated dose (MTD).

2565 Background: HSPPC-96 is derived from a patient’s individual tumor and contains glycoprotein-96 (gp96) polypeptide associated with cancer-specific antigenic peptides. Methods: This ongoing sing...