Vaccine immunotherapy may improve survival in Glioblastoma (GBM). A multicenter phase II trial was designed to determine: (1) the success rate of manufacturing the Aivita GBM vaccine (AV-GBM-1), (2) ...Adverse Events (AE) associated with AV-GBM-1 administration, and (3) survival.
Fresh suspected glioblastoma tissue was collected during surgery, and patients with pathology-confirmed GBM enrolled before starting concurrent Radiation Therapy and Temozolomide (RT/TMZ) with Intent to Treat (ITT) after recovery from RT/TMZ. AV-GBM-1 was made by incubating autologous dendritic cells with a lysate of irradiated autologous Tumor-Initiating Cells (TICs). Eligible patients were adults (18 to 70 years old) with a Karnofsky Performance Score (KPS) of 70 or greater, a successful TIC culture, and sufficient monocytes collected. A cryopreserved AV-GBM-1 dose was thawed and admixed with 500 μg of Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) before every subcutaneous (s.c.) administration.
Success rates were 97% for both TIC production and monocyte collection. AV-GBM-1 was manufactured for 63/63 patients; 60 enrolled per ITT; 57 started AV-GBM-1. The most common AEs attributed to AV-GBM-1 were local injection site reactions (16%) and flu-like symptoms (10%). Treatment-emergent AEs included seizures (33%), headache (37%), and focal neurologic symptoms (28%). One patient discontinued AV-GBM-1 because of seizures. Median Progression-Free Survival (mPFS) and median Overall Survival (mOS) from ITT enrollment were 10.4 and 16.0 months, respectively. 2-year Overall Survival (OS) is 27%.
AV-GBM-1 was reliably manufactured. Treatment was well-tolerated, but there were numerous treatment-emergent central nervous system AEs. mPFS was longer than historical benchmarks, though no mOS improvement was noted.
NCT, NCT03400917 , Registered 10 January 2018.
OBJECTIVE Glioblastoma multiforme (GBM) is composed of cells that migrate through the brain along predictable white matter pathways. Targeting white matter pathways adjacent to, and leading away ...from, the original contrast-enhancing tumor site (termed leading-edge radiosurgery LERS) with single-fraction stereotactic radiosurgery as a boost to standard therapy could limit the spread of glioma cells and improve clinical outcomes. METHODS Between December 2000 and May 2016, after an initial diagnosis of GBM and prior to or during standard radiation therapy and carmustine or temozolomide chemotherapy, 174 patients treated with radiosurgery to the leading edge (LE) of tumor cell migration were reviewed. The LE was defined as a region outside the contrast-enhancing tumor nidus, defined by FLAIR MRI. The median age of patients was 59 years (range 22-87 years). Patients underwent LERS a median of 18 days from original diagnosis. The median target volume of 48.5 cm
(range 2.5-220.0 cm
) of LE tissue was targeted using a median dose of 8 Gy (range 6-14 Gy) at the 50% isodose line. RESULTS The median overall survival was 23 months (mean 43 months) from diagnosis. The 2-, 3-, 5-, 7-, and 10-year actual overall survival rates after LERS were 39%, 26%, 16%, 10%, and 4%, respectively. Nine percent of patients developed treatment-related imaging-documented changes due to LERS. Nineteen percent of patients were hospitalized for management of edema, 22% for resection of a tumor cyst or new tumor bulk, and 2% for shunting to treat hydrocephalus throughout the course of their disease. Of the patients still alive, Karnofsky Performance Scale scores remained stable in 90% of patients and decreased by 1-3 grades in 10% due to symptomatic treatment-related imaging changes. CONCLUSIONS LERS is a safe and effective upfront adjunctive therapy for patients with newly diagnosed GBM. Limitations of this study include a single-center experience and single-institution determination of the LE tumor target. Use of a leading-edge calculation algorithm will be described to achieve a consistent approach to defining the LE target for general use. A multicenter trial will further elucidate its value in the treatment of GBM.
Background:
Identifying separate dimensions of concussion symptoms may inform a precision medicine approach to treatment. It was previously reported that a bifactor model identified distinct acute ...postconcussion symptom dimensions.
Purpose:
To replicate previous findings of a bifactor structure of concussion symptoms in the Concussion Assessment Research and Education (CARE) Consortium sample, examine measurement invariance from pre- to postinjury, and evaluate whether factors are associated with other clinical and biomarker measures.
Study Design:
Cohort study (Diagnosis); Level of evidence, 2.
Methods:
Collegiate athletes were prospectively evaluated using the Sport Concussion Assessment Tool–3 (SCAT-3) during preseason (N = 31,557); 2789 were followed at <6 hours and 24 to 48 hours after concussion. Item-level SCAT-3 ratings were analyzed using exploratory and confirmatory factor analyses. Bifactor and higher-order models were compared for their fit and interpretability. Measurement invariance tested the stability of the identified factor structure across time. The association between factors and criterion measures (clinical and blood-based markers of concussion severity, symptom duration) was evaluated.
Results:
The optimal structure for each time point was a 7-factor bifactor model: a General factor, on which all items loaded, and 6 specific factors—Vestibulo-ocular, Headache, Sensory, Fatigue, Cognitive, and Emotional. The model manifested strict invariance across the 2 postinjury time points but only configural invariance from baseline to postinjury. From <6 to 24-48 hours, some dimensions increased in severity (Sensory, Fatigue, Emotional), while others decreased (General, Headache, Vestibulo-ocular). The factors correlated with differing clinical and biomarker criterion measures and showed differing patterns of association with symptom duration at different time points.
Conclusion:
Bifactor modeling supported the predominant unidimensionality of concussion symptoms while revealing multidimensional properties, including a large dominant General factor and 6 independent factors: Headache, Vestibulo-ocular, Sensory, Cognitive, Fatigue, and Emotional. Unlike the widely used SCAT-3 symptom severity score, which declines gradually after injury, the bifactor model revealed separable symptom dimensions that have distinct trajectories in the acute postinjury period and different patterns of association with other markers of injury severity and outcome.
Clinical Relevance:
The SCAT-3 total score remains a valuable, robust index of overall concussion symptom severity, and the specific factors identified may inform management strategies. Because some symptom dimensions continue to worsen in the first 24 to 48 hours after injury (ie, Sensory, Fatigue, Emotional), routine follow-up in this time frame may be valuable to ensure that symptoms are managed effectively.
Background: Mental health disorders are linked to prolonged concussion symptoms. However, the association of premorbid anxiety/depression symptoms with postconcussion return-to-play timelines and ...total symptom burden is unclear. Objective: To examine the association of self-reported premorbid anxiety/depression symptoms in collegiate student-athletes with (1) recovery times until asymptomatic, (2) return-to-play, and (3) postconcussion symptom burden. Study Design: Athletes in the Concussion Assessment, Research and Education Consortium completed baseline concussion assessments (Sport Concussion Assessment Tool SCAT3 and Brief Symptom Inventory-18 BSI-18). Athletes were tested postinjury at <6 hours, 24 to 48 hours, time of asymptomatic and start of return-to-play protocol, unrestricted return-to-play, and 6 months after injury. Injured athletes were categorized into 4 groups based on BSI-18 scores: (1) B-ANX, elevated anxiety symptoms only; (2) B-DEP, elevated depression symptoms only; (3) B-ANX&DEP, elevated anxiety and depression symptoms; and (4) B-NEITHER, no elevated anxiety or depression symptoms. Relationship between age, sex, BSI-18 group, SCAT3 total symptom and severity scores, and time to asymptomatic status and return-to-play was assessed with Pearson’s chi-squared test and robust analysis of variance. Level of Evidence: Level 3. Results: Among 1329 athletes with 1352 concussions, no respondents had a self-reported premorbid diagnosis of anxiety/depression. There was no difference in time until asymptomatic or time until return-to-play between BSI-18 groups ( P = 0.15 and P = 0.11, respectively). B-ANX, B-DEP, and B-ANX&DEP groups did not have higher total symptom or severity scores postinjury compared with the B-NEITHER group. Conclusion: Baseline anxiety/depression symptoms in collegiate student-athletes without a mental health diagnosis are not associated with longer recovery times until asymptomatic, longer time to return-to-play, or higher postconcussion total symptom and severity scores compared with athletes without baseline symptoms. Clinical Relevance: Anxiety and depression symptoms without a clear mental health diagnosis should be considered differently from other comorbidities when discussing prolonged recovery in collegiate student-athletes.
Studies of football athletes have implicated repetitive head impact exposure in the onset of cognitive and brain structural changes, even in the absence of diagnosed concussion. Those studies imply ...accumulating damage from successive head impacts reduces tolerance and increases risk for concussion. Support for this premise is that biomechanics of head impacts resulting in concussion are often not remarkable when compared to impacts sustained by athletes without diagnosed concussion. Accordingly, this analysis quantified repetitive head impact exposure in a cohort of 50 concussed NCAA Division I FBS college football athletes compared to controls that were matched for team and position group. The analysis quantified the number of head impacts and risk weighted exposure both on the day of injury and for the season to the date of injury. 43% of concussed athletes had the most severe head impact exposure on the day of injury compared to their matched control group and 46% of concussed athletes had the most severe head impact exposure for the season to the date of injury compared to their matched control group. When accounting for date of injury or season to date of injury, 72% of all concussed athletes had the most or second most severe head impact exposure compared to their matched control group. These trends associating cumulative head impact exposure with concussion onset were stronger for athletes that participated in a greater number of contact activities. For example, 77% of athletes that participated in ten or more days of contact activities had greater head impact exposure than their matched control group. This unique analysis provided further evidence for the role of repetitive head impact exposure as a predisposing factor for the onset of concussion. The clinical implication of these findings supports contemporary trends of limiting head impact exposure for college football athletes during practice activities in an effort to also reduce risk of concussive injury.
This study was performed to obtain safety and survival data for patients with histologically confirmed recurrent glioblastoma multiforme (GBM) who received intralesional lymphokine-activated killer ...(LAK) cells following surgery. LAK cells were generated by incubating peripheral blood mononuclear cells with interleukin-2 for 3 to 5 days in vitro. Forty patients with pathologic confirmation of GBM at surgery had placement of autologous LAK cells into the tumor cavity. The 23 men and 17 women had a median age of 48 years (range 21-76). The median interval from the original diagnosis of glioma to LAK treatment was 10.9 months. Patients received an average of 2.0 +/- 1.0 x 10(9) LAK cells, with viability of 91 +/- 6.8%. Treatment was well tolerated; there was one death within 60 days. At a median follow-up of 2.3 years, median survival post-LAK was 9.0 months; 1-year survival was 34%. Gender, age, location of tumor, LAK cell lytic activity, number of cells implanted, and inclusion of interleukin-2 at cell instillation were not correlated with outcome. Median survival from the date of original diagnosis for 31 patients who had GBM at initial diagnosis was 17.5 months versus 13.6 months for a control group of 41 contemporary GBM patients (p2 = 0.012). This treatment is safe and feasible. The median survival rates are higher than reported in most published series of patients who underwent reoperation for recurrent GBM. A randomized trial would be needed to establish therapeutic benefit.
A multiinstitutional study was conducted to evaluate the technique, dose-selection parameters, and results of gamma knife stereotactic radiosurgery in the management of trigeminal neuralgia. Fifty ...patients at five centers underwent radio-surgery performed with a single 4-mm isocenter targeted at the nerve root entry zone. Thirty-two patients had undergone prior surgery, and the mean number of procedures that had been performed was 2.8 (range 1-7). The target dose of the radiosurgery used in the current study varied from 60 to 90 Gy. The median follow-up period after radiosurgery was 18 months (range 11-36 months). Twenty-nine patients (58%) responded with excellent control (pain free), 18 (36%) obtained good control (50%-90% relief), and three (6%) experienced treatment failure. The median time to pain relief was 1 month (range 1 day-6.7 months). Responses remained consistent for up to 3 years postradiosurgery in all cases except three (6%) in which the patients had pain recurrence at 5, 7, and 10 months. At 2 years, 54% of patients were pain free and 88% had 50% to 100% relief. A maximum radiosurgical dose of 70 Gy or greater was associated with a significantly greater chance of complete pain relief (72% vs. 9%, p = 0.0003). Three patients (6%) developed increased facial paresthesia after radiosurgery, which resolved totally in one case and improved in another. No patient developed other deficits or deafferentation pain. The proximal trigeminal nerve and root entry zone, which is well defined on magnetic resonance imaging, is an appropriate anatomical target for radiosurgery. Radiosurgery using the gamma unit is an additional effective surgical approach for the management of medically or surgically refractory trigeminal neuralgia. A longer-term follow-up review is warranted.
We compared data from the National Collegiate Athletic Association (NCAA) Concussion Study (1999-2001) and the NCAA-Department of Defense Concussion Assessment, Research and Education (CARE) ...Consortium (2014-2017) to examine how clinical management, return to play (RTP) and risk of repeat concussion in collegiate football players have changed over the past 15 years.
We analysed data on reported duration of symptoms, symptom-free waiting period (SFWP), RTP and occurrence of within-season repeat concussion in collegiate football players with diagnosed concussion from the NCAA Study (n=184) and CARE (n=701).
CARE athletes had significantly longer symptom duration (CARE median=5.92 days, IQR=3.02-9.98 days; NCAA median=2.00 days, IQR=1.00-4.00 days), SFWP (CARE median=6.00 days, IQR=3.49-9.00 days; NCAA median=0.98 days, IQR=0.00-4.00 days) and RTP (CARE median=12.23 days, IQR=8.04-18.92 days; NCAA median=3.00 days, IQR=1.00-8.00 days) than NCAA Study athletes (all p<0.0001). In CARE, there was only one case of repeat concussion within 10 days of initial injury (3.7% of within-season repeat concussions), whereas 92% of repeat concussions occurred within 10 days in the NCAA Study (p<0.001). The average interval between first and repeat concussion in CARE was 56.41 days, compared with 5.59 days in the NCAA Study (M difference=50.82 days; 95% CI 38.37 to 63.27; p<0.0001).
Our findings indicate that concussion in collegiate football is managed more conservatively than 15 years ago. These changes in clinical management appear to have reduced the risk of repetitive concussion during the critical period of cerebral vulnerability after sport-related concussion (SRC). These data support international guidelines recommending additional time for brain recovery before athletes RTP after SRC.
INTRODUCTION:To assess patient survival, tumor control, the risk of complications, and selected variables that predict outcome in chondrosarcoma patients who underwent Gamma Knife stereotactic ...radiosurgery (SRS) as primary or adjuvant management.
METHODS:Seven participating centers of the North American Gamma Knife Consortium (NAGKC) identified 45 patients who underwent SRS for chondrosarcoma. The median patient age was 43 years (15-75 years). Thirty-six patients had prior surgical resections and 5 had prior fractionated external beam radiation therapy (RT). Ten patients underwent SRS for recurrent tumors, 27 for residual tumors, and 8 for tumors newly diagnosed by neuroimaging criteria. The median target volume was 8.0 cc (0.9-41 cc) and median margin dose was 15 Gy (6.6-20 Gy).
RESULTS:With median follow-up of 63 months after SRS, 8 patients died due to tumor progression. The overall survival after SRS was 89% at 3 years, 86% at 5 years, and 75% at 10 years. Local tumor progression was confirmed in 9 patients. The progression-free survival after SRS was 83% at 3 years, 83% at 5 years, and 69% at 10 years. Prior RT was significantly associated with lower overall survival and poor progression-free survival. Tumor volume and margin dose were not associated with either overall survival or progression-free survival. Three patients developed remote tumor progression at 12, 27, and 34 months after SRS. Seven patients required surgical resection. Five patients developed adverse radiation effects. Twenty-two (56%) of 39 patients who had cranial deficits before SRS improved. The improvement rate after SRS was optic neuropathy in 38%, oculomotor paralysis in 45%, trochlear paralysis in 33%, trigeminal neuropathy in 13%, abducens paralysis in 61%, facial neuropathy in 38%, hearing loss in 13%, and lower cranial dysfunction in 60%.
CONCLUSION:Stereotactic radiosurgery for chondrosarcomas is an important management option, part of a team approach that includes surgical removal of larger tumors.National Brain Tumor Society Mahaley Clinical Research Award
Repetitive head impact exposure sustained by athletes of contact sports has been hypothesized to be a mechanism for concussion and a possible explanation for the high degree of variability in ...sport-related concussion biomechanics. In an attempt to limit repetitive head impact exposure during the football preseason, the NCAA eliminated two-a-day practices in 2017, while maintaining the total number of team practice sessions. The objective of this study was to quantify head impact exposure during the preseason and regular season in Division I college football athletes to determine whether the 2017 NCAA ruling decreased head impact exposure. 342 unique athletes from five NCAA Division I Football Bowl Subdivision (FBS) programs were consented and enrolled. Head impacts were recorded using the Head Impact Telemetry (HIT) System during the entire fall preseasons and regular seasons in 2016 and 2017. Despite the elimination of two-a-day practices, the number of preseason contact days increased in 2017, with an increase in average hourly impact exposure (i.e., contact intensity), resulting in a significant increase in total head impact burden (+ 26%) for the 2017 preseason. This finding would indicate that the 2017 NCAA ruling was not effective at reducing the head impact burden during the football preseason. Additionally, athletes sustained a significantly higher number of recorded head impacts per week (+ 40%) during the preseason than the regular season, implicating the preseason as a time of elevated repetitive head impact burden. With increased recognition of a possible association between repetitive head impact exposure and concussion, increased preseason exposure may predispose certain athletes to a higher risk of concussion during the preseason and regular season. Accordingly, efforts at reducing concussion incidence in contact sports should include a reduction in overall head impact exposure.
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