Burns, Terry C.

Abstract Background Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. Methods A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10−8. Results Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10−10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10−8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10−9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10−10). Conclusions Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

OBJECTIVE The nature of the volume-outcome relationship in cases with severe traumatic brain injury (TBI) remains unclear, with considerable interhospital variation in patient outcomes. The objective of this study was to understand the state of the volume-outcome relationship at different levels of trauma centers in the United States. METHODS The authors queried the National Trauma Data Bank for the years 2007–2014 for patients with severe TBI. Case volumes for each level of trauma center organized into quintiles (Q1–Q5) served as the primary predictor. Analyzed outcomes included in-hospital mortality, total hospital length of stay (LOS), and intensive care unit (ICU) stay. Multivariable regression models were performed for in-hospital mortality, overall complications, and total hospital and ICU LOSs to adjust for possible confounders. The analysis was stratified by level designation of the trauma center. Statistical significance was established at p < 0.001 to avoid a type I error due to a large sample size. RESULTS A total of 122,445 patients were included. Adjusted analysis did not demonstrate a significant relationship between increasing hospital volume of severe TBI cases and in-hospital mortality, complications, and nonhome hospital discharge disposition among level I–IV trauma centers. However, among level II trauma centers, hospital LOS was longer for the highest volume quintile (adjusted mean difference [MD] for Q5: 2.83 days, 95% CI 1.40–4.26 days, p < 0.001, reference = Q1). For level III and IV trauma centers, both hospital LOS and ICU LOS were longer for the highest volume quintile (adjusted MD for Q5: LOS 4.6 days, 95% CI 2.3–7.0 days, p < 0.001; ICU LOS 3.2 days, 95% CI 1.6–4.8 days, p < 0.001). CONCLUSIONS Higher volumes of severe TBI cases at a lower level of trauma center may be associated with a longer LOS. These results may assist policymakers with target interventions for resource allocation and point to the need for careful prehospital decision-making in patients with severe TBI.

AbstractA recent meeting was held on March 22, 2019, among the FDA, clinical scientists, pharmaceutical and biotech companies, clinical trials cooperative groups, and patient advocacy groups to discuss challenges and potential solutions for increasing development of therapeutics for central nervous system metastases. A key issue identified at this meeting was the need for consistent tumor measurement for reliable tumor response assessment, including the first step of standardized image acquisition with an MRI protocol that could be implemented in multicenter studies aimed at testing new therapeutics. This document builds upon previous consensus recommendations for a standardized brain tumor imaging protocol (BTIP) in high-grade gliomas and defines a protocol for brain metastases (BTIP-BM) that addresses unique challenges associated with assessment of CNS metastases. The “minimum standard” recommended pulse sequences include: (i) parameter matched pre- and post-contrast inversion recovery (IR)–prepared, isotropic 3D T1-weighted gradient echo (IR-GRE); (ii) axial 2D T2-weighted turbo spin echo acquired after injection of gadolinium-based contrast agent and before post-contrast 3D T1-weighted images; (iii) axial 2D or 3D T2-weighted fluid attenuated inversion recovery; (iv) axial 2D, 3-directional diffusion-weighted images; and (v) post-contrast 2D T1-weighted spin echo images for increased lesion conspicuity. Recommended sequence parameters are provided for both 1.5T and 3T MR systems. An “ideal” protocol is also provided, which replaces IR-GRE with 3D TSE T1-weighted imaging pre- and post-gadolinium, and is best performed at 3T, for which dynamic susceptibility contrast perfusion is included. Recommended perfusion parameters are given.

Prognosis for diffuse intrinsic pontine glioma (DIPG) and generally for diffuse midline gliomas (DMG) has only marginally improved over the last ~40 years despite dozens of chemotherapy and other therapeutic trials. The prognosis remains invariably fatal. We present here the rationale for a planned study of adding 5-aminolevulinic acid (5-ALA) to the current irradiation of DIPG or DMG: the 5aai regimen. In a series of recent papers, oral 5-ALA was shown to enhance standard therapeutic ionizing irradiation. 5-ALA is currently used in glioblastoma surgery to enable demarcation of overt tumor margins by virtue of selective uptake of 5-ALA by neoplastic cells and selective conversion to protoporphyrin IX (PpIX), which fluoresces after excitation by 410 nm (blue) light. 5-ALA is also useful in treating glioblastomas by virtue of PpIX’s transfer of energy to O2 molecules, producing a singlet oxygen that in turn oxidizes intracellular DNA, lipids, and proteins, resulting in selective malignant cell cytotoxicity. This is called photodynamic treatment (PDT). Shallow penetration of light required for PpIX excitation and resultant energy transfer to O2 and cytotoxicity results in the inaccessibility of central structures like the pons or thalamus to sufficient light. The recent demonstration that keV and MeV photons can also excite PpIX and generate singlet O2 allows for reconsideration of 5-ALA PDT for treating DMG and DIPG. 5-ALA has an eminently benign side effect profile in adults and children. A pilot study in DIPG/DMG of slow uptitration of 5-ALA prior to each standard irradiation session—the 5aai regimen—is warranted.

Abstract Purpose: Glioblastoma is the most frequent and lethal primary brain tumor. Development of novel therapies relies on the availability of relevant preclinical models. We have established a panel of 96 glioblastoma patient-derived xenografts (PDX) and undertaken its genomic and phenotypic characterization. Experimental Design: PDXs were established from glioblastoma, IDH-wildtype (n = 93), glioblastoma, IDH-mutant (n = 2), diffuse midline glioma, H3 K27M-mutant (n = 1), and both primary (n = 60) and recurrent (n = 34) tumors. Tumor growth rates, histopathology, and treatment response were characterized. Integrated molecular profiling was performed by whole-exome sequencing (WES, n = 83), RNA-sequencing (n = 68), and genome-wide methylation profiling (n = 76). WES data from 24 patient tumors was compared with derivative models. Results: PDXs recapitulate many key phenotypic and molecular features of patient tumors. Orthotopic PDXs show characteristic tumor morphology and invasion patterns, but largely lack microvascular proliferation and necrosis. PDXs capture common and rare molecular drivers, including alterations of TERT, EGFR, PTEN, TP53, BRAF, and IDH1, most at frequencies comparable with human glioblastoma. However, PDGFRA amplification was absent. RNA-sequencing and genome-wide methylation profiling demonstrated broad representation of glioblastoma molecular subtypes. MGMT promoter methylation correlated with increased survival in response to temozolomide. WES of 24 matched patient tumors showed preservation of most genetic driver alterations, including EGFR amplification. However, in four patient–PDX pairs, driver alterations were gained or lost on engraftment, consistent with clonal selection. Conclusions: Our PDX panel captures the molecular heterogeneity of glioblastoma and recapitulates many salient genetic and phenotypic features. All models and genomic data are openly available to investigators.

Abstract INTRODUCTION Central nervous system hemangioblastoma (CNS HGB) is a rare neoplasm, which predominantly arise in the posterior fossa and spinal cord. The etiology is divided into sporadic and von-Hippel Lindau (VHL) disease. The difference in clinical picture of these 2 types of HGB and differentiation of treatment have not been extensively unraveled yet. METHODS Retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic, 1988–2018. RESULTS 117 sporadic and 67 VHL HGBs were treated by Mayo Clinic. No significant difference in sex was observed. Compared with sporadic cases, VHL cases were younger (51.8 vs 36.0 years old, p&lt;0.0001), had more frequent family history (0.0 vs 41.5 %, p&lt;0.0001), and higher frequency of germline alteration (0.0 vs 84.2 %, p&lt;0.0001). Regarding imaging findings, VHL cases had multiple lesions at presentation more frequently (3.4 vs 82.1 %, p&lt;0.0001), it was more common for sporadic lesions to contain cysts (72.2 vs 51.0 %, p=0.0004), the solid portion rate in the entire lesion was larger in VHL lesions (60.2 vs 69.5 %, p=0.02), and the volume was larger in sporadic cases (15.1 vs 6.6 cc, p&lt;0.0001). Regarding treatment, 131 and 123 surgeries were performed for sporadic and VHL cases, respectively, among which the indication of surgery was preventative in 8.4 and 47.3 %, respectively (p&lt;0.0001). VHL cases had higher number of treatments per case in the follow-up (1.3 vs 2.1, p&lt;0.0001). Recurrence-free survival of sporadic cases was significantly longer than that of VHL cases (p=0.007) and overall survival was longer in sporadic cases than VHL, but not significant (p=0.07). CONCLUSION Clinical presentation and tumor appearance on imaging are highly dependent on the etiology. Differences in clinical manifestations require further study, but may reflect contrasting tumor biology that are tied to genetic differences.

Abstract Central nervous system hemangioblastoma (CNS HGB) is a rare neoplasm. Sporadic and von-Hippel Lindau (VHL)-associated forms exist. Predicting tumor growth is difficult, making the indication for intervention challenging. A retrospective analysis of consecutive, neurosurgically managed CNS HGB at Mayo Clinic spanning 1988–2018 was performed to clarify their characteristics. 117 sporadic and 67 VHL HGBs were reviewed. 9 sporadic lesions (8 cases) and 80 VHL lesions (35 cases) had tumor size data at ≥4 follow-up time-points beyond 1 year. The median follow-up was 8.0 years. No statistical difference existed between sporadic and VHL lesions regarding growth speed or growth latency (period of time without growth). Symptomatic lesions showed faster growth than asymptomatic lesions (2.79 vs 0.59 cm3/month, p=0.005). Solid and cystic portions often showed different growth patterns in cases harboring both (66.7%). Cyst growth was faster than solid portions (1.22 vs 1.05cm3/month, p=0.009) and growth latency was longer in the latter (15.2 vs 18.5%, p=0.25). Lesions’ growth were classified as linear (7), exponential (49), cubic (regressed to cubic function curve, 7), saltatory (19) and no-growth (7) patterns. Growth latency often existed in growing lesions (27-out-of-64 linear/exponential/cubic lesions, 57.8%), being average 8.3% of follow-up time. Contrarily, although saltatory lesions grew slower than exponential lesions (p=0.03), their overall growth speed was comparable to linear/cubic lesions (0.67cm3/month), and 9-out-of-19 showed growth surges at their ends. Growth speed at each follow-up roughly depended on the tumor size in cubic regression (R2=0.52). However, whereas total 18/821 time-point lesions showed rapid growth (≥1cm3/m, 2.2%), relatively small lesions (≤2cm3) also occasionally showed rapid growth (5/687, 0.73%). Not all large (>5cm3) lesions grew rapidly (8/62, 12.9%). These results revealed while symptomatic/large/cystic lesions tend to grow more rapidly, HGB behavior is difficult to predict, which stresses the importance of careful follow-up.

Abstract BACKGROUND High-grade gliomas (HGGs) of the brainstem represent a rarer subtype of central nervous system tumors compared to their supratentorial counterpart. Predictors of survival and patterns of care have not yet been established on a national, multi-institutional scale. METHODS The National Cancer Database was queried for adult cases surgically diagnosed with brainstem high-grade glioma. An array of patient demographics, comorbidities, tumor characteristics and treatment parameters were captured. Predictors of survival were investigated using multivariable Cox proportional hazards regression analysis adjusting for age, insurance status, Charlson comorbidity score, tumor grade, tumor size and type of treatment. RESULTS A total of 422 patients (median 51 years, 60% males) were analyzed. Two hundred eighty one received postoperative radiation with chemotherapy (66.6%), thirty-nine had radiation alone (9.2%), while the remaining had no adjuvant treatment (24.2%). Median radiation dosage was 54Gy. Overall median survival was 9.8 months (95% CI 8.8–12). Survival was significantly longer (p< .001) in the chemotherapy+radiation group (median: 14.2 months, 95% CI 11.7–17.1) compared to radiation alone (median: 5.7 months, 95% CI 3.7–12) and no adjuvant treatment (median:1.8 months, 95% CI 1.4–4). In multivariable analysis, increasing age (HR 1.87, 95% CI 1.47–2.37, p< .001) was associated with worse survival, whereas radiation with chemotherapy (HR 0.67, 95% CI 0.46–0.98, p=0.038) were associated with lower hazards of death compared to radiation alone. In subgroup analysis, the effect of adjuvant chemotherapy with radiation remained significant for grade IV (HR 0.46, 95% CI 0.28–0.76, p=0.003), but not for grade III tumors (HR 0.87, 95% CI 0.48–1.58, p=0.65). CONCLUSION Findings of the present analysis demonstrate the effectiveness of radiation with chemotherapy for adult patients with high-grade brainstem gliomas, particularly grade IV. Further research should aim on identifying specific patient profiles and molecular subgroups that are more likely to benefit from multimodality therapy.