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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.

Management of febrile neutropenia (FN) is an integral part of supportive care for patients undergoing cancer treatment. The NCCN Guidelines for Hematopoietic Growth Factors provide suggestions for appropriate evaluation, risk determination, prophylaxis, and management of FN. These NCCN Guidelines are intended to guide clinicians in the appropriate use of growth factors for select patients undergoing treatment of nonmyeloid malignancies. These NCCN Guidelines Insights highlight important updates to the NCCN Guidelines regarding the incorporation of newly FDA-approved granulocyte-colony stimulating factor biosimilars for the prevention and treatment of FN.

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<0.0001), had more frequent family history (0.0 vs 41.5 %, p<0.0001), and higher frequency of germline alteration (0.0 vs 84.2 %, p<0.0001). Regarding imaging findings, VHL cases had multiple lesions at presentation more frequently (3.4 vs 82.1 %, p<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<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<0.0001). VHL cases had higher number of treatments per case in the follow-up (1.3 vs 2.1, p<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.

OBJECTIVE With the revised WHO 2016 classification of brain tumors, there has been increasing interest in imaging biomarkers to predict molecular status and improve the yield of genetic testing for diffuse low-grade gliomas (LGGs). The T2-FLAIR–mismatch sign has been suggested to be a highly specific radiographic marker of isocitrate dehydrogenase ( IDH ) gene mutation and 1p/19q codeletion status in diffuse LGGs. The presence of T2-FLAIR mismatch indicates a T2-hyperintense lesion that is hypointense on FLAIR with the exception of a hyperintense rim. METHODS In accordance with PRISMA guidelines, we performed a systematic review of the Ovid Medline, Embase, Scopus, and Cochrane databases for reports of studies evaluating the diagnostic performance of T2-FLAIR mismatch in predicting the IDH and 1p/19q codeletion status in diffuse LGGs. Results were combined into a 2 × 2 format, and the following diagnostic performance parameters were calculated: sensitivity, specificity, positive predictive value, negative predictive value, and positive (LR+) and negative (LR−) likelihood ratios. In addition, we utilized Bayes theorem to calculate posttest probabilities as a function of known pretest probabilities from previous genome-wide association studies and the calculated LRs. Calculations were performed for 1) IDH mutation with 1p/19q codeletion ( IDHmut-Codel ), 2) IDH mutation without 1p/19q codeletion ( IDHmut-Noncodel ), 3) IDH mutation overall, and 4) 1p/19q codeletion overall. The QUADAS-2 (revised Quality Assessment of Diagnostic Accuracy Studies) tool was utilized for critical appraisal of included studies. RESULTS A total of 4 studies were included, with inclusion of 2 separate cohorts from a study reporting testing and validation (n = 746). From pooled analysis of all cohorts, the following values were obtained for each molecular profile— IDHmut-Codel : sensitivity 30%, specificity 73%, LR+ 1.1, LR− 1.0; IDHmut-Noncodel : sensitivity 33.7%, specificity 98.5%, LR+ 22.5, LR− 0.7; IDH : sensitivity 32%, specificity 100%, LR+ 32.1, LR− 0.7; 1p/19q codeletion: sensitivity 0%, specificity 54%, LR+ 0.01, LR− 1.9. Bayes theorem was used to calculate the following posttest probabilities after a positive and negative result, respectively— IDHmut-Codel : 32.2% and 29.4%; IDHmut-Noncodel : 95% and 40%; IDH : 99.2% and 73.5%; 1p/19q codeletion: 0.4% and 35.1%. CONCLUSIONS The T2-FLAIR–mismatch sign was an insensitive but highly specific marker of IDH mutation and I DHmut-Noncodel profile, although significant exceptions may exist to this finding. Tumors with a positive sign may still be IDHwt or 1p/19q codeleted. These findings support the utility of T2-FLAIR mismatch as an imaging-based biomarker for positive selection of patients with IDH -mutant gliomas.

Abstract INTRODUCTION Neuroimaging dogma for glioblastoma asserts that hyperintensity on T1Gd MRI reveals the bulk of the tumor, while T2/FLAIR signal indicates edema. However, it is unclear whether this edema results from immune response or increased tumor cells. Further, one significant driver of the known sex differences in glioblastoma may be differences in immune response, due to the X-linkage of many immune genes. Based on this, we hypothesized that assumptions regarding tumor cellularity in T2/FLAIR images should be tailored to the biological sex of the patient. METHODS Using a retrospective cohort of 18 primary glioblastoma patients receiving multiple image-localized biopsies (82 total) and standard MRI, we assessed: distance of biopsy from T1Gd and T2 areas; a pathologist’s score of percent tumor cell density; and an imaging-based invasion metric, D/ρ. This metric is derived from the biomathematical Proliferation-Invasion model of glioma growth, which features two parameters, net growth rate (ρ) and net invasion rate (D). Their ratio D/ρ is related to degree of invasion, and is estimated from volumetric measurements of MRI abnormalities. Additionally, 25 patient-derived xenograft models implanted in females were grown until moribund, at which point brains were excised and stained for DAPI (to show all cells) and Lamin (to highlight tumor cells). Image processing of lamin-stained sections defines contours of intensity correlating with cell density. RESULTS Outside both the T1Gd and T2 region, male patient biopsies had higher tumor cell densities than females. Males also tended to have higher invasion metrics. Although each set derived from different patients, preclinical metrics of invasion were positively correlated with clinical invasion in females but negatively correlated in males. CONCLUSION Our preliminary finding that cell distribution patterns correlate with imaging metrics differently between the sexes supports the hypothesis that the degree of tumor cell density represented on certain MRI sequences may be sex-specific.

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.

Abstract Glioblastoma (GBM) is a common deadly malignant brain cancer of the central nervous system (CNS), with a median survival of 12–15 months. Scientific advancements are lacking in developing effective therapies for both primary GBM, as well as secondary GBMs, that typically originate as malignant transformation of lower-grade isocitrate dehydrogenase (IDH) 1-mutant tumors. The unique metabolomic profile of IDH1-mutant tumors may present opportunities to develop biomarker signatures of therapeutic efficacy. Microdialysis is an extracellular fluid sampling collection technique utilizing a perfused semipermeable catheter to permit diffusion of molecules between brain interstitium and the perfusate. We hypothesized that microdialysis may identify a metabolomics-based biomarker response to therapy in IDH1-mutant tumors. To test this hypothesis, orthotopic xenografts were generated from two patient-derived GBM lines harboring mutations in IDH1. Perfusates were collected from intra-cranial tumors in aythmic nude mice sampled at baseline and 72h post treatment with temozolomide, an oral alkylating agent used to treat IDH1-mutant gliomas, compared with vehicle treatment, and TMZ-treated non-tumor bearing animals. Perfusates were analyzed via unsupervised metabolomic profiling using both gas and liquid chromatography-mass spectrometry (GC/LC-MS). Tumor specific metabolites such as carnitine and pyruvic acid were detected in microdialysate from tumor bearing mice compared to non-tumor bearing mice. Microdialysis is a feasible technology to identify metabolomics-based biomarker in IDH1-mutant PDX. This work is complemented by parallel analysis of non-IDH1-mutant and TMZ resistant xenografts to yield predictive in vivo tissue biomarkers of drug responsiveness translatable to clinical practice.