Citations

Posterior fossa (PF) diffuse gliomas in pediatric patients frequently harbor the H3 K27M mutation. Among adults, PF diffuse gliomas are rare, with limited data regarding molecular features and clinical outcomes. We identified 28 adult PF diffuse glioma patients (17 males; median: 50 y, range: 19 to 78 y), with surgery performed at our institution (13 brainstem; 15 cerebellum). Histologic subtypes included anaplastic astrocytoma (n=21), glioblastoma (n=6), and diffuse astrocytoma (n=1). Immunohistochemistry was performed for H3 K27M (n=26), IDH1-R132H (n=28), and ATRX (n=28). A 150-gene neuro-oncology-targeted next-generation sequencing panel was attempted in 24/28, with sufficient informative material in 15 (51.7%). Tumors comprised 4 distinct groups: driver mutations in H3F3A (brainstem=4; cerebellum=2), IDH1 (brainstem=4; cerebellum=4), TERT promotor mutation (brainstem=0; cerebellum=3), and none of these (n=5), with the latter harboring mutations of TP53 , PDGFRA , ATRX , NF1 , and RB1 . All TERT promoter–mutant cases were IDH-wild-type and arose within the cerebellum. To date, 20 patients have died of disease, with a median survival of 16.3 months, 1-year survival of 67.5%. Median survival within the subgroups included: H3F3A =16.4 months, IDH mutant=113.4 months, and TERT promoter mutant=12.9 months. These findings suggest that PF diffuse gliomas affecting adults show molecular heterogeneity, which may be associated with patient outcomes and possible response to therapy, and supports the utility of molecular testing in these tumors.

AbstractBranchio‐oto‐renal spectrum disorder (BORSD) is a rare autosomal dominant condition characterized by ear abnormalities with hard of hearing/deafness, second branchial arch malformations and renal anomalies. Pathogenic variations in EYA1 gene are found in the majority of clinically diagnosed individuals with BORSD. We describe an infant with BORSD related to a paternally inherited heterozygous pathogenic variation in EYA1 gene presenting with poor growth and hypoglycemia due to growth hormone deficiency. Magnetic resonance imaging revealed a diminutive pituitary gland and morphologically abnormal sella. Upon initiation of growth hormone therapy, the hypoglycemia resolved and catch up growth ensued. Pituitary abnormalities have not been reported previously in patients with BORSD. The zebrafish ortholog of eya1 is important for the development of adenohypophysis, suggesting that this patient's growth hormone deficiency and pituitary abnormality are part of BORSD. Inclusion of screening for pituitary hormone deficiency and pituitary imaging should be considered as a part of surveillance in patients with BORSD.

Abstract Advances in treatment of oligodendroglioma represent arguably the most significant recent development in the treatment of brain tumors, with multiple clinical trials demonstrating that median survival is approximately doubled in patients with World Health Organization grade II and III 1p/19q codeleted gliomas (ie, oligodendrogliomas) treated with procarbazine, lomustine, vincristine chemotherapy and radiation vs radiation alone. However, chemoradiotherapy itself is not without morbidity, including both short-term toxicities primarily related to chemotherapy and longer-term cognitive issues likely due to radiation. Patients and physicians both desire maximally effective therapy with minimal toxicity, and it remains unclear whether some patients with macroscopic residual disease after surgery can safely delay therapy, to avoid or delay toxicity, while simultaneously preserving the full benefits of treatment. In this article, experts in the field discuss the rationale for the approaches of up-front treatment with chemoradiotherapy and initial observation, respectively.

Abstract Patients with primary brain tumors often experience seizures, which can be the presenting symptom or occur for the first time at any point along the illness trajectory. In addition to causing morbidity, seizures negatively affect independence and quality of life in other ways, for example, by leading to loss of driving privileges. Long-term therapy with antiepileptic drugs (AEDs) is the standard of care in brain tumor patients with seizures, but the role of prophylactic AEDs in seizure-naive patients remains controversial. In this article, experts in the field discuss the issues of AED efficacy and toxicity, and explain their differing recommendations for routine use of prophylactic AEDs.

2065 Background: In the absence of proven environmental or behavioral risk factors, patient age and sex remain the most important predictors of primary brain tumor risk. In coming years, an increasing incidence of brain tumors in the United States can be anticipated based on shifts in the demographic structure of the population. This study provides estimates of glioblastoma and meningioma incidence through 2050. Methods: Group-specific glioblastoma and meningioma incidence rates based on age (eleven categories) and sex were calculated from National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) data for the period 2004-2008. United States Census projections based on data from the 2000 census were used to compute the size of the twenty-two demographic subpopulations of interest in 2010, 2020, 2030, 2040, and 2050. The estimated number of new glioblastoma and meningioma diagnoses for each of these years was calculated from the defined incidence rates and population size. Results: Crude annual tumor incidence rates were 3.13 per 100,000 persons for glioblastoma and 6.81 per 100,000 persons for meningioma. While the overall size of the population is expected to increase only 42% between 2010 and 2050, the number of Americans over 65 years of age, the group at highest risk of glioblastoma and meningioma, is expected to increase by 120%. We estimate that the number of new glioblastoma diagnoses will rise from 10,688 in 2010 to 18,466 in 2050, a 72% increase. Likewise, the number of new meningioma diagnoses will rise from 22,946 to 40,680 over the same period, a 77% increase. Conclusions: The number of new glioblastoma and meningioma diagnoses will increase substantially in the future. This analysis, which assumes a fixed incidence rate, may underestimate the true magnitude of the coming change given reports suggesting that incidence rates of glioblastoma and meningioma are rising over time.

Abstract AbstractThe T2-FLAIR (fluid attenuated inversion recovery) mismatch sign is an easily detectable imaging sign on routine clinical MRI studies that suggests diagnosis of isocitrate dehydrogenase (IDH)–mutant 1p/19q non-codeleted gliomas. Multiple independent studies show that the T2-FLAIR mismatch sign has near-perfect specificity, but low sensitivity for diagnosing IDH-mutant astrocytomas. Thus, the T2-FLAIR mismatch sign represents a non-invasive radiogenomic diagnostic finding with potential clinical impact. Recently, false positive cases have been reported, many related to variable application of the sign’s imaging criteria and differences in image acquisition, as well as to differences in the included patient populations. Here we summarize the imaging criteria for the T2-FLAIR mismatch sign, review similarities and differences between the multiple validation studies, outline strategies to optimize its clinical use, and discuss potential opportunities to refine imaging criteria in order to maximize its impact in glioma diagnostics.

Abstract Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described epileptogenic tumor characterized by oligodendroglioma-like components, aberrant CD34 expression, and genetic MAPK pathway activation through alterations such as BRAF V600E mutation, and FGFR2-KIAA1598/CTNNA3 and FGFR3-TACC3 fusions. We report the molecular profiling of PLNTY in 9 patients, 7 female: 2 male, median age at diagnosis of 16 years (range, 5–34). All tumors were supratentorial with diagnostic morphological features of PLNTY including oligodendroglioma-like areas and strong diffuse CD34 immunostaining. Four (of 9; 44%) tumors were positive for BRAF V600E immunostain, indicating the presence of a BRAF V600E mutation. The 6 cases evaluated for IDH status were negative by IDH1-R132H immunostain (n=5; 3 BRAF V600E-negative and 2 BRAF V600E-positive) or by NGS (n=1; BRAF V600E-negative). Oncoscan chromosomal microarray performed in 5 BRAF V600E-negative tumors showed recurrent copy number changes including gain of whole chromosomes 5, 7, 8, 9, 12, 18, 19, 20, 21 and X, and loss of chromosomes 1, 2, 10q, 13, 22 and Xq. The 10q losses (n=2) were highly suggestive of an FGFR2-KIAA1598 and of a potentially novel FGFR2 underlying fusion event in one case each. Custom targeted neuro-oncology DNA and RNA NGS panel performed in 2 cases revealed a fusion similar to fusions previously reported in pilocytic astrocytoma: one with a KIAA1549-BRAF (exon 15-exon 9) fusion associated with a 7q34 ~785 kilobase deletion rather than the characteristic ~2 megabase duplication seen in pilocytic astrocytoma, and another with a QKI-NTRK2 (exon 6-exon 15) fusion associated with a 9q21 ~191 kilobase duplication disrupting NTRK2. The KIAA1549-BRAF fusion-positive case also had a TP53 mutation with loss of whole chromosome 17, suggesting TP53 complete inactivation. This study confirms that PLNTY is a low-grade neuroepithelial tumor with frequent MAPK pathway activation and expands the spectrum of MAPK activating alterations observed in PLNTY.

Abstract BACKGROUND 177Lu-Dotatate (177Lu-DOTA0-Tyr3-Octreotate) is a beta-particle emitting somatostatin analog recently FDA approved for the treatment of somastatin receptor-positive gastroenteropancreatic neuroendocrine tumors. Somatostatin receptors are highly expressed in almost all meningiomas, therefore 177Lu-Dotatate may be a reasonable treatment strategy for this disease. Furthermore, the short path length of the beta particle should allow for treatment of previously radiated patients with low risk of cerebral radiation necrosis. CASE STUDY: A 61 year-old male presented with a history of atypical meningioma (WHO grade II), recurrent as anaplastic meningioma (WHO grade III). His previous treatments included multiple surgical resections, fractionated radiation therapy, stereotactic radiosurgery, everolimus/octreotide LAR, bevacizumab and hydroxyurea. MRI imaging revealed rapid volumetric progression over the prior nine months with a near tripling in size from 29.9 cm3 to 80.4 cm3. In-111 octreotide confirmed the presence of somatostatin receptors within the tumor. 177Lu-Dotatate was administered intravenously at a dose of 200 millicuries per dose, every eight weeks for four cycles. Treatment was tolerated very well, with no significant adverse events. Tumor volume initially increased to 98.3 cm3 after cycle 1 of treatment, and subsequently decreased to 91.2 cm3 after cycle 2. Eight months after treatment onset, the tumor volume remained stable (93.4 cm3). CONCLUSION 177Lu-Dotatate may be a safe and effective strategy for the treatment of somastatin receptor-positive meningioma. The transient increase in tumor volume after the first dose in this case may have represented delayed treatment effect or pseudoprogression. A phase II clinical trial is currently being activated to determine the progression-free survival associated with 177Lu-Dotatate in patients with recurrent meningioma.

Abstract The treatment of resected brain metastasis has shifted away from the historical use of whole-brain radiotherapy (WBRT) toward adjuvant radiosurgery (stereotactic radiosurgery [SRS]) based on a recent prospective clinical trial demonstrating less cognitive decline with the use of SRS alone and equivalent survival as compared with WBRT. Whereas all level 1 evidence to date concerns single-fraction SRS for postoperative brain metastasis, there is emerging evidence that fractionated stereotactic radiotherapy (FSRT) may improve local control at the resected tumor bed. The lack of direct comparative data for SRS vs FSRT results in a diversity in clinical practice. In this article, Greenspoon and Roberge defend the use of SRS as the standard of care for resected brain metastasis, whereas Palmer and Brown argue for FSRT.