e13540 Background: Mutations in the histone genes H3.3 and H3.1 are driver events in pediatric and adult gliomas and carry diagnostic and prognostic importance for tumors originating from midline structures. Patients with tumors affected by these mutations are notoriously difficult to treat, and the prevalence and molecular correlates of H3 mutations in a large glioma population have not been systematically reported. We aim to survey a large cohort of gliomas for H3-mutations. Methods: Consecutive gliomas submitted for tumor profiling at Caris Life Sciences from 2015- 2018 were analyzed. NextGen sequencing was done on 592 genes (NextSEQ Illumina); MGMT promoter methylation was tested by pyrosequencing; and EGFRvIII and gene fusions were tested by RNA-sequencing (ArcherDx FusionPlex). Results: Of the 1763 tumors analyzed, 41 harbored H3F3A alterations, including 33 with the K27M mutation (4 arose from the spinal cord, 1 from cerebellum, 1 from brain stem, 4 from thalamus, and 23 from brain, NOS). Eight G34R mutations were identified. A HIST1H3B-K27M was detected in a tumor from the brain stem. Overall, H3 mutations were more prevalent in pediatric tumors (8 of 26, 31%) than adult tumors (34 of 1737, 2%). All H3 mutations seen in pediatric tumors were from grade IV tumors. Among the 34 H3-mutated adult tumors, histology differed. There were 2 grade II tumors (diffuse astrocytoma), 1 low grade glioma from the spinal cord, 1 anaplastic ganglioglioma and 2 anaplastic astrocytomas. In the investigated cohort, H3-mutations were mutually exclusive of IDH1/2 mutations and EGFR alterations. Significantly higher mutation rates were seen in H3-mutated tumors for TP53 (69%. Vs. 37%), ATRX (46% vs. 24%), NF1 (23% vs. 12%) , PDGFRA (17% vs. 1%), FGFR1 (12% vs. 1%), FBXW7 (5% vs. 0), BLM (3% vs. 0) and TSC2 (2% vs.0) compared with H3-WT (p < 0.05). The H3-WT tumors were more enriched for MGMT-methylation (53% vs. 26%) and PTEN mutation (22% vs. 7%) (p < 0.05). In H3-mutated tumors that were MGMT-methylated (n = 10), most H3-mutations seen were G34R (n = 8) while K27M (n = 2) was largely exclusive. Conclusions: This survey of a large cohort of gliomas revealed a heterogeneous distribution of H3 mutations. The co-occurring molecular alterations seen in H3-mutated tumors further support the hypothesis that these tumors are a distinct molecular entity. By better characterizing these associations, we are closer to developing more insight into novel treatment strategies for a class of tumors with historically dismal prognosis.
Perfusion-weighted MRI (PWI) and amino acid PET are increasingly used for glioma imaging before and after initial treatment. While some studies found a good correlation between these two imaging modalities, others demonstrated discrepancies in various glioma groups and found only a limited spatial overlap of regions with the highest amino acid uptake and highest perfusion. In this study, we compared amino acid uptake measured by PET and relative cerebral blood volume (CBV) from PWI in contrast-enhancing and non-enhancing portions of glioblastomas. Contrast-enhanced T1, T2/FLAIR images, CBV maps from PWI, and alpha[C-11]-methyl-L-tryptophan (AMT)-PET images were co-registered in 23 patients (mean age: 56 years) with newly-diagnosed (n=10) or recurrent (n=13) glioblastoma. Tumoral amino acid uptake and CBV, expressed as tumor/contralateral normal brain (cortex for AMT, white matter for CBV, respectively) [T/N] ratios, were measured and compared in contrast-enhancing and non-enhancing (but T2/FLAIR-positive) regions. High AMT uptake on PET was measured in 23 contrast-enhancing regions of 21 patients (mean T/N ratio: 2.43). Similarly, high AMT uptake was also found in 18 adjacent non-enhancing regions of 16 patients (mean T/N: 2.35), indicating tumor-infiltrated brain. On the other hand, 27 contrast-enhancing regions (in 21 patients) showed significantly lower AMT uptake (mean T/N: 1.45; p<0.001). Relative CBV values showed very similar values in high-AMT and low-AMT contrast-enhancing tumor portions (mean T/N white matter ratios: 5.7 in both regions) and were slightly lower in non-enhancing PET+ brain regions (T/N: 4.9). Corresponding AMT and CBV T/N ratios showed no significant correlations. AMT/CBV comparative findings were similar in pre- and post-treatment glioblastoma subgroups. Amino acid PET and perfusion MRI provide substantially different diagnostic information in newly-diagnosed and recurrent glioblastomas. High amino acid uptake on PET can detect metabolically active tumor portions in contrast-enhancing and non-enhancing regions regardless of perfusion status.
✓ Residual seizures after functional hemispherectomy occur in approximately 20% of patients with catastrophic epilepsy. These episodes are traditionally attributed to incomplete disconnection, persistent epileptogenic activity in the ipsilateral insular cortex, or bilateral independent epileptogenic activity. The authors report on the case of an 8-year-old boy with an intractable seizure disorder who had classic frontal adversive seizures related to extensive unilateral left hemispheric cortical dysplasia. The initial intervention consisted of extensive removal of the epileptic frontal and precentral dysplastic tissue and multiple subpial transections of the dysplastic motor strip, guided by intraoperative electrocorticography. Subsequently, functional hemispherectomy including insular cortex resection was performed for persistent attacks. After a seizure-free period of 6 months, a new pattern ensued, consisting of an aura of fear, dystonic posturing of the right arm, and unusual postictal hyperphagia coupled with an interictal diencephalic-like syndrome. Electroencephalography and ictal/interictal single-photon emission computerized tomography were used to localize the residual epileptic discharges to deep ipsilateral structures. Results of magnetic resonance imaging indicated a complete disconnection except for a strip of residual frontobasal tissue. Therefore, a volumetric resection of the epileptogenic frontal basal tissue up to the anterior commissure was completed. The child has remained free of seizures during 21 months of follow-up review. Standard hemispherectomy methods provide extensive disconnection, despite the presence of residual frontal basal cortex. However, rarely, and especially if it is dysplastic, this tissue can represent a focus for refractory seizures. This is an important consideration in determining the source of ongoing seizures posthemispherectomy in patients with extensive cortical dysplasia. It remains important to assess them fully before considering their disease refractory to surgical treatment.
The knowledge of transporter protein expression and function at the human blood-brain barrier (BBB) is critical to prediction of drug BBB penetration and design of strategies for improving drug delivery to the brain or brain tumor. This study determined absolute transporter protein abundances in isolated microvessels of human normal brain (N = 30), glioblastoma (N = 47), rat (N = 10) and mouse brain (N = 10), and cell membranes of MDCKII cell lines, using targeted proteomics. In glioblastoma microvessels, efflux transporters (ABCB1 and ABCG2), monocarboxylate transporter 1 (MCT1), glucose transporter 1 (GLUT1), sodium-potassium pump (Na/K ATPase), and Claudin-5 protein levels were significantly reduced, while large neutral amino acid transporter 1 (LAT1) was increased and GLU3 remained the same, as compared with human normal brain microvessels. ABCC4, OATP1A2, OATP2B1, and OAT3 were undetectable in microvessels of both human brain and glioblastoma. Species difference in BBB transporter abundances was noted. Cellular permeability experiments and modeling simulations suggested that not a single apical uptake transporter but a vectorial transport system consisting of an apical uptake transporter and basolateral efflux mechanism was required for efficient delivery of poor transmembrane permeability drugs from the blood to brain.
Patients with low-grade glioma frequently have brain tumor–related epilepsy, which is more common than in patients with high-grade glioma. Treatment for tumor-associated epilepsy usually comprises a combination of surgery, anti-epileptic drugs (AEDs), chemotherapy, and radiotherapy. Response to tumor-directed treatment is measured primarily by overall survival and progression-free survival. However, seizure frequency has been observed to respond to tumor-directed treatment with chemotherapy or radiotherapy. A review of the current literature regarding seizure assessment for low-grade glioma patients reveals a heterogeneous manner in which seizure response has been reported. There is a need for a systematic approach to seizure assessment and its influence on health-related quality-of-life outcomes in patients enrolled in low-grade glioma therapeutic trials. In view of the need to have an adjunctive metric of tumor response in these patients, a method of seizure assessment as a metric in brain tumor treatment trials is proposed.
Supplementary Table from [<sup>89</sup>Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B–targeted Therapy in Triple-negative Breast Cancer
<div>Abstract<p>There is a need for prognostic markers to select patients most likely to benefit from antibody–drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with <sup>89</sup>Zr-labeled anti-gpNMB antibody ([<sup>89</sup>Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [<sup>89</sup>Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUV<sub>mean</sub> of [<sup>89</sup>Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 ± 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2–4 weeks after treatment with CDX-011 (Spearman ρ = −0.8). However, pretreatment PET imaging with [<sup>89</sup>Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.</p></div>
Supplementary Figure from [<sup>89</sup>Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B–targeted Therapy in Triple-negative Breast Cancer
