David S. Enterline

D2C7-immunotoxin (IT), a dual-specific IT targeting wild-type epidermal growth factor receptor (EGFR) and mutant EGFR variant III (EGFRvIII) proteins, demonstrates encouraging survival outcomes in a subset of patients with glioblastoma. We hypothesized that immunosuppression in glioblastoma limits D2C7-IT efficacy. To improve the response rate and reverse immunosuppression, we combined D2C7-IT tumor cell killing with αCD40 costimulation of antigen-presenting cells. In murine glioma models, a single intratumoral injection of D2C7-IT+αCD40 treatment activated a proinflammatory phenotype in microglia and macrophages, promoted long-term tumor-specific CD8 ⁺ T cell immunity, and generated cures. D2C7-IT+αCD40 treatment increased intratumoral Slamf6 ⁺ CD8 ⁺ T cells with a progenitor phenotype and decreased terminally exhausted CD8 ⁺ T cells. D2C7-IT+αCD40 treatment stimulated intratumoral CD8 ⁺ T cell proliferation and generated cures in glioma-bearing mice despite FTY720-induced peripheral T cell sequestration. Tumor transcriptome profiling established CD40 up-regulation, pattern recognition receptor, cell senescence, and immune response pathway activation as the drivers of D2C7-IT+αCD40 antitumor responses. To determine potential translation, immunohistochemistry staining confirmed CD40 expression in human GBM tissue sections. These promising preclinical data allowed us to initiate a phase 1 study with D2C7-IT+αhCD40 in patients with malignant glioma (NCT04547777) to further evaluate this treatment in humans.

BACKGROUND AND PURPOSE: Selumetinib is a promising MAP (mitogen-activated protein) kinase (MEK) 1/2 inhibitor treatment for pediatric low-grade gliomas. We hypothesized that MR imaging–derived ADC histogram metrics would be associated with survival and response to treatment with selumetinib. MATERIALS AND METHODS: Children with recurrent, refractory, or progressive pediatric low-grade gliomas who had World Health Organization grade I pilocytic astrocytoma with KIAA1549–BRAF fusion or the BRAF V600E mutation (stratum 1), neurofibromatosis type 1–associated pediatric low-grade gliomas (stratum 3), or sporadic non-neurofibromatosis type 1 optic pathway and hypothalamic glioma (OPHG) (stratum 4) were treated with selumetinib for up to 2 years. Quantitative ADC histogram metrics were analyzed for total and enhancing tumor volumes at baseline and during treatment. RESULTS: Each stratum comprised 25 patients. Stratum 1 responders showed lower values of SD of baseline ADC_total as well as a larger decrease with time on treatment in ADC_total mean, mode, and median compared with nonresponders. Stratum 3 responders showed a greater longitudinal decrease in ADC_total. In stratum 4, higher baseline ADC_total skewness and kurtosis were associated with shorter progression-free survival. When all 3 strata were combined, responders showed a greater decrease with time in ADC_total mode and median. Compared with sporadic OPHG, neurofibromatosis type 1–associated OPHG had lower values of ADC_total mean, mode, and median as well as ADC_enhancement mean and median and higher values of ADC_total skewness and kurtosis at baseline. The longitudinal decrease in ADC_total median during treatment was significantly greater in sporadic OPHG compared with neurofibromatosis type 1–associated OPHG. CONCLUSIONS: ADC histogram metrics are associated with progression-free survival and response to treatment with selumetinib in pediatric low-grade gliomas.

BACKGROUND AND PURPOSE: Contrast-enhanced MR imaging provides essential information for pediatric imaging applications. We evaluated gadobenate dimeglumine for contrast-enhanced MR imaging of infants younger than 2 years of age. MATERIALS AND METHODS: Ninety children younger than 2 years of age (including 55 children younger than 1 year) who underwent enhanced MR imaging of the CNS with gadobenate dimeglumine at 0.1 mmol/kg body weight ± 25% by volume were retrospectively enrolled at 2 imaging centers. Safety data were assessed for adverse events and, when available, vital signs and electrocardiogram and clinical laboratory values obtained from 48 hours before until 48 hours after the MR imaging examination. The efficacy of gadobenate dimeglumine–enhanced MR imaging was evaluated prospectively by 3 blinded, unaffiliated readers in terms of the accuracy of combined pre- and postcontrast images relative to precontrast images alone for differentiation of tumor from non-neoplastic disease and the correct diagnosis of specific disease. Differences were tested using the McNemar test. A possible effect of dose on diagnostic accuracy was assessed using the Fisher exact test. RESULTS: Nine nonserious adverse events were reported for 8 (8.8%) patients. Five adverse events occurred in patients 12 months of age or older. All events occurred at least 24 hours after gadobenate dimeglumine administration, and in each case, the investigating radiologist considered that there was no reasonable possibility of a relationship to gadobenate dimeglumine. No clinically meaningful changes in vital signs, electrocardiogram results, or laboratory parameters were reported. Accurate differentiation of tumor from non-neoplastic disease and exact matching of each specific MR imaging–determined diagnosis with the on-site final diagnosis were achieved in significantly more patients by each reader following evaluation of combined pre- and postcontrast images relative to precontrast images alone (91.0%–94.4% versus 75.3%–87.6%, P < .04, and 66.3%–73.0% versus 52.8%–58.4%, P < .02, respectively). No significant differences (P > .133) in diagnostic accuracy were noted between patients receiving ≤0.08 mmol/kg of gadobenate dimeglumine and patients receiving >0.08 mmol/kg of gadobenate dimeglumine. CONCLUSIONS: Gadobenate dimeglumine is safe and effective for pediatric MR imaging.

Chiari Type I Malformation (CMI) is characterized by herniation of the cerebellar tonsils through the foramen magnum at the base of the skull, resulting in significant neurologic morbidity. As CMI patients display a high degree of clinical variability and multiple mechanisms have been proposed for tonsillar herniation, it is hypothesized that this heterogeneous disorder is due to multiple genetic and environmental factors. The purpose of the present study was to gain a better understanding of what factors contribute to this heterogeneity by using an unsupervised statistical approach to define disease subtypes within a case-only pediatric population.

Background: The purpose of this study is to retrospectively review our experience with stent-assisted embolization of patients with an acutely ruptured cerebral aneurysm. Methods: Medical records and imaging were reviewed for 36 patients who underwent stent-assisted embolization of a ruptured cerebral aneurysm. Results: Seventeen patients (47%) received a preprocedural loading dose of clopidogrel and five patients (14%) received an intraprocedural dose of clopidogrel. The remaining 14 patients (36%) were treated with antiplatelet therapy following the procedure. Six (17%) stent related intraprocedural thromboembolic complications were encountered; four of these resolved (one partial, three complete) following treatment with abciximab and/or heparin during the procedure. Five of the six thromboembolic events occurred in patients who were not pretreated with clopidogrel (P = 0.043). Two patients in this series (6%) had a permanent thrombotic complication resulting in mild hemiparesis in one patient, and hemianopsia in the second. No procedure related hemorrhagic complications occurred in any patient. One patient had a spontaneous parenchymal hemorrhage contralateral to the treated aneurysm discovered 10 days after treatment. Twenty-eight patients (78%) had a Glasgow Outcome Score of 4 or better at discharge. Seven of 21 patients (33%) with angiographic follow-up required further treatment of the coiled aneurysm. Conclusion: Stent-assisted coil embolization is an option for treatment of ruptured wide neck ruptured aneurysms and for salvage treatment during unassisted embolization of ruptured aneurysms but complications and retreatment rates are higher than for routine clipping or coiling of cerebral aneurysms. Pretreatment with clopidogrel appears effective in reducing thrombotic complications without significant increasing risk of hemorrhagic complications.