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Objective: Immune checkpoint inhibitors such as anti-programmed cell death protein 1 (anti-PD-1) have shown promise for the treatment of cancers such as melanoma, but results for glioblastoma (GBM) have been disappointing thus far. It has been suggested that GBM has multiple mechanisms of immunosuppression, indicating a need for combinatorial treatment strategies. It is well understood that GBM increases glutamate in the tumor microenvironment (TME); however, the significance of this is not well understood. The authors posit that glutamate upregulation in the GBM TME is immunosuppressive. The authors utilized a novel glutamate modulator, BHV-4157, to determine synergy between glutamate modulation and the well-established anti-PD-1 immunotherapy for GBM., Methods: C57BL/6J mice were intracranially implanted with luciferase-tagged GL261 glioma cells. Mice were randomly assigned to the control, anti-PD-1, BHV-4157, or combination anti-PD-1 plus BHV-4157 treatment arms, and median overall survival was assessed. In vivo microdialysis was performed at the tumor site with administration of BHV-4157. Intratumoral immune cell populations were characterized with immunofluorescence and flow cytometry., Results: The BHV-4157 treatment arm demonstrated improved survival compared with the control arm (p < 0.0001). Microdialysis demonstrated that glutamate concentration in TME significantly decreased after BHV-4157 administration. Immunofluorescence and flow cytometry demonstrated increased CD4+ T cells and decreased Foxp3+ T cells in mice that received BHV-4157 treatment. No survival benefit was observed when CD4+ or CD8+ T cells were depleted in mice prior to BHV-4157 administration (p < 0.05)., Conclusions: In this study, the authors showed synergy between anti-PD-1 immunotherapy and glutamate modulation. The authors provide a possible mechanism for this synergistic benefit by showing that BHV-4157 relies on CD4+ and CD8+ T cells. This study sheds light on the role of excess glutamate in GBM and provides a basis for further exploring combinatorial approaches for the treatment of this disease.

Purpose: This study seeks to ascertain whether different primary tumor types have a propensity for brain metastases (BMs) in different cerebral vascular territories and cerebral edema., Methods: Consecutive adult patients who underwent surgical resection of a BM at a tertiary care institution between 2001 and 2011 were retrospectively reviewed. Only patients with the most common primary cancers (lung, breast, skin-melanoma, colon, and kidney) were included. Preoperative MRIs were reviewed to classify all tumors by cerebral vascular territory (anterior cerebral artery-ACA, lenticulostriate, middle cerebral artery-MCA, posterior cerebral artery-PCA, posterior fossa, and watershed), and T2-weighted FLAIR widths were measured. Chi square analyses were performed to determine differences in cerebral vascular distribution by primary tumor type, and one-way ANOVA analyses were performed to determine FLAIR signal differences., Results: 669 tumors from 388 patients were classified from lung (n = 316 BMs), breast (n = 144), melanoma (n = 119), renal (n = 47), and colon (n = 43). BMs from breast cancer were less likely to be located in PCA territory (n = 18 [13%]; χ 2  = 6.10, p = 0.01). BMs from melanoma were less likely to be located in cerebellar territory (n = 11 [9%]; χ 2  = 14.1, p < 0.001), and more likely to be located in lateral (n = 5 [4%]; χ 2  = 4.56, p = 0.03) and medial lenticulostriate territories (n = 2 [2%]; χ 2  = 6.93, p = 0.009). BMs from breast and melanoma had shorter T2-FLAIR widths, with an average [IQR] of 47.2 [19.6-69.2] mm (p = 0.01) and 41.2 [14.4-62.7] mm (p = 0.002) respectively. Conversely, BMs from renal cancer had longer T2-FLAIR widths (64.2 [43.6-80.8] mm, p = 0.002)., Conclusions: These findings suggest that different primary tumor types could have propensities for different cerebral vascular territories and cerebral edema.

Object: It is becoming well-established that increasing extent of resection with decreasing residual volume is associated with delayed recurrence and prolonged survival for patients with glioblastoma (GBM). These prior studies are based on evaluating the contrast-enhancing (CE) tumour and not the surrounding fluid attenuated inversion recovery (FLAIR) volume. It therefore remains unclear if the resection beyond the CE portion of the tumour if it translates into improved outcomes for patients with GBM., Methods: Adult patients who underwent resection of a primary glioblastoma at a tertiary care institution between January 1, 2007 and December 31, 2012 and underwent radiation and temozolomide chemotherapy were retrospectively reviewed. Pre and postoperative MRI images were measured for CE tumour and FLAIR volumes. Multivariate proportional hazards were used to assess associations with both time to recurrence and death. Values with p < 0.05 were considered statistically significant., Results: 245 patients met the inclusion criteria. The median [IQR] preoperative CE and FLAIR tumour volumes were 31.9 [13.9-56.1] cm 3 and 78.3 [44.7-115.6] cm 3 , respectively. Following surgery, the median [IQR] postoperative CE and FLAIR tumour volumes were 1.9 [0-7.1] cm 3 and 59.7 [29.7-94.2] cm 3 , respectively. In multivariate analyses, the postoperative FLAIR volume was not associated with recurrence and/or survival (p > 0.05). However, the postoperative CE tumour volume was significantly associated with both recurrence [HR (95%CI); 1.026 (1.005-1.048), p = 0.01] and survival [HR (95%CI); 1.027 (1.007-1.032), p = 0.001]. The postoperative FLAIR volume was also not associated with recurrence and/or survival among patients who underwent gross total resection of the CE portion of the tumour as well as those who underwent supratotal resection., Conclusions: In this study, the volume of CE tumour remaining after resection is more important than FLAIR volume in regards to recurrence and survival for patients with GBM.