Citations

Abstract Glioblastoma (GBM) is a rapidly fatal malignancy typically treated with radiation and temozolomide (TMZ), an alkylating chemotherapeutic. These cytotoxic therapies cause oxidative stress and DNA damage, yielding a senescent-like state of replicative arrest in surviving tumor cells. Unfortunately, recurrence is inevitable and may be driven by surviving tumor cells eventually escaping senescence. A growing number of so-called “senolytic” drugs have been recently identified that are defined by their ability to selectively eliminate senescent cells. A growing inventory of senolytic drugs is under consideration for several diseases associated with aging, inflammation, DNA damage, as well as cancer. Ablation of senescent tumor cells after radiation and chemotherapy could help mitigate recurrence by decreasing the burden of residual tumor cells at risk of recurrence. This strategy has not been previously explored for GBM. We evaluated a panel of 10 previously described senolytic drugs to determine whether any could exhibit selective activity against human GBM persisting after exposure to radiation or TMZ. Three of the 10 drugs have known activity against BCL-XL and preferentially induced apoptosis in radiated or TMZ-treated glioma. This senolytic activity was observed in 12 of 12 human GBM cell lines. Efficacy could not be replicated with BCL-2 inhibition or senolytic agents acting against other putative senolytic targets. Knockdown of BCL-XL decreased survival of radiated GBM cells, whereas knockdown of BCL-2 or BCL-W yielded no senolytic effect. Implications: These findings imply that molecularly heterogeneous GBM lines share selective senescence-induced BCL-XL dependency increase the significance and translational relevance of the senolytic therapy for latent glioma.

Abstract Background Glioblastoma (GBM), the most common primary brain tumor, has a median survival of 15–16 months. Immunotherapy is promising but GBM-mediated immunosuppression remains a barrier. GBMs express the interferon-gamma (IFN-γ)-responsive immunosuppressive molecules programmed cell death ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (IDO1). Extracellular vesicles (EVs) have also been implicated in GBM-mediated immunosuppression, in part through PD-L1. We therefore sought to determine if GBM IFN-γ exposure increased GBM EV-mediated immunosuppression and mechanisms underlying this. Methods Human GBM-derived cells were cultured in the presence/absence of IFN-γ. EVs were harvested. PD-L1, IDO1, and EV-associated protein expression was assessed. GBM EVs (+/−IFN-γ) were cultured with healthy donor monocytes. Immunosuppressive myeloid-derived suppressor cell (MDSC) and nonclassical monocyte (NCM) frequency was determined. Impact of GBM (+/−IFN-γ) EV-treated monocytes on CD3/CD28-mediated T cell proliferation was assessed. The impact of PD-L1 and IDO1 knockdown in GBM EVs in this system was evaluated. Results IFN-γ exposure increased PD-L1 and IDO1 expression in GBM cells and EVs without altering EV size or frequency. IFN-γ-exposed GBM EVs induced more MDSC and NCM differentiation in monocytes and these monocytes caused more T cell inhibition than IFN-γ-naive GBM EVs. PD-L1 and/or IDO1 knockdown in GBM cells abrogated the immunosuppressive effects of IFN-γ-exposed GBM EVs on monocytes. Conclusions IFN-γ exposure such as might occur during an antitumor immune response results in superinduction of GBM EVs’ baseline immunosuppressive effects on monocytes. These effects are mediated by increased PD-L1 and IDO1 expression in GBM EVs. These data highlight mechanisms of GBM EV-mediated immunosuppression and identify therapeutic targets (PD-L1, IDO1) to reverse these effects.

BACKGROUND: Increases in the extent of resection of both contrast-enhanced (CE) and non–contrast-enhanced (NCE) tissue are associated with substantial survival benefits in patients with isocitrate dehydrogenase wild-type glioblastoma. The fact, however, remains that these lesions exist within the framework of complex neural circuitry subserving cognition, movement, and behavior, all of which affect the ultimate survival outcome. The prognostic significance of the interplay between CE and NCE cytoreduction and neurological morbidity is poorly understood. OBJECTIVE: To identify a clinically homogenous population of 228 patients with newly diagnosed isocitrate dehydrogenase wild-type glioblastoma, all of whom underwent maximal safe resection of CE and NCE tissue and adjuvant chemoradiation. We then set out to delineate the competing interactions between resection of CE and NCE tissue and postoperative neurological impairment with respect to overall survival. METHODS: Nonparametric multivariate models of survival were generated via recursive partitioning to provide a clinically intuitive framework for the prognostication and surgical management of such patients. RESULTS: We demonstrated that the presence of a new postoperative neurological impairment was the key factor in predicting survival outcomes across the entire cohort. Patients older than 60 yr who suffered from at least one new impairment had the worst survival outcome regardless of extent of resection (median of 11.6 mo), whereas those who did not develop a new impairment had the best outcome (median of 28.4 mo) so long as all CE tissue was resected. CONCLUSION: Our data provide novel evidence for management strategies that prioritize safe and complete resection of CE tissue.

OBJECTIVE Although it has been shown that surgery for glioblastoma (GBM) at high-volume facilities (HVFs) may be associated with better postoperative outcomes, the use of such hospitals may not be equally distributed. The authors aimed to evaluate racial and socioeconomic differences in access to surgery for GBM at high-volume Commission on Cancer (CoC)–accredited hospitals. METHODS The National Cancer Database was queried for patients with GBM that was newly diagnosed between 2004 and 2015. Patients who received no surgical intervention or those who received surgical intervention at a site other than the reporting facility were excluded. Annual surgical case volume was calculated for each hospital, with volume ≥ 90th percentile defined as an HVF. Multivariable logistic regression was performed to identify patient-level predictors for undergoing surgery at an HVF. Furthermore, multiple subgroup analyses were performed to determine the adjusted odds ratio of the likelihood of undergoing surgery at an HVF in 2016 as compared to 2004 for each patient subpopulation (by age, race, sex, educational group, etc.). RESULTS A total of 51,859 patients were included, with 10.7% (n = 5562) undergoing surgery at an HVF. On multivariable analysis, Hispanic White patients (OR 0.58, 95% CI 0.49–0.69, p < 0.001) were found to have significantly lower odds of undergoing surgery at an HVF (reference = non-Hispanic White). In addition, patients from a rural residential location (OR 0.55, 95% CI 0.41–0.72, p < 0.001; reference = metropolitan); patients with nonprivate insurance status (Medicare [OR 0.78, 95% CI 0.71–0.86, p < 0.001], Medicaid [OR 0.68, 95% CI 0.60–0.78, p < 0001], other government insurance [OR 0.68, 95% CI 0.52–0.86, p = 0.002], or who were uninsured [OR 0.61, 95% CI 0.51–0.72, p < 0.001]); and lower-income patients ($50,354–$63,332 [OR 0.68, 95% CI 0.63–0.74, p < 0.001], $40,227–$50,353 [OR 0.84, 95% CI 0.76–0.92, p < 0.001]; reference = ≥ $63,333) were also found to be significantly associated with a lower likelihood of surgery at an HVF. Subgroup analyses revealed that elderly patients (age ≥ 65 years), both male and female patients and non-Hispanic White patients, and those with private insurance, Medicare, metropolitan residential location, median zip code–level household income in the first and second quartiles, and educational attainment in the first and third quartiles had increased odds of undergoing surgery at an HVF in 2016 compared to 2004 (all p ≤ 0.05). On the other hand, patients with other governmental insurance, patients with a rural residence, and those from a non-White racial category did not show a significant difference in odds of surgery at an HVF over time (all p > 0.05). CONCLUSIONS The present analysis from the National Cancer Database revealed significant disparities in access to surgery at an HVF for GBM within the United States. Furthermore, there was evidence that these racial and socioeconomic disparities may have widened between 2004 and 2016. The findings should assist health policy makers in the development of strategies for improving access to HVFs for racially and socioeconomically disadvantaged populations.

OBJECTIVE Recent studies have proposed resection of the T2 FLAIR hyperintensity beyond the T1 contrast enhancement (supramarginal resection [SMR]) for IDH–wild-type glioblastoma (GBM) to further improve patients’ overall survival (OS). GBMs have significant variability in tumor cell density, distribution, and infiltration. Advanced mathematical models based on patient-specific radiographic features have provided new insights into GBM growth kinetics on two important parameters of tumor aggressiveness: proliferation rate (ρ) and diffusion rate (D). The aim of this study was to investigate OS of patients with IDH–wild-type GBM who underwent SMR based on a mathematical model of cell distribution and infiltration profile (tumor invasiveness profile). METHODS Volumetric measurements were obtained from the selected regions of interest from pre- and postoperative MRI studies of included patients. The tumor invasiveness profile (proliferation/diffusion [ρ/D] ratio) was calculated using the following formula: ρ/D ratio = (4π/3) 2/3 × (6.106/[V T2 1/1 − V T1 1/1 ]) 2 , where V T2 and V T1 are the preoperative FLAIR and contrast-enhancing volumes, respectively. Patients were split into subgroups based on their tumor invasiveness profiles. In this analysis, tumors were classified as nodular, moderately diffuse, or highly diffuse. RESULTS A total of 101 patients were included. Tumors were classified as nodular (n = 34), moderately diffuse (n = 34), and highly diffuse (n = 33). On multivariate analysis, increasing SMR had a significant positive correlation with OS for moderately and highly diffuse tumors (HR 0.99, 95% CI 0.98–0.99; p = 0.02; and HR 0.98, 95% CI 0.96–0.99; p = 0.04, respectively). On threshold analysis, OS benefit was seen with SMR from 10% to 29%, 10% to 59%, and 30% to 90%, for nodular, moderately diffuse, and highly diffuse, respectively. CONCLUSIONS The impact of SMR on OS for patients with IDH–wild-type GBM is influenced by the degree of tumor invasiveness. The authors’ results show that increasing SMR is associated with increased OS in patients with moderate and highly diffuse IDH–wild-type GBMs. When grouping SMR into 10% intervals, this benefit was seen for all tumor subgroups, although for nodular tumors, the maximum beneficial SMR percentage was considerably lower than in moderate and highly diffuse tumors.

OBJECTIVE The objective of this study was to determine the frequency with which brain biopsy for presumed CNS relapse of systemic hematological malignancies yields new, actionable diagnostic information. Hematological malignancies represent a disparate group of genetic and histopathological disorders. Proclivity for brain involvement is dependent on the unique entity and may occur synchronously or metasynchronously with the systemic lesion. Diffuse large B-cell lymphomas (DLBCLs) have a high propensity for brain involvement. Patients in remission from systemic DLBCL may present with a lesion suspicious for brain relapse. These patients often undergo brain biopsy. The authors’ a priori hypothesis was that brain biopsy in patients with a history of systemic DLBCL and a new brain MRI lesion would have lower diagnostic utility compared with patients with non-DLBCL systemic malignancies. METHODS The authors performed a retrospective review of patients who underwent brain biopsy between 2000 and 2019. Inclusion criteria were patients ≥ 18 years of age with a prior systemic hematological malignancy in remission presenting with a new brain MRI lesion concerning for CNS relapse. Patients with a history of any CNS neoplasms, demyelinating disorders, or active systemic disease were excluded. The main outcome was the proportion of patients with a distinct histopathological brain diagnosis compared with the systemic malignancy. The authors secondarily assessed overall survival, procedure-related morbidity, and 30-day mortality. RESULTS Sixty patients met inclusion criteria (40 males and 20 females); the median age at brain biopsy was 67 years (range 23–88 years). The median follow-up was 8.5 months (range 0.1–231 months). Thirty-nine (65.0%) patients had DLBCL and 21 (35%) had non-DLBCL malignancies. Thirty-five of 36 (97.2%) patients with prior systemic DLBCL and a diagnostic biopsy had histopathological confirmation of the original systemic disease versus 0 of 21 patients with non-DLBCL systemic malignancies (p < 0.001). Morbidity and 30-day mortality were 8.3% and 10.0%, respectively; 2 of 6 30-day mortalities were directly attributable to the biopsy. The median overall survival following brain biopsy was 10.8 months. CONCLUSIONS Patients with a history of systemic DLBCL and presumed CNS relapse gained minimal clinical benefit from brain biopsy but were at high risk of morbidity and mortality. In patients with a history of non-DLBCL systemic malignancies, brain biopsy remained critical given the high likelihood for discovery of distinct diagnostic entities. It was determined that patients with a prior systemic DLBCL and presumed brain relapse should likely receive empirical therapy obviating treatment delay and the risks of brain biopsy.

OBJECTIVE The authors’ goal was to use a multicenter, observational cohort study to determine whether supramarginal resection (SMR) of FLAIR-hyperintense tumor beyond the contrast-enhanced (CE) area influences the overall survival (OS) of patients with isocitrate dehydrogenase–wild-type (IDH-wt) glioblastoma after gross-total resection (GTR). METHODS The medical records of 888 patients aged ≥ 18 years who underwent resection of GBM between January 2011 and December 2017 were reviewed. Volumetric measurements of the CE tumor and surrounding FLAIR-hyperintense tumor were performed, clinical variables were obtained, and associations with OS were analyzed. RESULTS In total, 101 patients with newly diagnosed IDH-wt GBM who underwent GTR of the CE tumor met the inclusion criteria. In multivariate analysis, age ≥ 65 years (HR 1.97; 95% CI 1.01–2.56; p < 0.001) and contact with the lateral ventricles (HR 1.59; 95% CI 1.13–1.78; p = 0.025) were associated with shorter OS, but preoperative Karnofsky Performance Status ≥ 70 (HR 0.47; 95% CI 0.27–0.89; p = 0.006), MGMT promotor methylation (HR 0.63; 95% CI 0.52–0.99; p = 0.044), and increased percentage of SMR (HR 0.99; 95% CI 0.98–0.99; p = 0.02) were associated with longer OS. Finally, 20% SMR was the minimum percentage associated with beneficial OS (HR 0.56; 95% CI 0.35–0.89; p = 0.01), but > 60% SMR had no significant influence (HR 0.74; 95% CI 0.45–1.21; p = 0.234). CONCLUSIONS SMR is associated with improved OS in patients with IDH-wt GBM who undergo GTR of CE tumor. At least 20% SMR of the CE tumor was associated with beneficial OS, but greater than 60% SMR had no significant influence on OS.