Dataset Information

Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma.

ABSTRACT: BACKGROUND:Checkpoint inhibition has demonstrated clinical efficacy in a variety of solid tumors. Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results. OBJECTIVE:To validate the prevalence and prognostic role of PD-L1 expression in a large cohort of diffuse gliomas according to the 2016 revised WHO classification. METHODS:Using tissue microarrays, we compared 5 PD-L1 monoclonal antibodies (n = 56) and validated expression (n = 183) using quantitative immunohistochemistry (IHC) and RNA in situ hybridization (RISH). Expression data from The Cancer Genome Atlas (TCGA) and published studies were compared with clinical outcome. Multiplexed immunophenotyping was used to identify PD-L1+ cell populations in post-treatment glioblastoma. RESULTS:Using a 5% cut-off, PD-L1 expression was significantly associated with a poor prognosis in both histologically defined (n = 125, log-rank P < .001) and recurrent isocitrate dehydrogenase (IDH)-wildtype glioblastoma (n = 60, log-rank P = .015). PD-L1 remained a significant negative prognosticator in Cox regression analysis (hazard ratio: 1.96, P = .021). Analysis of TCGA data confirmed decreased overall survival in recurrent non-glioma CpG island methylator phenotype (G-CIMP) glioblastoma (n = 12, log-rank P = .023), but not in glioblastoma as a group (n = 444, log-rank P = .135). PD-L1 RISH showed a significant correlation with IHC (P < .0001). PD-L1 was observed in the proliferating perivascular stem cell and immune niche of post-treatment glioblastoma. CONCLUSION:A 5% PD-L1 expression cut-off identified a subset of glioblastoma that is associated with a worse clinical outcome. This association remained significant within the newly defined IDH-wildtype classification. These findings could have implications for patient stratification in future clinical trials of PD-1/PD-L1 blockade.

SUBMITTER: Pratt D

PROVIDER: S-EPMC7137460 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma.

Pratt Drew D Dominah Gifty G Lobel Graham G Obungu Arnold A Lynes John J Sanchez Victoria V Adamstein Nicholas N Wang Xiang X Edwards Nancy A NA Wu Tianxia T Maric Dragan D Giles Amber J AJ Gilbert Mark R MR Quezado Martha M Nduom Edjah K EK

Neurosurgery 20190801 2

<h4>Background</h4>Checkpoint inhibition has demonstrated clinical efficacy in a variety of solid tumors. Reports of programmed death ligand 1 (PD-L1) expression in glioblastoma are highly variable (ranging from 6% to 88%) and its role as a prognostic marker has yielded conflicting results.<h4>Objective</h4>To validate the prevalence and prognostic role of PD-L1 expression in a large cohort of diffuse gliomas according to the 2016 revised WHO classification.<h4>Methods</h4>Using tissue microarra ...[more]

PMID: 30011045

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Project description:AimTo investigate the expression of cathepsins B, D, and G, in relation to the cancer stem cell (CSC) subpopulations, we have previously characterized within isocitrate dehydogenase (IDH)-wildtype glioblastoma (IDHWGB).Methods3,3-Diaminobezidine (DAB) immunohistochemical (IHC) staining for cathepsins B, D, and G, was performed on 4μm-thick formalin-fixed paraffin-embedded IDHWGB samples obtained from six patients. Two representative DHWGB samples from the original cohort of patients were selected for immunofluorescent (IF) IHC staining, to identify the localization of the cathepsins in relation to the CSC subpopulations. NanoString gene expression analysis and colorimetric in situ hybridization (CISH) were conducted to investigate the transcriptional activation of genes encoding for cathepsins B, D, and G. Data obtained from cell counting of DAB IHC-stained slides and from NanoString analysis were subjected to statistical analyses to determine significance.ResultsCathepsin B and cathepsin D were detected in IDHWGB by DAB IHC staining. IF IHC staining demonstrated the expression of both cathepsin B and cathepsin D by the OCT4+ and SALL4+ CSC subpopulations. NanoString gene analysis and CISH confirmed the abundant transcript expression of these cathepsins. The transcriptional and translational expressions of cathepsin G were minimal and were confined to cells within the microvasculature.ConclusionThis study demonstrated the expression of cathepsin B and cathepsin D but not cathepsin G within the CSC subpopulations of IDHWGB at both the transcriptional and translational level. Cathepsin G was expressed at low levels and was not localized to the CSC population of IDHWGB. The novel finding of cathepsin B and cathepsin D in IDHWGB suggests the presence of bypass loops for the renin-angiotensin system, which may facilitate the production of angiotensin peptides. Elucidating the precise role of these cathepsins may lead to better understanding and more effective treatment of this aggressive tumor.

Project description:PurposeThe survival times of glioblastoma (GB) patients after the standard therapy including safe maximal resection followed by radiotherapy plus concomitant and adjuvant temozolomide are heterogeneous. In order to define a simple, reliable method for predicting whether patients with isocitrate dehydrogenase (IDH)-wildtype GB treated with the standard therapy will be short- or long-term survivors, we analyzed the correlation of preoperative blood counts and their combined forms with progression-free survival (PFS) and overall survival (OS) in these patients.MethodsEighty-five patients with primary IDH-wildtype GB treated with the standard therapy between 2012 and 2019 were analyzed retrospectively. Cox proportional hazards models and Kaplan-Meier analysis were used to investigate the survival function of preoperative hematological parameters.ResultsPreoperative high neutrophil-to-lymphocyte ratio (NLR, >2.42), high platelet count (>236 × 109/L), and low red blood cell (RBC) count (≤4.59 × 1012/L) were independent prognostic factors for poorer OS (p = 0.030, p = 0.030, and p = 0.004, respectively). Moreover, a high NLR was an independent prognostic factor for shorter PFS (p = 0.010). We also found that, like NLR, preoperative high derived NLR (dNLR, >1.89) was of poor prognostic value for both PFS (p = 0.002) and OS (p = 0.033). A significant correlation was observed between NLR and dNLR (r = 0.88, p < 0.001), which had a similar prognostic power for OS (NLR: AUC = 0.58; 95% CI: [0.48; 0.68]; dNLR: AUC = 0.62; 95% CI: [0.51; 0.72]). Two scores, one based on preoperative platelet and RBC counts plus NLR and the other on preoperative platelet and RBC counts plus dNLR, were found to be independent prognostic factors for PFS (p = 0.006 and p = 0.002, respectively) and OS (p < 0.001 for both scores).ConclusionCheap, routinely ordered, preoperative assessments of blood markers, such as NLR, dNLR, RBC, and platelet counts, can predict the survival outcomes of patients with IDH-wildtype GB treated with the standard therapy.

Project description:PurposeGlioblastomas (GBM) are the most common malignant primary brain tumors in adults and have a dismal prognosis. Patients frequently suffer from local tumor recurrences, with limited therapeutic options. Re-irradiation represents a possible intervention, but given the recent 5th edition of the World Health Organization classification of central nervous system tumors, studies in isocitrate dehydrogenase wild type (IDH-wt) cohorts undergoing a second course of radiotherapy remain limited. Herein, we sought to describe our institutional experience and outcomes after GBM IDH-wt re-irradiation.Materials and methodsGBM patients with confirmed IDH-wt status undergoing re-irradiation were included in this single-center, retrospective analysis.ResultsA total of 88 patients were analyzed. The median clinical and radiographic follow-up periods were 4.6 months and 4.4 months, respectively. Most patients had a Karnofsky performance status of at least 80% (n = 57). The median biologically effective dose and 2 Gy equivalent dose (EQD2) for re-irradiations, assuming an α/β ratio of 10 Gy for GBM, were 51.4 and 42.8 Gy, respectively. In total, 71 deaths were recorded. The median overall survival (OS) was 8.0 months. Multivariable Cox regression of OS revealed a positive influence of gross total resection vs. biopsy or no resection (hazard ratio: 0.43, p = 0.02). The median progression-free survival (PFS) was 5.9 months. The multivariable Cox regression for PFS did not detect any significant factors. No clear evidence of radiation necrosis was recorded during the available follow-up. However, only a minority (n = 4) of patients underwent surgery after re-irradiation, none showing histopathological proof of radiation necrosis.ConclusionThe prognosis for recurrent IDH-wt GBM after re-irradiation is poor. Patients who are amenable and able to undergo re-resection may have a favorable OS. A second course of radiotherapy with a moderate cumulative EQD2 and small- to medium-sized planning target volumes appeared safe regarding the occurrence of radiation necrosis.

Project description:BackgroundThere is considerable interest in defining the metabolic abnormalities of IDH mutant tumors to exploit for therapy. While most studies have attempted to discern function by using cell lines transduced with exogenous IDH mutant enzyme, in this study, we perform unbiased metabolomics to discover metabolic differences between a cohort of patient-derived IDH1 mutant and IDH wildtype gliomaspheres.MethodsUsing both our own microarray and the TCGA datasets, we performed KEGG analysis to define pathways differentially enriched in IDH1 mutant and IDH wildtype cells and tumors. Liquid chromatography coupled to mass spectrometry analysis with labeled glucose and deoxycytidine tracers was used to determine differences in overall cellular metabolism and nucleotide synthesis. Radiation-induced DNA damage and repair capacity was assessed using a comet assay. Differences between endogenous IDH1 mutant metabolism and that of IDH wildtype cells transduced with the IDH1 (R132H) mutation were also investigated.ResultsOur KEGG analysis revealed that IDH wildtype cells were enriched for pathways involved in de novo nucleotide synthesis, while IDH1 mutant cells were enriched for pathways involved in DNA repair. LC-MS analysis with fully labeled 13C-glucose revealed distinct labeling patterns between IDH1 mutant and wildtype cells. Additional LC-MS tracing experiments confirmed increased de novo nucleotide synthesis in IDH wildtype cells relative to IDH1 mutant cells. Endogenous IDH1 mutant cultures incurred less DNA damage than IDH wildtype cultures and sustained better overall growth following X-ray radiation. Overexpression of mutant IDH1 in a wildtype line did not reproduce the range of metabolic differences observed in lines expressing endogenous mutations, but resulted in depletion of glutamine and TCA cycle intermediates, an increase in DNA damage following radiation, and a rise in intracellular ROS.ConclusionsThese results demonstrate that IDH1 mutant and IDH wildtype cells are easily distinguishable metabolically by analyzing expression profiles and glucose consumption. Our results also highlight important differences in nucleotide synthesis utilization and DNA repair capacity that could be exploited for therapy. Altogether, this study demonstrates that IDH1 mutant gliomas are a distinct subclass of glioma with a less malignant, but also therapy-resistant, metabolic profile that will likely require distinct modes of therapy.

Dataset Information

Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma.

Publications

Programmed Death Ligand 1 Is a Negative Prognostic Marker in Recurrent Isocitrate Dehydrogenase-Wildtype Glioblastoma.

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