Visual and semiquantitative 11C-methionine PET: an independent prognostic factor for survival of newly diagnosed and treatment-naïve gliomas.

Background: Few data exist regarding the prognostic value of L-[S-methyl-11C]methionine (MET) PET for treatment-naïve gliomas. Methods: A total of 160 glioma patients (89 men, 71 women; mean age: 45, range 18-84 y) underwent a MET PET prior to any therapy. The PET scans were evaluated visually and semiquantitatively by tumor-to-background (T/N) ratio thresholds chosen by analysis of receiver operating characteristics. Additionally, isocitrate dehydrogenase 1-R132H (IDH1-R132H) immunohistochemistry was performed. Survival analysis was done using Kaplan-Meier estimates and the Cox proportional hazards model. Results: Significantly shorter mean survival times (7.2 vs 8.6 y; P = 0.024) were seen in patients with amino acid avid gliomas (n = 137) compared with visually negative tumors (n = 33) in MET PET. T/N ratio thresholds of 2.1 and 3.5 were significantly associated with survival (10.3 vs 7 vs 4.3 y; P < 0.001). Mean survival differed significantly using the median T/N ratio of 2.4 as cutoff, independent of histopathology (P < 0.01; mean survival: 10.2 ± 0.8 y vs 5.5 ± 0.6 y). In the subgroup of 142 glioma patients characterized by IDH1-R132H status, METT/N ratio demonstrated a significant prognostic impact in IDH1-R132H wildtype astrocytomas and glioblastoma (P = 0.001). Additionally, multivariate testing revealed semiquantitative MET PET as an independent prognostic parameter for treatment-naïve glioma patients without (P = 0.031) and with IDH1-R132H characterization of gliomas (P = 0.024; odds ratio 1.57). Conclusion: This retrospective analysis demonstrates the value of MET PET as a prognostic parameter on survival in treatment-naïve glioma patients.

Correlation of immune phenotype with IDH mutation in diffuse glioma.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) and programmed death ligand 1 (PD-L1) are targets of immune checkpoint inhibitors. METHODS: Forty-three World Health Organization (WHO) grade II/III gliomas (39 IDH-mutant [mut], 4 IDH-wildtype [wt]) and 14 IDH-mut glioblastomas (GBM) were analyzed for TIL (CD3+; PD1+) infiltration and PD-L1 expression. Results were compared with the data of a previously published series of 117 IDH-wt glioblastomas. PD-L1 gene expression levels were evaluated in 677 diffuse gliomas grades II-IV from The Cancer Genome Atlas (TCGA) database. RESULTS: TIL and PD-L1 expression were observed in approximately half of WHO grade II/III gliomas. IDH-wt status was associated with significantly higher TIL infiltration and PD-L1 expression among all (grades II-IV) cases (n = 174, P < 0.001) and within the cohort of glioblastomas (n = 131, P < 0.001). In low-grade glioma (LGG) and glioblastoma cohorts of TCGA, significantly higher PD-L1 gene expression levels were evident in IDH-wt compared with IDH-mut samples (LGG: N = 516; P = 1.933e-11, GBM: N = 161; P < 0.009). Lower PD-L1 gene expression was associated with increased promoter methylation (Spearman correlation coefficient -0.36; P < 0.01) in the LGG cohort of TCGA. IDH-mut gliomas had higher PD-L1 gene promoter methylation levels than IDH-wt gliomas (P < 0.01). CONCLUSIONS: The immunological tumor microenvironment of diffuse gliomas differs in association with IDH mutation status. IDH-wt gliomas display a more prominent TIL infiltration and higher PD-L1 expression than IDH-mut cases. Mechanistically this may be at least in part due to differential PD-L1 gene promoter methylation levels. Our findings may be relevant for immune modulatory treatment strategies in glioma patients.

Tumor infiltrating lymphocytes and PD-L1 expression in brain metastases of small cell lung cancer (SCLC).

Brain metastases (BM) are frequent in small cell lung cancer (SCLC). Novel insights into their pathobiology are needed for development of better therapies. We investigated tumor-infiltrating lymphocyte (TIL) subsets (CD3+, CD8+, CD45RO+, FOXP3+ and PD-1+) and expression of PD-L1 in a series of 32 SCLC BM specimens and four matched primary tumor specimens using immunohistochemistry. 30/32 (93.8 %) BM specimens showed TIL infiltration. CD3+ TILs were observed in 30/32 (93.8 %) BM specimens, CD8+ TILs in 25/32 (78.1 %), CD45RO+ TILs in 15/32 (46.9 %), FOXP3+ TILs in 15/32 (46.9 %) and PD-1+ TILs in 1/32 (3.1 %) BM specimens. Patients with infiltration of CD45RO+ TILS had a significantly longer median survival time (11 months; 95 % CI 0.000-26.148) as compared to patients without the presence of CD45RO+ TILs (5 months; 95 % CI 0.966-9.034; p = 0.007; log rank test). Membranous PD-L1 on tumor cells was observed in 24/32 (75.0 %) BM specimens, with 11/32 (34.4 %) cases showing PD-L1 expression in over 5 % of viable BM tumor cells. PD-L1 expression on TILs was seen in 8/32 (25.0 %) and on tumor infiltrating macrophages in 9/32 (28.1 %) cases. Patients with PD-L1 expression on TILs presented with improved survival prognosis (6 versus 29 months; p = 0.002; log rank test). Among matched primary tumors, all (4/4; 100 %) specimens showed TIL infiltration, while PD-L1 expression found in only 1/4 (25.0 %) specimen. TIL infiltration and PD-L1 expression are commonly found in SCLC BM and presence of CD45RO+ memory T-cells and PD-L1+ TILs in SCLC BM seem to associate with favorable survival times. Our data suggest an active immune microenvironment in SCLC BM that may be targetable by immune-modulating drugs.