Distribution and prognostic relevance of tumor-infiltrating lymphocytes (TILs) and PD-1/PD-L1 immune checkpoints in human brain metastases

The focus of this paper is to identify and quantify risk factors for early hemorrhagic progression of brain contusions (HPC) in patients with traumatic brain injury (TBI) and to evaluate their impact on patients' outcome. Further, based on abnormal values in routine blood tests, the role of trauma-induced coagulopathy is analyzed in detail. Therefore, a prospective study of 153 TBI patients was completed at one institution between January 2008 and June 2012. The collected data included demographics, initial Glasgow Coma Scale pupillary response, initial and 6 h follow-up computed tomography scan findings, coagulation parameters (international normalized ratio, partial thromboplastin time, platelet count, fibrinogen, D-dimer and factor XIII), as well as outcome data using the modified Rankin score at discharge and after one year. The overall rate of early HPC within the first 6 h was 43.5%. The frequency of coagulopathy was 47.1%. When analyzing for risk factors that independently influenced outcome in the form of mRS ≥4 at both points, the following variables appeared: elevated D-dimer level (≥10,000 μg/L), HPC, and initial brain contusions ≥3 cm. Patients sustaining early HPC had a hazard ratio of 5.4 for unfavorable outcome at discharge (p=0.002) and of 3.9 after one year (p=0.006). Overall, patients who developed early HPC were significantly more likely to be gravely disabled or to die. Unfavorable neurological outcome after an isolated TBI is determined largely by early HPC and coagulopathy, which seem to occur very frequently in TBI patients, irrespective of the severity of the trauma.

Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas Intratumoral heterogeneity and TERT promoter mutations in progressive/higher-grade meningiomas

Background: Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. Methods: 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. Results: Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4% %, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p = 0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases—with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. Conclusions: Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB approval status: Reviewed and approved by Western IRB; Protocol No. 20152817.