•Currently, only patients with PD-L1 TPS ≥ 50% can receive immunotherapy (pembrolizumab) as first line treatment in clinical practice and they account for a maximum of 30% of all advanced NSCLC ...patients.•Several phase III studies demonstrated a survival advantage combining immunotherapy to chemotherapy.•An open issue is how to choose the most correct therapeutic strategy and to properly select patients for the different available treatment options.•To date, PD-L1 expression by immunohistochemistry (IHC) is the only approved marker to select patients for immunotherapy but other factors, for example TMB, are under evaluation.
Immunotherapy has dramatically changed the therapeutic scenario in treatment naïve advanced non-small cell lung cancer (NSCLC). While single agent pembrolizumab has become the standard therapy in patients with PD-L1 expression on tumor cells ≥ 50%, the combination of pembrolizumab or atezolizumab and platinum-based chemotherapy has emerged as an effective first line treatment regardless of PD-L1 expression both in squamous and non-squamous NSCLC without oncogenic drivers. Furthermore, double immune checkpoint inhibition has shown promising results in treatment naïve patients with high tumor mutational burden (TMB). Of note, the presence of both negative PD-L1 expression and low TMB may identify a subgroup of patients who has little benefit from immunotherapy combinations and for whom the best treatment option may still be platinum-based chemotherapy. To date, first-line single agent immune checkpoint blockade has demonstrated limited activity in EGFR mutated NSCLC and the combination of immunotherapy and targeted agents has raised safety concerns in both EGFR and ALK positive NSCLC patients. Finally, in EGFR mutated or ALK rearranged NSCLC, atezolizumab in combination with platinum-based chemotherapy and bevacizumab is emerging as a potential treatment option upon progression to first line tyrosine kinase inhibitors.
Mutations in receptor tyrosine kinase (RTK) growth factor receptors (epidermal growth factor receptor, platelet-derived growth factor receptor, MET and ERBB2), which result in downstream activation ...of the RAS/RAF/MEK/ERK mitogen-activated protein kinase (MAPK) pathway and PI(3)K/Akt pathway, are found in almost all high-grade gliomas and MAPK signaling is necessary for continued glioma maintenance. In addition, BRAF is mutated in the majority of low-grade gliomas and its expression and activity is significantly increased in the majority of high-grade gliomas. Although the importance of RTKs and RAS signaling in glioma development has been shown, the role of BRAF has yet to be characterized. We evaluated the effect of activated BRAF in glioma formation using the retroviral replication-competent avian leukosis virus long terminal repeat, splice acceptor (RCAS)/TVA system to transfer genes encoding activated forms of BRAF, KRas, Akt and Cre to nestin-expressing neural progenitor cells in Ink4a/Arf(lox/lox) mice in vivo. Although expression of activated BRAF alone is not sufficient for tumorigenesis, the combination of activated BRAF and Akt or BRAF with Ink4a/Arf loss is transforming. Interestingly, activated BRAF generates gliomas with characteristics similar to activated KRas in the context of Akt but not Ink4a/Arf loss. Our studies show a role for BRAF activation and signaling in glioma development and as potential target for glioma therapy.
Introduction
The efficacy of immune checkpoint inhibitors in patients with brain metastases (BMs) from non-oncogene addicted non-small cell lung cancer (NSCLC) is under investigation. Here, we sought ...to determine the optimal management of NSCLCs with PD-L1 ≥ 50% and asymptomatic BMs who were treated with first-line pembrolizumab.
Methods
Thirty patients from 15 institutions with PD-L1 ≥ 50% NSCLC had asymptomatic BMs, and met inclusion criteria. Patients were classified based on whether they had undergone upfront local radiotherapy for BMs as well as on the type of brain radiotherapy received.
Results
Nine patients were treated with upfront pembrolizumab alone, 8 patients with whole-brain radiotherapy (WBRT) followed by pembrolizumab and 13 patients with stereotactic radiosurgery (SRS) followed by pembrolizumab. Patients’ characteristics were similar among the three groups of patients except for a higher number of BMs ≥ 3 in the WBRT group. One complete and 4 partial intracranial responses were observed with upfront pembrolizumab alone. The median survival was not reached for the pembrolizumab and WBRT (
n
= 8) groups, and it was 7.6 months for the SRS (
n
= 13) group (
P
= 0.09), with 12-month survival rates being 55.5%, 62.5%, and 23.0%, respectively. Salvage WBRT was delivered in 1 patient in the upfront pembrolizumab group and in 4 patients in the SRS group.
Conclusions
Upfront pembrolizumab showed efficacy in selected patients with PD-L1 ≥ 50% non-oncogene addicted NSCLC and asymptomatic BMs. Prospective studies should address whether pembrolizumab alone, and deferral of radiotherapy, could be pursued in this patient population.
We reviewed 20 studies on wolf diet in Italy, to relate the changes in diet composition to the increase of wild ungulate population in Italy. Researches covered the period from 1976 to 2004 and the ...whole range of wolves from southern Apennines to western Alps. We used the frequency of occurrence of seven food categories and of the wild ungulate species occurring in the diet. Estimates of wild ungulate populations were obtained from the literature and we extrapolated their trend in the period considered. Differences among geographic areas (south-central Apennines, northern Apennines, and western Alps) were tested by nonparametric multivariate analysis of variance, while the trends of the wild ungulate and livestock use and of diet breadth were analysed by regression and curve-fit analyses. We used the same method to support the relationships between the use and availability of wild ungulates. Wolves preyed on wild herbivores more in the northern Apennines and in the western Alps than in the southern Apennines; the contrary was the case for livestock. Among wild ungulate species, wild boar, roe deer and red deer were the main prey of the wolf. The occurrence of wild ungulates in the wolf diet increased from 1976 to 2004 together with a decrease of livestock; the increase was mainly due to roe deer, red deer and chamois. The results of scat analysis in the province of Genoa showed an increase of the occurrence of wild ungulates from 1987 to 2005, in particular roe deer and fallow deer. Wolves in Italy seem to select wild ungulates over domestic ones where the former are available with rich and diversified guilds and abundant populations.
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