TILs and PD-L1 expression are detectable in the majority of glioblastoma samples but are not related to outcome. Because the target is present, a clinical study with specific immune checkpoint inhibitors seems to be warranted in glioblastoma.

Keywords: brain metastases, immunoscore, overall survival, prognosis, tumor infiltrating lymphocytesThe immune microenvironment of the brain differs from that of other organs and the role of tumor-infiltrating lymphocytes (TILs) in brain metastases (BM), one of the most common and devastating complication of cancer, is unclear. We investigated TIL subsets and their prognostic impact in 116 BM specimens using immunohistochemistry for CD3, CD8, CD45RO, FOXP3, PD1 and PD-L1. The Immunoscore was calculated as published previously. Overall, we found TIL infiltration in 115/116 (99.1%) BM specimens. PD-L1 expression was evident in 19/67 (28.4%) BM specimens and showed no correlation with TIL density (p > 0.05). TIL density was not associated with corticosteroid administration (p > 0.05). A significant difference in infiltration density according to TIL subtype was present (p < 0.001; Chi Square); high infiltration was most frequently observed for CD3C TILs (95/116; 81.9%) and least frequently for PD1C TILs (18/116; 15.5%; p < 0.001). Highest TIL density was observed in melanoma, followed by renal cell cancer and lung cancer BM (p < 0.001). The density of CD8 C TILs correlated positively with the extent of peritumoral edema seen on pre-operative magnetic resonance imaging (p D 0.031). The density of CD3C (15 vs. 6 mo; p D 0.015), CD8 C (15 vs. 11 mo; p D 0.030) and CD45ROC TILs (18 vs. 8 mo; p D 0.006) showed a positive correlation with favorable median OS times. Immunoscore showed significant correlation with survival prognosis (27 vs. 10 mo; p < 0.001). The prognostic impact of Immunoscore was independent from established prognostic parameters at multivariable analysis (HR 0.612, p < 0.001).In conclusion, our data indicate that dense TILs infiltrates are common in BM and correlate with the amount of peritumoral brain edema and survival prognosis, thus identifying the immune system as potential biomarker for cancer patients with CNS affection. Further studies are needed to substantiate our findings.

We recently reported a novel neurological syndrome characterized by a unique NREM and REM parasomnia with sleep apnea and stridor, accompanied by bulbar dysfunction and specific association with antibodies against the neuronal cell-adhesion protein IgLON5. All patients had the HLA-DRB1*1001 and HLA-DQB1*0501 alleles. Neuropathological findings in two patients revealed a novel tauopathy restricted to neurons and predominantly involving the hypothalamus and tegmentum of the brainstem. The aim of the current study is to describe the neuropathological features of the anti-IgLON5 syndrome and to provide diagnostic levels of certainty based on the presence of associated clinical and immunological data. The brains of six patients were examined and the features required for the neuropathological diagnosis were established by consensus. Additional clinical and immunological criteria were used to define “definite”, “probable” and “possible” diagnostic categories. The brains of all patients showed remarkably similar features consistent with a neurodegenerative disease with neuronal loss and gliosis and absence of inflammatory infiltrates. The most relevant finding was the neuronal accumulation of hyperphosphorylated tau composed of both three-repeat (3R) and four-repeat (4R) tau isoforms, preferentially involving the hypothalamus, and more severely the tegmental nuclei of the brainstem with a cranio-caudal gradient of severity until the upper cervical cord. A “definite” diagnosis of anti-IgLON5-related tauopathy is established when these neuropathological features are present along with the detection of serum or CSF IgLON5 antibodies. When the antibody status is unknown, a “probable” diagnosis requires neuropathological findings along with a compatible clinical history or confirmation of possession of HLA-DRB1*1001 and HLA-DQB1*0501 alleles. A “possible” diagnosis should be considered in cases with compatible neuropathology but without information about a relevant clinical presentation and immunological status. These criteria should help to identify undiagnosed cases among archival tissue, and will assist future clinicopathological studies of this novel disorder.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-016-1591-8) contains supplementary material, which is available to authorized users.

Deposition of amyloid-β (Aβ) in the brain parenchyma and vessels is one of the hallmarks of Alzheimer disease (AD). Recent observations of Aβ deposition in iatrogenic Creutzfeldt-Jakob disease (iCJD) after dural grafting or treatment with pituitary extracts raised concerns whether Aβ is capable of transmitting disease as seen in prion diseases by the disease-associated prion protein. To address this issue, we re-sampled and re-evaluated archival material, including the grafted dura mater of two cases with iCJD (28 and 33-years-old) without mutations in the AβPP, PSEN1 and PSEN2 genes, and carrying ε3/ε3 alleles of the APOE gene. In addition, we evaluated 84 dura mater samples obtained at autopsy (mean age 84.9 ± 0.3) in the community-based VITA study for the presence of Aβ deposition. We show that the dura mater may harbor Aβ deposits (13 %) in the form of cerebral amyloid angiopathy or amorphous aggregates. In both iCJD cases, the grafted dura mater had accumulated Aβ. The morphology and distribution pattern of cerebral Aβ deposition together with the lack of tau pathology distinguishes the Aβ proteinopathy in iCJD from AD, from that seen in young individuals without cognitive decline carrying one or two APOE4 alleles, and from that related to traumatic brain injury. Our novel findings of Aβ deposits in the dura mater, including the grafted dura, and the distinct cerebral Aβ distribution in iCJD support the seeding properties of Aβ. However, in contrast to prion diseases, our study suggests that such Aβ seeding is unable to reproduce the full clinicopathological phenotype of AD.

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.