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PurposeImmune modulatory therapies including immune checkpoint inhibitors have so far failed to result in clinically meaningful efficacy in glioma. We aimed to investigate lymphocyte activation gene 3 (LAG-3), an inhibitory receptor on immune cells and target of second-generation immune checkpoint inhibitors, in glioma.Methods97 patients with diffuse glioma (68 with glioblastoma, 29 with WHO grade II-III glioma) were identified from the Neuro-Biobank of the Medical University of Vienna. LAG-3 expression in the inflammatory microenvironment was assessed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4) and correlated to CD3+ , CD8+ , CD20+ and PD-1+ tumor-infiltrating lymphocytes (TILs) and PD-L1 expression on tumor cells.ResultsLAG-3+ TILs could be observed in 10/97 (10.3%) IDH-wildtype samples and in none of the included IDH-mutant glioma samples (p = 0.057). Further, LAG-3+ TILs were only observed in WHO grade IV glioblastoma, while none of the investigated WHO grade II–III glioma presented with LAG-3+ TILs (p = 0.03). No association of O6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation and presence of LAG-3+ TILs was observed (p = 0.726). LAG-3 expression was associated with the presence of CD3+ (p = 0.029), CD8+ (p = 0.001), PD-1+ (p < 0.001) TILs and PD-L1+ tumor cells (p = 0.021), respectively. No association of overall survival with LAG-3+ TIL infiltration was evident (median OS 9.9 vs. 14.2 months, p = 0.95).ConclusionsLAG-3 is only rarely expressed on TILs in IDH-wildtype glioma and associated with active inflammatory milieu as defined by higher TIL density. Immune microenvironment diversity should be considered in the design of future immunotherapy trials in glioma.

Abstract BACKGROUND Intraoperative histopathology and acquisition of multiple tissue samples in stereotactic biopsies results in a prolonged length of surgery and potentially increased complication rate. OBJECTIVE To investigate the clinical benefits of a novel strategy for stereotactic brain tumor biopsies with the assistance of 5-aminolevulinic acid (5-ALA) induced fluorescence. METHODS Patients that received 5-ALA prior to stereotactic biopsy of a suspected brain tumor were included. According to our strategy, the procedure was terminated in the case of strong fluorescence of the biopsy samples. In contrast, intraoperative histology was demanded in the case of vague/no fluorescence. Length of surgery, number of biopsy samples, diagnostic rate, and periprocedural complications were compared between these 2 groups. RESULTS Altogether, 79 patients were included, and strong fluorescence was present in 62 cases (79%), vague fluorescence was in 4 cases (5%), and no fluorescence was in 13 cases (16%). The diagnostic rate was comparable in biopsies with strong fluorescence without intraoperative histopathology and cases with vague/no fluorescence with intraoperative histopathology (98% vs 100%; P = 1.000). A significantly shorter length of surgery (41 vs 77 min; P < .001) and reduced average number of biopsy samples (3.6 vs 4.9; P = .011) was found in patients with strong compared to vague/no fluorescence. However, no statically significant difference in periprocedural complications between cases with strong and vague/no fluorescence was found (7% vs 18%; P = .166). CONCLUSION Our data demonstrate the clinical benefits of a novel strategy for stereotactic brain tumor biopsies with assistance of 5-ALA. Thus, this biopsy strategy will increase the efficiency of this standard neurosurgical procedure in the future.

Ganglioglioma is a rare CNS tumor with a benign biological behavior. Recently, the BRAF V600E mutation was identified in approximately 20 % of gangliogliomas. Here, we analyzed a total of 71 gangliogliomas for BRAF V600E mutational status by VE1 immunohistochemistry and direct DNA sequencing. The BRAF V600E mutation was detected in 41/71 (58 %) gangliogliomas by immunohistochemistry. DNA sequencing was concordant in 60 of 62 analyzed cases. BRAF status was compared with clinical, histological and immunohistochemical data. Presence of the BRAF V600E mutation was associated with expression of synaptophysin in the tumor ( p  = 0.0008), presence of dysplastic neurons ( p  = 0.011) and lymphocytic cuffs ( p  = 0.018), and with younger age ( p  = 0.0054). Extensive hemosiderin deposition within the tumor was significantly associated with BRAF wild-type status ( p  = 0.042). No significant association was found with proliferation ( p  = 0.053), presence of phospho ERK ( p  = 0.1) or senescence marker p16 INK4a ( p  = 0.22). Using VE1, we localized the BRAF V600E-mutated protein predominantly to the neuronal compartment, indicating that BRAF mutations occur in cells that have the capacity to differentiate into ganglionic cells. In many cases mutant BRAF is additionally expressed by the glial compartment, indicating that in these cases the cell targeted by BRAF mutation was likely capable of differentiating along both the ganglionic and glial lineages. No cases with an exclusive expression of BRAF V600E in the glial compartment were observed. Thus, using VE1 we identified the neuronal compartment as an essential part of this mixed glioneuronal tumor.

Neurodegenerative diseases are characterised by neuronal loss and cerebral deposition of proteins with altered physicochemical properties. The major proteins are amyloid-β (Aβ), tau, α-synuclein, and TDP-43. Although neuropathological studies on elderly individuals have emphasised the importance of mixed pathologies, there have been few observations on the full spectrum of proteinopathies in the ageing brain. During a community-based study we performed comprehensive mapping of neurodegeneration-related proteins and vascular pathology in the brains of 233 individuals (age at death 77–87; 73 examined clinically in detail). While all brains (from individuals with and without dementia) showed some degree of neurofibrillary degeneration, Aβ deposits were observed only in 160 (68.7 %). Further pathologies included α-synucleinopathies (24.9 %), non-Alzheimer tauopathies (23.2 %; including novel forms), TDP-43 proteinopathy (13.3 %), vascular lesions (48.9 %), and others (15.1 %; inflammation, metabolic encephalopathy, and tumours). TDP-43 proteinopathy correlated with hippocampal sclerosis ( p  < 0.001) and Alzheimer-related pathology (CERAD score and Braak and Braak stages, p  = 0.001). The presence of one specific variable (cerebral amyloid angiopathy, Aβ parenchymal deposits, TDP-43 proteinopathy, α-synucleinopathy, vascular lesions, non-Alzheimer type tauopathy) did not increase the probability of the co-occurrence of others ( p  = 0.24). The number of observed pathologies correlated with AD-neuropathologic change ( p  < 0.0001). In addition to AD-neuropathologic change, tauopathies associated well with dementia, while TDP-43 pathology and α-synucleinopathy showed strong effects but lost significance when evaluated together with AD-neuropathologic change. Non-AD neurodegenerative pathologies and their combinations have been underestimated, but are frequent in reality as demonstrated here. This should be considered in diagnostic evaluation of biomarkers, and for better clinical stratification of patients.

Background and Objectives: The biological behavior of gliomas is influenced by various factors including molecular features and treatment response. This study investigates the prognostic implications of a second tumor in patients with glioma at time of diagnosis. Given the increasing number of patients presenting with multiple primary malignancies due to improved cancer survival and diagnostic accuracy, understanding the influence of double tumor burden on glioma outcomes is of growing clinical relevance. Methods: We retrospectively analyzed adult patients with intracranial gliomas (WHO grade 2–4), who were surgically treated between 2015 and 2022 at our institution. Patients were categorized into two groups: glioma only and glioma plus additional solid malignancy. We compared progression-free survival (PFS) and overall survival (OS) using Kaplan–Meier and Cox regression analyses. Results: Among 426 glioma patients, 75 (17.6%) harbored a second non-brain tumor. Patients with multiple primaries showed significantly poorer OS (median 6 vs. 14 months, p = 0.002). No significant difference in PFS or OS was observed for patients in case the systemic tumor was in complete remission as compared to those with sole glioma. However, patients with progressive or stable systemic tumor had significantly worse outcomes regarding OS (p < 0.05). Conclusions: Our findings suggest that the presence of a second systemic malignancy is an independent prognostic factor for worse outcome. Further studies are mandated to elucidate genetic situations and refine therapeutic strategies for these patients.

Brain metastases (BM) are frequent and carry a dismal prognosis. BRAF V600E mutations are found in a broad range of tumor types and specific inhibitors targeting BRAF V600E protein exist. We analyzed tumoral BRAF V600E-mutant protein expression using the novel mutation-specific antibody VE1 in a series of 1,120 tumor specimens (885 BM, 157 primary tumors, 78 extra-cranial metastases) of 874 BM patients. In 85 cases, we performed validation of immunohistochemical results by BRAF exon 15 gene sequencing. BRAF V600E protein was expressed in BM of 42/76 (55.3%) melanomas, 1/15 (6.7%) ovarian cancers, 4/72 (5.5%) colorectal cancers, 1/355 (0.3%) lung cancers, 2/6 thyroid cancers and 1/2 choriocarcinomas. BRAF V600E expression showed high intra-tumoral homogeneity and was similar in different tumor manifestations of individual patients. VE1 immunohistochemistry and BRAF exon 15 sequencing were congruent in 68/70 (97.1%) cases, but VE1 immunostaining identified small BRAF V600E expressing tumor cell aggregates in 10 cases with inconclusive genetic results. Melanoma patients with BRAF V600E mutant protein expressing tumors were significantly younger at diagnosis of the primary tumor and at operation of BM than patients with non-mutated tumors. In conclusion, expression of BRAF V600E mutant protein occurs in approximately 6% of BM and is consistent in different tumor manifestations of the same patient. Thus, BRAF V600E inhibiting therapies seem feasible in selected BM patients. Immunohistochemical visualization of V600E-mutant BRAF protein is a promising tool for patient stratification. An integrated approach combining both, VE1 immunohistochemistry and genetic analysis may increase the diagnostic accuracy of BRAF mutation analysis.

IntroductionPilocytic astrocytoma (PA) is the most common primary brain neoplasm in children and treated in curative intent with gross total resection (GTR). However, PA is rare in adults, resulting in limited knowledge on the natural clinical course. This study aimed to describe the clinical course and identify prognostic factors of adult patients with PA.Methods46 patients ≥ 18 years at diagnosis of PA and neurosurgical resection or biopsy between 2000 and 2018 were identified from the Neuro-Biobank of the Medical University of Vienna. In two cases with differing histopathological diagnosis at recurrence, DNA methylation analysis was performed using Illumina Infinium HumanMethylation850 BeadChip (850 k) arrays and the Molecular Neuropathology classifier. Clinico-pathological features were correlated with patient outcomes.ResultsMedian age at diagnosis was 32.5 years (range: 19–75) and median Ki67 proliferation index was 2.8% (0.5–13.4%). Tumor location significantly correlated with resectability (p < 0.001). Tumor progression or recurrence was observed in 9/46 (19.6%) patients after a median follow up time of 53.0 months (range 0.5–300). 5-year overall and progression-free survival rates were 85.3% and 70.0%, respectively. 2/9 (22.2%) patients presented with histological changes in the recurrent tumor specimen. In detail, methylation classification redefined the histological diagnosis to anaplastic astrocytoma with piloid features and glioma in one patient, each. Age > 40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p < 0.05).ConclusionsTumor recurrence or progression in adult PA patients was higher than the one reported in pediatric patients. Higher age and BMI were associated with impaired prognosis.

Breast cancer is a leading cause of death in female patients worldwide. Further research is needed to get a deeper insight into the mechanisms involved in the development of this devastating disease and to find new therapy strategies. The zebrafish is an established animal model, especially in the field of oncology, which has shown to be a promising candidate for pre-clinical research and precision-based medicine. To investigate cancer growth in vivo in zebrafish, one approach is to explore xenograft tumor models. In this article, we present the investigation of a juvenile xenograft zebrafish model using a Jones matrix optical coherence tomography (JM-OCT) prototype. Immunosuppressed wild-type fish at 1-month post-fertilization were injected with human breast cancer cells and control animals with phosphate buffered saline in the tail musculature. In a longitudinal study, the scatter, polarization, and vasculature changes over time were investigated and quantified in control versus tumor injected animals. A significant decrease in birefringence and an increase in scattering signal was detected in tumor injected zebrafish in comparison to the control once. This work shows the potential of JM-OCT as a non-invasive, label-free, three-dimensional, high-resolution, and tissue-specific imaging tool in pre-clinical cancer research based on juvenile zebrafish models.

Neurodegenerative diseases are a major health burden. The underlying causes are not yet fully understood, but different mechanisms such as cell stress and chronic inflammation have been described as contributing factors. Neurodegenerative changes have been observed in the vicinity of brain tumors, typically around slowly growing benign lesions. Moreover, in‐vitro data suggest a potential induction of pathological tau deposits also in glioblastoma, a highly malignant and proliferative brain cancer. The aim of this study was to evaluate neurodegeneration‐associated protein deposition and autophagy as well as microglial activation within and surrounding glioblastoma. Post‐mortem brain tissue of 22 patients with glioblastoma was evaluated immunohistochemically for phosphorylated tau, beta‐amyloid, alpha‐synuclein and phosphorylated TDP‐43. Additionally, the autophagy marker p62 and the microglial marker HLA‐DR were investigated. The data was compared to 22 control cases and ten cases with other space occupying brain lesions. An increase of p62‐immunoreactivity was observed within and adjacent to the glioblastoma tumor tissue. Moreover, dense microglial infiltration in the tumor tissue and the immediate surrounding brain tissue was a constant feature. Deposition of neurodegeneration‐associated proteins was found in the majority of cases (86.4%) but in distant sites. These findings suggested a preexisting neurodegenerative pathology, which followed a typical distributional pattern: ten cases with Alzheimer disease neuropathological changes, including two severe cases, eight cases with primary age‐related tauopathy, six cases with aging‐related tau astrogliopathy and one case with progressive supranuclear palsy. Collectively, our data suggests enhanced autophagy in glioblastoma tumor cells and the surrounding brain. The variety and distribution of distant neurodegeneration‐associated protein aggregates observed in the majority of cases, suggest a preexisting rather than a tumor‐induced neurodegenerative condition. Neurodegenerative proteinopathies have been observed in the vicinity of brain tumors, typically around slowly growing benign lesions. In this study we analyzed postmortem brain tissue of glioblastoma patients for the presence of phosphorylated tau, beta‐amyloid, alpha‐synuclein and phosphorylated TDP‐43, as well as for the autophagy marker p62 and the microglial marker HLA‐DR. We observed enhanced autophagy in glioblastoma tumor cells and the surrounding brain, while the distant neurodegeneration‐associated protein aggregates were more likely related to silent, age‐related conditions.

Tuberous Sclerosis Complex (TSC) is a genetic hamartoma syndrome frequently associated with severe intractable epilepsy. In some TSC patients epilepsy surgery is a promising treatment option provided that the epileptogenic zone can be precisely delineated. TSC brain lesions (cortical tubers) contain dysmorphic neurons, brightly eosinophilic giant cells and white matter alterations in various proportions. However, a histological classification system has not been established for tubers. Therefore, the aim of this study was to define distinct histological patterns within tubers based on semi-automated histological quantification and to find clinically significant correlations. In total, we studied 28 cortical tubers and seven samples of perituberal cortex from 28 TSC patients who had undergone epilepsy surgery. We assessed mammalian target of rapamycin complex 1 (mTORC1) activation, the numbers of giant cells, dysmorphic neurons, neurons, and oligodendrocytes, and calcification, gliosis, angiogenesis, inflammation, and myelin content. Three distinct histological profiles emerged based on the proportion of calcifications, dysmorphic neurons and giant cells designated types A, B, and C. In the latter two types we were able to subsequently associate them with specific features on presurgical MRI. Therefore, these histopathological patterns provide consistent criteria for improved definition of the clinico-pathological features of cortical tubers identified by MRI and provide a basis for further exploration of the functional and molecular features of cortical tubers in TSC.