The plasma miRNome and venous thromboembolism in high-grade glioma: miRNA Sequencing of a nested case-control cohort.

Patients with high-grade gliomas are at high risk of venous thromboembolism (VTE). MicroRNAs (miRNAs) are small non-coding RNAs with multiple roles in tumour biology, haemostasis and platelet function. Their association with VTE risk in high-grade glioma has not been comprehensively mapped so far. We thus conducted a nested case-control study within 152 patients with WHO grade IV glioma that had been part of a prospective cohort study on VTE risk factors. At inclusion a single blood draw was taken, and patients were thereafter followed for a maximum of 2 years. During that time, 24 patients (16%) developed VTE. Of the other 128 patients, we randomly selected 24 age- and sex-matched controls. After quality control, the final group size was 21 patients with VTE during follow-up and 23 without VTE. Small RNA next-generation sequencing of plasma was performed. We observed that hsa-miR-451a was globally the most abundant miRNA. Notably, 51% of all miRNAs showed a correlation with platelet count. The analysis of miRNAs differentially regulated in VTE patients-with and without platelet adjustment-identified potential VTE biomarker candidates such as has-miR-221-3p. Therewith, we here provide one of the largest and deepest peripheral blood miRNA datasets of high-grade glioma patients so far, in which we identified first VTE biomarker candidates that can serve as the starting point for future research.

Mapping high-grade glioma immune infiltration to 5-ALA fluorescence levels: TCGA data computation, classical histology, and digital image analysis.

PURPOSE: Resection of high-grade gliomas has been considerably improved by 5-aminolevulinic acid (5-ALA). However, not all neurobiological properties of 5-ALA are fully understood. Specifically, potential differences in immune infiltration have not been conclusively examined, despite recent reports that immune cells might play a role. Thus, we here provide a systematic mapping of immune infiltration of different 5-ALA fluorescence levels. METHODS: Tumor-associated macrophages (CD68, CD163), cytotoxic T cells (CD8), and regulatory T cells (FoxP3) were quantified via three methods. First, data from The Cancer Genome Atlas (TCGA) of 172 patients was examined for correlations between 5-ALA fluorescence-related mRNA expression signatures and immune markers. Second, as classical histology, 508 stained slides from 39 high-grade glioma patients were analysed semi-quantitatively by two independent reviewers, generating 1016 data points. Third, digital image analysis was performed with automated scanning and algorithm-based cell quantification. RESULTS: TCGA mRNA data from 172 patients showed a direct, significant correlation between 5-ALA signatures and immune markers (p < 0.001). However, we were not able to confirm this finding in the here studied initial set of 39 patient histologies where we found a comparable immune infiltration in different fluorescence levels. Digital image analysis correlated excellently with standard histology. CONCLUSION: With mapping the immune infiltration pattern of different 5-ALA categories, we are adding fundamental basic insights to the field of 5-ALA and glioma biology. The observation that a significant correlation in TCGA data did not fully translate to detectable differences in immune infiltration in first histology data warrants further investigation in larger cohorts.

QSMxT: Robust masking and artifact reduction for quantitative susceptibility mapping.

PURPOSE: Quantitative susceptibility mapping (QSM) estimates the spatial distribution of tissue magnetic susceptibilities from the phase of a gradient-echo signal. QSM algorithms require a signal mask to delineate regions with reliable phase for subsequent susceptibility estimation. Existing masking techniques used in QSM have limitations that introduce artifacts, exclude anatomical detail, and rely on parameter tuning and anatomical priors that narrow their application. Here, a robust masking and reconstruction procedure is presented to overcome these limitations and enable automated QSM processing. Moreover, this method is integrated within an open-source software framework: QSMxT. METHODS: A robust masking technique that automatically separates reliable from less reliable phase regions was developed and combined with a two-pass reconstruction procedure that operates on the separated sources before combination, extracting more information and suppressing streaking artifacts. RESULTS: Compared with standard masking and reconstruction procedures, the two-pass inversion reduces streaking artifacts caused by unreliable phase and high dynamic ranges of susceptibility sources. It is also robust across a range of acquisitions at 3 T in volunteers and phantoms, at 7 T in tumor patients, and in an in silico head phantom, with significant artifact and error reductions, greater anatomical detail, and minimal parameter tuning. CONCLUSION: The two-pass masking and reconstruction procedure separates reliable from less reliable phase regions, enabling a more accurate QSM reconstruction that mitigates artifacts, operates without anatomical priors, and requires minimal parameter tuning. The technique and its integration within QSMxT makes QSM processing more accessible and robust to streaking artifacts.

Toward digital histopathological assessment in surgery for central nervous system tumors using stimulated Raman histology.

OBJECTIVE: Intraoperative neuropathological assessment with conventional frozen sections supports the neurosurgeon in optimizing the surgical strategy. However, preparation and review of frozen sections can take as long as 45 minutes. Stimulated Raman histology (SRH) was introduced as a novel technique to provide rapid high-resolution digital images of unprocessed tissue samples directly in the operating room that are comparable to conventional histopathological images. Additionally, SRH images are simultaneously and easily accessible for neuropathological judgment. Recently, the first study showed promising results regarding the accuracy and feasibility of SRH compared with conventional histopathology. Thus, the aim of this study was to compare SRH with conventional H&E images and frozen sections in a large cohort of patients with different suspected central nervous system (CNS) tumors. METHODS: The authors included patients who underwent resection or stereotactic biopsy of suspected CNS neoplasm, including brain and spinal tumors. Intraoperatively, tissue samples were safely collected and SRH analysis was performed directly in the operating room. To enable optimal comparison of SRH with H&E images and frozen sections, the authors created a digital databank that included images obtained with all 3 imaging modalities. Subsequently, 2 neuropathologists investigated the diagnostic accuracy, tumor cellularity, and presence of diagnostic histopathological characteristics (score 0 [not present] through 3 [excellent]) determined with SRH images and compared these data to those of H&E images and frozen sections, if available. RESULTS: In total, 94 patients with various suspected CNS tumors were included, and the application of SRH directly in the operating room was feasible in all cases. The diagnostic accuracy based on SRH images was 99% when compared with the final histopathological diagnosis based on H&E images. Additionally, the same histopathological diagnosis was established in all SRH images (100%) when compared with that of the corresponding frozen sections. Moreover, the authors found a statistically significant correlation in tumor cellularity between SRH images and corresponding H&E images (p < 0.0005 and R = 0.867, Pearson correlation coefficient). Finally, excellent (score 3) or good (2) accordance between diagnostic histopathological characteristics and H&E images was present in 95% of cases. CONCLUSIONS: The results of this retrospective analysis demonstrate the near-perfect diagnostic accuracy and capability of visualizing relevant histopathological characteristics with SRH compared with conventional H&E staining and frozen sections. Therefore, digital SRH histopathology seems especially useful for rapid intraoperative investigation to confirm the presence of diagnostic tumor tissue and the precise tumor entity, as well as to rapidly analyze multiple tissue biopsies from the suspected tumor margin. A real-time analysis comparing SRH images and conventional histological images at the time of surgery should be performed as the next step in future studies.

Improved susceptibility weighted imaging at ultra-high field using bipolar multi-echo acquisition and optimized image processing: CLEAR-SWI.

PURPOSE: Susceptibility Weighted Imaging (SWI) has become established in the clinical investigation of stroke, microbleeds, tumor vascularization, calcification and iron deposition, but suffers from a number of shortcomings and artefacts. The goal of this study was to reduce the sensitivity of SWI to strong B1 and B0 inhomogeneities at ultra-high field to generate homogeneous images with increased contrast and free of common artefacts. All steps in SWI processing have been addressed - coil combination, phase unwrapping, image combination over echoes, phase filtering and homogeneity correction - and applied to an efficient bipolar multi-echo acquisition to substantially improve the quality of SWI. PRINCIPAL RESULTS: Our findings regarding the optimal individual processing steps lead us to propose a Contrast-weighted, Laplace-unwrapped, bipolar multi-Echo, ASPIRE-combined, homogeneous, improved Resolution SWI, or CLEAR-SWI. CLEAR-SWI was compared to two other multi-echo SWI methods and standard, single-echo SWI with the same acquisition time at 7 T in 10 healthy volunteers and with single-echo SWI in 13 patients with brain tumors. CLEAR-SWI had improved contrast-to-noise and homogeneity, reduced signal dropout and was not compromised by the artefacts which affected standard SWI in 10 out of 13 cases close to tumors (as assessed by expert raters), as well as generating T2* maps and phase images which can be used for Quantitative Susceptibility Mapping. In a comparison with other multi-echo SWI methods, CLEAR-SWI had the fewest artefacts, highest SNR and generally higher contrast-to-noise. MAJOR CONCLUSIONS: CLEAR-SWI eliminates the artefacts common in standard, single-echo SWI, reduces signal dropouts and improves image homogeneity and contrast-to-noise. Applied clinically, in a study of brain tumor patients, CLEAR-SWI was free of the artefacts which affected standard, single-echo SWI.

Systemic inflammation scores correlate with survival prognosis in patients with newly diagnosed brain metastases.

BACKGROUND: Systemic inflammation measured by the neutrophil-to-lymphocyte ratio (NLR), leucocyte-to-lymphocyte ratio (LLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and CRP/albumin ratio (CRP/Alb) was shown to impact the survival prognosis in patients with extracranial solid cancer. METHODS: One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry. RESULTS: PLR and CRP/Alb were higher in patients with progressive extracranial disease and lower in patients with no evidence of extracranial disease. Lower NLR (cut-off = 5.07; 9.3 vs. 5.0 months), LLR (cut-off = 5.76; 10.0 vs. 5.3 months), PLR (cut-off = 335; 8.0 vs. 3.8 months), MLR (cut-off = 0.53; 6.0 vs. 3.5 months) and CRP/Alb (cut-off = 2.93; 8.5 vs. 3.7 months; padj < 0.05) were associated with longer overall survival (OS). In multivariate analysis with graded prognostic assessment (hazard ratio (HR) 1.45; 95% confidence interval (CI): 1.32-1.59; padj = 1.62e - 13), NLR (HR 1.55; 95% CI: 1.38-1.75; padj = 1.92e - 11), LLR (HR 1.57; 95% CI: 1.39-1.77; padj = 1.96e - 11), PLR (HR 1.60; 95% CI: 1.39-1.85; padj = 2.87955e - 9), MLR (HR 1.41; 95% CI: 1.14-1.75; padj = 0.027) and CRP/Alb (HR 1.83; 95% CI: 1.54-2.18; padj = 2.73e - 10) remained independent factors associated with OS at BM diagnosis. CONCLUSIONS: Systemic inflammation, measured by NLR, LLR, PLR, MLR and CRP/Alb, was associated with OS in patients with BM. Further exploration of immune modulating therapies is warranted in the setting of BM.

Circulating PD-L1 levels change during bevacizumab-based treatment in recurrent glioma.

PURPOSE: In primary brain tumors, the efficacy of immune-modulating therapies is still under investigation as inflammatory responses are restricted by tight immunoregulatory mechanisms in the central nervous system. Here, we measured soluble PD-L1 (sPD-L1) in the plasma of patients with recurrent glioblastoma (GBM) and recurrent WHO grade II-III glioma treated with bevacizumab-based salvage therapy. METHODS: Thirty patients with recurrent GBM and 10 patients with recurrent WHO grade II-III glioma were treated with bevacizumab-based salvage therapy at the Medical University of Vienna. Prior to each treatment cycle, EDTA plasma was drawn and sPD-L1 was measured applying a sandwich ELISA with a lower detection limit of 0.050 ng/ml. Leukocyte counts and C-reactive protein (CRP) levels were measured according to institutional practice. RESULTS: Median number of sPD-L1 measurements was 6 per patient (range: 2-24). At baseline, no significant difference in sPD-L1 concentrations was observed between WHO grade II-III glioma and GBM. Intra-patient variability of sPD-L1 concentrations was significantly higher in WHO grade II-III glioma than in GBM (p = 0.014) and tendentially higher in IDH-mutant than in IDH-wildtype glioma (p = 0.149) In WHO grade II-III glioma, sPD-L1 levels were significantly lower after one administration of bevacizumab than at baseline (median: 0.039 ng/ml vs. 0.4855 ng/ml, p = 0.036). In contrast, no significant change could be observed in patients with GBM. CONCLUSIONS: Changes in systemic inflammation markers including sPD-L1 are observable in patients with recurrent glioma under bevacizumab-based treatment and differ between WHO grade II-III glioma and GBM.

Influence of preoperative corticosteroid treatment on rate of diagnostic surgeries in primary central nervous system lymphoma: a multicenter retrospective study.

BACKGROUND: Corticosteroid therapy (CST) prior to biopsy may hinder histopathological diagnosis in primary central nervous system lymphoma (PCNSL). Therefore, preoperative CST in patients with suspected PCNSL should be avoided if clinically possible. The aim of this study was thus to analyze the difference in the rate of diagnostic surgeries in PCNSL patients with and without preoperative CST. METHODS: A multicenter retrospective study including all immunocompetent patients diagnosed with PCNSL between 1/2004 and 9/2018 at four neurosurgical centers in Austria was conducted and the results were compared to literature. RESULTS: A total of 143 patients were included in this study. All patients showed visible contrast enhancement on preoperative MRI. There was no statistically significant difference in the rate of diagnostic surgeries with and without preoperative CST with 97.1% (68/70) and 97.3% (71/73), respectively (p = 1.0). Tapering and pause of CST did not influence the diagnostic rate. Including our study, there are 788 PCNSL patients described in literature with an odds ratio for inconclusive surgeries after CST of 3.3 (CI 1.7-6.4). CONCLUSIONS: Preoperative CST should be avoided as it seems to diminish the diagnostic rate of biopsy in PCNSL patients. Yet, if CST has been administered preoperatively and there is still a contrast enhancing lesion to target for biopsy, surgeons should try to keep the diagnostic delay to a minimum as the likelihood for acquiring diagnostic tissue seems sufficiently high.

LAG-3 expression in the inflammatory microenvironment of glioma.

PURPOSE: Immune 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. METHODS: 97 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. RESULTS: LAG-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). CONCLUSIONS: LAG-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.

High Diagnostic Accuracy of Visible 5-ALA Fluorescence in Meningioma Surgery According to Histopathological Analysis of Tumor Bulk and Peritumoral Tissue.

BACKGROUND AND OBJECTIVES: Complete neurosurgical resection of intracranial meningiomas is essential to avoid residual tumor tissue and thus minimize the risk of tumor recurrence. However, local recurrence of meningiomas is not uncommon mainly due to insufficient intraoperative detection of residual tumor tissue within the tumor bulk or peritumoral tissue such as bone and satellite lesions. Although 5-aminolevulinic acid (5-ALA) induced fluorescence was found to visualize the majority of meningiomas, no comprehensive histopathological assessment of fluorescing samples from the tumor bulk and peritumoral tissue is available. The aim of our study was thus to histopathologically analyze a large series of tissue samples derived from meningioma surgery to assess the positive predictive value (PPV) of visible 5-ALA fluorescence. STUDY DESIGN/MATERIALS AND METHODS: In this study, we retrospectively investigated a series of tissue samples with visible 5-ALA fluorescence collected during surgery of intracranial meningiomas from the tumor bulk and peritumoral tissue including the bone flap, dura/dural tail, arachnoidea, adjacent cortex, and satellite lesions. The tumor diagnosis was established according to the World Health Organization (WHO) criteria and all collected fluorescing samples were screened for presence of tumor tissue to calculate the PPV. RESULTS: Altogether, 191 tissue samples with visible 5-ALA fluorescence derived during surgery of 85 meningiomas (63 WHO grade I, 17 WHO grade II, and 5 WHO grade III) were included. In detail, 158 samples from the tumor bulk and 33 specimens from the peritumoral tissue were investigated. According to histopathological analysis, the PPV of 5-ALA fluorescence was significantly higher in samples from the tumor bulk (100%) as compared with peritumoral tissue (73%; P < 0.001). With regard to peritumoral tissue, tumor tissue was present in most fluorescing samples from the satellite lesions (100%), the bone flap (92%), arachnoidea (83%), and dura/dural tail (75%). In contrast, tumor tissue was absent in the majority of samples from fluorescing cortex (six of seven samples; 86%). However, distinct reactive tissue alterations were found in all six tumor-free fluorescing cortex samples and additional vascular proliferation in two cases. CONCLUSION: In this largest series to date, visible 5-ALA fluorescence is characterized by a high PPV detecting tumor bulk and peritumoral tissue in intracranial meningiomas. Thus, 5-ALA fluorescence supports the neurosurgeon in identifying residual tumor tissue at relevant surgical sites to optimize meningioma surgery and minimize the risk of local recurrence. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC.

Neurological symptom burden impacts survival prognosis in patients with newly diagnosed non-small cell lung cancer brain metastases.

BACKGROUND: Brain metastases (BM) are a frequent complication of advanced cancer and are characterized by a variety of neurological symptoms. Although the presence of neurological symptoms is included in the response assessment in patients with primary brain tumors, to the authors' knowledge little is known regarding the prognostic impact of neurological symptoms in patients with BM. METHODS: Patients with newly diagnosed BM from non-small cell lung cancer were identified from the Vienna Brain Metastasis Registry and were evaluated according to the incidence, distribution, and prognostic impact of neurological symptoms at the time of diagnosis of BM. RESULTS: A total of 1608 patients (57.3% male and 42.7% female; median age, 62 years) were available for further analyses. Neurological symptoms including focal deficits (985 patients; 61.3%), signs of increased intracranial pressure (483 patients; 30.0%), epileptic seizures (224 patients; 13.9%), and neuropsychological symptoms (233 patients; 14.5%) were documented in 1186 of the 1608 patients (73.8%). Patients with asymptomatic BM presented with a longer median overall survival after the diagnosis of BM compared with patients with symptomatic BM (11 months vs 7 months; P < .001). In multivariate analysis with a diagnosis-specific graded prognostic assessment (hazard ratio, 1.41; 95% CI, 1.33-1.50 [P < .001]), the presence of neurological symptoms (hazard ratio, 1.39; 95% CI, 1.23-1.57 [P < .001]) was found to be independently associated with survival prognosis from the time of diagnosis of BM. CONCLUSIONS: Neurological symptoms at the time of BM diagnosis demonstrated a strong and independent association with survival prognosis. The results of the current study have highlighted the need for the integration of the presence of neurological symptoms into the prognostic assessment of patients with BM from non-small cell lung cancer. LAY SUMMARY: Neurological symptom evaluation is included regularly in the assessment of patients with primary brain tumors. However, to the authors' knowledge, little is known regarding the prognostic impact in patients with newly diagnosed brain metastases (BM). The current study has provided a detailed clinical characterization of the incidence, distribution, and prognostic impact of neurological symptoms in a large, real-life cohort of patients with BM from non-small cell lung cancer. In this cohort, neurological symptoms at the time of diagnosis of BM demonstrated a strong, independent prognostic impact on the survival prognosis. The results of the current study have highlighted the need for the integration of neurological symptom burden into the prognostic assessment of patients with BM from non-small cell lung cancer.

Perioperative imaging in patients treated with resection of brain metastases: a survey by the European Association of Neuro-Oncology (EANO) Youngsters committee.

BACKGROUND: Neurosurgical resection represents an important treatment option in the modern, multimodal therapy approach of brain metastases (BM). Guidelines for perioperative imaging exist for primary brain tumors to guide postsurgical treatment. Optimal perioperative imaging of BM patients is so far a matter of debate as no structured guidelines exist. METHODS: A comprehensive questionnaire about perioperative imaging was designed by the European Association of Neuro-Oncology (EANO) Youngsters Committee. The survey was distributed to physicians via the EANO network to perform a descriptive overview on the current habits and their variability on perioperative imaging. Chi square test was used for dichotomous variables. RESULTS: One hundred twenty physicians worldwide responded to the survey. MRI was the preferred preoperative imaging method (93.3%). Overall 106/120 (88.3%) physicians performed postsurgical imaging routinely including MRI alone (62/120 [51.7%]), postoperative CT (29/120 [24.2%]) and MRI + CT (15/120 [12.5%]). No correlation of postsurgical MRI utilization in academic vs. non-academic hospitals (58/89 [65.2%] vs. 19/31 [61.3%], p = 0.698) was found. Early postoperative MRI within ≤72 h after resection is obtained by 60.8% of the participants. The most frequent reason for postsurgical imaging was to evaluate the extent of tumor resection (73/120 [60.8%]). In case of residual tumor, 32/120 (26.7%) participants indicated to adjust radiotherapy, 34/120 (28.3%) to consider re-surgery to achieve complete resection and 8/120 (6.7%) to evaluate both. CONCLUSIONS: MRI was the preferred imaging method in the preoperative setting. In the postoperative course, imaging modalities and timing showed high variability. International guidelines for perioperative imaging with special focus on postoperative MRI to assess residual tumor are warranted to optimize standardized management and adjuvant treatment decisions for BM patients.

Clinical characteristics and prognostic factors of adult patients with pilocytic astrocytoma.

INTRODUCTION: Pilocytic 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. METHODS: 46 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. RESULTS: Median 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). CONCLUSIONS: Tumor 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.

Analysis of the inflammatory tumor microenvironment in meningeal neoplasms.

BACKGROUND: Properties of the inflammatory tumor microenvironment are associated with disease subtype, grade, and prognosis in various cancer entities. As immune-modulatory therapies are currently being explored in patients with meningeal neoplasms, we investigated their inflammatory microenvironment (meningiomas and solitary fibrous tumor/hemangiopericytoma (SFT/HPC)). MATERIALS AND METHODS: 74 meningeal tumor specimens: (10/74 (13.5%) atypical meningioma; 8/74 (10.8%) anaplastic meningioma; 8/74 (10.8%) chordoid meningioma; 9/74 (12.2%) fibroblastic meningioma; 10/74 (13.5%) transitional meningioma; 3/74 (4.1%) rhabdoid meningioma; 7/74 (9.5%) meningothelial meningioma; SFT/HPC (19/74 (25.7%) were retrieved from the Neuro-Biobank, Medical University of Vienna, Austria. RESULTS: Tumor-infiltrating lymphocyte (TIL) infiltration could be observed in the majority of the investigated specimens (CD3+: 66/74 (89.2%); CD8+: 47/74 (63.5%); CD45RO+: 29/73 (39.2%); FOXP3+ 19/74 (25.7%); PD1+: 3/74 (4.1%). No difference in TIL infiltration was observed between SFT/HPC and meningioma cases. Higher density of FOXP3+ TILs was observed with increasing WHO grade in meningioma specimens (p = 0.005). Membranous programmed cell death ligand 1 (PD-L1) expression was observed in 4/74 (5.4%) specimens, with 3/74 (4.1%) presenting with 1% and 1/74 (1.4%) with 3% PD-L1 expressing tumor cells. Lymphatic vessels as identified by podoplanin immunohistochemistry were observed in 10/74 (13.5%) specimens and were significantly associated with presence of membranous PD-L1 expression on tumor cells (p = 0.003). CONCLUSION: Infiltration by various TIL subtypes can be observed in the majority of meningeal neoplasms, with enrichment of FOXP3-positive regulatory T-cells in higher-grade meningioma. PD-L1 expression on tumor cells was only infrequently found. A better understanding of the pathobiological role of the immune system in meningeal neoplasms may facilitate development of immunomodulatory treatment approaches in meningeal tumors.

High Interobserver Agreement in the Subjective Classification of 5-Aminolevulinic Acid Fluorescence Levels in Newly Diagnosed Glioblastomas.

BACKGROUND AND OBJECTIVES: Fluorescence-guided resection of glioblastomas (GBM) using 5-aminolevulinic acid (5-ALA) improves intraoperative tumor visualization and is thus widely used nowadays. During resection, different fluorescence levels can usually be distinguished within the same tumor. Recently, we demonstrated that strong, vague, and no fluorescence correspond to distinct histopathological characteristics in newly diagnosed GBM. However, the qualitative fluorescence classification by the neurosurgeon is subjective and currently no comprehensive data on interobserver variability is available. The aim of this study was thus to investigate the interobserver variability in the classification of 5-ALA fluorescence levels in newly diagnosed GBM. STUDY DESIGN/MATERIALS AND METHODS: A questionnaire investigating the interobserver variability in 5-ALA fluorescence quantification was performed at a nation-wide neurosurgical oncology meeting. The participants involved in the neurosurgical/neurooncological field were asked to categorize 30 cases of 5-ALA fluorescence images derived from GBM resection on a lecture hall screen according to the widely used three-tier fluorescence classification scheme (negative, vague, or strong fluorescence). Additionally, participants were asked for information on their medical background such as specialty, level of training, and experience with 5-ALA fluorescence-guided procedures. Interobserver agreement was defined as the calculated mean κ values for each observer. RESULTS: A total of 36 questionnaires were included in the final analysis. The mean average κ value in fluorescence classification within the entire cohort was 0.71 ± 0.12 and 29 (81%) participants had a substantial or almost perfect interobserver agreement (κ values 0.6-1.0). Interobserver agreement was significantly higher in neurosurgeons (mean κ: 0.83) as compared with non-neurosurgeons involved in the neurooncological field (mean κ: 0.52; P < 0.001). Furthermore, interobserver agreement was significantly higher in participants who had experience with at least 25 5-ALA fluorescence-guided surgeries (mean κ: 0.87) compared with less experienced colleagues (mean κ: 0.82; P = 0.039). CONCLUSION: Our study found a high interobserver agreement in the qualitative classification of different 5-ALA fluorescence levels in newly diagnosed GBM. Interobserver agreement increases significantly in more experienced participants and therefore a high level of experience is crucial for reliable intraoperative fluorescence classification. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals, Inc.

High-resolution metabolic mapping of gliomas via patch-based super-resolution magnetic resonance spectroscopic imaging at 7T.

OBJECTIVES: To demonstrate the feasibility of 7 T magnetic resonance spectroscopic imaging (MRSI), combined with patch-based super-resolution (PBSR) reconstruction, for high-resolution multi-metabolite mapping of gliomas. MATERIALS AND METHODS: Ten patients with WHO grade II, III and IV gliomas (6/4, male/female; 45 ±â€¯9 years old) were prospectively measured between 2014 and 2018 on a 7 T whole-body MR imager after routine 3 T magnetic resonance imaging (MRI) and positron emission tomography (PET). Free induction decay MRSI with a 64 × 64-matrix and a nominal voxel size of 3.4 × 3.4 × 8 mm³ was acquired in six minutes, along with standard T1/T2-weighted MRI. Metabolic maps were obtained via spectral LCmodel processing and reconstructed to 0.9 × 0.9 × 8 mm³ resolutions via PBSR. RESULTS: Metabolite maps obtained from combined 7 T MRSI and PBSR resolved the density of metabolic activity in the gliomas in unprecedented detail. Particularly in the more heterogeneous cases (e.g. post resection), metabolite maps enabled the identification of complex metabolic activities, which were in topographic agreement with PET enhancement. CONCLUSIONS: PBSR-MRSI combines the benefits of ultra-high-field MR systems, cutting-edge MRSI, and advanced postprocessing to allow millimetric resolution molecular imaging of glioma tissue beyond standard methods. An ideal example is the accurate imaging of glutamine, which is a prime target of modern therapeutic approaches, made possible due to the higher spectral resolution of 7 T systems.

5-aminolevulinic acid induced protoporphyrin IX (ALA-PpIX) fluorescence guidance in meningioma surgery.

INTRODUCTION: 5-aminolevulinic acid induced protoporphyrin IX (5-ALA-PpIX) fluorescence guidance has emerged as a valuable surgical adjunct for resection of intracranial tumors. METHODS: Here we present a focused review on 5-ALA-PpIX fluorescence guidance for meningiomas. RESULTS: We discuss the clinical studies and specific applications to date as well as the two main intraoperative fluorescence technologies applied to meningiomas. CONCLUSIONS: The use of 5-ALA-PpIX in meningiomas holds promising potential so neurosurgeons can improve surgical outcomes for patients with meningiomas as well as be pioneers in developing improved fluorescence imaging technologies.

Prognostic assessment in patients with newly diagnosed small cell lung cancer brain metastases: results from a real-life cohort.

PURPOSES: Brain metastases (BM) are a frequent complication in small cell lung cancer (SCLC), resulting in a reduced survival prognosis. Precise prognostic assessment is an important foundation for treatment decisions and clinical trial planning. METHODS: Patients with newly diagnosed SCLC BM were identified from the Vienna Brain Metastasis Registry and evaluated concerning prognostic factors. RESULTS: 489 patients (male 62.2%, female 37.8%; median age 61 years) were included. Neurological symptoms were present in 297/489 (60.7%) patients. A- to oligosymptomatic patients (5 vs. 9 months, p = 0.030) as well as patients with synchronous diagnosis of BM and primary tumor (5 vs. 9 months, p = 0.008) presented with improved overall survival (OS) prognosis. RPA (HR 1.66; 95% CI 1.44-1.91; p < 0.001), GPA (HR 1.65; p < 0.001), DS-GPA (HR 1.60; p < 0.001) and LabBM score (HR 1.69; p < 0.001) were statistically significantly associated with OS. In multivariate analysis, DS-GPA (HR 1.59; p < 0.001), neurological deficits (HR 1.26; p = 0.021) and LabBM score (HR 1.57; p < 0.001) presented with statistical independent association with OS. CONCLUSION: A- to oligosymptomatic BM as well as synchronous diagnosis of SCLC and BM were associated with improved OS. Established prognostic scores could be validated in this large SCLC BM real-life cohort.

Increasing use of immunotherapy and prolonged survival among younger patients with primary CNS lymphoma: a population-based study.

Background: Primary CNS lymphoma is a highly aggressive and rare type of extranodal non-Hodgkin lymphoma. Although, new therapeutic approaches have led to improved survival, the management of the disease poses a challenge, practice patterns vary across institutions and countries, and remain ill-defined for vulnerable patient subgroups. Material and Methods: Using information from the Austrian Brain Tumor Registry we followed a population-based cohort of 189 patients newly diagnosed from 2005 to 2010 through various lines of treatment until death or last follow-up (12-31-2016). Prognostic factors and treatment-related data were integrated in a comprehensive survival analysis including conditional survival estimates. Results: We find variable patterns of first-line treatment with increasing use of rituximab and high-dose methotrexate (HDMTX)-based poly-chemotherapy after 2007, paralleled by an increase in median overall survival restricted to patients aged below 70 years. In the entire cohort, 5-year overall survival was 24.4% while 5-year conditional survival increased with every year postdiagnosis. Conclusion: In conclusion, we show that the use of poly-chemotherapy and immunotherapy has disseminated to community practice to a fair extent and survival has increased over time at least in younger patients. Annually increasing conditional survival rates provide clinicians with an adequate and encouraging prognostic measure.

The prognostic value of [123I]-vascular endothelial growth factor ([123I]-VEGF) in glioma.

PURPOSE: Recent studies have shown that tumor vascular endothelial cells and various tumor cells overexpress receptors for vascular endothelial growth factor (VEGF). The aim of this study was to investigate the prognostic value of [123I]-VEGF scintigraphy in patients with histologically verified brain tumors. METHODS: 23 consecutive patients (9 women and 14 men aged 30-83 years, mean age 56.6 ± 14.4 years) with histopathologically-verified primary brain tumors were included in the study. All patients had undergone [123I]-VEGF scintigraphy. SPECT examinations of brain were performed 30 min and 18 h after injection. Additional [11C]-methionine PET ([11C]-MET PET) was performed in eight of the 23 patients. Both [123I]-VEGF and [11C]-MET PET were evaluated visually and semiquantitatively by tumor-to-normal brain uptake ratio (T/N ratio). Thresholds of the T/N ratio were evaluated by analysis of receiver operating characteristics (ROC). Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: World Health Organization (WHO) grade IV glioma lesions showed [123I]-VEGF uptake 18 h after the injection, whereas other brain tumors of grade II or III showed negative results. There was no significant difference in the tumor size between VEGF positive and VEGF negative tumors. Patients with [123I]-VEGF T/N ratio threshold <1.32 showed significantly longer survival than patients with T/N ratio ≥ 1.32 (2680 days vs 295 days; P < 0.05). In the subgroup of 16 grade IV glioma patients, significant OS differences were found using a T/N ratio of 1.75 as threshold (T/N ratio < 1.75: 720 days; T/N ≥ 1.75: 183 days; P < 0.05). Significant difference (P < 0.05) was also found in [11C]-MET PET T/N ratios between the grade IV glioma (mean T/N ratio: 3.71) and the grade II or III glioma (mean T/N ratio: 1.74). CONCLUSION: Our results suggest that [123I]-VEGF scintigraphy may be useful for visualization of tumor angiogenesis. In addition, [123I]-VEGF may provide relevant prognostic information in patients with glioma.