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Background Oligodendrogliomas are glial tumors with a relatively favorable survival prognosis of >10 years. While immediate postoperative treatment prolongs survival, long-term toxicities of adjuvant radio-chemotherapy remain a concern. Predictive biomarkers guiding postoperative treatment decisions are limited. Material and Methods In this retrospective study, we included patients treated for a newly diagnosed oligodendroglioma (isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted, CNS WHO grades 2 and 3) in 1992 - 2019 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria). Early treatment was defined as radiotherapy, chemotherapy, or both within 6 months after resection, whereas benefit from early treatment was defined as progression-free survival (PFS) above the median in the overall cohort. DNA methylation analysis was performed using Illumina MethylationEPIC 850k microarrays. Results Of all 201 eligible patients, sufficient tumor tissue for DNA methylation analysis was available in 46 patients. Of these, 25/46 (54.3%) were diagnosed with CNS WHO grade 2 and 21/46 (45.6%) with grade 3 oligodendroglioma. Median age at diagnosis was 41 years (range: 23-70). In total, 21/46 (45.6%) patients received early treatment, of whom 13/21 (61.9%) received radio-chemotherapy, 6/21 (28.6%) radiotherapy only and 2/21 (9.5%) chemotherapy only. Median PFS was 134.0 months (95%CI: 78.3 - not reached) in patients receiving early treatment versus 87.2 months (95%CI: 66.8 - 150) in patients who did not. In patients receiving early treatment, differences in DNA methylation profiles could be detected between patients who drew benefit from postoperative treatment (group 1) versus those who did not (group 2). Based on the top 1000 differentially methylated CpG sites between both groups, two clusters were detected which comprised either patients of group 1 or 2. Clustering was independent from gender, WHO grade, extent of resection, type of postoperative treatment, treating center, and O6-methylguanine-methyltransferease (MGMT) promoter methylation status. Gene set enrichment analysis of the top 1000 differentially methylated gene sites mapped to 694 genes showed differential methylation in genes involved in fibroblast growth receptor 1 (FGFR1) signaling, Wnt signaling, integrin signaling, and actin cytoskeleton regulation. Conversely, in patients not receiving early treatment, PFS did neither correlate with DNA methylation clustering nor with MGMT promoter methylation. Conclusion In our cohort, whole genome DNA methylation was associated with PFS in patients who received early postoperative treatment, suggesting a predictive but not prognostic role. As the predictive value of MGMT promoter methylation is limited in oligodendroglioma, whole genome DNA methylation should be considered in future clinical trials.

Pediatric high-grade glioma (pHGG) is an incurable disease with a median survival of less than 6 months post-progression and no effective targeted therapy. PDGFRA is commonly altered in pHGG, but targeting PDGFRA in this disease has been unsuccessful, likely due to poor central nervous system (CNS) penetrance. Avapritinib is a novel and CNS-penetrant PDGFRA/KIT inhibitor that is FDA-approved for adults with unresectable or metastatic PDGFRA exon 18-mutant gastrointestinal stromal tumor (GIST) and is being studied in CNS tumors. We performed a pre-clinical and clinical assessment to determine the potential suitability of avapritinib therapy in PDGFRA-driven glioma. A multi-institutional cohort genetic analysis revealed PDGFRA amplification and mutation in 10.2% and 6.1% of pHGG, respectively. Additionally, PDGFRA expression in the absence of genetic events was significantly increased in H3K27-altered diffuse midline glioma (DMG) compared to H3-wildtype pHGG. Avapritinib performed well in: (i) mutant PDGFRA enzyme inhibition and wildtype inhibition at high dose, (ii) minimal off-target kinase inhibition, (iii) brain penetration (peak 10 µM), and (iv) proliferation/pPDGFRA reduction in PDGFRA-amplified and mutant pHGG cell lines. Avapritinib treatment in an aggressive PDX model of pHGG resulted in significant survival benefit. We pursued treatment of eight pediatric and young adult HGG patients with avapritinib across seven institutions. Patients were a mixture of local (N = 4) and metastatic disease (N = 4); all patients were post-initial radiation, with 7/8 having progressed on prior treatment. 7/8 patients had PDGFRA amplifications or mutations, and 7/8 had H3K27M mutations. Therapy was generally well-tolerated. 4/8 patients showed radiographic response to avapritinib, with one patient demonstrating complete response of target lesion and remains on therapy. Avapritinib levels in patients’ CSF and brain tumor tissue reached micromolar levels. These results demonstrate that avapritinib is a potent, selective, and CNS-penetrant PDGFRA/KIT inhibitor that is promising for further study in pHGG with relevant alterations.

Background T-DXd is a novel antibody-drug conjugate with high activity in HER2-positive metastatic breast cancer. The prospective, single-arm, single-centre phase II TUXEDO-1 trial showed clinically relevant activity of T-DXd in HER2-positive BC pts with active BM with an intracranial response rate of 73.3%. This biomarker sub-study of TUXEDO-1 aimed to investigate changes in the extent of metastases-induced brain damage in patients with and without response to therapy by measuring the serum levels of two proteins constitutively expressed in the human brain and measurable upon brain damage in the blood serum: NSE and S100. Material and Methods We assessed serum NSE (sNSE) and serum S100 (sS100) levels in a total of 37 blood samples drawn at cycles 1, 4 and end of treatment (EOT) in all patients of the intent-to-treat population of the TUXEDO-1 trial using commercially available ELISA assays. Intracranial radiological response was centrally assessed by a board-certified neuro-radiologist using RANO criteria. sNSE and sS100 levels were compared between responders and non-responders using the Mann Whitney U test and a significance level of 0.05. Results At baseline, we detected no significant difference of sNSE or sS100 levels between T-DXd responders and non-responders, respectively. Baseline median sNSE level was 10.6 ng/ml (interquartile range (IQR) 8.6-12.2) in T-DXd responders as compared with median 12.5 ng/ml (IQR 12.2-12.9) in the non-responder group (n.s.). At cycle 4, corresponding numbers were 8.1 ng/ml in responding patients (IQR 7-11.2) and 12.7 ng/ml (IQR 12.2-12.9) in non-responders, respectively (p=0.009). No differences in sS100 levels were observed between the groups at any time point. Conclusion In patients showing intracranial objective response to T-Dxd, sNSE levels were significantly lower at cycle 4 as compared with non-responders, suggesting a reduction in metastases-induced brain damage as a direct treatment effect. sNSE may be a clinically useful biomarker for longitudinal assessment of brain metastasis burden.

Background The incidence of brain metastases (BM) in patients with thyroid cancer (TC) depends on the histological subtype. About 1% of patients with differentiated (DTC), 3% with medullary (MTC) and up to 10% with anaplastic thyroid cancer (ATC) develop BM. The diagnosis of BM drastically worsens the prognosis of TC. Given the rare incidence, little is known about the presentation and outcome of this cohort. Material and Methods Patients with a histologically verified diagnosis of TC and BM were identified from the Vienna Brain Metastasis Registry, a comprehensive database managed by the Division of Oncology, Medical University of Vienna, including patients with cerebral metastasis since 1990. Data were obtained from medical records comprising clinicopathological features, treatment, BM-specific characteristics and outcome. Results 20/6074 patients included in the registry had a diagnosis of TC and radiologically verified BM. 13/20 (65%) were female and the median age at diagnosis of TC and manifestation of BM was 56 years (range 21-75) and 68 years (range 45-75), respectively. In terms of histology, 18/20 (90%) had DTC, one MTC and one ATC. Interestingly, 10/18 DTC presented with follicular histology which underlines the more aggressive course of this rare subtype. 6/20 (30%) had BM at primary diagnosis (DTC n=5, ATC n=1), while the remaining developed BM during follow-up. The median time to diagnosis of BM was 2.6 years for DTC (range 0-42), 22 years in the MTC patient and 2 months for ATC. Regarding BM-specific characteristics, all but one patient had symptoms due to BM (neurological deficits n=11, increased intracranial pressure n=5, seizures n=3). Most patients (13/20) had a singular BM, commonly located in the left hemisphere (8/13), and only one had more than three BMs. Upfront treatment for BM was local therapy (resection n=9, stereotactic radiosurgery n=7, whole brain radiotherapy n=3); one patient received supportive care only. The median overall survival (mOS) from diagnosis of TC was 6 years for DTC (range 2.5 months-42 years), 33 years for the MTC and 9 months for the ATC. The mOS from diagnosis of BM was 14 months for DTC (1.8 months-16 years), 22 years for the MTC and 3 months for the ATC. Conclusion Few patients with TC develop BM, which present commonly as single lesion. While in general BM constitute a poor prognostic factor, individual patients experience long-term survival following local therapy. More information about the optimal management of BM in TC is needed to enable guideline recommendations.

Background Immunotherapy (IO) has changed the treatment landscape of metastatic cancer patients, however, treatment resistance is frequent. We aimed to characterize the inflammatory tumor microenvironment in brain metastases (BM) after IO to gain a deeper understanding of immunologic escape mechanisms. Material and Methods Solid cancer patients who had BM resection after IO progression (IO cohort) were retrospectively identified. We analyzed tumor-infiltrating immune cell subsets (CD3, CD8, CD45RO, FOXP3) and expression of immune checkpoint molecules (PD-L1, PD-1, LAG-3) by immunohistochemistry. A control cohort of BM tissue samples without prior IO served for comparison (no immunotherapy cohort, NIO). Results Twenty-eight IO patients (12/28, 42.9% females; 16/28, 57.1% males; median 61 years; 14/28, 50% lung cancer; 5/28, 17.9% melanoma; 4/28, 14.3% renal cell carcinoma; 1/28, 3.6% breast cancer; 4/28, 14.3% other cancer entities) and 57 NIO patients (28/57, 49.1% females; 29/57, 50.9% males; median 58 years; 35/57, 61.4% lung cancer; 9/57, 15.8% breast cancer; 4/57, 7.0% melanoma; 3/57, 5.3% renal cell carcinoma; 6/57, 10.5% other cancer entities) were included. IO patients had a median of one (range 0-4) systemic therapy line prior to IO. Median time from last IO application until BM resection was 5.6 months (range 0.2-49.8 months). Patients received a median number of 7 (range 1-56) IO applications (14/28, 50% PD-1-targeting IO; 8/28, 28.6% PD-L1; 2/28, 7.1% CTLA4; 4/28, 14.3% CTLA4+PD-1; 3/28, 10.7% IO+chemotherapy). No statistically significant differences in the densities of investigated TILs or PD-L1 expression between the IO and the NIO cohort were observed. Patients of the IO cohort showed higher PD-L1 expression compared to the NIO cohort (57.1 vs. 42.1%, Chi-square, p>0.05). Overall survival (OS) was similar in both cohorts, with a median OS of 11.0 months (range 5.0-17.0) in the IO cohort and 11.0 months (range 5.5-16.5) in the NIO cohort. Conclusion Our findings show an upregulation of PD-L1 in BM occurring after prior IO therapy in the absence of other overt changes in the inflammatory microenvironment. Ongoing analyses in this cohort are investigating possible molecular driver of resistance by analyzing DNA methylation profiles of pre-and post-IO tissue samples of the IO cohort to potentially gain insights on inflammatory IO resistance mechanisms in BM patients.

Background Based on the the rising detection of asymptomatic brain metastases (BM) and the remarkable intracranial responses of targeted- and immunotherapy in specific subgroups of asymptomatic BM patients, we aimed to evaluate the clinical characteristics and prognostic value of neurological symptoms in BM from melanoma. Material and Methods 670 patients with newly diagnosed melanoma BM were identified from the Vienna Brain Metastasis Registry. We performed retrospective chart review and statistical outcome analyses. Results 370/670 (55.2%) patients presented with neurological symptoms including neurological deficits (316/370; 85.4%), signs of increased intracranial pressure (126/370; 34.1%) and epileptic seizures (53/370; 14.3%). 57.6% (80/139) of patients with BRAF mutated melanoma presented with asymptomatic BM at diagnosis. Absence of neurological symptoms at BM diagnosis was associated with a longer median overall survival after time of BM diagnosis (7 vs. 5 months; p< 0.001; log-rank test). In multivariate analysis with the diagnosis-specific graded prognostic assessment (DS-GPA: HR:1.4; 95% CI, 1.25-1.48; p Conclusion: Neurological symptoms at the time of BM diagnosis are an independent and strong prognostic factor in melanoma BM patients. Our results argue for the integration of neurological symptoms into the prognostic assessment of patients with BM from melanoma.

H3K27M-mutated diffuse midline glioma (H3K27M DMG) are an almost universally fatal disease with a median survival of less than 6 months post progression and no effective therapy. PDGFRA-signaling has shown to promote and sustain a subset of oligodendrocyte precursor-like tumor cells that are responsible for tumor propagating potential and high proliferation rates. However, first attempts to target PDGFRA in adult glioblastoma with dasatinib/imatinib or pediatric refractory brain tumors with sunitinib were not successful. We report on the first experience in two patients receiving avapritinib, a highly potent, selective, brain penetrant PDGFRA/KIT inhibitor under a compassionate use program. Our first patient with spinal H3K27M DMG developed supratentorial metastases ten months after initial diagnosis. Molecular profiling revealed de novo PDGFRA and KIT amplifications and treatment with dasatinib was initiated. Due to disease progression and novel metastases, therapy was switched to avapritinib showing near complete resolution of the previously unirradiated frontal lesion with additional disease stabilization of other metastatic sites. Following re-resection and irradiation of progressing cerebellar lesions, the patient remains clinically stable on avapritinib therapy over 12 months. The second patient with diffuse intrinsic pontine glioma showed disease progression nine months after diagnosis and was treated with focal re-irradiation (30Gy). As the tumor harbored a PDGFRA R841del alteration, avapritinib was initiated seven weeks after radiation upon further tumor progression resulting in partial response. Pharmacokinetic sampling of cerebrospinal fluid (CSF) detected an increasing CSF/plasma ratio over time and up to 4 µM avapritinib in tumor tissue. Avapritinib CSF levels in both patients were distinctly higher than dasatinib levels. Avapritinib was generally well tolerated besides lower limb edema, elevated LDH and liver enzymes. Hence, effective CNS penetration of avapritinib at pharmacologically relevant brain tumor concentrations resulted in clinical response in two patients with rapidly progressive H3K27M DMG.

Pediatric high-grade gliomas (pHGG) account for approximately 12% of pediatric brain tumors. Despite advances in molecular diagnosis and identification of discrete molecular subtypes, pHGG are the leading cause of cancer-related death in children. Thus, current research focuses on identifying novel therapeutic targets. Sequencing analyses across pediatric cancer types identified DNA repair perturbations as potentially targetable events in certain types of pediatric brain tumors. Herein, we investigated the potential of PARP inhibitors (PARPi), impeding the central role of PARP in DNA damage repair, in pHGG. We screened a patient-derived primary pHGG cell line panel (n=7) for their sensitivity towards 6 different PARPi (niraparib, olaparib, pamiparib, rucaparib, talazoparib, veliparib) using cell viability assays. Basal expression of DNA repair related proteins was assessed by immunoblot, and propidium iodide-based flow cytometry was used for cell cycle analysis. All pHGG were resistant towards single compound PARP inhibition. Interestingly, two H3F3A-G34R mutant pHGG models harboring inactivating ATRX mutations were characterized by elevated basal levels of pH2AX, suggesting increased stress resulting from DNA damage. Consequently, simultaneous targeting of PARP and other components of DNA repair in the respective models showed strong synergistic effects on cell viability, which was not observed to a comparable extent in other models such as BRAFV600E/TERT promotor mutant pHGG. Combination of talazoparib and irinotecan resulted in S-phase arrest. Within a precision oncology approach, we treated a 11-year-old child suffering from H3F3A-G34R mutant pHGG with ATRX mutation, that progressed during radiation, with niraparib and topotecan. The patient achieved partial remission and disease stabilization for 1 year. Taken together, PARPi combinations show potential for the treatment of pHGG with ATRX mutations. Currently, all cell models are characterized for DNA repair signatures by DNA sequencing. Further, in depth characterization of DNA damage responses upon concomitant PARP and topoisomerase inhibition in ATRX-mutated pHGG are ongoing.

H3K27M-mutated diffuse midline glioma (H3K27M-DMG) may arise in the pons, thalamus and spinal cord generally having a dismal prognosis. Notably, H3K27M-DMG are driven by oligodendrocyte precursor-like cells which are partly sustained by PDGFRA signaling. Co-mutations including TP53, ACVR1, PDGFRA, KIT and PI3K pathway alterations are present in a subset of cases, and molecular profiling may allow detection of additional targetable alterations. However, small-molecule inhibitors often have limited efficacy associated with low blood-brain-barrier (BBB) penetration. Here, we report on a patient with spinal, leptomeningeal disseminated H3K27M-DMG treated with avapritinib, an orally administered, BBB-penetrant and highly selective KIT and PDGFR inhibitor, provided through a compassionate-use program. Initial therapy consisted of subtotal resection, focal radiotherapy and temozolomide (TMZ) resulting in disease stabilization. Ten months after diagnosis, leptomeningeal metastases were detected, biopsied and treated with local irradiation and TMZ. The patient subsequently received systemic and intrathecal chemotherapy augmented with dasatinib. Molecular analyses of the biopsy revealed the H3F3A and TP53 mutations present in the primary tumor, as well as de novo PDGFRA and KIT amplifications with gene copy numbers of 25 and 21, respectively. Upon further disease progression, therapy with avapritinib was initiated. Assessment of treatment response according to RANO criteria after four months revealed stable disease of the target lesion in the cerebellum and partial response of all non-target lesions. Avapritinib was generally well tolerated with lower limb edema (Grade 2), small intratumoral bleeding (Grade 1) and unrelated hydrocephalus (Grade 3) as reported adverse events. As precaution, treatment was interrupted and re-initiated after one week as the bleeding was stable. A ventriculoperitoneal shunt was implanted resolving the hydrocephalus. Pharmacokinetic analyses revealed up to 65% avapritinib plasma exposure and clinically relevant levels in cerebrospinal fluid. In summary, we report on first effective therapy of treatment-resistant H3K27M-DMG with avapritinib as clinical proof of concept.

BACKGROUND We aimed to investigate the changing clinical characteristics of patients with brain metastases (BM) over the last three decades as the foundation for modern BM specific clinical trial planning. MATERIAL AND METHODS 6031 patients with newly diagnosed BM from different solid tumors treated between 1986–2020 were identified from the Vienna Brain Metastasis Registry. RESULTS The fraction of BM originating from the most common BM causing primary tumors (lung cancer, breast cancer and melanoma) was stable over the observation period from 1986–2020. BM from renal cell carcinoma, colorectal cancer and cancer of unknown primary (CUP) decreased over time (p CONCLUSION We observed changes of BM presentation and clinical parameters during the observation period depending on primary tumor origins. Future BM studies should follow an entity-specific approach and address the characteristics of modern BM cohorts.

BACKGROUND Embryonal tumor with multilayered rosettes (ETMR) is a rare, aggressive embryonal central nervous system tumor characterized by LIN28A expression and alterations in the C19MC locus. ETMRs predominantly occur in young children, have a dismal prognosis, and no definitive treatment guidelines have been established. We report on our experience in nine consecutive patients. METHODS Between 2006 and 2017, nine patients were diagnosed with ETMR. Median age was 25 months (5–38), seven were treated for primary diagnosis, two referred with progressing tumors, seven diagnosed prospectively, two retrospectively, five were located supratentorially, three pineal, one in the brainstem. RESULTS Seven patients had a gross total resection, one a partial resection and one a biopsy at initial diagnosis, followed by second resections at progression. Six patients were treated with intensive chemotherapy regimens including high-dose chemotherapy in three patients and all recurred after a median of 6 months (range 2–11) and all except one patient who died after high-dose chemotherapy, succumbed to their disease after a median of 13 months (range 7–28). Two patients were treated with gross total tumor resection, early focal radiotherapy and concomitant temozolomide followed by temozolomide and intrathecal therapy for one year and both are in continuous complete remission 51 and 46 months after diagnosis. CONCLUSION Gross total resection followed by early focal radiotherapy, temozolomide, and intrathecal chemotherapy seem to be superior to intensive chemotherapy including high-dose chemotherapy. Steady progression was observed in both patients with initial biopsy and PR only despite intensive therapy. Radiotherapy at recurrence/progression was not successful.

PURPOSE To evaluate prognostic factors and impact of participation in a randomized trial in non-metastatic medulloblastoma. METHODS AND PATIENTS 382 patients with non-metastatic medulloblastoma aged 4–21 years with primary neurosurgical resections between 2001 and 2011 were enrolled into the HIT 2000 trial and centrally reviewed. Between 2001 and 2006, 176 of these patients participated in the randomized trial HIT-SIOP PNET 4. Three different radiotherapy protocols were applied. Molecular subgroup was available for 157 patients. RESULTS Median follow-up was 6.35 [0.09–13.86] years. The 5-year progression-free (PFS) and overall survival (OS) rates were 80.3 % ± 2.1 % and 86.5 % ± 1.8 %, respectively. On univariate analysis, there was no difference in PFS and OS according to radiotherapy protocols or in patients who participated in the HIT-SIOP PNET 4 trial or not, while histology, molecular subgroup and postoperative residual tumor influenced PFS significantly. Time interval between surgery and irradiation (≤48 days vs. ≥49 days) failed the significance level (p=0.052). On multivariate analyses, molecular subgroup (WNT activated vs. Group3 HR 5.49; p=0.014) and time interval between surgery and irradiation (HR 2.2; p=0.018) were confirmed as independent risk factors. CONCLUSION Using a centralized review system, multiprofessional and multiinstitutional collaboration as established for pediatric brain tumor patients in Germany, and risk-stratified therapy, outcome for non-metastatic medulloblastoma treated within HIT-SIOP PNET4 could be maintained outside the randomized trial. Prolonged time to radiotherapy negatively influenced survival.

Background Ependymomas account for up to 10% of childhood CNS tumors and have a high rate of tumor recurrence despite gross total resection. Recently, classification into molecular ependymoma subgroups has been established, but the mechanisms underlying the aggressiveness of certain subtypes remain widely enigmatic. The aim of this study was to dissect the clinical and biological role of telomerase reactivation, a frequent mechanism of cancer cells to evade cellular senescence, in pediatric ependymoma. Methods We determined telomerase enzymatic activity, hTERT mRNA expression, promoter methylation, and the rs2853669 single nucleotide polymorphism located in the hTERT promoter in a well-characterized cohort of pediatric intracranial ependymomas. Results In posterior fossa ependymoma group A (PF-EPN-A) tumors, telomerase activity varied and was significantly associated with dismal overall survival, whereas telomerase reactivation was present in all supratentorial RelA fusion-positive (ST-EPN-RELA) ependymomas. In silico analysis of methylation patterns showed that only these two subgroups harbor hypermethylated hTERT promoters suggesting telomerase reactivation via epigenetic mechanisms. Furthermore, chromosome 1q gain, a well-known negative prognostic factor, was strongly associated with telomerase reactivation in PF-EPN-A. Additional in silico analyses of gene expression data confirmed this finding and further showed enrichment of the E-twenty-six factor, Myc, and E2F target genes in 1q gained ependymomas. Additionally, 1q gained tumors showed elevated expression of ETV3, an E-twenty-six factor gene located on chromosome 1q. Conclusion Taken together we describe a subgroup-specific impact of telomerase reactivation on disease progression in pediatric ependymoma and provide preliminary evidence for the involved molecular mechanisms.

We aimed to investigate the potential of standard hematologic and serum biochemical parameters to provide an independent and substantial contribution to the prediction of survival in patients with newly diagnosed brain metastases (BM).Hemoglobin, white blood cell count, platelet count, serum albumin, creatinine, lactate dehydrogenase (LDH), and C-reactive protein (CRP) were assessed at diagnosis of BM in a discovery cohort of 1200 cancer patients. A multivariable Cox regression model was used to derive the LabBM score. The LabBM score was externally validated in an independent cohort consisting of 366 patients.Hemoglobin below lower limit of normal (LLN; hazard ratio [HR] 1.28; P = .001), platelet countLLN (HR: 1.36; P = .013), albuminLLN (HR: 1.19; P = .038), LDH above upper limit of normal (ULN; HR: 1.51; P.001), and CRPULN (HR: 1.52; P.001) were associated with survival in a multivariable Cox regression model and were included in the calculation of the LabBM score. Multivariable analysis including the LabBM score and graded prognostic assessment class revealed an independent and significant association of the LabBM score with overall survival (OS) (HR: 1.42; 95% CI: 1.29-1.57; P.001). The strong and independent association of LabBM score (HR: 1.93; 95% CI: 1.54-2.42) with OS prognosis was confirmed in the validation cohort.Standard clinical blood parameters, combined in the easy-to-calculate LabBM score, provide strong and independent prognostic information in patients with BM. The LabBM score is an objective, inexpensive, and reproducible tool to plan clinical management strategies in BM patients and to improve patient selection and stratification for clinical trials.

BACKGROUND Immune checkpoint inhibitors targeting programmed cell death 1 (PD1) or its ligand (PD-L1) showed activity in several cancer types. METHODS We performed immunohistochemistry for CD3, CD8, CD20, HLA-DR, phosphatase and tensin homolog (PTEN), PD-1, and PD-L1 and pyrosequencing for assessment of the O6-methylguanine-methyltransferase (MGMT) promoter methylation status in 135 glioblastoma specimens (117 initial resection, 18 first local recurrence). PD-L1 gene expression was analyzed in 446 cases from The Cancer Genome Atlas. RESULTS Diffuse/fibrillary PD-L1 expression of variable extent, with or without interspersed epithelioid tumor cells with membranous PD-L1 expression, was observed in 103 of 117 (88.0%) newly diagnosed and 13 of 18 (72.2%) recurrent glioblastoma specimens. Sparse-to-moderate density of tumor-infiltrating lymphocytes (TILs) was found in 85 of 117 (72.6%) specimens (CD3+ 78/117, 66.7%; CD8+ 52/117, 44.4%; CD20+ 27/117, 23.1%; PD1+ 34/117, 29.1%). PD1+ TIL density correlated positively with CD3+ (P < .001), CD8+ (P < .001), CD20+ TIL density (P < .001), and PTEN expression (P = .035). Enrichment of specimens with low PD-L1 gene expression levels was observed in the proneural and G-CIMP glioblastoma subtypes and in specimens with high PD-L1 gene expression in the mesenchymal subtype (P = 5.966e-10). No significant differences in PD-L1 expression or TIL density between initial and recurrent glioblastoma specimens or correlation of PD-L1 expression or TIL density with patient age or outcome were evident. CONCLUSION 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.

BACKGROUND Immune modulating therapies are a promising treatment approach in patients with primary brain tumors, however their clinical efficacy is still under investigation as the systemic inflammatory responses are potentially challenged by the brain’s tight immune regulatory mechanisms. Here, we aimed to investigate soluble PD-L1 (sPD-L1) in the plasma of recurrent glioblastoma (GBM) and recurrent WHO grade II - III glioma (LGG) patients over their course of disease. MATERIAL AND METHODS 30 patients with recurrent GBM and 10 patients with recurrent LGG were treated with bevacizumab (400mg, q14 days) as a salvage therapy at the Medical University of Vienna. EDTA plasma samples were drawn prior to each treatment cycle. sPD-L1 was analyzed using a sandwich ELISA (Millipore ABF133 and clone 5H1). The lower limit of detection was 0.050 ng/ml as determined by serial dilutions of recombinant human PD-L1. RESULTS sPD-L1 values could be retrieved in a median of 6 timepoints per patient (range: 2 - 24). No significant difference in sPD-L1 concentrations between GBM and LGG patients was present at baseline (p > 0.05). After 2 weeks of bevacizumab treatment, LGG patients presented with statistically significant lower sPD-L1 concentrations as compared to baseline (p = 0.036, Wilcoxon signed rank test), while no difference in sPD-L1 concentration was observed in GBM patients. Significantly higher sPD-L1 intra-patient variability was evident in LGG patients compared to GBM patients (p = 0.012, Mann-Whitney-U). In LGG patients, sPD-L1 correlated with leukocyte count (Spearman’s r = 0.397, p = 0.001) as well as with C-reactive protein level (Spearman’s r = -0.424, p = 0.001), while in GBM patients no correlation of sPD-L1 and systemic markers of inflammation was evident (-0.3 < Spearman’s r < 0.3). CONCLUSION sPD-L1 as a systemic marker of inflammation was lower in recurrent LGG patients compared to recurrent GBM patients after bevacizumab-based treatment, arguing that the glioma-immune system interactions differ between LGG and GBM. SUPPORT/DISCLOSURE This project was funded by the research budget of the Medical University of Vienna.

Receiving a diagnosis of glioblastoma is a devastating personal stroke of fate. The incidence of glioblastoma is 3–4 cases/100 000 population per year according to the current World Health Organization (WHO) Classification Tumors of the Nervous System, 3.19 cases/100 000 population according to Central Brain Tumor Registry of the United States (CBTRUS) 2011 (http://www.cbtrus.org/2007-2008/2007-20081.html), and 3.4 cases/100 000 population according to the Austrian Brain Tumor Registry (ABTR) 2009.1,2 Glioblastoma is still an invariably fatal disease with limited survival time and leads mostly to loss of independence for the last month(s) of survival.3–6 The peak incidence is among older adults. The mean age in a population-based study in the Canton of Zurich was 61.3 years; >80% of the study population was >50 years of age at diagnosis.7 Increasing age is known as an adverse prognostic factor for survival with glioblastoma. This has been uniformly reported since the first therapeutic studies from the 1970s to actual large multicenter-based data, as from the French study by Bauchet et al., and the latest population-based data from brain tumor registries, such as CBTRUS and ABTR.2,8–12 This prompted us to examine the outcome in young patients with glioblastoma multiforme (GBM) in our own center, focusing on duration of survival, time to progression, and the expression of known clinical and molecular predictive and prognostic factors, such as performance status, extent of resection, MGMT (O6-methyl-guanine- methyl-transferase) promoter methylation, and isocitrate dehydrogenase (IDH)1 mutation status. Recently, Turcan et al. revealed that IDH1/2 mutation triggers CpG island methylator phenotype (CIMP), which is associated with the proneural subgroup of GBM that is predictive of improved survival.13 These single amino acid substitutions—either at arg 132 (IDH1) or arg 172 (IDH2)—induce loss of the normal catalytic activity of oxidizing isocitrate to alpha-ketoglutarate. This leads to >300-fold increase of D-2-hydroxyglutarate (D-2-HG) in the mutated cells. In these supraphysiological concentrations, D-2-HG inhibits histone demethylases and hydroxylases, leading to a genome-wide increase and decrease of histone methylation and, thus, interfering with epigenetic control and changing the expression of multiple genes.14 IDH1 mutations were described in a high prevalence of 60%–80% in diffuse gliomas, anaplastic astrocytomas, secondary glioblastomas, oligodendrogliomas of WHO grade II and WHO grade III, but with a low occurrence of 5%–15%15–31 in primary glioblastomas. In the series by Balls et al.,23 patients with GBM showing IDH1 mutation achieved the same duration of overall survival with 27 months as did patients in the present study. IDH1/2 mutations were defined as a reliable genetic marker for secondary glioblastomas.30,32,33 Moreover, genomic profiling of glioblastomas has shown that the more favorable subgroups (eg, the proneural subgroup according to Verhaak et al.,34 the glioma CpG island methylator phenotype [G-CIMP] according to Noushmehr et al.21, and IDH 1 mutation according to Jha et al.18) are more prevalent among younger patients. Patients with secondary glioblastoma, which is defined as a glioblastoma arising from a lower-grade glioma precursor lesion, tend to cluster within the latter genomic subgroups that are more likely to respond to radio-and chemotherapy and are, thus, associated with a longer survival time.35 The social impact of glioblastoma might even be worse when young adults are affected. Each year, nearly 70 000 adolescents and young adults (AYA) aged 15–39 years receive a diagnosis of cancer in the United States.36 Although the incidence of GBM among young adults is low, approximately 2000 persons

BACKGROUND: Little is known about patterns of care during long term follow-up of patients with glioma Patients and Methods: By retrospective chart review, patterns of care of patients surviving at least for ten years were analyzed Results: 57 patients (30 men, 27 women, aged 18 to 73, in median 36 years at diagnosis) with gliomas that were followed for a minimum of ten years (10 to 25y) were identified. First histological diagnosis was diffuse glioma in fifteen patients, oligo-astrocytoma in WHO grade II in nine, and WHO grade III in six, oligodendroglioma WHO grade II in six, WHO grade III in five, anaplastic astrocytoma in six and glioblastoma in 8 patients respectively. The patients underwent 1–7 surgical procedures. Fifty (80%) of patients were treated with radiotherapy, fourteen (28%) patients received salvage radiation therapy and five patients radiosurgery in relapse. All patients were treated with alkylating chemotherapy, 36 (63%)patients had at least one and up to seven drug therapy lines for relapsing gliomas (alkylating drugs n= 46, anti-angiogenic treatment n=16, Imatinib n=16, Thalidomide 50 mg n=14) Seven patients (12.3%) developed a secondary glioblastoma, fifteen patients (26%) progressed from WHO grade II to WHO grade III gliomas. However, fifty-two patients showed a KPS ≥70 during 75% of their respective survival time. Fifty-four (95%) had at least three years without any therapy and twenty -one (37%) still survive recurrence free after first line therapy. Thirty six patients (63%) remained professionally active after first line treatment and forty-one (72%) were still alive at the end of study. CONCLUSION: this highly selected cohort represents the right end of the Gaussian curve of outcomes for long term surviving glioma patients

Patients with recurrent malignant CNS tumors have a poor prognosis irrespective of salvage therapy applied. We used a metronomic antiangiogenic combination therapy and report on the response of individual tumor types to this approach. Since 2006, 81 patients with various recurrent malignant brain tumors started treatment with an antiangiogenic multidrug-regimen at the Medical University of Vienna. Therapy consisted of daily oral thalidomide, fenofibrate, celecoxib, and 21-day cycles of low dose oral etoposide alternating with cyclophosphamide augmented with IV bevacizumab and intraventricular therapy (etoposide and liposomal cytarabine). Excluding the 10 patients with recurrent medulloblastoma treated in the formal international protocol (MEMMAT; ClinicalTrials.gov Identifier: NCT01356290), 71 patients were treated according to the same strategy “off trial”. Diagnoses were medulloblastoma (n=20), atypical teratoid rhabdoid tumor (ATRT) (n=11), ependymoma (n=9), high grade glioma/diffuse intrinsic pontine glioma (HGG/DIPG) (n=9), and various other entities in the remaining patients. As of the end of 2017, 3-year and 5-year OS for the 20 patients with recurrent medulloblastoma was 64.2 ± 10.9% and for the 11 patients with recurrent ATRT 45.7 ± 16.6% and 30.5 ± 16.7%, respectively. Remission could be maintained after discontinuation of treatment in a certain percentage of patients with medulloblastoma, ATRT and ependymoma. Patients with HGG and DIPG did not respond to this approach. The proposed antiangiogenic regimen seems most promising in medulloblastoma and ATRT and possibly also ependymoma. In a number of other tumor entities time to progression could be prolonged while maintaining good quality of life.