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Antibody–drug conjugates (ADCs), a class of targeted cancer therapeutics combining monoclonal antibodies with a cytotoxic payload via a chemical linker, have already been approved for the treatment of several cancer types, with extensive clinical development of novel constructs ongoing. Primary and secondary brain tumours are associated with high mortality and morbidity, necessitating novel treatment approaches. Pharmacotherapy of brain tumours can be limited by restricted drug delivery across the blood–brain or blood–tumour barrier, although data from phase II studies of the HER2-targeted ADC trastuzumab deruxtecan indicate clinically relevant intracranial activity in patients with brain metastases from HER2+ breast cancer. However, depatuxizumab mafodotin, an ADC targeting wild-type EGFR and EGFR variant III, did not provide a definitive overall survival benefit in patients with newly diagnosed or recurrent EGFR-amplified glioblastoma in phase II and III trials, despite objective radiological responses in some patients. In this Review, we summarize the available data on the central nervous system activity of ADCs from trials involving patients with primary and secondary brain tumours and discuss their clinical implications. Furthermore, we explore pharmacological determinants of intracranial activity and discuss the optimal design of clinical trials to facilitate development of ADCs for the treatment of gliomas and brain metastases.

SummaryNearly 40 abstracts regarding tumors of the central nervous system were presented at the European Society for Medical Oncology (ESMO) Congress in September 2022. While no practice-changing data were shown, interesting early phase clinical trial results on immune-modulating agents, targeted treatments and other therapeutic modalities were revealed (Table 1). In this short review, we aim to summarize our personal highlights of the presented data and outline future perspectives in the field.

Young oncologists around the globe face many challenges when it comes to their career and professional development. Aspects such as time management, work-life balance, career progression, and educational opportunities are only some of them. Professional societies have identified these challenges in this professional group and designed programs to tackle them specifically. The importance of this strategy cannot be overstated, as young oncologists, defined by most societies as oncologists under 40 years of age, compose almost 50% of the oncology workforce. On the other hand, recent surveys have shown that many young oncologists are considering alternative career paths due to burnout issues aggravated by the COVID-19 pandemic, on top of all other challenges. The virtual setting that has been forcedly introduced into our professional life has shortened distances between professionals and might have contributed to more accessible access to information and opportunities that some young oncologists could not profit from due to their traveling constraints. On the other hand, this virtual setting has shown us the asymmetries in opportunities for these professionals. Knowledgeable of all this, we summarize in this article some of the career and professional development offers available to all young oncologists, which we consider could help them deal with current and future challenges.

Purpose: The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited. Experimental Design: Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays. Results: One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed. Conclusions: In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.

Purpose:The treatment of oligodendroglioma consists of tumor resection and radiochemotherapy. The timing of radiochemotherapy remains unclear, and predictive biomarkers are limited.Experimental Design:Adult patients diagnosed with isocitrate dehydrogenase (IDH)-mutated, 1p/19q-codeleted CNS WHO grade 2 and 3 oligodendroglioma at the Medical University of Vienna and the Kepler University Hospital Linz (Austria) in 1992 to 2019 were included. Progression-free (PFS) and overall survival (OS) between early postoperative treatment and initial observation were compared using propensity score–weighted Cox regression models. DNA methylation analysis of tumor tissue was performed using Illumina MethylationEPIC 850k microarrays.Results:One hundred thirty-one out of 201 (65.2%) patients with CNS WHO grade 2 and 70 of 201 (34.8%) with grade 3 oligodendroglioma were identified. Eighty-three of 201 (41.3%) patients underwent early postoperative treatment, of whom 56 of 83 (67.5%) received radiochemotherapy, 15 of 84 (18.1%) radiotherapy (RT) only and 12 of 83 (14.5%) chemotherapy only. Temozolomide-based treatment was administered to 64 of 68 (94.1%) patients, whereas RT + procarbazine, lomustine (CCNU), and vincristine (PCV) were applied in 2 of 69 (3.5%) patients. Early treatment was not associated with PFS [adjusted hazard ratio (HR) 0.74; 95% CI, 0.33–1.65, P = 0.459] or OS (adjusted HR: 2.07; 95% CI, 0.52–8.21, P = 0.302) improvement. Unsupervised clustering analysis of DNA methylation profiles from patients receiving early treatment revealed two methylation clusters correlating with PFS, whereas no association of clustering with O6-methylguanine methyltransferase (MGMT) promoter methylation, CNS WHO grade, extent of resection, and treating center could be observed.Conclusions:In this retrospective study, early postoperative treatment was not associated with improved PFS/OS in oligodendroglioma. The potentially predictive value of whole-genome methylation profiling should be validated in prospective trials.

Background Patients with cancer are at high risk for severe courses of COVID-19. Based on (pre-)clinical data suggesting a potential protective effect due to the immunomodulating properties of azithromycin, we have initiated a prospective randomized trial. Methods This randomized, single-center, single-blinded, placebo-controlled phase 2 trial included adult patients with cancer undergoing systemic treatment. Patients were 1:1 randomized to oral azithromycin (1500 mg once weekly for 8 weeks) or placebo. The primary endpoint was the cumulative number of SARS-CoV-2 infections 12 weeks after treatment initiation. Results In total, 523 patients were screened, 68 patients were randomized, and 63 patients received at least one dose of the study drug. Due to low acceptance and a lack of SARS-CoV-2 infections in the study cohort, the study was prematurely closed. With no reported grade III–IV possibly treatment-related adverse events, azithromycin was generally well tolerated. Overall survival (OS) rates after 12 months were 83.5% and 70.3% in the azithromycin and placebo group, respectively (p = 0.37). Non-SARS-CoV-2 infections occurred in 4/32 (12.5%) in the azithromycin and 3/31 (9.7%) in the placebo group (p = 1). No emergence of azithromycin-resistant S. aureus strains could be observed. According to treatment group, longitudinal alterations in systemic inflammatory parameters were detected for neutrophil/lymphocyte and leukocyte/lymphocyte ratios. Conclusion Although efficacy could not be assessed due to premature closure and low incidence of SARS-CoV-2 infections, azithromycin was associated with a favorable side effect profile in patients with cancer. As other prophylactic treatments are limited, SARS-CoV-2 vaccination remains a high priority in oncological patients. ClinicalTrials.gov registration number and date (dd/mm/yyyy): NCT04369365, 30/04/2020.

During the V Siena Immuno-Oncology (IO) Think Tank meeting in 2021, conditions were discussed which favor immunotherapy responses in either primary or secondary brain malignancies. Core elements of these discussions have been reinforced by important publications in 2021 and 2022. In primary brain tumors (such as glioblastoma) current immunotherapies have failed to deliver meaningful clinical benefit. By contrast, brain metastases frequently respond to current immunotherapies. The main differences between both conditions seem to be related to intrinsic factors (e.g., type of driver mutations) and more importantly extrinsic factors, such as the blood brain barrier and immune suppressive microenvironment (e.g., T cell counts, functional differences in T cells, myeloid cells). Future therapeutic interventions may therefore focus on rebalancing the immune cell population in a way which enables the host to respond to current or future immunotherapies.

SummaryMore than 140 abstracts were presented in the Central Nervous System Tumors track during the 2021 American Society of Clinical Oncology (ASCO) virtual meeting. Here, we review our personal highlights of the presented data. In rare entities such as papillary craniopharyngioma and neurotrophic tyrocine receptor kinase (NTRK)-fusion-positive tumors, promising data on targeted therapies were reported. In addition, early data on olaparib in high-grade glioma and combinational immunotherapy approaches will be briefly reviewed. Furthermore, the eagerly awaited results of the EORTC-1709 phase III trial on the pan-proteasome inhibitor marizomib in newly diagnosed glioblastoma were shown at the meeting. Although no practice-changing trials were presented for glioma patients, new treatments are on the horizon and results from modern platform trials are awaited in the near future.

Purpose Meningiomas are the most frequently diagnosed intracranial neoplasms. Usually, they are treated by surgical resection in curative intent. Radiotherapy and stereotactic radiosurgery are commonly applied in the adjuvant setting in newly diagnosed atypical (CNS WHO grade 2), and anaplastic (CNS WHO grade 3) meningioma, especially if gross total resection is not feasible, and in recurrent cases. Conversely, the evidence for pharmacotherapy in meningioma is scarce. Methods The available literature of systemic treatment in meningioma was screened using PubMed, and ongoing clinical trials were explored using ClinicalTrials.gov. Results Classical cytotoxic agents, somatostatin analogs, and antihormone treatments have shown only limited efficacy. In contrast, tyrosine kinase inhibitors and monoclonal antibodies, especially those targeting angiogenic signaling such as sunitinib and bevacizumab, have shown promising antitumoral activity in small phase 2 trials. Moreover, results of recent landmark studies on (epi-)genetic alterations in meningioma revealed potential therapeutic targets which are currently under investigation. These include inhibitors of mammalian target of rapamycin (mTOR), focal adhesion kinase (FAK), cyclin-dependent kinases (CDK), phosphoinositide-3-kinase (PI3K), sonic hedgehog signaling, and histone deacetylases. In addition, clinical trials evaluating immune checkpoint inhibitors such as ipilimumab, nivolumab, pembrolizumab and avelumab are currently being conducted and early results suggest clinically meaningful responses in a subset of patients. Conclusions There is a paucity of high-level evidence on systemic treatment options in meningioma. However, interesting novel treatment targets have been identified in the last decade. Positive signals of anti-angiogenic agents, genomically targeted agents and immunotherapy in early phase trials should be confirmed in large prospective controlled trials.

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.

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 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.

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 40 and higher body mass index (BMI) were associated with impaired progression-free and overall survival (p 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.

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.One thousand two hundred and fifty patients with newly diagnosed brain metastases (BM) were identified from the Vienna Brain Metastasis Registry.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; pSystemic 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.

Background Due to potentially immune-escaping virus variants and waning immunity, a third SARS-CoV-2 vaccination dose is increasingly recommended. However, data in patients with cancer are limited. Patients and methods We measured anti-SARS-CoV-2 spike protein antibody levels after the third vaccination dose in 439 patients with cancer and 41 health care workers (HCW) at an academic center in Austria and a rural community hospital in Italy. Adverse events were retrieved from questionnaires. Results Overall, 439 patients and 41 HCW were included. SARS-CoV-2 infections were observed in 62/439 (14.1%) patients before vaccination and in 5/439 (1.1%) patients after ≥1 dose. Longitudinal analysis revealed a decrease of antibody levels between 3 and 6 months after second vaccination in patients with solid tumors (p

Background No systemic treatment has been established for meningioma progressing after local therapies. Methods This randomized, multicenter, open-label, phase II study included adult patients with recurrent WHO grade 2 or 3 meningioma. Patients were 2:1 randomly assigned to intravenous trabectedin (1.5 mg/m2 every 3 weeks) or local standard of care (LOC). The primary endpoint was progression-free survival (PFS). Secondary endpoints comprised overall survival (OS), objective radiological response, safety, quality of life (QoL) assessment using the QLQ-C30 and QLQ-BN20 questionnaires, and we performed tissue-based exploratory molecular analyses. Results Ninety patients were randomized (n = 29 in LOC, n = 61 in trabectedin arm). With 71 events, median PFS was 4.17 months in the LOC and 2.43 months in the trabectedin arm (hazard ratio [HR] = 1.42; 80% CI, 1.00-2.03; P = .294) with a PFS-6 rate of 29.1% (95% CI, 11.9%-48.8%) and 21.1% (95% CI, 11.3%-32.9%), respectively. Median OS was 10.61 months in the LOC and 11.37 months in the trabectedin arm (HR = 0.98; 95% CI, 0.54-1.76; P = .94). Grade ≥3 adverse events occurred in 44.4% of patients in the LOC and 59% of patients in the trabectedin arm. Enrolled patients had impeded global QoL and overall functionality and high fatigue before initiation of systemic therapy. DNA methylation class, performance status, presence of a relevant co-morbidity, steroid use, and right hemisphere involvement at baseline were independently associated with OS. Conclusions Trabectedin did not improve PFS and OS and was associated with higher toxicity than LOC treatment in patients with non-benign meningioma. Tumor DNA methylation class is an independent prognostic factor for OS.

INTRODUCTION The CeTeG/NOA-09 trial demonstrated superior median overall survival (mOS, 48.1 months) in MGMT-methylated glioblastoma treated with lomustine/temozolomide compared to temozolomide. We retrospectively analyzed an off-study cohort of patients treated with lomustine/temozolomide to gather real-world data on this new regimen. METHODS Adult patients from 20 centers in Germany, Austria and Switzerland were included. Inclusion criteria were MGMT-methylated IDHwt glioblastoma newly diagnosed prior to end of 2020, and lomustine/temozolomide treatment as part of first-line therapy. RESULTS 321 patients with a median age of 57 years (range, 21-78) and a median follow-up of 19.9 months were included. In the whole cohort, mOS was 41.0 months (95%CI, 33.0 – not reached). In patients starting lomustine/temozolomide immediately upon initiation of radiotherapy strictly following the CeTeG protocol (88%), mOS was 52.8 months (35.8 – not reached) as compared to 24.6 months (17.6 – not reached) in patients starting lomustine/temozolomide after completion of radiotherapy/concomitant temozolomide (12%, logrank test: p = 0.06). Patients with a KPS < 80 had a shorter mOS of 19.7 months (95%CI, 16.6 – not reached) compared to 41.0 months (33.0 – not reached, p = 0.009) in KPS 80-100. Gross total resection (GTR, 53.9%) was associated with longer mOS (52.8 months, 95%CI 24.1 – not reached) compared to partial resection/biopsy (30.5 months, 95%CI 36.8 – not reached, p=0.004). Multivariable Cox regression analysis confirmed GTR (HR 0.66, p = 0.033) and younger age ( ≤ 50 years: HR 0.42, p = 0.001), but not KPS (80-100 vs. lower: HR 0.66, p = 0.12) as independent prognostic factors. DISCUSSION In this real-world multicenter cohort, survival was similar to the promising results of CeTeG/NOA-09. Further analyses should investigate a potentially reduced benefit from lomustine/temozolomide in patients with low KPS/no GTR and a possible detrimental effect from deferred lomustine/temozolomide initiation. The median follow-up is admittedly short, updated data will be presented.

This cohort study assesses the capacity of passive immunization and tixagevimab and cilgavimab to inhibit interaction between receptor-binding domains and angiotensin-converting enzyme 2 in patients with hemato-oncologic diseases.

Introduction: As thyroid hormones modulate proliferative pathways it is surmised that they can be associated with cancer development. Since the potential association of gastroesophageal cancer and thyroid disorders has not been addressed so far, the aim of this study was to investigate the association of thyroid hormone parameters with the outcome of these patients, so novel prognostic and even potentially therapeutic markers can be defined. Material and Methods: Clinical and endocrinological parameters of patients with resectable gastroesophageal cancer treated between 1990 and 2018 at the Vienna General Hospital, Austria, including history of endocrinological disorders and laboratory analyses of thyroid hormones at first cancer diagnosis were investigated and correlated with the overall survival (OS). Results: In a total of 865 patients, a tendency towards prolonged OS in hypothyroid patients (euthyroid, n = 647: median OS 29.7 months, hyperthyroid, n = 50: 23.1 months, hypothyroid, n = 70: 47.9 months, p = 0.069) as well as a significant positive correlation of thyroid hormone replacement therapy with the OS was observed (without, n = 53: median OS 30.6 months, with, n = 67: 51.3 months, p = 0.017). Furthermore, triiodothyronine (T3) levels were also associated with the OS (median OS within the limit of normal: 23.4, above: 32.4, below: 9.6 months, p = 0.045). Conclusions: Thyroid disorders and their therapeutic interventions might be associated with the OS in patients with resectable gastroesophageal cancer. As data on the correlation of these parameters is scarce, this study proposes an important impulse for further analyses concerning the association of thyroid hormones with the outcome in patients with gastroesophageal tumors.

Importance: To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. Objective: To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. Design, Setting, and Participants: This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Main Outcomes and Measures: Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. Results: In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). Conclusions and Relevance: In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

We retrospectively analyzed the epidemiological characteristics of cancer patients with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and their correlations with publicly available mobility data. Between 19 October 2020 and 28 February 2021, 4754 patient visits were carried out, and 1454 treatments have been applied at the Haemato‐Oncology Day Hospital Merano. Additional measures to prevent local SARS‐CoV‐2 transmission included a specific questionnaire for coronavirus disease 2019 (COVID‐19) symptoms as well as a SARS‐CoV‐2 real‐time polymerase‐chain reaction (RT‐PCR) 2 days prior to any intravenous or subcutaneous therapy. Community mobility was assessed through publicly available mobile phone tracking data from Google; 106/719 (14.7%) cancer patients have been tested positive for SARS‐CoV‐2 by PCR during the second wave compared to 5/640 (0.8%) within the first wave (P, What's new? Patients with cancer constitute a vulnerable population to severe COVID‐19 disease, and the effects of social restrictions on this risk group remain unclear. Here, despite maintenance of strict local mitigation strategies including testing, the authors report a >20‐fold increase in the number of confirmed SARS‐CoV‐2‐positive cancer patients in an outpatient department during the second wave compared to the first wave. Early relaxation of movement restrictions was associated with SARS‐CoV‐2 spread in cancer patients, even though to a lower extent than in the general population. The findings highlight the importance of strict preventive control measures and testing strategies in cancer patients.

BACKGROUND Oligodendrogliomas are rare, slow-growing brain tumors with a survival prognosis of >10 years. Although adjuvant radio-chemotherapy has been shown to prolong survival, aggressive treatment comes at the cost of increased toxicity. Systematic data on the optimal timing of adjuvant treatment in oligodendroglioma are lacking. MATERIAL AND METHODS Patients treated for a newly diagnosed IDH-mutated, 1p/19q-codeleted oligodendroglioma (WHO grades II/III) in 2000 - 2018 at the Medical University of Vienna or the Kepler University Hospital Linz (Austria) were included in this retrospective study. Adjuvant treatment was defined as radiotherapy (RT), chemotherapy (CHT) or radio-chemotherapy (R-CHT) within 6 months after resection in the absence of progression. “Wait and see” was defined as regular follow up with magnetic resonance imaging and treatment at progression. RESULTS 185 patients were identified, comprising 123/185 (66.5%) WHO grade II and 62/185 (33.5%) WHO grade III oligodendrogliomas. Median age at diagnosis was 42 years (range: 20–82). Gross total resection (GTR) could be achieved in 77/178 (42.3%) evaluable patients. Adjuvant treatment was applied in 63/185 (38.2%) patients, of whom 43/63 (68.3%) underwent R-CHT, 9/63 (14.3%) CHT only and 11/63 (17.5%) RT only. 43/52 (82.7%) received temozolomide-based treatment, 1/52 (1.9%) procarbazine, lomustine and vincristine (PCV), 1/52 dacarbazine/fotemustine and in 7/52 (13.5%) patients, no data on used regimens was available. Adjuvant treatment was more frequently applied in WHO grade 3 tumors (p CONCLUSION The application of adjuvant therapy was associated with favorable PFS in patients who underwent resection of newly diagnosed oligodendroglioma in this retrospective study. Prospective clinical trials should investigate the risks and benefits of adjuvant treatment versus initial observation in patients with oligodendroglioma.

Introduction Adult brainstem gliomas (BSGs) are rare central nervous system tumours characterized by a highly heterogeneous clinical course. Median survival times range from 11 to 84 months. Beyond surgery, no treatment standard has been established. We investigated clinical and radiological data to assess prognostic features providing support for treatment decisions. Methods 34 BSG patients treated between 2000 and 2019 and aged ≥ 18 years at the time of diagnosis were retrospectively identified from the databases of the two largest Austrian Neuro-Oncology centres. Clinical data including baseline characteristics, clinical disease course, applied therapies, the outcome as well as neuroradiological and neuropathological findings were gathered and analysed. The tumour apparent diffusion coefficient (ADC), volumetry of contrast-enhancing and non-contrast-enhancing lesions were determined on magnetic resonance imaging scans performed at diagnosis. Results The median age at diagnosis was 38.5 years (range 18–71 years). Tumour progression occurred in 26/34 (76.5%) patients after a median follow up time of 19 months (range 0.9–236.2). Median overall survival (OS) and progression-free survival (PFS) was 24.1 months (range 0.9–236.2; 95% CI 18.1–30.1) and 14.5 months (range 0.7–178.5; 95% CI 5.1–23.9), respectively. Low-performance status, high body mass index (BMI) at diagnosis and WHO grading were associated with shorter PFS and OS at univariate analysis (p p = 0.018). Conclusion ECOG, BMI, WHO grade and ADC values were associated with the survival prognosis of BSG patients and should be included in the prognostic assessment.

Purpose: As thyroid hormones modulate proliferative pathways, it is surmised that they can be associated with cancer development. Since the potential association of gastroesophageal cancer and thyroid disorders has not been addressed so far, the aim of this study was to investigate the association of thyroid hormone parameters with the outcome of these patients, so novel prognostic and even potentially therapeutic markers can be defined. Methods: Clinical and endocrinological parameters of patients with resectable gastroesophageal cancer treated between 1990 and 2018 at the Vienna General Hospital, Austria including history of endocrinological disorders and laboratory analyses of thyroid hormones at first cancer diagnosis were investigated and correlated with the overall survival (OS).Results: In a total of 865 patients, a tendency towards prolonged OS in hypothyroid patients (euthyroid, n=647: median OS 29.7 months; hyperthyroid, n=50: 23.1 months; hypothyroid, n=70: 47.9 months; p=0.069) as well as a significant positive correlation of thyroid hormone replacement therapy with the OS was observed (without, n=53: median OS 30.6 months; with, n=67: 51.3 months; p=0.017). Furthermore, triiodothyronine (T3) levels were also associated with the OS (median OS within limit of normal: 23.4, above: 32.4, below: 9.6 months; p=0.045).Conclusion: Thyroid disorders and their therapeutic interventions might be associated with the OS in patients with resectable gastroesophageal cancer. As data on the correlation of these parameters is scarce, this study proposes an important impulse for further analyses concerning the association of thyroid hormones with the outcome in patients with gastroesophageal tumors.

International audience; Immunotherapy has emerged as a powerful therapeutic approach in many areas of clinical oncology and hematology. The approval of ipilimumab, a monoclonal antibody targeting the immune cell receptor CTLA-4, has marked the beginning of the era of immune checkpoint inhibitors. In the meantime, numerous antibodies targeting the PD-1 pathway have expanded the class of clinically approved immune checkpoint inhibitors. Furthermore, novel antibodies directed against other immune checkpoints are currently in clinical evaluation. More recently, bispecific antibodies, which link T cells directly to tumor cells as well as adoptive T cell transfer with immune cells engineered to express a chimeric antigen receptor, have been approved in certain indications. Neurological complications associated with the use of these novel immunotherapeutic concepts have been recognized more and more frequently. Immune checkpoint inhibitors may cause various neurological deficits mainly by alterations of the peripheral nervous system's integrity. These include radiculopathies, neuropathies, myopathies as well as myasthenic syndromes. Side effects involving the central nervous system are less frequent but may result in severe clinical symptoms and syndromes. The administration of chimeric antigen receptor (CAR) T cell is subject to rigorous patient selection and their use is frequently associated with neurological complications including encephalopathy and seizures, which require immediate action and appropriate therapeutic measures. Close clinical monitoring for neurological symptoms is key for early recognition of immunotherapy-related side effects. Comprehensive diagnostic work-up and adequate therapeutic measures are essential to avoid further clinical deterioration and residual neurological deficits.

BACKGROUND: Despite of the ongoing improvements in gastrointestinal oncology, it remains unclear whether results of randomized controlled trials are achievable in daily clinical practice of nonacademic environments. AIM: This study aims at assessing a potential efficacy‐effectiveness gap in gastrointestinal cancer treatment. METHODS AND RESULTS: Data from 656 gastrointestinal cancer patients treated between 2007 and 2015 in a medium‐sized, nonacademic day hospital oncology unit in Italy were analyzed. Probability of survival and median overall survival as efficacy indicators and the occurrence of grades 3 to 4 adverse events as safety indicators were compared with randomized phase II/III trials of respective entities. Outcomes were well comparable between published data and the real‐life setting. In resectable gastroesophageal cancer, 1‐year survival after treatment initiation was greater (relative risks [RR] = 1.3, p = .007), while patients with adjuvant chemotherapy for pancreatic cancer exhibited inferior 2‐year survival (RR = 0.7, p = .048) compared with referenced trials. At our unit, neutropenia was less frequent (5.8% vs 27.8%, p = .039) in palliative chemotherapy for pancreatic cancer, as was peripheral neuropathy for stage II/III colon cancer (3.9% vs 12.5%, p = .027). CONCLUSION: The “real‐life” findings of this study support the efficacy and safety data achieved in landmark trials of gastrointestinal oncology.

High-dose chemotherapy followed by autologous stem cell transplantation (HD-ASCT) as well as the introduction of novel agents (NA) significantly improved survival for patients with multiple myeloma (MM). A total of 150 unselected newly diagnosed MM patients treated at our institution from 1998 to 2017 were retrospectively analyzed. Median age at diagnosis was 69 years (range 33-93 years) with a median follow-up of 48.6 months. The median overall survival (OS) for the entire cohort was 60.7 months (range 0.3-280.1). Patients who received frontline HD-ASCT (p 0.01) or NA-based first-line treatment (p = 0.043) had a significantly better OS. According to the revised Myeloma Comorbidity Index (R-MCI), patients were defined as fit (36.5%), intermediate-fit (44.5%), or frail (19%) with a significant difference in OS between these categories (p 0.01). Multivariate analysis revealed R-MCI as an independent prognostic factor for OS (p 0.01). Presence of subclinical amyloid deposits (A+) was detected in 18 out of 66 patients (27.3%) and significantly correlated with a serum free light chain (sFLC) ratio ≥ 100 (p = 0.01) and bone marrow plasma cell infiltration 60% (p = 0.04). Furthermore, patients with A+ had significantly worse OS compared with their counterparts (p = 0.048). Our results corroborate the efficacy of both early HD-ASCT and the use of new agents as initial therapy of MM patients in "real-world" daily clinical practice. The R-MCI is an easily applicable tool to stratify MM patients and may support treatment decisions. The prognostic value of subclinical amyloid deposition should be validated within prospective studies.

Background Tumor mutational burden (TMB) and density of tumor-infiltrating lymphocytes (TIL) have been postulated as predictive biomarkers for immunotherapy. Therefore, we investigated the concordance of TMB and TIL of primary/extracranial renal cell carcinoma (RCC) specimens and matched brain metastases (BM). Patients and methods Twenty specimens from 10 patients were retrieved from the Vienna Brain Metastasis Registry (6/10 primary tumor, 4/10 lung metastasis, 10/10 matched BM). TMB was assessed using the TruSight Oncology 500 gene panel with libraries sequenced on a NextSeq instrument. TIL subsets (CD3+, CD8+, CD45RO+, FOXP3+, PD-L1+) were investigated using immunohistochemistry (Ventana Benchmark Ultra system) and automated tissue analysis (Definiens software). Results No significant difference in TMB, CD3+, CD8+, CD45RO+, FOXP3+ or PD-L1+ expression was observed between extracranial and matched intracranial specimens (P > 0.05). Higher CD8+ TIL (P = 0.053) and CD45RO+ TIL (P = 0.030) densities in the primary tumor compared with the intracranial samples were observed in specimens collected after exposure to systemic treatment. Neither extracranial sample origin (lung metastasis versus primary RCC) nor extracranial disease status at BM diagnosis (progressive versus stable disease) were significantly associated with TMB or TIL densities in extracranial and intracranial samples (P > 0.05). No significant correlation was found between the median differences of TMB or TIL densities from extracranial to intracranial samples and BM-free survival. Conclusion The comparable immunological microenvironment of extra- and intracranial tumor samples in our study underscores the immunological activation also in BM from RCC, and therefore, supports the development of immune modulatory treatments also in patients with brain metastatic RCC., Highlights • Immunological microenvironment characteristics were comparable in extra- and intracranial RCC samples. • Numerically higher CD45RO+ and CD8+ TIL densities in extracranial compared to intracranial samples after systemic therapy. • The inflammatory microenvironment is a promising therapeutic target in RCC BM.

Background: Colorectal carcinoma (CRC) is the third most common cancer worldwide. Platinum-based anticancer compounds still constitute one mainstay of systemic CRC treatment despite limitations due to adverse effects and resistance development. Trabectedin has shown promising antitumor effects in CRC, however, again resistance development may occur. In this study, we aimed to develop strategies to circumvent or even exploit acquired trabectedin resistance in novel CRC treatment regimens. Methods: Human HCT116 CRC cells were selected for acquired trabectedin resistance in vitro and characterised by cell biological as well as bioinformatic approaches. In vivo xenograft experiments were conducted. Results: Selection of HCT116 cells for trabectedin resistance resulted in p53-independent hypersensitivity of the selected subline against cisplatin. Bioinformatic analyses of mRNA microarray data suggested deregulation of nucleotide excision repair and particularly loss of the ubiquitin ligase CUL4A in trabectedin-selected cells. Indeed, transient knockdown of CUL4A sensitised parental HCT116 cells towards cisplatin. Trabectedin selected but not parental HCT116 xenografts were significantly responsive towards cisplatin treatment. Conclusions: Trabectedin selection-mediated CUL4A loss generates an Achilles heel in CRC cancer cells enabling effective cisplatin treatment. Hence, inclusion of trabectedin in cisplatin-containing cancer treatment regimens might cause profound synergism based on reciprocal resistance prevention.

WHO grade II-III gliomas are rare primary brain tumors occurring at a median age of about 35–55 years. Median survival is longer in WHO grade II-III glioma compared with WHO grade IV glioblastoma as survival times of up to 10 years and longer can be observed. Maximal safe resection and adjuvant therapies including chemotherapy and radiotherapy are the mainstay of treatment. Clinical trials in WHO grade II-III tumors are challenging due to the rarity and the long follow up times. The 2016 WHO Classification of Central Nervous Tumours introduced a new diagnostic framework relying on molecular characteristics, providing the definition of prognostically more homogenous subgroups compared to the histopathological analysis. Most available evidence on the adjuvant treatment of WHO II-III gliomas was generated in the pre-molecular era, challenging the interpretation of study results. The present review therefore summarizes the available data from prospective trials on systemic treatment options in WHO grade II-III glioma, considering molecular markers, recently published results and future outlooks in the field.

2528 Background: Radiotherapy was postulated to impact the inflammatory microenvironment composition in patients with lung cancer brain metastases (BM). Methods: Formalin fixed and paraffin embedded BM specimens from treatment naïve patients (group 1) and from patients treated with radiation therapy including whole brain radiotherapy and/or stereotactic radiosurgery (group 2) or prophylactic cranial irradiation (group 3) before BM resection were identified from the Vienna Brain Metastasis Registry. T cell subsets (CD3+,CD8+,CD45RO+,FOXP3+,PD-L1+) were investigated using the Ventana Benchmark Ultra system Definiens software. Results: Specimens from 41 patients (28/41;68.3% NSCLC, 13/41;31.7% SCLC) were included in the study. A significant difference in CD3+TIL density between group 1 (median: 964.5cells/mm2) and group 2 (median: 283.4cells/mm2; p-value=0.021; Mann-Whitney-U test), as well as group 3 (median: 168.8 cells/mm2; p-value= 0.028; Mann-Whitney-U test) were observed. Furthermore, CD8+ and FOXP3+TIL densities of group 2 (CD8+ median: 172.1cells/mm2; FOXP3+ median: 210.7cells/mm2) were numerically lower compared to group 1 (CD8+ median: 190.1 cells/mm2; FOXP3+ median: 221.2 cells/mm2). Of 10/41 (24.4%) patients further resected BM tissue specimens after initial resection were available. Here, the inflammatory microenvironment of BM treated with radiation therapy between the resections was significantly associated with lower densities of CD3+ (median: 105.1 cells/mm2) and CD8+ (median: 20.3cells/mm2) compared to radiation-naïve patients (CD3+ median: 825.4cells/mm2; CD8+median: 105.5cells/mm2; p=0.037; Mann-Whitney U-test). Conclusions: Radiation treatment was associated with lower densities of TIL subsets in our BM cohort. Although results have to be interpreted with caution due to the limited sample size, further studies investigating the sequencing of radiotherapy and immune modulating therapies might be of interest. [Table: see text]

2553 Background: The blockade of lymphocyte-activation gene 3 (LAG-3), an inhibitory receptor on tumor-infiltrating lymphocytes, is currently under investigation in many extracranial tumor entities. Methods: 54 patients with diffuse glioma were included: 35 patients with glioblastoma (GBM, median age at diagnosis: 61 years) as well as 14 with WHO grade II and 5 with WHO grade III glioma (lower-grade glioma, LGG, median age at diagnosis: 45 years). Isocitrate dehydrogenase 1/2 mutations (IDH-mt) were present in 17/54 patients and 37/54 patients had IDH wildtype (IDH-wt) tumors. LAG-3 expression on tumor-infiltrating lymphocytes (TILs) was analyzed by immunohistochemistry (monoclonal anti-LAG-3 antibody, clone 17B4, LSBio Inc.). Results: LAG-3+ TILs could be observed in 5/54 (9.3%) samples, while CD3+ TILs were present in 32/54 (59.3%) and CD8+ TILs in 24/54 (44.4%) samples. Only IDH-wt glioma presented with LAG-3+ TILs (p = 0.168). Samples with LAG-3+ TILs presented with a numerical trend towards higher presence of CD3+ (5/27 CD3+ vs. 0/22 CD3−, p = 0.072) and CD8+ TILs (4/24 CD8+ vs. 1/30 CD8−, p = 0.159). 4/7 (57.1%) samples presenting with PD-1+ TILs also presented with LAG-3+ TILs (p = 0.001). Furthermore, glioma samples with LAG3+ TILs presented with higher expression of PD-L1 (median: 1% vs. 0%; p = 0.166). There was no difference in overall survival (OS) according to LAG-3+ TIL infiltration (median OS in LAG-3+: 21.7 months vs. LAG-3−: 41.4 months, p > 0.05). Conclusions: LAG-3+ TILs are rarely observed in IDH-wt and absent in IDH-mt glioma. Gliomas with an active inflammatory microenvironment present more frequently with LAG3+ TILs. The diverse composition of the inflammatory microenvironment and particular inflammatory subgroups should be considered in future clinical trials on immune-modulating therapies in glioma.

Background Cancer - immune system interactions are currently in focus of oncology research as immune modulating therapies have shown remarkable activity, also in patients with brain metastases (BM). Therefore, we aimed to investigate markers of systemic inflammation and their impact on survival prognosis in a large real-life cohort of BM patients. Methods 1250 patients with newly diagnosed BM were identified from the Vienna Brain Metastasis Registry. Systemic inflammation markers included: neutrophil-to-lymphocyte ratio (NLR), leucocyte/lymphocyte ratio (LLR), platelet/lymphocyte ratio (PLR), CRP/Albumin ratio (CRP/Alb). Median was chosen as a cut-off value. Results Low NLR was associated with statistically significantly longer OS compared to high NLR (9 vs. 5 months; p 0.05; Kruskal-Wallis). CRP/Alb was highest in patients with progressive disease, followed by patients with diagnosis of BM simultaneously with primary cancer diagnosis and lowest in patients with stable disease (p = 0.004; Kruskal-Wallis). PLR was highest in patients with progressive disease, followed by patients with stable disease and lowest in patients with BM diagnosis at primary cancer diagnosis (p = 0.02; Kruskal-Wallis). In multivariate analysis with DS-GPA, NLR (HR 1.40; 95% CI:1.2-1.6; p Conclusions Markers of systemic inflammation including NLR, LLR, CRP/Alb and PLR were associated with survival prognosis of newly diagnosed BM patients underscoring the importance of cancer – immune system interactions in patients with CNS metastatic disease. Legal entity responsible for the study The authors. Funding Has not received any funding. Disclosure M. Preusser: Research grant / Funding (self): Bohringer-Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Merck Sharp & Dome; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Gerson Lehrman Group; Honoraria (self), Advisory / Consultancy: CMC Contrast; Honoraria (self), Advisory / Consultancy: Mundipharma; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Medahead; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo. A.S. Berghoff: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Meyers Squibb; Honoraria (self), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: AbbVie. All other authors have declared no conflicts of interest.

Background Immune therapies targeting the programmed cell death receptor (ligand) 1 (PD-1/PD-L1) axis have shown remarkable activity in a variety of solid tumors. While substantial responses were observed in asymptomatic patients with brain metastases (BM), their clinical activity in primary brain tumors remains limited. In a cohort of adult brain tumor patients, we aimed to analyze soluble PD-L1 (sPD-L1) levels in patient plasma as a systemic marker of tumor - immune system interactions. Methods We obtained EDTA plasma from 55 glioblastoma, 26 lower-grade (WHO grade II - III) glioma (LGG), 17 meningioma and 43 BM patients (29/43 lung cancer, 6/43 renal cell carcinoma, 4/43 breast cancer, 4/43 melanoma) as well as 25 controls. sPD-L1 concentrations were measured by a sandwich ELISA using an anti-PD-L1/CD274 antibody (Millipore ABF133) as capture antibody and a non-commercial anti-PD-L1 antibody (clone 5H1) as detection antibody. The lower detection limit as determined by serial dilutions of recombinant human PD-L1 was 0.050 ng/ml. Results sPD-L1 was identified in 41/81 (50.6%) glioma, 5/17 (29.4%) meningioma and 6/43 (14.0%) BM patient samples and in 9/25 (36.0%) controls (p = 0.001, Chi-square), with a median concentration of 0.415 ng/ml (range: 0.050 – 42.150 ng/ml). sPD-L1 concentrations were significantly lower in BM as compared to glioma patients (p Conclusions Circulating PD-L1 levels differ between patients with distinct CNS malignancies, suggesting diverse tumor - immune system interactions between primary and secondary brain tumors. Moreover, our results indicate a differential prognostic impact of sPD-L1 in glioma which should be further studied. Legal entity responsible for the study The authors. Funding Medical University of Vienna. Disclosure A. Ilhan-Mutlu: Advisory / Consultancy: MSD; Advisory / Consultancy: Servier. M. Preusser: Research grant / Funding (self): Boehringer Ingelheim; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): GlaxoSmithKline; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): MSD; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Novartis; Honoraria (self), Advisory / Consultancy: Gerson Lehrman Group (GLG); Honoraria (self), Advisory / Consultancy: CMC Contrast; Honoraria (self), Advisory / Consultancy: Mundipharma; Honoraria (self), Advisory / Consultancy: AstraZeneca; Honoraria (self), Advisory / Consultancy: AbbVie; Honoraria (self), Advisory / Consultancy: Lilly; Honoraria (self), Advisory / Consultancy: Medahead; Honoraria (self), Advisory / Consultancy: Daiichi Sankyo. A.S. Berghoff: Honoraria (self), Advisory / Consultancy, Research grant / Funding (self): Daiichi Sankyo; Honoraria (self), Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Roche; Honoraria (self), Advisory / Consultancy: Bristol-Myers Squibb; Honoraria (self), Advisory / Consultancy: Merck; Travel / Accommodation / Expenses: Amgen; Travel / Accommodation / Expenses: AbbVie. All other authors have declared no conflicts of interest.

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.