Immune cell distribution and DNA methylation signatures differ between tumor and stroma enriched compartment in pancreatic ductal adenocarcinoma.

The presence of abundant tumor stroma is a prominent characteristic of pancreatic ductal adenocarcinomas (PDAC) that potentially influences disease progression and therapy response. This study aims to investigate immune cell infiltration and epigenetic profiles in tumor cell enriched ("Tumor") and stroma cell enriched ("Stroma") regions within human PDAC tissue samples. By comparing those regions, we identified 25,410 differentially methylated positions (DMPs) distributed across 6,963 unique genes. Pathway enrichment analysis using the top 2,000 DMPs that were either hyper- or hypomethylated indicated that immune response pathways and the estrogen receptor pathway are epigenetically dysregulated in Tumor and Stroma regions, respectively. In terms of immune cell infiltration, we observed overall low levels of T cells in both regions. In Tumor regions however, occurrence of tumor-associated macrophages (TAMs) was higher than in Stroma regions (p = 0.02) concomitant with a dualistic distribution that stratifies PDAC patients into those with high and low TAM infiltration. By categorizing TAM levels into quartiles, our analysis revealed that PDAC patients with more than 1,515 TAMs per mm² exhibited significantly shorter overall survival (p = 0.036). Our data suggest that variations in inflammatory characteristics between the Tumor and Stroma defined compartments of PDAC may primarily stem from the presence of macrophages rather than lymphocytes. The abundance of TAMs within regions enriched with tumor cells correlates with patient survival, underscoring the potential significance of exploring therapeutic interventions targeting TAMs. Furthermore, directing attention towards the estrogen receptor pathway may represent a promising strategy to address the stroma cell component within the PDAC tumor microenvironment.

DNA Methylation Signatures Correlate with Response to Immune Checkpoint Inhibitors in Metastatic Melanoma.

BACKGROUND: DNA methylation profiles have emerged as potential predictors of therapeutic response in various solid tumors. OBJECTIVE: This study aimed to analyze the DNA methylation profiles of patients with stage IV metastatic melanoma undergoing first-line immune checkpoint inhibitor treatment and evaluate their correlation with a radiological response according to immune-related Response Evaluation Criteria in Solid Tumors (iRECIST). METHODS: A total of 81 tissue samples from 71 patients with metastatic melanoma (27 female, 44 male) were included in this study. We utilized Illumina Methylation EPIC Beadchips to retrieve their genome-wide methylation profile by interrogating >850,000 CpG sites. Clustering based on the 500 most differentially methylated genes was conducted to identify distinct methylation patterns associated with immune checkpoint inhibitor response. Results were further aligned with an independent, previously published data set. RESULTS: The median progression-free survival was 8.5 months (range: 0-104.1 months), and the median overall survival was 30.6 months (range: 0-104.1 months). Objective responses were observed in 29 patients (40.8%). DNA methylation profiling revealed specific signatures that correlated with radiological response to immune checkpoint inhibitors. Three distinct clusters were identified based on the methylation patterns of the 500 most differentially methylated genes. Cluster 1 (12/12) and cluster 2 (12/24) exhibited a higher proportion of responders, while cluster 3 (39/45) predominantly consisted of non-responders. In the validation data set, responders also showed more frequent hypomethylation although differences in the data sets limit the interpretation. CONCLUSIONS: These findings suggest that DNA methylation profiling of tumor tissues might serve as a predictive biomarker for immune checkpoint inhibitor response in patients with metastatic melanoma. Further validation studies are warranted to confirm the efficiency of DNA methylation profiling as a predictive tool in the context of immunotherapy for metastatic melanoma.

Direct image to subtype prediction for brain tumors using deep learning.

Background: Deep Learning (DL) can predict molecular alterations of solid tumors directly from routine histopathology slides. Since the 2021 update of the World Health Organization (WHO) diagnostic criteria, the classification of brain tumors integrates both histopathological and molecular information. We hypothesize that DL can predict molecular alterations as well as WHO subtyping of brain tumors from hematoxylin and eosin-stained histopathology slides. Methods: We used weakly supervised DL and applied it to three large cohorts of brain tumor samples, comprising N = 2845 patients. Results: We found that the key molecular alterations for subtyping, IDH and ATRX, as well as 1p19q codeletion, were predictable from histology with an area under the receiver operating characteristic curve (AUROC) of 0.95, 0.90, and 0.80 in the training cohort, respectively. These findings were upheld in external validation cohorts with AUROCs of 0.90, 0.79, and 0.87 for prediction of IDH, ATRX, and 1p19q codeletion, respectively. Conclusions: In the future, such DL-based implementations could ease diagnostic workflows, particularly for situations in which advanced molecular testing is not readily available.

Clinical characteristics, treatment, and long-term outcome of patients with brain metastases from thyroid cancer.

Brain metastases (BM) in patients with thyroid cancer (TC) are rare with an incidence of 1% for papillary and follicular, 3% for medullary and up to 10% for anaplastic TC (PTC, FTC, MTC and ATC). Little is known about the characteristics and management of BM from TC. Thus, we retrospectively analyzed patients with histologically verified TC and radiologically verified BM identified from the Vienna Brain Metastasis Registry. A total of 20/6074 patients included in the database since 1986 had BM from TC and 13/20 were female. Ten patients had FTC, 8 PTC, one MTC and one ATC. The median age at diagnosis of BM was 68 years. All but one had symptomatic BM and 13/20 patients had a singular BM. Synchronous BM at primary diagnosis were found in 6 patients, while the median time to BM diagnosis was 13 years for PTC (range 1.9-24), 4 years for FTC (range 2.1-41) and 22 years for the MTC patient. The overall survival from diagnosis of BM was 13 months for PTC (range 1.8-57), 26 months for FTC (range 3.9-188), 12 years for the MTC and 3 months for the ATC patient. In conclusion, development of BM from TC is exceedingly rare and the most common presentation is a symptomatic single lesion. While BM generally constitute a poor prognostic factor, individual patients experience long-term survival following local therapy.

Frequent Overexpression of HER3 in Brain Metastases from Breast and Lung Cancer.

PURPOSE: HER3 belongs to a family of receptor tyrosine kinases with oncogenic properties and is targeted by a variety of novel anticancer agents. There is a huge unmet medical need for systemic treatment options in patients with brain metastases (BM). Therefore, we aimed to investigate HER3 expression in BM of breast (BCa) and non-small cell lung cancer (NSCLC) as the basis for future clinical trial design. EXPERIMENTAL DESIGN: We analyzed 180 BM samples of breast cancer or NSCLC and 47 corresponding NSCLC extracranial tissue. IHC was performed to evaluate protein expression of HER3, and immune cells based on CD3, CD8, and CD68. To identify dysregulated pathways based on differential DNA methylation patterns, we used Infinium MethylationEPIC microarrays. RESULTS: A total of 99/132 (75.0%) of BCa-BM and 35/48 (72.9%) of NSCLC-BM presented with HER3 expression. Among breast cancer, HER2-positive and HER2-low BM showed significantly higher rates of HER3 coexpression than HER2-negative BM (87.1%/85.7% vs. 61.0%, P = 0.004). Among NSCLC, HER3 was more abundantly expressed in BM than in matched extracranial samples (72.9% vs. 41.3%, P = 0.003). No correlation of HER3 expression and intratumoral immune cell density was observed. HER3 expression did not correlate with overall survival from BM diagnosis. Methylation signatures differed according to HER3 status in BCa-BM samples. Pathway analysis revealed subtype-specific differences, such as TrkB and Wnt signaling pathways dysregulated in HER2-positive and triple-negative breast cancer BM, respectively. CONCLUSIONS: HER3 is highly abundant in BM of breast cancer and NSCLC. Given the promising results of antibody-drug conjugates in extracranial disease, BM-specific trials that target HER3 are warranted. See related commentary by Kabraji and Lin, p. 2961.

Trastuzumab deruxtecan in HER2-positive breast cancer with brain metastases: a single-arm, phase 2 trial.

Trastuzumab deruxtecan is an antibody-drug conjugate with high extracranial activity in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer. We conducted the prospective, open-label, single-arm, phase 2 TUXEDO-1 trial. We enrolled patients aged ≥18 years with HER2-positive breast cancer and newly diagnosed untreated brain metastases or brain metastases progressing after previous local therapy, previous exposure to trastuzumab and pertuzumab and no indication for immediate local therapy. Patients received trastuzumab deruxtecan intravenously at the standard dose of 5.4 mg per kg bodyweight once every 3 weeks. The primary endpoint was intracranial response rate measured according to the response assessment in neuro-oncology brain metastases criteria. A Simon two-stage design was used to compare a null hypothesis of <26% response rate against an alternative of 61%. Fifteen patients were enrolled in the intention-to-treat population of patients who received at least one dose of study drug. Two patients (13.3%) had a complete intracranial response, nine (60%) had a partial intracranial response and three (20%) had stable disease as the best intracranial response, with a best overall intracranial response rate of 73.3% (95% confidential interval 48.1-89.1%), thus meeting the predefined primary outcome. No new safety signals were observed and global quality-of-life and cognitive functioning were maintained over the treatment duration. In the TUXEDO-1 trial (NCT04752059, EudraCT 2020-000981-41), trastuzumab deruxtecan showed a high intracranial response rate in patients with active brain metastases from HER2-positive breast cancer and should be considered as a treatment option in this setting.

DNA Methylation Associates With Clinical Courses of Atypical Meningiomas: A Matched Case-Control Study.

Background: Accounting for 15-20% of all meningiomas, WHO grade II meningiomas represent an intermediate group regarding risk of tumor recurrence. However, even within this subgroup varying clinical courses are observed with potential occurrence of multiple recurrences. Recently, DNA methylation profiles showed their value for distinguishing biological behaviors in meningiomas. Therefore, aim of this study was to investigate DNA methylation profiles in WHO grade II meningiomas. Methods: All patients that underwent resection of WHO grade II meningiomas between 1993 and 2015 were screened for a dismal course clinical course with ≥2 recurrences. These were matched to control cases with benign clinical courses without tumor recurrence. DNA methylation was assessed using the Infinium Methylation EPIC BeadChip microarray. Unsupervised hierarchical clustering was performed for identification of DNA methylation profiles associated with such a dismal clinical course. Results: Overall, 11 patients with WHO grade II meningiomas with ≥2 recurrences (Group dismal) and matched 11 patients without tumor recurrence (Group benign) were identified. DNA methylation profiles revealed 3 clusters-one comprising only patients of group dismal, a second cluster comprising mainly patients from group benign and a third cluster comprising one group dismal and one group benign patient. Based on differential methylation pattern associations with the Wnt and the related cadherin signaling pathway was observed. Conclusion: DNA methylation clustering showed remarkable differences between two matched subgroups of WHO grade II meningiomas. Thus, DNA methylation profiles may have the potential to support prognostic considerations regarding meningioma recurrence and radiotherapeutic treatment allocation after surgical resection.

DNA methylation profiles differ in responders versus non-responders to anti-PD-1 immune checkpoint inhibitors in patients with advanced and metastatic head and neck squamous cell carcinoma.

BACKGROUND: Biomarkers for response prediction to anti-programmed cell death 1 (PD-1) immune checkpoint inhibitors (ICI) in patients with head and neck squamous cell carcinoma (HNSCC) are urgently needed for a personalized therapy approach. We investigated the predictive potential of inflammatory parameters and DNA methylation profiling in patients with HNSCC treated with anti-PD-1 ICI. METHODS: We identified patients with HNSCC that were treated with anti-PD-1 ICI therapy in the recurrent or metastatic setting after progression to platinum-based chemotherapy in two independent centers. We analyzed DNA methylation profiles of >850.000 CpG sites in tumor specimens of these patients by Infinium MethylationEPIC microarrays, immune cell density in the tumor microenvironment (CD8, CD3, CD45RO, forkhead box P3 (FOXP3), CD68), PD-1 and programmed cell death ligand 1 (PD-L1) expression by immunohistochemistry, and blood inflammation markers (platelet-to-lymphocyte ratio, leucocyte-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, neutrophil-to-lymphocyte ratio). DNA methylation profiles and immunological markers were bioinformatically and statistically correlated with radiological response to anti-PD-1 ICI. RESULTS: 37 patients with HNSCC (median age of 62 years; range 49-83; 8 (21.6%) women, 29 (78.4%) men) were included (Center 1 N=26, 70.3%; Center 2 N=11, 29.7%). Median number of prior systemic therapies was 1 (range 1-4). Five out of 37 (13.5%) patients achieved an objective response to ICI. Median progression-free survival and median overall survival times were 3.7 months (range 0-22.9) and 9.0 months (range 0-38.8), respectively. Microarray analyses revealed a methylation signature including both hypomethylation and hypermethylation which was predictive for response to ICI and included several genes involved in cancer-related molecular pathways. Over-represented differentially methylated genes between responders and non-responders were associated with 'Axon guidance', 'Hippo signaling', 'Pathways in cancer' and 'MAPK signaling'. A statistically significant correlation of PD-L1 expression and response was present (p=0.0498). CONCLUSIONS: Our findings suggest that tumor DNA methylation profiling may be useful to predict response to ICI in patients with HNSCC.

New Approaches with Precision Medicine in Adult Brain Tumors.

Primary central nervous system (CNS) tumors represent a heterogenous group of tumors. The 2021 fifth edition of the WHO Classification of Tumors of the CNS emphasizes the advanced role of molecular diagnostics with routine implementation of molecular biomarkers in addition to histologic features in the classification of CNS tumors. Thus, novel diagnostic methods such as DNA methylome profiling are increasingly used to provide a more precise diagnostic work-up of CNS tumors. In addition to these diagnostic precision medicine advantages, molecular alterations are also addressed therapeutically with targeted therapies. Like in other tumor entities, precision medicine has therefore also arrived in the treatment of CNS malignancies as the application of targeted therapies has shown promising response rates. Nevertheless, large prospective studies are currently missing as most targeted therapies were evaluated in single arm, basket, or platform trials. In this review, we focus on the current evidence of precision medicine in the treatment of primary CNS tumors in adults. We outline the pathogenic background and prevalence of the most frequent targetable genetic alterations and summarize the existing evidence of precision medicine approaches for the treatment of primary CNS tumors.

EVI1 Promotes the Proliferation and Invasive Properties of Human Head and Neck Squamous Cell Carcinoma Cells.

Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor prognosis. So far, the EGFR inhibitor cetuximab is the only approved targeted therapy. A deeper understanding of the molecular and genetic basis of HNSCC is needed to identify additional targets for rationally designed, personalized therapeutics. The transcription factor EVI1, the major product of the MECOM locus, is an oncoprotein with roles in both hematological and solid tumors. In HNSCC, high EVI1 expression was associated with an increased propensity to form lymph node metastases, but its effects in this tumor entity have not yet been determined experimentally. We therefore overexpressed or knocked down EVI1 in several HNSCC cell lines and determined the impact of these manipulations on parameters relevant to tumor growth and invasiveness, and on gene expression patterns. Our results revealed that EVI1 promoted the proliferation and migration of HNSCC cells. Furthermore, it augmented tumor spheroid formation and the ability of tumor spheroids to displace an endothelial cell layer. Finally, EVI1 altered the expression of numerous genes in HNSCC cells, which were enriched for Gene Ontology terms related to its cellular functions. In summary, EVI1 represents a novel oncogene in HNSCC that contributes to cellular proliferation and invasiveness.

Prognostic factors in adult brainstem glioma: a tertiary care center analysis and review of the literature.

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 < 0.05, log rank test, respectively). ADC values below the median were significantly associated with shorter OS (14.9 vs 44.2 months, 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.

Focal Radiotherapy of Brain Metastases in Combination With Immunotherapy and Targeted Drug Therapy.

BACKGROUND: Advances in systemic treatment and in brain imaging have led to a higher incidence of diagnosed brain metastases. In the treatment of brain metastases, stereotactic radiotherapy and radiosurgery, systemic immunotherapy, and targeted drug therapy are important evidence-based options. In this review, we summarize the available evidence on the treatment of brain metastases of the three main types of cancer that give rise to them: non-small-cell lung cancer, breast cancer, and malignant melanoma. METHODS: This narrative review is based on pertinent original articles, meta-analyses, and systematic reviews that were retrieved by a selective search in PubMed. These publications were evaluated and discussed by an expert panel including radiation oncologists, neurosurgeons, and oncologists. RESULTS: There have not yet been any prospective randomized trials concerning the optimal combination of local stereotactic radiotherapy/radiosurgery and systemic immunotherapy or targeted therapy. Retrospective studies have consistently shown a benefit from early combined treatment with systemic therapy and (in particular) focal radiotherapy, compared to sequential treatment. Two metaanalyses of retrospective data from cohorts consisting mainly of patients with non-small-cell lung cancer and melanoma revealed longer overall survival after combined treatment with focal radiotherapy and checkpoint inhibitor therapy (rate of 12-month overall survival for combined versus non-combined treatment: 64.6% vs. 51.6%, p <0.001). In selected patients with small, asymptomatic brain metastases in non-critical locations, systemic therapy without focal radiotherapy can be considered, as long as follow-up with cranial magnetic resonance imaging can be performed at close intervals. CONCLUSION: Brain metastases should be treated by a multidisciplinary team, so that the optimal sequence of local and systemic therapies can be determined for each individual patient.

Favourable outcome of patients with breast cancer brain metastases treated with dual HER2 blockade of trastuzumab and pertuzumab.

BACKGROUND: Dual human epidermal growth factor receptor 2 (HER2) blockade with trastuzumab and pertuzumab (TP) is a standard therapy of metastatic and localized HER2-positive breast cancer (BC), but its activity in breast cancer brain metastases (BCBM) is unknown. METHODS: Patients with HER2-positive BCBM were identified from the Vienna Brain Metastasis Registry and clinical data including patient characteristics, therapies and overall survival (OS) were obtained. Patients were grouped into 'TP', 'other-HER2-targeted therapy' and 'no-HER2-targeted therapy' according to received first-line systemic therapy after diagnosis of BCBM. Radiological re-assessment of intracranial lesions was performed in patients treated with TP as systemic first-line therapy according to RANO response criteria for brain metastases (BM). RESULTS: A total of 252 HER2-positive BC patients with BM were available for this analysis. Patients treated with TP as systemic first-line therapy after diagnosis of BM had a significantly longer OS compared with treatment with other-HER2-targeted therapy and no-HER2-targeted therapy (44 versus 17 versus 3 months, p < 0.001; log-rank test). Among radiologically re-assessed patients treated with TP as systemic first-line therapy after diagnosis of BM, 5/14 patients (35.7%) had complete intracranial remission (CR), 8/14 patients (57.1%) partial intracranial remission (PR), 1/14 patients (7.1%) stable intracranial disease (SD) and 0/14 patients (0.0%) progressive intracranial disease (PD) as best response resulting in an intracranial objective response rate (iORR) of 92.9% and an intracranial clinical benefit rate (iCBR) of 100.0%. CONCLUSION: First-line therapy with dual HER2-inhibition of TP after BM diagnosis was associated with the longest median OS times in patients with BCBM.

International Multi-Center Analysis of In-hospital Morbidity and Mortality of Low-Voltage Electrical Injuries.

Background : Patients with high- and low-voltage electrical injuries differ in their clinical presentation from minor symptoms to life-threatening conditions. For an adequate diagnosis and treatment strategy a multidisciplinary team is often needed, due to the heterogeneity of the clinical presentation. To minimize costs and medical resources, especially for patients with mild symptoms presenting after low-voltage electrical injuries, risk stratification for the development of further complications is needed. Methods : During 2012-2019 two independent patient cohorts admitted with electrical injuries in two maximum care university hospitals in Germany and Austria were investigated to quantify risk factors for prolonged treatment, the need of surgery and death in low-voltage injuries. High-voltage injuries were used as reference in the analysis of the low-voltage electrical injury. Results : We analyzed 239 admitted patients with low-voltage (75%; 276 ± 118 V), high-voltage (17%; 12.385 ± 28.896 V) or unclear voltage (8%). Overall mortality was 2% (N = 5) associated only with high-voltage injuries. Patients with low-voltage injuries presented with electrocution entry marks (63%), various neurological symptoms (31%), burn injuries (at least second degree) (23%), pain (27%), and cardiac symptoms (9%) including self-limiting thoracic pain and dysrhythmia without any therapeutic need. Seventy three percentage of patients with low-voltage injury were discharged within 24 h. The remaining patients stayed in the hospital (11 ± 10 days) for treatment of entry marks and burns, with an overall need for surgery of 12% in all low-voltage injuries. Conclusions : The only identified risk factors for prolonged hospital stay in patients with low-voltage electrical injuries were the treatment of burns and electric marks. In this multi-center analysis of hospitalized patients, low-voltage electrical injuries were not associated with cardiac arrhythmia or mortality. Therefore, we suggest that asymptomatic patients, without preexisting conditions, with low-voltage injury can be discharged after an initial check-up without prolonged monitoring.

SARS-CoV-2 seroprevalence in oncology healthcare professionals and patients with cancer at a tertiary care centre during the COVID-19 pandemic.

BACKGROUND: During the COVID-19 outbreak, healthcare professionals (HCP) are at the frontline of clinical management and at increased risk for infection. The SARS-CoV-2 seroprevalence of oncological HCP and their patients has significant implications for oncological care. METHODS: HCP and patients with cancer at the Division of Oncology, Medical University of Vienna were included between 21 March and 4 June and tested for total antibodies against SARS-CoV-2 employing the Roche Elecsys Anti-SARS-CoV-2 immunoassay. Reactive samples were confirmed or disproved by the Abbott SARS-CoV-2 IgG test. Additionally, a structured questionnaire regarding basic demographic parameters, travel history and COVID-19-associated symptoms had to be completed by HCP. RESULTS: 146 subjects (62 HCP and 84 patients with cancer) were enrolled. In the oncological HCP cohort, 20 (32.3%) subjects were medical oncologists, 28 (45.2%) nurses at our ward and 14 (22.6%) fulfil other functions such as study coordinators. In the patient cohort, most individuals are on active anticancer treatment (96.4%). 26% of the HCP and 6% of the patients had symptoms potentially associated with COVID-19 since the end of February 2020. However, only in 2 (3.2%) HCP and in 3 (3.6%) patients, anti-SARS-Cov-2 total antibodies were detected. The second assay for anti-SARS-Cov-2 IgG antibodies confirmed the positive result in all HCP and in 2 (2.4%) patients, suggesting an initial assay's unspecific reaction in one case. In individuals with a confirmed test result, an active COVID-19 infection was documented by a positive SARS-CoV-2 RNA PCR test. CONCLUSION: Specific anti-SARS-CoV-2 antibodies were found solely in persons after a documented SARS-CoV-2 viral infection, thus supporting the test methods' high sensitivity and specificity. The low prevalence of anti-SARS-CoV-2 antibodies in our cohorts indicates a lack of immunity against SARS-CoV-2. It highlights the need for continued strict safety measures to prevent uncontrolled viral spread among oncological HCPs and patients with cancer.

Analysis of the inflammatory tumor microenvironment in meningeal neoplasms.

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

Bevacizumab-based treatment as salvage therapy in patients with recurrent symptomatic brain metastases.

BACKGROUND: Salvage treatment for recurrent brain metastases (BM) of solid cancers is challenging due to the high symptomatic burden and the limited local treatment options. METHODS: Patients with recurrent BM with no option for further local therapies were retrospectively identified from BM databases. Bevacizumab-based treatment was initiated as a salvage treatment. Radiological imaging before and after bevacizumab-based treatment was reevaluated for treatment response using the Response Assessment in Neuro-Oncology (RANO) BM criteria. RESULTS: Twenty-two patients (36.4% male) with recurrent BM from breast cancer (40.9%), colorectal cancer (31.8%), or lung cancer (27.3%) were identified. Previous BM-directed therapies were radiosurgery in 16/22 (72.7%) patients, whole-brain radiotherapy in 8/22 (36.4%), and neurosurgical resection in 11/22 (50.0%). Time since BM diagnosis to initiation of bevacizumab treatment was 16.5 months. Of 22 patients 14 (63.6%) received concurrent systemic therapies. Neurological symptom improvement could be achieved in 14/22 (63.6%) and stabilization in 6/22 (27.3%) patients, resulting in a clinical benefit in 20/22 (90.9%) patients. Steroids could be reduced or stopped in 15/22 (68.2%) patients. Rate of improvement on T1-weighted imaging was 15/19 (78.9%; median reduction: -26.0% ± 32.9) and 19/20 (95%; median reduction: -36.2% ± 22.2) on T2-weighted FLAIR imaging. According to RANO-BM best response was partial response in 7/19 (36.8%), stable disease in 9/19 (47.3%), and progressive disease in 3/19 (15.7%) patients. Median CNS-specific progression-free survival was 8 months and median overall survival after initiation of bevacizumab treatment was 17 months. CONCLUSIONS: Bevacizumab-based treatment had clinically relevant intracranial activity in the vast majority of patients suffering from recurrent, symptomatic BM. The data supports a prospective clinical trial of bevacizumab as a salvage treatment in BM.

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

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

Viennese risk prediction score for Advanced Gastroesophageal carcinoma based on Alarm Symptoms (VAGAS score): characterisation of alarm symptoms in advanced gastro-oesophageal cancer and its correlation with outcome.

INTRODUCTION: The prognostic value of symptoms at disease presentation of advanced gastro-oesophageal cancer is unknown. Thus, the aim of this study was to characterise these symptoms and correlate them with the outcome, so new prognostic markers can be defined. METHODS: We analysed clinical data including symptoms, therapies and survival of patients with stage IV gastro-oesophageal cancer treated between 2002 and 2018 at the Vienna General Hospital, Austria. Initial symptoms as well as stenosis in endoscopy and HER2 positivity were evaluated in a cross-validation model to ascertain the impact of each variable on patient survival. RESULTS: In total, 258 patients were evaluated. Five factors (stenosis in endoscopy, weight loss, HER2 positivity, dyspepsia, ulcer or active bleeding) have proven to be statistically relevant prognostic factors and were given a count of +1 and -1, if applicable. The resulting score ranges between -3 and +2. The survival probability for 180 days with a score of -3/-2, -1, 0, +1 and +2 is 90%, 80%, 73%, 72% and 42%, whereas for 2 years, it is 30%, 30%, 8%, 7% and 3%, respectively. The median overall survival of a score of -3/-2, -1, 0, +1 and +2 was 579 (95% CI 274 to not measurable), 481 (95% CI 358 to 637), 297 (95% CI 240 to 346), 284 (95% CI 205 to 371), 146 (95% CI 120 to 229) days, respectively. CONCLUSION: The data from this retrospective study indicate that the Viennese risk prediction score for Advanced Gastroesophageal carcinoma based on Alarm Symptoms score provides independent prognostic information that may support clinical decision making at diagnosis of advanced gastro-oesophageal cancer. Our findings should be evaluated in prospective studies.

Low Systemic Levels of Chemokine C-C Motif Ligand 3 (CCL3) are Associated with a High Risk of Venous Thromboembolism in Patients with Glioma.

A tight interplay between inflammation and hemostasis has been described as a potential driver for developing venous thromboembolism (VTE). Here, we investigated the association of systemic cytokine levels and risk of VTE in patients with glioma. This analysis was conducted within the prospective, observational Vienna Cancer and Thrombosis Study. Patients with glioma were included at time of diagnosis or progression and were observed for a maximum of two years. Primary endpoint was objectively confirmed VTE. At study entry, a single blood draw was performed. A panel of nine cytokines was measured in serum samples with the xMAP technology developed by Luminex. Results: Overall, 76 glioma patients were included in this analysis, and 10 (13.2%) of them developed VTE during the follow-up. Chemokine C-C motif ligand 3 (CCL3) levels were inversely associated with risk of VTE (hazard ratio [HR] per double increase, 95% confidence interval [CI]: 0.385, 95% CI: 0.161-0.925, p = 0.033), while there was no association between the risk of VTE and serum levels of interleukin (IL)-1ß, IL-4, IL-6, IL-8, IL-10, IL-11, tumor necrosis factor (TNF)-α and vascular endothelial growth factor (VEGF), respectively. In conclusion, low serum levels of CCL3 were associated with an increased risk of VTE. CCL3 might serve as a potential biomarker to predict VTE risk in patients with glioma.