Interleukin-33 in human gliomas: Expression and prognostic significance

Interleukin-33 (IL-33) is a nuclear and pleiotropic cytokine with regard to its cellular sources and its actions. IL-33 is involved in the pathogenesis of brain diseases. Several factors account for the tumorigenicity of human gliomas, including cytokines and their receptors. The present study assessed the expression and prognostic significance of IL-33 in human astroglial brain tumors. Protein levels of IL-33 were determined by immunohistochemistry using a tissue microarray containing 95 human gliomas. mRNA expression data of IL-33, as well as of its receptors, IL-1 receptor-like 1 protein and IL-1 receptor accessory protein (IL1RAcP), were obtained from The Cancer Genome Atlas database. IL-33 protein was expressed heterogeneously in tumor tissue, but was, however, not detected in normal brain tissue. There was no differential IL-33 protein expression by tumor grade, while IL-33 protein expression was associated with inferior survival in patients with recurrent glioblastomas. Interrogations of the TCGA database indicated that mRNA expression of IL-33 and the IL-33 receptors was heterogeneous, and that IL-33 and IL1RAcP mRNA levels were correlated with the tumor grade. Elevated IL-33 mRNA levels were associated with the inferior survival of glioblastoma patients. Therefore, IL-33 may play an important role in the pathogenesis and prognosis of human gliomas

Anaplastic ganglioglioma-A diagnosis comprising several distinct tumour types

AIMS Anaplastic ganglioglioma is a rare tumour, and diagnosis has been based on histological criteria. The 5th edition of the World Health Organization Classification of Tumours of the Central Nervous System (CNS WHO) does not list anaplastic ganglioglioma as a distinct diagnosis due to lack of molecular data in previous publications. We retrospectively compiled a cohort of 54 histologically diagnosed anaplastic gangliogliomas to explore whether the molecular profiles of these tumours represent a separate type or resolve into other entities. METHODS Samples were subjected to histological review, desoxyribonucleic acid (DNA) methylation profiling and next-generation sequencing. Morphological and molecular data were summarised to an integrated diagnosis. RESULTS The majority of tumours designated as anaplastic gangliogliomas resolved into other CNS WHO diagnoses, most commonly pleomorphic xanthoastrocytoma (16/54), glioblastoma, isocitrate dehydrogenase protein (IDH) wild type and diffuse paediatric-type high-grade glioma, H3 wild type and IDH wild type (11 and 2/54), followed by low-grade glial or glioneuronal tumours including pilocytic astrocytoma, dysembryoplastic neuroepithelial tumour and diffuse leptomeningeal glioneuronal tumour (5/54), IDH mutant astrocytoma (4/54) and others (6/54). A subset of tumours (10/54) was not assignable to a CNS WHO diagnosis, and common molecular profiles pointing to a separate entity were not evident. CONCLUSIONS In summary, we show that tumours histologically diagnosed as anaplastic ganglioglioma comprise a wide spectrum of CNS WHO tumour types with different prognostic and therapeutic implications. We therefore suggest assigning this designation with caution and recommend comprehensive molecular workup

Venous thromboembolic events in glioblastoma patients: An epidemiological study

BACKGROUND AND PURPOSE Venous thromboembolic events (VTEs) are a major complication in cancer patients, and therefore, also in brain cancer patients, anticoagulants are considered appropriate in the treatment of VTEs. METHODS Frequency, risk factors, and treatment of VTEs, as well as associated complications, were assessed in a population-based cohort of glioblastoma patients in the Canton of Zurich, Switzerland. Correlations between clinical data and survival were retrospectively analyzed using the log-rank test and Cox regression models. RESULTS Four hundred fourteen glioblastoma patients with isocitrate dehydrogenase wild-type status were identified. VTEs were documented in 65 patients (15.7%). Median time from tumor diagnosis to the occurrence of a VTE was 1.8 months, and 27 patients were diagnosed with VTEs postoperatively (within 35 days; 42.2%). History of a prior VTE was more common in patients who developed VTEs than in those who did not (p = 0.004). Bevacizumab treatment at any time during the disease course was not associated with occurrence of VTEs (p = 0.593). Most patients with VTEs (n = 61, 93.8%) were treated with therapeutic anticoagulation. Complications occurred in 14 patients (23.0%), mainly intracranial hemorrhages (n = 7, 11.5%). Overall survival did not differ between patients diagnosed with VTEs and those who had no VTE (p = 0.139). Tumor progression was the major cause of death (n = 283, 90.7%), and only three patients (1.0%) died in association with acute VTEs. CONCLUSIONS Venous thromboembolic events occurred early in the disease course, suggesting that the implementation of primary venous thromboembolism prophylaxis during first-line chemoradiotherapy could be explored in a randomized setting

Antidepressant drug use in glioblastoma patients: an epidemiological view.

Background: Antidepressant drugs have shown antitumor activity in preclinical glioblastoma studies. Antidepressant drug use, as well as its association with survival, in glioblastoma patients has not been well characterized on a population level. Methods: Patient characteristics, including the frequency of antidepressant drug use, were assessed in a glioblastoma cohort diagnosed in a 10-year time frame between 2005 and 2014 in the Canton of Zurich, Switzerland. Cox proportional hazards regression models were applied for multivariate analysis. Kaplan-Meier survival curves were used to estimate overall survival (OS) data and the log-rank test was performed for comparisons. Results: A total of 404 patients with isocitrate dehydrogenase wild-type glioblastoma were included in this study. Sixty-five patients (16.1%) took antidepressant drugs at some point during the disease course. Patients were most commonly prescribed selective serotonin reuptake inhibitors at any time (N = 46, 70.8%). Nineteen patients (29.2%) were on antidepressant drugs at the time of their tumor diagnosis. No differences were observed in OS between those patients who had taken antidepressants at some point in their disease course and those who had not (P = .356). These data were confirmed in a multivariate analysis including age, Karnofsky Performance Scale (KPS), sex, extent of resection, O$^{6}$-methylguanine DNA methyltransferase (MGMT) promoter methylation status, and first-line treatment as cofounders (P = .315). Also, there was no association of use of drugs modulating voltage-dependent potassium channels (citalopram; escitalopram) with survival (P = .639). Conclusions: This signal-seeking study does not support the hypothesis that antidepressants have antitumor efficacy in glioblastoma on a population level

A risk model for prediction of diagnosis of cancer after ischemic stroke

It remains controversial which characteristics may predict occult cancer in stroke patients. Characteristics of patients with ischemic stroke registered in the Zurich Swiss Stroke Registry (2014 to 2016) were tested for associations with cancer diagnosis after stroke with consideration of death as competing risk for cancer diagnosis. Among 1157 patients, 34 (3%) and 55 patients (5%) were diagnosed with cancer within 1 and 3 years after stroke. Levels of white blood cells (WBC) > 9,600/µl (subdistribution hazard ratio (SHR) 3.68, p = 0.014), platelets > 400,000/µl (SHR 7.71, p = 0.001), and d-dimers ≥ 3 mg/l (SHR 3.67, p = 0.007) were independently associated with cancer diagnosis within 1 year after stroke. Occurrence of ischemic lesions in ≥ 2 vascular territories not attributed to cardioembolic etiology was associated with cancer diagnosed within 1 year after stroke in univariable analysis (SHR 3.69, p = 0.001). The area under the curve of a score from these parameters (score sum 0-4) was 0.73. A score of ≥ 2 had a sensitivity of 43% and specificity of 92% for prediction of cancer diagnosis within 1 year after stroke. We suggest further validation of a score of WBC, platelets, d-dimers and multiple ischemic lesions without cardioembolic stroke etiology for prediction of cancer diagnosis after stroke

DNA methylation-based classification of ependymomas in adulthood: implications for diagnosis and treatment

Background Ependymal tumors are glial tumors that commonly manifest in children and young adults. Their classification has remained entirely morphological until recently, and surgery and radiotherapy are the main treatment options, especially in adults. Here we sought to correlate DNA methylation profiles with clinical and pathological characteristics in the prospective cohort of the German Glioma Network. Methods Tumors from 122 adult patients with myxopapillary ependymoma, ependymoma, anaplastic ependymoma, subependymoma or RELA fusion-positive ependymoma classified according to the World Heath Organization classification (WHO) 2016 were subjected to DNA methylation profiling using the Illumina HumanMethylation450 BeadChip platform. Molecular data were correlated with histologic features and clinical characteristics. Results At a median follow-up of 86.7 months, only 22 patients experienced progression (18.0%) and 13 patients (10.7%) died. Each tumor could be assigned to one of the previously defined molecular ependymoma subgroups. All histologic subependymomas corresponded to subependymoma (SE) DNA methylation subgroups, but the reverse was not true: 19 histologic ependymomas (WHO grade II) were allocated to molecular SE groups. Similarly, all histological myxopapillary ependymomas were assigned to the molecularly defined SP-MPE class, but this molecular subgroup additionally included 15 WHO grade II ependymomas by histology. Overall, WHO grade II ependymomas distributed into seven molecular subgroups. Conclusions Most adult patients with ependymoma show a favorable prognosis. Molecular classification may provide diagnostic and prognostic information beyond histology and facilitate patient stratification in future clinical trials. The prognostic significance of a subependymoma or myxopapillary ependymoma DNA methylation phenotype without according histology requires further study

Association of perioperative adverse events with subsequent therapy and overall survival in patients with WHO grade III and IV gliomas

Background Maximum safe resection followed by chemoradiotherapy as current standard of care for WHO grade III and IV gliomas can be influenced by the occurrence of perioperative adverse events (AE). The aim of this study was to determine the association of AE with the timing and choice of subsequent treatments as well as with overall survival (OS). Methods Prospectively collected data of 283 adult patients undergoing surgery for WHO grade III and IV gliomas at the University Hospital Zurich between January 2013 and June 2017 were analyzed. We assessed basic patient characteristics, KPS, extent of resection, and WHO grade, and we classified AE as well as modality, timing of subsequent treatment (delay, interruption, or non-initiation), and OS. Results In 117 patients (41%), an AE was documented between surgery and the 3-month follow-up. There was a significant association of AE with an increased time to initiation of subsequent therapy (p = 0.005) and a higher rate of interruption (p < 0.001) or non-initiation (p < 0.001). AE grades correlated with time to initiation of subsequent therapy (p = 0.038). AEs were associated with shorter OS in univariate analysis (p < 0.001). Conclusion AEs are associated with delayed and/or altered subsequent therapy and can therefore limit OS. These data emphasize the importance of safety within the maximum-safe-resection concept

Chimeric antigen receptor T cell-based targeting of CD317 as a novel immunotherapeutic strategy against glioblastoma

BACKGROUND: Chimeric antigen receptor (CAR) T cell therapy has proven to be successful against hematological malignancies. However, exploiting CAR T cells to treat solid tumors is more challenging for various reasons including the lack of suitable target antigens. Here, we identify the transmembrane protein CD317 as a novel target antigen for CAR T cell therapy against glioblastoma, one of the most aggressive solid tumors. METHODS: CD317-targeting CAR T cells were generated by lentivirally transducing human T cells from healthy donors. The anti-glioma activity of CD317-CAR T cells toward various glioma cells was assessed in vitro in cell lysis assays. Subsequently, we determined the efficacy of CD317-CAR T cells to control tumor growth in vivo in clinically relevant mouse glioma models. RESULTS: We generated CD317-specific CAR T cells and demonstrate strong anti-tumor activity against several glioma cell lines as well as primary patient-derived cells with varying CD317 expression levels in vitro. A CRISPR/Cas9-mediated knockout of CD317 protected glioma cells from CAR T cell lysis, demonstrating the target specificity of the approach. Silencing of CD317 expression in T cells by RNA interference reduced fratricide of engineered T cells and further improved their effector function. Using orthotopic glioma mouse models, we demonstrate the antigen-specific anti-tumor activity of CD317-CAR T cells, which resulted in prolonged survival and cure of a fraction of CAR T cell-treated animals. CONCLUSIONS: These data reveal a promising role of CD317-CAR T cell therapy against glioblastoma, which warrants further evaluation to translate this immunotherapeutic strategy into clinical neuro-oncology

Glioblastoma in the oldest old: Clinical characteristics, therapy, and outcome in patients aged 80 years and older

Background: Incidence rates of glioblastoma in very old patients are rising. The standard of care for this cohort is only partially defined and survival remains poor. The aims of this study were to reveal current practice of tumor-specific therapy and supportive care, and to identify predictors for survival in this cohort. Methods: Patients aged 80 years or older at the time of glioblastoma diagnosis were retrospectively identified in 6 clinical centers in Switzerland and France. Demographics, clinical parameters, and survival outcomes were annotated from patient charts. Cox proportional hazards modeling was performed to identify parameters associated with survival. Results: Of 107 patients, 45 were diagnosed by biopsy, 30 underwent subtotal resection, and 25 had gross total resection. In 7 patients, the extent of resection was not specified. Postoperatively, 34 patients did not receive further tumor-specific treatment. Twelve patients received radiotherapy with concomitant temozolomide, but only 2 patients had maintenance temozolomide therapy. Fourteen patients received temozolomide alone, 35 patients received radiotherapy alone, 1 patient received bevacizumab, and 1 took part in a clinical trial. Median progression-free survival (PFS) was 3.3 months and median overall survival (OS) was 4.2 months. Among patients who received any postoperative treatment, median PFS was 3.9 months and median OS was 7.2 months. Karnofsky performance status (KPS) ≥70%, gross total resection, and combination therapy were associated with better outcomes. The median time spent hospitalized was 30 days, accounting for 23% of the median OS. End-of-life care was mostly provided by nursing homes (n = 20; 32%) and palliative care wards (n = 16; 26%). Conclusions: In this cohort of very old patients diagnosed with glioblastoma, a large proportion was treated with best supportive care. Treatment beyond surgery and, in particular, combined modality treatment were associated with longer OS and may be considered for selected patients even at higher ages