The oncolytic features of several naturally oncolytic viruses have been shown on Glioblastoma Multiforme cell lines and in xenotransplant models. However, orthotopic glioma studies in immunocompetent animals are lacking. Here we investigated Newcastle disease virus (NDV) in the orthotopic, syngeneic murine GL261 model. Seven days after tumor induction, mice received NDV intratumorally. Treatment significantly prolonged median survival and 50% of animals showed long‐term survival. We demonstrated immunogenic cell death (ICD) induction in GL261 cells after NDV infection, comprising calreticulin surface exposure, release of HMGB1 and increased PMEL17 cancer antigen expression. Uniquely, we found absence of secreted ATP. NDV‐induced ICD occurred independently of caspase signaling and was blocked by Necrostatin‐1, suggesting the contribution of necroptosis. Autophagy induction following NDV infection of GL261 cells was demonstrated as well. In vivo, elevated infiltration of IFN‐γ⁺ T cells was observed in NDV‐treated tumors, along with reduced accumulation of myeloid derived suppressor cells. The importance of a functional adaptive immune system in this paradigm was demonstrated in immunodeficient Rag2^−/− mice and in CD8⁺ T cell depleted animals, where NDV slightly prolonged survival, but failed to induce long‐term cure. Secondary tumor induction with GL261 cells or LLC cells in mice surviving long‐term after NDV treatment, demonstrated the induction of a long‐term, tumor‐specific immunological memory response by ND virotherapy. For the first time, we describe the therapeutic activity of NDV against GL261 tumors, evidenced in an orthotopic mouse model. The therapeutic effect relies on the induction of ICD in the tumor cells, which primes adaptive antitumor immunity.

Glioblastoma (GBM) is the most common and aggressive primary brain tumor. Despite recent advances in therapy modalities, the overall survival of GBM patients remains poor. GBM diagnosis relies on neuroimaging techniques. However, confirmation via histopathological and molecular analysis is necessary. Given the intrinsic limitations of such techniques, liquid biopsy (mainly via blood samples) emerged as a non-invasive and easy-to-implement alternative that could aid in both the diagnosis and the follow-up of GBM patients. Cancer cells release tumoral content into the bloodstream, such as circulating tumor DNA, circulating microRNAs, circulating tumor cells, extracellular vesicles, or circulating nucleosomes: all these could serve as a marker of GBM. In this narrative review, we discuss the current knowledge, the advantages, and the disadvantages of each circulating biomarker so far proposed.

Cancer immunotherapy is currently the hottest topic in the oncology field, owing predominantly to the discovery of immune checkpoint blockers. These promising antibodies and their attractive combinatorial features have initiated the revival of other effective immunotherapies like dendritic cell (DC) vaccinations. Although DC-based immunotherapy can induce objective clinical and immunological responses in several tumor types, the immunogenic potential of this monotherapy is still considered suboptimal. Hence, focus should be directed on potentiating its immunogenicity by making step-by-step protocol innovations to obtain next-generation Th1-driving DC vaccines. We review some of the latest developments in the DC vaccination field, with a special emphasis on strategies that are applied to obtain a highly immunogenic tumor cell cargo to load and to activate the DCs. To this end, we discuss the effects of three immunogenic treatment modalities (ultraviolet light, oxidizing treatments and heat shock) and five potent inducers of immunogenic cell death (radiotherapy, shikonin, high-hydrostatic pressure, oncolytic viruses and (hypericin-based) photodynamic therapy) on DC biology and their application in DC-based immunotherapy in preclinical as well as clinical settings.

BACKGROUND: Although digital subtraction angiography (DSA) may be considered the gold standard for intraoperative vascular imaging, many neurosurgical centers rely only on indocyanine green videoangiography (ICG-VA) for the evaluation of clipping accuracy. Many studies have compared the results of ICG-VA with those of intraoperative DSA; however, a systematic review summarizing these results is still lacking.OBJECTIVE: To analyze the literature in order to evaluate ICG-VA accuracy in the identification of aneurysm remnants and vessel stenosis after aneurysm clipping.METHODS: We performed a systematic literature review of ICG-VA accuracy during aneurysm clipping as compared to microscopic visual observation (primary endpoint 1) and DSA (primary endpoint 2). Quality of studies was assessed with the QUADAS-2 tool. Meta-analysis was performed using a random effects model.RESULTS: The initial PubMed search resulted in 2871 records from January 2003 to April 2016; of these, 20 articles were eligible for primary endpoint 1 and 11 for primary endpoint 2. The rate of mis-clippings that eluded microscopic visual observation and were identified at ICG-VA was 6.1% (95% CI: 4.2-8.2), and the rate of mis-clippings that eluded ICG-VA and were identified at DSA was 4.5% (95% CI: 1.8-8.3).CONCLUSION: Because a proportion of mis-clippings cannot be identified with ICG-VA, this technique should still be considered complementary rather than a replacement to DSA during aneurysm surgery. Incorporating other intraoperative tools, such as flowmetry or electrophysiological monitoring, can obviate the need for intraoperative DSA for the identification of vessel stenosis. Nevertheless, DSA likely remains the best tool for the detection of aneurysm remnants.

Cerebral collaterals are dynamically recruited after arterial occlusion and highly affect tissue outcome in acute ischemic stroke. We investigated the efficacy and safety of four pathophysiologically distinct strategies for acute modulation of collateral flow (collateral therapeutics) in the rat stroke model of transient middle cerebral artery (MCA) occlusion. A composed randomization design was used to assign rats (n = 118) to receive phenylephrine (induced hypertension), polygeline (intravascular volume load), acetazolamide (cerebral arteriolar vasodilation), head down tilt (HDT) 15° (cerebral blood flow diversion), or no treatment, starting 30 min after MCA occlusion. Compared to untreated animals, treatment with collateral therapeutics was associated with lower infarct volumes (62% relative mean difference; 51.57 mm³ absolute mean difference; p < 0.001) and higher chance of good functional outcome (OR 4.58, p < 0.001). Collateral therapeutics acutely increased cerebral perfusion in the medial (+40.8%; p < 0.001) and lateral (+19.2%; p = 0.016) MCA territory compared to pretreatment during MCA occlusion. Safety indicators were treatment-related mortality and cardiorespiratory effects. The highest efficacy and safety profile was observed for HDT. Our findings suggest that acute modulation of cerebral collaterals is feasible and provides a tissue-saving effect in the hyperacute phase of ischemic stroke prior to recanalization therapy.

Glioblastoma (GBM) is the most aggressive intrinsic brain tumor in adults. Despite maximal therapy consisting of surgery and radio/chemotherapy, GBM remains largely incurable with a median survival of less than 15 months. GBM has a strong immunosuppressive nature with a multitude of tumor and microenvironment (TME) derived factors that prohibit an effective immune response. To date, all clinical trials failed to provide lasting clinical efficacy, despite the relatively high success rates of preclinical studies to show effectivity of immunotherapy. Various factors may explain this discrepancy, including the inability of a single mouse model to fully recapitulate the complexity and heterogeneity of GBM. It is therefore critical to understand the features and limitations of each model, which should probably be combined to grab the full spectrum of the disease. In this review, we summarize the available knowledge concerning immune composition, stem cell characteristics and response to standard-of-care and immunotherapeutics for the most commonly available immunocompetent mouse models of GBM.