Explore the vast range of titles available.

The microvasculature and immune cells are major components of the tumor microenvironment (TME). Hypoxia plays a pivotal role in the TME through hypoxia-inducible factor 1-alpha (HIF-1α) which upregulates vascular endothelial growth factor (VEGF). VEGF, an angiogenesis stimulator, suppresses tumor immunity by inhibiting the maturation of dendritic cells, and induces immunosuppressive cells such as regulatory T cells, tumor-associated macrophages, and myeloid-derived suppressor cells. HIF-1α directly induces immune checkpoint molecules. VEGF/VEGF receptor (VEGFR)-targeted therapy as a cancer treatment has not only anti-angiogenic effects, but also immune-supportive effects. Anti-angiogenic therapy has the potential to change the immunological “cold tumors” into the “hot tumors”. Glioblastoma (GB) is a hypervascular tumor with high VEGF expression which leads to development of an immuno suppressive TME. Therefore, in the last decade, several combination immunotherapies with anti-angiogenic agents have been developed for numerous tumors including GBs. In particular, combination therapy with an immune checkpoint inhibitor and VEGF/VEGFR-targeted therapy has been suggested as a synergic treatment strategy that may show favorable changes in the TME. In this article, we discuss the cross talk among immunosuppressive cells exposed to VEGF in the hypoxic TME of GBs. Current efficient combination strategies using VEGF/VEGFR-targeted therapy are reviewed and proposed as novel cancer treatments.

Macrophages are significant in immune responses, assuming a defensive role. In contrast, macrophages often cause undesirable changes. These reactions are processes by which macrophages express different functional programs in response to microenvironmental signals, defined as M1/M2 polarization. Tumor immunity has been acknowledged for contributing to the elucidation of the mechanism and clinical application in cancer therapy. One of the mechanisms for the refractoriness to cancer immunotherapy is the production of inhibitory cytokines by tumor cells or macrophages. Therefore, therapeutic strategy targeting macrophage or macrophage-derived cytokines may be effective and attractive. This review aims to investigate macrophage-associated pathophysiology and biological behavior in cancers, especially related to microenvironment, such as hypoxia, and current topics regarding some therapies involving macrophages.

Although vascular endothelial growth factor (VEGF) promotes the immunosuppressive microenvironment, the efficacy of bevacizumab (Bev) on tumor immunity has not been fully investigated. The present study used 47 glioblastoma tissues obtained at 3 different settings: tumors of initial resection (naïve Bev group), tumors resected following Bev therapy (effective Bev group), and recurrent tumors after Bev therapy (refractory Bev group). The paired samples of the initial and post‐Bev recurrent tumors from 9 patients were included. The expression of programmed cell death‐1 (PD‐1)/PD ligand‐1 (PD‐L1), CD3, CD8, Foxp3, and CD163 was analyzed by immunohistochemistry. The PD‐L1+ tumor cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The PD‐1+ cells significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (P < .01 for each). The amount of CD3+ and CD8+ T cell infiltration increased in the refractory Bev group compared with the naïve Bev group (CD3, P < .01; CD8, P = .06). Both Foxp3+ regulatory T cells and CD163+ tumor‐associated macrophages significantly decreased in the effective or refractory Bev group compared with the naïve Bev group (Foxp3, P < .01 for each; CD163, P < .01 for each). These findings were largely confirmed by comparing paired initial and post‐Bev recurrent tumors. Bevacizumab restores the immunosupportive tumor microenvironment in glioblastomas, and this effect persists during long‐term Bev therapy. The present study showed, using human glioblastoma specimens resected at 3 different settings, that bevacizumab (Bev) downregulates the expression of programmed cell death‐1 and programmed cell death ligand‐1 immune checkpoint molecules, reduces immunosuppressing regulatory T cells, and tumor‐associated macrophages, and possibly increases the infiltration of cytotoxic T cells. Most of those changes began immediately after the initial Bev treatment and persisted during long‐term Bev therapy. Although vascular endothelial growth factor promotes immunosuppressive microenvironment, this study is the first to elucidate the overall picture of the key molecules/cells in tumor immunity regarding antiangiogenic therapy in actual human specimens. These findings suggest that the immune microenvironment under Bev therapy is persistently favorable, and novel strategies with the combination of Bev and some certain cancer immunotherapies appear to be reasonable treatment.

Vascular endothelial growth factor (VEGF) is an attractive target of antiangiogenic therapy in glioblastomas. Bevacizumab (Bev), a humanized anti-VEGF antibody, is associated with the improvement of progression-free survival and performance status in patients with glioblastoma. However, randomized trials uniformly suggest that these favorable clinical effects of Bev do not translate into an overall survival benefit. The mechanisms of action of Bev appear to include the inhibition of tumor angiogenesis, as well as indirect effects such as the depletion of niches for glioma stem cells and stimulation of antitumor immunity. Although several molecules/pathways have been reported to mediate adaptation and resistance to Bev, including the activation of alternative pro-angiogenic pathways, the resistance mechanisms have not been fully elucidated; for example, the mechanism that reinduces tumor hypoxia remains unclarified. The identification of imaging characteristics or biomarkers predicting the response to Bev, as well as the better understanding of the mechanisms of action and resistance, is crucial to improve the overall clinical outcome and optimize individual therapy. In this article, the authors review the results of important clinical trials/studies, the current understanding of the mechanisms of action and resistance, and the knowledge of imaging characteristics and biomarkers predicting the response to Bev.

Glioblastoma (GBM) involves disruptions in the blood–brain barrier (BBB) and alterations in the immune microenvironment, including the activation of glioma‐associated macrophages (GAMs). Vascular endothelial growth factor inhibitors, commonly used in recurrent GBM treatment, can influence these processes. This study investigates the relationship between BBB disruption and GAM activation, focusing on plasmalemma vesicle‐associated protein (PLVAP), a marker of BBB disruption, and α1‐acid glycoprotein (AGP), an inflammatory protein implicated in tumor progression. PLVAP expression was analyzed by immunohistochemistry (IHC) in human GBM samples to determine correlations with tumor grade, proliferation, and GAM activation. Pre‐ and post‐bevacizumab treatment GBM samples were compared to assess changes in BBB integrity and macrophage activity. AGP's role in GAM activation was studied through in vitro assays and glioma implantation in AGP knockout mice, with assessments of tumor growth and angiogenesis. Results showed elevated PLVAP expression in higher‐grade gliomas, correlating with increased tumor proliferation and GAM activation, particularly around PLVAP‐positive vessels. Bevacizumab treatment reduced PLVAP expression and macrophage activity. AGP localized to regions of BBB disruption, promoting macrophage‐mediated tumor growth in vitro. AGP knockout mice demonstrated reduced angiogenesis and prolonged survival. Spatial analysis revealed increased expression of macrophage‐inducing molecules near PLVAP‐positive vessels. These findings suggest PLVAP as a marker of BBB disruption and glioma malignancy. AGP, associated with BBB leakage, contributes to GAM activation and tumor progression, highlighting its potential as a therapeutic target for GBM. Plasmalemma vesicle‐associated protein (PLVAP) is a marker of BBB disruption and correlates with GBM malignancy and tumor progression. Bevacizumab treatment potentially suppressed protumor activation of macrophages and improve the GBM microenvironment. AGP leakage was shown in BBB disrupted area, and potentially induced protumor activation of macrophages which were associated to tumor growth and angiogenesis.

Glioblastoma multiforme (GBM) acquires resistance to bevacizumab (Bev) treatment. Bev affects angiogenic factors other than vascular endothelial growth factor (VEGF), which are poorly understood. We investigated changes in angiogenic factors under and after Bev therapy, including angiopoietin-1 (ANGPT1), angiopoietin-2 (ANGPT2), placental growth factor (PLGF), fibroblast growth factor 2, and ephrin A2 (EphA2). Fifty-four GBM tissues, including 28 specimens from 14 cases as paired specimens from the same patient obtained in three settings: initial tumor resection (naïve Bev), tumors resected following Bev therapy (effective Bev), and recurrent tumors after Bev therapy (refractory Bev). Immunohistochemistry assessed their expressions in tumor vessels and its correlation with recurrent MRI patterns. PLGF expression was higher in the effective Bev group than in the naïve Bev group ( p  = 0.024) and remained high in the refractory Bev group. ANGPT2 and EphA2 expressions were higher in the refractory Bev group than in the naïve Bev group ( p  = 0.047 and 0.028, respectively). PLGF expression was higher in the refractory Bev group compared with the naïve Bev group for paired specimens ( p  = 0.036). PLGF was more abundant in T2 diffuse/circumscribe patterns ( p  = 0.046). This is the first study to evaluate angiogenic factors other than VEGF during effective and refractory Bev therapy in patient-derived specimens.

The role of mental stress in intracranial aneurysm rupture remains unclear. Serum anti–SITH-1 antibody titers have been proposed as a potential biomarker of chronic mental stress. This study investigated the association between serum anti–SITH-1 antibody titers and intracranial aneurysm rupture. Between June 2021 and September 2023, patients with ruptured intracranial aneurysms (RIAs), patients with unruptured intracranial aneurysms (UIAs), and healthy controls were prospectively enrolled from five institutions. Baseline characteristics, aneurysm morphology, and lifestyle factors were recorded. Serum anti–SITH-1 antibody titers were quantified using a fluorescent antibody technique. Blood samples were obtained once in each participant: within 1 month after enrollment in the UIA and Control groups, and within 24 h of subarachnoid hemorrhage onset in the RIA group. The primary outcome was the association between serum anti–SITH-1 antibody titer and aneurysm rupture. Eighty-five participants were registered; after exclusions, 24 patients with RIAs were included for analysis, along with 26 patients with UIAs and 23 controls. Baseline characteristics were generally comparable, except for higher statin use in the UIA group (p = 0.012). Larger aneurysm size (p < 0.001), the presence of aneurysmal blebs (p < 0.001), and distinct aneurysm locations (p = 0.001) were more frequent in the RIA group. Anti–SITH-1 antibody titers differed significantly among groups (p = 0.008), being highest in the UIA group, followed by the RIA and Control groups. In the UIA group, antibody titers showed a significant positive correlation with time from diagnosis to study enrollment (p = 0.028). Anti–SITH-1 antibody titers, used as a marker of mental stress, were significantly higher in patients with UIAs than in those with RIAs or in healthy controls. These findings suggest that chronic mental stress is unlikely to play a critical role in aneurysm rupture but may be more prominent in individuals diagnosed with UIAs.

Thromboembolism is the most frequent complication of coil embolisation for intracranial aneurysm. Complications of thromboembolism can lead to stroke and have a serious impact on sequelae and mortality, necessitating appropriate rescue therapy. Here, we succeeded in recanalisation of an occluded stent by balloon-assisted local infusion of a thrombolytic agent following stent-assisted coil embolisation of an unruptured posterior communicating artery aneurysm. This method involves inflating a microballoon just distal to the occluded vessel and then administering a thrombolytic agent through a microcatheter. This technique may increase the rate of vessel reopening by maximising the local drug concentration. This method can be applied to any type of thrombolytic agent and helps reduce the dose of systemic drugs, which might decrease the incidence of haemorrhagic complications. Balloon-assisted intra-arterial thrombolytic infusion for an occluded vessel during endovascular coil embolisation could offer an alternative rescue therapy when conventional thrombolytic agent administration fails to improve thromboembolism.

Background/Objectives: Immune checkpoint inhibitors (ICIs) have improved outcomes in advanced lung cancer, but their real-world impact on patients with brain metastases remains insufficiently characterized. This study aimed to compare treatment outcomes before and after the introduction of ICIs and to identify prognostic factors in patients with lung cancer brain metastases. Methods: We retrospectively analyzed 186 patients treated for brain metastases from lung cancer at our institution between 2014 and 2023. Patients were classified into a Pre-ICI group (N = 93, 2014–2018) and a Post-ICI group (N = 93, 2019–2023). Overall survival (OS) was analyzed by Kaplan–Meier method and Cox regression. Baseline factors included age, sex, histology, Charlson–Deyo score, extracranial metastases, radiotherapy, systemic therapy, and neutrophil-to-lymphocyte ratio (NLR, cutoff = 4). Results: Median OS improved significantly in the Post-ICI group compared with the Pre-ICI group (10.9 vs. 4.7 months, p < 0.01). When stratified by systemic therapy, median OS was 4.7 months with conventional chemotherapy, 14.7 months with molecular targeted therapy overall, further prolonged to 25.5 months in the Post-ICI era, and 23.4 months for all patients receiving ICIs. The most notable benefits were observed in patients with squamous cell carcinoma and small cell carcinoma. Patients with NLR ≥ 4 showed shorter OS, but NLR did not remain significant in multivariate analysis. In EGFR-mutant adenocarcinoma, the survival benefit from ICIs was limited. Conclusions: ICIs significantly improved survival in patients with lung cancer brain metastases, particularly those with squamous cell carcinoma or small cell carcinoma. NLR may provide supportive prognostic information, while molecular targeted therapy and ICIs represent major drivers of improved survival in this population.