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.
The authors reviewed the clinical role of computational fluid dynamics (CFD) in assessing the risk of intracranial aneurysm rupture.
A literature review was performed to identify reports on CFD ...assessment of aneurysms using PubMed. The usefulness of various hemodynamic parameters, such as wall shear stress (WSS) and the Oscillatory Shear Index (OSI), and their role in aneurysm rupture risk analysis, were analyzed.
The authors identified a total of 258 published articles evaluating rupture risk, growth, and endovascular device assessment. Of these 258 articles, 113 matching for CFD and hemodynamic parameters that contribute to the risk of rupture (such as WSS and OSI) were identified. However, due to a lack of standardized methodology, controversy remains on each parameter's role.
Although controversy continues to exist on which risk factors contribute to predict aneurysm rupture, CFD can provide additional parameters to assess this rupture risk. This technology can contribute to clinical decision-making or evaluation of efficacy for endovascular methods and devices.
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.
This is a post hoc multivariate analysis of the modified World Federation of Neurosurgical Societies (WFNS) grading project, multicenter prospective observational study including 38 neurosurgical ...institutions across Japan. Japan Neurosurgical Society WFNS grading committee conducted a modified WFNS grading project as a nationwide prospective registry study. We investigate the clinical outcome of both surgical and endovascular interventions after aneurysmal subarachnoid hemorrhage (SAH) in Japan. A total of 792 patients received surgical intervention and 417 patients received endovascular treatment. Eight hundred patients were female, and 409 patients were male. The mean age was 61.5 ± 13.7 years. At 3 month follow-up, there was no statistically significant difference in good clinical outcome between surgical (68.2%) and endovascular (60.9%) group (odds ratio, 0.89; 95% confidence interval, 0.68-1.16; p = 0.381). Unfavorable outcome rate was 31.8% (238 patients) in the surgical group and 39.1% (154 patients) in the endovascular group. Male, elderly people, modified Rankin scale condition before onset, high-grade modified WFNS clinical grading scale, intracerebral hematoma, posttreatment normal pressure hydrocephalus, and neurological deficit due to symptomatic vasospasm were risk factors for the clinical outcome. Treatment modality was not a statistical factor for clinical outcomes. Surgical clipping has still a major role in the management of SAH in Japan. The present study was not a randomized controlled study, but clinical outcome is not influenced by treatment modalities.
Neurosurgery has tremendous possibilities for development of innovative medical devices. However, most of the neurosurgical devices used in Japan are imported products. Promotion and development of ...domestic medical devices is highly encouraged and it is one of the pillars of Prime Minister Shinzo Abe’s growth strategy of Japanese economy. Innovative “Made in Japan” medical devices can be developed by interdisciplinary collaboration between industries and academic institutions. Proper orientation of medical and engineering education, social and administrative awareness of the need of facilitating the medical devices creative process with corresponding regulatory changes, and appropriate medical and technological infrastructure establishment are needed for stimulating medical device innovation.
We evaluated several hemodynamic parameters for the prediction of rupture in a data set of initially unruptured aneurysms, including aneurysms that ruptured during follow-up observation.
Aneurysm ...geometry was extracted from CT angiographic images and analyzed using a mathematical formula for fluid flow under pulsatile blood flow conditions. Fifty side-wall internal carotid posterior communicating artery aneurysms and 50 middle cerebral artery bifurcation aneurysms of medium size were investigated for energy loss, pressure loss coefficient, wall shear stress, and oscillatory shear index. During follow-up observation, 6 internal carotid posterior communicating artery and 7 middle cerebral artery aneurysms ruptured (44 and 43 remained unruptured, respectively, with the same location and a similar size as the ruptured cases).
A significant difference in the minimum wall shear stress between aneurysms that ruptured and those that remained unruptured was noted only in internal carotid artery aneurysms (P<0.001). Energy loss showed a higher tendency in ruptured aneurysms but statistically not significant. For pressure loss coefficient, a significant difference was noted in both internal carotid artery (P=0.0046) and middle cerebral artery (P<0.001) aneurysms.
Pressure loss coefficient may be a potential parameter to predict future rupture of unruptured aneurysms.
To develop a risk score that estimates 3-year and 5-year absolute risks for aneurysm growth.
From 10 cohorts of patients with unruptured intracranial aneurysms and follow-up imaging, we pooled ...individual data on sex, population, age, hypertension, history of subarachnoid hemorrhage, and aneurysm location, size, aspect ratio, and shape but not on smoking during follow-up and family history of intracranial aneurysms in 1,507 patients with 1,909 unruptured intracranial aneurysms and used aneurysm growth as outcome. With aneurysm-based multivariable Cox regression analysis, we determined predictors for aneurysm growth, which were presented as a risk score to calculate 3-year and 5-year risks for aneurysm growth by risk factor status.
Aneurysm growth occurred in 257 patients (17%) and 267 aneurysms (14%) during 5,782 patient-years of follow-up. Predictors for aneurysm growth were earlier subarachnoid hemorrhage, location of the aneurysm, age >60 years, population, size of the aneurysm, and shape of the aneurysm (ELAPSS). The 3-year growth risk ranged from <5% to >42% and the 5-year growth risk from <9% to >60%, depending on the risk factor status.
The ELAPSS score consists of 6 easily retrievable predictors and can help physicians in decision making on the need for and timing of follow-up imaging in patients with unruptured intracranial aneurysms.
The precise mechanism underlying the conversion of normal prion protein (PrPC) into abnormal prion protein (PrPSc) remains unclear. Protein misfolding cyclic amplification (PMCA), an in vitro ...technique used for amplifying PrPSc, results in PrPSc replication that preserves the strain-specific characteristics of the input PrPSc; thus, PMCA mimics the process of in vivo PrPSc replication. Previous work has demonstrated that in PMCA, nucleic acids are critical for PrPSc amplification, but little information has been reported on glycosaminoglycan (GAG) participation in PrPSc replication in vitro. Here, we investigated whether GAGs play a role in the faithful replication of PrPSc by using a modified PMCA performed with baculovirus-derived recombinant PrP (Bac-PrP) as a substrate. The addition of heparan sulfate (HS) or its analog heparin (HP) restored the conversion efficiency in PMCA that was inhibited through nucleic acid depletion. Moreover, the PMCA products obtained under these conditions were infectious and preserved the properties of the input PrPSc. These data suggest that HS and HP play the same role as nucleic acids in facilitating faithful replication of prions in PMCA. Furthermore, we showed that HP binds to both Bac-PrP and Bac-PrPSc through the sulfated groups present on HP and that the N-terminal domain of Bac-PrPSc might potentially not be involved in the binding to HP. These results suggest that the interaction of GAGs such as HS and HP with PrPC and/or PrPSc through their sulfate groups is critical for the faithful replication of prions.
Background and objectives
Communication-type medical smartphone applications enable text, neuroimaging, photos, and videos to be shared securely among the stroke team. Our aim was to investigate ...whether use of a smartphone application would shorten the duration from admission to reperfusion therapy in patients with hyper-acute ischemic stroke.
Methods
Enrolled were acute ischemic stroke patients who underwent reperfusion therapy (intravenous tissue plasminogen activator (IV t-PA) and mechanical thrombectomy (MT)) at our hospital between October 2012 and September 2018. We divided the patients into two groups based on the date of availability on smartphones of communication-type medical application: (1) Control group, conventional communication prior to September 2015, and (2) App group, communication via the smartphone app from October 2015 onwards. We compared door-to-image time (DIT), image-to-needle time (INT), door-to-needle time (DNT) for thrombolysis, and DIT, image-to-puncture time (IPT), and door-to-puncture time (DTP) for thrombectomy between the groups.
Results
We retrospectively enrolled 139 patients (68% male; median age, 69 years; median NIHSS score, 7) who were assigned into the App group (
n
= 86) and Control group (
n
= 53). Of the overall patients, 109 underwent IV t-PA (IV t-PA alone, 79 patients), and 63 underwent MT (MT alone, 30 patients), and 33 patients underwent combined IV t-PA and MT. There was no significant difference in DIT between the App and Control groups (23 min vs. 22 min,
p
= 0.493). DNT, DPT, INT, and IPT were significantly shorter in the App group than in the Control group (DNT, 62 min for the App group vs. 72 min for Control group,
p
= 0.038; INT, 42 vs. 48 min,
p
= 0.009; DPT, 106 vs. 129 min,
p
= 0.046; IPT, 89 vs. 117 min,
p
= 0.004).
Conclusion
The present findings indicate that communication-type medical smartphone apps have potential for shortening the time elapsed between admission and reperfusion therapy, especially INT and IPT.
Objective Just before the Tokyo 2020 Olympic and Paralympic Games in Japan, the number of people infected with coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome ...coronavirus 2 (SARS-CoV-2), started to increase at an unprecedented rate. This study investigated the effectiveness of vaccines in large-scale sporting events under difficult circumstances, such as during adherence to a bubble system and confinement inside the Olympic/Paralympic Village. Methods In collaboration with medical clinics inside and outside the Village, a prospective cohort study was conducted among overseas participants using the results of polymerase chain reaction (PCR) tests for SARS-CoV-2 upon leaving Japan. Results A total of 12,072 foreign participants were enrolled, 13 (0.11%) of whom had a positive PCR test result. None of these cases were broadcasters or members of the press, were tested outside the Olympic Village, or had a history of COVID-19 infection. The effectiveness of full vaccination and vaccination at least once (≥14 days ago) was 74% (95% confidence interval CI: 6-93%) and 81% (95% CI: 30-95%), respectively. Three breakthrough infections with the Delta variant were observed in 6,485 fully vaccinated participants (0.05%). The positivity rate was 0.09% among adherents to the bubble system and 0.28% among non-adherents, but this difference was not significant. Conclusion These findings indicate that even huge sporting events such as the Olympic and Paralympic Games can proceed while pandemics are ongoing in the host country by combining countermeasures such as vaccination, frequent testing, social distancing, and adherence to a bubble system.
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