Search

BACKGROUND Development in mechanical thrombectomy is progressing dramatically. Tumor embolism has been rarely reported on the basis of pathological study of the retrieved thrombus. Herein, the authors report a case of cerebral tumor embolism from advanced thyroid cancer, which was successfully treated with mechanical thrombectomy. OBSERVATIONS A 57-year-old man was diagnosed with thyroid cancer with multiple lung metastases and chemotherapy was planned. He experienced left hemiparesis and was bought to the emergency section of the authors’ hospital. Magnetic resonance angiography revealed right internal carotid artery occlusion and endovascular treatment was performed. Using a combination of aspiration catheter and stent retriever, white jelly-like embolus was retrieved. The pathological study demonstrated thyroid cancer embolism. Pulmonary vein invasion following lung metastasis of thyroid cancer was most presumably the cause of the tumor embolism. LESSONS Lung metastasis invading the pulmonary vein may be a cause of tumor embolism. Mechanical thrombectomy using a combination of stent retriever and aspiration catheter is effective in removing the tumor embolus and the pathological examination of the embolus is essential.

BACKGROUND AND HYPOTHESES SCD1, a major enzyme of saturated fatty acids, has been implicated to be important for tumor metabolic reprograming. Our previous study show that a high level of SCD1 mRNA is associated with IDH1mut lower grade gliomas. IDH1mut glioma cells are more sensitive to SFA induced apoptosis. However, the underlying mechanism remains unclear. In this study, we investigate the functions of SCD1 in IDHmut glioma and the potential contribution of SCD1 for cancer therapy of glioma. STUDY DESIGN AND METHODS The genetically engineered IDH wild-type, IDHmut and patient derived glioma cell lines were used to evaluate SCD1 functions. The expression of proteins were checked by Western-blotting assay. SCD1 was silenced by CRISPR or siRNA. The transcriptome change after SCD1 knockdown was profiled by RNA-seq or single cell RNA-seq (scRNA-seq). RESULTS AND CONCLUSIONS SCD1 transient silencing slowed down the cell growth, suggesting that SCD1 may possess an oncogenic property. RNA-seq analysis revealed that SCD1 inhibition decreased the expression of wnt-signaling pathway genes in IDH-1mut cells. scRNA confirmed that CRISPR SCD1 significantly decreased wnt signaling in the patient cell line Ts603. Therefore, we activated wnt pathway using a small chemical compound, BML-2838. Consistent with recent studies, wnt pathway induction led to a dramatically suppression of glioma cells growth. However, SCD1 silencing reversed this inhibitory effect. Further investigation revealed that SCD1 inhibition reduced the nucleus translocation of phosphorylated beta-catenin. Overall, the results suggest that SCD1 is vital for the onset of wnt pathway in glioma cells. High level of SCD1 expression may render the IDHmut glioma cells more sensitive to wnt pathway induced apoptosis. RELEVANCE AND IMPORTANCE In clinical, the 5-years survival rate of glioma remains low. SCD1 have been considered as a target for glioma therapy, recently. Our data provides a new insight on the strategy to target SCD1 in clinical.

This study aimed to determine the prevalence and risk factors for brain white matter changes in normal young and middle-aged participants who underwent Brain Dock (brain screening). We analyzed 5,000 consecutive healthy participants from the Brain Dock registry between August to December 2018. Age, sex, body mass index (BMI), medical history, deep subcortical white matter high intensity (DSWMH), periventricular high intensity (PVH), and enlargement of perivascular space (EPVS) were investigated in relation to age. The prevalence of DSWMH, PVH, and EPVS were 35.3%, 14.0%, and 17.8%, respectively. Multivariate logistic regression analyses for brain white matter changes were conducted. The significant risk factors in participants aged < 50 years were: age (OR:1.09, 95% CI:1.07-1.12), the female sex (1.29, 1.03-1.60), BMI obesity (1.86, 1.12-3.08), and hypertension (1.67, 1.18-2.35) for DSWMH; age (1.08, 1.04-1.13) and the female sex (1.56, 1.03-2.36) for PVH; and age (1.07, 1.05–1.10) and the female sex (0.77, 0.60-1.00) for EPVS. In conclusion, age was consistently identified as a significant risk factor in young and middle-aged participants. Some risk factors for brain white matter changes were identified even in young and middle-aged participants in this study. Further longitudinal studies should be done in the future.

Creation of a distal re-entry site is widely performed to treat subintimal hematoma. However, this method has a risk of further vessel damage. The present aspiration technique after sealing the entry site by stenting is more promising because the hematoma can be reduced without additional vessel damage. (Level of Difficulty: Advanced.), Graphical abstract

Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications., The understanding of altered lipid metabolism by isocitrate dehydrogenase 1 (IDH1) mutations in gliomas at a compartment-specific level is limited. Here, the authors use Raman spectroscopy to monitor organelle-specific metabolic changes and report that IDH1 mutations induce phospholipid imbalances which lead to ER and Golgi dilation.

Herpes simplex virus thymidine kinase (HSVTK)/ganciclovir (GCV) suicide gene therapy has a long history of treating malignant gliomas. Recently, stem cells from human exfoliated deciduous teeth (SHED), which are collected from deciduous teeth and have excellent harvestability, ethical aspects, and self-renewal, have been attracting attention mainly in the field of gene therapy. In the present study, we assessed SHED as a novel cellular vehicle for suicide gene therapy in malignant gliomas, as we have previously demonstrated with various cell types. SHED was transduced with the HSVTK gene (SHEDTK). In vitro experiments showed a significant bystander effect between SHEDTK and glioma cell lines in coculture. Furthermore, apoptotic changes caused by caspase 3/7 activation were simultaneously observed in SHEDTK and glioma cells. Mice implanted with a mixture of U87 and SHEDTK and treated with intraperitoneal GCV survived for longer than 100 days. Additionally, tumors in treatment model mice were significantly reduced in size during the treatment period. SHEDTK implanted at the contralateral hemisphere migrated toward the tumor crossing the corpus callosum. These results suggested that SHEDTK-based suicide gene therapy has potent tumor tropism and a bystander-killing effect, potentially offering a new promising therapeutic modality for malignant gliomas.

Introduction We investigated HSVTK/GCV suicide gene therapy for malignant glioma, and demonstrated the migration ability and antitumor effect of various tissue-derived pluripotent stem cells. In recent years, stem cells from human exfoliated deciduous teeth (SHED), which have excellent ethical and self-renewal ability, have attracted attention, especially in regenerative medicine. In this study, using SHEDTK transfected with TK, we examined the migration ability and antitumor effect against malignant glioma and metastasis models. Methods In vitro assay: Using Matrigel chamber, the migration ability of SHEDTK to conditioned medium (CM) of glioma cells, lung carcinoma cells, and various tumor growth factors (TGF) was examined. The antitumor effect was examined for cell viability by co-culturing SHEDTK and each tumor cell under the addition of GCV. in vivo assay: Using glioma model mice, SHEDTK migrating around the tumor was confirmed in brain sections. In addition, we co-implanted SHEDTK and administered GCV to glioma and metastasis model as therapeutic models, evaluated tumor reduction effect by bioluminescence, and confirmed survival curves. Results In vitro assay: SHEDTK significantly migrated to CM and TGF compared to control. The antitumor effect was observed even when the ratio of each tumor cell to SHEDTK was 128-256 times. in vivo assay: In glioma model mice, SHEDTK migrated around contralateral tumor. In the treatment experiment, the control group died of tumors, whereas the tumor in the treatment group disappeared within the period of GCV administration, and they survived without neurological deficits until 100 days later, and the overall survival time was improved with a statistically significant difference. Conclusions We confirmed the migration ability and antitumor effect of SHEDTK on malignant glioma and metastasis models. Suicide gene therapy using SHEDTK was suggested as novel gene therapy. In the future, we plan to conduct translational research such as preclinical studies and physician -initiated clinical trials.

BACKGROUND IDHwt gliomas exhibit sphingolipid rheostat balance that permits tumors to evade apoptosis by elevating the sphingosine-1-phosphate (S1P)-to-ceramide ratio. Overexpression of sphingosine kinase (SPHK) and consequent accumulation of S1P contribute to progression, chemoresistance, migration, and metastasis in malignant glioblastoma (GBM). We discovered that IDH1mut gliomas present a characteristic sphingolipid rheostat in which pro-apoptotic ceramides and sphingosines are elevated over oncopotent S1P. This characteristic involves inherent silencing of the SPHK2; obliging spheroids to rely on SPHK1 exclusively. We postulated that targeting this unique metabolic vulnerability would abrogate the growth-promoting and anti-apoptotic effects of S1P. METHODS IDH1mut glioma cell lines (TS603, BT142 & NCH1681) and empty vector-induced normal human astrocytes (NHAEV) were cultured and treated with a combination of SPHK1 inhibitor, N,N-dimethylsphingosine and C17-sphingosine to dysregulate sphingolipid rheostat. Biostatic response (i.e., IC50) was measured via spectrophotometric assay. Metabolic and signaling mechanisms were investigated by LC-MS lipidomic and RNA sequencing analysis. Mechanism of apoptosis was determined via western-blotting. RESULTS Following combination treatment, a global increase in ceramides, sphingosines, and their derivatives over S1P was detected in the sphingolipid rheostat. A decline in growth-promoting MAPK signaling enzymes and elevation of enzymes indicative of mitochondria-driven apoptosis occurred. Elevation of TNFα-related regulatory enzymes (NR1H3, MYLIP, INSIG, ABCA1) negatively impacted cholesterol homeostasis along with catalytic enzymes involved in cholesterol (and isoprenoid) biosynthesis. The effective concentration against IDH1mut spheroids was not cytotoxic to NHA spheroids. CONCLUSION The combination treatment potentiated a pro-apoptotic shift in sphingolipidome and revealed a novel mechanism of drug action involving concomitant global attenuation of cholesterol metabolism. While previous studies reported that decreasing cholesterol in gliomas compromises viability and induces apoptosis a link between cholesterol and sphingolipid metabolism remains unknown. Our data demonstrated that targeting sphingolipid rheostat triggers a cascade of pro-apoptotic signaling and metabolic activity that lower the threshold for apoptosis in IDHmut gliomas.

BACKGROUND Excess neurological stress by hemorrhagic stoke induces cardiomyopathy, namely takotsubo cardiomyopathy. Here, the authors report a case of takotsubo myopathy following mechanical thrombectomy for acute large vessel occlusion. OBSERVATIONS A 73-year-old man was emergently brought to the authors’ hospital because of left hemiparesis and consciousness disturbance. An ischemic lesion of the right cerebral hemisphere and the right internal carotid artery occlusion was revealed. Emergently, endovascular treatment was performed, and occlusion of the artery was reanalyzed. However, he suffered from hypotension with electrocardiogram abnormality. Subsequently, coronary angiography was performed, but the arteries were patent. The authors made a diagnosis of takotsubo cardiomyopathy. LESSONS Endovascular recanalization for large cerebral artery occlusion is so effective that it is becoming widely used. Even in the successful recanalization, we need to care for the takotsubo cardiomyopathy.

Visual Abstract, Highlights • KUS121 was developed to selectively inhibit the adenosine triphosphatase activity of valosin-containing protein without affecting other cellular functions of valosin-containing protein. • KUS121 preserved adenosine triphosphate levels, reduced endoplasmic reticulum stress, and suppressed cell death in H9C2 rat cardiomyoblast cells, treated with tunicamycin or hydrogen peroxide, or cultured in glucose-free medium. • In murine ischemia and reperfusion injury models, KUS121 treatment after reperfusion attenuated the infarcted size and preserves cardiac function by maintaining adenosine triphosphate levels and reducing ER stress. • In porcine ischemia and reperfusion injury models, intracoronary administration of KUS121 also attenuated the infarcted area in a dose-dependent manner. • These results indicated that KUS121 is a promising novel therapeutic agent for myocardial infarction., Summary No effective treatment is yet available to reduce infarct size and improve clinical outcomes after acute myocardial infarction by enhancing early reperfusion therapy using primary percutaneous coronary intervention. The study showed that Kyoto University Substance 121 (KUS121) reduced endoplasmic reticulum stress, maintained adenosine triphosphate levels, and ameliorated the infarct size in a murine cardiac ischemia and reperfusion injury model. The study confirmed the cardioprotective effect of KUS121 in a porcine ischemia and reperfusion injury model. These findings confirmed that KUS121 is a promising novel therapeutic agent for myocardial infarction in conjunction with primary percutaneous coronary intervention.

Patient: Male, 77 Final Diagnosis: Cerebral amyloid angiopathy Symptoms: Aphasia • hemiparesis Medication: — Clinical Procedure: Hematoma evacuation Specialty: Neurosurgery Objective: Unusual clinical course Background: Cerebral amyloid angiopathy (CAA) results from progressive deposition of amyloid-β in the walls of cortical and leptomeningeal vessels, leading to CAA-associated intracerebral hemorrhage (ICH). Hematoma expansion is a common early complication of spontaneous ICH, and is a strong independent predictor of poor outcome. However, there are limited reports of hematoma expansion related to CAA-associated ICH. Herein, we describe a novel case of hematoma expansion with a fluid-blood level in the cystic cavity of CAA-associated ICH. Case report: A 76-year-old male was initially diagnosed with probable CAA according to the modified Boston criteria, and presented with lobar ICH in the left frontal lobe 4 months later. Admission computed tomography scans showed an ICH including a high-density hematoma within a cystic cavity, revealing a clearly lower-density fluid component. Serial computed tomography scans showed no evidence of an expansion of the high-density clot, but obvious expansion of the fluid component containing a fluid-blood level. We recognized a bleeding site with no enhancement on preoperative magnetic resonance imaging. Left frontal craniotomy revealed a liquefied hematoma, which was removed by suction. We subsequently evacuated the blood clot extending into the left frontal sulcus, and confirmed and cauterized the bleeding site, leading to successful hemostasis. Conclusions: We report a CAA-associated ICH case showing hematoma expansion with a fluid-blood level. Intraparenchymal fluid-blood level suggests extravasation of blood into pre-existing cystic cavities because of hematoma lique-faction. Thus, fluid-blood levels are an important finding of hematoma expansion in acute CAA-associated ICH, and early treatment should be considered.

Objectives This study sought to compare the procedural outcomes of percutaneous coronary intervention for chronic total occlusion between the periods before and after introduction of 3-dimensional (3D) wiring. Background Previously, we reported a 3D wiring method by which the operator can construct real-time mental 3D images from 2 perpendicular angles of X-ray system monitor during percutaneous coronary intervention for chronic total occlusion. Methods A total of 137 chronic total occlusion lesions that could not be passed by tapered soft wires in our hospital between 2012 and 2017 were retrospectively enrolled in the study. Results Overall success rate was significantly higher in the 3D wiring group (n = 69) than the non-3D wiring group (n = 68) (98% vs. 90%, respectively; p = 0.027). In the primary antegrade cases, the first antegrade approach time was significantly shorter in the 3D wiring group than the non-3D wiring group (42 ± 29 vs. 30 ± 16 min, respectively; p = 0.01). In cases where the antegrade approach was continued throughout the procedure, the success rate was significantly higher in the 3D wiring group than the non-3D wiring group (100% vs. 89.2%, respectively; p = 0.033). Vessel perforation by the antegrade wire tended to be lower in the 3D wiring group than the non-3D wiring group (1% vs. 11%, respectively; p = 0.055). Conclusions 3D wiring enables accurate guidewire control, which improves the success rate of antegrade wiring and reduces the antegrade procedure time, resulting in improvement of the overall success rate.