Wataro Tsuruta

Application of liposomes incorporating doxorubicin with sialyl Lewis X to prevent stenosis after rat carotid artery injury

Restenosis remains a serious complication that can occur after angioplasty. This study investigated the efficiency of an active targeting chemotherapy using liposomes, including doxorubicin, whose surface was decorated with sialyl Lewis X (SLX) (Dox-Lipo-SLX) to prevent stenosis after angioplasty. Its delivery was controlled via the affinity between SLX and E-selectin proteins, which are expressed on vessel walls with injury. In vitro experiments confirmed the accumulation of doxorubicin as a consequence of Dox-Lipo-SLX adhering to E-selectin-positive cells. Significant doxorubicin accumulation was observed on injured vessel walls in rats treated with Dox-Lipo-SLX. In contrast, there was little accumulation using free doxorubicin or a liposome containing doxorubicin (Dox-Lipo), but without SLX. Rats were assigned to one of four groups: Dox-Lipo-SLX, Dox-Lipo, free doxorubicin, or no treatment. Dox-Lipo-SLX, Dox-Lipo, and free doxorubicin, including a dose of 0.08mg/kg doxorubicin, were intravenously administered three times in each group after angioplasty. The residual lumen area of rats in the group treated with Dox-Lipo-SLX was significantly larger than those in all other groups. These results demonstrate that an active targeting drug delivery system utilizing Dox-Lipo-SLX effectively prevents stenosis after angioplasty.

Photodynamic Diagnosis Using 5-Aminolevulinic Acid in 41 Biopsies for Primary Central Nervous System Lymphoma

We evaluated the feasibility of 5‐aminolevulinic acid (5‐ALA)‐mediated photodynamic diagnosis (PDD) in the biopsy for primary central nervous system lymphoma (PCNSL). 5‐ALA (20 mg kg−1) was administered orally 4 hours preoperatively. Forty‐one biopsies obtained under PDD in 47 consecutive biopsies (46 patients) that were finally pathologically diagnosed as PCNSL were evaluated. Positive fluorescence was observed in 34 of those 41 biopsies (82.9%). An intraoperative pathological diagnosis (IOD) of suspected PCNSL was made in 21 of the biopsies with positive fluorescence (61.8%). However, the eight IODs in the remaining 13 biopsies (23.5%) were not correct (atypical cell, 4; high‐grade glioma, 1; gliosis, 1; unremarkable, 2). In those 8 biopsies, PCNSL was confirmed by the final pathological diagnosis. There was no difference in the mean Mib‐1 labeling index between the biopsies with positive fluorescence (86.5%) and those without positive fluorescence (90.0%). IOD was not performed in 6 biopsies; however, 5 of those biopsies (83.3%) showed positive fluorescence and were finally pathologically diagnosed as PCNSL. Use of PDD in biopsies for patients with suspected PCNSL is a reliable way of obtaining specimens of adequate quality for the final pathological diagnosis and may lead to improved diagnostic yield in the biopsy of PCNSL.

Percutaneous transluminal angioplasty for atherosclerotic stenoses of intracranial vessels.

To study the efficacy and long-term outcome of percutaneous transluminal angioplasty (PTA) with/without stent placement for intracranial atherosclerotic stenoses, we reviewed our treated cases retrospectively. Between May 1992 and October 2003, PTA with/without stents was performed in 64 intracranial and skull base vessels in 62 patients, including 24 middle cerebral arteries, 16 internal carotid arteries, 13 vertebral arteries, and 11 basilar arteries. PTA was technically successful in 55 vessels (86%). However, four vessels (6%) failed to achieve satisfactory dilatation. We encountered five periprocedural strokes as symptomatic complications, for a mortality rate of 4.7% and a morbidity rate of 3.1%. All the patients with stent placements survived angioplasty without any complication. In the clinical follow-up available for one week to 11.5 years (mean, 4.7 years), there were three strokes related to the treated vessels. The annual stroke rate in the affected territory was estimated at 1.2% per year. According to these results, PTA for intracranial atherosclerotic stenoses seems to be a beneficial therapy for immediate anatomical results and long-term stroke prevention. Stent-assisted PTA could help patients achieve successful dilatation and avoid complications.

Cilostazol suppression of arterial intimal hyperplasia is associated with decreased expression of sialyl Lewis X homing receptors on mononuclear cells and E-selectin in endothelial cells

BACKGROUND An inflammatory reaction in vascular tissue is a potential factor linking restenosis after angioplasty. Although cilostazol, a selective phosphodiesterase type 3 inhibitor that is a unique antiplatelet drug and vasodilator, has been reported to be anti-inflammatory, its effect on the inflammatory action of mononuclear cells homing to endothelial cells is not clearly understood. In this study, whether cilostazol inhibits neointimal formation and improves inflammatory actions by inhibiting sialyl Lewis X (SLX) expression on mononuclear cells and E-selectin expression on endothelial cells was evaluated. METHODS The effect of cilostazol (1, 3, 10, 30 μM) on expression of E-selectin in human umbilical vein endothelial cells and SLX in rat mononuclear cells stimulated with lipopolysaccharide by immunofluorescence and real-time polymerase chain reaction (n = 3) was studied. Additionally, a double-balloon injury model was used on rat carotid arteries to evaluate vascular intimal hyperplasia. 0.1% cilostazol was administered 3 days before the first balloon injury, and the second balloon injury was performed 7 days after the first injury. Cilostazol administration was continued until rats were sacrificed 14 days after the second angioplasty. The expression of SLX on mononuclear cells and E-selectin on endothelial cells by immunofluorescence (n = 10) and real-time polymerase chain reaction (n = 5) were studied. RESULTS Cilostazol effectively inhibited the expression of SLX on mononuclear cells and E-selectin on endothelial cells. Cilostazol inhibited the migration of mononuclear cells in neointimal regions and neointimal hyperplasia after balloon injury. The numbers of macrophages and T-lymphocytes and the hyperplasia area in neointimal regions decreased from 71.06 ± 20.04, 1121 ± 244.4 cells per section, 206,400 ± 96,150 mm(2) to 29.65 ± 16.73, 374.2 ± 124.5 cells per section, and 101,900 ± 16,150 mm(2) due to the administration of cilostazol. CONCLUSIONS These results demonstrate that the protective effect of cilostazol against neointimal hyperplasia may be mediated by its anti-inflammatory actions of mononuclear cells homing to endothelial cells by decreasing SLX and E-selectin expression. CLINICAL RELEVANCE It is reported that cilostazol inhibits neointimal hyperplasia by decreasing the expression of some cell-adhesion molecules. We evaluated the effects of cilostazol for the expression of sialyl Lewis X (SLX) on mononuclear cells and E-selectin on endothelial cells, which interaction is the first step of inflammation action. Cilostazol was thought to show the anti-inflammatory actions by decreasing SLX and E-selectin expression in addition to decreasing the expression of some cell-adhesion molecules.

Combined use of sodium borocaptate and buthionine sulfoximine in boron neutron capture therapy enhanced tissue boron uptake and delayed tumor growth in a rat subcutaneous tumor model

We have previously reported that buthionine sulfoximine (BSO) enhances sodium borocaptate (BSH) uptake by down regulating glutathione (GSH) synthesis in cultured cells. This study investigated the influence of BSO on tissue BSH uptake in vivo and the efficacy of BSH-BSO-mediated boron neutron capture therapy (BNCT) on tumor growth using a Fisher-344 rat subcutaneous tumor model. With BSO supplementation, boron uptake in subcutaneous tumor, blood, skin, muscle, liver, and kidney was significantly enhanced and maintained for 12h. Tumor growth was significantly delayed by using BSO. With further improvement in experimental conditions, radiation exposure time, together with radiation damage to normal tissues, could be reduced.

Bioactive Coils Cause Headache and Fever After Endovascular Treatment of Intracranial Aneurysms

Background.— Based on our encounters with patients who have been treated for unruptured intracranial aneurysms by endovascular coil embolization using bioactive coils, we observed that such patients often present with headaches and fever.

Neurovascular Unit Protection From Cerebral Ischemia?Reperfusion Injury by Radical-Containing Nanoparticles in Mice

Background and Purpose— Reperfusion therapy by mechanical thrombectomy is used to treat acute ischemic stroke. However, reactive oxygen species generation after reperfusion therapy causes cerebral ischemia–reperfusion injury, which aggravates cerebral infarction. There is limited evidence for clinical efficacy in stroke for antioxidants. Here, we developed a novel core-shell type nanoparticle containing 4-amino-4-hydroxy-2,2,6,6-tetramethylpiperidine-1-oxyl (nitroxide radical-containing nanoparticles [RNPs]) and investigated its ability to scavenge reactive oxygen species and confer neuroprotection. Methods— C57BL/6J mice underwent transient middle cerebral artery occlusion and then received RNPs (9 mg/kg) through the common carotid artery. Infarction size, neurological scale, and blood-brain barrier damage were visualized by Evans blue extravasation 24 hours after reperfusion. RNP distribution was detected by rhodamine labeling. Blood-brain barrier damage, neuronal apoptosis, and oxidative neuronal cell damage were evaluated in ischemic brains. Multiple free radical-scavenging capacities were analyzed by an electron paramagnetic resonance–based method. Results— RNPs were detected in endothelial cells and around neuronal cells in the ischemic lesion. Infarction size, neurological scale, and Evans blue extravasation were significantly lower after RNP treatment. RNP treatment preserved the endothelium and endothelial tight junctions in the ischemic brain; neuronal apoptosis, O2− production, and gene oxidation were significantly suppressed. Reactive oxygen species scavenging capacities against OH, ROO, and O2− improved by RNP treatment. Conclusions— An intra-arterial RNP injection after cerebral ischemia–reperfusion injury reduced blood-brain barrier damage and infarction volume by improving multiple reactive oxygen species scavenging capacities. Therefore, RNPs can provide neurovascular unit protection.

Endovascular treatment of spinal vascular lesion in Japan: Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2.

A subgroup analysis of spinal vascular lesions in the Japanese Registry of Neuroendovascular Therapy (JR-NET) and JR-NET2, retrospective registry studies conducted in 2005–2009, was performed to understand the current status of treatment in Japan. Of 201 spinal lesions enrolled, 98 analyzable cases of spinal dural arteriovenous fistula (SDAVF), 43 of spinal perimedullary arteriovenous fistula (SPAVF), and 23 of spinal intramedullary arteriovenous malformation (SIAVM) were assessed. Treatment was radical in the majority (83.6%) of SDAVF, palliative in the majority (70.6%) of SIAVM, and radical and palliative in a similar number of cases of SPAVF. Total occlusion was achieved in 26 (54.2%) SDAVF cases, 9 (29.0%) SPAVF, and 4 (23.5%) SIAVM. Treatment-related complications occurred in 3 (3.1%) SDAVF cases, 7 (16.3%) SPAVF, and 1 (4.3%) SIAVM. Post-treatment neurological improvement was achieved in 49 (50.0%) of SDAVF cases, 15 (34.9%) SPAVF, and 5 (21.7%) SIAVM. The modified Rankin Scale (mRS) of 0, 1, or 2 on postoperative day 30, the primary endpoint, was achieved in 62 (63.3%) SDAVF cases, 26 (60.5%) SPAVF, and 12 (52.2%) SIAVM. The mRS of 0–2 on postoperative day 30 was correlated with pre-symptomatic mRS of 0–2 [P < 0.0001, odds ratio (OR): 42.88, 95% confidence interval (CI): 14.83–123.97] and postoperative neurological improvement (P = 0.046, OR: 2.57, 95% CI: 1.02–6.48). In Japan, endovascular treatment of spinal vascular lesions was administered safely. Good mRS on postoperative day 30 was highly correlated with good pre-symptomatic mRS, suggesting necessity of early diagnosis and treatment.

Anatomical risk factors for ischemic lesions associated with carotid artery stenting.

The purpose of this study was to investigate the anatomical risk factors for ischemic lesions detected by diffusion-weighted imaging (DWI) associated with carotid artery stenting (CAS). DWI was performed within four days after CAS in 50 stenotic lesions between January 2008 and September 2013. We retrospectively analyzed the correlation between the anatomical factors and ischemic lesions associated with CAS. Post-procedural DWI revealed new ischemic lesions after 24 (48%) of the 50 CAS procedures. All three patients with common carotid artery tortuosity, defined as the presence of severe angulation (less than 90 degrees) in the common carotid artery, developed new ischemic lesions. However, there were no significant differences between the patients with and without tortuosity, likely due to the small number of cases. Meanwhile, seven of eight patients with internal carotid artery tortuosity, defined as the presence of severe angulation (less than 90 degrees) in the cervical segment of the internal carotid artery, developed new ischemic lesions. A multivariate analysis showed internal carotid artery tortuosity (odds ratio: 11.84, 95% confidence interval: 1.193–117.4, P= 0.035) to be an independent risk factor for the development of ischemic lesions associated with CAS. Anatomical factors, particularly severe angulation of the internal carotid artery, have an impact on the risk of CAS. The indications for CAS should be carefully evaluated in patients with these factors.

A useful side-hole on a guiding catheter for transvenous embolization of a transverse-sigmoid sinus dural arteriovenous fistula.

OBJECTIVE To report the usefulness of a side-hole on a guiding catheter for transvenous embolization of transverse-sigmoid sinus (TSS) dural arteriovenous fistulae (DAVF) by a contralateral approach with a reversed Y-shaped confluence. CLINICAL PRESENTATION A 66-year-old woman presented after an epileptic seizure. Magnetic resonance imaging revealed venous infarctions of the left temporal area. Angiography showed a DAVF in the left TSS with retrograde drainage toward the superior sagittal sinus and remarkable cortical reflux. INTERVENTION A transvenous approach through the right jugular vein was attempted after failure of the approach through the angiographically invisible left jugular vein. Catheterization beyond the confluence failed because the shape of the confluence was a reversed Y. A 5-French catheter with a side-hole was then placed in the superior sagittal sinus from the right TSS, and the microcatheter was successfully navigated into the left TSS through the side-hole. Subsequently, the DAVF was completely occluded by transvenous embolization without any adverse events. CONCLUSION A side-hole on a guiding catheter was found to be useful for the navigation of a microcatheter to override a reversed Y-shaped confluence in transvenous embolization of TSS DAVF. This technique could be applicable to difficult configurations for transvenous catheterization, although attention should be paid to disruption of the catheter.