Publications by authors named "Hitoshi Hasegawa"

121 Publications

Usefulness of tissue inhibitor of metalloproteinase 1 as a predictor of sustained remission in patients with antineutrophil cytoplasmic antibody-associated vasculitis.

Arthritis Res Ther 2021 Mar 20;23(1):91. Epub 2021 Mar 20.

Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, 791-0295, Japan.

Background: We previously identified tissue inhibitor of metalloproteinase 1 (TIMP-1) as a biomarker of disease activity that distinguished mildly or highly active antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) from remission 6 months after the initiation of remission-induction therapy. In the present study, we investigated whether TIMP-1 is clinically useful as a predictor of relapse and sustained remission in AAV patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) during maintenance therapy.

Methods: The relationship between serum TIMP-1 levels and clinical outcomes in AAV patients receiving maintenance therapy was assessed using the follow-up data of a Japanese large-cohort study (the RemIT-JAV-RPGN study) and data collected from AAV patients on maintenance therapy in our hospital (the MAAV-EU study).

Results: In the RemIT-JAV RPGN study, serum levels of TIMP-1 were significantly higher in mildly active AAV patients with MPA and GPA 6 months after the initiation of remission-induction therapy than in patients in remission. Regarding maintenance therapy, elevated levels of TIMP-1 in patients in remission were associated with relapse and/or difficulty reducing the glucocorticoid dosage after 6 to 12 months. In the MAAV-EU study, serum levels of TIMP-1 were elevated in relapsed patients 6 months before relapse, earlier than the increase in serum levels of CRP. Analyses of both studies revealed that approximately 30% of patients in remission with a serum TIMP-1 level ≥ 150 ng/mL relapsed after 6 to 12 months, while the majority of patients with a TIMP-1 level < 150 ng/mL sustained remission for at least 12 months.

Conclusion: We herein demonstrated that TIMP-1 is more useful as a predictive biomarker of sustained remission than as a predictor of relapse in maintenance therapy for AAV. TIMP-1 levels < 150 ng/mL are important for the long-term maintenance of remission and may be an indicator for the tapering or cessation of treatment.
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http://dx.doi.org/10.1186/s13075-021-02471-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980538PMC
March 2021

Hemodynamic features of an intracranial aneurysm rupture predicted by perianeurysmal edema: A case report.

Surg Neurol Int 2021 10;12:49. Epub 2021 Feb 10.

Department of Neurosurgery, Niigata University, Brain Research Institute, Niigata, Japan.

Background: Perianeurysmal edema (PAE) has been suggested as an indicator of potential aneurysm rupture; however, the hemodynamic features of these aneurysms are still unknown. A computational fluid dynamic (CFD) analysis was performed to evaluate the hemodynamic features of a very rare case of a ruptured middle cerebral artery (MCA) aneurysm with PAE.

Case Description: A 65-year-old woman presented with disturbed consciousness. A subarachnoid hemorrhage due to an azygos anterior cerebral artery (ACA) aneurysm rupture was suspected. An unruptured MCA aneurysm with PAE was identified in the left temporal lobe. Although the ACA aneurysm was clipped to prevent re-bleeding, the MCA aneurysm subsequently ruptured 6 days later. Clipping of the MCA aneurysm was performed, and hemosiderin deposits suggestive of sentinel bleeding were found on the surface of the aneurysm dome. CFD analysis revealed unstable hemodynamic stress at the expanded bleb area after rupture, localized to the rupture site. Moreover, this analysis revealed flow impingement with pressure elevation and low wall shear stress, which indicated increased inflammation and aneurysm wall thinning that likely led to rupture.

Conclusion: Hemosiderin deposits at the aneurysm wall and PAE indicates leakage from a cerebral aneurysm. Hemodynamic stress at the aneurysm may promote an inflammatory response and lead to wall weakening accompanied by PAE. Based on our findings, we recommend that surgical intervention should be considered as the first line of treatment for such aneurysms to prevent rupture.
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http://dx.doi.org/10.25259/SNI_780_2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911146PMC
February 2021

Delayed Bleeding of Unruptured Intracranial Aneurysms After Coil Embolization: A Retrospective Case Series.

World Neurosurg 2021 Feb 20. Epub 2021 Feb 20.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Objective: Delayed bleeding of unruptured intracranial aneurysms (UIAs) after coil embolization is rare; this study aimed to analyze the occurrence of delayed bleeding of UIAs after coil embolization.

Methods: We retrospectively analyzed patients with UIAs after coil embolization between January 2002 and December 2018 and assessed the features of UIAs with delayed bleeding after coil embolization.

Results: Analysis included 307 patients with 335 UIAs. Mean follow-up was 7.1 ± 4.9 years, and total follow-up was 2365 aneurysm-years. There were 271 (80.9%) aneurysms located in the anterior circulation and 64 (19.1%) aneurysms located in the posterior circulation. Significant differences were observed between the 2 groups in terms of maximum size of the aneurysm (P < 0.01), width of the aneurysm neck (P < 0.01), and number of retreatment cases (P < 0.01). During the follow-up period, delayed bleeding occurred in 4 aneurysms (annual bleeding rate of 0.17%); all were located in the posterior circulation. The original size was not relatively large (mean 8.6 ± 2.4 mm). All aneurysms bled within 5 years (mean 35 ± 9.6 months) after the initial treatment. Two were de novo aneurysms that developed adjacent to the coiled aneurysms and were not detected on follow-up magnetic resonance angiography.

Conclusions: Cautious follow-up of UIAs with digital subtraction angiography is important, articularly within the first 5 years after the procedure. If there are changes in the anatomic outcomes, short-term reassessment or additional treatment should be actively considered, particularly for aneurysms in the posterior circulation.
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http://dx.doi.org/10.1016/j.wneu.2021.02.061DOI Listing
February 2021

Syngenetic rapid growth of ellipsoidal silica concretions with bitumen cores.

Sci Rep 2021 Feb 19;11(1):4230. Epub 2021 Feb 19.

Quintessa, Videcom House, Newtown Road, Henley-on-Thames, Oxfordshire, UK.

Isolated silica concretions in calcareous sediments have unique shapes and distinct sharp boundaries and are considered to form by diagenesis of biogenic siliceous grains. However, the details and rates of syngenetic formation of these spherical concretions are still not fully clear. Here we present a model for concretion growth by diffusion, with chemical buffering involving decomposition of organic matter leading to a pH change in the pore-water and preservation of residual bitumen cores in the concretions. The model is compatible with some pervasive silica precipitation. Based on the observed elemental distributions, C, N, S, bulk carbon isotope and carbon preference index (CPI) measurements of the silica-enriched concretions, bitumen cores and surrounding calcareous rocks, the rate of diffusive concretion growth during early diagenesis is shown using a diffusion-growth diagram. This approach reveals that ellipsoidal SiO concretions with a diameter of a few cm formed rapidly and the precipitated silica preserved the bitumen cores. Our work provides a generalized chemical buffering model involving organic matter that can explain the rapid syngenetic growth of other types of silica accumulation in calcareous sediments.
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http://dx.doi.org/10.1038/s41598-021-83651-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895967PMC
February 2021

Giant Cell Arteritis Presenting with Ptosis and Diplopia.

Intern Med 2021 Feb 15. Epub 2021 Feb 15.

Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Japan.

Giant cell arteritis (GCA) is vasculitis of large-sized vessels that can lead to vision loss. We herein report a rare case of GCA accompanied by ptosis and diplopia as early symptoms, which were caused by third nerve palsy. A 78-year-old male presented with fever, right temporal headache, right eyelid ptosis, and diplopia. GCA was confirmed by a temporal artery biopsy. The symptoms disappeared after a slight delay following the administration of prednisolone. Unlike vision loss, ptosis and diplopia are considered to be reversible and responsive to treatment. GCA should not be ruled out if patients exhibit these ophthalmic symptoms.
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http://dx.doi.org/10.2169/internalmedicine.6521-20DOI Listing
February 2021

Possibility of Worsening Flow Diversion Effect Due to Morphological Changes of a Stented Artery With Multiple Overlapping Stents for Partially Thrombosed Vertebral Artery Aneurysms.

Front Neurol 2020 15;11:611124. Epub 2020 Dec 15.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Morphological changes of a stented artery can cause a flow diversion effect to reduce intra-aneurysmal flow; however, there is a potential for the negative effect of increased intra-aneurysmal flow. We present cases with multiple overlapping stents for a partially thrombosed vertebral artery aneurysm and characterize the hemodynamic properties of a recurrent case by focusing on the morphological changes of the stented artery. Between October 2017 and April 2019, four consecutive cases of symptomatic unruptured large and giant partially thrombosed vertebral artery aneurysms were treated with multiple overlapping low-profile visualized intraluminal support stents and no coils. Both angiographic and clinical outcomes were assessed. Computational fluid dynamics analysis was performed to clarify hemodynamic features. The degree of pressure elevation was calculated as the pressure difference (Pd). Wall shear stress (WSS) was also calculated. In three of the four cases, successful flow reduction was achieved with no morphological change of the stented arteries. The patients' symptoms were gradually improved. The remaining case required additional stents after the initial treatment. In the recurrent case, Pd was noticeably elevated at the aneurysm neck after treatment, and WSS was generally increased in the area due to altered blood flow into the aneurysm dome caused by morphological changes of the stented artery. Overlapping stents can be used for the treatment of large and giant thrombosed vertebral artery aneurysms with flow diversion effect; however, morphological changes of the stented artery requires careful attention as it may lead to an increase in the intra-aneurysmal flow, causing negative outcomes.
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http://dx.doi.org/10.3389/fneur.2020.611124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770215PMC
December 2020

BAC-DROP: Rapid Digestion of Proteome Fractionated via Dissolvable Polyacrylamide Gel Electrophoresis and Its Application to Bottom-Up Proteomics Workflow.

J Proteome Res 2021 Mar 24;20(3):1535-1543. Epub 2020 Dec 24.

Division of Analytical Bio-Medicine, Advanced Research Support Center, Ehime University, Toon 790-8577, Ehime, Japan.

The GeLC-MS workflow, which combines low-cost, easy-to-use sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis (SDS-PAGE) with liquid chromatography-mass spectrometry (LC-MS), is very popular in current bottom-up proteomics. However, GeLC-MS requires that PAGE-separated proteins undergo overnight enzymatic digestion in a gel, resulting in more than 20 h of sample preparation for LC-MS. In this study, we overcame the limitations of GeLC-MS by developing a rapid digestion workflow for PAGE separation of proteins using ,'-bis(acryloyl)cystamine (BAC) cross-linked gels that can be solubilized by reductive treatment. Making use of an established workflow called BAC-DROP (BAC-gel dissolution to digest PAGE-resolved objective proteins), crude proteome samples were fractionated based on molecular weight by BAC cross-linked PAGE. After fractionation, the gel fragments were reductively dissolved in under 5 min, and in-solution trypsin digestion of the protein released from the gel was completed in less than 1 h at 70 °C, equivalent to a 90-95% reduction in time compared to conventional in-gel trypsin digestion. The introduction of the BAC-DROP workflow to the MS assays for inflammatory biomarker CRP and viral marker HBsAg allowed for serum sample preparation to be completed in as little as 5 h, demonstrating successful marker quantification from a 0.5 μL sample of human serum.
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http://dx.doi.org/10.1021/acs.jproteome.0c00749DOI Listing
March 2021

Unilateral oculomotor nerve palsy caused by arterial compression accompanying subarachnoid hemorrhage: a case report.

Acta Neurochir (Wien) 2021 03 5;163(3):813-816. Epub 2020 Nov 5.

Department of Neurosurgery, Brain Research Institute, Niigata University, 1-757 Asahimachidori, Chuo-ku, Niigata, Niigata, 951-8585, Japan.

Unilateral oculomotor nerve palsy, often caused by aneurysmal compression, is one of the decisive findings for confirming the site of a ruptured aneurysm. However, arterial compression can also cause unilateral oculomotor nerve palsy. Here, we present the case of a 59-year-old woman with a ruptured right internal carotid-posterior communicating artery aneurysm accompanied by contralateral oculomotor nerve palsy. The nerve was found to be compressed by the posterior cerebral artery and was isolated from the ruptured aneurysm. When confirming a ruptured aneurysm based on the evidence of unilateral oculomotor palsy, the arteries surrounding the nerve must be thoroughly assessed.
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http://dx.doi.org/10.1007/s00701-020-04633-xDOI Listing
March 2021

Vascular endothelial growth factor (VEGF)-A and VEGF-Ab are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

Ann Clin Biochem 2021 03 22;58(2):86-94. Epub 2020 Nov 22.

Nagoya University, Nagoya, Japan.

Background: Effective prognostic markers are needed for antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study evaluated the clinical associations of serum vascular endothelial growth factor-A (sVEGF-A) and sVEGF-Ab (an antiangiogenic isoform of VEGF-A) concentrations with time to remission of AAV in a nationwide Japanese prospective follow-up cohort.

Methods: We collected samples from patients with AAV who were enrolled in the nationwide Japanese cohort study (RemIT-JAV-RPGN). We measured sVEGF-A and sVEGF-Ab concentrations using enzyme-linked immunosorbent assays in 57 serum samples collected 6 months before and after initiation of AAV treatment. Patients were classified based on AAV disease subtypes: microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis (EGPA).

Results: Results revealed significant reductions in sVEGF-A and sVEGF-Ab concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-Ab during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log-transformed concentrations of sVEGF-A and sVEGF-Ab were inversely correlated with time to remission in granulomatosis with polyangiitis patients.

Conclusion: These results suggest that sVEGF-A and -Ab can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.
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http://dx.doi.org/10.1177/0004563220968371DOI Listing
March 2021

Experiences of Negotiations for Improving Research Environment and Burnout among Young Physician Researchers in Japan.

Int J Environ Res Public Health 2020 07 20;17(14). Epub 2020 Jul 20.

Department of Public Health, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.

Physician scientists in Japan are often too busy to be sufficiently involved in research work. This cross-sectional study aimed to investigate their experiences negotiating with their superiors to improve their research environment and determine its relationship with psychological burnout. Among 1790 physician awardees of Grants-in-Aid for Young Scientists in 2014-2015, 490 responded (response rate 27.4%) and 408 were eligible for analysis. Outcome measures included two negotiation experiences: for reduction of clinical duty hours/promotion opportunities and for increased space or equipment/increased research budget. The main explanatory variables were personal, patient-related, and work-related burnout measured by the Copenhagen Burnout Inventory. The percentages of the above-mentioned two types of negotiations were 20-24% in women and 17-20% in men. Multivariable stepwise logistic regression analyses demonstrated that (1) the negotiation for reduction of clinical duty hours/promotion opportunities was significantly associated with physician scientists who had a short amount of weekly research time and high patient-related burnout score, and (2) the negotiation for increased space or equipment/increased research budget was significantly associated with older age, single status, and high personal and patient-related burnout scores. High burnout is related to negotiation experiences among physician researchers in Japan.
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http://dx.doi.org/10.3390/ijerph17145221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400125PMC
July 2020

Clinical impact of urinary CD11b and CD163 on the renal outcomes of anti-neutrophil cytoplasmic antibody-associated glomerulonephritis.

Nephrol Dial Transplant 2020 Jul 8. Epub 2020 Jul 8.

Nagoya University, Nagoya, Japan.

Background: The detection of leukocyte-derived CD11b (α subunit of integrin Mac-1) and CD163 (scavenger receptor) in urine may reflect renal inflammation in antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). The objective of this study was to evaluate the clinical significance of urinary CD11b (U-CD11b) and CD163 (U-CD163) in ANCA-GN.

Methods: U-CD11b and U-CD163 were examined using enzyme-linked immunosorbent assay in ANCA-GN urine samples from our institutional cohort (n = 88) and a nationwide cohort (n = 138), and their association with renal histology was subsequently analyzed. Logistic regression analyses were performed on a nationwide ANCA cohort to determine the associations of the two urinary molecules with renal remission failure at 6 months or with yearly estimated glomerular filtration rate (eGFR) slope over a 24-month observation period.

Results: U-CD11b and U-CD163 were significantly associated with cellular crescent formation and leukocyte accumulation in glomerular crescents. With regard to interstitial inflammation, both levels of U-CD11b and U-CD163 at diagnosis remarkably increased in ANCA-GN compared with the levels observed in nonglomerular kidney disorders including nephrosclerosis, immunoglobulin G4-related disease and tubulointerstitial nephritis; however, the presence of U-CD11b alone was significantly correlated with tubulointerstitial leukocyte infiltrates. Although neither U-CD11b nor U-CD163 at diagnosis was associated with remission failure at 6 months, multivariate analysis demonstrated that the baseline U-CD11b levels were significantly associated with the increase in eGFR following immunosuppressive therapy.

Conclusions: Although both U-CD11b and U-CD163 reflect renal leukocyte accumulation, U-CD11b at diagnosis provides additional clinical value by predicting the recovery rate after the treatment of ANCA-GN.
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http://dx.doi.org/10.1093/ndt/gfaa097DOI Listing
July 2020

[Endovascular Revascularization for Acute Ischemic Stroke Related to Blunt Carotid Injury:A Case Report].

No Shinkei Geka 2020 Jun;48(6):527-532

Department of Neurosurgery, Brain Research Institute, Niigata University.

Although blunt carotid artery injury is known as an important cause of ischemic stroke, the role of the endovascular treatment for acute ischemic stroke related to blunt carotid injuries remains unclear. We report the case of a patient with acute ischemic stroke secondary to blunt carotid artery injury who was treated with endovascular revascularization. A 46-year-old man suffered from sudden left-sided hemiparesis a day after a strike from a Japanese fencing staff on his right neck. 3D-CT angiography revealed tandem internal carotid artery occlusions of the cervical and C1 portions. We performed endovascular revascularization with carotid artery stenting and direct aspiration of the thrombus and achieved complete recanalization. The patient recovered almost completely. We conclude that endovascular revascularization should not be withheld from patients with acute ischemic stroke related to blunt carotid injury.
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http://dx.doi.org/10.11477/mf.1436204223DOI Listing
June 2020

PEPPI-MS: Polyacrylamide-Gel-Based Prefractionation for Analysis of Intact Proteoforms and Protein Complexes by Mass Spectrometry.

J Proteome Res 2020 09 11;19(9):3779-3791. Epub 2020 Jul 11.

Division of Analytical Bio-Medicine, Advanced Research Support Center, Ehime University, Toon 791-0295, Ehime, Japan.

Prefractionation of complex mixtures of proteins derived from biological samples is indispensable for proteome analysis via top-down mass spectrometry (MS). Polyacrylamide gel electrophoresis (PAGE), which enables high-resolution protein separation based on molecular size, is a widely used technique in biochemical experiments and has the potential to be useful in sample fractionation for top-down MS analysis. However, the lack of a means to efficiently recover the separated proteins in-gel has always been a barrier to its use in sample prefractionation. In this study, we present a novel experimental workflow, called Passively Eluting Proteins from Polyacrylamide gels as Intact species for MS ("PEPPI-MS"), which allows top-down MS of PAGE-separated proteins. The optimization of Coomassie brilliant blue staining followed by the passive extraction step in the PEPPI-MS workflow enabled the efficient recovery of proteins, separated on commercial precast gels, from a wide range of molecular weight regions in under 10 min. Two-dimensional separation combining offline PEPPI-MS with online reversed-phase liquid chromatographic separation resulted in identification of over 1000 proteoforms recovered from the target region of the gel (≤50 kDa). Given the widespread availability and relatively low cost of traditional sodium dodecyl sulfate (SDS)-PAGE equipment, the PEPPI-MS workflow will be a powerful prefractionation strategy for top-down proteomics.
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http://dx.doi.org/10.1021/acs.jproteome.0c00303DOI Listing
September 2020

[Dural arteriovenous fistula causing complex visual hallucinations without an anopsia].

Rinsho Shinkeigaku 2020 Jun 19;60(6):425-428. Epub 2020 May 19.

Department of Neurology, Brain Research Institute, Niigata University.

We report the case of a 76-year-old woman who presented with recurrent episodes of complex visual hallucinations in her right visual field without an anopsia. The electroencephalogram showed sharp transients in the left parietotemporal region with phase reversals at T5 and P3. FLAIR MRI revealed hyperintense lesions in the left temporo-occipital lobe, located mainly in the left inferior temporal lobe. Cerebral angiography revealed an arteriovenous shunt from the left occipital artery to the left transverse sinus with cortical venous reflux. The complex visual hallucinations were resolved after transarterial embolization. We therefore hypothesize that this patient's complex visual hallucinations were caused by epileptic seizures or changes in cortical blood flow caused by the cortical venous reflux from the arteriovenous fistula. In general, epileptic hallucinations expand into the bilateral visual field. We reveal that in rare cases, complex visual hallucinations can also be limited to the unilateral visual field without an anopsia. Additionally, we reveal that a dural arteriovenous fistula can cause visual hallucinations without hemianopia.
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http://dx.doi.org/10.5692/clinicalneurol.60.cn-001371DOI Listing
June 2020

Safety and feasibility of the distal transradial approach: A novel technique for diagnostic cerebral angiography.

Interv Neuroradiol 2020 Dec 13;26(6):713-718. Epub 2020 May 13.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Purpose: We aimed to evaluate the safety and feasibility of the distal transradial approach (DTRA) as a novel technique for cerebral angiography based on our institutional initial experience.

Methods: We retrospectively analyzed our institutional database of consecutive diagnostic cerebral angiographies performed with DTRA from December 2018 to August 2019. Patient demographics and clinical and procedural data were recorded.

Results: In total, 51 diagnostic cerebral angiographies in 51 patients (age, 15-83 years; mean age, 59.4 years, SD 13.5; 35 (69%) females) were performed or attempted with DTRA. Ultrasound evaluation showed that the mean inner distal radial artery diameter was significantly smaller than the mean inner forearm radial artery diameter (2.19 mm vs. 2.56 mm, P < 0.001). Cannulation via the distal radial artery was successful in 47 (92%) procedures. In the four procedures that failed, operators converted to the ipsilateral transradial approach without repositioning or redraping. Selective catheterization of the intended vessel was achieved in 64 (91%) of 70 vessels. In the remaining six, operators achieved the objective of the examination with angiography injecting from proximal and conversion to another approach was not required. One patient experienced temporary numbness around the puncture site after the procedure. No radial artery occlusion was identified in the patients who underwent ultrasound evaluation.

Conclusion: Our results demonstrate that DTRA could become a standard approach for diagnostic cerebral angiography owing to the low complication rate and the high cannulation success rate.
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http://dx.doi.org/10.1177/1591019920925709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724605PMC
December 2020

Associated factors of poor treatment outcomes in patients with giant cell arteritis: clinical implication of large vessel lesions.

Arthritis Res Ther 2020 04 7;22(1):72. Epub 2020 Apr 7.

Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Relapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA.

Methods: We enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model.

Results: Cranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52-8.24, p = 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes.

Conclusion: The initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.
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http://dx.doi.org/10.1186/s13075-020-02171-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137303PMC
April 2020

Vascular Hyperintensity on Fluid-Attenuated Inversion Recovery Indicates the Severity of Hypoperfusion in Acute Stroke.

J Stroke Cerebrovasc Dis 2020 Feb 22;29(2):104467. Epub 2019 Nov 22.

Department of Neurosurgery, Brain Research Institute, University of Niigata, Chuo-ku, Niigata, Japan. Electronic address:

Background And Aim: Although fluid-attenuated inversion recovery vascular hyperintensities may be frequently seen in acute large-artery ischemic stroke, reports on their prognostic utility had been conflicting due to lack of quantitative evaluation of the perfusion status based on the signal intensity. We hypothesized that greater hyperintensity represents more severe hypoperfusion.

Methods: Overall, 27 patients with acute occlusion of the proximal middle cerebral artery were divided into 2 groups, based on their signal intensity in the insular segment of middle cerebral artery on the affected side, relative to that of the insular cortex: the low signal intensity group (hypo- or isointense signals, n = 12) and the high signal intensity group (hyperintense signals, n = 15). Using dynamic susceptibility contrast magnetic resonance imaging, we assessed the time of the maximum value of the residue function and mean transit time, in the entire middle cerebral artery cortical area and diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score regions, including the corona radiata.

Results: The high signal intensity group had significantly longer time of the maximum value of the residue function in all the diffusion-weighted imaging-Alberta Stroke Program Early Computed Tomography Score regions, except the M3 and M6 regions, and significantly longer mean transit time in the M1 and M4 regions.

Conclusions: Quantitative analysis of the perfusion parameters revealed more severely compromised and widely disturbed perfusion status in the high signal intensity group than in the low signal intensity group.
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http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2019.104467DOI Listing
February 2020

Biogenically induced bedded chert formation in the alkaline palaeo-lake of the Green River Formation.

Sci Rep 2019 11 11;9(1):16448. Epub 2019 Nov 11.

Graduate School of Science, Shizuoka University, Shizuoka, 790-8577, Japan.

Rhythmically bedded cherts are observed in both pelagic marine and lacustrine deposits, but the formation mechanism in the latter remains highly uncertain. Our study of alternating chert-dolomite beds in the Eocene Green River Formation, Utah, USA reveals dense accumulations of organic-matter spheres (30-50 μm diameter) of probable algal cyst origin in the chert layers, and centennial- to millennial-scale periodicities in chert layer deposition. A positive correlation between the degree of degradation of the organic spheres and Si distribution implies decomposition of algal organic matter lead to precipitation of lacustrine chert. As both alkalinity and dissolved silica were likely high in the palaeo-lake waters of the Green River Formation, we hypothesize that decomposition of algal organic matter lowered the pH of sediment pore waters and caused silica precipitation. We propose a formation model in which the initial abundance of algal organic matter in sediment varies with productivity at the lake surface, and the decomposition of this algal matter controls the extent of silica precipitation in sediment. The formation of rhythmically bedded chert-dolomite may be linked to centennial- to millennial-scale climatic/environmental factors that modulate algal productivity, which are possibly tied to solar activity cycles known to have similar periodicities.
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http://dx.doi.org/10.1038/s41598-019-52862-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6848130PMC
November 2019

Treatment Strategies for Infectious Intracranial Aneurysms: Report of Three Cases and Review of the Literature.

Neurol Med Chir (Tokyo) 2019 Sep 4;59(9):344-350. Epub 2019 Jul 4.

Department of Neurosurgery, Brain Research Institute, Niigata University.

We retrospectively reviewed the cases of three patients with infectious intracranial aneurysms (IIAs), and discuss the indications for surgical and endovascular treatments. We treated two men and one woman with a total of six aneurysms. The mean age was 43.3 years, ranging from 36 to 51 years. One patient presented initially with an intraparenchymal hemorrhage, one with mass effect, and the other one had four aneurysms (one causing subarachnoid hemorrhages and the other causing delayed intraparenchymal hemorrhages). The average size of all aneurysms was 12.2 mm (range, 2-50 mm). They were preferentially located in the distal posterior cerebral artery, and then, in the middle cerebral artery. All cases were caused by infective endocarditis. We selected endovascular treatments for five aneurysms and treated all but one within 24 h from detection. One aneurysm was treated by combined therapy with endovascular intervention and surgery. After treatment, none of the IIAs presented angiographical recurrence or re-bleeding. If feasible, endovascular treatment is probably the first choice, but a combined surgical and endovascular approach should be considered if surgery or endovascular treatment alone are not feasible. The method of treatment should be individualized. For cases with high risk of aneurysm rupture, treatment should be performed as soon as possible.
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http://dx.doi.org/10.2176/nmc.oa.2019-0051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6753255PMC
September 2019

Malignant Hyperthermia and Cerebral Venous Sinus Thrombosis After Ventriculoperitoneal Shunt in Infant with Schizencephaly and COL4A1 Mutation.

World Neurosurg 2019 Jul 25;127:446-450. Epub 2019 Apr 25.

Department of Neurosurgery, Brain Research Institute, Niigata University, Niigata, Japan.

Background: Schizencephaly is a rare congenital central nervous system malformation characterized by linear, thickened clefts of the cerebral mantle. Recently, germline mutations in collagen type IV alpha 1 (COL4A1) have been reported to be a genetic cause of schizencephaly as a result of prenatal stroke. Patients with COL4A1 mutation demonstrate a variety of disease phenotypes. However, little is known about the potential complications of patients with COL4A1 mutations before and after neurologic surgery.

Case Description: A 9-month-old boy with schizencephaly and a congenital cataract underwent a ventriculoperitoneal shunt for progressive hydrocephalus. Postoperatively, he developed malignant hyperthermia and cerebral venous thrombosis. Early treatment with dantrolene sodium and hydration was effective. Genetic testing revealed a germline COL4A1 mutation.

Conclusions: To our knowledge, malignant hyperthermia and cerebral venous thrombosis have not been reported in the literature in patients with COL4A1 mutations after surgery. Schizencephaly arising from COL4A1 mutations might be a disease prone to these adverse effects because this mutation is known to be associated with venous tortuosity, venous vulnerability, and muscle spasms due to basement membrane protein abnormalities. We need to better understand the wide spectrum of clinical phenotypes of COL4A1 mutations and potential complications in order to better manage surgery of patients with schizencephaly.
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http://dx.doi.org/10.1016/j.wneu.2019.04.156DOI Listing
July 2019

Assessment of Disease Activity, Structural Damage, and Function in Rheumatoid Arthritis.

Authors:
Hitoshi Hasegawa

Methods Mol Biol 2018 ;1868:243-250

Department of Hematology, Clinical Immunology, and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

The primary goal in the treatment of rheumatoid arthritis (RA) should be achieving control of disease activity, prevention of structural damage in joints, and normalization of function. Therefore, reliable tools are necessary to evaluate RA. Here, we describe methods recently used to assess RA.
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http://dx.doi.org/10.1007/978-1-4939-8802-0_25DOI Listing
May 2019

Design an Intervention Study.

Authors:
Hitoshi Hasegawa

Methods Mol Biol 2018 ;1868:235-241

Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Randomized controlled trials are commonly designed to compare the effectiveness of treatments in rheumatoid arthritis (RA). In a clinical trial (intervention study), researchers apply interventions or preventive services to patients and examine outcomes. Clinical trial design consists of the following categories: choice of intervention, selection of patients, informed consent, baseline measurement, bank specimens, randomized allocation and blinding, and outcome measurements. Here, we discuss the design of clinical trials for RA.
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http://dx.doi.org/10.1007/978-1-4939-8802-0_24DOI Listing
May 2019

Production of Neutralizing Antibody.

Methods Mol Biol 2018 ;1868:79-92

Department of Hematology, Clinical Immunology, and Infection Diseases, Ehime University Graduate School of Medicine, Toon, Ehime, Japan.

Techniques employing monoclonal antibodies (mAbs) are widely used in the initial development phase of biologics. The usefulness of mAbs in basic RA research has been established based on their characteristics, including specificity of binding, homogeneity, and ability to be produced on a large scale. MAb immunoglobulins are the starting material for the generation of smaller antibody fragments and other engineered immunomodulatory antibodies. In this chapter, the basic hybridoma technique, which is a well-established and feasible method for the production of mAbs involving animal immunization, cell fusion, hybridoma screening, expanding positive hybridomas, and purification, is introduced. Aiming at specific affinity to a membrane protein, synthetic proteoliposomes are used in the immunization and screening steps.
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http://dx.doi.org/10.1007/978-1-4939-8802-0_9DOI Listing
May 2019

Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data.

Lancet Neurol 2018 10 14;17(10):885-894. Epub 2018 Aug 14.

Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.

Background: Intracerebral haemorrhage growth is associated with poor clinical outcome and is a therapeutic target for improving outcome. We aimed to determine the absolute risk and predictors of intracerebral haemorrhage growth, develop and validate prediction models, and evaluate the added value of CT angiography.

Methods: In a systematic review of OVID MEDLINE-with additional hand-searching of relevant studies' bibliographies- from Jan 1, 1970, to Dec 31, 2015, we identified observational cohorts and randomised trials with repeat scanning protocols that included at least ten patients with acute intracerebral haemorrhage. We sought individual patient-level data from corresponding authors for patients aged 18 years or older with data available from brain imaging initially done 0·5-24 h and repeated fewer than 6 days after symptom onset, who had baseline intracerebral haemorrhage volume of less than 150 mL, and did not undergo acute treatment that might reduce intracerebral haemorrhage volume. We estimated the absolute risk and predictors of the primary outcome of intracerebral haemorrhage growth (defined as >6 mL increase in intracerebral haemorrhage volume on repeat imaging) using multivariable logistic regression models in development and validation cohorts in four subgroups of patients, using a hierarchical approach: patients not taking anticoagulant therapy at intracerebral haemorrhage onset (who constituted the largest subgroup), patients taking anticoagulant therapy at intracerebral haemorrhage onset, patients from cohorts that included at least some patients taking anticoagulant therapy at intracerebral haemorrhage onset, and patients for whom both information about anticoagulant therapy at intracerebral haemorrhage onset and spot sign on acute CT angiography were known.

Findings: Of 4191 studies identified, 77 were eligible for inclusion. Overall, 36 (47%) cohorts provided data on 5435 eligible patients. 5076 of these patients were not taking anticoagulant therapy at symptom onset (median age 67 years, IQR 56-76), of whom 1009 (20%) had intracerebral haemorrhage growth. Multivariable models of patients with data on antiplatelet therapy use, data on anticoagulant therapy use, and assessment of CT angiography spot sign at symptom onset showed that time from symptom onset to baseline imaging (odds ratio 0·50, 95% CI 0·36-0·70; p<0·0001), intracerebral haemorrhage volume on baseline imaging (7·18, 4·46-11·60; p<0·0001), antiplatelet use (1·68, 1·06-2·66; p=0·026), and anticoagulant use (3·48, 1·96-6·16; p<0·0001) were independent predictors of intracerebral haemorrhage growth (C-index 0·78, 95% CI 0·75-0·82). Addition of CT angiography spot sign (odds ratio 4·46, 95% CI 2·95-6·75; p<0·0001) to the model increased the C-index by 0·05 (95% CI 0·03-0·07).

Interpretation: In this large patient-level meta-analysis, models using four or five predictors had acceptable to good discrimination. These models could inform the location and frequency of observations on patients in clinical practice, explain treatment effects in prior randomised trials, and guide the design of future trials.

Funding: UK Medical Research Council and British Heart Foundation.
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http://dx.doi.org/10.1016/S1474-4422(18)30253-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143589PMC
October 2018

The treatment outcomes of rituximab for intractable otitis media with ANCA-associated vasculitis.

Auris Nasus Larynx 2019 Feb 7;46(1):38-42. Epub 2018 Jun 7.

Department of Otolaryngology, Head and Neck Surgery, Ehime University Graduate School of Medicine, Toon, Japan.

Objective: To investigate treatment outcomes, hearing outcomes, and adverse effects of rituximab (RTX) for intractable otitis media with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (OMAAV).

Methods: Twenty-three patients who met the criteria proposed by the OMAAV study group were included. RTX was used for patients who had difficulty achieving induction of remission using glucocorticoids (GC) and intravenous cyclophosphamide (IVCY).

Results: Six patients were treated with RTX (RTX group), while 17 patients did not require RTX for induction of remission (non-RTX group). All six patients in the RTX group achieved remission. Age, sex, and months from onset to diagnosis did not differ significantly between the groups. The air-conduction hearing thresholds at diagnosis and remission were 71.7±6.3dB and 50.1±5.1dB in the RTX group, and 56.8±4.8dB and 35.8±4.8dB in the non-RTX group, respectively. Hearing level at remission was significantly better in the non-RTX group (p<0.05), while hearing gain did not differ significantly between the groups. Infectious complications were similar between the groups.

Conclusions: Our findings suggest that RTX is effective and safe for intractable OMAAV patients who have a poor response to GC and IVCY.
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http://dx.doi.org/10.1016/j.anl.2018.05.011DOI Listing
February 2019

Mechanisms of Tolerance Induction by Dendritic Cells .

Front Immunol 2018 26;9:350. Epub 2018 Feb 26.

Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Toon, Japan.

Dendritic cells (DCs) are a heterogeneous population playing a pivotal role in immune responses and tolerance. DCs promote immune tolerance by participating in the negative selection of autoreactive T cells in the thymus. Furthermore, to eliminate autoreactive T cells that have escaped thymic deletion, DCs also induce immune tolerance in the periphery through various mechanisms. Breakdown of these functions leads to autoimmune diseases. Moreover, DCs play a critical role in maintenance of homeostasis in body organs, especially the skin and intestine. In this review, we focus on recent developments in our understanding of the mechanisms of tolerance induction by DCs in the body.
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http://dx.doi.org/10.3389/fimmu.2018.00350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5834484PMC
March 2019

Penetrative trace fossils from the late Ediacaran of Mongolia: early onset of the agronomic revolution.

R Soc Open Sci 2018 Feb 28;5(2):172250. Epub 2018 Feb 28.

Department of Earth Science, Tohoku University, Sendai 980-8578, Japan.

The Cambrian radiation of complex animals includes a dramatic increase in the depth and intensity of bioturbation in seafloor sediment known as the 'agronomic revolution'. This bioturbation transition was coupled with a shift in dominant trace fossil style from horizontal surficial traces in the late Precambrian to vertically penetrative trace fossils in the Cambrian. Here we show the existence of the first vertically penetrative trace fossils from the latest Ediacaran: dense occurrences of the U-shaped trace fossil from late Precambrian marine carbonates of Western Mongolia. Their Ediacaran age is established through stable carbon isotope chemostratigraphy and their occurrence stratigraphically below the first appearance of the trace fossil . These are large in diameter, penetrate down to at least 4 cm into the sediment, and were presumably formed by the activity of bilaterian animals. They are preserved commonly as paired circular openings on bedding planes with maximum diameters ranging up to almost 1 cm, and as U- and J-shaped tubes in vertical sections of beds. Discovery of these complex penetrative trace fossils demonstrates that the agronomic revolution started earlier than previously considered.
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http://dx.doi.org/10.1098/rsos.172250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5830798PMC
February 2018

Risk Factors for Relapse of Antineutrophil Cytoplasmic Antibody-associated Vasculitis in Japan: A Nationwide, Prospective Cohort Study.

J Rheumatol 2018 04 1;45(4):521-528. Epub 2018 Feb 1.

From the Department of Environmental and Preventive Medicine, and Department of Nephrology and Laboratory Medicine, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa; Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama; Department of Rheumatology and Clinical Immunology, Saitama Medical Center, Saitama; Division of Endocrinology and Metabolism, Hematology, Rheumatology and Respiratory Medicine, Department of Internal Medicine, Faculty of Medicine, Kagawa University, Kagawa; Division of Rheumatology and Allergology, Departments of Internal Medicine and Dermatology, St. Marianna University School of Medicine, Kawasaki; Department of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Matsuyama; Department of Rheumatology, Faculty of Medicine, University of Tsukuba, Tsukuba; Department of Hemovascular Medicine and Artificial Organs, Faculty of Medicine, University of Miyazaki, Miyazaki; Center for Nephrology and Urology, Division of Nephrology and Dialysis, Kitano Hospital, Tazuke Kofukai Medical Research Institute, Osaka; Third Department of Internal Medicine, Division of Immunology and Rheumatology, Hamamatsu University School of Medicine, Hamamatsu; Division of Rheumatology, Niigata Rheumatic Center, Shibata; Department of Pharmacovigilance, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University; Department of Internal Medicine and Rheumatology, Juntendo University School of Medicine; Department of Respiratory Medicine, Toho University Omori Medical Center; Division of Nephrology, Tokyo Medical University Hachioji Medical Center; Department of Nephrology and Endocrinology, Graduate School of Medicine, The University of Tokyo; Nephrology and Rheumatology, First Department of Internal Medicine, Kyorin University School of Medicine, Tokyo, Japan.

Objective: The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV).

Methods: Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections.

Results: The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1-8.5).

Conclusion: One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.
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http://dx.doi.org/10.3899/jrheum.170508DOI Listing
April 2018

Long-term outcomes of coil embolization of unruptured intracranial aneurysms.

J Neurosurg 2018 12;129(6):1492-1498

2Department of Neurosurgery, Kyoto University Graduate School of Medicine, Kyoto.

OBJECTIVELong-term follow-up results of the treatment of unruptured intracranial aneurysms (UIAs) by means of coil embolization remain unclear. The aim of this study was to analyze the frequency of rupture, retreatment, stroke, and death in patients with coiled UIAs who were followed for up to 20 years at multiple stroke centers.METHODSThe authors retrospectively analyzed data from cases in which patients underwent coil embolization between 1995 and 2004 at 4 stroke centers. In collecting the late (≥ 1 year) follow-up data, postal questionnaires were used to assess whether patients had experienced rupture or retreatment of a coiled aneurysm or any stroke or had died.RESULTSOverall, 184 patients with 188 UIAs were included. The median follow-up period was 12 years (interquartile range 11-13 years, maximum 20 years). A total of 152 UIAs (81%) were followed for more than 10 years. The incidence of rupture was 2 in 2122 aneurysm-years (annual rupture rate 0.09%). Nine of the 188 patients with coiled UIAs (4.8%) underwent additional treatment. In 5 of these 9 cases, the first retreatment was performed more than 5 years after the initial treatment. Large aneurysms were significantly more likely to require retreatment. Nine strokes occurred over the 2122 aneurysm-years. Seventeen patients died in this cohort.CONCLUSIONSThis study demonstrates a low risk of rupture of coiled UIAs with long-term follow-up periods of up to 20 years. This suggests that coiling of UIAs could prevent rupture for a long period of time. However, large aneurysms might need to be followed for a longer time.
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http://dx.doi.org/10.3171/2017.6.JNS17174DOI Listing
December 2018