Posterior cerebral artery involvement in unilateral moyamoya disease is exclusively ipsilateral and influenced by RNF213 mutation gene dose: The SUPRA Japan study: PCA involvement in unilateral moyamoya.

OBJECTIVES: The characteristics and clinical implications of posterior cerebral artery (PCA) involvement in unilateral moyamoya disease (U-MMD), such as laterality, frequency of the RNF213 p.R4810K mutation, and clinical outcomes, have not been well studied. POPULATION AND METHODS: We analyzed a cohort of 93 patients with U-MMD who participated in the SUPRA Japan study. Clinical characteristics and radiological examinations were collected from medical records. The presence of the p.R4810K mutation was determined using a TaqMan assay. The clinical outcome was assessed using the modified Rankin Scale (mRS). Univariate and multivariate logistic regression analyses were performed to assess the associations. RESULTS: Among the patients with U-MMD, PCA involvement was observed in 60.0 % (3/5) of patients with homozygous mutation, 11.3 % (7/62) of those with heterozygous mutation, and 3.8 % (1/26) of those with wild type, showing a significant linear trend (p < 0.001 for trend). PCA involvement was observed exclusively on the same side as the affected anterior circulation. Dyslipidemia and cerebral infarction at initial onset were independently associated with mRS ≥1. Hypertension was associated with mRS ≥1 and it was also linked to infarction at initial onset, suggesting a potential confounding effect. Although PCA involvement showed a trend for higher mRS, it was not statistically significant. CONCLUSIONS: Our findings indicate a gene dose effect of the p.R4810K mutation on PCA involvement, with the homozygous state showing the most significant effect. Both genetic and modifiable factors such as dyslipidemia may influence the progression of U-MMD.

Superior Visualization of Neovascularization with Silent Magnetic Resonance Angiography Compared to Time-of-Flight Magnetic Resonance Angiography After Bypass Surgery in Moyamoya Disease.

OBJECTIVE: The evaluation of postsurgical neoangiogenesis in patients with moyamoya disease (MMD) is crucial for appropriate patient management. This study aimed to assess the visualization of neovascularization after bypass surgery using noncontrast-enhanced silent magnetic resonance angiography (MRA) with ultrashort echo time and arterial spin labeling. METHODS: After bypass surgery, 13 patients with MMD were followed up for >6 months between September 2019 and November 2022. They underwent silent MRA in the same session as time-of-flight magnetic resonance angiography (TOF-MRA) and digital subtraction angiography (DSA). Two observers independently rated the visualization of neovascularization in both types of MRA from 1 (not visible) to 4 (nearly equal to DSA), with reference to DSA images as the standard. RESULTS: The mean scores were significantly higher for silent MRA compared with TOF-MRA (3.81 ± 0.48 and 1.92 ± 0.70, respectively) (P < 0.01). The intermodality agreements were 0.83 and 0.71 for silent MRA and TOF-MRA, respectively. TOF-MRA depicted the donor artery and recipient cortical artery after direct bypass surgery, although fine neovascularization developed after indirect bypass surgery was poorly visualized. Silent MRA could reveal the developed bypass flow signal and perfused middle cerebral artery territory, which was almost equal to the DSA images. CONCLUSIONS: Silent MRA achieves better visualization of postsurgical revascularization in patients with MMD than TOF-MRA. Moreover, it may have the potential to provide visualization of the developed bypass flow equivalent to DSA.

[Arteriovenous Malformations:Endovascular Techniques and Devices].

Endovascular embolization using liquid materials is a safe and effective treatment option for cerebral arteriovenous malformations(AVM). Onyx and n-butyl cyanoacrylate, currently available in Japan, have specific features. Appropriate embolic agents should be selected based on their characteristics. Transarterial embolization(TAE)is the standard endovascular treatment approach. However, there have been some recent reports regarding the efficacy of transvenous embolization(TVE). TVE is potentially curative for small AVM with hemorrhagic onset, inaccessible arterial feeders, deep location, and/or a single draining vein. In specific cases, TVE may provide a higher chance of complete obliteration of the AVM than TAE. Some unsolved problems need further clarification, such as the relative positions of liquid embolization against direct surgery, dealing with unruptured AVM, and effective treatment for high-grade AVM.

Psoriatic arthritis successfully treated with second-line anti-interleukin-6 treatment: a case report and review of the literature.

BACKGROUND: Psoriatic arthritis treatment with antitumor necrosis factor has been shown to reduce disease activity. Nonetheless, more than 30% of patients do not achieve a sufficient response to tumor necrosis factor blockers. Currently, treatment with interleukin-6 inhibitors is expected to be effective and suppress the joint destruction in patients with psoriatic arthritis; however, evidence regarding their efficacy is limited to a few reports. CASE PRESENTATION: A 78-year-old Japanese woman with psoriatic arthritis associated with rapid joint destruction was successfully treated with a second-line anti-interleukin-6 receptor agent. In this case, a tumor necrosis factor inhibitor induced an inadequate response, and the right knee and left hip joints required artificial joint replacement surgery. However, second line treatment with anti-interleukin-6 treatment was effective, and the right elbow joint function was preserved. CONCLUSIONS: We experienced a case of psoriatic arthritis, in which anti-interleukin-6 treatment repaired a bone cyst in the lateral epicondyle of the humerus and enthesitis of the distal interphalangeal joints. The patient is currently in clinical remission with no restrictions in daily life activities. Anti-interleukin-6 treatment may address the unmet needs of patients with psoriatic arthritis who are resistant or intolerant to antitumor necrosis factor treatment, with rapidly destructive large joints but with well-managed skin manifestations.

A case of clinically amyopathic dermatomyositis that was refractory to intensive immunosuppressive therapy including tofacitinib, but successfully treated with plasma exchange therapy.

Clinically amyopathic dermatomyositis (CADM) patients often develop rapidly progressive interstitial lung disease (RP-ILD). A high level of anti-melanoma differentiation-associated gene 5 antibodies (anti-MDA5 Ab) before treatment is associated with RP-ILD development, a poor treatment response, and poor survival. The prognosis of CADM patients remains poor due to ILD even with combined intensive immunosuppressive therapy. Recently, several additional therapies, including tofacitinib (TOF) and plasma exchange (PE) therapy, have been reported to be effective. We herein report a case of CADM-ILD with a high level of anti-MDA5 Ab that was refractory to combined intensive immunosuppressive therapy including TOF, but successfully treated with PE. The following are possible reasons why TOF was ineffective: (1) cytokines that were not suppressed by TOF played an important role in RP-ILD; (2) TOF was administered later than previously reported; and (3) TOF did not suppress pathological substances such as antibodies. On the other hand, PE removes cytokines and various pathological substances. Therefore, PE may be a more reasonable additional therapy for intractable CADM-ILD.

Genetic and nongenetic factors for contralateral progression of unilateral moyamoya disease: the first report from the SUPRA Japan Study Group.

OBJECTIVE: Although many studies have analyzed risk factors for contralateral progression in unilateral moyamoya disease, they have not been fully elucidated. The aim of this study was to examine whether genetic factors as well as nongenetic factors are involved in the contralateral progression. METHODS: The authors performed a multicenter cohort study in which 93 cases with unilateral moyamoya disease were retrospectively reviewed. The demographic features, RNF213 R4810K mutation, lifestyle factors such as smoking and drinking, past medical history, and angiographic findings were analyzed. A Cox proportional hazards model was used to find risk factors for contralateral progression. RESULTS: Contralateral progression was observed in 24.7% of cases during a mean follow-up period of 72.2 months. Clinical characteristics were not significantly different between 67 patients with the R4810K mutation and those without it. Cox regression analysis showed that the R4810K mutation (hazard ratio [HR] 4.64, p = 0.044), childhood onset (HR 7.21, p < 0.001), male sex (HR 2.85, p = 0.023), and daily alcohol drinking (HR 4.25, p = 0.034) were independent risk factors for contralateral progression. CONCLUSIONS: These results indicate that both genetic and nongenetic factors are associated with contralateral progression of unilateral moyamoya disease. The findings would serve to help us better understand the pathophysiology of moyamoya disease and to manage patients more appropriately.

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

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.

Giant Cell Arteritis Presenting with Ptosis and Diplopia.

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 man 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.

Development and natural course of lateral posterior choroidal artery aneurysms arising from fragile choroidal collaterals in moyamoya disease: illustrative cases.

BACKGROUND: Choroidal collaterals are a risk factor for hemorrhagic stroke, even in the nonhemorrhagic hemisphere, among patients with moyamoya disease (MMD). Peripheral choroidal aneurysms rupture in fragile collaterals; however, the development and natural course of these aneurysms remain elusive. OBSERVATIONS: A 51-year-old woman, who had experienced a right cerebral hemorrhage 3 years earlier, presented with asymptomatic minor bleeding from a left lateral choroidal artery aneurysm in a predeveloped choroidal anastomosis. Although the aneurysm spontaneously thrombosed within 2 months, the choroidal collaterals persisted. After bypass surgery, the choroidal anastomosis regressed, and neither a de novo aneurysm nor a hemorrhagic stroke occurred. A 75-year-old woman with MMD, who had experienced a left frontal infarction 6 years earlier, experienced recurrent right intraventricular hemorrhage from a ruptured lateral choroidal artery aneurysm that developed in the choroidal anastomosis. The aneurysm spontaneously regressed 3 days after the rebleeding with no recurrence over the following 7 years. LESSONS: Choroidal artery aneurysms may develop in the choroidal anastomosis and rupture in the nonsurgical or contralateral hemispheres. Patients with MMD who have a history of hemorrhagic or ischemic stroke and impaired cerebral blood flow require careful observation. Although aneurysms may rapidly regress spontaneously, bypass surgery can stabilize hemodynamic stress and prevent further hemorrhage.

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

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 N,N'-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.

Vascular endothelial growth factor (VEGF)-A and VEGF-A165b are associated with time to remission of granulomatosis with polyangiitis in a nationwide Japanese prospective cohort study.

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-A165b (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-A165b 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-A165b concentrations in patients with microscopic polyangiitis and EGPA, respectively. However, despite the comparable concentrations of sVEGF-A and sVEGF-A165b during the 6 months of treatment in granulomatosis with polyangiitis patients, correlation analysis revealed that the differences in log2-transformed concentrations of sVEGF-A and sVEGF-A165b were inversely correlated with time to remission in granulomatosis with polyangiitis patients. CONCLUSION: These results suggest that sVEGF-A and -A165b can serve as potential markers of time to remission in patients with granulomatosis with polyangiitis.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

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

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.

Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis.

BACKGROUND: Targeted proteomics, which involves quantitative analysis of targeted proteins using selected reaction monitoring (SRM) mass spectrometry, has emerged as a new methodology for discovery of clinical biomarkers. In this study, we used targeted serum proteomics to identify circulating biomarkers for prediction of disease activity and organ involvement in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: A large-scale SRM assay targeting 135 biomarker candidates was established using a triple-quadrupole mass spectrometer coupled with nanoflow liquid chromatography. Target proteins in serum samples from patients in the active and remission (6 months after treatment) stages were quantified using the established assays. Identified marker candidates were further validated by enzyme-linked immunosorbent assay using serum samples (n = 169) collected in a large-cohort Japanese study (the RemIT-JAV-RPGN study). RESULTS: Our proteomic analysis identified the following proteins as biomarkers for discriminating patients with highly active AAV from those in remission or healthy control subjects: tenascin C (TNC), C-reactive protein (CRP), tissue inhibitor of metalloproteinase 1 (TIMP1), leucine-rich alpha-2-glycoprotein 1, S100A8/A9, CD93, matrix metalloproteinase 9, and transketolase (TKT). Of these, TIMP1 was the best-performing marker of disease activity, allowing distinction between mildly active AAV and remission. Moreover, in contrast to CRP, serum levels of TIMP1 in patients with active AAV were significantly higher than those in patients with infectious diseases. The serum levels of TKT and CD93 were higher in patients with renal involvement than in those without, and they predicted kidney outcome. The level of circulating TNC was elevated significantly in patients with lung infiltration. AAV severity was associated with markers reflecting organ involvement (TKT, CD93, and TNC) rather than inflammation. The eight markers and myeloperoxidase (MPO)-ANCA were clustered into three groups: MPO-ANCA, renal involvement (TKT and CD93), and inflammation (the other six markers). CONCLUSIONS: We have identified promising biomarkers of disease activity, disease severity, and organ involvement in AAV with a targeted proteomics approach using serum samples obtained from a large-cohort Japanese study. Especially, our analysis demonstrated the effectiveness of TIMP1 as a marker of AAV activity. In addition, we identified TKT and CD93 as novel markers for evaluation of renal involvement and kidney outcome in AAV.

Clinical characteristics of arteriovenous malformations in the cerebellopontine angle cistern.

OBJECTIVE Arteriovenous malformations (AVMs) in the cerebellopontine angle cistern (CPAC) are specific lesions that can cause neurovascular compression syndromes as well as intracranial hemorrhage. Although case reports describing the CPAC AVMs, especially those presenting with trigeminal neuralgia (TN), have been accumulating by degrees, the pathophysiology of CPAC AVMs remains obscure. The authors' purpose in the present study was to evaluate the clinical and radiographic features of CPAC AVMs as well as the treatment options. METHODS This study defined a CPAC AVM as a small AVM predominantly located in the CPAC with minimal extension into the pial surface of the brainstem and closely associated with cranial nerves. All patients with CPAC AVMs treated in the authors' affiliated hospitals over a 16-year period were retrospectively identified. Clinical charts, imaging studies, and treatment options were evaluated. RESULTS Ten patients (6 men and 4 women), ranging in age from 56 to 77 years (mean 65.6 years), were diagnosed with CPAC AVMs according to the authors' definition. Six patients presented with hemorrhage, 3 with TN, and the remaining patient developed a hemorrhage subsequent to TN. Seven AVMs were associated with the trigeminal nerve (Group V), and 3 with the facial-vestibulocochlear nerve complex (Group VII-VIII). All patients in Group VII-VIII presented with the hemorrhage instead of hemifacial spasm. Regarding angioarchitecture, the intrinsic pontine arteries provided the blood supply for all CPAC AVMs in Group V. In addition, 5 of 7 AVMs with hemorrhagic episodes accompanied flow-related aneurysms, although no aneurysm was detected in patients with TN alone. With respect to treatment, all patients with hemorrhagic presentation underwent Gamma Knife surgery (GKS), resulting in favorable outcomes except for 1 patient who experienced rebleeding after GKS, which was caused by the repeated rupture of a feeder aneurysm. The AVMs causing TN were managed with surgery, GKS, or a combination, according to the nidus-nerve relationship. All patients eventually obtained pain relief. CONCLUSIONS Clinical symptoms caused by CPAC AVMs occur at an older age compared with AVMs in other locations; CPAC AVMs also have distinctive angioarchitectures according to their location in the CPAC. Although GKS is likely to be an effective treatment option for the CPAC AVMs with hemorrhagic presentations, it seems ideal to obliterate the flow-related aneurysms before performing GKS, although this is frequently challenging. For CPAC AVMs with TN, it is important to evaluate the nidus-nerve relationship before treatment, and GKS is especially useful for patients who do not require urgent pain relief.