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Introduction: We investigated whether apixaban is safe for the prevention of further adverse events in non-valvular atrial fibrillation (NVAF) patients with intra-/extracranial artery stenosis (Stenosis group) compared with acute large vessel occlusion without intra-/extracranial artery stenosis (No stenosis group). We also examined whether combination therapy using apixaban and antiplatelet is safe. Methods: ALVO (Apixaban on clinical outcome of patients with Large Vessel Occlusion [LVO] or stenosis) was a historical and prospective multicenter registry at 38 centers in Japan. Patients with NVAF and acute LVO or stenosis who received apixaban within 14 days after onset were included. We conducted the post hoc analysis using the ALVO dataset. We compared patients with stenosis versus those without stenosis in terms of the primary outcome, which was defined as a composite of all-cause death, major bleeding events, and ischemic events 365 days after onset. Results: Of the 662 patients, 54 (8.2%) patients were classified into the Stenosis group, and 104 patients of the total (16%) reached the primary outcome. The cumulative incidence of primary outcome was not significantly different between the No stenosis and the Stenosis groups (hazard ratio [HR] 1.2, 95% confidence interval [CI]: 0.64–2.4; p = 0.52). Even after adjustment for predictive clinical variates, no significant difference in the primary endpoint between the No stenosis and the Stenosis groups was shown (adjusted HR 1.2, 95% CI: 0.59–2.5; p = 0.60). Fifty patients (7.6%) used an antiplatelet with apixaban. Among the Stenosis group patients, the cumulative incidence of the primary outcome was significantly higher among patients treated with an antiplatelet and apixaban (HR 3.5, 95% CI: 1.0–12; p = 0.048). Conclusion: Apixaban monotherapy appears safe for the prevention of further adverse events in the Stenosis group patients similar to the No stenosis group patients. Concomitant use of an antiplatelet might not be favorable in patients with stenosis.

After the new molecular-based classification was reported to be useful for predicting prognosis, the T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign has gained interest as one of the promising methods for detecting lower grade gliomas (LGGs) with isocitrate dehydrogenase (IDH) mutations and chromosome 1p/19q non-codeletion (IDH mut-Noncodel) with high specificity. Although all institutions could use T2-FLAIR mismatch sign without any obstacles, this sign was not completely helpful because of its low sensitivity. In this study, we attempted to uncover the mechanism of T2-FLAIR mismatch sign for clarifying the cause of this sign's low sensitivity. Among 99 patients with LGGs, 22 were T2-FLAIR mismatch sign-positive (22%), and this sign as a marker of IDH mut-Noncodel showed a sensitivity of 55.6% and specificity of 96.8%. Via pathological analyses, we could provide evidence that not only microcystic changes but the enlarged intercellular space was associated with T2-FLAIR mismatch sign (p = 0.017). As per the molecular analyses, overexpression of mTOR-related genes (m-TOR, RICTOR) were detected as the molecular events correlated with T2-FLAIR mismatch sign (p = 0.020, 0.030. respectively). Taken together, we suggested that T2-FLAIR mismatch sign could pick up the IDH mut-Noncodel LGGs with enlarged intercellular space or that with overexpression of mTOR-related genes.

The increased use of neuroimaging and the aging of society have changed the incidence and proportion of histological types of intracranial tumors in Japan. A population-based epidemiological survey has been reported only from Kumamoto Prefecture. We performed a 10-year survey in Miyazaki Prefecture to compare our findings with the incidence rate (IR) of primary intracranial tumors (PIT) reported in the Kumamoto survey. Our study included 1915 new cases of PIT diagnosed in Miyazaki Prefecture between 2007 and 2016. The crude IR was 16.97/100000/year. The most common tumor was meningioma (46.3%), followed by glioma (17.1%), pituitary adenoma (13.1%), schwannoma (8.2%), and malignant lymphoma (3.8%). The age-specific IR of all PITs and of meningiomas, gliomas, pituitary adenomas, schwannomas, lymphomas, and germ cell tumors was similar in both prefectures. To directly compare with the age-adjusted IRs reported in the Kumamoto survey, we calculated the IR for the two prefectures. The age-adjusted IR of primary brain tumors in Miyazaki Prefecture was 14.65/100000/year, which was slightly higher than in the Kumamoto survey (14.09/100000/year between 1989 and 2008). The age-adjusted IR of glioma, schwannoma, and malignant lymphoma showed only a small difference between Miyazaki and Kumamoto. However, the age-adjusted IR of meningiomas was higher in Miyazaki than Kumamoto (6.15- vs. 4.97/100000/year), but the IR of pituitary adenoma was higher in Kumamoto than Miyazaki (2.66- vs. 2.13/100000/year). Although there were some differences between the two surveys, the IR of PIT showed a similar pattern in Kumamoto and Miyazaki, which are neighboring districts on Kyushu Island.

Objective: Herein, we report a patient with acute cerebral infarction with a favorable prognosis after being managed by a general physician with support from the telestroke program. Patient and Methods: An 85-year-old man was transferred to a regional hospital due to sudden onset of dysarthria and left hemiparesis. As no neurosurgeons or neurologists were available in that hospital or area, the patient was examined by a general physician who diagnosed him with cardioembolic stroke on the left middle cerebral artery territory. The physician consulted a stroke specialist using the telestroke system; with the support from the telestroke program, the physician administered thrombolytic therapy 4 hours and 10 minutes after the onset of symptoms. Results: The patient’s National Institutes of Health Stroke Scale score improved from 9 to 3 and he was subsequently transferred to the stroke center. However, the occluded left middle cerebral artery had already re-canalized. His hemiparesis completely improved one week after the onset. Conclusion: A telemedicine system for general physicians is indispensable in areas without accessible stroke specialists as it provides access to a standard of care for hyper-acute stroke patient assessment and management, and helps improve neuroprognosis.

Pancreatic panniculitis (PP) is a rare clinical variant of subcutaneous fat necrosis, developing in patients with a variety of pancreatic diseases such as acute or chronic pancreatitis, tumors and cysts. The tumor-associated PP represents a noteworthy skin manifestation of underlying internal malignancies, also known as dermadrome. Among causative pancreatic tumors, acinar cell carcinoma is the most frequent malignancy; however, little is known about how the origin of tumor cells and progression stage of pancreatic tumors potentially contribute to the establishment of panniculitis. Here, we present a 69-year-old Japanese male case of clinically aggressive PP on the bilateral legs, whose skin lesions developed prior to the diagnosis of occult pancreatic tumor and liver metastasis. Moreover, the immunopathology of the pancreatic lesion revealed neuroendocrine tumor (NET), a rare pathological variant. Skin lesions immediately spread to the upper limbs with extensive ulcerations and necrosis, accompanied by high levels of serum lipase and elastase, but not with other pancreatic enzymes. He died 2 months after the initial development of the skin lesion due to rapid deterioration of general condition. We reviewed 14 cases, including ours, of PP with NET in the pancreas thus far reported, to identify the clinicopathological characteristics regarding to what extent this rare complication could reflect the clinical course of pancreatic tumors and overall prognosis. Our published work review found that the disease has a significant male predominance (male : female, 13:1) and cases with occult pancreatic tumors died within 4 months after the development of their skin lesions. Our case was the poorest prognostic outcome. This report emphasizes that dermatologists should recognize PP with NET, reflecting a fatal prognosis, and to make a prompt diagnosis.

Early administration of direct oral anticoagulants in patients with acute large vessel occlusion (LVO) and nonvalvular atrial fibrillation (NVAF) is a concern, as endovascular therapy (EVT) became highly utilized. We conducted a historical and prospective multicenter registry at 38 centers in Japan from July 2016 to February 2018. Patients aged ≥ 20 years with NVAF and acute LVO or stenosis who received apixaban within 14 days from onset were included. We compared patients who received apixaban p = 0.003; EVT 62% vs. 46%, p http://www.clinicaltrials.gov. Unique identifier: NCT02818868 (June 30, 2016)

Objective We aimed to examine the dynamics of serum Wisteria floribunda agglutinin-positive human Mac-2-binding protein glycosylation isomer (M2BPGi) in patients with acute liver injury. Methods Serum M2BPGi levels at the time of the diagnosis (n=77) and normalization of the serum alanine aminotransferase (ALT) level (n=26) were examined retrospectively. The difference in the serum M2BPGi level according to the etiology, and the correlations with other laboratory parameters were evaluated. Results The serum M2BPGi level at the time of the diagnosis was increased in 59 of 77 patients [2.3 cutoff index (COI); range, 0.31-11.1 COI] and was significantly decreased at the time of serum ALT normalization (0.68 COI; range, 0.15-1.87 COI; p

Background To provide updates on clinical practice of acute pancreatitis (AP) in Japan, we conducted a nationwide epidemiological survey. Methods This study consisted of a two-staged survey; the number of AP patients was estimated by the first-stage survey and their clinical features were examined by the second-stage survey. We surveyed AP patients who had visited hospitals in 2016. Results The estimated number of AP patients in 2016 was 78,450, with an overall incidence of 61.8 per 100,000 persons. We obtained detailed clinical information of 2994 AP patients, including 706 (23.6%) severe cases classified according to the Japanese severity criteria. The male-to-female sex ratio was 2.0, and the mean age at onset was 59.9 years in males and 66.5 years in females. Alcohol was the most common etiology (42.8%) in males and gallstones in females (37.7%). The AP-associated mortality was 6.1% in severe AP cases, which was decreased by 40% compared to the 2011 survey. Antibiotics were administered to most cases, with carbapenem being frequently used. Enteral nutrition was given in 31.8% of severe cases, but majority cases received after 48 h. Among the 107 patients who received intervention for walled-off necrosis, five patients received surgery-first approach, 66 received endoscopic ultrasound-guided transluminal drainage, and 19 underwent step-up approach. Conclusions We clarified the current status of AP in Japan including the significant reduction of mortality in severe cases, shift to endoscopic approaches for walled-off necrosis, and poor compliance of the recommendations in the guidelines including management of enteral nutrition and antibiotic administration.

Background and Purpose— The treatment and prognosis of acute large vessel occlusion with mild symptoms have not been sufficiently studied. The present study aimed to investigate the clinical or radiological predictors of clinical outcome in patients with stroke with mild symptoms due to acute large vessel occlusion. Methods— Of 2420 patients with acute large vessel occlusion in the RESCUE-Japan Registry 2 (Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism-Japan Registry 2), a multicenter prospective registry in Japan, patients with modified Rankin Scale scores of 0 to 2 before onset and initial National Institutes of Health Stroke Scale (NIHSS) scores of 0 to 5 were examined in post hoc analysis. We examined the clinical and radiological characteristics associated with a favorable outcome (modified Rankin Scale score, 0–2 at 90 days) using multivariate analysis, as well as the factors associated with a favorable outcome in patients treated with endovascular therapy. Results— We analyzed 272 patients (median age, 73 years; median NIHSS score on admission, 3). Eighty-six (31.6%) patients were treated with intravenous recombinant tissue-type plasminogen activator, 54 (19.9%) underwent endovascular therapy, and 208 (76.5%) showed a favorable outcome. In multivariate analysis, age P Conclusions— Younger age, lower initial NIHSS score, intravenous recombinant tissue-type plasminogen activator, and absence of hyperglycemia were independently associated with a favorable outcome in patients with acute large vessel occlusion with low NIHSS scores. Registration— URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02419794.

Genome‐wide association studies (GWASs) in European and East Asian populations have identified more than 40 disease‐susceptibility genes in primary biliary cholangitis (PBC). The aim of this study is to computationally identify disease pathways, upstream regulators, and therapeutic targets in PBC through integrated GWAS and messenger RNA (mRNA) microarray analysis. Disease pathways and upstream regulators were analyzed with ingenuity pathway analysis in data set 1 for GWASs (1,920 patients with PBC and 1,770 controls), which included 261 annotated genes derived from 6,760 single‐nucleotide polymorphisms (P 2 versus controls (P

The initiation of anticoagulant administration after large vessel occlusion (LVO) or stenosis with nonvalvular arterial fibrillation (NAVF) is controversial. We evaluate the timing of anticoagulation and its relationship with clinical factors.We enrolled 595 anterior circulation LVO or stenosis with NAVF cases from 38 stroke centers. Laboratory data; activities of daily living; the Alberta Stroke Program Early CT Score (ASPECTS); the National Institutes of Health Stroke Scale (NIHSS) score; occluded artery; treatment methods; date of the initiation of apixaban administration and outcome were recorded. Multivariate analyses were performed after univariate analysis.The median start of apixaban administration after the stroke was 2 days (interquartile range, 1-5; range, 0-14). Multivariate analysis of variance showed that non-internal carotid artery occlusion (F value 4.60), reperfusion therapy (31.1), high ASPECTS (6.27) before anticoagulant intake, and absence of intracranial hemorrhage (12.9) were significantly correlated with early apixaban administration. Multiple logistic regression analysis for independent living at 90 days after the stroke showed significant factors: aging (odds, 0.94; 95% confidence interval [CI], 0.91-0.97); male (odds, 0.46; 95% CI, 0.26-0.79); prestroke independence (odds, 20.7; 95% CI, 6.48-93.9); number of white blood cells (odds, 0.99; 95% CI, 0.97-1.00); non-internal carotid artery occlusion; NIHSS score at 72 hours after the stroke (odds 0.92; 95% CI, 0.89-0.96); ASPECTS before apixaban intake (odds, 1.15; 95% CI, 1.00-1.31) and initiation of apixaban (odds, 0.91; 95% CI, 0.83-0.99).Early administration of apixaban is induced by nonsevere infarction, reperfusion therapy or none of intracranial hemorrhage and it correlates with an independent long-term outcome.

International audience; BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I(2)=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [\textless1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Early administration of direct oral anticoagulants in patients with acute large vessel occlusion (LVO) and nonvalvular atrial fibrillation (NVAF) is a concern, as endovascular therapy (EVT) became highly utilized. We conducted a historical and prospective multicenter registry at 38 centers in Japan from July 2016 to February 2018. Patients aged ≥ 20 years with NVAF and acute LVO or stenosis who received apixaban within 14 days from onset were included. We compared patients who received apixaban 48 h (Early group) and ≥ 48 h (Late group) after onset in terms of the primary outcome (a composite of ischemic events, major bleeding events, and all-cause deaths). The secondary outcomes were each component of the primary outcome. Among the 686 patients, the median time from onset to administration was 2.5 days (range, 0-14; Early 263, Late 423). The Alberta Stroke Program Early CT Score (ASPECTS) and diffusion-weighted imaging (DWI)-ASPECTS) were significantly higher in the Early group than in the Late group. Recombinant tissue plasminogen activator (rt-PA) and EVT were more utilized in the Early group (rt-PA 46% vs. 35%, p = 0.003; EVT 62% vs. 46%, p 0.0001). The cumulative incidence of primary outcome was similar between groups (ischemic events: Early 1.9% vs. Late 0.5% at 30 days; 3.5% vs. 0.7% at 90 days, major bleeding 3.4% vs. 2.9% at 30 days; 5.0% vs. 3.4% at 90 days). Early administration of apixaban ( 48 h), after onset of acute LVO in patients with NVAF, was generally safe compared with those who received it Late (≥ 48 h). http://www.clinicaltrials.gov . Unique identifier: NCT02818868 (June 30, 2016).

OBJECTIVEThe methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene promoter is a prognostic factor in adults with glioblastoma (GBM); it also yields information that is useful for clinical decision-making in elderly GBM patients. While pyrosequencing is the gold standard for the evaluation of the methylation status of MGMT, methylation-sensitive polymerase chain reaction (MS-PCR) assay continues to be used widely. Although MS-PCR results exhibited a good correlation with the prognosis of patients with GBM treated under the Stupp protocol, interpretation of the bands is based on subjective judgment, and the assay cannot be used to analyze heterogeneously methylated samples. We assessed whether methylation-sensitive high-resolution melting (MS-HRM) is an alternative to MS-PCR.METHODSThe authors prepared 3 primer sets that covered CpG 72–89 for MS-HRM analysis to determine the methylation levels of 6 human glioma cell lines. The results were validated by bisulfite sequencing of cloned alleles. The authors also subjected surgical samples from 75 GBM patients treated with temozolomide (TMZ) to MS-HRM to assess the MGMT methylation status and compared the findings with MS-PCR results using receiver operating characteristic (ROC), univariate, and multivariate analyses.RESULTSThere was a strong correlation between the methylation levels of the 6 glioma cell lines evaluated by MS-HRM and by bisulfite sequencing; with primers 1 and 2, the correlation was significant (r = 0.959 and r = 0.960, respectively, p < 0.01). Based on log-rank analysis, MS-HRM was significantly better than MS-PCR for predicting progression-free survival (PFS) and overall survival (OS) based on the methylation status of the MGMT promoter (PFS predicted by MS-HRM and MS-PCR = 0.00023 and 0.0035, respectively; OS = 0.00019 and 0.00028, respectively). ROC analysis showed that the area under the curve was larger with MS-HRM than with MS-PCR (PFS: 0.723 vs 0.635; OS: 0.716 vs 0.695). Based on multivariate Cox regression analysis, MS-HRM was significantly better than MS-PCR for predicting the treatment outcome (MS-HRM vs MS-PCR: PFS, p = 0.001 vs 0.207; OS, p = 0.013 vs 0.135).CONCLUSIONSThe authors’ findings show that MS-HRM is superior to MS-PCR for the detection of MGMT promoter methylation. They suggest MS-HRM as an alternative to MS-PCR for assessing the prognosis of patients with GBM.

Background Cold polypectomy has been increasingly used to remove diminutive colorectal polyps. We evaluated the local recurrence rate of diminutive polyps at the 1-year follow-up after cold forceps polypectomy (CFP). Methods In a prospective, multicenter, observational cohort study, patients with diminutive colorectal polyps ( ≤ 5 mm) were treated by CFP using jumbo forceps followed by magnified narrow-band imaging (NBI). Patients were assessed for local recurrence at 1-year follow-up. Risk factors associated with local recurrence were analyzed using logistic regression analysis. Results Overall, 955 lesions were resected in 471 patients who completed the 1-year follow-up. The endoscopic complete resection rate was 99.4 %. Immediate and delayed bleeding occurred in 0.8 % and 0.2 % of cases, respectively, with no perforations observed. Local recurrence occurred in 2.1 % of cases at the 1-year follow-up. Univariable analyses indicated that polyps > 3 mm (P 3 mm were significantly associated with local recurrence (odds ratio 3.4, P = 0.02). Conclusions CFP with jumbo forceps followed by NBI-magnified observation had a low local recurrence rate and is an acceptable therapeutic option for diminutive colorectal polyps. Although we recommend limiting the use of CFP with jumbo forceps to polyps ≤ 3 mm in size, future comparative studies are needed to make recommendations on cold polypectomy using either forceps or snares as the preferred approach for diminutive polyp resection.

Aim. Hepatitis B virus (HBV) infection is a major public health concern worldwide. Entecavir (ETV), a first-line nucleos(t)ide analogue (NA) for HBV, has a low risk of resistance. We evaluated the efficacy of ETV monotherapy, ratio of ETV-resistant, and the clinical features of patients with ETV resistance. Methods. A total of 130 patients (72 males, 58 females; mean age, 61 ± 15 years) were divided into a NA-naïve group (n = 108) and NA-experienced group (n = 22). We examined the clinical outcomes of ETV monotherapy and associated factors. We also assessed the clinical features of 15 patients with resistance to ETV (mean, 51.0 ± 27.4 weeks). Results. Among the 130 patients, 94.1% achieved ALT normalization and 63.6% achieved serum HBV DNA negativity after ETV monotherapy for 96 weeks. Of the patients in the NA-naïve group, 93.1% and 60.4% achieved ALT normalization and HBV DNA negativity, respectively. Of the patients in the NA-experienced group, 100% and 74.9% achieved ALT normalization and HBV DNA negativity, respectively. Compared to patients on ETV continuously, 15 ETV-resistant patients had a higher baseline HBV viral load. There was a significant difference in the time to HBV DNA negativity, but not ALT normalization after ETV monotherapy in these groups. Rescue treatment with other NAs led to ALT normalization in all of these patients, but not HBV DNA negativity. Conclusions. ETV monotherapy has a long-term clinical efficacy. While some patients especially with HBV DNA high viral load developed ETV resistance, rescue treatment led to ALT normalization in these patients.

Cerebellar hemangioblastomas remain surgically challenging because of the narrow, deep surgical corridors and tumor hypervascularity. Various surgical approaches are used according to the location, but optimal approaches have not been established. We propose a system of surgical approaches based on the venous drainage systems to facilitate surgical planning and achieve acceptable neurological outcomes. Cerebellar hemangioblastomas were divided into fivefour types based on the main drainage systems: suboccipital hemangioblastomas draining to the transverse sinus (TS) or torcular, tentorial hemangioblastomas draining to the tentorial and straight sinus, petrosal hemangioblastomas draining to the superior petrosal sinus (SPS),, and quadrigeminal hemangioblastomas draining to the galenic system, and tonsillar hemangioblastomas draining to the TS or torcular in conjunction with jugular bulb or SPS. Microsurgical approaches and patient outcome were retrospectively reviewed according to this classification. This study included 17 patients who underwent 21 operations for resection of 19 cerebellar hemangioblastomas, classified into 911 suboccipital, 4 tentorial, 2 petrosal, and 2 quadrigeminal, and 2 tonsillar. Standard suboccipital craniotomies were utilized for suboccipital hemangioblastomas, the occipital transtentorial approach (OTA) and supracerebellar infratentorial approach for tentorial hemangioblastomas, the retrosigmoid approach for petrosal hemangioblastomas, and OTA for quadrigeminal hemangioblastomas, and midline suboccipital approach for tonsillar hemangioblastomashemangioblastomass. Gross total resection was achieved in all patients except one. Two patients with large hemangioblastomas (tonsillarsuboccipital and quadrigeminal) required second-stage operation which finally achieved gross total removal. No single approach had a significantly higher incidence of postoperative neurological deficits. Selection of the optimum surgical approach for cerebellar hemangioblastomas was successful based on the main drainage systems. Understanding of tumor growth and extension with respect to the venous drainage system is critical to select the appropriate surgical approach.

Background Statins have been associated with reduced recurrence and better functional outcomes in patients with acute ischemic stroke. However, the effect of statins in patients with acute large vessel occlusion (LVO) is not well scrutinized. Methods and Results RESCUE (Recovery by Endovascular Salvage for Cerebral Ultra‐Acute Embolism)‐Japan Registry 2, a physician‐initiated registry, enrolled 2420 consecutive patients with acute LVO who were admitted to 46 centers across Japan within 24 hours of onset. We compared patients with and without statin use after acute LVO onset (statin group and nonstatin group, respectively) in terms of the modified Rankin scale at 90 days. We estimated that the odds ratios for the primary outcome was modified Rankin scale and we estimated the odds ratios for a 1‐scale lower modified Rankin scale adjusting for confounders. After excluding 12 patients without LVO and 9 patients without follow‐up, the mean age of 2399 patients was 75.9 years; men accounted for 55% of patients. Statins were administered to 447 (19%) patients after acute LVO onset. Patients in the statin group had more atherothrombotic cerebral infarctions (34.2% versus 12.1%, P P P P =0.02). The mortality at 90 days was lower in the statin group (4.7%) than the nonstatin group (12.5%; P P =0.02). Conclusions Statin administration after acute LVO onset is significantly associated with better functional outcome and mortality at 90 days.

We report the short-term results with aspiration embolectomy using an ACE68 reperfusion catheter to treat patients with acute embolic superior mesenteric artery (SMA) occlusion. Our study included 4 consecutive male patients ranging in age from 72 to 86 years (mean age 79 years). In all patients, the main trunk of the SMA was occluded. The technical success rate was 100% for all procedures. There were no major procedure-related complications. One patient underwent laparotomy with intestinal resection after successful recanalization. No patient reported clinical symptoms of abdominal ischemia at follow-up. Our short-term experience shows that percutaneous aspiration embolectomy using an ACE68 reperfusion catheter is an effective treatment for acute mesenteric ischemia.

Herein, we report a rare case of penetrating transorbital cavernous sinus injury caused by a bamboo stick, treated by craniotomy in a hybrid operating room. A 63-year-old gardener presented at our hospital with right upper orbital injury after falling on a bamboo basket. Neurological examination revealed right II, III, IV, and VI cranial nerve palsies. CT and MRI revealed a right transorbital penetrating injury by a small sharp wooden foreign body, extending from the orbit to the cavernous sinus via the superior orbital fissure. Preoperative digital subtraction angiography revealed partial occlusion of the right cavernous sinus by the foreign body and no internal carotid artery(ICA)injury. There was a nine-day waiting period after the injury because the patient was on dual antiplatelet therapy for ischemic heart disease. Subsequently, the bamboo stick was completely removed through the right fronto-temporo-orbito-zygomatic approach in a hybrid operating room. To treat the potential massive hemorrhage, a five-French balloon catheter was inserted in the right ICA at its origin via the right transfemoral approach before the craniotomy. The bamboo stick was completely removed with minor hemorrhage in the cavernous sinus; this was controlled using hemostatic materials. The postoperative course was uneventful. The patient was discharged with blindness and total ophthalmoplegia in the right eye but he was able to return to his prior job. This is the first report of such a treatment of a transorbital penetrating injury in a hybrid operating room.

We report a case of anterior cranial fossa dural arteriovenous fistula(ACF-DAVF)in a patient whose diagnosis was made according to characteristic findings on arterial spin labeling(ASL)MRI. CASE:A 68-year-old man was admitted to our hospital because of intractable epilepsy. Based on the initial MRI findings, an initial diagnosis of limbic encephalitis was made. Steroids and anticonvulsant drugs were administered;however, the seizures could not be controlled. A second MRI with ASL revealed abnormal vessel signals in the base segments of the left frontal and temporal lobes toward the basal vein of Rosenthal. Digital subtraction angiography(DSA)revealed an arteriovenous shunt in the left anterior cranial fossa, which drained toward the medial side of the left temporal lobe. A diagnosis of ACF-DAVF with status epilepticus was made, and the main drainer was cauterized. After the surgical procedure, the epilepsy was controlled with antiepileptic drugs, and postoperative MRI revealed obliteration of ACF-DAVF, disappearance of the high-intensity area on FLAIR sequences, and disappearance of the high-intensity signal area on ASL.

Aim We aimed to establish a telestroke system for general physicians in areas without a nearby stroke center and investigate its usefulness for recombinant tissue plasminogen activator (rt‐PA) therapy for patients with acute cerebral infarction. Methods We used a hub and spoke model, in which a hub hospital provided telestroke support to the spoke hospitals in rural areas that were not nearby a stroke center. The telestroke support device enabled the sharing of images and real‐time face‐to‐face discussion with a stroke specialist for diagnosis and treatment. We evaluated the effect of this telestroke system on shortening time to start rt‐PA therapy. Result One hub and three spoke hospitals were selected. From May 2017 to November 2018, seven patients (77.2 ± 6.3 years old) suspected to have acute cerebral infarction were treated at the spoke hospitals via this system, three of whom received intravenous rt‐PA administration by a general physician under telestroke support. If these patients would have been sent via ground ambulance to the nearby stroke center, it would have taken approximately 48 min more to administer rt‐PA. Conclusion Establishment of a telestroke support system for general physicians in areas without a nearby stroke center was useful for promptly performing rt‐PA therapy., Telemedicine device. We used iPad mini installed with a thin client viewer system and the video call system, which allowed specialists in the “hub” hospital to review computed tomography images, assess the patient, and make recommendations face‐to‐face in real time.

A 37-year-old obese man who was a social drinker was admitted to our hospital to undergo a detailed examination for liver injury with anti-mitochondrial antibody positivity. Abdominal ultrasonography revealed moderate fatty liver. A histological analysis showed steatosis of approximately 30% of the hepatocytes, focal necrosis, a few ballooning hepatocytes and lobular inflammation suggestive of steatohepatitis, epithelioid granuloma and irregularity of the sequence of the bile duct epithelium accompanied by lymphocyte infiltration suggestive of chronic cholangitis. He was diagnosed with non-alcoholic steatohepatitis complicated with primary biliary cholangitis. His liver injury was improved by weight loss and high-dose ursodeoxycholic acid treatment.

A 60-year-old man with an unruptured cerebral aneurysm and family history of moyamoya disease was admitted to our hospital with epigastric pain since the previous day. Serum levels of pancreatic enzyme were elevated and abdominal contrast-enhanced computed tomography showed localized enlargement of the pancreatic tail in the arterial phase and revealed numerous areas of fine mesh-like vascular hyperplasia consistent with an enlarged pancreatic tail. We diagnosed pancreatic arteriovenous malformation (P-AVM) with acute pancreatitis. Furthermore, in the pancreatic body, endoscopic ultrasonography showed lobularity (honeycombing type) and hyperechoic foci (non-shadowing), which suggests chronic pancreatitis. Acute management was performed with conservative treatment including administration of replacement fluids and proteolytic enzyme inhibitor. Distal pancreatectomy for P-AVM was performed because P-AVM is associated with acute pancreatitis recurrence, development of portal hypertension, progression of chronic pancreatitis, and refractory duodenal bleeding. Histological findings on the resected specimens revealed the anastomosis of abnormal arteries and veins, which suggested P-AVM. In addition, inflammation accompanied by fat necrosis due to ischemic infarction in the pancreatic tail, which suggested acute pancreatitis, and mild fibrosis in the pancreatic body, which suggested chronic pancreatitis, were shown. Although P-AVM is associated with various complications, symptomatic P-AVM should be considered a chronic and progressive disease.

The WHO2016 CNS update requires a combined histological and molecular assessment. To assess the major aberrations such as co-deletion of complete chromosome arms 1p and 19q (Co-del), isocitrate dehydrogenase and histone H3 mutations, direct sequencing, multiplex ligation-dependent probe amplification and/or FISH are methods considered to be "golden standard" in the community. However, these methods are expensive and complicated. The aim of this study is verification of the sensitivity of the simple PCR-based techniques for assessment of molecular information in daily diagnosis. We analyzed a total number of 80 patients with gliomas. FISH and PCR-based microsatellite analysis were compared for Co-del assessment. Direct sequencing and qPCR using hig-resolution melting (HRM) were compared for IDH and histone H3 mutations. The sensitivity and specificity of FISH were 0.71 and 0.79, respectively. FISH using a commercially available Vysis probe had a risk of high false-positive rate (0.25). For assessment of IDH1 mutations, the sensitivity and specificity of HRM were 1.0 and 0.96, respectively. For assessment of IDH2 and H3 mutations by HRM, both sensitivity and specificity were 1.0. We consider PCR-based molecular analysis to be a simple and accurate technique in daily diagnosis that is readily available for a small scientific facility.

Since diffuse hepatic hemangiomatosis (DHH) is an extremely rare disease especially in adults, the etiology and natural course of adult-onset DHH has not been well understood. We report a case of DHH complicated with multiple organic dysfunction and Kasabach-Merritt syndrome (KMS) in an 83-year-old female. She presented with mild abdominal distension and laboratory findings revealed thrombocytopenia and abnormal coagulation, indicating disseminated intravascular coagulation (DIC). Enhanced computed tomography revealed diffuse, hypodense hepatic nodules with delayed enhancement involving the whole liver, and multiple hypodense splenic legions. To obtain a definitive diagnosis, laparoscopic-guided biopsy was performed. Histological findings revealed irregularly dilated non-anastomotic vascular spaces, which were lined with flat endothelial cells without cellular atypia. We diagnosed this as DHH complicated with splenic lesions and KMS. Although the patient was treated with symptomatic treatment, such as anti-coagulation therapy, hemangiomatous lesions, especially in the spleen, progressed rapidly, leading to worsening of DIC. Finally, the patient died of multiple organ failure at 12 months after diagnosis. A postmortem examination demonstrated diffuse hemangiomatosis of not only the liver and spleen, but also the adrenal glands and bone marrow. Despite no malignant histologically, DHH can be fatal if it progresses rapidly within a short period of time.

Introduction We evaluated the effect of prior antiplatelet therapy on large vessel occlusion (LVO) in patients with non-valvular atrial fibrillation (NVAF) newly initiated on apixaban. Methods Patients with acute LVO with acute stroke due to NVAF or stenosis with NVAF started on apixaban within 14 days of onset were enrolled. We compared incidence of major bleeding, cerebral hemorrhage, ischemic events, cerebral infarction, and all-cause mortality between patients with and without prior antiplatelet therapy for acute LVO. We also compared these events between patients who continued antiplatelet therapy after onset (continued group) and those who discontinued it (discontinued group). Hazard ratios were estimated after adjusting for confounders; interaction was evaluated considering intravenous thrombolysis (IVT) or endovascular treatment (EVT) according to major bleeding. Results The study comprised 686 eligible patients (excluded [n = 194]; enrolled [n = 492]). The antiplatelet group consisted of older patients (mean: 79 vs. 76 years; p = 0.006) and had a higher cumulative incidence of major bleeding (7.3% vs. 2.9%, p = 0.003). The incidence of ischemic events and all-cause mortality was similar between the groups. Among the 109 patients in the antiplatelet group, the cumulative incidence of major bleeding, ischemic events, and all-cause mortality was comparable between continued group (n = 26) and discontinued group (n = 83). There were no significant differences between groups with and without IVT/EVT. However, major bleeding occured more frequently in the antiplatelet group without IVT. Conclusion Prior antiplatelet therapy for LVO in patients with NVAF newly initiated on apixaban was associated with major bleeding, which was more frequent in the antiplatelet group without IVT.

Microvascular proliferation (MVP), an aberrant vascular structure is a histopathological hallmark of glioblastoma multiforme (GBM). Although MVP tends to be associated with high-grade glioma, it has also been detected in WHO grade I pilocytic astrocytoma (PA). However, little is known about the mechanism underlying its formation. Using TP53 point mutations as a marker for tumor-derived cells, we earlier reported that MVP was partially converted from tumor cells via mesenchymal transition. In the current study we used the KIAA1549-BRAF fusion gene as a marker to assess whether MVPs in PA contained tumor-derived cells and/or phenotypically distinct tumor cells expressing vascular markers. Samples from three PA patients harbored the KIAA1549 exon 15, BRAF exon 9 fusion gene. In two patient samples with abundant MVP, RT-PCR assay detected strong bands arising from the KIAA1549-BRAF fusion gene in both tumor cells and cellular components of MVP. Digital PCR showed that vis-à-vis tumor tissue, its relative expression in cellular components of MVP was 42% in one- and 76% in another sample. FISH revealed amplified signals in both tumor cells and cellular components of MVP indicative of tandem duplication. Our findings suggest that in patients with PA, some cellular components of MVP contained tumor derived cell and/or phenotypically distinct tumor cells expressing vascular markers.

Background and Purpose— Arterial spin-labeling magnetic resonance imaging is sensitive for detecting hyperemic lesions (HLs) in patients with acute ischemic stroke. We evaluated whether HLs could predict blood–brain barrier (BBB) disruption and hemorrhagic transformation (HT) in acute ischemic stroke patients. Methods— In a retrospective study, arterial spin-labeling was performed within 6 hours of symptom onset before revascularization treatment in 25 patients with anterior circulation large vessel occlusion on baseline magnetic resonance angiography. All patients underwent angiographic procedures intended for endovascular therapy and a noncontrast computed tomography scan immediately after treatment. BBB disruption was defined as a hyperdense lesion present on the posttreatment computed tomography scan. A subacute magnetic resonance imaging or computed tomography scan was performed during the subacute phase to assess HTs. The relationship between HLs and BBB disruption and HT was examined using the Alberta Stroke Program Early Computed Tomography Score locations in the symptomatic hemispheres. Results— A HL was defined as a region where CBF relative ≥1.4 (CBF relative =CBF HL /CBF contralateral ). HLs, BBB disruption, and HT were found in 9, 15, and 15 patients, respectively. Compared with the patients without HLs, the patients with HLs had a higher incidence of both BBB disruption (100% versus 37.5%; P =0.003) and HT (100% versus 37.5%; P =0.003). Based on the Alberta Stroke Program Early Computed Tomography Score locations, 21 regions of interests displayed HLs. Compared with the regions of interests without HLs, the regions of interests with HLs had a higher incidence of both BBB disruption (42.8% versus 3.9%; P P Conclusions— HLs detected on pretreatment arterial spin-labeling maps may enable the prediction and localization of subsequent BBB disruption and HT.

The epidemiology of patients with traumatic brain injury (TBI) has changed dramatically over recent decades as a result of rapid advances in aging societies. We assessed the influence of age on outcomes of patients with TBI and sought to identify prognostic factors for in-hospital mortality of TBI among elderly patients.Using a nationwide database, we analyzed data from 5651 patients with TBI. Univariate analysis was conducted to compare patient demographics, neurologic status on admission, radiologic findings, systemic complication rates, length of hospital stay, in-hospital mortality, and home discharge rates between elderly and nonelderly groups. Multivariable analysis was conducted to determine prognostic factors for in-hospital mortality among elderly patients.Overall in-hospital mortality was significantly higher in elderly patients (12.8% vs. 19.3%; P0.001). In-hospital mortality of elderly patients with mild TBI increased significantly at7 days after admission, whereas that of elderly patients with moderate or severe TBI was significantly higher immediately after admission. Age (odds ratio [OR], 1.62; P = 0.024), male sex (OR, 1.30; P = 0.004), Japan Coma Scale score on admission (OR, 5.95, P0.001), and incidence of acute subdural hematoma (OR, 1.89; P0.001) were associated with in-hospital mortality in elderly patients with TBI.Elderly patients with TBI showed significantly higher in-hospital mortality. Delayed increases in in-hospital mortality were observed among elderly patients with mild TBI. Level of consciousness on admission was the strongest predictor of in-hospital mortality among elderly patients.

Article, Scientific reports.9 :102(2019)

Microvascular proliferation (MVP), an aberrant vascular structure containing multilayered mitotically active endothelial- and smooth-muscle cells/pericytes, is a histopathological hallmark of glioblastoma multiforme (GBM). Although MVP tends to be associated with high-grade glioma, it has also been detected in WHO grade I pilocytic astrocytoma (PA). However, little is known about the mechanism underlying its formation. Using TP53 point mutations as a marker for tumor-derived cells, we earlier reported that MVP was partially converted from tumor cells via mesenchymal transition. In the current study we used the KIAA1549-BRAF fusion gene as a marker to assess whether MVPs in PA contained tumor-derived cells and/or phenotypically distinct tumor cells expressing vascular markers. cDNA synthesized from frozen tissue of six PA patients operated at our institute was analyzed to detect the KIAA1549-BRAF fusion gene by reverse transcription polymerase chain reaction (RT-PCR) assay. The breakpoint in the fusion gene was identified by long and accurate PCR (LA-PCR) and Sanger sequencing of genomic DNA. Distinct tumor cells and cellular components of MVP were obtained by laser microdissection. For the qualitative and quantitative detection of the KIAA1549-BRAF fusion gene we performed genomic and digital PCR assays. Fluorescence in situ hybridization (FISH) was used to assess gene fusion in cellular components of MVP. Samples from three PA patients harbored the KIAA1549 exon 15, BRAF exon 9 fusion gene. In two patient samples with abundant MVP, RT-PCR assay detected strong bands arising from the KIAA1549-BRAF fusion gene in both tumor cells and cellular components of MVP. Digital PCR showed that vis-à-vis tumor tissue, its relative expression in cellular components of MVP was 42% in one- and 76% in another sample. FISH revealed amplified signals in both tumor cells and cellular components of MVP indicative of tandem duplication. Our findings suggest that in patients with PA, some cellular components of MVP contained tumor derived cell and/or phenotypically distinct tumor cells expressing vascular markers.

Autoimmune hepatitis (AIH) is an autoimmune liver disease that is characterized by a progressive destruction of the liver parenchyma and the development of liver fibrosis. We aimed to examine the relationship between circulating cytokines/chemokines and the Mac-2 binding protein glycosylation isomer (M2BPGi) levels in Japanese patients with autoimmune hepatitis (AIH). We investigated the relationship between circulating cytokines/chemokines and M2BPGi levels in Japanese patients with AIH. Seventy-seven patients with well-documented AIH were enrolled in the National Hospital Organization (NHO)-AIH-liver-network database. We measured the serum levels of 20 cytokines in 31 selected AIH patients before and after steroid treatment using multisuspension cytokine array. Eleven cytokines and soluble adhesion molecules were increased in untreated AIH patients compared with treated AIH patients. Among these cytokines and soluble adhesion molecules, soluble intercellular adhesion molecule-1 (sICAM-1) and interferon-γ-inducible protein 10 (IP-10) were most downregulated by steroid therapy in AIH patients. We measured serum sICAM-1 and IP-10 by ELISA and found the levels were significantly higher in AIH patients (n = 77) compared with chronic viral hepatitis C patients (n = 32). Furthermore, there was a positive correlation between sICAM-1 or IP-10 and alanine aminotransferase, total bilirubin, and circulating M2BPGi levels. M2BPGi levels were increased in AIH patients with high stages of liver fibrosis. Additionally, M2BPGi levels were correlated with the histological grade of inflammation in AIH. Circulating M2BPGi levels were significantly reduced by steroid treatment in AIH patients. sICAM-1 and IP-10 are useful markers to assess immune-mediated hepatitis activity in AIH and they correlate with circulating M2BPGi. Serum M2BPGi levels increased in untreated AIH patients with active hepatitis and were decreased by steroid therapy. M2BPGi reflects autoimmune-mediated hepatic inflammation as well as liver fibrosis.

Tocilizumab, an anti-human interleukin 6 receptor (IL-6R) monoclonal antibody, is widely used to treat rheumatoid arthritis (RA) and is expected to exhibit clinical efficacy when used to treat other autoimmune diseases. However, a risk of opportunistic infection is occasionally recognized. A 54-year-old woman had received an oral corticosteroid and methotrexate to treat RA. Despite receiving these treatments, she received additional treatment with tocilizumab due to poor control of the disease activity. She presented at our hospital with a high fever and epigastralgia 19 days after receiving this treatment. A laboratory evaluation revealed liver injury and cytomegalovirus (CMV) viremia. Abdominal ultrasonography and computed tomography (CT) revealed hepatosplenomegaly, but no ascites. Upper gastrointestinal endoscopy revealed gastric erosions induced by CMV, which were confirmed immunohistochemically. Hence, we diagnosed the patient with CMV reactivation-induced acute hepatitis and gastric erosions under tocilizumab treatment. She received an anti-cytomegalovirus drug, ganciclovir, for 14 days due to her viremia and impaired general condition, which was suggestive of a severe infection. Her general condition subsequently improved, the liver function test results normalized, and the gastric erosions disappeared. In conclusion, although tocilizumab is very useful for treating certain autoimmune and inflammatory diseases, and will be prescribed more widely in the future, associated CMV infections must be closely monitored, as these can be lethal.

Background FOLFIRINOX (FFX) and gemcitabine (GEM) plus nab-paclitaxel (GnP) have recently been available for treating pancreatic ductal adenocarcinoma (PDAC). We investigated trends in characteristics, treatment and outcomes of unselected patients with unresectable PDAC in real-life practice in Japan. Methods We retrospectively reviewed the medical records of 1085 patients diagnosed as having unresectable or recurrent PDAC in multiple centers in the Hokuriku area between January 2009 and July 2015. Results The incidence of pathologically proven PDAC had increased from 18.7% in 2009 to 56.2% in 2015. Oncological therapy was administered to 779 patients (71.8%): chemotherapy (n = 675), chemo-radiotherapy (n = 92) or radiotherapy (n = 12); the remaining patients were treated with best supportive care. Of 100 patients diagnosed in 2009, 62.0% received GEM as first-line chemotherapy; whereas 30.7% of the 75 patients diagnosed in 2015 received FFX, 25.3% GnP, 22.7% GEM and 17.3% S-1. The objective response rates of patients treated with FFX, GnP and GEM were 14.9%, 35.0% and 5.5%, respectively and the OS 10.3, 9.9 and 7.5 months after FFX, GnP and GEM, respectively. Grade 3 or greater any hematological toxicity occurred in 70.2%, 70.0% and 18.8% of the patients treated with FFX, GnP and GEM, respectively. The reasons for treatment discontinuation were adverse events in 9.8%, 26.7% and 24.1% of the patients treated with FFX, GnP and GEM, respectively. Conclusion Chemotherapeutic protocols changed dramatically between 2009 and 2015. Continuous collection and analysis for our cohort with longer follow-up provides useful information about treatment selection and prediction of outcome.