Direct oral anticoagulants versus vitamin K antagonists after recent ischemic stroke in patients with atrial fibrillation

Objective: We compared outcomes after treatment with direct oral anticoagulants (DOAC) and Vitamin‐K antagonists (VKA) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. Methods: We conducted an individual patient data analysis of 7 prospective cohort studies. We included patients with AF and a recent cerebral ischemia (<3 months before starting oral anticoagulation) and a minimum follow‐up of 3 months. We analyzed the association between type of anticoagulation (DOAC vs. VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HR) with 95% confidence intervals (95% CI). Results: We included 4912 patients (median age 78 years [IQR 71‐84]; 2331 [47.5%] women, median NIHSS at onset 5 [IQR 2‐12]); 2256 (45.9%) patients received VKA and 2656 (54.1%) DOAC. The median time from index event to starting oral anticoagulation was 5 days (IQR 2‐14) for VKA and 5 days (IQR 2‐11) for DOAC (p=0.53). There were 262 AIS (4.4%/year), 71 ICH (1.2%/year) and 439 deaths (7.4%/year) during the total follow‐up of 5970 patient‐years. Compared to VKA, DOAC treatment was associated with reduced risks of the composite endpoint (HR 0.82, 95%CI 0.67‐1.00, p=0.05) and ICH (HR 0.42, 95%CI 0.24‐0.71, p<0.01); we found no differences for the risk of recurrent AIS (HR 0.91, 95%CI 0.70‐1.19, p=0.5) and mortality (HR 0.83, 95%CI 0.68‐1.03, p=0.09). Interpretation: DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly due to lower risks of ICH

Ischemic stroke despite oral anticoagulant therapy in patients with atrial fibrillation

Objective: It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. Methods: We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OACprior ) with those without prior oral anticoagulation (OACnaive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OACchanged ) with those who continued the same anticoagulation as secondary prevention (OACunchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine-Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71-84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2-12]). The median CHA2 DS2 -Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) was 5 (IQR = 4-6) and was similar for OACprior (n = 1,195) and OACnaive (n = 4,119, p = 0.103). During 6,128 patient-years of follow-up, 289 patients had AIS (4.7% per year, 95% CI = 4.2-5.3%). OACprior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2-2.3, p = 0.005). OACchanged (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7-2.1, p = 0.415) compared with OACunchanged (n = 585). Interpretation: Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA2 DS2 -Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high-risk patient group

Major-nerve schwannomas versus intramuscular schwannomas

Background: A schwannoma is a benign peripheral nerve tumor. Predicting the involvement of a nerve on symptoms or MR findings is crucial to the diagnostic process. Purpose: To compare symptoms, MR findings, and histological findings between major nerve schwannomas and intramuscular schwannomas. Material and Methods: Thirty-four patients with 36 schwannomas (29 major nerve schwannomas and 7 intramuscular schwannomas) surgically excised and proven histologically were retrospectively reviewed. Results: Frequencies of the Tinel - like sign, split-fat sign, entering and exiting nerve, and low-signal margin indicate the presence of the nerve and were significantly higher in major nerve schwannomas than in intramuscular schwannomas. In tumor morphological patterns (the target sign, inhomogeneous pattern, and homogeneous pattern), there were no significant differences between major nerve schwannomas and intramuscular schwannomas. Schwannomas showing the target sign histologically tended to be less degenerative. All major nerve schwannomas and 5 intramuscular schwannomas produce some characteristic symptoms and/or MR findings, but two intramuscular schwannomas didn't have any characteristic symptoms and findings. Conclusion: In major nerve schwannomas, the Tinel - like sign, split-fat sign, entering and exiting nerve, and low-signal margin are commonly observed and useful for diagnosis. In intramuscular schwannomas, these characteristic findings are less common, which makes diagnosis difficult

Interferon-alpha/beta Receptor as a Prognostic Marker in Osteosarcoma

Background: A large-scale randomized trial of adjuvant interferon-a therapy for patients with osteosarcoma has been initiated as a joint protocol by the European and American Osteosarcoma Study Group. Because the expression of functional interferon-α/β receptor is necessary for interferon-a agents to interact with osteosarcoma cells, we examined the expression of interferon-α/β receptor in a series of osteosarcoma specimens. Methods: Forty patients with high-grade resectable osteosarcoma, from whom surgical specimens had been obtained at the time of biopsy, were included in this retrospective study. Biopsy specimens were immunohistochemically stained with anti-interferon-α/β receptor antibodies. Survival was estimated with the Kaplan-Meier method. The Cox proportional hazards model was used for multivariate analysis to determine the independent prognostic factors. Furthermore, we used Holm and Benjamini-Hochberg procedures to adjust for multiple comparisons in setting the level of significance. The median follow-up period was five years and two months (range, four to 195 months). Results: The expression of interferon-α/β receptor was positive in eighteen (45%) of the forty patients with high-grade osteosarcoma. American Joint Committee on Cancer surgical stage IIA, a good histologic response to chemotherapy, and expression of interferon-α/β receptor correlated significantly with better disease-free survival (p < 0.05). Multivariate analysis showed that interferon-α/β receptor expression alone retained its power to predict an improved prognosis (p = 0.042). There were no significant variables after corrections for multiple comparisons. Conclusions: Interferon-α/β receptor may be a useful marker for assessing tumor prognosis in patients with osteosarcoma and may play an important role in tumor progression. These findings are encouraging and support the ongoing clinical trials of adjuvant interferon-a therapy by the multinational Osteosarcoma Study Group. Our pilot study was based on a small sample size, and larger trials are needed to confirm this finding. Level of Evidence: Prognostic Level II. See Instructions to Authors for a complete description of levels of evidence

Hemodynamic state of periictal hyperperfusion revealed by arterial spin-labeling perfusion MR images with dual postlabeling delay

Background: Magnetic resonance imaging (MRI), including perfusion MRI with arterial spin labeling (ASL) and diffusion-weighted imaging (DWI), are applied in the periictal detection of circulatory and metabolic consequences associated with epilepsy. Although previous report revealed that prolonged ictal hyperperfusion on ASL can be firstly detected and cortical hyperintensity of cytotoxic edema on DWI secondarily obtained from an epileptically activated cortex, the hemodynamic state of the periictal hyperperfusion has not been fully demonstrated. Methods: study-1: We retrospectively analyzed the relationship between seizure manifestations and the development of periictal MRI findings, in Case 1 with symptomatic partial epilepsy, who underwent repeated periictal ASL/DWI examination for three epileptic ictuses (one examination for each ictus). Study-2: We evaluated the hemodynamic state of periictal hyperperfusion with the ASL technique using a dual postlabeling delay (PLD) of 1.5 and 2.5 s in nine patients, according to the presence or absence of the localized epileptogenic lesion (EL) on conventional 3 T-MRI, who were divided into Group EL+ (six patients) and Group EL− (three patients). Results: Study-1 confirmed that the stratified representation of the periictal MRI findings depends on the time interval between the ictal cessation and MRI examination in addition to the magnitude and duration of the epileptic activity. In Study-2, two types of periictal hyperperfusion were noted. In all six Group EL+ patients, periictal ASL findings showed “fast flow type”. Markedly increased ASL signals were noted at the epileptically activated cortex, having a tight topographical relationship with EL, on ASL with a PLD of 1.5 s, which is decreased on ASL with a PLD of 2.5 s. In all three Group EL− patients, periictal ASL findings showed “gradual flow type”, which is characterized by gradual signal increase of the epileptically activated cortex on ASL with a PLD of 1.5 and 2.5 s. Conclusion: We confirmed that ASL hyperperfusion is superior to DWI in the periictal detection of epileptic events. ASL with dual PLD offers the ability to document two types of hemodynamics of periictal hyperperfusion. Keywords: Arterial spin labeling, Cytotoxic edema, Diffusion-weighted image, Ictal hyperperfusio

Dominant Expression of DCLK1 in Human Pancreatic Cancer Stem Cells Accelerates Tumor Invasion and Metastasis

<div><p>Patients with pancreatic cancer typically develop tumor invasion and metastasis in the early stage. These malignant behaviors might be originated from cancer stem cells (CSCs), but the responsible target is less known about invisible CSCs especially for invasion and metastasis. We previously examined the proteasome activity of CSCs and constructed a real-time visualization system for human pancreatic CSCs. In the present study, we found that CSCs were highly metastatic and dominantly localized at the invading tumor margins in a liver metastasis model. Microarray and siRNA screening assays showed that doublecortin-like kinase 1 (DCLK1) was predominantly expressed with histone modification in pancreatic CSCs with invasive and metastatic potential. Overexpression of DCLK1 led to amoeboid morphology, which promotes the migration of pancreatic cancer cells. Knockdown of DCLK1 profoundly suppressed in vivo liver metastasis of pancreatic CSCs. Clinically, DCLK1 was overexpressed in the metastatic tumors in patients with pancreatic cancer. Our studies revealed that DCLK1 is essential for the invasive and metastatic properties of CSCs and may be a promising epigenetic and therapeutic target in human pancreatic cancer.</p></div