Impact of qualifying artery on the efficacy of stenting plus medical therapy versus medical therapy alone in patients with symptomatic intracranial stenosis: a post-hoc analysis of the CASSISS trial.

BACKGROUND: A recent trial failed to show any benefit of stenting plus medical therapy over medical therapy alone in patients with symptomatic intracranial stenosis. We aimed to examine whether the symptomatic qualifying artery modifies the effect of stenting plus medical therapy. METHODS: This is a post-hoc analysis of the CASSISS trial that included patients with symptomatic intracranial stenosis, randomly assigned to undergo stenting plus medical therapy or medical therapy alone; 358/380 patients were included. Multivariable logistic regression analysis was used with an interaction term to estimate the altered treatment effect by the qualifying artery. The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The five secondary outcomes included stroke or death related to the qualifying artery territory at 2 and 3 years. RESULTS: No significant treatment allocation-by-stenosis site interaction was observed (Pinteraction=0.435). Compared with medical therapy alone, the adjusted ORs for stenting plus medical therapy were 2.73 (95% CI 0.42 to 17.65) for internal carotid artery stenosis, 1.20 (95% CI 0.29 to 4.99) for M1 stenosis, 0.23 (95% CI 0.02 to 2.31) for vertebral artery stenosis, and 1.33 (95% CI 0.34 to 5.28) for basilar artery stenosis. Of the five secondary outcomes, none showed a significant treatment allocation-by-stenosis site interaction including stroke in the qualifying artery territory at 2 years (Pinteraction=0.659) and 3 years (Pinteraction=0.493). CONCLUSIONS: Among patients with transient ischemic attacks or ischemic stroke due to severe intracranial atherosclerotic stenosis, there was no evidence that the symptomatic qualifying artery could determine the addition of stenting to medical therapy.

Effect of Stenting Plus Medical Therapy vs Medical Therapy Alone on Risk of Stroke and Death in Patients With Symptomatic Intracranial Stenosis: The CASSISS Randomized Clinical Trial.

Importance: Prior randomized trials have generally shown harm or no benefit of stenting added to medical therapy for patients with symptomatic severe intracranial atherosclerotic stenosis, but it remains uncertain as to whether refined patient selection and more experienced surgeons might result in improved outcomes. Objective: To compare stenting plus medical therapy vs medical therapy alone in patients with symptomatic severe intracranial atherosclerotic stenosis. Design, Setting, and Participants: Multicenter, open-label, randomized, outcome assessor-blinded trial conducted at 8 centers in China. A total of 380 patients with transient ischemic attack or nondisabling, nonperforator (defined as nonbrainstem or non-basal ganglia end artery) territory ischemic stroke attributed to severe intracranial stenosis (70%-99%) and beyond a duration of 3 weeks from the latest ischemic symptom onset were recruited between March 5, 2014, and November 10, 2016, and followed up for 3 years (final follow-up: November 10, 2019). Interventions: Medical therapy plus stenting (n = 176) or medical therapy alone (n = 182). Medical therapy included dual-antiplatelet therapy for 90 days (single antiplatelet therapy thereafter) and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. There were 5 secondary outcomes, including stroke in the qualifying artery territory at 2 years and 3 years as well as mortality at 3 years. Results: Among 380 patients who were randomized, 358 were confirmed eligible (mean age, 56.3 years; 263 male [73.5%]) and 343 (95.8%) completed the trial. For the stenting plus medical therapy group vs medical therapy alone, no significant difference was found for the primary outcome of risk of stroke or death (8.0% [14/176] vs 7.2% [13/181]; difference, 0.4% [95% CI, -5.0% to 5.9%]; hazard ratio, 1.10 [95% CI, 0.52-2.35]; P = .82). Of the 5 prespecified secondary end points, none showed a significant difference including stroke in the qualifying artery territory at 2 years (9.9% [17/171] vs 9.0% [16/178]; difference, 0.7% [95% CI, -5.4% to 6.7%]; hazard ratio, 1.10 [95% CI, 0.56-2.16]; P = .80) and 3 years (11.3% [19/168] vs 11.2% [19/170]; difference, -0.2% [95% CI, -7.0% to 6.5%]; hazard ratio, 1.00 [95% CI, 0.53-1.90]; P > .99). Mortality at 3 years was 4.4% (7/160) in the stenting plus medical therapy group vs 1.3% (2/159) in the medical therapy alone group (difference, 3.2% [95% CI, -0.5% to 6.9%]; hazard ratio, 3.75 [95% CI, 0.77-18.13]; P = .08). Conclusions and Relevance: Among patients with transient ischemic attack or ischemic stroke due to symptomatic severe intracranial atherosclerotic stenosis, the addition of percutaneous transluminal angioplasty and stenting to medical therapy, compared with medical therapy alone, resulted in no significant difference in the risk of stroke or death within 30 days or stroke in the qualifying artery territory beyond 30 days through 1 year. The findings do not support the addition of percutaneous transluminal angioplasty and stenting to medical therapy for the treatment of patients with symptomatic severe intracranial atherosclerotic stenosis. Trial Registration: ClinicalTrials.gov Identifier: NCT01763320.

Classification modeling method for hyperspectral stamp-pad ink data based on one-dimensional convolutional neural network.

In the questioned document, the examination of stamp-pad ink is crucial scientific evidence to discern the difference between genuine and forged documents. In this study, a new method for rapid and non-destructive identification of types of stamp-pad inks by combining hyperspectral imaging (HSI) technology and deep learning was developed. Twenty stamp-pad inks of different brands and models were collected and numbered in turn, and then, each of them was sealed six times repeatedly on the A4 printing paper for the test. After that, the hyperspectral imager was used to collect the hyperspectral images and the reflectance spectral data were obtained after pixel fusion. Principal component analysis (PCA) and non-negative matrix factorization (NMF) were used to deal with the dataset, but visual results were not good. Then, back propagation neural network (BPNN) and one-dimensional convolutional neural network (1D-CNN) were constructed and their merits and drawbacks were compared. The final loss function of the BPNN of training set and validation set was stable at 0.27 and 0.42, and the classification accuracy of the training set and validation set reached 90.02% and 83.99%, respectively. Compared with the BPNN, the 1D-CNN had better stability and efficiency for the classification. The loss function of the training set and validation set was as low as 0.068 and 0.075, and the final classification accuracy reached 98.30% and 97.94%, respectively. Therefore, the combination of hyperspectral imaging technology and 1D-CNN represents a potentially simple, non-destructive, and rapid method for stamp-pad inks detection and classification.

Safety of endovascular therapy for symptomatic intracranial artery stenosis: a national prospective registry.

INTRODUCTION: The safety outcomes of endovascular therapy for intracranial artery stenosis in a real-world stetting are largely unknown. The Clinical Registration Trial of Intracranial Stenting for Patients with Symptomatic Intracranial Artery Stenosis (CRTICAS) was a prospective, multicentre, real-world registry designed to assess these outcomes and the impact of centre experience. METHODS: 1140 severe, symptomatic intracranial arterial stenosis (ICAS) patients treated with endovascular therapy were included from 26 centres, further divided into three groups according to the annual centre volume of intracranial angioplasty and stent placement procedures over 2 years: (1) high volume for ≥25 cases/year; (2) moderate volume for 10-25 cases/year and (3) low volume for <10 cases/year. RESULTS: The rate of 30-day stroke, transient ischaemic attack or death was 9.7% (111), with 5.4%, 21.1% and 9.7% in high-volume, moderate-volume and low-volume centres, respectively (p<0.05). Multivariable logistic regression confirmed high-volume centres had a significantly lower primary endpoint compared with moderate-volume centres (OR=0.187, 95% CI: 0.056 to 0.627; p≤0.0001), while moderate-volume and low-volume centres showed no significant difference (p=0.8456). CONCLUSION: Compared with the preceding randomised controlled trials, this real-world, prospective, multicentre registry shows a lower complication rate of endovascular treatment for symptomatic ICAS. Non-uniform utilisation in endovascular technology, institutional experience and patient selection in different volumes of centres may have an impact on overall safety of this treatment.

Hyalinizing trabecular tumor of the thyroid: a clinicopathological analysis of four cases and review of the literature.

OBJECTIVE: To explore the clinicopathological features, diagnosis and differential diagnosis of hyalinizing trabecular tumor (HTT) of the thyroid. METHODS: The four HTT specimens were collected including demographics, clinical information, relevant images, the extent of thyroidectomy, the follow-up and representative pathological data of tumors were available for analysis. In addition, the immumohistochemical staining related to the tumor as well as the BRAF and N-ras mutation analysis were analysed. RESULTS: The mean age of four patients was 47 years old and the mean size of the tumor was 2.8 cm. Most of the patients were asymptomatic, while detecting incidentally by using neck ultrasound test. Ultrasound imaging of all cases showed demarcated substantial hypoechoic nodules in ipsilateral thyroid lobe. Computed Tomography (CT) showed a clear low density shadow in the affected thyroid lobe. Tumors of three cases were located at the left, but the other one was located at the right thyroid gland with a complete fibrous capsule. The cytological features resembled papillary thyroid carcinoma (PTC). The histological test indicated that the tumors had characteristic of trabecular growth pattern with hyalinizing material. The tumor cells were in shape of polygonal, oval or high columnar with an acidophilic or clear cytoplasm. The nuclei were oval with inconspicuous small nucleoli, prominent grooves and pseudoinclusion body in cell nucleus. Mitosis and psammoma bodies were rare to be observed. Cytoplasmic "yellow bodies" were frequently observed. The hyaline material was prominent, with positive periodic acid-Schiff (PAS) and negative Congo red staining. Immunohistochemically, tumor cells were positive for thyroglobulin (Tg), thyroid transcription factor-1 (TTF-1), CD56 and negative for calcitonin, cytokeratin 19 (CK19), HBME-1, S-100 and synaptophysin (SyN). Chromogranin A (CgA) and galectin-3 were expressed weakly in some cases. Staining with the MIB-1 antibody showed membranous/cytoplasmic immunoreactivity. Whereas, another clone of Ki-67 (SP6) showed a common nuclear pattern with an index of <1%. None of the four cases exhibited the BRAF V600E protein reactivity. Gene mutation analysis demonstrated no BRAF and N-ras mutation. There was no evidence of local recurrence or metastasis after 6 to 36 months of follow-up. CONCLUSIONS: HTT is an uncommon thyroid tumor with very low malignant potential. It has no particular clinical features, so it's often misdiagnosed in fine needle aspiration cytology (FNAC)/Ultrasonography-guided fine needle aspiration cytology (US-FNAC) and frozen section (FS). Its final diagnosis mainly relies on typical histopathological features and characteristic expression pattern of MIB-1 immunohistochemical staining.

HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells.

Activator protein 1 (AP-1) is a transcriptional factor composed of the dimeric members of bZIP proteins, which are frequently deregulated in human cancer cells. In this study, we aimed to identify an oncogenic AP-1 dimer critical for the proliferation of neuroblastoma cells and to investigate whether histone deacetylase inhibitors (HDACIs), a new generation of anticancer agents, could target the AP-1 dimer. We report here that HDACIs including trichostatin A, suberoylanilidehydroxamic acid, valproic acid and M344 can transcriptionally suppress both c-Jun and Fra-1, preceding their inhibition of cell growth. c-Jun preferentially interacting with Fra-1 as a heterodimer is responsible for AP-1 activity and critical for cell growth. Mechanistically, HDACIs suppress Fra-1 expression through transcriptionally downregulating Raf1 and subsequently decreasing MEK1/2-ERK1/2 activity. Unexpectedly, HDACI treatment caused MKK7 downregulation at both the protein and mRNA levels. Deletion analysis of the 5'-flanking sequence of the MKK7 gene revealed that a major element responsible for the downregulation by HDACI is located at -149 to -3 relative to the transcriptional start site. Knockdown of MKK7 but not MKK4 remarkably decreased JNK/c-Jun activity and proliferation, whereas ectopic MKK7-JNK1 reversed HDACI-induced c-Jun suppression. Furthermore, suppression of both MKK-7/c-Jun and Raf-1/Fra-1 activities was involved in the tumor growth inhibitory effects induced by SAHA in SH-SY5Y xenograft mice. Collectively, these findings demonstrated that c-Jun/Fra-1 dimer is critical for neuroblastoma cell growth and that HDACIs act as effective suppressors of the two oncogenes through transcriptionally downregulating MKK7 and Raf1.

China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS): A new, prospective, multicenter, randomized controlled trial in China.

BACKGROUND: Patients with symptomatic stenosis of intradural arteries are at high risk for subsequent stroke. Since the SAMMPRIS trial, stenting is no longer recommended as primary treatment; however, the results of this trial, its inclusion criteria and its center selection received significant criticism and did not appear to reflect our experience regarding natural history nor treatment complications rate. As intracranial atherosclerosis (ICAS) is the most common cause for stroke in Asian countries, we are hereby proposing a refined prospective, randomized, multicenter study in an Asian population with strictly defined patient and participating center inclusion criteria. METHODS: The China Angioplasty and Stenting for Symptomatic Intracranial Severe Stenosis (CASSISS) trial is an ongoing, government-funded, prospective, multicenter, randomized trial. It recruits patients with recent TIA or stroke caused by 70%-99% stenosis of a major intracranial artery. Patients with previous stroke related to perforator ischemia will not be included. Only high-volume centers with a proven track record will enroll patients as determined by a lead-in phase. Patients will be randomized (1:1) to best medical therapy alone or medical therapy plus stenting. Primary endpoints are any stroke or death within 30 days after enrollment or after any revascularization procedure of the qualifying lesion during follow-up, or stroke in the territory of the symptomatic intracranial artery beyond 30 days. The CASSISS trial will be conducted in eight sites in China with core imaging lab review at a North American site and aims to have a sample size of 380 participants (stenting, 190; medical therapy, 190). Recruitment is expected to be finished by December 2016. Patients will be followed for at least three years. The trial is scheduled to complete in 2019. CONCLUSION: In the proposed trial, certain shortcomings of SAMMPRIS including patient and participating center selection will be addressed. The present manuscript outlines the rationale and design of the study. We estimate that this trial will allow for a critical reappraisal of the role of intracranial stenting for selected patients in high-volume centers.

Multiple intracranial aneurysms associated with multiple dural arteriovenous fistulas and cerebral arteriovenous malformation.

BACKGROUND: The association between intracranial aneurysms and arteriovenous malformations (AVMs) or dural arteriovenous fistulas (DAVFs) has been well documented, and the changes in cerebral blood flow dynamics were thought to be one of the major causes. There has not been a report on intracranial aneurysms associated with multiple DAVFs and AVMs in the same patient. METHODS: The authors report a unique case of multiple intracranial vascular pathologies, including 5 aneurysms, 2 DAVFs, and 1 AVM coexisting in a single patient. The patient presented with headache and left hemiparesis and was found to have 4 bilateral internal carotid aneurysms, 1 ruptured right pericallosal aneurysm, 2 frontoparietal DAVFs, and 1 right temporal AVM. RESULTS: Endovascular coiling and Onyx embolization successfully occluded 4 aneurysms and both DAVFs. The patient remained asymptomatic at 1-year follow-up. CONCLUSIONS: To our knowledge, this is the first report of a very rare case with a unique combination of cerebrovascular pathologies including multiple aneurysms, DAVFs, and 1 high-grade AVM. Analyzing the hemodynamic relationships of these concurrent lesions is essential to determine the hemorrhage risk of each lesion and the order of priority in management. Flow-related aneurysms with irregular morphology require early, aggressive treatment.

Opposing roles for E2F1 in survival and death of cerebellar granule neurons.

The transcription factor E2F1 is upregulated when cerebellar granular neurons (CGNs) undergo apoptosis under potassium deprivation. In this study, we examined the effects of E2F1 upregulation on the survival and death of CGNs isolated from C57 mice and Sprague-Dawley (SD) rats. Plasmid- and adenovirus-mediated expression of E2F1 dose-dependently induced apoptosis in mouse CGNs but unexpectedly failed to induce apoptosis in rat CGNs. Caspase 3, a marker for neuronal apoptosis, was significantly activated by ectopic E2F1 expression in mouse CGNs but not in rat CGNs. Furthermore, overexpression of E2F1 significantly promoted apoptotic progression in mouse CGNs following potassium deprivation but attenuated apoptosis in rat CGNs, whereas E2F1 lacking DNA binding ability (E2F1-M132) lost its pro-apoptotic role in mouse CGNs and anti-apoptotic role in rat CGNs. Together, our results demonstrated that upregulation of E2F1 by potassium deprivation promotes apoptosis in C57 mouse CGNs but antagonizes apoptosis in SD rat CGNs, suggesting opposing roles for E2F1 in regulating CGN fate.

High electrochemiluminescence of a new water-soluble iridium(III) complex for determination of antibiotics.

A new water-soluble iridium(III) diimine complex with appended sugar was synthesized and characterized. The electrochemiluminescent behavior of the new complex in aqueous buffer was first studied and the ECL signal was found to be much higher than that of [Ru(bpy)(3)](2+) at a Pt working electrode. Tri-n-propylamine (TPA) and antibiotics were determined by the ECL of the iridium(III) complex in aqueous buffer at the Pt electrode and the method was found to show good sensitivity and reproducibility. The new iridium(III) complex was found to display good solubility in aqueous solution and a strong ECL signal at the Pt electrode, which might open up the possibility of its application in analysis.