The JMJD6/HURP axis promotes cell migration via NF-κB-dependent centrosome repositioning and Cdc42-mediated Golgi repositioning.

Golgi apparatus (GA) and centrosome reposition toward cell leading end during directional cell migration in a coupling way, thereby determining cell polarity by transporting essential factors to the proximal plasma membrane. The study provides mechanistic insights into how GA repositioning (GR) is regulated, and how GR and centrosome repositioning (CR) are coupled. Our previous published works reveals that PRMT5 methylates HURP at R122 and the HURP m122 inhibits GR and cell migration by stabilizing GA-associated acetyl-tubulin and then rigidifying GA. The current study further shows that the demethylase JMJD6-guided demethylation of HURP at R122 promotes GR and cell migration. The HURP methylation mimicking mutant 122 F blocks JMJD6-induced GR and cell migration, suggesting JMJD6 relays GR stimulating signal to HURP. Mechanistic studies reveal that the HURP methylation deficiency mutant 122 K promotes GR through NF-κB-induced CR and subsequently CR-dependent Cdc42 upregulation, where Cdc42 couples CR to GR. Taken together, HURP methylation statuses provide a unique opportunity to understand how GR is regulated, and the GA intrinsic mechanism controlling Golgi rigidity and the GA extrinsic mechanism involving NF-κB-CR-Cdc42 cascade collectively dictate GR.

Phase I study of expanded natural killer cells in combination with cetuximab for recurrent/metastatic nasopharyngeal carcinoma.

BACKGROUND: Nasopharyngeal carcinoma (NPC) cells express high levels of epidermal growth factor receptor (EGFR). Cetuximab is an anti-EGFR monoclonal antibody that promotes natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) via engagement of CD16. We studied safety and efficacy of combining cetuximab with autologous expanded NK cells in patients with recurrent and/or metastatic NPC who had failed at least two prior lines of chemotherapy. METHODS: Seven subjects (six patients) received cetuximab every 3 weeks (six doses maximum) in the pre-trial phase. Autologous NK cells, expanded by co-culture with irradiated K562-mb15-41BBL cells, were then infused on the day after administration of cetuximab. Primary and secondary objectives were to determine safety of this combination therapy and to assess tumor responses, respectively. RESULTS: Median NK cell expansion from peripheral blood mononucleated cells after 10 days of culture with K562-mb15-41BBL was 274-fold (range, 36-534, n = 10), and the median expression of CD16 was 98.4% (range, 67.8-99.7%). Skin rash, the commonest side effect of cetuximab in the pre-trial phase, was not exacerbated by NK cell infusion. No intolerable side effects were observed. Stable disease was observed in four subjects and progressive disease in three subjects. Three patients who received NK cells twice had time to disease progression of 12, 13, and 19 months. CONCLUSION: NK cells with high ADCC potential can be expanded from patients with heavily pre-treated NPC. The safety profile and encouraging clinical responses observed after combining these cells with cetuximab warrant further studies of this approach. (clinicalTrials.gov NCT02507154, 23/07/2015). PRECIS: Engaging NK cell-mediated ADCC using cetuximab plus autologous NK cells in EGFR-positive NPC was well tolerated among heavily pre-treated recurrent NPC. Promising results were observed with 3 out of 7 subjects demonstrating durable stable disease.

Magnetic Resonance Imaging Study of the Pericranial Flap and Its Local Effects Following Endoscopic Craniofacial Resection.

OBJECTIVES/HYPOTHESIS: To describe the magnetic resonance imaging (MRI) characteristics of the pericranial flap, changes in the pericranial flap thickness over time, presence of frontal sinus opacification, and presence of frontal lobe herniation into the nasal cavity. STUDY DESIGN: Retrospective case series. METHODS: Seventeen consecutive endoscopic craniofacial resections with pericranial flap reconstruction performed at a tertiary hospital from 2010 to 2019 were reviewed. Sixty-eight serial MRI scans were evaluated. RESULTS: All pericranial flaps consistently featured a homogenous appearance on T1-weighted sequence and enhanced with contrast. On T2-weighted sequence, the skull base reconstruction demonstrated four layers of alternating hypo- and hyperintensity, which corresponded with the inlay synthetic graft or neodura (hypointense), loose areolar tissue (hyperintense), fibrous pericranium (hypointense), and nasal mucosa or granulation tissue (hyperintense). The mean pericranial flap thickness was 9.9 mm. In thicker flaps, the loose areolar layer contributed the bulk of the thickness. Of 13 patients who underwent three or more serial MRI scans, 11 flaps (84.6%) were stable and two (15.4%) had >50% reduction in their original thickness over time. Thirteen of 17 (76.5%) patients had frontal sinus opacification on follow-up. None developed frontal sinus mucoceles or frontal lobe herniation. CONCLUSIONS: The pericranial flap has a distinctive MRI appearance, especially on T2-weighted sequence. The thickness of the flap remains relatively stable over time for most patients even following radiotherapy. It is a sturdy flap that is able to support the frontal lobe. Frontal sinus obstruction is common, although complications from this appear to be rare. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E90-E97, 2021.

Imaging findings on contrast-enhanced ultrasound, magnetic resonance imaging and hybrid positron emission tomography in Takayasu arteritis: a case report.

This case report demonstrates the potential of contrast-enhanced ultrasound (CEUS) in diagnosing active arterial wall inflammation in a symptomatic patient with Takayasu arteritis (TA). To our knowledge, this is the first case which demonstrates pictorial correlation of arterial wall neovascularity on CEUS with mural edema on magnetic resonance imaging and metabolic activity on positron emission tomography - computed tomography in the same patient. As TA is a chronic disease which requires long-term follow-up, CEUS could be the potential imaging modality of choice as it is radiation-free, non-nephrotoxic and easily available.

Temporal Evolution of Intramural Esophageal Dissection with 3D Reconstruction and Cinematic Virtual Fly-Through.

Intramural esophageal dissection is an uncommon condition, involving the separation of the esophageal mucosa from the muscular layers. To our knowledge, the temporal evolution of intramural esophageal dissection on computed tomography has not been previously demonstrated. We present a case of a 51-year-old male who first presented to the emergency department with fever, odynophagia, and dysphagia. He was treated for acute tonsillitis and discharged, but presented again after 10 days with worsening symptoms. A series of radiographs and computed tomography studies, with 3D reconstruction and cinematic virtual fly-through, in these 2 admissions depicts the temporal evolution of intramural hematoma to subsequent intramural esophageal dissection. Recognizing its appearance on imaging is invaluable in distinguishing it from other important differential diagnoses. A complete description of the case, relevant radiologic imaging, and review of the relevant literature are provided.

The "Blush" Sign on Computed Tomography Angiography is an Independent Predictor of Hematoma Progression in Primary Hypertensive Hemorrhage.

BACKGROUND AND PURPOSE: Hypertension is an important etiology of intracerebral hemorrhage (ICH) in neurosurgical practice. Contrast extravasation on computed tomography angiography, known as the "spot sign", has been described as an independent predictor of hematoma progression and clinical deterioration. However, its role in hypertensive ICH alone has not been determined and is the primary aim of this study. MATERIALS AND METHODS: A retrospective review was carried out of patients with hypertensive ICH admitted to our institution between May 2014 and December 2016. Evaluation of the neuroimaging studies of these patients revealed two distinct morphologies, "spot" and "blush" sign. These distinct signs and covariates were tested for association with hematoma expansion and mortality using multivariate logistic regression. The accuracy of the "spot" and "blush" signs as predictors of hematoma expansion and mortality was determined using receiver-operator characteristic (ROC) analysis. RESULTS: A total of 54 patients were identified as hypertensive ICH during the study period. "spot" sign was observed in 11 (20.4%) of the study population. Contrast extravasation (blush-sign) was seen in 7 (14.8%) patients. The "blush" was an independent predictor of hematoma expansion (odds ratio [OR] 6.052; confidence interval [CI] 1.036-15.945 [P = .012]) and mortality (OR 3.305; CI 1.240-25.414 [P = .032]). With ROC analysis, the "blush" sign was found to have a better predictive value for significant hematoma expansion (area under the curve [AUC]: .795) than the spot sign (AUC: .432). CONCLUSION: The "blush" sign has better accuracy for predicting hematoma expansion in hypertensive ICH and could be used to risk stratify these patients for early therapeutic interventions.

Coronal CT is Comparable to MR Imaging in Aiding Diagnosis of Dementia in a Memory Clinic in Singapore.

PURPOSE: The present study investigated (a) the agreement between computerized tomography (CT) and 3 T magnetic resonance imaging (MRI) in the visual grading of medial temporal atrophy (MTA); and (b) whether MTA on CT differentiated patients with dementia from no dementia in memory clinics. MATERIALS AND METHODS: Data were obtained from patients who underwent CT scans at the National University Hospital of Singapore, and from a subsample who subsequently underwent 3 T MRI scans in a research study. Agreements and disagreements between CT and MRI were determined. Area under the curve (AUC) analyses determined if CT-graded MTA distinguished patients with dementia from no dementia. RESULTS: Of the 107 patients in the subsample, MTA scores of 71 agreed on both CT and MRI. The true positive rate between CT and MRI for MTA scores ≥2 was 79.7%. The true negative rate for MTA scores between 0 and 1 was 96.4%. CT underestimated MTA severity in 33 of 36 disagreements with the MRI. MTA scores ≥2 on CT distinguished dementia from no dementia in both discovery [n=263; AUC (95% confidence interval)=0.77 (0.72-0.83); sensitivity=0.69; specificity=0.74] and validation [n=264; AUC (95% confidence interval)=0.77 (0.71-0.82); sensitivity=0.72; specificity=0.72] groups. CONCLUSIONS: MTA graded on CT is a viable alternative to MRI to aid in the diagnosis of dementia in memory clinics.

Cabergoline-induced fibrosis of prolactinomas: a neurosurgical perspective.

Presently, the standard of care for prolactinomas, a type of pituitary adenoma, is dopaminergic agents such as bromocriptine and cabergoline. However, dopaminergic agents may induce fibrosis of cardiac valves leading to valvular insufficiency, necessitating surgical treatment of prolactinoma. Fibrosis of prolactinoma can be induced by prolonged medical treatment with bromocriptine, and this usually occurs after years of treatment. In comparison to bromocriptine, there have been no reports of cabergoline-induced fibrosis of prolactinoma. There is a potential for greater emphasis to be placed on assessing the tumour consistency from preoperative MRI scans, or even preoperative contrast-enhanced 3D Fast Imaging Employing Steady-state Acquisition imaging to allow better planning of the surgery. We report a rare case of fibrosis of prolactinoma after cabergoline treatment resulting in its subsequent difficult surgical removal. This patient had early MRI changes of fibrosis of prolactinoma after a short period of 6 months of cabergoline treatment.

Validation of Serial Alberta Stroke Program Early CT Score as an Outcome Predictor in Thrombolyzed Stroke Patients.

BACKGROUND: The Alberta Stroke Program Early CT Score (ASPECTS) on baseline imaging is an established predictor of functional outcome in anterior circulation acute ischemic stroke (AIS). We studied ASPECTS before intravenous thrombolysis (IVT) and at 24 hours to assess its prognostic value. METHODS: Data for consecutive anterior circulation AIS patients treated with IVT from 2006 to 2013 were extracted from a prospectively managed registry at our tertiary center. Pre-thrombolysis and 24-hour ASPECTS were evaluated by 2 independent neuroradiologists. Outcome measures included symptomatic intracranial hemorrhage (SICH), modified Rankin Scale (mRS) at 90 days, and mortality. Unfavorable functional outcome was defined by mRS >1. Dramatic ASPECTS progression (DAP) was defined as deterioration in ASPECTS by 6 points or more. RESULTS: Of 554 AIS patients thrombolyzed during the study period, 400 suffered from anterior circulation infarction. The median age was 65 years (interquartile range (IQR): 59-70) and the median National Institutes of Health Stroke Scale score was 18 points (IQR: 12-22). Compared with the pre-IVT ASPECTS (area under the curve [AUC] = .64, 95% confidence interval [CI]: .54-.65, P = .001), ASPECTS on the 24-hour CT scan (AUC = .78, 95% CI: .73-.82, P < .001), and change in ASPECTS (AUC = .69, 95% CI: .64-.74, P < .001) were better predictors of unfavorable functional outcome at 3 months. DAP, noted in 34 (14.4%) patients with good baseline ASPECTS (8-10 points), was significantly associated with unfavorable functional outcome (odds ratio [OR]: 9.91, 95% CI: 3.37-29.19, P ≤ .001), mortality (OR: 21.99, 95% CI: 7.98-60.58, P < .001), and SICH (OR: 8.57, 95% CI: 2.87-25.59, P < .001). CONCLUSION: Compared with the pre-thrombolysis score, ASPECTS measured at 24 hours as well as serial change in ASPECTS is a better predictor of 3-month functional outcome.

Prognostic significance of cystic lymph nodal metastasis in nasopharyngeal carcinoma.

BACKGROUND: The purpose of this study was to determine the prevalence of cystic lymph nodal metastasis (CLNM) and its prognostic value in patients with nasopharyngeal carcinoma (NPC). METHODS: A retrospective review was conducted on 257 patients with NPC, analyzing the presence of CLNM on MRI or CT scans. Oncologic outcomes were performed using the Kaplan-Meier analysis. RESULTS: One hundred eleven patients (43.2%) had CLNM at diagnosis. Overall, patients with CLNM had a poorer disease-specific survival (DSS; P < .001) and overall survival (OS; P < .001) compared with patients without CLNM. When analyzed according to nodal status, CLNM was associated with a higher rate of distant metastasis recurrence (P = .007), a poorer DSS (P < .001), and a poorer OS (P < .001) among patients with N2 disease. CONCLUSION: The prevalence of CLNM was 43.2%. In patients with N2 disease, the presence of CLNM was significantly associated with a poorer DSS, OS, and increased risk of distant metastasis recurrence.

CT features in surgically proven cases of ovarian torsion-a pictorial review.

Ovarian torsion is a surgical emergency characterized by a partial or complete rotation of the ovarian vascular pedicle, causing obstruction to venous outflow followed by arterial inflow. Clinically, ovarian torsion frequently mimics other causes of acute pelvic pain such as appendicitis, diverticulitis, renal colic etc. Ultrasonography is the first-line imaging modality of choice for evaluation of ovarian torsion. MRI is useful as a problem-solving tool in patients with equivocal or non-diagnostic ultrasonography studies. CT is ordinarily not utilized in a young female with suspected ovarian torsion due to the radiation dose. However, the significant expansion in use of CT imaging in emergency departments for female patients presenting with acute abdominal pain has increased the likelihood that ovarian torsion may be first seen on CT. In addition, a non-specific clinical presentation may lead to an initial imaging with CT rather than ultrasonography. Ultrasound features of the ovarian torsion are well known and sufficiently described across literature as compared with the CT scan findings. In view of the increasing usage of CT as the modality of choice in emergency settings, it is imperative for the radiologist to familiarize with the CT features of ovarian torsion. An early correct diagnosis by the radiologist in clinically unsuspected cases, facilitating a prompt surgery to restore the ovarian blood flow can prevent permanent irreversible damage. There is limited published data available on the CT features of ovarian torsion. This pictorial essay illustrates CT findings with histological correlation of surgically proven ovarian torsion in our institution. These patients were primarily investigated with CT scan for acute pelvic pain ascribed to non-gynaecological causes such as bowel or urinary tract lesions.

Nongated Cardiac Computed Tomographic Angiograms for Detection of Embolic Sources in Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: We assessed the feasibility of obtaining diagnostic quality images of the heart and thoracic aorta by extending the z axis coverage of a non-ECG-gated computed tomographic angiogram performed in the primary evaluation of acute stroke without increasing the contrast dose. METHODS: Twenty consecutive patients with acute ischemic stroke within the 4.5 hours of symptom onset were prospectively recruited. We increased the longitudinal coverage to the domes of the diaphragm to include the heart. Contrast administration (Omnipaque 350) remained unchanged (injected at 3-4 mL/s; total 60-80 mL, triggered by bolus tracking). Images of the heart and aorta, reconstructed at 5 mm slice thickness in 3 orthogonal planes, were read by a radiologist and cardiologist, findings conveyed to the treating neurologist, and correlated with the transthoracic or transesophageal echocardiogram performed within the next 24 hours. RESULTS: Of 20 patients studied, 3 (15%) had abnormal findings: a left ventricular thrombus, a Stanford type A aortic dissection, and a thrombus of the left atrial appendage. Both thrombi were confirmed by transesophageal echocardiography, and anticoagulation was started urgently the following day. None of the patients developed contrast-induced nephropathy on follow-up. The radiation dose was slightly increased from a mean of 4.26 mSV (range, 3.88-4.70 mSV) to 5.17 (range, 3.95 to 6.25 mSV). CONCLUSIONS: Including the heart and ascending aorta in a routine non-ECG-gated computed tomographic angiogram enhances an existing imaging modality, with no increased incidence of contrast-induced nephropathy and minimal increase in radiation dose. This may help in the detection of high-risk cardiac and aortic sources of embolism in acute stroke patients.

Intracranial hemorrhage in a patient with sub-massive pulmonary embolism treated with EkoSonic endovascular system directed thrombolysis.

Ultrasound-assisted catheter-directed thrombolysis therapy has emerged more recently as a management strategy for patients with intermediate risk pulmonary embolism and has shown promising results in clinical trials by early reversal of right ventricle dilation, reduced pulmonary hypertension, and decreased anatomic thrombus burden. This therapeutic strategy requires a small fraction of the systemic fibrinolytic dose and is therefore associated with a reduced bleeding risk. Although intracranial hemorrhage has not been reported in clinical trials, it is a possible complication. Here we report the first case of intracranial hemorrhage related to the use of EkoSonic™ Endovascular System directed thrombolysis in a patient with large bilateral pulmonary embolism without any identifiable bleeding risks. © 2017 Wiley Periodicals, Inc.

Synchronous cardiocerebral infarction in the era of endovascular therapy: which to treat first?

A cardiocerebral ischemic attack (CCI) or a concurrent acute ischemic stroke (AIS) and myocardial infarction (AMI) is a severe event with no clear recommendations for ideal management because of the rarity of the scenario. The narrow time window for treatment and complexity of the treatment decision puts immense pressure on the treating physician. We evaluated this challenging situation at our tertiary center. Using our prospective stroke database out of a total of 555 patients with acute ischemic stroke between 2009 and 2014, we identified five consecutive cases with CCI (incidence 0.009%). Demography, risk factor characteristics, vascular occlusions and treatment approach were recorded. Good functional outcome was defined by the modified Rankin scale (mRS) score of 0-2 points. Out of five patients, AIS was treated with endovascular treatment in three cases, while two were treated with intravenous thrombolysis only. One out of three patients had embolectomy of the brain performed prior to the coronary intervention, while the other two patients underwent coronary intervention first. One patient developed sudden cardiac arrest on day-2 and passed away. CCI is an uncommon and devastating clinical scenario, further research is needed for the ideal management strategy that provides the best outcomes. However, the rarity of the disease does not lend itself to the conduct of a trial easily. We have proposed a considered treatment algorithm based on the current literature and our experience.

Good Intracranial Collaterals Trump Poor ASPECTS (Alberta Stroke Program Early CT Score) for Intravenous Thrombolysis in Anterior Circulation Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: In acute ischemic stroke, large early infarct size estimated by the Alberta Stroke Program Early CT Score (ASPECTS) is associated with poorer outcomes and is a relative contraindication for recanalization therapies. The state of the intracranial collateral circulation influences the functional outcome and may be a variable to consider before thrombolysis. We evaluated the prognostic effect of the collateral circulation in patients with thrombolyzed acute ischemic stroke who have large early infarct sizes as indicated by low ASPECTS. MATERIALS AND METHODS: Patients with anterior circulation acute ischemic stroke who received a computed tomographic angiogram and subsequent treatment with intravenous tissue-type plasminogen activator from 2010 to 2013 were studied. Two independent neuroradiologists determined their ASPECTS. We stratified patients using ASPECTS into 2 groups: large volume infarcts (ASPECTS≤7 points) and small volume infarcts (ASPECTS 8-10). In addition, we evaluated a third group with very large volume infarcts (ASPECTS≤5 points). We then analyzed the 3 subgroups using the Maas, Tan, and ASPECTS-collaterals grading systems of the computed tomographic angiogram intracranial collaterals. Good outcomes were defined by modified Rankin Scale score of 0 to 2 at 3 months. RESULTS: A total of 300 patients were included in the final analysis. For patients with very large volume infarcts (ASPECTS≤5 points), univariable analysis showed that younger age, male sex, lower National Institute of Health Stroke Scale (NIHSS), lower systolic blood pressure, and good collaterals by Maas, Tan, or ASPECTS-collaterals grading were predictors of good outcomes. On multivariate analysis, younger age (odds ratio, 0.93; 95% confidence interval, 0.89-0.97; P=0.002) and good collaterals by ASPECTS-collaterals system (odds ratio, 1.34; 95% confidence interval, 1.15-1.57; P<0.001) were associated with good outcomes. CONCLUSIONS: In patients with large and very large volume infarcts, good collaterals as measured by the ASPECTS-collaterals system is associated with improved outcomes and can help select patients for intravenous thrombolysis.

Intravenous Thrombolysis for Acute Ischemic Stroke due to Cervical Internal Carotid Artery Occlusion.

BACKGROUND: Internal carotid artery (ICA) occlusions are poorly responsive to intravenous thrombolysis with tissue plasminogen activator (IV-tPA) in acute ischemic stroke (AIS). Most study populations have combined intracranial and extracranial ICA occlusions for analysis; few have studied purely cervical ICA occlusions. We evaluated AIS patients with acute cervical ICA occlusion treated with IV-tPA to identify predictors of outcomes. METHODS: We studied 550 consecutive patients with AIS who received IV-tPA and identified 100 with pure acute cervical ICA occlusion. We evaluated the associations of vascular risk factors, National Institutes of Health Stroke Scale (NIHSS) score, and leptomeningeal collateral vessel status via 3 different grading systems, with functional recovery at 90 days, mortality, recanalization of the primary occlusion, and symptomatic intracranial hemorrhage (SICH). Modified Rankin Scale score 0-1 was defined as an excellent outcome. RESULTS: The 100 patients had mean age of 67.8 (range 32-96) and median NIHSS score of 19 (range 4-33). Excellent outcomes were observed in 27% of the patients, SICH in 8%, and mortality in 21%. Up to 54% of the patients achieved recanalization at 24 hours. On ordinal regression, good collaterals showed a significant shift in favorable outcomes by Maas, Tan, or ASPECTS collateral grading systems. On multivariate analysis, good collaterals also showed reduced mortality (OR .721, 95% CI .588-.888, P = .002) and a trend to less SICH (OR .81, 95% CI .65-1.007, P = .058). Interestingly, faster treatment was also associated with favorable functional recovery (OR 1.028 per minute, 95% CI 1.010-1.047, P = .001). CONCLUSIONS: Improved outcomes are seen in patients with early acute cervical ICA occlusion and better collateral circulation. This could be a valuable biomarker for decision making.

How temporal evolution of intracranial collaterals in acute stroke affects clinical outcomes.

OBJECTIVE: We compared intracranial collaterals on pretreatment and day 2 brain CT angiograms (CTA) to assess their evolution and relationship with functional outcomes in acute ischemic stroke (AIS) patients treated with IV tissue plasminogen activator (tPA). METHODS: Consecutive AIS patients who underwent pretreatment and day 2 CTA and received IV tPA during 2010-2013 were included. Collaterals were evaluated by 2 independent neuroradiologists using 3 predefined criteria: the Miteff system, the Maas system, and 20-point collateral scale by the Alberta Stroke Program Early CT Score methodology. We stratified our cohort by baseline pre-tPA state of their collaterals and by recanalization status of the primary vessel for analysis. Good outcomes at 3 months were defined by a modified Rankin Scale score of 0-1. RESULTS: This study included 209 patients. Delayed collateral recruitment by any grading system was not associated with good outcomes. All 3 scoring systems showed that collateral recruitment on the follow-up CTA from a baseline poor collateral state was significantly associated with poor outcome and increased bleeding risk. When the primary vessel remained persistently occluded, collateral recruitment was significantly associated with worse outcomes. Interestingly, collateral recruitment was significantly associated with increased mortality in 2 of the 3 grading systems. CONCLUSIONS: Not all collateral recruitment is beneficial; delayed collateral recruitment may be different from early recruitment and can result in worse outcomes and higher mortality. Prethrombolysis collateral status and recanalization are determinants of how intracranial collateral evolution affects functional outcomes.