Wenjun Xin

Computed Tomography Workup of Patients Suspected of Acute Ischemic Stroke Perfusion Computed Tomography Adds Value Compared With Clinical Evaluation, Noncontrast Computed Tomography, and Computed Tomography Angiogram in Terms of Predicting Outcome

Background and Purpose— To determine whether perfusion computed tomography (PCT) adds value to noncontrast head CT (NCT), CT angiogram (CTA), and clinical assessment in patients suspected of acute ischemic stroke. Methods— We retrospectively reviewed 165 patients with acute ischemic stroke. PCT was used to calculate the volumes of infarct core and ischemic penumbra on admission. Other imaging data included Alberta Score Program Early CT Score, site of occlusion, and collateral flow. Clinical data included age, time, National Institutes of Health Stroke Scale at baseline, treatment type, and modified Rankin score (mRS) at 90 days. Recanalization status was assessed on follow-up imaging. In a first multivariate regression analysis, we assessed whether volumes of PCT penumbra and infarct core could be predicted from clinical variables, NCT, or CTA, or whether they represented independent information. In a second multivariate regression analysis, we used mRS at 90 days as outcome and determined which variables predicted it best. Results— Of 165 patients identified, 76 had a mRS score of 0 to 2 at 90 days, 89 had a mRS score >2. PCT infarct could be predicted by clinical data, NCT, CTA, and combinations of this data (P<0.05). PCT penumbra could not be predicted by clinical data, NCT, and CTA. All of the variables but NCT and CTA were significantly associated with 90-day mRS outcome. The single most important predictor was recanalization status (P<0.001). PCT penumbra volume (P=0.001) was also a predictor of clinical outcome, especially when considered in conjunction with recanalization through an interaction term (P<0.001). Conclusions— PCT penumbra represents independent information, which cannot be predicted by clinical, NCT, and CTA data. PCT penumbra is an important determinant of clinical outcome and adds relevant clinical information compared with a stroke CT workup, including NCT and CTA.

Diacylglycerol kinase alpha is a critical signaling node and novel therapeutic target in glioblastoma and other cancers

Although diacylglycerol kinase α (DGKα) has been linked to several signaling pathways related to cancer cell biology, it has been neglected as a target for cancer therapy. The attenuation of DGKα activity via DGKα-targeting siRNA and small-molecule inhibitors R59022 and R59949 induced caspase-mediated apoptosis in glioblastoma cells and in other cancers, but lacked toxicity in noncancerous cells. We determined that mTOR and hypoxia-inducible factor-1α (HIF-1α) are key targets of DGKα inhibition, in addition to its regulation of other oncogenes. DGKα regulates mTOR transcription via a unique pathway involving cyclic AMP. Finally, we showed the efficacy of DGKα inhibition with short hairpin RNA or a small-molecule agent in glioblastoma and melanoma xenograft treatment models, with growth delay and decreased vascularity. This study establishes DGKα as a central signaling hub and a promising therapeutic target in the treatment of cancer.

Prediction of Recanalization Trumps Prediction of Tissue Fate: The Penumbra: A Dual-edged Sword

Background and Purpose— To determine whether infarct core or penumbra is the more significant predictor of outcome in acute ischemic stroke, and whether the results are affected by the statistical method used. Methods— Clinical and imaging data were collected in 165 patients with acute ischemic stroke. We reviewed the noncontrast head computed tomography (CT) to determine the Alberta Score Program Early CT score and assess for hyperdense middle cerebral artery. We reviewed CT-angiogram for site of occlusion and collateral flow score. From perfusion-CT, we calculated the volumes of infarct core and ischemic penumbra. Recanalization status was assessed on early follow-up imaging. Clinical data included age, several time points, National Institutes of Health Stroke Scale at admission, treatment type, and modified Rankin score at 90 days. Two multivariate regression analyses were conducted to determine which variables predicted outcome best. In the first analysis, we did not include recanalization status among the potential predicting variables. In the second, we included recanalization status and its interaction between perfusion-CT variables. Results— Among the 165 study patients, 76 had a good outcome (modified Rankin score ⩽2) and 89 had a poor outcome (modified Rankin score >2). In our first analysis, the most important predictors were age (P<0.001) and National Institutes of Health Stroke Scale at admission (P=0.001). The imaging variables were not important predictors of outcome (P>0.05). In the second analysis, when the recanalization status and its interaction with perfusion-CT variables were included, recanalization status and perfusion-CT penumbra volume became the significant predictors (P<0.001). Conclusions— Imaging prediction of tissue fate, more specifically imaging of the ischemic penumbra, matters only if recanalization can also be predicted.

Epidemiology of uveitis in the mid-Atlantic United States

Purpose To demonstrate the demographic, anatomic, and diagnostic classification of patients with uveitis seen in a tertiary care center in central Virginia. Methods Retrospective chart review of patient demographics, disease characteristics, and disease severity-related outcomes (therapies, visual outcomes, and complications) from 1984 to 2014. Results There were 491 patients (644 eyes) with mean age of 46 years (±21.4 years) and mean duration of follow up of 4.8 years (±6.8 years). Of these, 278 patients were female (56.6%). Further, 60.5% were Caucasian, and 27.3% were African American. The anatomic types seen were anterior uveitis (67.3%), panuveitis (14.5%), posterior uveitis (12.6%), and intermediate uveitis (5.3%). The most common etiology was post-traumatic (12.2%), followed by post-procedural (10.0%), herpetic (7.9%), human leukocyte antigen (HLA)-B27-associated (6.7%), and sarcoidosis (6.7%). Herpetic uveitis was more common among Caucasians than African Americans (sex-adjusted odds ratio [OR]: 7.69, 95% confidence interval [CI] [2.12, 50.00]), and sarcoidosis was more common among African Americans than Caucasians (sex-adjusted OR: 6.54, 95% CI [2.98, 15.29]). Herpetic anterior uveitis was more common among females than males (race-adjusted OR: 3.03, 95% CI [1.32, 7.71]). Multifocal choroiditis was more common among males than females (race-adjusted OR: 9.09, 95% CI [1.47, 100.00]). Mean logMAR visual acuity was 0.18 at initial and final visit. A total 388 (79%) and 133 (27.3%) patients received local and systemic steroids, respectively. A total 52 patients (10.6%) received an antimetabolite. A total 116 patients (23.7%) were managed with topical glaucoma medication. A total 43 (8.8%), 129 (26.4%), and 46 patients (9.4%) underwent glaucoma surgery, cataract surgery, and vitrectomy, respectively. Conclusion Over the period of this study, Caucasian patients were more frequently seen than non-Caucasians, although African Americans constituted a considerable size of study population. The most common diagnoses were undifferentiated anterior uveitis, traumatic uveitis, post-procedural uveitis, herpetic disease, HLA-B27 associated uveitis, and sarcoidosis. Unlike previous reports, traumatic and post-procedural uveitis were frequently reported. Mean visual acuity remained stable from initial to final visit.

Hepatocyte Growth Factor Sensitizes Brain Tumors to c-MET Kinase Inhibition

Purpose: The receptor tyrosine kinase (RTK) c-MET and its ligand hepatocyte growth factor (HGF) are deregulated and promote malignancy in cancer and brain tumors. Consequently, clinically applicable c-MET inhibitors have been developed. The purpose of this study was to investigate the not-well-known molecular determinants that predict responsiveness to c-MET inhibitors and to explore new strategies for improving inhibitor efficacy in brain tumors. Experimental Design: We investigated the molecular factors and pathway activation signatures that determine sensitivity to c-MET inhibitors in a panel of glioblastoma and medulloblastoma cells, glioblastoma stem cells, and established cell line–derived xenografts using functional assays, reverse protein microarrays, and in vivo tumor volume measurements, but validation with animal survival analyses remains to be done. We also explored new approaches for improving the efficacy of the inhibitors in vitro and in vivo. Results: We found that HGF coexpression is a key predictor of response to c-MET inhibition among the examined factors and identified an ERK/JAK/p53 pathway activation signature that differentiates c-MET inhibition in responsive and nonresponsive cells. Surprisingly, we also found that short pretreatment of cells and tumors with exogenous HGF moderately but statistically significantly enhanced the antitumor effects of c-MET inhibition. We observed a similar ligand-induced sensitization effect to an EGF receptor small-molecule kinase inhibitor. Conclusions: These findings allow the identification of a subset of patients that will be responsive to c-MET inhibition and propose ligand pretreatment as a potential new strategy for improving the anticancer efficacy of RTK inhibitors. Clin Cancer Res; 19(6); 1433–44. ©2013 AACR.

Multimodal MR imaging model to predict tumor infiltration in patients with gliomas

IntroductionGliomas remain difficult to treat, in part, due to our inability to accurately delineate the margins of the tumor. The goal of our study was to evaluate if a combination of advanced MR imaging techniques and a multimodal imaging model could be used to predict tumor infiltration in patients with diffuse gliomas.MethodsInstitutional review board approval and written consent were obtained. This prospective pilot study enrolled patients undergoing stereotactic biopsy for a suspected de novo glioma. Stereotactic biopsy coordinates were coregistered with multiple standard and advanced neuroimaging sequences in 10 patients. Objective imaging values were assigned to the biopsy sites for each of the imaging sequences. A principal component analysis was performed to reduce the dimensionality of the imaging dataset without losing important information. A univariate analysis was performed to identify the statistically relevant principal components. Finally, a multivariate analysis was used to build the final model describing nuclear density.ResultsA univariate analysis identified three principal components as being linearly associated with the observed nuclear density (p values 0.021, 0.016, and 0.046, respectively). These three principal component composite scores are predominantly comprised of DTI (mean diffusivity or average diffusion coefficient and fractional anisotropy) and PWI data (rMTT, Ktrans). The p value of the model was <0.001. The correlation between the predicted and observed nuclear density was 0.75.ConclusionA multi-input, single output imaging model may predict the extent of glioma invasion with significant correlation with histopathology.

Dynamic CT for Parathyroid Disease: Are Multiple Phases Necessary?

BACKGROUND AND PURPOSE: A 4D CT protocol for detection of parathyroid lesions involves obtaining unenhanced, arterial, early, and delayed venous phase images. The aim of the study was to determine the ideal combination of phases that would minimize radiation dose without sacrificing diagnostic accuracy. MATERIALS AND METHODS: With institutional review board approval, the records of 29 patients with primary hyperparathyroidism who had undergone surgical exploration were reviewed. Four neuroradiologists who were blinded to the surgical outcome reviewed the imaging studies in 5 combinations (unenhanced and arterial phase; unenhanced, arterial, and early venous; all 4 phases; arterial alone; arterial and early venous phases) with an interval of at least 7 days between each review. The accuracy of interpretation in lateralizing an abnormality to the side of the neck (right, left, ectopic) and localizing it to a quadrant in the neck (right or left upper, right or left lower) was evaluated. RESULTS: The lateralization and localization accuracy (90.5% and 91.5%, respectively) of the arterial phase alone was comparable with the other combinations of phases. There was no statistically significant difference among the different combinations of phases in their ability to lateralize or localize adenomas to a quadrant (P = .976 and .996, respectively). CONCLUSIONS: Assessment of a small group of patients shows that adequate diagnostic accuracy for parathyroid adenoma localization may be achievable by obtaining arterial phase images alone. If this outcome can be validated prospectively in a larger group of patients, then the radiation dose can potentially be reduced to one-fourth of what would otherwise be administered.

Optimal Perfusion Computed Tomographic Thresholds for Ischemic Core and Penumbra Are Not Time Dependent in the Clinically Relevant Time Window

Background and Purpose— This study aims to determine whether perfusion computed tomographic (PCT) thresholds for delineating the ischemic core and penumbra are time dependent or time independent in patients presenting with symptoms of acute stroke. Methods— Two hundred seventeen patients were evaluated in a retrospective, multicenter study. Patients were divided into those with either persistent occlusion or recanalization. All patients received admission PCT and follow-up imaging to determine the final ischemic core, which was then retrospectively matched to the PCT images to identify optimal thresholds for the different PCT parameters. These thresholds were assessed for significant variation over time since symptom onset. Results— In the persistent occlusion group, optimal PCT parameters that did not significantly change with time included absolute mean transit time, relative mean transit time, relative cerebral blood flow, and relative cerebral blood volume when time was restricted to 15 hours after symptom onset. Conversely, the recanalization group showed no significant time variation for any PCT parameter at any time interval. In the persistent occlusion group, the optimal threshold to delineate the total ischemic area was the relative mean transit time at a threshold of 180%. In patients with recanalization, the optimal parameter to predict the ischemic core was relative cerebral blood volume at a threshold of 66%. Conclusions— Time does not influence the optimal PCT thresholds to delineate the ischemic core and penumbra in the first 15 hours after symptom onset for relative mean transit time and relative cerebral blood volume, the optimal parameters to delineate ischemic core and penumbra.

Prediction of recanalization in acute stroke patients receiving intravenous and endovascular revascularization therapy

Background and purpose The study aims to assess the recanalization rate in acute ischemic stroke patients who received no revascularization therapy, intravenous thrombolysis, and endovascular treatment, respectively, and to identify best clinical and imaging predictors of recanalization in each treatment group. Methods Clinical and imaging data were collected in 103 patients with acute ischemic stroke caused by anterior circulation arterial occlusion. We recorded demographics and vascular risk factors. We reviewed the noncontrast head computed tomographies to assess for hyperdense middle cerebral artery and its computed tomography density. We reviewed the computed tomography angiograms and the raw images to determine the site and degree of arterial occlusion, collateral score, clot burden score, and the density of the clot. Recanalization status was assessed on recanalization imaging using Thrombolysis in Myocardial Ischemia. Multivariate logistic regressions were utilized to determine the best predictors of outcome in each treatment group. Results Among the 103 study patients, 43 (42%) received intravenous thrombolysis, 34 (33%) received endovascular thrombolysis, and 26 (25%) did not receive any revascularization therapy. In the patients with intravenous thrombolysis or no revascularization therapy, recanalization of the vessel was more likely with intravenous thrombolysis (P = 0·046) and when M1/A1 was occluded (P = 0·001). In this subgroup of patients, clot burden score, cervical degree of stenosis (North American Symptomatic Carotid Endarterectomy Trial), and hyperlipidemia status added information to the aforementioned likelihood of recanalization at the patient level (P < 0·001). In patients with endovascular thrombolysis, recanalization of the vessel was more likely in the case of a higher computed tomography angiogram clot density (P = 0·012), and in this subgroup of patients gender added information to the likelihood of recanalization at the patient level (P = 0·044). Conclusion The overall likelihood of recanalization was the highest in the endovascular group, and higher for intravenous thrombolysis compared with no revascularization therapy. However, our statistical models of recanalization for each individual patient indicate significant variability between treatment options, suggesting the need to include this prediction in the personalized treatment selection.

Demographic and clinical predictors of leptomeningeal collaterals in stroke patients.

BACKGROUND Leptomeningeal collaterals improve outcome after stroke, including reduction of hemorrhagic complications after thrombolytic or endovascular therapy, smaller infarct size, and reduction in symptoms at follow-up evaluation. The purpose of this study was to determine the demographic and clinical variables that are associated with a greater degree of cerebral collaterals. METHODS Clinical data of patients presenting with M1 occlusions of the middle cerebral artery (MCA) and associated computed tomography angiography studies after admission from 3 separate institutions were retrospectively compiled (n = 82). Occluded hemispheres were evaluated against the intact hemisphere for degree of collateralization in the MCA territory. Regression analysis of variance was conducted between clinical variables and collateral score to determine which variables associate with greater collateral development. RESULTS Smaller infarct size corresponded to greater collateral scores, whereas older age and statin use corresponded to lower collateral scores (P < .001). CONCLUSIONS Cerebral collateralization is influenced by age and statin use and influences infarct size.