Bilateral Dilated Superior Ophthalmic Veins in a Patient With an Arteriovenous Dialysis Fistula.

A 64-year-old man presented with 4 months of diplopia. He had end-stage renal disease requiring a cephalic transposition brachiocephalic fistula that was no longer in use following successful renal transplantation. On presentation, he had bilateral proptosis, extraocular movement restriction, chemosis, tortuous episcleral vessels, and caruncular injection. Non-contrast CT of the orbits demonstrated dilation of both superior ophthalmic veins, and CT angiography showed asymmetric enlargement of both cavernous sinuses and superior ophthalmic veins. A carotid-cavernous fistula was suspected, but cerebral angiography revealed shunting from the old fistula with intracranial drainage and cerebral venous hypertension. Aberrant retrograde drainage resulted from anatomical compression of the left brachiocephalic vein. The fistula was ligated, and at 1-week follow-up, the patient had marked improvement in extraocular movements and orbital congestion with near complete resolution of diplopia. Postoperative CT angiography obtained 2 months later demonstrated decreased size of both superior ophthalmic veins, consistent with improvement of venous hypertension.

Integrated genomic analysis identifies the mitotic checkpoint kinase WEE1 as a novel therapeutic target in medulloblastoma.

BACKGROUND: Medulloblastoma is the most common type of malignant brain tumor that afflicts children. Although recent advances in chemotherapy and radiation have improved outcomes, high-risk patients do poorly with significant morbidity. METHODS: To identify new molecular targets, we performed an integrated genomic analysis using structural and functional methods. Gene expression profiling in 16 medulloblastoma patient samples and subsequent gene set enrichment analysis indicated that cell cycle-related kinases were associated with disease development. In addition a kinome-wide small interfering RNA (siRNA) screen was performed to identify kinases that, when inhibited, could prevent cell proliferation. The two genome-scale analyses were combined to identify key vulnerabilities in medulloblastoma. The inhibition of one of the identified targets was further investigated using RNAi and a small molecule inhibitor. RESULTS: Combining the two analyses revealed that mitosis-related kinases were critical determinants of medulloblastoma cell proliferation. RNA interference (RNAi)-mediated knockdown of WEE1 kinase and other mitotic kinases was sufficient to reduce medulloblastoma cell proliferation. These data prompted us to examine the effects of inhibiting WEE1 by RNAi and by a small molecule inhibitor of WEE1, MK-1775, in medulloblastoma cell lines. MK-1775 inhibited the growth of medulloblastoma cell lines, induced apoptosis and increased DNA damage at nanomolar concentrations. Further, MK-1775 was synergistic with cisplatin in reducing medulloblastoma cell proliferation and resulted in an associated increase in cell death. In vivo MK-1775 suppressed medulloblastoma tumor growth as a single agent. CONCLUSIONS: Taken together, these findings highlight mitotic kinases and, in particular, WEE1 as a rational therapeutic target for medulloblastoma.

Development of machine learning models for predicting outcome in patients with distal medium vessel occlusions: a retrospective study.

Background: While numerous prognostic factors have been reported for large vessel occlusion (LVO)-acute ischemic stroke (AIS) patients, the same cannot be said for distal medium vessel occlusions (DMVOs). We used machine learning (ML) algorithms to develop a model predicting the short-term outcome of AIS patients with DMVOs using demographic, clinical, and laboratory variables and baseline computed tomography (CT) perfusion (CTP) postprocessing quantitative parameters. Methods: In this retrospective cohort study, consecutive patients with AIS admitted to two comprehensive stroke centers between January 1, 2017, and September 1, 2022, were screened. Demographic, clinical, and radiological data were extracted from electronic medical records. The clinical outcome was divided into two categories, with a cut-off defined by the median National Institutes of Health Stroke Scale (NIHSS) shift score. Data preprocessing involved addressing missing values through imputation, scaling with a robust scaler, normalization using min-max normalization, and encoding of categorical variables. The data were split into training and test sets (70:30), and recursive feature elimination (RFE) was employed for feature selection. For ML analyses, XGBoost, LightGBM, CatBoost, multi-layer perceptron, random forest, and logistic regression algorithms were utilized. Performance evaluation involved the receiver operating characteristic (ROC) curve, precision-recall curve (PRC), the area under these curves, accuracy, precision, recall, and Matthews correlation coefficient (MCC). The relative weights of predictor variables were examined using Shapley additive explanations (SHAP). Results: Sixty-nine patients were included and divided into two groups: 35 patients with favorable outcomes and 34 patients with unfavorable outcomes. Utilizing ten selected features, the XGBoost algorithm achieved the best performance in predicting unfavorable outcomes, with an area under the ROC curve (AUROC) of 0.894 and an area under the PRC curve (AUPRC) of 0.756. The SHAP analysis ranked the following features in order of importance for the XGBoost model: mismatch volume, time-to-maximum of the tissue residue function (Tmax) >6 s, diffusion-weighted imaging (DWI) volume, neutrophil-to-platelet ratio (NPR), mean corpuscular volume (MCV), Tmax >10 s, hemoglobin, potassium, hypoperfusion index (HI), and Tmax >8 s. Conclusions: Our ML models, trained on baseline quantitative laboratory and CT parameters, accurately predicted the short-term outcome in patients with DMVOs. These findings may aid clinicians in predicting prognosis and may be helpful for future research.

Prediction of Poor Outcome after Successful Thrombectomy in Patients with Severe Acute Ischemic Stroke: A Pilot Retrospective Study.

Several baseline hematologic and metabolic laboratory parameters have been linked to acute ischemic stroke (AIS) clinical outcomes in patients who successfully recanalized. However, no study has directly investigated these relationships within the severe stroke subgroup. The goal of this study is to identify potential predictive clinical, lab, and radiographic biomarkers in patients who present with severe AIS due to large vessel occlusion and have been successfully treated with mechanical thrombectomy. This single-center, retrospective study included patients who experienced AIS secondary to large vessel occlusion with an initial NIHSS score ≥ 21 and were recanalized successfully with mechanical thrombectomy. Retrospectively, demographic, clinical, and radiologic data from electronic medical records were extracted, and laboratory baseline parameters were obtained from emergency department records. The clinical outcome was defined as the modified Rankin Scale (mRS) score at 90 days, which was dichotomized into favorable functional outcome (mRS 0-3) or unfavorable functional outcome (mRS 4-6). Multivariate logistic regression was used to build predictive models. A total of 53 patients were included. There were 26 patients in the favorable outcome group and 27 in the unfavorable outcome group. Age and platelet count (PC) were found to be predictors of unfavorable outcomes in the multivariate logistic regression analysis. The areas under the receiver operating characteristic (ROC) curve of models 1 (age only model), 2 (PC only model), and 3 (age and PC model) were 0.71, 0.68, and 0.79, respectively. This is the first study to reveal that elevated PC is an independent predictor of unfavorable outcomes in this specialized group.

Multiple Thrombectomies in the Same Patient within One Month: Case Report of a Patient with Trousseau Syndrome and Acute Ischemic Stroke.

BACKGROUND AND IMPORTANCE: Since Trousseau's initial publication, the development of thromboembolic events related to malignancy has been well established. The pathophysiology of this is understood to be through activation of the coagulation cascade through neoplastic cells themselves or the therapy initiated (chemotherapy or surgery). To date, there have been a variety of studies, such as the OASIS-CANCER trial, which highlight the relationship of hypercoagulability to ischemic stroke. Despite these efforts, clear evidence is lacking for the utilization of antiplatelet or anticoagulation therapy in the secondary prevention of stroke following mechanical thrombectomy in patients with suspected or confirmed malignancy. CLINICAL PRESENTATION: A 71-year-old female with a history of immune thrombocytopenia, diabetes mellitus, and hypertension who was undergoing an evaluation for a lung nodule, later determined to be adenocarcinoma of the lung, underwent three successful mechanical thrombectomies for acute ischemic stroke with large vessel occlusion over a one month period. This patient had improved National Institutes of Health Stroke Scale (NIHSS) scores following each of her thrombectomies. However, her history of immune thrombocytopenia and underlying malignancy complicated her discharge medication regimen following each of her thrombectomies and may have contributed to her repeat strokes. CONCLUSION: Clear guidance is lacking regarding the utilization of antiplatelet and anticoagulation therapy in patients with suspected or confirmed malignancy following mechanical thrombectomy. Review of the literature suggests that controlling a patient's hypercoagulability may lead to improved clinical outcomes, but further clinical trials are warranted.

Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma.

Medulloblastoma is a pediatric brain tumor with a variable prognosis due to clinical and genomic heterogeneity. Among the 4 major genomic sub-groups, patients with MYC amplified tumors have a particularly poor prognosis despite therapy with surgery, radiation and chemotherapy. Targeting the MYC oncogene has traditionally been problematic. Here we report that MYC driven medulloblastoma can be targeted by inhibition of the bromodomain protein BRD4. We show that bromodomain inhibition with JQ1 restricts c-MYC driven transcriptional programs in medulloblastoma, suppresses medulloblastoma cell growth and induces a cell cycle arrest. Importantly JQ1 suppresses stem cell associated signaling in medulloblastoma cells and inhibits medulloblastoma tumor cell self-renewal. Additionally JQ1 also promotes senescence in medulloblastoma cells by activating cell cycle kinase inhibitors and inhibiting activity of E2F1. Furthermore BRD4 inhibition displayed an anti-proliferative, pro-senescence effect in a medulloblastoma model in vivo. In clinical samples we found that transcriptional programs suppressed by JQ1 are associated with adverse risk in medulloblastoma patients. Our work indicates that BRD4 inhibition attenuates stem cell signaling in MYC driven medulloblastoma and demonstrates the feasibility BET domain inhibition as a therapeutic approach in vivo.