Tailored Hemispherotomy Using Tractography-Guided Laser Interstitial Thermal Therapy.

BACKGROUND: Medically refractory hemispheric epilepsy is a devastating disease with significant lifetime costs and social burden. Functional hemispherotomy is a highly effective treatment for hemispheric epilepsy but is associated with significant complication rates. Percutaneous hemispherotomy through laser interstitial thermal therapy (LITT) based on morphological MRI has been recently described in a single patient but not replicated in the literature. OBJECTIVE: To describe the first 2 cases of tractography-guided interstitial laser hemispherotomy and their short-term outcomes. METHODS: Two 11-year-old male patients with medically refractory epilepsy secondary to perinatal large vessel infarcts were referred for hemispherotomy. Both patients underwent multitrajectory LITT to disconnect the remaining pathological hemisphere, using tractography to define targets and assess structural outcomes. RESULTS: Both cases had minor complication of small intraventricular/subarachnoid hemorrhage not requiring additional intervention. Both patients remain seizure-free at all follow-up visits. CONCLUSION: LITT hemispherotomy can produce seizure freedom with short hospitalization and recovery. Tractography allows surgical planning to be tailored according to individual patient anatomy, which often is distorted in perinatal stroke. Minimally invasive procedures offer the greatest potential for seizure freedom without the risks of an open hemispherotomy.

Opioid Use, Risk Factors, and Outcome in Lumbar Fusion Surgery.

OBJECTIVE: Inappropriate opioid use resulted in 68% of all U.S. drug overdoses in 2017-nearly 75% of all opioid deaths-costing $80 billion per year. It is imperative to understand the impact of opioid use on outcome from surgery for lower back pain disorders. METHODS: A retrospective review of lumbar spinal fusion registry data at a single center from 2015-2018 was performed. A novel algorithm was used to extract opioid utilization from the electronic health record. Number of levels fused, fusion type, and minimally invasive surgery status were collected from the registry, as were depression status, European Quality of Life 5 level score, and Oswestry Disability Index at 6 months to 1 year postoperatively. RESULTS: We included 294 patients (mean age 62 years, 48% male). Patients younger than 65 years trended toward more opioid use before surgery and significantly higher opioid use after surgery (P < 0.0001). Depression trended toward increasing opioid use after surgery (P = 0.08). Fusions of 4 or more levels were associated with overall greater opioid use after surgery (P = 0.03). Higher rate of opioid use before and after surgery is associated with worse European Quality of Life 5 level scores after surgery (P = 0.01 and P = 0.04) and worse Oswestry Disability Index scores after surgery (P = 0.006 and P = 0.002). CONCLUSIONS: This registry finds that younger age and lower functional status scores are associated with higher opioid use before surgery. Opioid use before surgery, younger age, and >4 levels of fusion are associated with higher opioid use after surgery. Overall, opioid use is associated with worse functional outcome and may serve as a marker of disease progression.

Characterization of an Inducible Alcoholic Liver Fibrosis Model for Hepatocellular Carcinoma Investigation in a Transgenic Porcine Tumorigenic Platform.

PURPOSE: This study used the Oncopig Cancer Model (OCM) to develop alcohol-induced fibrosis in a porcine model capable of developing hepatocellular carcinoma. MATERIALS AND METHODS: Liver injury was induced in 8-week-old Oncopigs (n = 10) via hepatic transarterial infusion of 0.75 mL/kg ethanol-ethiodized oil (1:3 v/v). Feasibility was assessed in an initial Oncopig cohort (n = 5) by histologic analysis at 8 weeks after induction, and METAVIR results were compared to age- and sex-matched healthy controls (n = 5). Liver injury was then induced in a second OCM cohort (n = 5) for a time-course study, with post-induction disease surveillance via biweekly physical exam, lab analysis, and liver biopsies until 20 weeks after induction. RESULTS: In Cohort 1, 8-week post-induction liver histologic analysis revealed median METAVIR F3 (range, F3-F4) fibrosis, A2 (range, A2-A3) inflammation, and 15.3% (range, 5.0%-22.9%) fibrosis. METAVIR and inflammation scores were generally elevated compared to healthy controls (F0-F1, P = 0.0013; A0-A1, P = .0013; median percent fibrosis 8.7%, range, 5.8%-12.1%, P = .064). In Cohort 2, histologic analysis revealed peak fibrosis severity of median METAVIR F3 (range, F2-F3). However, lack of persistent alcohol exposure resulted in liver recovery, with median METAVIR F2 (range, F1-F2) fibrosis at 20 weeks after induction. No behavioral or biochemical abnormalities were observed to indicate liver decompensation. CONCLUSIONS: This study successfully validated a protocol to develop METAVIR F3-F4 fibrosis within 8 weeks in the OCM, supporting its potential to serve as a model for hepatocellular carcinoma in a fibrotic liver background. Further investigation is required to determine if repeated alcohol liver injury is required to develop an irreversible METAVIR grade F4 porcine cirrhosis model.

Hemodynamic characteristics associated with cerebral aneurysm formation in patients with carotid occlusion.

OBJECTIVE: The pathogenesis of cerebral aneurysms in patients with internal carotid artery (ICA) occlusion is hypothesized to be hemodynamic. For the first time, the authors quantify the hemodynamic characteristics associated with aneurysm formation in patients with ICA occlusion. METHODS: Records of patients with unilateral ICA stenosis or occlusion ≥ 90% who underwent hemodynamic assessment before treatment using quantitative MR angiography were retrospectively reviewed. The patients were classified into 2 groups based on the presence or absence of aneurysms. The hemodynamic parameters of flow volume rate, flow velocity, and wall shear stress (WSS) were measured in each vessel supplying collateral flow-bilateral A1 segments and bilateral posterior communicating arteries-and then compared between the groups. RESULTS: A total of 36 patients were included (8 with and 28 without aneurysms). The mean flow (72.3 vs 48.9 ml/min, p = 0.10), flow velocity (21.1 vs 12.7 cm/sec, p = 0.006), and WSS (22.0 vs 12.3 dynes/cm2, p = 0.003) were higher in the A1 segment contralateral to the side of the patent ICA in patients with versus without aneurysms. All de novo or growing aneurysms in our cohort were located on the anterior communicating artery (ACoA) or P1 segment. CONCLUSIONS: Flow velocity and WSS are significantly higher across the ACoA in patients who harbor an aneurysm, and de novo or growing aneurysms are often located on collateral vessels. Thus, robust primary collaterals after ICA occlusion may be a contributing factor in cerebral aneurysm formation.

Gastric Varices Bleed at Lower Portosystemic Pressure Gradients than Esophageal Varices.

PURPOSE: To quantify and compare portosystemic pressure gradients (PSGs) between bleeding esophageal varices (EV) and gastric varices (GV). MATERIALS AND METHODS: In a single-center, retrospective study, 149 patients with variceal bleeding (90 men, 59 women, mean age 52 y) with EV (n = 69; 46%) or GV (n = 80; 54%) were selected from 320 consecutive patients who underwent successful transjugular intrahepatic portosystemic shunt (TIPS) creation from 1998 to 2016. GV were subcategorized using the Sarin classification as gastroesophageal varices (GEV) (n = 57) or isolated gastric varices (IGV) (n = 23). PSG before TIPS was measured from the main portal vein to the right atrium. PSGs were compared across EV, GEV, and IGV groups using 1-way analysis of variance. RESULTS: Overall mean baseline PSG was 21 mm Hg ± 6. PSG was significantly higher in patients with EV versus GV (23 mm Hg vs 19 mm Hg; P < .001). Mean PSG was highest among EV (23 mm Hg) with lower PSGs identified for GEV (20 mm Hg) and IGV (16 mm Hg); this difference was statistically significant (P < .001). Among 95 acute bleeding cases, a similar pattern was evident (EV 23 mm Hg vs GEV mm Hg 20 vs IGV 17 mm Hg; P < .001). At baseline PSG < 12 mm Hg, 13% (3/23) of IGV bled versus 9% (5/57) of GEV and 3% (2/69) of EVs (P = .169). Mean final PSG after TIPS was 8 mm Hg (IGV 6 mm Hg vs EV and GEV 8 mm Hg; P = .005). CONCLUSIONS: GV bleed at lower PSGs than EV. EV, GEV, and IGV bleeding is associated with successively lower PSGs. These findings highlight distinct physiology, anatomy, and behavior of GV compared with EV.

Cerebral arteriovenous malformation draining vein stenosis is associated with atherosclerotic risk factors.

OBJECTIVE: The pathogenesis of venous outflow stenosis associated with cerebral arteriovenous malformation (AVM) draining veins is poorly understood. We sought to determine the relationship between venous stenosis and atherosclerotic risk factors. MATERIALS AND METHODS: All patients with an AVM seen at our institution between 1990 and 2016 were retrospectively reviewed. Patients <18 years of age were excluded. Patients were classified into two groups based on the presence or absence of venous stenosis. Patient charts were reviewed for the following atherosclerotic risk factors: age >50 years, sex, race, hypertension, type 2 diabetes mellitus, hyperlipidemia, coronary artery disease, chronic kidney disease stage III, and cigarette smoking. The relationship between venous stenosis and atherosclerotic risk factors was assessed using univariate and multivariate analyses. RESULTS: 278 patients were included (mean age 41 years, 55% men). Venous stenosis was present in 87 patients (31% of the cohort). The presence of venous stenosis was significantly associated with age >50 years (P=0.05), hypertension (P=0.05), diabetes (P=0.02), and hyperlipidemia (P=0.001). Multivariate analysis showed that hyperlipidemia (P=0.05) was predictive of draining vein stenosis. CONCLUSIONS: Venous stenosis is associated with several atherosclerotic risk factors, suggesting that cerebral AVM venous outflow stenosis occurs by a degenerative process. Additional studies can show whether these modifiable risk factors may be targeted to prevent draining vein stenosis and AVM rupture.

The Oncopig Cancer Model: An Innovative Large Animal Translational Oncology Platform.

Despite an improved understanding of cancer molecular biology, immune landscapes, and advancements in cytotoxic, biologic, and immunologic anti-cancer therapeutics, cancer remains a leading cause of death worldwide. More than 8.2 million deaths were attributed to cancer in 2012, and it is anticipated that cancer incidence will continue to rise, with 19.3 million cases expected by 2025. The development and investigation of new diagnostic modalities and innovative therapeutic tools is critical for reducing the global cancer burden. Toward this end, transitional animal models serve a crucial role in bridging the gap between fundamental diagnostic and therapeutic discoveries and human clinical trials. Such animal models offer insights into all aspects of the basic science-clinical translational cancer research continuum (screening, detection, oncogenesis, tumor biology, immunogenicity, therapeutics, and outcomes). To date, however, cancer research progress has been markedly hampered by lack of a genotypically, anatomically, and physiologically relevant large animal model. Without progressive cancer models, discoveries are hindered and cures are improbable. Herein, we describe a transgenic porcine model-the Oncopig Cancer Model (OCM)-as a next-generation large animal platform for the study of hematologic and solid tumor oncology. With mutations in key tumor suppressor and oncogenes, TP53R167H and KRASG12D , the OCM recapitulates transcriptional hallmarks of human disease while also exhibiting clinically relevant histologic and genotypic tumor phenotypes. Moreover, as obesity rates increase across the global population, cancer patients commonly present clinically with multiple comorbid conditions. Due to the effects of these comorbidities on patient management, therapeutic strategies, and clinical outcomes, an ideal animal model should develop cancer on the background of representative comorbid conditions (tumor macro- and microenvironments). As observed in clinical practice, liver cirrhosis frequently precedes development of primary liver cancer or hepatocellular carcinoma. The OCM has the capacity to develop tumors in combination with such relevant comorbidities. Furthermore, studies on the tumor microenvironment demonstrate similarities between OCM and human cancer genomic landscapes. This review highlights the potential of this and other large animal platforms as transitional models to bridge the gap between basic research and clinical practice.

Decision Making for Selection of Transarterial Locoregional Therapy of Metastatic Neuroendocrine Tumors.

Transarterial locoregional therapies (LRTs) are indispensable components of the modern interventional oncologic therapy of liver-dominant metastatic neuroendocrine tumors (NETs). The scope of available LRTs and their nuanced differences mandates a thorough understanding of their relative applicability and effectiveness in certain clinical circumstances to prescribe appropriate, patient-specific, image-guided therapy. This article aims to provide an overview of transarterial LRT options for liver-dominant metastatic NETs and therapy selection by reviewing procedure types, their advantages and disadvantages, and comparative efficacy in common case scenarios.

Effects of context-drug learning on synaptic connectivity in the basolateral nucleus of the amygdala in rats.

Context-drug learning produces structural and functional synaptic changes in the circuitry of the basolateral nucleus of the amygdala (BLA). However, how the synaptic changes translated to the neuronal targets was not established. Thus, in the present study, immunohistochemistry with a cell-specific marker and the stereological quantification of synapses was used to determine if context-drug learning increases the number of excitatory and inhibitory/modulatory synapses contacting the gamma-aminobutyric acid (GABA) interneurons and/or the pyramidal neurons in the BLA circuitry. Amphetamine-conditioned place preference increased the number of asymmetric (excitatory) synapses contacting the spines and dendrites of pyramidal neurons and the number of multisynaptic boutons contacting pyramidal neurons and GABA interneurons. Context-drug learning increased asymmetric (excitatory) synapses onto dendrites of GABA interneurons and increased symmetric (inhibitory or modulatory) synapses onto dendrites but not perikarya of these same interneurons. The formation of context-drug associations alters the synaptic connectivity in the BLA circuitry, findings that have important implications for drug-seeking behavior.

Aberrant restoration of spines and their synapses in L-DOPA-induced dyskinesia: involvement of corticostriatal but not thalamostriatal synapses.

We examined the structural plasticity of excitatory synapses from corticostriatal and thalamostriatal pathways and their postsynaptic targets in adult Sprague-Dawley rats to understand how these striatal circuits change in l-DOPA-induced dyskinesias (LIDs). We present here detailed electron and light microscopic analyses that provide new insight into the nature of the structural and synaptic remodeling of medium spiny neurons in response to LIDs. Numerous studies have implicated enhanced glutamate signaling and persistent long-term potentiation as central to the behavioral sensitization phenomenon of LIDs. Moreover, experience-dependent alterations in behavior are thought to involve structural modifications, specifically alterations in patterns of synaptic connectivity. Thus, we hypothesized that in the striatum of rats with LIDs, one of two major glutamatergic pathways would form new or altered contacts, especially onto the spines of medium spiny neuron (MSNs). Our data provide compelling evidence for a dramatic rewiring of the striatum of dyskinetic rats and that this rewiring involves corticostriatal but not thalamostriatal contacts onto MSNs. There is a dramatic increase in corticostriatal contacts onto spines and dendrites that appear to be directly linked to dyskinetic behaviors, since they were not seen in the striatum of animals that did not develop dyskinesia. There is also an aberrant increase in spines receiving more than one excitatory contact(i.e., multisynaptic spines) in the dyskinetic animals compared with the 6-hydroxydopamine-treated and control rats. Such alterations could substantially impair the ability of striatal neurons to gate cortically driven signals and contribute to the loss of bidirectional synaptic plasticity.