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Background and ObjectivesRepeated concussive and sub-concussive impacts in high-contact sports can affect the brain’s microstructure, which can be studied using diffusion MRI. Most prior imaging studies, however, employ a cross-sectional design, do not include low-contact players as controls, or use traditional diffusion tensor imaging without investigating novel tractspecific microstructural metrics.MethodsWe examined brain microstructure in 63 high-contact (American football) and 34 low-contact (volleyball) collegiate athletes with up to 4 years of follow-up (315 total scans) using advanced diffusion MRI, a comprehensive set of multi-compartment models, and automated fiber quantification tools. We investigated diffusion metrics along the length of tracts using nested linear mixed-effects models to ascertain the acute and chronic effects of sub-concussive and concussive impacts, as well as associations between diffusion changes with clinical, behavioral, and sports-related measures.ResultsSignificant longitudinal increases in fractional anisotropy and axonal water fraction were detected in volleyball players, but not in football players, along with decreases in radial and mean diffusivity as well as orientation dispersion index (all findings absolute T-statistic > 3.5, p < .0001). This pattern was present in the callosum forceps minor, left superior longitudinal fasciculus, left thalamic radiation, and right cingulum hippocampus. Longitudinal group differences were more prominent and observed in a larger number of tracts in concussed (previously or in-study) football players (p < .0001), while smaller effects were noted in un-concussed players. An analysis of immediate-post concussion scans in football players demonstrated a transient localized increase in axial diffusivity, mean and radial kurtosis in the left uncinate and right cingulum hippocampus (p < .0001). Finally, football players with high position-based sub-concussive risk demonstrated increased orientation dispersion index over time (p < .0001).DiscussionThe observed longitudinal changes in our volleyball cohort likely reflect normal development in this age range, while the relative attenuation of these effects seen in football, and especially concussed athletes, could possibly reveal diminished myelination, altered axonal calibers, or depressed pruning processes leading to a static, non-decreasing axonal dispersion. This prospective longitudinal study demonstrates significantly divergent tract-specific trajectories of brain microstructure, possibly reflecting a concussive and/or repeated sub-concussive impact-related alteration of normal white matter development in football athletes.

Collegiate football athletes are subject to repeated traumatic brain injuriesthat may cause brain injury. The hippocampus is composed of several distinct subfields with possible differential susceptibility to injury. The aim of this study is to determine whether there are longitudinal changes in hippocampal subfield volume in collegiate football. A prospective cohort study was conducted over a 5-year period tracking 63 football and 34 volleyball male collegiate athletes. Athletes underwent high-resolution structural magnetic resonance imaging, and automated segmentation provided hippocampal subfield volumes. At baseline, football (n = 59) athletes demonstrated a smaller subiculum volume than volleyball (n = 32) athletes (−67.77 mm(3); p = 0.012). A regression analysis performed within football athletes similarly demonstrated a smaller subiculum volume among those at increased concussion risk based on athlete position (p = 0.001). For the longitudinal analysis, a linear mixed-effects model assessed the interaction between sport and time, revealing a significant decrease in cornu ammonis area 1 (CA1) volume in football (n = 36) athletes without an in-study concussion compared to volleyball (n = 23) athletes (volume difference per year = −35.22 mm(3); p = 0.005). This decrease in CA1 volume over time was significant when football athletes were examined in isolation from volleyball athletes (p = 0.011). Thus, this prospective, longitudinal study showed a decrease in CA1 volume over time in football athletes, in addition to baseline differences that were identified in the downstream subiculum. Hippocampal changes may be important to study in high-contact sports.

Objective To reevaluate asymmetric sensorineural hearing loss (ASNHL) criteria used to justify magnetic resonance imaging (MRI) in the evaluation of retrocochlear tumors in a military population. Study Design Retrospective case-control study. Setting Tertiary care military medical center. Subjects and Methods Patients with military service and a history of ASNHL prompting referral for MRI, with or without retrocochlear tumors, were compared between 2005 and 2016. Predictor variables included pure tone ASNHL, speech audiometry, and a history of noise exposure. Logistic regression models for hearing asymmetries were performed, and receiver operator curves were used to calculate sensitivity and specificity. Results Thirty-eight retrocochlear tumors were identified. The MRI diagnosis rate for patients with ASHNL was 0.85%. Patients with tumors were slightly older (42 vs 37 years, P = .021) and had less noise exposure (47% vs 85%, P < .001). A sensitivity of 0.83 and a specificity of 0.58 were calculated for asymmetries ≥10 dB at 2000 Hz without adjusting for noise exposure. Instituting this imaging threshold would have reduced the number of MRI scans by half while missing 16% of tumors. Conclusion The tumor diagnosis rate among those undergoing MRI for ASNHL is low in the military population, likely because service-related noise exposure commonly causes ASNHL. Optimal MRI referral criteria should conserve resources while balancing the risks of over- and underdiagnosis. For those with a history of military service, an asymmetry ≥10 dB at 2000 Hz among patients meeting current ANSHL referral criteria is most predictive of a retrocochlear tumor.

Collegiate football athletes are subject to repeated head impacts. The purpose of this study was to determine whether this exposure can lead to changes in brain structure. This prospective cohort study was conducted with up to 4 years of follow-up on 63 football (high-impact) and 34 volleyball (control) male collegiate athletes with a total of 315 MRI scans (after exclusions: football n ​= ​50, volleyball n ​= ​24, total scans ​= ​273) using high-resolution structural imaging. Volumetric and cortical thickness estimates were derived using FreeSurfer 5.3’s longitudinal pipeline. A linear mixed-effects model assessed the effect of group (football vs. volleyball), time from baseline MRI, and the interaction between group and time. We confirmed an expected developmental decrement in cortical thickness and volume in our cohort (p ​

Author(s): Liu, Tiffany T; Achrol, Achal S; Mitchell, Lex A; Rodriguez, Scott A; Feroze, Abdullah; Iv, Michael; Kim, Christine; Chaudhary, Navjot; Gevaert, Olivier; Stuart, Josh M; Harsh, Griffith R; Chang, Steven D; Rubin, Daniel L | Abstract: BackgroundIn previous clinical trials, antiangiogenic therapies such as bevacizumab did not show efficacy in patients with newly diagnosed glioblastoma (GBM). This may be a result of the heterogeneity of GBM, which has a variety of imaging-based phenotypes and gene expression patterns. In this study, we sought to identify a phenotypic subtype of GBM patients who have distinct tumor-image features and molecular activities and who may benefit from antiangiogenic therapies.MethodsQuantitative image features characterizing subregions of tumors and the whole tumor were extracted from preoperative and pretherapy perfusion magnetic resonance (MR) images of 117 GBM patients in 2 independent cohorts. Unsupervised consensus clustering was performed to identify robust clusters of GBM in each cohort. Cox survival and gene set enrichment analyses were conducted to characterize the clinical significance and molecular pathway activities of the clusters. The differential treatment efficacy of antiangiogenic therapy between the clusters was evaluated.ResultsA subgroup of patients with elevated perfusion features was identified and was significantly associated with poor patient survival after accounting for other clinical covariates (P values l.01; hazard ratios g 3) consistently found in both cohorts. Angiogenesis and hypoxia pathways were enriched in this subgroup of patients, suggesting the potential efficacy of antiangiogenic therapy. Patients of the angiogenic subgroups pooled from both cohorts, who had chemotherapy information available, had significantly longer survival when treated with antiangiogenic therapy (log-rank P=.022).ConclusionsOur findings suggest that an angiogenic subtype of GBM patients may benefit from antiangiogenic therapy with improved overall survival.

Background and purposeTumor location has been shown to be a significant prognostic factor in patients with glioblastoma. The purpose of this study was to characterize glioblastoma lesions by identifying MR imaging voxel-based tumor location features that are associated with tumor molecular profiles, patient characteristics, and clinical outcomes.Materials and methodsPreoperative T1 anatomic MR images of 384 patients with glioblastomas were obtained from 2 independent cohorts (n = 253 from the Stanford University Medical Center for training and n = 131 from The Cancer Genome Atlas for validation). An automated computational image-analysis pipeline was developed to determine the anatomic locations of tumor in each patient. Voxel-based differences in tumor location between good (overall survival of >17 months) and poor (overall survival of

BACKGROUND AND PURPOSE: Pediatric cranial sutures are often evaluated for abnormal diastasis upon presentation to the emergency department after trauma or during a neurologic consultation; however, few normative data for CT measurements exist. This study establishes normal means for the sagittal and coronal suture widths during the first year of life by using CT. MATERIALS AND METHODS: The sagittal suture and bilateral coronal sutures were evaluated for 483 patients, ages 1 day to 395 days collected retrospectively from electronic medical records. Histograms as well as normality and boxplots were used to view the distribution of the data. An analysis of variance was performed for each suture measured by using month of age as the independent class variable. RESULTS: The average proximal suture widths for the sagittal and coronal sutures at zero months of age were 5.0 ± 0.2 and 2.5 ± 0.1 mm, respectively. From zero to 1 month of age, these sutures narrowed significantly to 2.4 ± 0.1 and 1.3 ± 0.1 mm, respectively. From 1 to 12 months of age, sutures narrowed gradually. The proximal coronal suture widths showed a significant reduction from 1 month to 12 months (1.3 ± 0.1–0.8 ± 0.1 mm). CONCLUSIONS: The normative values for suture widths established by CT scan among this large population may be used to assess the infant calvaria for suture diastasis.

Pyomyositis, a suppurative infection of skeletal muscle, is a disease not frequently encountered by neurosurgical providers. While previously considered an infection localized to tropical and semitropical locations, clinical reports of pyomyositis in temperate climates have increased over the past decade. Paraspinal involvement is uncommon in pyomyositis; however, the potential exists for spread into the epidural space resulting in a spinal epidural abscess (SEA). Early diagnosis of an SEA is frequently hampered by the absence of specific signs, unfamiliarity with the disease, atypical manifestations, and a broad differential diagnosis that includes more common causes of back pain. To date, 1 such case of paraspinal pyomyositis associated with an SEA has been reported in the neurosurgical literature. The authors present 2 cases of pyomyositis with an SEA and review the epidemiology, pathophysiology, diagnostic workup, and management of this disorder.

The role of imaging in obstetrics and gynecology has undergone a revolution over the past few decades. Well-established methods such as endovaginal ultrasound have had a central role in the evaluation of nongravid patients with pelvic pain, as well as in the workup for ectopic pregnancy and evaluation of adnexal masses. Additional tools include MRI in the evaluation of appendicitis and other potentially surgical conditions in pregnant patients and MRI and CT in the evaluation of surgical complications. Newer tools in the radiology armamentarium include PET scanning which, alongside MRI and CT, are often helpful in staging gynecologic malignancy. The role of imaging in the obstetric and gynecology patient will continue to change as new modalities and techniques are introduced.

We sought to discover subtypes of glioblastoma (GBM) defined by quantitative imaging features and to identify their canonical signaling pathways. Preoperative MR imaging from 121 Stanford patients with de novo, focal, unilateral GBM were analyzed. Two board-certified neuroradiologists and a neurosurgeon reached consensus in delineating Regions-of-Interest (ROIs) around areas of enhancement in each T1 post-contrast MR. We extracted 138 quantitative image features representing signal intensity and morphology of each lesion. We then used Consensus Clustering to define subtypes in the Stanford group. Next, Prediction Analysis for Microarrays (PAM) and the In-Group Proportion (IGP) statistic were used to validate the reproducibility and robustness of our subtype classification in a second cohort of subjects from The Cancer Genome Atlas (TCGA, n = 145). Finally, to map imaging subtypes to particular molecular signaling pathways, we performed Significance Analysis of Microarrays (SAM) on pathway activity estimates derived from analysis of TCGA tumor copy number and RNA sequencing data with the PARADIGM algorithm. Consensus Clustering analysis of the training set identified three clusters whose validity was confirmed in the TCGA cohort (p < 0.0001, p< 0.0001, p = 0.015). Cluster sizes for the TCGA validation cohort (i.e. 45%, 21% and 35%) were similar to those in the Stanford training set (57%, 17% and 26%). Cluster 1 was associated with 49 overexpressed pathways (FDR < 5%) including Wnt, hypoxia, apoptosis, cell proliferation, and angiogenesis signaling pathways while Cluster 2 was characterized by downregulation of these pathways (FDR < 5%). No pathway was significantly associated with Cluster 3. We identified three distinct, robust clusters of focal, unilateral GBM defined by quantitative image signatures. Subtypes identified in a homogeneous Stanford training set were validated in the heterogeneous multi-institutional TCGA data set. Two of our three clusters had significant associations with canonical signaling pathways.

BACKGROUND AND PURPOSE: Pediatric brain tumors have diverse pathologic features, which poses diagnostic challenges. Although perfusion evaluation of adult tumors is well established, hemodynamic properties are not well characterized in children. Our goal was to apply arterial spin-labeling perfusion for various pathologic types of pediatric brain tumors and evaluate the role of arterial spin-labeling in the prediction of tumor grade. MATERIALS AND METHODS: Arterial spin-labeling perfusion of 54 children (mean age, 7.5 years; 33 boys and 21 girls) with treatment-naive brain tumors was retrospectively evaluated. The 3D pseudocontinuous spin-echo arterial spin-labeling technique was acquired at 3T MR imaging. Maximal relative tumor blood flow was obtained by use of the ROI method and was compared with tumor histologic features and grade. RESULTS: Tumors consisted of astrocytic (20), embryonal (11), ependymal (3), mixed neuronal-glial (8), choroid plexus (5), craniopharyngioma (4), and other pathologic types (3). The maximal relative tumor blood flow of high-grade tumors (grades III and IV) was significantly higher than that of low-grade tumors (grades I and II) (P < .001). There was a wider relative tumor blood flow range among high-grade tumors (2.14 ± 1.78) compared with low-grade tumors (0.60 ± 0.29) (P < .001). Across the cohort, relative tumor blood flow did not distinguish individual histology; however, among posterior fossa tumors, relative tumor blood flow was significantly higher for medulloblastoma compared with pilocytic astrocytoma (P = .014). CONCLUSIONS: Characteristic arterial spin-labeling perfusion patterns were seen among diverse pathologic types of brain tumors in children. Arterial spin-labeling perfusion can be used to distinguish high-grade and low-grade tumors.

Linoleic acid monoepoxides have been correlated with many pathological conditions. Studies using insect cells derived from Spodoptera frugiperda (Sf-21 cells) have suggested that conversion of the epoxides to the diols is required for toxicity. However, more recent studies using rabbit renal proximal tubules have suggested that linoleic acid monoepoxides are direct mitochondrial toxins. To better understand these discrepancies, we compared the toxicity of these linoleic acid metabolites in Sf-21 cells using mitochondrial respiration as an end point. Linoleic acid (100 microM) and 12,13-epoxy-9-octadecenoic acid (12,13-EOA, 100 microM) increased the rate of oligomycin-insensitive respiration by approximately 3.5- and 3-fold, respectively, decreased the rate of oligomycin-sensitive respiration by approximately 52 and 68%, respectively, and had no effect on the integrity of the electron transport chain. These effects were concentration-dependent, occurred within 1 min, and recovered to basal levels within 45 min. 12,13-Dihydroxy-9-octadecenoic acid (12,13-DHOA, 100 microM) had no effect on oligomycin-insensitive respiration but decreased the rate of oligomycin-sensitive respiration and uncoupled respiration in a concentration-dependent manner. Approximately 79 and 68% of oligomycin-sensitive respiration and uncoupled respiration was inhibited by 12,13-DHOA (100 microM), respectively. These effects occurred within 1 min and were not reversible in 6 h. Effects similar to those induced by 12,13-DHOA (100 microM) were observed using 12,13-EOA (100 microM) in Sf-21 cells expressing human soluble epoxide hydrolase. These data suggest that in this Sf-21 model linoleic acid and linoleic monoepoxides have transient uncoupling effects, whereas the primary mechanism of toxicity for linoleic acid diols in this model is inhibition of the electron transport chain.

Pyomyositis, a suppurative infection of skeletal muscle, is a disease not frequently encountered by neurosurgical providers. While previously considered an infection localized to tropical and semitropical locations, clinical reports of pyomyositis in temperate climates have increased over the past decade. Paraspinal involvement is uncommon in pyomyositis; however, the potential exists for spread into the epidural space resulting in a spinal epidural abscess (SEA). Early diagnosis of an SEA is frequently hampered by the absence of specific signs, unfamiliarity with the disease, atypical manifestations, and a broad differential diagnosis that includes more common causes of back pain. To date, 1 such case of paraspinal pyomyositis associated with an SEA has been reported in the neurosurgical literature. The authors present 2 cases of pyomyositis with an SEA and review the epidemiology, pathophysiology, diagnostic workup, and management of this disorder.

We present the case of a 13-year-old patient who presented to the Emergency Department with low back and flank pain. Cross sectional imaging revealed paraspinal pyomyositis and epidural abscess. A detailed patient history revealed a recent lower extremity skin infection consistent with tropical pyomyositis. Review of this case shows the importance for recommending either contrast enhanced computed tomography (CT) imaging of the spine and/or magnetic resonance imaging (MRI) in patients with a recent skin infection and acute onset of back pain.

To derive quantitative image features from magnetic resonance (MR) images that characterize the radiographic phenotype of glioblastoma multiforme (GBM) lesions and to create radiogenomic maps associating these features with various molecular data.Clinical, molecular, and MR imaging data for GBMs in 55 patients were obtained from the Cancer Genome Atlas and the Cancer Imaging Archive after local ethics committee and institutional review board approval. Regions of interest (ROIs) corresponding to enhancing necrotic portions of tumor and peritumoral edema were drawn, and quantitative image features were derived from these ROIs. Robust quantitative image features were defined on the basis of an intraclass correlation coefficient of 0.6 for a digital algorithmic modification and a test-retest analysis. The robust features were visualized by using hierarchic clustering and were correlated with survival by using Cox proportional hazards modeling. Next, these robust image features were correlated with manual radiologist annotations from the Visually Accessible Rembrandt Images (VASARI) feature set and GBM molecular subgroups by using nonparametric statistical tests. A bioinformatic algorithm was used to create gene expression modules, defined as a set of coexpressed genes together with a multivariate model of cancer driver genes predictive of the module's expression pattern. Modules were correlated with robust image features by using the Spearman correlation test to create radiogenomic maps and to link robust image features with molecular pathways.Eighteen image features passed the robustness analysis and were further analyzed for the three types of ROIs, for a total of 54 image features. Three enhancement features were significantly correlated with survival, 77 significant correlations were found between robust quantitative features and the VASARI feature set, and seven image features were correlated with molecular subgroups (P.05 for all). A radiogenomics map was created to link image features with gene expression modules and allowed linkage of 56% (30 of 54) of the image features with biologic processes.Radiogenomic approaches in GBM have the potential to predict clinical and molecular characteristics of tumors noninvasively. Online supplemental material is available for this article.

Previous in vivo studies in dogs suggest that the 9,10-monoepoxide of linoleic acid (9,10-cis-epoxyoctadecenoic acid [9,10-EOA]) has toxic cardiovascular effects that result in death at higher doses. More recent work with rabbit renal proximal tubule cells suggests that the 12,13-metabolites of linoleic acid are more toxic than the 9,10-isomers. Thus, in the current study, we tested the hypothesis that 12,13-EOA and 12,13-dihydroxyoctadecadienoic acid (12,13-DHOA) have direct adverse effects on the heart. Langendorff-perfused rat hearts were exposed to 30 microM linoleic acid, 30 microM 12,13-EOA, or 30 microM 12,13-DHOA for 60 min followed by a 30-min recovery period. As indicated by peak left intraventricular pressure and/or +dP/dt(max), all three of the agents elicited moderate increases in contractile function that peaked within 10 20 min. The effects of linoleic acid and 12,13-EOA returned to control values during the remainder of the 60-min exposure, whereas the positive inotropic response to 12,13-DHOA was maintained until washout. Sustained arrhythmias and negative inotropic actions were not observed with any of the three compounds. Subsequently, the monoepoxides were infused into conscious rats (35 mg/kg/h) while blood pressure, heart rate, and EKG were monitored for 24 h using biotelemetry techniques. The only effect observed was a slight decline in blood pressure. Thus, current data suggest that linoleic acid and its oxidative metabolites do not have direct cardiotoxic effects during acute exposure.

Conversion of 12,13-cis-epoxyoctadecenoic acid (12,13-EOA) to 12,13-dihydroxyoctadecenoic acid (12,13-DHOA) by soluble epoxide hydrolase has been suggested to be a critical step in mediating the toxicity of epoxidized linoleic acid. The current study tests the hypothesis that low levels of albumin in the normal culturing media of Sf-21 cells can protect these cells from exposures to 12,13-EOA, but not 12,13-DHOA. In albumin-free media, Sf-21 cells exposed to 100 microM 12,13-EOA, and 12,13-DHOA for 1 min showed significant signs of mitochondrial dysfunction which led to cytotoxicity. The addition of bovine serum albumin (BSA) at a concentration (3 microM) found in normal serum-supplemented media protected Sf-21 cells exposed to 12,13-EOA, but not 12,13-DHOA while BSA (500 microM) fully protected Sf-21 cells exposed to these fatty acids. These data resolve previous discrepancies observed among in vitro models and help clarify our understanding of how these metabolites affect human health.

Despite many studies elucidating the mechanisms of necrotic cell death, the role of fatty acids released during necrosis remains to be determined. The goals of this study were to determine whether linoleic acid could protect rabbit renal proximal tubules (RPT) from necrotic cell death associated with mitochondrial dysfunction and oxidative injury and to determine the mechanisms involved. Exposure to antimycin A (10 μM) for 1 h or hypoxia (perfusion with 95% N 2 /5% CO 2 ) for 1 or 2 h induced approximately 70% cellular lysis, as measured by lactate dehyrogenase release, versus 10% in controls. Preincubation with linoleic acid (100 μM) fully protected RPT from cellular lysis. RPT were also protected from lysis if linoleic acid was added 15 min after the addition of antimycin A. Measurements of free intracellular Ca 2+ concentrations showed that linoleic acid did not prevent the rise in intracellular Ca 2+ associated with a 30-min exposure to antimycin A. However, the influx of extracellular 36 Cl − following a 30-min exposure to antimycin A was ameliorated in the presence of linoleic acid. Linoleic acid did not prevent cellular lysis after exposure to hypoxia/reoxygenation (1 h/1 h) or t -butyl hydroperoxide (500 μM, 3 h). These data suggest that linoleic acid protects RPT during the late phase of cell death associated with inhibition of the electron transport chain but not oxidative injury. Several other fatty acids also protected RPT from lysis, and structure–activity relationship studies suggest that a free carboxyl terminus and at least one double bond are required for this action.

Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by sudden-onset thunderclap headache and focal neurologic deficits. Once thought to be a rare syndrome, more advanced non-invasive imaging has led to an increase in RCVS diagnosis. Unilateral vertebral artery dissection has been described in fewer than 40% of cases of RCVS. Bilateral vertebral artery dissection has rarely been reported. We describe the case of a patient with RCVS and bilateral vertebral artery dissection presenting with an intramedullary infarct treated successfully with medical management and careful close follow-up. This rare coexistence should be recognized as the treatment differs.

Objective: To predict mutations of key genes in glioblastoma multiforme (GBM) from MR image features. Methods: We obtained mutational and MR image data from 35 patients in the Cancer Genome Atlas (TCGA) GBM database. T1-weighted axial images pre and post gadolinium contrast MRI were processed as follows: a board certified neuro-radiologist traced a region of interest (ROI) around the enhanced part of the largest lesion in the T1 post-contrast MRI and confirmed by comparing it with the T1 pre-contrast image. This ROI was then used to compute features that characterized the intensity of the enhanced lesion, the sharpness of lesion boundaries and the boundary shape. We used the resulting data set to build a linear regression model with regularization to predict the presence of a mutation in terms of image features. We focused on predicting mutations in EGFR because several drugs target it and because EGFR mutations are prevalent in the TCGA GBM data. We evaluated the performance of predicting EGFR mutations from MR imaging data using 5-fold cross validation (5F-CV) and the area under the ROC Curve (AUC). The optimal ROC operating point was defined as the point with the maximal sum of sensitivity and specificity when the cost of false positives and false negatives are considered equivalent. Results: We found that computationally-derived MR image features can predict the presence of EGFR mutations with an AUC of 0.80. The optimal operating point had a sensitivity and specificity of 83% and 93% respectively. The top ranked features in the image-based EGFR-predictor model suggest that EGFR-mutated tumors have blurrier edges than EGFR-wild-type tumors. Conclusion: Our preliminary radiogenomic analysis of GBM suggests MR images may be used to non-invasively determine the mutation status of EGFR, an important drug target in glioblastoma. The ability to determine important genomic aberrations based on image data suggests a increasingly important role for imaging in personalized medicine and warrants further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5561. doi:1538-7445.AM2012-5561

Cytochrome P450 epoxidation of linoleic acid produces biologically active metabolites which have been associated with many pathological conditions that often lead to acute renal failure. In the present study, we evaluated the ability of specific cytochrome P450s to produce linoleic acid monoepoxides. We then tested the cytotoxic properties of linoleic acid, linoleic acid monoepoxides, and corresponding diols in a rabbit renal proximal tubule model. CYP1A2, CYP2E1, CYP2J2, CYP2J3, CYP2J5, and CYP2J9 metabolized linoleic acid at rates comparable to arachidonic acid and produced linoleic acid monoepoxides as major products. Cytotoxicity studies showed that linoleic acid, linoleic acid monoepoxides, and corresponding diols are toxic at pathologically relevant concentrations (100–500 μM). Concentration-dependent studies showed that linoleic acid and linoleic acid monoepoxides are the most toxic and induce mitochondrial dysfunction prior to cell death. Cytoprotectants known to block cell death associated with mitochondrial dysfunction and oxidative stress did not prevent cell death induced by linoleic acid and linoleic acid monoepoxides. This study shows that P450s in the CYP1 and CYP2 gene families metabolize linoleic acid to linoleic acid monoepoxides and that the monoepoxides, as well as linoleic acid, disrupt mitochondrial function without causing oxidative stress.