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PURPOSE: To investigate practice patterns related to MR technique and structured reporting for MRI of rectal cancer at academic centers and private practice groups in the United States. METHODS AND MATERIALS: A survey developed by active members of the Society of Abdominal Radiology Rectal and Anal Cancer Disease Focus Panel was sent to 100 private practice and 189 academic radiology groups. The survey asked targeted questions about practice demographics and utilization, technical MR parameters and reporting practices related to MRI of rectal cancer. The results were analyzed using software in an online survey program. RESULTS: The survey received 47 unique responses from academic (37/47, 78.7%) and private practice (10/47, 21.3%) groups. Most practices report using rectal MR for staging newly diagnosed rectal cancer always (29/47, 61.7%), and less than half always do so for re-staging after neoadjuvant chemoradiation (20/47, 42.6%). Most groups perform between 1 to 5 rectal MR studies for baseline staging per week (32/47, 68.1%) and most groups perform 0 to 2 MR studies for re-staging per week (27/47, 57.4%). Regarding patient preparation and MR technical parameters, there is variability, but a few key points include most practices (27/47, 57.4 %) acquire axial T2-weighted images at a slice thickness of 3mm or less, axial T2-weighted images with 2D acquisition (30/47, 63.8%), a T2-weighted axial oblique sequence through the tumor (43/47, 91.5%), and T2-weighted images without fat suppression (37/47, 78.7%). Equal numbers of groups report using a maximal b-value less than 1000 s/mm(2) (19/43, 44.2%) and 1000 s/mm(2) or greater (19/43, 44.2%); the rest were unsure. A substantial portion of respondents do not use intravenous contrast (13/47, 27.7%). Most believe that structured report templates contribute to uniformity of reporting practices (39/47, 83.0%), though there is considerable heterogeneity in usage and included elements. CONCLUSION: There is considerable technical heterogeneity among respondents’ answers and reporting practices in MR for rectal cancer, and most of the groups report reading only a modest number of studies per week. Our findings suggest there may be room for improvement in terms of radiologist education for performance and standardization of clinical practice for MR imaging of rectal cancer.

To study the association between gallbladder dimensions and acute cholecystitis and to define a sensitive cutoff for excluding the disease. 456 consecutive patients with an abdominal ultrasound performed for right upper quadrant pain, from 1/2019 to 4/2019, were retrospectively collected. Length and width of the gallbladder were measured by a blinded radiology fellow. Patient charts were examined for prospective sonographic findings, clinical data, and pathology from subsequent cholecystectomy or at least 1 month of follow-up with symptom resolution. Univariable and multivariable logistic regression analysis were conducted to define the association of gallbladder dimensions and other sonographic and clinical variables with acute cholecystitis. Optimal and sensitive cutoffs of gallbladder widths were defined. The determined sensitive cutoff was validated with a separate cohort of 501 consecutive patients. 319 patients (median age 48 ± 19 years) including 11%, 19%, and 70% with acute, chronic, and no cholecystitis were included in the experimental cohort, respectively, and 298 patients (median age 50 ± 19 years) including 10%, 12%, and 79% with acute, chronic, and no cholecystitis were included in the validation cohort, respectively. Of all sonographic findings and clinical data, gallbladder width produced the best univariate ROC curve with an AUC of 0.91 (Odds ratio 5.1, 95% CI 3.1–8.5, p

Rationale: The computed tomography (CT) pattern of definite or probable usual interstitial pneumonia (UIP) can be diagnostic of idiopathic pulmonary fibrosis and may obviate the need for invasive surgical biopsy. Few machine-learning studies have investigated the classification of interstitial lung disease (ILD) on CT imaging, but none have used histopathology as a reference standard. Objectives: To predict histopathologic UIP using deep learning of high-resolution computed tomography (HRCT). Methods: Institutional databases were retrospectively searched for consecutive patients with ILD, HRCT, and diagnostic histopathology from 2011 to 2014 (training cohort) and from 2016 to 2017 (testing cohort). A blinded expert radiologist and pulmonologist reviewed all training HRCT scans in consensus and classified HRCT scans based on the 2018 American Thoracic Society/European Respriatory Society/Japanese Respiratory Society/Latin American Thoracic Association diagnostic criteria for idiopathic pulmonary fibrosis. A convolutional neural network (CNN) was built accepting 4 × 4 × 2 cm virtual wedges of peripheral lung on HRCT as input and outputting the UIP histopathologic pattern. The CNN was trained and evaluated on the training cohort using fivefold cross validation and was then tested on the hold-out testing cohort. CNN and human performance were compared in the training cohort. Logistic regression and survival analyses were performed. Results: The CNN was trained on 221 patients (median age 60 yr; interquartile range [IQR], 53–66), including 71 patients (32%) with UIP or probable UIP histopathologic patterns. The CNN was tested on a separate hold-out cohort of 80 patients (median age 66 yr; IQR, 58–69), including 22 patients (27%) with UIP or probable UIP histopathologic patterns. An average of 516 wedges were generated per patient. The percentage of wedges with CNN-predicted UIP yielded a cross validation area under the curve of 74% for histopathological UIP pattern per patient. The optimal cutoff point for classifying patients on the training cohort was 16.5% of virtual lung wedges with CNN-predicted UIP and resulted in sensitivity and specificity of 74% and 58%, respectively, in the testing cohort. CNN-predicted UIP was associated with an increased risk of death or lung transplantation during cross validation (hazard ratio, 1.5; 95% confidence interval, 1.1–2.2; P = 0.03). Conclusions: Virtual lung wedge resection in patients with ILD can be used as an input to a CNN for predicting the histopathologic UIP pattern and transplant-free survival.

The goal of the current study was to evaluate the effect of a standardized prostate mpMRI reporting template on urologists’ understanding and confidence in counselling a patient on the results of the MRI. To do this we performed a survey study to assess the understanding and confidence of urologists reviewing reports prior to (pre) and after (post) adoption of a standardized mpMRI template. Six urologists reviewed ten pre- and post- mpMRI templated reports and completed a survey to assess the clarity of key elements and the confidence in counseling the patient. The urologists were blinded to the study objective. Nonparametric constrained permutation test for significance was performed to compare the results prior to and after implementation of the template. 29 pre- and 30 post-template mpMRI reports were reviewed. The average score for the post-template reports was significantly higher (10.7 ± 0.6 vs 7.5 ± 2.7 [ p

Over the past decade, the Prostate Imaging-Reporting and Data System (PI-RADS) has revolutionized the manner in which prostate cancer is screened for, detected, biopsied, and managed. The single greatest contribution of PI-RADS has been the standardization of interpretation and reporting of findings on MRI of the prostate. This standardization has led to the wide acceptance of the PI-RADS lexicon at a time when structured reporting templates are becoming more widespread in radiology and other medical fields. The author reviews the benefits of structured reporting templates with a focus on prostate MRI, prior studies on this topic, and details of a suggested template.

OBJECTIVE. The purpose of this study was to calculate the negative predictive value of a prostate MRI study with a Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) score of 1 (hereafter referred to as a PI-RADS 1 MRI study) and to explore the patient characteristics and MRI-based factors associated with an MRI study with false-negative results. MATERIALS AND METHODS. A total of 542 consecutive patients with a PI-RADS 1 MRI study obtained between January 2016 and July 2019 were retrospectively identified. Patient charts were examined to identify those patients who subsequently underwent systematic prostate biopsy within 1 year of undergoing MRI or at any later date if the biopsy was negative. Patient characteristics and MRI-specific factors were recorded. Two blinded radiologists evaluated the quality of the axial T2-weighted, DWI, and apparent diffusion coefficient sequences; measured the volume of the bladder, the prostate gland, and rectal gas; and determined whether the peripheral zone was avidly enhancing and whether low signal intensity was seen in 50% or more of the peripheral zone on T2-weighted images. Interobserver agreement was tested. Univariable and multivariable logistic regression models were built. RESULTS. A total of 150 patients (median age, 63 years; interquartile range, 56-70 years) were included. Of these patients, 19 (13%) had prostate cancer with a Gleason score of 3 + 4 or greater, yielding a negative predictive value of 87%. Both low T2 signal intensity in the peripheral zone and the prostate-specific antigen level were associated with a false-negative PI-RADS 1 assessment (odds ratio, 4.9 [95% CI, 1.6-14.9; p = 0.006] and 1.1 [95% CI, 1.0-1.2; p = 0.03], respectively). A cutoff prostate-specific antigen level of 3.97 ng/mL resulted in sensitivity and specificity of 89% and 21%, respectively. There was moderate interobserver agreement for low T2 signal intensity in the peripheral zone (κ coefficient = 0.75). CONCLUSION. Even among select patients who undergo subsequent biopsy because of a high clinical suspicion of prostate cancer, a PI-RADS 1 prostate MRI study has a high negative predictive value. A T2-hypointense peripheral zone and an elevated prostate-specific antigen level are significantly associated with a false-negative MRI study.

INTRODUCTION AND OBJECTIVE:Renal colic due to obstructing ureteral stones is a common cause of emergency department (ED) visits. In the absence of sepsis or overt infectious symptoms, it is often c...

Evaluate the fluid percentage (FP) and enhancing solid volume (SV) of small (

Background Low tissue concentrations of carotenoids have been suggested to contribute to insulin resistance in obesity. Objectives The objectives of the study were to 1) evaluate the relations of adipose tissue and serum carotenoids with body fat, abdominal fat distribution, muscle, adipose tissue and liver insulin resistance, and dietary intake; 2) evaluate the relations and distributions of carotenoids detected in adipose tissue and serum; and 3) compare serum carotenoids and retinol concentrations in subjects with and without obesity. Methods Post hoc analysis of serum and adipose tissue carotenoids in individuals [n = 80; 31 men, 49 women; age (mean ± SEM): 51.4 ± 1.1 y] who participated in 2 separate studies conducted at the Clinical Research Facility at the Garvan Institute of Medical Research (Sydney) between 2008 and 2013. Retinol, α-carotene, β-carotene, ζ-carotene, lutein, lycopene, phytoene, and phytofluene were measured using HPLC. Body composition was measured by dual-energy X-ray absorptiometry. Insulin resistance was measured by 2-step hyperinsulinemic-euglycemic clamps with deuterated glucose (n = 64), and subcutaneous and visceral abdominal volume and liver and pancreatic fat by MRI (n = 60). Periumbilical subcutaneous fat biopsy was performed and carotenoids and retinol measured in the tissue (n = 16). Results We found that ζ-carotene, phytoene, and phytofluene were stored in considerable amounts in adipose tissue (25% of adipose tissue carotenoids). Carotenoid concentrations in adipose tissue and serum correlated significantly, but they followed different distributions: ζ-carotene was 3-fold higher in adipose tissue compared with serum, while lutein and lycopene made up 20% and 21% of serum carotenoids compared with 2% and 12% of adipose tissue carotenoids, respectively. Liver (P ≤ 0.028) and adipose tissue (P = 0.023), but not muscle (P ≥ 0.16), insulin resistance correlated inversely with many of the serum carotenoids. Conclusions Multiple serum and adipose tissue carotenoids are associated with favorable metabolic traits, including insulin sensitivity in liver and adipose tissue in humans.

Objective: We aim to test the hypothesis that neurovascular bundle (NVB) displacement by rectal hydrogel spacer combined with NVB delineation as an organ at risk (OAR) is a feasible method for NVB-sparing stereotactic body radiotherapy. Methods: Thirty-five men with low- and intermediate-risk prostate cancer who underwent rectal hydrogel spacer placement and pre-, post-spacer prostate MRI studies were treated with prostate SBRT (36.25 Gy in five fractions). A prostate radiologist contoured the NVB on both the pre- and post-spacer T2W MRI sequences that were then registered to the CT simulation scan for NVB-sparing radiation treatment planning. Three SBRT treatment plans were developed for each patient: (1) no NVB sparing, (2) NVB-sparing using pre-spacer MRI, and (3) NVB-sparing using post-spacer MRI. NVB dose constraints include maximum dose 36.25 Gy (100%), V34.4 Gy (95% of dose) Results: Rectal hydrogel spacer placement shifted NVB contours an average of 3.1 ± 3.4 mm away from the prostate, resulting in a 10% decrease in NVB V34.4 Gy in non-NVB-sparing plans (p < 0.01). NVB-sparing treatment planning reduced the NVB V34.4 by 16% without the spacer (p < 0.01) and 25% with spacer (p < 0.001). NVB-sparing did not compromise PTV coverage and OAR endpoints. Conclusions: NVB-sparing SBRT with rectal hydrogel spacer significantly reduces the volume of NVB treated with high-dose radiation. Rectal spacer contributes to this effect through a dosimetrically meaningful displacement of the NVB that may significantly reduce RiED. These results suggest that NVB-sparing SBRT warrants further clinical evaluation. Advances in knowledge: This is a feasibility study showing that the periprostatic NVBs can be spared high doses of radiation during prostate SBRT using a hydrogel spacer and nerve-sparing treatment planning.

Vitamin A deficiency (VAD) is a major health problem, especially in developing countries. In this study, we investigated the effect of VAD from weaning to adulthood in apoE-/- mice. Three-week-old male mice were allocated into four diet groups: I. VAD II. VAD+vitamin A (VA), 1500 IU retinyl-palmitate, III. VAD+&beta, carotene (BC), 6 g/kg feed, containing 50% all-trans and 50% 9-cis BC. IV. VAD with BC and VA (BC+VA). After 13 weeks, we assessed the size of atherosclerotic plaques and measured VA in tissues and BC in plasma and tissues. VAD resulted in diminished hepatic VA levels and undetectable brain VA levels compared to the other groups. BC completely replenished VA levels in the liver, and BC+VA led to a two-fold elevation of hepatic VA accumulation. In adipose tissue, mice fed BC+VA accumulated only 13% BC compared to mice fed BC alone. Atherosclerotic lesion area of BC group was 73% lower compared to VAD group (p &lt, 0.05). These results suggest that BC can be a sole source for VA and inhibits atherogenesis.

The purpose of this study is to determine whether a convolutional neural network (CNN) can predict the maximum standardized uptake value (SUVConsecutive initial staging PET/CT scans obtained in 2017 for patients with pathologically proven malignancy were collected. Two blinded radiologists selected one to 10 lymph nodes from the unenhanced CT portion of each PET/CT examination. The SUVA total of 400 lymph nodes (median SUVA CNN is able to predict with moderate accuracy the SUV

International audience; Bladder cancer (BC) is the 10th most common cancer worldwide. Approximately one quarter of patients with BC have muscle-invasive disease (MIBC). Muscle-invasive disease carries a poor prognosis and choosing the optimal treatment option is critical to improve patients’ outcomes. Ongoing research supports the role of 2-deoxy-2-(18F)fluoro-D-glucose positron emission tomography (18F-FDG PET) in guiding patient-specific management decisions throughout the course of MIBC. As an imaging modality, 18F-FDG PET is acquired simultaneously with either computed tomography (CT) or MRI to offer a hybrid approach combining anatomical and metabolic information that complement each other. At initial staging, 18F-FDG PET/CT enhances the detection of extravesical disease, particularly in patients classified as oligometastatic by conventional imaging. 18F-FDG PET/CT has value in monitoring response to neoadjuvant and systemic chemotherapy, as well as in localizing relapse after treatment. In the new era of immunotherapy, 18F-FDG PET/CT may also be useful to monitor treatment efficacy as well as to detect immune-related adverse events. With the advent of artificial intelligence techniques such as radiomics and deep learning, these hybrid medical images can be mined for quantitative data, providing incremental value over current standard-of-care clinical and biological data. This approach has the potential to produce a major paradigm shift toward data-driven precision medicine with the ultimate goal of personalized medicine. In this review, we highlight current literature reporting the role of 18F-FDG PET in supporting personalized management decisions for patients with MIBC. Specific topics reviewed include the incremental value of 18F-FDG PET in prognostication, pre-operative planning, response assessment, prediction of recurrence, and diagnosing drug toxicity.

Objective Evaluate the accuracy of an obscured surgical capsule (OSC) for detecting diffuse prostate cancer (PCa) in the setting of diffusely T2 hypointense peripheral zones (PZs) on prostate magnetic resonance imaging. Methods Axial T2-weighted sequences of prostate magnetic resonance imaging performed on July 1, 2015, to August 1, 2017, were blindly assessed for diffusely T2 hypointense PZs, OSC, and focal diffusion abnormalities by 2 radiologists. Diffuse PCa was defined by the presence of bilateral PCa on at least 4 contiguous biopsy cores involving 2/3 levels. Interobserver agreement and multivariate analysis were performed. Results Seven (10%) of 70 patients had diffuse PCa. There was weak interreader agreement for OSC (κ coefficient = 0.58). Obscured surgical capsule was 57% sensitive and 89% specific for the presence of diffuse PCa and was associated with it (odds ratio, 17.6; P = 0.0008). Multivariate logistic regression demonstrated that OSC was the only significant predictor for the presence of diffuse PCa. Conclusion Obscured surgical capsule is a strong independent predictor for diffuse PCa in T2 hypointense PZs.

OBJECTIVES This study aimed to quantify nonenhancing tumor (NT) component in clear cell renal cell carcinoma (ccRCC) and assess its association with histologically defined tumor necrosis, stage, and survival outcomes. METHODS Among 183 patients with ccRCC, multi-institutional changes in computed tomography attenuation of tumor voxels were used to quantify percent of NT. Associations of NT with histologic tumor necrosis and tumor stage/grade were tested using Wilcoxon signed rank test and with survival outcomes using Kaplan-Meier curves/Cox regression analysis. RESULTS Nonenhancing tumor was higher in ccRCC with tumor necrosis (11% vs 7%; P = 0.040) and higher pathological stage (P = 0.042 and P < 0.001, respectively). Patients with greater NT had higher incidence of cancer recurrence after resection (P < 0.001) and cancer-specific mortality (P < 0.001). CONCLUSION Nonenhancing tumor on preoperative computed tomographic scans in patients with ccRCC correlates with tumor necrosis and stage and may serve as an independent imaging prognostic biomarker for cancer recurrence and cancer-specific survival.

Objective The aim of this study was to determine which apparent diffusion coefficient-derived texture features are associated with malignancy in Bosniak IIF and III renal cystic lesions. Methods Twenty benign and 7 malignant Bosniak IIF (22) or III (5) renal cysts, as evaluated with magnetic resonance imaging, were assessed for progression to pathology-confirmed malignancy. Whole-cyst volumes of interest were manually segmented from apparent diffusion coefficient maps. Texture features were extracted from each volume of interest, including first-order histogram-based features and higher-order features, and data were analyzed with the Mann-Whitney U test to predict malignant progression. Results Eleven of 17 first-order features were significantly greater in benign compared with malignant cysts. Eight higher-order gray-level co-occurrence matrix (GLCM) texture features were significantly different between groups, 5 of which were greater in the benign population. Conclusions Apparent diffusion coefficient-derived texture measures may help differentiate between benign and malignant Bosniak IIF and III cysts.

Background Prior research has shown that retrospectively measured apparent diffusion coefficient (ADC) of prostate magnetic resonance imaging (MRI) lesions is associated with clinically significant prostate cancer (csPCa) on targeted biopsy suggesting that ADC should be measured and reported prospectively. Purpose To assess the impact of mandatory prospective measurement of ADC on the rates of positivity across PI-RADS scores for csPCa. Material and Methods Consecutive patients who underwent ultrasound (US)-MRI fusion prostate biopsy from August 2018 to July 2019 and who had prospectively reported ADC were compared to control patients who did not. Rates of positivity by PI-RADS category were computed and compared using Chi-square. Multivariable regression was performed. Results In total, 126 patients (median age 65 years) with 165 prostate lesions (19, 51, 70, and 25 PI-RADS 2, 3, 4, and 5, respectively) and prospectively reported ADC values were compared to 113 control patients (median age 66 years) with 157 prostate lesions (17, 42, 64, and 34 PI-RADS 2, 3, 4, and 5, respectively). Rates of positivity across PI-RADS scores were similar between the two cohorts; 11%, 25%, 55%, and 76% and 0%, 21%, 56%, and 62% for PI-RADS 2, 3, 4, and 5 in the test and control cohorts, respectively (Chi-square P = 0.78). Multivariate logistic regression showed no significant association between the presence of prospectively measured ADC and csPCa (odds ratio 1.1, 95% confidence interval 0.7–1.7, P = 0.82). Conclusion Prospective ADC measurement may not impact PI-RADS category assignments or positivity rates for csPCa under current guidelines. Future versions of PI-RADS may need to incorporate ADC into scoring rules to realize their potential.

To investigate whether pretreatment MRI-based radiomics of locally advanced rectal cancer (LARC) and/or the surrounding mesorectal compartment (MC) can predict pathologic complete response (pCR), neoadjuvant rectal (NAR) score, and tumor regression grade (TRG). One hundred thirty-two consecutive patients with LARC who underwent neoadjuvant chemoradiation and total mesorectal excision (TME) were retrospectively collected from 2 centers in the USA and Italy. The primary tumor and surrounding MC were segmented on the best available T2-weighted sequence (axial, coronal, or sagittal). Three thousand one hundred ninety radiomic features were extracted using a python package. The most salient radiomic features as well as MRI parameter and clinical-based features were selected using recursive feature elimination. A logistic regression classifier was built to distinguish between any 2 binned categories in the considered endpoints: pCR, NAR, and TRG. Repeated k-fold validation was performed and AUCs calculated. There were 24, 87, and 21 T4, T3, and T2 LARCs, respectively (median age 63 years, 32 to 86). For NAR and TRG, the best classification performance was obtained using both the tumor and MC segmentations. The AUCs for classifying NAR 0 versus 2, pCR, and TRG 0/1 versus 2/3 were 0.66 (95% CI, 0.60–0.71), 0.80 (95% CI, 0.74–0.85), and 0.80 (95% CI, 0.77–0.82), respectively. Radiomics of pretreatment MRIs can predict pCR, TRG, and NAR score in patients with LARC undergoing neoadjuvant treatment and TME with moderate accuracy despite extremely heterogenous image data. Both the tumor and MC contain important prognostic information. • Machine learning of rectal cancer on images from the pretreatment MRI can predict important patient outcomes with moderate accuracy. • The tumor and the tissue around it both contain important prognostic information.

Maternal docosahexaenoic acid (DHA) is required during pregnancy to supply for normal fetal growth and development. This pilot study aimed to assess the unknown fatty acid (FA) composition in a cohort of non-pregnant and pregnant Israeli women at term and their offspring on a normal diet without n-3 FA supplementation. The fatty acid profile, analyzed using gas chromatography, showed significantly higher plasma monounsaturated (MUFA) and lower n-6 FA percent distribution with similar n-3 index, in pregnant compared to non-pregnant women. RBC exhibited significantly higher MUFA with similar n-3 index, in pregnant compared to non-pregnant women. N-3 FA significantly correlated between neonates’ plasma, with higher n-3 index, and pregnant women's DHA. Conclusion: DHA levels in non-pregnant and pregnant Israeli women at term were comparable and the DHA in pregnant women's plasma positively correlated with their neonate's level, suggesting an efficient mother-fetus FA transfer and/or fetal fatty acid metabolism to longer FA products.

Improvements in prostate MR imaging techniques and the introduction of MR imaging-targeted biopsies have had central roles in prostate cancer (PCa) management. The role of MR imaging has progressed from largely staging patients with biopsy-proven PCa to detecting, characterizing, and guiding the biopsy of suspected PCa. These diagnostic advances, combined with improved therapeutic interventions, have led to a more sophisticated and individually tailored approach to patients' unique PCa profile. This review discusses the MR imaging, a standardized reporting scheme, and the role of fusion-targeted prostate biopsy.

• There is great variation in the CT urogram protocol throughout the literature. • The study by Renard-Penna et al provides a useful rigorous expert consensus on CT urography technique. • The study by Rud et al suggests that the excretory phase may not be as necessary as previously thought for visualizing upper tract urothelial carcinoma.

TPS4598 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: NCT04322955.

The purpose of the study is to perform a meta-analysis of studies investigating the diagnostic performance of apparent diffusion coefficient (ADC) values in separating high-risk from low-risk prostate cancer (PCa). MEDLINE and EMBASE databases were searched in December 2015 for studies reporting diagnostic performance of ADC values for discriminating high-risk from low-risk PCa and providing sufficient data to construct 2 × 2 contingency tables. Diagnostic performance was quantitatively pooled using a bivariate random-effects model including subgroup analysis and assessment of study heterogeneity and methodological quality. 13 studies were included, providing 1107 tumor foci in 705 patients. Heterogeneity among studies was moderate (τ2 = 0.222). Overall sensitivity was 76.9% (95% CI 68.6–83.6%); overall specificity was 77.0% (95% CI 69.9–82.8%); and summary AUC was 0.67. Inverse correlation between sensitivity and specificity (ρ = −0.58) indicated interstudy heterogeneity was partly due to variation in threshold for test positivity. Primary biases were readers’ knowledge of Gleason score during ADC measurement, lack of prespecified ADC thresholds, and lack of prostatectomy as reference in some studies. Higher sensitivity was seen in studies published within the past 2 years and studies not using b value of at least 2000; higher specificity was associated with involvement of one, rather than two, readers measuring ADC. Field strength, coil selection, and advanced diffusion metrics did not significantly impact diagnostic performance. ADC values show moderate accuracy in separating high-risk from low-risk PCa, although important biases may overestimate performance and unexplained sources of heterogeneity likely exist. Further studies using a standardized methodology and addressing identified weaknesses may help guide the use of ADC values for clinical decision-making.

TPS371 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: AAAS6927 .

INTRODUCTION AND OBJECTIVE:Multiparametric magnetic resonance imaging (mpMRI) of the prostate along subsequent grading with the Prostate Imaging Reporting and Data System version 2 (PI-RADSv2) scor...

Purpose Lipoxygenases (LOX) have been implicated in carcinogenesis, however both pro- and anti-carcinogenic effects have been reported in different cancer models. Using transgenic mice, which specifically overexpress human 15-lipoxygenase (ALOX15) in endothelial cells (EC), we previously demonstrated significant inhibition of tumor development. In the Lewis lung carcinoma (LLC) model, the primary tumor developed similarly in both wild type (WT) and ALOX15 overexpressing mice. However, metastases development was significantly inhibited in the transgenic mice. Here, we explored the molecular basis for the anti-metastatic effect of endothelial cell specific ALOX15 overexpression. Materials/methods We used ALOX15 overexpressing mice, and in-vitro cell model to evaluate the molecular effect of ALOX15 on EC and LLC cells. Results When LLC cells were injected in WT and ALOX15 overexpressing mice, we observed a higher degree of apoptosis and necrosis in primary and metastatic tumors of ALOX15 overexpressing animals. These anti-carcinogenic and anti-metastatic effects were paralleled by augmented expression of cyclin-dependent kinase inhibitor 1A (CDKN1A; p21) and of the peroxisome proliferators-activated receptor (PPAR)γ and by downregulation of the steady state concentrations of connexin26 mRNA. Consistent with these in vivo effects, ALOX15 overexpression in LLC and HeLa cancer cells in vitro significantly reduced cell viability in culture. In contrast, similar treatment of non-cancerous B2B epithelial cells did not impact cell viability. Conclusions Taken together, our data suggests that endothelial cell specific overexpression of ALOX15 promotes apoptosis and necrosis in primary and metastatic tumors in mice, by upregulation of P21 and PPARγ expression in adjacent cancer cells.

Hypertension, advanced age, postprandial hyperlipidemia, and insulin resistance are major risk factors for atherosclerosis. The calcium channel blocker nifedipine is reported to ameliorate insulin resistance possibly by activating PPARγ. This is expected to become accentuated in elderly individuals due to age-related insulin resistance. Insulin resistance modulates lipoprotein metabolism. Therefore, we reasoned that nifedipne offers the potential for improving postprandial lipemia in association with increasing age. We studied the effect of nifedipine on fasting lipids, postprandial lipemia, insulin sensitivity, and plasma lipolytic activity in 24 and 15 hypertensive subjects aged 70-75 years and 40-45 years, respectively. As expected, nifedipine significantly lowered systolic and diastolic blood pressure. Nifedipine decreased fasting triglyceride level (23%) and increased HDL-C (15%) in the elderly group. At baseline, postprandial triglyceride levels were remarkably elevated in elderly compared to younger patients (1 288±798 vs. 501±260 mg·dl(-1)·h, p

The aim of this study was to assess the impact of a structured reporting template on adherence to the Prostate Imaging Reporting and Data System (PI-RADS) version 2 lexicon and on the diagnostic performance of prostate MRI to detect clinically significant prostate cancer (CS-PCa).An imaging database was searched for consecutive patients who underwent prostate MRI followed by MRI-ultrasound fusion biopsy from October 2015 through October 2017. The initial MRI reporting template used included only subheadings. In July 2016, the template was changed to a standardized PI-RADS-compliant structured template incorporating dropdown menus. Lesion, patient characteristics, pathology, and adherence to the PI-RADS lexicon were extracted from MRI reports and patient charts. Diagnostic performance of prostate MRI to detect CS-PCa using combined ultrasound-MRI fusion and systematic biopsy as a reference standard was assessed.Three hundred twenty-four lesions in 202 patients (average age, 67 years; average prostate-specific antigen level, 5.9 ng/mL) were analyzed, including 217 MRI peripheral zone (PZ) lesions, 84 MRI non-PZ lesions, and 23 additional PZ lesions found on systematic biopsy but missed on MRI. Thirty-three percent (106 of 324) were CS-PCa. Adherence to the PI-RADS lexicon improved from 32.9% (50 of 152) to 88.4% (152 of 172) (P.0001) after introduction of the structured template. The sensitivity of prostate MRI for CS-PCa in the PZ increased from 53% to 70% (P = .011). There was no significant change in specificity (60% versus 55%, P = .458).A structured template with dropdown menus incorporating the PI-RADS lexicon and classification rules improves adherence to PI-RADS and may increase the diagnostic performance of prostate MRI for CS-PCa.

Atherosclerosis and Alzheimer's disease (AD) are a major cause of morbidity and mortality in Western societies. These diseases share common risk factors, which are exhibited in old age, including hypertension, diabetes, hypercholesterolemia and apolipoprotein (Apo) e4 allele. We previously demonstrated that factor XI (FXI) deficiency in mice reduced the atherosclerotic plaque area in coronary sinuses and the aortic arch. This led us to investigate whether FXI deficiency in elderly ApoE knockout (KO) mice would decrease pathological alterations compatible with atherosclerosis and AD. The present study used ApoE/factor XI double KO (ApoE/FXI DKO) mice aged 64 weeks and age‑matched ApoE KO mice to serve as a control group. The ApoE KO mice developed an advanced atherosclerotic lesion area in the aortic arch, which was reduced by 33% in the DKO mice. However, neither atherosclerosis nor AD‑associated pathological alterations in the elderly mice brains were observed in either the DKO mice or the ApoE KO mice. The results advocate a dichotomy between the brain and peripheral blood vessels. Therefore, the ApoE KO and DKO mice cannot serve as mouse models for studying AD or pathological brain changes compatible with atherosclerosis. The mechanism by which ApoE KO protects against brain pathology should be further studied as it may prove helpful for future treatment of senile dementia.

To determine the accuracy of split-bolus CT urogram (SB-CTU) without special maneuvers for ureteral distention in diagnosing upper urinary tract urothelial carcinoma (UCA). A hospital database was searched from 1/1/10, to 9/1/15, for SB-CTU exams without special maneuvers for ureteral distention. Accuracy of SB-CTU for detecting upper and lower urinary tract UCA was computed by comparing the prospective radiology report with cystoscopy, ureteroscopy, and/or urologic clinical follow-up. Patients with less than 12 months of clinical follow-up were excluded. 339 studies were identified in 334 patients (60% male 40% female, avg. age 64). 119 studies were performed for microhematuria, 150 for gross hematuria, 13 for hematuria not otherwise specified, 57 for history of UCA, and one for a collecting system mass on a prior CT. There were five upper tract and 33 bladder tumors with overall prevalence of 1.5% and 9.7%, respectively. The prevalence varied significantly with patient age and clinical indication for SB-CTU. There were one false negative and four false positives for upper urinary tract UCA. Sensitivity, specificity, positive predictive value, and negative predictive value for detecting upper tract and bladder tumors were 80%, 99%, 44%, and 100%, respectively, and 55%, 98%, 78%, and 95%, respectively. Based on this study, SB-CTU without special maneuvers for ureteral distention is highly sensitive for detecting upper tract UCA, although with a low positive predictive value, false positives do occur. The clinical utility of increasing accuracy in diagnosing this low-prevalence disease through other more complex CT urogram protocols should be weighed against the added cost and radiation dose associated with these protocols.

ObjectiveWhile extensive research revealed that interleukin (IL)-1β contributes to insulin resistance (IR) development, the role of IL-1α in obesity and IR was scarcely studied. Using control, whole body IL-1α knockout (KO) or myeloid-cell-specific IL-1α-deficient mice, we tested the hypothesis that IL-1α deficiency would protect against high-fat diet (HFD)-induced obesity and its metabolic consequences.Research design and methodsTo induce obesity and IR, control and IL-1α KO mice were given either chow or HFD for 16 weeks. Glucose tolerance test was performed at 10 and 15 weeks, representing early and progressive stages of glucose intolerance, respectively. Liver and epididymal white adipose tissue (eWAT) samples were analyzed for general morphology and adipocyte size. Plasma levels of adiponectin, insulin, total cholesterol and triglyceride (TG), lipoprotein profile as well as hepatic lipids were analyzed. Expression of lipid and inflammation-related genes in liver and eWAT was analyzed. Primary mouse hepatocytes isolated from control mice were treated either with dimethyl sulfoxide (DMSO) (control) or 20 ng/mL recombinant IL-1α for 24 hours and subjected to gene expression analysis.ResultsAlthough total body weight gain was similar, IL-1α KO mice showed reduced adiposity and were completely protected from HFD-induced glucose intolerance. In addition, plasma total cholesterol and TG levels were lower and HFD-induced accumulation of liver TGs was completely inhibited in IL-1α KO compared with control mice. Expression of stearoyl-CoA desaturase1 (SCD1), fatty acid synthase (FASN), elongation of long-chain fatty acids family member 6 (ELOVL6), acetyl-CoA carboxylase (ACC), key enzymes that promote de-novo lipogenesis, was lower in livers of IL-1α KO mice. Treatment with recombinant IL-1α elevated the expression of ELOVL6 and FASN in mouse primary hepatocytes. Finally, mice with myeloid-cell-specific deletion of IL-1α did not show reduced adiposity and improved glucose tolerance.ConclusionsWe demonstrate a novel role of IL-1α in promoting adiposity, obesity-induced glucose intolerance and liver TG accumulation and suggest that IL-1α blockade could be used for treatment of obesity and its metabolic consequences.

TPS3154 Background: Assessing treatment response in castrate resistant prostate cancer (CRPC), remains a challenge due to the limited sensitivity and specificity of existing imaging modalities. Understanding prostate cancer biology with tumor biopsies does not address the issue of tumor heterogeneity or cellular degradation during the decalcification process of bone biopsies. Next generation positron emission tomography (PET) imaging and circulating biomarkers might provide additional insights on treatment responses and inform clinical decision-making earlier in therapy. 18F-DCFPyL (PyL) is a second-generation fluorinated PSMA PET tracer that has superior sensitivity and specificity to detect prostate cancer compared to standard imaging. Its role in assessing tumor response to therapy has not been evaluated. Circulating tumor DNA (ctDNA) in blood can provide tumor genomic information, while exosomes in serum and urine may provide data on the proteomic landscape of tumors. Methods: We are conducting a prospective study of 15 men with metastatic CRPC who are scheduled to start a new systemic therapy for their disease. Upon enrollment, subjects will have baseline assessments with standard cross-sectional imaging, 99mTc bone scan, and blood work. Standard scans will be performed every 8-12 weeks until progression of disease. PyL PET/CT scans and liquid biopsies (ctDNA and exosomes) will occur at baseline, 6 weeks after starting their new therapy, and at disease progression. Lesions seen on PET/CT images will be identified by a certified reader. The maximum standardized uptake value (SUVmax) will be measured and recorded in up to the five hottest lesions and normalized to a background SUVmean measured in the liver, spleen, kidney, mediastinum, and parotid glands. Changes in the normalized SUV from baseline to the 6-week PyL PET scan will be correlated to PSA response by the Pearson’s correlation coefficient. The Kaplan-Meier method will be used to evaluate progression free survival and overall survival dichotomized by the median value of SUV change. Blood for ctDNA and exosomes will be stored for future analysis. The study is open with two patients enrolled at the time of submission. One patient has completed his initial PyL PET/CT scan. Clinical trial information: NCT03585114.

Lipoxygenases regulate vascular function by metabolizing arachidonic acid (AA) to dilator eicosanoids. Previously, we showed that endothelium-targeted adenoviral vector-mediated gene transfer of the human 15-lipoxygenase-1 (h15-LO-1) enhances arterial relaxation through the production of vasodilatory hydroxyepoxyeicosatrienoic acid (HEETA) and trihydroxyeicosatrienoic acid (THETA) metabolites. To further define this function, a transgenic (Tg) mouse line that overexpresses h15-LO-1 was studied. Western blot, immunohistochemistry and RT-PCR results confirmed expression of 15-LO-1 transgene in tissues, especially high quantity in coronary arterial wall, of Tg mice. Reverse-phase HPLC analysis of [14C]-AA metabolites in heart tissues revealed enhanced 15-HETE synthesis in Tg vs. WT mice. Among the 15-LO-1 metabolites, 15-HETE, erythro-13-H-14,15-EETA, and 11(R),12(S),15(S)-THETA relaxed the mouse mesenteric arteries to the greatest extent. The presence of h15-LO-1 increased acetylcholine- and AA-mediated relaxation in mesenteric arteries of Tg mice compared to WT mice. 15-LO-1 expression was most abundant in heart; therefore, we used the Langendorff heart model to test the hypothesis that elevated 15-LO-1 levels would increase coronary flow following a short ischemia episode. Both peak flow and excess flow of reperfused hearts were significantly elevated in hearts from Tg compared to WT mice being 2.03 and 3.22 times greater, respectively. These results indicate that h15-LO-1-derived metabolites are highly vasoactive and may play a critical role in regulating coronary blood flow.

Synthetic retinoids are one of the mainstay treatments of psoriasis. However, their use is occasionally limited by adverse effects, especially mucocutaneous, hepatic, and lipid profile toxicity. Thus, a search for retinoid metabolites that are both safe and active is essential. The alga Dunaliella bardawil is a natural source of the retinoid precursor 9-cis β-carotene that has a good adverse effect profile.To test the effect of the alga Dunaliella bardawil on psoriasis.Thirty-four adult patients with mild, chronic, plaque-type psoriasis were included in this monocentric, prospective, randomized, double-blinded pilot study. Patients received either capsules of the alga D. bardawil or starch powder capsules, as the placebo, for 12 weeks. The response to treatment was evaluated by changes in Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI) scores. Safety of the treatment was evaluated.At the end of 6 weeks, the reduction in the mean PASI score was significantly higher in the Dunaliella group than in the placebo group (61.3% vs 34%, respectively, p = 0.002). The DLQI change did not reach significance (8.5% and 5.9% in the Dunaliella and in the control group, respectively, p = 0.9). We observed no significant change in the liver function tests or in the lipid profile.9-cis β-carotene, in the form of D. bardawil, is an effective and safe treatment for patients with mild, chronic, plaque-type psoriasis. A larger study is warranted.

AIMS To determine whether low-dose calcitriol attenuates atherosclerosis in apoE-null mice and, if so, through which predominant mechanism. METHODS Starting at the age of 6 weeks, mice received intraperitoneal injections of either 0.25 ng/g body weight of calcitriol or the vehicle, every other day for 8 weeks. RESULTS Calcitriol treatment resulted in 35% reduction of atherosclerosis at the aortic sinus, and in a significant decrease in blood pressure. These effects were possibly mediated by downregulation of the renin-angiotensin system (RAS), as there was a 64% decrease in the aortic level of renin mRNA. None of the other components of the RAS or the prorenin receptor were affected by treatment. Low-dose calcitriol treatment did not modify the plasma level of monocyte chemoattractant protein-1, interferon γ, interleukin-4 and interleukin-10, which were similar in control and treated mice. Likewise, there was no difference in the percentage of splenic Foxp3+ regulatory T cells. Calcitriol treatment resulted in an unfavorable metabolic profile (glucose and lipids), as determined after a limited fast, a difference that disappeared after food was withheld for a longer time. CONCLUSIONS At a relatively low dosage, calcitriol attenuates the development of atherosclerosis in apoE-null mice, most probably by down regulation of RAS, and not through immunomodulation; however, even at this low dose, calcitriol appears to elevate calcium and to have potentially adverse metabolic effects. Exploring the potential antiatherogenic effects of non-calcemic and safer analogues is therefore warranted.

BACKGROUND Fundus albipunctatus is a retinal dystrophy caused by a mutation in the gene encoding 11-cis-retinol dehydrogenase which delays the recovery of rod photoreceptor cells from light stimulation leading to night blindness. A recent study of a mouse model of fundus albipunctatus treated with 9-cis-retinal showed an improvement in visual function and structure. METHODS Seven patients with fundus albipunctatus were given a daily food supplement of four capsules containing high-dose 9-cis-beta-carotene for 90 days. The subjects were tested before and after treatment by visual field and electroretinogram in both eyes. This non-randomised prospective phase I study was registered at http://www.clinicaltrials.gov (NCT00478530). RESULTS All patients showed significant improvements in peripheral visual field (mean deviation improved from -4.77+/-2.0 to -3.28+/-2.28, p=0.009, t test) and a highly significant improvement in rod recovery rates measured electroretinographically (maximal scotopic b-wave amplitude responses, improved from 197+/-49 muV to 292+/-48 muV, p

Diabetes carries a high risk of atherosclerosis, and cardiovascular disease, especially coronary heart disease (CHD) and stroke, is by far the leading cause of death among patients with type 2 diabetes. Although statins reduce the risk of major vascular events by about one-fifth per millimole per liter reduction in LDL cholesterol, with similar proportional reductions in major coronary events, stroke, and the need for coronary revascularization, the residual risk remains high. In the Scandinavian Simvastatin Survival Study (4S) (1), although the relative risk reduction in diabetic patients was larger than in nondiabetic patients, simvastatin-treated diabetic patients were still at higher risk of death than the placebo-treated nondiabetic patients. Multifactorial intervention reduces the risk even further, but significant danger remains. Current guidelines call for an aggressive treatment strategy to reduce LDL cholesterol, blood pressure, and glucose levels in diabetic patients, but data concerning the management of high triglyceride (TG) levels and low HDL cholesterol levels remains inconclusive. This article reviews the data concerning diabetic dyslipidemia and its management. The cluster of lipid abnormalities associated with type 2 diabetes is defined by a high concentration of TG and small dense LDL and a low concentration of HDL cholesterol. Plasma LDL cholesterol levels are generally normal. Insulin resistance is believed to contribute to this atherogenic dyslipidemia by increasing the hepatic secretion of VLDL and other apolipoprotein (apo)B-containing lipoprotein particles, as a result of increased free fatty acid flux to the liver (2,3). This may also be the result of a diminished suppressive effect of insulin on apoB secretion, either at the level of the regulation of apoB degradation, or inhibition of microsomal TG transfer protein activity (4). Through the action of cholesterol ester transfer protein, TGs are transferred from VLDL to HDL, creating TG-rich HDL particles, which are hydrolyzed by hepatic …

The prevalence of diabetes for all age-groups worldwide was estimated to be 2.8% (171 million) in the year 2000, and the projected number could rise to 4.4% (366 million) in 2030 (1). This rapid rise is mainly attributable to the increase of diabetes. The continuing escalation of obesity and the metabolic syndrome contribute to the upsurge in frequency of diabetes (2,3). Interestingly, the appreciation in the number of people >65 years of age was found to be the most important demographic change to diabetes prevalence around the world, indicating that the “diabetes epidemic” will continue even if levels of obesity remain constant. Therefore, it is likely that future diabetes preponderance is underestimated, given the growing frequency of obesity (1). Because the vast majority of diabetic patients have type 2 diabetes and almost all the studies were performed in such subjects, in this article, “type 2 diabetes” will be referred to as “diabetes.” Cardiovascular disease (CVD) is one of the foremost causes of mortality and is a major contributor to morbidity for individuals with diabetes. In addition, diabetes is an independent risk factor for macrovascular disease, as are the common coexisting conditions (hypertension and dyslipidemia). The U.K. Prospective Diabetes Study (UKPDS) evaluated baseline risk factors for coronary artery disease in patients with newly diagnosed diabetes without evidence of vascular disease. When comparing the relative contribution of the three modifiable coexisting conditions (dyslipidemia, hypertension, and hyperglycemia) with development of future coronary heart disease (CHD), the estimated hazard ratio (HR) for the upper third, relative to the lower third, for LDL cholesterol, systolic blood pressure, and A1C were 2.26, 1.82, and 1.52, respectively (4). This finding supports the notion that dyslipidemia, and specifically LDL cholesterol, are major contributors to the increased CHD risk in patients with diabetes (4,5 …

Objective— Atherosclerosis and atherothrombosis are still major causes of mortality in the Western world, even after the widespread use of cholesterol-lowering medications. Recently, an association between local thrombin generation and atherosclerotic burden has been reported. Here, we studied the role of factor XI (FXI) deficiency in the process of atherosclerosis in mice. Approach and Results— Apolipoprotein E/FXI double knockout mice, created for the first time in our laboratory. There was no difference in cholesterol levels or lipoprotein profiles between apolipoprotein E knockout and double knockout mice. Nevertheless, in 24-week-old double knockout mice, the atherosclerotic lesion area in the aortic sinus was reduced by 32% ( P =0.004) in comparison with apolipoprotein E knockout mice. In 42-week-old double knockout mice, FXI deficiency inhibited atherosclerosis progression significantly in the aortic sinus (25% reduction, P =0.024) and in the aortic arch (49% reduction, P =0.028), with a prominent reduction of macrophage infiltration in the atherosclerotic lesions. Conclusions— FXI deprivation was shown to slow down atherogenesis in mice. The results suggest that the development of atherosclerosis can be prevented by targeting FXI.

The lymphatic system is responsible for the absorption of fats from the digestive system, conveying 60–70 % of ingested fat to the blood stream. From the anatomical point of view, all the lymphatic drainage from the lower half of the body converges in the abdomen to enter the thoracic duct. This experimental study aim was to study the result of thoracic duct narrowing (TDN), an innovative surgical technique, on weight gain restrain in high-fat diet-fed rats. Forty-seven rats were allocated into three groups: thoracic duct narrowing (“S”—surgery), sham operation (“CS”—control surgery), and no surgery (“C”—control). All rats were fed with high-fat, cholesterol-rich diet. Food consumption and metabolic syndrome parameters including weight gain, plasma lipids and glucose, blood pressure, and viscera weight and histopathology were analyzed. Thoracic duct narrowing was proved simple and safe surgical procedure in the rat model. TDN induced weight gain restrain, associated with mild hepatic steatosis compared to moderate-severe hepatic steatosis in control groups. Splenomegaly and splenic fatty histiocytes were shown in the treated animals. TDN improved several parameters of the metabolic syndrome in high-fat diet-fed rats. TDN carries the potential of innovative obesity treatment using the lymphatic route of lipid absorption.

In evaluating the gastrointestinal tract, whether in the emergency room setting, the inpatient setting or the outpatient setting, the radiologist may encounter a myriad of intraluminal radio-opaque, non-anatomic entities. It is the radiologist’s role to distinguish between true foreign bodies and medical paraphernalia. Further, the later must be evaluated for proper positioning vs. improper, potentially detrimental positioning. While many foreign bodies from the community may be distinctly familiar to the radiologist, the large variety of medical tools in existence may not be. Furthermore, many medical devices are designed to transiently traverse, or interact with the gastrointestinal tract, requiring the radiologist to become familiar with their natural history. We explore a select group of common and uncommon intraluminal foreign bodies and will divide them into medical paraphernalia that are properly positioned; medical paraphernalia that are in abnormal locations and miscellaneous foreign bodies from the community. For each medical tool, we will discuss its development and medical utility, natural history as it relates to the gastrointestinal tract, optimal positioning as assessed radiologically, malpositioning, and subsequent complications. A small selection of unusual foreign bodies from the community will be presented. Finally, a selection of medical conditions which produce symptoms due to acquired intraluminal objects will be reviewed.

Background: Solid evidence suggests that atheroscleosis is associated with immune reactions. Most of the activated T cells in the plaque are T helper 1 subtype (Th1), which secrete interferon-gamma (IFN-gamma), now generally accepted as a proatherogenic cytokine. Interferon-alpha (IFN-alpha) has been found to inhibit the secretion of IL-12 and IFN-gamma and to increase IL-10 production. It may, therefore, be atheroprotective. The aim of the present study was to clarify the effect of IFN-alpha on atherogenesis in a transgenic mouse model of atherosclerosis. Methods: 8-week-old low-density lipoprotein (LDL) receptor-deficient mice were allocated randomly into treatment and control groups (n=13 each). The treatment group received 1000 units of IFN-alpha i.p. every other day for 5 weeks and the control mice received 0.9% NaCl. The mice were fed a Western diet. Results: The IFN-alpha-treated and the control mice showed a similar weight gain (mean 3.9+/-1.0 g vs. 3.4+/-1.8 g, respectively). Treatment with IFN-alpha significantly increased the plasma cholesterol levels in both treated and untreated mice (mean 31.03+/-5.53 mmol/l vs. 24.91+/-6.03 mmol/l, respectively; p0.022) as well as the plasma triglyceride levels (mean 4.79+/-1.57 mmol/l vs. 3.10+/-1.85 mmol/l, respectively; p0.033). The IFN-alpha treated mice had a significantly increased atherosclerotic plaque area (mean 61,590+/-22,368 microm(2) vs. 37,272+/-15,469 microm(2), respectively; p0.008). Conclusion: The putative atheroprotective effect of IFN-alpha by the decrease in IL-10 and IFN-gamma is abolished by hyperlipidemia. Therefore, the net effect of IFN-alpha in this murine model is the exacerbation of atherosclerosis.

BACKGROUND The administration of peroxisome proliferator-activated receptor gamma (PPARgamma) agonists to low-density lipoprotein (LDL)-receptor-deficient mice resulted in a reduction in the atherosclerotic lesion area in male mice, but not in female mice. The male mice also exhibited reduction in insulin resistance while the female mice did not. To further examine the relationship between PPARgamma agonists, insulin resistance and atherosclerosis, we used the model of accelerated atherosclerosis in male apolipoprotein E (apoE)-deficient mice rendered diabetic by low-dose streptozotocin (STZ). METHODS Male, apoE-deficient mice (n = 48) were randomly divided into four groups. To induce diabetes, two groups received low-dose STZ and two groups served as controls. After diabetes induction, rosiglitazone (a PPARgamma agonist) was administered by oral gavage to one of the diabetic and one of the non-diabetic groups. RESULTS Rosiglitazone reduced significantly the atherosclerotic aortic plaque area in both diabetic and non-diabetic apoE-deficient mice: 340 +/- 54 vs. 201 +/- 27 micromol2 (p = 0.001) in diabetic mice; 243 +/- 22 vs. 158 +/- 27 micromol2 (p = 0.001) in non-diabetic mice. Also, rosiglitazone reduced the correlation coefficient between plasma glucose and the degree of atherosclerosis (p < 0.0025) without affecting plasma glucose levels. The rosiglitazone-treated mice, both diabetic and non-diabetic, had higher lipid levels. CONCLUSIONS Rosiglitazone-treated animals showed less atherosclerosis despite higher lipid levels and similar glucose levels. These data suggest a direct anti-atherogenic effect of rosiglitazone on the arterial wall.

Omapatrilat inhibits both angiotensin-converting enzyme (ACE) and neutral endopeptidase (NEP). ACE inhibitors have been shown to inhibit atherosclerosis in apoE-deficient mice and in several other animal models but failed in low-density lipoprotein (LDL) receptor– deficient mice despite effective inhibition of the reninangiotensin- aldosterone system. The aim of the present study was to examine the effect of omapatrilat on atherogenesis in diabetic and nondiabetic LDL receptor–deficient mice. LDL receptor–deficient male mice were randomly divided into 4 groups (n = 11 each). Diabetes was induced in 2 groups by low-dose STZ, the other 2 groups served as nondiabetic controls. Omapatrilat (70 mg/kg/day) was administered to one of the diabetic and to one of the nondiabetic groups. The diabetic and the nondiabetic mice were sacrificed after 3 and 5 weeks, respectively. The aortae were examined and the atherosclerotic plaque area was measured. The atherosclerotic plaque area was significantly smaller in the omapatrilat-treated mice, both diabetic and nondiabetic, as compared to nontreated controls. The mean plaque area of omapatrilattreated nondiabetic mice was 9357 ± 7293μm2, versus 71977 ± 34610μm2in the nontreated mice (P= .002). In the diabetic animals, the plaque area was 8887 ± 5386μm2and 23220 ± 10400μm2, respectively for treated and nontreated mice (P= .001). Plasma lipids were increased by omapatrilat: Meanplasma cholesterol in treated mice, diabetic and nondiabetic combined, was 39.31 ± 6.00 mmol/L, versus 33.12 ± 7.64 mmol/L in the nontreated animals (P= .008). The corresponding combined mean values of triglycerides were 4.83 ± 1.93 versus 3.00 ± 1.26 mmol/L (P= .02). Omapatrilat treatment did not affect weight or plasma glucose levels. Treatment with omapatrilat inhibits atherogenesis in diabetic as well as nondiabetic LDL receptor–deficient mice despite an increase in plasma lipids, suggesting a direct effect on the arterial wall.