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OBJECTIVE: Current guidelines recommend dual antiplatelet (AP) therapy (DAPT) before carotid artery stenting (CAS); however, the true clinical effect of single AP therapy vs DAPT is unknown. We examined the efficacy and safety of preoperative single AP therapy vs DAPT in patients who had undergone transfemoral CAS (tfCAS) or transcarotid artery revascularization (TCAR).METHODS: We identified all patients who had undergone tfCAS or TCAR in the Vascular Quality Initiative database from 2016 to 2021. We stratified the patients by procedure and identified those who had received the following preoperative AP regimens: DAPT (acetylsalicylic acid [ASA] + P2Y12 inhibitor [P2Yi]), no AP therapy, ASA only, ASA + AP loading dose, P2Yi only, and P2Yi + AP loading dose. The AP loading dose was given within 4 hours of CAS. We generated propensity scores for each treatment regimen and assessed in-hospital outcomes using inverse probability weighted log binomial regression, with DAPT as the reference and adjusting for intraoperative protamine use. The primary efficacy outcome was a composite end point of stroke and death, and the primary safety outcome was access-related bleeding.RESULTS: Of the 18,570 tfCAS patients, 70% had received DAPT, 5.6% no AP therapy, 10% ASA only, 8.0% ASA + AP loading dose, 4.6% P2Yi only, and 2.9% P2Yi + AP loading dose. The corresponding unadjusted rates of stroke/death were 2.2%, 6.8%, 4.1%, 5.1%, 2.4%, and 2.3%. After adjustment, compared with DAPT, the incidence of stroke/death was higher with no AP therapy (relative risk [RR], 2.3; 95% confidence interval [CI], 1.7-3.2), ASA only (RR, 1.6; 95% CI, 1.2-2.1), and ASA + AP loading dose (RR, 2.0; 95% CI, 1.5-2.7) but was similar with P2Yi only (RR, 0.99; 95% CI, 0.58-1.7) and P2Yi + AP loading dose (RR, 1.1; 95% CI, 0.49-2.5). Of the 25,459 TCAR patients, 81% had received DAPT, 2.0% no AP therapy, 5.5% ASA only, 3.5% ASA + AP loading dose, 4.9% P2Yi only, and 2.4% P2Yi + AP loading dose. The corresponding unadjusted rates of stroke/death were 1.5%, 3.3%, 3.3%, 2.9%, 1.2%, and 1.1%. After adjustment, compared with DAPT, the incidence of stroke/death was higher with no AP therapy (RR, 2.0; 95% CI, 1.2-3.3) and ASA only (RR, 2.2; 95% CI, 1.5-3.1), with a trend toward a higher incidence with ASA + AP loading dose (RR, 1.6; 95% CI, 0.99-2.6), and was similar with P2Yi only (RR, 0.98; 95% CI, 0.54-1.8) and P2Yi + AP loading dose (RR, 0.66; 95% CI, 0.27-1.6). No differences were found in the incidence of access-related bleeding between the treatment groups after tfCAS or TCAR.CONCLUSIONS: Compared with DAPT, no AP therapy or ASA monotherapy was associated with higher rates of stroke/death after CAS and should be discouraged as unsafe practice. Meanwhile, P2Yi monotherapy was associated with similar rates of stroke/death. No differences were found in the incidence of bleeding complications, and adding an AP loading dose to ASA or P2Yi monotherapy within 4 hours of the procedure did not affect the outcomes. Overall, these findings support the current guidelines recommending DAPT before CAS but also suggest that P2Yi monotherapy might confer thromboembolic benefits similar to those with DAPT. However, an immediate preoperative AP loading dose might not provide additional thromboembolic benefits.

Supplementary Figure 3 - PDF file 97K, HIF1{alpha} and PLOD2 mediate sarcoma cell migration

Supplementary Figure 1 - PDF file 122K, Sarcoma cell lung colonization is dependent on HIF1{alpha} and PLOD2

Supplementary Figure 8 - PDF file 134K, Tumor cells are the major in vivo source of sarcoma collagen

Supplementary Figure 7 - PDF file 786K, Minoxidil treatment does not affect primary tumor volume or overall animal weight

Supplementary Figure 4 - PDF file 151K,HIF1{alpha} and PLOD2 mediate migration via a cell extrinsic mechanism in KP cells

Supplementary Figure 5 - PDF file 173K, HIF1{alpha} and PLOD2 mediate migration via a cell extrinsic mechanism in HT-1080 cells

Supplementary Figure 2 - PDF file 124K, HIF1{alpha} is not required for primary sarcoma formation

Supplementary Figure 6 - PDF file 110K, Expression of WT and mutant PLOD2 in sarcoma cells

Supplementary Figure Legends - PDF file 104K, Supplementary Figure Legends

Traumatic brain injury (TBI) and blunt thoracic aortic injury (BTAI) are the top two leading causes of death after blunt force trauma. Patients presenting with concomitant BTAI and TBI pose a specific challenge with respect to management strategy, because the optimal hemodynamic parameters are conflicting between the two pathologies. Early thoracic endovascular aortic repair (TEVAR) is often performed, even for minimal aortic injuries, to allow for the higher blood pressure parameters required for TBI management. However, the optimal timing of TEVAR for the treatment of BTAI in patients with concomitant TBI remains an active matter of controversy.The Aortic Trauma Foundation international prospective multicenter registry was used to identify all patients who had undergone TEVAR for BTAI in the setting of TBI from 2015 to 2020. The primary outcomes included delayed ischemic or hemorrhagic stroke, in-hospital mortality, and aortic-related mortality. The outcomes were examined among patients who had undergone TEVAR at emergent (6 vs ≥6 hours) or urgent (24 vs ≥24 hours) intervals.A total of 100 patients (median age, 43 years; 79% men; median injury severity score, 41) with BTAI (Society for Vascular Surgery BTAI grade 1, 3%; grade 2, 10%; grade 3, 78%; grade 4, 9%) and concomitant TBI who had undergone TEVAR were identified. Emergent repair was performed for 51 patients (51%). Comparing emergent repair (6 hours) to urgent repair (≥6 hours), no difference was found in delayed cerebral ischemic events (2.0% vs 4.1%; P = .614), in-hospital mortality (15.7% vs 22.4%; P = .389), or aortic-related mortality (2.0% vs 2.0%; P = .996) and no patient had experienced delayed hemorrhagic stroke. Likewise, repairs conducted in an urgent (24 hours) setting showed no differences compared with those completed in an emergent (≥24 hours) setting regarding delayed ischemic stroke (2.6% vs 4.3%; P = .548), in-hospital mortality (18.2% vs 21.7%; P = .764), or aortic-related mortality (1.3% vs 4.3%; P = .654), and no patient had experienced delayed hemorrhagic stroke.In contrast to prior retrospective efforts, results from the Aortic Trauma Foundation international prospective multicenter registry have demonstrated that neither emergent nor urgent TEVAR for patients with concomitant BTAI and TBI was associated with delayed stroke, in-hospital mortality, or aortic-related mortality. In these patients, the timing of TEVAR did not have an effect on the outcomes. Therefore, the decision to intervene should be guided by individual patient factors rather than surgical timing.

Recent studies have highlighted socioeconomic disparities in the severity and management of abdominal aortic aneurysm (AAA) disease. However, these studies focus on individual measures of social disadvantage such as income and insurance status. The area deprivation index (ADI), a validated measure of neighborhood deprivation, provides a more comprehensive assessment of social disadvantage. Therefore, we examined the impact of ADI on AAA severity and its management.We identified all patients who underwent endovascular or open repair of an AAA in the Vascular Quality Initiative registry between 2003 and 2020. An ADI score of 1 to 100 was assigned to each patient based on their residential zip code, with higher ADI scores corresponding with increasing deprivation. Patients were categorized by ADI quintiles. Outcomes of interest included rates of ruptured AAA (rAAA) repair versus an intact AAA repair and rates of endovascular repair (EVAR) versus the open approach. Logistic regression was used to evaluate for an independent association between ADI quintile and these outcomes.Among 55,931 patients who underwent AAA repair, 6649 (12%) were in the lowest ADI quintile, 11,692 (21%) in the second, 15,958 (29%) in the third, 15,035 (27%) in the fourth, and 6597 (12%) in the highest ADI quintile. Patients in the two highest ADI quintiles had a higher proportion of rAAA repair (vs intact repair) compared with those in the lowest ADI quintile (8.8% and 9.1% vs 6.2%; P .001). They were also less likely to undergo EVAR (vs open approach) when compared with the lowest ADI quintile (81% and 81% vs 88%; P .001). There was an overall trend toward increasing rAAA and decreasing EVAR rates with increasing ADI quintiles (P .001). In adjusted analyses, when compared with patients in the lowest ADI quintile, patients in the highest ADI quintile had higher odds of rAAA repair (odds ratio, 1.4; 95% confidence interval, 1.2-1.8; P .001) and lower odds of undergoing EVAR (odds ratio, 0.54; 95% confidence interval, 0.45-0.65; P .001).Among patients who underwent AAA repair in the Vascular Quality Initiative, those with higher neighborhood deprivation had significantly higher rates of rAAA repair (vs intact repair) and lower rates of EVAR (vs open approach). Further work is needed to better understand neighborhood factors that are contributing to these disparities to identify community-level targets for improvement.

Few studies adequately evaluate the impact of wound location on patient outcomes after lower extremity revascularization. Consequently, we evaluated the relationship between lower extremity wound location and long-term outcomes.We reviewed all patients at our institution undergoing any first-time open surgical bypass or percutaneous transluminal angioplasty with or without stenting for tissue loss between 2005 and 2014. We categorized wounds into three distinct groups: forefoot (ie, toes and metatarsal heads), midfoot (ie, dorsal, plantar, lateral, medial surfaces excluding toes, metatarsal heads, or heel), and heel. Limbs with multiple wounds were excluded from analyses. We compared rates of perioperative complications, wound healing, reintervention, limb salvage, amputation-free survival, and survival using χOf 2869 infrainguinal revascularizations from 2005 to 2014, 1126 underwent a first-time revascularization for tissue loss, of which 253 patients had multiple wounds, 197 had wounds proximal to the ankle, 100 had unreliable wound information, and 576 (forefoot, n = 397; midfoot, n = 61; heel, n = 118) fit our criteria and had a single foot wound with reliable information regarding wound specifics. Patients with forefoot, midfoot, and heel wounds had similar rates of coronary artery disease, hypertension, diabetes, and smoking history (all P.05). Conversely, there were significant differences in patient age (71 vs 69 vs 70 years), prevalence of gangrene (41% vs 5% vs 21%), and dialysis dependence (18% vs 17% vs 30%) (all P .05). There were no statistically significant differences in perioperative mortality (1.3% vs 4.9% vs 4.2%; P = .06) or postoperative complications among the three groups. Between forefoot, midfoot, and heel wounds, there were significant differences in unadjusted 6-month rates of complete wound healing (69% vs 64% vs 53%), 3-year rates of amputation-free survival (54% vs 57% vs 35%), and survival (61% vs 72% vs 41%) (all P .05). After adjustment, compared with forefoot wounds, heel wounds were associated with higher rates of incomplete 6-month wound healing (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1-2.]), major amputation or mortality (HR, 1.7; 95% CI, 1.1-2.7), and all-cause mortality (HR, 1.8; 95% CI, 1.1-3.0), but not major amputation alone (HR, 2.1; 95% CI, 0.9-4.5). In open surgical bypass-first patients, heel wounds were solely associated with an increased risk of all-cause mortality (HR, 1.7; 95% CI, 1.1-2.8), whereas heel wounds in percutaneous transluminal angioplasty-first patients were associated with an increased risk of incomplete wound healing (HR, 2.2; 95% CI, 1.3-3.7), major amputation or mortality (HR, 2.3; 95% CI, 1.1-5.4), and all-cause mortality (HR, 2.8; 95% CI, 1.1-7.2).Heel wounds confer considerably higher short- and long-term morbidity and mortality compared with midfoot or forefoot wounds in patients undergoing any first-time lower extremity revascularization.

Although the current guidelines have recommended single antiplatelet therapy (SAPT) for patients undergoing revascularization for chronic limb-threatening ischemia (CLTI), antithrombotic management has varied by patient and provider. Our aim was to examine the effects of different postoperative antithrombotic regimens on 3-year clinical outcomes after infrapopliteal bypass for CLTI.We identified patients who had undergone infrapopliteal bypass for CLTI in the Vascular Quality Initiative (VQI) registry from 2003 to 2017 with linkage to Medicare claims for long-term outcomes. We divided the patients into three cohorts according to the discharge antithrombotic regimen: SAPT (aspirin or clopidogrel), dual antiplatelet therapy (DAPT; aspirin and clopidogrel), or anticoagulation (AC) plus any antiplatelet (AP) agent. To reduce selection bias, we restricted the analysis cohorts to patients treated by providers who discharged50% of patients with each antithrombotic regimen. Our primary outcome was 3-year major adverse limb events (MALE; major amputation or reintervention). The secondary outcomes included 3-year major amputation, reintervention, and mortality. We used Kaplan-Meier and Cox regression analyses to assess these outcomes stratified by antithrombotic regimen and adjusted for demographic, comorbid, clinical, and operative differences between the treatment groups with clustering at the center level.Among 1812 patients (median follow-up,2 years), 693 (38%) were discharged with SAPT, 544 (30%) with DAPT, and 575 (32%) with AC+AP. At 3 years, the MALE rates were 75% with DAPT, 74% with AC+AP, and 68% with SAPT. In adjusted analyses with SAPT as the reference group, no differences were found in 3-year MALE with DAPT (adjusted hazard ratio [aHR], 1.0; 95% confidence interval [CI], 0.85-1.3; P = .71) or AC+AP (aHR, 1.1; 95% CI, 0.96-1.3; P = .14). Across the treatment groups, we also found no differences in the individual end points of 3-year major amputation (DAPT: aHR, 0.98; 95% CI, 0.72-1.3; AC+AP: aHR, 1.3; 95% CI, 0.96-1.7), reintervention (DAPT: aHR, 1.0; 95% CI, 0.84-1.3; AC+AP: aHR, 1.1; 95% CI, 0.96-1.3), or mortality (DAPT: aHR, 1.1; 95% CI, 0.88-1.4; AC+AP: aHR, 0.95; 95% CI, 0.74-1.2). In a sensitivity analysis evaluating patients treated by providers who discharged60%,70%, or80% of patients with these regimens, the association between antithrombotic regimen and MALE was unchanged.Compared with SAPT, DAPT and anticoagulation therapy were not associated with improved outcomes among Medicare beneficiaries who had undergone infrapopliteal bypass for CLTI at VQI participating centers. These findings support current guidelines recommending SAPT after lower extremity bypass and suggest that the routine use of DAPT or anticoagulation therapy might not provide clinical benefit in this high-risk, elderly population. However, further evaluation of the risks and benefits of various antithrombotic regimens in relevant subgroups is warranted.

Blunt thoracic aortic injury (BTAI) is the second leading cause of death from blunt trauma. In the present study, we aimed to determine the outcomes of medical management (MM) for BTAI. We hypothesized from the results of several previously reported studies, that patients with a minimal aortic injury (BTAI grades 1 and 2) could safely be treated with definitive MM alone.The Aortic Trauma Foundation international prospective multicenter registry was used to examine the demographics, injury characteristics, management, and outcomes of patients with BTAI. We analyzed a subset of patients for whom MM was initiated as definitive therapy.From November 2016 to April 2020, 432 patients (median age, 41 years; 76% male; median injury severity score, 34) with BTAI (Society for Vascular Surgery grade 1, 23.6%; grade 2, 14.4%; grade 3, 51.2%; grade 4, 10.9%) were evaluated. Of the 432 patients, 245 (57%) had received MM in the initial period and 114 (26.4%) had received MM as the planned definitive therapy (grade 1, 59.6%; grade 2, 23.7%; grade 3, 15.8%; grade 4, 0.9%). The most common mechanism of BTAI was a motor vehicle collision (60.4%). Hypotension was present on arrival in 74 patients (17.2%). Continuous titratable infusion of antihypertensive medication was used for 49.1%, followed by intermittent bolus administration (29.8%), with beta-blockers (74.6%) the most common agent used. Treatments were targeted to a goal systolic blood pressure for 83.3%, most often to a target goal systolic blood pressure120 mm Hg (66.3%). The MM goals based on blood pressure control were attained in 64.0% (73 of 114). Twelve patients (10.5%; grade 1, 1; grade 2, 0; grade 3, 10; grade 4, 1) had required subsequent intervention after MM. Eleven patients (9.6%) had undergone thoracic endovascular aortic repair and one (0.9%) had required open repair for a grade 4 injury. The overall in-hospital mortality for patients selected for definitive MM was 7.9%. No aortic-related deaths had occurred in the patients receiving definitive MM.Approximately one in four patients with BTAI will receive MM as definitive therapy. The variation in the pharmacologic therapies used is considerable. MM for patients with minimal aortic injury (BTAI grades 1 and 2) is safe and effective, with a low overall intervention rate and no aortic-related deaths. These findings support the use of definitive MM for grade 2 BTAI.

Background: The optimal revascularization strategy for acute limb ischemia (ALI) remains unclear, and contemporary comparative effectiveness data on endovascular versus surgical revascularization are lacking. Methods: We used the 2010 to 2014 National Inpatient Sample databases to identify hospitalizations with a primary diagnosis of ALI. Patients were propensity-score matched on the likelihood of undergoing endovascular versus surgical revascularization using a logistic regression model. The primary outcome was in-hospital mortality. Secondary outcomes included myocardial infarction, stroke, composite of death/myocardial infarction/stroke, any amputation, fasciotomy, acute kidney injury, major bleeding, transfusion, vascular complications, length of stay, and hospital costs. Results: Of 10 484 (weighted national estimate=51 914) hospitalizations for ALI, endovascular revascularization was performed in 5008 (47.8%) and surgical revascularization in 5476 (52.2%). In the propensity-score matched cohort (n=7746; 3873 per group), patients who underwent endovascular revascularization had significantly lower in-hospital mortality (2.8% versus 4.0%; P =0.002), myocardial infarction (1.9% versus 2.7%; P =0.022), composite of death/myocardial infarction/stroke (5.2% versus 7.5%; P P =0.043), fasciotomy (1.9% versus 8.9%; P P P P =0.002), compared with those undergoing surgical revascularization. Rates of any amputation were similar between the 2 groups (4.7% versus 5.1%; P =0.43). Median length of stay was shorter and hospital costs higher with endovascular versus surgical revascularization. Conclusions: In patients with ALI, endovascular revascularization was associated with better in-hospital clinical outcomes compared with surgical revascularization. Contemporary randomized controlled trials are needed to determine the optimal revascularization strategy for ALI.

High-definition fluoroscopic imaging is required to perform endovascular procedures safely and precisely, especially in complex cases, resulting in longer procedures and increased radiation exposure. This is of importance for training institutions as trainees, even with sound instruction in as low as reasonably achievable (ALARA) principles, tend to have high radiation exposures. Recently, there was an upgrade in the imaging system allowing for comparison of radiation exposure to patients and providers. We performed an analysis of consecutive endovascular aneurysm repair (EVAR) and superficial femoral artery (SFA) interventions in the years 2013 to 2014. We recorded body mass index (BMI) and fluoroscopy time (FT) and subsequently matched 1:1 based on BMI, FT, or both. We determined radiation dose using air kerma (AK) and also recorded individual surgeons’ badge readings. Allura Xper FD20 was upgraded to AlluraClarity with ClarityIQ. We identified a total of 77 EVARs (52 pre and 25 post) and 134 SFA interventions (99 pre and 35 post). Unmatched results for EVAR were BMI pre 26.2 versus post 25.8 (kg/m2, P = .325), FT 28.1 versus 21.2 (minutes, P = .051), and AK 1178.5 versus 581 (mGy, P < .001), respectively. After matching, there was a 53.2% reduction in AK (846.1 vs 395.9 mGy; P = .004) for EVAR. Unmatched results for SFA interventions were BMI pre 28.1 versus post 26.6 ( P = .327), FT 18.7 versus 16.2 ( P = .282), and AK 285.6 versus 106.0 ( P < .001), respectively. After matching, there was a 57.0% reduction in AK (305.0 vs 131.3, P < .001). The total deep dose equivalent from surgeons’ badge readings decreased from 39.5 to 17 mrem ( P = .029). Aortic and peripheral endovascular interventions can be performed with reduced radiation exposure to patients and providers, employing modern fixed imaging systems with advanced dose reduction technology. This is of particular importance in the light of the increasing volume and complexity of endovascular and hybrid procedures as well as the prospect of decades of radiation exposure during training and practice.

Objective Increasing experience and improving technology have led to the expansion of endovascular aneurysm repair (EVAR) for ruptured abdominal aortic aneurysms (AAA). We investigated whether the 5-year survival after both EVAR and open repair for ruptured AAA changed over the last 14 years. Methods We identified repairs for ruptured infrarenal AAA within the Vascular Quality Initiative registry between 2004 and 2018. We compared the 5-year survival of both EVAR and open repair between the early (2004-2012) and late (2013-2018) cohorts. In addition, we compared EVAR with open repair in the early and late cohorts. We used propensity score modeling to create matching cohorts for each analysis. Kaplan-Meier analysis was used to estimate survival proportions and univariate Cox proportional hazards analysis was used to compare differences in hazard of mortality in the matched cohorts. Results We identified 4638 ruptured AAA repairs. This included 409 EVARs in the early cohort and 2250 in the late cohort, as well as 558 open repairs in the early cohort and 1421 in the late cohort. Propensity matching resulted in 366 matched pairs of late vs early EVAR and 391 matched-pairs of late vs early open repair. When comparing EVAR with open repair, propensity matching resulted in 277 matched pairs of early EVAR versus open, and 1177 matched pairs of late EVAR versus open. In matched EVAR patients, 5-year survival was higher in the late cohort (63% vs 49%; hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.61-0.97; P = .027), whereas there was no difference between matched late vs early for open repair patients (52% vs 59%; HR, 1.04; 95% CI, 0.85-1.28; P = .69). In the early cohort, there was no survival difference between EVAR and open repair (51% vs 46%; HR, 0.88; 95% CI, 0.69-1.11; P = .28). However, in the late cohort EVAR was associated with higher survival compared with open repair (63% vs 54%; HR, 0.69; 95% CI, 0.60-0.79; P Conclusions The 5-year survival after EVAR for ruptured AAA has improved over time, whereas survival after open repair remained constant. Consequently, the relative survival benefit of EVAR over open repair has increased over time, which should encourage further adoption of EVAR for ruptured AAA.

Practitioners of endovascular surgery have historically used 2-dimensional (2D) intraoperative fluoroscopic imaging, with intravascular contrast opacification, to treat complex 3-dimensional (3D) pathology. Recently, major technical developments in intraoperative imaging have made image fusion techniques possible, the creation of a 3D patient-specific vascular roadmap based on preoperative imaging which aligns with intraoperative fluoroscopy, with many potential benefits. First, a 3D model is segmented from preoperative imaging, typically a computed tomography scan. The model is then used to plan for the procedure, with placement of specific markers and storing of C-arm angles that will be used for intraoperative guidance. At the time of the procedure, an intraoperative cone beam computed tomography is performed, and the 3D model is registered to the patient's on-table anatomy. Finally, the system is used for live guidance in which the 3D model is codisplayed with overlying fluoroscopic images. There are many applications for image fusion in endovascular surgery. We have found it to be particularly useful for endovascular aneurysm repair (EVAR), complex EVAR, thoracic EVAR, carotid stenting, and for type 2 endoleaks. Image fusion has been shown in various settings to lead to decreased radiation dose, less iodinated contrast use, and shorter procedure times. In the future, fusion models may be able to account for vessel deformation caused by the introduction of stiff wires and devices, and the user-dependent steps may become more automated. In its current form, image fusion has already proven itself to be an essential component in the planning and success of complex endovascular procedures.

The volume and complexity of endovascular procedures are increasing. Multidetector computed tomography (CT) made precise three-dimensional (3D) planning of these procedures possible, but intraoperative imaging, even with the use of modern flat-panel detectors, is limited to two dimensions. Flat detectors, however, allow C-arm cone-beam CT. This technology can be used to generate a 3D data set that can be fused with a preoperative high-resolution CT scan, thus generating a live 3D roadmap. We hypothesized that use of a novel image fusion software, VesselNavigator (Philips Healthcare, Best, The Netherlands), facilitates precise and expeditious procedures and therefore reduces radiation exposure and contrast agent dose.A retrospective review of patients undergoing standard aortobi-iliac endovascular aneurysm repair at our institution between January 2011 and April 2014 was performed. Conventional imaging was compared with VesselNavigator-assisted imaging, and a matched analysis based on body mass index (BMI) was performed because of the dependence of radiation dose on body habitus. Outcome parameters were procedure time, fluoroscopy time, radiation, and contrast agent dose.A total of 75 patients were identified. After matching based on BMI, control and VesselNavigator groups each had 16 patients with BMI of 27.0 ± 3.6 kg/m(2) and 27.0 ± 3.6 kg/m(2), respectively (mean ± standard deviation). R(2) was 6.37 × 10(-7). Radiation dose measured as air kerma was lower with VesselNavigator (1067 ± 470.4 mGy vs 1768 ± 696.2 mGy; P = .004). Fluoroscopy time was shorter (18.4 ± 6.8 minutes vs 26.8 ± 10.0 minutes; P = .01) and contrast agent dose was lower (37.4 ± 21.3 mL vs 77.3 ± 23.0 mL; P.001) with VesselNavigator compared with control. Procedure time was also shorter with VesselNavigator (80.4 ± 21.2 minutes vs 110.0 ± 29.1 minutes; P = .005).Image fusion using VesselNavigator enhances the functionality of conventional fluoroscopy in standard endovascular aneurysm repair. It reduces radiation exposure to patients and providers. It also limits the amount of contrast agent and shortens the overall procedure length. The benefit of this technology is demonstrated on this typically straightforward procedure but may be even more useful for complex procedures.

Intratumoral hypoxia and expression of hypoxia-inducible factor-1α (HIF-1α) correlate with metastasis and poor survival in patients with sarcoma. We show here that hypoxia controls sarcoma metastasis through a novel mechanism wherein HIF-1α enhances expression of the intracellular enzyme procollagen-lysine, 2-oxoglutarate 5-dioxygenase 2 (PLOD2). We show that loss of HIF-1α or PLOD2 expression disrupts collagen modification, cell migration, and pulmonary metastasis (but not primary tumor growth) in allograft and autochthonous LSL-KrasG12D/+; Trp53fl/fl murine sarcoma models. Furthermore, ectopic PLOD2 expression restores migration and metastatic potential in HIF-1α–deficient tumors, and analysis of human sarcomas reveals elevated HIF1A and PLOD2 expression in metastatic primary lesions. Pharmacologic inhibition of PLOD enzymatic activity suppresses metastases. Collectively, these data indicate that HIF-1α controls sarcoma metastasis through PLOD2-dependent collagen modification and organization in primary tumors. We conclude that PLOD2 is a novel therapeutic target in sarcomas and successful inhibition of this enzyme may reduce tumor cell dissemination. Significance: Undifferentiated pleomorphic sarcoma (UPS) is a commonly diagnosed and particularly aggressive sarcoma subtype in adults, which frequently and fatally metastasizes to the lung. Here, we show the potential use of a novel therapeutic target for the treatment of metastatic UPS, specifically the collagen-modifying enzyme PLOD2. Cancer Discov; 3(10); 1190–1205. ©2013 AACR. See related commentary by Vanharanta and Massagué, p. 1103 This article is highlighted in the In This Issue feature, p. 1083

To explore how the 2 most important components of surgical performance--speed and accuracy-are influenced by different forms of stress and what the impact of music is on these factors.On the basis of a recently published pilot study on surgical experts, we designed an experiment examining the effects of auditory stress, mental stress, and music on surgical performance and learning and then correlated the data psychometric measures to the role of music in a novice surgeon's life.Thirty-one surgeons were recruited for a crossover study. Surgeons were randomized to 4 simple standardized tasks to be performed on the SurgicalSIM VR laparoscopic simulator (Medical Education Technologies, Inc, Sarasota, FL), allowing exact tracking of speed and accuracy. Tasks were performed under a variety of conditions, including silence, dichotic music (auditory stress), defined classical music (auditory relaxation), and mental loading (mental arithmetic tasks). Tasks were performed twice to test for memory consolidation and to accommodate for baseline variability. Performance was correlated to the brief Musical Experience Questionnaire (MEQ).Mental loading influences performance with respect to accuracy, speed, and recall more negatively than does auditory stress. Defined classical music might lead to minimally worse performance initially but leads to significantly improved memory consolidation. Furthermore, psychologic testing of the volunteers suggests that surgeons with greater musical commitment, measured by the MEQ, perform worse under the mental loading condition.Mental distraction and auditory stress negatively affect specific components of surgical learning and performance. If used appropriately, classical music may positively affect surgical memory consolidation. It also may be possible to predict surgeons' performance and learning under stress through psychological tests on the role of music in a surgeon's life. Further investigation is necessary to determine the cognitive processes behind these correlations.

Preoperative testing for carotid endarterectomy (CEA) often includes blood typing and antibody screen (TS). In our institutional experience, however, transfusion for CEA is rare. We assessed transfusion rate and risk factors in a national clinical database to identify a cohort of patients in whom TS can safely be avoided with the potential for substantial cost savings.With use of the National Surgical Quality Improvement Program database, transfusion events and timing were established for all elective CEAs in 2012-2013. Comorbidities and other characteristics were compared for patients receiving intraoperative or postoperative transfusion and those who did not. After random assignment of the total data to either a training or validation set, a prediction model for transfusion risk was created and subsequently validated.Of 16,043 patients undergoing CEA in 2012-2013, 276 received at least one transfusion before discharge (1.7%); 42% of transfusions occurred on the day of surgery. Preoperative hematocrit 30% (odds ratio [OR], 57.4; 95% confidence interval [CI], 29.6-111.1), history of congestive heart failure (OR, 2.8; 95% CI, 1.1-7.1), dependent functional status (OR, 2.7; 95% CI, 1.5-5.1), coagulopathy (OR, 2.5; 95% CI, 1.7-3.6), creatinine concentration ≥1.2 mg/dL (OR, 2.3; 95% CI, 1.6-3.3), preoperative dyspnea (OR, 2.0; 95% CI, 1.4-3.1), and female gender (OR, 1.6; 95% CI, 1.1-2.3) predicted transfusion. A risk prediction model based on these data produced a C statistic of 0.85; application of this model to the validation set demonstrated a C statistic of 0.81. In the validation set, 93% of patients received a score of 6 or less, corresponding to an individual predicted transfusion risk of 5% or less. Omitting a TS in these patients would generate a substantial annual cost saving for National Surgical Quality Improvement Program hospitals.Whereas TS are commonly performed for patients undergoing CEA, transfusion after CEA is rare and well predicted by a transfusion risk score. Avoidance of TS in this low-risk population provides a substantial cost-saving opportunity without compromise of patient care.

Aims The transglutaminase factor XIII (FXIII) emerges as a key enzyme in healing after myocardial infarction (MI). Here we assess the impact of transglutaminase-modulating therapies on healing and evolution of heart failure using a novel, non-invasive molecular imaging technique. Methods and results Immunoblotting revealed lower FXIII levels in the myocardium of nine patients with infarct rupture when compared to MI patients without rupture ( P < 0.0045). In a murine model of MI, we assessed healing while modulating local FXIII activity. Infarct tissue activity was monitored with molecular in vivo single photon emission computed tomography-computed tomography (SPECT-CT) imaging, and activity was found to be increased by 80% in FXIII-treated mice (400 IU FXIII/kg iv.), and decreased by 65% in dalteparin (DP)-treated mice (600 IU/kg DP sc., P < 0.05). DP-treated mice exhibited increased mortality due to infarct rupture (64% by day 7, P < 0.018). Serial Magnetic Resonance Imaging (MRI) showed that left ventricular dilation post-MI was attenuated by FXIII treatment when compared to saline control-treated mice with MI ( P = 0.04). Quantitative histological and reverse transcription–polymerase chain reaction analyses revealed that FXIII treatment induced a faster resolution of the neutrophil response, enhanced macrophage recruitment, increased collagen content and augmented angiogenesis in the healing infarct ( P < 0.05 vs. control-treated mice with MI). Conclusion FXIII tissue levels are decreased in patients with insufficient healing. Therapeutic strategies that modulate FXIII activity impact murine myocardial healing. Molecular imaging of FXIII activity predicts prognosis in mice with experimental MI.

Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6Chi and -6Clo monocytes via CCR2 and CX3CR1, respectively. Ly-6Chi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6Clo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6Chi monocytes digest damaged tissue, whereas Ly-6Clo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6Chi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.

Chronic mesenteric ischemia (CMI) is a rare disease that affects about 1 in 100,000 individuals. It is usually the result of atherosclerotic changes of the aorta at the ostia of the mesenteric vessels. This leads to stenosis and eventually occlusion of celiac artery as well as superior and inferior mesenteric artery. It is classically characterized by abdominal pain, weight loss, and food fear. The abdominal pain is caused by a mismatch of splanchnic blood flow and intestinal metabolic demand, which leads to the onset of symptoms within 15–45 min after food intake and lasts about 3–4 h. The diagnosis of CMI is very challenging due to its low prevalence and the lack of a definitive test. Conventional angiography was the gold standard but has been largely replaced as a diagnostic tool by duplex ultrasonography (DUS) and computed tomographic angiography (CTA).

Two-way communication between the mammalian nervous and immune systems is increasingly recognized and appreciated. An intriguing example of such crosstalk comes from clinical observations dating from the 1930s: Patients who suffer a stroke and then develop rheumatoid arthritis atypically present with arthritis on only one side, the one not afflicted with paralysis. Here we successfully modeled hemiplegia-induced protection from arthritis using the K/BxN serum-transfer system, focused on the effector phase of inflammatory arthritis. Experiments entailing pharmacological inhibitors, genetically deficient mouse strains, and global transcriptome analyses failed to associate the protective effect with a single nerve quality (i.e., with the sympathetic, parasympathetic, or sensory nerves). Instead, there was clear evidence that denervation had a long-term effect on the limb microvasculature: The rapid and joint-localized vascular leak that typically accompanies and promotes serum-transferred arthritis was compromised in denervated limbs. This defect was reflected in the transcriptome of endothelial cells, the expression of several genes impacting vascular leakage or transendothelial cell transmigration being altered in denervated limbs. These findings highlight a previously unappreciated pathway to dissect and eventually target in inflammatory arthritis.

OBJECTIVE To determine the factors that may predict music-induced relaxation in friends and family of patients in the emergency department. BACKGROUND It remains unclear to date which demographic and experiential factors predict the effectiveness of music-induced relaxation. Furthermore, in-hospital stressors for friends and family of patients rather than patients themselves are underresearched and deserve in-depth investigation to improve this group's experience in health care environments. METHODS A total of 169 relatives and friends of patients in the emergency department-waiting area completed a series of questionnaires, including the Spielberger State-Trait Anxiety Inventory (STAI), the Music Experience Questionnaire (MEQ), and a demographic survey. They were then randomly assigned to either Case Group (1 hour in the waiting area with classical music in the background) or Control Group (1 hour with no music) before completing a second, identical copy of the STAI to measure change from baseline. Data were analyzed for associations between music intervention, change in STAI scores, MEQ scores, and demographic characteristics. RESULTS Participants who underwent the music intervention experienced a 9.8% decrease in overall mean State Anxiety, whereas those in the Control Group experienced no change over time (P = 0.001). Higher education significantly inversely correlated with the effectiveness of music intervention: participants with no formal education beyond high school showed a greater overall mean decrease in State Anxiety than those with a college education or beyond in response to classical music (P = 0.006). Furthermore, MEQ scores indicated that the Social Uplift scale (a measure of one's tendency to be uplifted in a group-oriented manner by music) was highly predictive of the effectiveness of music intervention. CONCLUSIONS Music is an effective and inexpensive means of reducing anxiety in friends and family of patients, who are underresearched in medicine. Moreover, low educational attainment and tendency to respond positively to music in a group setting can predict the effectiveness of music-induced relaxation.

We present an optical molecular imaging approach to measure the efficacy of the cyclooxygenase-2 (COX-2) inhibitor celecoxib on tumor growth rate through its effect on matrix metalloproteinase (MMP) activity. A xenograft model of colorectal cancer was generated in nude mice, which were then randomized to receive celecoxib versus vehicle. MMP activity was measured by an enzyme-activatable optical molecular probe. A novel genetically engineered mouse (GEM) model of colorectal cancer was also used to assess celecoxib's effect on MMP activity, which was measured by quantitative fluorescence colonoscopy. Subcutaneously implanted xenograft tumors were 84% (SD 20.2%) smaller in volume in the treatment group versus the control group. Moreover, treated animals exhibited only a 7.6% (SEM 9%) increase in MMP activity versus 106% (SEM 8%) for untreated animals. There was an apparent linear relationship (r = .91) between measured MMP activity and tumor growth rate. Finally, in the GEM model experiment, treated murine tumors remained relatively unchanged in volume and MMP activity; however, untreated tumors grew significantly and showed an increase in MMP activity. This method may provide for the improved identification of patients for whom COX-2 inhibition therapy is indicated by allowing one to balance the patient's cardiovascular risk with the cancer's responsiveness to celecoxib.

Undifferentiated pleomorphic sarcoma/Malignant Fibrous Histiocytoma (MFH) is one of the most common subtypes of human soft tissue sarcoma. Using cross species genomic analysis, we define a geneset from the LSL-Kras[superscript G12D]; Trp53[superscript Flox/Flox] mouse model of soft tissue sarcoma that is highly enriched in human MFH. With this mouse geneset as a filter, we identify expression of the RAS target FOXM1 in human MFH. Expression of Foxm1 is elevated in mouse sarcomas that metastasize to the lung and tissue microarray analysis of human MFH correlates overexpression of FOXM1 with metastasis. These results suggest that genomic alterations present in human MFH are conserved in the LSL-Kras[superscript G12D]; p53[superscript Flox/Flox] mouse model of soft tissue sarcoma and demonstrate the utility of this pre-clinical model.

Objective: To test a novel self-activating viridin (SAV) prodrug that slowly releases wortmannin, a potent phosphoinositide 3-kinase inhibitor, in a model of antibody-mediated inflammatory arthritis. Methods: The SAV prodrug was administered to K/BxN mice or to C57BL/6 (B6) mice that had been injected with K/BxN serum. Ankle thickness was measured, and histologic changes were scored after a 10-day disease course (serum-transfer arthritis). Protease activity was measured by a near-infrared imaging approach using a cleavable cathepsin–selective probe. Further near-infrared imaging techniques were used to analyze early changes in vascular permeability after serum injection, as well as neutrophil–endothelial cell interactions. Neutrophil functions were assessed using an oxidative burst assay as well as a degranulation assay. Results: SAV prevented ankle swelling in mice with serum-transfer arthritis in a dose-dependent manner. It also markedly reduced the extent of other features of arthritis, such as protease activity and histology scores for inflammation and joint erosion. Moreover, SAV was an effective therapeutic agent. The underlying mechanisms for the antiinflammatory activity were manifold. Endothelial permeability after serum injection was reduced, as was firm neutrophil attachment to endothelial cells. Endothelial cell activation by tumor necrosis factor α was impeded by SAV, as measured by the expression of vascular cell adhesion molecule. Crucial neutrophil functions, such as generation of reactive oxygen species and degranulation of protease-laden vesicles, were decreased by SAV administration. Conclusion: A novel SAV prodrug proved strongly antiinflammatory in a murine model of antibody-induced inflammatory arthritis. Its activity could be attributed, at least in part, to the inhibition of neutrophil and endothelial cell functions., National Institutes of Health (U.S.) (Grant P01-AI-054904), National Institutes of Health (U.S.) (Grant R01-EB-001872), National Institutes of Health (U.S.) (Grant R01-AR-046580), National Institutes of Health (U.S.) (Grant R24-CA-92782), National Institutes of Health (U.S.) (Grant P50-CA-86355)

Purpose Sunitinib (SU) is a multitargeted receptor tyrosine kinase inhibitor of the vascular endothelial growth factor and platelet-derived growth factor receptors. The present study examined SU and radiotherapy (RT) in a genetically engineered mouse model of soft tissue sarcoma (STS). Methods and Materials Primary extremity STSs were generated in genetically engineered mice. The mice were randomized to treatment with SU, RT (10 Gy × 2), or both (SU+RT). Changes in the tumor vasculature before and after treatment were assessed in vivo using fluorescence-mediated tomography. The control and treated tumors were harvested and extensively analyzed. Results The mean fluorescence in the tumors was not decreased by RT but decreased 38–44% in tumors treated with SU or SU+RT. The control tumors grew to a mean of 1378 mm[superscript 3] after 12 days. SU alone or RT alone delayed tumor growth by 56% and 41%, respectively, but maximal growth inhibition (71%) was observed with the combination therapy. SU target effects were confirmed by loss of target receptor phosphorylation and alterations in SU-related gene expression. Cancer cell proliferation was decreased and apoptosis increased in the SU and RT groups, with a synergistic effect on apoptosis observed in the SU+RT group. RT had a minimal effect on the tumor microvessel density and endothelial cell-specific apoptosis, but SU alone or SU+RT decreased the microvessel density by >66% and induced significant endothelial cell apoptosis. Conclusion SU inhibited STS growth by effects on both cancer cells and tumor vasculature. SU also augmented the efficacy of RT, suggesting that this combination strategy could improve local control of STS., National Cancer Institute (U.S.) (Grant U54 CA119349), National Cancer Institute (U.S.) (Grant P30-CA14051)