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The bony venous thoracic outlet creates significant extrinsic force upon the subclavian vein, and intravascular stents in this location thus perform very poorly. There is some literature supporting the use of stents after decompression, but no level I evidence exists. At present the use of stents in venous thoracic outlet syndrome should not be considered until the bony thoracic outlet has been decompressed, and even then should be reserved for isolated cases with thorough followup.

The purpose of this study is to evaluate the results of color-flow duplex ultrasound (CFD) soon after carotid endarterectomy (CEA) to determine the incidence of residual abnormalities and their effect on subsequent outcome and management.We reviewed 318 consecutive CEAs performed over a 48 month-period. Of these, 206 were followed up with CFD, 195 prior to discharge and 11 at first follow-up (within 9 weeks). Patients (43) followed up with only oculoplethysmography (OPG) or those with no OPG or CFD (69) were excluded from the study. All CEAs were performed under general anesthesia with routine shunting and patch angioplasty.Twelve of the 206 studies (5.8%) were abnormal. Two patients with an abnormal CFD sustained perioperative stroke, both of whom had distal intimal lesions of60% diameter stenosis by velocity criteria. Four patients had60% stenosis and were reoperated upon to correct technical errors. The remaining 6 patients are asymptomatic. Four had residual lesions of60% stenosis, three of which have returned to normal on subsequent CFD. Two residual lesions had60% stenosis; one returned to normal by CFD and the other remains abnormal at 10 months. In the group of 192 normal postoperative CFD studies, there were no strokes, deaths, or redo procedures (0%, 95% confidence interval 0% to 1.54%) compared with a combined 50% rate (6 of 12) of either stroke (2 of 12) or redo procedure (4 of 12) when the postoperative CFD was abnormal (95% confidence interval 22.3% to 77.7%, P0.0001). During the study period the CEA stroke rate was 0.9% (3 of 318), with a combined stroke-mortality rate of 1.3% (4 of 318).Early postoperative CFD identified residual abnormalities in 5.8% of carotid endarterectomies despite a low overall stroke mortality rate. One half of these abnormalities resulted in stroke or required operative correction. Colorflow duplex ultrasound is useful in identifying residual abnormalities following CEA and should be considered for intraoperative use.

The in situ bypass procedure for lower extremity limb salvage requires a long continuous incision or multiple interrupted incisions over the greater saphenous vein to ligate the saphenous vein side branches. This can result in wound complications that frequently prolong hospital stay and threaten the graft. In an effort to reduce the incidence of wound complications, alternate methods of occluding the vein side branches have been used. One method is to deliver coils under angioscopic vision into the saphenous vein side branches. This report details a simplified technique that uses widely available catheter-based equipment to perform saphenous vein side branch occlusion under fluoroscopic guidance.

The use of endovascular techniques to treat traumatic vascular injuries was first reported by Marin et al in 1993. In this report, seven vascular injuries to the superficial femoral artery or subclavian arteries were treated using transluminally placed covered stents. These grafts were successfully inserted percutaneously or through open arteriotomies that were remote from the site of vascular trauma. Endovascular treatment of these traumatic injuries resulted in decreased blood loss, reduced requirements for anesthesia, and limited need for extensive dissection in the traumatized field.

Objective The risk of postdischarge venous thromboembolism (VTE) (either deep vein or pulmonary embolism) is increasingly recognized yet the prescription of postdischarge thromboprophylaxis is inconsistent. There is a paucity of information to aid clinicians in identifying surgical patients who are at increased risk for postdischarge VTE. This study aimed to determine the incidence and risk factors associated with symptomatic postdischarge VTE and develop a risk score to identify patients who may benefit from extended duration thromboprophylaxis. Methods This was a retrospective study. All nonorthopedic cases in which the patient was discharged alive without inpatient VTE were selected from the 2005-2009 National Surgical Quality Improvement Program database. A multivariate logistic regression was used to create a risk score for postdischarge VTE prediction. The dataset was split into two-thirds for risk score development and validated in the remaining one-third. Results The overall incidence of early postdischarge VTE for 2005-2009 National Surgical Quality Improvement Program was 0.3%. The risk score stratified patients into low, moderate, and high risk for postdischarge VTE with the incidence based on the risk score ranging from 0.07% to 2.2%. The risk score had good predictive ability with c-statistic = 0.72 for model development and c-statistic = 0.71 in the validation dataset. Factors associated with postdischarge VTE on multivariate analysis included race, increasing age, steroid use, body mass index ≥30, malignancy, higher American Society of Anesthesiologists class, increasing operative time, length of postsurgical stay, and major postoperative complication. Conclusions This novel postdischarge VTE prediction score utilizes patient, operative, and early outcome factors to accurately identify patients at increased risk of a postdischarge thromboembolic event. The development of a patient- specific postdischarge VTE risk profile may help address the challenge of determining postdischarge prophylaxis requirements.

Objectives: Iliofemoral venous outflow stenting has been used to treat both acute and chronic venous thrombosis. It may be beneficial to understand the properties of the normal venous wall and the flow through collapsible tubes to develop new stent technology and improve long-term patency. We hypothesize that radial and circumferential strain can be modeled and measured using intravascular ultrasound (IVUS) techniques to describe venous geometry and asymmetric vessel wall characteristics. Methods: A hydrogel phantom was used to mimic the mechanical properties of a homogeneous vein, including geometry and wall compliance. Radio-frequency (RF) echo frames were acquired using a modified IVUS system with an 8.5 Mhz catheter. All RF signals were digitized to 14 bits at 50 MHz. Radial strain was estimated by applying an intensity matching, image registration based algorithm to the digitized frames. Results: The radial strain images (Figure 1) show increasing positive strain (radial wall thickening) on the top and bottom of the phantom with decreasing negative values (radial wall thinning) at either side. Results suggest an asymmetric compression pattern typical of a vessel collapsing under negative pressure. Conclusions: In conclusion, our data suggest that novel strain analysis can be performed on a phantom vessel consistent with the mechanical properties of the venous system. Further work with venous elastography will help define the mechanical properties of the venous wall and facilitate the development of new stent technology to treat venous disease.

Objective: Little is known about the molecular biology of endothelial cells from different venous vascular beds. As a result, our treatment of deep vein thrombosis (DVT) and pulmonary artery embolism (PE) remain identical. PAI-1 and tPA are important regulators of thrombosis and fibrinolysis, while ICAM-1 is known to bind fibrinogen. Here, we aim to investigate differences in fibrinolytic reactivity between human iliac vein endothelial cells (HIVECs) and human pulmonary artery endothelial cells (HPAECs). Methods: Confluent HIVECs and HPAECs, passages 3 - 6, were cultured in the absence or presence of TNFα (10 ng/mL) for 24 hours. Cellular expression of tPA and PAI-1 as analyzed by Western blot analysis and ICAM-1 as analyzed by flow cytometry were compared to controls. Results: Following TNFα stimulation, PAI-1 was upregulated in both HPAECs and HIVECs, however the upregulation observed in HPAECs was approximately 9-fold the increase observed in HIVECs (relative expression: 3.23 ± 0.52 vs 1.26 ± 0.27, n = 3, p < 0.05). While TNFα had no effect on tPA expression in HIVECs, tPA expression in HPAECS was upregulated by 33% (n = 3, p < 0.05). Although TNFα stimulation increased the number of ICAM-1 positive to approximately 100% in both cell types, a 3-fold greater increase in the Mean Fluorescence Intensity (MFI) was observed in HIVECs when compared to HPAECs (relative MFI: 69.28 ± 13.58 vs 21.92 ± 7.22, n = 3, p Conclusions: HPAECs and HIVECs react differently in terms of fibrinolytic potential when challenged with a cytokine associated with systemic inflammation, such as in DVT and PE. These findings suggest that endothelial cells from distinct venous vascular beds may differentially regulate the fibrinolytic pathway, thus demonstrating unique properties of the deep veins and the pulmonary artery to respond to thromboembolism.

Objective: Atherosclerotic plaque instability has been linked to cardiovascular events. We hypothesized that novel serum and intraplaque markers of plaque instability could be identified through analysis of serum and atherosclerotic plaques obtained from symptomatic and asymptomatic patients undergoing carotid endarterectomy (CEA). Methods: Under an IRB approved protocol, 6 symptomatic patients (5 transient ischemic attack, 1 amaurosis fugax) and their age- and gender-matched controls were analyzed for intraplaque markers of plaque instability. 8 symptomatic patients and their age- and gender-matched controls were analyzed for serum activity of proteolytic enzymes MMP-2 and MMP-9. Plaques were removed intraoperatively, placed in RNAlater and processed immediately after CEA. Blood samples were drawn prior to incision to determine serum activity of MMP-2 and MMP-9 using gelatin zymography. Intraplaque expression of MMP-2, MMP-9, proteolytic enzymes (uPA, tPA and PAI-1) and inflammatory markers (TF, TSP-1, and TNF-α) were evaluated by Western blot analysis. Results: The activity of proteolytic enzymes MMP-2 and MMP-9 detected in serum was significantly higher in symptomatic patients when compared to asymptomatic controls, with a 1.5- and 2.2-fold increase, respectively (P Conclusion: Levels of matrix metalloproteinases, proteolytic enzymes and inflammatory markers found in serum and plaque samples of symptomatic and asymptomatic patients may be different. Testing for biomarkers may help diagnose atherosclerotic plaque instability and identify patients at high risk for cerebrovascular events.

Objectives: The molecular mechanisms leading to the development of Adnominal Aortic Aneurysms (AAA) remain poorly understood. Vascular Smooth Muscle Cells (VSMCs) are fundamental to maintaining a healthy arterial wall and changes in VSMC phenotype may be pivotal to aneurysm development. We have recently determined a role for a Hedgehog (Hh)/Notch signaling cascade in regulating adult VSMC phenotype. The aim of this study was to investigate Hh/Notch signaling components in aneurysmal and non-aneurysmal aorta. As crosstalk between Notch and Transforming Growth Factor Beta (TGFβ) has been postulated we also investigated expression of this growth factor. Methods: Tissue samples were obtained from aneurysmal and non-aneurysmal segments of the aortic wall of at least 5 patients with suitable anatomy undergoing open repair of infrarenal AAA. All samples analyzed were paired from the same patient with aneurysmal and non-aneurysmal specimens. Protein and mRNA expression levels were determined by western blot analysis and quantitative Real-time PCR respectively. Results: SHh, Notch 1 and 3 IC protein expression was decreased by at least 50% in aneurysmal tissue when compared to non-aneurysmal tissue. In addition, SHh mRNA expression was also decreased by 65%, while there was a decrease in Dll4, Notch 1 and Notch 3 by 66%, 57% and 54% respectively. In contrast, aneurysmal tissue had significantly increased expression of TGFβ and MMP9. TGFB protein and mRNA expression was significantly increased by 5.45±2.13 and 2.5±.2 fold respectively in aneurysmal tissue when compared to non-aneurysmal tissue. Furthermore, MMP9 mRNA expression was significantly increased by 4.7±1.6 fold. In parallel experiments, SMC alpha actin protein expression was significantly decreased by 90% in aneurysmal tissue when compared to non-aneurysmal tissue. Conclusion: These results suggest that SHH/Notch and TGFβ signaling is altered in aneurysmal tissue, compared with non-aneurysmal tissue. Changes in these signaling pathways and resulting changes in VSMC phenotype may play a role in the development of AAA.

BackgroundThe anticoagulant treatment of acute deep venous thrombosis (DVT) has been historically directed toward the prevention of recurrent venous thromboembolism. However, such treatment imperfectly protects against late manifestations of the postthrombotic syndrome. By restoring venous patency and preserving valvular function, early thrombus removal strategies can potentially decrease postthrombotic morbidity.ObjectiveA committee of experts in venous disease was charged by the Society for Vascular Surgery and the American Venous Forum to develop evidence-based practice guidelines for early thrombus removal strategies, including catheter-directed pharmacologic thrombolysis, pharmacomechanical thrombolysis, and surgical thrombectomy.MethodsEvidence-based recommendations are based on a systematic review and meta-analysis of the relevant literature, supplemented when necessary by less rigorous data. Recommendations are made according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, incorporating the strength of the recommendation (strong: 1; weak: 2) and an evaluation of the level of the evidence (A to C).ResultsOn the basis of the best evidence currently available, we recommend against routine use of the term “proximal venous thrombosis” in favor of more precise characterization of thrombi as involving the iliofemoral or femoropopliteal venous segments (Grade 1A). We further suggest the use of early thrombus removal strategies in ambulatory patients with good functional capacity and a first episode of iliofemoral DVT of

Purpose: Air plethysmography (APG) is an established, noninvasive means of evaluating lower extremity venous outflow. Methods: To determine whether APG could identify deep venous thrombosis (DVT) of the upper extremity, we measured the percentage of venous outflow in the first second (maximum venous outflow [MVO]) of four groups of arms: (1) normal volunteers (no previous central vein catheters), (2) the affected, (3) the unaffected arms of the patients with DVT (proven by venography or duplex scanning), and (4) hospital patients (no previous central vein catheters). Results: The results of an analysis of variance were as follows: the mean MVO (%) of the affected arms of patients with DVT, 29.4 ± 2.6, was significantly less than their unaffected arms, 55.3 ± 3.9, hospital controls, 64.3 ± 2.2, and normal volunteers, 64.2 ± 0.9 ( p p Conclusions: We conclude that APG clearly discriminated arms with documented DVT from controls and is a highly accurate means of identifying upper extremity DVT. (J VASC SURG 1993;18:808-13.)

Over a 14-month period at Boston City Hospital, 93 consecutive patients who had received a blunt or penetrating extremity injury in proximity to a major vascular structure were evaluated. All patients were totally asymptomatic and underwent arteriography for proximity as a sole indication. Twenty-seven patients (27%) were found to have abnormal arteriograms. Muscular branches of the profunda femoris artery were the most frequently injured arteries (28%). Arterial spasm (41%) was the most common radiographic finding. All patients were managed nonoperatively and followed closely by serial pulse examinations. Follow-up arteriography or duplex scanning was used in isolated cases. No patients in this study required operative intervention based on arteriographic findings. No patients have subsequently required operative intervention for delayed arterial abnormalities. Based on these findings we believe the use of arteriography for asymptomatic injuries in proximity to major vascular structures is unwarranted.

Methylation of DNA is responsible for gene silencing by establishing heterochromatin structure that represses transcription, and studies have shown that cytosine methylation of CpG islands in promoter regions acts as a precursor to early cancer development. The naturally occurring methyl binding domain (MBD) proteins from mammals are known to bind to the methylated CpG dinucleotide (mCpG), and subsequently recruit other chromatin-modifying proteins to suppress transcription. Conventional methods of detection for methylated DNA involve bisulfite treatment or immunoprecipitation prior to performing an assay. We focus on proof-of-concept studies for a direct microarray-based assay using surface-bound methylated probes. The recombinant protein 1xMBD-GFP recognizes hemi-methylation and symmetric methylation of the CpG sequence of hybridized dsDNA, while displaying greater affinity for the symmetric methylation motif, as evaluated by SPR. From these studies, for symmetric mCpG, the KD for 1xMBD-GFP ranged from 106 nM to 870 nM, depending upon the proximity of the methylation site to the sensor surface. The KD values for non-symmetrical methylation motifs were consistently greater (> 2 µM), but the binding selectivity between symmetric and hemi-methylation motifs ranged from 4 to 30, with reduced selectivity for sites close to the surface or multiple sites in proximity, which we attribute to steric effects. Fitting skew normal probability density functions to our data, we estimate an accuracy of 97.5% for our method in identifying methylated CpG loci, which can be improved through optimization of probe design and surface density.

The development of an objective, noninvasive method to assess the hemodynamic effects of venous surgery has long been awaited. Previous methods used to evaluate the results of surgery for varicose veins and venous stasis ulceration have been limited in their quantitative assessment. Now, by use of air plethysmography (APG), we can accurately quantify the effectiveness of corrective venous surgery. Twenty-five extremities that had evidence of venous insufficiency were examined with use of APG before and after venous surgical procedures. Surgery was directed at specific sites of venous incompetence as defined by physical examination and high-resolution duplex imaging. Twenty-one extremities underwent ligation and stripping of the greater saphenous vein. In these patients, APG showed an improvement in venous reflux as demonstrated by a decrease in the venous filling index from 6.6 ± 0.7 ml/sec to 1.8 ± 0.3 ml/sec ( p = 0.0001) and venous volume from 177.1 ± 14.5 ml to 139.2 ± 8.9 ml ( p = 0.0008). In addition, these patients showed a mild improvement in calf muscle pump function as noted by an improvement in ejection fraction from 45.8% ± 2.0% to 50.8% ± 2.5% ( p = 0.07). The residual volume fraction decreased from 45.0% ± 3.4% to 42.0% ± 3.7%, a difference that was not statistically significant ( p = 0.4). Four extremities with grade III chronic venous insufficiency underwent popliteal vein valve transplantation with use of an autogenous axillary vein valve. Venous reflux in these patients was reduced dramatically in the early postoperative period, with the venous filling index dropping from 14.2 ± 2.3 ml/sec before the operation to 5.1 ± 1.4 ml/sec after the operation ( p = 0.08) in conjunction with a drop in venous volume from 190.9 ± 35.4 ml to 135.2 ± 10.7 ml ( p = 0.15). APG offers a unique and quantitative technique to evaluate the results of reconstructive venous surgery. It is simple and noninvasive, and we believe it represents an improvement on older methods for evaluating the effect of surgery on the venous hemodynamics of the leg. (J Vasc Surg 1992;16:674–8.)

Arteriography for proximity of injury was studied prospectively at a trauma center. Findings in 85 patients with penetrating extremity wounds were analyzed to determine the prevalence and types of vascular abnormalities seen with these injuries. Ninety-two limb segments were studied for 77 gunshot and 15 stab wounds. Arteriographic findings were positive in 24% overall but in only 5% for injuries confined to major vessels. A 60% positive rate was seen in a small subgroup of 10 patients with fractures due to gunshot wounds. The most frequently injured vessels were muscular branches of the deep femoral artery (59%); the most common injury was focal, non-occlusive spasm (42%). All patients were treated conservatively, without sequelae at follow-up. In this study, the vascular injuries found at arteriography for proximity of injury in penetrating trauma due to bullets of knives, particularly in the thigh, did not require surgical or radiologic intervention.

ObjectiveTo evaluate the cost-effectiveness of endovascular repair (EVAR) for small abdominal aortic aneurysms (AAA).MethodsWe developed a Markov model of a hypothetical 68-year-old cohort to determine the cost-effectiveness of early EVAR for “small” AAAs (4.0 cm-5.4 cm) compared with elective repair (open or endovascular) at the traditional cut-off of 5.5 cm. Repair options for 5.5-cm AAAs include both endovascular and open procedures. Probabilities were obtained from the literature. Costs reflected direct costs in 2007 dollars. Outcomes were reported as quality-adjusted life-years (QALYs).ResultsThe model demonstrated that early EVAR for 4.0 cm-5.4 cm AAAs led to fewer QALYs at greater costs when compared with observational management with elective repair at 5.5 cm. Sensitivity analyses suggested that early EVAR of 4.6 cm-4.9 cm AAAs can be cost-effective if the long-term mortality rate after EVAR is ≤1.91% per year or if the quality of life after EVAR is improved. Likewise, if the quality of life before repair is low, EVAR for AAAs ≥4.6 cm may be cost-effective. With a >70% probability, observational management until AAA diameter is 5.5 cm will be the cost-effective option.ConclusionsThis analysis demonstrated that early EVAR for AAAs

Higher-grade gliomas are distinguished by increased vascular endothelial cell proliferation and peritumoral edema. These are thought to be instigated by vascular endothelial growth factor, which in turn is regulated by cellular oxygen tension. Hypoxia inducible factor-1alpha (HIF-1alpha) is a main responder to intracellular hypoxia and is overexpressed in many human cancers, including gliomas. Here we present methods for investigating the role of HIF-1alpha in glioma growth in vivo and in vitro using RNA interference in U251, U87, and U373 glioma cells.

Traumatic pseudoaneurysms of the popliteal artery are an uncommon late complication of arterial injury. Although reviewed extensively in wartime, they occur less frequently in civilian trauma and have accordingly been less frequently studied. A case report of a traumatic popliteal artery pseudoaneurysm and review of the literature are presented.

Introduction Early recurrent carotid artery stenosis, defined as stenosis occurring within 2 years of carotid endarterectomy, occurs in 4% to 36% of patients. Management of asymptomatic early recurrent stenosis is controversial because of different outcomes in multiple natural history studies. Optimal follow-up post–carotid endarterectomy has not been defined. The purpose of this study was to determine the natural history of early recurrent stenosis and to define the optimal duplex surveillance strategy during follow-up. Methods Patients who underwent carotid endarterectomy between January 1995 and June 1998 at a single tertiary-care institution were reviewed retrospectively. Data were collected regarding degree of stenosis, closure technique, neurologic morbidity, mortality, and the intervals between postoperative duplex studies. These results were compared with accepted rates in the literature. Life-table analysis was done on restenosis-free survival. Discrete variables were tested for significance by chi-square analysis and Fisher’s exact test. A p value less than or equal to 0.05 was considered significant. Results Two hundred thirty-one carotid endarterectomies in 226 patients were evaluated. A total of 57 (24.6%) of 231 carotid endarterectomies had recurrent stenosis. These 57 sites were in 56 patients. Fifty-four (23.4%) of 231 sites had a stenosis of 16% to 59%. All of these lesions were asymptomatic and found within 1 year of carotid endarterectomy on duplex imaging. The 3 (1.3%) remaining sites had a restenosis of greater than 60%. Early recurrent stenosis occurred more frequently in women (women 28/80 [35%] vs. men 28/146 [19.2%]). High-grade stenosis occurred more often with primary (1/5 [20%]) than with patch (2/226 [0.8%]) closure and in patients less than 65 years of age.

Higher-grade gliomas are distinguished by increased vascular endothelial cell proliferation and peritumoral edema. These are thought to be instigated by vascular endothelial growth factor, which in turn is regulated by cellular oxygen tension. Hypoxia inducible factor-1alpha (HIF-1alpha) is a main responder to intracellular hypoxia and is overexpressed in many human cancers, including gliomas. Here we present methods for investigating the role of HIF-1alpha in glioma growth in vivo and in vitro using RNA interference in U251, U87, and U373 glioma cells.

BACKGROUND. Regions of hypoxia within glioblastoma multiforme (GBM) are common and may influence a tumor's aggressiveness, response to treatment, and the patient's overall survival. In this study, the authors examined 4 markers of hypoxia (hypoxia-inducible factor 1 [HIF-1α], glucose transporter 1 [GLUT-1], vascular endothelial growth factor [VEGF], and carbonic anhydrase 9 [CA IX]), cellular proliferation and microvascular density (MVD) indices, extent of surgical resection, and preoperative imaging characteristics and compared them with the overall survival rates of adults with GBM. METHODS. In this retrospective cohort study, patients who had lower grade astrocytomas were compared with patients who had GBM to verify that the methods used could establish differences between tumor grades. By using preoperative imaging, the amount of necrosis was established versus the overall tumor area. The authors also compared preoperative images with postoperative images to define the amount of tumor resected; and they compared molecular markers, proliferation, MVD, and imaging studies with survival among patients who had GBM. RESULTS. The hypoxia-regulated molecules (HRMs) and indices for MVD and cellular proliferation were associated significantly with tumor grade. Survival was improved when ≥95% of the tumor was resected. Although the total tumor area was associated with overall survival, no differences were observed when the amount of necrosis or a tumor necrosis index (area of necrosis/area of tumor) was compared with survival. The findings indicated that GLUT-1 and VEGF were correlated with survival after controlling for age. CONCLUSIONS. Tumor grade was differentiated with HRMs, MVD, and proliferation, but only GLUT-1 predicted survival in this group of patients with GBM. The results suggested that GLUT-1 may be an important independent prognostic indicator. Cancer 2008. © 2008 American Cancer Society.

Background: Hemorrhage from extremity wounds is a leading cause of potentially preventable death during modem combat operations. Optimal management involves rapid hemostasis and reversal of metabolic derangements utilizing damage control principles. The traditional practice of damage control surgery favors a life over limb approach and discourages elaborate, prolonged vascular reconstructions. We hypothesized that limb preservation could be successful when the damage control approach combines advanced resuscitative strategies and modern vascular techniques. Methods: Trauma Registry records at a Combat Support Hospital from April to June 2006 were retrospectively reviewed. Patients with life-threatening hemorrhage (defined as >4 units of packed red blood cells) who underwent simultaneous revascularization for a pulseless extremity were included. Data collection included the initial physiologic parameters in the emergency department (ED), total and 24-hour blood product requirements, and admission physiology and laboratory values in the intensive care unit (ICU). Outcome measures were survival, graft patency, and amputation rate at 7 days. Results: Sixteen patients underwent 20 vascular reconstructions for upper (3) or lower extremity (17) wounds. Patients were hypotensive (blood pressure 105/ 60 ± 29/18), acidotic (pH 7.27 ± 0.1; BD -7.50 ± 5.5), and coagulopathic (international normalized ratio 1.3 ± 0.4) on arrival to the ED and essentially normal upon admission to the ICU, 4 hours later. Vein grafts (19/20, 95%) were used preferentially. Prosthetic grafts (1), shunting and delayed repair (4) or amputation (1) were infrequent. Heparin was not used or limited to a half dose (5/20, 25%). Tourniquets (12/16, 75%) and fasciotomies (13/16, 81%) were routine. Most (75%) received recombinant factor VIIa in the ED and in the operating room. All survived with normalized physiology on arrival in the ICU. Twenty-four-hour crystalloid use averaged 7.1 ± 3.2 L, whereas packed red blood cells averaged 23 ± 18 units, and 88% were massively transfused. Median operative time was 45 hours (range, 1.7-8.4 hours). Conclusions: Aggressive damage control resuscitation maneuvers in critically injured casualties successfully permitted prolonged, complex extremity revascularization with excellent early limb salvage and graft patency. Recombinant VIIa and liberal resuscitation with fresh whole blood, plasma, platelets and cryoprecipitate, while minimizing crystalloid, allowed limb salvage and did not result in early graft failures.

Objectives: Major vascular injury is a leading cause of potentially preventable hemorrhagic death in modern combat operations. An optimal resuscitation approach for military trauma should offer both rapid hemorrhage control and early reversal of metabolic derangements. The objective of this report is to establish the use and effectiveness of a damage control resuscitation (DCR) strategy in the setting of wartime vascular injury. Methods: A retrospective two-cohort case control study was performed using the Joint Theater Trauma Registry to identify patients with an extremity vascular injury treated at two different points in time: group 1 (n = 16) from April to June 2006 when DCR concepts were put into practice and group 2 (n = 24) 1 year later in a period when DCR strategies were not employed. Results: Baseline demographics, injury severity, admission physiology, and operative details were similar between groups 1 and 2. Group 1 patients received more total blood products (23 vs. 12 units, p < 0.05), fresh frozen plasma (16 vs. 7 units,p < 0.01), cryoprecipitate (11 vs. 1.2 units, p < 0.05), whole blood (19% vs. 0%, p = 0.06), and early recombinant factor VIIa (75% vs. 0%,p < 0.001) than group 2 patients. Group 1 patients had a more complete early physiologic recovery after vascular reconstruction (heart rate: 38 vs. 12, p < 0.001; systolic blood pressure, 39 vs. 14, p < 0.001; base deficit: 7.36 vs. 2.72, p < 0.001; International Normalized Ratio, 0.3 vs. 0.1,p < 0.001). There was no significant difference in early amputation rates (group 1: 6.2% vs. group 2: 4.2%) or 7-day mortality (0% in both groups). Conclusions: This study was the first to use the Joint Theater Trauma Registry for follow-up on an established clinical practice guideline. DCR goals appear now to be met during the management of acute wartime vascular injuries with effective correction of physiologic shock. The overall impact of this resuscitation strategy on long-term outcomes such as limb salvage and mortality remains to be determined.

Background Trauma to the head and neck with military munitions often presents with complex multisystem injury patterns. Vascular evaluation typically focuses on the carotid and vertebral arteries; however, trauma to branches of the external carotid artery may also result in devastating complications. Pseudoaneurysms are the most frequent finding on delayed evaluation and can result in life-threatening episodes of rebleeding. Methods Patients evacuated from the Afghanistan and Iraq conflicts with penetrating injury to the face and neck were evaluated by the vascular surgery service to determine the potential for unsuspected vascular injury. Patients with significant penetrating injury underwent computed tomography angiography (CTA) as the initial evaluation and subsequent arteriography in cases where injuries were suspected or metallic fragments produced artifacts obscuring the vasculature. Data on all vascular evaluations were entered prospectively into a database and retrospectively reviewed. Results Between February 2003 and March 2007, 124 patients were evaluated for significant penetrating trauma to the head and neck. Thirteen pseudoaneurysms of the head and neck were found in 11 patients: two in the internal carotid artery, one of the vertebral artery, and 10 involving branches of the external carotid. Seven pseudoaneurysms were symptomatic, of which two presented with episodes of massive bleeding and airway compromise. Seven pseudoaneurysms were treated with coil embolization, 1 with Gelfoam (Upjohn, Kalamazoo, Mich) embolization, 2 with stent grafts, 2 with open repair, and 1 with observation alone. None of the patients undergoing embolization had complications; however, a stent graft of the internal carotid artery occluded early, without stroke. All of the pseudoaneurysms had resolved on follow-up CTA or angiogram. Conclusions Pseudoaneurysms are a common finding in patients with high-velocity gunshot wounds or blast injuries to the head and neck. Most involve branches of the external carotid artery and can be treated by embolization. CTA should be performed on all patients with high-velocity gunshot wounds or in cases of blast trauma with fragmentation injuries of the head and neck.

BACKGROUND. Treatments for recurrent meningiomas are limited. We previously demonstrated universal expression of COX-2 in meningiomas and dose-dependent growth inhibition in vitro with celecoxib, a COX-2 inhibitor. We therefore tested the effects of celecoxib on meningioma growth in a mouse xenograft model. METHODS. Meningioma cell lines (IOMM-Lee, CH157-MN, WHO grade I primary cultured tumor) were transplanted into flanks of nude mice fed mouse chow with celecoxib at varying concentrations (0, 500, 1000, 1500 ppm) ad libitum. Tumors were measured biweekly and processed for MIB-1, Factor VIII, COX-2, and VEGF, and assayed with transferase-mediated dUTP-biotin nick-end labeling (TUNEL). RESULTS. Celecoxib reduced growth of mean tumor volume by 66% (P .05), and 65% (P < .05) compared with untreated controls in IOMM-Lee, CH157-MN, and benign tumors, respectively. IOMM-Lee tumors removed from celecoxib treatment regained a growth rate similar to the control. Blood vessel density decreased and apoptotic cells increased in treated flank tumors. Diminished COX-2 expression and VEGF were observed in treated IOMM-Lee tumors. Mean plasma celecoxib levels were 845, 1540, and 2869 ng/mL, for low-, medium-, and high-dose celecoxib, respectively. CONCLUSIONS. Celecoxib inhibits meningioma growth in vivo at plasma levels achievable in humans. Celecoxib-treated tumors were less vascular with increased apoptosis. IOMM-Lee tumors treated with celecoxib showed decreased COX-2 and VEGF expression. COX-2 inhibitors may have a role in the treatment of recurrent meningiomas. Cancer 2007;109:588–597. © 2006 American Cancer Society.

Overcoming the metabolic restrictions of hypoxia may allow the progression of lower-grade tumors to glioblastoma multiforme. Our findings of up-regulation of HIF-1alpha and its downstream targets VEGF, GLUT-1, and CAIX in higher-grade gliomas support this hypothesis. We compared the gene expression profiles of the U-251 malignant glioma cell line under normoxic and hypoxic conditions to discover future research targets. U-251 cells were grown to 75% confluence and exposed to either normoxic or hypoxic conditions for 24 h. RNA was extracted, amplified, and hybridized to a cDNA microarray chip containing ~8,800 universal cellular genes. A threefold increase in mRNA expression was used as a threshold value for differential expression. Identified genes were divided into cell cycle control, stress response, and "newly connected" genes. Hybridization identified 11 hypoxia-induced genes: 1 involved with cell cycle control (CCNG2), 6 in stress response (IGFBP3, SLC2A3, GSTT2, FOS, DDIT3, AKR1C3), and 2 newly connected genes (Depp, AKAP4). One stress-related gene (AKR1C3) encodes for an enzyme that synthesizes progesterone. Of newly connected genes, the gene decidual protein induced by progesterone (Depp) showed the highest expression (4.2-fold increase). Possible future targeting for "hypoxic" glioma cells includes the targets for the AP-1 transcription factor complex (FOS), as well as blockade of the enzyme AKR1C3 with nonsteroidal anti-inflammatory drugs. Possible functions of the highly expressed gene Depp include tumor vascularization. Future studies will focus on the hypothesis that Depp is up-regulated in an autocrine fashion by the AKR1C3 enzyme in U-251 glioma cells under hypoxic conditions.

Background: The optimal material for carotid patch angioplasty after endarterectomy remains uncertain. This study compares the early outcome and recurrent stenosis rates between saphenous vein (SV) and expanded polytetrafluoroethylene (ePTFE) carotid patch angioplasty. Methods: The results of 421 consecutive carotid endarterectomies performed over a 72-month period were reviewed. Postoperative complications and restenosis rates, defined as ≥ 60% narrowing measured by color flow duplex, were compared. Results: Patch angioplasty was performed with SV in 287 and with ePTFE in 110 cases. Patients who had undergone primary closure (n = 20) or whose form of closure was unknown (n = 4) were excluded. The mean age of patients and length of follow-up was similar between groups. Women were more likely to be patched with ePTFE than were men (36% versus 23%, P = 0.02). One death occurred in each group (0.3% SV, 0.9% ePTFE, P = 0.47), and four strokes occurred in each group (1.4% SV, 3.6% ePTFE, P = 0.22). Cervical hematomas requiring operative evacuation occurred in five SV closures and in three ePTFE closures (1.7% versus 2.7%, P = 0.69). Vein harvest site complications occurred in 6 patients (2%) who had undergone SV patch angioplasty. Recurrent stenosis occurred in 3 patients with SV closure and in 3 patients with ePTFE closure (1.0% versus 2.7%, P = 0.35). The 60-month restenosis rates by life table analysis were 2.6% ± 2.1% for SV and 10.7% ± 7.9% for ePTFE (P = 0.17). Conclusions : The incidence of postoperative complications is similar with SV or ePTFE patch angioplasty; however, vein harvest site complications are avoided with the use of ePTFE. Recurrent stenosis at 5 years occurs infrequently with either SV or ePTFE.

Hypoxia inducible factor-1alpha (HIF-1alpha) regulates vascular endothelial growth factor (VEGF), the presumed principal mediator of angiogenesis in malignant gliomas, under normal physiologic conditions. We examined the effect of HIF-1alpha on VEGF secretion, tumor growth, and angiogenesis in malignant gliomas.We examined 175 human gliomas for expression of HIF-1alpha and its downstream-regulated proteins. HIF-1alpha expression and VEGF secretion in glioma cell lines under normoxia and hypoxia were examined using ELISA and Western blot. Malignant glioma cell lines were transfected with dominant-negative HIF-1alpha (DN-HIF-1alpha) expression vector or siRNA constructs against the HIF-1alpha gene. Growth studies were conducted on cells with the highest VEGF/HIF-1alpha inhibition isolated from stable transfected cell lines. MIB-1-labeling index and microvascular density (MVD) measurements were performed on the in vivo tumors.HIF-1 expression correlates with malignant glioma phenotype and was not confined to perinecrotic, pseudopalisading cells. VEGF and HIF-1 expression was high in glioma cell lines even under normoxia, and increased after exposure to hypoxia or growth factor stimulation. Cells transfected with DN-HIF-1alpha or HIF-1alpha siRNA demonstrated decreased HIF-1alpha and VEGF secretion. In vivo but not in vitro growth decreased in response to VEGF and HIF-1 inhibition. HIF-1 siRNA studies showed decreased VEGF secretion and in vitro and in vivo growth of glioma cell lines. MVD was unchanged but MIB-1 proliferation index decreased for both types of HIF-1 inhibition.VEGF and HIF-1alpha are elevated in malignant gliomas. HIF-1alpha inhibition results in VEGF secretion inhibition. HIF-1alpha expression affects glioma tumor growth, suggesting clinical applications for malignant glioma treatment.

Object. Meningiomas are the second most common symptomatic primary central nervous system tumor in adults. Findings of epidemiological studies link meningiomas with a history of head trauma, indicating a causal relationship between the inflammatory response and meningioma tumorigenesis. Cyclooxygenase-2 (COX-2), an inducible inflammatory enzyme, converts arachidonic acid to prostaglandins, which have angiogenic, cell-proliferative, and antiapoptotic effects. The authors investigated COX-2 expression in meningiomas and the effects of celecoxib, a COX-2 inhibitor, on meningioma cell growth in vitro. Methods. Four meningioma surgical specimens were immunohistochemically stained and graded (0 to 4) for COX-2. In addition, a Western blot analysis was performed to detect the presence of COX-2. Human meningioma cells grown in cell culture were treated with vehicle or celecoxib (0.25‐1 mM). An immunohistochemical analysis of COX-2, a methylthiotetrazole cell proliferation assay, a TUNEL apoptosis assay, and a Western blot analysis for the proapoptotic protein BAX were performed in vitro. One hundred eleven (87%) of 128 benign meningiomas and six (86%) of seven atypical meningiomas displayed a high COX-2 immunoreactivity (Grade 4 staining). In the Western blot analysis all four surgical specimens (100%) stained positive for a 70-kD band consistent with COX-2. Celecoxib inhibited cell growth in a dose-dependent fashion and induced apoptosis by Day 2, with no change noted in the expression of the BAX protein. Conclusions. The COX-2 enzyme is universally expressed in meningiomas. Celecoxib inhibits meningioma growth in vitro in a dose-dependent fashion, with evidence of apoptosis. Inhibitors of COX-2 may have a role in the treatment of recurrent meningiomas.

Military operations may represent a high-risk environment for venous thromboembolism (VTE). We sought to identify and describe cases of venous thromboembolism among US military personnel serving in Southwest Asia, and estimate relative disease rates compared to non-deployed personnel.Retrospective review of imaging archives, hospital discharge codes, case logs and autopsy records for the diagnosis of deep vein thrombosis or pulmonary embolism occurring from 1 March 2003 through 29 February 2004 among U.S. military personnel deployed to Southwest Asia. Rates of disease in deployed and non-deployed active-duty soldiers were estimated using personnel data and deployment experience obtained from automated rosters.Forty cases of venous thromboembolism were identified. The case-fatality rate was 16% (3/19) among those with pulmonary embolism. Antecedent trauma followed by prolonged air evacuation was present in 55% (22/40). Compared to trauma-associated cases, non-trauma cases were more commonly over 40 years old (44% vs. 5%; p0.05), assigned to a transportation or quartermaster company (56% vs. 14%; p0.05), or had a history of remote venous thromboembolism (31% vs. 0%; p0.05). The overall incidence among deployed active-duty soldiers was 22.1/100,000 person-years. Compared to non-deployed active-duty soldiers, the age-adjusted incidence rate ratio was 1.06 (CI(0.95) 0.68-1.67).VTE rates among deployed soldiers are relatively low compared to the general population, and are comparable to non-deployed soldiers. Fatalities from PE are not uncommon, and vigilance among clinicians remains warranted. Trauma followed by prolonged air evacuation or ground transport during military operations may represent unique interactive risk factors for venous thromboembolism.

Object. Endolymphatic sac (ELS) tumors are low-grade malignancies of the temporal bone that are associated with von Hippel—Lindau (VHL) disease but can also occur sporadically. The VHL gene product VHL protein is important in the regulation of hypoxia inducible factor (HIF)-1α, which controls expression of molecules that are important in angiogenesis and cell metabolism. In this study the authors examine the role of VHL and HIF-1 in ELS tumors. Methods. The ELS tumors from three patients were examined using the following method: DNA from tumor tissue was isolated, amplified by polymerase chain reaction and the VHL gene sequence was compared with the known wild-type sequence. Loss of heterozygosity (LOH) studies were performed to confirm the sequencing data. Immunohistochemical evaluation for VHL, HIF-1α, vascular endothelial growth factor (VEGF), and carbonic anhydrase IX (CA IX) was performed. Snap-frozen tumor tissue was examined using Western blot and HIF-1 immunoassays for HIF-1α and VHL expression. Two patients had sporadic ELS tumors and the other one suffered from VHL disease. Results of VHL gene sequencing were normal in the tissue derived from the sporadic ELS tumors. The ELS tumor, pheochromocytoma, and spinal hemangioblastoma were heterozygous for the same C-to-A transversion found in the germline carried by the patient with VHL disease. No LOH was detected in the tumor tissue obtained in the patient with VHL disease. Expression of HIF-1α, VEGF, and CA IX evaluated using immunohistochemical studies was elevated in the VHL-associated tumors. Nevertheless, Western blots and immunoassays for HIF-1α did not show elevated expression in these tumors. Conclusions. The sporadic and VHL disease—associated ELS tumors in this study had normal VHL-mediated HIF-1 regulation. This is a result of normal VHL gene expression in the case of the sporadic ELS tumor. In the VHL-associated ELS tumor, this is due to one normal copy of the VHL gene and adequate VHL gene expression.

A healthy 29-year-old male suffered bilateral lower extremity fragment wounds resulting in a tense right calf shortly following a wound that required a four-compartment fasciotomy. During treatment of other injuries after medical evacuation he complained of increasing right calf pain. A peroneal pseudoaneurysm (PSA) with a concomitant arteriovenous fistula (AVF) was diagnosed. The distal one-third of the peroneal artery was not visualized, and the posterior tibial and anterior tibial arteries were normal. The patient underwent percutaneous coil embolization of the pseudoaneurysm. Completion arteriography demonstrated no evidence of the PSA and AVF. The patient's bruit and pain resolved.

A young, otherwise healthy man had chronic cough of 16 months' duration. Evaluation revealed an aberrant right subclavian artery. Kommerell's diverticulum without aneurysmal degeneration was present. Imaging studies showed compression of the esophagus but not the trachea. Results of methacholine challenge test were negative for evidence of reactive airway disease, but suggested mild variable intrathoracic obstruction. While aberrant right subclavian artery syndrome most commonly involves dysphagia, our patient's only symptom was cough. Right subclavian artery to right common carotid artery transposition was performed, with oversewing of the subclavian artery stump to the left of the esophagus through a right supraclavicular incision. This treatment was curative, with complete resolution of symptoms.