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Purpose To provide evidence-based recommendations on the use of inferior vena cava (IVC) filters in the treatment of patients with or at substantial risk of venous thromboembolic disease. Materials and Methods A multidisciplinary expert panel developed key questions to address in the guideline, and a systematic review of the literature was conducted. Evidence was graded based on a standard methodology, which was used to inform the development of recommendations. Results The systematic review identified a total of 34 studies that provided the evidence base for the guideline. The expert panel agreed on 18 recommendations. Conclusions Although the evidence on the use of IVC filters in patients with or at risk of venous thromboembolic disease varies in strength and quality, the panel provides recommendations for the use of IVC filters in a variety of clinical scenarios. Additional research is needed to optimize care for this patient population.

Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1R132H (loss of wild-type allele), heterozygous IDH1R132H is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1R132H biology and the underlying mechanism of the glutamate effect. RNA sequencing data of IDH1R132H-heterozygous and IDH1R132H-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1R132H-heterozygous and IDH1R132H-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 gene (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1R132H-heterozygous cells. In contrast to IDH1R132H-heterozygous cells, 3D-cultured but not 2D-cultured IDH1R132H-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1R132H-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation. 3D culture is more relevant to IDH1R132H glioma biology. The importance of redox homeostasis in IDH1R132H glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1R132H inhibitors may have counterproductive consequences in patient treatment.

Anticoagulation is the cornerstone for the treatment of deep venous thrombosis (DVT) and pulmonary embolism (PE). On occasion this is not possible because of bleeding complications or, rarely, breakthrough PE associated with this treatment method. The development of vena cava interruption in the 1970s was a critical advance in the treatment of these patients. Inferior vena cava (IVC) filter placement has been steadily increasing since their introduction. Nonetheless, the incidence of complications associated with placement of these devices is largely unknown. Most of the evidence regarding IVC filter complications relies on case reports, with very scarce data coming from larger randomized controlled trials. We aim to present a summary addressing long-term complications of IVC filters, as published in recent articles addressing problems such as IVC thrombosis, IVC filter migration, perforation, filter fracture, embolization, and tilting. We performed a PubMed search and Google Scholar search using different combination of “long term,” “complications,” “IVC filter,” and “vena cava filter.” We reviewed the publications available in English and reported the findings in this summary.

To provide evidence-based recommendations on the use of inferior vena cava (IVC) filters in the treatment of patients with or at substantial risk of venous thromboembolic disease.A multidisciplinary expert panel developed key questions to address in the guideline, and a systematic review of the literature was conducted. Evidence was graded based on a standard methodology, which was used to inform the development of recommendations.The systematic review identified a total of 34 studies that provided the evidence base for the guideline. The expert panel agreed on 18 recommendations.Although the evidence on the use of IVC filters in patients with or at risk of venous thromboembolic disease varies in strength and quality, the panel provides recommendations for the use of IVC filters in a variety of clinical scenarios. Additional research is needed to optimize care for this patient population.

// Patricia D.B. Tiburcio 1, 2, * , Bing Xiao 1, 3, * , Yi Chai 1, 3 , Sydney Asper 1 , Sheryl R. Tripp 4 , David L. Gillespie 1 , Randy L. Jensen 1 and L. Eric Huang 1, 2 1 Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA 2 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA 3 Department of Neurosurgery, Nanchang University Second Affiliated Hospital, Nanchang, Jiangxi, People’s Republic of China 4 ARUP Institute for Clinical and Experimental Pathology, Salt Lake City, Utah, USA * These authors contributed equally to this work Correspondence to: L. Eric Huang, email: eric.huang@hsc.utah.edu Keywords: glioma; glutamate; isocitrate dehydrogenase 1; mouse model; RCAS Received: September 13, 2018 Accepted: September 21, 2018 Published: October 12, 2018 ABSTRACT Recurrent heterozygous mutation of isocitrate dehydrogenase 1 gene ( IDH1 ), predominantly resulting in histidine substitution at arginine 132, was first identified in glioma. The biological significance of IDH1 R132H , however, has been controversial, and its prevalent association with glioma remains enigmatic. Although recent studies indicate that IDH1 R132H is nonessential to tumor growth or even anti-tumor growth, whether IDH1 R132H initiates gliomagenesis remains obscure. In this study, we report that IDH1 R132H is intrinsically tumor-suppressive but the activity can be attenuated by glutamate—the cerebral neurotransmitter. We observed that IDH1 R132H was highly suppressive of subcutaneous tumor growth driven by platelet-derived growth factor B (PDGFB), but IDH1 R132H tumor growth and glioma penetrance were virtually indistinguishable from those of IDH1-wildtype tumors in orthotopic models. In vitro , addition of glutamate compromised IDH1 R132H inhibition of neurosphere genesis, indicating glutamate promotion of oncogenic dominance. Furthermore, we observed that IDH1 R132H expression was markedly decreased in tumors but became more permissible upon the deletion of tumor-suppressor gene Cdkn2a . To provide direct evidence for the opposing effect of IDH1 R132H on PDGFB-driven glioma development, we explored tandem expression of the two molecules from a single transcript to preclude selection against IDH1 R132H expression. Our results demonstrate that when juxtaposed with oncogenic PDGFB, IDH1 R132H overrides the oncogenic activity and obliterates neurosphere genesis and gliomagenesis even in the glutamate-rich microenvironment. We propose therefore that IDH1 R132H is intrinsically suppressive of glioma initiation and growth but such tumor-suppressive activity is compromised by the glutamate-rich cerebral cortex, thereby offering a unifying hypothesis for the perplexing role of IDH1 R132H in glioma initiation and growth.

Meningiomas are the most common adult primary tumor of the central nervous system, but there are no known effective medical therapies for recurrent meningioma, particularly for World Health Organization grade II and III tumors. Meningiomas arise from the meninges, located outside the blood-brain barrier, and therefore may be directly targeted by antibody-mediated immunotherapy. We found that programmed cell death ligand 1 (PD-L1) was highly expressed in multiple human malignant meningioma cell lines and patient tumor samples. PD-L1 was targeted with the anti–PD-L1 antibody avelumab and directed natural killer cells to mediate antibody-dependent cellular cytotoxicity (ADCC) of PD-L1–expressing meningioma tumors both in vitro and in vivo. ADCC of meningioma cells was significantly increased in target cells that upregulated PD-L1 expression and, conversely, abrogated in tumor cells that were depleted of PD-L1. Additionally, the high-affinity natural killer cell line, haNK, outperformed healthy donor NK cells in meningioma ADCC. Together, these data support a clinical trial designed to target PD-L1 with avelumab and haNK cells, potentially offering a novel immunotherapeutic approach for patients with malignant meningioma.

PURPOSE: Somatic mutations of the isocitrate dehydrogenase 1 (IDH1) gene, mostly substituting Arg132 with histidine, are associated with better patient survival, but glioma recurrence and progression are nearly inevitable, resulting in disproportionate morbidity and mortality. Our previous studies demonstrated that in contrast to hemizygous IDH1(R132H) (loss of wild-type allele), heterozygous mutation is intrinsically glioma suppressive but its suppression of three-dimensional (3D) growth is negated by extracellular glutamate and reducing equivalent. This study sought to understand the importance of 3D culture in IDH1(R132H) biology and the underlying mechanism of the glutamate effect. METHODS: RNA sequencing data of IDH1(R132H)-heterozygous and IDH1(R132H)-hemizygous glioma cells cultured under two-dimensional (2D) and 3D conditions were subjected to unsupervised hierarchal clustering and gene set enrichment analysis. IDH1(R132H)-heterozygous and IDH1(R132H)-hemizygous tumor growth were compared in subcutaneous and intracranial transplantations. Short-hairpin RNA against glutamate dehydrogenase 2 (GLUD2) expression was employed to determine the effects of glutamate and the mutant IDH1 inhibitor AGI-5198 on redox potential in IDH1(R132H)-heterozygous cells. RESULTS: In contrast to IDH1(R132H)-heterozygous cells, 3D-cultured but not 2D-cultured IDH1(R132H)-hemizygous cells were clustered with more malignant gliomas, possessed the glioblastoma mesenchymal signature, and exhibited aggressive tumor growth. Although both extracellular glutamate and AGI-5198 stimulated redox potential for 3D growth of IDH1(R132H)-heterozygous cells, GLUD2 expression was required for glutamate, but not AGI-5198, stimulation. CONCLUSION: We demonstrated that 3D culture is more relevant to IDH1(R132H) glioma biology. The importance of redox homeostasis in IDH1(R132H) glioma suggests that metabolic pathway(s) can be explored for therapeutic targeting, whereas IDH1(R132H) inhibitors may have counterproductive consequences in patient treatment.

Background Death from venous thromboembolism remains a significant cause of death worldwide. Although anticoagulation is the cornerstone of treatment in patients at risk for venous thromboembolism, inferior vena cava (IVC) filter use has increased exponentially over the last decade driven predominantly by the prophylactic use in patients at risk for venous thromboembolism despite limited evidence supporting this practice. The Predicting the Safety and Effectiveness of Inferior Vena Cava Filters (PRESERVE) Study is being implemented by the Society for Vascular Surgery, Society of Interventional Radiology, U.S. Food and Drug Administration, and several IVC filter manufactures to better understand the safety, effectiveness, and current patterns of real-world use of IVC filters. Methods The PRESERVE Study includes IVC filters from seven manufacturers: ALN (ALN ± hook), Argon (Option Elite), B. Braun (LP, Vena Tech Convertible), CR Bard (Denali), Cook (Gunther Tulip), Cordis (OptEase, TrapEase), and Philips Volcano (Crux). The indications for filter placement, filter brand, complications, stability, frequency and success of retrieval, and clinical effectiveness of each filter will be recorded. Approximately 2100 patients (300 for each filter brand included in the study) are intended to be enrolled at 60 U.S. centers. Results Men and women age 18 years or older requiring IVC filters for prevention of venous thromboembolism will be included in the study if no contrast allergy is present and they are willing to commit to the prescribed study follow-up. Participants will be evaluated at discharge, 3, 6, 12, 18, and 24 months after filter placement and/or 1 month after retrieval, which ever occurs first. Intravascular ultrasound examination or venography will be done before and after IVC filter placement, with abdominal plain film at 3 months, and contrast enhanced computed tomography scans at 12 and 24 months to evaluate filter stability. The primary safety end point is a composite of clinical end points, including freedom from perforation, embolization, thrombosis, recurrent DVT, and defined serious adverse events. Secondary end points include mechanical stability and procedure related complications at 3 months, major adverse events at 6, 12, 18, and 24 months, and filter tilt of more than 15° at any point. Conclusions The PRESERVE Study represents the largest prospective study ever undertaken to investigate real-world outcomes with contemporary use of IVC filters. The investigators await results with the hope that it can improve patient care.

Objective Previous in vitro and in vivo results suggested that hydroxyurea (HU) and verapamil could suppress meningioma growth individually and synergistically. We evaluated the clinical efficacy and safety of this approach for the treatment of refractory recurrent/progressive meningiomas and expanded our studies in a xenograft orthotopic mouse model. Methods Six women and 1 man, aged 26–76 years (median, 56 years), with magnetic resonance imaging-proven progression of ≥25% in cross-sectional area of recurrent meningioma (2 World Health Organization grade I, 5 grade II) within the preceding 6 months received HU 1000 or 1500 mg/day (20 mg/kg/day, twice daily) as well as verapamil sustained-release tablets with dose escalation every 2 weeks (120–240 mg/day). They underwent magnetic resonance imaging every 3 months during therapy. To augment the clinical trial results, we performed mouse orthotopic xenograft experiments using similar dosing to test tumor growth, vascularity, and drug bioavailability. Results After a mean of 8.1 cycles of treatment, the patients demonstrated no significant radiographic responses during mean follow-up of 14.5 ± 4.8 months. Median progression-free survival (PFS) was 8.0 months, and 6-month PFS was 85%. Side effects occurred in 6 (86%) patients. Xenograft studies showed no effect of individual or combined treatments on meningioma growth. Neither HU nor verapamil was detectable in mouse brain tumor tissue despite adequate serum levels within therapeutic ranges. Conclusions Our results showed no effect of HU or verapamil on tumor recurrence, PFS, and in vivo tumor burden reduction. Drug delivery to the tumor may be a major limitation.

BACKGROUND: Meningiomas are the most common primary brain tumor. Standard of care includes surgery and radiation therapy. There are no known effective medical therapies for recurrent meningioma, particularly for WHO grades II and III. As such, novel therapeutic approaches are desperately needed. PD-L1 is highly expressed in malignant meningioma, including the cell lines we tested, creating a potential target for ADCC-mediated killing. Therefore, we investigated the ability of avelumab, a PD-L1-specific antibody, to direct NK-mediated ADCC against malignant meningioma cells using healthy donor NK cells and the engineered NK cell line, haNK. METHODS: PD-L1 expression was assayed by flow cytometry and Western blotting in five human malignant meningioma cell lines. Avelumab-targeted ADCC was measured with healthy donor NK and haNK cells. Efficacy of avelumab+haNK was determined in vivo against meningioma implanted subcutaneously and orthotopically in a skull-base intracranial model. PD-L1 was deleted from tumor cells using CRISPR knockout to test specificity of the target. RESULTS: Avelumab directed healthy donor NK and haNK cells to mediate ADCC against all five meningioma cell lines in vitro. ADCC was enhanced by using NK cells with a high-avidity Fc receptor, haNK cells, or by upregulating PD-L1 in target cells. Avelumab+haNK significantly extended survival in mice bearing orthotopic meningioma and subcutaneous tumors. Conversely, killing (and survival benefit) was abrogated against cells in which PD-L1 was deleted. No toxicity was noted in pre-clinical models. CONCLUSIONS: We demonstrate that avelumab can target meningioma for ADCC by healthy donor NK cells, and killing is significantly enhanced with haNKs. haNK cells have demonstrated safety in humans, and avelumab has shown promising clinical activity in a variety of solid tumors. These data support the design of a clinical trial targeting PD-L1 with avelumab and haNK cells, potentially offering a novel immunotherapeutic approach for patients with malignant meningioma.

Gliomas are the most common type of primary, malignant brain tumor and significantly impact patients, who have a median survival of ~1 year depending on mutational background. Novel imaging modalities such as luciferase bioluminescence, micro-magnetic resonance imaging (micro-MRI), micro-computerized tomography (micro-CT), and micro-positron emission tomography (micro-PET) have expanded the portfolio of tools available to study this disease. Hypoxia, a key oncogenic driver of glioma and mechanism of resistance, can be studied in vivo by the concomitant use of noninvasive MRI and PET imaging. We present a protocol involving stereotactic injection of syngenic F98 luciferase-expressing glioma cells generated by our laboratory into Fischer 344 rat brains and imaging using luciferase. In addition, 18-F-fludeoxyglucose, 18F-fluoromisonidazole, and 18F-fluorothymidine PET imaging are compared with quantified luciferase flux. These tools can potentially be used for assessing tumor growth characteristics, hypoxia, mutational effects, and treatment effects.

Chronic venous occlusion is frequently associated with moderate to severe postphlebetic syndrome and sometimes venous ulceration affecting negatively quality of life. Despite a widely adopted strategy of early thrombus removal, patients commonly present at a later stage with extensive chronic total occlusions. This chapter describes tips and techniques for endovascular recanalization and stenting of major veins to provide adequate venous outflow and relieve peripheral venous hypertension

Acceptable complication rates after carotid endarterectomy (CEA) are drawn from decades-old data. The recent Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated improved stroke and mortality outcomes after CEA compared with carotid artery stenting, with 30-day periprocedural CEA stroke rates of 3.2% and 1.4% for symptomatic (SX) and asymptomatic (ASX) patients, respectively. It is unclear whether these target rates can be attained in "normal-risk" (NR) patients experienced outside of the trial. This study was done to determine the contemporary results of CEA from a broader selection of NR patients.The Society for Vascular Surgery (SVS) Vascular Registry was examined to determine in-hospital and 30-day event rates for NR, SX, and ASX patients undergoing CEA. NR was defined as patients without anatomic or physiologic risk factors as defined by SVS Carotid Practice Guidelines. Raw data and risk-adjusted rates of death, stroke, and myocardial infarction (MI) were compared between the ASX and SX cohorts.There were 3977 patients (1456 SX, 2521 ASX) available for comparison. The SX group consisted of more men (61.7% vs 57.0%; P = .0045) but reflected a lower proportion of white patients (91.3% vs 94.4%; P = .0002), with lower prevalence of coronary artery disease (P.0001), prior MI (P.0001), peripheral vascular disease (P = .0017), and hypertension (P = .029), although New York Heart Association grade3 congestive heart failure was equally present in both groups (P = .30). Baseline stenosis80% on duplex imaging was less prevalent among SX patients (54.2% vs 67.8%; P.0001). Perioperative stroke rates were higher for SX patients in the hospital (2.8% vs 0.8%; P.0001) and at 30 days (3.4% vs 1.0%; P.0001), which contributed to the higher composite death, stroke, and MI rates in the hospital (3.6% vs 1.8; P = .0003) and at 30 days (4.5% vs 2.2%; P.0001) observed in SX patients. After risk adjustment, the rate of stroke/death was greater among SX patients in the hospital (odds ratio, 2.05; 95% confidence interval, 1.18-3.58) although not at 30 days (odds ratio, 1.36; 95% confidence interval, 0.85-2.17). No in-hospital or 30-day differences were observed for death or MI by symptom status.The SVS Vascular Registry results for CEA in NR patients are similar by symptom status to those reported for CREST and may serve as a benchmark for comparing results of alternative therapies for treatment of carotid stenosis in NR patients outside of monitored clinical trials. The contemporary perioperative risk of stroke after CEA in NR patients continues to be higher for SX than for ASX patients.

Objective Pelvic congestion syndrome (PCS) is widely thought to be due to ovarian or internal iliac vein reflux. This report of a retrospective review of treatment of nonthrombotic common iliac vein (CIV) or inferior vena cava (IVC) obstruction with relief of symptoms demonstrates an often overlooked pathologic process. Stent placement is evaluated as an effective treatment of PCS due to venous obstruction even if observed left ovarian vein (OV) reflux is left untreated. Methods Records from two institutions were reviewed for patients with nonthrombotic venous outflow obstruction and symptoms of PCS severely affecting quality of life. The patients were evaluated with ultrasound, computed tomography (CT), and intravascular ultrasound before stent placement. From January 2008 through May 2013, 19 patients were treated with stents for severe venous outflow obstruction. Although seven patients also were found to have OV reflux, only one of these was treated with left OV coil occlusion. Results Whereas 10 of the 19 patients presented with a chief complaint of lower extremity pain, edema, or varicose veins, all patients described their pelvic symptoms as their dominant complaint. Ultrasound and CT suggested moderate to severe compression of the left CIV in 18 patients and a high-grade stenosis of the suprarenal IVC in one patient. Venography showed outflow obstruction with pelvic collaterals, and intravascular ultrasound confirmed focal severe stenosis of the involved vein. Follow-up of 1 to 59 months (median, 11 months) revealed complete resolution of pelvic pain in 15 of 19 patients and of dyspareunia in 14 of 17 sexually active patients. Of the 15 patients who experienced left lower extremity pain or edema before treatment, 13 experienced complete resolution after treatment. Imaging follow-up by ultrasound or CT showed 16 of the stents to be widely patent, with 3 minor asymptomatic stenoses. Conclusions Nonthrombotic obstruction of the left CIV or IVC is an underappreciated cause of PCS. Venous angioplasty and stenting provide excellent short-term results for such patients, with resolution of chronic pelvic pain and dyspareunia. Venous obstruction should be considered and carefully evaluated in patients presenting with pelvic congestion, and treatment of obstruction alone may solve the patient's symptoms.

Background Glioblastoma is a malignant World Health Organization (WHO) grade IV glioma with a poor prognosis in humans. New therapeutics are desperately required. The nitrone OKN-007 (2,4-disulfophenyl-PBN) has demonstrated effective anti-glioma properties in several rodent models and is currently being used as a clinical investigational drug for recurrent gliomas. We assessed the regional effects of OKN-007 in the tumor necrotic core and non-necrotic tumor parenchyma. Methods An F98 rat glioma model was evaluated using proton magnetic resonance spectroscopy (1H-MRS), diffusion-weighted imaging (DWI), morphological T2-weighted imaging (T2W) at 7 Tesla (30 cm-bore MRI), as well as immunohistochemistry and microarray assessments, at maximum tumor volumes (15–23 days following cell implantation in untreated (UT) tumors, and 18–35 days in OKN-007-treated tumors). Results 1H-MRS data indicates that Lip0.9/Cho, Lip0.9/Cr, Lip1.3/Cho, and Lip1.3/Cr ratios are significantly decreased (all P

OBJECT High-grade gliomas are the most common form of adult brain cancer, and patients have a dismal survival rate despite aggressive therapeutic measures. Intratumoral hypoxia is thought to be a main contributor to tumorigenesis and angiogenesis of these tumors. Because hypoxia-inducible factor 1α (HIF-1α) is the major mediator of hypoxia-regulated cellular control, inhibition of this transcription factor may reduce glioblastoma growth. METHODS Using an orthotopic mouse model with U87-LucNeo cells, the authors used RNA interference to knock down HIF-1α in vivo. The small interfering RNA (siRNA) was packaged using a novel multifunctional surfactant, 1-(aminoethyl) iminobis[N-(oleicylcysteinylhistinyl-1-aminoethyl)propionamide] (EHCO), a nucleic acid carrier that facilitates cellular uptake and intracellular release of siRNA. Stereotactic injection was used to deliver siRNA locally through a guide-screw system, and delivery/uptake was verified by imaging of fluorescently labeled siRNA. Osmotic pumps were used for extended siRNA delivery to model a commonly used human intracranial drug-delivery technique, convection-enhanced delivery. RESULTS Mice receiving daily siRNA injections targeting HIF-1α had a 79% lower tumor volume after 50 days of treatment than the controls. Levels of the HIF-1 transcriptional targets vascular endothelial growth factor (VEGF), glucose transporter 1 (GLUT-1), c-MET, and carbonic anhydrase-IX (CA-IX) and markers for cell growth (MIB-1 and microvascular density) were also significantly lower. Altering the carrier EHCO by adding polyethylene glycol significantly increased the efficacy of drug delivery and subsequent survival. CONCLUSIONS Treating glioblastoma with siRNA targeting HIF-1α in vivo can significantly reduce tumor growth and increase survival in an intracranial mouse model, a finding that has direct clinical implications.

Background Chronic pelvic pain accounts for up to 30% of outpatient gynecologic visits in the United States, potentially affecting up to 40% of the female population during their lifetime. Pelvic congestion syndrome (PCS) is defined as chronic pelvic pain resulting from reflux or obstruction of the gonadal, gluteal, or periuterine veins, sometimes associated with perineal or vulvar varices. It can also be caused by compression of the left renal vein (LRV) between the superior mesenteric artery and the aorta, also known as the nutcracker syndrome. Whereas PCS accounts for up to 30% of patients presenting with chronic pelvic pain, it is frequently underdiagnosed. We reviewed the literature to investigate the current state of the diagnosis and treatment of this disorder. Methods An online database search was performed with MEDLINE. MeSH headings included PCS, chronic pelvic pain, ovarian vein reflux, nutcracker syndrome, renal vein obstruction, pelvic varicosities, labial varicosities, embolization, treatment, and therapies. Results Our MEDLINE search revealed more than 3756 references to chronic pelvic pain. Specific references to PCS, pelvic chronic pain, ovarian vein reflux, nutcracker syndrome, renal vein obstruction, pelvic varicosities, labial varicosities, embolization, treatment, and therapies, however, included only 260 references. Thirty-seven references were small series including fewer than 50 patients or individual case reports documenting medical, surgical, or endovascular treatment of PCS. The majority of these papers demonstrated successful treatment of symptoms from PCS with embolization of one or both ovarian veins in addition to treatment of refluxing internal iliac vein branches. In addition, open surgery and, more recently, endovascular stenting of LRV obstruction have shown some promise in alleviating symptoms attributed to nutcracker syndrome. Conclusions Diagnosis of PCS requires a careful history, physical examination, and noninvasive imaging. Several large case series have demonstrated the efficacy of embolotherapy in the reduction of pelvic pain; thus, it is the most favored treatment option for patients with PCS. For patients with outflow obstruction due to nutcracker syndrome, a limited number of studies have demonstrated remission of symptoms with stenting of the LRV as an alternative to open surgery.

Anticoagulation is the cornerstone for the treatment of deep venous thrombosis and pulmonary embolism. On occasion, this is not possible because of bleeding complications or, rarely, breakthrough pulmonary embolism associated with this treatment method. The development of vena cava interruption in the 1970s was a critical advance in the treatment of these patients. Placement of inferior vena cava (IVC) filters has been steadily increasing since their introduction. Nonetheless, the incidence of complications associated with placement of these devices is largely unknown. Most of the evidence regarding IVC filter complications relies on case reports, with scarce data coming from larger randomized controlled trials. We aimed to present a summary addressing long-term complications of IVC filters as published in recent articles addressing problems such as IVC thrombosis and IVC filter migration, perforation, fracture, embolization, and tilting. We performed a PubMed search and Google Scholar search using different combinations of "long term," "complications," "IVC filter," and "vena cava filter." We reviewed the available English publications and reported the findings in this summary.

Congenital vascular malformations may involve arterial, venous, and lymphatic structures and are present in 1.5% of the population. By definition, they exist at the time of birth, but clinical manifestations can evolve during life. As a vascular condition typically involving the extremities, the vascular laboratory diagnostics can be a challenge regarding imaging and test interpretation. Testing utilizes the same instrumentation applied to evaluation of peripheral arterial disease and dialysis access fistula. Other imaging modalities such as computer tomography (CT) scans, magnetic resonance imaging, and radioisotope studies can be used to assess the involvement of surrounding vital structures and even quantify the amount of blood flow shunted through a malformation or a fistula. Duplex testing combined with indirect physiologic testing of the limb and digit arterial perfusion is vital for the clinical decision-making regarding treatment modalities. In this chapter, the assessment of patients with known or suspected congenital arteriovenous malformations is described with an emphasis on clinical interpretation and relevance to symptoms and signs.

Background Validation of carotid duplex ultrasound velocity criteria (CDUS VC) to grade the severity of extracranial carotid artery stenosis has traditionally been based on conventional angiography measurements. In the last decade, computed tomographic angiography (CTA) has largely replaced conventional arch and carotid arteriography (CA) for diagnostic purposes. Given the low number of CA being performed, it is impractical to expect noninvasive vascular laboratories to be validated using this modality. CDUS VC have not been developed with the use of CTA-derived measurements. The objective was to determine optimal CDUS VC from CTA-derived measurements with the North American Symptomatic Carotid Endarterectomy Trial (NASCET) method for 50% and 80% stenosis. Methods A retrospective review of all patients who underwent CDUS and CTA from 2000 to 2009 was performed. Vessel diameters were measured on CTA, and corresponding CDUS velocities were recorded. Percent stenosis was calculated using the NASCET method. Receiver operating characteristic (ROC) curves were generated for internal carotid artery (ICA) peak systolic velocity (PSV), ICA end diastolic velocity (EDV), and ICA PSV to common carotid artery PSV ratio (PSVR) for 50% and 80% stenosis. Velocity cut points were determined with equal weighting of sensitivity and specificity. Results A total of 575 vessels were analyzed to create the ROC curves. A 50% stenosis analysis yielded ideal cut points for PSV, EDV, and PSVR of 130 cm/sec, 42 cm/sec, and 1.75. An 80% stenosis analysis yielded ideal cut points for PSV, EDV, and PSVR of 297 cm/sec, 84 cm/sec, and 3.06. Conclusions CTA-derived CDUS VC appeared to be reliable in defining 50% and 80% stenosis in patients with carotid artery stenosis. Although CDUS VC defined in this study were different from many of the previously published VC for the same percent stenosis, there were many similarities to those reported by the Society of Radiologists in Ultrasound consensus conference. We feel that CTA should be the gold standard imaging technique for validating CDUS VC.

ObjectiveThe single puncture intravascular ultrasound (IVUS)-guided bedside placement of inferior vena cava (IVC) filters has been shown to be an effective technique. The major disadvantage of this procedure is a steep learning curve that can lead to an increased risk of filter malposition. In an effort to increase the safety and efficacy of IVUS-guided bedside IVC filter placement, we proposed that preoperative planning could reduce the incidence of IVUS-guided filter malpositions. As a first step, we examined the correlation between preoperative abdominal computed tomography (CT) scan measurements and intraprocedural IVUS derived measurements of vena cava anatomy and its surrounding structures. As a second step, we attempted to determine the safety of this protocol by assessing the incidence of malposition.MethodsA retrospective review of prospectively collected data was performed on all patients receiving bedside IVUS-guided filters from July 1, 2010 to August 31, 2011. Measurements of the IVC length from the atrial-IVC junction to the midportion of the crossing right renal artery, the lowest renal vein, and iliac vein confluence were obtained prior to IVC filter placement by both CT-based measurement, as well as intraprocedural IVUS pullback lengths. Regression analysis (significant for P < .05) was used to determine the correlation between these imaging modalities.ResultsForty-six patients had adequate CT scans available to perform the analysis and were candidates for bedside IVUS-guided IVC filter placement. All IVUS-guided filters were placed using a single puncture technique with the Cook Celect Filter. This study found there was a close correlation between IVUS and CT derived measurements of the right atrium to right renal artery distance, lowest renal vein distance, and iliac confluence distance. In addition, we found that the IVUS distances from the atrial-IVC junction to the right renal artery and lowest renal vein were statistically similar. Nine patients had 10 vascular anatomic variations, all identified by both IVUS and CT. There were no complications or malpositions of IVC filters using this protocol.ConclusionsThese data suggest that IVUS pullback measurements from the right atrium used in combination with preprocedure CT derived measurements of the distance from the right atrium to the lowest renal vein and iliac vein confluence provide an accurate roadmap for the placement of bedside IVC filters under IVUS guidance. We provide a method for organizing this information in a preplanning document to aid this procedure. We suggest this easily employed technique be more fully utilized to help decrease the incidence of malpositioned filters using single puncture IVUS guidance.

BACKGROUND The Senior Visiting Surgeon (SVS) program at Landstuhl Regional Medical Center (LRMC), Germany, was developed during the wars in Afghanistan and Iraq as a measure to build military-civilian interaction in trauma care and research. The objective of this study was to provide a summary of the program including workload and experiences. An additional objective was to identify factors needed for sustainment of this program during an interwar period. METHODS An electronic, 34-question survey was distributed to 192 surgeons who participated in the SVS program at LRMC, either through the American Association for the Surgery of Trauma or the Society of Vascular Surgery between 2005 and 2012. The survey was composed of multiple-choice and open-ended questions. RESULTS The response rate was 61% (n = 118), with 24% (n = 28) indicating previous military service. These 117 respondents provided 24.5 months of volunteer coverage at LRMC, with 22% (n = 26) performing multiple, 2-week rotations. Visiting surgeons participated in two to five operative cases per week, with the majority of operations related to the management of soft tissue wounds and burns followed by abdominal and vascular procedures, conducted daily multidisciplinary intensive care unit rounds, and collaborated with military surgeons in research projects resulting in 22 publications. More than half (n = 59) of the respondents maintained contact with military colleagues during the 12 months following the rotation. The majority of surveyed surgeons support continuation of the SVS at military facilities in the United States and hosting military surgeons at their civilian trauma center. CONCLUSION This study is the first to quantify the SVS program during the wars in Afghanistan and Iraq. Visiting surgeons provided more than 2 years of combat casualty care during these, the longest wars in US history. Continuation of this program will require expanded military-civilian interaction in trauma care, training, and research during any interwar period.

The aim of this study was to develop a quantitative 16S rRNA assay for determination of bacterial nucleic acid load in cerebrospinal fluid (CSF) shunt infection and to compare quantitative 16S rRNA polymerase chain reaction (PCR) findings to those of conventional bacterial culture in patients treated for CSF shunt infection. We developed a quantitative 16S rRNA PCR assay that detected bacterial load across a range of 2.5 × 109 down to 2.5 × 104 16S copies/mL CSF under experimental conditions for numerous Gram-positive and Gram-negative organisms. However, when applied to archived CSF samples from 25 shunt infection episodes, correlations between positive bacterial culture and 16S rRNA levels were seen in only half of infections, and 16S rRNA levels dropped precipitously after an initial peak on the first day of sample collection. Bacterial load measured using 16S rRNA PCR does not provide sufficient information beyond bacterial culture to inform CSF shunt infection treatment.

The objective of this report is to describe our experience of pediatric vascular injuries in a U.S. military combat support hospital in Baghdad, Iraq. A retrospective study was designed using Joint Theater Trauma Registry (JTTR) records in order to evaluate the pediatric (age18 years) population presenting with vascular trauma to a combat hospital in Baghdad, Iraq between April 2006 and August 2008. Demographic data comprised casualty, age, gender, and mechanism of injury. Physiologic data included presenting vital signs (rectal temperature, blood pressure, and heart rate), arterial pH, base deficit, hemoglobin (g/dL), and international normalized ratio.Twenty-five children, median age 14 years (range, 5-17 years), median weight 48 kg (range, 15-80 kg) sustained 18 (72%) blast and 7 (28%) gunshot wounds. The mean Injury Severity Score was 25 ± 16.2. The median operative time for the vascular repairs was 189 minutes (range, 41-505 minutes). Patients were tachycardic (mean ± standard deviation, 136 ± 29 bpm), hypotensive (109/63 ± 29/19 mm Hg), and acidemic (pH 7.26 ± 0.07; BD -5.57 ± 5.1 mEq/L) on arrival to the emergency department and were physiologically improved upon admission to the intensive care unit 3 hours later. Repair techniques were ligation (14; 39%), saphenous graft (11; 31%), lateral suture (7; 19%), end anastomosis (2; 5%), patch (1; 3%), and thrombectomy (1; 3%). Twenty-four hour mean transfusion requirements included crystalloid 102 mL/kg (range, 19-253), transfused blood 47 mL/kg (range, 0-119), fresh frozen plasma 14 mL/kg (range, 0-68), and apheresis platelets (1.2 ± 3.68 units). Over a follow-up of 22 ± 5.5 days, the amputation-free survival was 80%.This is the largest reported wartime series to demonstrate in children that damage control resuscitation despite high injury severity permits simultaneous limb salvage.

Venous thromboembolism is a national health concern. Up to 58% of patients suffering from major multisystem trauma will experience venous thromboembolism if no measures are taken to prevent it. Of those, 10% to 30% will be fatal. The appropriate use of lower extremity compression, anticoagulation, and the use of inferior vena cava (IVC) filters has helped reduce the overall morbidity and mortality from this disease. The development of lower-profile devices and the ability to retrieve IVC filters has led to a liberalization of their use. The majority of the filters used today have achieved U.S. Food and Drug Administration approval through the 510K mechanism (approval based on prior similar devices rather than safety studies of the proposed device), and therefore, no rigorous investigations have been performed on them. Initially seeming safe, a recent increase in reports of filter migration, vena cava perforation, and vena cava thrombosis has prompted the Food and Drug Administration to ask for more information on their patterns of use, safety, efficacy, and retrievability. This report details some of the available data on the subject of IVC filters and the discussion surrounding the topic of prophylactic IVC filters in trauma patients.

BACKGROUND Glioblastoma multiforme (GBM), a high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM. OBJECTIVE To identify ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) as a putative glioma-associated marker via a bioinformatic method. METHODS We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a potential novel biomarker that is associated with gliomas. Validation was done with immunohistochemistry, which was used to detect levels of ELTD1 in human high-grade gliomas and rat F98 glioma tumors. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular magnetic resonance imaging. RESULTS ELTD1 was found to be significantly higher (P = .03) in high-grade gliomas (50 patients) compared with low-grade gliomas (21 patients) and compared well with traditional immunohistochemistry markers including vascular endothelial growth factor, glucose transporter 1, carbonic anhydrase IX, and hypoxia-inducible factor 1α. ELTD1 gene expression indicates an association with grade, survival across grade, and an increase in the mesenchymal subtype. Significantly high (P < .001) in vivo levels of ELTD1 were additionally found in F98 tumors compared with normal brain tissue. CONCLUSION Results of this study strongly suggests that associative analysis was able to accurately identify ELTD1 as a putative glioma-associated biomarker. The detection of ELTD1 was also validated in both rodent and human gliomas and may serve as an additional biomarker for gliomas in preclinical and clinical diagnosis of gliomas.

VS between the patients’ symptoms and their clinical signs (P 1⁄4 .175 and r 1⁄4 .219). Conclusions: These results indicate that the VCSS and the C of CEAP may also be useful in the assessment of PTS severity, and that the VFI may provide a clinically meaningful hemodynamic evaluation. These results also confirm that the VS remains the gold standard disease specific assessment in the evaluation of PTS.

Vascular trauma of the lower extremities is associated with high rates of morbidity and mortality and is especially challenging when it involves the junctional zone between the torso and the lower extremities. Lower extremity junctional injuries are those that occur to the distal iliac and proximal femoral vessels. In the absence of hard signs of injury, lower extremity junctional vascular trauma may be challenging to diagnose; and, in the presence of hard signs, they may be hard to control, expose, and repair. The successful management of lower extremity vascular injury is dependent on early diagnosis and control of hemorrhage, resuscitation of the patient, and prompt intervention to minimize associated ischemia. The most important factors in life- and limb-saving interventions relate to prompt control of hemorrhage and time to reperfusion in the setting of ischemia. The anatomic level of lower extremity vascular injury (iliac-femoral, femoral-popliteal, tibial), the severity of the mangled extremity, and the presence of associated injuries are also important factors influencing patient outcomes.

Background The 0+5 integrated vascular residency training pathway was established in 2006 to allow for trainee-focused training culminating in vascular surgery certification only. An early concern was whether enough medical students could be recruited directly into a vascular internship without the exposure that a general surgery residency provides. We hypothesized that programs that send a large percentage of their general surgical graduates to vascular fellowships have models that can be adapted to medical student recruitment. Methods Opinions and practices were sought from program directors through survey and from trainees taking the Vascular Surgery In-Training Examination. Results Eight programs were identified that sent 20% or more of their residents to vascular fellowships over the past 5 years (projecting a mean of 1.6 residents entering vascular fellowships in 2011). Almost all such programs have a formal mentoring system in place that match mentors to residents by interest, and almost all send residents to academic meetings before their senior year. Seventy-five percent of such programs have formal vascular lecture exposure to the first and second year medical student classes, offer clinical shadowing experiences, and have time on the vascular service during the MS3 clerkship; 83% offer a third- or fourth-year elective in vascular surgery. Vascular Surgery In-Training Examination responses were collected from 156 fellows and 13 “0+5” residents. Although fellows had initially been attracted to vascular surgery by the technical aspects of the field learned during residency (43%), the most important factor initially attracting medical students was an interested mentor (46%). However, the most important factor for both residents and students in making a final decision was the technical aspects of the field (66% and 63%, respectively). Conclusions Although residents are automatically exposed to the field during residency, students can only be exposed to vascular surgery if a conscious effort is made by interested educators. Programs that send a high proportion of students and residents into vascular surgery tend to have planned exposure at the MS1 and MS2 levels, formal clinical rotations in place at the MS3 and MS4 levels, and pay personal attention to those who display interest. A guide is presented to help specifically plan these steps. Successful recruiting of students into a 0+5 integrated training program requires specific planning and action.

R-flurbiprofen, a nonsteroidal anti-inflammatory drug derivative, has been shown to inhibit colonic adenoma formation in mice. We investigated the effects of R-flurbiprofen on cell proliferation and apoptosis in pituitary adenoma cell lines. GH4C1 rat pituitary cell line cultures and low-passage human primary pituitary cell cultures were treated with varying concentrations of R-flurbiprofen (0.1-1.0 mM). R-flurbiprofen inhibited cell proliferation in a dose-dependent fashion. A terminal deoxynucleotidyl transferase dUTP nick end labeling assay and chromatin condensation/dead cell apoptosis assay demonstrated induction of apoptosis at higher concentrations of R-flurbiprofen. R-flurbiprofen decreases cell proliferation and induces apoptosis in pituitary adenoma cells in vitro. This may be a potential therapy in the management of pituitary adenoma.

Rationnelle Les fistules arterio-veineuses autologues sont frequemment menacees par une obstruction veineuse centrale. Bien que ceci soit frequemment attribue aux catheters centraux et au remodelage veineux neointimal, nous croyons que la compression extrinseque de la veine sous-claviere a la traversee de la jonction costo-claviculaire (JCC) peut jouer un role significatif dans un sous-groupe de dialyses. Methodes Nous avons passe en revue notre experience de la decompression de la JCC pour dysfonctionnement de fistule arterio-veineuse dans notre etablissement. La decompression a suivi les principes du traitement du syndrome du defile thoraco-brachial veineux : decompression osseuse avec la phlebolyse complete, suivi de phlebographie central par la fistule et traitement endovasculaire si besoin. Les patients ont eu une resection de la premiere cote par voie axillaire, ou resection de la clavicule en position en supination dans les cas quand une reconstruction etait prevue. Dans tous les cas, l'exposition minimum a inclus la mobilisation 360° de la veine sous-claviere avec la resection du tissus cicatriciel environnant la jonction jugulaire/innominee. Resultats Un total de 10 patients ayant besoin d'une decompression entre novembre 2008 et fevrier 2010 ont ete inclus. Tous avaient un œdeme severe du bras, quatre avaient un dysfonctionnement de dialyse (saignement de apres cannulation ou echec de maturation), deux avaient une douleur severe du bras, et un avait un faux-anevrysme. Tous les patients avaient une stenose de veine sous-claviere a la JCC a la phlebographie ou a l'echographie endovasculaire. La majorite de patients avaient eu une dilatation par ballon (moyenne : 2,3 tentatives) sans succes. Six patients ont eu une resection par voie axillaire de la premiere cote et quatre une resection de la clavicule mediale. Aucun patient n'a necessite une reconstruction veineuse chirurgicale. En tout, 80% des fistules sont restees fonctionnellement permeable, et tous sauf un patient (qui a eu une ligature) ont eu une disparition complete de l'œdeme de membre superieur. La duree mediane de sejour etait de 2 jours et le suivi moyen etait de 7 mois (extremes, 1-13). Il n'y a eu aucun deces ni morbidite significative. Cinq patients ont eu besoin secondairement de plastie de veine centrale (quatre sous-claviere, moyenne : 1,8 tentative et un tronc veineux innomine) et trois ont necessite la mise en place de stents (deux sous-claviers, un innomine). Conclusion Un nombre significatif de patients presentant l'acces vasculaire pour hemodialyse menace par une obstruction veineuse centrale ont des lesions attribuables a la compression de la JCC. La decompression chirurgicale par resection de la premiere cote ou de la clavicule et phlebolyse a permis une recuperation fonctionnelle asymptomatique chez 80% de ces patients, qui auraient tous perdu leur acces autrement. Puisque la reconstruction chirurgicale est rarement necessaire, la voie axillaire peut etre preferable a la resection de la clavicule. Cette lesion devrait etre specifiquement recherchee, et les principes du traitement du syndrome du defile thoraco-brachial veineux semblent s'appliquer et etre efficaces.

Historically, epidemiology, diagnosis, and management of venous trauma have not been well understood. Venous injuries often have subtle presentations, unclear consequences, and debatable treatment options. Many venous injuries are asymptomatic and are diagnosed only during surgical exploration for other injuries. The obvious venous injury is the one found during surgical exploration of an arterial trauma. Isolated venous injuries are difficult to diagnose and often only discovered if massive swelling or life-threatening hemorrhage occurs. Once discovered, the question is how to treat: ligation or repair. The answer is the prudent use of both methods. For patients at the brink of hemodynamic collapse, ligation is the best choice. For stable patients, an effort should be made to reestablish venous outflow. Definitive repair in unstable patients should not attempted, instead temporary solutions should be used that will allow the patient to leave the operating room quickly and began correction of hypothermia, acidosis, and coagulopathy.

The Society for Vascular Surgery (SVS) and the American Venous Forum (AVF) have developed clinical practice guidelines for the care of patients with varicose veins of the lower limbs and pelvis. The document also includes recommendations on the management of superficial and perforating vein incompetence in patients with associated, more advanced chronic venous diseases (CVDs), including edema, skin changes, or venous ulcers. Recommendations of the Venous Guideline Committee are based on the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system as strong (GRADE 1) if the benefits clearly outweigh the risks, burden, and costs. The suggestions are weak (GRADE 2) if the benefits are closely balanced with risks and burden. The level of available evidence to support the evaluation or treatment can be of high (A), medium (B), or low or very low (C) quality. The key recommendations of these guidelines are: We recommend that in patients with varicose veins or more severe CVD, a complete history and detailed physical examination are complemented by duplex ultrasound scanning of the deep and superficial veins (GRADE 1A). We recommend that the CEAP classification is used for patients with CVD (GRADE 1A) and that the revised Venous Clinical Severity Score is used to assess treatment outcome (GRADE 1B). We suggest compression therapy for patients with symptomatic varicose veins (GRADE 2C) but recommend against compression therapy as the primary treatment if the patient is a candidate for saphenous vein ablation (GRADE 1B). We recommend compression therapy as the primary treatment to aid healing of venous ulceration (GRADE 1B). To decrease the recurrence of venous ulcers, we recommend ablation of the incompetent superficial veins in addition to compression therapy (GRADE 1A). For treatment of the incompetent great saphenous vein (GSV), we recommend endovenous thermal ablation (radiofrequency or laser) rather than high ligation and inversion stripping of the saphenous vein to the level of the knee (GRADE 1B). We recommend phlebectomy or sclerotherapy to treat varicose tributaries (GRADE 1B) and suggest foam sclerotherapy as an option for the treatment of the incompetent saphenous vein (GRADE 2C). We recommend against selective treatment of perforating vein incompetence in patients with simple varicose veins (CEAP class C2; GRADE 1B), but we suggest treatment of pathologic perforating veins (outward flow duration >500 ms, vein diameter >3.5 mm) located underneath healed or active ulcers (CEAP class C5-C6; GRADE 2B). We suggest treatment of pelvic congestion syndrome and pelvic varices with coil embolization, plugs, or transcatheter sclerotherapy, used alone or together (GRADE 2B). (J Vasc Surg 2011;53:2S-48S.)