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Importance Sex equity is elusive in academic surgery departments across the United States. Persistent inequities remain a considerable problem and inhibit professional advancement for female surgeons. Identifying the factors that promulgate sex discrepancies may provide a framework for institutional growth and personal progress for women. Objective To identify barriers and facilitators to success at the individual and organizational level to develop evidence-based interventions designed to close the sex gap in surgery. Design, Setting, and Participants This qualitative study included 26 female participants who were current and former surgical faculty employed by Michigan Medicine, the health system of the University of Michigan, between 2000 and 2017. Semistructured personal interviews were conducted from June 28 to September 29, 2017, via telephone. Each interview lasted 45 minutes to 1 hour. Interviews were recorded and then transcribed for analysis. Main Outcomes and Measures The interview included 7 questions referring to the surgeon’s experience with the Michigan Medicine Department of Surgery and 7 questions referring to nonspecific areas of interest. Results The 26 participants in this study ranged in age from 32 to 64 years, with faculty experience ranging from 3 to 22 years. Thematic analysis was used to locate, analyze, and report patterns within the data related to barriers and facilitators for women in academic medicine. Three major themes were identified by researchers. Participants reported that (1) organizational culture and institutional policies affect opportunities for advancement; (2) relational interactions with leadership, mentors, colleagues, and staff affect promotion and attrition; and (3) individual characteristics mediate the perception of professional and personal success. Conclusions and Relevance In this qualitative study of 26 female academic surgeons, a complex matrix of organizational and individual factors were found to contribute to sex inequities in academic surgery. This research may provide insight into the sex biases that inhibit advancement, may inform strategies that facilitate progress, and may inspire interventions that could help eliminate institutional and individual barriers to the academic success of women.

Background With the growing prevalence of endovascular repair for abdominal aortic aneurysm (AAA), the number of patients requiring graft explantation is increasing. Therefore, knowledge related to outcomes after explantation may lead to improvement in surgical options. In this study we compare our experience with explantation of aortic endografts, based on indication. Methods The medical records of all aortic procedures performed at our center were queried during the period from 2002 to 2012. Relevant data from patients needing explantation of aortic endografts were analyzed using Fisher’s exact test, t-test, and Kaplan-Meier analysis. Results Thirty-nine patients underwent aortic endograft explantation (64.1% men). Mean age was 71.9 years with a mean aneurysm size of 6.8 cm (range 3.5–10.7 cm). Hypertension (97.4%), hyperlipidemia (76.9%), and history of smoking (82%) were the most prevalent risk factors. Mean time to explant was 41.7 months (range 2.2–118.4 months). The primary explant indication was endoleak in 27 (69.2%) and infection in 12 (30.8%) patients. The endoleak group consisted of 13 type I, 8 type II, 1 type III, 4 endotension, 1 rupture, and 4 patients with multiple endoleaks. Seven patients were symptomatic, whereas 2 had ruptured aneurysms. Half of the patients in the infection group required supraceliac clamping for explantation. Operative blood loss (P = 0.08) and need for transfusion (P = 0.005) were significantly higher in the infection group. Thirty-day morbidity was 51.8% for the endoleak group and 83% for the infection group (P = 0.08). There were only 2 deaths in the cohort within 30 days, both in the infection group. Twenty-seven patients were alive at a mean follow-up of 1.9 years (range 0.1–8.4 years). Conclusions Endograft explantation is a challenging operation with high morbidity and mortality. Furthermore, patients with an infectious etiology have significantly worse outcomes than those requiring explantation for endoleaks.

Introduction Flow-limiting lesions or embolic phenomena can produce vertebrobasilar ischemia. This study aims to differentiate the pathophysiology of vertebral ischemia and examine contemporary outcomes after distal vertebral reconstruction. Methods Between February 2005 and November 2011, 41 consecutive distal vertebral artery (VA) reconstructions were performed in 34 patients, including bypass to the third portion of the VA (V3) at the C1-2 level (n = 24) or the C0-1 level (n = 7); transposition of the external carotid artery or its occipital branch onto V3 (n = 6); transposition of V3 onto the internal carotid artery (n = 3); and bypass from the ipsilateral subclavian artery to V3 (n = 1). Six patients required a concomitant carotid intervention, and nine patients required a partial resection of the C1 transverse process. Symptoms, present in 91% of patients, were attributed to a flow-limiting lesion in 16 (52%), to embolization in nine (29%), and to a mixed etiology in six (19%). Results Intraoperatively, five patients required graft revision or conversion of a transposition to a bypass, and two patients required vertebral ligation. Median blood loss was 260 mL. Median hospital length of stay was 1 day. Postoperatively, one patient (2%) required re-exploration for bleeding, a stroke occurred in one patient (2%), and cranial nerve injury occurred in three patients (7%). There were no perioperative deaths. Survival analysis showed that primary patency at 1, 2, and 5 years, respectively, was 74%, 74%, and 54%. Secondary patency was 80% at 1 year and remained so through the end of follow-up at 80 months. A statistically significant difference in patency was noted favoring arterial transposition over vertebral bypass of 100%, 100%, and 83% at 1, 2, and 5 years, respectively, vs 65%, 65%, and 39% ( P = .018). Considering successful redo bypass grafting for late failure, 97% of patients demonstrated preserved patency at their last follow-up. There were two late deaths of unknown etiology and no late strokes. Conclusions Distal VA reconstruction for flow-limiting or embolic lesions provides excellent stroke protection and symptomatic relief with acceptable perioperative risk in selected patients.

Background Chronic occlusion of the femoral or the proximal popliteal vein responsible for venous obstruction and the constellation of clinical sequelae that ensue remains a surgical challenge that carries notable patient morbidity. Sapheno-popliteal bypass (SPB) remains a surgical reconstructive option for select patients that demonstrate patency of the popliteal vein, great saphenous vein, saphenofemoral junction, and iliac veins. We sought to analyze our single-institution experience with this technique. Methods A retrospective review of a single-center experience with SPB was performed. Preoperative risk factors and indications for intervention (ie, venous claudication, ulceration) were identified. Duration of follow-up and endpoints, including clinical improvement, wound healing, patency, and limb loss were assessed. A Kaplan-Meier analysis for primary and secondary patency was performed. Results Seventeen patients underwent SPB for chronic lower extremity venous obstruction between July 1988 and August 2011. Median age at operation was 41 years (range, 23-69 years). There was a male predominance noted (n = 12; 71%). All patients had chronic edema and venous claudication. Five patients (29%) had evidence of venous ulceration preoperatively. Eight patients (47%) underwent a preceding venous intervention (ie, iliac stenting or venous thrombolysis). Three patients had a concomitant arteriovenous fistula, created at the time of bypass to enhance in-flow; three patients underwent concomitant femoral-femoral venous bypass. Four patients (24%) experienced hematoma postoperatively that required operative evacuation; in two patients, compression from this hematoma resulted in early graft occlusion. After a median follow-up of 103 months (range, 3-271 months), 82% of patients experienced near or complete resolution of venous claudication. Three of the five patients with venous ulceration healed their wounds (67%). Of the 16 patients that underwent Duplex scan follow-up, primary patency after a median follow-up of 103 months was 56%, primary-assisted patency was 69%, and secondary patency was 75%. One patient required amputation approximately 21 years after SPB and there were no deaths. This secondary patency rate exceeds previously published patency rates. Conclusions SPB may be indicated for certain patients with chronic venous stasis disease secondary to femoral venous obstruction that have failed other standard therapies. SPB remains a satisfactory and reliable procedure that produces clinical improvement in a selected group of patients and should be considered in a contemporary venous surgical practice.

Anticoagulation remains the standard of care for line-associated upper extremity deep venous thrombosis (UEDVT). This treatment carries the risk of hemorrhagic complications, possibly more so in surgical patients. Considering the low-risk profile of UEDVT-which is associated with fewer, less severe pulmonary emboli than lower extremity deep venous thrombosis-current UEDVT treatment guidelines may be overly aggressive. The goal of this study was to review outcomes of line-associated UEDVT in critically ill patients and to define the efficacy of current treatment protocols in pulmonary embolism (PE) prevention while avoiding hemorrhagic complications.A retrospective review was performed of 193 consecutive patients admitted to the medical and surgical intensive care unit (ICU) at a tertiary care hospital between 2009 and 2014 diagnosed with acute line-associated UEDVT by duplex ultrasound. The examined treatment arms included anticoagulation with intent to reach therapeutic levels, prophylactic or subtherapeutic anticoagulation, and no anticoagulation. Primary outcomes included major hemorrhage (defined as any intracranial hemorrhage or any hemorrhage resulting in transfusion, ICU readmission, or death), PE, in-hospital mortality, total hospital length of stay (LOS), and ICU LOS.Of the 10,907 patients, 161 (1.48%) were diagnosed with acute line-associated UEDVT, 81 of 6027 in the medical ICU (1.34%) and 80 of 4880 in the surgical ICU (1.64%), after exclusion of 32 patients with concurrent lower extremity deep venous thrombosis. In total, 122 patients (75.8%) received anticoagulation with intent to reach therapeutic levels, 23 (14.3%) received prophylactic anticoagulation, and 16 (9.94%) received no anticoagulation. Major hemorrhage was significantly more common than symptomatic PE in all patients (15.5% vs 4.97%; P .001). A single fatal PE and two fatal hemorrhages were recorded across the series. There was no significant difference in in-hospital mortality (34.8% vs 16.7%; P = .726) or ICU LOS (33.1 vs 18.3 days; P = .739) for patients who developed major hemorrhage or symptomatic PE. On multivariate analysis, incidence of symptomatic PE was not significantly related to Acute Physiology and Chronic Health Evaluation III score (P = .963), anticoagulation regimen (P = .940), catheter type (P = .313), or bacteremia (P = .833).Major hemorrhagic complications are more common than symptomatic PE after anticoagulation for line-associated UEDVT in ICU patients, raising concern that current treatment guidelines are too aggressive. These data necessitate further prospective investigation to determine the optimal treatment protocol for line-associated UEDVT in this critically ill cohort.

Background The purpose of this study is to better define the clinical relevance of aneurysms affecting collateral vessels in patients with celiac artery (CA) occlusive disease. Methods True pancreaticoduodenal artery (PDA) and gastroduodenal artery (GDA) aneurysms associated with CA stenoses or occlusions reported from 1970 to 2010 in the English literature and similar cases treated at the University of Michigan were reviewed. Clinical presentations and differing treatment modalities were documented and analyzed. Results One hundred twenty-five patients having CA occlusive disease exhibited true arterial aneurysms affecting the PDA (105 patients), GDA (10 patients), or both PDA and GDA and their branches (10 patients). Aneurysm size averaged 2.1 cm. Included were 110 patients culled from the literature and 15 treated by the authors. The mean age of patients in this series was 59 years and there was no gender predilection. Aneurysms were asymptomatic in 26%. Abdominal pain affected 54% of the patients, including all who experienced rupture. Rupture occurred in 48 patients of whom 15 were hemodynamically unstable, including 6 who died. Surgical interventions included endovascular embolization (39), aneurysmectomy alone (25), and aneurysmectomy with arterial reconstruction (20). Salutary outcomes occurred in 91% of the cases. Open surgical procedures have remained constant, but were equaled by endovascular interventions in 1996, with the latter having increased 3-fold in the past 15 years. Conclusions PDA and GDA aneurysms associated with CA occlusive disease carry a high risk of nonfatal rupture, warranting early treatment. Endovascular and open interventions may be successfully undertaken with minimal risks in treating these uncommon aneurysms.

Background Iatrogenic femoral artery trauma complicates the course of critically ill neonates and children. Complications from persistent arterial occlusion may include claudication and limb length discrepancies. Data supporting risk factors for such and need for revascularization are lacking. Methods Review of a prospectively maintained database at a tertiary institution of iatrogenic pediatric femoral artery injuries incurred between 2013 and 2014 was performed. Additional injuries were identified by review of pediatric arterial duplex performed between 2008 and 2013. Demographics, risk factors, and outcomes were queried. Data analysis utilized Fischer's exact t-test and logistic regression. Results Seventy-six patients were identified of which 68 presented with acute limb ischemia (ALI) and 8 with chronic iliofemoral arterial occlusion resulting in claudication (n = 6) or limb length discrepancy (n = 2). Mean weight at injury was 6.3 kg; mean age at injury was 49 weeks (50% aged

The spectrum of chronic venous disease (CVD) is well documented in adults; clinical guidelines standardize diagnosis and treatment. There is a paucity of data published commenting on pediatric CVD exclusive of Klippel-Trénaunay syndrome (KTS) and post-thrombotic syndrome.This study aimed to define patterns of pediatric venous disease. All venous reflux studies performed on patients 18 years of age between January 2012 and June 2014 were reviewed. Study indication, patient history, clinical examination, and duplex ultrasound results were queried and described. Venous reflux parameters were compared using one-way analysis of variance.Twenty patients were evaluated. All presented through the vascular surgery or multidisciplinary venous clinic at a tertiary academic medical center. Indications for referral included swelling (n = 10), varicose veins (n = 9), and rubor/acrocyanosis (n = 3); two patients carried a diagnosis of KTS. Mean age at study was 13 years (range, 5-17 years). Clinical examination revealed the following: dependent rubor (n = 3); edema (n = 9); and varicose veins or venous abnormality concerning for venous malformation (n = 9). There were no stigmata of chronic inflammation, hyperpigmentation, or ulceration; 90% of patients (n = 18) demonstrated venous reflux by duplex ultrasound interrogation. Mean right great saphenous vein (GSV) diameter was 0.49 cm (range, 0.31-0.66 cm); mean left GSV diameter was 0.55 cm (range, 0.24-0.93 cm). Adjunctive studies were often used (including magnetic resonance venography and lymphoscintigraphy). Despite the presence of venous reflux on imaging, an alternate diagnosis was made in 8 of 18 children (44%), including postural orthostatic hypotension syndrome (n = 2), vascular malformation (n = 2), lymphedema (n = 2), complex regional pain syndrome (n = 1), and acrocyanosis of disuse (n = 1). An additional case of KTS was identified. Three cases referred for varicose veins were diagnosed with venous malformation. Maximum GSV diameter and venous reflux time were compared across patients with isolated CVD, KTS, or an alternate diagnosis (as before). Whereas there was no significant difference in maximum GSV diameter, superficial venous reflux time was significantly increased in the patients with primary CVD and KTS (P = .0394).The differential diagnosis for pediatric lower extremity edema and varicosities is broad; workup often requires adjunctive studies to secure the appropriate diagnosis. Often there is venous reflux present despite an alternative clinical diagnosis. Superficial venous reflux time may aid in the diagnosis of primary CVD. Whereas the clinical significance of pediatric venous reflux remains unclear, ongoing work to expand on venous parameters in healthy pediatric controls is warranted, as is additional follow-up to assess the natural history of pediatric venous disease.

Aneurysmal disease of the internal iliac vein is rare, with no standard indication for or accepted modality of treatment. Here we report an instance of unilateral, primary left internal iliac venous aneurysm and associated pelvic venous insufficiency. Following extensive workup for alternative causes, the aneurysm and left gonadal vein were coil embolized with good effect.

Objective Pediatric abdominal aortic aneurysms (AAAs) are rare. The intent of this report was to review the presentation and surgical management of AAAs in infancy and early childhood. Methods The clinical courses of young children undergoing AAA surgery were subjected to a retrospective review and analysis. Results Eleven children, nine boys and two girls, ranging in age from 2 weeks to 6 years, underwent surgical treatment of AAA at the University of Michigan from 2002 to 2014. Aneurysms were supraceliac (2), suprarenal (2), pararenal (2), or infrarenal (5). Associated iliac aneurysms (3) affected two children. Concomitant stenoses affected the renal (14), superior mesenteric (4), and celiac (3) arteries. AAAs were attributed to developmental defects (7), including three arising immediately beyond aortic narrowings; infection after umbilical artery catheterization (2); tuberous sclerosis (1); and trauma (1). Primary operative interventions included aneurysmectomy with a thoracoabdominal bypass (4), open aneurysmorrhaphy (2), closed aneurysmorrhaphy (2), and aneurysmectomy with an infrarenal aortoaortic bypass (1) or an aortoiliac bypass (2). Perioperative death occurred in one child who had preoperative heart and renal failure. Aortic graft occlusion affected two children at 1 month and 3 years postoperatively. The remaining children incurred no aortic reconstruction-related morbidity. Follow-up among the 10 survivors averaged 4.9 years. Conclusions Successful surgical treatment of AAAs in infants and young children requires careful execution of a diverse group of surgical techniques based on the etiology, the child's size and growth potential, and the aneurysm's location and coexisting branch involvement.

Macrophages are involved in venous thrombus (VT) resolution and vein wall remodeling. This study was undertaken to identify variations in macrophage phenotypes in thrombi and vein wall in multiple models of VT to clarify the natural history of macrophage polarization in clearance of VT. We also sought to demonstrate the feasibility of macrophage phenotyping in human VT.Established murine models of VT were used to mimic the clinical spectrum of human VT (stasis and nonstasis models). Vein wall and thrombi were isolated at acute (2 days) or chronic (6-21 days) time points and analyzed by Bio-Plex assay (Bio-Rad, Carlsbad, Calif) for cytokines (interleukin [IL]-1β, IL-6, IL-10, IL-12), by immunohistochemistry for "M1-like" (IL-12) or "M2-like" (arginase 1 [Arg-1]) markers, and by histology for intimal thickness and collagen content (Sirius red staining). Bone marrow was harvested from animals 2 days after undergoing sham, stasis, or nonstasis surgery. Macrophages were skewed toward M1 using lipopolysaccharide, and RNA analysis was done for inflammatory cytokine genes (IL-1β, IL-12). Human blood samples were similarly analyzed with reverse transcription polymerase chain reaction for macrophage polarization markers (CD206, inducible nitric oxide synthase, CCR2) and thrombi with immunohistochemistry (inducible nitric oxide synthase, Arg-1).Stasis (chronic) and nonstasis (acute and chronic) thrombi were characterized by a predominance in anti-inflammatory (M2) macrophages (n = 4-5/group; P .05). Larger thrombi were found in the stasis model at both time points (n = 3; P .01), correlating with decreased intrathrombus inflammatory (M1) cytokines (IL-1β, P = .03; IL-12, P = .17; n = 4) and diminished inflammatory response of bone marrow-derived macrophages to lipopolysaccharide (IL-1β, P = .03; IL-12, P = .04; n = 4) compared with nonstasis model. Anti-inflammatory (M2 [Arg-1]) macrophage cell counts were elevated in the post-thrombotic vein wall of stasis mice compared with nonstasis mice (acute: n = 4, P .05; chronic: n = 5, P .01), consistent with increased intimal thickness (P .01; n = 4-6) and collagen deposition chronically (P = .005; n = 12). M2-like thrombi (Arg-1, P .05; n = 4-7) and circulating markers (CD206, P .05; n = 9-17) decreased over time in human VT.Experimental VT is characterized by an anti-inflammatory predominant macrophage phenotype, possibly impairing thrombus resolution, and is model dependent. Altering the M1/M2 macrophage balance may accelerate thrombus resolution and allow the development of translatable novel therapies to treat VT and to prevent post-thrombotic syndrome.

Severe hypertension in infancy is a rare cause of failure to thrive. The successful surgical management of this disease in an infant having refractory renovascular hypertension and growth failure is reported.

Renal artery aneurysms are rare in the general population, although the true incidence and natural history remain elusive. Controversy over criteria for repair persists across decades. Indications for repair presently include aneurysm size >2 cm, female gender within childbearing age, symptoms like pain and hematuria, medically refractory hypertension including that associated with functionally important renal artery stenosis, thromboembolism, dissection, and rupture. Conventional surgical reconstruction options are variable and continue to offer technically sound and durable results. Endovascular therapies with novel devices also offer technical success with few major adverse events, and are increasingly employed as indications for intervention broaden. This review summarizes the accumulated evidence on true renal artery aneurysms with a particular focus on contemporary treatment criteria, natural history, options for repair and outcomes following such.

Background—Duplex ultrasonography remains the diagnostic modality of choice used to assess for venous reflux. Historically, our institution's practice assessed for deep venous reflux at the level o...

Although imaging surveillance is mandatory for all patients after endovascular aneurysm repair (EVAR), many patients are not compliant with follow-up. We sought to determine predictors of compliance with EVAR surveillance and to examine how compliance with current surveillance protocols correlates with survival.We analyzed 188 patients who underwent EVAR at our institution for infrarenal abdominal aortic aneurysms (AAAs) between 2001 and 2011. The primary end point was compliance with post-EVAR surveillance recommendations. Univariate analysis included patient demographics and socioeconomic information, AAA characteristics, EVAR hospital course variables, late complications and secondary interventions, length of follow-up, smoking status, family history of AAA, driving distances, primary care providers, and medical comorbidities. Mortality was determined by the Social Security Death Index. Multinomial logistic regressions were fit to identify independent predictors of compliance. Survival plots were generated with the Kaplan-Meier method and compared with the log-rank test. Univariate and multivariate Cox regression analysis was used to determine effect of compliance on survival after adjusting for confounders.Of 188 patients, 89 (47.3%) were 100% compliant with follow-up visits and imaging, 21 (11.1%) were moderately compliant by missing appointments, and 78 (41.4%) were lost to follow-up completely. Overall median age was 74 years, and 81.9% of patients were male. Late complications occurred in 77 patients (40.9%), secondary interventions were performed in 32 patients (17%), and 5-year mortality was 21.2%. Mean follow-up interval was40 months for 100% compliant and moderately compliant patients and20 months for those lost to follow-up (P.0001). In adjusted analysis, late complications (odds ratio [OR], 2.71; 95% confidence interval [CI], 1.32-5.55; P = .007), absence of social work consultation (OR, 2.43; 95% CI, 1.12-5.27; P = .024), and family history of AAA (OR, 2.67; 95% CI, 1.06-6.75; P = .037) were associated with 100% compliance, whereas shorter driving distances (P = .051) and shorter hospital stay (P = .056) approached significance. Transient ischemic attack or stroke (OR, 3.59; 95% CI, 1.18-10.91; P = .024) was the only variable independently associated with moderate compliance. Compared with patients lost to follow-up, 100% compliant patients had worse survival (log-rank test, P = .033), whereas moderately compliant patients' survival was not significantly different (log-rank test, P = .149). In adjusted Cox regression analysis, 100% compliant patients had decreased survival duration (rate ratio, 2.67; 95% CI, 1.18-6.06; P = .018) compared with those lost to follow-up.Follow-up surveillance is incomplete for more than half of patients who undergo EVAR at our institution, and patient compliance can be predicted by covariates mentioned before. Compliance with current surveillance regimens does not confer a survival benefit. Further research individualizing surveillance protocols based on risk level of late complications and noncompliance and prospective studies examining resulting survival benefits of compliance are warranted.

Introduction: Diabetic wounds are characterized by a chronic inflammatory state that is maintained by overexpression of pro-inflammatory cytokines generated by macrophages. In normal wound healing, macrophages mobilized from the circulation initially exhibit an M1 phenotype and secrete pro-inflammatory mediators (i.e., IL-12) followed by a prolonged M2 anti-inflammatory phase. In type 2 diabetes (T2D), this M1 to M2 switch appears to be markedly attenuated. We have previously demonstrated that post-translational histone methylation changes in BM cells are maintained in peripheral macrophages and promote an M1 dominant phenotype in T2D wounds that result in impaired wound healing. We hypothesize that chimeric mice reconstituted with bone marrow from our T2D murine model will demonstrate delayed wound healing and expression of this epigenetic signature in peripheral wound macrophages. Methods: BM chimeras were created using GFP+ mice on a C57BL/6 background. GFP+ mice were fed a high-fat diet (HFD, 60% fat) for 14 weeks and BM from these mice and normal diet (ND, 12% fat) mice was transferred into irradiated recipients. Change in wound area compared to initial wound size using Image J software (NIH) at day 3 post-wounding. Levels of the demethylase enzyme, Jmjd3, in macrophages (CD11b + ) MACS isolated from wounds at day 3 were quantified by RT-PCR in ND→ND and HFD→ND GFP + chimeric mice. (N=8) Data are expressed as mean ± S.E. Results: Peripheral blood analysis was performed weekly and at 8 weeks confirmed 96.5% donor chimerism. Wound healing was significantly delayed in HFD→ND GFP + chimeric mice compared to controls and analysis of wound tissue macropahges in mice at day 3 post-wounding demonstrated increased Jmjd3 and IL-12 production. Discussion: Epigenetic changes in BM cells appear to be maintained in peripheral wound macrophages and contribute to increased M1 macrophages and impaired wound healing in T2D wounds.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays. ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC. Our results identify a DNA repair pathway leading from MK2 and ATM to ATDC, suggesting its candidacy as a therapeutic target to radiosensitize PDAC and improve the efficacy of DNA-damaging treatment. Cancer Res; 74(6); 1778–88. ©2014 AACR.

Infections involving the aorta are associated with high rates of morbidity and mortality, and their management is complex. Saturating Dacron grafts in rifampin (60 mg/mL) inhibits the growth of organisms commonly found to be involved in both primary aortic infections and aortoenteric fistulas. Open repair and replacement of the aorta with rifampin-soaked Dacron grafts is frequently used in clinical practice and is considered a viable option for open repair with a low recurrence of infection; however, the morbidity and mortality of the procedure is significant. More recently, patients who are high risk for open surgery have been managed with endografts to treat infected aortas and aortoenteric fistulas with limited success, a high recurrence rate, and elevated mortality. We describe a technique to expose Dacron endografts with rifampin delivered via injection port or into the sheath before deployment in selected patients with aortic infections. We used this novel technique in 2 patients who were high risk for open repair: 1 with a bleeding aortoenteric fistula and 1 with mycotic abdominal aortic aneurysm. The first patient tolerated 1.5 years without surgical correction of the duodenal defect after placement of a rifampin-treated endograft. This allowed her to recover and ultimately undergo definitive repair under elective circumstances. Our second patient remains without evidence of recurrence 1 year after implantation for a mycotic abdominal aortic aneurysm. Following the principles of rifampin use in open vascular repairs, treating Dacron endografts with rifampin may add similar antimicrobial resistance when used to treat selected aortic infections.

Introduction Cigarette smoke has a strong correlation with abdominal aortic aneurysm (AAA) formation and is characterized by increased levels of MMP9 in the aorta. We hypothesized that smoke-induced MMP9 regulation is mediated by the Jak/Stat pathway thereby contributing to AAA formation. Methods Aqueous extract of cigarette smoke (AEC) was applied to male rat aortic vascular smooth muscle cells (RASMC) for 24 hours (h) in serum free medium (SFM), using SFM alone for controls. Media were collected for MMP2 and MMP9 zymography and proteins extracted from cells for phospho-Stat3 (pStat3), total Stat3 (T-Stat3), phospho-Jak2 (pJak2) and total Jak2 (T-Jak2) western blots. RASMC were transfected by siRNAs for Jak2 and Stat3 before AEC treatment to evaluate induction of MMPs. Coimmunoprecipitation and immunofluorescence microscopy investigated complex formation and cellular distribution of Jak2 and Stat3 following AEC treatment. Results MMP9 was increased in the medium of the AEC treated RASMC (P=0.005) and pro-MMP2 slightly elevated (P=0.055) at 24h compared to controls. By western blot protein extracts from AEC treated RASMC showed up regulation of pStat3, pJak2 and T-Jak2 and stable T-Stat3 compared with controls. siRNA transfection of RASMC for Jak2, Stat3 and a combination of Jak2 and Stat3 reduced MMP9 (P Conclusion This study suggests that cigarette smoke may result in AAA formation through Jak/Stat-mediated MMP9 production. siRNA inhibition of the Jak/Stat pathway greatly reduced AEC-induced MMP9 by RASMC and suggests a potential therapeutic target for the treatment of AAA.

Results: 312 patients underwent revascularization; 194 with open and 118 with endoscopic GSV harvest. There were no differences between groups in age, medical comorbidities, smoking status, prior interventions, treatment indication (CLI: 81% OVH, 83% EVH), or proximal/distal anastomotic site. Mean operative times were 262 minutes for OVH and 323 minutes for EVH (P < .001). Mean follow-up was 556 days (OVH) and 595 days (EVH). 18% of OVH grafts and 28% of EVH grafts had an intervention during follow-up (P 1⁄4 .048). Median time to intervention was 201 days (OVH) vs 126 days (EVH) (P 1⁄4 .192). Amongst interventions, there was no difference in the number that were surgical: 51.4% (OVH) vs 63.6% (EVH) (P 1⁄4 .337). Mean number of stenoses treated per intervention was 1.1 (OVH) vs 1.2 (EVH) (P 1⁄4 .552). Median stenosis length was 2.1 cm (OVH) vs 2.6 cm (EVH) (P 1⁄4 .724). Three-year primary patency was 51% (OVH) vs 41% (EVH) (P 1⁄4 .057). Secondary patency at three years was 72% (OVH) vs 63% (EVH) (P 1⁄4 .325). Overall and harvest related wound complications were 44.8% and 28% (OVH) vs 33.9% and 10.8% (EVH) (P 1⁄4 .059 and P < .001). Limb salvage for CLI was 88.9% (OVH) and 91.2% (EVH) at 3 years (P 1⁄4 .646). Conclusions: OVH and EVH have similar long-term patency, failure mechanisms and limb salvage. Harvest related wound complications are less with EVH but overall wound complications are similar and operative times are longer for EVH and more interventions are required for EVH to maintain patency. Open GSV harvest is preferred to EVH for infrainguinal reconstructions in a predominantly CLI population.

Venous thromboembolic disease (VTE) remains a significant source of morbidity and mortality. As non-specific subjective complaints and a paucity of objective clinical examination findings complicate the diagnosis of both deep venous thrombosis (DVT) and pulmonary embolism, diagnostic modalities remain essential. Compression ultrasound remains the gold standard for DVT diagnosis. Reliable imaging is not always available making a serologic diagnosis, or biomarker, highly desirable. While D-dimer, a highly sensitive biomarker, is useful for excluding acute VTE, it lacks the specificity necessary for diagnostic confirmation. As such, ongoing research efforts target and support the utility of alternative plasma biomarkers to aid in the diagnosis of VTE including selectins, microparticles, IL-10 and other inflammatory markers. These molecular markers may also predict recurrence risk, guide length and modality of treatment, and predict which thrombi will resolve spontaneously or recanalize, thus potentially identifying patients who would benefit from more aggressive therapies than standard anticoagulation.

The treatment of occlusive vascular disease has evolved considerably over the past decades, with management strategies shifting from open surgical approaches toward less-invasive endovascular solutions or hybrid open and endovascular therapies. The treatment of aortoiliac occlusive disease has followed a similar pattern, with a more aggressive, minimally invasive approach being used even for long-segment iliac artery occlusions. Regardless of the type of treatment, however, optimal results are still limited by restenosis. This is also true in virtually all locations undergoing treatment of arterial occlusive disease. The current review seeks to explore the medical therapy and treatment options available for preventing restenosis in the iliac artery following intervention. Here we include data regarding prevention of restenosis in other arterial locations. Finally, novel therapies not currently available for iliac artery use but showing promise in prevention of arterial restenosis are reviewed.

Objective Pediatric arterial aneurysms are extremely uncommon. Indications for intervention remain poorly defined and treatments vary. The impetus for this study was to better define the contemporary surgical management of pediatric nonaortic arterial aneurysms. Methods A retrospective analysis was conducted of 41 children with 61 aneurysms who underwent surgical treatment from 1983 to 2015 at the University of Michigan. Arteries affected included: renal (n = 26), femoral (n = 7), iliac (n = 7), superior mesenteric (n = 4), brachial (n = 3), carotid (n = 3), popliteal (n = 3), axillary (n = 2), celiac (n = 2), ulnar (n = 2), common hepatic (n = 1), and temporal (n = 1). Intracranial aneurysms and aortic aneurysms treated during the same time period were not included in this study. Primary outcomes analyzed were postoperative complications, mortality, and freedom from reintervention. Results The study included 27 boys and 14 girls, with a median age of 9.8 years (range, 2 months-18 years) and a weight of 31.0 kg (range, 3.8-71 kg). Multiple aneurysms existed in 14 children. Obvious factors that contributed to aneurysmal formation included: proximal juxta-aneurysmal stenoses (n = 14), trauma (n = 12), Kawasaki disease (n = 4), Ehlers-Danlos type IV syndrome (n = 1), and infection (n = 1). Preoperative diagnoses were established using arteriography (n = 23), magnetic resonance angiography (n = 6), computed tomographic arteriography (n = 5), or ultrasonography (n = 7), and confirmed during surgery. Indications for surgery included risk of expansion and rupture, potential thrombosis or embolization of aneurysmal thrombus, local soft tissue and nerve compression, and secondary hypertension in the case of renal artery aneurysms. Primary surgical techniques included: aneurysm resection with reanastomsis, reimplantation, or angioplastic closure (n = 16), interposition (n = 10) or bypass grafts (n = 2), ligation (n = 9), plication (n = 8), endovascular occlusion (n = 3), and nephrectomy (n = 4) in cases of unreconstructable renal aneurysmal disease. Later secondary operations were required to treat stenoses at the site of the original aneurysm repairs (n = 2) and new aneurysmal development (n = 1). Postoperative follow-up averaged 47 months (range, 1-349 months). No major perioperative morbidity and no mortality was encountered in this experience. Conclusions Pediatric arterial aneurysms represent a complex disease that affects multiple vascular territories. Results of the current series suggest that individualized surgical treatment, ranging from simple ligations to major arterial reconstructions, was durable and can be undertaken with minimal risk.

Pancreatic cancer is a highly lethal disease characterized by chemotherapy and radiation resistance. We have previously shown that Ataxia-Telangiectasia Group D-Associated gene (ATDC) is highly expressed in pancreatic cancer and stimulates cell proliferation via activation of the β-catenin pathway (Cancer Cell, 2009). In addition, ATDC expression induces cellular resistance to ionizing radiation and ATDC harbors a putative SQ motif (unpublished data). The ATM signaling pathway is induced in response to ionizing radiation (IR) and activates the DNA damage response (DDR) by phosphorylation of downstream targets including H2AX, p53 and other cell cycle checkpoint and DNA repair proteins having SQ motifs. We postulated that ATDC induces cellular resistance to ionizing radiation via participation in the ATM-induced DDR and sought to define the mechanism(s) by which this occurs. To explore the role of ATDC in radio- resistance, ATDC was either overexpressed in HEK293 cells or knocked down in several pancreatic cancer cell lines and sensitivity to IR was measured by clonogenic and apoptosis assays. ATDC overexpression in HEK293 cells, that lack endogenous expression of ATDC, promoted resistance to IR and ATDC knockdown sensitized pancreatic cell lines with high endogenous levels of ATDC to IR. IR induces DNA double strand breaks (DSBs) which are marked by γ-H2AX foci in cellular nuclei. ATDC overexpression correlated with more rapid resolution of γ-H2AX foci consistent with faster repair of DSBs. To test whether ATDC induces radioresistance in vivo, we treated mice with established orthotopic BxPC-3 xenograft tumors with ATDC shRNA-targeting nanovectors which reduced ATDC levels in the tumors. Treatment of orthotopic pancreatic tumors with ATDC shRNA-targeting nanovectors decreased tumor growth, and consistent with in vitro data, also sensitized tumors to fractionated IR, confirming the importance of ATDC in pancreatic tumor radioresistance. To explore the mechanism by which ATDC induces resistance to IR, we next interrogated the ATM signaling pathway. ATDC harbors serine residues at 550 and 552 and S550 is a putative SQ motif that may be phosphorylated by ATM. Consistent with a role in the ATM-induced DDR signaling pathway, ATDC was phosphorylated on S550 following exposure to IR in an ATM-dependent manner. To determine if phosphorylation of S550 was responsible for the radioresistant phenotype, S550 and S552 were replaced with alanines. Overexpression of ATDC S550A, but not S552A, blocked ATDC- associated radioresistance, and left β-catenin-stimulated cell proliferation by ATDC intact, suggesting a separation of function between ATDC-dependent induction of the β-catenin pathway and radioresistance. Although ATDC S550 phosphorylation was dependent upon ATM activation, ATM was unable to directly phosphorylate ATDC on S550 as determined in an in vitro kinase assay. MK2 also plays an important role in ATM-induced DDR in p53 mutant cells and its kinase activity is induced by ATM after IR. MK2 was able to phosphorylate ATDC on S550 in vitro and siRNA-mediated knockdown of MK2 blocked ATDC’s radioprotective effect in cell lines. Moreover, MK2 colocalized with ATDC in cells following IR. In summary, these results suggest that ATDC is a member of the DDR and is phosphorylated directly at its S550 site by MK2 kinase in an ATM-dependent manner following exposure to ionizing radiation. Phosphorylation at S550 is specifically required for the radio-protective function of ATDC. Our data suggest that ATDC, and potentially MK2, represent promising new therapeutic targets for the sensitization of pancreatic adenocarcinoma to radiation therapy. Citation Format: Lidong Wang, Theodore Lawrence, Liang Xu, Chris Canman, Mats Ljungman, Diane Simeone, Huibin Yang, Phillip Palmbos, Gina Ney, Taylor Ann Detzler, Dawn Coleman, Mary Davis, Kevin Hicks, Corey M. Helchowski. Radiation-induced phosphorylation of ATDC via ATM/MAPKAP kinase 2 signaling mediates radioresistance of pancreatic cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr A93.

To examine the outcomes following interventions for type II endoleaks in patients with aneurysm sac expansion after endovascular aneurysm repair (EVAR).A retrospective review was conducted of all patients who underwent treatment for type II endoleak from July 2001 to September 2010 in a single center. In this time period, 29 (4.7%) patients (22 men; mean age 78.6 years, range 54-87) were identified as having a type II endoleak and enlargement of the aneurysm sac, meeting the criterion for treatment. All patients had at least one attempted percutaneous intervention. Patients were followed both clinically and radiographically, with computed tomographic angiography every 3 to 12 months, over a follow-up period that ranged from 1 to 10 years (mean 3.5).Forty-eight interventions were performed on the 29 patients. Of these, 15 (56%) patients underwent multiple (2-4) procedures. Of the 11 endoleaks with an isolated inferior mesenteric artery identified as the source, initial success for transarterial embolization at 2 years was 72%, with 2 of the failures having successful secondary interventions. For the 18 endoleaks with a lumbar source, the success of the initial intervention was 17% at 2 years; repeated embolization attempts produced a 40% secondary success rate. Seven (24%) patients had continued endoleak despite multiple treatment attempts; 3 ultimately required elective aortic graft explantation. There were no ruptures or deaths during the study period. In a comparison of type II endoleak patients who had stable aneurysm sacs and those who had persistent sac expansion, the only significant differences in preoperative anatomical characteristics were a lower prevalence of mural thrombus (p = 0.036) and longer right iliac arteries (p = 0.012) in the group with sac expansion. Independent predictors of type II endoleak were mural thrombus (p0.001), patent lumbar arteries (p = 0.004), aneurysm length (p = 0.011), and iliac artery length (p = 0.004).This study demonstrates that most patients require multiple reinterventions to treat type II endoleaks; specifically, lumbar artery embolization carries a low midterm success rate.

Developmental coarctation, hypoplasia, and occlusion of the abdominal aorta is a rare disease encompassing many differing etiologies and diverse methods of treatment. Long-segment thoracoabdominal aortic occlusion, an extreme manifestation of this disorder, has not previously been reported in children. Two pediatric patients with this entity, a 5- and 13-year-old with uncontrolled hypertension, underwent extensive arterial reconstructions for this entity and provided the impetus for this report. An ascending thoracic aorta to infrarenal aortic expanded polytetrafluoroethylene bypass was undertaken in the younger child. A distal thoracic aorto-bi-iliac artery expanded polytetrafluoroethylene bypass, with implantation of the left renal artery to one graft limb and a right renal artery bypass originating from the other limb, was performed in the older child. There were no major perioperative complications. Both patients were discharged with easily controlled blood pressures. They have remained normotensive at 13 and 14 months follow-up.

ObjectiveRenal dysfunction following endovascular abdominal aortic aneurysm repair (EVAR) remains a significant source of morbidity and mortality. We studied the use of carbon dioxide (CO2) as a non-nephrotoxic contrast agent for EVAR.MethodsRecorded data from 114 consecutive patients who underwent EVAR with CO2 as the contrast agent over 44 months were retrospectively analyzed. CO2 was used exclusively in 72 patients and in an additional 42 patients iodinated contrast (IC) was given (mean, 37 mL). Renal and hypogastric artery localization and completion angiography were done with CO2 in all patients, including additional arterial embolization in 16 cases. Preoperative National Kidney Foundation glomerular filtration rate (GFR) classification was normal in 16 patients, mildly decreased in 52, moderate to severely decreased in 44, and two patients were on dialysis.ResultsAll graft deployments were successful with no surgical conversions. CO2 angiography identified 20 endoleaks (two type 1, 16 type 2, and two type 4) and three unintentionally covered arteries. Additional use of IC in 42 patients did not modify the procedure in any case. When compared with a cohort of patients who underwent EVAR using exclusively IC, the operative time was shorter with CO2 (177 vs 194 minutes; P = .01); fluoroscopy time was less (21 vs 28 minutes; P = .002), and volume of IC was lower (37 vs 106 mL; P < .001). Postoperatively, there were two deaths, two instances of renal failure requiring dialysis, and no complications related to CO2 use. Among patients with moderate to severely decreased GFR, those undergoing EVAR with IC had a 12.7% greater decrease in GFR compared with the CO2 EVAR group (P = .004). At 1, 6, and 12-month follow-up, computed tomography angiography showed well-positioned endografts with the expected patent renal and hypogastric arteries in all patients and no difference in endoleak detection compared with the IC EVAR group. During follow-up, eight transluminal interventions and one open conversion were required, and no aneurysm-related deaths occurred.ConclusionsCO2-guided EVAR is technically feasible and safe; it eliminates or reduces the need for IC use, may expedite the procedure, and avoids deterioration in renal function in patients with pre-existing renal insufficiency. A prospective trial comparing CO2 with IC during EVAR is warranted.