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OBJECTIVE To compare outcomes of fenestrated (FEVAR) and open repairs of complex abdominal aortic aneurysms (cAAA). BACKGROUND FEVAR has emerged as an alternative to open surgery for treating cAAA, but direct comparisons are limited. METHODS We studied all repairs of intact or symptomatic cAAA in the Vascular Quality Initiative between 2012 and 2018, excluding chimney/snorkels and any devices implanted under Investigational Device Exemption studies. We compared open repairs, commercially available FEVAR devices and physician-modified endografts (PMEG) using inverse probability weighting. As a secondary analysis, we compared PMEG separately. RESULTS We identified 3253 cAAA repairs: 2125 open (65%), 877 FEVAR (27%), and 251 PMEG (8%). Patients undergoing FEVAR were older, with larger aneurysms, and more comorbidities. Propensity-weighted perioperative mortality was similar between open repair and FEVAR (4.7% vs 3.3%, respectively, P = 0.17), but open repair was associated with higher rates of myocardial infarction (5.0% vs 3.0%, P = 0.03), acute kidney injury (25% vs 16%, P < 0.001), and new dialysis (4.3% vs 2.1%, P = 0.003). However, propensity-weighted long-term mortality was higher following FEVAR [Hazard Ratio (HR) 1.7 (1.1-2.6), P = 0.02]. Although outcomes of commercially available FEVAR and PMEG were similar, there was a trend toward higher long-term mortality with PMEG compared to FEVAR [HR 1.7 (0.9-3.1), P = 0.09). CONCLUSIONS In patients undergoing cAAA repair, open surgery was associated with higher overall survival than FEVAR and similar perioperative mortality, but longer lengths of stay, and higher rates of postoperative renal dysfunction and MI. PMEG were associated with similar perioperative results as commercially available FEVAR, but further study is needed to establish their long-term durability.

Dyskeratosis congenita is an inherited disorder characterized by defects in the ability of cells to maintain telomeres. Patients commonly present with pediatric bone marrow failure and liver and/or pulmonary fibrosis in the fourth to fifth decade of life. The prevalence of dyskeratosis congenita is estimated as 1 in 1 million; however, due to the incomplete penetrance of disease, the true prevalence is unknown.[1] Defects in at least 10 distinct telomere-associated genes lead to the development of premature stem cell and tissue failure. Patients with dyskeratosis congenita also have a predisposition to develop cancer; approximately 5% develop hepatocellular carcinoma.[2] Interestingly, in the general population, hepatocellular carcinoma often arises in the setting of cirrhosis and shortened hepatic telomeres and is associated with reactivation of hepatic telomerase in more than 90% of patients.

There is limited data on the effect of antiviral therapies on clinical outcomes in HIV and hepatitis B virus (HBV)-infected individuals in sub-Saharan Africa.Single center, prospective longitudinal cohort study at Management and Development for Health supported HIV Care and Treatment clinics in Dar es Salaam, Tanzania.Between April 2014 and December 2015, HIV-infected, HBV-infected and HIV/HBV-coinfected, treatment naïve, Tanzanian adults more than 18 years of age were eligible for enrollment and followed for 10-18 months after initiating antivirals. All HIV-infected and HIV/HBV-coinfected participants received tenofovir, lamivudine and efavirenz; HBV-infected participants received lamivudine. Multivariate regression models were constructed to identify factors associated with mortality in HIV-infected and HIV/HBV-coinfected participants.A total of 265 HIV-infected, 165 HBV-infected and 64 HIV/HBV-coinfected participants were analyzed. At baseline, HBV-infected participants were younger and had a higher BMI than HIV-infected and HIV/HBV-coinfected participants. After a median of 371 (interquartile range 50) days on treatment, there were 40 deaths. Mortality was significantly higher among HIV/HBV-coinfected participants compared with HIV and HBV-infected participants [HIV/HBV-coinfected 12 of 64 (19%) vs. HIV-infected 26 of 265 (10%) and HBV-infected two of 265 (1%), P 0.01]. High baseline HIV RNA and low hemoglobin levels, but not HBV coinfection were independently associated with early mortality in multivariate analyses of HIV-infected participants.High rates of early mortality were observed after treatment initiation in HIV/HBV-coinfected individuals compared with participants with HIV or HBV alone, despite robust aspartate aminotransferase to platelet ratio index declines and high rates of virologic suppression. HIV rather than HBV-related factors are more important contributors to mortality in these individuals.

In sub-Saharan Africa, the burden of liver disease associated with chronic hepatitis B virus (HBV) and HIV is unknown. We characterized liver disease using aspartate aminotransferase-to-platelet ratio index (APRI) and FIB-4 in patients with HIV, HBV, and HIV/HBV coinfection in Tanzania.Using a cross-sectional design, we compared the prevalence of liver fibrosis in treatment-naive HIV monoinfected, HBV monoinfected, and HIV/HBV-coinfected adults enrolled at Management and Development for Health (MDH)-supported HIV treatment clinics in Dar es Salaam, Tanzania. Risk factors associated with significant fibrosis (APRI0.5 and FIB-41.45) were examined.Two hundred sixty-seven HIV-infected, 165 HBV-infected, and 63 HIV/HBV-coinfected patients were analyzed [44% men, median age 37 (interquartile range 14), body mass index 23 (7)]. APRI and FIB-4 were strongly correlated (r = 0.78, P0.001, R = 0.61). Overall median APRI scores were low {HIV/HBV [0.36 (interquartile range 0.4)], HIV [0.23 (0.17)], HBV [0.29 (0.15)] (P0.01)}. In multivariate analyses, HIV/HBV coinfection was associated with APRI0.5 [HIV/HBV vs. HIV: odds ratio (OR) 3.78 (95% confidence interval: 1.91 to 7.50)], [HIV/HBV vs. HBV: OR 2.61 (1.26 to 5.44)]. HIV RNA per 1 log10 copies/mL increase [OR 1.53 (95% confidence interval: 1.04 to 2.26)] and HBV DNA per 1 log10 copies/mL increase [OR 1.36 (1.15, 1.62)] were independently associated with APRI0.5 in HIV-infected and HBV-infected patients, respectively.HIV/HBV coinfection is an important risk factor for significant fibrosis. Higher levels of circulating HIV and HBV virus may play a direct role in liver fibrogenesis. Prompt diagnosis and aggressive monitoring of liver disease in HIV/HBV coinfection is warranted.

In humans with nonalcoholic fatty liver, diabetes is associated with more advanced disease. We have previously shown that diabetic db/db mice are highly susceptible to methionine choline-deficient diet (MCD)-induced hepatic injury. Because activation of the unfolded protein response (UPR) is an important adaptive cellular mechanism in diabetes, obesity, and fatty liver, we hypothesized that dysregulation of the UPR may partially explain how diabetes could promote liver injury. Db/db and db/m mice were fed the MCD or control diet for 4 weeks to characterize differences in UPR activation and downstream injury. Wildtype mice (C57BLKS/J) fed the MCD or control diet were treated with SP600125; a c-Jun N-terminal kinase (JNK) inhibitor and its effect on liver injury and UPR activation was measured. The MCD diet resulted in global up-regulation of the UPR in both diabetic db/db and nondiabetic db/m mice. db/db mice had an inadequate activation of recovery pathways (GADD34, XBP-1(s)) and accentuated activation of injury pathways related to persistent eif2-α phosphorylation (activating transcription factor 4 [ATF-4], C/EBP homologous transcription factor [CHOP], oxireductase endoplasmic reticulum oxidoreductin-1 [ERO-1α], JNK, nuclear factor kappaB [NF-κB]) compared to db/m mice. This led to increased expression of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), ICAM-1, and MCP-1 compared to db/m mice. Interestingly, whereas pharmacologic JNK inhibition did not prevent the development of MCD diet-induced steatohepatitis, it did attenuate UPR and downstream inflammatory signaling. Conclusion: MCD-fed db/db mice develop a more proinflammatory milieu than db/m mice associated with an impaired ability to dephosphorylate eif2-α through GADD34, impairing cellular recovery. These data may enhance our understanding of why diabetics with nonalcoholic steatohepatitis are prone to develop more severe liver injury than nondiabetic patients. (HEPATOLOGY 2011;)

Background: Ependymoma is a rare type of glioma, representing 5% of all CNS malignancies. Radiotherapy (RT) is commonly administered, but there is no standard chemotherapy. At recurrence, ependymoma is notoriously refractory to therapy and the prognosis is poor. In recurrent glioblastoma, encouraging responses with bevacizumab have been observed. Methods: In this Institutional Review Board–approved study, we retrospectively analyzed the records of 8 adult patients treated for recurrent ependymoma and anaplastic ependymoma with bevacizumab containing chemotherapy regimens. We determined radiographic response (Macdonald criteria), median time to progression (TTP), and median overall survival (OS; Kaplan-Meier method). Results: There were 4 men and 4 women with a median age of 40 years (range, 20–65). Prior treatment included surgery (n = 8), RT (8), temozolomide (5), and carboplatin (4). Bevacizumab (5–15 mg/kg every 2–3 weeks) was administered alone (2) or concurrently with cytotoxic chemotherapy including irinotecan (3), carboplatin (2), or temozolomide (1). Six patients achieved a partial response (75%) and 1 remained stable for over 8 months. Median TTP was 6.4 months (95% confidence interval 1.4–7.4) and median OS was 9.4 months (95% confidence interval 7.0–not reached), with a median follow-up of 5.2 months among 5 surviving patients (63%). Conclusions: The radiographic response rate to bevacizumab-containing regimens is high. A prospective study is warranted.

Background— It has been demonstrated recently that carotid stenting can be performed safely in patients ≥80 years of age. However, it is uncertain whether these patients will derive benefit because longevity after revascularization is an important consideration. This study was conducted to determine survival and predictors of mortality of selected elderly patients after stenting. Methods and Results— One hundred forty-two consecutive elderly patients who were non–high risk for stenting underwent 153 procedures. Patients had either symptomatic stenosis ≥50% or asymptomatic stenosis ≥70%. Demographics and in-hospital outcomes were entered into a database; subsequent outcomes and mortality data were obtained retrospectively. Mean±SD age was 83.3±3.1 years. Symptomatic patients accounted for 28%. Overall survival at 3 years was 76% (85% at 2 years). At 1 year, 1 fatal stroke had occurred, with 97% of survivors (n=114) free of neurological events (neurological status was undetermined in the remaining 3%). Predictors of mortality were remote (≥6 months) transient ischemic attack or cerebrovascular accident, smoking history, and creatinine clearance (hemoglobin level showed a strong trend toward achieving significance); for the asymptomatic subgroup, predictors of mortality were smoking history, previous carotid endarterectomy, hemoglobin level, and increasing age. In particular, symptom status and sex were not independent predictors of mortality. Conclusions— This study demonstrates that in selected elderly patients, a high proportion (85%) survived 2 years and >75% survived 3 years after stenting. Carotid stenting may be considered a revascularization option in such patients. Better selection of patients using the predictors of mortality may help to reduce unwarranted procedures and to optimize survival likelihood.

The G2A receptor is a member of the ovarian cancer G protein–coupled receptor 1 family of stress-inducible G protein–coupled receptors. In this study, we examined the hepatobiliary effects of loss of function of G2A in mice fed either a chow or lithogenic diet. G2A-deficient (G2A−/−) mice fed chow had a 25% reduction in biliary phosphatidylcholine content, reduced hepatic gene expression of the phosphatidylcholine transporter adenosine triphosphate–binding cassette B4, and an 8-fold increase in expression of the nuclear receptor liver X receptor (LXR). Despite the increased expression of LXR, transcription of several LXR target genes was reduced. G2A−/− mice fed a lithogenic diet had rapid gallstone formation, an increased cholesterol saturation index, a 2.5-fold increase in farnesoid X receptor expression, a 5-fold increase in LXR expression, and a 90% reduction in cholesterol 7α-hydroxylase expression in comparison with wild-type mice. There were no changes in gallbladder volume. Conclusion: These data demonstrate that the G2A receptor is important for hepatobiliary bile salt, cholesterol, and phospholipid homeostasis and for the pathogenesis of cholesterol gallstone formation. (HEPATOLOGY 2008;48:1138–1148.)

Advances in free-tissue transfer have allowed for lower limb salvage in patients with significant peripheral vascular disease and limb-threatening soft-tissue wounds. The authors retrospectively reviewed their 10-year experience with free flaps for limb salvage in patients with peripheral vascular disease to assess postoperative complication rates and long-term functional outcome. They identified all patients undergoing free-tissue transfer with significant peripheral vascular disease and otherwise unreconstructible soft-tissue defects. Charts were reviewed for perioperative and long-term outcome. Parameters studied included perioperative morbidity and mortality, flap success, bypass graft patency, ambulatory results, and long-term limb and patient survival. Survival data were analyzed using life-table analysis, Kaplan-Meier survival analysis, and Cox testing. A total of 79 flaps were examined in 75 patients with peripheral vascular disease from July of 1990 to November of 1999. All patients would have required a major amputation had free-tissue transfer not been performed. Mean age was 60 years, average hospital stay was 32 days, and perioperative mortality was 5 percent. Within the first 30 days after operation, there were four cases of primary flap loss, and another two were lost as the result of bypass graft failure (8 percent); five of these cases resulted in amputation. There were no primary flap failures after 30 days. Follow-up ranged to 91 months (mean, 24 months). During this time, another 14 limbs were lost, most commonly because of progressive gangrene and/or infection in sites remote from the still-viable free flap. Using Kaplan-Meier survival analysis, 5-year flap survival was 77 percent, limb salvage 63 percent, and patient survival 67 percent. Sixty-six percent of patients were able to ambulate independently with the use of their reconstructed limb at least 1 year after hospital discharge, although some of these later went on to amputation. Free-tissue transfer for lower extremity reconstruction can be performed with acceptable morbidity and mortality in patients with peripheral vascular disease. Flap loss is low, and limb salvage, ambulation, and long-term survival rates in these patients are excellent.

RATIONALE Chronic liver disease is a major cause of morbidity and mortality in patients with HIV. However, autoimmune hepatitis (AIH) in patients with HIV has rarely been reported. Our aim was to evaluate a cohort of patients with HIV and AIH and identify clinical presentations and outcomes. PATIENT CONCERNS Management of autoimmune hepatitis in context of human immunodeficiency virus, long-term outcomes, and safety in setting of underlying immunocompromised state. DIAGNOSES Autoimmune Hepatitis, Human Immunodeficiency Virus, Hepatotoxicity, Liver Injury, Liver Transplantation. INTERVENTIONS We retrospectively reviewed the charts of patients with HIV and AIH based on histological, serologic, biochemical demographic, and clinical data. OUTCOMES Five patients were identified with autoimmune hepatitis; 4 of 5 were women, and all were African or African-American. The age at the time of AIH diagnosis was 46.6 ± 13.4 years. All patients acquired HIV sexually and all had CD4 counts >250 cells/uL (456-1011 cells/uL) and undetectable HIV viral loads at the time of AIH diagnosis. One patient presented with acute liver failure necessitating liver transplantation and developed AIH posttransplantation. At the time of diagnosis, the AST were 350 ± 448 U/L, ALT 247 ± 190 U/L, bilirubin 7 ± 12 mg/dL, and alkaline phosphatase 126 ± 53 U/L. All patients had histologic evidence of AIH on liver biopsies. Patients were successfully treated with prednisone and azathioprine, without a decrease in CD4

Irradiation has been shown to inhibit postangioplasty intimal hyperplasia ("restenosis") in unbranched tubes. It seems likely that irradiation will similarly be able to inhibit intimal hyperplasia after a surgical anastomosis at a biochemical and cellular level, but whether it will produce a clinically relevant or even clinically detectable difference is unproved. One possibility is that no clinical effect may occur; the search for a "cure" for intimal hyperplasia has been long and, as yet, unsuccessful. On the other hand, if a strong effect without insurmountable logistical problems could be produced, one major cause of bypass graft failure would be preventable. Not only would the incidence of late graft occlusion, need for reoperation, and limb loss be reduced, but, if patency of prosthetics could be sufficiently improved, the initial operation could be made much easier, faster, and perhaps safer.

Hepatic uptake of organic cations is essential for the metabolism and secretion of numerous endobiotics and drugs. Several hepatic organic cation transporters have been kinetically defined, yet have not been isolated or cloned. We have isolated a complementary DNA (cDNA) from both murine liver and kidney cDNA libraries (mOct1/Slc22a1), and have functionally expressed it in Xenopus laevis oocytes. Although mOct1/Slc22a1 is homologous to previously cloned rat and human organic cation transporters, organic cation transport kinetics differed markedly. mOct1/Slc22a1-RNA injection of oocytes resulted in the saturable, time- and temperature-dependent uptake of the quaternary organic cation [14C]-tetraethylammonium ([14C]-TEA), with a Km of 38 micromol/L. TEA uptake was inhibited by several other organic cation drugs, but was not inhibited by the organic cation n-methyl-nicotinamide (NMN), being instead stimulated by it (fourfold). [14C]-TEA uptake was also stimulated by an inside-outside proton gradient. mOct1/Slc22a1-injected oocytes transported the organic cations [3H]-1-methyl-4-phenylpyridium and [3H]-choline chloride, but did not transport other classes of organic compounds. mOct1/Slc22a1 encodes for a hepatic and renal organic cation transporter which may be important for the uptake and secretion of cationic drugs and endobiotics.

Objective: We hypothesized that bevacizumab (bev) with or without temozolomide (TMZ) might be effective in treating unresectable pilocytic astrocytoma (PA) in adults. Background PA is a WHO Grade I tumor that is often not completely resectable. TMZ, an alkylating agent, and bev, a blocker of vascular endothelial growth factor (VEGF), are both approved for treatment of glioblastoma. Pathological studies have shown VEGF expression in PA. Design/Methods: We reviewed cases of unresectable PA treated with bev with or without TMZ. We identified 9 patients, 5 male and 4 female, with a median age of 40 years. Six tumors were in the hypothalamus, and 1 each in the thalamus, pineal region, and cerebral peduncle. Two patients were treated in the up-front setting, and 7 were treated for progression after radiation therapy. Three patients had received prior chemotherapy, 1 each PCV, carboplatin, or TMZ. Treatment consisted of bev 5 mg/kg every 14 days, with or without TMZ 150-200 mg/sq m every 5 of 28 days. MR scans were graded according to Macdonald criteria. Results: Seven patients were treated with TMZ plus bev and 2 with bev monotherapy. Median duration of therapy was 351 days for bev and 308 days for TMZ. Seven patients (78%) achieved a partial response, 1 a minor response, and 1 no response. Cyst volumes were decreased in 3 of 4 tumors (75%) with multicystic change. Both patients treated with bev monotherapy achieved a partial response, as did both patients treated in the up-front setting. Visual field or extraocular movement deficits improved significantly in 4 patients. One patient experienced symptomatic intratumoral hemorrhage. One patient died after craniotomy for hemorrhagic tumor progression. Median time to progression on bev was 593 days. Conclusions: Bev when administered with or without TMZ is effective in unresectable adult PA and deserves a Phase II study. Disclosure: Dr. Green has nothing to disclose. Dr. Woyshner has nothing to disclose. Dr. Quan has nothing to disclose. Dr. Cloughesy has received personal compensation for activities with Genentech, Inc., and Roche Diagnostics Corporation.

Glutaraldehyde treated human umbilical veins (Dardik Biograft) were used to bypass short segments of the femoral artery in 15 dogs and were compared to autogenous jugular veins placed in the contralateral femoral artery of each animal. All 15 autogenous jugular veins remained patent for the four month period of observation whereas thrombosis occurred in seven of 15 umbilical vein grafts. This patency rate of 53% was significantly lower than that observed for autogenous jugular veins (p less than 0.01). Neointimal Fibrous Hyperplasia (NFH) a the proximal anastomosis was responsible for six of the seven umbilical vein graft occlusions. Of the eight patent umbilical veins, five had varying degrees of proximal anastomotic stenosis secondary to NFH. Histological examination of each graft revealed significant fibroblastic proliferation and collagen deposition within the lumen of stenosed and thrombosed grafts. Although human umbilical veins have distinct advantages over other prosthetics, such as availability and flexibility, the incidence of experimental neointimal fibrous hyperplasia causing anastomotic stenosis and thrombosis is prohibitively high.

A 5-year experience with 562 carotid endarterectomies, using electroencephalogram (EEG) monitoring and selective shunting, was reviewed. EEG changes occurred in 102 patients (18%). The frequency of EEG changes, as related to cerebral vascular symptoms, was as follows: transient ischemic attacks, seven per cent (19/259); completed strokes, 37% (36/98); vertebral basilar insufficiency, 24% (32/135); asymptomatic, 21% (15/71). Patients with contralateral carotid occlusion exhibited EEG changes in 37% (28/76) of operations. Fifteen patients suffered perioperative strokes (2.6%). Nine of the 15 were associated with a technical problem of either thrombosis of the internal carotid artery (five) or emboli (four). Technical problems were more common when shunts were used (five per cent) than when they were not (0.9%). Patients who suffered strokes prior to surgery were more at risk to develop a perioperative stroke (three per cent) than those not suffering prior strokes (0.3%). The EEG did not change in three patients who had lacunar infarcts prior to surgery and who awoke with a worsened deficit. Our series does not clearly establish the advantages of EEG monitoring, which is expensive (+375/patient) and may not detect ischemia in all areas of the brain. However, the use of shunts may introduce a risk of stroke due to technical error that is equal or greater than the risk of stroke due to hemodynamic ischemia. Since the need for protection is unpredictable by angiographic or clinical criteria, the benefit of EEG monitoring may be in reducing the incidence of shunting in those patients whose tracing remains normal after clamping. The decision to shunt, however, when there is electrical dysfunction after carotid clamping should be based not only on the EEG but also on the clinical signs and computed tomography (CT) scan. Our data does not show a net benefit in selective shunting unless the patient has sustained a stroke prior to surgery.