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Background: Frailty is known to be associated with poorer outcomes in individuals admitted to hospital for medical conditions requiring intensive care. However, little evidence is available for the effect of frailty on patients' outcomes after traumatic brain injury. Many frailty indices have been validated for clinical practice and show good performance to predict clinical outcomes. However, each is specific to a particular clinical context. We aimed to develop a frailty index to predict 6-month outcomes in patients after a traumatic brain injury., Methods: A cumulative deficit approach was used to create a novel frailty index based on 30 items dealing with disease states, current medications, and laboratory values derived from data available from CENTER-TBI, a prospective, longitudinal observational study of patients with traumatic brain injury presenting within 24 h of injury and admitted to a ward or an intensive care unit at 65 centres in Europe between Dec 19, 2014, and Dec 17, 2017. From the individual cumulative CENTER-TBI frailty index (range 0-30), we obtained a standardised value (range 0-1), with high scores indicating higher levels of frailty. The effect of frailty on 6-month outcome evaluated with the extended Glasgow Outcome Scale (GOSE) was assessed through a proportional odds logistic model adjusted for known outcome predictors. An unfavourable outcome was defined as death or severe disability (GOSE score ≤4). External validation was performed on data from TRACK-TBI, a prospective observational study co-designed with CENTER-TBI, which enrolled patients with traumatic brain injury at 18 level I trauma centres in the USA from Feb 26, 2014, to July 27, 2018. CENTER-TBI is registered with ClinicalTrials.gov, NCT02210221; TRACK-TBI is registered at ClinicalTrials.gov, NCT02119182., Findings: 2993 participants (median age was 51 years [IQR 30-67], 2058 [69%] were men) were included in this analysis. The overall median CENTER-TBI frailty index score was 0·07 (IQR 0·03-0·15), with a median score of 0·17 (0·08-0·27) in older adults (aged ≥65 years). The CENTER-TBI frailty index score was significantly associated with the probability of an increasingly unfavourable outcome (cumulative odds ratio [OR] 1·03, 95% CI 1·02-1·04; p<0·0001), and the association was stronger for participants admitted to hospital wards (1·04, 1·03-1·06, p<0·0001) compared with those admitted to the intensive care unit (1·02, 1·01-1·03 p<0·0001). External validation of the CENTER-TBI frailty index in data from the TRACK-TBI (n=1667) cohort supported the robustness and reliability of these findings. The overall median TRACK-TBI frailty index score was 0·03 (IQR 0-0·10), with the frailty index score significantly associated with the risk of an increasingly unfavourable outcome in patients admitted to hospital wards (cumulative OR 1·05, 95% CI 1·03-1·08; p<0·0001), but not in those admitted to the intensive care unit (1·01, 0·99-1·03; p=0·43)., Interpretation: We developed and externally validated a frailty index specific to traumatic brain injury. Risk of unfavourable outcome was significantly increased in participants with a higher CENTER-TBI frailty index score, regardless of age. Frailty identification could help to individualise rehabilitation approaches aimed at mitigating effects of frailty in patients with traumatic brain injury., Funding: European Union, Hannelore Kohl Stiftung, OneMind, Integra LifeSciences Corporation, NeuroTrauma Sciences, NIH-NINDS-TRACK-TBI, US Department of Defense., Competing Interests: Declaration of interests GC reports grants, personal fees, and being an advisory board member for Integra and Neuroptics, all outside of the submitted work. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Objective: Target vessel instability is a relevant complication after thoracoabdominal aortic aneurysms branched endovascular aortic repair (BEVAR). Long-term bridging stent graft (BSG) durability has already been established, but the incidence of long-term complications as component fractures was not deeply investigated. This paper aims to assess BSG fracture incidence and risk factors after BEVAR., Methods: This was a dual-center observational retrospective cohort study. Data of each patient treated with BEVAR between April 2008 and December 2019 were prospectively collected. The primary outcome was the incidence of BSG fracture during follow-up. A logistic regression analysis was performed, including preoperative and postoperative measurements as well as intraoperative details to identify potential risk factors., Results: Two hundred ninety-five target visceral vessels in 91 patients were considered suitable for cannulation. Technical success was 96.9% (286/295 target visceral vessels). The median follow-up was 32.5 months (interquartile range, 14.3-50.1 months). Five BSG fractures (1.75%; 5/286) were detected. Four BSG fractures involved the superior mesenteric artery, and one the celiac trunk. Four different types of fractured stents were detected during follow-up: two Advanta, one BeGraft, one Fluency, and one Viabahn. The median time to BSG fracture was 28.2 months (interquartile range, 11.7-50.8 months). The use of multiple stents (P = .030) and different stent types on the same vessel (P = .004) were associated with BSG fracture at univariable analysis. Using bare-metal stents for distal relining (P = .045) was the only significant factor predisposing to BSG fracture at multiple logistic regression., Conclusions: BSG fracture is a rare but severe complication after BEVAR. It is not related to the stent type used as bridging stent, and it is hardly predictable based on preoperative anatomy. Using multiple and different stents on the same vessel and relining the bridging stents with bare-metal stents may increase BSG fracture risk. A strict computed tomography angiography follow-up remains the best strategy to detect target vessel instability., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: Complex aortic aneurysms (juxtarenal aortic aneurysms [JAAA], pararenal aortic aneurysms [PAAAs], thoracoabdominal aortic aneurysms TAAAs) are treated with increasing frequency through fenestrated and branched endovascular repair (F/B-EVAR); however, the outcome of these procedures is usually reported separately by single experiences and wider overviews are not frequent. The aim of this study was therefore to report an Italian experience analyzing the results obtained in four academic centers to evaluate the predictors of outcomes., Methods: Between 2008 and 2019, all consecutive patients undergoing F/B-EVAR in four Italian university centers were recorded prospectively and analyzed retrospectively. Preoperative comorbidities and postoperative complications were classified according with the Society for Vascular Surgery reporting standard. Postoperative complications and 30-day/in-hospital mortality were assessed as early outcomes. Survival, freedom from reinterventions and target visceral vessels patency were assessed as follow-up outcomes by Kaplan-Meier analysis. Risk factors for 30-day/in-hospital mortality and spinal cord ischemia (SCI) were determined by multivariate analysis. Risk factors for follow-up mortality and reinterventions were evaluated by Cox regression model., Results: Five hundred ninety-six patients underwent F/B-EVAR for 124 JAAAs (21%), 121 PAAAs (20%), and 351 TAAAs (59%). Elective and urgent procedures were performed in 520 (87%) and 76 (13%) cases, respectively. Postoperative cardiac, pulmonary, and renal complications were reported in 41 (7%), 50 (8%), and 80 (13%) patients, respectively. Seven bowel ischemia (1%) and 23 cerebrovascular complications (4%) occurred. Forty-seven (8%) patients suffered SCI with 17 cases (3%) of permanent paraplegia. Crawford's extent I-II-III TAAAs (odds ratio [OR], 13.41; 95% confidence interval [CI], 1.77-101.65; P = .012) and postoperative renal complications (OR, 3.84; 95% CI, 1.70-8.69; P = .001) independently predicted SCI. Thirty-two patients (5%) died in the perioperative period. Preoperative chronic renal failure (OR, 7.81; 95% CI, 7.81-26.31; P = .001), postoperative bowel ischemia (OR, 26.97; 95% CI, 3.37-215.5; P = .002), cardiac complications (OR, 5.77; 95% CI, 1.41-23.64; P ≤ .001), cerebrovascular complications (OR, 28.63; 95% CI, 5.20-157.5; P < .001), and SCI (OR, 5.99; 95% CI, 1.12-32.5; P = .036) were independently correlated with 30-day/in-hospital mortality. The mean follow-up was 25 ± 7 months. Freedom from target visceral vessels occlusion and freedom from reintervention were 96% and 92% at 1 year and 93% and 85% at 3 years, respectively. TAAAs (hazard ratio [HR]. 3.16; 95% CI, 1.68-5.92; P ≤ .001), postdissection TAAAs (HR, 2.20; 95% CI, 1.30-4.90; P = .05) and postoperative bowel ischemia (HR, 11.98; 95% CI, 1.53-93.31; P = .018) were independent predictors of reinterventions. Survival was 88% and 78% at 1 and 3 years, respectively. Preoperative chronic renal failure (HR, 2.39; 95% CI, 1.59-3.59; P ≤ .001), urgent repair (HR, 1.80; 95% CI, 1.03-3.20; P = .039), TAAAs (HR, 2.01; 95% CI, 1.13-3.56; P = .017), postoperative bowel ischemia (HR, 5.55; 95% CI, 2.11-14.59; P = .001), cardiac complications (HR, 3.89; 95% CI, 2.25-6.71; P ≤ .001), and pulmonary complications (HR, 1.97; 95% CI, 1.56-3.35; P = .013) were independent predictors of mortality during follow-up., Conclusions: F/B-EVAR is associated with satisfactory midterm outcomes in a nationwide experience. A variety of risk factors should be considered in F/B-EVAR indications and postoperative patient management to decrease the risk of postoperative complications and improve midterm outcomes., (Copyright © 2021 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The Anaconda stent graft device presents peculiar and unique features in its design and deployment sequence, available on the market for many years with minor modifications, among different generations. The aim of this study was to assess the long-term, real-life, outcomes obtained in two high-volume centers with this endograft for infrarenal aortic aneurysms treatment over a period of 19 years., Methods: All patients treated with the investigated device between 2000 and 2019, with at least 1 year of follow-up, were entered into a prospective database and data were reviewed retrospectively. The long-term results were assessed according to the Kaplan-Meier method. Primary outcomes were overall survival, freedom from AAA rupture, and freedom from AAA-related death. Secondary outcomes were freedom from late reintervention, freedom from late conversion to open repair, freedom from late limb occlusion, and freedom from late EVAR failure., Results: A total of 260 consecutive patients were treated during the study period. Technical success was achieved in 98.5% (256/260) of the cases. Two perioperative deaths (0.8%) and four major complications (1.5%) were recorded. At a mean follow-up of 54 ± 38 months (summary follow-up index = 0.86), the late survival estimate was 94.8% at 1 year, 75.2% at 5 years, 50.5% at 10 years, and 43.3% at 13 years, with no case of late AAA rupture or late AAA-related death. Late freedom from conversion was 99.2% at 1 year, 96.9% at 5 years, 94.0% at 10 years, and 94.0% at 13 years. Freedom from late limb thrombosis was 96.8% at 1 year and 91.0% at 5, 10, and 13 years. Estimates of freedom from late reintervention was 95.6% at 1 year, 87.0% at 5 years, 77.4% at 10 years, and 77.4% at 13 years. Estimates of limb thrombosis at 11 years were significantly different in patients receiving or not intraoperative iliac kissing balloon maneuver with noncompliant angioplasty catheters (98.0% vs 88.4%; P = .029)., Conclusions: The Anaconda stent graft demonstrated effective and durable outcomes for AAA treatment over a 19-year period, with no case of late AAA rupture or AAA related death in the studied population. Late limb occlusion was the leading cause of reintervention; however, a positive prevention strategy was found in intraoperative kissing balloon, which was associated with significant reduced rate of iliac thrombosis over time., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Current guidelines indicate iliac-branched endografts (IBDs) as the ideal means to preserve pelvic perfusion during endovascular aortic repair. Because patient vascular anatomy represents the main limitation to extensive use of these devices, off-label application may be considered to expand the number of patients being treated. The aim of this study is to evaluate long-term outcomes obtained using the Cook ZBIS endograft in the treatment of aortoiliac aneurysms as per or outside manufacturer's instruction for use (IFU)., Methods: Data from all patients who underwent IBD implant in a single center were reviewed. Study population was divided into two subgroups: Group I treated as per manufacturer's IFU and group II treated outside IFU., Results: During the study period (2008-2018), 119 patients were treated with 130 IBDs. Eighty-six patients were treated as per IFU (group I) and 44 outside IFU (group II). Overall technical success was 99.2%. Mean follow-up was of 63.5 ± 38.3 months for group I and 58.3 ± 35.9 months for group II (P = 0.45). Freedom from reintervention at ten years was 79.8% in group I and 69.6% in group II (P = 0.29). Freedom from IBD-related reintervention rate was 98.7% and 95.3% in groups I and II, respectively (P = 0.240). Iliac-branched module thrombosis occurred significantly more in patients treated outside IFU with 4 cases in group I (4.7%) and 10 cases in group II (22.7%), (P = 0.005). Cox regression analysis identified hypogastric artery aneurysm as the only independent predictor for both IBD thrombosis and hypogastric artery occlusion during follow-up., Conclusions: When used by an experienced team, Cook IBDs are safe and effective in the treatment of aortoiliac aneurysms both inside and outside IFU. Anyway a lower target hypogastric patency rate should be expected when treating patients with hypogastric aneurysms., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aim of this paper is to describe a simple and helpful technique for challenging visceral vessel catheterization during complex aortic endovascular procedures. In demanding anatomies when standard visceral vessel cannulation maneuvers result ineffective, inflating a compliant balloon above the target arteries may allow easy and safe advancement of the introducer sheath inside selected vessel. This approach lowers the shear forces enhancing device pushability. The use of a compliant aortic balloon with the Ceiling technique is a useful, easy and reproducible endovascular option that can be adopted for challenging vessel catheterization during advanced endovascular procedures., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: To report the use of the Oscor Destino steerable sheath in challenging target visceral vessel (TVV) cannulation/bridging stenting in fenestrated and branched endovascular aneurysm repair (FB-EVAR)., Methods: Between 2016 and 2018, patients undergoing FB-EVAR for juxtarenal/pararenal aneurysms (j/p-AAAs) and thoracoabdominal aortic aneurysms (TAAAs) were recorded. Cases requiring the use of the steerable sheath as planned or unplanned maneuvers were analyzed. Technical success, freedom from reinterventions, and TVV patency were assessed., Results: Two hundred sixty patients underwent FB-EVAR to treat j/p-AAAs and TAAAs, for an overall of 956 TVVs. Among these, the Oscor Destino steerable sheath was used in 33 (13%) cases to cannulate a total of 62 (7%) TVVs. FB-EVAR was performed for 7 (21%) j-AAAs, 4 (12%) p-AAAs, 11 (61%) TAAAs, and 2 (6%) previously failed EVAR. The TVVs were 37 (60%) renal arteries, 9 (15%) superior mesenteric arteries, and 16 (25%) celiac trunks. The Oscor Destino steerable sheath was used as the primary cannulation approach in 29 (47%) cases and after failure of the standard cannulation technique in 33 (53%) cases. Technical success was achieved in 61/62 (98%) TVVs. There was no 30-day mortality or bowel ischemia. At the discharge, there were no type I/III endoleaks, whereas 4 type II endoleaks were detected. The median follow-up was 12 months (interquartile range: 8). One patient died at 6 months because of aneurysm-unrelated cause. No TVV occlusion or TVV-related reinterventions occurred. There were no type I-III endoleaks., Conclusions: The use of the steerable sheath could be an effective adjunctive tool and can be used primarily as a planned technique or in case of failure of the standard cannulation technique in challenging TVV anatomy during FB-EVAR., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Introduction: Contrast medium (CM) use in computed tomography (CT) is limited by nephrotoxicity and possible allergic reactions. The purpose of this study is to introduce a tool for the diagnosis of abdominal aortic aneurysms (AAAs) by avoiding the use of CM., Methods: With and without CM CTs of patients with AAA were evaluated. A mathematical algorithm was implemented to allow visualization of the inner aortic lumen in the series without CM. The first step of the algorithm consisted in manually highlighting a squared region of interest (ROI) close to the target aortic area. The rest of the algorithm is completely automated and performs the following flow of operations: The "Kantorovich" algorithm is applied to the ROI for image enhancement. Then, a wavelet decomposition method is applied to identify the different frequency components of the image. Exploiting the wavelet decomposition, the system selects the low-frequency components of the image, corresponding to the major structures. Thresholding method, based on the analysis of the gray-level histogram, is then performed to extract the contours of the vessel. At this point, the extraction of the pervious area is completed. Final images were compared with the contrast enhanced scans, valued as gold standard. To validate the algorithm, an analysis of the results has been performed considering the following types of error: E n  = #m/#ROI ΔA = |1-(#CM/#CEX)| (# m = number of misclassified pixels; # ROI = number of pixels in the ROI; # CM = number of pixels belonging to the CM; #CEX = extracted areas). E n provided a measure on the pixels wrongly classified, and Δ A the difference of extracted areas., Results: The algorithm was applied to 233 CT images. Extracted images were compared with the ones with CM. Mean values of the numerical errors ranged from 0.12 to 0.17 for E n and 0.11 to 0.35 for Δ A . For all the 233 CT images in the analyzed sequences, the mean error was 0.14 (E n ) and 0.28 (ΔA)., Conclusions: The developed mathematical algorithm allows to detect the position of the vessel lumen and to extract its contours with a good accuracy. Our experience shows encouraging results and suggests a possible future clinical application to reduce CT CM use., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Catastrophic events have been correlated to increased incidence of cardio-vascular events, but no correlation between RAA and seismic activities have ever been investigated., Methods: Hospital admissions related to RAA between January 2014 and December 2016 were retrospectively assessed in nine vascular centers of central Italy and correlated with date-matched seismic events. Correlation between RAA presentation and seismic event was first evaluated by Linear Regression analysis. Incidence of RAA events, mortality rate, and type of intervention were analyzed during seismic days (SD) and compared to outcomes during non-seismic days (nSD)., Results: A total of 376 patients were admitted with a diagnosis of RAA, and a total of 783 seismic events were reviewed. Twenty patients died before intervention (untreated). Open surgery was performed in 72.8%, endovascular treatment in 27.2%. General mortality at 30 days was 26.6% (30.5% for open surgery; 21.6% for endovascular treatment; P=0.24). Linear regression analysis between RAA and seismic periods revealed a significant correlation (slope=0.11±0.04, equation: y = 0.1143 x + 3.034, P=0.02). Incidence of RAA was 0.34 event per day during the entire period, 0.32 during nSD and 0.44 during SD (P=0.006). During seismic days, patients with RAA were older (80.5 years during SD vs. 77 years during nSD, P=0.12), were in poorer general condition at admission and remained untreated more frequently (8% SD vs. 4.7% nSD, P=0.3), and had a higher mortality rate at 30 days (46.2% SD vs. 27.2% nSD, P=0.012)., Conclusions: During seismic days, the incidence of RAA is higher in comparison to non-seismic days. Patients with rupture during seismic days have a higher risk of death.

Purpose To test the efficacy of adding cisplatin to first-line treatment for elderly patients with advanced non-small-cell lung cancer (NSCLC) within a combined analysis of two parallel phase III trials, MILES-3 and MILES-4. Patients and Methods Patients with advanced NSCLC who were older than age 70 years with Eastern Cooperative Oncology Group performance status 0 to 1 were randomly assigned to gemcitabine or pemetrexed, without or with cisplatin. In each trial, 382 events were required to detect a hazard ratio (HR) of death of 0.75, with 80% power and two-tailed α of .05. Trials were closed prematurely because of slow accrual, but the joint database allowed us to analyze the efficacy of cisplatin on the basis of intention-to-treat and adjusted by trial, histotype, non-platinum companion drug, stage, performance status, sex, age, and size of the study center. Results From March 2011 to August 2016, 531 patients (MILES-3, 299; MILES-4, 232) were assigned to gemcitabine or pemetrexed without (n = 268) or with cisplatin (n = 263). Median age was 75 years, 79% were male, and 70% had nonsquamous histology. At a median 2-year follow-up, 384 deaths and 448 progression-free survival events were recorded. Overall survival was not significantly prolonged with cisplatin (HR, 0.86; 95% CI, 0.70 to 1.05; P = .14) and global health status score of quality of life was not improved, whereas progression-free survival (HR, 0.76; 95% CI, 0.63 to 0.92; P = .005) and objective response rate (15.5% v 8.5%; P = .02) were significantly better. Significantly more severe hematologic toxicity, fatigue, and anorexia were found with cisplatin. Conclusion The addition of cisplatin to single-agent chemotherapy does not significantly prolong overall survival, and it does not improve global health status score of quality of life in elderly patients with advanced NSCLC.

During implantation of an Ovation endograft for abdominal aortic aneurysm (AAA) correction, a patient experienced anaphylactic reaction after polymer leakage outside the device circuit. Procedure was completed after hemodynamic stabilization. Since postoperative day 2, patient complained of loss of legs strength. Medullar injury was excluded by electromyography test, and the clinical signs attributed to muscular necrosis and peripheral nerve involvement after arterial embolization. Furthermore, immediately after surgery, a wide erythematous area appeared in the lumbar region. During the next few days, the lesion developed from extensive blisters and necrosis to deep loss of substance. The wound needed to be medicated 2 or 3 times per week. One year after surgery, the patient still needs crutches for deambulation, and the back injury is currently under treatment. In conclusion, surgeons performing aortic endovascular repair with the Ovation endograft, as well as anesthesiologists participating in the procedure, should be aware of the possibility of embolization and ready to promptly treat possible complications., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Acute occlusion of the visceral arteries is a threatening complication following branched endovascular aortic repair (EVAR). Its prompt diagnosis and treatment are mandatory to restore renal function. Several techniques have been used to manage this complication. We report 2 clinical cases of patients, previously treated with implantation of an off-the-shelf thoracoabdominal aortic endograft, with acute bilateral occlusion of the renal arteries. Both patients were successfully treated with AngioJet rheolytic thrombectomy. Acute occlusion of the renal arteries can dramatically complicate the outcome of patients treated with branched EVAR. Prompt diagnosis and treatment are required. Rheolytic thrombectomy rapidly removes intra-arterial thrombus through Bernoulli effect, preventing the risk of distal embolization and rapidly restoring the renal function., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Recent technological developments allowed significant improvements in interventional approach to carotid artery stenosis. Tapered stents were specifically designed for extracranial carotid artery stenting (CAS) to deal with vessels mismatch with the objective of decreasing the risk of thrombosis. Nevertheless, whether the stent geometry may affect the outcomes of CAS is uncertain. This study aims to investigate the impact of stent configuration on perioperative and long-term results of this procedure., Methods: All CAS procedures performed between 2005 and 2012 at a single high-volume center were reviewed. Primary end points of the study were 30-day mortality and any ipsilateral neurological event. Secondary end points were any late (>30 days) neurological event and restenosis >50%., Results: About 1,368 procedures were performed in the period 2005-2012. 9.1% of the patients were symptomatic for recent focal neurological event. 883 patients were treated with a cylindrical stent while the others underwent a tapered design device implantation. Technical success was achieved in 96% of the procedures. No perioperative mortality was recorded; perioperative stroke occurred in 1.2% vs. 1.6% (P = not significant) in tapered and straight stent group respectively. Stent design did not predict perioperative ipsilateral neurological events neither at bivariate nor at multivariate analysis. At a mean follow-up of 30 months, late neurological events occurred in 26 cases (1.9%); conic stents resulted protective at Kaplan-Meier analysis (P = 0.027)., Conclusions: The use of conic stents appears to be associated with similar perioperative results when compared with straight stents. Late outcomes suggest a lower risk of restenosis and late neurological events in patients with conical shape stents., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Giant cell arteritis (GCA) is an inflammatory vasculopathy affecting large- and middle-sized vessels, specifically cranial arteries derived from carotid artery. Isolated extracranial vessel involvement can occur. Interest in extravascular manifestations is recently increasing because of diffusion of sensitive and specific imaging tools such as fluorodeoxyglucose positron emission tomography computerized tomography (18 FDG PET CT). Patients have an increased relative risk of severe infection. Listeria monocytogenes infection risk is increased, and vascular system involvement and graft infection have been, although rarely, reported. We report the case of a 72-year-old woman with a history of suspected giant cell aortitis, previous surgical treatment of ascendant and descendant thoracic aortic aneurysm, presenting 7 years after thoracic endovascular aneurysm repair with thoracic pain, fever, inflammatory indexes increase, leukocytosis, Listeria sepsis, and rapidly increasing type I proximal endoleak on CT. 18 FDG PET positivity was associated. Endograft listeria infection on aortitis reactivation was suspected, but death for multiorgan failure and absence of autopsy data could not confirm diagnosis. Listeria vascular graft infection has been reported previously. GCA is a predisposing condition. We report the first case of endograft infection by L monocytogenes in a patient with a positive history of suspected giant cell aortic aneurysm., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: Long-term results of abdominal aortic aneurysm (AAA) endovascular repair are affected by graft design renewals that tend to improve the performance of older generation prostheses but usually reset the follow-up times to zero. The present study investigated the long-term outcomes of endovascular AAA repair (EVAR) using the Zenith graft, still in use without major modification, in a single center experience., Methods: Between 2000 and 2011, 610 patients underwent elective EVAR using the Zenith endograft (Cook Inc, Bloomington, Ind) and represent the study group. Primary outcomes were overall survival, freedom from AAA rupture, and freedom from AAA-related death. Secondary outcomes included freedom from late (>30 days) reintervention, freedom from late (>30 days) conversion to open repair, freedom from aneurysm sac enlargement >5.0 mm and freedom from EVAR failure, defined as a composite of AAA-related death, AAA rupture, AAA growth >5 mm, and any reintervention., Results: Mean age was 73.2 years. Mean aneurysm diameter was 55.3 mm. There were five perioperative deaths (0.8%) and three intraoperative conversions. At a mean follow-up of 99.2 (range, 0-175) months, seven AAA ruptures occurred, all fatal except one. Overall survival was 92.8% ± 1.1% at 1 year, 70.1% ± 1.9% at 5 years, 37.8% ± 2.9% at 10 years, and 24 ± 4% at 14 years. Freedom from AAA-rupture was 99.8% ± 0.02 at 1 year (one case), 99.4% ± 0.04 at 5 years (three cases), and 98.1% ± 0.07 at 10 and 14 years. Freedom from late reintervention and conversion was 98% ± 0.6 at 1 year, 87.7% ± 1.5 at 5 years, 75.7% ± 3.2 at 10 years, and 69.9% ± 5.2 at 14 years. Freedom from aneurysm sac growth >5.0 mm was 99.8% at 1 year, 96.6% ± 0.7 at 5 years, 81.0% ± 3.4 at 10 years, and 74.1% ± 5.8% at 14 years. EVAR failure occurred in 132 (21.6%) patients at 14 years. At multivariate analysis, independent predictors of EVAR failure resulted type I and III endoleak (hazard ratio [HR], 6.7; 95% confidence interval [CI], 4.6- 9.7; P < .001], type II endoleak (HR, 2.3; 95% CI, 1.6-3.4; P < .001), and American Society of Anesthesiologists grade 4 (HR, 1.6; 95% CI, 1.0-2.6; P = .034)., Conclusions: EVAR with Zenith graft represents a safe and durable repair. Risk of rupture and aneurysm-related death is low, whereas overall long-term survival remains poor. Novel endograft models should be tested and evaluated considering that one-fourth of the operated patients will still be alive after 14 years., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Sex differences in presentation and outcomes of abdominal aortic aneurysms (AAA) with increased mortality rates in women are suggested. This study aimed to assess mortality risk after repair of ruptured AAA (rAAA) in women in the endovascular abdominal aortic repair (EVAR) era., Methods: Patients treated between 2006 and 2015 for rAAA were included in a prospective database. Characteristics at presentation and outcomes were compared between women and men. Multivariable logistic regression and Cox proportional analyses were performed to identify the effect of sex adjusted for other predictors on mortality., Results: One hundred thirteen patients were identified; of these, 17.7% (20/113) of the patients were women. Forty-four procedures (38.9%) were by EVAR, with comparable rates in women (45%) and men (37.6%, P = 0.62). On admission, women and men shared similar comorbidities and presentation (shock 45% vs. 43.0%, P = 0.81; free rupture 65.0% vs. 67.7%, P = 0.80) and comparable mean aneurysm diameter (76.5 vs. 78.8 mm, P = 0.68), but women were older (mean age 86.4 + 5.5 vs. 75.2 ± 10.6 years, P < 0.0001) and octogenarian women were twice as likely as men (90% vs. 40%, P < 0.0001). Perioperative mortality was comparable between women and men (40.0% vs. 38.7%) either after EVAR (22.2% vs. 40.0% in women and men respectively; odds ratio [OR] 0.45, 95% confidence interval [CI] 0.77-2.37) or after open surgery (54.5% vs. 37.9%; OR 2.0, 95% CI 0.54-7.21), even though there was a trend for lower mortality in women with EVAR. In adjusted analyses, female sex was not associated with perioperative mortality as it was for older age (octogenarians: OR 6.6, 95% CI 2.08-20.82, P = 0.001) and free rupture (OR 4.2, 95% CI 1.29-13.73, P = 0.02). Mean follow-up was 34.32 months. After controlling for age, surgical repair, free rupture, cardiac disease, and shock at presentation, female sex was not a predictor of late mortality., Conclusions: AAA repair is often delayed in women and applied at older age; nevertheless, currently women do not show increased perioperative mortality risks from rAAA treatment after the introduction of EVAR., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Repair of isolated iliac aneurysm with stent-graft implantation and internal iliac coverage may induce significant type II endoleak from patent internal iliac refilling leading to ongoing aneurysm growth. Subsequent treatment of such complication can be challenging especially in case of bilateral iliac involvement. Open repair is technically demanding and often a high risk procedure, while embolization via transfemoral approach is unviable due to the stent-graft coverage precluding direct antegrade access between the common and the internal iliac lumen. Percutaneous retrograde embolization from superior gluteal artery is a feasible technique in case of impossible access through the origin of internal iliac artery., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: Elderly patients are often turned down from receiving treatment for descending thoracic aortic diseases (DTADs) because of the uncertain benefits, especially in acute settings. This study investigated the impact of old age and timing of thoracic endovascular aortic repair (TEVAR) on outcomes of DTAD in patients older than 75 years of age., Methods: Patients from a prospective TEVAR database were dichotomized by age (75 and 80 years of age). Older and young patients were compared in three timing scenarios: (1) elective procedures, (2) any emergency (within 15 days from onset), and (3) acute ruptures (any emergency subgroup). Primary outcome was perioperative mortality assessed at 30 and 90 days., Results: Between 2003 and 2015, 141 consecutive TEVARs (71.6% men) were performed. Fifty-seven patients (40.4%) were older than 75 years of age; 28 were octogenarians. Eighty-three TEVARs were performed electively and 58 emergently. Among overall emergencies, 42 TEVARs were for acute ruptures. In the elective scenario, the 30-day mortality rate was 5.0% vs 0 (odds ratio [OR], 1.1; 95% confidence interval [CI], 0.98-1.1; P = .23), and 90-day mortality was 7.5% vs 0, for patients older than 75 years of age vs those who were younger than 75, respectively (P = .11). No octogenarian died. In the emergency scenario, 30-day mortality was 41.2% vs 9.8%, for patients older than 75 years of age vs those who were younger than 75, respectively (OR, 6.5; 95% CI, 1.6-26.6; P = .01) with unchanged rates at 90 days. The mortality rate was 50% for octogenarians. In the acute rupture scenario, 30-day mortality was 40% vs 11.1% (OR, 5.3; 95% CI, 1.10-25.99; P = .05) for patients older than 75 years of age vs those younger than 75 years of age and 46% vs 10% (OR, 7.5; 95% CI, 1.47-37.46; P = .016) for octogenarians vs younger patients. Rates remained unchanged at 90 days. Patients older than age 75 survived for a mean of 53.98 ± 7.7 months after TEVAR., Conclusions: In the elderly patient population with DTAD, mortality risks from TEVAR are strongly related to timing and age. When compared to younger patients, those older than 75 years of age have three to five times the risk of mortality after urgent or emergent TEVAR. However, older patients should still be considered for emergent life-saving treatment, given that the majority survives., (Copyright © 2016 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Objective: The objective of this multicenter registry was to review current treatments and late results of repair of aneurysm of aberrant right subclavian artery (AARSA)., Methods: All consecutive AARSA repairs from 2006 to 2013 in seven centers were reviewed. End points were 30-day and late mortality, reintervention rate, and AARSA-related death., Results: Twenty-one AARSA repairs were included (57% men; mean age, 67 years); 3 ruptures (14%) required emergent treatment; 12 (57%) were symptomatic for dysphagia (33%), dysphonia (24%), or pain (19%). Eight cases (38%) presented with thoracic aortic aneurysm, two with intramural hematoma, and one with acute type B aortic dissection. Mean AARSA diameter was 4.2 cm; a single bicarotid common trunk was present in 38% of cases. The majority of patients underwent hybrid intervention (n = 15; 71%) consisting of single (n = 2) or bilateral (n = 12) subclavian to carotid transposition or bypass or ascending aorta to subclavian bypass (n = 1) plus thoracic endovascular aortic repair (TEVAR); 19% of cases underwent open repair and 9% simple TEVAR with AARSA overstenting. Perioperative death occurred in two patients (9%): in one case after TEVAR in ruptured AARSA, requiring secondary sternotomy and aortic banding; and in an elective case due to multiorgan failure after a hybrid procedure. Median follow-up was 30 (interquartile range, 15-46) months. The Kaplan-Meier estimate of survival at 36 months was 90% (standard error, 0.64). Late AARSA-related death in one case was due to AARSA-esophageal fistula presenting with continuing backflow from distal AARSA and previous TEVAR. At computed tomography controls, one type I endoleak and one type II endoleak were detected; the latter required reintervention by aneurysm wrapping and ligature of collaterals. AARSA-related death was more frequent after TEVAR, a procedure reserved for ruptures, compared with elective open or hybrid repair., Conclusions: Hybrid repair is the preferred therapeutic option for patients presenting with AARSA. Midterm results show high rates of clinical success with low risk of reintervention. Simple endografting presents high risk of related death; these findings underline the importance of achieving complete sealing to avoid treatment failures., (Copyright © 2015 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Purpose: To evaluate the late results of endovascular aneurysm repair (EVAR) with the endografts currently in use and compare outcomes to older devices., Methods: Clinical, demographic, and imaging data on consecutive patients undergoing elective EVAR from January 1997 to December 2011 at a single center were retrieved from an electronic database and reviewed. Newer stent-grafts (NSG) were defined as those introduced after 2004 (second-generation Excluder and Anaconda) or currently in use without modifications (Zenith, Endurant). Of the 1412 consecutive patients (1290 men; mean age 73 years) who underwent elective EVAR in a tertiary university hospital, 882 were treated with NSGs and 530 with older stent-grafts (OSGs)., Results: In the NSG group, the abdominal aortic aneurysms (AAA) were larger (55.7 vs. 53.2 mm, p<0.0001) and the patients were older (p<0.0001) and less frequently smokers or had pulmonary disease, while hypertension and diabetes were more frequent (all p<0.0001). Thirty-day mortality was 0.8% in the NSG group vs. 1.1% in the OSG group (p=NS). Follow-up ranged from 1 to 174 months (mean 54.1±42.4); the OSG patients had longer mean follow-up compared to the NSG group (80.2±47.9 vs. 38.4±29.1 months, p<0.0001). All-cause survival rates were comparable in both groups. Freedom from late conversion (96.1% vs. 89.1% at 7 years, p<0.0001) or reintervention (83.6% vs. 74.2% at 7 years, p=0.015) and freedom from AAA diameter growth >5 mm (p=0.022) were higher in the NSG group. In adjusted analyses, the use of a new-generation device was a negative independent predictor of reintervention [hazard ratio (HR) 0.67, 95% confidence interval (CI) 0.49 to 0.93, p=0.015] and aneurysm growth (HR 0.63, 95% CI 0.45 to 0.89, p=0.010)., Conclusion: Newer-generation endografts can perform substantially better than the older devices. In the long term, incidences of reintervention, conversion, and AAA growth are decreased in patients treated with devices currently in use. However, the need for continuous surveillance is still imperative for all endografts.

Background: This study analyzed predictors and the long-term consequence of type II endoleak in a large series of elective endovascular abdominal aneurysm repairs (EVARs)., Methods: Baseline characteristics and operative and follow-up data of consecutive patients undergoing EVAR were prospectively collected. Patients who developed type II endoleak according to computed tomography angiography and those without type II endoleak were compared for baseline characteristics, mortality, reintervention, conversion, and aneurysm growth after repair., Results: In 1997-2011, 1412 consecutive patients (91.4% males; mean age, 72.9 years) underwent elective EVAR and were subsequently followed up for a median of 45 months (interquartile range, 21-79 months). Type II endoleak developed in 218. Adjusted analysis failed to identify significant independent predictors for type II endoleak with the exception of age (odds ratio, 1.03; 95% confidence interval, 1.01-1.05; P = .003) and intraluminal thrombus (odds ratio, 0.69; 95% confidence interval, 0.53-0.92; P = .010). Type II endoleak rates were comparable regardless of the device model. Late aneurysm-related survival was comparable (98.4% vs 99.5% at 60 months; P = .73) in patients with and without type II endoleak. However, at 60 months after EVAR, rates of aneurysm sac growth >5 mm (35.3% vs 3.3%; P < .0001) were higher in patients with type II endoleak. Cox regression identified type II endoleak as an independent predictor of aneurysm growth along with age and cardiac disease. The presence of type II endoleak led to reinterventions in 40% of patients and conversion to open surgery in 8%. However, assessment of these patients after reintervention showed similar 60-month freedom rates of persisting type II endoleak (present in more than two after computed tomography angiography scan studies) among those with and without reinterventions (49.8% vs 45.6%; P = .639). Aneurysm growth >5 mm persisted with comparable rates in type II endoleak patients after reintervention and in those who remained untreated (42.9% vs 57.4% at 60 months; P = .117)., Conclusions: Reintervention for type II endoleak was common in our practice, yet such intervention did not reliably prevent the continued expansion of the abdominal aortic aneurysm. Our data indicate type II endoleak appears to be a marker of EVAR failure that is difficult to predict and treat effectively., (Copyright © 2014 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Although currently there is a trend of using percutaneous transluminal angioplasty (PTA) and stenting for the treatment of long occlusions of superficial femoral artery, many studies reported comparable results in terms of mid- and long-term patency between PTA and stenting and plaque debulking techniques such as remote endarterectomy, directional atherectomy catheter atherectomy and laser guided atherectomy. A successful debulking procedure is strongly associated with patients comorbidities, length of lesions and clinical presentation. In the last decade many new devices have been proposed to improve debulking results. Despite encouraging data about technical feasibility and limb salvage rate, debulking is still associated with a low rate of long-term primary and secondary patency. However, randomized clinical trials are expected and can hopefully provide conclusions on the effective durability of these procedures.

Background: Paradoxical pulmonary embolisms are uncommon emergencies and can occur as a consequence of an aortocaval fistula due to unrecognized dislodgement of thrombus from aortic sac into pulmonary circulation. This study reviewed current literature and therapeutic options in this emergency condition requiring prompt management and repair., Methods: Literature was systematically searched for paradoxical pulmonary embolism associated with aortocaval rupture., Results: Eight published cases were identified. However, many other paradoxical pulmonary emboli could have remained undiagnosed due to challenging clinical presentation. Symptoms of high-output cardiac failure and respiratory distress in the presence of large aortoiliac aneurysm and venous hypertension are findings of a possible major abdominal arteriovenous fistula with paradoxical pulmonary embolism. Successful treatment depends on prevention of new embolism and proper management of perioperative hemodynamics and massive bleeding during fistula repair. Endovascular procedures have been recently used as useful tools in this field. Cava filter placement may be a first step to prevent further thrombus dislodgements during aortocaval repair. Immediate subsequent aortic stent-grafting can allow repair of aortocaval communication and exclusion of the abdominal aortic aneurysm from circulation with successful reversal of altered hemodynamic features. However, experience (especially in the long-term) is limited., Conclusions: Paradoxical pulmonary embolism from aortocaval fistula represents an extremely rare but true clinical emergency with high fatality rate. Recent advances in diagnostic technology and endovascular techniques can substantially improve outcomes of the disease. Clinical competence in early detection and diagnosis is essential for appropriate emergent management., (Copyright © 2012 Annals of Vascular Surgery Inc. Published by Elsevier Inc. All rights reserved.)

Even though differences between first-bypass vs. first-endovascular approach in below the knee (BTK) lesions have never been adequately compared, endovascular strategy first approach can be currently successfully used to treat BTK lesions in patients with critical limb ischemia (CLI). Success however is strongly associated with risk groups, severity of disease and degree of clinical presentation beside the method of revascularization. From available data, the best results of endovascular first approach for BTK lesions can be achieved with multivessel and tibial (more than peroneal alone) recanalization and Rutherford 4 or 5 ischemia changes, especially if the correct angiosome can be revascularized (direct flow to the feeding artery of the foot) and there is no renal failure. For patients in Rutherford class 6 and extensive gangrene/tissue loss, BTK endovascular strategy alone does not seem to provide ideal results. Outcomes of interventional therapy for BTK lesions are consistently better when applied in experienced centers with the use of more advanced technology and use of eluting materials. According to limited but randomized evidence, drug-eluting stent (DES) placement might be recommended in BTK lesions under 40 mm long since yields significantly better results than angioplasty alone or implantation of bare metal stents in this lesion subset. Nevertheless, this policy raises doubts on the efficacy of treatment due to limitations in generalizability of outcomes in common hospital settings and related costs. Furthermore, there are still no consistent numbers to provide the efficacy of this approach and long-term data are lacking. Waiting for the long-term results of ongoing trials and new researches, a more comprehensive analysis of outcomes with BTK endovascular first strategy can be provided in the next future.

Background: Diabetes is prevalent in most patients undergoing carotid revascularization and is suggested as a marker of poor outcome after carotid endarterectomy (CEA). Data on outcome of diabetic patients undergoing carotid artery stenting (CAS) are limited. The aim of this study was to investigate early and 6-year outcomes of diabetic patients undergoing carotid revascularization with CAS and CEA., Methods: The database of patients undergoing carotid revascularization for primary carotid stenosis was queried from 2001 to 2009. Diabetic patients were defined as those with established diagnosis and/or receiving oral hypoglycemic or insulin therapy. Multivariate and Kaplan- Meier analyses, stratified by type of treatment, were performed on perioperative (30 days) and late outcomes., Results: A total of 2196 procedures, 1116 by CEA and 1080 by CAS (29% female, mean age 71.3 years), were reviewed. Diabetes was prevalent in 630 (28.7%). Diabetic patients were younger (P < .0001) and frequently had hypertension (P = .018) or coronary disease (P = .019). Perioperative stroke/death rate was 2.7% (17/630) in diabetic patients vs 2.3% (36/1566) in nondiabetic, (P = .64); the rate was 3.4% in diabetic CEA group and 2.1% in diabetic CAS group (P = .46). At multivariate analyses, diabetes was a predictor of perioperative stroke/death in the CEA group (odds ratio [OR], 2.83; 95% confidence interval [CI], 1.05-7.61; P = .04) but not in the CAS group (P = .72). Six-year survival was 76.0% in diabetics and 80.8% in nondiabetics (P = .15). Six-year late stroke estimates were 3.2% in diabetic and 4.6% in nondiabetic patients (P = .90). The 6-year risk of restenosis was similar (4.6% % vs 4.2%) in diabetic and nondiabetic patients (P = .56). Survival, late stroke, and restenosis rates between diabetics and nondiabetics were similar in CAS and CEA groups., Conclusions: Diabetic patients are not at greater risk of perioperative morbidity and mortality or late stroke after CAS, however, the perioperative risk can be higher after CEA. This may help in selecting the appropriate technique for carotid revascularization in patients best suited for the type of procedure., (Copyright © 2012 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

Objectives: Increasing data suggest that statins can significantly decrease cardiovascular and cerebrovascular events due to a plaque stabilization effect. However, the benefit of statins in patients undergoing carotid angioplasty and stenting (CAS) for carotid stenosis is not well defined. The aim of this study was to investigate whether statins use was associated with decreased perioperative and late risks of stroke, mortality, and restenosis in patients undergoing CAS., Methods: All patients undergoing CAS for primary carotid stenosis from 2004 to 2009 were reviewed. The independent association of statins and perioperative morbidity was assessed using multivariable analysis. Survival curves and Cox regression models were used to assess late morbidity and restenosis. Propensity score adjustment was employed., Results: A total of 1083 consecutive CAS were performed (29% females, mean age 71.5 years; 24.7% symptomatic); 465 (43%) were on statins medication before treatment that was not discontinued at discharge. Statins use was associated with a reduction of perioperative stroke and death (odds ratio [OR] 0.327, 95% confidence interval [CI] 0.13-0.80, P = .016) according to multivariable analysis. Statins effect was more significant in reducing stroke and death in symptomatic patients (OR 0.13; P = .032) and in males (OR 0.27, P = .01). At 5 years, survival (87.2% vs 78.3%; P = .009) and ischemic stroke-free interval (88.9% vs 99.7%; P = .02) rates were higher in the statins group of patients. Adjusting for propensity score and covariates in Cox regression analyses, statins use was independently associated with reduced long-term mortality risk (HR 0.56, 95% CI 0.32-0.97; P = .039) and borderline associated with decreased late ischemic stroke risk (HR 0.14; 95% CI 0.018-1.08, P = .059). There was no effect on restenosis rates., Conclusions: These data suggest that statins use is associated with decreased perioperative and late ischemic strokes risk and reduced mortality rates in patients undergoing CAS. Statins therapy should be considered part of the best medical treatment in current CAS practice., (Copyright © 2011 Society for Vascular Surgery. Published by Mosby, Inc. All rights reserved.)

MDA-468 human breast cancer cells overexpress the EGFR and exhibit a functional TGFalpha-EGFR autocrine pathway. Loss of EGFR expression following stable transfection with an antisense EGFR cDNA containing plasmid down-regulates type I cAMP-dependent protein kinase (PKAI) expression with acquisition of cell growth resistance to the PKAI inhibitor 8-Cl-cAMP. These results suggest that PKAI expression and function are controlled by a TGFalpha-EGFR autocrine pathway in human breast cancer cells overexpressing the EGFR.

8-Chloro-cAMP (8-Cl-cAMP) is a novel agent that is able to inhibit the growth of a wide variety of cancer cell types in vitro and in vivo and, at doses devoid of toxicity, to achieve plasma concentrations in cancer patients in a range effective for cancer cell growth inhibition. In this study, we have demonstrated that 8-Cl-cAMP, at a dose causing mild or no growth inhibition, synergistically increased the growth-inhibitory effect of paclitaxel or cisplatin in a wide series of cell lines including human breast, lung, ovary, colon, and head carcinomas and melanoma. A similar effect was also observed with another taxane, docetaxel, and with the platinum-derivative carboplatin. 8-Cl-cAMP also markedly enhanced apoptotic cell death induced by each cytotoxic drug. A cooperative antitumor effect was also observed in vivo, because treatment with paclitaxel followed by 8-Cl-cAMP markedly inhibited the growth of GEO human colon cancer xenografts as compared to paclitaxel alone without signs of toxicity. These data demonstrate that 8-Cl-cAMP synergistically increases the antiproliferative activity of taxanes and platinum-derived compounds and provide a rationale to use 8-Cl-cAMP in combination with taxanes and platinum-derived compounds.

The sensitivity of human tumor cells to activated lymphocytes is considered to play an essential role in the antitumor activity of recombinant interleukin-2 (rIL-2)-based immunotherapy. We have investigated the effects of several genes involved in the regulation of cell growth and transformation on the sensitivity of human mammary epithelial MCF-10A cells to non-MHC-restricted, rIL-2-activated lymphocytes. Therefore, the lysability of MCF-10A cells overexpressing activated oncogenes (Ha-ras, erbB-2, and a mutated p53), growth factors [transforming growth factor alpha (TGFalpha)], or cAMP-dependent protein kinase A subunits (RIalpha, RIIbeta, and Calpha) was evaluated comparatively at different effector:target ratios by a 51Cr release assay. Parental MCF-10A, MCF-10A p53-mutated, and MCF-10A RIIbeta cells showed an intermediate sensitivity. Lysability was increased significantly in MCF-10A Ha-ras, MCF-10A TGFalpha, and MCF-10A RIalpha cells, reduced in MCF-10A Calpha cells, and completely abrogated in MCF-10A erbB-2 cells. These differences could not be explained by simple changes in the cell surface expression of MHC class I and intercellular adhesion molecule-1 proteins or by secretion of TGFbeta. Treatment with TAb 250, a mouse anti-p185(erbB-2) monoclonal antibody, or down-regulation of p185(erbB-2) expression resulted in circumvention of MCF-10A erbB-2 cell resistance. We conclude that molecular changes at the single-gene level resulting in alterations of intracellular signaling and/or cell transformation modulate sensitivity of human mammary epithelial cells to non-MHC-restricted, rIL-2-induced cytotoxicity, regardless of MHC class I and/or intercellular adhesion molecule-1 expression or TGFbeta secretion. Furthermore, anti-p185(erbB-2) monoclonal antibodies may be useful as adjuncts to rIL-2 treatment in patients with erbB-2-overexpressing tumors.

Topoisomerase II (Topo II) is an essential enzyme that catalyzes the breakage of double-strand DNA and is the target of several effective anticancer drugs, including the epipodophyllotoxins. The regulatory subunits of the cyclic AMP-dependent protein kinase are differentially expressed in normal and cancer cells. The RIalpha subunit is overexpressed in cells transformed by transforming growth factor-alpha (TGF-alpha) or Ha-ras oncogene. It has been shown that murine cells transformed by Ha-ras become hypersensitive to Topo II-targeting anticancer drugs. In this report we have tested whether any correlation exists between the expression of RIalpha protein and cellular sensitivity of Topo II-targeting drugs. Normal human breast MCF-10A cells and their derivatives overexpressing TGF-alpha, Ha-ras, or the different protein kinase subunits were treated with either Topo II inhibitors, such as etoposide, teniposide, or amsacrine, or with drugs which act independently of Topo II, such as bleomycin. Here we show that MCF-10A TGF-alpha and MCF-10A Ha-ras cells overexpress the RIalpha protein and become hypersensitive to epypodophyllotoxins and amsacrine but not to bleomycin. Direct introduction of the RIalpha gene into MCF-10A induces hypersensitivity to Topo II inhibitor drugs. In contrast, the overexpression of the other protein kinase subunits, RIIbeta or Calpha, does not modify the drug sensitivity of MCF-10A cells. No differences in the mRNA/protein content or in the activity of Topo II were found between hypersensitive cells and parental MCF-10A cells, suggesting that RIalpha may influence drug sensitivity via modulation of events downstream of the Topo II-DNA cleavable complex.