Adipocyte-conditioned medium induces resistance of breast cancer cells to lapatinib.

BACKGROUND: The existence of a cross-talk between peritumoral adipocytes and cancer cells has been increasingly investigated. Several studies have shown that these adipocytes protect tumor cells from the effect of anticancer agents. METHODS: To investigate a potential protective effect of adipocyte-conditioned medium on HER2 positive breast cancer cells exposed to tyrosine kinase inhibitors (TKI) such as lapatinib, we analyzed the sensitivity of HER2 positive breast cancer models in vitro and in vivo on SCID mice in the presence or absence of adipocytes or adipocyte-conditioned medium. RESULTS: Conditioned medium from differentiated adipocytes reduced the in vitro sensitivity of the HER2+ cell lines BT474 and SKBR3 to TKI. Particularly, conditioned medium abrogated P27 induction in tumor cells by lapatinib but this was observed only when conditioned medium was present during exposure to lapatinib. In addition, resistance was induced with adipocytes derived from murine NIH3T3 or human hMAD cells but not with fibroblasts or preadipocytes. In vivo studies demonstrated that the contact of the tumors with adipose tissue reduced sensitivity to lapatinib. Soluble factors involved in this resistance were found to be thermolabile. Pharmacological modulation of lipolysis in adipocytes during preparation of conditioned media showed that various lipolysis inhibitors abolished the protective effect of conditioned media on tumor cells, suggesting a role for adipocyte lipolysis in the induction of resistance of tumor cells to TKI. CONCLUSIONS: Overall, our results suggest that contact of tumor cells with proximal adipose tissue induces resistance to anti HER2 small molecule inhibitors through the production of soluble thermolabile factors, and that this effect can be abrogated using lipolysis inhibitors.

[Isolated iliac artery aneurysms : Interventional treatment]. / Isolierte Aneurysmen der Iliakalarterien : Interventionelle Therapie.

CLINICAL ISSUE: Isolated iliac artery aneurysms occur considerably less often than abdominal aortic aneurysms. Mainly older men are affected by this disease. Most of these aneurysms are asymptomatic and are incidentally detected during cross-sectional imaging. Iliac aneurysms with a diameter larger than 3 cm are at risk for rupture, which is associated with high morbidity and mortality. STANDARD TREATMENT: To prevent their rupture as well as for symptomatic or ruptured aneurysms, endovascular treatment has recently been established as the primary approach due to the decreased morbidity and mortality compared to open repair. Endovascular aneurysm exclusion is performed with stent grafts, and depending on the anatomy, by adjunctive internal iliac artery embolization. TREATMENT INNOVATIONS: Up to a quarter of treated patients will require additional endovascular revisions during the long term. Reliable imaging follow-up likely increases the safety of elective or emergent endovascular iliac artery aneurysm repair.

Mid-term Results of Chimney and Periscope Grafts in Supra-aortic Branches in High Risk Patients.

PURPOSE: Report mid-term outcomes of thoracic endovascular aneurysm repair (TEVAR) with chimney and periscope grafts (CPG) in supra-aortic branches (SAB). METHODS: Retrospective analysis, from October 2009 to May 2014, of patients with aneurysms requiring TEVAR with zone 0/1/2 proximal landing in association with at least one CPG in the SAB. All patients were considered at high risk for conventional surgery. Peri-operative mortality and morbidity, retrograde type A dissection, maximum aortic transverse diameter (TD) and its post-operative evolution, endoleak, survival, freedom from cardiovascular re-interventions, and CPG freedom from occlusion during the follow-up were analysed. RESULTS: Forty-one patients (28.05% EuroScore II) with thoraco-abdominal aortic aneurysm (17%), arch aneurysm (39%), descending aneurysm (34%), and aneurysm extending from the arch to the visceral aorta (10%) were included. Fifteen (37%) patients were treated non-electively. Fifty-nine SABs were treated with the CPG technique: one, two, three, and four CPG were employed in 71%, 19%, 5%, and 5% of patients, respectively. The proximal landing was in zone 0 in 49% of patients, zone 1 in 17%, and zone 2 in 34%. Technical success was 95%. Peri-operative complications and neurological events were registered in six (14.6%) patients and there were 5 deaths (12%). At a median follow-up of 21.2 (mean 22, SD 18; range 0-65) months, type I/III endoleaks were registered in three (7%) cases and re-intervention in six (15%) patients. A significant aneurysm sac shrinkage (p<.001) was reported at mean follow-up and no significant aneurysm sac increase (>5 mm). The estimated 2 year survival, freedom from re-intervention, freedom from endoleak, and freedom from branch occlusion were 75%, 77%, 86%, and 96%, respectively. CONCLUSION: The chimney and periscope grafts technique was shown to be safe in aortic aneurysm disease involving the supra aortic branches, even in an emergency setting using off the shelf devices. Mid-term follow-up results in this high risk population are good, but longer follow-up is mandatory before this technique is used in intermediate-risk patients.

A Multicentre Trial of Patient specific Rehearsal Prior to EVAR: Impact on Procedural Planning and Team Performance.

OBJECTIVE: Patient specific rehearsal (PsR) prior to endovascular aneurysm repair (EVAR) enables the endovascular team to practice and evaluate the procedure prior to treating the real patient. This multicentre trial aimed to evaluate the utility of PsR prior to EVAR as a pre-operative planning and briefing tool. MATERIAL AND METHODS: Patients with an aneurysm suitable for EVAR were randomised to pre-operative or post-operative PsR. Before and after the PsR, the lead implanter completed a questionnaire to identify any deviation from the initial treatment plan. All team members completed a questionnaire evaluating realism, technical issues, and human factor aspects pertinent to PsR. Technical and human factor skills, and technical and clinical success rates were compared between the randomised groups. RESULTS: 100 patients were enrolled between September 2012 and June 2014. The plan to visualise proximal and distal landing zones was adapted in 27/50 (54%) and 38/50 (76%) cases, respectively. The choice of the main body, contralateral limb, or iliac extensions was adjusted in 8/50 (16%), 17/50 (34%), and 14/50 (28%) cases, respectively. At least one of the abovementioned parameters was changed in 44/50 (88%) cases. For 100 EVAR cases, 199 subjective questionnaires post-PsR were completed. PsR was considered to be useful for selecting the optimal C-arm angulation (median 4, IQR 4-5) and was recognised as a helpful tool for team preparation (median 4, IQR 4-4), to improve communication (median 4, IQR 3-4), and encourage confidence (median 4, IQR 3-4). Technical and human factor skills and technical and initial clinical success rates were similar between the randomisation groups. CONCLUSION: PsR prior to EVAR has a significant impact on the treatment plan and may be useful as a pre-operative planning and briefing tool. Subjective ratings indicate that this technology may facilitate planning of optimal C-arm angulation and improve non-technical skills. TRIAL REGISTRATION: URL://www.clinicaltrials.gov. Unique identifier: NCT01632631.

Mid- and Longer-term Follow up of Chimney and/or Periscope Grafts and Risk Factors for Failure.

OBJECTIVE: The aim was to report on chimney and periscope grafts (CPGs) and their mid- and longer-term outcomes when they are used to preserve reno-visceral artery (RVA) perfusion in endovascular repair of pararenal (PRAAs) or thoraco-abdominal aortic aneurysm (TAAAs). In addition, factors associated with CPG failure are presented. Limited data exist on the outcomes of CPGs, and mid- and long-term results are generally not reported. METHODS: This was a prospective study in a cohort of 100 patients with PRAA (69) or TAAA (31). A total of 224 (mean 2.24 per patient) RVAs were preserved with 136 (61%) chimney and 88 (39%) periscope grafts. CPGs were constructed mainly using self expandable stent grafts. Patients were followed by clinical examination, CTA (82%), and/or duplex (18%). Data were collected until February 2015. RESULTS: CPG immediate technical success was 99% (222/224 branches). Mean follow up was 29 months (range 0-65; SD 17); 59% patients were followed > 2 years, 30% > 3 years, and 16% > 4 years. Post-operatively, CPG occlusion was observed early (≤30 days) in three (1.3%) branches and during follow up in 10 (4.5%). At 36 and 48 months, the estimated primary patency was 93% and 93%. After corrective percutaneous (10) or surgical (3) re-interventions, the estimated secondary patency was 96% and 96%. Thirty day mortality was 2%; at 36 and 48 months the estimated patient survival was 79%. Significant shrinkage (72 [SD 23] vs. 62 [SD 24] mm; p < .001) was observed, with a substantial reduction (>5 mm) in 55 patients, and sac enlargement in four. Incomplete aneurysm sac sealing was treated successfully by a secondary intervention in 15 patients. CONCLUSIONS: Self expandable CPGs have proved to be a highly successful and durable treatment for RVA preservation up to 5 years. Incomplete CPG expansion, inadequate length, and CPG use in small and diseased target arteries were risk factors for occlusion. These mid- and longer-term results support CPG use to treat PRAAs or TAAAs in patients unfit for open surgery or fenestrated/branched stent grafts.

Editor's Choice ­ Durability of Endovascular Repair in Blunt Traumatic Thoracic Aortic Injury: Long-Term Outcome from Four Tertiary Referral Centers.

OBJECTIVES: To analyze the early and long-term survival and re-intervention rate in patients undergoing TEVAR for blunt traumatic thoracic aortic injury. METHODS: This was a consecutive case series. Between the years 2001 and 2010, a total of 74 patients underwent TEVAR for blunt traumatic thoracic aortic injury at four tertiary referral centers, three in Sweden and one in Switzerland. The median age of the patients was 41 years, and 16% were women. Demographic, procedural, and outcome data were collected and reviewed retrospectively. The patients were followed up during 2013-2014. RESULTS: Early (30 day) mortality was 9% (7 patients), with only two cases directly related to the aortic injury; in hospital mortality was 14% as three patients died during the primary hospital admission within the first 6 months. Most patients had sustained severe injuries to other organ systems, and among all in hospital deaths brain injury was the predominant cause. Five year survival in the whole group was 81%. Re-intervention was needed in 16% (12 patients) during the first year, half of them within the first month. Only one patient underwent re-intervention more than 1 year after the initial procedure. Infolding and partial stentgraft collapse was the reason for the secondary procedure in five of the 13 patients; in three it occurred within 3 weeks of the acute TEVAR. CONCLUSION: TEVAR allows rapid and effective therapy in trauma patients with blunt aortic injury. The outcome is dependent on the severity of the concomitant injuries. The treatment is durable during the first decade after the procedure, but even longer follow up is needed to determine the impact of TEVAR in young patients on the degenerative changes that take place in the aging aorta.

Value and limitations of chimney grafts to treat arch lesions.

AIM: The endovascular debranching with chimney stents provides a minimally invasive alternative to open surgery with readily available devices and has extended the option of endoluminal therapy into the realm of the aortic arch. But a critical observation at the use of this technique at the aortic arch is important and necessary because of the lack of long-term results and long term patency of the stents. Our study aims to review the results of chimney grafts to treat arch lesions. METHODS: A systematic health database search was performed in December 2014 according to the Prisma Guidelines. Papers were sought through a meticulous search of the MEDLINE database (National Library of Medicine, Bethesda, MA) using the Pubmed search engine. RESULTS: Twenty-two articles were eligible for detailed analysis and data extraction. A total of 182 patients underwent chimney techniques during TEVAR (Thoracic Endovascular Aneurysm Repair). A total of 217 chimney grafts were implanted: 36 to the IA, 1 to the RCCA, 91 to the LCCA and 89 to the LSA. The type of stent-graft used for TEVAR was described in 132 patients. The type and name of chimney graft was described in 126 patients. In 53 patients information was limited to the type. Primary technical success, defined as a complete chimney procedure was achieved in 171 patients (98%). In 8 patients it was not clearly reported. The overall stroke rate was 5.3%. The overall endoleak rate, in those papers were it was clearly reported, was 18.4% (31 patients); 23(13,6%) patients developed a type IA endoleak, 1 patient (0.6%) developed type IB endoleak and 7 patients (4.1%) developed a type II endoleak CONCLUSION: The total endovascular aortic arch debranching technique represent a good option to treat high-risk patients, because it dramatically reduces the aggressiveness of the procedure in the arch. Many concerns are still present, mainly related to durability and material interaction during time. Long-term follow-up is exceptionally important in light of the interactions of the stents, the thoracic endograft, the aortic arch, and every variation in systolic and diastolic pressure. Actually this technique has acceptable short and mid-term results. Long term data are available just from a very small number of patients and more data from a wider number are needed in order to embrace this method as a safe one.

Case report of an endovascular repair of a residual type A dissection using a not CE not FDA-approved Najuta thoracic stent graft system.

This report describes an endovascular repair of a residual type A dissection using a medical device that is not marked by european conformity (CE) or Food and Drug Administration (FDA).The patient underwent ascending aortic surgery for acute type A dissection. The 2-year angio-computed tomography demonstrated patency of the residual false lumen with evolution into a 6 cm aneurysm, the extension of the dissection from the aortic arch to the aortic bifurcation with thrombosis of the right common iliac artery. There was no CE- or FDA-marked medical device indicated for this case or any other acceptable therapeutic alternative.We used the Najuta thoracic stent graft and successfully handled the pathology in a multiple-phase treatment.Technology is evolving with specific grafts for the ascending and fenestrated grafts for the aortic arch. In this single case the Najuta endograft, in spite of the periprocedural problems, was a valid therapeutic option.

The impact of pretransplantation urgency status and the presence of a ventricular assist device on outcome after heart transplantation.

INTRODUCTION: There are conflicting reports on the posttransplantation morbidity and mortality of patients listed urgently and/or supported by a ventricular assist device (VAD). The aim of this study was to analyze the outcomes with regard to pretransplantation condition (elective, urgent, VAD). METHODS: All adult recipients between January 1, 2005, and October 31, 2012, were included. Demographics; preoperative, operative, and postoperative data; outpatient follow-up; and donor characteristics were collected and analyzed. RESULTS: Of a total of 74 patients, 19 were listed urgently, 20 had a Berlin Heart EXCOR BVAD (biventricular assist device) (Berlin Heart, Berlin, Germany) (8 urgent), 7 had a Berlin Heart INCOR left VAD (Berlin Heart, Berlin, Germany) (2 urgent), and 2 had a HeartWare left VAD (HeartWare International, Framingham, Mass, USA) (none urgent). Mean age was 52 ± 12years. The overall 30-day, 1-year, and 3-year survival was 90% ± 3%, 79% ± 5%, and 66% ± 7%. There was no difference in survival when comparing urgently listed (95% ± 5%, 84% ± 8%, 74% ± 12%) and elective patients (89% ± 4%, 77% ± 6%, 63% ± 8%; P = .4), and VAD patients (86% ± 6%, 76% ± 8%, 63% ± 11%) and those without mechanical support (93% ± 4%, 81% ± 6%, 69% ± 9%; P = .6). In-hospital outcomes and long-term complications were also comparable. CONCLUSIONS: Our series suggests that urgent patients and patients on a VAD have a posttransplantation outcome comparable to elective patients and patients without a VAD. These data support the effectiveness of the current practice of listing for heart transplantation.

How to diagnose and treat abdominal compartment syndrome after endovascular and open repair of ruptured abdominal aortic aneurysms.

Intra-abdominal hypertension (IAH) and abdominal compartment syndrome (ACS) are frequently encountered in patients treated for ruptured abdominal aortic aneurysms (rAAA) and carry a high morbidity and mortality risk. Despite these facts, IAH/ACS are still overlooked by many physicians, timely diagnosis is missed and treatment often inadequate. All staff involved in the treatment of rAAA should be aware of the risk factors predicting IAH/ACS, the profound implications and derangements on all organ systems, the clinical presentation, the appropriate measurement of intra-abdominal pressure to detect IAH/ACS and the current treatment options for these detrimental syndromes. This comprehensive review provides contemporary knowledge that should help to improve patient survival and long-term outcome.

Team training in ruptured EVAR.

Ruptured abdominal aortic aneurysms are almost always a fatal condition. The incidence of ruptured aortic aneurysms (rAAA) is declining, the number of teams is increasing and there is an increased focus on patient safety resulting in limited real life training opportunities to maintain or improve the technical and human factor skills required to manage this acute aortic pathology. The availability and experience of the multidisciplinary team together with accessibility of appropriate resuscitation and efficient logistics all influence the modality of rAAA repair. A standardised patient's pathway for rAAA management and reliable multidisciplinary team are the keys to improve patient outcomes. Whole rEVAR team training using high fidelity simulation may be the one answer to allow clinicians to learn, practice, rehearse, improve and maintain team-based knowledge, technical and human factor skills and team attitudes to manage this challenging pathology.

Distinction between acute and chronic type B aortic dissection: is there a sub-acute phase?

OBJECTIVES: This study aims to assess the relevance of the definition of acute dissection, to analyse whether there is a sub-acute phase and to determine early outcome of thoracic endovascular aortic repair (TEVAR) in acute complicated type B aortic dissection. DESIGN: Dual-centre consecutive case series. MATERIALS: Between 1999 and 2011, 102 patients underwent TEVAR for non-traumatic acute complicated type B dissection in Zurich, Switzerland, and Uppsala, Sweden. In addition, 22 patients treated for an acute dissection-related complication occurring >14 days after onset of symptoms were included. Median age was 68 years, 35% were women. METHODS: Demographic, procedural and outcome data were collected prospectively. The patients were followed up on 1 January 2012. RESULTS: In the 22 sub-acute patients (18%), there were no early deaths or neurological complications. The predominant complication in these patients was rapid aortic enlargement, whereas rupture was more prevalent in patients treated within 14 days. In total, there were nine (7%) early deaths, three (2%) post-intervention paraplegias and six cases of stroke (5%). CONCLUSIONS: TEVAR was performed with low early mortality and few neurological complications. A significant proportion of patients presented with acute complications >14 days after onset of symptoms, indicative of a sub-acute phase in the transition between acute and chronic dissection, questioning the relevance of the current definition.

Patient-specific rehearsal prior to EVAR: a pilot study.

OBJECTIVES: This study aims to evaluate feasibility, face validity, influence on technical factors and subjective sense of utility of patient-specific rehearsal (PsR) prior to endovascular aortic aneurysm repair (EVAR). DESIGN: A prospective, multicentre pilot study. METHODS: Patients suitable for EVAR were enrolled and a three-dimensional (3D) model of the patient's anatomy was generated. Less than 24 h prior to the real case, rehearsals were conducted in the laboratory or clinical angiosuite. Technical metrics were recorded during both procedures. A subjective questionnaire was used to evaluate realism, technical and human factor aspects (scale 1-5). RESULTS: Ten patients were enrolled. In one case, the treatment plan was altered based on PsR. In 7/9 patients, the rehearsal significantly altered the optimal C-arm position for the proximal landing zone and an identical fluoroscopy angle was chosen in the real procedure. All team members found the rehearsal useful for selecting the optimal fluoroscopy angle (median 4). The realism of the EVAR procedure simulation was rated highly (median 4). All team members found the PsR useful to prepare the individual team members and the entire team (median 4). CONCLUSIONS: PsR for EVAR permits creation of realistic case studies. Subjective evaluation indicates that it may influence optimal C-arm angles and be valuable to prepare the entire team. A randomised controlled trial (RCT) is planned to evaluate how this technology may influence technical and team performance, ultimately leading to improved patient safety.

Less invasive (common) femoral artery aneurysm repair using endografts and limited dissection.

OBJECTIVE: We report our experience with the treatment of femoral artery aneurysms (FAAs) under local anaesthesia with limited dissection, using endografts to facilitate the proximal anastomosis and some distal anastomoses. METHOD: Between January 2006 and December 2010, six males, mean age 72 years (range, 65-80 years) with FAAs were treated at the University Hospital of Zurich. All operations were performed under local anaesthesia with analgosedation, except for one performed under spinal anaesthesia. After limited dissection and puncture of the anterior wall of the FAA, a sheath and a self-expanding endograft were introduced over a guide wire and with fluoroscopy they were guided intraluminally into the proximal normal neck of the FAA and deployed. Proximal arterial control was achieved with a balloon catheter introduced through the endograft. Then the FAAs were opened and distal arterial control is obtained with balloon catheters. The distal end of the stent graft was then sutured to the normal-sized distal arteries or to stent grafts placed within them. RESULTS: Of the six FAAs, four were true and two were false anastomotic aneurysms. Mean FAA diameter was 5.0 cm (range, 3.0-6.5 cm). Four patients also had aneurysmal involvement of the external iliac artery, one patient also had deep femoral aneurysms, but deep femoral circulation was always preserved. In three of the patients, the distal anastomosis was created to the femoral artery bifurcation, in two patients to the deep femoral artery when the superficial femoral artery (SFA) was chronically occluded and in one patient to the SFA. Immediate technical success was achieved in all six patients, and graft patency was observed from 9 to 48 months (mean 29 months). There were no amputations, complications or deaths. CONCLUSION: This technique for repair of FAAs can be performed under local anaesthesia, minimises dissection and complications and simplifies exclusion of these lesions. It is of particular value in high-risk patients with large FAAs.

Complete replacement of open repair for ruptured abdominal aortic aneurysms by endovascular aneurysm repair: a two-center 14-year experience.

OBJECTIVE: To present the combined 14-year experience of 2 university centers performing endovascular aneurysm repair (EVAR) on 100% of noninfected ruptured abdominal aortic aneurysms (RAAA) over the last 32 months. BACKGROUND: Endovascular aneurysm repair for RAAA feasibility is reported to be 20% to 50%, and EVAR for RAAA has been reported to have better outcomes than open repair. METHODS: We retrospectively analyzed prospectively gathered data on 473 consecutive RAAA patients (Zurich, 295; Örebro, 178) from January 1, 1998, to December 31, 2011, treated by an "EVAR-whenever-possible" approach until April 2009 (EVAR/OPEN period) and thereafter according to a "100% EVAR" approach (EVAR-ONLY period).Straightforward cases were treated by standard EVAR. More complex RAAA were managed during EVAR-ONLY with adjunctive procedures in 17 of 70 patients (24%): chimney, 3; open iliac debranching, 1; coiling, 8; onyx, 3; and chimney plus onyx, 2. RESULTS: Since May 2009, all RAAA but one have been treated by EVAR (Zurich, 31; Örebro, 39); 30-day mortality for EVAR-ONLY was 24% (17 of 70). Total cohort mortality (including medically treated patients) for EVAR/OPEN was 32.8% (131 of 400) compared with 27.4% (20 of 73) for EVAR-ONLY (P = 0.376). During EVAR/OPEN, 10% (39 of 400) of patients were treated medically compared with 4% (3 of 73) of patients during EVAR-ONLY. In EVAR/OPEN, open repair showed a statistically significant association with 30-day mortality (adjusted odds ratio [OR] = 3.3; 95% confidence interval [CI], 1.4-7.5; P = 0.004). For patients with no abdominal decompression, there was a higher mortality with open repair than EVAR (adjusted OR = 5.6; 95% CI, 1.9-16.7). In patients with abdominal decompression by laparotomy, there was no difference in mortality (adjusted OR = 1.1; 95% CI, 0.3-3.7). CONCLUSIONS: The "EVAR-ONLY" approach has allowed EVAR treatment of nearly all incoming RAAA with low mortality and turndown rates. Although the observed association of a higher EVAR mortality with abdominal decompression needs further study, our results support superiority and more widespread adoption of EVAR for the treatment of RAAA.

The use of Endurant stent-graft for abdominal aortic aneurysm: the story about extension of instruction for use with persistent good results of stent-graft latest generation.

The Endurant stent-graft (Medtronic, Inc., Minneapolis, MN, USA) is a latest generation device for the treatment of abdominal aortic aneurysm. The idea behind designing such a graft came from the intention to broad the instruction for use (IFU) and to enable it to treat more challenging anatomy including the 10mm neck lengths, and more severe suprarenal and infrarenal angulations. Endurant stent-graft has active fixation through suprarenal stent with anchoring pins to provide migration resistance, optimized heights of stents and spacing between them for improved flexibility and conformability, low-profile delivery system with hydrophilic coating and controlled simple deployment mechanism. Short term results are excellent. Technical and clinical success is confirmed in Regulatory trials (EU and USA), as well as in ENGAGE and the Canadian registry. Many current publications record the use of Endurant stent-graft outside the Instruction for use. The results in a group of patients outside the instruction for use are comparable to those within instruction for use; with the exception of perioperative proximal endoleak type I. Mid-term results are consistent with short-term results. The long-term results are lacking.