Author + information
- Received March 6, 2012
- Revision received May 8, 2012
- Accepted May 23, 2012
- Published online October 9, 2012.
- Subhash Banerjee, MD⁎,†,⁎ (, )
- Tony S. Das, MD‡,
- Mazen S. Abu-Fadel, MD§,
- Eric J. Dippel, MD∥,
- Nicolas W. Shammas, MD∥,
- Daniel L. Tran, MSc†,
- Ahmad Zankar, MD⁎,†,
- Cyril Varghese, MS⁎,
- Kevin C. Kelly, PharmD†,
- Rick A. Weideman, PharmD†,
- Bertis B. Little, PhD†,¶,
- Robert F. Reilly, MD⁎,†,
- Tayo Addo, MD⁎ and
- Emmanouil S. Brilakis, MD, PhD⁎,†
- ↵⁎Reprint requests and correspondence:
Dr. Subhash Banerjee, University of Texas Southwestern Medical Center and Veterans Affairs North Texas Health Care System, 4500 South Lancaster Road, 111a, Dallas, Texas 75216
Objectives The purpose of this study is to compare post-dilation strategies of nitinol self-expanding stents implanted in the superficial femoral artery of diabetic patients with peripheral arterial disease.
Background Endovascular treatment of superficial femoral artery disease with nitinol self-expanding stents is associated with high rates of in-stent restenosis in patients with diabetes mellitus.
Methods We conducted a prospective, multicenter, randomized, controlled clinical trial of diabetic patients to investigate whether post-dilation of superficial femoral artery nitinol self-expanding stents using a cryoplasty balloon reduces restenosis compared to a conventional balloon. Inclusion criteria included diabetes mellitus, symptomatic peripheral arterial disease, and superficial femoral artery lesions requiring implantation of stents >5 mm in diameter and >60 mm in length. Primary endpoint was binary restenosis at 12 months, defined as ≥2.5-fold increase in peak systolic velocity by duplex ultrasonography.
Results Seventy-four patients, with 90 stented superficial femoral artery lesions, were randomly assigned to post-dilation using cryoplasty (n = 45 lesions) or conventional balloons (n = 45 lesions). Mean lesion length was 148 ± 98 mm, mean stented length was 190 ± 116 mm, mean stent diameter was 6.1 ± 0.4 mm, and 50% of the lesions were total occlusions. Post-dilation balloon diameters were 5.23 ± 0.51 mm versus 5.51 ± 0.72 mm in the cryoplasty and conventional balloon angioplasty groups, respectively (p = 0.02). At 12 months, binary restenosis was significantly lower in the cryoplasty group (29.3% vs. 55.8%, p = 0.01; odds ratio: 0.36, 95% confidence interval: 0.15 to 0.89).
Conclusions Among diabetic patients undergoing implantation of nitinol self-expanding stents in the superficial femoral artery, post-dilation with cryoplasty balloon reduced binary restenosis compared to conventional balloon angioplasty. (Study Comparing Two Methods of Expanding Stents Placed in Legs of Diabetics With Peripheral Vascular Disease [COBRA]; NCT00827853)
Percutaneous revascularization of superficial femoral artery (SFA) lesions can be accomplished with high procedural success rates (1). Implantation of nitinol self-expanding stents significantly reduces the risk of restenosis compared to balloon angioplasty with provisional secondary stenting. Restenosis rates, however, remain high (30% to 50% at 1 year) (2,3). Patients with diabetes mellitus are at an increased risk of restenosis because of exaggerated intimal hyperplasia (4,5).
Cryoplasty is performed with a Food and Drug Administration approved angioplasty balloon catheter (PolarCath, Boston Scientific, Natick, Massachusetts) that is positioned at the arterial lesion and inflated with nitrous oxide, which cools the surface of the balloon and freezes the plaque in the artery (6). This action has 3 potential beneficial effects: 1) weakens plaque, thereby promoting uniform dilation resulting in less vessel trauma; 2) reduces vessel wall recoil; and 3) induces smooth muscle cell apoptosis, limiting neointima formation (7).
We hypothesized that cryoplasty, by inducing smooth muscle cell apoptosis when applied for post-dilation of SFA stents, will reduce restenosis compared to a conventional balloon post-dilation strategy. To test our hypothesis, we conducted a pilot, randomized trial comparing cryoplasty to conventional balloon post-dilation of nitinol self-expanding stents implanted in the SFA of diabetic patients presenting with symptomatic peripheral arterial disease.
The COBRA (Study Comparing Two Methods of Expanding Stents Placed in Legs of Diabetics With Peripheral Vascular Disease) study was approved by the institutional review boards of all 4 participating centers, and all patients provided written informed consent.
From August 2008 to December 2010, consecutive patients referred for endovascular treatment of SFA disease were screened for enrollment at 4 participating centers. Patients who satisfied all the inclusion criteria and had none of the exclusion criteria were randomly allocated in a 1:1 fashion to either cryoplasty or conventional balloon post-dilation of the SFA stented segment.
Key clinical inclusion criteria were diabetes mellitus (insulin requiring or noninsulin requiring), referral for endovascular treatment of peripheral arterial disease for severe intermittent claudication (Rutherford-Becker stage 3), chronic critical limb ischemia with rest pain (Rutherford-Becker stage 4), or chronic critical limb ischemia with ischemic ulcers (Rutherford-Becker stage 5) symptoms.
Key angiographic inclusion criteria were de novo SFA lesion with ≥50% diameter stenosis by visual estimation requiring implantation of self-expanding stent >60 mm in length and >5 mm in diameter. Patients were excluded if they were allergic to aspirin, clopidogrel, or iodine-based radiographic contrast, had obstructive (≥50% diameter stenosis) iliofemoral artery disease, or absence of at least 1-vessel infrapopliteal run-off. All patients had radio-opaque tape in the imaging field as a reference for determining vessel dimensions. A SFA lesion with ≥50% diameter stenosis was considered significant. The selection of pre-dilation, stent deployment, and adjunctive pharmacologic therapy was at the discretion of the primary operator.
The primary study endpoint was binary restenosis, as assessed by duplex ultrasonography performed at 12 months post-procedure or earlier if clinically indicated. Binary restenosis was defined as ≥2.5-fold increase in peak systolic velocity within the stented segment and within 10 mm of its proximal and distal edges to that recorded proximal to the stented segment or by the presence of an occluded stent with no flow. Secondary endpoints included change of resting ankle-brachial index (ABI) and symptoms (Rutherford-Becker stages) at 12 months post-procedure. Patients were asked to complete a walking impairment questionnaire (score range 0 to 14,080) pre-intervention, and then every 6 months for the first year post-procedure (8).
All analyses were performed in a blinded fashion at the Veterans Affairs North Texas Clinical Angiographic and Ultrasound Core Laboratory, and clinical adjudication and adverse events monitoring were performed by an independent data oversight and safety monitoring board.
All patients underwent a complete medical history and physical examination, including assessment of symptoms using the Rutherford-Becker classification and a walking impairment questionnaire. The ABI was measured in both lower extremities. All assessments were performed pre-procedure, before hospital discharge, and at 6 and 12 months post-procedure.
The SFA interventions were performed using 6F or 7F arterial sheaths inserted through the contralateral common femoral artery. Diagnostic imaging of the femoropopliteal arteries was performed using digital subtraction angiography. Crossing of the SFA lesions, lesion preparation, and stent implantation was performed using standard percutaneous interventional techniques. If patients required stent implantation, they were randomly assigned to 1 of the 2 treatment strategies. After successful stent implantation, post-dilation was performed with either a cryoplasty or a conventional balloon per the randomized treatment assignment. Conventional balloon dilation of the stent to ensure its maximal expansion could be performed before cryotherapy. Cryoplasty was delivered using the PolarCath peripheral dilation system, which consists of a balloon catheter, nitrous oxide canister, and a microprocessor-controlled inflation unit. The inflation unit activates the device through a pre-programmed series of steps, resulting in the inflation of the cryoplasty balloon at 8 atm for 20 s to deliver nitrous oxide, which brings the outer balloon temperature to −10°C, followed by a deflation and rewarming phase. Final post-intervention angiograms were recorded with digital subtraction angiography using projections similar to diagnostic angiography.
Technical success was defined as <10% diameter stenosis within the stented segment after balloon post-dilation. The study protocol allowed inclusion of patients with bilateral symptomatic SFA disease. The post-dilation strategy was randomly assigned for the first limb, and the contralateral SFA segment was treated with the opposite post-dilation strategy. Such staged procedures were separated by at least 30 days. After each procedure, patients were admitted to the hospital and monitored for periprocedural complications for at least 24 h, and discharged on indefinite aspirin therapy (≥81 mg/day) and at least 30 days of clopidogrel (300 mg loading dose followed by 75 mg/day).
Duplex ultrasonography assessment
All duplex ultrasound studies were performed by experienced ultrasonography technicians with 5 to 12 MHz linear-array transducers and were analyzed off-line in a blinded fashion. The extremity was positioned in a neutral position, and the SFA segment was identified. The ultrasound probe was positioned perpendicular to the surface for optimal gray scale imaging of the arterial wall and stented segment. Duplex imaging was performed using an angle of 60° between the Doppler insonation beam and vessel wall. Color Doppler interrogation (with pulse repetition frequency scale adjusted to show normal laminar flow as a region of homogeneous flow) was performed to detect a high-velocity jet, suggestive of significant stenosis. Maximum peak systolic velocity was measured at 4 different locations: proximal to the stent (reference segment), within 10 mm of the proximal stent edge, within the stent, and within 10 mm distal of the stent. The ratio of the maximum peak systolic velocity recorded within the stent and within 10 mm of the proximal and distal edge to the maximum reference segment was calculated. Patients who met the primary endpoint were allowed to undergo angiographic evaluation and revascularization at the discretion of the treating physician. If the SFA was occluded proximal to the stent or if a single or multiple lesions were treated in the stented SFA segment, then angiographic restenosis was considered to have occurred.
We calculated a priori that 43 vascular segments would be needed in each study arm to have 80% power to detect a reduction in binary restenosis from 65% in the conventional balloon post-dilation to 35% in the cryoplasty post-dilation arm, assuming 10% attrition and an alpha of 0.05. Continuous variables were summarized as mean ± SD and compared using t test or the Wilcoxon rank-sum test, as appropriate. Discrete variables were presented as frequencies, and group percentages compared using the chi-square test or Fisher's exact test, as appropriate. Freedom from restenosis was assessed using Kaplan-Meier curves and the log-rank test. For all comparisons a 2-sided probability of <0.05 was considered statistically significant. All analyses were performed using SAS version 9.1 (SAS Institute, Cary, North Carolina).
In all, 121 consecutive patients consented, and 74 patients with 90 stented SFA segments were enrolled (Fig. 1). Forty-seven patients (39%) were not included because stent implantation was not performed, or they did not meet the eligibility criteria or withdrew consent. The primary indication for stent implantation was >50% residual stenosis after balloon pre-dilation. Baseline demographic, disease management, and procedural characteristics for treated patients and lesions are shown in Tables 1 and 2.⇓ In the cryoplasty group, 87%, 6%, and 7% of patients presented with Rutherford-Becker stages 3, 4, and 5 symptoms, respectively. In the conventional balloon dilation group, 86%, 12%, and 2% presented with Rutherford-Becker stages 3, 4 and 5 symptoms, respectively. The S.M.A.R.T. CONTROL (Cordis, Bridgewater, New Jersey) nitinol self-expanding stent was used in 87% of lesions; 6% received LifeStent (Bard, Tempe, Arizona), 3% Sentinol (Boston Scientific), 1% each Everflex (ev3, Plymouth, Minnesota) and Absolute (Abbott, Santa Clara, California), and 2% of lesions received >1 stent type.
Lesion length and implanted stent dimensions were similar in both treatment groups (Tables 1 and 2). Nitinol self-expanding stents were implanted in all cases. Patients with bilateral interventions had significantly more total occlusions (p = 0.04), required post-dilation balloons with larger diameters (p = 0.05), and greater number of post-dilations (p = 0.02) (Table 1). One-half of the lesions were total occlusions, with longer lesion and stent lengths compared to lesions without total occlusions (see Online Tables 1A and 1B). Analysis of lesion-based treatment assignments revealed use of larger post-dilation balloon diameters in the conventional balloon angioplasty group, but balloon lengths and number of inflations were similar in both treatment groups (Table 1), as were procedural complications (Table 3). Conventional balloon dilation of stents before cryoplasty was performed in 51% of patients enrolled in the cryoplasty arm. Minimal luminal diameter of lesions in the cryoplasty and conventional balloon post-dilation arms were 0.86 ± 0.95 mm and 0.89 ± 1.12 mm, respectively (p = 0.80). Post-stent dimensions were 5.50 ± 0.98 mm in the cryoplasty arm and 5.54 ± 1.00 mm in the conventional arm (p = 0.91). Acute gain was 4.56 ± 1.41 mm in the cryoplasty arm and 4.67 ± 1.42 mm in the conventional arm (p = 0.73).
The ABI immediately after the intervention was 0.96 ± 0.14 in the cryoplasty group and 0.89 ± 0.21 in the conventional balloon dilation group (p < 0.001 compared to baseline for both groups).
During the 12-month follow-up period, 5 patients died: 3 patients in the cryoplasty arm, 1 patient in the conventional balloon post-dilation arm, and 1 patient who underwent bilateral intervention. None of the deaths was related to the index procedure, and deaths were not significantly different between the 2 study arms (p = 0.31). Three deaths were sudden cardiac death, and 2 were secondary to infection and sepsis. Thus, duplex ultrasonography and clinical follow-up at 12 months were available in 41 (91.1%) arterial segments in the cryoplasty arm and 43 (95.5%) segments in the conventional balloon post-dilation arm, respectively (Fig. 1). Medical management of patients post-intervention was similar in both treatment groups. Glycosylated hemoglobin level for the cryoplasty arm was 7.43 ± 1.77 at baseline and 7.46 ± 1.57 at 12 months (p = 0.96). For the conventional arm, it was 7.63 ± 2.16 at baseline and 7.11 ± 1.36 at 12 months (p = 0.24). Low-density lipoprotein levels for the cryoplasty arm were 72.83 ± 28.73 at baseline and 64.73 ± 24.17 at 12 months (p = 0.25). In the conventional arm, it was 87.10 ± 34.51 at baseline and 75.18 ± 35.19 at 12 months (p = 0.25). Rate-pressure product for the cryoplasty arm was 9,894 ± 2,360 at baseline and 9,310 ± 2,315 at 12 months (p = 0.64). Rate-pressure product for the conventional arm was 9,608 ± 2,036 at baseline and 9,093 ± 2,072 at 12 months (p = 0.17). At 12 months, 16% of patients in both groups reported active tobacco use.
Binary restenosis occurred in 55.8% in the conventional balloon dilation group, compared to 29.3% in the cryoplasty group (p = 0.01, odds ratio: 0.36, 95% confidence interval: 0.15 to 0.89) (Fig. 2A). Cumulative hazard of restenosis is shown in Figure 2B (p = 0.02, hazard ratio: 2.28, 95% confidence interval: 1.14 to 4.61). Cumulative hazard of all-cause death and restenosis is 2.39 (95% confidence interval: 1.19 to 4.78, p = 0.01).
Compared to baseline, the ABI at 12 months was higher in the cryoplasty group (0.59 ± 0.21 to 0.77 ± 0.30, p = 0.004) but was unchanged in the conventional post-dilation group (0.62 ± 0.19 to 0.65 ± 0.26, p = 0.66) (Fig. 3). Excluding patients with bilateral treatment, the mean walking impairment scores at 12 months were similar (p = 0.53), but were higher compared to baseline in both treatment strategy groups (cryoplasty, 1,406 to 6,157, p = 0.005; conventional balloon post-dilation, 1,549 to 5,109, p = 0.002). For the cryoplasty group, Rutherford stage was 3.18 ± 0.54 at baseline, 0.94 ± 1.16 at 6 months (p < 0.0001), and 1.51 ± 1.56 at 12 months (p < 0.0001). In the conventional treatment arm, Rutherford stage was 3.14 ± 0.41 at baseline, 1.33 ± 1.33 at 6 months (p < 0.0001), and 1.50 ± 1.42 at 12 months (p < 0.0001). There was no significant difference in Rutherford stages between the 2 study arms at baseline or at 6 months and 12 months of follow-up.
Among SFA segments with a total occlusion at baseline (n = 45), 70% in the conventional post-dilation group and 36% in the cryoplasty group had binary restenosis (p = 0.06). For bilaterally treated SFA segments (n = 16), 66.7% in the conventional post-dilation group and 26.7% in cryoplasty group had in-stent restenosis (p = 0.03). These treatments were separated by a mean interval of 3.9 ± 0.4 weeks.
Angiographic follow-up was obtained for all patients who met the primary endpoint in the cryoplasty group and for 75% of patients in the conventional balloon dilation group (p = 0.19). Target vessel revascularization procedures were performed in 17.8% and 26.7% of SFA segments in the cryoplasty group and conventional balloon dilation group, respectively, and the remaining were medically managed. Target lesion revascularization in the cryoplasty arm was 10% compared to 16% in the conventional arm (p = 0.29). Restenosis patterns were similar in both treatment groups. In the cryoplasty group, 33% were occlusions and the rest were diffuse restenosis; in the conventional arm, 29% were occlusions and the rest were diffuse restenosis (p = 0.74, for occlusions). One stent fracture (2.5%) was reported in the cryoplasty group; none was found in the conventional balloon dilation group. Procedure-related adverse events were 8.9% and 6.7% in the cryoplasty group and conventional balloon dilation group, respectively (p = 0.50), and were predominantly related to access site (Table 3). No patients were referred for procedure-related surgical revascularization or amputation.
The key finding of this study is that, for patients with diabetes mellitus who underwent SFA stenting using self-expanding stents, post-dilation using cryoplasty significantly reduced the 12-month in-stent restenosis rates compared to post-dilation using a conventional balloon.
Implantations of stents in the SFA have significantly improved periprocedural and long-term outcomes; however, the durability of stents is limited by restenosis (9,10). The FAST (Femoral Artery Stenting Trial) reported no difference in 1-year binary restenosis rates with balloon angioplasty and nitinol stent implants in the SFA (11). In contrast, data from 3 other randomized trials—the ABSOLUTE (Randomized Comparison between Sirolimus [Cypher]/Sirolimus-Analogous [Xience; Promus] vs. Paclitaxel [Taxus vs. Costar] Eluting Stents in Coronary Lesions) trial (12,13), the RESILIENT (Randomized Study Comparing the Edwards Self-Expanding LifeStent Versus Angioplasty-Alone in Lesions Involving the Superficial Femoral Artery and/or Proximal Popliteal Artery) trial , and the Zilver PTX trial (15)—showed improved primary stent patency at 12 months (12,14,15) and at 24 months (13) compared to angioplasty, especially with paclitaxel-eluting stents (15). The mean lesion lengths of femoropopliteal arterial segments included in the FAST, RESILIENT, ABSOLUTE, and Zilver PTX trials were 45 mm, 67 mm, 97 mm, and 65 mm, respectively.
Despite this evidence, there are limited data, and to the best of our knowledge no published randomized trials of endovascular treatment of peripheral arterial disease in diabetic patients with long segment SFA stenting. Diabetic patients have more diffuse and angiographically more severe peripheral arterial disease than nondiabetic patients (16). Femoropopliteal stenting remains highly prevalent among patients with diabetes mellitus, given the poor patency rates after balloon angioplasty of long or occluded SFA segments (2,17,18). Thus, a strategy to improve stent outcomes in diabetic patients using cryoplasty was tested in the COBRA trial.
Although the mechanism of cryoplasty continues to be debated and actively researched, it is widely accepted that cryoplasty, by delivering cryotherapy precisely at −10°C to the arterial wall (19), induces smooth muscle cell apoptosis while limiting cell necrosis (7). In the present investigation, it was hypothesized that cryoplasty may reduce restenosis, especially in diabetic patients, who already have a greater smooth muscle cell proliferative response to vascular injury (20).
Prior studies involving cryoplasty have reported either improved patency rates (21,22) or higher restenosis rates (21,23,24), including 1 demonstrating lower patency in a diabetic population compared to balloon angioplasty (25). However, all such studies were retrospective and observational.
In a single-center randomized trial, Jahnke et al. (26) reported a 9-month patency rate of 79% with cryoplasty compared to 67% with conventional balloon angioplasty (p = 0.14) for focal popliteal artery occlusive disease. Laird et al. (27), in a prospective, multicenter trial of cryoplasty for femoropopliteal disease reported a clinical patency of 82.2% and primary patency determined by duplex ultrasonography of 70.1% at 9 months. Both of these studies evaluated focal lesions and lesions that were not high risk, and they did not use cryotherapy adjunctive to stents. The COBRA study is the first trial to deliver cryotherapy in addition to a vascular scaffold, which are often used to treat complex SFA disease (28,29) as a strategy to limit smooth muscle cell proliferation and reduce in-stent restenosis.
An important study by Karthik et al. (30) evaluated cryoplasty for the treatment of in-stent restenosis in femoropopliteal distribution and reported no efficacy. These findings are in contrast to those observed in the COBRA trial. This difference in outcomes can be potentially attributed to the biological heterogeneity of nascent vascular smooth muscle cells of the arterial wall, compared to its proliferation in restenotic lesions (31). Vascular smooth muscle cells of an atherosclerotic arterial wall are known to be associated with greater proliferative activity, enhanced migratory capacity, poor level of differentiation, and much higher sensitivity to apoptotic stimuli compared to a restenotic response (31).
The complexity of SFA lesions treated in the COBRA trial is greater than those in prior randomized studies performed in this area. A comparison of outcomes in the total occlusion and bilateral treatment groups provides the opportunity to analyze the effect of cryoplasty for stent post-dilation in complex and unbiased subsets unique to this trial. The strategy of affecting outcomes with a post-dilation balloon may also be relevant to drug-coated stents.
Our study is limited by the relatively small number of patients included, although it is the first peripheral intervention trial to exclusively enroll diabetic patients. The results could also have been affected by the type of nitinol stent implanted, although most stents were of a single type, and by the lack of a systematic radiographic monitoring for stent fracture. Finally, the pre-stent implantation strategies, along with other periprocedural aspects, were also at the discretion of the primary operator, but it reflects the contemporary clinical practice in this area. The findings of this proof-of-concept trial need to be studied in a larger, randomized controlled trial with a greater diversity of patients.
Post-dilation of SFA stents with cryoplasty can significantly reduce the risk of restenosis in patients with diabetes mellitus.
The authors acknowledge Preeti Kamath, MHA, Lauren Makke, RVT, Christopher Lichtenwalter, MD, and Ravi Sarode, MD, for their help with data collection, monitoring, and analysis.
For supplemental tables, please see the online version of this article.
Institutional grant support was provided by Boson Scientific Corporation.
Dr. Banerjee receives research grants from Boston Scientific and The Medicines Company; consultant/speaker honoraria from Gilead, St. Jude, Cordis, Boehringer Ingelheim, Sanofi, and Medtronic; is a consultant to Covidien; and has ownership in MDCARE GLOBAL (spouse) and intellectual property in HygeiaTel. Dr. Das is a member of the advisory board of Boston Scientific; and receives consultant/speaker honoraria from Abbott Vascular, Medtronic, and Terumo. Dr. Abu-Fadel receives consultant/speaker honoraria from Abbott Vascular. Dr. Dippel receives research grants from Covidien, eV3, and Spectranetics; consultant/speaker honoraria from Abbott Vascular, IDEV Technologies, Vessix Vascular, Spectranetics, Covidien, and WL Gore; and is a shareholder of Spectranetics. Dr. Shammas receives research grants from Boston Scientific, Cordis, and Abbott Vascular; and is the Research Director of the Midwest Cardiovascular Research Foundation. Dr. Brilakis receives research grants from Abbott Vascular and Infraredex; consultant/speaker honoraria from Terumo and St. Jude; and has employment link to Medtronic (spouse). Dr. Addo is a consultant to and receives speakers' fees from AstraZeneca. All other authors have reported they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- ankle-brachial index
- superficial femoral artery
- Received March 6, 2012.
- Revision received May 8, 2012.
- Accepted May 23, 2012.
- American College of Cardiology Foundation
- Hiatt W.R.,
- Regensteiner J.G.,
- Hargarten M.E.,
- Wolfel E.E.,
- Brass E.P.
- Bosiers M.,
- Torsello G.,
- Gissler H.M.,
- et al.
- Krankenberg H.,
- Schluter M.,
- Steinkamp H.J.,
- et al.
- Schillinger M.,
- Sabeti S.,
- Dick P.,
- et al.
- Laird J.R.,
- Katzen B.T.,
- Scheinert D.,
- et al.
- Dake M.D.,
- Ansel G.M.,
- Jaff M.R.,
- et al.
- Jude E.B.,
- Oyibo S.O.,
- Chalmers N.,
- Boulton A.J.
- Sabeti S.,
- Mlekusch W.,
- Amighi J.,
- Minar E.,
- Schillinger M.
- Lyden S.P.
- Suzuki L.A.,
- Poot M.,
- Gerrity R.G.,
- Bornfeldt K.E.
- Diaz M.L.,
- Urtasun F.,
- Barberena J.,
- Aranzadi C.,
- Guillen-Grima F.,
- Bilbao J.I.
- Gisbertz S.S.,
- de Borst G.J.,
- Overtoom T.T.,
- Moll F.L.,
- de Vries J.P.
- Spiliopoulos S.,
- Katsanos K.,
- Karnabatidis D.,
- et al.
- Hao H.,
- Gabbiani G.,
- Bochaton-Piallat M.L.