Elias Al Sarraf

Christophe Almarcha

Joël Quinard

Basile Radisson

Bruno Denet

Pedro Garcia-Ybarra

Darrieus-Landau instability and Markstein numbers of premixed flames in a Hele-Shaw cell

Keywords: Premixed flames, Darrieus-Landau instability, Hele-Shaw burner, Markstein length

Hydrodynamic flame instabilities are studied in a Hele-Shaw burner. By studying the development of perturbations, starting from a 2D Bunsen flame at the top of the burner, growth rates are measured for propane and methane-air mixtures, and compared to theoretical predictions. It is found that the dispersion relation in a Hele-Shaw cell has the same dependence with wavenumber σ = k -k 2 as the one predicted in tubes. Markstein numbers relative to fresh gases are obtained for propane and methane flames and compared to the literature.

Introduction

Hydrodynamic flame instabilities can be important for turbulent burning, particularly at high pressure [START_REF] Fogla | The turbulent flame 370 speed for low-to-moderate turbulence intensities: Hydrodynamic theory vs. experiments[END_REF] . Even without turbulence, the propagation of a laminar flame in a tube can lead to a very complex non-linear evolution (these flames are often called self-turbulent) if the tube is large enough [START_REF] Almarcha | Premixed flames propagating freely in tubes[END_REF]. However it is difficult to study quantitatively the instability in three dimensions. It has therefore been suggested by Joulin and Sivashinsky in [START_REF] Joulin | Influence of momentum and heat losses on the large-scale stability of quasi-2D premixed flames[END_REF] to study quasi two dimensional flames in a Hele-Shaw cell. Ronney was the first to report [START_REF] Sharif | Premixed-gas flame propagation in Hele-Shaw cells[END_REF] the experimental observation of flames in this configuration (see also the numerical simulation in [START_REF] Kang | Effects of heat and momentum losses on the stability of premixed flames in a narrow channel[END_REF]).

In the paper [START_REF] Almarcha | Experimental two dimensional cellular flames[END_REF], qualitative results on selfturbulent flames in a Hele-Shaw burner were presented. We show in the present paper that these self-turbulent flames are caused by hydrodynamic instabilities which are very close to the ones observed in tubes.

The experiment, which will be described in more

1 * Corresponding author email bruno.denet@irphe.univ-mrs.fr detail in [START_REF] Sarraf | Quantitative analysis of flame instabilities in a Hele-Shaw burner[END_REF], is summarized here: the Hele-Shaw burner consists of two glass plates 50 cm wide and 150 cm high, separated by a gap width of 4.7 mm. It is mounted vertically with the inlet gas mixture 25 at the bottom, open at the upper end. The equivalence ratio φ of the premixed gas is regulated by mass-flow controllers Bronkhorst EL-Flow. A 2D Bunsen flame is ignited at the top of the burner where it remains anchored thanks to a flow rate 30 in excess. Closing the valve at the bottom of the burner stops the flow and the downwards flame propagation is recorded using a high-speed video camera. The initial Bunsen flame is forced at a certain wavelength by using a plate with periodic 35 indentation at the top of the burner. A typical situation, including the linear and non linear stage of the evolution is shown in Figure 1. As seen in this figure, this very large burner contains a lot of unstable modes, a situation typical of applications 40 using premixed flames at high pressure. In the rest of the paper, we will show that by looking at the linear stage of this figure close to the top of the burner, growth rates can be measured, for propane and methane-air flames, leading to a quantitative 45 analysis of the instability, which is usually difficult to obtain in three dimensions. However, although the quasi two dimensional character of the flame in the Hele-Shaw burner leads to a much easier image analysis, there is the obvious drawback that the flame is affected by heat and viscous losses. We provide in Figure 2 a qualitative illustration that the flame in the burner is essentially subjected to the usual Darrieus-Landau instability. In this figure, the velocity field obtained by PIV measurements close to one of the cusps seen in Figure 1 is shown. This velocity field is typical of a Darrieus-Landau instability seen from a reference frame where the flame is advancing (this figure can be compared to the streamlines obtained by numerical simulation in [START_REF] Fogla | The turbulent flame 370 speed for low-to-moderate turbulence intensities: Hydrodynamic theory vs. experiments[END_REF] for instance) The purpose of the present paper is to present the quantitative results we get in this burner for the growth rates of the hydrodynamic instability. We will even use these results in order to get indirect measurements of the Markstein number in the Hele-Shaw cell. Before discussing the different curves of propane and methane flames let us first try to collapse our growth rates measurements by using as reference values the maximum growth rate σ max and the wavenumber corresponding to this maximum growth rate k max . In 1982 Frankel and Sivashinsky [START_REF] Frankel | The effect of viscosity on hydrodynamic stability of a plane flame front[END_REF], Pelcé and Clavin [START_REF] Pelce | Influence of hydrodynamics and diffusion upon the stability limits of laminar premixed flames[END_REF] and Matalon and Matkowsky [START_REF] Matalon | Flames as gasdynamic discontinuities[END_REF], obtained a dispersion relation, valid for small wavenumbers, for constant ρD (ρ is the density, D a diffusion coefficient) which was found to be of the form σ ∝ k -k 2 . We show in Figure 3 that all our measurements collapse on this the parameters of Figure 3 are given in the next sections. In the propane-air case, the equivalence ratio where we were able to measure growth rates is limited to a range φ = 0.81 to φ = 1, so it can-85 not be excluded that a thermodiffusive instability could be present for rich propane flames. It must be noted that in the hydrogen-air case, it has been shown only recently by a direct numerical simulation with complex chemistry, that a thermodiffusive 90 instability (σ ∝ k + k 2 -k 4 , the pure thermodiffusive instability without Darrieus-Landau terms being σ ∝ k 2 -k 4 ) is present for very lean flames [START_REF] Frouzakis | Numerical study of unstable hydrogen/air flames: Shape and propagation speed[END_REF].

Modified Clavin-Garcia dispersion relation

We have found in the previous section that the dispersion relation for various mixtures of methane and propane with air is of the form σ ∝ k -k 2 . We would like however to study slow flames, thus tak-100 ing into account the Froude number. A dispersion relation valid for temperature-dependent diffusivities (as in most indirect measurements of Markstein lengths [START_REF] Searby | Direct and indirect measurements of Markstein numbers of premixed flames[END_REF][START_REF] Truffaut | Experimental study of the Darrieus-Landau instability on an inverted-V flame, and measurement of the Markstein number[END_REF], we limit ourselves to the following temperature dependence: ρD ∝ √ T , T being the temperature) has been proposed by Clavin and Garcia [START_REF] Clavin | The influence of the temperature dependence of diffusivities on the dynamics[END_REF] (see also [START_REF] Truffaut | Experimental study of the Darrieus-Landau instability on an inverted-V flame, and measurement of the Markstein number[END_REF]) in the form of a quadratic equation:

A(k)σ 2 + B(k)σ + C(k) = 0 (1) With A(k), B(k) C(k) coefficients depending on gas expansion E = ρ u /ρ b , Markstein number M a, 110
Froude number F r = u 2 l /gδ l (where u l is the laminar flame speed and δ l the flame thickness, g is the acceleration of gravity) and Prandtl number P r :

A(k) = E + 1 E + E -1 E k M a -J E E -1 B(k) = 2k + 2Ek 2 (M a -J) C(k) = E -1 E k F r + (E -1) k 3 k m -(E -1)k 2 1 + 1 EF r M a -J E E -1 , (2)
where

k -1 m = √ E + 3E-1 E-1 M a -2E E-1 J + (2P r -1)
H. The integrals J and H can be found in [START_REF] Clavin | The influence of the temperature dependence of diffusivities on the dynamics[END_REF][START_REF] Truffaut | Experimental study of the Darrieus-Landau instability on an inverted-V flame, and measurement of the Markstein number[END_REF].

This dispersion relation has the advantage of including explicitly the Froude number, but for very unstable flames, it leads for large values of k to very asymmetrical dispersion relations (see [START_REF] Truffaut | Experimental study of the Darrieus-Landau instability on an inverted-V flame, and measurement of the Markstein number[END_REF] for instance). We have seen in Figure 3 that on the contrary, the experimental dispersion relation is very symmetrical.

Anyway the theoretical dispersion relations are only valid for low values of k, so we search for a de-velopment of the Clavin-Garcia dispersion relation,

125 valid for small k and 1/F r = O(k) σ = a g k + b g k 2 + O(k 3 ) (3)
where coefficients a g et b g are functions of k including Froude number effects: A staightforward development leads to

a g = E E + 1 S -1 (4)
130

where [START_REF] Markstein | Nonsteady combustion propagation[END_REF] Darrieus-Landau result with gravity, but without Markstein number effect, and

S = 1 + E -1 E -E 2 -1 E 2 F rk , the relation σ = a g k being the known
b g = -a 2 g E -1 E -2a g E + E -1 EkF r M a + J(a 2 g - 1 kF r + 2a g E) - E -1 k m /2S (5)
The same type of dispersion relation has been ob-135 tained by Matalon and coworkers for temperature dependent diffusivities, in the case without gravity (see [START_REF] Matalon | Hydrodynamic theory of premixed flames: effects of stoichiometry, variable transport coefficients and arbitrary reaction orders[END_REF] for the derivation, the correct results are to be found in Altantzis et al. [START_REF] Altantzis | Hydrodynamic and thermodiffusive instability effects on the evolution of laminar planar lean premixed hydrogen flames[END_REF] ). Figure 4 shows that the modified Clavin-Garcia rela-140 tion agrees with Reference [START_REF] Altantzis | Hydrodynamic and thermodiffusive instability effects on the evolution of laminar planar lean premixed hydrogen flames[END_REF] for the case without gravity. Furthermore, it should be noted that in the region of vanishingly small wavenumbers, the gravity effects lead to complex values of the growth rate whose small k-expansion has to be sought now in powers of k 1/2 . A straightforward calculation shows that the real part is still linear in k but with a negative slope whereas the imaginary part is proportional to k 1/2 . Anyway, in the present experimental conditions, this region appears to be of negligible extent.

We will use the modified Clavin Garcia dispersion relation in the rest of the paper, taking as units the thermal flame thickness δ l = D th /u l and the transit time τ t = δ l /u l . The laminar flame speeds u l to be used will be the values measured by Bosschaart and de Goey by the heat flux method [START_REF] Bosschaart | Detailed analysis of the heat flux method for measuring burning velocities[END_REF] for propane and methane air flames. Note that we have not taken into account that the flame is curved in the thickness, which could lead to a larger effective propagation velocity. Unfortunately Joulin and Sivashinsky [START_REF] Joulin | Influence of momentum and heat losses on the large-scale stability of quasi-2D premixed flames[END_REF], the available theory in a Hele-Shaw cell neglects Markstein lengths effects and supposes that the flame is flat in the thickness, which is not the case in the experiment, where the flame adopts a convex shape as a result of Darrieus-Landau instability and the lateral quenching on the cell plates. This is partially counterbalanced by stretch and by the back slope of temperature due to the burnt gas cooling. Our experiments show a net increase of the flame propagation velocity, except for lean flames, and the effects on the instability appears to be reduced just to quantitative modifications (ca. 30% reduction on the growth rates, see [START_REF] Sarraf | Quantitative analysis of flame instabilities in a Hele-Shaw burner[END_REF]). This could show that the transverse directions are independent.

Experimental results for propane and methane-air mixtures

In this section, we will present our measures of growth rates of propane and methane-air flames compared to a fit using the modified Clavin-Garcia formula of the previous section. Errors caused by the transient observed after closing the valve are discussed in the supplemental material. Figure 5 shows the case of propane-air flames for the three equivalence ratios φ = 0.81, φ = 0.9 and φ = 1.0.

As in previous experiments with propane [START_REF] Clanet | First experimental study of the Darrieus-Landau instability[END_REF][START_REF] Truffaut | Experimental study of the Darrieus-Landau instability on an inverted-V flame, and measurement of the Markstein number[END_REF] the range of equivalence ratios where it was possible to measure growth rates is limited. For low equivalence ratios, we are close to the extinction limit for the Hele-Shaw cell with a gap width of 4.7mm, which probably explains the low growth rates observed for φ = 0.81. The maximum growth rate for φ = 1.0 is approximately more than three times larger than for φ = 0.81, and more than 50% larger than the φ = 0.9 case. This rapid variation can be seen in the effective expansion ratios reported on the figure, which also shows the Markstein length given by a two-parameter (E and M a) In the methane case (figure 6), the accessible 210 range of equivalence ratio was larger, from φ = 0.9 to φ = 1.3. Starting from lean flames, the maximum growth rate increases up to φ = 1.1. the value of expansion ratio and Markstein lengths are also given, for the stoichiometric case, we obtain 215 E = 6.4 for φ = 1.0, with a difference larger than in the propane case compared to the value obtained by Cantera with a Grimech 3.0 mechanism E = 7.47.

Indirect measurement of Markstein numbers 220

We compare in this section the Markstein lengths measured for propane and methane air mixtures, with the existing values in the literature. Let us recall that the Markstein lengths we discuss are Markstein lengths relative to fresh gases, with less measurements than the burnt gases Markstein length Our measurements are indirect measurements, the Markstein length is determined here by a comparison with a theoretical formula. In our case we recall that the theory predicts a growth rate of the form σ ∝ k -k 2 , a two-parameter fit of the experimental dispersion relation allows the determination of the coefficient of the k term which depends on gas expansion, and of the coefficient of the k 2 term which depends on the Markstein number. Other indirect measurements exist. Searby and Quinard [START_REF] Searby | Direct and indirect measurements of Markstein numbers of premixed flames[END_REF] reported Markstein lengths at the stability threshold for very slow flames (methane and propane) highly diluted with nitrogen, Clanet and Searby [START_REF] Clanet | First experimental study of the Darrieus-Landau instability[END_REF] used a parametric restabilization of the plane front by an acoustic field to measure growth rates at one wavelength for very lean propane flames, Truffaut and Searby [START_REF] Truffaut | Experimental study of the Darrieus-Landau instability on an inverted-V flame, and measurement of the Markstein number[END_REF] studied the development of perturbations on oblique flames for rich propane-air mixtures.

Our values will also be compared to direct measurements of Markstein lengths. These direct measurements are often performed in conditions where one component of the total stretch, strain or curvature, dominates. Durox et al [START_REF] Durox | Experiments on 440 collapsing cylindrical flames[END_REF], have obtained values dominated by curvature by studying imploding cylindrical flames in the propane and methane case. Another experiment dominated by curvature is Garcia Soriano et al [START_REF] García-Soriano | Curvature and velocity of methane-air Bunsen flame tips[END_REF] who studied rich Bunsen burner methane flames. Most other direct measurements are dominated by strain. Clavin and Joulin in 1989 [START_REF] Clavin | Flamelet library for turbulent wrinkled flames[END_REF] (see also Clavin and Graña-Otero [START_REF] Clavin | Curved and stretched flames: the two Markstein numbers[END_REF]) showed that in a strain dominated case, there is an important diffi-260 culty. If the velocity used in the measurement corresponds to a low temperature, the Markstein length obtained has a tendency to be negative [START_REF] Bradley | Burning velocities, Markstein lengths, and flame quenching for spherical methane-air flames: a computational study[END_REF][START_REF] Balusamy | Direct measurement of local instantaneous laminar burning velocity by a new PIV algorithm[END_REF][START_REF] Varea | Measure-460 ment of laminar burning velocity and Markstein length relative to fresh gases using a new postprocessing procedure: Application to laminar spherical flames for methane, ethanol and isooctane/air mixtures[END_REF], contrary to most indirect or curvature dominated values. In [START_REF] Clavin | Flamelet library for turbulent wrinkled flames[END_REF][START_REF] Clavin | Curved and stretched flames: the two Markstein numbers[END_REF] the following procedure was sug-265 gested, first extrapolate the velocity field toward the reaction zone (the maximum of heat release for instance) to determine the Markstein length. Here we only present strain dominated values using extrapolation , the experiment of Deshaies and Cam-270 bray [START_REF] Deshaies | The velocity of a premixed flame as a function of the flame stretch: an experimental study[END_REF] and the numerical simulation with complex chemistry of Davis et al [START_REF] Davis | Markstein numbers in counterflow, methane-and propane-air flames: a 470 computational study[END_REF] for propane and methane. Let us note however that the following correction has been proposed (see [START_REF] Clavin | Curved and stretched flames: the two Markstein numbers[END_REF]) for non extrapolated strain Markstein numbers: if the Mark-

275
stein number is measured at a distance δx f from the flame in the fresh gases, simply add δx f /δ l to the reported value. As seen in [START_REF] Balusamy | Direct measurement of local instantaneous laminar burning velocity by a new PIV algorithm[END_REF] (Figure 12), where a typical δx f is shown, this would generally lead to positive Markstein numbers. Different explanations of this discrepancy are possible, we do not have many experiments, some experiments could have a huge error bar, for instance the extrapolation in the strain rate dominated values could lead to Markstein numbers too high. Another possible explanation has been proposed by Clavin and Graña-Otero [START_REF] Clavin | Curved and stretched flames: the two Markstein numbers[END_REF], the values of Markstein lengths relative to strain and curvature could simply be different, a possibility also suggested in a recent paper by Thiesset et al [START_REF] Thiesset | Distinct dependence of flame speed to stretch and curvature[END_REF] (see also the

Conclusion

In this paper, we have reported values of growth 345 rates of the Darrieus-Landau instability in a Hele-Shaw burner. Although heat losses lead to lower growth rates than in a tube, we were surprised to see that the Darrieus-Landau instability in the cell is essentially of the same type as in a tube. Using 350 a fit with a theoretical dispersion relation (a modified Clavin-Garcia dispersion relation, introduced here) we were able to obtain indirect measurements of Markstein numbers relative to fresh gases, which compare reasonably well to the indirect measure-355 ments of Markstein numbers in the literature. As recalled here, the discrepancy with direct measurements is much higher.

Acknowledgements

This work was supported by the French National

Figure 1 :

 1 Figure 1: Spatio temporal evolution (50x50cm) of a propaneair flame with equivalence ratio φ = 0.81

Figure 2 :

 2 Figure 2: Velocity field for a propane-air flame with equivalence ratio φ = 0.81.

Figure 3 :

 3 Figure 3: Normalized growth rate σnr = σ/4σmax versus normalized wavevector knr = k/2kmax for different mixtures (corresponding to different colors) of methane and propane. The black curve is the function k -k 2 .

Figure 4 :

 4 Figure 4: Comparison between the modified Clavin-Garcia model without gravity (green continuous curve) with the work of Altantzis et al. (red dashed curve), E = 7.9, U l = 39.5cm/s and M a = 3.69. The curves are superimposed

200 fit with equation 3 , 8 Figure 5 :

 385 Figure 5: Growth rates of propane-air mixtures at different equivalence ratios compared to the modified Clavin-Garcia relation

9 Figure 6 :

 96 Figure 6: Growth rates of methane-air mixtures at different equivalence ratios compared to the modified Clavin-Garcia relation

  280

Figure 7

 7 Figure 7 shows the Markstein numbers in the propane case. The present measurements correspond to the black curve for the three equivalence ratios shown in Figure 5. The last point showing an increase of the Markstein number is possibly 285

  Durox et al to the light blue curve, Davis et al to the green curve, Garcia-Soriano et al[START_REF] García-Soriano | Curvature and velocity of methane-air Bunsen flame tips[END_REF] to the red point for a very rich methane flame. As expected because of the different dilutions our Markstein numbers are above those measured by Searby and Quinard. As in the propane case, the curvature dominated Markstein numbers are much lower than the strain dominated Davis et al values, our indirect values are still in between. There is of course the difference with the propane case that for the 340 methane-air mixtures, the Markstein numbers are lower for lean flames, the exact opposite of the situation for propane.

Figure 7 :

 7 Figure 7: Markstein numbers for propane flames versus equivalence ratio.

Figure 8 :

 8 Figure 8: Markstein numbers for methane flames versus equivalence ratio.

Let us turn to the direct measurements. If Deshaies

Research Agency under agreement ANR-14-CE05-0006, The project leading to this publication has received funding from Excellence Initiative of Aix-Marseille University -A*MIDEX, a French "Investissements d'Avenir" programme. It has been 365 carried out in the framework of the Labex MEC. We thank Guy Joulin, Paul Clavin and Colette Nicoli for many stimulating discussions .

model with volumetric heat losses of Nicoli and Clavin [START_REF] Nicoli | Effect of variable heat loss intensities on the dynamics of a premixed flame front[END_REF]). In Figure 8 is presented the methane case. As before, our Markstein numbers correspond to the black curve, Searby and Quinard to the blue curve,


M.D Abdel-Rahmène Azzouzi

M.D Sébastien Vincendeau

M.D Eric Barret

M.D Antony Cicco

M.D François Kleinclauss

M.D Henk G Van Der Poel

M.D Christian G Stief

M.D Jens Rassweiler

M.D Georg Salomon

M.D Eduardo Solsona

Antonio 10

M.D Alcaraz

Teuvo T 11

M.D Tammela

Derek J 12

M.D Rosario

Francisco 13

M.D Gomez- Veiga

Göran 14

M.D Ahlgren

Fawzi 15

M.D Benzaghou

Bertrand 16

M.D Gaillac

Billy 16

Ph.D Amzal

Frans M J 17

M.D Debruyne

Gaëlle 18

M.D Fromont

Christian 19

M.D Gratzke

Mark Emberton
email: m.emberton@ucl.ac.uk

Fmedsci

Prof Mark Emberton

Padeliporfin vascular-targeted photodynamic therapy versus active surveillance in men with low-risk prostate cancer (CLIN1001 PCM301): an open-label, phase 3, randomised controlled trial

SUMMARY

Background

Vascular-targeted photodynamic therapy (VTP), a novel tissue-preserving treatment for lowrisk prostate cancer (PC), has shown favorable safety and efficacy results in single-arm Phase I and II studies. This report presents results of a randomised, controlled, parallel-group clinical trial of padeliporfin VTP versus the standard of care, active surveillance (AS).

Methods

Men with low-risk, localised PC (no Gleason patterns 4 or 5) and no previous treatment were recruited from March 8, 2011 to April 30, 2013 at 47 European university centres and community hospitals. They were randomised (stratification by centre using balanced blocks) to VTP or AS. VTP consisted of 4 mg/kg padeliporfin administered intravenously over ten minutes via optical fibres inserted into the prostate to cover the desired treatment zone and subsequent activation by laser light for 22 minutes and 15 seconds. Both groups were followed-up for 24 months in accordance with best AS practice at the time of study design, i.e., biopsy at 12-month intervals and prostate-specific antigen measurement and digital rectal exam at 3-month intervals. The prespecified co-primary efficacy endpoints were histological progression of cancer and absence of any histology result definitively positive for cancer at Month 24. Treatment was open-label, but primary efficacy outcomes were evaluated in a blinded manner.

Findings

Of the 206 subjects randomised to VTP, 196 received treatment. At completion of the trial, all 413 randomised subjects (intention-to-treat population) were analysed for efficacy. VTP doubled time to progression (from 14•1 [95% CI: 12.9 to 23.8] months to 28•3 [95% CI: 26.0 to 30.6] months; p<0•0001) and reduced the progression rate to approximately one-third that of AS (adjusted hazard ratio = 0•34; 95% CI: 0•24, 0•46; p<0•0001). VTP increased the probability of a negative prostate biopsy at 24 months post-treatment from 13•5% (28 of 207 subjects) to 49•0% (101 of 206 subjects) (adjusted risk ratio: 3•67; 95% CI: 2•53, 5•33); p<0•0001).

VTP was well tolerated. Genitourinary function showed transient deterioration in the VTP group, but no significant effects were seen at Month 24. The most common AEs in the VTP group were urinary tract infections (21 subjects) and AEs in the renal and urinary disorders (133 subjects) and reproductive system and breast disorders system organ classes (121 subjects). The most common serious side effect was retention of urine. Typically this event occurred on the first attempt to withdraw the urinary catheter (day-1 post-op). This was managed with immediate re-catheterization. The timing of a second attempt at removal of the urinary catheter was left to the discretion of the local investigator. This event occurred in 15 subjects, was severe in 3 subjects, and resolved within two months in all cases.

Interpretation

Padeliporfin VTP is a safe effective treatment for low-risk, localised PC that reduces the rate of histological progression compared to AS. It may allow more men to consider a tissuepreserving approach and defer or avoid radical therapy. Funding STEBA Biotech S.A.

Registration

ClinicalTrials.gov NCT01310894

RESEARCH IN CONTEXT

Evidence before this study

The idea of modifying our therapeutic target from the host organ to the tumour plus a margin has been the mainstay of surgical oncology during the latter half of the 20 th century. The principle is probably best exemplified in breast cancer, for which the previous standard of care, the Halsted radical mastectomy, has, with time and accumulating evidence, largely been replaced by breast preservation achieved by local excision with or without radiotherapy. We have seen the same process in renal cancer. Radical nephrectomy is currently performed only when partial nephrectomy and nephron preservation is neither practical nor possible. Ten years ago it was performed in all patients. The principles behind this transition are equivalence in terms of cancer-related outcomes but better function, greater patient acceptability, quicker recovery, and enhanced survivorship. Prostate cancer (PC) is the only solid organ cancer left for which this principle is not generally applied. Over the last decade several proof-of-concept studies of focal therapy for PC have been published, but they have typically been single-centre, small, and of relatively low quality. Having said this, these studies demonstrated the feasibility of more targeted treatment for PC and more importantly suggested high levels of patient acceptability because of excellent functional outcomes. More recently we have seen registered prospective development studies and formal Phase I and Phase II studies that demonstrate both safety and early (short-term) oncological efficacy.

These studies have been summarised in Valerio's systematic review.

Added value of this study

Valerio's systematic review identified the need for comparative studies. To our knowledge, ours is the first such study. Because vascular-targeted photodynamic therapy (VTP) is an intervention involving both a drug (in this case, padeliporfin) and a device (laser light introduced into the prostate), it was subject to regulatory approval as a drug through the European Medicines Agency (EMA). A pivotal comparative study was thus necessary but was challenging to design in a manner that would be acceptable to both patients and clinicians and in which the same primary outcome could be assessed for both VTP and the comparator. We had three options for the comparator: surgery, radiotherapy, or active surveillance (AS). The first two were problematic in arriving at a primary outcome that could be applied to both the experimental arm and the control. Surgery (radical prostatectomy) would not be suitable for a biopsy-based outcome because there would be no prostate to biopsy. Radiotherapy, on the other hand, would be amenable to a protocol-required biopsy, but the histological outcome would be confounded by the necessary neoadjuvant and adjuvant androgen suppression that comprises the standard of care. Therefore, AS was the only comparator that could reasonably be employed over the intended time frame of the study. The task for the EMA and the PCM301 Study Group was to determine the upper and lower risk thresholds of this low-risk group that would define the upper and lower bounds of the study entry criteria. These criteria had the effect of excluding, within the limits of precision of the diagnostic methods available to us at the time, men that were at very low risk and therefore unlikely to progress and men that were at higher risk and therefore unlikely to be offered or indeed consent to AS. These thresholds of low risk were in keeping with standard practice at the time of study design. Recent publications from Scandinavia and Canada on mature AS populations have subsequently shown that men towards the upper threshold of low-risk PC do fare worse in progression than men with very-low-risk disease. Modern diagnostic methods, including magnetic resonance imaging, allow us to identify these risk groups with considerably greater precision today than was possible at the time when the study was being considered by the EMA. Our results show that men with localised, low-risk PC can be treated in a way that not only preserves their genitourinary function but also results in a lower progression rate, greater chance of being declared disease-free, and reduction in need for whole-gland radical therapy in the form of surgery or radiotherapy.

Implications of all the available evidence

When this study was designed, our risk stratification methods at diagnosis were poor. The correction that was applied to mitigate the consequences of this imprecision was to offer radical therapy to nearly all men, irrespective of attributed risk. Today we attribute risk with greater precision using risk calculators, biomarkers, and imaging. Our study adds considerable weight to the argument that we need to move away from a one-size-fits-all approach to treatment and gradually replace it with a more risk-stratified approach to care.

We have AS for men at very low risk. We have radical therapy and multimodality treatments for men at high risk for whom the consequences of treatment are matched by benefit.

Between these two extremes, we now have VTP, an intervention that preserves prostate tissue when it is both possible and practical to do so. Given the precision of today's risk stratification, future research will need to explore both the patient preferences and the upper threshold of risk (as defined by tumour grade, volume, location, multiplicity) that should determine where the transition point exists where tissue preservation is likely to confer diminishing returns and should be supplanted by whole-gland radical therapy.

INTRODUCTION

Active surveillance (AS), a policy of delayed selective intervention, is an appropriate therapeutic option for low-risk prostate cancer (PC) that helps to mitigate the consequences of overtreatment. [START_REF] Mottet | Guidelines on Prostate Cancer[END_REF] Most studies-though admittedly single-centre and noncomparative-have demonstrated favorable outcomes, but AS has been associated with fairly high intervention rates especially in cohorts with less stringent eligibility criteria. [START_REF] Klotz | Long-term follow-up of a large active surveillance cohort of patients with prostate cancer[END_REF] Intervention, or crossover to radical treatment (surgery or radiotherapy) or systemic therapy (androgen suppression), tends to be driven by-in descending order of frequency-pathological upgrading on repeat biopsy, biochemical progression, and patient choice. [START_REF] Klotz | Management of low risk prostate cancer: active surveillance and focal therapy[END_REF] Focal therapy and AS are both tissue-preserving strategies. They share the goal of preserving prostate tissue and consequently function by delaying or avoiding radical whole-gland treatment in men in whom it is safe to do so. [START_REF] Van Den Bergh | Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review[END_REF] However, focal therapy differs from AS in that it treats disease-by the process of selective tissue ablation-above a certain risk threshold and monitors disease below that threshold, as the latter is deemed to be clinically insignificant. A risk-stratified clinical pathway that offers men focal therapy in a manner complementary to AS might result in two potential benefits: a reduction in the probability of failure or crossover to radical therapy and an increase in the proportion of men eligible and willing to undergo a tissue-preserving treatment.

Neither focal therapy nor AS has previously been assessed in a prospective, comparative efficacy study. Both have been assessed only in single-centre series, [START_REF] Klotz | Long-term follow-up of a large active surveillance cohort of patients with prostate cancer[END_REF][START_REF] Ahmed | Focal therapy for localised unifocal and multifocal prostate cancer: a prospective development study[END_REF][START_REF] Valerio | The role of focal therapy in the management of localised prostate cancer: a systematic review[END_REF] in which the outcomes were dependent on the population studied, the diagnostic precision at baseline, the intensity and manner of the reclassification tests, and the study duration. These limitations challenge informed decision-making by the patient because the attributes that are most likely to influence treatment selection are the failure rates and toxicity profiles of the two approaches and the likelihood of avoiding radical therapy. We present the results of what is to our knowledge both the first prospective comparative evaluation of the efficacy and safety of focal therapy and the first evaluation of AS in a comparative setting-rather surprisingly given that it is a recommended standard of care. The selective ablation in our focal therapy arm was achieved using vascular-targeted photodynamic therapy (VTP) with padeliporfin, an agent that achieves its tissue effects nonthermally and had previously been evaluated in both preclinical and clinical settings. [START_REF] Azzouzi | TOOKAD® soluble focal therapy: pooled analysis of three phase II studies assessing the minimally invasive ablation of localized prostate cancer[END_REF][START_REF] Azzouzi | TOOKAD(®) Soluble vascular-targeted photodynamic (VTP) therapy: determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer[END_REF]

METHODS

Study design and participants

Study CLIN1001 PCM301 was a randomised, controlled, parallel-group clinical trial of padeliporfin VTP versus AS for treatment of low-risk, localised PC. Men aged ≥18 years with low-risk, localised PC diagnosed by transrectal ultrasound (TRUS)-guided biopsy and no previous treatment were enrolled, provided they were eligible to be exposed to a photosensitising agent and had no contraindications to undergoing magnetic resonance imaging (MRI). Participants were required to have low-risk PC but not very-low-risk PC.

Men were eligible if one core of cancer that was free of Gleason patterns 4 or 5 was present provided that the cancer core length was between 3 and 5 mm. In other words, if only one core was positive, only Gleason pattern 3 was permitted but in order to qualify the cancer core length had to be greater than or equal to 3mm and less than or equal to 5mm. Men with 2 or 3 cores positive were also permitted, but cancer core length could not exceed 5 mm.

Clinical stage was limited to ≤T2a (pathological or radiological up to T2c disease permitted), prostate-specific antigen (PSA) ≤10 ng/mL, and prostate volume ≥25 and <70 cc). These criteria were based on a study of prediction determinants prediction in AS subsequently reported by Welty et al. [START_REF] Welty | Extended followup and risk factors for disease reclassification in a large active surveillance cohort for localized prostate cancer[END_REF] The performance status of the subjects was not a criterion for study inclusion. Instead, two overarching requirements had to be satisfied: men had to have a predicted life expectancy of 10 years or more and, in addition, had to be free of any medical conditions that were deemed to be a contraindication to general anaesthesia. Men with a contraindication to MRI (e.g. cardiac pacemaker), factors excluding accurate reading of pelvic MRI (e.g. bilateral hip replacements), or any condition or history of illness or surgery that may have posed an additional risk to men undergoing VTP procedure were excluded.

Criteria for subject removal from the study were occurrence of a serious adverse event (SAE) if recommended by the investigator, subject withdrawal, or a major protocol violation.

The study was conducted in compliance with Good Clinical Practice and according to a written protocol approved by each centre's ethics committee. All subjects provided written informed consent. The trial was completed in accordance with the protocol.

Randomisation and masking

Investigators enrolled subjects and allocated them to the VTP and AS groups in a 1:1 ratio using a web-based randomisation system generated by the sponsor and stratified by centre using balanced blocks of varied size (2 or 4 subjects). Treatment was open-label (subjects and investigational site staff were not blinded to study treatment), but primary efficacy outcomes were evaluated in a blinded manner.

Procedures

AS was conducted according to best practice at the time of study design. [START_REF] Heidenreich | EAU guidelines on prostate cancer. Part 1: screening, diagnosis, and treatment of clinically localised disease[END_REF][START_REF]Guideline for the Management of Clinically Localized Prostate Cancer[END_REF] It comprised a protocol-directed biopsy at 12-month intervals and 3-monthly PSA measurement coupled with a digital rectal exam.

The aim of VTP was to treat a complete prostate lobe. Subjects randomised to padeliporfin VTP underwent pretreatment multiparametric MRI, which was centrally reviewed with the biopsy results by a committee composed of radiologists and urologists who made detailed recommendations on the number, length, and position of interstitial optical fibres using treatment guidance software. [START_REF] Azzouzi | TOOKAD(®) Soluble vascular-targeted photodynamic (VTP) therapy: determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer[END_REF][START_REF] Moore | Determination of optimal drug dose and light dose index to achieve minimally invasive focal ablation of localised prostate cancer using WST11-vascular-targeted photodynamic (VTP) therapy[END_REF] The treatment-guidance software was used to generate a light-density index (LDI; a measure of the energy exposure per unit volume of target tissue) of >1, which had been associated with a high probability of a single-lobe ablation in earlier studies. [START_REF] Azzouzi | TOOKAD(®) Soluble vascular-targeted photodynamic (VTP) therapy: determination of optimal treatment conditions and assessment of effects in patients with localised prostate cancer[END_REF] However, the urologist in charge of the treatment was allowed to adapt the treatment recommendations to the actual volume and shape of the prostate observed on the TRUS images at the time of the procedure. Once the fibres were accurately positioned in the prostate to cover the desired treatment zone, 4 mg/kg padeliporfin (Aptuit Glasgow Ltd, Glasgow, UK) was administered intravenously over ten minutes. The drug was activated in the treatment zone by laser light at 753 nm with a fixed power of 150 mW/cm over 22 minutes and 15 seconds, corresponding to an energy dose of 200 J/cm. [START_REF] Azzouzi | Vascular-targeted photodynamic therapy with TOOKAD® Soluble in localized prostate cancer: standardization of the procedure[END_REF] Subjects with bilateral cancer received a second procedure for contralateral lobe treatment. Retreatment of lobes positive for PC at the Month 12 biopsy was permitted. The VTP procedure was carried out under a general anaesthetic during a 2-hour operating theatre allocation with a planned overnight stay. The urethral catheter was removed the morning after the procedure.

For subjects in both groups, PSA was measured and digital rectal examination performed every three months. TRUS-guided, 12-core biopsy (6 cores directed to each prostate lobe) was performed at Months 12 and 24. Thus, the sampling density (number of cores per unit volume of tissue) in the subjects who received VTP was greater than in those in the AS group, particularly for VTP-treated lobe(s) with reduced volume associated with posttreatment fibrosis. Biopsy samples were read centrally by an independent pathologist blinded to treatment assignment and local pathologist reading. An independent, blinded Outcomes Review Panel reviewed all PSA data and TRUS-guided biopsy reports to assess these results and determined the number and location of positive cores. In the case of discrepancy between the local and central biopsy readings, the panel's pathologist adjudicated. Any additional radical PC treatments, metastases, evidence of T3 disease, and severe PC-related events were recorded at Months 12 and 24. Any man who underwent radical PC treatment without histological progression (because of patient or physician preference) continued in the study until the end (Month 24) and returned to standard care after that.

The International Prostate Symptom Score (IPSS) and International Index of Erectile Function -15 Questions (IIEF-15) questionnaires were administered every three months through Month 12 and at Month 24 (and at seven days postprocedure for subjects who received padeliporfin VTP). Validity and sensitivity of these questionnaires to detect change in genitourinary function have been established. [START_REF] Barry | The American Urological Association symptom index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association[END_REF][START_REF] Rosen | The international index of erectile function (IIEF): a multidimensional scale for assessment of erectile dysfunction[END_REF] The EuroQol-5D (EQ-5D) questionnaire was administered at Month 12 and Month 24 to assess quality of life. All adverse events (AEs) were recorded from the signing of the consent form through the end of the study (including any occurring after the initiation of additional PC treatment). At each study visit, the investigator questioned the subject about AEs and intercurrent illnesses since his last visit.

Outcomes

The prespecified co-primary efficacy endpoints were treatment failure (histological progression of cancer from low to moderate or higher risk over 24 months follow-up) and absence of definitive cancer (absence of any histology result definitively positive for cancer at Month 24). Moderate or higher risk was defined as the observation of one of the following events: more than three cores definitively positive for cancer when considering all histological results available during follow-up in the study, any Gleason primary or secondary pattern of 4 or more, at least one cancer core length >5 mm, PSA> 10 ng/mL in three consecutive measures, any T3 PC, metastasis, PC-related death. The prespecified secondary objective was to determine any differences between the two groups in the following outcomes: total cancer burden in the prostate; rate of additional PC radical therapy; rate of severe PC-related events (cancer extension to T3, metastasis, PC-related death); rate of AEs; rate of incontinence, erectile dysfunction, and urinary symptoms.

Statistical analysis

The sample size was based on an expected rate of progression from low to moderate or higher risk of ≥15% over 2 years in the AS group and 5% in the VTP group. Using these assumptions, the sample size required was 400 subjects (200 subjects per group), and at least 40 events (subjects with progression of cancer) needed to be observed for the final analysis to take place.

Statistical analyses were conducted using SAS version 9.3. All randomised subjects were analysed for efficacy according to assigned treatment in an intention-to-treat analysis.

Treatment failure (progression) was analysed by survival analysis. Times to progression were compared between the two treatment groups using the log-rank test and quantified using a Cox proportional-hazards regression model to derive hazard ratios at Month 24, and treatment group and age, number of positive cores, prostate volume, and disease status at baseline were used as covariates. Absence of definitive cancer (positive biopsy) was analysed as a dichotomous outcome. Proportions of subjects with observed success at Month 24 were compared by 2-sided Pearson's chi-square test, and odds and risk ratios were calculated. Time to initiation of radical therapy was estimated by the Kaplan-Meier method, and the logrank test was used for comparison. The mean number of positive cores and maximum cancer core length at Months 12 and 24 were compared by Student t test. Other efficacy data were summarised descriptively.

All subjects randomised to VTP who received any padeliporfin or initiated any study treatment-related procedure and all subjects randomised to AS were analysed for safety by treatment received. IIEF-15, IPSS, and EQ-5D results were analysed by analysis of covariance. Other safety data, including, AEs, were summarised descriptively.

The trial is registered at ClinicalTrials.gov (NCT01310894).

Role of the funding source

The study sponsor and funder, STEBA Biotech S.A., developed the protocol in consultation with the study investigators and the European Medicines Agency (EMA). STEBA performed data management and statistical analysis and provided medical writing support for this report.

AAzzouzi and ME had full access to all data in the study. The final decision to submit this report for publication was made jointly by all the authors. The corresponding author (ME) had the final responsibility to submit for publication. received both contralateral treatment and retreatment. An LDI ≥1 was achieved in 252 (98%) of 254 initial treatments of a lobe. Prostate lobes that were retreated were less likely to achieve an LDI ≥ 1, although they were exposed to the same energy of 200 J/cm (appendix p.2).

All 413 randomised subjects were included in the efficacy analysis (Figure 1). Padeliporfin VTP delayed progression from low-risk to moderate or higher-risk PC and reduced the probability of a positive biopsy results at Month 24 compared to AS (Table 2). Padeliporfin VTP doubled time to progression from 14•1(95% CI: 12.9 to 23.8]) months to 28•3 (95% CI: 26.0 to 30.6) months (p<0•0001). The rate of progression over 24 months was reduced to approximately one-third that of AS (adjusted hazard ratio = 0•34; 95% CI: 0•24, 0•46; p<0•0001). The distribution of predefined progression criteria showed that padeliporfin VTP was efficacious against the individual parameters of the composite progression endpoint. The principal determinants of progression were Gleason grade ≥4 and increases in number of positive cores and cancer core length, which all showed substantial reduction in the padeliporfin VTP group. The regression coefficients showed no effect of treatment group or baseline characteristics. Padeliporfin VTP also increased the probability of a negative Month 24 biopsy by from 13•5% (28 of 207 subjects) to 49•0% (101 of 206 subjects) (adjusted risk ratio: 3•67; 95% CI: 2•53, 5•33); p<0•0001). Eight subjects experienced a severe PC-related event within 24 months, but only one of the subjects who did have such an event (both T3 PC and metastasis) was in the VTP group. This subject was probably under-staged at study entry.

His first protocol-required biopsy resulted in a Gleason upgrading that, for the purposes of the study, constituted his first-and therefore reported-progression event. Subsequent investigation revealed a locally advanced PC, and metastasis was detected on further staging investigation. VTP exposure was associated with a reduction in the rate of radical therapy compared to men allocated to AS (12 [5.8%] of 206 subjects versus 60 [29.0%] of 207 subjects; p<0•0001) and in time to radical therapy (p<0•0001) (Figure 2). For subjects whose PC did not progress during the study, padeliporfin VTP also produced clinically and statistically significant decrease compared to AS at Month 24 in all mean tumour burden parameters: total number of positive cores (0.9 vs 2.3; p<0•0001), total cancer core length (2.6 vs 6.8 mm; p<0•0001), and maximum cancer core length (1.6 vs 3.4 mm; p<0•0001).

Moreover, VTP produced a stable reduction in PSA of about 3 ng/mL over the course of the study.

The nine subjects randomised to VTP but who had no treatment-related procedure were excluded from the safety analysis (Figure 1). In the VTP group, IIEF-15 and IPSS assessments showed transient deterioration in erectile and urinary function, but the Month 24 result was comparable between the two groups (appendix p.3). Month 24 IPSS was 6.6 (standard deviation [SD]: 5.47) for VTP and 8.2 (SD: 6.47) for AS, and Month 24 IIEF-15 was 15 (SD: 10.70) for VTP and 16.8 (SD: 11.17) for AS. These results show no significant effect of padeliporfin VTP on genitourinary function compared to AS. The mean EQ-5D questionnaire scores at Month 24 in both the VTP and AS groups were slightly decreased from baseline with no difference in the two groups (82.5 [SD: 12.31] in the VTP group and 81.8 [SD: 12.09] in the AS group), indicating no decrease in quality of life associated with VTP at Month 24 (appendix p.2).

As expected, both the incidence and severity of AEs and SAEs were higher in the VTP group than in the AS group (Table 3). Most subjects in the VTP group experienced an AE, most of which were mild or moderate in severity and self-limited. The most commonly reported AEs in the padeliporfin VTP group were urinary tract infections (23 AEs in 21 [10.7%] subjects) and AEs in the renal and urinary disorders (280 AEs in 133 [67.5%] of 197 subjects) and reproductive system and breast disorders system organ classes (197 AEs in 121 [61.4%] of 197 subjects), and these AEs accounted for the largest differences between the treatment groups. AEs related to the study drug, device, or procedure were common but generally not severe. Most of these related AEs occurred during the procedure or in the days immediately after the procedure and resolved quickly without sequelae. The reporting of pain that was thought to be related to the procedure (due to the transcutaneous needle placement, due to the swelling of the prostate or both) was captured by the term 'perineal pain'. This was reported by 30 (15%) men allocated to the VTP group and by 1(0.5%) man in the AS group.

Three subjects experienced events that were more long-lasting: two with urethral strictures requiring endoscopic dilation and one case of urinary incontinence in a subject who had previously undergone transurethral prostatectomy (TURP). Men with a history of surgery for benign prostatic hypertrophy (including TURP) were subsequently excluded from the study (via protocol amendment 23 October 2012) for safety reasons. All other reports of incontinence were self-limited, were usually urge-related and occurred in the period after catheter withdrawal. Incontinence management was at the discretion of the investigator. The most common related SAE in the VTP group was urinary retention. Typically this event occurred on the first attempt to withdraw the urinary catheter (day-1 post-op). This was managed with immediate recatheterization. The timing of a second attempt at removal of the urinary catheter was left to the discretion of the local investigator. All 15 retention cases resolved within two months. No subject discontinued VTP because of an AE. Three subjects discontinued the study because of AEs. One subject in the AS group developed ureteric cancer. One subject in the VTP group had an anaphylactic reaction to the anaesthesia administered at the start of the VTP procedure; he had received no padeliporfin or VTP. One subject in the VTP group died from a myocardial infarction during mountain climbing approximately eight months after padeliporfin VTP, and the investigator assessed the AE as unrelated to study drug, device, or procedure.

An independent Data and Safety Monitoring Board reviewed safety data approximately every 3 months throughout the study and advised the study sponsor on matters of subject safety. At all meetings, the members unanimously agreed that no safety issues had emerged in the study.

DISCUSSION

VTP doubled time to progression (from 14•1 to 28•3 months), reduced the progression rate to approximately one-third that of AS, and increased the probability of a negative prostate biopsy at 24 months post-treatment from 13•5% to 49•0%. VTP was also safe and well tolerated with only minor and transient deterioration in genitourinary function. Our study has shown that partial-gland ablation by VTP influences the course of PC in the short-to-medium term. First, the proportion of men who transition from a cancer status to cancer-free status was increased. Second, the proportion of men who progress from a histologically defined low-risk status to a higher one is diminished. As a result, fewer men chose to undergo radical therapy during the study period. Moreover, these benefits were achieved safely, efficiently, and without compromising genitourinary function when assessed at 12 and 24 months after VTP.

Since this is the first comparative efficacy study of its type, it is important to consider the methodological considerations that were inherent in its design and conduct. The first relates to the population studied. By today's standards this population might be considered low risk.

However, whilst the study was in development and being discussed with the EMA, neither AS nor focal therapy were accepted as standard care. The EMA agreed that we could reasonably exclude very-low-risk patients. Therefore, lower and upper thresholds of risk (defined by Gleason pattern and tumour burden) were set, below which and above which men were excluded. This low-risk group was the only one that could have been studied at the time.

Were the study designed today, given the changes to risk categorisation, it is likely that men with well characterised PC and low volume secondary Gleason pattern 4 would be included. [START_REF] Epstein | A new contemporary prostate cancer grading system[END_REF] A second limitation relates to rapidly changing practice in risk stratification of PC patients, most significantly the use of MRI in the diagnostic and the re-evaluation phases of both AS and focal therapy. [START_REF] Panebianco | Multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study[END_REF][START_REF] Recabal | The efficacy of multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy in risk classification for patients with prostate cancer on active surveillance[END_REF] When the study began, few units offered MRI to patients on AS or as part of the work-up for focal therapy. Now it is difficult to imagine using either strategy without MRI. Although only men assigned to VTP had MRI in this study, images were used only for treatment planning, not for detection or staging. The only way in which unilateral use of MRI could have biased subjects' allocation was the detection of colorectal or bladder cancer, which would have triggered a study withdrawal. If the study were repeated today, MRI would play an important role in subject selection and risk stratification for both interventions. [START_REF] Jarow | Partial gland ablation for prostate cancer: report of a Food and Drug Administration, American Urological Association, and Society of Urologic Oncology Public Workshop[END_REF] A third concern is discriminating true progression from reclassification. When using a biopsy-based strategy to refine the risk stratification at given intervals in AS, upgrading (transition from an exclusive Gleason pattern 3 status to one with elements of Gleason pattern 4 or 5) occurs. Determining whether the observed increase in the Gleason pattern is a correction of inherent diagnostic imprecision or the product of true disease progression has proved challenging. Whilst no universal definition of clinical significance exists, recently published MRI studies have used the presence of Gleason pattern 4 as the minimum definition of clinically significant PC. [START_REF] Panebianco | Multiparametric magnetic resonance imaging vs. standard care in men being evaluated for prostate cancer: a randomized study[END_REF][START_REF] Recabal | The efficacy of multiparametric magnetic resonance imaging and magnetic resonance imaging targeted biopsy in risk classification for patients with prostate cancer on active surveillance[END_REF] Physicians have recommended treatment upon upgrading irrespective of its underlying cause. This strategy appears prudent given that recently published data from two mature AS series have identified higher risk groups (within the risk profile suitable for AS) that are at greater risk of progression. [START_REF] Klotz | Long-term follow-up of a large active surveillance cohort of patients with prostate cancer[END_REF][START_REF] Henderson | Nine-year follow-up for a study of diffusion-weighted magnetic resonance imaging in a prospective prostate cancer active surveillance cohort[END_REF][START_REF] Godtman | Long-term results of active surveillance in the Göteborg randomized, population-based prostate cancer screening trial[END_REF] The final issue relates to the efficacy endpoints evaluated. If endpoints such as progression to metastases or death had been used, the natural history of low-risk PC would have required a very large study conducted over two decades. Some experts advocate prioritizing of shorterterm, relevant outcomes that are important to patients to support patients and their physicians in their clinical decision-making. [START_REF] Amico | Personalizing the use of active surveillance as an initial approach for men with newly diagnosed prostate cancer[END_REF] This multicentre study has demonstrated that padeliporfin VTP can be implemented widely and delivered effectively and safely. The latter issue deserves some qualification. Exposure to VTP resulted in an increase in the frequency of SAEs from 1 in 10 men on AS to 1 in 3 men who received VTP. Most of the events were expected, genitourinary in nature, and selflimited. The most important of these events was failure to void on catheter removal (urinary retention). The event was managed by replacement of the urethral catheter and extension of the period of dependent urinary drainage.

It is worth noting that most study sites had no prior experience in delivering focal therapy, let alone VTP. Study recruitment was timely over a large geographical area, a scenario that contrasts with the many previous attempts to undertake randomised, comparative studies of early PC treatment, which either failed to recruit completely or closed because of poor recruitment. [START_REF] Ahmed | Can we deliver randomized trials of focal therapy in prostate cancer?[END_REF] Feasibility is an important attribute for surgical interventions, and our results demonstrate that VTP can be taught, learned, and delivered by a range of health care providers and systems. This study was performed at a large number of centres and in a variety of healthcare systems, few of which had any previous experience with VTP, and yet we managed to achieve a very low rate of permanent urinary toxicity. Since our understanding and management of early PC have changed so much in the last few years, it is worth speculating on how padeliporfin VTP might be used with current diagnostics and risk stratification, which are unrecognizable from those at the time of study design. Adoption of MRI and targeted biopsy into the clinical pathway has created more precise risk stratification, allowing a more nuanced approach to men with a new PC diagnosis. Given that MRI is now widely used within the diagnostic pathway but was not used for diagnosis or risk stratification in our study, it is worth speculating on how the diagnostic process may be influenced by the results of this study. First, it is likely that a pathway based on MRI-because of its role as a triage test between an elevated PSA and biopsy-will result in a reduction of the number of men biopsied and in the proportion of men receiving the diagnosis of clinically insignificant PC. In contrast, men with an MRI abnormality will undergo targeted biopsy (something that was not possible without MRI), resulting in a greater sensitivity for clinically significant disease. It is very likely that the men with clinically significant isolated lesions will be the candidates for focal prostate therapy. Men who do not need treatment should not have it. Men who require whole-gland treatment because of bilateral clinically significant disease should be offered it. Men with locally advanced disease should be offered multimodality therapy.

However, men who have low-risk, localised disease can now choose, on the basis of the evidence that our study has generated, how to approach tissue preservation.

More research is needed to address unanswered questions, the principal one being the longterm effect of tissue-preserving treatment on PC control rates. One unknown element is the efficacy of padeliporfin VTP in eradicating cancers of different grades within the target volume. A study in men with Gleason pattern 4 (NCT01875393) has been submitted for publication. Another uncertainty relates to the stability of the tissue that lies beyond the treatment zone. This question requires long-term follow-up, which has been initiated in the men from Study CLIN1001 PCM301.

CONTRIBUTORS

The sponsor, STEBA Biotech S.A., developed the study design in consultation with the study investigators and the EMA. BA performed the statistical analysis and interpretation on behalf of the sponsor. AAzzouzi, SV, EB, AC, FK, HVP, CGS, JR, GS, ES, AAlcaraz, TTT, DJR, FGV, GA, ME, and the PCM301 Study Group conducted the study and collected the data. 0 a , 14 0 a , 11 0,14 SD = standard deviation; TNM = tumour, nodes, metastasis; VTP = vascular-targeted photodynamic therapy. a Some of the subjects included on the basis of two biopsies at the beginning of the study had one of those two biopsies negative. •001 e CI = confidence interval; NA = not applicable; NC = not calculated; VTP = vascular-targeted photodynamic therapy. a The Hochberg procedure was used to adjust for multiplicity of the two co-primary endpoints.

TABLES (IN-TEXT)

b Cox proportional-hazards model with treatment as fixed effect and baseline age, number of cores positive, prostate volume, and disease status (unilateral/bilateral) as covariates. c From the log-rank test of equality of survival curves across treatment groups Cox proportional-hazards model with treatment as fixed effect and baseline age, number of cores positive, prostate volume, and disease status (unilateral/bilateral as covariates. d A subject might have met > 1 criterion for progression. e From Pearson's chi-square test for observed success. f Logistic regression model with treatment as fixed effect and baseline age, number of cores positive, prostate volume, and disease status (unilateral/bilateral) as covariates.

Ureteric cancer regional 0 1 (0.5)

Nervous system disorders

Cerebrovascular accident 1 (0. * The nine subjects randomised to VTP but who had no treatment-related procedure were excluded from analysis of safety.

FIGURE LEGENDS (IN-TEXT)

  The questions were general, and the presence or absence of specific AEs was not solicited from subjects. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. The investigator assessed the relationship of each AE to the study drug (padeliporfin), device, and procedure. AEs were coded and categorised according to the Medical Dictionary for Regulatory Activities (version: 18.0). Haematology, coagulation, serum chemistry, and urinalysis were evaluated every three months. Troponin was measured before discharge and quantitative D-Dimer before anaesthesia, before discharge, and at 7 days post-treatment for subjects who received VTP. Vital signs, electrocardiogram, and physical examination were performed preprocedure and postprocedure for subjects who received padeliporfin VTP. An independent Data Safety Monitoring Board (composed of two urologists, a laser surgery expert, and a statistician) reviewed safety data and SAE reports throughout the study and advised the sponsor on matters of subject safety.

FMJD

  chaired the Data Safety Monitoring Board and GF and CG served on the Outcomes Review Panel. ME prepared the first draft of the manuscript and with Anne McDonough, a professional medical writer funded by the sponsor. All authors contributed to the final data interpretation and final draft of the report and approved submission for publication.

  event; SAE = serious adverse event; VTP = vascular-targeted photodynamic therapy.

Figure 1 .Figure 2 .

 12 Figure 1. Disposition of subjects by treatment group

Table 1 . Demographic and baseline prostate cancer characteristics

 1

		Padeliporfin VTP	Active surveillance	Total
	Characteristic	N = 206	N = 207	N = 413
	Age (years)
	Mean (SD)	64.2 (6.7)	62.9 (6.7)	63.5 (6.7)
	Range: minimum, maximum	45, 85	44, 79	44, 85
	Race
	Caucasian, n (%)	202 (98.1)	206 (99.5)	408 (98.8)
	Other, n (%)	4 (2.9)	1 (0.5)	5 (1.2)
	Body mass index (kg/m 2 )
	Mean (SD)	26.5 (3.3)	27.3 (4.0)	26.9 (3.7)
	Range: minimum, maximum	18.8, 38.6	18.8, 44.8	18.8, 44.8
	Time since diagnosis (months)
	Mean (SD)	6.3 (8.5)	6.0 (7.9)	6.2 (8.2)
	Range: minimum, maximum	0.2, 54.2	0.2, 47.4	0.2, 54.2
	TNM staging
	T1a, n (%)	1 (0.5)	0	1 (0.2)
	T1c, n (%)	177 (85.9)	180 (87.0)	357 (86.4)
	T2a, n (%)	28 (13.6)	27 (13.0)	55 (13.3)
	PSA (ng/mL)
	Mean (SD)	6.2 (2.1)	5.9 (2.0)	6.1 (2.1)
	Range: minimum, maximum	0.1, 10.0	0.5, 10.0	0.1, 10.0
	Estimated prostate volume (cc)
	Mean (SD)	42.5 (12.5)	42.5 (11.8)	42.5 (12.1)
	Unilateral disease, n (%)	157 (76.2)	163 (78.7)	320 (77.5)
	Bilateral disease, n (%)	49 (23.8)	44 (21.3)	93 (22.5)
	Total number of pretreatment biopsy cores
	Mean (SD)	13.6 (3.3)	13.6 (3.6)	13.6 (3.4)
	Range: minimum, maximum	10, 25	10, 26	10, 26
	Total number of pretreatment biopsy cores
	with cancer
	Mean (SD)	2.1 (0.7)	2.0 (0.7)	2.1 (0.7)
	Range: minimum, maximum	1, 3	1, 3	1, 3
	1 core, n (%)	39 (18.9)	52 (25.1)	91 (22.0)
	2 cores, n (%)	110 (53.4)	100 (48.3)	210 (50.8)
	3 cores, n (%)	57 (27.7)	55 (26.6)	112 (27.1)
	Total cancer core length (mm)
	Mean (SD)	4.3 (2.3)	3.8 (2.4)	4.1 (2.4)
	Range: minimum, maximum

Table 2 . Co-primary efficacy endpoints Endpoint a

 2

		Padeliporfin VTP	Active surveillance	Padeliporfin VTP vs active surveillance
		N = 206	N = 207
		n (%)	n (%)	Ratio (95% CI)	p value
	Progression	58 (28.2)	120 (58.0)	Adjusted b hazard ratio 0.34 (0.24, 0.46)	<0•001 c
	Criteria for progression d
	More than three cores positive	23 (11.2)	58 (28.0)	NC	<0•001 e
	Gleason ≥4	49 (23.8)	91 (44.0)	NC	<0•001 e
	Cancer core length >5 mm	25 (12.1)	51 (24.6)	NC	0•001 e
	PSA >10 ng/mL in three consecutive measures	3 (1.5)	14 (6.8)	NC	0•007 e
	Any T3 prostate cancer	0	4 (1.9)	NC	NA
	Metastasis	0	0	NC	NA
	Prostate cancer-related death	0	0	NC	NA
	Negative Biopsy at Month 24	101 (49.0)	28 (13.5)	Adjusted f risk ratio 3.67 (2.53, 5.33)	<0

ACKNOWLEDGEMENTS

We thank the patients who agreed to participate in this study.

We thank Drs. Peter Scardino and Michael Zelefsky (Memorial Sloane Kettering Cancer

Center, New York, USA) for their very helpful comments and advice on earlier versions of this manuscript.

Dr. Emberton is a United Kingdom National Institute of Health Research (NIHR) Senior

Investigator. His research is supported by the UCLH/UCL NIHR Biomedical Research Centre, London, UK.

RESULTS

Subjects were recruited from March 8, 2011 to April 30, 2013 and followed for approximately 24 months at 47 university centres at community hospitals in ten European countries (Belgium, Finland, France, Germany, Italy, Netherlands, Spain, Sweden, Switzerland, and the United Kingdom). Tables showing investigational sites, principal investigators, and numbers enrolled at each site and in each country are included in the Appendix (pp. 1-2). The study was completed on June 25, 2015, and atotal of 413 men were enrolled: 206 randomised to the VTP group and 207 to the AS group. More subjects in the AS group (n=6) than in the VTP group (n=17) withdrew consent before study completion.

Although unwillingness to accept randomisation to either group was an exclusion criterion, the sponsor anticipated that subjects randomised to AS might withdraw because they had entered the study to receive active treatment. The percentage of such withdrawals was less than expected. Otherwise, study completion and reasons for withdrawal were similar between the two groups (Figure 1). Demographic and baseline disease characteristics were well balanced between the two groups and fit the profile of low-risk PC patients (Table 1). Of the 206 subjects randomised to VTP, nine did not subsequently start the VTP procedure: three who withdrew consent, three who were excluded because for exclusion criteria (bladder cancer discovered on pretreatment MRI, previous Gleason 3+4 biopsy, history of transurethral prostate resection), one who was discontinued by the investigator because of noncompliance, one who had a myocardial infarction, and one who was claustrophobic so unable to undergo the pretreatment MRI.

Of the 197 subjects who started the VTP procedure, one had an anaesthesia reaction before receipt of any padeliporfin or laser treatment. In all, 196 subjects received initial VTP (Figure 1). Of these, 62 received subsequent contralateral treatment, 11 received retreatment, and two

DECLARATION OF INTEREST

AAzzouzi, SV, EB, AC, FK, HGV, CGS, JR, GS, ES, AAlcaraz, TTT, DJR, FGV, GA, and ME received payment from STEBA as investigators on this study. AA and ME have also acted as consultants and proctors for STEBA. FMJD, GF, and CG received payment from STEBA for other roles on the study (Data Safety Monitoring Board, Outcomes Review Panel). BA is a statistical consultant to STEBA. FB and BG are employees of STEBA. FGV reports receipt of funding for research from Astellas Pharma and acting as a paid proctor for Intuitive Surgical, Inc. AAlcaraz reports payment for speaking engagements from several companies (Astellas Pharma, Janssen Pharmaceutica, Sanofi, Bayer, STEBA Biotech S.A., Olympus Corporation). TTT reports being an advisor for Astellas Pharma, Ferring Pharmaceuticals, Orion Corporation, and Bayer and receiving institutional funding from Astellas Pharma, Ferring Pharmaceuticals, Medivation, Inc, Orion Corporation, and Bayer. ME reports acting as a principal/co-investigator in a number of PC studies supported by SonaCare Medical, Sophiris Bio Inc, and TROD Medical and as a consultant/advisor to GSK and Sanofi-Aventis, being a founding partner of London Urology Associates, and shareholdings in Nuada Medical Ltd.


Ahmad Batikh
email: ahmad.batikh@insa-toulouse.fr

Lucien Baldas

Stéphane Colin

APPLICATION OF ACTIVE FLOW CONTROL ON AIRCRAFTS -STATE OF THE ART

This paper reviews and highlights the current state of the art on active flow control applied to civil aircrafts. A brief introduction presents the flow control research field and the technology readiness levels already reached to answer civil aircrafts needs. Then different types of flows around an aircraft are discussed as a potential applications of flow control. A short review of active flow control actuators is made with a focus on those more adaptable to be applied on civil aircrafts. Finally, the main difficulties to overcome in order to reach technology readiness levels allowing application on civil aircrafts are mentioned.

INTRODUCTION

Flow control (FC) strategies are generally employed to delay/advance transition, to enhance/eliminate turbulence and/or to prevent/induce separation in order to increase the lift, decrease the drag, increase the mixing or suppress the flow-induced noise [START_REF] Gad-El-Hak | The Taming of the Shrew: Why Is It so Difficult to Control Turbulence?[END_REF]. In aeronautics, the ultimate goal is to reduce the environmental footprint by reducing fuel consumption by enhancing aircraft aerodynamics. Even though many passive FC techniques (riblets, fences, vortex generators, etc.) have been successfully applied on aircrafts, active FC ones drew researchers attention for their ability to be activated only when and where they are needed. Thus, a huge amount of studies have been conducted during the last two decades, during which researchers tested many types and concepts of actuators. While results obtained numerically by CFD and experimentally in wind tunnel are promising, they need to be relevant, as noted in a relatively recent paper [START_REF] Crowther | Flow control fallacies: a review of commonpitfalls in flow control research[END_REF]. According to this later, on a few of the recently published research works in the field of flow control dealt with 'flight test' or 'integration' of Active Flow Control (AFC) technologies. These studies stay thus far away from any maturity allowing them to be adopted by aircraft industry (Figure 1). On the other hand, most of these researches had focused on the idea of replacing existing technical solutions (high lift devices for example) by Flow Control Systems (FCSs), which is still too difficult to achieve considering the present maturity level of the FC research field [START_REF] Liddle | Systems and certification issues for active flow control systems for separation control on civil transport aircraft[END_REF], ignoring industrial feasibility, cost effectiveness and certification issues. In the following sections, we will highlight the industrial needs and research done until now to satisfy these needs.

WHERE ACTIVE FLOW CONTROL CAN BE APPLIED ON CIVIL AIRCRAFTS?

Generally speaking, AFC is mainly employed to overcome flow separation (caused by high adverse pressure gradients) on smooth surfaces, on after-bodies and on two surfaces junctions [START_REF] Ashill | A review of recent developments in flow control[END_REF]. On a civil aircraft, it could help to increase the effectiveness of high lift systems and control surfaces, to reduce the noise due to undercarriage, and finally, to modify locally the flow in some areas (e.g. flap slide edges, wing-pylon junctions) [START_REF] Liddle | Systems and certification issues for active flow control systems for separation control on civil transport aircraft[END_REF].

As aircraft wings are the main generator of lift on aircrafts, but also a main source of induced drag, designers have to optimize wings design and, of course, the whole other parts serving the principal mission of the airplane. A civil aircraft is optimized for cruising flight, and equipped with high-lift devices (HLD) (leading edge slats and trailing edge flaps) to soften the impact of high angle of attack during take-off and landing phases. These mechanical devices allow, via a geometrical modification of the wing, a favourable modification of the pressure distribution and to re-energize the boundary layer, thus obtaining more lift for higher critical angles of attack. But modern civil aircraft wings equipped with HLD are still vulnerable to airflow separation in three critical zones: the wing root, the wing-pylon junction and the wingtip. More engines with high/ultra-high-bypass are used nowadays on civil aircraft. To keep a reasonable clearance with ground, the engine nacelle must be closer to the wing, and consequently, leading edge slats suffer a cut-out to avoid collision with the nacelle during their deployment for take-off or landing. It was found [START_REF] Lengers | Industrial Assessment of Overall Aircraft Driven Local Active Flow Control[END_REF] that air flow around the wing-pylon junction is dominated by seven different types of vorticities as shown on Figure 2. Similarly, longitudinal vortices are generated at wing root (inboard side of slats) because of the slat less leading edge portion [START_REF] Bauer | Design and Application of a Fluidic Actuator System for High-lift Flow Control[END_REF]. On the other hand, the curved wing tips (called sharklets) are designed and optimized to reduce wing tip vortices and thus lift-induced drag, and to contribute in lift generation during cruise phase. So, at high angles of attack, airflow may separate decreasing lift [START_REF] Bauer | Wing Tip Drag Reduction at Nominal Take-Off Mach Number: An Approach to Local Active Flow Control with a Highly Robust Actuator System[END_REF].

Active flow control techniques could be employed not only to overcome these undesirable phenomena, but also to enhance the performance of other parts of aircrafts such like the vertical tail surface. The latter has a vital mission not only for the stability of the aircraft during several normal phases of flight but also for the case of loss of an engine during flight, where it must generate a side force to keep a directional stability with asymmetric thrust and overcome the drag generated by the lost engine. However, this part has the same size for all aircraft versions belonging to the same family where it is sized for the smallest one; as a result, it is oversized for the longer versions and represents an unnecessary load and drag. Using a series of 31 actuators, the side force was increased of more than 20% for the maximum rudder deflection (30°) at 100 knots in a wind tunnel (Figure 3), and estimated to be in the range (13%-16%) for inflight test for the same conditions. They estimate that the induced reduction in fuel consumption can achieve 15,500 gallons/airplane/year.

ACTIVE FLOW CONTROL ACTUATORS

As cited in many papers such as [START_REF] Bauer | Design and Application of a Fluidic Actuator System for High-lift Flow Control[END_REF], [START_REF] Cattafesta | Actuators for Active Flow Control[END_REF], the flow control field dates back to early experiments on boundary layer conducted by Prandtl. Generally, flow control methods can be classified in two categories: Active, which requires an external source of energy to feed actuators, and passive, which involves a geometrical modification and do not require any external source of energy [START_REF] Gad-El-Hak | Flow control passive, active, and reactive flow management[END_REF]. In an AFCS, the actuator is an essential element and the characterization of its behavior and its effect on the controlled flow is required to establish effective control laws. AFC actuators can be classified according to many criteria, such as input energy (mechanical, fluidic, acoustic or thermal) [START_REF] Batikh | Controle de l'aérodynamique externe des véhicules aériens par des dispositifs microfluidiques : étude de l'effet de mini et micro-jets synthétiques sur des écoulements pariétaux[END_REF], topology: orientation relative to external flow (tangential or lateral) [START_REF] Batikh | Controle de l'aérodynamique externe des véhicules aériens par des dispositifs microfluidiques : étude de l'effet de mini et micro-jets synthétiques sur des écoulements pariétaux[END_REF], function [START_REF] Cattafesta | Actuators for Active Flow Control[END_REF] (Figure 4). In addition, an actuator can also be characterized by its frequency response (variation of magnitude and phase of the output versus actuation frequency) and bandwidth (range of actuation frequencies for which the output is large enough) [START_REF] Cattafesta | Actuators for Active Flow Control[END_REF]. The choice of a suitable type for a given application depends on its capability to reach the control goals with the least energy consumption. Most of these actuators have been well studied and characterized in research laboratory conditions at low speed (low Reynolds number), but their Technology Readiness Level (TRL) is not yet high enough to allow an application on civil aircraft, mainly due to industrial issues related to robustness, cost effectiveness, reliability and certification and finally integration [START_REF] Crowther | Flow control fallacies: a review of commonpitfalls in flow control research[END_REF] [3] [START_REF] Bauer | Design and Application of a Fluidic Actuator System for High-lift Flow Control[END_REF].

In order to compare the efficiency of different type of actuators for a given configuration, each device can be defined by three normalized parameters. These are [START_REF] Bauer | Design and Application of a Fluidic Actuator System for High-lift Flow Control[END_REF]:  the momentum coefficient C (Actuation amplitude) defined as the ratio of the momentum flux introduced by the actuator (J) to the momentum flux of the main airflow, which is the product of the main airflow dynamic pressure (½U 2  ; U is the main airflow velocity), and a reference area (Aref), hence written as [Cµ=J/½U 2 .Aref]. Actuation with low Cµ allows controlling boundary layer separation, but a high Cµ allows controlling circulation. The critical value separating these two types of control varies between 2% and 5% depending on the configuration [START_REF] Graff | Sweeping Jet Actuators -a New Design Tool for High Lift Generation[END_REF].

Flow control actuators

 the Velocity Ratio VR (Actuation velocity) defined as the ratio of the actuator output velocity (ujet) to a reference velocity (local velocity or main airflow velocity) (uref), hence written as [VR= ujet/ uref]. It is also called authority level and must be  1 to be considered high enough for flow separation control applications, unless it will be considered as low authority and could be efficient for transition control and skin friction drag reduction [START_REF] Jabbal | Active Flow Control Systems Architectures for Civil Transport Aircraft[END_REF].

 the dimensionless Frequency F + (Actuation frequency) defined as the product of the actuation frequency (fAFC) and a reference length scale (lref) divided by a reference velocity (e.g. uref), hence written as [F + = fAFC. lref /uref]. It is reported that the recommended value of F + allowing reattachment is approximately in the range 1 to 1.3, and between 3 and 4 to prevent separation [START_REF] Bauer | Design and Application of a Fluidic Actuator System for High-lift Flow Control[END_REF].

Mechanical actuators

Including moving surfaces, e.g. piezo-electric flaps, shape memory alloys, electroactive polymers [START_REF] Liu | Review of actuators for high speed active flow control[END_REF], mechanical actuators present the advantage of a higher force to weigh ratio but their performances are limited by a low frequency and a high power consumption. Another functional disadvantage of these actuators is the moving part in contact with external flow, which leads to difficulties concerning maintenance and robustness when used on aircrafts.

Plasma actuators

Having many advantages including low mass, fast response time, no moving part and easy to install [START_REF] Cattafesta | Actuators for Active Flow Control[END_REF], these actuators could be used in low and high speed flows. Their main disadvantage is the high voltage (kV) they need which imposes potential issues related to electromagnetic interferences, noise level and heating.

Fluidic actuators

Actuators based on fluid flow are most suitable for low speed airflow control (turbulent skin friction drag reduction) [16] [18]. Fluidic actuators are the most common type [START_REF] Cattafesta | Actuators for Active Flow Control[END_REF], and have been studied widely during last three decades. They have the advantage of having no moving parts in direct contact with the external flow. By adding highmomentum fluid (by blowing) into the external flow or removing the low-momentum fluid (by suction) from it, they could be efficiently employed in airflow separation applications. The zero-net-mass flux (ZNMF) type, also called synthetic jet actuator (SJA), does not require any fluidic source. It consists in a closed cavity with an orifice/slot on one side and a moving wall/membrane (electrically, mechanically or electromechanically excited) on the other one. On the other hand, non ZNMF actuators require an external fluid source that can be steady (e.g. continuous jet) or unsteady (e.g., pulsed jet). Depending on their technology, the input energy can be electrical, fluidic, mechanical, electro-mechanical or electro-fluidic. Recent studies were conducted to evidence the efficiency, identify the system architecture and power requirements and deal with the integration issues of many types of fluidic actuators on real-size civil aircraft parts, in wind tunnel [START_REF] Lengers | Industrial Assessment of Overall Aircraft Driven Local Active Flow Control[END_REF] [8] [START_REF] Andino | Flow Separation Control on a Full-Scale Vertical Tail Model using Sweeping Jet Actuators[END_REF] [2], [START_REF] Jabbal | Active Flow Control Systems Architectures for Civil Transport Aircraft[END_REF], [START_REF] Jabbal | Sensitivity Analysis of Active Flow Control Systems: Operating Parameters and Configuration Design[END_REF], and inflight [START_REF] Lin | An Overview of Active Flow Control Enhanced Vertical Tail Technology Development[END_REF] conditions. In addition to the fluidic actuators mentioned previously, two promising innovative devices based on existing concepts have been explored for AFC on civil aircrafts: the sweeping jet actuator (SWJA) [START_REF] Graff | Sweeping Jet Actuators -a New Design Tool for High Lift Generation[END_REF] and the two-stages fluidic actuator [START_REF] Bauer | High-Lift Performance Investigation of a Two-Element Configuration with a Two-Stage Actuator System[END_REF]. We will highlight these actuators in the two following sections.

Sweeping Jet Actuator

Firstly invented in the middle of last century, the main advantages of this type of actuator, shown in Figure 5, are that it only needs a steady supply of compressed air, it have no moving parts, and that it can re-energize, thanks to sweeping output, a wide area of the boundary layer [START_REF] Lin | An Overview of Active Flow Control Enhanced Vertical Tail Technology Development[END_REF]. In addition, even with a low level of Cµ, it has been able to remove airflow separation on an NACA0021 airfoil [START_REF] Graff | Sweeping Jet Actuators -a New Design Tool for High Lift Generation[END_REF]. With an increased Cµ, it even causes a general augmentation of the lift over drag ratio. The flow control efficiency of this type of actuator was tested on a sub-scale and full-scale vertical tail of a civil aircraft in wind tunnel tests [START_REF] Arnold | Performance Enhancement of aFull-scale Vertical Tail with Active Flow Control TeModelchnology[END_REF], [START_REF] Seele | Improving Rudder Effectiveness with Sweeping Jet Actuators[END_REF] and inflight tests [START_REF] Lin | An Overview of Active Flow Control Enhanced Vertical Tail Technology Development[END_REF] respectively.

Two-stages Fluidic Actuator

Based on a combination of two different types of fluidic actuators, the two-stages fluidic actuator consists in a first oscillator named "driver stage" connected to an array of five diverters that form the second stage (Figure 6). Both stages are supplied by compressed air in such a way that the first stage produces a control mass flow which pilot the second stage diverters via five control port pairs. Two pulsed jets can be obtained from each diverter with 2 phased outputs. Using two stages allows a simple design as only the first stage oscillator needs feedback loops. Using different input pressure for each stage gives flexibility to control actuation amplitude and frequency independently. Studies in wind tunnel were conducted on a realistic outer wing model [START_REF] Bauer | Wing Tip Drag Reduction at Nominal Take-Off Mach Number: An Approach to Local Active Flow Control with a Highly Robust Actuator System[END_REF], [START_REF] Bauer | High-Lift Performance Investigation of a Two-Element Configuration with a Two-Stage Actuator System[END_REF] at take-off speed and showed that both stall angle and lift could be increased and that drag could be decreased using actuation. AFC might even be more efficient when the actuator outlets are largely spaced.

DIFFICULTIES TO OVERCOME 4.1 Filling the gap between academic research and actual applications

Even if a huge numbers of studies were related to flow control during the last 50 years (Figure 1), more than 75% of these studies focused on flow control fundamentals, technological developments or numerical tools for modelling but still from an academic viewpoint and quite far from what aircraft manufacturing really needs. Crowther and co-authors discussed this issue in a recent paper [START_REF] Crowther | Flow control fallacies: a review of commonpitfalls in flow control research[END_REF] and pointed out the main weaknesses making lot of research works on AFC irrelevant with regards to possible application on aircrafts (e.g. lack of deep knowledge in AFC aerodynamics, test of unrealistic configurations or focusing on one side of the real phenomenon and ignoring other important sides). To summarize, even if fundamental research in this field is still useful, the developed technologies should be tested, as far as possible, in industrially environments to get closer to the real application configurations.

Integration and power supply

Taking into account that high lift systems contribute to 6%-11% of an aircraft cost and add many tonnes to its mass, they could be the most suitable candidate to take advantage of FC technology [START_REF] Liddle | Systems and certification issues for active flow control systems for separation control on civil transport aircraft[END_REF] in low flight speed during take-off and landing for example. The geometrical properties of the part that could take advantage of FC technology and the availability of energy have an important impact on the AFC system architecture, mass and the choice of its components. The more efficiency required by the AFC system, the more the mass of this system is important [START_REF] Jabbal | Active Flow Control Systems Architectures for Civil Transport Aircraft[END_REF] (1kg/kW for all electric AFC based on SJA without redundancy [START_REF] Liddle | Systems and certification issues for active flow control systems for separation control on civil transport aircraft[END_REF]).

One study conducted on a full-size Airbus A320 wing using pulsed jet actuators [START_REF] Jabbal | Sensitivity Analysis of Active Flow Control Systems: Operating Parameters and Configuration Design[END_REF] showed that the choice of input energy (electrical or pneumatic) depends on the required amount of AFC output power. Full electrically powered actuators are more effective in mass for a power transmission lower than 20kW, and pneumatically ones are more competitive in mass for a power transmission higher than 20kW and up to 60kW. A hybrid powering system (electro-pneumatic) is recommended for more power transmission. According to the total power consumption and considering safety requirements, the power could be supplied by the main aircraft power system or by an individual source.

Reliability and certification

According to Figure 1, only a small part of AFC research have dealt with flow control systems integration and certification, and inflight performances. After half a century of research and development on the AFC concepts, the applicability of these systems and their conformity with civil aircraft regulations must now be tested. As any new technology, the AFC systems have to make proof in many fields, such as cost effectiveness, noise generated and reliability, to be fully applicable on civil aircraft, [START_REF] Liddle | Systems and certification issues for active flow control systems for separation control on civil transport aircraft[END_REF].

Considering the current TRL of the research works in this field, researchers expect a very late entry of AFC technology on civil aircraft. It could thus be more beneficial to implement these control systems on new aircrafts which could be designed taking them in consideration thus ensuring high compatibility and integration with aircraft systems, than to adapt existing civil aircrafts in order to integrate AFC systems.

As redundancy is a key feature of flight safety, the same safety measures must certainly be applied to AFC systems. This will increase both, the mass to power ratio of AFC systems and the ratio of the mass of the whole system with AFC to the mass of the original system without AFC.

CONCLUSION

Active flow control was regarded as the revolution that aerodynamics was waiting for, for a long time. One of the most important fields of applications of AFC, civil aircrafts, has been explored in this paper. Reviewing studies that have dealt with AFC techniques on civil aircrafts can be summarised by the following points:

 Despite the high number of researches conducted during more than fifty years, only a small portion has treated in depth the application of AFC on full-size civil aircrafts.

 AFC could be applied to enhance wing and control surface performance, to reduce noise and modify locally airflow in some critical areas on aircraft such as wing-pylon junction.

 Researches confirmed the efficiency of fluidic actuators to control flow separation on civil aircrafts. Actuators input energy type depends on the amount of energy to be transmitted to the controlled airflow (electric then fluidic and finally electro-fluidic).

 There are still many difficulties to overcome in order to achieve an operating AFC system on a civil aircraft, such as conducting research using realistic parameters and taking into account integration and certification issues for the final product.

To conclude, even if many active flow control concepts have proved to be efficient in laboratory environments, the technology readiness level of most of the research works conducted up to now is not yet high enough to envisage an integration on civil aircrafts in the near future. However, the next steps which will make a bridge between academic research and industrial applications are now well identified.

Figure 1 -

 1 Figure 1 -Historical growth of engineering research areas based on the number of records per year in the Compendex engineering database (1949-2007) according to [2] (a) specific aerospace related research areas, (b) flow control actuator technologies

Figure 2 -

 2 Figure 2 -Flow topology around wing-pylon junction (according to [5])Employing AFC technology could be useful to delay flow separation for high deflection angles of the rudder in case of engine-out or high crosswind. Enhancing the performance of the vertical tail will open the possibility to resize it. Authors of[START_REF] Lin | An Overview of Active Flow Control Enhanced Vertical Tail Technology Development[END_REF]-[START_REF] Seele | Improving Rudder Effectiveness with Sweeping Jet Actuators[END_REF] tested an AFC system based on sweeping jet on a full-size Boeing 757 vertical tail. Using a series of 31 actuators, the side force was increased of more than 20% for the maximum rudder deflection (30°) at 100 knots in a wind tunnel (Figure3), and estimated to be in the range (13%-16%) for inflight test for the same conditions. They estimate that the induced reduction in fuel consumption can achieve 15,500 gallons/airplane/year.

Figure 3 -

 3 Figure 3 --Vertical tail side force enhancement using sweeping jet (according to [9]) (U = 100 knots, =side slip angle, %Cy = difference in side force coefficient)

Figure 4 -

 4 Figure 4 -Classification of flow control actuators based on function (according to [12])

Fluidic

Figure 5 -

 5 Figure 5 -Working principle of a sweeping jet actuator and visualization of internal flow (according to [15])

Figure 6 -

 6 Figure 6 -Two-stages fluidic actuator system architecture (according to [20])