Etienne Garin
email: e.garin@rennes.unicancer.fr

Yan Rolland

90Y-Loaded Microsphere SIRT of HCC Patients With Portal Vein Thrombosis High Clinical Impact of 99mTc-MAA SPECT/CT-Based Dosimetry

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Introduction

Liver selective internal radiation therapy (SIRT) is primarily aimed to deliver a tumoricidal absorbed dose to tumors, while sparing the surrounding healthy liver tissues . [START_REF] Lau | Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres[END_REF][START_REF] Sangro | Radioembolization for hepatocellular carcinoma[END_REF] To achieve optimal efficacy along with the lowest possible toxicity, the tumor absorbed dose (TD) and absorbed dose by normal injected liver tissue (NLD) should be evaluated prior to therapy initiation. Despite this evidence, the rules applied for activity planning are still widely based on the BSA method for resin microspheres, with a mean dose of between 80 to 150 Gy to be delivered to the liver for glass microspheres, including tumors and healthy liver. This strategy is referred to as standard dosimetric approach.

SIRT must at all times be preceded by a workup consisting of a mapping angiography and technetium-99m macroaggregated albumin (MAA) scintigraphy. These techniques are designed to select the correct position for treatment and to verify the presence of lung and digestive shunts. Recent advances have been made while using quantitative MAA scintigraphy as an accurate dosimetric tool. [START_REF] Lau | Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study[END_REF][START_REF] Hermann | Role of 99mTC-macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response on patient whith locally advanced and inoperable hepatocellular carcinoma treated by selective internal radiation therapy with yttrium-90 resin microspheres, a cohort from SARAH study[END_REF][START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF][START_REF] Garin | 99m Tc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90 Yloaded glass microspheres : preliminary results[END_REF][START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] This work-up combined with MAA-based dosimetry has become a real treatment simulation with potential impact on the treatment schedule and prescribed absorbed dosing, resulting in a fully-personalized approach.

This chapter has been meant to summarize the clinical results obtained so far with SIRT using standard dosimetric approaches, to review both the interest and limitation of MAA-based dosimetry, and to outline the clinical impact of a personalized dosimetric approach on HCC patients with PVT.

Clinical results obtained with SIRT using standard dosimetric approaches in PVT patients.

Non-comparative studies

Several studies using both resin or glass microspheres have produced interesting results concerning overall survival (OS) of PVT patients, [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF][START_REF] Abouchaleh | 90 Y Radioembolization for Locally Advanced Hepatocellular Carcinoma with Portal Vein Thrombosis: Long-Term Outcomes in a 185-Patient Cohort[END_REF][START_REF] Spreafico | Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion[END_REF][START_REF] Hilgard | Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and longterm survival[END_REF][START_REF] Sangro | European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation[END_REF][START_REF] Mazzaferro | Yttrium(90) radioembolization for intermediate-advanced hepatocarcinoma: A phase II study[END_REF] ranging from 10 to 13 months (mo), [START_REF] Hilgard | Radioembolization with yttrium-90 glass microspheres in hepatocellular carcinoma: European experience on safety and longterm survival[END_REF][START_REF] Sangro | European Network on Radioembolization with Yttrium-90 Resin Microspheres (ENRY). Survival after yttrium-90 resin microsphere radioembolization of hepatocellular carcinoma across Barcelona clinic liver cancer stages: a European evaluation[END_REF][START_REF] Mazzaferro | Yttrium(90) radioembolization for intermediate-advanced hepatocarcinoma: A phase II study[END_REF] thus comparing favorably with the 8.1-month OS achieved with sorafenib in the SHARP trial, considered the standard of care in this indication.

In all of these studies, several classical parameters have been demonstrated to significantly impact OS. The most important OS-impacting parameters from the two largest studies recently reported and involving 120 and 185 PVT patients, respectively, 9,10 comprised the following: Child-Pugh (CP) status, performance status, bilirubin level, ascites, tumor size, number of lesions (solitary vs multifocal), as well as PVT involvement level (Table 1). As example, in the Abouchaleh et al 8 study, median OS was 13.3 mo (95% confidence interval [CI]: 8.7-15.7 mo) for CP-A patients, 6.9 mo (95% CI: 5.3-10.1 mo) for CP-B7 patients, and only 3.9 mo (95% CI: 2.9-5.0 mo) for ≥CP-8 patients. [START_REF] Abouchaleh | 90 Y Radioembolization for Locally Advanced Hepatocellular Carcinoma with Portal Vein Thrombosis: Long-Term Outcomes in a 185-Patient Cohort[END_REF] Regarding PVT extension, the larger the extension, the lower the results obtained, with the poorest OS observed for main PVT versus segmental PVT involvement. These figures clearly demonstrate the relevance of appropriate patient selection.

Based on these results, patients exhibiting one of the following items are not considered good PVT candidates for SIRT: bilirubin level higher than 2mg/dL, significant ascites, CP ≥CP-8, performance status ≥2, and complete occlusion of the main portal vein.

For MAA SPECT/CT-based dosimetry, two other major prognostic factors have been identified when using glass microspheres, namely TD and PVT targeting. [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] The relative risk (RR) of death was 6.99 (95% CI: 1.98-24.39) for TD< 205 Gy (vs TD≥ 205 Gy) and 14.7 (95% CI: 3.09-69.12) for patients with poor PVT MAA targeting (vs good PVT targeting). [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] Figure 1 shows a typical case of good MAA PVT targeting. These results underline the necessity of accurate dosimetric evaluation prior to treatment selection.

Comparative studies

To date, only a single retrospective study focused on PVT patients and comparing SIRT versus sorafenib has been published. [START_REF] Edeline | Selective internal radiation therapy compared with sorafenib for hepatocellular carcinoma with portal vein thrombosis[END_REF] Overall, 24 patients treated using 90 Y-loaded glass microspheres along with a personalized approach applied in most cases were matched with 24 patients treated with sorafenib based on a propensity score. A trend towards superior OS was observed for SIRT, though between-group differences did not reach statistical significance, with an estimated median OS of 26.2 mo for SIRT-vs 8.7 mo for sorafenib-treated patients (p=0.054).

Considering randomized studies, only one single study involving PVT patients was published in 1994. [START_REF] Raoul | Randomized controlled trial for hepatocellular carcinoma with portal vein thrombosis: intra-arterial iodine-131iodized oil versus medical support[END_REF] This study using 131 I-lipiodol SIRT versus best supportive care (BSC) revealed a significant improvement in the survival rate at 6 mo in the SIRT arm as compared to the BSC arm, with figures of 48% and 0%, respectively (p<0.01). These results have been considered to be the first prove supporting SIRT use in PVT patients. For ethical reasons owing to the dramatically-positive results, the study was stopped. On account of the small number of patients included (n=27), the outcome remains controversial, yet this is the sole randomized trial carried out in this setting, with positive and sustained results.

Three randomized studies, yet not focused on PVT patients, have been published to date. [START_REF] Vilgrain | Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial[END_REF][START_REF] Chow | SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma[END_REF][START_REF] Ricke | The impact of combining Selective Internal Radiation Therapy (SIRT) with sorafenib on overall survival in patients with advanced hepatocellular carcinoma: The SORAMIC trial palliative cohort[END_REF] The SARAH [START_REF] Vilgrain | Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial[END_REF] and SIRveNIB 16 trials were designed to compare resin microspheres versus sorafenib, along with the SORAMIC trial [START_REF] Ricke | The impact of combining Selective Internal Radiation Therapy (SIRT) with sorafenib on overall survival in patients with advanced hepatocellular carcinoma: The SORAMIC trial palliative cohort[END_REF] comparing resin microspheres combined along with sorafenib versus sorafenib alone. The primary endpoint was OS in all trials, with all of them failing to demonstrate any survival improvement in the SIRT arm, as based on either the intent-to-treat (ITT) or per-protocol approach (PP), (Table 2). No OS benefit was seen for PVT patients, with an OS disfavoring SIRT (RR of 1.19), even in the SARAH trial. [START_REF] Vilgrain | Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial[END_REF] It should, however, be emphasized that response rate and tolerance was significantly better with SIRT. [START_REF] Vilgrain | Efficacy and safety of selective internal radiotherapy with yttrium-90 resin microspheres compared with sorafenib in locally advanced and inoperable hepatocellular carcinoma (SARAH): an open-label randomised controlled phase 3 trial[END_REF][START_REF] Chow | SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma[END_REF] The results of a fourth randomized Phase III study, namely the STOP-HCC study (NCT01556490), comparing glass microspheres associated with sorafenib versus sorafenib alone are still awaited and should be made available in the course of 2019.

Several parameters possibly related to trial failure have been discussed in the meantime, such as absence of dosimetric endpoints and inclusion of too-severely advanced patients. [START_REF] Garin | Negative phase 3 study of 90 Y microspheres versus sorafenib in HCC[END_REF] The ITT approach used is similarly a matter of debate, given that excessive lung or digestive shunting are recognized contra-indications rather than ITT failures, with an abnormally high ITT failure rate in the SIRT arm (between 26 and %, depending on the studies).

The negativity of the Phase 3 trials without any dosimetric endpoints, along with the promising preliminary results obtained with MAA SPECT/CT-based dosimetry, clearly justify the further development of personalized dosimetry.

Dosimetry and MAA-based dosimetry

Dosimetry concept

From a physical perspective, an absorbed dose represents an energy (Joule) divided by a mass (Kg), expressed in either J/Kg or Gy with 1 Gy= 1 J/Kg. Several dosimetric approaches have been described to date, namely the classical medical internal radiation dose (MIRD) approach, biological effective dose evaluation (BED), uniform equivalent dose calculation (EUD), Monte Carlo simulation, and Kernel density estimation. [START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF] The MIRD approach, the most widely applied, assumes a homogeneous dose distribution.

Given that following initial embolization, microspheres are not biodegradable and remain trapped within the vessels, the effective half-life is supposed to be the physical half-life of 90 Y, and the MIRD equation can thus be simplified:

The absorbed dose D (Gy) to a volume of interest (VOI) of mass M (Kg) containing an activity A (GBq) of 90 Y is then calculated using the following simplified MIRD formula:

D (Gy) = A (GBq) . 50/ M (Kg)
Doses can be calculated for different VOIs, especially for tumor, perfused liver, normal perfused liver, and lung tissues. Typically, the liver mass (in Kg) is assumed to be equal to its volume (L) multiplied by a factor 1.03; the lung mass is assumed to be equal to 1 Kg. It must be underlined that this formula is used for both resin or glass microspheres.

One difficulty is that the radiobiological effect depends not only on the absorbed dose but also on the dose rate, and on the heterogeneity of dose distribution as well.

On account of this property, external bean radiotherapy (EBR) and selective internal radiation therapy (SIRT) are critically different. [START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF][START_REF] Garin | Clinical impact of 99m Tc-MAA SPECT/CTbased dosimetry in radioembolization of liver malignancies with 90 Y-loaded microspheres[END_REF] This is mainly due to a high difference in radiation exposure rate (high in EBR and low in SIRT) and in dose distribution homogeneity (homogeneous with EBR; heterogeneous with SIRT depending of the therapeutic agent's biodistribution). Therefore, it is impossible to compare the radiobiological effect provided by 1 Gy of EBRT with the radiobiological effect provided by 1 Gy of SIRT, or by 1 Gy of glass or resin SIRT, as previously demonstrated in a stimulation study. [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] In this study, for a whole liver irradiation, the dose to the liver producing 50% of toxicity was 40 Gy for resin microspheres and slightly >60 Gy for glass microspheres.

Another example of the differing radiobiology observed between glass and resin microspheres consists in the reported threshold dose for HCC resulting in a response, ranging between 100 and 120 Gy for resin microspheres [START_REF] Lau | Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study[END_REF][START_REF] Hermann | Role of 99mTC-macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response on patient whith locally advanced and inoperable hepatocellular carcinoma treated by selective internal radiation therapy with yttrium-90 resin microspheres, a cohort from SARAH study[END_REF] and being around 200 Gy for glass microspheres. [START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF][START_REF] Garin | 99m Tc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90 Yloaded glass microspheres : preliminary results[END_REF][START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] These results are further supported by the high difference in specific activity observed among 90 Y-loaded microspheres (50 Bq/ sphere for resin and 2500 Bq/sphere for glass, at qualibration time), leading to differences in dose distribution heterogeneity. [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] At present, two dosimetric approaches can be applied for SIRT, namely a simulation-based dosimetry (e.g., MAA-based dosimetry) enabling treatment personalization, and a direct dosimetric evaluation based on 90 Y-PET quantification recognized as gold standard approach, because based on direct therapeutic compound quantification. However, as 90 Y-PET dosimetry cannot be used for treatment personalization, this approach will not be further developed in this paper.

Technical considerations regarding dosimetry evaluation

Several issues concerning dosimetry evaluation have been reported, [START_REF] Garin | Clinical impact of 99m Tc-MAA SPECT/CTbased dosimetry in radioembolization of liver malignancies with 90 Y-loaded microspheres[END_REF] including tumor histology, tumor size, tumor vascularity, product used as previously mentioned, previous therapy, response and toxicity criteria applied, underlying cirrhosis, and hepatic reserve.

Two technical considerations that have not yet been fully evaluated must be highlighted here, namely the segmentation method used and angiographic considerations for simulation-based dosimetry.

Segmentation approach

For the segmentation of VOIs, two approaches are presently available. [START_REF] Garin | Clinical impact of 99m Tc-MAA SPECT/CTbased dosimetry in radioembolization of liver malignancies with 90 Y-loaded microspheres[END_REF] The gold standard approach is based on diagnostic imaging using CT, MRI, or CBCT. This imaging is then co-registered with SPECT or SPECT/CT, with solely the counts within the anatomically delineated VOIs taken into consideration for dose calculation of this VOI. The presumed advantage of this approach is to achieve the most accurate and reproducible volume definition. However, in case of coregistration error, a significant amount of counts of the SPECT image is possibly excluded from the VOI, leading to a significant underestimation of the absorbed dose of this VOI.

The second approach available is based on full SPECT/CT segmentation. It has been demonstrated in a phantom study that the mean error in the volume measurement was lower than 7%, with good reproducibility (inter-observer concordance: 99%). The approach's advantage is that coregistration with a diagnostic imaging is not mandatory, while the counts include in the VOI are taken into account, thereby resulting in a lower risk of underestimation of the absorbed dose. In cases of hepatic vascularization variability or aberration, using MAA SPECT/CT for volume measurement offers the advantage of providing a more functional evaluation of the truly perfused volume. [START_REF] Garin | Effectiveness of quantitative MAA SPECT/CT for the definition of vascularized hepatic volume and dosimetric approach: phantom validation and clinical preliminary results in patients with complex hepatic vascularization treated with yttrium-90-labeled microspheres[END_REF] As a result, cases of full liver perfusion identified with MAA SPECT/CT despite a lobar injection were reported in the literature. [START_REF] Garin | Effectiveness of quantitative MAA SPECT/CT for the definition of vascularized hepatic volume and dosimetric approach: phantom validation and clinical preliminary results in patients with complex hepatic vascularization treated with yttrium-90-labeled microspheres[END_REF] However, in complex clinical cases, the thresholding required for segmentation may prove difficult to perform, thereby leading to volume definition errors.

As for glass microsphere use in HCC, it must be emphasized that one study using 90 Y-PET dosimetry based on CT segmentation and PET co-registration failed to reveal a dose response relationship, with segmentation errors impacting tumor dose as main explanation. [START_REF] Haste | Correlation of Technetium-99m Macroaggregated Albumin and Yttrium-90 Glass Microsphere Biodistribution in Hepatocellular Carcinoma: A Retrospective Review of Pretreatment Single Photon Emission CT and Posttreatment Positron Emission Tomography/CT[END_REF] On the other hand, in several studies using a full SPECT/CT segmentation, a clear dose response relationship has been evidenced. [START_REF] Hermann | Role of 99mTC-macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response on patient whith locally advanced and inoperable hepatocellular carcinoma treated by selective internal radiation therapy with yttrium-90 resin microspheres, a cohort from SARAH study[END_REF][START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF][START_REF] Garin | 99m Tc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90 Yloaded glass microspheres : preliminary results[END_REF][START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] The key message is that the segmentation method used has a direct impact on the dosimetric evaluation and must, therefore, be carefully described in the studies. This will likely enable us to confirm the results' validity and to additionally compare the results of different studies.

Simulation-based dosimetry, specific angiographic requirements, and dosimetric angiography concept.

An essential fact we must consider is that a simulation-based dosimetry, irrespective of the surrogate used, represents a global approach including angiographic considerations.

Therefore, this approach cannot be limited to an accurate quantification of the surrogate itself.

The difficulty in performing a simulation angiography with a full dosimetric purpose, including tumor and healthy liver dose evaluation, is that several specific endpoints are required, as compared to a classical work-up. The concept of "dosimetric angiography" should thus be introduced.

Initially, the only dosimetric endpoint of the work-up was to evaluate both LSF and lung dose.

Given this context, it was admitted that, in case of bilobar disease and two treatments separated by 4-6 weeks, one work-up with MAA injection into the common or the proper hepatic artery was proven sufficient.

For a dosimetric angiography, the situation proves quite different, given that the blood flow must be kept similar between both simulation (namely dosimetric angiography) and treatment itself (namely therapeutic angiography). To this end, the following four technical issues must be taken into account: spams occurrence, proximity of arterial bifurcation, slow surrogate injection, and catheter repositioning:

-A direct impact of spasm occurrence on simulation angiography has previously been reported. [START_REF] Garin | Clinical impact of 99m Tc-MAA SPECT/CTbased dosimetry in radioembolization of liver malignancies with 90 Y-loaded microspheres[END_REF][START_REF] Garin | Is there a place for nuclear medicine in the radioembolization of liver tumors?[END_REF] Limiting the risk of spasm occurrence as much as possible necessitates both of the following: 1) avoiding whenever technically possible coil embolization; 2) favoring whenever technically possible the use of catheter as floppy. [START_REF] Chow | SIRveNIB: Selective Internal Radiation Therapy Versus Sorafenib in Asia-Pacific Patients With Hepatocellular Carcinoma[END_REF] -The arterial bifurcation proximity, within 1cm of the catheter tip, has also been reported to impact the blood flow. [START_REF] Wondergem | 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization[END_REF] -A slow injection of the microsphere surrogate has been recommended, namely over 20 to 30 seconds for a 5mL syringe, in order to mimic the microspheres injection flow. [START_REF] Garin | Clinical impact of 99m Tc-MAA SPECT/CTbased dosimetry in radioembolization of liver malignancies with 90 Y-loaded microspheres[END_REF] -Lastly, injecting the surrogate and 90 Y-microspheres must be carried out exactly at the same position, with the same catheter tip orientation in the arterial tree, given that catheter repositioning have been reported to result in a poor correlation between surrogate and microsphere uptakes. [START_REF] Haste | Correlation of Technetium-99m Macroaggregated Albumin and Yttrium-90 Glass Microsphere Biodistribution in Hepatocellular Carcinoma: A Retrospective Review of Pretreatment Single Photon Emission CT and Posttreatment Positron Emission Tomography/CT[END_REF][START_REF] Wondergem | 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization[END_REF] In an effort for accuracy, a simulation-based dosimetry thus requires a multidisciplinary approach where IRs must be highly involved while taking into account the specific angiographic endpoints required for a dosimetric angiography.

Additional limitation when using MAA as microsphere surrogate

The physical properties of MAA and microspheres are not exactly the same. MAA is made up of biodegradable particles, with sizes estimated to range from 10 to 150µm, without being well calibrated. The majority, namely about 90%, measure between 10 and 40µm, whereas 1 to 2% measure <15µm. The fact that MAA causes an overestimation of lung shunting, along with an underestimation of tumor and liver doses, is no longer a matter of debate. This observation has been clearly demonstrated in a recent study comparing lung shunt measurement by either MAA or by holmium microsphere quantification. [START_REF] Elschot | 99m)Tc-MAA overestimates the absorbed dose to the lungs in radioembolization: a quantitative evaluation in patients treated with (166)Ho-microspheres[END_REF] However, it must be noted that high lung shunting is not very common, occurring is less than 10% of HCC cases.

Several disappointing study results have been obtained to date. However, it should be noted that these studies were primarily carried out in patients with metastatic disease using either resin microspheres [START_REF] Wondergem | 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization[END_REF][START_REF] Ulrich | Predictive value of intratumoral 99mTcmacroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y-microspheres[END_REF][START_REF] Ilhan | Predictive Value of 99mTc-MAA SPECT for 90Y-Labeled Resin Microsphere Distribution in Radioembolization of Primary and Secondary Hepatic Tumors[END_REF] or encountering several technological issues not clearly assessed like catheter repositioning [START_REF] Ulrich | Predictive value of intratumoral 99mTcmacroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y-microspheres[END_REF][START_REF] Ilhan | Predictive Value of 99mTc-MAA SPECT for 90Y-Labeled Resin Microsphere Distribution in Radioembolization of Primary and Secondary Hepatic Tumors[END_REF][START_REF] Kucuk | Evaluation of the response to selective internal radiation therapy in patients with hepatocellular cancer according to pretreatment (99m)Tc-MAA uptake[END_REF] or absence of spasm evaluation. [START_REF] Haste | Correlation of Technetium-99m Macroaggregated Albumin and Yttrium-90 Glass Microsphere Biodistribution in Hepatocellular Carcinoma: A Retrospective Review of Pretreatment Single Photon Emission CT and Posttreatment Positron Emission Tomography/CT[END_REF][START_REF] Wondergem | 99mTc-macroaggregated albumin poorly predicts the intrahepatic distribution of 90Y resin microspheres in hepatic radioembolization[END_REF][START_REF] Ulrich | Predictive value of intratumoral 99mTcmacroaggregated albumin uptake in patients with colorectal liver metastases scheduled for radioembolization with 90Y-microspheres[END_REF][START_REF] Ilhan | Predictive Value of 99mTc-MAA SPECT for 90Y-Labeled Resin Microsphere Distribution in Radioembolization of Primary and Secondary Hepatic Tumors[END_REF][START_REF] Kucuk | Evaluation of the response to selective internal radiation therapy in patients with hepatocellular cancer according to pretreatment (99m)Tc-MAA uptake[END_REF] Nevertheless, MAA-based dosimetry has so far been proven to accurately predict treatment response for HCC, when using either glass [START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF][START_REF] Garin | 99m Tc-MAA SPECT/CT based dosimetry accurately predicts tumour response and survival in HCC patients treated with 90 Yloaded glass microspheres : preliminary results[END_REF][START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] or resin microspheres, [START_REF] Lau | Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study[END_REF][START_REF] Hermann | Role of 99mTC-macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response on patient whith locally advanced and inoperable hepatocellular carcinoma treated by selective internal radiation therapy with yttrium-90 resin microspheres, a cohort from SARAH study[END_REF] yet in studies not focused on HCC with PVT.

Different studies based on 90 Y-PET-dosimetry have confirmed the accuracy of MAA-based dosimetry in HCC. Kao et al 30 demonstrated a strong correlation between MAA SPECT/CT tumor and 90 Y-PET doses when using resin microspheres. The median relative error between both dosimetric evaluations was only 3.8%, with a trend towards a slight tumor dose overestimation observed with 99m Tc-MAA SPECT/CT. A recent prospective study using PET found a threshold dose of 200 Gy for glass microspheres, [START_REF] Chan | Prospective Trial Using Internal Pair-Production Positron Emission Tomography to Establish the Yttrium-90 Radioembolization Dose Required for Response of Hepatocellular Carcinoma[END_REF] while another study using glass microspheres demonstrated a very good correlation between the T/NT ratio calculated on MAA and on 90 Y PET, being 5.6±3.2 versus 5.9±3.5, r=0.918, respectively. [START_REF] Ho | Radioembolization with 90Y glass microspheres for hepatocellular carcinoma: significance of pretreatment 11C-acetate and 18F-FDG PET/CT and posttreatment 90Y PET/CT in individualized dose prescription[END_REF] Evidence of a close MAA-based dose response relationship in HCC and OS impact.

Several studies using MAA-based dosimetry have demonstrated a dose response relationship in HCC (Table 2). Reported threshold doses were 100-120 Gy for resin microspheres [START_REF] Lau | Treatment of inoperable hepatocellular carcinoma with intrahepatic arterial yttrium-90 microspheres: a phase I and II study[END_REF][START_REF] Hermann | Role of 99mTC-macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response on patient whith locally advanced and inoperable hepatocellular carcinoma treated by selective internal radiation therapy with yttrium-90 resin microspheres, a cohort from SARAH study[END_REF] and 205-257 Gy for glass microspheres. [START_REF] Chiesa | Need, feasibility and convenience of dosimetric treatment planning in liver selective internal radiation therapy with 90Y microspheres: the experience of the National Tumor Institute of Milan[END_REF][START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] In the larger study with resin microspheres involving 109 patients evaluated for response (RECIST 1.1), the mean TD for patients with disease control was 121.4 Gy versus only 85.1 Gy for patients with progression, p=0.0204.

In the larger study with glass microspheres involving 130 evaluated lesions, [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] the response rate based on EASL criteria was 91% for lesion with a TD≥205 versus only 5.5% for a TD<205, p<10 -3 . In addition, it has been demonstrated that the false-positive rate was proven high, corresponding to non-responding lesions with a TD≥205 Gy, 33.3% for TDs ≥205 Gy and <260 Gy, and very low, 3.2% only, for TD ≥260 Gy (p=0.0012), in accordance with a fundamental radiobiology law: "the higher the dose above the threshold dose, the more severe the damage".

Its impact on OS has likewise been demonstrated in several studies. When using resin microspheres, a median OS of 14.1mo (95% CI: 9.6-18.6 mo) has been reported for patients with a TD >100 Gy versus only 6.1mo (95% CI: 4.9-6.8 mo) for those with a TD <100 Gy, p<0.0001. [START_REF] Hermann | Role of 99mTC-macroaggregated Albumin SPECT/CT based dosimetry in predicting survival and tumor response on patient whith locally advanced and inoperable hepatocellular carcinoma treated by selective internal radiation therapy with yttrium-90 resin microspheres, a cohort from SARAH study[END_REF] For glass microspheres, the largest study involving 85 patients reported an OS of 21 mo (95% CI: 15-27 mo) for a TD ≥ 205 Gy versus 6.5 mo (95% CI: 3-24 mo) for a TD < 205 Gy, the difference being statistically significant (p=0.0052); the relative risk of death (RR) was 2.35 (95% CI: 1.26-4.4) for a TD < 205 Gy (p=0.0053). [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] The TD's impact on OS was proven to be even higher for PVT patients with a median OS of 15.7 mo (95% CI: 9.5-25.7) for a TD ≥205 Gy versus 4.35 mo (95% CI: 2-8) for a TD <205 Gy, p=0.0004; the RR of death was 6.99 (95% CI: 1.98-24.39) for a TD < 205 Gy (p=0.0025). 7

Normal liver dose and liver toxicity

The maximal liver tolerated dose is more complex to define, as several confounding factors must be taken into account, such as toxicity definition, treatment line, severity of underlying liver disease, and hepatic reserve; [START_REF] Garin | Clinical impact of 99m Tc-MAA SPECT/CTbased dosimetry in radioembolization of liver malignancies with 90 Y-loaded microspheres[END_REF] For resin microspheres, based on Bremsstrahlung 90 Y SPECT dosimetry, a treated normal liver dose of 52 Gy has been reported to provide a risk of G2 liver toxicity in 50% of cases. [START_REF] Strigari | Efficacy and toxicity related to treatment of hepatocellular carcinoma with 90Y-SIR spheres: radiobiologic considerations[END_REF] For glass microspheres, Chiesa et al [START_REF] Chiesa | Radioembolization of hepatocarcinoma with (90)Y glass microspheres: development of an individualized treatment planning strategy based on dosimetry and radiobiology[END_REF] calculated the global dose to the healthy liver, including both the irradiated and non-irradiated parenchyma. Based on the authors' assumptions, fixing a limit of 75 Gy for the global healthy liver dose corresponded to a 15% probability of liver decompensation consisting of any liver decompensation, irrespective of its severity and eventual reversibility, with glass microspheres implanted 3.75 days after the calibration date with a defined specific activity.

A published study has evaluated the normal injected liver dose (NLD), [START_REF] Garin | Boosted selective internal radiation therapy with 90 Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept[END_REF] with the mean dosimetric evaluation performed as standard using the MIRD approach. The patient cohort comprised 71 carefully-selected patients, with 94.4% of them exhibiting a CP-A score. The normal NLD and hepatic reserve did not correlate with severe (CTCAE V3, G ≥3) clinical permanent liver toxicity. Only the association of a NLD >100 Gy or >120 Gy with a hepatic reserve <30% correlated with severe permanent liver toxicity upon univariate analysis (p = 0.032 and 0.017, respectively). Upon multivariate analyses, only the association of a NLD dose >120 Gy with a hepatic reserve <30% remained significantly correlated with severe permanent liver toxicity (p<0.0001).

In a recent study NLD evaluated either alone or associated with a low hepatic reserve, was not associated with liver toxicity for PVT patients. [START_REF] Garin | High impact of macroaggregated albumin-based tumour dose on response and overall survival in hepatocellular carcinoma patients treated with 90 Y-loaded glass microsphere radioembolization[END_REF] For PVT patients, the only parameter strongly associated with liver toxicity was the absence of MAA PVT targeting. 7

Development of a MAA-based personalized dosimetry

When using resin microspheres, one expert group has recommended targeting 120 Gy for delineable HCC, without exceeding a NLD of 50 or 70 Gy, depending on the underlying disease. [START_REF] Lau | Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres[END_REF] When using glass microspheres, a personalized dosimetric approach concept, along with treatment intensification as necessary, has been previously described, targeting a tumor dose >205 Gy. [START_REF] Garin | Boosted selective internal radiation therapy with 90 Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept[END_REF] The patients who underwent treatment intensification were administered an injected liver dose ≥150 Gy, contrasting with the 80-150 Gy delivered in the classical approach. In this concept, the NLD was kept <120 Gy. In this study, 38% of patients underwent treatment intensification. The response rates were significantly higher when using the personalized dosimetric approach versus the standard dosimetric approach, estimated at 86% versus only 55%, respectively (p=0.01). The toxicity rate did not differ between patients who underwent treatment intensification and those who did not, respectively 5.8% vs 9.2%. [START_REF] Garin | Boosted selective internal radiation therapy with 90 Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept[END_REF] This intensification concept proves to be of particular value for PVT patients. Personalized dosimetry, as previously described, [START_REF] Garin | Boosted selective internal radiation therapy with 90 Y-loaded glass microspheres (B-SIRT) for hepatocellular carcinoma patients: a new personalized promising concept[END_REF] was evaluated in a study involving 41 PVT cases. [START_REF] Garin | Personalized dosimetry and intensification concept with 90Y-loaded glass microsphere radioembolization induce prolonged overall survival in hepatocelluar carcinoma patients with portal vein thrombosis[END_REF] In this study, 37% of patients received treatment intensification. A high 85% response rate was achieved without causing any concomitant increase in permanent liver Grade ≥III toxicity (6% in the intensified patients versus 12% in the non-intensified ones, ns). The TD was found to significantly impact OS, which was 4.3 mo (95% CI: 3.7-5) vs 18.2 months (95% CI: 8.5-28.7) for patients with a TD below 205 Gy or over 205 Gy, respectively (p=0.005). Patients with a TD ≥205 Gy and good PVT targeting (n=36, ie 87%) exhibited an OS of 20.2 mo. It has to be underlined that in this study using treatment intensification, tumor size was not correlated with OS, as in several studies using a standardized dosimetric approach, indicating that it has been possible to provide a sufficient amount of radiation in large lesions. Five patients exhibiting a complete portal vein recanalization were downgraded towards surgery and resected at a later time. The objective median OS was not reached, though exceeding 24.5 mo and being significantly longer (p=0.0493) for the five patients who underwent lobar hepatectomy. [START_REF] Garin | Personalized dosimetry and intensification concept with 90Y-loaded glass microsphere radioembolization induce prolonged overall survival in hepatocelluar carcinoma patients with portal vein thrombosis[END_REF] Figure 1 shows an interesting case of PVT patient down-staged by 1 90 Y loaded glass microspheres injection followed by surgery.

A randomized multicenter Phase 2 study, DOSISPHERE-01 trial (2015-A00894-45), was designed to compare a personalized dosimetric arm targeting at least 205 Gy to the tumor (and if possible, TD higher than 250-300 Gy) against a standard dosimetric arm targeting 120±20

Gy to the injected liver, involving HCC patients treated with glass microspheres. For this study, patient recruitment has presently been completed, with results possibly available in 2019.

Take home messages

PVT patients prove to be good candidates for SIRT, provided that patient selection is accurately performed. Treatment has been proven associated with better results in CP A patients, with no ascites and bilirubin levels <2mg/dL.

In several studies, MAA SPECT/CT-based dosimetry has been demonstrated to be a good predictor of treatment response and OS, with a threshold dose between 100-120 Gy for resin microspheres and between 205-257 Gy for glass microspheres.

For accuracy, MAA SPECT/CT-based dosimetry must meet several requirements:

-Consider several diagnostic angiography specifications, including limitation of spasm occurrence, main bifurcation proximity, slow MAA injection, as well as accurate catheter positioning;

-Use an accurate segmentation method (CT based or MAA SPECT/CT based), with superior results described based on full SPECT/CT segmentation.

MAA PVT targeting proves to be paramount, as as absence of PVT targeting for lobar and main PVT were previously reported correlating with a high risk of liver failure.

The clinical impact of MAA personalized dosimetry is high as prolonged OS reaching up to 20.2 mo and down-staging rate of 12% have been reported.

Figure 1 :

 1 Figure 1 : Clinical case of good PVT targeting and down-staging

Table 2 . Randomized studies using 90 Y loaded resin microspheres SIRT and sorafenib (S) in advance HCC (not focussed on PVT patients).

 2 ITT= intent to treat, HR= hazard ratio, Response rate was evaluated using RECIST

		SARAH trial 15	SIRveNIB trial 16	SORAMIC Trial 17
	Treatment	SIRT alone vs S	SIRT alone vs S	SIRT + S vs S
	% of patients not	22% for SIRT	28.6% for SIRT	47.2% for SIRT+S
	receiving the		9.0% for S	16. 3% for S
	assigned treatment
	OS ITT	8 mo (6.7-9.9) for SIRT	8.8 mo for SIRT vs	12.1 mo (12.6-14.6)
		vs		for SIRT+S vs 11.5 mo
		9.9 mo (8.7-11.4) for S	10 mo for S	(9.8-13.8) for S
		ns	ns	ns
	OS per protocol	mo 9.9 (8-12.7) for	11.3 mo vs for SIRT vs	14.1mo (10.9-16.4)
		SIRT vs		for SIRT+S 11.1 mo
		9.9 mo (9-11.6) for S	10.4 mo for S	(9.7-13.9) for S
		ns	ns	ns
	OS and PVT	HR = 1.19 (0.92-1.54)	na	na
		for SIRT
	Response rate	19% for SIRT vs	16.5% for SIRT vs	na
		12% for S	1.7% for S
		p=0.0421	p<0.001
	% patient with at least	41% for SIRT vs	27.7% for SIRT vs	72.3% for SIRT+S vs
	one Grade ≥3 AE	63% for S	50.6% for S	68.5% for S
			p<0.001
	Quality of life	Significantly improved	na	na
		for the SIRT arm

Table 3 : Studies with MAA based tumor dose/response corelation in HCC Lau 3 Kao 30 Chiesa 5 Garin 35 Garin 36

 3 Nb= number, na = non available, TTD= Threshol tumor dose, w = week, m = months

	Product	resin	resin	glass	glass	glass
	Nb patients/	18/	10/	48/	71/	41 PVT patien
	Nb lesions	na	na	65	na
	Lesion size	na	na	5.6	7.1	8.5
	(cm)
	Prior therapy	na	50%	28.9%	51%	34%
	Response	WHO	RECIST1.1	EASL	EASL	EASL
	Evaluation
	Threshold	120	< 91	257	205	205
	TD (Gy)
	RR for TD	87.5% vs	100%	85% vs na	na	na
	≥TTD Vs < TTD	12.5%
		p=0.005
	OS for TD	55.9w	na	na	23m (17.5-	18.2m (8.5-
	≥Thresold TD	vs			28.5)	28.7)
	Vs < Thresold TD	26.6w			Vs	vs
		p=0.005			11.5m (2-30.7)	4.3m (3.7-5)
					ns	p=0.005

Table 1 :

Median OS (mo) and CI 95% for the main prognostic parameters reported to be associated with OS at multivariate analysis.

Abouchaleh et al [START_REF] Abouchaleh | 90 Y Radioembolization for Locally Advanced Hepatocellular Carcinoma with Portal Vein Thrombosis: Long-Term Outcomes in a 185-Patient Cohort[END_REF] Spreafico et al [START_REF] Spreafico | Development of a prognostic score to predict response to Yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion[END_REF] Garin et al


P Malbois

Erwan Salaün

Alexis Vandel

G Godard

G Cabot

B Renou

A Boukhalfa

Frederic Grisch
email: frederic.grisch@coria.fr

Frédéric Grisch

Experimental investigation of aerodynamics and structure of a swirl-stabilized kerosene spray flame with laser diagnostics

Keywords: High-speed PIV, High-speed OH-PLIF, Turbulent swirled flame, atmospheric pressure, spray combustion, Aeronautical fuel injector, Kerosene

de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Aero-engine emissions are becoming a global environmental issue as air traffic continues to rise. Environmental concerns and legislative regulations laid down by governing organizations are therefore driving aircraft combustor manufacturers to meet more stringent emission standards on NOx, CO and soot while maintaining or improving the efficiency and reliability of future aero-engine combustors. In the case of small operating pressure range aero-engines such as helicopter combustors, the concept of lean premixed (LP) combustion has been introduced as one of the best solutions to significantly reduce NOx emissions [START_REF] Correa | A review of NOx formation under gas-turbine combustion conditions[END_REF][START_REF] Lefebvre | Gas turbine combustion: alternative fuels and emissions[END_REF][START_REF] Janicka | Flow and Combustion in Advanced Gas Turbine Combustion[END_REF][START_REF] Lieuwen | Combustion Instabilities In Gas Turbine Engines[END_REF]. The LP concept is based on the action of two air flows, one devoted to the fuel atomisation and the second to mixing and fuel evaporation. Their combination acts as a promoter for the stabilisation of the flame in the combustion chamber. Too sharp a reduction in the emission of NOx can, unfortunately, lead automatically to a decline in flame stability as well as a drastic increase in CO and hydrocarbon (HC) emissions [START_REF] Huang | Dynamics and stability of lean-premixed swirl-stabilized combustion[END_REF]. Generally, enhancement of the flame stabilization is provided by means of swirl flows. Swirling flames are commonly characterised by unsteady flow structures, including irregular highly turbulent motion and dynamics of coherent flow structures which interact with the flame downstream from the fuel injection system. Furthermore, the large expansion of the flow induced by the heat release rate can produce recirculation zones that promote the transportation of hot reaction products back to the flame base, thereby enhancing the local ignition of fuel and thus the flame stability. Between the inflow and recirculation zones, unsteady shear layers allow the mixing between fresh and hot gases. Finally, typical dynamics related to vortex breakdown, such as helical structures or Precessing Vortex Core (PVC) can be a source of flow and heat release rate unsteadiness which may trigger instabilities such as thermo-acoustic oscillations [START_REF] Steinberg | Flow-flame interactions causing acoustically coupled heat release fluctuations in a thermo-acoustically unstable gas turbine model combustor[END_REF][START_REF] Oberleithner | Formation and flame-induced suppression of the precessing vortex core in a swirl combustor: Experiments and linear stability analysis[END_REF]. Of course, all of these physical processes may compete or interact together [START_REF] Dhanuka | Unsteady Aspects of Lean Premixed Prevaporized Gas Turbine Combustors: Flame-Flame Interactions[END_REF], which complicates their modelling. Further detailed experimental studies are then required to conduct a better comprehensive analysis of these interaction mechanisms in order to improve the performances of future aero-engine combustors.

In recent years, strong efforts have been made experimentally to improve the knowledge of the related phenomena and to explore ideas for circumventing flame stability issues in LP combustors. Effects of swirl on the flame structure were initially studied with laser diagnostics in GT model combustors powered by gaseous fuel [START_REF] Meier | Laser-based investigations in gas turbine model combustors[END_REF][START_REF] Stopper | Experimental study of industrial gas turbine flames including quantification of pressure influence on flow field, fuel/air premixing and flame shape[END_REF]. The role of PVC on the reaction zone under unstable conditions was also investigated using high-speed laser diagnostics [START_REF] Boxx | High-speed laser diagnostics for the study of flame dynamics in a lean premixed gas turbine model combustor[END_REF]. Local interactions between the aerodynamic flowfield and the reaction zone in CH4/air flames [START_REF] Oberleithner | Formation and flame-induced suppression of the precessing vortex core in a swirl combustor: Experiments and linear stability analysis[END_REF][START_REF] Boxx | High-speed laser diagnostics for the study of flame dynamics in a lean premixed gas turbine model combustor[END_REF][START_REF] Stöhr | Phase-resolved characterization of vortexflame interaction in a turbulent swirl flame[END_REF][START_REF] Boxx | Study of the mechanisms for flame stabilization in gas turbine model combustors using kHz laser diagnostics[END_REF], thermoacoustic oscillations/flow field interactions [START_REF] Meier | Laser-based investigations in gas turbine model combustors[END_REF] and fuel-to-air mixing [START_REF] Stöhr | Transient effects of fuel-air mixing in a partially-premixed turbulent swirl flame[END_REF] were also addressed. More recently, high-speed PIV and OH-PLIF laser diagnostics were applied in a pressurized natural gas fuelled burner to study the flame/flow interactions in pressures up to 5 bar [START_REF] Slabaugh | Simultaneous 5 kHz OH-PLIF/PIV for the study of turbulent combustion at engine conditions[END_REF][START_REF] Boxx | 3 kHz PIV/OH-PLIF measurements in a gas turbine combustor at elevated pressure[END_REF]. Unfortunately, all of these studies were only performed with gaseous fuels that are not realistic of operating conditions relevant to real aero-engine combustors. To better understand the physical processes that take place in relevant gas turbines, efforts were initiated by first investigating the effects of spray fuel injection on the flame characteristics. As an example, an experimental study on confined swirl flames fuelled by methane or kerosene fuels showed similarities in the aerodynamic flow properties in both flames but significant differences in the flame structures [START_REF] Marinov | Similarity issues of kerosene and methane confined flames stabilized by swirl in regard to the weak extinction limit[END_REF]. One explanation formulated by the authors was related to the combustion of liquid fuel droplets that modifies the diffusion of fuel vapour and oxidizer species and thus the reaction rates. The chemical properties of liquid fuels and their associated fuel atomization are also scalar parameters that change the characteristics of swirl combustion systems [START_REF] Chong | Spray flame structure of rapeseed biodiesel and Jet-A1 fuel[END_REF]. Indeed, the authors observed different droplet size distributions and flame structures when comparing biofuel (RME)/air and Jet-A1/air swirl spray flames. The lower viscosity and higher volatility of Jet-A1 then promote the fuel atomization leading to faster evaporation and better mixing while the velocity distributions in both flames are similar. The dynamics of swirled flames was also investigated using high-speed PIV and/or OH-PLIF laser diagnostics. For instance, various types of swirl-stabilized flames close to blow-off limits were studied by high-speed OH-PLIF [START_REF] Cavaliere | A comparison of the blow-off behaviour of swirl-stabilized premixed, non-premixed and spray flames[END_REF]. The results of this study showed that spray swirl-stabilized flames are more sensitive to lift-off and local extinction than gaseous premixed swirl-stabilized flames. The timescale of the blow-off event was also shorter in spray flames than in premixed and non-premixed gaseous CH4/air swirlstabilized flames. Interaction between the fuel droplets and the aerodynamic conditions is also a mechanism that significantly affects the overall characteristics of swirl-stabilized spray flames [START_REF] Johchi | Investigation on the acoustic behavior of a turbulent swirl-stabilized combustor fed with liquid fuel[END_REF]. The effect of pressure on swirled-stabilized spray flames is another physical parameter which has an influence on the flame characteristics. For instance, large interactions between the mean flame location and the aerodynamic flow field were underlined in a GT model combustor equipped with an LP injection system fuelled with kerosene at 4.5 bar [START_REF] Lantz | High-speed imaging of fuel/OH distributions in a gas turbine pilot burner at elevated pressure[END_REF]. Flame structure and droplet distribution were also analysed at 3 bar by visualising the fuel and the OH distribution with high-speed PLIF in a gas turbine fuelled with various fuels such as Jet-A1 and biofuel [START_REF] Lantz | High-speed imaging of fuel/OH distributions in a gas turbine pilot burner at elevated pressure[END_REF]. Another work focused on the quantitative effect on the unsteadiness produced in LPP injection systems operated at various pressures (1 to 4.5 bar) with Jet-A1 fuel was investigated using PIV and PLIF diagnostics [START_REF] Dhanuka | Unsteady Aspects of Lean Premixed Prevaporized Gas Turbine Combustors: Flame-Flame Interactions[END_REF]. More recently the interaction between fuel vapour and liquid, aerodynamics and flame was investigated in a high pressure combustor up to 5 bar, using high-speed diagnostics [START_REF] Chterev | Simultaneous imaging of fuel, OH, and three component velocity fields in high pressure, liquid fueled, swirl stabilized flames at 5 kHz[END_REF]. While these studies have provided considerable insight into the physical mechanisms governing swirling spray combustion, the design, power and operating conditions relative to the fuel injection system are generally far different from industrial aeronautical combustion systems. It is therefore crucial to better understand the underlying physical and chemical processes in order to optimize the architecture of future aircraft fuel injection systems. This involves performing detailed experiments on relevant swirl-stabilized spray flames so as to improve the industrial aircraft engine performances.

The current paper deals with a detailed experimental study of an advanced helicopter LP fuel injection system operating at atmospheric pressure in an optically accessible GT model combustor. This injector is fuelled with commercial Jet-A1 fuel and preheated air. In a first step, various experiments using laser diagnostics were performed. First of all, the aerodynamic conditions were investigated using highspeed PIV and stereoscopic PIV laser diagnostics. Experiments on the characterization of the flame structure were pursued with OH-PLIF operating at low frequency. Finally, the dynamics of flame structure/flow field interactions were investigated thanks to the combination of high-speed OH-PLIF and PIV techniques. From the analysis of the velocity measurements, the distributions of the averaged 2D flow velocity as well as information about the strain rate and vorticity distributions provided an overview of the aerodynamic flow field. In particular, the results illustrated the mechanisms of generation of the shear layers and their effects on the flame front. A specific tool was developed in the current study to extract the accurate flame front position via the analysis of the OH gradient. An analysis of the experimental high-speed velocity data was then performed with a Proper Orthogonal Decomposition (POD) tool to obtain a detailed description of the dynamics of the aerodynamic flow. Finally, a careful analysis of high-speed flow velocity and POD analysis combined with OH distributions was used to study the formation of unusual flame pinching mechanisms and their effects on the transporting of unburned pockets into the burned gases.

Experimental set-up

Combustion facility and operating conditions

A visualization of the experimental facility is given in Fig. 1. The mono-sector gas turbine combustor is composed of two parts, the combustion chamber and the fuel injection system (Fig. 1a). The combustion chamber is the same as the one described in [START_REF] Cordier | Laser-induced spark ignition of premixed confined swirled flames[END_REF]. It has a square cross-section of 100 mm × 100 mm and a height of 230 mm. It is equipped with three UV fused-silica windows that guarantee large optical access (80 × 200 mm 2 ). The exhaust opens directly on the ambient air with a 56 mm diameter nozzle. The LP fuel injection system is located at the bottom of the combustion chamber and fuelled with commercial liquid Jet A1 fuel.

Air is fully injected into the fuel injector and acts as a promoter to atomize the liquid fuel. The LP injection system is based on a premixing of air with a liquid spray fuel issued from a fuel nozzle and a thin liquid film produced along the wall of the injection system. A schematic of the LP fuel injection is depicted in Fig. 1b. The injection system includes two co-rotating swirlers and a hollow cone central fuel injector. The central swirl air flow is radial while the one used for the outer annular air flow is axial. The liquid fuel is injected via two channels. The main injection circuit consists of the radial injection of kerosene to the radial swirl air through eight radial holes of diameter 1 mm staggered in two rows. A hole drilled along the fuel nozzle with an internal diameter of 1 mm, constitutes the pilot injection. This one is used to axially inject the remaining kerosene in the air stream. The atomization of the liquid fuel injected through the main injection system is similar to the one obtained from the injection of a liquid jet in a cross-flow. Radial kerosene jets are destabilized by the axial swirl air stream, resulting in jet breaks and droplet formations. According to the geometry of the injector, the larger "inertial" fuel droplets also impact the wall of the external tube of the central flow, thus forming a thin liquid film. This one is then atomized through the action of the external swirl air flow which provides a shear force resulting from the interaction of the free liquid surface with an airflow stream. This interaction forces the liquid film to move towards the lip of the pre-filmer where the axial swirl air stream deforms its edge and leads to the disintegration of the liquid film in form of ligaments and then to small droplets as schematically shown in Fig. 1b. Finally, the axial swirl air stream thus makes it possible to homogenize the mixture between air and fuel at the outlet of the injector. Finally, the pilot injection system enables to produce a rich zone in the center of the flow to promote the stabilization of the flame at the outlet of the injector.

The exit plane of the fuel injector is located in the bottom plane of the combustion chamber (z/D = 0). The operating condition investigated in the current study delivers a thermal power of 65.6 kW, with a global equivalence ratio of ϕ= 0.7, = 30 g/s and = 1.417 g/s. In order to ensure operating conditions representative of those encountered in industrial gas turbines, the air inlet at the entrance of the combustion chamber is preheated to 473 K. The flame stability is controlled by the analysis of the pressure fluctuations measured inside the combustion chamber with a pressure transducer.

Laser diagnostics

Two regions of interest were considered in the current study (Fig. 2). The first one allows measurements of velocity in a cross section of the reactive flow field (Fig. 2a) while the second one was used to perform measurements of velocity and OH distributions in the axial plane centred along the flow axis (Fig. 2b). These measurements were performed with a variety of PLIF and PIV diagnostics. The size of the regions investigated as well as the associated spatial resolution selected for PIV and OH-PLIF measurements are reported in Table 1.

PIV systems

Two PIV systems were used to perform 2D axial (x-z plane) and radial (x-y plane) measurements of velocity. For measurements in the radial plane, a stereoscopic PIV system was used. A schematic representation of the experimental setup is given in Fig. 2a. The PIV system consisted of a dual-cavity Q-switched Nd:YAG laser running at 5 Hz and providing two 532 nm laser pulses with a pulse timing separation of 2 µs.

The laser beam was formed into a 70 mm tall planar light sheet using a cylindrical telescope (f1 = -20 mm, f2 = 500 mm) and focused to a waist of 500 µm using a spherical lens (f = 1000 mm). Mie scattering produced from the illumination of solid zirconium oxide (ZrO2) particles of several µm nominal diameter seeded into the flow and kerosene droplets by the laser beam were detected and imaged using visible cameras (Dantec Dynamics FlowSense 4M). To minimize the scattered light from kerosene droplets, the laser sheet was located at a minimal distance of 25 mm downstream from the exit of the injection system in which the sizes of ZrO2 particles and fuel droplets had typically the same order of magnitude. The cameras operated with a 2048 × 2048 pixel resolution. For each camera, a Nikkor f/1.2 50 mm lens was mounted with a Scheimpflug mount tilted with an angle of 35°. A narrowband optical filter centred at 532 nm with a 10 nm spectral width was placed in front of the lens in order to suppress the background flame luminosity. Calibration of cameras was performed to correct the perspective distortion and images were then de-warped and cross-correlated to extract GmbH) was mounted on a Scheimpflug mount to ensure a camera tilt angle of 27.5° ( Fig. 2b). The filters used in the high-speed OH-PLIF measurements were the same ones used in the low repetition rate PLIF measurements.

Image Data Processing

OH-PLIF image filtering and flame front detection

Once the OH fluorescence images has been corrected from the distortion and spatial energy distribution of the laser sheet, a filtering procedure was applied to detect the flame front contour. In many studies, linear diffusion filtering using Gaussian routines is applied to reduce noise before extracting the flame contour. However, this type of filtering generally smoothes the noise but blurs important features such as the edges and thus makes them harder to identify [START_REF] Weickert | Efficient and reliable schemes for nonlinear diffusion filtering, Image Process[END_REF]. To limit these constraints, non-linear diffusion filtering routines are used to improve the Signal to Noise Ratio (SNR) while enhancing the contours in images [START_REF] Meier | Laser-based investigations in gas turbine model combustors[END_REF][START_REF] Malm | Nonlinear diffusion filtering of images obtained by planar laser-induced fluorescence spectroscopy[END_REF][START_REF] Abu-Gharbieh | Flame front matching and tracking in PLIF images using geodesic\npaths and level sets[END_REF]. This procedure offers the advantage of locally modifying the diffusion coefficient according to the type of object observed on the images. Thus, a large diffusion coefficient can be used to smooth the noise while a negligible one is applied when approaching to the object boundaries. As a result, flame contours can be enhanced, gradients are sharpened and detection of the boundaries is highlighted. The non-linear diffusion method used in the current study then solves the following partial differential equation (PDE):

= !"#($(|& | )& ) (1)
in which g is a diffusivity function and u(t, x, y) is the OH fluorescence signal on the image. Considering that the edges of the object are detected by the gradient of u, |&u| , a diffusivity function $(|& | ) can be introduced by using the formalism proposed by Perona and Malik [START_REF] Perona | Scale-space and edge detection using anisotropic diffusion[END_REF]:

$(|& | ) = 1 1 + ) |& | λ + (2)
where , is defined as a contrast parameter. With this expression, only gradient intensity values lower than , are diffused. To provide a better converging effect of averaging the gradient within the diffusivity, the diffusivity function $(|& | )

proposed by Perona and Malik was replaced by the expression $(|& -| ) with -= .

-and . -denoting a Gaussian function with a standard deviation σ. The numerical implantation of this filtering method was achieved by discretizing the PDE equation with an iterative process. The simplest procedure consisted in the use of an explicit scheme, but for stability reasons, this method is severely restricted to very small time steps, leading to a high time cost. A solution to circumvent this constraint was to use the additive operator splitting (AOS) method proposed by [START_REF] Weickert | Efficient and reliable schemes for nonlinear diffusion filtering, Image Process[END_REF]. Using a semi-implicit scheme, the computational cost was then increased compared to the case of the explicit scheme but time steps are no longer limited. Thus, the global computation time is reduced. To illustrate the potential of this filtering method, the instantaneous profiles of the OH signal intensity at z/D = 2 from the raw OH images and the filtered OH images are plotted in Fig. 3a. One can observe that the noise is smoothed by the filtering tool (green line)

while the sharp gradients of OH signals are well preserved. To isolate the sharp gradients, filtered OH images were converted into binary images with black regions corresponding to fresh gas and gray to white zones denoting the burned gases. The threshold limit adopted for this binary conversion was defined using Otsu's method [START_REF] Otsu | A threshold selection method from gray-level histograms[END_REF]. The frontier separating both the two zones was then defined. The advantage of this method is highlighted in

Proper Orthogonal Decomposition analysis

The Proper Orthogonal Decomposition (POD) is a statistical tool for identifying and extracting coherent structures and energetic events in flows. POD consists in the determination of a set of bases of linear functions, the so-called proper orthogonal modes which contribute most of the energy of the flow. The approach selected in the current study is based on the snapshots method introduced by [START_REF] Sirovich | Turbulence and the dynamics of coherent structures[END_REF]. POD reconstruction is used as a low-pass filtering to remove small velocity fluctuations and enable identification of the most energetic coherent structures that cannot be clearly observed on the raw experimental velocity fields [START_REF] Adrian | Analysis and interpretation of instantaneous turbulent velocity fields[END_REF]. To illustrate the potentialities of POD on realistic reactive flows, it was applied on the velocity field measured in a focused region of interest (i.e. on the left side of the flow since the flame is assumed to be symmetrical). 3750 instantaneous velocity fields recorded at 5 kHz were used. A typical comparison of the POD reconstruction of the fluctuation energy ( Fig. 4b) with the experimental vorticity ( Fig. 4a) is displayed. By using only 50 modes which accounts for 70% of the energy of the fluctuations, the POD reconstruction enables the position and intensity of the experimental vorticity to be captured.

Results and discussion

Averaged velocity field

A set of 3750 instantaneous velocity fields was used to compute time-averaged statistics with a good convergence. The mean flow field was found to be axisymmetric.

To illustrate the main properties of the time-averaged flow pattern, Fig. 5 displays a streamline plot superimposed on the mean velocity flow (Fig. 5a) and the turbulence kinetic energy (TKE) fields (Fig. 5b). In the current study, TKE was calculated as ∑ 0 ′ in which 0 is the fluctuation of the velocity component in the direction i (x, y or z). Since only the axial and radial velocity components are measured, the out of plane velocity fluctuations are assumed to be equal to the radial fluctuations for the calculation of TKE.

The averaged flow velocity is typical of those observable in enclosed swirled flames [START_REF] Meier | Laser-based investigations in gas turbine model combustors[END_REF][START_REF] Samarasinghe | The three-dimensional structure of swirl-stabilized flames in a lean premixed multinozzle can combustor[END_REF]. The air/fuel fresh mixture expands downstream from the injector along a conical spatial distribution with a magnitude of axial velocity that may exceed 150 m/s. The geometry of this flow, in a time-averaged approach, consists of several main regions: a large inner recirculation zone (IRZ) that is developed through the positive axial pressure gradient associated with the vortex breakdown of the swirling flow, an outer recirculation zone (ORZ), a toroidal recirculating region generated by the rapid expansion of the nozzle in the combustor, an annular jet flow at elevated velocity that separates these two regions and two annular shear layers that divide the ORZ and the jet inner flow, and IRZ and inner flow, denoted here as the outer shear layer (OSL) and the inner shear layer (ISL). Each shear layer originates from the existence of a large velocity gradients between the inner flow and the recirculation flows, thus generating strong velocity fluctuations. Analysing the RMS of the velocity (Fig. 6), the highest velocity fluctuation is produced in ISL for the axial component (Fig. 6b) and in OSL for the radial component (Fig. 6a). It can be noted that the fluctuations associated with ISL are two times larger than that of OSL. To complete the description of the turbulence of the flow field, large turbulent scale structures are also observable on the instantaneous

The pressure effect is usually neglected in experimental studies since it is difficult to obtain. The quantities 7 and 6 stand for the axial and azimuthal velocities at the outlet of the injection system. Pressure and density effects are neglected in the calculation. A value of S = 0.62 was calculated assuming a characteristic length equal to the radius of the nozzle exit < => and an integration domain ranging from x/D = 0 to 1.3. The existence of a high degree of swirl (larger than 0.62 at the exit of the fuel injection system) confirms the experimental results, namely that an axial recirculation bubble in the form of a central toroidal recirculation zone occurs in this type of flame.

Strain rate and vorticity

The 2D flow velocity distribution from PIV measurements was used for a direct calculation of gradient-based quantities such as the strain tensor and vorticity. These quantities provide a useful basis for the analysis of the non-linear coupling between turbulence and chemical processes leading to a wrinkling and a straining of flames.

The strain tensor in the x-z plane was obtained from the following expression:

2 @7 = 1 2 ) @ A + 7 B + (4)
in which the quantity denotes the turbulent velocity in the direction xi. The out-ofplane component of vorticity (C D ) was computed using the curl of the velocity field.

For a planar 2D flow velocity field, the out-of-plane vorticity is computed as

C D = 7 B - @ A (5)
Fig. 9a presents the mean strain rate component in the x-z (measurement) plane.

Maximum values of the strain rates (regardless of its sign) occur at the interfaces between the inlet flow and each recirculation zone (ORZ and IRZ). More remarkably, the thicknesses of the two shear layers differ among themselves.

In an open channel sudden expansion, the main stream separates from the corner of the expansion and reattaches downstream. The separating streamline is thus defined as the frontier between the main inlet stream issued from the injection system and the ORZ. One specificity of the ORZ is its low velocity magnitude compared to the inlet stream. Consequently, the separation streamline is representative of high turbulent mixing layers with presence of large velocity gradients. The growth rate of the mixing layer is then generally piloted by the Kelvin-Helmholtz instability mechanism [START_REF] Sirovich | Turbulence and the dynamics of coherent structures[END_REF].

Even for high Reynolds numbers (up to 200 000), Kelvin-Helmholtz instability generates primarily two-dimensional, spanwise-oriented vortices (rollers) that are transported downstream with a convective velocity function of the free stream speed ratio r=U2/U1. The velocity with the subscript "2" is associated with the low speed of the positive stream-wise developed in the ORZ and the velocity with the subscript "1" refers to the high-speed inlet stream. For incompressible mixing layers, the growth rate of the shear layer driven by the Kelvin-Helmholtz mode can be then expressed as a function of the velocity ratio (r) and the density ratio (E = 4 /4 ) by the following expression [START_REF] Papamoschou | The compressible turbulent shear layer : an experimental study[END_REF]:

G A = 0.17 (1 -9)I1 + √EK I1 + 9√EK (6)
G is the visual thickness of the shear layer and z is the downstream distance from the corner of the outlet wall of the injector. In our case, assuming U1 = 120 m/s, U2 = 30 m/s and a density ratio of 1/5 (ratio of temperature between the hot gases contained in the recirculation zone and those of the inlet jet), the value of the thickness is calculated for different heights above the burner and plotted on Fig. 9b. The evolution of the theoretical thicknesses versus the height is then compared to the experimental values measured in the shear layers. For instance, at z/D=1.1, the theoretical thickness is about 4.1 mm which agrees well with the experimental value of 4.4 mm acquired in the ORZ. By contrast, the thickness observed experimentally in the ISL is noticeably larger, around 9 mm. This value is apparently too large to originate from the development of the ISL by only Kelvin-Helmholtz instabilities. As IRZ is not attached to the injection system (i.e. no existence of a bluff body at the center of the outlet injection system), the ISL is no longer driven solely by Kelvin-Helmholtz instabilities but is likely piloted by another mechanisms that also produce smaller-scale, streamwise-oriented vortices lying along the outer edges of the spanwise rollers and grouping in counter-rotating pairs. According to the literature [START_REF] Dimotakis | The mixing layer at high Reynolds number: largestructure dynamics and entrainment[END_REF], one possible mechanism could be related to the sudden increase in three-dimensionality and the accompanying increase in the amount of molecularly-mixed fluid associated with the mixing transition. Therefore, the existence of highly turbulent motions inside the inlet flow (see Fig. 5) are key parameters which enable the strain and the distortion of the volume of hot exhaust gases circulating in IRZ, breaking then the interfacial zone between the main flow and the reverse flow in the IRZ into smaller volumes and accelerating an homogenization of the mixing layer in a larger section. Thus, the mixing taking place along the interface between the inlet stream and the hot gases circulating inside the IRZ is more efficient and provides a favorable zone for the ignition of the incoming fresh gases and flame stabilization, compared to the OSL (see section 3.3). A second instability mechanism which could explain the thickness of the ISL is the presence of a precessing vortex core (PVC). Indeed, formation of the IRZ may be accompanied by the occurrence of a PVC which strongly impacts the flame stability and may affect stretch and local quenching of the reactions zones [START_REF] An | Coupled dynamics of liftoff and precessing vortex core formation in swirl flames[END_REF]. However, no evidence of remaining PVC structures in the flow regions investigated can be found in PIV images and it is therefore difficult to assess the presence of PVC. Furthermore, oscillations in the flow field arising from the PVC (if any) would decay rather rapidly as the flow is propagating downstream from the injector [START_REF] Stöhr | Phase-resolved characterization of vortexflame interaction in a turbulent swirl flame[END_REF][START_REF] Moeck | Nonlinear interaction between a precessing vortex core and acoustic oscillations in a turbulent swirling flame[END_REF]. Oscillation amplitudes would significantly decrease at axial distances from the breakdown corresponding to about one to two nozzle diameters. Considering an exit nozzle diameter of D ~ 2 cm, the effect of PVC is expected to be negligible in the IRZ where flame pinching effect is observed.

Positive and negative values of the shear strain rate observed in Fig. 9a to the corresponding strain rate, which suggests a dominance of the axial-velocitygradient term in Eqs. ( 4) and ( 5). Regions of positive and negative (red and blue) vorticity properly identify the counter-clockwise and clockwise rotating flows on the left hand side of the flowfield. A peak vorticity magnitude of more than 15 000 s -1 is observed in ISL and OSL. This high level of vorticity shows that intense mixing takes place between the input reactants and hot products circulating in the ORZ and IRZ and confirms the observations already observed on the strain rates. This intense mixing also promotes the heat transfer between the hot gases and the fresh incoming mixing required for the ignition and the burning of the fuel/air mixing penetrating into the shear layers (see the next section for more information). As noted on both instantaneous OH-PLIF images, the edge zones delimiting the interface between the fresh gases and the reverse flows (i.e. ORZ and IRZ) are highly wrinkled. However, a careful examination of Fig. 13a shows that OSL and ISL display reactive flow structures with different scales. The prevailing inner flame structures are noticeably smaller than those observed in OSL. These apparent differences arise from the reasons already mentioned to explain the existence of dissimilar shear layers. In the case of the inner flame, the intense level of turbulence in ISL leads to an enhancement of the transport of fresh air/fuel gaseous pockets within the flame front by small size eddies that can easily penetrate into IRZ. As a result, the fresh gaseous mixture contained in these eddies is preheated and mixed with radicals faster, enhancing the reaction rates as shown by the large production of OH radicals in this region (Fig. 13a). Returning to OSL, the structure of the interface delimiting ORZ and the inner flow is also prone to similar physical mechanisms. However, the burning of the fresh incoming reactants seems to be reduced. As observed in Fig. 13a, the fluorescence intensity delivered by the OH radicals in ORZ is significantly lower than the one issued from OH radicals in the inner flame. Furthermore, the structures of the hot/fresh gas interface are now tightly rolled-up by large-scale eddies caused by the Kelvin-Helmholtz instability developed at the outer corner of the injection system.

Flame structure

These large-scale vortices result in curvature induced stretch flames which unfortunately hamper the efficient mixing between fresh reactants and combustion products. Furthermore, the heat transfer between the combustion products circulating in ORZ and the combustor walls leads to large heat losses that significantly reduce the local temperature of hot gas products, see for example the work of Mercier et al. on this subject [START_REF] Mercier | Experimental and numerical investigation of the influence of thermal boundary conditions on premixed swirling flame stabilization[END_REF]. Under these conditions, the reactivity of the fresh mixture upstream of the interface is then reduced to such a low level that the flame leading edge can ultimately lead to flame extinction. The frontier observed experimentally may be only characteristic of an interface between hot combustion products and fresh incoming reactants and not that of a flame front. To support these assumptions, the progress rate of combustion in the two shear layers was determined by extracting the gradient of the OH fluorescence signals from instantaneous OH-PLIF images. A recent study revealed that OH-gradients related to strong temperature gradients and/or presence of OH in superequilibrium conditions can be a good marker of the flame front of swirl flames [START_REF] Sadanandan | Simultaneous OH-PLIF and PIV measurements in a gas turbine model combustor[END_REF]. In the current study, the intensity distributions of the OH-gradients in ISL and OSL were deduced from the post-processing of instantaneous OH-PLIF images.

This post-processing consists of the detection of the OH-gradient using Sobel filtering followed by thresholding the gradient and "cleaning" residual small structures by a morphological operation [START_REF] Malbois | Experimental investigation with optical diagnostics of a LP aero-engine injection system under relevant operating conditions[END_REF]. An inspection of the literature shows that the propagation of unburned mixtures in the exhaust products is a physical process already observed in academic turbulent premixed flames classified in the corrugated-flamelet regime [START_REF] Donbar | Reaction zone structure in turbulent nonpremixed jet flames -From CH-OH PLIF images[END_REF][START_REF] Joulin | Pockets in premixed flames and combustion rate[END_REF][START_REF] Tanahashi | CH double-pulsed PLIF measurement in turbulent premixed flame[END_REF][START_REF] Dhanuka | Instantaneous flow structures in a reacting gas turbine combustor[END_REF][START_REF] Ueda | Measurement of threedimensional flame structure by combined laser diagnostics[END_REF][START_REF] Borghi | Turbulent reactive flow[END_REF]. Their origin has been attributed to the engulfment of coherent structures in the flame front due to high levels of turbulence and their resulting sizes were estimated to be equal to or larger than the integral length of turbulence [START_REF] Tanahashi | CH double-pulsed PLIF measurement in turbulent premixed flame[END_REF]. Results from DNS simulations on a turbulent premixed H2-air flame also revealed that these isolated pockets are threedimensionally connected to the unburned zone by a flame structure called "handgrip" [START_REF] Nada | Effect of turbulence Characteristics on lacal structure of H2-air premixed flames[END_REF]. This three-dimensional handgrip structure was confirmed experimentally in the case of relatively high Reynolds number turbulent jet premixed flames [START_REF] Ueda | Measurement of threedimensional flame structure by combined laser diagnostics[END_REF]. The flow structure and the occurrence of a pair of counter-rotating vortices from either side of the incoming jet interacting with the flame front were responsible for the pinch-off of the flame, leading to the generation of unburned pockets. It is worth noting that this mechanism was numerically studied for academic gaseous premixed flame [START_REF] Peters | Laminar flamelet concepts in turbulent combustion[END_REF][START_REF] Poinsot | Quenching process and premixed turbulent combustion diagrams[END_REF] and spray flame configurations by [START_REF] Franzelli | Characterizing the regimes of spray flame-vortex interactions : a spray spectral diagram for extinction and re-ignition[END_REF]. It was demonstrated that vortices with sufficient intensity can pass through the flame front and remove an oxidizer pocket on the spray side.

However to the best of our knowledge, no detailed experimental data are available to understand the flame-flow interactions leading to the penetration of such large-scale unburned pockets into the exhaust gases. To overcome this lack of information, their surface was initially estimated by the data processing tool already described and used to determine the flame contour. Assuming that the unburned pockets are threedimensional, an average diameter of 9 mm with a standard deviation of 3.9 mm was estimated. This diameter is comparable to the integral length scale of 11 mm that was obtained from the data processing of the instantaneous 2D velocity fields.

To gain deeper insight into the formation of unburned pockets in IRZ, the dynamics of formation of these unburned pockets was then experimentally investigated by performing time-evolving combined OH-PLIF and PIV measurements. All the results of these experiments are now detailed in the next section.

Dynamics of flame/flow interactions

Experiments were focused in a region located between z/D=1 and z/D=2.5 in which flame pinching phenomena with similar time evolutions are often observed. To illustrate their mechanism of formation, Fig. 14 displays successive instantaneous OH-PLIF images recorded with a time interval of 0.1 ms. The OH-PLIF images presented in Fig. 14a-d are superimposed with the streamlines obtained from high-speed PIV measurements. Complementary to these data, Fig. 14e-f shows the vorticity fields deduced from the POD filtering of the instantaneous flow velocity distributions recorded at 5 kHz as well as their associated streamlines. The interface separating the fresh gases from the burnt gases was calculated using the processing tool detailed in section 2.3.1 and results are plotted on each image. Analysis of the time evolution of the flame pinching starts at the reference time t = 0 ms (Fig. 14a). This physical process is initiated when the fresh reactants transported at high velocity impact the lower part of IRZ. As supported by the large OH signals detected in Fig. 14a, the reaction zone is mainly located on the right side of the reactant jet and to a lesser extent on the upper part of the incoming reactant jet. Furthermore, the vorticity map (Fig. 14e) calculated from the velocity field displayed in Fig. 14a highlights islands of large vorticity that reveals the location of counter-rotating vortices between the reactants and the burnt gases circulating in IRZ. These vortices shown schematically on Fig. 14e contribute then to the production of SL along the contours of the reaction jet. At t = 0.1 ms, both sides of the reactant jet are slightly tightened by the stretching and the movement in opposite directions of vortices. The reaction zone is still maintained on the right side of the reactant jet (Fig. 14b). The velocity field recorded at t = 0.2 ms (Fig. 14c) and the POD-reconstructed vorticity fields (Fig. 14f) indicates that the two vortices are convected further downstream, rapidly pushing part of the reactants into the burnt gas region. At the same time, a careful examination of the POD-reconstructed vorticity field image (Fig. 14f) also indicates the emergence of a second set of vortices on the left and right edges of the reactant jet, thus deflecting the streamlines in the bottom part of the investigated region. At t=0.3 ms (Fig. 14d), these effects, combined with a stretch generated by the vortices cause a separation of a large pocket of reactants from the bulk of the fresh gases. This pocket is then convected and diluted at high velocity through the burnt gases without burning. On the contrary, the reaction zone on the right side continued and even intensified since the roll-up of the flame front induced by vortices enables larger strain rates; the reaction rate is then intensified following the convection and diffusion of the reactants through the flame front. This effect makes it effective the penetration of the reactant flow through the braid of the vortex, offering physical conditions similar to those encountered in the vicinity of a stagnation point.

In particular, as the velocity of the reactants is nearly equal to zero, the heat release transferred to the reactants by hot gases through the roll-up in the vortex is then significantly increased, giving rise to favourable conditions for their ignition [START_REF] Stöhr | Transient effects of fuel-air mixing in a partially-premixed turbulent swirl flame[END_REF].

This investigation of the flame splitting is partial, since the out of plane component of velocity is unknown, making it impossible to accurately evaluate the gradient in the third direction. However, as demonstrated in the current study, for most of the timeseries of measurements, it is possible to track the temporal evolution of the flame front and an analysis of these data reveals in many occasions this sequence of flame pinching, consolidating then this analysis.

Conclusions

A gas turbine model combustor equipped with an industrial lean premixed fuel injection system and supplied by liquid kerosene was experimentally investigated.

Non-intrusive laser diagnostics were applied in operating conditions representative of the ones encountered in real aeronautic propulsion systems, i.e. with a high swirl number (larger than 0.62 in the current study) and elevated inlet fresh gas velocities (∼ 120 m/s). First, the interaction between the flame structure and the aerodynamic conditions were studied by PIV and OH-PLIF. The mean velocity and the flame shape distributions are typical of those encountered in confined swirled flames with the production of intense outer recirculation zones located on the corners of the combustion chamber and an inner recirculation zone located at the center of the reactive flowfield. This inner zone contributes to stabilizing the flame by the transporting hot products to the base of the fuel spray. Data processing of the strain rate and vorticity fields highlighted the existence of two shear layers that interfere differently with the inlet air/fuel mixing jet. The inner shear layer between IRZ and the fresh inlet flow that is not anchored to the injection system is developed at the upper base of the fuel spray. The growth rate of the shear layer is then governed by the high level of turbulence that promotes, over a large three-dimensional zone the mixing of the fresh incoming products with hot products circulating in IRZ. The existence of a good mixing with a high level of local temperature in ISL provide favorable ignition conditions as well as the production of a flame front with an intense chemical reaction as noted from the large OH-gradient signals measured. On the contrary, the shear layer located between ORZ and the fresh incoming flow is mainly governed by a Kelvin-Helmholtz instability mechanism. This shear layer, anchored on the external corner of the injection system, develops spanwise-oriented vortices with a growth rate as a function of the free stream speed ratio (fresh incoming reactants and the flow circulating inside the ORZ). Data processing of the OH-PLIF images into OHgradient distributions shows that these structures result in curvature induced stretch flames that reduce the mixing between the fresh reactants and combustion products.

Added to this, heat transfer between the combustion products circulating in ORZ and the combustor walls also leads to significant heat losses that reduce the local temperature and hence the burning of the fresh gases close to the ORZ frontier.

1 Experimental 1 :

 11 Investigation of Aerodynamics and Structure of a Swirl-Stabilized Kerosene Spray Flame with Laser Diagnostics. P. Malbois 1, 2* , E. Salaün 1, 3* , A. Vandel 1 , G. Godard 1 , G. Cabot 1 , B. Renou 1 , A. M. Boukhalfa 1 , F. Grisch 1 Normandie Univ., INSA Rouen, UNIROUEN, CNRS, CORIA, Rouen 76000, France 2 : SAFRAN Tech, Paris-Saclay, France 3 : SAFRAN Aircraft Engines, Moissy-Cramayel, France 1 Introduction

  Fig. 2b. The high-speed OH-PLIF system consisted of an Nd-YAG laser operating at 527 nm, generating laser pulses at a repetition rate of 10 kHz and delivering an average power of 105 W. The resulting green laser pulses pumped a tuneable dye laser (Sirah Credo with a mixing of Rhodamine 590 and ethanol) that produced at 10 kHz ∼ 350 µJ/pulse with a 20 ns pulse duration. The laser wavelength was tuned to the Q1(5) rotational line. This wavelength was controlled using OH fluorescence signals recorded in a laminar CH4/air flame. The UV laser beam was superimposed with the PIV laser beams, using a dichroic mirror and was expanded through a set of fused silica lenses ( = 1000 , = -20 , = 500 ) to form a 50 mm tall planar light sheet. OH fluorescence signals were collected with an intensifier (High-Speed IRO, LaVision) coupled with a high-frame rate CMOS camera (Fastcam SA5) operating with a 896 × 848 pixel resolution. A 100 mm, f/2 UV objective lens (B. Halle Nachfl.

Fig. 3b in

  Fig. 3b in which the OH flame contours deduced from non-filtered and filtered instantaneous OH fluorescence images are compared. It can be seen that the detection contour based on the Otsu's method on non-filtered OH images fails in regions with low SNR (red lines at the top of Fig 3b). Indeed, the application of the Otsu's method on weak signals in which gradients are difficult to isolate does not significantly reduce the blurring at edges. On the contrary, the filtered OH image enhances the contrast of the OH signals, this enabling unambiguous detection of the contour between the burned gases and fresh gases.

2D flow velocity displayed in Fig 7 .

 7 These ones are mainly located in the ISL and OSL regions, zones in which mixing between fresh gases and hot products is highly promoted.Radial velocity flow components were also measured by using stereo-PIV in a crosssection perpendicular to the flow axis. The streamlines of the averaged flow velocity, coloured by the axial flow velocity and the associated TKE are presented in Fig.8a.Results were obtained from the data processing of 250 instantaneous 2D flow velocities recorded at z/D= 1.1. As expected, results demonstrated that the averaged velocity flow and TKE distributions are axisymmetric. The radial profiles (x/D= 0) of the average and RMS values of the three velocity components are also reported in Fig.8b.Measurements show that the flow velocity field presents a high three-dimensional feature since tangential and radial velocity components are of the same order of magnitude. The tangential velocity uy in the ORZ is around 30% larger than the radial velocity ux. On the contrary, the radial velocity component displays a larger value compared to the tangential velocity in the inner flow, in which axial velocity is maximal. This difference of behavior in IRZ and the inner flow highlights the large velocity gradients in ISL.Based on experimental knowledge of the three components of the velocity flow, the aerodynamic Swirl number at z/D = 1.1 was calculated using the following relation:

  Fig. 10 displays the mean vorticity field C D LLLL calculated from the average of 3750 instantaneous vorticity fields. To locate the high vorticity regions in the velocity flowfield, streamlines are added on vorticity maps. The vorticity field appears similar

Figure 11

 11 Figure 11 shows the 2D distribution of the OH* chemiluminescence after an Abel transform downstream from the injector as well as the streamlines of the averaged 2D flow velocity. A false colormap directly correlated to the pixel signal intensity was applied to provide a visual representation of the location of the highest OH* intensity in the reaction zone, and thus indication of the localization of heat release. Therefore, the time-averaged OH* distribution shows a rather V-shape flame with a central region of heat release located between z/D = 0.2 and z/D = 2.7.

  Fig.11. Indeed, it can be seen that the most intense reaction zone occurs at the edge

  Consequently, the flame front developed in OSL is most commonly quenched. A careful analysis of high-speed flow velocity and POD results combined with highspeed OH distributions showed unusual flame pinching mechanisms leading to the release of subsequent unburned pockets propagating in the burned gases.

Fig. 1 .Fig. 2 .Fig. 3 .Fig. 4 .Fig. 5 .Fig. 6 .Fig. 7 .Fig. 8 :Fig. 9 .

 123456789 Fig. 1. (a) Combustion facility equipped with the LP injection system. (b) General schematic of the LP injection system

Fig. 10 .Fig. 11 .Fig. 12 .Fig. 13 .

 10111213 Fig. 10. Mean Out of plane vorticity C D LLLL

Fig. 14 .

 14 Fig. 14. Time sequence of flame splitting event (Left row) OH-PLIF time-series images superimposed with the velocity field coloured by the axial flow velocity. (Right row) Streamlines of POD reconstructed velocity fields coloured by vorticity. Red lines represent the contour of the flame. The schematic positions of vortices are indicated on the vorticity images.

Acknowledgements

The authors are grateful for the financial support of the French aircraft motorist SAFRAN and the French National Research Agency (Industrial Chair PERCEVAL ANR-15-CHIN-0001). We also thank Benjamin Quevreux and Félix Frindt for their technical support.