Anna Tournier

Marlène Murris

Anne Prevotat

Annlyse Fanton

Célia Bettiol

Jean Parinaud
email: parinaud.j@chu-toulouse.fr

Prof J Parinaud

Fertility of women with cystic fibrosis: a French survey

Keywords: Cystic fibrosis, women fertility, pregnancy, live birth

Even though the impact of cystic fibrosis (CF) on male fertility is well known, very few studies have investigated its effect on women fertility. In order to evaluate the fertility status of women with cystic fibrosis a questionnaire was sent to 220 women with cystic fibrosis. The questions concerned their desire to become a parent, achievement or not of a pregnancy, the time to became pregnant, the way to obtain pregnancy (spontaneously or with medical assistance) and the outcome of the pregnancy.. Ninety eight patients responded to the questionnaire. Twenty-five (54%) had at least 1 live birth without treatment, while 11 (24%) required infertility treatment to obtain a live birth and 10 (22%) had no delivery. The mean time to pregnancy was 12 months . The reasons for preferring not to be pregnant were mainly the fear of the interaction between CF and pregnancy and of the transmission of CF to children. Fertility seems to be slightly impaired in CF women since 37% of them failed to become pregnant without medical assistance.

Since the outcome of pregnancies appears normal, patients should be informed of the possibility of becoming mothers and be made aware of the risk of unwanted pregnancies.

Introduction

Cystic Fibrosis (CF) is a chronic disease marked by multiple-organ failure, with a prognosis that historically is very unfavourable. However, improvements in the screening and care of the disease in recent years has brought about a much better life expectancy since it is estimated at over 40 years in most western countries [START_REF] Salvatore | An overview of international literature from cystic fibrosis registries. Part 4: update 2011[END_REF]. In this context of an enlarging adult population, questions regarding parenthood become legitimate and more and more common.

Pregnancies are observed in women with CF, and the knowledge regarding management, progression, and problems arising from pregnancy are more and more complete, with quite a few recent studies on this topic [START_REF] Burden | Current pregnancy outcomes in women with cystic fibrosis[END_REF][START_REF] Thorpe-Beeston | The outcome of pregnancies in women with cystic fibrosis--single centre experience 1998-2011[END_REF], as well as a practical guide established by the team of [START_REF] Edenborough | Guidelines for the management of pregnancy in women with cystic fibrosis[END_REF][START_REF] Edenborough | Guidelines for the management of pregnancy in women with cystic fibrosis[END_REF]. When a pregnancy is planned with a complete preconception workup and contraindications are respected, pregnancies in women with CF turn out well in most cases [START_REF] Edenborough | Women with cystic fibrosis and their potential for reproduction[END_REF][START_REF] Boyd | Fertility and pregnancy outcomes in men and women with cystic fibrosis in the United Kingdom[END_REF]. The obstetric complications that are more common than in the general population are diabetes (pre-existing or gestational) as well as the risk of a premature birth [START_REF] Patel | Medical and obstetric complications among pregnant women with cystic fibrosis[END_REF]. There is no increase in other gestational or obstetric complications [START_REF] Patel | Medical and obstetric complications among pregnant women with cystic fibrosis[END_REF][START_REF] Girault | Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis--A single centre case-control study[END_REF]. Furthermore, pregnancy does not appear to be a factor leading to mortality in those with CF, with studies following women for up to 10 years postpartum [START_REF] Goss | The effect of pregnancy on survival in women with cystic fibrosis[END_REF][START_REF] Ahluwalia | Cystic fibrosis and pregnancy in the modern era: a case control study[END_REF]. Neonatal results are also reassuring [START_REF] Girault | Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis--A single centre case-control study[END_REF].

The impact of CF on fertility is well known in men, since most of them (>95%) have congenital bilateral absence of vas deferens (CBAVD), which makes them sterile [START_REF] Popli | Fertility issues in men with cystic fibrosis: survey of knowledge and opinion of patients[END_REF]. Concerning women fertility, even if pregnancies have been reported, there is only one study, published in 1995, which reported in a cohort study among 55 CF women a 67% clinical pregnancy rate [START_REF] Sawyer | Reproductive health in young women with cystic fibrosis: knowledge, behavior and attitudes[END_REF]. Therefore, there is a lack of knowledge for patients and their parents on their fertility [START_REF] Korzeniewska | Sexual and reproductive health knowledge in cystic fibrosis female patients and their parents[END_REF].

The aim of the present study was to evaluate, through a questionnaire, the fertility of CF women and the information they have received on this subject.

Materials and Methods

This is a multicentric observational study conducted between March 2016 and September 2018 in the CRCM [French acronym: Cystic Fibrosis resource and competence center] for adults of the university hospital of Toulouse (48; 49%), Lille (40; 41%) and Dijon (10; 10%).

The population involved was women CF patients, over 18 years old, who accepted to participate in the study after an informed consent.

The patients received a first information sheet on the methods and aims of the study and later received a questionnaire. If they wished to participate in the study, they returned the questionnaire complete with their written and signed consent. A phone call reminder was made to patients who did not respond.

The questionnaire included 12 questions regarding: Marital status; Gynecological life: age at menarche, gynecological history, periods, contraception.

Attempts to become pregnant, healthcare, problems, and the time-to-pregnancy (time elapsed between the termination of contraception for a pregnancy desire and the onset of pregnancy , with regular sexual intercourses).

Pregnancy outcomes

The roadblocks to the desire to become pregnant.

The information they received and desired concerning the possibilities of parenthood.

We received approval from the Research Ethics Committee of the Toulouse university hospital.

Statistical analyses were performed using StatView software (Abacus Concepts Inc., Berkeley, CA). Data are means ± SD or medians [range] according to their distribution.

The study was approved by Toulouse University Hospital's Clinical Research Ethics Committee. No funding was obtained for this study.

Results

Demographic data

We sent the questionnaire to 220 CF women and received 98 responses (45%).

The average age of the population was 33.7 ± 13.0 years. 70 patients (71%) were in a relationship. The median age at the first menses was 14 years [10][11][12][13][14][15][16][17][18][19][20][21].

Forty-five patients used contraception: 25 women used oral contraception (56%), 17 women had an intrauterine device (38%) 1 woman had a tubal ligation (2%), 2 women used condoms exclusively (4%). No woman used contraceptive implant in our population.

Fertility data (Figure 1)

Among the 46 CF women who wanted and sought a pregnancy, 40 (87%) had at least one pregnancy, and 36 (78%) had delivered at least once. The median time-to-pregnancy was 12 months [range: 1-180].

Seventeen (17/46: 37%) had no spontaneous pregnancy, from whom 13 (76%) had infertility treatment and 11 (85%) were successful.

Four patients (4/10: 10%) who had a spontaneous pregnancy never carried a pregnancy to term due to early spontaneous abortions.

Three patients had unwanted pregnancies, and had 4 induced abortions (one had a further wanted spontaneous pregnancy).

Out of the 77 wanted pregnancies, 61 (79%) resulted in live birth, 15 (19%) in spontaneous miscarriage and 1 (1%) in induced abortion due to a fetal abnormality.

Of all 61 pregnancies resulting in live births: the delivery term was 38.3 ± 3.5 gestational age, the birth weight was 2,847g ± 731g, the method of delivery was vaginal 84% (spontaneous or with instrumental extraction) and cesarean 16%.

Reasons for not wanting a pregnancy

Out of 52 patients, who did not want to be pregnant, 27 (52%) gave the reasons for their absence pregnancy wish. Thirteen (48%) feared that a pregnancy could aggravate the disease, 11 (41%) were afraid of a negative impact of the CF on pregnancy outcomes and 9 (33%) did not want to risk of transmitting the disease to their children. Moreover, 10 (37%) preferred to avoid childhood due to their uncertain future.

Discussion

Our results show that CF patients have a slightly reduced fertility since, despite 3 patients who had unwanted pregnancies, 37% failed to conceive spontaneously. The prevalence of subfertility has been reported from 10% to 24% in the general population [START_REF] Thonneau | Incidence and main causes of infertility in a resident population (1,850,000) of three French regions (1988-1989)[END_REF][START_REF] Slama | Time to pregnancy and semen parameters: a cross-sectional study among fertile couples from four European cities[END_REF][START_REF] Gnoth | Definition and prevalence of subfertility and infertility[END_REF][START_REF] Thoma | Prevalence of infertility in the United States as estimated by the current duration approach and a traditional constructed approach[END_REF]. Moreover, the median time-to-pregnancy was 12 months which was particularly long since the definition of moderately or seriously subfertility is 12 unsuccessful cycles [START_REF] Gnoth | Definition and prevalence of subfertility and infertility[END_REF]. However, the fertility of CF women is far from that of CF men, since the latter are sterile while the former have only an increase in subfertility [START_REF] Popli | Fertility issues in men with cystic fibrosis: survey of knowledge and opinion of patients[END_REF]. This increase in subfertility can be due to an impaired nutritional status often found in CF women [START_REF] Calella | Cystic fibrosis, body composition, and health outcomes: a systematic review[END_REF], which is well known to have a great impact on fertility [START_REF] Pinelli | Nutrition and fertility[END_REF].

The spontaneous abortion rate (18%) was in the range of that reported in the general population (15 to 20%) [START_REF] Jauniaux | The role of ultrasound imaging in diagnosing and investigating early pregnancy failure[END_REF][START_REF] Blohm | A prospective longitudinal population-based study of clinical miscarriage in an urban Swedish population[END_REF]. Our results are in good agreement with those reported by [START_REF] Gillet | Cystic fibrosis and pregnancy. Report from French data[END_REF]Thorpe-Beeston et al. (Gillet et al., 2002, Thorpe-Beeston et al., 2013) with a miscarriage rate similar to the one of the general population. On the opposite, Epelboin et al. have reported 3 miscarriages out of 7 pregnancies obtained by ART [START_REF] Epelboin | Indications and modalities of assisted reproductive techniques in infertile women with cystic fibrosis[END_REF].

Premature delivery (<37 weeks of gestation; 19%) and low weight babies (<2500g; 16%) appeared to be higher than in the total French population (7.5%) [START_REF] Blondel | Trends in perinatal health in metropolitan France from 1995 to 2016: Results from the French National Perinatal Surveys[END_REF]. Low weight and unbalanced diabetes (hyperglycemia in preconception phase) of CF women could explain these findings (Steegers-Theunissen, 1995, Triunfo and[START_REF] Triunfo | Impact of maternal under nutrition on obstetric outcomes[END_REF]. However, the average delivery term and average birth weight were reassuring, also in agreement with the literature, which confirmed the good obstetric and neonatal results of the pregnancies well followed [START_REF] Gillet | Cystic fibrosis and pregnancy. Report from French data[END_REF][START_REF] Goss | The effect of pregnancy on survival in women with cystic fibrosis[END_REF][START_REF] Thorpe-Beeston | The outcome of pregnancies in women with cystic fibrosis--single centre experience 1998-2011[END_REF][START_REF] Ahluwalia | Cystic fibrosis and pregnancy in the modern era: a case control study[END_REF].One surprising result was the significant number of patients who did not want to have a child for fear of aggravating their disease during pregnancy or for fear of a pregnancy disease connected to their disease. These fears seem unjustifiable since the studies on these subjects are very reassuring [START_REF] Patel | Medical and obstetric complications among pregnant women with cystic fibrosis[END_REF][START_REF] Girault | Maternal and perinatal outcomes of pregnancies in women with cystic fibrosis--A single centre case-control study[END_REF]. When asked about the quality of information received on this issue, it appeared satisfactory when it originated from a CF specialist but unsatisfactory from a gynecologist. Patients must correctly be informed about their fertility to avoid unwanted pregnancies and about the interactions of CF and pregnancy (Kazmerski et al., 2017a, Kazmerski et al., 2017b).

New therapies regulating the cystic fibrosis transmembrane conductance regulator (CFTR) such as ivacalfor alone or in association with lumacaftor, have provided real benefits for the health of CF patients [START_REF] Ratjen | Efficacy and safety of lumacaftor and ivacaftor in patients aged 6-11 years with cystic fibrosis homozygous for F508del-CFTR: a randomised, placebo-controlled phase 3 trial[END_REF]. However, their effects on pregnancy outcomes and on the fetus remain unknown, so that they cannot be used during pregnancy, making more difficult the decisions for being pregnant [START_REF] Kroon | Drugs during pregnancy and breast feeding in women diagnosed with Cystic Fibrosis -An update[END_REF].

The main limitation of this study is the lack of genetic data and we cannot exclude that the results could be different among the various mutations. Moreover, the health status at the time of trial to become pregnant was not known. Since only 45% of patients have answered the questionnaire, we cannot be sure that these results are the actual reflect of the fertility status of the whole CF patients. These limitations are due the fact that the study was based on self-administrated questionnaire, and thus the best way to explore this topic would be the follow-up of a prospective cohort of CF women desiring to become pregnant.

Conclusion

Our study emphasizes the need for CF women to be informed regarding their fertility and the outcome of their pregnancies of CF women. These patients must benefit from a early collaboration between CF specialists and ob/gyn to ensure an optimal fertility care. Taking together the fertility and pregnancy data, CF women who desire motherhood must be aware of the importance of their nutritional status to insure an optimal fertility and a good pregnancy outcome.

Figure 2 .

 2 Figure 1. Flow chart of the main responses to the questionnaire


Francis Bonnet

Hôpital Tenon

RUBRIQUE JUDICIAIRE La péridurale n'est pas responsable de tout ! Epidural analgesia does not plead guilty

Keywords: accouchement, lombalgies, analgésie péridurale, epidural analgesia

l'analgésie péridurale n'est pas un facteur de risque de lombalgies chroniques post accouchement, elle est donc sans lien de causalité avec ces symptomes. Les lombalgies du post-partum ne peuvent donc pas être considérées non plus comme un aléa de la péridurale. Les facteurs de risque sont liés à la durée du travail obstétrical, l'âge des parturientes et aux antécédents de lombalgies.

Summary : Epidural analgesia is not responsible for chronic low back pain after delivery. There is no relationship between epidurals and the occurrence of such a complication. Post delivery back pain is no more a hazard of epidurals. Risk factors are the duration of labour, the young age of parturients and a previous history of low back pain.

Mots clés :

médecin anesthésiste a fait appel à l'échographie pour s'aider à repérer l'espace péridural. Bien qu'il n'existe pas (encore) de recommandation sur ce point on ne peut que féliciter cette approche dans un contexte où l'obésité rend la réalisation de la péridurale plus difficile mais où l'obtention d'un péridurale fiable est importante, compte tenu du risque augmenté de passage en césarienne (du fait du risque de dystocie qui n'était pas présent dans le cas évoqué). L'échographie du rachis est une pratique difficile qui nécessite un apprentissage. Pour pouvoir bénéficier de l'aide de l'échographie dans les situations compliquées, il est important de s'être formé auparavant dans des situations simples. Les praticiens ne font pas toujours cette démarche du fait de leur maitrise de la péridurale « à l'aveugle » et éventuellement de l'absence de disponibilité immédiate de l'échographie. Cependant, cette technique pour l'instant limitée à l'écho-repérage de l'espace péridural, mériterait d'être plus répandue.

2

  Une femme de 38 ans, mène une sixième grossesse dans des conditions normales. Elle présente cependant une obésité morbide avec un index de masse corporelle à 53 (145kg pou 1m65). Elle est également atteinte d'un diabète insulino-requérant. De ce fait, il est décidé de déclencher l'accouchement à 38 semaines. Dans ce contexte il lui est proposé une analgésie péridurale durant le travail. La mise en place de la péridurale est réalisée en position assise et se révèle difficile du fait de l'obésité. Une première et une deuxième tentative sont infructueuses. Ces tentatives déclenchent quelques paresthésies dans le membre inférieur gauche. L'anesthésiste en charge décide donc d'effectuer une échographie de repérage qui localise l'espace péridural à 13 cm et permet de préciser avec certitude le niveau de ponction en L4-L5. La réalisation de la tentative suivante est un succès, un cathéter est mis en place et une solution analgésique contenant 5 mcg de sufentanil, 20 mg de ropivacaine et 60 mg de lidocaine, est injectée avec pour conséquence une parésie des membres inférieurs et une bonne analgésie. Le travail obstétrical se déroule sans problème et l'accouchement a lieu deux heures plus tard sans qu'il ait été besoin de réinjecter dans la péridurale. Après avoir quitté la salle de travail, la parturiente peut se lever et s'occuper de son nouveau-né sans problème. Un mois plus tard elle ressent en se levant des lombalgies de forte intensité. Les douleurs lombaires irradient dans le membre inférieur gauche selon une topographie L5. Malgré un traitement antalgique associant paracétamol et codéine, prescrit pas son médecin généraliste, les douleurs persistent pendant plusieurs mois selon les dires de la patiente et la conduisent à entreprendre une action en justice car elle fait le lien entre les lombalgies et la sciatalgie, et la réalisation de la péridurale. Dans le bilan des douleurs lombaires, elle est amenée à faire une IRM lombo-sacrée qui objective un spondylolisthesis antérieur de L5 sur S1 par lyse isthmique bilatérale. En L4-L5 il existe une saillie discale focale postéro-latérale gauche, conflictuelle avec l'émergence de la racine L5 gauche. En L5-S1 il existe un conflit disco-radiculaire sur les deux racines L5 dans leur passage foraminal qui est très réduit du fait du spondylolisthésis. Lors de la réunion contradictoire avec l'ensemble des parties, l'examen clinique neurologique de la patiente plaignante n'objective aucun déficit sensitif ou moteur. Les experts expliquent donc l'absence de relation entre l'anesthésie péridurale et la survenue ultérieure des lombalgies-sciatalgies, en rapport avec une dégénérescence discale favorisée par le surpoids. La tentative de lien entre la réalisation d'une péridurale pour le travail obstétrical et la survenue de lombalgies en post-partum, n'est pas nouvelle. Ce lien a été évoqué au début des années 90 dans un article de Mac Arthur et coll., basé sur l'envoi d'un questionnaire adressé à plus de 3000 femmes ayant accouché 2 ans et 9 ans plus tôt (1). Il s'explique par deux considérations : d'une part les patientes rapportent d'autant plus facilement leur symptomatologie à la péridurale que celle ci ne s'est pas déroulée facilement et a pu occasionnellement provoquer des douleurs locales ou référées ; d'autre part la période du post-partum est une période à risque pour la survenue de lombalgies, comme d'ailleurs la période de la grossesse. Le sujet a fait couler beaucoup d'encre d'autant que les lombalgies sont fréquentes aussi bien durant la grossesse que dans le post-partum. En 1997, c'est un autre Mac Arthur et ses collaborateurs qui concluaient à l'absence de relation entre la réalisation d'une péridurale et la survenue de lombalgies en postpartum (2). Cette affirmation reposait sur le suivi prospectif à un an, d'une cohorte de 329 femmes dont la moitié avait eu une péridurale au cours de l'accouchement. L'incidence de lombalgies était la même dans les deux groupes (respectivement 10% et 14% chez les femmes ayant eu ou non une péridurale). Cette étude a été confirmée par des études prospectives de cohorte et d'autres études randomisées. En revanche, l'existence de lombalgies au cours de la grossesse, une durée prolongée du travail et le jeune âge des parturientes sont des facteurs de risque reconnus de lombalgie dans le postpartum (3). Vingt ans plus tard, Benzon et coll. ont fait le point dans le contexte non plus obstétrical mais des patients anesthésiés pour une intervention chirurgicale (4). Ils ont conclu que l'incidence des lombalgies était comparable après une anesthésie générale ou péridurale, et que les facteurs de risque de développer des lombalgies incluaient notamment la position de lithotomie, la durée de la chirurgie, et les antécédents de lombalgie. D'un point de vue médico-judiciaire, le fait que l'analgésie péridurale puisse être un facteur de risque de lombalgies (ce qui n'est donc pas démontré) n'entrainerait pas forcément la condamnation des praticiens. Il faudrait pour cela que la patiente n'en ait pas été informée et que le geste ait été réalisé d'une façon non conforme par rapport aux bonnes pratiques cliniques. Dans le cas présent, il faut noter que le


Nicolas Monnier

David Guibert

Cyril Tasse

Nicolas Gac

Franc ¸ois Orieux

Erwan Raffin

Oleg M Smirnov

Benjamin V Hugo

Multi-core multi-node parallelization of the radio interferometric imaging pipeline DDFacet

Keywords: HPC, DDFacet, Parallelization, Distributed memory, SKA

The next generation of radio telescopes, such as the Square Kilometer Array (SKA), will need to process an incredible amount of data in real-time. In addition, the sensitivity of SKA will require a new generation of calibration and imaging software to exploit its full potential. The wide-field directiondependent spectral deconvolution framework, called DDFacet, has been successfully used in several existing SKA pathfinders and precursors like MeerKAT and LOFAR. This imager allows a multi-core execution based on facets parallelization and a multinode execution based on observations parallelization. However, because of the amount of data to be computed, the data on a single observation will have to be distributed on several nodes. This paper proposes the first two-level parallelization of DDFacet in the case of a single observation. A multi-core parallelization based on facets and a multi-node parallelization based on frequency distribution grouped in Measurement Sets. We show that this multi-core multi-node parallelization has successfully reduced the total execution time by a factor of 5.7 on a LOFAR dataset.

I. INTRODUCTION

The Square Kilometer Array (SKA) is one of the World's largest science projects [START_REF] Acero | French SKA White Book -The French community towards the Square Kilometer Array[END_REF]. Besides building a radio telescope observatory to make fundamental discoveries about the universe over the next 50 years with the broadest range of science of any facility worldwide, it is also the largest Big Data project and the largest international computing collaboration. With thousands of dishes and millions of antennas, the SKA equipment will generate an unprecedented amount of data. The equipment will be built in South Africa's Karoo region and Western Australia's Murchison Shire. Processing the vast quantities of data produced by the SKA will require highperformance central supercomputers capable of more than 100 petaflops of raw processing power. The data computations will start on-site and be distributed all over the World.

As an intermediate step towards SKA, MeerKAT or LOFAR are radiotelescopes already operational, delivering real data to process [START_REF] Smirnov | Modern radio interferometric imaging challenges: From meerkat towards the ska[END_REF]. The raw data provided by MeerKAT in a few hours involves the computations unprecedent amount of data. Compared with previous generation of radio telescopes, MeerKAT and LOFAR show that this new generation must consider direction-dependent signal distortions (DDEs), such as ionospheric distortion or antenna beams, in computing data to benefit from the telescope sensitivity.

Each antenna's pair is defined as a baseline (physical distance between the antennas). Each baseline, at a time t and frequency ν generates a sample by correlating the voltages of these two antennas. This measurement is called visibility. These antennas are combined into a single virtual telescope using a mathematical approach called aperture synthesis [START_REF] Brouw | Aperture synthesis[END_REF]. This technique makes images of high resolution and high sensitivity that a single extremely large receiving element could not make. However, it is also computationally intensive, with a complexity dependent on the number of visibilities generated by the radio interferometer and the quality of the desired result.

An imaging pipeline is composed of many algorithmic bricks that are easily differentiated from each other. Those responsible for the interpolation of data, applying at the same time direction-dependent corrections, called gridding and degridding, are the most expensive. Tasse [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF] has shown that they can reach 80% of the total execution time. There is a lot of literature about how to reduce this computation time. On the side of the standard methods, we find computation optimization on CPU parallelization [START_REF] Barnett | A parallel non-uniform fast Fourier transform library based on an "exponential of semicircle" kernel[END_REF], as well as GPU and multi-GPU parallelization [START_REF] Romein | An efficient work-distribution strategy for gridding radiotelescope data on GPUs[END_REF], [START_REF] Merry | Faster GPU-based convolutional via thread coarsening[END_REF]. At the same time, some methods allow reducing the memory consumption linked to these methods [START_REF]Approximating W projection as a separable kernel[END_REF]. The literature also proposes alternative methods, such as Image Domain Gridding (IDG), allowing to speed up the computation while keeping a high accuracy in the results [START_REF] Van Der Tol | Image domain gridding: a fast method for convolutional resampling of visibilities[END_REF]. We also find the implementation of these methods on accelerator platforms such as the GPU or FPGA [START_REF] Veenboer | Image-domain gridding on graphics processors[END_REF], [START_REF] Veenboer | Radio-Astronomical Imaging: FPGAs vs GPUs[END_REF].

Because of the large amount of data to be processed by current radio telescopes, computational methods have to be integrated on a larger scale by complete imaging pipelines. The main reference is CASA (Common Astronomy Software Applications) [START_REF] Jaeger | The Common Astronomy Software Application (CASA)[END_REF], which was developed to support data postprocessing needs of radio astronomical telescopes such as ALMA and VLA in the 90'. CASA package is also continuously updated to support the most recent scientific advances with the third generation of radiotelescope Imaging. WSClean [START_REF] Offringa | WSClean: an implementation of a fast, generic wide-field imager for radio astronomy[END_REF] is another more advanced imager integrating the IDG algorithm. Both of these pipelines allow a distributed execution using MPI [START_REF] Gropp | Using MPI: portable parallel programming with the message-passing interface[END_REF]. We can also find a pipeline, from the data generation to the image, based on the workflow execution system DALiuGE [START_REF] Wu | DALiuGE: A graph execution framework for harnessing the astronomical data deluge[END_REF], allowing large-scale execution [START_REF] Wang | Processing full-scale square kilometre array data on the summit supercomputer[END_REF]. We can also find imaging pipeline based on the Dask 1 framework, such as Codex-Africanus [START_REF] Perkins | A dask distributed radio astronomy reduction framework[END_REF]. Most of these pipelines and workflows have in common to dispatch computationnaly intensive jobs such as gridding, degridding and FFT.

A new generation of calibration and imaging algorithms, also called the 3rd generation of calibration and imaging [START_REF] Parekh | Third-Generation Calibrations for MeerKAT Observation[END_REF], is implemented in DDFacet 2 (Direction Dependent Facet) framework to compensate and correct the DDEs. This paper presents the first two-level parallelization paradigm for the DDFacet imager to distribute the computation of observation over multi-core and multi-node. The first level of parallelization uses Concurrent Futures for multi-core parallelization on a shared memory system [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF]. The second level allows multinode parallelization on a distributed or shared memory system. The challenge is to distribute data and computations on the distributed memory architecture of a multi-node HPC system, especially when addressing the balance between data transfers between compute nodes and performance.

The layout of this paper is as follows. An overview of DDFacet and radio interferometry is given in section II. The shared and distributed memory parallelization scheme we implemented is described in section III. The experiments we performed and the associated results are presented in section IV. Finally, the conclusion and future work is found in section V.

II. DDFACET AND RADIO INTERFEROMETRY IMAGING

This section describes the mathematical basis of radio interferometric imaging, taking into account direction-dependent effects. In a second step, we present DDFacet, an imaging pipeline that considers these effects.

A. Radio Interferometry Imaging

An interferometer array is a network of antennas and dishes distributed spatially on earth (or space). Each antenna's pair is defined as a baseline (physical distance between the antennas). Each baseline, at a time t and frequency ν generates a sample by correlating the voltages of these two antennas. This measurement is called visibility. For a non-polarized interferometer, the number of visibilities generated is: N vis = nb baseline x t integ x nb channel, where t integ is the number of sample for one baseline during the integration time, nb channel is the number of frequency channel.

The Radio Interferometric Measurement Equation (RIME [START_REF] Smirnov | Revisiting the radio interferometer measurement equation. i. a full-sky jones formalism[END_REF]) describes the relationship between the sky model and the various direction-dependent and direction-independent Jones matrices, map to the measured visibilities as a linear transformation. For a given antenna pair pq, at time t and frequency ν, the RIME is :

1 https://dask.org/ 2 https://github.com/saopicc/DDFacet V meas pq,tν = G ptν D ptν,s K p,s x s K H q,s D H qtν,s ds G H qtν + ϵ (1)
where G ptν is the 2x2 direction-independent Jones matrix for the antenna p, D ptν,s is the 2x2 direction-dependent Jones matrix, K p,s is the effect of the array geometry and correlator and is purely scalar, such as K p,s K H q,s = e -2iπ(ul+vm+w(n-1)) , x s is the four-polarization sky contribution for the direction s = (l, m, n), and ϵ is a 2x2 random matrix following a normal distribution.

If G pq = G *
qtν ⊗ G ptν and J pq,s = D * qtν,s ⊗ D ptν,s are the direction-independent and direction-dependent 4x4 Mueller matrices for the baseline pq, at time t and frequency ν, then eq (1) can be written :

V ec(V meas pq,tν ) = G pq D pq,s V ec(x s )e -2iπ(ul+vm+w(n-1)) +ϵ (2)
where V ec() is the vectorization operator and ⊗ the Kronecker product. The effects in G pq describe the direction-independent effects such as the individual station electronics or their clock drifts and offsets. The effects in D pq,s describes the DDE, which include the ionospheric effect such as the Faraday rotation or phase shift, and the phased array station's beam that depend on time, frequency and antenna.

From eq (2), if the W -term (e -2iπw(n-1) ) and the DDE (J pq ) are not taken into account, the relation between the sky and the visibilities becomes a Direct Fourier Transform (DFT). Since the cost of the DFT, O(N vis N 2 pix ), becomes quickly prohibitive, we rather use the Fast Fourier Transform (F F T ) algorithm (O(N 2 pix logN pix )). However, the visibilities are not sampled on a uniform grid, which is mandatory to use the F F T . In order to generate a sky image, the visibilities are first gridded on a uniform grid by applying a convolution. Then a 2D inverse F F T is performed on the grid to obtain the so-called dirty image y. The w-term and the DDE from eq (2) are taken into account during the gridding step. Similarly, we define degridding as the step to obtain visibilities from the Fourier transform of the discretized sky image.

Usually, a CLEAN major/minor cycle deconvolution algorithm is used to reconstruct the true sky. This kind of algorithm in the case of DDFacet is described in sec III-A.

B. DDFacet

It is extremely challenging to synthesize high-resolution images with the new generation of radio telescopes like LO-FAR or MeerKAT. This latter operates at very low frequency, observing a wide field of view and combining short and long baselines.

The estimation of the true sky I, assuming the Jones terms constant, from Eq (2) is done by the imager DDFacet (Direction Dependant Facet) [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF]. The specificity of the DDFacet framework is to solve the imaging problems due to the DDE by using the faceting approach. The purpose of faceting is to approximate a wide field of view with many small narrowfield images. One independent grid is used per-facet and a constant DDE D pq,sφ (where s φ is the direction of the facet φ) is applied to each facet. Experience shows that we need to split the sky model into a few tens of directions to be able to describe the spatial variation of the direction-dependent Jones matrices [START_REF] Van Haarlem | LOFAR: The LOw-frequency ARray[END_REF]. Moreover, in order to reduce the amount of data to be processed, an averaging of visibilities is performed using the BDA algorithm [START_REF] Atemkeng | Using baseline-dependent window functions for data compression and field-of-interest shaping in radio interferometry[END_REF], [START_REF] Wijnholds | Baseline-dependent averaging in radio interferometry[END_REF]. Depending on the baseline and a decorrelation factor considered acceptable, the visibilities are more or less averaged together.

DDFacet incorporates a few deconvolution algorithms natively incorporated and compensated for the DDE. For instance, one can use the standard Multi-Scale Multi-Frequency (MSMF) CLEAN algorithm. As it is well-known that the CLEAN-like algorithms are not robust in deconvolution of extended emission, the SubSpace Deconvolution algorithm (SSD) is implemented. As described in [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF], one can also find an extension of SSD using a genetic algorithm (SSDGA). For the next of this paper, every mention of the deconvolution algorithm will reference the MSMF described in [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF].

III. PARALLELIZATION

This section describes the parallelization paradigms implemented in DDFacet. First, we will see the simplified sequential algorithm to introduce notations. Then, we will see the multicore parallelization with a modified implementation compared to the native version to simplify the implementation of the multi-node parallelization. Finally, we will see the multi-node parallelization to reduce the latency to generate a reconstructed sky image.

A. Sequential algorithm

The DDFacet imaging algorithm is described by Alg 1. For simplicity, the visibilities of a MS file are represented by v M Sj . The imager is an iterative algorithm going to K major cycles, using J MS files to reconstruct a hypercube x divided into I facets.

B. Multi-core parallelization

In order to facilitate the implementation of the distributed memory parallelization, a new implementation of the multicore parallelization has been made using Concurrent-Futures 3 . This new implementation, following the same parallelization paradigm as the native version [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF], is illustrated in Fig 1 .  In the case of DDFacet, the image is divided into facets whose calculations are independent of each other. Thus each loop implying facets of Alg 1 is parallelized. The parallelization framework is based on an asynchronous behavior between the computational and I/O phases. The main process of the imager manages a bunch of workers, where each worker is a process, depending on the number of cores available or set by the user. The main process then dispatches the different 3 https://docs.python.org/3/library/concurrent.futures.html Algorithm 1: DDFacet sequential imaging pipeline.

Data: ( x, v, I, J, K, PSF) Initialization(v); for k in K MajorCycles do for j in J MS do for i in I Facets do g φi,M Sj = F F T ( x, i, j); v φi,M Sj = Degrid( g φi,M Sj , i, j); end δv M Sj = v M Sj -v M Sj ; for i in I Facets do g φi,M Sj = Grid(δv M Sj , i, j); end end for i in I Facets do δy+ = F F T inv(g φi , i, j); end x = Deconvolution(δy, P SF ); end jobs in a dedicated queue. A compute queue is dedicated for the computational jobs like gridding, degridding, and FFT for each facet φ, and an I/O queue for the I/O relative jobs.

C. Multi-node parallelization with data distribution

The naive multi-node parallelization paradigm used to increase the image production rate is to distribute observation on each node. However, this method, illustrated by Fig 2 , only increases the throughput of image production. Indeed, in the case of a large dataset, each image can take several hours/days to produce. Hence the need to reduce the latency of an image. Our approach, illustrated by Fig 3, distributes the computation of a dataset composed of several MS files on several nodes to generate the corresponding image. The dataset is equally distributed over a number N of nodes to balance the computational load. The nodes gather the necessary metadata after an initialization phase specific to each sub-dataset such as BDA computation and weight computation. After that, the computational core of each node is identical, using the multi-core parallelization described in Sec III-B. The FFT, degridding, and gridding operators will be applied depending on the dataset. After the gridding of all MS for each node, the subgrids g (k)

1..N are transferred and reduced to the master node, also called rank0, such as

g (k) = N i=1 g (k) i (3)
Only the master node is in charge of moving into the spatial domain and applying the deconvolution algorithm to the residual image δy. The resulting hypercube x (k) is then broadcast to all nodes, such that each node receives only the slices whose frequency band is associated with its subset in order to reduce IO communication.

The software implementation has been done in python using the Concurrent Futures interface of mpi4py 4 based on MPI [START_REF] Gonzalez | Python Code Parallelization, Challenges and Alternatives[END_REF]. The master MPI process is in charge of spawning MPI processes on one or several nodes.

Thus, this multi-node implementation makes two levels of parallelism of DDFacet. The first native one is based on facets parallelization and shared memory. The second one is based on Measurement Set parallelization, which allows for a distributed memory system. Moreover, this implementation allows better use of the computational resources within a node. Indeed, when the processor has a large number of cores or when we use few facets to reconstruct an image, such as it results in an under-utilization of the computational resources. Therefore, we can take advantage of this two-level parallelization by spawning several MPI processes per compute node. In this case, each MPI processes share the computation resources equally and is optimal when

I f acets nb cores < 1, (4)
I f acets ( nb cores nb mpi ) ≥ 1. (5)
IV. EXPERIMENTS This experiment aims to show the interest in using a distributed version of DDFacet to reduce the latency to obtain a result. A data set from the LOFAR radiotelescope artificially inflated to obtain 48 MS files for a total of 1.1TB of data is used. The experiments were performed on a BullSequana X400 system based on AMD EPYC 7742 64-Core processor. Each node, a dual-socket, is composed of 256 logical cores.

The purpose of this test case is to reconstruct a 10.000 × 10.000 pixels image after 20000 iterations of MSMF CLEAN, i.e. three major cycles, and the result is shown by Fig 4 . The image is decomposed into 11 × 11 = 121 facets. The intranode multi-core parallelization thus allows using 121 cores of our dual-socket processor. It results in an under-utilization of this processor. Our experiment will use 1, 2, and 4 MPI processes per node to maximize the computational cores' use and study each case's scalability and memory impact. Thus, in the case of one MPI process per node, 256 logical cores are allocated for the MPI process. For two MPI processes per The total execution time and the profiling of the different steps of the algorithm are illustrated by Fig 5. For the case of 1 MPI process on one node, the gridding and degridding steps represent 73%, which confirms the result of [START_REF] Tasse | Faceting for direction-dependent spectral deconvolution[END_REF]. This result highlights the need to distribute this core computation to reduce the total execution time. As expected, the total execution time tends to decrease with distribution on several nodes, demonstrating the interest of this implementation to reduce the latency. In this profiling, we find two types of computational blocks. Blocks with variable computational cost, such as gridding/degridding and initialization, whose computational cost decreases with the distribution on several nodes, following the parallelization scheme presented in Fig 3 . And blocks with a fixed computational cost, such as Deconvolution, or Others, which gather all non-profiled timing, including some I/O and saving times. Additionally, the MPI communication time remains very low but increases with the number of MPI processes. The MPI communication waiting time varies with the balanced distribution of MS files among MPI processes.

The scalability factor of the distributed part on several MPI processes, i.e. the gridding, degridding, and FFT steps depending on the number of nodes used, is defined as

α(p, n) = t p,1 t p,n , (6)
β(p, n) = t 1,1 t p,n . (7)
The speedup reaches an asymptote at 5.3 with a peak for β(1, 16) = 5.7. Moreover, on a lower number of nodes, the higher the number of MPI processes, the higher the speedup.

For instance, on one node β(4, 1) reaches 2.01.

(n) = t 1,n t 4,n . (8)
The gridding speedup remains constant with a factor γ around 2, which demonstrates an improvement of the multicore parallelization. However, the total execution time speedup decreases. We can therefore conclude that the main limiting factor for the reduction of the execution time is the fixed cost times. Finally, We can also observe an increase in memory consumption during gridding and degridding, as indicated by the Tab I. This increase is expected because we load in memory the data necessary for the processing of each MPI process.

V. CONCLUSION AND FUTURE WORK

This paper presents the parallelization of DDFacet, a wideband wide-field spectral deconvolution framework on a distributed memory HPC system.

We have presented a two-level parallelization paradigm with facet-based parallelization for the multi-core shared memory aspect and MS-based parallelization for the multi-node distributed-memory aspect. This implementation allowed for distributing the most expensive computational blocks, such as gridding and degridding, ensuring perfect scalability. Using a LOFAR dataset, the total time to generate a reconstructed image was reduced to a factor up to 5.7. Finally, we showed that this implementation could also improve the multi-core parallelization depending on the number of facets and the processor used. The perspective for the future is to continue working on ways to reduce the execution time. The first track is to apply our multi-node framework to distribute the deconvolution computation on several nodes. Moreover, to optimize the computational load between several nodes because of the compression applied by the BDA algorithm. Finally, to implement optimization for gridding and degridding on accelerator card for DDFacet.

Fig. 1 .

 1 Fig. 1. Multi-core parallelization

Fig. 2 .

 2 Fig.2. Existing DDFacet multi-node parallelization. Each node generates an independent image using different dataset of a specific observation.

Fig. 3 .

 3 Fig.3. Multi-node and multi-node parallelization based on independent MS files using distributed memory system.

Fig. 4 .

 4 Fig. 4. Left : Dirty Image. Right : Restored image after 20.000 iterations of MSMF Clean.

Fig. 5 .

 5 Fig.5. Profiling of the master MPI process for a complete execution regarding the number of MPI processes per node (1, 2, and 4), and the number of nodes used for the parallel execution.

Fig. 6 .Fig. 7 .

 67 Fig.6. Scaling of the gridding/degridding using one MPI per node.

8 .

 8 Total execution time SpeedUp regarding the number of nodes used.

Fig 9

 9 Fig 9 shows the gridding speedup and the total execution time for each node between 4 MPI processes and 1 MPI process, such as the speedup is defined as

  γ

Fig. 9 .

 9 Fig.9. Speedup of gridding/degridding and total execution time between 4 MPI processes and 1 MPI process regarding the number of nodes.

TABLE I MAXIMUM

 I MEMORY CONSUMPTION DURING GRIDDING/DEGRIDDING.

ACKNOWLEDGMENT

This work was supported by grants from Région Ile-de-France and DARK-ERA (ANR-20-CE46-0001-01).


Vincent Compère

Julie Ramen

Jérôme Moriceau Correspondance

Le « Lean santé » pour améliorer le parcours de l'opéré Lean management to improve postoperative patients' clinical pathway

Le lean management a été défini au Japon dans l'industrie automobile. Le lean santé permet d'optimiser les organisations pour répondre aux besoins des patients dans un système économique contraint. Le lean management repose sur le pragmatisme, la simplicité, la transparence et le respect de l'autre. Il repose sur la résolution de problèmes quotidiens et l'éviction des gaspillages Après une phase d'évaluation et d'innovation, succède une phase d'implantation des nouvelles solutions et de contrôle de leur impact. L'impact du lean management en santé sur la morbidité ou la durée d'hospitalisation a fait l'objet de nombreux travaux avec des résultats variables Summary: the concept of lean management has been described in Japanese car manufacturer Toyota. Health lean management aims optimizing organisation to achieve patients' needs despite restrictive economical conditions. The lean management is based on pragmatism, simplicity, transparency and each other respect. After a first evaluation, and innovation phase is followed by implantation of new solutions and by the control of their impact. However this last point remains controversial Mots clés : lean management, organisation des soins, Key words : lean management La recherche de l'amélioration de la performance des organisations autour de la prise en charge médicale des patients, est devenue un sujet de préoccupation majeure dans cette période de transformation de notre système de santé. Il existe un sentiment d'urgence face à la nécessaire mutation de nos organisations. C'est dans un contexte identique que, juste après la deuxième guerre mondiale, Toyota a inventé le concept de Lean. La philosophie du Lean santé, directement issue du Lean manufacturier tel que

défini par Toyota, positionne le patient au centre de l'organisation avec comme objectif de favoriser les « services » de soins (considérés comme une valeur ajoutée pour le patient) tout en éliminant ou tout au moins en diminuant les gaspillages. Nous sommes donc bien sur une recherche de performance de nos organisations avec le développement d'une culture et d'outils adaptés à cet objectif. Bien que souvent perçu à tort comme une méthode permettant de gérer la pénurie de moyens et donc de générer des économies, le Lean santé devrait être davantage considéré comme une approche humanisée améliorant les organisations axées sur le patient en diminuant les nombreux gaspillages dans nos institutions au bénéfice des soins directs. Le développement de ce concept dans les établissements de santé engendre potentiellement un triple bénéfice :

1) Pour le patient en premier lieu 2) mais aussi pour les soignants 3) et pour les gestionnaires en augmentant potentiellement le nombre de patients rentrant dans le processus via une diminution des délais de prise en charge tout en préservant la qualité de prise en charge sans majorer les coûts.

Les changements culturels sont longs et difficiles. Comme disait W Churchill « mieux vaut prendre le changement par la main avant qu'il ne vous prenne par la gorge ». De ce point de vue, le Lean Santé est une des approches conceptuelles intéressantes pour accompagner ce changement.

HISTORIQUE

Le Lean, également appelé système de production Toyota, est une méthode d'optimisation de la production manufacturière qui a été développée dans le contexte économique difficile du Japon au sortir de la deuxième guerre mondiale. Ce système est un modèle global de gestion qui a permis d'améliorer considérablement la production du groupe Toyota. Intrigué par le succès de ce groupe automobile, des chercheurs américains (Jim Womack et Daniel Jones) ont analysé les éléments ayant conduit à l'augmentation de la production de voitures fiables avec des coûts maitrisés. Ces derniers reposent sur la réduction voire la suppression des gaspillages pour mieux servir le client tout en respectant les employés travaillant dans l'entreprise. Le fruit de leur recherche a été publié en 1990 : « The machine That Changed the World » et a été le début d'une intense réflexion sur cette philosophie managériale. Les concepts ont été ensuite déclinés dans de nombreux autres environnements professionnels (Lean Engineering, Lean Office, Lean Startup, Lean Management) pour arriver au secteur de la santé. Le Lean santé (Lean Healthcare) est un système global de gestion permettant d'optimiser les organisations a fin de répondre aux besoins croissants de santé d'une population avec des ressources de plus en plus limitées. Celui-ci a été développé dans un premier temps en Amérique du Nord avec les expériences du Virginia Mason, de la Mayo Clinic, de ThedaCare aux USA et celles de la province de Saskatchewan ou du CHU de Québec au Canada. En Europe, l'hôpital de Namur a été précurseur dans le déploiement du Lean santé au sein de son institution. De nombreux hôpitaux français sont actuellement en cours d'expérimentation (CHU Dijon, Lille, Lyon, Rouen,...).

PRINCIPES DU LEAN

Comme toute approche managériale, il faut rappeler les fondamentaux que sont le pragmatisme, la simplicité, la transparence et le respect des professionnels a fin de mener tout changement dans une organisation de travail.

Le Lean va intégrer ces notions dans le cadre d'une philosophie dont l'objectif principal va être l'identification et le suivi des objectifs à long terme centrés sur le client (en abandonnant la vision à court terme très souvent délétère) en intégrant différents outils qui vont permettre de répondre efficacement aux problématiques soulevées par une réflexion reposant sur l'évaluation d'un processus dans sa globalité et non pas issue d'une vision parcellaire.

Le client qui est au centre de la réflexion va définir lui-même le service et/ou le bien qu'il s'attend à recevoir. L'organisation vise ensuite à optimiser la chaîne de production en identifiant la succession des tâches (dans le cadre d'un processus) pour fournir le service/bien souhaité par le client dans les meilleurs temps. Ces tâches sont ensuite identifiées comme soit des valeurs ajoutées (ce qui est bien pour le client) ou alors soit des non valeurs ajoutées (considéré comme des gaspillages ou alors comme des valeurs de processus inévitables pour faire fonctionner la chaîne de production mais desquelles le client ne tire aucun bénéfice direct). L'optimisation du processus a pour but de favoriser les valeurs ajoutées directes pour le client, diminuer les non valeurs ajoutées de processus et d'éliminer les gaspillages. Le Lean a donc pour objectif principal de réduire les gaspillages pour obtenir le service/ bien souhaité par le client, tout en préservant les coûts et en garantissant la qualité/sécurité des processus. Pour ce faire, le Lean est constitué de 4 grandes orientations (regroupés selon les 4 P : Philosophie/Personnes/résolution de Problèmes/Processus) déclinées en 14 principes (tableau 1). Il s'agit d'une véritable culture, incluant des outils méthodologiques, qui est mise au service du client.

TABLEAU 1 : Les principes fondamentaux du Lean

PHILOSOPHIE

Baser les décisions de gestion sur une philosophie à long terme, au détriment des objectifs financiers à court-terme

PERSONNES ET PARTENAIRES

  Lors de la phase « mesurer », les données pertinentes permettant de décrire l'état de l'organisation actuelle liée au problème sont collectées. Dans cette phase, la vision du patient mais aussi des professionnels est primordiale (recueillie par des entrevus, sondages, questionnaires de satisfaction,...). Elle vient se surajouter aux éléments spécifiques qui vont s'intéresser à l'organisation/processus. La cartographie va permettre une représentation des activités/tâches réalisées. Elle va permettre entre autre de mesurer les valeurs ajoutées directes pour le patient (exemple : temps de présence du patient auprès du médecin), les valeurs de processus (exemple : le temps passé pour enregistrer l'admission administrative) et les gaspillages. Les 8 grands types de gaspillage rencontrés dans nos organisations sont répertoriés dans le tableau 2.Les phases « analyser » et « innovation » se font sous la forme d'un atelier participatif (atelier Kaizen) qui incluent tous les protagonistes liés au processus et les patients. Celui-ci, d'une durée assez longue (minimum 3 jours), permet d'identifier le processus actuel (à l'aide des éléments issus de la phase « évaluer ») et tous les problèmes associés a fin d'imaginer un nouveau processus qui intègre toutes les solutions trouvées de façon collective. La dernière étape concerne la mise en place du plan d'action et de son planning. Le groupe sera aidé par un méthodologiste qui s'appuiera sur des outils de résolution de problème éprouvés (recherche des causes profondes par la technique des 5 pourquoi permettant de déterminer une chaine causale, diagramme d'ishikawa et de Pareto). La phase « innover » repose sur la créativité de chaque personne participant à l'atelier qui va stimuler son talent pour trouver des solutions concrètes aux problèmes posés. Cette étape se fait toujours avec en ligne de mire les principaux objectifs liés à la philosophie Lean : tous les participants sont préalablement formés aux concepts et à De plus, très souvent, l'approche Lean est confondue avec un concept appelé Six Sigma qui est une autre méthodologie d'amélioration de la qualité qui a été développée par Motorola au milieu des années 1980. Ce principe repose sur l'utilisation de méthodes statistiques pour réduire les sources d'erreur (la probabilité de l'erreur recherchée est inférieure à 6 déviations standards= sigma) et donc minimiser la variabilité dans les processus et les résultats. Malgré les différences conceptuelles entre ces deux approches, elles sont parfois combinées en une seule approche appelée Lean Sigma et rend difficile l'analyse des publications.Dans le contexte de la médecine, une première revue a été publiée en 2009 [1] Sur 207 articles éligibles, seuls 19 ont été intégrés à l'analyse. Plus récemment, une autre revue systématique a retenu uniquement 22 travaux sur les plus de 1000 sélectionnés initialement [2] Les résultats de ces travaux, qui restent critiquables sur le plan méthodologique, ne sont pas probants et montrent que le Lean n'améliore ni la satisfaction du patient ni son pronostic, qu'il influe négativement sur les coûts et sur la satisfaction des soignants mais qu'il pourrait avoir un impact positif sur le processus (gain de temps pour le patient, amélioration du flux de malade,...). La conclusion de cette revue est qu'il est nécessaire d'améliorer la méthodologie d'évaluation du Lean Santé pour pouvoir conclure sur son intérêt potentiel. Ces résultats illustrent aussi le fait que le Lean Santé n'est pas un outil permettant d'améliorer la pratique médicale et donc le devenir du patient mais bien une approche d'optimisation des organisations par le biais de l'amélioration du processus.En ce qui concerne plus spécifiquement l'utilisation de cette approche au sein des blocs opératoires, une récente revue a exploré l'utilisation et l'intérêt des méthodologies Lean et Six Sigma dans le parcours du patient chirurgical[3] . Sur les 124 études potentiellement éligibles, 23 ont été inclues. Onze intéressaient le Lean Santé, 6 la méthode Six Sigma et 6 le Lean Sigma. Ces travaux évaluaient 6 grands objectifs : optimiser l'efficacité des services de chirurgie ambulatoire, améliorer la performance organisationnelle du bloc opératoire, réduire les complications opératoires et la mortalité, limiter les coûts inutiles et diminuer la durée du séjour. De façon globale, la majorité de ces études (88 %) montre une amélioration de ces objectifs avec toutefois de nombreux biais et imprécisions qui limitent la portée des résultats. Quoiqu'il en soit, dans le cadre de la chirurgie ambulatoire, 2 études ont rapporté une réduction significative du délai moyen d'attente pour être opéré, du nombre de consultations dans le parcours du patient ainsi qu'une diminution du temps de consultation 'une culture du changement est devenue un impératif absolu dans le contexte contraint de notre système de santé. Pour reprendre les mots de Marc Aurèle, "que la force me soit donnée de supporter ce qui ne peut être changé et le courage de changer ce qui peut l'être mais aussi la sagesse de distinguer l'un de l'autre". A fin de trouver cette force pour soutenir le changement, la philosophie et les outils que propose le Lean Santé permettent de s'appuyer sur une méthodologie éprouvée depuis plus de 60 ans dans le Lean manufacturier. Le niveau de preuve permettant de valider cette approche dans le milieu de la santé reste encore faible même si les différentes expériences semblent intéressantes. Une approche évaluative méthodologiquement plus robuste devrait permettre d'appuyer l'implantation d'un Lean humanisé dans notre système de santé et particulièrement autour du patient opéré Mason SE, Nicolay CR, Darzi A. The use of Lean and Six Sigma methodologies in surgery : a systematic review. Surg J R Coll Surg Edinb Irel. avr 2015;13(2) :91-100. . [4] Van Vliet EJ, Sermeus W, van Gaalen CM, Sol JCA, Vissers JMH. Ef cacy and ef ciency of a lean cataract pathway : a comparative study. Qual Saf Health Care. [6] Cima RR, Brown MJ, Hebl JR, Moore R, Rogers JC, Kollengode A, et al. Use of lean and six sigma methodology to improve operating room ef ciency in a highvolume tertiary-care academic medical center. J Am Coll Surg. juill 2011; 213(1) :83-92; discussion 93-94. . [7] Warner CJ, Walsh DB, Horvath AJ, Walsh TR, Herrick DP, Prentiss SJ, et al. Lean principles optimize on-time vascular surgery operating room starts and decrease resident work hours. J Vasc Surg. nov 2013; 58(5) :1417-22. . [8] Collar RM, Shuman AG, Feiner S, McGonegal AK, Heidel N, Duck M, et al. Lean management in academic surgery. J Am Coll Surg. juin 2012; 214(6) :928-36. . [9] Schwarz P, Pannes KD, Nathan M, Reimer HJ, Kleespies A, Kuhn N, et al. Lean processes for optimizing OR capacity utilization : prospective analysis before and after implementation of value stream mapping (VSM). Langenbecks Arch Surg. oct 2011; 396(7) :1047-53. . [10] Parker BM, Henderson JM, Vitagliano S, Nair BG, Petre J, Maurer WG, et al. Six sigma methodology can be used to improve adherence for antibiotic prophylaxis in patients undergoing noncardiac surgery. Anesth Analg. janv

	Surproduction	rapidement Faire plus que requis ou trop tôt TABLEAU 2 Les 8 sources de gaspillage goulot goulot	Test diagnostic excessif
			Maintenir l'apprentissage organisationnel par des ateliers Dans un processus, il y a toujours
	Défaut		d'amélioration continue. Toute activité découlant d'erreur un goulot et il n'y en a qu'un seul	Oubli de saisie d'un rendez-vous en consultation
	PROCESSUS LEAN SANTÉ Méthode inefficace Attente Transport et déplacement Inventaire Manipulation et recherche Mauvaise utilisation du potentiel humain TABLEAU 3 : Notions importantes dans l'analyse d'un processus Organiser le processus sous la forme d'un flux continu pour faire émerger les problèmes Utiliser des systèmes à flux tirés pour éviter la surproduction Niveler la charge de travail sur l'ensemble des éléments Arrêter lorsqu'il y a un problème Standardisation le travail pour favoriser l'amélioration continue Utiliser le contrôle visuel pour voir les problèmes Utiliser des technologies fiables et éprouvées Solution de problèmes Tâche superflue Vérification multiple de la même information auprès du patient Interrompre le flux de travail Attendre un lit avant de faire monter un patient au bloc opératoire Déplacement du patient ou du personnel de façon indue Aller chercher des boîtes chirurgicales dans un autre bloc Trop ou pas assez de matériel Sur stockage de médicament qui atteignent la date de péremption Manutentionner ou chercher de façon indue Chercher le dossier dans le tas sur le bureau de consultation Ne pas écouter les experts de terrain ou alors pas la bonne personne pour la bonne tâche Chirurgien qui cherche un lit d'hospitalisation pour un malade aux urgences Notion Description Exemple Flux tiré Exécution d'une tâche en fonction de la demande immédiate de la prochaine étape, plutôt qu'en On ne commence un nouveau chantier sur les routes que quand le premier est terminé. Moins de travaux au global avec des utilisateurs Le goulot dicte la capacité de tout le processus C'est souvent l'activité la plus complexe On agit en priorité sur le goulot Cellule de travail Création d'un regroupement physique de postes ou de ressources pour permettre de réaliser en une seule fois les étapes nécessaires au traitement d'un dossier, d'un patient ou la fabrication d'un produit Un représentant de chaque service ensemble pour le traitement d'un dossier (soin, informatique, achats...) Gestion visuelle Sert à connaître l'état du travail de manière autonome, sans avoir à demander. Mieux comprendre, mieux communiquer sans s'interrompre! Système de rangement à base de couleurs chirurgicale [4,5] . Sur 5 études, 2 ont montré le bénéfice d'une approche Lean pour débuter à l'heure les interventions [6,7] et 2 autres pour diminuer le temps entre deux interventions [8,9] . Une amélioration de la prise en charge des patients a été observée notamment en optimisant l'observance de l'antibioprophylaxie [10,11] , le lavage des mains par les professionnels [12,13] ou encore en intervenant sur le parcours du patient porteur d'une fracture de l'extrémité supérieure du fémur [14] . Deux travaux sur les 6 analysés ont observé une diminution significative de la durée d'hospitalisation de 31 et 36 % (les autres travaux montraient une tendance à la diminution sans que celle-ci soit significative) [15,16] . Enfin, 3 études sur 4 montraient une diminution des coûts [8,16,17] . Un travail très récent issu de l'équipe de Québec a montré qu'une approche Lean permettait aussi de réduire entre 25 à 68% le temps passé en salle de surveillance post-interventionnelle [18] . CONCLUSION . [1] Vest JR, Gamm LD. A critical review of the research literature on Six Sigma, Lean and StuderGroup's Hardwiring Excellence in the United States : the need to demonstrate and communicate the effectiveness of transformation strategies in healthcare. Implement Sci IS. 1 juill 2009; 4 :35. . [2] Moraros J, Lemstra M, Nwankwo C. Lean interventions in healthcare : do they actually work ? A systematic literature review. Int J Qual Health Care. avr 2016;28(2) :150-65. L'implantation dBIBLIOGRAPHIE . [3]
			fonction de prévisions du besoin	plus satisfaits
		Flux unitaire	Développer des leaders qui incarnent la philosophie Respecter, développer et stimuler les équipes et les personnes Favoriser un travail continu pour Un escalator amène plus de personnes diminuer le temps de passage et plus rapidement à l'étage qu'un ascenseur
		Respecter, développer et stimuler les partenaires Aller voir par soi-même pour comprendre la situation Prendre des décisions lentement par consensus et implanter Théorie dictant la façon efficace SOLUTIONS DE PROBLEMES Gestion processus, basée sur la gestion du du de gérer la capacité d'un Un pont à la jonction de plusieurs autoroutes

Le Lean santé est directement issu de cette culture. Dans le reste du document, les éléments décrits sont issus de la vision initiée et déployée par le CHU de Québec (équipe de D. Laroche). Le Lean santé dans cette vision s'inscrit dans une démarche humanisée d'amélioration continue des organisations de soins centrées sur le patient. Il ne cible que les organisations et exclut donc l'amélioration des pratiques médicales ou soignantes qui concernent plus la pertinence des soins. Cette démarche humanisée consiste alors à interroger les processus lors d'un dysfonctionnement en s'éloignant de la culture du « shame and blame » qui ne consiste qu'à trouver un coupable lorsqu'un problème survient et d'en faire l'unique responsable de l'erreur. Cette culture du coupable ne permet pas alors de s'interroger sur les causes profondes des dysfonctionnements au sein du processus global et au bout du compte de les régler.

Définition Exemples

Les outils du Lean santé ont pour principal objectif de permettre de résoudre des problématiques liées au processus pour optimiser ce dernier. La résolution de problème simple du quotidien se fait en temps réel sous la forme d'une réunion très structurée (appelée Scrum) courte, rapide et hebdomadaire réalisée devant un tableau intégrant l'ensemble des professionnels. Les problèmes sont énoncés et les solutions sont discutées et validées par les professionnels de terrain (intelligence collective au plus près du problème) et implantées immédiatement sous la forme du « just do it » avec une analyse de l'impact sur le processus concerné.

La résolution de problème complexe dans cette vision du Lean santé va quant à elle reposer sur une démarche/ méthodologie de DMAIIC (Définir, Mesurer, Analyser, Innover, Implanter et Contrôler). La phase « définir » consiste à cibler le problème. l'utilisation des outils, éliminer les gaspillages, identifier dans le processus l'étape limitant la capacité du système pour l'optimiser, mettre en place un flux unitaire et tiré et enfin mettre en place des outils de gestion visuelle (tableau 3).

La phase « implanter » consiste à mettre en place les solutions trouvées durant l'atelier participatif dans un laps de temps le plus court possible tout en ayant réfléchi à la gestion du changement qui doit accompagner le projet. Enfin, la dernière phase dite de « contrôle » consiste à évaluer les impacts du projet (rôle important des indicateurs produits en routine) mais aussi rentrer dans une véritable vision d'amélioration continue avec la poursuite d'une expression des problématiques vécues au quotidien et leurs résolutions de façon collective en équipe avec les réunions courtes hebdomadaires très structurées appelée Scrum. (lignes au sol...) des tableaux de bord; salles de pilotage Un bon système de signalisation (code de la route)

INTÉRÊT EN MÉDECINE

De nombreux travaux rapportant l'intérêt du Lean Santé ont été publiés mais leur méthodologie n'est pas suffisamment robuste pour apporter actuellement un niveau de preuve satisfaisant. déc 2010;19(6) :e13.

. [5] Siddique K, Elsayed SEA, Cheema R, Mirza S, Basu S. One-stop cholecystectomy clinic : an application of lean thinking--can it improve the outcomes ? J Perioper Pract. nov 2012;22(11) :360-5.

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MD Christol Fabre
email: cfabre2@chu-grenoble.fr

MD Hugo Gil

MD-PhD Christian Adrien Righini

An unusual palatine tonsil lesion

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

Case report: A 56-year-old woman with no particular medical history and no smoking or drinking risk factors, attended the emergency department for left supraclavicular oedema present for three days, that had become worse despite treatment with clarithromycin. Clinical interview revealed moderate dysphagia to solids and the appearance of bilateral cervical lymph nodes two weeks previously in a context of nasopharyngitis. She presented a good general state of health with no weight loss. The patient also reported abdominal pain for one month, for which colonoscopy and abdominal CT scan had been requested, but not yet performed at the time of management. Physical examination revealed: 1) left supraclavicular induration ascending to the jugular region; 2) bilateral, non-inflammatory, painless, mobile, and indurated superior and middle jugular lymph nodes measuring about one centimetre.

Serology (EBV, CMV, HIV, toxoplasmosis) was not contributive.

The patient was referred to the ENT department for diagnostic lymphadenectomy. Physical examination revealed an exophytic granulating lesion of the inferior pole of the right palatine tonsil. Contrast-enhanced neck, chest and abdomen CT scan revealed: 1) heterogeneous bilateral cervical lymphadenopathy, with a necrotic centre and a left supraclavicular lymph node conglomerate associated with internal jugular vein thrombosis; 2) suspicion of an appendicular tumour (Figure 1A). 18 FDG PET-CT (Figure 1B) and diagnostic tonsillectomy were performed. Histological examination confirmed the presence of a tonsillar tumour (Figure 1C).

What is your diagnosis?

Answer: This tumour was a tonsillar metastasis from a mucinous signet-ring cell adenocarcinoma of intestinal origin, probably arising from the appendix ( 18 FDG PET-CT and abdominal CT). Tumour cells were non-cohesive and were floating in mucoid material. These zones of mucus dissected the lamina propria, resulting in an alveolar-like architecture.

Tumour cells comprised hypertrophic nucleolated nuclei with the presence of mitotic figures, and some cells had a "signet-ring" appearance with a nucleus displaced towards the periphery of the cell by intracytoplasmic mucin (blue arrows on the histological section).

Tumour morphology and immunophenotyping looking for proteins of the DNA mismatch repair (MMR) system failed to specify the exact tissue of origin or the presence of mutations or genetic instability of the MMR system. Colonoscopy visualized an infiltrated and ulcerated appearance at the centre of the caecal mucosa over the zone of implantation of the appendix.

Biopsies of the periphery of the appendicular orifice did not reveal any signs of malignant proliferation. However, according to the gastroenterologist, these biopsies were too superficial and should have been repeated, but this examination could not be performed due to rapid disease progression. Upper GI endoscopy was normal.

Due to the presence of multiple metastases and disease progression, 5-fluorouracil, oxaliplatin and bevacizumab chemotherapy was initiated, but was complicated by hepatorenal insufficiency requiring discontinuation of treatment. Palliative care was therefore decided and the patient died one month later.

Metastases of the palatine tonsils are rare, as less than 100 cases have been reported in the literature. In more than 90% of cases, the primary tumour is a melanoma (cutaneous or mucosal), lung cancer or kidney cancer [START_REF] Irani | Metastasis to the oral soft tissues: A review of 412 cases[END_REF].

Intestinal signet-ring cell adenocarcinoma is characterized by intracytoplasmic mucin accumulation that displaces the nucleus towards the periphery of the cell, as in the case reported here. The majority of primary gastrointestinal tumours of this type are gastric tumours, but they can also arise throughout the gastrointestinal tract [START_REF] Bittorf | Primary signet-ring cell carcinoma of the colorectum[END_REF]. The appendicular origin of this type of carcinoma is extremely rare and remains controversial [START_REF] Khan | Peritoneal carcinomatosis from signet-ring cell adenocarcinoma of the appendix[END_REF][START_REF] Wu | Survival in signet ring cell carcinoma varies based on primary tumor location: a Surveillance, Epidemiology, and End Results database analysis[END_REF]. This aggressive cancer is often only discovered at the metastatic stage due to its highly lymphophilic nature, consequently resulting in a very poor prognosis [START_REF] Bittorf | Primary signet-ring cell carcinoma of the colorectum[END_REF]. Tonsillar metastasis as the first sign of the disease, leading to the discovery of an intestinal primary cancer, has been reported only once in the literature in a case of caecal mucinous signet-ring cell adenocarcinoma [START_REF] Güvenç | Tonsillar metastasis of primary signet-ring cell carcinoma of the cecum[END_REF]. In the presence of a tumour of the palatine tonsil, although rare, a tonsillar metastasis from a primary tumour situated outside of the upper aerodigestive tract constitutes the main differential diagnosis, while the two most common histological types of primary tumours of the palatine tonsil are squamous cell carcinoma and lymphoma. A very cautious diagnostic approach is therefore essential, particularly in the absence of smoking and drinking. In this case, the presence of symptoms and physical signs suggesting metastases from a primary tumour situated outside of the upper aerodigestive tract must be systematically investigated.

Conflicts of interest: None

Figure 1 :

 1 Figure 1: Staging of the case reported here: Metabolic (B) and radiological (A) imaging of the tonsillar tumour. Histological appearance after fixation and staining (C).


C Gervais

E Florescu

D Babin

De

Thariat

Audrey Rambeau
email: audrey.rambeau@gmail.com

I Licaj

B Gery

R Gervais

C Florescu

E Babin

D De Raucourt

J Thariat

Platinum rechallenge in recurrent head and neck squamous cell carcinoma after primary chemoradiation

Keywords: recurrence, cisplatin, carboplatin

published or not. The documents may come

INTRODUCTION

Half of patients treated for locally advanced head and neck squamous cell carcinoma (HNSCC) relapse after multimodal treatment [START_REF] Bernier | Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer[END_REF][START_REF] Adelstein | An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in patients with unresectable squamous cell head and neck cancer[END_REF]. The standard treatment for recurrent/metastatic HNSCC is based on the standard EXTREME therapy regimen, associating platinum, 5FU and cetuximab, with median overall survival (OS) of 10.1 months [START_REF] Vermorken | Platinum-based chemotherapy plus cetuximab in head and neck cancer[END_REF]. About 30% of patients treated for recurrent or metastatic HNSCC have already undergone platinum-based treatment [START_REF] Vermorken | Platinum-based chemotherapy plus cetuximab in head and neck cancer[END_REF]. This population has not been specifically studied, despite the fact that their sensitivity to platinum might be lower than the rest of population after the first-line treatment. Moreover, on progression, only nivolumab improves OS; taxane and methotrexate monochemotherapy shows clinical response but no impact on survival [START_REF] Catimel | Docetaxel (Taxotere®): An active drug for the treatment of patients with advanced squamous cell carcinoma of the head and neck[END_REF][START_REF] Forastiere | Final report of a phase II evaluation of paclitaxel in patients with advanced squamous cell carcinoma of the head and neck[END_REF][START_REF] Capizzi | Methotrexate therapy of head and neck cancer: improvement in therapeutic index by the use of leucovorin "rescue&quot[END_REF]. Treatment options being limited, clinicians may resort to "rechallenging" platinumbased chemotherapy, especially in patients who showed initial benefit. Platinum rechallenge has not been studied in HNSCC, but its efficacy is well known in other cancer types, and it is standard practice in ovarian cancer, small-cell pulmonary carcinoma and colorectal cancer in case of relapse more than 6 months after last platinum injection [START_REF] Ledermann | Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2[END_REF][START_REF] Genestreti | Final outcome results of platinum-sensitive small cell lung cancer ( SCLC ) patients treated with platinum-based chemotherapy rechallenge : A multi-institutional retrospective analysis[END_REF][START_REF] Chibaudel | Platinum-sensitivity in metastatic colorectal cancer: Towards a definition[END_REF]. Patients with recurrence within 6 months, on the other hand, are considered platinum-refractory, and alternative treatments are proposed. This attitude is currently under assessment in non-small-cell pulmonary carcinoma [START_REF] Bluthgen | Second-line combination therapies in nonsmall cell lung cancer without known driver mutations[END_REF].

Patients with early recurrence of HNSCC after chemoradiotherapy show median OS <6 months [START_REF] Saloura | An open-label single-arm, phase II trial of zalutumumab, a human monoclonal anti-EGFR antibody, in patients with platinum-refractory squamous cell carcinoma of the head and neck[END_REF], poorer than in case of recurrence later than 6 months. Recent studies suggested that, in recurrence within 6 months, the same treatment may be used as in recurrence after first-line treatment for metastasis [START_REF] Ferris | Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck[END_REF]. On the hypothesis that patients with early recurrence are platinum-refractory, some teams have proposed a combination of paclitaxel and cetuximab in first line in this situation [START_REF] Fayette | Paclitaxel in relapsed squamous cell carcinoma of head and neck (SSCHN): Retrospective study of a single institution[END_REF][START_REF] Péron | Paclitaxel and cetuximab combination efficiency after the failure of a platinum-based chemotherapy in recurrent/metastatic head and neck squamous cell carcinoma[END_REF][START_REF] Bernad | Activity of weekly paclitaxel-cetuximab chemotherapy in unselected patients with recurrent/metastatic head and neck squamous cell carcinoma: prognostic factors[END_REF].

No studies have compared this attitude versus the EXTREME protocol in early recurrence, although this could lower the number of subsequent chemotherapy lines. In particular, the synergistic effect of cetuximab and platinum would be lost.

Tolerance is a key-point in platinum rechallenge. About 20% of patients present cisplatinrelated kidney failure, although this is usually reversible [START_REF] Yao | Cisplatin Nephrotoxicity: A Review[END_REF]. The risk of kidney failure after rechallenge is not known, especially in case of transient creatinine elevation on first-line treatment.

In this context, we aimed to assess the efficacy of platinum rechallenge and tolerance in patients presenting recurrent HNSCC after platinum-based chemoradiotherapy.

METHODS

Study design

A single-center retrospective study was performed in François Baclesse Cancer Center, Caen (France). Analyses were based on medical computer records.

The primary endpoint was disease control rate (DCR) on platinum rechallenge. Secondary endpoints were clinical factors associated with progression-free survival (PFS) and overall survival (OS), subsequent treatment lines, and renal tolerance of rechallenge.

Patients

Inclusion criteria comprised: squamous cell carcinoma of the head and neck treated by platinum-based polychemotherapy, with prior exclusive or postoperative platinum-based chemoradiotherapy, treated between 2007 and 2016; first-line induction chemotherapy was also included. Nasopharyngeal and sinonasal primary tumors were excluded. Patients who underwent primary treatment at another hospital could not be included, due to missing data. Screening used the local chemotherapy software. In patients treated by the EXTREME protocol, any previous chemoradiation therapy was checked.

Treatment schedule

The radiation dose was 70 Gy in case of exclusive chemoradiotherapy and ranged between 66 and 70 Gy in post-operative treatment. Initial chemotherapy associated to radiation therapy consisted of: cisplatin 20 mg/m²/d days 1 to 5, 5fluorouracil (5FU) 1,000 mg/m²/d days 1 to 4 every 3 weeks [START_REF] Pignon | Metaanalysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients[END_REF][START_REF] Taylor | Improved control in advanced head and neck cancer with simultaneous radiation and cisplatin/5-FU chemotherapy[END_REF][START_REF] Taylor | Concomitant cisplatin/5-FU infusion and radiotherapy in advanced head and neck cancer: 8-year analysis of results[END_REF], or carboplatin 70 mg/m²/d + 5FU 600 mg/m²/d days 1 to 4 every 5 weeks [START_REF] Calais | Randomized Trial of Radiation Therapy Versus Concomitant Chemotherapy and Radiation Therapy for Advanced-Stage Oropharynx Carcinoma[END_REF][START_REF] Denis | Final results of the 94-01 French Head and Neck Oncology and Radiotherapy Group randomized trial comparing radiotherapy alone with concomitant chemoradiation in advanced-stage oropharynx carcinoma[END_REF] followed by cisplatin 100mg/m² every 3 weeks [START_REF] Bernier | Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer[END_REF].

Chemotherapy for recurrence associated platinum (cisplatin 100 mg/m² or carboplatin AUC5), 5FU (4,000 mg/m² every 3 weeks) and weekly cetuximab (400mg/m² then 250 mg/m²/week) [START_REF] Vermorken | Platinum-based chemotherapy plus cetuximab in head and neck cancer[END_REF].

Patients treated without 5 FU or with low platinum dose due to comorbidities or poor general health status were also included. Treatment was selected in a multidisciplinary team meeting, but choice of platinum salt was at the discretion of the physician during clinical evaluation.

Endpoints

Disease control was defined as complete or partial response or stable disease at best response on CT scan using the Response Evaluation Criteria In Solid Tumor v1.1 (RECIST 1.1). Progression or death from any cause was considered as treatment failure. Disease-free interval (DFI) was defined as the time from the last day of chemoradiotherapy to day of first progression. Early recurrence was defined as DFI ≤6 months. Progression-free survival 1 (PFS1) was defined as the interval between first day of platinum rechallenge and day of treatment failure after rechallenge, and PFS2 as the interval between first day of second-line treatment and progression or death or end of study (whichever came first). Overall survival (OS) after diagnosis was defined as the interval between initial biopsy to death, and OS after relapse as the interval between first disease on CT and death.

Toxicity was graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Severe comorbidity was defined as a Cumulative Illness Rating Scale item (CIRS) ≥3 [START_REF] Linn | Cumulative Illness Rating Scale[END_REF]. Malnutrition was defined as body mass index (BMI) <18.5 kg/m² or weight loss >10% of body weight [START_REF]Évaluation diagnostique de la dénutrition protéino-énergétique des adultes hospitalisés[END_REF].

Statistical analysis

Quantitative variables were reported as median and range, and qualitative variables as number and percentage. PFS and OS with 95% confidence intervals (CI) were estimated following Kaplan-Meier.

The log-rank test was used to compare survival. Chi-square or Fisher's exact test was used for categoric variables. Maximum Youden index, calculated as sensitivity+specificity-1, was used to determine optimal cut-off. Analyses used Stata software version 14.0, with two-tailed p-values of <0.05 considered statistically significant.

RESULTS

Patient characteristics at diagnosis and primary treatment

Seventy-four out of 190 patients treated by platinum-based therapy for recurrent/metastatic HNSCC had been previously treated by radiotherapy with concomitant platinum-based chemotherapy, 45 of whom were initially treated at our center.

Table 1 shows patient and tumor characteristics at diagnosis. Median age was 56 years (range, 22-71 years). Thirteen patients had severe comorbidity, but none had more than 1 severe comorbidity.

Twenty patients had active nicotine-alcohol co-intoxication. The most frequent primary site was the oral cavity; median stage was IVa.

Table 2 shows primary treatments: surgery followed by concomitant chemoradiation with cisplatin for 14 patients; 7 patients received induction chemotherapy (docetaxel, cisplatin, 5FU) before chemoradiotherapy; 22 had exclusive concomitant chemotherapy with cisplatin-5FU and 9 with carboplatin-5FU.

Patient characteristics at recurrence

Median DFI was 5.7 months (range, 0.1-45.4 months). Disease progression occurred within 3 months following primary treatment in 5 patients (11.1%), at 3-6 months for 18 (40%), and 6-12 months for 13 (28.9%). Nine patients (20%) had recurrence more than 1 year after primary treatment.

Performance status at recurrence was 0-1 for 24 patients (53.3%). Malnutrition was diagnosed at recurrence in 30 cases (66.7%). Progression site was locoregional in16 cases (35.6%), metastatic in 15 (33.3%), and both locoregional and metastatic in 14 (31.1%). A majority of patients with relapse within 6 months after primary treatment showed metastasis (n=18/23: 78.3%). Four of the patients with locoregional progression had salvage surgery and 1 had repeat locoregional radiation therapy ahead of chemotherapy.

Platinum rechallenge

Therapy regimen at relapse was: cisplatin-5FU-cetuximab (n=25), carboplatin-5FU-cetuximab (n=19), or cisplatin-docetaxel-cetuximab (n=1). Type of platinum administered according to platinum used as primary treatment is detailed in Table 3. Type of platinum in primary treatment was not associated with platinum type used at relapse (p=0.264).

Median number of chemotherapy cycles was 3 (range, 1-6). Eighteen patients completed 4 cycles of chemotherapy or more (40%). Two patients discontinued cetuximab administration due to anaphylactic reaction. Sixteen patients (35.6%) underwent maintenance treatment with cetuximab monotherapy. Median number of maintenance cycles was 4.5 (range, 1-42).

Efficacy of rechallenge

Twenty-one patients (40%) showed disease control with platinum rechallenge: stable disease in 5 (11.1%), partial response in 14 (24.4%) and complete response in 2 (4.4%). No clinical benefit was observed in 24 patients: progressive disease in 13 (28.9%) and death in 11 (24.4%).

Median follow-up after relapse was 17.2 months. Median PFS1 was 3.0 months (range, 2.3-4.6 months) (Figure 1); PFS1 was >6 months for 11 patients (24.4%) and >1 year for 5 patients (11.1%). Maximum treatment response duration was 82 months. Eleven of the 23 patients with early recurrence showed disease control (47.8%). DFI >6 months or >3 months was not significantly associated with better disease control rate (DCR) (p=0.555 and p=0.217 respectively). The DFI cut-off with the best specificity and sensitivity for DCR appeared to be 4.5 months (p=0.043) (28.6% versus 54.8% disease control). Other patient, disease and treatment characteristics were not significantly associated with disease control.

Median OS after initial diagnosis was 17.2 months (range, 12.8-25.5, and 5.0 months (range, 3.7-8.0) after recurrence. There was a significant difference in OS (p<0.0001) using the 4.5 months DFI cut-off: median OS after initial diagnosis was 7.3 (range, 7.0-12.1) and 21.7 months (range, 17.2-32.2) respectively (specificity = 0.42; sensitivity = 0.86; Youden index = 0.27).

Renal tolerance at primary treatment

Six of the 36 patients who received concomitant cisplatin as primary treatment (17.7%) presented acute kidney failure during treatment (5 grade 3, 1 grade 2), leading to cancelation of the last cisplatin dose. Only 2 patients (5.6%) presented grade 2 chronic deterioration of glomerular filtration rate.

Renal tolerance at rechallenge

Nineteen patients received cisplatin treatment at relapse, including 3 who had had transient nephrotoxicity at primary treatment. Two patients had their treatment changed to carboplatin due to grade 3 acute kidney failure at platinum rechallenge, 1 of whom had shown transient nephrotoxicity at primary treatment. Median cumulative cisplatin dose was 600 mg/m² (range, 300-1,100).

Second-and third-line chemotherapy after platinum rechallenge

Ten of the 41 patients with progressive disease after platinum rechallenge received second-line systemic treatment (Table 4), with taxanes, immunotherapy (clinical trial), or new platinum rechallenge. Disease control was achieved in 6 patients (60%): stable disease (n=3), or partial response (n=3). Median PFS2 was 3.5 months (range, 1.9-15.6).

One of the 3 patients who had second platinum rechallenge showed complete response to first platinum rechallenge and the other 2 showed partial response. Two presented an objective clinical response to second rechallenge (1 stable disease and 1 partial response, with PFS2 of 3 and 6 months, respectively).

Five patients (11.1%) received third line chemotherapy, with taxanes or immunotherapy. Only 1 presented partial response, with taxane-based treatment.

DISCUSSION

Platinum rechallenge in case of recurrent HNSCC after chemoradiotherapy showed a 40% DCR. The usual 6 month DFI cut-off was not associated with poorer outcome: almost half of the patients presenting early recurrence showed benefit from platinum rechallenge. In the present series, a 4.5 month DFI cut-off was significantly associated with better DCR and OS.

In this study, median PFS1 was 3.7 months and median OS at relapse was 5.0 months. Those survival rates are dramatically shorter than in Vermorken's study [START_REF] Vermorken | Platinum-based chemotherapy plus cetuximab in head and neck cancer[END_REF] where PFS and OS were 5.6 and 10.1 months, respectively, and objective response rate (ORR) was 81% using platinum in combination with cetuximab. Many poor prognostic factors were more frequent in our study compared to Vermorken's and can explain the differences in outcome. First, early relapse within 6 months following primary treatment is known to be a major prognostic factor [START_REF] Saloura | An open-label single-arm, phase II trial of zalutumumab, a human monoclonal anti-EGFR antibody, in patients with platinum-refractory squamous cell carcinoma of the head and neck[END_REF], and was an exclusion criterion for Vermorken but not in the present study. Furthermore, oral cavity primary site and metastatic spread are known to be of negative prognosis [START_REF] Leeman | Patterns of Treatment Failure and Postrecurrence Outcomes Among Patients With Locally Advanced Head and Neck Squamous Cell Carcinoma After Chemoradiotherapy Using Modern Radiation Techniques[END_REF][START_REF] Argiris | Prognostic factors and long-term survivorship in patients with recurrent or metastatic carcinoma of the head and neck[END_REF] and were more frequent in our study.

Retrospective inclusion of non-selected patients also entails more frequent severe comorbidity and malnutrition than in clinical trials, and decreases life expectancy. Another retrospective study [START_REF] Mello | Cetuximab plus platinumbased chemotherapy in head and neck squamous cell carcinoma: A retrospective study in a single comprehensive European cancer institution[END_REF] with metastatic or recurrent population reported a comparable 48.9% DCR and 11-month median OS; the most frequent primary site was also the oral cavity in their population. Among patients eligible for the EXTREME therapy regimen, those presenting recurrence after chemoradiotherapy are likely a subgroup with poorer prognosis. However, our survival data have to be interpreted with caution due to small sample size and do not allow any specific conclusion to be drawn.

Twenty-two percent of the study population received second-line chemotherapy, which is notably lower than in global metastatic/recurrent HNSCC populations [START_REF] Siano | Outcome of recurrent and metastatic head and neck squamous cell cancer patients after first line platinum and cetuximab therapy[END_REF]. This might be explained by the poor prognosis of the present population. In case of progression, immunotherapy is the only therapeutic option to have shown a gain in OS, with a median 7.5 months but is not yet available in HNSCC in France. Ferris [START_REF] Ferris | Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck[END_REF] reported a response rate of 13.3% to nivolumab versus 5.8% to chemotherapy, in second-line treatment or first-line in case of early recurrence after chemoradiotherapy. We found a 47.8% DCR in the early recurrence subgroup, which was dramatically higher than the overall response rate (ORR) in the nivolumab study (subgroup ORR data according to interval to recurrence were not available). Moreover, recent data suggest that immunotherapy could be associated with hyperprogression phenomena in HNSCC, especially in irradiated fields [28]. Thus, in case of early recurrence after chemoradiotherapy, the present study suggests that platinum rechallenge should remain a therapeutic option despite the marketing approval for nivolumab.

Benefit has not been proven for concomitant cisplatin compared to concomitant carboplatin in radiation therapy, although a recent meta-analysis showed a trend for improved outcome [29]. In recurrence, cisplatin showed superiority to carboplatin for overall survival, but no difference in terms of progression-free survival [START_REF] Vermorken | Platinum-based chemotherapy plus cetuximab in head and neck cancer[END_REF]. This is why clinicians prefer to reintroduce cisplatin at relapse, if tolerance was acceptable in primary treatment. Renal toxicity depends on cumulative cisplatin dose, and is more frequent with ≥100mg/m². History of hypertension and low serum albumin level are also associated with nephrotoxicity [30]. All these factors are often combined in recurrent HNSCC, which explains why this population is at high risk of kidney failure following cisplatin therapy. Nevertheless, platinum-induced acute kidney failure concerned 5.6% of cases at primary treatment and 10.5% at relapse in our cohort, and moreover is usually transient. Two in 3 patients with kidney failure at primary treatment had cisplatin rechallenge without incurring any nephrotoxicity. This suggests that cisplatin rechallenge can be considered even in case of primary toxicity, if clinical benefit is expected.

Prolonged hydration with saline and biological renal function monitoring would help prevent irreversible toxicity [START_REF] Yao | Cisplatin Nephrotoxicity: A Review[END_REF].

This single-center retrospective study included 45 patients. Statistical analyses did not identify prognostic factors for disease control apart from a 4.5 month DFI cut-off. Due to the small number of patients, a lack of sensitivity cannot be excluded. Furthermore, retrospective recruitment did not include data for certain prognostic factors such as HPV status in oropharyngeal cancers, as P16 status was not systematically assessed at the time of recruitment.

CONCLUSION

Survival in the present population was poorer than in the literature for metastatic or recurrent HNSCC. Nevertheless, disease control was found with platinum rechallenge in 40% of cases, including patients with early recurrence. Optimal disease-free cut-off for clinical response was 4.5 months. Platinum rechallenge showed acceptable renal tolerance and should continue to play a key role in the therapeutic arsenal for recurrent HNSCC despite the advent of immunotherapies.

Disclosure of

Figure 1 :Figure 2 :Figure 1 :Figure 2 :

 1212 Figure 1: Progression free survival from relapse (PFS1)

Table 1 : Patient and tumor characteristics at diagnosis

 1 Interest: The authors declare that they have no conflicts of interest concerning this article head and neck squamous cell carcinoma. Ann Oncol . 2017;28[START_REF] Ledermann | Paclitaxel plus platinum-based chemotherapy versus conventional platinum-based chemotherapy in women with relapsed ovarian cancer: the ICON4/AGO-OVAR-2[END_REF]:1605-11.29.Aguiar PN, Tadokoro H, Da Silva GF, Landgraf MM, Noia Barreto CM, Filardi BA, et al.

		Definitive chemoradiotherapy for squamous head and neck cancer: Cisplatin versus
		carboplatin? A meta-analysis. Futur Oncol. 2016;12(23):2755-64.
	30.	Motwani SS, McMahon GM, Humphreys BD, Partridge AH, Waikar SS, Curhan GC.
		Development and Validation of a Risk Prediction Model for Acute Kidney Injury After the
		First Course of Cisplatin. J Clin Oncol . 2018 Jan 10 ;JCO2017757161.

Table 2 : Primary treatment modalities At primary treatment

 2

			Cisplatin	Carboplatin
	At relapse	Cisplatin	19	7
		Carboplatin	17	2

Table 3 : Distribution of platinum regimen used at primary treatment and at relapse

 3

		Total	10	22.2%
	2nd Line	Taxane	5
		Immunotherapy	2
		Platinum rechallenge	3
		Total	5	11.1%
	3rd line	Taxane	4
		Immunotherapy	1

Table 4 : Second-and third-line chemotherapy

 4