Mikaël Kedzierski
email: mikael.kedzierski@univ-ubs.fr

Dominique Frère

Gwénaël Le Maguer

Stéphane Bruzaud

Why is there plastic packaging in the natural environment? Understanding the roots of our individual plastic waste management behaviours

Keywords: Plastic waste, waste management behaviours, waste management history, environment

Highlights

-Intention to discard waste is at the heart of the understanding of plastic pollution.

-A cost-benefit balance modulates our individual plastic waste management behaviours.

-Underestimation of plastic impacts is one explanation for individual mismanagement of waste.

-Landfilling can be linked to the persistence of old waste management behaviour.

-The study of waste reuse behaviour could be a source of innovation to improve waste management.

Over the millennia, ceramic, glass, wood, wicker and textiles have been the main materials used for containing and trading organic products and materials until the recent invention of plastics which marked the dawning of a new era (Fig. 1) [START_REF] Bevan | Mediterranean containerization[END_REF]. Different properties explain the rise of plastics after the Second World War such as their extremely large physico-chemical properties that enable it to be applied to a wide range of applications at a cost that is often lower than traditional alternatives (e.g. metal, glass, ceramic). Plastics are also very simple to process, making easy to manufacture them in a wide range of objects. Thus, from the 1950s onwards, food packaging and containers, which had previously been made with traditional materials, were increasingly made from plastic materials, thus allowing better preservation of foodstuffs [START_REF] Risch | Food Packaging History and Innovations[END_REF]. At the same time, the world population increased sharply from 2.5 billion to 7.6 billion between 1950 and 2017 (United Nations, 2017). These populations also moved, migrating from the countryside to the cities where they tended to concentrate [START_REF] Cheng | Who should take the garbage out? Public opinion on waste management in Dar es Salaam, Tanzania[END_REF]. Thus, between 1950 and 2019, the world population living in urban areas increased from 30% (751 million inhabitants) to 55% (4.2 billion inhabitants) (United Nations, 2018). These populations have increasingly easy access to consumer society, implying an increasing accessibility to consumer goods and services [START_REF] Paek | Spreading Global Consumerism: Effects of Mass Media and Advertising on Consumerist Values in China[END_REF]). These three factors (i.e. replacement of traditional manufacturing materials by plastic, increase and concentration of populations, and access to a consumer society) are widely responsible for the increasing use of plastic materials in packaging.

Fig. 1. Time lines of packaging history (data from [START_REF] Berger | A Brief History of Packaging[END_REF][START_REF] Risch | Food Packaging History and Innovations[END_REF]. The first ceramics used to preserve food were dated to the Upper Palaeolithic Period and were widely used for this purpose until the 19 th century, after which their use gradually declined. The use of glass is also ancient since the first traces of its industrialisation can be found as early as the Bronze Age in Egypt. From this period, manufacturing techniques were constantly improving, but it was not until the 19th century that the reduction in the cost of manufacturing glass containers made glass containers accessible to a larger part of the population. It was also in the 19 th century that cardboard packaging and paper bags were invented. Finally, the first metal cans were developed at the beginning of the 19 th century. These new kinds of packaging, which made it possible to preserve food efficiently and facilitate its transport, experienced a major increase in demand until the beginning of the second half of the 20th century. Plastic materials then began to be mass marketed, passing from 1.7 Mt in 1950 to 348 Mt in 2017 (PlasticsEurope, 2018(PlasticsEurope, , 2013(PlasticsEurope, , 2012)). Their physico-chemical properties made it possible, among other things, to replace glass bottles, paper bags and cardboard. In the end, food packaging will extensively be made of plastic materials. As early as the 1970s, the presence and impacts of plastic waste were observed in the natural environment and from this period, continuous scientific research on plastic pollution began. Nevertheless, it was not until the end of the 2000s that this topic became fully important (Data: Scopus database; Key words: 'plastic' and 'pollution').

Voluntary abandonment of plastic waste: a source of plastics pollution

First discussed in the 1980s, the amount of knowledge about the sources of plastic waste in the environment has continuously increased since then [START_REF] Li | Plastic waste in the marine environment: A review of sources, occurrence and effects[END_REF][START_REF] Pruter | Sources, quantities and distribution of persistent plastics in the marine environment[END_REF]. These sources are originally divided into two categories: those of accidental origin and those resulting from voluntary human actions. While accidental sources may sometimes be identified as they occur, the individual behaviour of the discarding of plastic waste, although closer to our daily lives, is much more dispersed in the scientific literature. Thus, the transition from 'object' to 'waste' is poorly understood, despite the fact that it is one of the fundamental sources of plastic pollution.

According to the United Nations, waste can be defined as 'materials that are not prime products […] for which the generator has no further use in terms of his/her own purposes of production, transformation or consumption, and of which he/she wants to dispose' (Department for Economic and Social Information and Policy Analysis, 1997). Similarly, the European Union defines waste as 'any substance or object which the holder discards or intends or is required to discard' (European Union, 2008). In these two cases, the intention to discard an object is a central idea to define the waste, perhaps even more than the action itself.

From plastic waste to pollution

Approximately 50% of plastic objects made are intended for single use and only 20% to 25%

for long-term use [START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF][START_REF] Hopewell | Plastics recycling: challenges and opportunities[END_REF]. Thus, as the use of plastic materials has increased, the quantities of waste generated have also increased: of the 8,300 million tonnes of plastic produced worldwide between 1950 and 2015, 4,900 million tonnes were discarded [START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF]. Despite the potential for recovery, about 50% of the plastics produced are of too little value for their recovery to be economically viable. Finally, less than 2% of the plastic waste produced since the 1950s has been recycled, less than 6% incinerated and the vast majority (about 92%) has been landfilled or disposed of in the natural environment (Fig. 2) [START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF]. However, plastic waste is not limited to continents since approximately 4.8 to 12.7 million tonnes of plastic ends up in the oceans each year [START_REF] Agamuthu | Marine debris: A review of impacts and global initiatives[END_REF].

However, unlike natural organic material such as wood, plastic materials degrade very slowly in the environment. Thus, it is likely that a few decades to a few centuries will be necessary for plastics to degrade if the environment is favourable in terms of physical, chemical and biological conditions. As a result, plastics tend to accumulate in the environment and are not harmless to it [START_REF] Ballerini | Plastic pollution in the ocean: what we know and what we don't know about[END_REF][START_REF] Brandon | Multidecadal increase in plastic particles in coastal ocean sediments[END_REF]. This implies implementing the necessary means to reduce their impact, but also to be able to understand the reasons why human beings do not manage their plastic waste properly.

Fig. 2. Waste management hierarchy (modified after [START_REF] Davies | The Geographies of Garbage Governance[END_REF][START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF].

Objectives

The objective of this article is therefore to synthesise scientific knowledge on some of the factors that control this intention to dispose our plastic objects, and on those that influence the way we dispose of our waste. Thus, the objective of the first part of the article is to explain why our perception of the risks associated with plastic waste discarded in our environment modulates the way we manage our plastic waste. The second part aims to present more specifically the origins of landfilling and the limits of the means conventionally implemented to fight against this type of practice. The objective of the third part is to present the case of reuse behaviour, and why this type of behaviour constitutes an underestimated way to fight against plastic pollution. Finally, we introduce a synthesis, summarising the main elements highlighted by this publication.

This article will also propose an original approach by introducing and illustrating the main elements highlighted by examples from different fields such as ethology, archaeology and history.

2. A cost-benefit balance that modulates our individual plastic waste management behaviours

Risk avoidance mechanisms: general cases

The risk of infection by parasites is a significant threat to many living organisms and behaviours allowing to avoid this risk is often a first line of defence [START_REF] Buck | Ecological and Evolutionary Consequences of Parasite Avoidance[END_REF][START_REF] Hart | Behavioral adaptations to pathogens and parasites: Five strategies[END_REF]. Humans generally avoid objects that they believe to be contaminated by potential parasites, and tend to eliminate waste that can harbour or feed parasitic organisms [START_REF] Curtis | Infection-avoidance behaviour in humans and other animals[END_REF]. Disgust is an emotion that is considered as one of these strategies for avoiding pathogens [START_REF] Buck | Ecological and Evolutionary Consequences of Parasite Avoidance[END_REF].

It can be induced by different stimuli from senses such as sight, taste and smell [START_REF] Buck | Ecological and Evolutionary Consequences of Parasite Avoidance[END_REF][START_REF] Hart | Behavioral adaptations to pathogens and parasites: Five strategies[END_REF]. This emotion is a powerful way for the body to avoid a situation presenting a risk of contamination by parasites [START_REF] Buck | Ecological and Evolutionary Consequences of Parasite Avoidance[END_REF][START_REF] Hart | Behavioral adaptations to pathogens and parasites: Five strategies[END_REF][START_REF] Weinstein | A landscape of disgust[END_REF]. This can be illustrated by shell middens (i.e. large accumulations of shellfish observed on the coasts around the entire world), which is interpreted by archaeologists as a desire to remove the organic remains whose decomposition can be a source of bad smells from living areas [START_REF] Barton | The lateglacial or late and final upper palaeolithic colonization of britain[END_REF]. Avoidance strategies originate both from innate reflexes, and also in learning from cultural origins or through the experience acquired by the organism [START_REF] Curtis | Dirt, disgust and disease: a natural history of hygiene[END_REF]. The development of avoidance strategies acquired at a personal or societal level can be illustrated by the example of the major epidemics of the Middle Ages. Thus, waste, particularly organic waste, had a negative impact on the quality of life of people living in the Middle Ages. It is for example the case of organic residues that infiltrated the soil and contaminated drinking water resources [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. These poor health conditions probably favoured the spread of the Black Death, which ravaged Europe from 1347 to 1351 [START_REF] Tammemagi | The Waste Crisis: Landfills, Incinerators, and the Search for a Sustainable Future[END_REF]. At the end of these epidemics, the link between heaps of waste and diseases appears in many testimonies [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. Similarly, it appears from that period that the neighbourhoods the most exposed to waste are more often and more severely affected by disease. The origins of epidemics were unknown at the time and the attributions were often multiple, but the senses, particularly taste and smell, took on an increasingly important role in the perception of the danger posed by waste from this period [START_REF] Leguay | La pollution au Moyen Âge[END_REF].

Avoidance behaviours are modulated by a cost-benefit balance [START_REF] Weinstein | A landscape of disgust[END_REF]. Thus, if the maintenance of a healthy community and a healthy environment is an important motivation for individuals to properly manage their waste, the perceived cost to the individual must be acceptable in relation to the perceived benefit [START_REF] Davies | The Geographies of Garbage Governance[END_REF][START_REF] Weinstein | A landscape of disgust[END_REF].

Out of sight, out of mind?

Of all the waste generated every day, plastic materials are probably not the most disgusting.

These materials are recent on the evolutionary time scale (PlasticsEurope, 2015) and are therefore not the subject of innate avoidance behaviour on the part of living beings, as shown by the numerous cases of plastic waste ingestion described in the scientific literature [START_REF] Boerger | Plastic ingestion by planktivorous fishes in the North Pacific Central Gyre[END_REF][START_REF] Colabuono | Plastic ingestion by Procellariiformes in Southern Brazil[END_REF][START_REF] Fossi | Fin whales and microplastics: The Mediterranean Sea and the Sea of Cortez scenarios[END_REF][START_REF] Nicolau | Ingestion of marine litter by loggerhead sea turtles, Caretta caretta, in Portuguese continental waters[END_REF]. In addition, most plastic materials can be considered relatively inert on a time scale of a few months to a few years [START_REF] Hamid | Handbook of Polymer Degradation[END_REF][START_REF] Hamid | Lifetime prediction of polymers[END_REF]. Thus, plastic materials do not follow the same degradation processes, such as putrefaction processes for example, which are observable for other biological materials and for which we have an instinctive aversion. Their ageing in our environment does not cause any particular odours for human beings either. Smell, which plays such an important role in the processes of disgust, has no role here. Although specific bacterial communities are known to develop on the surface of plastics, no associated risk has ever been shown [START_REF] Amaral-Zettler | The biogeography of the Plastisphere: implications for policy[END_REF][START_REF] Dussud | Evidence of niche partitioning among bacteria living on plastics, organic particles and surrounding seawaters[END_REF][START_REF] Frère | Microplastic bacterial communities in the Bay of Brest: Influence of polymer type and size[END_REF]Zettler et al., 2013).

Thus, in the first approach plastic materials do not seem likely to activate avoidance mechanisms likely to initiate particular plastic waste management behaviours.

However, while the direct consequences of plastics waste mismanagement for the individual are modest, the consequences for the environment and ecosystems are greater. For example, the ingestion of nano-and microplastics by planktonic organisms affects a wide range of functions such as reproduction, growth or feeding behaviour [START_REF] Besseling | Nanoplastic affects growth of S. obliquus and reproduction of D. magna[END_REF][START_REF] Cole | The impact of polystyrene microplastics on feeding, function and fecundity in the marine copepod Calanus helgolandicus[END_REF].

The ingestion of plastics has an energy cost for organisms that can result in reduced growth, reproduction and health of the organism [START_REF] Sussarellu | Oyster reproduction is affected by exposure to polystyrene microplastics[END_REF][START_REF] Watts | Ingestion of Plastic Microfibers by the Crab Carcinus maenas and Its Effect on Food Consumption and Energy Balance[END_REF]. However, while the ingestion of plastic can be observed by an informed fisherman, when cleaning his catch for example, these kinds of impacts can only be highlighted by scientific means. In addition to direct impacts during ingestion, it should also be noted that plastics interact with additives and micropollutants in the natural environment. Some additives pose significant risks to the environment and health such as DEHP, an endocrine disruptor commonly used as plasticisers in PVC, and which desorbs during the plastic ageing process [START_REF] Doyle | Transgenerational Effects of Di-(2-ethylhexyl) Phthalate on Testicular Germ Cell Associations and Spermatogonial Stem Cells in Mice[END_REF][START_REF] Jeddi | Concentrations of phthalates in bottled water under common storage conditions: Do they pose a health risk to children?[END_REF][START_REF] Kedzierski | Threat of plastic ageing in marine environment. Adsorption/desorption of micropollutants[END_REF][START_REF] Manikkam | Plastics Derived Endocrine Disruptors (BPA, DEHP and DBP) Induce Epigenetic Transgenerational Inheritance of Obesity, Reproductive Disease and Sperm Epimutations[END_REF]. Plastics also adsorb micropollutants in water such as metals [START_REF] Boucher | The influence of cosmetic microbeads on the sorptive behavior of cadmium and lead within intertidal sediments: A laboratory study[END_REF][START_REF] Brennecke | Microplastics as vector for heavy metal contamination from the marine environment[END_REF][START_REF] Holmes | Interactions between trace metals and plastic production pellets under estuarine conditions[END_REF][START_REF] Holmes | Adsorption of trace metals to plastic resin pellets in the marine environment[END_REF], endocrine disruptors [START_REF] Fossi | Large filter feeding marine organisms as indicators of 28 microplastic in the pelagic environment: The case studies of the Mediterranean basking shark (Cetorhinus maximus) and fin whale (Balaenoptera physalus)[END_REF][START_REF] Fossi | Are baleen whales exposed to the threat of microplastics? A case study of the Mediterranean fin whale (Balaenoptera physalus)[END_REF] or persistent organic pollutants [START_REF] Bakir | Competitive sorption of persistent organic pollutants onto microplastics in the marine environment[END_REF][START_REF] Lee | Relationships among the abundances of plastic debris in different size classes on beaches in South Korea[END_REF][START_REF] Rios | Persistent organic pollutants carried by synthetic polymers in the ocean environment[END_REF]. The ingestion by living organisms of contaminated plastics could therefore constitute an additional pathway for these pollutants, although this type of transfer is probably very secondary to micropollutant transfers occurring between an ingested prey and its predator [START_REF] Galafassi | Plastic sources: A survey across scientific and grey literature for their inventory and relative contribution to microplastics pollution in natural environments, with an emphasis on surface water[END_REF][START_REF] Rist | A critical perspective on early communications concerning human health aspects of microplastics[END_REF].

Most of these risks associated with plastic waste are unknown to the general public. Thus, while plastic waste has a clear impact on the marine environment and ecosystems [START_REF] Wright | The physical impacts of microplastics on marine organisms: a review[END_REF]. These impacts are not very sensitive from a human point of view and, even if they can be intellectualised, they are still far removed from the everyday life of users of plastic. This is undoubtedly a key to understand plastic pollution (Science Advice for Policy by European Academies, 2019): by not understanding the impact of plastic waste on the natural environment and by not feeling its impact, users restrict their management efforts to a minimum. This type of psychological limitation was also identified in studies on factors limiting behavioural change in the context of climate change [START_REF] Dietz | Support for Climate Change Policy: Social Psychological and Social Structural Influences*[END_REF][START_REF] Gifford | The Dragons of Inaction: Psychological Barriers That Limit Climate Change Mitigation and Adaptation[END_REF][START_REF] Van Der Linden | Improving Public Engagement With Climate Change: Five "Best Practice" Insights From Psychological Science[END_REF].

Two particular cases?

While it is likely that the avoidance mechanisms, which normally play an important role in our individual waste management, may not be conducive to the proper management of plastic waste, two particular cases are worth mentioning.

In Europe, nearly 40% of the demand for plastic materials comes from the packaging industry (PlasticsEurope, 2018). Most of the plastic materials used in packaging are impermeable to fluids (e.g. blood, fats, drinks) present in food. Nevertheless, traces of these foods can generally be observed only on the surface of the plastic material. Thus, expanded (EPS) and extruded (XPS) poly(styrene) are very often used for food packaging because of their excellent insulating properties, impact resistance and light weight. These materials also have good impermeability to biological fluids despite their very porous structure. The presence of food residues on their surface leads to the necessary management of these wastes to avoid the appearance of odours related to maceration of organic residues. This is the case, for example, for fish trays where organic residues can quickly generate unpleasant odours. This immediate management is also important to avoid the appearance of species attracted by organic residues such as flies, or to limit handling once parasites have contaminated the packaging. Thus, the classic behaviour is to quickly manage this packaging waste in a confined space or at least to keep this packaging waste away from living spaces. Thus, people are more sensitive to health risks, as well as to waste odour issues, than to maintaining a preserved natural environment [START_REF] Tadesse | Household waste disposal in Mekelle city, Northern Ethiopia[END_REF].

In the case of plastic waste that has been in contact with food, avoidance mechanisms are therefore likely to be involved in waste management behaviours, however, in an indirect way.

Plastic waste on beaches or in exceptional natural sites illustrates a second potential example of waste avoidance behaviour [START_REF] Kaseva | Problems of solid waste management on Mount Kilimanjaro: A challenge to tourism[END_REF]. The environmental quality of a beach is often a major concern for tourists [START_REF] Santos | Influence of socioeconomic characteristics of beach users on litter generation[END_REF]. Apart from affecting the recreational capacities of the environment, most of the plastic waste observed in the natural environment does not pose a direct threat to human beings. However, this waste is perceived as 'disgusting' by some users, while others at the same time do not pay attention to it. It seems that certain cultural or experiential aspects of each individual contribute to the perception of these wastes and make the intensity of the experienced discomfort vary from one person to another. In addition, this type of behaviour has economic consequences since the presence of a considerable amount of waste on beaches can result in avoidance behaviours: summer visitors tend to avoid or no longer return to beaches contaminated by plastic waste [START_REF] Free | Highlevels of microplastic pollution in a large, remote, mountain lake[END_REF][START_REF] Retama | Microplastics in tourist beaches of Huatulco Bay, Pacific coast of southern Mexico[END_REF][START_REF] Microplastics Stolte | Microplastic concentrations in beach sediments along the German Baltic coast[END_REF].

Uncontrolled landfilling

A behaviour deeply rooted in time

In the epidemic context of the end of the 15th century in Europe, hygienic trends appear and lead to waste management measures being taken [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. Thus, in the cities of 12th, 13th and 14th century England, household or commercial waste piles were not allowed for more than a few days in the city (Schofield, 2002). In France, a city like Amiens had a waste disposal service and the regulations required that this waste must be disposed of outside the city before sunrise [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. Waste is often exported out of the city, and is either dumped into rivers or transported to areas of natural or artificial depressions (e.g. wells) [START_REF] Bertolini | Déchets et archéologie[END_REF].

If in the Middle Ages the export of waste from the cities and its abandonment in the natural environment was considered an adequate management measure, nowadays this type of management is to be proscribed. However, similar mismanagement behaviours are still observed even in the most developed countries. In France, for example, local political actors consider that this type of waste mismanagement has been constant or even increasing over the last ten years or so [START_REF] Ademe | Caractérisation de la problématique des déchets sauvages[END_REF]. Packaging waste is often observed in the terrestrial environment in a diffuse manner, but with a high frequency. Packaging waste is often abandoned along roadsides, or near voluntary waste drop-off receptacles. While it can also be abandoned in natural environments, this type of waste is more frequently observed in urban areas and are mainly discarded by the inhabitants of the territory or surrounding areas. They are therefore most of the time abandoned in the immediate vicinity of the place of use. individual selfishness and denounce the laxity of law enforcement officials [START_REF] Leguay | La pollution au Moyen Âge[END_REF].

Resistance of populations

These complaints were particularly numerous during the 15th century, when the sharp increase in urban populations, as well as epidemics, probably contributed to an awareness of the risks associated with dumping waste on the streets [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. The lack of awareness among populations of the impact that waste disposal has on the environment and ecosystems is known to be a source of reluctance to change practices. Thus, in Ethiopia, environmental security is a secondary concern for its population [START_REF] Tadesse | Household waste disposal in Mekelle city, Northern Ethiopia[END_REF]. Furthermore, in the particular case of packaging waste, it is often even less of a concern to local authorities than other wastes. In

France, the involvement of the police and the judiciary is therefore often less than for other wastes (e.g. asbestos) (ADEME, 2007). The release of waste into the environment may be partly due to a lack of knowledge among the population about the impact of this waste on the environment and its ecosystems (Pettipas et al., 2016). In the case of plastic waste, it has been shown that awareness-raising actions on the theme of plastic pollution, as well as the identification of human behaviour that has a negative impact on the environment, can facilitate

Sanctions

The texts of the Middle Ages also highlight the struggle for the authorities to impose the policies necessary to preserve public health. Indifference, hostility of residents disturbed in their habits or forced to take responsibility for keeping clean roads often limits the impact of the decisions taken [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. Sanctions have often been proposed to impose virtuous waste management behaviours on populations. However, waste regulations appear in the archives of many European cities, but were rarely enforced by residents. Active policies involving sanitation measures, the relocation of polluting activities, the cleaning of watercourses and the development of cleaning and street state management services seem to be more successful [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. Thus, while in the Middle Ages repressive policies appeared, they generally remained ineffective [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. Nowadays, the lack of sanctions that could encourage good behaviour is commonly cited by local authorities as a major limit to good practice [START_REF] Ademe | Caractérisation de la problématique des déchets sauvages[END_REF]. According to this report, in France sanctions are often initiated by local authorities and sometimes by national entities. They most frequently consist of a reminder of the law, the establishment of infringements and the lodging of a complaint.

The contraventions, disciplinary sanctions and reports to higher authorities are much rarer.

However, these sanctions face many difficulties. First of all, the identification of the responsible is difficult and requires significant resources (e.g. video surveillance), whereas it is considered by those working in the field as one of the most effective means of reducing this type of pollution. In fact, complaints are often dismissed for lack of a responsible person. Furthermore, sanctions, where they can be applied, are often considered to be too lenient and not very dissuasive. These procedures are also often complex and difficult for local authorities to carry out. Moreover, the procedures are often very long, which limits their effectiveness. Thus, these authorities often lack of resources not only to implement these procedures, but also to enforce these sanctions. The final limitations are organisational: the distribution of competences and powers can be complex to allocate and implement by the different actors involved.

Impacts of collection facilities on uncontrolled landfills

The possibilities for collecting plastic waste have an influence on the discharge of waste into the natural environment or the creation of uncontrolled landfills [START_REF] Ademe | Caractérisation de la problématique des déchets sauvages[END_REF]. These include the cost of proper waste management, the distance to waste management centres and public opposition to the establishment of waste management infrastructure.

The problem of waste management costs can be identified in certain texts of the European Middle Ages. For example, waste management initiatives suffer from financial problems, as illustrated by documents from this period describing the difficulties of raising taxes and financing cleaning services in cities. [START_REF] Leguay | La pollution au Moyen Âge[END_REF]. The question of the cost of waste management was a clear limiting factor to its proper management, and it is still an important issue. Consequently, the most common solution used by populations is to discard waste in natural depressions, rivers, near roads or on land with a low market value [START_REF] Tadesse | Household waste disposal in Mekelle city, Northern Ethiopia[END_REF].

Then, it is often local actors who bear the costs of managing and cleaning up abandoned waste.

In the case of beaches frequented by tourists, to limit the economic impact on tourismdependent economic activities that this kind of behaviour has, clean-ups are generally organised by volunteers or local authorities. The costs of cleaning actions can sometimes be compensated when the perpetrators of the pollution are identified. However, as they are difficult to identify, the final cost often lies with the local population and, if it does not have the human and financial means, then the pollution is not eliminated properly. At the global level, the amount of waste management infrastructure is often too small in relation to needs, in particular because of the costs involved in good waste management.

The extensive use of pottery such as amphoras has sometimes led to significant accumulations of waste. For example, Monte Testaccio in Rome is entirely made of 30 and 50 million amphora broken between the first century BC and the third century AD and forming an artificial hill of 600,000 m3 [START_REF] Havlíček | Waste and Pollution in the Ancient Roman Empire[END_REF]. Modern landfilling is a continuous practice of collective waste disposal practises in specific areas and currently the most common and economical solution of waste management [START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF]. In modern times, and more particularly between 1960 and 2002, the mass of household waste collected increased threefold in line with the gradual increase in the population, but also because of the increase in plastic consumption, as well as the best waste collection methods [START_REF] Miller | Garbage and Recycling[END_REF]. At the same time, waste regulations were becoming increasingly stringent, leading to a gradual decrease in the number of landfills from about 8,000 in 1988 to 1,654 in 2005 [START_REF] Miller | Garbage and Recycling[END_REF]. A similar observation can be made in some European countries such as France, where between 1990 and 2013, the amount of household waste storage centres decreased from 500 to around 220 [START_REF] Haeusler | Déchets chiffresclés[END_REF]. This reduction in the number of sites may in some cases have led to the exclusion of part of the population, particularly rural populations, from landfilling sites, which are not very efficient from the point of view of good waste management, but have very low management costs. In some cases, this may have encouraged the return of uncontrolled landfills.

In general, the reluctance to pay for efficient waste management is also one of the major points to explain the existence of some uncontrolled landfills [START_REF] Ademe | Caractérisation de la problématique des déchets sauvages[END_REF].

Reluctance to develop waste management infrastructure can also be observed in some particular context. Waste collection, for example, implies the existence of containers that must be as close as possible to the areas where waste is generated. If the effort to reach the containers is too great, waste is often dumped outside the collection areas. Populations may also oppose the establishment of a collection area, if it is considered too close to residential areas [START_REF] Tadesse | Household waste disposal in Mekelle city, Northern Ethiopia[END_REF]. Thus, sanitary risks, unpleasant smells and inconveniences associated with the presence of this waste are cited by Ethiopian populations to explain the reluctance of using collection facilities. Thus, in this context, the cost-benefit balance is unfavourable to good waste management.

Reuse: a (lost) cultural legacy

The question of the management of packaging and food container waste is a long-standing issue. In this context, the reuse of materials was most widely used before final disposal.

Management of ceramic packaging waste in the past

If ceramic techniques appeared as early as the Palaeolithic period, it was not until the diffusion of Neolithic pottery that ceramic-based waste appeared in archaeological records (Fig. 2) [START_REF] Rice | On the Origins of Pottery[END_REF][START_REF] Vandiver | The Origins of Ceramic Technology at Dolni Věstonice[END_REF][START_REF] Wu | Early Pottery at 20,000 Years Ago in Xianrendong Cave[END_REF]. With them, the first non-degradable packaging waste appears. As early as the 19th century, the Italian geologist Antonio Stoppani proposed considering ceramic fragments as one of the possible markers of the 'Anthropozoic' era due to the high amount of ceramic he found in soils (Stoppani, 1873;[START_REF] Turpin | A new element, a new force, a new input: Antonio Stoppani's Anthropozoic[END_REF].

However, despite their durability, the length of time of their use is sometimes relatively similar to that of a comparable modern packaging. Thus, the duration of the use of an amphora during the Roman Empire is in the order of a few months to a year, comparable to that of modern plastic bottles [START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF][START_REF] Peña | Roman Pottery in the Archaeological Record[END_REF]. Their relative fragility exposes them to the risk of breakage and since the generated debris were generally quickly disposed of [START_REF] Bertolini | Déchets et archéologie[END_REF].

These breakages are often reused to make a floor or wall, or crushed for the manufacture of new building materials or to fill a topographic depression [START_REF] Bertolini | Déchets et archéologie[END_REF][START_REF] Peña | Roman Pottery in the Archaeological Record[END_REF].

The transition to the consumer society

Waste management choices can be related to different demographic factors such as the level of education, house size, or age of the individual [START_REF] Tadesse | Household waste disposal in Mekelle city, Northern Ethiopia[END_REF]. To the extent that these parameters change over time, the associated behaviours also change. Thus, behaviours involving the reuse of functioning objects and the discarding of damaged and useless objects into the natural environment are deeply rooted in the generations born before the arrival of the consumer society [START_REF] Yukalang | Solid Waste Management Solutions for a Rapidly Urbanizing Area in Thailand: Recommendations Based on Stakeholder Input[END_REF]. For those born afterwards, reuse behaviours decrease while those involving the discharge of waste into the environment persist, especially when waste management infrastructure is weak or difficult to access [START_REF] Tadesse | Household waste disposal in Mekelle city, Northern Ethiopia[END_REF].

Considering an object that is perfectly functional to be waste, or that could easily be diverted from its original use, seems to be a major step backwards when compared to the practices observed in the history of mankind. Many reasons can explain why a still functional plastic object is considered as waste. Examples include a low market value or the perception of this object, considered cumbersome or unnecessary at a given time. This is the case, for example whose actual duration of use (i.e. a few weeks to a few months) is no longer correlated to the potential duration of use of the object (i.e. a few years to a few decades) [START_REF] Geyer | Production, use, and fate of all plastics ever made[END_REF].

4.3. Reuse behaviour: an under-exploited source of innovation to improve plastic waste management?

In developing countries, object reuse is the main management behaviour far ahead of reducing consumption or recycling [START_REF] Innocent Sinthumule | Participation in Community-Based Solid Waste Management in Nkulumane Suburb, Bulawayo, Zimbabwe, Resources[END_REF]United Nations Development Programme, 2018). This is due in particular to the fact that waste is more easily perceived as having a value and can therefore be a source of income [START_REF] Yukalang | Solid Waste Management Solutions for a Rapidly Urbanizing Area in Thailand: Recommendations Based on Stakeholder Input[END_REF].

However, despite the predominance of this type of behaviour, scientific knowledge about it is comparatively lower than that of recycling [START_REF] Barr | Defining the multi-dimensional aspects of household waste management: A study of reported behavior in Devon[END_REF][START_REF] Corral-Verdugo | Situational and personal determinants of waste control practices in northern Mexico: a study of reuse and recycling behaviors[END_REF][START_REF] Kaplan | A Behavioral Economic Approach to Green Consumerism: Demand for Reusable Shopping Bags[END_REF]. For example, whether it is for articles on recycling or reuse, in both cases, about 70% of these publications were made by countries with a very high Human Development Index (HDI) [0.8-1.0], but which account for about 20% of the world's population (UNDP, 2019;

United Nations, 2019) (Fig. 3). Countries with a high HDI ([0.7-0.8]) account for about 20% of the publications. Nevertheless, this result is skewed by the fact that China published between 65 and 70% of these publications. The share of scientific publications from countries with HDI below 0.7 is less than 5% for a population of about 3 billion people (about 42% of the world's population). Thus, global scientific research on these behaviours is therefore mainly carried out by the richest countries and probably reflects their needs (recycling rather than reuse). This imbalance leads to a profound lack of knowledge about one of the most important practices involved in the reduction of plastic pollution. Thus, one of the main modes of waste management is poorly documented from the scientific point of view, whilst this type of information could contribute to the development of relevant solutions contributing to the fight against plastic pollution. The use of plastics takes place in a particular context in the history of mankind: that of the consumer society. Thus, the extensive use of plastics combined with a marginal rate of reuse and recycling has generated significant quantities of plastic waste. Some of them are the result of voluntary disposal, while the other has an accidental origin. The intention and manner of disposing of waste are therefore at the heart of the understanding of plastic pollution. Necessity and uselessness are two elements often put forward to explain the disposal of waste. This necessity to discard waste has much to do with the importance of human beings avoiding risks of injury and infection. To this end, communities developed laws that make it easier to maintain a good quality living environment. Thus, in an epidemic context, hygienic trends emerge or become stronger, and this sometimes leads to specific waste management measures. In the absence of an objective measurement of the risks associated with waste, the senses play a fundamental role in the perception of this risk. These senses can lead to disgust, a feeling that plays a very important protective role, especially against pathogens. This feeling is rooted both in innate reflexes, in our culture, but also in our learning. In the case of plastic waste, the associated risks are new, little known by people and the consequences are not very sensitive in everyday life. Thus, the studies carried out on the impact of plastic waste and microplastics

show that if they have consequences on humans, these are mostly indirect and therefore not very obvious from an individual point of view. The underestimation of the social and environmental impact of plastic waste disposal is a part of the explanation for this poor management behaviour. Thus, the dumping of plastic in the natural environment too often remains an act whose consequences are considered harmless.

It also means that the perception of plastics pollution can provide positive feedback on our waste management behaviour. A complex balance must therefore exist between the perceived level of pollution and the way we manage plastics waste. A better understanding of the mechanisms of this balance may help to identify new approaches to address plastics pollution.

Behavioural issues

It is also possible to see the discarding of plastic waste in the natural environment as the persistence of ancient waste management behaviours. In developing countries, a shift has taken place in the chemical composition of everyday objects with the replacement of traditional materials by plastic materials. At the same time, persistence in the habits of waste management (being discarded on the periphery of urbanised areas or directly in the natural environment) is observed and illustrated by the dumping of plastics in the environment, even in the most developed countries.

Where they exist, management efforts may be limited by a combination internal or external user factors. Internal factors may include selfishness, indifference to the consequences, or hostility to actions that will disrupt user habits or force users to take responsibility. For example, measures aimed at installing infrastructure for the collection, landfilling, incineration or recycling of plastic waste may be the subject of 'not in my backyard' behaviours. The availability of these waste collection points and waste treatment sites is, however, a major lever for reducing uncontrolled dumping of plastics. At the same time, repressive policies to fight against poor waste management behaviour are not very efficient as they are often difficult to make effective. Active policies including, for example, awareness-raising among the population, seem more efficient, but have a cost that is sometimes difficult to justify, especially in the poorest countries.

Ways to reduce waste abandonment

Various emerging ways would make it possible to reduce these individual behaviours. One potential path consists of delaying as long as possible the moment when a plastic object is considered useless by its owner. To do this, several lines of thought can be proposed. First of all, facilitate the conversion of the object for another use. This must be considered as soon as the industrialist thinks about the design of the object. The idea is to identify how an object whose initial use is very limited in time (e.g. <1 year), but durable enough to serve for several years, can be diverted from its initial use for other functions. Next, it is necessary to replace single-use objects such as cutlery or plastic bags with objects designed to withstand several dozen or several hundred phases of use. Banning certain single-use plastic objects is now quite common in many countries around the world. It is also necessary to promote the reuse of the material by avoiding, for example, overly complex formulations and additives that are dangerous for humans and the environment. Finally, it is necessary to restore the value of plastics (e.g. taxation of the plastics that have the greatest impact on man and the environment).

Increasing the value of plastic waste and turning it into a source of economic income is an interesting way of encouraging more virtuous behaviour.

It is also important to be able to identify the authors of waste abandonment. For many stakeholders, this issue is an important barrier in the fight against illegal dumping of plastic waste. A reflection should therefore be conducted on the issue of individual traceability of plastic waste in order to identify its last owner. A data file associating the owner and an individual barcode present on the plastic packaging could, in accordance with state legislation, be a relatively simple way for field actors to identify the last owner of a waste.

The factors that control our individual plastic waste management behaviours are numerous and others would benefit from further research. One example is the impact of public policies on our plastic packaging management behaviours. It would also be very interesting having a more global vision of the cultural elements that promote or discourage virtuous waste management behaviours. The acquisition of new scientific knowledge on the issue of plastic pollution is fundamental to determine the most relevant solutions. However, if the dynamics are well underway in the 'hard' sciences, the contributions of the humanities and social sciences remain comparatively marginal on this theme. An important investment in favour of the humanities and social sciences applied to the problem of plastic pollution therefore appears indispensable.

Garbage archaeology applies the principle of the study of the rubbish testimonies [START_REF] Rathje | Rubbish!: The Archaeology of Garbage[END_REF]. In this sense, garbage is a legacy and a study topic for the knowledge of the way of life of our ancestors. Our descendants will have to face a daunting legacy and will seek the reasons why we were unable to find strategies to effectively solve the problem of plastic end of life.

  1. Introduction ........................................................................................................................ 4 1.1. The rise of plastic packaging ....................................................................................... 4 1.2. Voluntary abandonment of plastic waste: a source of plastics pollution..................... 6 1.3. From plastic waste to pollution ................................................................................... 6 1.4. Objectives .................................................................................................................... 8 2. A cost-benefit balance that modulates our individual plastic waste management behaviours 9 2.1. Risk avoidance mechanisms: general cases ................................................................. 9 2.2. Out of sight, out of mind? .......................................................................................... 10 2.3. Two particular cases? ................................................................................................ 12 3. Uncontrolled landfilling ................................................................................................... 13 3.1. A behaviour deeply rooted in time ............................................................................ 13 3.2. Resistance of populations to good waste management practices .............................. 14 4. Reuse: a (lost) cultural legacy .......................................................................................... 18 4.1. Management of ceramic packaging waste in the past ............................................... 18 4.2. The transition to the consumer society ...................................................................... 19 4.3. Reuse behaviour: an under-exploited source of innovation to improve plastic waste management? ........................................................................................................................ 19 5. Synthesis and conclusions ................................................................................................ 21 5.1. The weight of the consequences ................................................................................ 21 5.2. Behavioural issues ..................................................................................................... 22 5.3. Ways to reduce waste abandonment ........................................................................

  to good waste management practices 3.2.1. Incivility Incivility is the main reason evoked by local actors to explain uncontrolled landfilling (ADEME & ECOGEOS, 2019). Public archives of the Middle Ages testify to complaints against

  behavioural changes(Mcnicholas & Cotton, 2019). More generally, prevention actions ranging in communication actions and the setting up of collection systems are generally developed by local actors. However, these actions are judged to be moderately effective by those working in the field (ADEME & ECOGEOS, 2019).

Fig. 3 .

 3 Fig. 3. Although reuse behaviours are very common in many countries (Innocent Sinthumule and Helen Mkumbuzi, 2019; United Nations Development Programme, 2018), scientific publications including the terms 'recycling' and 'behaviour' in their titles are 4 to 5 times more

Table of contents

 of

Acknowledgement .................................................................................................................... 24 References ................................................................................................................................ 24

Acknowledgement

The authors are grateful to the OceanWise project that made this publication possible.

OceanWise is funded by the European Regional Development Fund (ERDF) INTERREG Atlantic Area, under Priority Axis 4: Enhancing biodiversity and the natural and cultural assets.


Ramiro Fernández-Placencia

MD Nicolas Golse

Garcia Cano

PhD Marc-Antoine Allard

PhD Gabriella Pittau

MD Oriana Ciacio

MD Antonio Sa Cunha

MD Denis Castaing

MD Chady Salloum

MD Daniel Azoulay

MD Luis Cano

PhD Daniel Cherqui

PhD René Adam

PhD E Vibert
email: eric.vibert@aphp.fr

Didier Samuel

Spleen volumetry and liver transient elastography: Predictors of persistent posthepatectomy decompensation in patients with hepatocellular carcinoma

Keywords: liver failure, volumetry, liver stiffness, spleen volumetry, hepatocellular carcinoma

ABSTRACT

Background: Post-hepatectomy decompensation (PHD) remains a frequent and poor outcome after hepatectomy, but its prediction is still inaccurate. Liver Stiffness Measurement (LSM) can predict PHD, but there is a so-called "grey zone" that requires another predictor. Because splenomegaly is an objective sign of portal hypertension, we hypothesized that spleen volumetry (SV) could help in the better identification of patients at risk. Methods: Patients with hepatocellular carcinoma who underwent hepatectomy in our tertiary center between August 2014 and December 2017 were reviewed. The primary endpoint was to determine if the SV and LSM were independent predictors of PHD, and secondarily, to determine if they were synergistic through a theoretic predictive model.

Results: One hundred and seven patients were included. The median follow-up time was 3 months [START_REF] Ray | Post hepatectomy liver failure -A comprehensive review of current concepts and controversies[END_REF][START_REF] Gilg | The impact of post-hepatectomy liver failure on mortality: a population-based study[END_REF][START_REF] Golse | New paradigms in post-hepatectomy liver failure[END_REF]. Postoperative 90-day mortality was 4.7%. By multivariate analysis, LSM and SV predicted PHD. The LSM had a cut-off point of 11.6kPa (area under receiver operating curve [AUROC] = 0.71 CI 95% 0.71-0.88, Sensitivity: 89%, Specificity: 47%). The SV cutoff point was 381.1cm 3 (AUROC = 0.78 CI 95% 0.77-0.93, Sensitivity: 55%, Specificity: 91%). The SV improved prediction of PHD, because use of the SV increased sensitivity (from 62% to 97%) and NPV (from 96 to 100%) along with a negligible decrease in specificity (from 96.7 to 93.4) and PPV (from 64 to 59%), (p=0.003).

Conclusions: An SV (>380cm 3 ) and LSM (>12kPa) are non-invasive, independent, and synergistic tools that appear to be able to predict PHD. The importance of this finding is that these measurements may help to anticipate PHD and possibly be used to direct alternative treatments to resection. Key words: liver failure; volumetry; liver stiffness; spleen volumetry; hepatocellular carcinoma INTRODUCTION Hepatocellular carcinoma (HCC), i the most common primary neoplasm of the liver, can be managed via many different treatment modalities. [START_REF] Galle | EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF] Operative treatment that includes either liver resection and transplantation, is the most effective treatment; however, these options may not be applicable, appropriate, or safe in all patients. The biologic behavior of neoplasm and the patients' own clinical characteristics play a preeminent role in the selection process (i.e. tumor burden, liver function, degree of portal hypertension, and patient performance status). [START_REF] Galle | EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF][START_REF] Jarnagin | Surgical treatment of hepatocellular carcinoma: expert consensus statement[END_REF] Although current perioperative management protocols of HCC have decreased the postoperative mortality rates to levels <5%. [START_REF] Ray | Post hepatectomy liver failure -A comprehensive review of current concepts and controversies[END_REF][START_REF] Gilg | The impact of post-hepatectomy liver failure on mortality: a population-based study[END_REF], morbidity after a hepatectomy remains a major concern, especially liver failure. [START_REF] Golse | New paradigms in post-hepatectomy liver failure[END_REF][START_REF] Lafaro | Defining Post Hepatectomy Liver Insufficiency: Where do We stand?[END_REF] Amongst the definitions of post-hepatectomy liver failure (PHLF), the most commonly used are the ISGLS consensus [START_REF] Rahbari | Posthepatectomy liver failure: A definition and grading by the International Study Group of Liver Surgery (ISGLS)[END_REF] and the "50:50 criteria" [START_REF] Balzan | The "50-50 criteria" on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy[END_REF]. Depending on the definition and grading, the presence of PHLF can lead to death in of up to 60%of such patients with postoperative liver failure.(4) Clinical manifestations (i.e. ascites, jaundice, or encephalopathy) that develop or persist more than 3 months postoperatively after liver surgery are known as persistent post-hepatectomy decompensation (PHD) [START_REF] Bruix | Patients : Prognostic Value of Preoperative Portal Pressure[END_REF] and can appear even in the absence of early post-operative PHLF criteria. The incidence of PHD in patients with HCC who undergo liver resection is about 18%. [START_REF] Bruix | Patients : Prognostic Value of Preoperative Portal Pressure[END_REF] depending on the severity of underlying liver disease or the extent of resection Regardless of its cause, hepatic decompensation is a crucial event in the history of cirrhotic patients, which negatively impacts their survival and involves a mortality rate that can vary from 20% to 75%. [START_REF] D'amico | Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies[END_REF] Of relevant implication, PHD is more frequent in patients with clinically important portal hypertension [START_REF] Berzigotti | Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: A systematic review and meta-analysis[END_REF] and is a well-known risk factor of morbidity and mortality after hepatic resection [START_REF] Kulik | Evaluation and Management of Hepatocellular Carcinoma[END_REF]. The preoperative measurement of hepatic venous pressure gradient (HVPG) is the gold standard to diagnose this entity and values <10mmHg are considered appropriate for resection [START_REF] Llovet | EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF]. Currently, the presence of clinically important portal hypertension as a contraindication for hepatectomy h is a subject of considerable debate [START_REF] Lim | Safety of laparoscopic hepatectomy in patients with hepatocellular carcinoma and portal hypertension: interim analysis of an open prospective study[END_REF][START_REF] Cucchetti | Hepatic venous pressure gradient in the preoperative assessment of patients with resectable hepatocellular carcinoma[END_REF][START_REF] Ishizawa | Neither Multiple Tumors Nor Portal Hypertension Are Surgical Contraindications for Hepatocellular Carcinoma[END_REF][START_REF] Cucchetti | Is portal hypertension a contraindication to hepatic resection?[END_REF][START_REF] Tang | Influence of Clinically Significant Portal Hypertension on Hepatectomy for Hepatocellular Carcinoma: a Meta-analysis[END_REF] and its sole presence should not preclude liver resection [START_REF] Galle | EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF][START_REF] Cucchetti | Is portal hypertension a contraindication to hepatic resection?[END_REF][START_REF] Zhong | Controversies and evidence of hepatic resection for hepatocellular carcinoma[END_REF]. Multiple studies have demonstrated that patients with clinically important portal hypertension can be operated with comparable rates of morbidity and mortality to those without clinically important portal hypertension [START_REF] Zhong | Hepatic Resection Is Safe and Effective for Patients with Hepatocellular Carcinoma and Portal Hypertension[END_REF][START_REF] He | The role of clinically significant portal hypertension in hepatic resection for hepatocellular carcinoma patients: A propensity score matching analysis[END_REF][START_REF] Belli | Liver resection for hepatocellular carcinoma in patients with portal hypertension : the role of laparoscopy[END_REF].

Nevertheless, HPVG remains the gold standard for careful patient selection.

Liver Stiffness Measurement (LSM) by Transient Elastography (TE) is a recognised, noninvasive test for the diagnosis of cirrhosis that has been proposed to predict PHLF [START_REF] Cescon | Value of Transient Elastography Measured With Fibroscan in Predicting the Outcome of Hepatic Resection for Hepatocellular Carcinoma[END_REF] and PHD. [START_REF] Rajakannu | Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma[END_REF][START_REF] Procopet | Good performance of liver stiffness measurement in the prediction of postoperative hepatic decompensation in patients with cirrhosis complicated with hepatocellular carcinoma[END_REF] But there is a so-called "grey zone" (12 to 22kPa), where the prediction of outcomes remains challenging and requires the addition of another predictor of PHD.

Splenomegaly is a clinical sign of portal hypertension [START_REF] Mejias | Relevance of the mTOR signaling pathway in the pathophysiology of splenomegaly in rats with chronic portal hypertension[END_REF][START_REF] Procopet | Diagnosis of cirrhosis and portal hypertension: imaging, noninvasive markers of fibrosis and liver biopsy[END_REF][START_REF] Iranmanesh | Accurate computed tomography-based portal pressure assessment in patients with hepatocellular carcinoma[END_REF] that is associated with hemodynamic changes in the portal territory, cytokine release [START_REF] Li | The spleen in liver cirrhosis: revisiting an old enemy with novel targets[END_REF], liver fibrosis, and decreased functional reserve. Therefore, a reliable, non invasive measure of portal hypertension and cirrhosis could help in identifying patients classified as "borderline compensated". In these patients, additional stress factors such as a hepatectomy become the trigger for decompensation. Thus, we hypothesized that the measurement of spleen volume for the prediction of PHD could improve the accuracy of LSM alone in these cases.

This study had the objective of assessing this predicament. First, we attempted to determine if the spleen volume (SV) and LSM were independent predictors of PHD, and then, through a theoretic predictive "decision tree" model, to establish if these factors could have a synergistic effect and decrease this "grey zone".

PATIENTS AND METHODS

We reviewed all patients with a diagnosis of HCC who underwent a hepatectomy between August 2014 and December 2017 at our tertiary centre. Operative variables (intraoperative data and TE results) were collected prospectively. Epidemiologic and biologic variables as well as SV data were abstracted retrospectively into a database. Patients with lacking data (particularly TE, computed tomography of the abdomen, and preoperative biologic tests) were excluded. Nine patients were excluded, because LSM was not accurate because the liver parenchyma was replaced by a large tumor in the region of interest. Informed consent was signed by all patients in compliance with the Helsinki declaration. All cases were included notwithstanding their liver status (presence or absence of cirrhosis) nor the operative approach (open or laparoscopic surgery).

We specifically analysed the following parameters: the LSM, the controlled attenuation parameter (CAP), and the SV. Post-operative variables were collected until postoperative (POD) 90, and the last follow-up was recorded on July 2018.

Spleen Volumetry

All patients included in this study had a pre-operative computed tomography (CT) or magnetic resonance imaging (MRI) performed within a three-month period prior to operation. These images were stored in the DICOM format and were exported retrospectively from the imaging archives to the Myrian ® volumetry software (Intrasense, Montpellier, France). The portal phase was preferred to determine the spleen volume, and the region of interest was semi-automatically delimitated (see Figure 1a-b). When the semi-automatic delimitation of the region of interest extended beyond the spleen, a single operator (RF) corrected the region of interest manually. The dedicated software returned the volumetry in cubic centimetres (cm 3 ).

Transient Elastography

All the reported patients underwent a TE that was performed by either a radiologist or a dedicated nurse. The patients were placed in the supine position with maximum abduction of the right arm with the intention of better evaluating the right liver through the intercostal space and obtaining a thicker cut (6cm minimum) void of large vessels or neoplasm. From each patient, 10 successful measurements were obtained, and the median value was logged.

The equipment used for this study was the FibroScan Touch502 with M/XL probes (Echosens, Paris, France) and the results were expressed in kilopascals (kPa). All patients underwent operation within two weeks from when the measurements were performed. The resulting LSM determined the parenchymal fibrosis.

The Controlled Attenuation Parameter (CAP), another modality obtained by Transient

Elastography and used to determine the grade of steatosis, was collected systematically and analysed (results expressed in dB/m).

Hepatectomy

All patients had a preoperative liver function assessment, (i.e. Child-Pugh Score, MELD score), imaging, and TE. Determined on a case-by-case decision during multi-disciplinary sessions, a few patients were considered to generally not candidates for operative intervention when any of the following items were found: platelet count of <80,000/mm 3 , MELD score >12, >2 HCCs, portal vein tumor thrombosis (macrovascular), ICG-R15>15%, or a poor general overall physical status. In rare and selected cases, these thresholds could have been crossed.

If a patient did not have a sufficient liver remnant, a portal vein embolization (PVE) was performed [START_REF] Farges | Portal Vein Embolization before Right Hepatectomy: Prospective Clinical Trial[END_REF]. Patients for whom tumors were superficially located in the inferior-medial or lateral sections preferentially underwent laparoscopic surgery, whereas patients with large tumors (>5cm), when the tumour was located more deeply, or when i=in in the posteriorsuperior segments, usually underwent open surgery.

The abdominal cavity was carefully explored to rule out the presence of extrahepatic disease.

An intraoperative ultrasonography was performed routinely; and intermittent pedicle clamping was performed in the majority of cases. For parenchymal transection, different energy devices were used, such as bipolar forceps, ultrasonic dissector (CUSA Excel+, Valley Lab Inc, Boulder, USA), and the Ligasure (Medtronic, USA) or the Thunderbeat® (Olympus, Tokyo, Japan) for laparoscopic approach. The goal of the liver resection was to obtain a clean operative margin of at least 2cm, [START_REF] Shi | Partial hepatectomy with wide versus narrow resection margin for solitary hepatocellular carcinoma: A prospective randomized trial[END_REF] or a full anatomic resection when possible [START_REF] Shindoh | Complete removal of the tumor-bearing portal territory decreases local tumor recurrence and improves disease-specific survival of patients with hepatocellular carcinoma[END_REF]. The first control (CT) was performed on POD 7. Minor hepatectomies are defined as resection of ≤2 segments.

Follow-up

Morbidity and mortality were recorded throughout the 90 days of follow-up, which was discontinued when the patient did not exhibit any of the symptoms throughout the 90days or if the patient returned to her/his primary care provider. If hepatic decompensation was present after POD 90, it was considered a PHD. PHLF was defined by the "50:50 criteria"(8) (serum bilirubin >50µmol/L and prothrombin time <50% on POD 5); post-hepatectomy decompensation was defined by the presence of any of the following signs: ascites (determined clinically or detected by ultrasonographyor CT), jaundice (determined clinically) or encephalopathy. Follow-up CTs were obtained at 1-and 3-months post resection simultaneously with the measurements of alpha fetoprotein (AFP). Patients who exhibited ascites during the post-operative period were managed medically with aldactone ± furosemide and albumin infusion as deemed necessary; if these measures were not effective, a paracentesis was performed until all the ascitic fluid was drained. These patients were followed-up every 2 weeks. Liver transplant was considered when there was no resolution of the decompensation after 6 months, unless the transplantation procedure was contraindicated.

Statistical analysis.

The continuous variables were reported as median (range) and categorical variables as counts (percentage). Variables with missing data were excluded from analysis. The Mann-Whitney U test was used for the analysis of continuous variables. The Chi-Square or Fisher's exact tests (when appropriate) were used for qualitative variables.

Parameters with a p<0.05 were included for binary logistic regression (backward elimination) to determine independent factors of PHD. Receiver operating characteristic (ROC) analysis was performed to determine the cut-off points of statistically significant variables (p<0.05) along with their respective sensitivity, specificity, anerepositive and negative predictive values (PPV and NPV, respectively).

As secondary endpoint, a decision tree model was proposed (using clinically relevant variables) after sampling through the bootstrap technique (random of 1000 repetitions).

Afterwards, the data was divided into two groups: a training group (with 70% of all cases) and a validation group (remaining 30%) following Pareto's Principle [START_REF] Macek | Pareto principle -data mining[END_REF][START_REF] Guyon | A Scaling Law for the Validation-Set Training-Set Size Ratio[END_REF]. The decision tree method is a predictive model used widely for classification purposes. It is a nonparametric classification method composed of two parts: the nodes (input variables) and the rules (decision outcomes) [START_REF] Zolbanin | Predicting overall survivability in comorbidity of cancers: A data mining approach[END_REF][START_REF] Kourou | Machine learning applications in cancer prognosis and prediction[END_REF]. The concept of this method of machine learning is to draw a flowchart with a root node on top with a determining question (variable value) and two branches (yes or no). If a given value satisfies a new question, then a node is created. This arrangement repeats itself until the leaf node is determined (final result). This method was selected due to its advantages compared to conventional methods [START_REF] Henrard | Classification and regression tree analysis vs. multivariable linear and logistic regression methods as statistical tools for studying haemophilia[END_REF] that can be used in a complementary fashion to logistic regression as well [START_REF] Fernández | Risk Factors Predicting Infectious Lactational Mastitis: Decision Tree Approach versus Logistic Regression Analysis[END_REF]. The decision tree provides an easy interpretation and flexibility at the time of capturing and classifying the nonlinear behaviors of the data, which are more frequent in daily clinical practice.

Finally, the values of sensitivity, specificity, and PPV and NPV were obtained from the validation group. In order to obtain the differences in the diagnostic ability of the model with and without spleen volumetry, the ROC curves were obtained and compared. In this setting, the sensitivity, specificity, and PPV and NPV were obtained, and the ROC curves were compared using De Long's test. The data were analysed using the following statistical software applications: SPSS v21.0 (IBM Corp, NY, USA) and R (The R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Preoperative and operative characteristics (Table 1).

Among the 208 patients resected for HCC during the study period, 107 patients had complete data and were included in the analysis. Of these, 84 were male and 23 were female, with a median age of 68 (31-87) years. Fifty-eight percent of patients were Child-Pugh A. The median MELD score was 8 [START_REF] Lafaro | Defining Post Hepatectomy Liver Insufficiency: Where do We stand?[END_REF][START_REF] Rahbari | Posthepatectomy liver failure: A definition and grading by the International Study Group of Liver Surgery (ISGLS)[END_REF][START_REF] Balzan | The "50-50 criteria" on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy[END_REF][START_REF] Bruix | Patients : Prognostic Value of Preoperative Portal Pressure[END_REF][START_REF] D'amico | Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies[END_REF][START_REF] Berzigotti | Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: A systematic review and meta-analysis[END_REF][START_REF] Kulik | Evaluation and Management of Hepatocellular Carcinoma[END_REF][START_REF] Llovet | EASL-EORTC Clinical Practice Guidelines: Management of hepatocellular carcinoma[END_REF][START_REF] Lim | Safety of laparoscopic hepatectomy in patients with hepatocellular carcinoma and portal hypertension: interim analysis of an open prospective study[END_REF][START_REF] Cucchetti | Hepatic venous pressure gradient in the preoperative assessment of patients with resectable hepatocellular carcinoma[END_REF][START_REF] Ishizawa | Neither Multiple Tumors Nor Portal Hypertension Are Surgical Contraindications for Hepatocellular Carcinoma[END_REF][START_REF] Cucchetti | Is portal hypertension a contraindication to hepatic resection?[END_REF][START_REF] Tang | Influence of Clinically Significant Portal Hypertension on Hepatectomy for Hepatocellular Carcinoma: a Meta-analysis[END_REF][START_REF] Zhong | Controversies and evidence of hepatic resection for hepatocellular carcinoma[END_REF][START_REF] Zhong | Hepatic Resection Is Safe and Effective for Patients with Hepatocellular Carcinoma and Portal Hypertension[END_REF]; 68 had a score between 6 and 8 points. Viral hepatitis (B and/or C) was the most common cause of chronic liver disease. Before hepatectomy, 10 patients (9.3%) underwent PVE.

The median LSM was 12kPa [3.4-69], and the median spleen volume was 186cm 3 [53.9-1,528]. Laparoscopic resections were performed in 34.6% of patients (n=37) and minor hepatectomies were performed in 80 patients (74.7%). Specifically, partial hepatectomies were completed in 33 patients, anatomic segmentectomies, bi-segmentectomies and left lateral sectionectomies were accomplished in 32, 14 and one patient respectively (n=80). The median follow-up time was 3 months [START_REF] Ray | Post hepatectomy liver failure -A comprehensive review of current concepts and controversies[END_REF][START_REF] Gilg | The impact of post-hepatectomy liver failure on mortality: a population-based study[END_REF][START_REF] Golse | New paradigms in post-hepatectomy liver failure[END_REF]. Barring the deceased patients, the postoperative follow-up extended beyond 90 days.

Pathologic and postoperative outcomes (Table 2).

The median number of HCC tumors was 1 (1-6) and the average tumour size was 3.5cm [0.7-32]; METAVIR scores of F0-F2 and F3-F4 were present in 32.7% and 67.3% of cases respectively (formal cirrhosis F4 in 57.3%). The median duration of hospital stay was 7 days [START_REF] Lafaro | Defining Post Hepatectomy Liver Insufficiency: Where do We stand?[END_REF][START_REF] Rahbari | Posthepatectomy liver failure: A definition and grading by the International Study Group of Liver Surgery (ISGLS)[END_REF][START_REF] Balzan | The "50-50 criteria" on postoperative day 5: an accurate predictor of liver failure and death after hepatectomy[END_REF][START_REF] Bruix | Patients : Prognostic Value of Preoperative Portal Pressure[END_REF][START_REF] D'amico | Natural history and prognostic indicators of survival in cirrhosis: A systematic review of 118 studies[END_REF][START_REF] Berzigotti | Portal hypertension and the outcome of surgery for hepatocellular carcinoma in compensated cirrhosis: A systematic review and meta-analysis[END_REF]. Severe morbidity (Clavien-Dindo ≥ III) was observed in 18 patients (16.8%). Twentyfour patients (22.4%) developed hepatic decompensation during the hospital stay, four (3.7%) of whom fitted the "50:50 criteria" for PHLF, 9 patients (8.4%) persisted after three months with HD. Of note, only one of these patients had PHLF. There were five postoperative deaths before POD 90 (4.7%); two of these patients had evident hepatic decompensation. The first patient had ascites followed by an anastomotic leak of an ileocolic anastomosis that resulted in peritonitis; and the second patient had ascites, jaundice, and encephalopathy followed by pneumonia and respiratory failure. The other 3 patients died with causes unrelated to hepatic decompensation. One patient suffered of decompensated chronic kidney disease and died after being discharged from a geriatric center, a second patient went into cardiogenic shock with subsequent multi-organ failure ,and the third patient died of an undetermined cause (a cardiac event is suspected).

All patients who developed with PHD (n=9) had a METAVIR score of F3-F4. Major hepatectomies were performed in three of these 9 patients. Ascites, the most common manifestation that categorized the designation of PHD was managed with diuretics and albumin. It was noteworthy that three of them required draining paracentesis, another required placement of a drain because of infection of the ascitic fluid. One patient required a repeat laparotomy because of suspicion of peritonitis. Two patients developed jaundice that resolved with supportive measures and one patient was diagnosed with encephalopathy that resolved after 6 days with clinical management that included lactulose enemas. Of the 9 patients diagnosed with PHD, only one received a liver transplant.

Postoperative events, such as a greater hospital stay and hospital readmissions, were more likely to occur in patients with PHD. Of particular importance, none of the patients discharged without evidence of any hepatic decompensation developed PHD afterwards. Other comparative postoperative outcomes are presented in Table 3.

Predictors of PHD (Table 4).

Univariate analysis determined that the following markers were potential risk factors for PHD: hemoglobin, platelet count, total bilirubin, LSM. and SV. The etiology of HCC was not a risk factor for PHD (p=0.504) nor previous PVE (p=0.138) Hemoglobin, LSM, and SV were identified as preoperative risk factors of PHD by binary logistic regression analysis. The LSM had a cut-off point of 11.6kPa (AUROC 0.71 CI 95% 0.71-0.88), with a sensitivity of 89%, specificity of 47%, and a PPV of 14% and an NPV of 98% (Fig. 2). The SV showed a cut-off point of 381.1cm 3 (AUROC 0.78 CI 95% 0.77-0.93), with a sensitivity of 55%, a specificity of 91%, and a PPV of38.5% and NPV of 96% (Fig. 3).

The CAP values were not an independent predictor for PHD (p=0.984).

The decision tree model was performed using SV and LSM; the ROC curves with SV (AUROC 0.983) and without SV (AUROC 0.889) were obtained (Fig. 4) and compared with the De Long's test (p=0.003). If SV was added in the model (Table 5), there was an increase in both the sensitivity (from 62% to 97%) and the NPV (from 96 to 100%) but with a small decrease in both specificity (from 96.7 to 93.4) and the PPV (from 64 to 59%); we maintain that these decreases might be interpreted as negligible if the gain of sensitivity is considered.

Noteworthy, the hemoglobin level was not included in the decision tree, because many factors could have influenced this value (i.e chronic anemia, gastrointestinal bleeding of variceal origin, etc).

DISCUSSION

According to the presented data, Spleen Volumetry and Liver Stiffness Measurements arppear to be potentially important, non-invasive tests with independent and synergistic ability to predict PHD with cut-off values of 380cm 3 and 12kPa, respectively.

The present study shows the findings of a recent and prospectively followed cohort in a tertiary center that manages a high volume of patients with liver disease in which a wide array of therapies is available. Among them, laparoscopic liver resections (35% in the present cohort) are performed frequently, but neither laparoscopy nor minor resections prevented the occurrence of PHD. Of note, 2 of 3 patients who underwent major hepatectomy and developed PHD had both predictors (LSM and SV), while 5 of the other 6 patients who had a minor resection followed by PHD had both criteria. All these patients were scheduled for hepatectomy after multi-disciplinary meetings and a case-by-case evaluation including when available the ICG clearance [START_REF] Roy | Indocyanine Green Retention Rates at 15 min Predicted Hepatic Decompensation in a Western Population[END_REF]., however, this variable had to be excluded from analysis due to the larger number of missing data points (not all patients had an ICG-R15 as part of their assessment) and in those patients who did have the test, it was part of the selection criteria for hepatectomy so its prognostic impact could not be assessed objectively (low range of ICR R15 values in the cohort). In spite of such a careful evaluation of patients and a discussion of their cases, nine patients developed PHD. This finding justifies our search of a new predictor (SV).

The inherent limitations of this study are related to the small number of patients who developed the primary end point of the study-PHD compounded by the careful patient selection using the standard criteria. This low prevalence also determined that laparoscopic and open approaches were analysed together despite the proven benefits of laparoscopic surgery in relation to ascites [START_REF] Belli | Liver resection for hepatocellular carcinoma in patients with portal hypertension : the role of laparoscopy[END_REF][START_REF] Wakabayashi | Recommendations for laparoscopic liver resection: a report from the second international consensus conference held in Morioka[END_REF] and PHLF [START_REF] Morise | Can we expand the indications for laparoscopic liver resection? A systematic review and meta-analysis of laparoscopic liver resection for patients with hepatocellular carcinoma and chronic liver disease[END_REF][START_REF] Xiong | Meta-analysis of laparoscopic vs open liver resection for hepatocellular carcinoma[END_REF]. Another limitation was that not all patients had preoperative measurements of HPVG. Nevertheless, a previous study from our group reported a positive correlation between HPVG, ICG-R15, and LSM [START_REF] Rajakannu | Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma[END_REF] The LSMis a prognostic factor for outcomes after a liver resection for HCC. The mean cut-off predicting poor outcomes were 20-22 kPa in Europe [START_REF] Cescon | Value of Transient Elastography Measured With Fibroscan in Predicting the Outcome of Hepatic Resection for Hepatocellular Carcinoma[END_REF][START_REF] Rajakannu | Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma[END_REF][START_REF] Procopet | Good performance of liver stiffness measurement in the prediction of postoperative hepatic decompensation in patients with cirrhosis complicated with hepatocellular carcinoma[END_REF] and 16 kPa in Asia.(43) Cescon et al. reported that patients had a greater risk of cirrhosis and PHLF when their LSM values were >13 and 20 kPa, respectively.( 23) By considering the previous cut-off points described for LSM (22kPa), our group described a sensitivity of 43% and a specificity of 93%, and the wide "grey zone" of between 14 and 22kPa justified the present study. The threshold observed in the present study was decreased to 11.6kPa with a sensitivity of 89% and a specificity of 47% compared to the previous study by Rajakannu et al [START_REF] Rajakannu | Liver stiffness measurement by transient elastography predicts late posthepatectomy outcomes in patients undergoing resection for hepatocellular carcinoma[END_REF] where the cut-off from previous studies was used. CAP proved to be of no value in predicting PHD, probably because steatotic livers do not necessarily have concomitant fibrosis which is one of the main factors to develop PHD.

The spleen volume was demonstrated to be an independent risk factor for PHD as was LSM.

Spleen volume is an objective and easy-to-use predictor because dedicated software can delimitate the region of interest and calculate spleen volumes accurately in a short time.

LSM is related to the degree of fibrosis and is a marker of the quality of the parenchymal architecture, while splenomegaly is a sign related to hemodynamic changes of the portal venous system. Abnnormalities of in liver stiffness and spleen volume are a result of a complex interaction of the etiology of liver disease,(44) hemodynamic changes [START_REF] Mckenzie | Splenomegaly: Pathophysiological bases and therapeutic options[END_REF], and molecular mediators [START_REF] Li | The spleen in liver cirrhosis: revisiting an old enemy with novel targets[END_REF]. Chronicity of liver disease could play a role in this setting as well.

Thus, splenomegaly portends hepatic decompensation after hepatectomy in cirrhotic patients, but splenomegaly is a clinical manifestation of other conditions that are not necessarily related with clinically important portal hypertension [START_REF] Li | The spleen in liver cirrhosis: revisiting an old enemy with novel targets[END_REF][START_REF] Curovic Rotbain | Splenomegaly -Diagnostic validity, work-up, and underlying causes[END_REF][START_REF] Rajekar | Noncirrhotic Portal Hypertension[END_REF][START_REF] Petrovai | Mechanisms of splenic hypertrophy following hepatic resection[END_REF]. Even in cirrhosis, Kashani et al [START_REF] Kashani | Spleen size in cirrhosis of different etiologies[END_REF], have reported different spleen sizes according to aetiology. Spleen stiffness has also been studied in the context of clinically important portal hypertension, but more studies are required to validate a wider use [START_REF] Huang | Performance of spleen stiffness measurement in prediction of clinical significant portal hypertension: A meta-analysis[END_REF][START_REF] Colecchia | Liver and spleen stiffness and other noninvasive methods to assess portal hypertension in cirrhotic patients: A review of the literature[END_REF]. Nonetheless, the data obtained has a good correlation with the degree of fibrosis and clinically important portal hypertension , depending on the etiology and technique applied [START_REF] Giunta | Role of spleen elastography in patients with chronic liver diseases[END_REF][START_REF] Colecchia | Measurement of spleen stiffness to evaluate portal hypertension and the presence of esophageal varices in patients with HCV-related cirrhosis[END_REF]. Of note is that recently, spleen stiffness and spleen volume have been also reported as predictors of PHLF as well [START_REF] Peng | Spleen stiffness and volume help to predict posthepatectomy liver failure in patients with hepatocellular carcinoma[END_REF].

In our proposed decision tree model, the SV associated with LSM offered a better sensitivity and specificity to predict PHD than using only the LSM. The prediction of PHD should improve the selection of patients in order to decrease severe morbidity rates (present in 8 of 11 patients with PHD), a greater duration of hospital stay, and a greater rate of re-admissions.

Therefore, we maintain that patients with LSM>12kPa and SV>380cc should be offered less invasive treatments (i.e. ablation) that can provide almost comparable cure rates if the HCC is small , without putting the patient at a serious risk during the postoperative period. This selection could also influence the decision to proceed with liver transplantation (when applicable) instead of liver resection and prevent the development of PHD.

To the extent of our knowledge, this study is the first to present the association between SV and LSM for the prediction of PHD after 3 months. The accuracy of this non-invasive association could be used also in the setting of patients where the results of LSM are in the "grey zone". LSM and SV are potentially important, non-invasive tests that should be used in association for predicting PHD and to determine high-risk patients for hepatectomy Thus, these tests might enhance the selection of patients with HCC with or without chronic liver disease who are fit for either resection or who should receive other therapies than hepatectomy.

Fig. 1

 1 Fig. 1 Spleen volumetry (SV) obtained by dedicated software (Myrian®) Normal SVis

Fig. 2 .Fig. 3 .Fig. 4 .

 234 Fig. 2. ROC curve for Liver Stiffness Measurements (LSM) for prediction of PHD

Table 1 . Clinical, laboratory and operative patient characteristics

 1

	n=107 (100%)

Table 2 . Pathologic and post-operative patient characteristics

 2

	n=107 (100%)

Table 4 . Preoperative Independent Risk Factors for PHDat 3 months (n=107)

 4 Variables with a univariate p<0.05 were included for multivariate analysis and are marked in italics. † Independent risk factors are defined by p<0.05 and shown with OR and CI at 95% (marked in bold).ᵠ Mann-Withney U test; ᵡ Fisher's exact test

	Univariate analysis*	Multivariate analysis †

Table 5 .

 5 Area under the ROC Curve (AUROC), Sensitivity, Specificity, PPV, and NPV depending on whether SVis retained in the model

	Model Without	Model With

ACKNOWLEDGEMENTS L.C is supported by the Young Research Teams Associated with IRD Program (INCAncer). . COI/DISCLOSURE: The authors of this manuscript have no conflicts of interest to disclose. FUNDING/SUPPORT: Luis Cano, M.D. is supported by the Young Research Teams Associated with IRD Program (INCAncer).