Leslie Adda
email: leslie.adda@hotmail.fr

Benjamin Batteux

Zuzana Saidak

PhD Claire Poulet

MD Jean-Philippe Arnault

MD Bruno Chauffert

Alice Sejourne

Pharmd

PhD Alice Séjourné

Rheumatic and musculoskeletal disorders induced by immune checkpoint inhibitors: Consequences on overall survival

Keywords: Arthritis, Autoimmunity, Biomarkers, Immunotherapy, T Lymphocytes

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

INTRODUCTION

Under normal physiological conditions, immune checkpoints function as a negative feedback to regulate inflammatory responses following T-cell activation. However, tumor cells are able to evade the host immune system response through activation of immune checkpoints [START_REF] Drake | Mechanisms of immune evasion by tumors[END_REF]. The immune checkpoints cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) with its ligand CD80-CD86 and programmed cell death 1 (PD-1) with its ligands PD-L1 and PD-L2, are currently used as therapeutic targets in oncology. Immune checkpoint inhibitors (ICIs), such as anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab and pembrolizumab), and anti-PD-L1 (avelumab, atezolizumab and durvalumab) have been approved by the Food and Drug Administration (FDA) for the treatment of melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), head and neck cancer, Hodgkin lymphoma, and urothelial cancer. These agents have significantly improved the prognosis of many patients with advanced cancer. However, by removing the natural brakes of T-cell activation, ICIs can disrupt the immunological self-tolerance, leading to immune mediated damage to healthy tissues, also called immune-related adverse events (irAEs). Various organs can be affected, mainly skin, gastrointestinal tract, endocrine glands, liver and lung. The frequency of adverse events (AEs) due to ICIs varies between 61 and 86% of patients treated with anti-CTLA-4 [START_REF] Larkin | Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma[END_REF][START_REF] Weber | Patterns of onset and resolution of immune-related adverse events of special interest with ipilimumab: detailed safety analysis from a phase 3 trial in patients with advanced melanoma[END_REF] and 38 to 82% of patients treated with anti-PD-1 [START_REF] Larkin | Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma[END_REF][START_REF] Topalian | Safety, activity, and immune correlates of anti-PD-1 antibody in cancer[END_REF]. Rheumatic and musculoskeletal AEs have been described in previous studies. Two recent prospective studies reported an incidence of 6.6% [START_REF] Kostine | Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study[END_REF] and 3.5% [START_REF] Lidar | Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors[END_REF] for these events. A variety of clinical presentations have been observed. Arthralgia and myalgia are the most commonly reported symptoms, with a frequency of up to 26% and 12% under anti-PD-1 treatment [START_REF] Baxi | Immune-related adverse events for anti-PD-1 and anti-PD-L1 drugs: systematic review and meta-analysis[END_REF], and 17% and 13% under anti-CTLA-4 treatment [START_REF] Cappelli | Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature[END_REF], respectively. Case series dedicated to rheumatic manifestations under ICIs reported clinical presentations related to inflammatory rheumatism, such as rheumatoid arthritis (RA), polymyalgia rheumatica (PMR), psoriatic arthritis (PA) and other non-classified inflammatory arthritis [START_REF] Cappelli | Rheumatic and Musculoskeletal Immune-Related Adverse Events Due to Immune Checkpoint Inhibitors: A Systematic Review of the Literature[END_REF][START_REF] Belkhir | Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment[END_REF][START_REF] Calabrese | Rheumatic immunerelated adverse events of checkpoint therapy for cancer: case series of a new nosological entity[END_REF]. These rheumatic manifestations are mostly mild to moderate, even if particularly severe forms of myositis have been reported [START_REF] Anquetil | Immune Checkpoint Inhibitor-Associated Myositis[END_REF][START_REF] Eggermont | Adjuvant Pembrolizumab versus Placebo in Resected Stage III Melanoma[END_REF].

According to several studies, the occurrence of irAEs due to ICIs appears to be associated with improved response rate and overall survival (OS). In melanoma [START_REF] Hua | Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab[END_REF] or NSCLC [START_REF] Teraoka | Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study[END_REF] patients treated with anti-PD-1, irAEs have been associated with a higher tumor response rate. Improved OS associated to irAEs was also observed in patients with melanoma [START_REF] Freeman-Keller | Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes[END_REF][START_REF] Teulings | Vitiligolike depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis[END_REF][START_REF] Okada | Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study[END_REF],

NSCLC [START_REF] Owen | Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer[END_REF][START_REF] Sato | Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab[END_REF][START_REF] Haratani | Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer[END_REF], RCC [START_REF] Verzoni | Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program[END_REF] and gastric cancer [START_REF] Masuda | Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab[END_REF]. Moreover, some types of irAEs seem to be particularly associated with these better prognoses. Cutaneous irAEs, like vitiligo in melanoma was were associated with a better response rate [START_REF] Hua | Association of Vitiligo With Tumor Response in Patients With Metastatic Melanoma Treated With Pembrolizumab[END_REF] and better OS [START_REF] Freeman-Keller | Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes[END_REF][START_REF] Teulings | Vitiligolike depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis[END_REF].

Likewise, better OS has been observed in patients with NSCLC who developed thyroid toxicity [START_REF] Osorio | Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer[END_REF]. The same has been observed with rheumatic irAEs, which have been associated with a higher tumor response rate, compared to patients without irAEs [START_REF] Kostine | Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study[END_REF][START_REF] Liew | Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy[END_REF]. Moreover, in a retrospective study, patients with arthralgia showed a better treatment response and improved progression-free survival (PFS) and OS [START_REF] Buder-Bakhaya | Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies[END_REF]. Nevertheless, this question remains controversial, as some studies concluded that there was no association between the appearance of irAEs and OS [START_REF] Horvat | Immune-Related Adverse Events, Need for Systemic Immunosuppression, and Effects on Survival and Time to Treatment Failure in Patients With Melanoma Treated With Ipilimumab at Memorial Sloan Kettering Cancer Center[END_REF], or an associations between the appearance of irAEs and the tumor response, without improved OS [START_REF] Judd | Immune-Related Adverse Events as a Biomarker in Non-Melanoma Patients Treated with Programmed Cell Death 1 Inhibitors[END_REF].

In this context we conducted a single-center retrospective study to analyze the association between the appearance of rheumatic AEs induced by anti-PD-1 or anti-CTLA-4 and OS and tumour response in patients with any type of cancer. We also studied the association between OS and dermatologic AEs, endocrine AEs or any type of AE, to find out if their appearance had a similar effect on survival in our population as the rheumatic AEs.

METHODS

Study design

Patients aged 18 years and older treated that started treatment with anti-CTLA-4 (ipilimumab), anti-PD-1 (nivolumab and pembrolizumab) and anti-PD-L1 agents (avelumab, atezolizumab and durvalumab) alone or in combination, in routine clinical practice in the departments of oncology, dermatology, pulmonology, hematology and gastro-enterology from December 2010 to May 2019 September 2018 were included in this retrospective observational study. Patients were followed up until May 2019. All patients receiving ICI were identified using oncological pharmacy dispensing records. Patients enrolled in clinical trials or receiving concurrent chemotherapy/targeted therapy or with joint or bone pain due to metastatic disease were not included. The baseline patient characteristics were assessed from electronic medical records.

The study was approved by the French National Data Protection Commission (Commission Nationale de l'Informatique et des Libertés (Paris, France); registration number: PI2018_843_0062). Patients were provided with information about the study, and were free to refuse to participate. In line with the French legislation on non-interventional studies, approval by an investigational review board was neither required nor sought.

Collection of baseline patient characteristics

Demographic characteristics (age and sex), body-mass index, and comorbidities were retrospectively collected from electronic medical records: smoking status (defined as "never" or "current/past"), alcohol consumption (defined as daily consumption or not, regardless of the dose), a history of cardiovascular disease (including myocardial infarction, stroke, obliterating arteriopathy of the lower limbs, and deep vein thrombosis, the presence or absence of diabetes mellitus (regardless of the severity), the presence or absence of high blood pressure, the presence or absence of dyslipidemia), a history of cancer and a history of other auto-immune diseases. The type of current cancer, its metastatic status, and the Eastern Cooperative Oncology Group (ECOG) performance status were collected.

Evaluation of AEs, tumor response and OS

AEs were defined as adverse events which were considered to be treatment-related. All AEs related to ICI were identified from electronic medical records, by clinical or biological diagnosis established by the treating clinician, with or without clinical intervention (e.g. treatment, complementary examinations). Rheumatic AEs were assessed if they were recurrent (mentioned in at least two medical reports) or if medication or additional medical examination were required. Patients were included regardless of the fact that they had a history of rheumatic disease. Rheumatic AEs were systematically validated by two rheumatologists (AS and BB), in particular to ensure that joint or bone pain due to metastasis were excluded, and to classify rheumatic AEs as arthritis or arthralgia/myalgia. Cases of arthritis were either clinically confirmed by medical examination or by complementary examinations (e.g. echography). Acute and subacute joint or muscle pain with no other symptoms following ICI initiation were classified as arthralgia/myalgia. For patients with history of similar symptoms, we ensured that they were free of similar symptoms during the months preceding ICI initiation. If the onset of arthralgia was clearly associated with osteoarthritis in the medical records, it was not considered as a rheumatic AE. All AEs were graded using the Common Terminology Criteria for Adverse Events, version 5.0 [START_REF]Common Terminology Criteria for Adverse Events[END_REF].

Tumor response was defined according to RECIST criteria version 1.1 and gathered from the conclusions of the Multidisciplinary Collaborative Meetings (MCM) and from Control Imaging results. Good response to treatment included complete response, partial response and stable disease, as opposed to dissociated response (defined as the concomitant decrease in certain tumoral elements and increase in other sites) or progression of disease. OS was calculated from the date of the initiation of the ICI to death from any cause or the date of the last follow-up examination.

Statistics

In our descriptive analysis, categorical variables were expressed as the number (percentage), and continuous variables were expressed as the mean ± standard deviation (SD) or the median (range), depending on the data distribution. The Shapiro-Wilk test was used to determine whether or not the data were normally distributed.

In bivariate analysis comparing rheumatic AEs and no AE groups, continuous variables were compared using Student's t test or a Wilcoxon's rank sum test (depending on the data distribution), and categorical variables were compared using a chi-square test or Fisher's exact test. Kaplan Meier curves and a log-rank test were performed to compare the OS between rheumatic AEs and non-rheumatic AEs groups. In multivariate analysis, a Cox proportional-hazards model was used. Significant variables (P<0.05) from the bivariate analysis, as well as the most common predictors of death (i.e. age, sex, body-mass index, smoking, alcohol consumption, history of cardiovascular disease, cancer duration and ECOG performance status), were included in the Cox model. If a patient had multiple rheumatic AEs, the event (occurrence of an AE) was the first rheumatic AE.

The same methodology was performed to compare the OS between rheumatic AEs and (i) dermatologic AEs and (ii) endocrine AEs groups.

In order to compare our population with the literature data, the same methodology was performed to compare the OS between AEs and no AE groups.

In order to determine the predictors of the occurrence of rheumatic AEs when using immunotherapy and to determine whether the occurrence of a rheumatic AE was predictive of tumor response, continuous variables were compared using Student's t test or a Wilcoxon's rank sum test (depending on the data distribution), and categorical variables were compared using a chi-square test or Fisher's exact test. In multivariate analysis, a logistic regression was performed. Variables significantly associated with rheumatic AEs (P<0.05) in the previous analysis were included in the model.

All analyses were performed using R software (version 3.6.0, R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

Patient characteristics

Two hundred and sixty-six patients started treatment with ipilimumab, nivolumab or pembrolizumab, monotherapy or combination therapy, between December 1, 2010 and September 1, 2018. Two patients were excluded because of lack of data. A total of 264 patients were included in the analysis. The average age was 65.3 ± 12.5 years. The most prescribed ICI was nivolumab, with 153 patients (58%). Five patients received a combination therapy (nivolumab + ipilimumab). There was no patient treated with anti-PD-L1 therapy.

The majority of cancers were pleuro-pulmonary (46.2%) and melanomas (33.7%). Detailed demographic data are listed in table 1.

Description of AEs

Global description

A total of 50 rheumatic AEs and 324 non-rheumatic AEs were identified, for a total of 374 AEs. Of the 264 patients, 39.8% had no AEs. Among the 374 AEs, the most commonly reported ones were cutaneous (27.0%), gastrointestinal (18.4%), general (15.8%), rheumatic (13.4%) and endocrine (11.2%). The earliest effects were gastrointestinal (median onset at 8.1 weeks) and cutaneous (median onset at 12 weeks); the latest ones were hepatic (median onset at 20.9 weeks).

Rheumatic AEs

Forty-three patients (16.3%) developed at least one rheumatic AE due to ICI. Thirty-seven of the patients (86.1%) had only one rheumatic AE, but six patients presented several separate rheumatic AEs: 5 patients had 2 rheumatic AEs, 1 patient had 3 rheumatic AEs, for a total of 50 rheumatic AEs in 43 patients.

Three patients (7%) had a history of autoimmune or inflammatory rheumatism (1 rheumatoid arthritis (RA), 1 polymyalgia rheumatica (PMR), 1 ankylosing spondylitis (AS)), 5 patients (11,6%) had a history of crystal-induced arthritis and 12 patients (27.9%) had a history of non-inflammatory rheumatic disease. Regarding the 50 rheumatic AEs reported, 36 (72%) were arthralgia/myalgia and 14 (28%) were arthritis, of which 7 were crystalinduced arthritis cases (5 de novo and 2 flares) and 7 cases of inflammatory rheumatism.

Among the inflammatory rheumatic AEs, there were 4 (1.5%) de novo cases (2 PMR, 1 RA and 1 RS3PE syndrome) and 3 (1.1%) flares of preexisting rheumatic disease (1 PMR, 1 RA and 1 AS). Among the cases of arthralgia/myalgia, 6 (16.7%) were flare ups of an existing rheumatic disease condition.

The severity was classified as grade 1 in 50% of the cases, grade 2 in 40% of the cases and grade 3 in 10% of the cases. The median time of occurrence of rheumatic AEs was at 18 weeks after the start of treatment, with extreme values ranging from 0.1 to 133 weeks.

Among the 43 patients with a rheumatic AE, 39 (90%) experienced at least one other type of AE. Among these, the most frequent types were cutaneous (experienced by 47% of patients), gastro-intestinal (35%) and endocrine (23%) adverse events.

The severity was classified as grade 1 in 50% of the cases (n = 25), grade 2 in 40% of the cases (n = 20) and grade 3 in 10% of the cases (n = 5: 1 PMR de novo, 1 RS3PE syndrome, 1 crystal-induced arthritis with knee swelling, 1 case of worsening of RA, 1 case of arthralgia).

Most rheumatic AEs were resolved using grade I or grade II analgesics and NSAIDs. Grade III analgesics were necessary for two three patients: one with crystal-induced arthritis (grade 3), one with a worsening of RA (grade 3) and one with shoulder arthralgia (grade 2). Crystalinduced arthritis cases were treated either by colchicine or by increasing the dose of allopurinol. The use of immunosuppressants (corticosteroids and methotrexate) was required for 9 patients (21%), including 5 patients with grade 3 rheumatic AEs. Eighteen patients (41.9%) received a medical consultation or advice from a rheumatology specialist.

Effect of rheumatic AEs vs. no AE on overall survival and tumor response

Of the 43 patients experiencing at least one rheumatic AE and the 105 patients without any AEs (no AE group), 17 patients and 51 patients died, respectively. The median OS in the no AEs group was 42.7 weeks (95% CI [25.6-not reached]) versus 132 weeks (95% CI [69.3-not reached]) in the rheumatic AEs group (log-rank, P<0.01) (Figure 1).

In multivariate analysis, the OS was significantly improved in the rheumatic AEs group compared to the no AE group (HR 0.54, 95% CI [0.30-0.97], P<0.05). In addition, in this population, the higher the ECOG performance status, the poorer was the survival (Table 2).

There were more responders in the rheumatic AEs group compared to the no AE group (76.8% vs. 21.0% respectively, P<0.001, Table 3). In multivariate analysis, the occurrence of a rheumatic AE was strongly associated with better tumor response (OR = 10.5, 95% CI [3.96-230], P<0.001, Table 4).

Effect of rheumatic AEs vs. dermatologic AEs on OS

OS did not differ significantly in dermatologic AEs and rheumatic AEs groups (log-rank, P=NS, supplementary, figure S1). In this population (n = 97, supplementary, table S1), 17 patients in the rheumatic AEs group and 15 in the dermatologic AEs group died. The median survival in the dermatologic AEs group was not reached and it was 132 weeks (95% CI [69.3 -not reached]) in the rheumatic AEs group.

Effect of rheumatic AEs vs. endocrinologic AEs on OS

OS did not differ significantly in endocrinologic AEs and rheumatic AEs groups (log-rank, P=NS, supplementary, figure S2). In this population (n = 74, supplementary, table S2)), 17 patients in the rheumatic AEs group and 9 in the endocrinologic AEs group died. The median survival in the endocrinologic AEs group was not reached.

Effect of overall AEs vs. no AE on OS

We investigated whether the occurrence of overall AEs (OAEs) was associated with better tumor response and survival compared to patients without AEs. In this population (n = 264, supplementary, table S3), 56 patients in the OAEs group and 51 patients in the no AE group died. The median survival in the OAE group was not reached while it was 42.7 weeks (95% CI [25.6 -not reached]) in the no AE group (log-rank, P<0.001, supplementary, figure S3). In multivariate analysis, the OS was significantly higher in the OAEs group compared to the no AE group (HR: 0.44, 95% CI [0.29-0, 68], P<0.001, supplementary, figure S4). In addition, a high ECOG performance score at the start of treatment with ICIs was associated with poorer survival.

DISCUSSION

In this study, we showed that ICI-induced rheumatic AEs improve OS. The median survival in the rheumatic AEs group was significantly higher compared to the no AE group, reaching 132 weeks and 42.7 weeks, respectively. Multivariate analysis confirmed these results. Our observations are in line with those obtained in studies comparing overall survival in patients without AEs to patients with arthralgia [START_REF] Buder-Bakhaya | Characterization of arthralgia induced by PD-1 antibody treatment in patients with metastasized cutaneous malignancies[END_REF], at least one irAE [START_REF] Freeman-Keller | Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes[END_REF][START_REF] Okada | Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study[END_REF][START_REF] Owen | Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer[END_REF][START_REF] Sato | Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab[END_REF][START_REF] Haratani | Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer[END_REF][START_REF] Verzoni | Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program[END_REF][START_REF] Masuda | Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab[END_REF], a thyroid irAE [START_REF] Owen | Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer[END_REF], or a dermatologic irAE [START_REF] Freeman-Keller | Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes[END_REF][START_REF] Teulings | Vitiligolike depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis[END_REF]. In addition, we observed a better tumor response in the rheumatic AEs group, with 76.8% responders, compared to the no AE group, with 21% responders. Our results also confirm the recent findings of the study by Kostine M. et al. [START_REF] Kostine | Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study[END_REF], in which patients with rheumatic irAEs had a tumor response rate of 85.7% vs 35.3% for patients without irAEs, and the study by Liew DFL. et al. [START_REF] Liew | Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy[END_REF], in which rheumatic irAEs were more common in patients with a good oncological response to therapy (relative risk of 11.2).

Therefore, the occurrence of a rheumatic AE could be a potential predictor of better survival in patients treated with ICIs. One possible hypothesis is that the occurrence of immunological toxicity induced by ICIs reflects the effective T cell response, directed against tumor antigens, leading to anti-tumor activity in tumor tissues, as well as side effects in normal tissues [START_REF] Passat | Physiopathological mechanisms of immune-related adverse events induced by anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies in cancer treatment[END_REF]. Tumor cell lysis by CD8+ cytotoxic activated T lymphocytes releases tumor antigens and neo-antigens which can lead to cross-reactivity with healthy tissues. This phenomenon, called "epitope spreading", as well as bystander activation of T lymphocytes, could be a provide hypotheses to explain the development of irAEs [START_REF] Passat | Physiopathological mechanisms of immune-related adverse events induced by anti-CTLA-4, anti-PD-1 and anti-PD-L1 antibodies in cancer treatment[END_REF][START_REF] Michot | Immune-related adverse events with immune checkpoint blockade: a comprehensive review[END_REF][START_REF] June | Is autoimmunity the Achilles' heel of cancer immunotherapy?[END_REF], including rheumatic and musculoskeletal disorders. In addition to rheumatic AEs, we identified another factor that influences OS, the ECOG performance score. In a multivariate analysis, patients with an ECOG performance score of 0 at the introduction of at the start of treatment with immunotherapy showed better OS than patients with an ECOG performance score of 1, 2 or 3. According to the literature, patients suffering from melanoma have a better tumor response rate compared to patients with other types of cancer (NSCLC, renal cell carcinoma and head and neck carcinoma) [START_REF] Matsuki | Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma[END_REF]. However, in our population, we did not find any association between melanoma and OS in a multivariate analysis: compared to other types of cancer, melanoma was not associated either with better OS or better tumor response.

The study of factors associated with efficacy of ICIs is particularly interesting because a limited proportion of patients respond to treatment [START_REF] Matsuki | Checkpoint Inhibitors and Other Immune Therapies for Hodgkin and Non-Hodgkin Lymphoma[END_REF]. Thus, the identification of predictive response markers for ICIs is a major research area in the field of anti-tumor immunotherapy. The hypothesis that the occurrence of rheumatic AEs could be an early marker of tumor response remains difficult to use in clinical practice. In our study, the median time of onset of rheumatic AEs was at 18 weeks, whereas the first radiological evaluation occurred earlier, usually between 9 and 12 weeks after the beginning of treatment. Furthermore, this median time of 18 weeks was consistent with data in the literature and was within the range of extreme median values reported, from 4 to 45 weeks [START_REF] Lidar | Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors[END_REF][START_REF] Calabrese | Rheumatic immunerelated adverse events of checkpoint therapy for cancer: case series of a new nosological entity[END_REF][START_REF] Burel | Prevalence of immune-related systemic adverse events in patients treated with anti-Programmed cell Death 1/anti-Programmed cell Death-Ligand 1 agents: A single-centre pharmacovigilance database analysis[END_REF].

In our population, the OS did not differ significantly between the dermatologic AEs, the endocrinologic AEs and the rheumatic AEs groups. In the literature, the occurrence of a dermatologic AE [START_REF] Teraoka | Early Immune-Related Adverse Events and Association with Outcome in Advanced Non-Small Cell Lung Cancer Patients Treated with Nivolumab: A Prospective Cohort Study[END_REF][START_REF] Freeman-Keller | Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes[END_REF] or an endocrinologic AE [START_REF] Owen | Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer[END_REF][START_REF] Osorio | Antibody-mediated thyroid dysfunction during T-cell checkpoint blockade in patients with non-small-cell lung cancer[END_REF] has been identified as a predictor of better OS. Therefore, in addition to dermatologic or endocrinologic AEs, the occurrence of rheumatic AEs is another factor that could be considered to be associated with a better OS.

We also investigated whether the occurrence of overall AEs was associated with better tumor response and survival compared to patients without any AEs. The median survival in the no AEs group was 42.7 weeks, while it was not reached in the OAEs group. Multivariate analysis confirmed that survival, as well as tumor response, were significantly higher in the AEs patient group compared to the group of patients without any AEs. Our results are therefore similar in this regard to those obtained in previous studies, in various cancer types [START_REF] Freeman-Keller | Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes[END_REF][START_REF] Okada | Association Between Immune-Related Adverse Events and Clinical Efficacy in Patients with Melanoma Treated With Nivolumab: A Multicenter Retrospective Study[END_REF][START_REF] Owen | Incidence, Risk Factors, and Effect on Survival of Immune-related Adverse Events in Patients With Non-Small-cell Lung Cancer[END_REF][START_REF] Sato | Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab[END_REF][START_REF] Haratani | Association of Immune-Related Adverse Events With Nivolumab Efficacy in Non-Small-Cell Lung Cancer[END_REF][START_REF] Verzoni | Real-world efficacy and safety of nivolumab in previously-treated metastatic renal cell carcinoma, and association between immune-related adverse events and survival: the Italian expanded access program[END_REF][START_REF] Masuda | Correlation between immune-related adverse events and prognosis in patients with gastric cancer treated with nivolumab[END_REF].

The use of immunosuppressants (corticosteroids and methotrexate) was required in a minority of patients (21%). Current data suggest that they should be used with caution, especially at the beginning of treatment, because of their deleterious impact on OS [START_REF] Tison | Safety and Efficacy of Immune Checkpoint Inhibitors in Patients with Cancer and Preexisting Autoimmune Disease: A Nationwide Multicenter Cohort Study[END_REF][START_REF] Arbour | Impact of Baseline Steroids on Efficacy of Programmed Cell Death-1 and Programmed Death-Ligand 1 Blockade in Patients With Non-Small-Cell Lung Cancer[END_REF].

Our observations indicated that their use was decided on collegially, between the referring oncologist and a rheumatologist in most cases (6 cases out of 9 cases). As only a few patients received immunosuppressive therapy, we were not able to study their impact on OS in our population. Therefore, this could involve interpretation bias, since the use of immunosuppressive treatment, that might reduce ICIs efficacy, was limited. The majority of rheumatic AEs observed in this study were mild (90% were grade 1 and 2). No temporary or permanent interruption of ICIs was necessary. This is particularly interesting because, as shown in this study, since patients with rheumatic AEs are more likely to be good responders to ICIs, premature discontinuation of therapy due to severe toxicity would not be beneficial. In addition, except for two patients, all rheumatic AEs were resolved by the end of the follow up. The grade of severity of the rheumatic disorders described in the literature has rarely been reported. This might be explained by the fact that CTCAE grading used by oncologists in ICI trials does not appear to be totally appropriate for rheumatic AEs, due to their heterogeneity, especially regarding rare rheumatic manifestations. Moreover, when the grading of rheumatic AE is made by rheumatologists, there might be some confusion as it differs from their usual evaluation systems, such as Disease Activity Score or the Rheumatology Common Toxicity Criteria used in rheumatological clinical trials [START_REF] Zhong | Rheumatic immune-related adverse events induced by immune checkpoint inhibitors[END_REF].

Nevertheless, with the exception of rare reported cases [START_REF] Calabrese | Rheumatic immunerelated adverse events of checkpoint therapy for cancer: case series of a new nosological entity[END_REF], relatively few rheumatic AEs appear to be at the origin of an interruption of treatment. In this study, less than half of the patients (41.9%) who experienced a rheumatic AE were examined by a rheumatologist. This could indicate that, during the first years following ICI initiation, oncologists were not alerted enough about rheumatic AE screening. Moreover, after reviewing medical reports, we noticed that some patients would have required further rheumatological investigations or an optimized management of rheumatic AEs. Therefore, we recommend a consultation with a rheumatologist upon first clinical symptoms in ICI treated-patients. In our center, this study raised awareness among oncologists and the number of rheumatology consultations increased.

Combination of ICI (nivolumab + ipilimumab) has been described to be associated with a higher rate of AEs [START_REF] Hodi | Nivolumab plus ipilimumab or nivolumab alone versus ipilimumab alone in advanced melanoma (CheckMate 067): 4-year outcomes of a multicentre, randomised, phase 3 trial[END_REF], which was not the case in this study, probably because of a lack of statistical power (n = 5 patients).

Our study had several limitations. First, two patients were excluded due to lack of data.

Then, because of the retrospective nature of the study, information about rheumatic AEs was collected through medical reports and was not systematically evaluated by a rheumatologist. We have collected all rheumatic AEs attributable to the ICIs, even the milder ones, insofar as they appeared under ICI treatment. In the same way, we chose to collect all AEs following ICI initiation, even if their immune character was uncertain. However, it seems difficult to exclude any immune implication in arthralgia/myalgia manifestations, especially since, in some patients, subclinical inflammation could not be verified in the absence of additional examinations (e.g. medical imaging or biological tests). This could explain the relatively high incidence of rheumatic AEs in this study, compared to other prospective [START_REF] Kostine | Rheumatic disorders associated with immune checkpoint inhibitors in patients with cancer-clinical aspects and relationship with tumour response: a single-centre prospective cohort study[END_REF][START_REF] Lidar | Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors[END_REF] or retrospective [START_REF] Liew | Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy[END_REF] studies. That said, if we consider only new inflammatory rheumatisms, their incidence was low (1.5%), which is closer to previously published data [START_REF] Lidar | Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors[END_REF][START_REF] Liew | Association of good oncological response to therapy with the development of rheumatic immune-related adverse events following PD-1 inhibitor therapy[END_REF]. On the other hand, However, some patients suffered from severe comorbidities related to cancer (deterioration of the general state, pain related to metastases, etc.), or even related to the ICI (mainly digestive or pulmonary disorders). In such a context, the inquiry about rheumatic symptoms may have been relegated to the background, or have been more complex, especially in patients with low mobility a poorer ECOG status or those treated with powerful analgesics masking possible joint or muscle pain. This could explain the difference in ECOG status between the rheumatic AEs and no AEs groups.

In conclusion, Immune checkpoint inhibitor-induced rheumatic and musculoskeletal disorders are associated with improved OS and a better tumor response. Their occurrence could be a predictor of better OS. Afflicting 16.3% of patients treated with ICIs, they were generally mild and manageable without any temporary or permanent cessation of ICIs.

These results are encouraging given the long-term response potential of these patients. In this context, the careful detection of rheumatic AEs and their early management seem to be essential, in order to maintain the quality of life of these patients as satisfactory as possible.

Tables 524 525

Table 1 : Characteristics of the study population and comparisons between the RAEs and no AEs groups 526

 1

	Population	No AEs group	RAEs group
	n = 264	n = 105	n = 43

AEs, adverse events; ICIs, immune checkpoint inhibitors; RAEs, rheumatic adverse events; m, mean; max, maximum; med, 529 median; min, minimum; sd, standard deviation 530 531 *P<0.05; **P<0.01; ***P<0.001 532 20

Table 2 : Effect of predictors on overall survival 533

 2

			Crude model	Adjusted model
		N (%)
			HR (95% CI)	HR (95% CI)
	Age	148 (100)	0.99 (0.97 -1.02)	1.00 (0.97 -1.02)
	Body mass index	148 (100)	0.95 (0.91 -1.00)	1.01 (0.95 -1.07)
	Cancer duration	148 (100)	0.99 (0.98 -1.00)	0.99 (0.98 -1.00)
	Sex
	Male	102 (68.9)	Reference	Reference
	Female	46 (31.1)	0.81 (0.47 -1.39)	0.79 (0.44 -1.41)
	History of cardiovascular disease
	Absence of cardiovascular disease	52 (35.1)	Reference	Reference
	Presence of cardiovascular disease	96 (64.9)	0.87 (0.53 -1.42)	0.69 (0.40 -1.19)
	ECOG performance status
	0	41 (27.7)	Reference	Reference
	1	61 (41.2)	2.02 (1.02 -4.01)*	2.39 (1.04 -5.49)*
	2	28 (18.9)	6.14 (2.90 -13.0)***	7.85 (3.09 -20.0)***
	> 3	18 (12.2)	5.80 (2.56 -13.1)***	5.51 (2.08 -14.6)***
	Smoking
	Never	41 (27.7)	Reference	Reference
	Current or past	107 (72.3)	1.85 (1.02 -3.34)*	1.06 (0.51 -2.23)
	Alcohol consumption
	No	106 (71.2)	Reference	Reference
	Yes	42 (28.8)	1.47 (0.89 -2.46)	0.99 (0.98 -1.00)
	Tumor type
	Other	110 (74.3)	Reference	Reference
	Melanoma	38 (25.7)	0.47 (0.26 -0.87)**	1.26 (0.55 -2.91)
	Rheumatic AE
	No	105 (70.9)	Reference	Reference
	Yes	43 (29.1)	0.45 (0.26 -0.79)**	0.54 (0.30 -0.97)*

Table 4 : Multivariate analysis of the association of different parameters to the occurrence of rheumatic AEs 542

 4

			Crude model	Adjusted model
		N (%)
			OR (95% CI)	OR (95% CI)
	Body mass index	138 (100)	1.09 (1.02 -1.17)*	1.02 (0.92 -1.13)
	ICIs duration	138 (100)	1.02 (1.00 -1.05)*	0.98 (0.95 -1.01)
	ECOG performance status
	0	39 (28.3)	Reference	Reference
	1	56 (40.6)	0.34 (0.14 -0.77)*	4.68 (0.62 -98.1)
	2	27 (19.6)	0.21 (0.06 -0.61)**	3.48 (0.51 -74.5)
	> 3	16 (11.5)	0.06 (0.00 -0.31)**	3.01 (0.36 -66.9)
	Smoking
	Never	38 (27.5)	Reference	Reference
	Current or past	100 (72.5)	0.53 (0.25 -1.14)	1.16 (0.39 -3.64)
	Tumor type
	Other	102 (73.9)	Reference	Reference
	Melanoma	36 (26.1)	4.2 (1.93 -9.34)***	2.49 (0.58 -11.24)
	Nivolumab
	No	45 (32.6)	Reference	Reference
	Yes	93 (67.4)	0.40 (0.19 -0.83)*	1.14 (0.39 -3.53)
	Responders
	No	83 (60.1)	Reference	Reference
	Yes	55 (39.9)	10.95 (4.82 -26.8)***	9.67 (3.59 -23.3)***
	543
	*P<0.05; **P<0.01; ***P<0.001

Overall survival in rheumatic AE and no AE groups

  Kaplan-Meier analysis comparing the OS in cancer patients treated with ICI with rheumatic adverse events (RAE group, n=43) or without rheumatic adverse events (no AE-group, n=105). No AE, no adverse event; RAEs, rheumatic adverse events

*P<0.05; **P<0.01; ***P<0.001

Funding

This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Contributors

LA, BB and AS contributed to the conception and design of the study and were involved in the acquisition of data; LA, BB, ZS, BC and AS contributed to the analysis and interpretation of data. All authors contributed to drafting and/or revising the manuscript.

Competing interests

The authors declare that they have no conflict of interest to disclose for this work.

Ethics approval and consent to participate

The study was approved by the French National Data Protection Commission (Commission Nationale de l'Informatique et des Libertés (Paris, France); registration number: PI2018_843_0062). Patients were provided with information about the study, and were free to refuse to participate. In line with the French legislation on non-interventional studies, approval by an investigational review board was neither required nor sought. 21


S Klaimy

J.-F Lamonier

M Casetta

S Heymans

S Duquesne
email: sophie.duquesne@ensc-lille.fr

Recycling of plastic waste using flash pyrolysis -Effect of mixture composition

Keywords: Flash Pyrolysis, Plastic Waste, Model Mixture

Recovery of plastic waste is becoming crucial since the amount of such waste increases continuously.

The objective of this study is to investigate the potential of the pyrolysis technique for the recovery of plastic waste. In that frame, the influence of temperature (550°C or 600°C) on the pyrolysis of pure polypropylene (PP), polyethylene (PE), polystyrene (PS) and polyethylene terephthalate (PET) was first studied. It is shown that whatever the type of polymer, aromatic compounds are mainly formed and could reach 55wt.-% of the oil fraction for PP and 31wt.-% for PE at 550°C. In a second step, a PP/PE mixture and a model mixture representative of the packaging plastic waste stream were pyrolyzed to investigate the influence of a combination of polymers on the proportions and composition of the different fractions. The pyrolysis of the polymer mixtures shows that, even if the aromatic compounds formed are similar to those obtained for the virgin polymers, the proportion of aromatic compounds is much more important than when the polymers are pyrolyzed alone. Indeed, mixing PE with PP at a 50/50 ratio does not affect the amount of liquid, gas and solid fractions but leads to the formation of a higher quantity of xylene (39 wt-%) at 550°C. The combination of the plastics in the model mixture has also led to a decrease of the amount of waxy compounds. Furthermore, it was shown that a higher amount of aromatics than expected was formed. As a conclusion, this study demonstrates that pyrolysis is an effective technique to recover plastic waste as aromatic compounds for the petroleum industry. In the specific conditions used in this study (proposed model mixture and pyrolysis conditions), it will favor the idea that sorting is not needed to recover plastic waste through pyrolysis since aromatics formation is favored when the stream is composed of a mixture of polymers.

Introduction

Europe is a major plastic consumer and produces around 20% of the plastic in the world [START_REF] Plasticseurope | Plastics -the facts 2014/2015: An analysis of European plastics production, demand and waste data[END_REF]. Such materials provide a fundamental contribution to our society due to their wide range of applications [START_REF] Del Remedio Hernández | Catalytic flash pyrolysis of HDPE in a fluidized bed reactor for recovery of fuel-like hydrocarbons[END_REF] in various sectors such as food packaging, textile, automotive, electrical and electronic equipment… Packaging represents around 40% of the plastic consumption including mainly polypropylene (PP), polyethylene (PE), polystyrene (PS) and polyethylene terephthalate (PET). The increasing use of plastics has led to an increase of plastic waste for which different end of life scenarios can be considered. Among them, landfill consumes a lot of space and can cause serious environmental problems. On the other hand, plastic waste incineration does not constitute a longterm solution because of greenhouse gases emission. Moreover, it has a very bad image due to potential risk of toxic gases release such as dioxins, even if those aspects are under control nowadays. Finally, mechanical recycling represents an interesting way to recover plastic waste even if the need for sorting leads to an increased cost of recovered materials [START_REF] Pierella | Catalytic degradation of high density polyethylene over microporous and mesoporous materials[END_REF][4] [START_REF] Merrington | Recycling of Plastics[END_REF]. Moreover, many multi-materials are used in the packaging industry that cannot be separated and thus valorized.

Finally, in France, selective collection of plastics actually concerns bottles (PET) and other plastic containers (PE and PP). The gradual extension of sorting instructions to all plastic types (packaging films, bags, polyester trays, etc.) [START_REF]L'extension des consignes de tri en France : on fait le point[END_REF] should lead to new mixtures of plastic waste that will need valorization. In this context, alternative ways to recover plastic waste as mixture have to be developed and chemical recycling through the pyrolysis technique appears as an attractive solution [START_REF] Kaminsky | Recycling of mixed plastics by pyrolysis in a fluidised bed[END_REF].

Pyrolysis appears to be a promising way to recover plastics since it could transform polymers into liquid fuel or valuable products [START_REF] Ragaert | Mechanical and chemical recycling of solid plastic waste[END_REF][START_REF] Wong | Current state and future prospects of plastic waste as source of fuel: A review[END_REF][START_REF] Kumar | A review on tertiary recycling of high-density polyethylene to fuel[END_REF][START_REF] Al-Salem | Recycling and recovery routes of plastic solid waste (PSW): A review[END_REF]. The pyrolysis of polyolefins leads to the formation of a complex mixture composed of alkanes, alkenes and aromatics. Pyrolysis consists in cracking molecules in absence of oxygen at a temperature between 300 and 900°C in order to obtain liquid, gas and solid fractions. Many parameters affect the pyrolysis and among them, the temperature can be considered as the most important variable in the process. It is generally accepted that low temperatures of pyrolysis favor liquid phase formation and the production of long hydrocarbon chains. By increasing the temperature, the amount of liquid fraction decreases while that of gas increases. Small chains are formed due to breaking of C-C bonds [START_REF] Zorriqueta | Pyrolysis of Polypropylene By Ziegler-Natta Catalysts[END_REF]. Flash pyrolysis is distinguished from the other pyrolysis technics by its relatively higher heating rate and lower retention time [START_REF] Karaduman | Flash pyrolysis of polystyrene wastes in a free-fall reactor under vacuum[END_REF]. It favors the formation of low molecular weight products whereas low heating rate pyrolysis will be used when a higher solid fraction is wanted.

A number of studies have been carried out to investigate the pyrolysis products of PE. As an example, Uddin [START_REF] Md Azhar Uddin | Thermal and catalytic degradation of structurally different types of polyethylene into fuel oil[END_REF] studied the decomposition of different types of polyethylene and showed that the pyrolysis of HDPE at 430°C produces 58.4 wt.-% of liquid, 26.3 wt.-% of waxy compounds, 6.3wt.-% of gas and 9 wt.-% of residue whereas that of LDPE produces 75.6wt.-% of liquid, 8.7wt.-% of waxy compounds, 8.7 wt.-% of gas and 7.5wt.-% of residue also at the same temperature. . The thermal pyrolysis of PE leads to the formation of wax instead of oil. Wax consists of long linear hydrocarbons chains (> C20) which solidify at room temperature [START_REF] Kassargy | Experimental study of catalytic pyrolysis of polyethylene and polypropylene over USY zeolite and separation to gasoline and diesel-like fuels[END_REF]. As the yield of liquid and gas fractions is more important for LDPE, the study of Uddin [START_REF] Md Azhar Uddin | Thermal and catalytic degradation of structurally different types of polyethylene into fuel oil[END_REF] shows that thermal pyrolysis is easier for LDPE than for HDPE. In another study [START_REF] Milne | Recycling of waste plastics by ultrapyrolysis using an internally circulating fluidized bed reactor[END_REF], the pyrolysis of low density polyethylene (LDPE) in a pilot-plant scale internally circulating fluidized bed was carried out and it was shown that more than 90wt.-% of the gas fraction mainly composed of polyolefins can be obtained. At the opposite, Scott et al. [START_REF] Scott | Fast Pyrolysis of Plastic Wastes[END_REF] demonstrate that considering fast pyrolysis of linear low density polyethylene (LLDPE), the condensate (liquid and wax) can reach more than 30wt.-% depending on the experimental conditions. Those results thus demonstrate the importance of the experimental conditions considering recovery of plastic waste through pyrolysis. As far as polypropylene is concerned, Jin et al. investigates the pyrolysis of polypropylene (PP) in a vertical falling film reactor [START_REF] Jin | Molten waste plastic pyrolysis in a vertical falling film reactor and the in fl uence of temperature on the pyrolysis products ☆[END_REF]. They show that, depending on the temperature the recovered oil fraction can varied from 74.4 wt% to 53.5 wt% and is mainly composed of alkenes and naphtenes, aromatics and alkanes are also evolved but in a lower amount. On the other hand, according to R. Miandad et al., the pyrolysis of PP produces 42wt.-% of oil, 54.6wt.-% of gas and 3.5wt.-% of solid residue at 450°C [START_REF] Miandad | Effect of plastic waste types on pyrolysis liquid oil[END_REF]. In this study, a batch reactor using 10°C/min heating ramp was used. The difference in fraction yields can thus be attributed to the type of reactor used and this parameter is crucial considering the fraction yield of pyrolysis products as well as their composition. PS, being composed of an aromatic side chain, decomposes at low temperature following a depolymerisation process presenting a low activation energy [START_REF] Kim | Pyrolysis characteristics of polystyrene and polypropylene in a stirred batch reactor[END_REF].

Therefore, considering PP, PE and PS, the degradation of PS is the fastest followed by that of PP and finally that of PE [START_REF] Singh | Thermal degradation of waste plastics under non-sweeping atmosphere : Part 1 : Effect of temperature , product optimization , and degradation mechanism[END_REF] and the pyrolysis of PS can be performed at a lower temperature than that of PE. The pyrolysis of PET was only studied by very few authors [START_REF] Adnan | Effect of polyethylene terephthalate on the catalytic pyrolysis of polystyrene: Investigation of the liquid products[END_REF][START_REF] Anuar Sharuddin | A review on pyrolysis of plastic wastes[END_REF][START_REF] Fakhrhoseini | Predicting Pyrolysis Products of PE , PP , and PET Using NRTL Activity Coefficient Model[END_REF]. Cepeliogullar and Putun [START_REF] Cepeliogullar | Utilization of Two Different Types of Plastic Wastes from Daily and Industrial Life[END_REF] observed that the liquid oil yield (23.1wt%) was less important than that of the gaseous products (76.9wt%) when pyrolysis is carried out at 500°C with a 10°C/min heating rate while no solid residue is remaining. The main component was benzoic acid which accounts for around 50wt.-%.

Fakhrhoseini and Dastanian [START_REF] Fakhrhoseini | Predicting Pyrolysis Products of PE , PP , and PET Using NRTL Activity Coefficient Model[END_REF] also studied the pyrolysis of PET in the same conditions (temperature and heating rate). The liquid yield was 39.9wt%, 52.1wt% for the gas fraction and a 9.0wt% solid residue was obtained.

Even if the pyrolysis of pure polymers has been widely investigated, that of plastic mixtures is less reported. -% [START_REF] Miandad | Effect of plastic waste types on pyrolysis liquid oil[END_REF]. In those studies, the objective of the recovered oil was to obtained fuel and low attention was paid to clearly establish and study the interaction between the polymers considering the composition of the oil phase.

In this context, the aim of this study is to investigate the flash pyrolysis of packaging plastic waste. In a first step, the composition of a model mixture representative of the packaging plastic waste stream collected in French municipal solid waste (MSW) was established, taking into account literature data and through the analysis of the composition of post-consumer plastic waste. In a second step, flash pyrolysis is carried out on pure PP, PE, PS and PET in order to quantify the different pyrolysis fractions. Then, the composition of liquid oil, which is the main fraction of interest, is determined by GC-MS. Finally, the pyrolysis of a PP/PE mixture and of the model mixture is performed to study the influence of combinations of different polymers on the pyrolysis products formed.

Experimental

Materials

Polypropylene pellets with a density of 0.906g/cm 3 shredded into small pieces was obtained from Baudelet (Blaringhem, France) to determine the composition of the model mixture.

Determination of the model mixture

The determination of the composition of a model mixture (called "model mixture" (MM))

representative of the plastic composition of municipal solid waste (MSW) in France that is poorly valorized, including the evolution of the selective collection policy is crucial to carry out such a study.

Two studies coming from the literature as well as an experimental determination of the composition of a solid recovery fuel sample collected in North of France were used to determine this model mixture.

The first study concerns plastic waste coming from the sorting centers and was carried out by

Valorplast. Based on those data, assumptions were made to evaluate the percentage of each polymer in the model mixture ( The second study was carried out by ADEME [28]. In 2015, ADEME studied the quantity of waste produced in France and its composition. In the report [START_REF] Ademe | Analyse de la chaine de valeur du recyclage des plastiques en France-Synthèse[END_REF], only the uncollected plastic waste was considered (Table 3) as they represent the type of plastic waste directly concerned by the extension of sorting instructions. From the analysis of ADEME data, the composition of the mixture is: 32wt.-% of PP, 42wt.-% of PE, 11 wt.-% of PS and 15wt.-% of PET. The third study was based on experimental considerations. The composition of a solid recovery fuel (SRF) obtained from Baudelet environment (North of France) was determined. To determine the plastic composition, paper, cardboard and wood were first removed manually. Then, the flotation method was used to separate the different polymers according to their density. The SRF sample (about 20g) containing different types of plastics is placed in a beaker containing water (3L).

According to the densities of these plastics (Figure 1), PE and PP will float on the surface whereas the other plastics will sink downward. Polyolefins are further separated using a solution containing 57.9% of ethanol. PS and PET, remaining at the bottom of the water solution, are separated using a solution containing 12 wt-% of NaCl. The samples are then dried, weighted and analyzed by FTIR in order to verify the nature of the plastic material. To ensure the homogeneity of the results, each analysis was repeated three times. Results are summarized in Table 4. From those data, it was thus possible to determine the SRF sample plastic composition: 32% of PP, 24% of PE, 17% of PS and 27% of PET. Table 5 gathers the different data obtained from the three studies. First, it can be seen that the amount of PP and PS are comparable for the three studies. On the contrary, the amount of PET determined in the SFR sample is much more important (around twice as much important) than those obtained from Valorplast and ADEME studies. This discrepancy can be explained by the heterogeneity of the SFR composition. Moreover, in the first two studies, recycled PET was not taken into account in the calculations. So, the amount of PET calculated from literature data is more representative of the real percentage found in the French MSW stream and is thus taken into account to determine the composition of the model mixture (MM). Consequently, the amount of PE in the MM will also be determined from the first two studies.

Finally, from these different studies (Table 5), the composition of the model mixture is defined as, 30wt.-% of PP, 45wt.-% of PE, 10wt.-% of PS and 15wt.-% of PET.

Thermogravimetric analyses

Thermogravimetric analyses (TGA) were carried out to study the thermal decomposition of single and mixed polymers. The analyses were carried out by heating 8 to 10 mg of polymer samples from 25 to 800°C at a 100°C/min heating rate under nitrogen flow (40 ml/min) using a TG 209 F1 LIBRA apparatus. In order to compare the experimental curves to the expected ones, calculated curves were obtained in the case of mixture of polymers by a linear combination of the TGA curves of the virgin polymers weighted by their amount in the mixture. As a consequence, for PP/PE and for the model mixture (MM) that will be detailed in part 3, those curves were determined as follows:

TGAcalculated PP/PE wt% (PP/PE)= 0.5 x TGAexperimental PP wt% (50% PP)+ 0.5 x TGAexperimental PE wt% (50% PE), TGAcalculated MM wt% (MM)= 0.3 x TGAexperimental PP wt% (30%PP) + 0.45 x TGAexperimental PE wt% (45%PE) + 0.1 x TGAexperimental PS wt% (10%PS) + 0.15 x TGAexperimental PET wt% (15%PET).

Pyrolysis equipment and experimental conditions

The laboratory set-up for pyrolysis process investigation is mainly composed of a pyrolysis furnace containing the reactor and a liquid condensation system. The pyrolysis furnace is a CARBOLITE CERGO 30-3000°C and the condensation system is composed of two condensation baths soaked in liquid nitrogen. A schematic representation of the pyrolysis reactor is given in Figure 2. The reactor is made of stainless steel with a length of 700 mm and a diameter of 60.

Liquid phase analysis

The chemical composition of pyrolysis liquid oils i.e. the liquid phase was determined by GC-MS. The GC-MS equipment used was a Thermo Scientific focus GC equipped with a TG-5MS capillary column (15 m long, 0.25 mm diameter and 0.25 µm film thickness) and a DSQII MS. The program used is described in Table 1. Chromatographic peaks were recognized by Replieb and Mainlib library based on their retention times using standard compounds. The percentages of the peaks were calculated from total ion chromatogram (TIC) peak area. The composition of the liquid phase reported in this paper is as a consequence semi-quantitative. Such an approach allow a comparison of the data obtained between each other. Since the objective of the paper is to establish the influence of the composition of the stream on the pyrolysis products, such an approach is well adapted.

Results and discussions

Determination of the Model mixture composition

Thermal pyrolysis of virgin polymers

Thermogravimetric analyses

Figure 3 shows the thermal decomposition of the single polymer (PP, PE, PS and PET) obtained by TGA in the conditions of the flash pyrolysis (N2, 100 K.min -1 ). Considering a 50% weight loss for all polymers, the ranking according to the decomposition temperature is as follows: PS (457°C) < PET (470°C) <PP (487°C) < PE (505°C). Other authors observed this behavior. Demirbas showed that the decomposition of PS is faster than PP and PE and attributes that to the macromolecular structure of polymers and pyrolysis mechanism [START_REF] Demirbas | Pyrolysis of municipal plastic wastes for recovery of gasoline-range hydrocarbons[END_REF]. According to S.M. Al-Salem, the ranking of the decomposition of these polymers is the same as for our study [START_REF] Al-Salem | A review on thermal and catalytic pyrolysis of plastic solid waste[END_REF]. A Lopez et al who studied the influence of time and temperature on pyrolysis of plastic wastes showed that the temperature at which decomposition is maximum of PE is the highest (500°C) followed by PP (475°C) , PET (460°C)

and PS (425°C) [START_REF] López | Influence of time and temperature on pyrolysis of plastic wastes in a semi-batch reactor[END_REF]. Fanfan Xu et al studied also the degradation of PP and LDPE at 100K/min and showed that the maximum weight loss was observed at 491°C and at 508°C for LDPE [START_REF] Xu | Thermal degradation of typical plastics under high heating rate conditions by TG-FTIR : Pyrolysis behaviors and kinetic analysis[END_REF]. It must be emphasized that PET is not completely degraded in our experimental conditions since 7.2 wt% of residue remains. Several authors have already observed this phenomenon [22][34]. They consider that an interlinking reaction between the decomposed products can form stabilized products that can increase the amount of residue [START_REF] Yoshioka | Pyrolysis of poly ( ethylene terephthalate ) in a fluidised bed plant[END_REF]. The amount of each fraction (liquid, wax/viscous liquid, gas and residue), formed during the pyrolysis, changes according to the nature of the polymer and to the pyrolysis temperature. As previously observed in TGA experiments, no residue remains at the end of the experiment except for PET with around 12 wt-.% of residue for both pyrolysis temperatures (Figure 4).

In the case of PP, when the pyrolysis temperature increases from 550°C to 600°C, the amount of liquid increases from 31 to 37wt.-%. This can be related to the decrease of the amount of waxy compounds from 8 to 2wt.-% since the yield of gas is similar for both temperatures. This result is in good agreement with literature studies that generally demonstrate that a temperature increase promotes the cracking of C-C bonds and thus leads to hydrocarbons with shorter carbon chains [START_REF] Aguado | feedstock recycling of plastic waste[END_REF][START_REF] López | Catalytic pyrolysis of plastic wastes with two different types of catalysts: ZSM-5 zeolite and Red Mud[END_REF]. For PE, increasing the pyrolysis temperature decreases notably the yield of wax from 25wt.-% at 550°C to 4wt.-% at 600°C. Wax is formed due to random chain scission of straight long carbon chains of PE. As for PP, the temperature increase affects the degradation of PE and lighter molecular weight compounds are formed [START_REF] Kassargy | Experimental study of catalytic pyrolysis of polyethylene and polypropylene over USY zeolite and separation to gasoline and diesel-like fuels[END_REF]. It can however be observed that in the case of PP, the cracking of waxy compounds leads to the formation of liquid whereas in the case of PE, it contributes to increase the The literature demonstrates that for a given pyrolysis temperature, the gas yield should be superior for PP than for PE. However, in our study, the pyrolysis at 600°C leads to 61wt.-% and 66wt.-% of gas respectively for PP and PE. In the case of PP, it can be supposed that the formation of smaller chains that can interact together to form longer chain of hydrocarbons is favored, leading to an increase in the amount of condensable gases when the conversion is complete and when the residence time is relatively high. Thus, the amount of gases is similar for both temperatures (550°C and 600°C) for PP whereas this amount increases largely for PE.

In the case of PS, the amount of liquid increases slightly from 28 to 34wt.-% when the temperature increases and the yield of gas decreases from 70 to 65wt.-%. These results are surprising and opposite to those of Karaduman et al. who showed that the flash pyrolysis of polystyrene leads to a decrease of the liquid phase from 25 to 21wt.-% and of the solid phase from 40 to 34wt.-% whereas an increase of the gas phase from 35 to 45wt.-% is observed at 825 and 875°C respectively [START_REF] Karaduman | Flash pyrolysis of polystyrene wastes in a free-fall reactor under vacuum[END_REF].

Among all the studied polymers, PS pyrolysis should lead to the maximum conversion into liquid oil due to its simple decomposition process [START_REF] Miandad | Effect of plastic waste types on pyrolysis liquid oil[END_REF]: thermal degradation of PS is mainly a depolymerisation process and a high fraction of styrene is produced. However, the amount of liquid is smaller than expected because of the relatively significant losses during pyrolysis due to the reactor shape and the presence of cold spots where the gases can condense before reaching the condensation system. This phenomenon was not observed during the pyrolysis of the other polymers because the degradation of PS takes place much faster and thus the nitrogen flow inside the reactor is not high enough to allow the evacuation of the degradation gases as they are formed. Thus, the residence time of the degradation products is too high, leading to the condensation of some gases in the cold spots.

Finally, PET pyrolysis was carried out using 0.3 g of polymer instead of 1 g due to the high production of residue that can overflow the spoon of the reactor and can stick to the walls. From the pyrolysis at 550°C, 44% of pale yellow particles were collected in the condensation baths and were thus considered as viscous liquid and this fraction will be further analyzed by GC-MS. Increasing the temperature do not affect the yield of viscous liquid and gas taking into consideration the standard deviation. Whatever the temperature (550 or 600°C), around 12wt.-% of residue remain at the end of the pyrolysis process, far more than for PP, PE and PS. These results are similar to those of Fakhrhoseini et al. who studied the pyrolysis of PET at 500°C. They obtained approximately 40 wt% of liquid oil, 52 wt% of gas and 9 wt.% of solid residue [START_REF] Fakhrhoseini | Predicting Pyrolysis Products of PE , PP , and PET Using NRTL Activity Coefficient Model[END_REF]. As mentioned at the end of the introduction, the fraction of interest is the liquid phase. Thus the next step concerns the determination of the composition of the liquid phase.

Composition of liquid phase obtained from thermal pyrolysis of virgin polymers

Figure 6 shows the composition of the liquid fraction according to the carbon number distribution for the two considered pyrolysis temperatures of the different polymers. At 550°C, a distribution from C6 to C25 with a maximum fraction between C6 and C9 is obtained for PP (Figure 6a). Increasing the pyrolysis temperature increases the amount of C6 and C7 from 15 to 21% and from 24 to 39% respectively. At the same time, the yield of C8 decreases from 35 to 8%. As previously discussed, the cracking of the C-C bonds is favored when the pyrolysis temperature increases, leading to the formation of lighter hydrocarbons. The liquid fraction analyzed using GC-MS contains many compounds and the main ones are listed in Table 6. The liquid oil contains mainly alkenes and cycloalkenes (1,3 cyclohexadiene, 2,4 dimethyl 1,4 pentadiene, 4,4 dimethylcyclopentene) and aromatics (benzene, toluene and p-xylene). The total amount of alkenes and cycloalkenes decreases (30 and 28% at 550 and 600°C respectively) while increasing the temperature whereas the amount of aromatics increases (55 and 61 % at 550 and 600°C respectively). The formation of aromatics in the pyrolysis of polyolefin is accomplished through a Diels-Alder reaction followed by a dehydrogenation. This reaction is favored at higher temperatures [START_REF] Raimbault | Vapocraquage des Vapocraquage des hydrocarbures[END_REF]. 6b and Table 7), the distribution range of carbon number is almost the same as the one observed for PP. C7 compounds are mainly produced whatever the pyrolysis temperature (550 or 600°C). Increasing the temperature increases the amount of C7 and C8 from 37 to 48% and from 16 to 24% respectively. The amount of aromatic compounds formed during PE pyrolysis is lower for PP (31% at 550°C versus 55% for PP). The formation of aromatic compounds may arise from the intramolecular abstraction of an hydrogen atom to give a stable aromatic ring [START_REF] Conesa | Comparison between the Pyrolysis of Two Types of Polyethylenes in a Fluidized Bed Reactor[END_REF]. The easier formation of propene in the pyrolysis of polypropylene may take part in the Diels-Alder reaction favoring the aromatization [START_REF] Aguado | feedstock recycling of plastic waste[END_REF]. The formation of benzene, toluene and xylene during PP and PE pyrolysis was already reported by R. Miandad et al. [START_REF] Miandad | Effect of plastic waste types on pyrolysis liquid oil[END_REF]. They also observed that the amount of aromatics is more important for PP pyrolysis. On the other hand, it could be noted that this high amount of aromatics is not always observed in the literature reporting the pyrolysis of polyolefins such as for example [START_REF] Jin | Molten waste plastic pyrolysis in a vertical falling film reactor and the in fl uence of temperature on the pyrolysis products ☆[END_REF]. It thus demonstrate that the pyrolysis condition are crucial considering the oil composition obtained from pyrolysis. The thermal pyrolysis of PS leads to the formation of C6-C18 range of carbon number (Figure 6c) with two major peaks: the first one between C7 and C9 and the second one between C13 and C17. It can be observed that the amount of light molecules increases when the reaction temperature is raised while the amount of heavier molecules decreases significantly. In fact, the second peak, corresponding to dimers, decreases when the temperature increases. The composition of the liquid fraction obtained from thermal decomposition of PS at different temperatures is shown in Table 8. Only aromatic compounds are detected. Styrene, that can be easily formed from the degradation of PS, represents the main compound with 27.0 and 35.6% at 550 and 600°C respectively. Shah and Jan [START_REF] Adnan | Thermo-catalytic pyrolysis of polystyrene in the presence of zinc bulk catalysts[END_REF] also reported that increasing the temperature leads to an increase in the production of styrene. On the contrary, according to Demirbas et al [START_REF] Demirbas | Pyrolysis of municipal plastic wastes for recovery of gasoline-range hydrocarbons[END_REF], using temperatures higher than 500°C decreases the production of styrene. The amount of toluene and styrene increases with temperature whereas the amount of diphenylethane and 1,3 diphenylpropane decreases. These results are in agreement with literature works [START_REF] Karaduman | Flash pyrolysis of polystyrene wastes in a free-fall reactor under vacuum[END_REF][41] [START_REF] Liu | Pyrolysis of polystyrene waste in a fluidized-bed reactor to obtain styrene monomer and gasoline fraction[END_REF]. Yirong Liu et al [START_REF] Liu | Pyrolysis of polystyrene waste in a fluidized-bed reactor to obtain styrene monomer and gasoline fraction[END_REF] studied the thermal pyrolysis of PS in a fluidized bed reactor at various temperatures and observed that PS is cracked to form lighter hydrocarbons when the temperature increases from 450 to 600°C. Finally, in the case of PET, a carbon number distribution from C6 to C15 with two maximum peaks for C7 and C13 is observed at 550°C. Increasing the temperature decreases the yield of C7-C8 from 53 to 19% and increases C6 yield from 2 to 38%. As shown in Table 9, this peak corresponds to the formation of benzene whose amount increases significantly with temperature while the amount of benzoic acid derivatives decreases sharply from 46 at 550 to 11% at 600°C. The thermal pyrolysis experiments performed with the virgin polymers show that the temperature has an important influence on the composition of the liquid phase. Moreover, each kind of polymer has its own degradation mechanism and thus the composition of the liquid oil differs from one polymer to another. The following step is to see if combining various polymers has an influence on the proportion of the different fractions and on the composition of the liquid oil. As PP and PE are the main plastics used in the packaging industry and as these polymers represent 75wt.-% of the total amount in the model mixture, the pyrolysis of a 50/50 PP/PE binary mixture was investigated.

Thermal pyrolysis of PP/PE binary mixture

Thermogravimetric analyses

TGA experiments were performed for the mixture 50/50 PP/PE in order to see if there is any interactions between these two polymers than can affect the degradation temperature of the mixture (Figure 7). This mixture was selected since PP and PE represent the main constituents of municipal solid waste and also of MM. As it can be seen, the experimental curve tend to degrade faster than the calculated one. The presence of PP in the mixture has led to degrade the PE at a lower temperature. As a result, the maximum degradation temperature shifted to a lower value (499°C) as appears in the DTG curve. These results can conclude that there is an interaction between PP and PE.

Fractions yield

The yields of liquid, gas, wax and residue obtained at 550 and 600°C from the thermal pyrolysis of PP/PE mixture are presented in Figure 8. The yield of liquid and gas increases from 29 to 32wt.-% and from 59 to 67wt.-% respectively when the temperature increases from 550 to 600°C. At the same time, the amount of waxy compounds decreases from 12 to 1 wt.-%. These data have been compared with those theoretically obtained by a linear combination of the virgin PP and PE yields, considering a 50/50 ratio (Figure 8). It can be observed that there is a difference between experimental and calculated value where the amount of wax reaches 17% for calculated value versus 12% for the experimental one. For the gas phase, its amount reaches 55% for calculated value versus 59 % for the experimental value. This behavior prove that the combination of PP and PE has an influence on the pyrolysis fractions. This result was previously explained by thermogravimetric

analyses that shows that the mixture of these polymers can lead to an easier degradation and thus a higher amount of gas is obtained. PP/PE binary mixture. When the temperature is increased from 550°C to 600°C, an increase in the C6 component and a decrease in the C8-C9 amount is observed. Compared to the theoretical values calculated from the pyrolysis of virgin polymers at 550°C and 600°C, it can be seen that, at 550°C, the maximum peak has shifted from C7 to the production of C8 compounds whereas at 600°C, the maximum peak has shifted from C7 to the formation of C6 compounds. In order to understand the reason for these results, the composition of the main compounds is given in Table 10.

Pyrolysis of the PP/PE mixture at a 50/50 ratio leads to the formation of 88% of C6-C9 products.

Increasing the temperature increases the amount of all C6-C9 products to 92%. Benzene, toluene and xylene (BTX products) are the main compounds formed and account for around 65% of the oil fraction. At 550°C (Table 10), the percentages of benzene (at 550°C) and toluene are in good agreement with the calculated ones obtained by linear combination of the results obtained for the virgin polymers weighted by their content. On the contrary, the amount of benzene at 600°C (14%) is slightly higher than the theoretical value (10%). Furthermore, the amount of xylene is almost twice the theoretical value at 550°C (39 and 20.3% for the experimental and theoretical values respectively) and 7 times more than the theoretical value at 600°C (35 and 6% for the experimental and theoretical values respectively). Thus, even if mixing PP with PE does not really affect the yield of the liquid oil fraction, the composition is different when both polymers are combined. Ciliz et al studied also a PP/PE mixture from waste plastics and observed the formation of 32 wt-% of aliphatic compounds while the mono aromatics constitute 30 wt-% [START_REF] Ciliz | Pyrolysis of virgin and waste polypropylene and its mixtures with waste polyethylene and polystyrene[END_REF]. In this study, propylbenzene has reached 16 wt-% while the percentage of toluene and xylene were both 5 wt-%. Thus, combining PP and PE in the pyrolysis mixture is of significant advantage for pyrolysis purpose as TGA experiments prove that the decomposition is slightly accelerated when PP and PE are combined.

Moreover, this mixture allows obtaining a better selectivity in the composition of the liquid fraction compared to the pure polymers: around 65% of BTX compounds. However, the thermal degradation mechanism is similar for both PP and PE, being a radical mechanism. But, what happens when polymers having potentially a different thermal degradation process are incorporated in the mixture?

The next section is thus devoted to the pyrolysis of the model mixture (MM) composed of PP, PE, PS and PET.

Thermal pyrolysis of the model mixture

Thermogravimetric analyses

The test was carried out for the model mixture MM composed of 30 wt-% of PP, 45 wt-% of PE, 10 wt-% for PS and 15 wt-% of PET and was compared to the calculated curve in order to see the influence of the mixture on the process of the degradation. As it can be seen from Figure 10, the degradation of the model mixture is accelerated where there is 20°C of difference between the two curves. This result shows that adding PS and PET to the mixture even with a small amount has led to a faster degradation than expected. Furthermore, the degradation of the model mixture is extended in a wide degradation temperature span as appears in the derivative weight curve. Therefore, the large peak of degradation can be a combination of peaks of the individual plastics due to the different temperature range. As the degradation of PS is the faster, this decisive step will initiate the reaction of degradation. The radicals formed will be the primary radicals for PP and PP degradation.

The mechanism of degradation of the mixture is detailed by Costa et al [START_REF] Costa | Study of the Pyrolysis Kinetics of a Mixture of Polyethylene , Polypropylene , and Polystyrene[END_REF]. This result is the reason of the acceleration of the degradation process of the MM.

Fractions yield

The pyrolysis of the model mixture (30%PP/45%PE/10%PS/15%PET) was carried out and the yields obtained (weight %) for the different fractions are presented in Figure 11. An increase from 26 to 32wt.-% and from 61 to 63 wt.-% of the liquid and gas fraction fraction is observed when the temperature increases from 550°C to 600°C, while the amount of wax decreases from 11 to 3 wt.-%.

It is also possible to compare those data with the theoretical yield values calculated by a linear combination of the yields obtained for the virgin polymers (Figure 11). A reduction by half of the amount of wax and an increase of the amounts of liquid and gas are observed compared to the theoretical values. This phenomenon can be attributed to the increase in the number of free radicals when adding PS to the mixture that can accelerate the decomposition of the reaction and thus decrease the amount of waxy compounds [START_REF] Kim | Catalytic recycling of the mixture of polypropylene and polystyrene[END_REF]. This result is in agreement with TGA curves that proves also the interaction between the polymers and the acceleration of the degradation process.

The presence of a residue can mainly be attributed to the presence of PET in the mixture and is supported by TGA experiments that demonstrate the formation of 0.4 wt-% of residue in the case of the MM.

Composition of the liquid phase for the model mixture

Mixing PP, PE, PS and PET leads to a new distribution of the liquid products that do not fit with the theoretical values at 550 and 600°C as shown in Figure 12. The amount of light hydrocarbons is higher than the theoretical values especially for C6 at 550°C and C7 at 600°C. Furthermore, the formation of new products that were not detected with virgin polymers occurs at 550°C like 4 methyl 3 penten 2-ol and 1,4 cyclohexadiene (Table 11). Indeed, aromatic compounds represent 59% of the total amount of liquid at 550°C. Surprisingly, increasing the temperature from 550°C to 600°C leads to an increased amount of C7 fraction, especially the quantity of toluene, from 24 to 61% while the amount of benzene and styrene decreases from 13 to 6 and from 16 to 7% respectively. The pyrolysis of the PP/PE mixture leads to an amount of xylene twice as important as the theoretical yield whereas the liquid fraction obtained after the pyrolysis of the MM at 600°C is mainly composed of toluene (around 6 times more than the theoretical value). This large amount of toluene could be interesting if the valorization of the liquid fraction is considered. The main objective of this study was to evaluate the effect of mixture composition on the pyrolysis oil yield and composition. For that, in a first part, a model mixture composition was determined in order to establish a mixture representative of the plastic waste in France. Then, the virgin plastics were pyrolyzed at 550 and 600°C. It was shown that the pyrolysis of PP, PE, PS and PET leads to the formation of C6-C25 hydrocarbons in the pyrolysis oil. This oil is mainly composed of aromatic compounds (BTX and Styrene). Liquid oil from PP pyrolysis contains benzene, toluene and xylene as major compounds at 550 and 600°C. PE produces also aromatics and the major compounds are toluene and xylene at 550°C and 4,4 dimethylcyclopentene and xylene at 600°C. PS pyrolysis leads to the formation of styrene (27 and 34%) at 550 and 600°C. In the case of PET, it was shown that benzoic acid derivatives are mainly formed at 550°C. The study of the pyrolysis products obtained in the case of mixture of polymer (PP/PE and model mixture) shows that, even if aromatics compounds are also obtained similarly to the results obtained for virgin polymers, the ratio between the aromatics compounds varies when the polymers are pyrolyzed alone or in the case of a mixture.

Indeed, mixing PE with PP at a ratio of 50/50 does not affect the amount of the liquid, gas and solid phase but it leads to form a high quantity of xylene at 550°C where the amount is twice the theoretical value. For the model mixture, it was observed that adding PS and PET to PP and PE leads to obtain 61% of toluene which is six times more than the theoretical value. These results are promising for valorizing the liquid phase especially for a mixture of plastic that is representative of the waste in France. Thus, this study demonstrates that pyrolysis is an effective technique to recover plastic waste. In particular, aromatics compounds can be obtained and recovered in the petroleum industry.

Figure 1 :

 1 Figure 1 : Densities of plastic materials

  3 mm. As flash pyrolysis is considered in this study. Prior to the start of the experiment, the sample carrier is placed in the cooling coil possessing a 152 mm length and a 25 mm diameter and which is coupled to a water shiller ( LAUDA ECO SILVER) to maintain a constant temperature of 20°C. When the equilibrium temperature is reached in the reactor, the sample carrier allows introducing directly the sample into the center of the furnace at the pyrolysis temperature. It permits a rapid increase of the temperature of the sample and a flash pyrolysis can thus be considered.The experimental protocol is defined as follows: 1g of polymer is placed in the sample carrier located in the cooling coil. The reactor is then purged with a nitrogen flow at 5L/min for 5 minutes and an oxygen analyzer controls the absence of oxygen in the furnace. The nitrogen flow is then fixed at 200ml/min for the whole experiment Once the furnace is purged and the desired temperature equilibrated, the sample is rapidly introduced into the reactor thanks to the sample carrier. The reaction time is fixed at 40 minutes. This time corresponds to the time required for the complete pyrolysis of the polymers (considering modification of temperatures and polymer types). At the end of the experiment, the liquid phase, corresponding to the vapors trapped thanks to two condensation baths, and the solid residue are weighed; the waxy compounds located at the end of the reactor (prior to the condensation bath) are also collected and weighed. The gas yield is calculated by subtracting the liquid, the wax and the residue content from the initial polymer weight.The liquid fraction contains molecules containing from 6 to 25C. Each experiment is repeated at least twice to ensure the repeatability of the pyrolysis pilot experiments. The results presented in this paper correspond to the average data. It was determined data are obtained with an experimental error of 3wt.-%.

Figure 2 :

 2 Figure 2: Home-made reactor used for the flash pyrolysis

Figure 3 :

 3 Figure 3 : TGA of the pure plastic materials

Figure 4 :

 4 Figure 4: Effect of the temperature on the pyrolysis fractions yield (liquid, wax, gas and residue) of PP, PE, PS and PET carried out at 550°C and 600°C

  since the temperature slightly affects the amount of liquid obtained(26 wt.-% at 550°C vs. 29 wt.-% at 600°C).On the other hand, thermal pyrolysis of PP leads to a high yield of gas (61wt.-%) compared to that of PE (48wt.-%) at 550°C. The difference in the structure between the two polymers can explain these results because PP is characterized by the presence of a methyl group that leads to an easier decomposition compared to PE. The presence of tertiary carbons allows an easier decomposition of this polymer and a stronger cracking of C-C bonds[START_REF] Kassargy | Experimental study of catalytic pyrolysis of polyethylene and polypropylene over USY zeolite and separation to gasoline and diesel-like fuels[END_REF]. The thermal decomposition mechanism of these polymers is a radical mechanism. It consists in the formation of free radicals either by random chain scission or by end chain scission. This step can be followed by the formation of random radicals via hydrogen transfer. For PP, β-cleavage is the dominant type of cleavage during propagation because the energy of the C-C bond in β position is the lowest. It leads to the formation of an olefinic group with a terminal chain and a radical. The reaction is done either by assembly of two radicals or by the disproportionation[18][36]. The degradation mechanism of PE is presented in Figure5.

Figure 5 :

 5 Figure5: The degradation mechanism for thermal pyrolysis of PE[START_REF] Karaduman | Flash pyrolysis of polystyrene wastes in a free-fall reactor under vacuum[END_REF]

Figure 6 :

 6 Figure 6: Carbon number distribution of oil derived from thermal pyrolysis at 550 and 600°C of a) PP; b) PE; c) PS; d) PET

Figure 7 :

 7 Figure 7 : TG and DTG for PP/PE mixture compared to TG calculated curve for 50%PP+50%PE

Figure 8 :Figure 9

 89 Figure 8: Amount of the different pyrolysis fractions for the PP/PE mixture: comparison between experimental results and calculated ones (by linear combination) at 550 a) and 600°C b)

Figure 9 :

 9 Figure 9: Carbon number distribution of liquid fraction for the PP/ PE mixture at 550 and 600°C

Figure 10 :

 10 Figure 10 : TG and DTG curves for the MM compared to the calculated curve

Figure 11 :

 11 Figure 11: Amount of the different pyrolysis fractions for the MM: comparison between experimental results and calculated ones (by linear combination) at 550 a) and 600°C b)

Figure 12 :

 12 Figure 12: Carbon number distribution of the thermal pyrolysis of the model mixture

  Kaminsky et al. studied the pyrolysis of a plastic mixture composed of 75wt.-% of PP and PE and 25wt.-% of PS at 730°C. The amount of liquid oil was 48.4wt.-%[START_REF] Kaminsky | Thermal degradation of mixed plastic waste to aromatics and gas[END_REF]. The mixture of PP, PE, PS and PET (40/20/20/20) coming from disposable plates, grocery bags and cups leads after pyrolysis to 40wt.-% of liquid oil, while gases and char yields represent respectively 42 and 18wt.

Table 2

 2

	). PET was not taken into account in the calculation since PET
	bottles are usually well sorted and valorized in France. Then, only PP, PE, PS and PET (not coming
	from the bottles) were considered in the calculation (PVC and multi-materials were not included).
	Finally, the percentage of PE/PP in the bottles and flasks corresponds to the selective collection of
	plastics from MSW in France with 75% of PE and 25% of PP in the PP/PE mixture since PE is largely
	more used than PP.
	This study leads to a first model mixture composed of 27wt.-% PP, 47wt.-% PE (including HDPE, LDPE
	and LLDPE), 14wt.-% PS and 12wt.-% PET.

Table 2 :

 2 Quantity of plastics (in tonnes) used according to the study of ValorPlast

Table 3

 3

	: Quantity of plastics (in kTonnes) used according to the study of ADEME [25]
		PP PE (HDPE and LDPE)	PS	PET	Total
	Total solid waste	650	1 150	200	420	2420
	Collected amount to be recycled	160	500	30	180	870
	Potential amount of plastic to be recovered 490	650	170	240	1550
	Composition from ADEME data (wt.-%)	32	42	11	15	100

Table 4 :

 4 Determination of the SFR sample composition (in %)

	Analysis	PP	PE	PS	PET
	1	33	19	16	32
	2	30	29	18	23
	3	34	23	18	25

Table 5 :

 5

	Composition from Valorplast data	27	47	14	12
	Composition from ADEME data	32	42	11	15
	Composition from SFR sample	32	24	17	27
	Model mixture composition	30	45	10	15

Comparison of the polymeric compositions determined from the 3 previous studies (Tables

2 to 4

) Study PP (wt.-%) PE (wt.-%) PS (wt.-%) PET(wt.-%)

Table 1 :

 1 GC-MS protocol

	Column	TG5-MS
	Carrier gas	He
	Carrier gas flow	1ml/min
	Initial temperature/ initial time 40°C/15min
	Heating rate	0.5°C/min
	Final temperature/ final time	160°C/ 15min
	Injection temperature	300°C
	Injection volume	split (10:1)
	split flow	10ml/min
	Transfer line	300°C

Table 6 :

 6 Major compounds formed in the liquid phase obtained from PP pyrolysis

	Compounds	% at 550°C	% at 600°C
	Benzene (C6H6)	6	11
	1,3 cyclohexadiene (C6H8)	10	9
	Toluene (C7H8)	19	25
	2,4 dimethyl 1,4 pentadiene (C7H12)	6	2
	4,4 dimethylcyclopentene (C7H12)	0	6
	p-xylene (C8H10)	31	4
	propylbenzene (C9H12)	0	10
	1,2,4 trimethylbenzene (C9H12)	0	5
	Considering PE (Figure

Table 7 :

 7 Major compounds formed in the liquid phase obtained from PE pyrolysis

	Compounds	% at 550°C % at 600°C
	Benzene (C6H6)	5	8
	1,3 cyclohexadiene (C6H8)	9	3
	Toluene (C7H8)	16	4
	1,3 cycloheptadiene (C7H10)	7	3
	4,4dimethylcyclopentene (C7H12) 5	32

Table 8 :

 8 Major compounds formed in the liquid phase obtained from PS pyrolysis

	Compounds	% at 550°C % at 600°C
	Toluene (C7H8)	17	20
	Styrene (C8H8)	27	36
	Methylstyrene (C9H12)	6	12
	1,2,4 trimethylbenzene (C9H12)	0	6
	Diphenylethane (C14H14)	12	5
	α-methylbibenzyl (C15H16)	5	1
	1,3 diphenylpropane (C15H16)	13	5
	1,2,3,4 tetrahydro 2 phenyl naphatalene (C16H16)	11	5

Table 9 :

 9 Major compounds formed in the liquid phase obtained from PET pyrolysis

	Compounds	% at 550°C % at 600°C
	Benzene (C6H6)	2	38
	benzoic acid (C7H6O2)	32	11
	3 methylbenzoicacid (C8H8O2)	14	0
	Styrene (C8H8)	0	7
	2,4 dimethylphenylbenzene (C13H12O)	9	11
	2 ethenylnaphtalene (C12H10)	15	16

Table 10 :

 10 Major compounds formed from the pyrolysis of the PP/PE mixture at 550°C and 600°C (Calculated value are obtained by linear combination of the results obtained for pure polymers weighted by their content i.e. 50% for PE and 50%

	for PP)
		Exp % at	Calculated	Exp % at	Calculated
		550°C	% at 550°C	600°C	% at 600°C
	Benzene	7	5	14	10
	Toluene	19	18	14	15
	Xylene	39	20	35	6
	Total	65	43	64	30

Acknowledgments

The authors would like to thank the Région Hauts-de-France and University of Lille (France) for funding this project.