Penny Kong
email: penny.kong@tum-create.edu.sg

Flore Vallet

Al Maghraoui

Henriette Cornet

; Frenkler

Seeking Emotions in Mobility Experience Elicitation: A Singapore-France Comparison

Keywords: emotional design, empirical design, data collection methods, user experience, mobility

Designing mobility experiences is complex. Technical issues can be out of a designer's scope or require the long-term development of solutions. Emotions and contexts shape user perceptions of experiencesthe stronger the emotional reaction, the better people remember the experience. In this exploratory study, the focus is on the research stage of the design process and seeks to identify and characterise the interactions leading to emotional responses in users' mobility experiences. Three methods were applied to two studies in Singapore and Paris, France to collect people's lived experiences with mobility: diary cards, user journey maps and text stimuli. Results showed that people tend not to perceive mobility experiences emotionally. When they do, the emotions trend negatively due to deviations from expected service performance. An evaluation of the methods used led to a proposed set of parameters for the development of a tool to design emotional experiences.

Introduction

Designing mobility experiences on public transport is an endeavour due to the complexity of product-service systems, which include infrastructural and operational requirements reliant on non-design departments. The drivers of public transport passenger satisfaction and affect have multiple directions of causalityvariables play both positive and negative roles in impacting fatigue or un/pleasantness [START_REF] Mokhtarian | What makes travel pleasant and/or tiring? An investigation based on the French National Travel Survey[END_REF]. Since people best remember experiences associated with strong emotion [START_REF] Van Hagen | Enhancing the Experience of the Train Journey: Changing the Focus from Satisfaction to Emotional Experience of Customers[END_REF], emotion can aid designers in the research stage with users to identify key concerns [START_REF] Desmet | Emotion-Driven Product Design[END_REF]. The overall goal of the study is to identify opportunities for 'quick wins', instead of solving the problem with technical solutions. The authors propose to modify users' perspectives of their experiences by inserting emotionallydriven design interventions at key moments to amplify positive and mitigate negative emotions for improved mobility experiences (Figure 1). 2 Deconstructing Mobility Experiences and Emotions [START_REF] Woodcock | Deconstructing the Whole Journey Traveler Experience[END_REF] propose a description of door-to-door passenger experiences in 7 travel stages. Al Maghraoui et al. (2019) propose a traveller experience conceptual model (TXCM) connecting traveller interactions with artefacts, travel episodes, and travel problems experienced by people in their everyday life, whatever the transport mode. [START_REF] Law | Understanding, scoping and defining user experience[END_REF] include in the experience framework what happens before and after the interaction between the user and mobility system. An important subjective dimension relates to emotions. [START_REF] Desmet | Faces of Product Pleasure: 25 Positive Emotions in Human-Product Interactions[END_REF] elaborates the emotional state in user experiences by breaking down the sources of emotions: the system, meaning of the system to the user, interaction, activity facilitated by this interaction, effect of the system on the user, and other people involved.

Methodology

The main research question is: which data collection methods are most suitable for collecting affective data from mobility experiences? Two qualitative studies using three approaches were conducted in Singapore and Paris, France. Each approach aimed to deconstruct the travel experience to provoke participants' recollection of their lived mobility experiences. The diary cards and user journey maps focused on both positive and negative experiences, while the text stimulus stressed negative experiences or problems. The cards and text stimulus were expected to lead to isolated instances of experiences, while journey maps would produce storylines. Methods were chosen to elicit emotions related to an activity based on text and/or graphic prompts.

In Singapore, two methods were used: diary cards [START_REF] Brown | A diary study of information capture in working life[END_REF] and user journey maps [START_REF] Oliveira | Understanding passengers' experiences of train journeys to inform the design of technological innovations[END_REF]. Participants (n=8; 4 females; age groups of 15-44 years) were recruited, through online ads, to represent diverse genders and ages. They received cash tokens for their time.

In France, an approach derived from text stimuli was used [START_REF] Goldschmidt | Inspiring design ideas with texts[END_REF]. The participants (n=6; 3 females; mean age: 29 years) were researchers from the institute. Participants in the 'expert' groups had experience in urban mobility. The 'non-expert' group had expertise in engineering. The setup was designed to detect the influence of mobility expertise on the formulation of mobility problems. The assumption was that mobility experts would be able to generate a larger number and span of mobility problems.

Diary Cards

The diary cards (Figure 2) comprised 7 open-ended questions to provoke organic perceptions about mobility and public transportation. Each took about 5-10 minutes to complete at home. The cards started with 'What words or phrases come to your mind when you think about mobility?' Some broader questions included 'How or what do you feel about public transport?' while more specific ones were: 'What infrastructural elements did you interact with? How did you interact with it?'

Figure 2 Cards from the sensitising exercise to increase participants' consciousness of their mobility experiences.

User Journey Maps

After one week, participants returned for a 1.5-hour group workshop where they mapped their experiences in response to different prompts. Journey maps broke down experiences into their elements to identify key interactions and their specific details. In addition to details like 'people' and 'artefact', the template aimed to capture emotions on a bipolar positiveneutral-negative scale. When detailing their experiences and resulting emotional responses, participants were encouraged to describe the emotional valence and intensity, or add labels, e.g. angry, relieved. The journey maps were digitally transcribed and organised into the seven travel stages [START_REF] Woodcock | Deconstructing the Whole Journey Traveler Experience[END_REF] and the categories 'pre-trip', 'intra-trip' and 'posttrip'.

Text Stimulus

Similarly, the Paris study provided 11 textual categories as stimuli to elicit responses. The case study was a rapid transit bus line connecting a public transport hub to a business district where the participants commuted daily. The control group was instructed to record travel problems without the stimulus. The experimental group was prompted by textual categories after 15 minutes of unprompted problem generation. Objective' categories described technical or contextual sources of problems (e.g. Weather, Operation -'For me, the system is not well operated'), while the 'subjective' categories represented elements connected to personal perceptions or actions (e.g. Emotion -'My emotions feel troubled when there is a problem with my trip'). The categories were obtained through a grounded theory approach (Al Maghraoui, 2019): individual interviews covering a large spectrum of travel problems exclusive to specific transportation modes (e.g. cycling, driving) were conducted until saturation.

Results

Diary Cards

Participants' answers fell into six general themes (Table 1). Two participants used emoji in their responses (Figure 3); these were considered emotional responses.

User Journey Maps

One prompt asked participants to describe their most recent mobility experience, which was the journey to the study venue. Another prompt asked participants to describe a recent positive or negative experience (Figure 4). Participants' responses varied in style, content and detail. The mappings showed that experiences perceived as positive or negative could contain emotional responses of either valence. In an echo of the diary cards, functional attributes were a common cause of travel problems.

Text Stimulus

Statements containing affective responses are presented in Table 2 (non-expert group) and Table 3 (urban mobility expert group). For both groups, the travel problems either caused negative emotions during the pre-trip stage or left a lasting negative effect on participants' emotional states post-trip.

Time Travel problems

26"

After a bad trip, we are not in the right mood for work

38"

Prices don't motivate people to take the bus, partially as tickets are expensive 50"

We feel less safe/comfortable when there are a lot of people around on the bus Due to the structure of the diary cards, responses generated isolated instances of issues. Upon examination of the timestamps from the category stimuli in Table 2 and Table 3, no proximity was found, also confirming the expected output of isolated instances.

The next section compares the findings from each method to identify dominant themes and define parameters for an emotional design tool.

5 Discussion: Implications for the Design of Emotional Mobility Experiences

Practical Perspectives on Mobility

Participants began the diary cards and text stimulus without prior priming. The problems expressed resulted from mismatches between functional service expectations and the actual service rendered. The results support the finding that people tend to focus on practical concerns for mobility experiences (Guell, Panter, Jones, & Ogilvie, 2012) and generally do not perceive commuting as positive or negative experiences [START_REF] Krome | Contextual Inquiry of Future Commuting in Autonomous Cars[END_REF]. The meaning [START_REF] Desmet | Faces of Product Pleasure: 25 Positive Emotions in Human-Product Interactions[END_REF][START_REF] Shove | The Dynamics of Social Practice[END_REF]) of mobility appears to correlate strongly to functional attributes, suggesting that they are fundamental to positive mobility experiences.

Intra-trip Interventions and Pre-trip Preparations

The stages which most shaped Singaporean participants' experiences happened intra-trip, i.e. stages 3 to 6, when they are physically on the move. Peaks of either valence tended to occur during stages 4 (interaction with the transport service) to 6 (interchanges/transfers). This suggests that interventions should occur during the intra-trip stage for greater impact on experience evaluations, since most participants consider pre-or post-trip interactions to a lesser extent. However, in the Paris study, participants entered negative emotional states pre-and post-trip. The subjective categories 'mind', 'emotion and 'arrival' in the text stimulus might have prompted such reflection. Whether this is a cultural difference in experience evaluation, or a result of the method used, could be further investigated.

Feeling Emotional… or Not

The journey map results support the finding in [START_REF] Van Hagen | Enhancing the Experience of the Train Journey: Changing the Focus from Satisfaction to Emotional Experience of Customers[END_REF] that people tend to remember the extremes in their experiences. However, it is unclear why some experiences are remembered positively despite emotional dips, and vice versa. This could be because people disregard subtle emotions when evaluating an experience [START_REF] Kahneman | Thinking, fast and slow[END_REF]. Additionally, the duration of effect for each interaction resulting in an emotion could be explored. For instance, a trip's cost has longer-lasting effects as it permanently alters a user's financial state, whereas crowded vehicles are a temporary problem, resolving once the user or other passengers alight. For several participants, the cessation of the negative interaction led to a spike in positive affect. This could be because the user is removed from the event, e.g. leaving the bus where the poor riding experience occurred. In other words, it is not a positive pull factor but the elimination of a negative push factor which resulted in the concluding positive perception of these experiences. Using push/pull factors in designing interventions can help to achieve target emotional responses.

Reflections on Methodology

The phrase 'how or what do you feel' in the diary cards sparked more affective responses than 'what words or phrases come to your mind…', suggesting that the language used can better provoke emotion elicitation. Narratives produced by the user journey maps showed clearer links between interactions and emotions than in the text stimulus. However, it is unclear how individual events influence a passenger's overall perception of the experience. Future work could delve into understanding the value of using journey maps over text stimuli.

In the journey maps, some participants could only remember emotions felt at specific points during the experience, while others were able to chart their emotional journey throughout. This could be because participants were asked to recall experiences which may have occurred some time ago. The challenge in collecting self-report emotional data on lived experiences lies in closing the distance between event occurrence and data collection, without interrupting the flow of the experience and resulting emotions. An ethnographic video captured on the move and replayed to participants could "articulate their experiences of fleeting sensations" [START_REF] Spinney | A chance to catch a breath: Using mobile video ethnography in cycling research[END_REF].

A simple bipolar scale was used in the journey maps in an inductive approach. Having a set of labelled emotionse.g. angry, frustrated, joyfulfor subjects to refer to when expressing the type and intensity of emotions felt could better guide dialogues.

As the three methods were conducted in two locations, the generalisability of findings is limited. All three methods should be repeated in each country with more rigorous sampling. However, the study identified challenges associated with each method to elaborate a methodology for the mobility context in future work, as discussed in the next section.

Proposed Parameters for an Emotional Design Tool for Experiences

Existing tools measure emotional responses for product design [START_REF] Desmet | Measuring Emotions: Development and application of an instrument to measure emotional responses to products[END_REF], psychotherapy [START_REF] Bradley | Measuring Emotion: The Self-Assessment Manikin and the Semantic Differential[END_REF], environments [START_REF] Han | A consumption emotion measurement development: a fullservice restaurant setting[END_REF][START_REF] Russell | A description of the affective quality attributed to environments[END_REF], advertising [START_REF] Morris | SAM: The Self-Assessment Manikin -An efficient cross-cultural measurement of emotional response[END_REF][START_REF] Sacharin | Geneva emotion wheel rating study[END_REF] and marketing [START_REF] Richins | Measuring Emotions in the Consumption Experience[END_REF]. Based on the findings from the three methods, parameters are proposed to guide the development of an emotional design tool (Table 4). Feeds into a storyline framework Record and link emotional reactions to specific instances (of interactions) within an experience 5.4

Self-report, ease of use to collect data during / shortly after the experience Take-home questionnaires which can be distributed to subjects 5. 1, 5.3, 5.4 Able to collect varying granularities and types of data, For greater granularity, use a Likert scale with 7 anchor points compared to 3.

To include labels, such as "happy, sad, upset"

Based on the case study

Application to experience design in product-service systems

Mobility experiences on public transport

Expected benefits of the tool include capturing data on affective responses to guide the design of experiences for emotional contrast, i.e. experiences containing both positive and negative affect. Furthermore, identifying specific affective responses can lead to the definitions of emotional harmonies, which are proposed as combinations of emotions leading to positive (or negative) evaluations of the experience.

Since the results indicated slight variances in responses between Paris and Singapore, the tool could be tested in both contexts to explore sociocultural effects.

Conclusion

Designing experiences with emotions changes how research and analysis is conducted. Through the identification of key positive or negative moments, designers can improve the creation of desirable mobility experiences. Findings from this paper will aid the development of a tool for the emotional design of experiences in complex product-service systems. While the case study focuses on mobility, the methods described could be applied to other domains to compare results.

Figure 1

 1 Figure 1 Amplifying peaks and mitigating dips, based on the peak-end rule (adapted from Van Hagen & Bron, 2014).

Figure 3

 3 Figure 3 Using emoji was categorised as an emotional response.

Figure 4

 4 Figure 4 The affective state of one participant improved whenever she reached her destination in two positive experiences. (top) A ride-hailing trip; (bottom) A bus and MRT trip.

Table 1

 1 Sample answers for the diary cards fell into six distinct themes. Emphasis added in bold.

	Theme	n	Sample answers
	Functional	8	"Time of arrival; crowdedness"
	attributes		"Reliability; convenience; comfort"
	Relation to daily	4	"Necessity! I have license & can't drive."
	life		"Convenient way for daily commute"
	Emotional	4	"Disappointment when it comes to the frequent train
	responses		breakdown… it is frustrating to see the train breakdown as
			a normality…"
			"Mad if they are spoilt [because] you are LATE & not your
			fault."
	Enhancing	3
	personal ability

"To be able to travel between places" Abstract concepts 2 "Movement. Connectedness. Inclusive. Fast. Time and space." Related elements 2 "Public transport; electric scooters, bicycles; cars, buses, trains; walking"

Table 2

 2 Selected travel problems of the non-expert group illustrating affective responses. Emphasis added in bold.

	Time	Travel problems with emotional responses
	9"	Shocking driving
	15"	Always crowded, so we arrive without motivation to work
	32"	When the bus is full, attitudes of a few people can be disturbing
	40"	It feels like we play sports when we take the bus, so it feels like a physical and
		emotional effort
	46"	Why don't we have Wi-Fi by bus, or a little music to relax people!

Table 3

 3 Travel problems of the expert group illustrating affective responses. Emphasis added in bold.

Table 4

 4 Proposed parameters based on findings in the discussion in Section 5.

	Findings	Proposed Parameters	Application Examples
	5.1, 5.2	Captures data from functional	Data on emotional reactions to the
		attributes and each stage of the	presence/absence of information at bus
		experience	stations, or long travel times
	5.2, 5.4	Phrased and structured to	Ask subjects about their emotions
		discretely provoke affective	without emphasising one dimension
		responses	(e.g. positive-negative, arousal levels)
			over another
	5.3	Captures intensities and temporal	Capture data, with valence and levels of
		dimensions to determine the effect	intensity over time, to see how
		of affect over time	emotional responses interact throughout
			the experience


Prof Judith Trotman
email: judith.trotman@health.nsw.gov.au

Sally F Barrington

David Belada

Michel Meignan

Robert Macewan

Carolyn Owen

Václav Ptáčn'ik

András Rosta

MD Günter R Fingerle-Rowson

Jiawen Zhu

Václav Ptáčník

MD, D Sahin BSc Tina Nielsen

Deniz Sahin

Prof Wolfgang Hiddemann

Robert E Marcus

for the PET Andrew Davies

Prof J Trotman Mbchb

MD Davies

Prognostic value of end-of-induction PET response after first-line immunochemotherapy for follicular lymphoma (GALLIUM): secondary analysis of a randomised, phase 3 trial

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

Summary

Background Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.

Methods

GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m² on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria.

IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968. Interpretation Our results suggest that PET is a better imaging modality than contrastenhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.

Funding F. Hoffmann-La Roche.

Research in context

Evidence before this study On Dec 12, 2017, we searched PubMed using combinations of the terms "fluorodeoxyglucose OR fludeoxyglucose OR 2-fluoro-2-deoxy-d-glucose OR 2-[F-18]-fluoro-2-deoxy-D-glucose OR FDG OR 18F-FDG OR positron emission tomography OR positron emission tomography-computed tomography OR PET OR PET-CT OR PET/CT", "follicular lymphoma OR FL OR indolent", "prognostic OR prognosis", "predictive", "progression-free survival OR PFS", and "overall survival OR OS", with no restrictions on language. Several studies have suggested that 2-18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) PET response at the end of induction therapy is prognostic for progression-free survival in patients with follicular lymphoma primarily treated with first-line R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) without maintenance therapy. There is also some evidence that end of induction PET response could be prognostic for overall survival, although small sample sizes have prevented a robust assessment. In this secondary analysis of the GALLIUM trial, the first randomised study to compare first-line immunochemotherapy with obinutuzumab versus rituximab plus maintenance therapy in patients with follicular lymphoma, we further investigate the potential prognostic role of PET in this setting.

Added value of this study

This secondary analysis from GALLIUM provides prospective PET data from a large population of patients with follicular lymphoma receiving a wide spectrum of modern immunochemotherapies, including bendamustine-based treatment and different anti-CD20 maintenance antibodies. The results of retrospective analysis applying the current, internationally accepted Lugano 2014 response criteria (which incorporates the ordinal 5point scale [Deauville criteria] for evaluating PET scans) presented here suggests that, for patients with follicular lymphoma, achieving a complete metabolic response is prognostic for improved progression-free and overall survival in this indolent but heterogeneous lymphoma. These data support the use of end-of-induction PET response status as a practical, early predictor of progression-free and overall survival, helping to identify patients with the greatest risk of relapse.

Implications of all the available evidence

Evidence from this secondary analysis and previous studies suggest PET as a superior imaging modality compared with contrast-enhanced CT for response assessment in patients with follicular lymphoma treated with first-line immunochemotherapy. PET-response assessment at the end of induction therapy could inform patients and their clinicians of the probability of both progression-free and overall survival. The data also support the use of PET assessment according to Lugano 2014 response criteria as a platform to study responseadapted therapeutic approaches in future clinical trials to improve outcomes for patients with follicular lymphoma.

Introduction

Follicular lymphoma is the most common indolent non-Hodgkin lymphoma, and has heterogeneous clinical behaviour. Follicular lymphoma is highly sensitive to initial therapy, but is characterised by recurrent relapses and risk of histological transformation. In the modern era of combined immunochemotherapy, with the promise shown with the type 2 anti-CD20 antibody obinutuzumab in the ongoing GALLIUM trial in this setting, 1 the lengthy remission and overall survival for some patients (possibly beyond 20 years after diagnosis) now challenges the perception of follicular lymphoma as incurable.

2,3

Many patients are more likely to die from other causes while in remission or with asymptomatic disease than from the diagnosed follicular lymphoma itself. Nonetheless, a substantial minority of patients (approximately 20%) have a poor prognosis, and these patients are not reliably identified at diagnosis by conventional response assessment based on CT and bone marrow analyses.

4,5

There is preliminary evidence from studies suggesting that 2-18 F-fluoro-2-deoxy-D-glucose ( 18 F-FDG) PET-CT response after induction therapy is prognostic for outcomes in follicular lymphoma. Findings from three prospective studies of first-line immunochemotherapy for high-tumour-burden follicular lymphoma showed almost universal 18 F-FDG uptake in follicular lymphoma, and progression-free survival was significantly longer in those patients with a negative PET at end of treatment compared with those with a positive PET. In another study, with a median follow-up of 23 months, 2-year progression-free survival was 51% for patients who remained PET-positive versus 87% for patients who became PET-negative (p<0•001). In the third study, with a median follow-up of 34 months, the 3-year progression-free survival was 35% and 66%, respectively, for patients with positive and negative postinduction PET (p<0•001). A pooled analysis of these studies with longer follow-up was conducted; scans were centrally reviewed by three independent PET physicians. Post-treatment PET with a cutoff score of four or greater (defined as ¹ ⁸ F-FDG uptake in tumour higher than that in the liver) on the 5-point scale (also known as the Deauville criteria) The phase 3 GALLIUM study (NCT01332968) was designed to compare the efficacy and safety of induction therapy with obinutuzumab versus induction therapy with rituximab, combined with chemotherapy (bendamustine, CHOP [cyclophosphamide, doxorubicin, vincristine, and prednisone], or CVP [cyclophosphamide, vincristine, and prednisone]) in both groups and followed by maintenance with the same antibody alone, in responding patients with previously untreated, advanced, indolent non-Hodgkin lymphoma.

The study was powered to evaluate investigator-assessed progression-free survival in patients with follicular lymphoma, enrolling 1202 such patients between July 6, 2011 and we hypothesised that patients with follicular lymphoma who achieved PET negativity in the GALLIUM trial could have better prognosis in terms of both progression-free and overall survival than PET-positive patients. The aim of the current prespecified secondary analysis was to evaluate the PET response at end of induction with immunotherapy and to explore its prognostic value in patients with follicular lymphoma treated within the GALLIUM study.

Methods

Study design and participants

This is a secondary analysis of PET results from GALLIUM, an ongoing randomised, open-label, parallel-group, phase 3 trial. An early protocol amendment on July 26, 2011 made PET mandatory at baseline and at the end-of-induction therapy for a minimum of 170 patients recruited for the GALLIUM trial at sites where PET scanning was available, becoming optional thereafter. The updated study protocol is available in the appendix (pp 9-

235).

The study design and patient population for GALLIUM including full eligibility criteria have been described previously. The study is being done in accordance with the International Conference on Harmonisation guidelines for Good Clinical Practice, and the protocol was approved by the ethics committee at each participating centre. Patients provided written informed consent before any study-specific procedures were performed.

Randomisation and masking

During GALLIUM, patients were randomly assigned 1:1 to receive intravenous infusions of obinutuzumab or rituximab plus chemotherapy of choice. Randomisation was done by means of an interactive voice-response or online response system with the use of a hierarchical dynamic randomisation scheme and stratified by induction chemotherapy regimen (bendamustine, CHOP, or CVP), Follicular Lymphoma International Prognostic Index (FLIPI) risk category (low, intermediate, or high), and geographical region. The trial was open label, and only the independent review committee (IRC) were masked to treatment assignment.

Procedures

Patients received either intravenous infusions of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) plus chemotherapy of choice or rituximab (375 mg/m² on day 1 of each cycle) plus chemotherapy of choice, for six 28-day cycles for those receiving bendamustine-containing chemotherapy or six 21-day cycles for those receiving CHOP or eight 21-day cycles for CVP as chemotherapy. Patients receiving CHOP received six cycles of obinutuzumab or rituximab plus CHOP and two cycles of antibody monotherapy, for eight cycles in total. The choice of chemotherapy was stipulated by each site, with all patients at that site receiving the same regimen. Doses of chemotherapy were as follows: for CHOP, cyclophosphamide 750 mg/m², doxorubicin 50 mg/m², and vincristine 1•4 mg/m² (maximum dose 2 mg) by intravenous infusion on day 1 plus prednisone 100 mg orally per day on days 1-5 of six 21-day cycles; for CVP, the same doses of cyclophosphamide, vincristine, and prednisone as in CHOP for eight 21-day cycles; and for bendamustine, 90 mg/m² by intravenous infusion on days 1 and 2 of six 28-day cycles.

Patients with a CT-based complete response or partial response at end of induction received maintenance treatment with the antibody they received during induction (1000 mg obinutuzumab or 375 mg/m² rituximab) every 2 months for 2 years, or until progressive disease or study withdrawal; no crossover was permitted. Those with stable disease at end of induction were followed on the same schedule as patients receiving maintenance, but were not prescribed antibody maintenance. Disease assessments including CT scans were done every 4 months for the first year and every 6 months for the second year of maintenance. Patients were then followed up every 3 months for 3 years (with CT scans every 6 months), then every 6 months for 2 years (with annual CT scans) until the end of the study or until disease progression. Patients with disease progression were followed up for overall survival every 6 months until the end of the study, and were treated at the discretion of the investigator, according to institutional practice.

PET scans were done at baseline (≤35 days before randomisation) and at end of induction (6-8 weeks after day 1 of the last cycle of chemotherapy) or early study termination. Scans were assessed by investigators and an IRC, comprising two radiologists who were masked to clinical outcome, and a third adjudicating radiologist whose role was to resolve any disagreements between the radiologists relating to the attributed response; the final IRC response was determined by an independent clinician (masked to treatment and outcome) who considered the final radiological response in addition to bone marrow and other biopsy information.

CT and PET response was evaluated for patients achieving a partial response or complete response as per the International Harmonisation Project (IHP) 2007 response criteria. [START_REF] Cheson | Revised response criteria for malignant lymphoma[END_REF][START_REF] Juweid | Use of positron emission tomography for response assessment of lymphoma: consensus of the Imaging Subcommittee of International Harmonization Project in Lymphoma[END_REF] Both investigator and IRC reporting adhered to IHP 2007 response criteria.

According to these criteria, any end-of-induction PET with ¹ ⁸ F-FDG uptake greater than or equal to uptake in the mediastinum in lesions of 2 cm or larger, or uptake greater than that of adjacent background tissue in lesions smaller than 2 cm, was defined as PET positive.

These assessments were prespecified in the GALLIUM study protocol (appendix pp 9-235). PET scans to assess metabolic response were also retrospectively assessed by the IRC only according to the more recent Lugano 2014 response criteria, [START_REF] Barrington | Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group[END_REF][START_REF] Cheson | Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification[END_REF] incorporating the 5point scale as an exploratory analysis. By these criteria, positive scans were defined by a residual ¹ ⁸ F-FDG uptake score of 4 or greater (ie, uptake greater than the maximum standardised uptake value in a large region of normal liver). In accordance with the Lugano 2014 criteria, recognised causes for ¹ ⁸ F-FDG uptake other than follicular lymphoma were assigned as unrelated to follicular lymphoma. For CT scans, as per IHP 2007 criteria, patients formerly assigned to unconfirmed complete response 14 are generally classified as partial response. Bone marrow biopsy was done in all patients at baseline and was required in patients with conventional CT-based complete response at end of induction.

Outcomes

The primary endpoint of the GALLIUM trial was investigator-assessed progression-free survival (defined as the time from randomisation to the first occurrence of progression or relapse) in patients with follicular lymphoma. Key secondary efficacy endpoints were progression-free survival in all randomised patients, overall survival (defined as the time from the date of randomisation to the date of death from any cause) in all patients with follicular lymphoma and all randomised patients, and the proportion of patients achieving an overall and complete response in all patients with follicular lymphoma and all randomised patients, as previously reported.

This secondary analysis, which will report CT and PET-based responses at end-ofinduction therapy and explore their relation with progression-free and overall survival outcomes in patients with available scans, was prespecified as an exploratory analysis of the trial in a protocol amendment on July 26, 2011.

Statistical analysis

The data reported in the primary GALLIUM study report were from a preplanned interim analysis, when the prespecified significance level for the primary endpoint had been crossed (cutoff Jan 31, 2016). [START_REF] Marcus | Obinutuzumab for the first-line treatment of follicular lymphoma[END_REF] The results reported in this Article are from an updated analysis (cutoff Sept 10, 2016).

As a secondary analysis of the GALLIUM trial, the analyses presented in this report are not powered. Demographic and baseline characteristics were summarised using descriptive statistics in the PET population (defined as all randomly assigned patients with available baseline and end-of-induction PET scans; the non-PET population included all other randomly assigned patients). Kaplan-Meier methodology was used to estimate landmark progression-free and overall survival distributions from end-of-induction therapy for each group. Landmark analyses of progression-free and overall survival, which considered response at a fixed point in time and removed patients with an event (or censored) before the landmark analysis, were used to avoid immortal bias. disease before the end-of-induction assessment were excluded. The starting point for the landmark analysis of overall survival was the same as for the progression-free survival analyses, except that patients with progressive disease were not excluded. If a patient had IRCassessed progressive disease on the basis of IHP 2007 assessment, or any antilymphoma medication before the last dose of study treatment, then the start date for the landmark analysis was set to the randomisation date plus 180 days (the planned duration of the induction therapy phase). Patients with end-of-induction visits who had started maintenance therapy were excluded from the landmark analyses.

Estimates of the differences between groups were determined using a stratified Cox proportional hazards analysis and expressed as HRs and 95% CIs. Estimated 2•5-year probabilities, including 95% CIs, were also used to describe progression-free and overall survival. Exploratory univariate and multivariable Cox analyses were undertaken to investigate factors that were prognostic for progression-free and overall survival. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.

Role of the funding source

The funder was involved in trial design, and in data collection, analysis, and interpretation. Authors who were employees of the funder (TN, DS, and GRF-R) contributed to the writing and approval of the manuscript. JZ and DS have full access to the raw data, and all authors had limited access to the data and statistical results. All authors have approved the final draft of the manuscript and the corresponding author had the final responsibility to submit for publication.

Results

Patients were enrolled into GALLIUM between July 6, 2011, and Feb 4, 2014. The trial profile for the primary study population has been published previously. (appendix pp 6-8). Of 609 patients with a baseline PET scan, 595 (98%) also had an end-ofinduction scan (PET population; figure 1). Among these 595 patients, 543 (91%) qualified for landmark assessment of overall survival by IHP 2007 response criteria; 10 (2%) of 543 had disease progression before the end-of-induction therapy and were excluded from progression-free survival analyses. 519 (87%) of 595 patients had both baseline and end-ofinduction PET scans available for central review, and qualified for landmark assessment of overall survival by Lugano 2014 response criteria; 11 (2%) of 519 progressed before end of induction and were excluded from the landmark progression-free survival analyses (figure 1).

End-of-induction PET scans were done a median of 19 days (IQR 14-25) after the end of the last cycle of rituximab chemotherapy and 20 days (IQR [START_REF] Anderson | Analysis of survival by tumor response[END_REF][START_REF] Hiddemann | Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety[END_REF][START_REF] Salles | Long term follow-up of the PRIMA study: half of patients receiving rituximab maintenance remain progression free at 10 years[END_REF][START_REF] Shi | Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy: an individual patient-level analysis of multiple randomized trials[END_REF][START_REF] Casulo | Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study[END_REF][START_REF] Launonen | Early disease progression predicts poorer survival in patients with follicular lymphoma (FL) in the GALLIUM study[END_REF][START_REF] Casulo | Validation of POD24 as a robust early clinical endpoint of poor survival in follicular lymphoma: results from the Follicular Lymphoma Analysis of Surrogacy Hypothesis (FLASH) investigation using individual data from 5453 patients on 13 clinical trials[END_REF][START_REF] Gritti | Is there a role for minimal residual disease monitoring in follicular lymphoma in the chemo-immunotherapy era? Meditter[END_REF][START_REF] Luminari | Positron emission tomography response and minimal residual disease impact on progression-free survival in patients with follicular lymphoma: a subset analysis from the FOLL05 trial for the Fondazione Italiana Linfomi[END_REF][START_REF] Galimberti | Minimal residual disease after conventional treatment significantly impacts on progression-free survival of patients with follicular lymphoma: the FIL FOLL05 trial[END_REF][START_REF] Trotman | Relationship between MRD and PET responses and PFS in previously untreated follicular lymphoma in the GALLIUM trial. Abstract accepted for poster presentation at the ASCO Annual Meeting 2018[END_REF][START_REF] Meignan | Baseline metabolic tumor volume predicts outcome in high-tumor-burden follicular lymphoma: a pooled analysis of three multicenter studies[END_REF] 2). The proportion of patients achieving a PET complete response and complete metabolic response more than doubled compared with the proportion achieving CT complete response (table 2). Among the patients who qualified for the landmark analysis of progression-free survival, the proportion with complete metabolic response was 88% (448/508) as assessed by Lugano 2014. By IRC assessment, the proportion with complete response was higher for patients who received obinutuzumab-based chemotherapy than for those who received rituximab-based chemotherapy when assessed by IHP 2007 response criteria; the proportion of patients achieving complete metabolic response according to Lugano 2014 criteria was similar (tables 2, 3). For all patients, 17 patients who had a complete metabolic response did not have a partial response on CT assessment: four had stable disease, two had progressive disease, evaluation was impossible in nine patients, and data were missing in two patients. the IRC applied the Lugano 2014 response criteria, end-of-induction complete metabolic response was also prognostic for progression-free survival (figure 2C). Patients obtaining complete metabolic response at end-of-induction PET as per IRC assessment according to Lugano 2014 criteria also had significantly improved overall survival compared with those who did not (figure 3). 37 of the 519 patients included in the landmark overall survival analysis per PET Lugano 2014 criteria died (13 [19%] of 69 who did not have a complete metabolic response before the end-of-induction therapy and 24 [5%] of 450 of those who had a complete metabolic response). The cause of death was adverse event in 16 patients (43%), progressive disease in 14 (38%), and other reasons in seven (19%). Nine (13%) of 69 patients not achieving complete metabolic response and five (1%) of 450 achieving complete metabolic response died from lymphoma.

The improvement in progression-free survival observed in patients who achieved a complete metabolic response was irrespective of whether or not they achieved a complete response on CT (figure 4).

Progression-free survival according to IRC-assessed PET status by Lugano 2014 response criteria in patients who received rituximab-based chemotherapy versus those treated with obinutuzumab-based chemotherapy is presented in the appendix (p 5). Irrespective of the antibody used, having a complete metabolic response was associated with improved progression-free survival (at 2•5 years from end of induction, progression-free survival in those who achieved a complete metabolic response was 89•5% [95% CI 84•5-93•0] for those who received obinutuzumab vs 85•0% [95% CI 79•3-89•3] for those treated with rituximab; HR 0•7, 95% CI 0•4-1•1, p=0•0078). Among patients who did not achieve a complete metabolic response, progression-free survival at 2•5 years from end of induction was 69•7% (95% CI 46•5-84•3) for those treated with obinutuzumab compared with 43•5% (95% CI 25•2-60•4) in the rituximab-treated group (HR 0•5, 95% CI 0•2-1•3, p=0•14). 12% (60/508) of patients in the landmark population of GALLIUM did not obtain complete metabolic response at the end-of-induction landmark but had a median progressionfree survival of approximately 32 months, despite the use of maintenance.

An exploratory multivariate analysis confirmed the univariate analysis (table 4), showing that complete metabolic response status and obinutuzumab treatment group were the only significant independent predictors of progression-free survival. Complete metabolic response status was the only significant independent predictor of overall survival.

The safety data for this updated analysis have been reported elsewhere.

16

Discussion

This secondary analysis of GALLIUM is, to our know-ledge, the first large study of PET response assessment in follicular lymphoma. The secondary endpoint of PET-based response as assessed with the IHP 2007 response criteria was prognostic in terms of progression-free survival; however, the more recent Lugano 2014 response criteria served as a better tool for prognosis, detecting a five-times increase in risk of progression and early death in patients who did not achieve a complete metabolic remission compared with those who did not achieve a complete metabolic response.

The proportion of patients achieving a complete metabolic response as per PET assessment established with the current, internationally accepted Lugano 2014 criteria, [START_REF] Barrington | Role of imaging in the staging and response assessment of lymphoma: consensus of the International Conference on Malignant Lymphomas Imaging Working Group[END_REF][START_REF] Cheson | Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification[END_REF] incorporating the 5-point scale, was more than two-times higher than the proportion achieving complete response determined by CT-based assessment by the IHP 2007 criteria. We suggest that this discrepancy between the two imaging modalities might be due to PET imaging more accurately distinguishing between viable lymphoma and non-lymphoma residual lesions than CT. Most patients who qualified for the landmark analysis achieved a complete metabolic response. Notably, there was a significant separation of the progression-free and overall survival curves between patients achieving a complete metabolic response and those who did not. Of considerable importance was the worse overall survival in patients who did not achieve a complete metabolic response. With a five-times increased risk of death in these patients on multivariate analysis, and 16% of this population dying within just 2•5 years of the end of induction (13% due to their lymphoma), this finding suggests PET status as an early predictor of decreased overall survival in this disease.

With better predictive ability than CT-based response assessment, PET status could be used to guide patients in making important life decisions and to assist physicians in determining the frequency of clinical follow-up.

This study has a few limitations. We acknowledge that the Lugano 2014 analysis was performed retrospectively in response to updated international guidelines and that valid per-protocol PET scans were only available in half of the follicular lymphoma population from GALLIUM. We also acknowledge that there was a higher frequency of CT scans during the 2-year maintenance period of the GALLIUM study than would currently be considered standard of care. Another limitation of this study is the effect on management of patients with stable disease, who were not mandated antibody maintenance. However, only four patients in the PET population had stable disease by CT as assessed by investigators, three of whom also received maintenance therapy, which suggests little effect on the results.

When assessing the GALLIUM data in the context of earlier research, we note findings from a previous retrospective pooled analysis [START_REF] Trotman | Prognostic value of PET-CT after firstline therapy in patients with follicular lymphoma: a pooled analysis of central scan review in three multicentre studies[END_REF] of three multicentre studies, consisting of patients with follicular lymphoma predominantly treated with rituximab and CHOP without maintenance therapy, showing that the 17% (41/246) of patients who remained PET-positive (with scores of 4-5 on the 5-point scale) had worse progression-free survival than those who became PET-negative. The 12% (60/508) of patients in the landmark population of GALLIUM who did not obtain complete metabolic response at the end-of-induction landmark had a median progression-free survival of approximately 32 months, despite the use of maintenance. Similarly, although the absolute number of patient deaths during early follow-up was low, the worse overall survival of patients who did not obtain complete metabolic response in GALLIUM is consistent with the decreased overall survival documented previously.

There was no difference between the proportion of patients achieving a complete metabolic response according to Lugano 2014 response criteria when comparing those treated with obinutuzumab-based chemotherapy and those who received rituximab-based chemotherapy. No difference in end-of-induction complete metabolic response between the three chemotherapy backbones was observed. [START_REF] Hiddemann | Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety[END_REF] However, we note that GALLIUM was not designed to compare differences between the different chemotherapy backbones. [START_REF] Hiddemann | Immunochemotherapy with obinutuzumab or rituximab for previously untreated follicular lymphoma in the GALLIUM study: influence of chemotherapy on efficacy and safety[END_REF] Faced with a heterogeneous disease, clinicians treating follicular lymphoma have previously lacked robust and clinically useful early post-induction predictors of survival.

With modern immunochemotherapy, the median progression-free survival after first-line therapy and maintenance is estimated to be approximately 10 years, 17 making progression-free survival per se an increasingly impractical endpoint in clinical trials, which require more than 1000 participants and several years of follow-up to demonstrate incremental advances. [START_REF] Shi | Thirty-month complete response as a surrogate end point in first-line follicular lymphoma therapy: an individual patient-level analysis of multiple randomized trials[END_REF] Similarly, overall survival is not a feasible primary endpoint in this setting. Although studies published since 2015 have shown the value of disease progression within 2 years of diagnosis and 30-month complete response on CT as prognostic indicators, 18-21 both parameters require an extended waiting time before they can be applied. By contrast, end-ofinduction PET status provides clinicians with an immediate marker of prognosis at a timepoint when there is potential to study early intervention approaches. It will be important to conduct a formal trial-level surrogacy analysis of pooled data from the GALLIUM study and other prospective studies to confirm if PET response assessment can be used as an earlier surrogate for progression-free and overall survival, and thus can become a legitimate primary endpoint in trials of first-line therapy for follicular lymphoma. Given the cost implications, inconvenience, and radiation dose concerns, the undertaking of both full-dose, contrast-enhanced CT and PET scanning after first-line therapy is impractical for most patients with follicular lymphoma. Furthermore, with cumbersome calculations to compare up to six target lesions, CT scans are rarely reported in accordance with formal response assessment criteria in routine clinical practice. Our results suggest that combined PET-low-dose CT is the preferred imaging that should be done in patients after initial immunochemotherapy to assess response. Contrast-enhanced CT at end of induction should, therefore, be reserved only for the small number of patients requiring subsequent radiotherapy. Bone marrow biopsy was required in GALLIUM only to confirm a CT-based complete response after induction therapy. Of this population, the incidence of persisting bone marrow involvement was documented in 2% of patients achieving a complete metabolic response, suggesting little additional value of bone marrow biopsy in this population. Our data suggest that prognostic value could be obtained with PET alone for the purposes of clinical decision-making.

Notwithstanding this finding, minimal residual disease analysis is showing some promise as a prognostic tool in follicular lymphoma, There is a growing body of evidence to suggest that quantitative PET measures could be prognostic in follicular lymphoma. 26,27 Analysis of baseline total metabolic tumour volume, incorporated with pretreatment prognostic indices and metabolic response, might increase separation between the progression-free survival curves of the patients with or without a complete metabolic response, specifically to better identify the 10-15% of patients with complete metabolic response who do progress early. Further PET analyses might also contribute to improved understanding of why some patients without complete metabolic response do not progress early, particularly the obinutuzumab-treated population, for whom we hypothesise that residual 18 F-FDG-avidity could reflect inflammation related to ongoing antibody-dependent cellular cytotoxicity (one of the mechanisms of action of obinutuzumab) 28,29 immediately after induction therapy. Future studies of sequential PET scans in the months following obinutuzumab chemotherapy induction might show a similar effect and clarify the optimal time for PET assessment after obinutuzumab-based therapy.

In conclusion, these data suggest that PET is a better assessment modality than contrastenhanced CT in patients with follicular lymphoma treated with first-line immunochemotherapy. has received honoraria from Roche, Celgene, Gilead, Takeda, CTI, Mundipharma, Janssen, and Pfizer; and has received support for travel to scientific conferences from Roche, Takeda, CTI, and Mundipharma. RM and AR declare no competing interests.

Findings

  1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65•5% [95% CI 61•6-69•4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75•6% [95% CI 72•0-79•0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43•3 months of observation (IQR 36•2-51•8), 2•5-year progression-free survival from end of induction was 87•8% (95% CI 83•9-90•8) in PET complete responders and 72•0% (63•1-79•0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0•4, 95% CI 0•3-0•6, p<0•0001). According to Lugano 2014 criteria, 2•5-year progression-free survival in complete metabolic responders was 87•4% (95% CI 83•7-90•2) and in non-complete metabolic responders was 54•9% (40•5-67•3; HR 0•2, 95% CI 0•1-0•3, p<0•0001).

4, 6 , 7

 67 In one study, patients remaining PET positive had a significantly (p=0•001) inferior progression-free survival at 42 months of 32•9% (95% CI 17•2-49•5) compared with 70•7% (59•3-79•4) in those who became PET negative.

4

 4

6

 6

7

 7

5 Furthermore

 5 survival was only 23•2% [95% CI 11•1-37•9] in patients remaining PETpositive, compared with 63•4% [55•9-70•0] for those who had a negative postinduction-PET; p<0•0001). Patient numbers were too small and duration of follow-up too short to make robust estimates of overall survival (4-year overall survival was 87•2% [95% CI 71•9-94•5] vs 97•1% [93•2-98•8], respectively; p<0•0001). , most of these patients did not receive rituximab maintenance, which has been shown to provide a progression-free survival benefit after first-line treatment. The findings from these studies led to a recommendation by the International Conference on Malignant Lymphomas Imaging Working Group to include follicular lymphoma in the most recent Lugano 2014 classification for response assessment of ¹ ⁸ F-FDG-avid lymphomas (lymphomas that take up FDG during PET scans), which incorporated the established cutoff score on the 5-point scale. 4,5,7,8,10-15

Feb 4 ,

 4 2014. Despite a similar proportion of patients achieving an overall response based on contrast-enhanced CT assessment, obinutuzumab chemotherapy and maintenance significantly reduced the risk of relapse, progression, or death compared with rituximab chemotherapy and maintenance (hazard ratio [HR] 0•66, 95% CI 0•51-0•85, p=0•001), thus meeting the primary endpoint of the study (no medians were reached). 1 On the basis of the above mentioned findings from several cohort studies suggesting the prognostic value of post-treatment PET in follicular lymphoma, 4-7,10

1

  Briefly, eligible patients were aged 18 years or older; had previously untreated, histologically confirmed, CD20-positive follicular lymphoma (grades 1-3a); advanced disease (stage III/IV, or stage II with largest tumour diameter ≥7 cm); an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; adequate haematological function (haemoglobin ≥9•0 g/dL, absolute neutrophil count ≥1•5 × 10⁹/L, platelet count ≥75 × 10⁹/L); and required treatment according to Groupe d'Etude des Lymphomes Folliculaires criteria. Details of previous and concomitant permitted treatments are provided in the appendix (p 1).

  Response was reported in the PET population only. Complete response was compared between the two treatment groups using Cochran-Mantel-Haenszel tests, with FLIPI and chemotherapy regimen used as stratification factors. Concordance between response as assessed by investigator versus IRC with IHP 2007 criteria was assessed through crosstabulation tables and Cohen's Kappa estimates. PET complete response or complete metabolic response was compared with baseline characteristics, including individual components of the FLIPI and FLIPI2 prognostic indices, conventional CT-based response, progression-free survival, and overall survival. Progression-free survival and overall survival were analysed by complete response (assessed by CT alone), complete response or complete metabolic response (assessed by PET) status, or both, and by treatment group. All patients with an end-of-induction PET available for central review were included in the IHP response assessment. Patients in whom baseline scans were unavailable but with end-ofinduction scans available for central review were excluded from IRC assessment in accordance with Lugano 2014 criteria.

  Investigated covariables included Lugano 2014 PET-based response (non-complete metabolic response [partial metabolic response, no metabolic response, or progressive metabolic disease] vs complete metabolic response), treatment group (rituximab chemotherapy vs obinutuzumab chemotherapy), and the prespecified stratification factors: induction chemotherapy (bendamustine vs CHOP or CVP), FLIPI risk category (low vs intermediate, low vs high), and geographical region. The covariates were entered simultaneously into the Cox model. The level of statistical significance was set at 0•05 (two-sided test) and analyses were done with SAS version 9.4.

1

  Compared with a median follow-up of 34•5 months (IQR 0-54•5) in the original report, this updated analysis reports after a median follow-up of 43•3 months (IQR 36•2-51•8). PET scans were done in 669 (65%) of 1029 patients enrolled after July 26, 2011, at 103 of the 177 recruiting centres

  Investigator-assessed overall responses according to IHP 2007 response criteria in the PET population were achieved in 496 (83•4%; 95% CI 80•1-86•3) of 595 patients, and complete responses were achieved in 353 (59•3%; 55•3-63•3) patients; there was 72•4% agreement between investigator and IRC assessments, with a Kappa coefficient of 0•49 (95% CI 0•43-0•56). Overall concordance between IHP 2007 and Lugano 2014 PET assessment by IRC was 0•46 (95% CI 0•40-0•52; appendix p 3). Patients who achieved IRC-assessed PET complete response according to IHP 2007 or complete metabolic response as per Lugano 2014 criteria at end of induction were younger than those who did not (median age 55•0 years [IQR 47•0-64•0] for responders vs 60•0 years [51•0-67•0] for non-responders as per IHP 2007; p=0•0019; and 56•0 years [47-65] for responders vs 63•0 years [52-66] for non-responders as per Lugano 2014;

  Median observation time was 43•3 months (IQR 36•17-51•8) in the PET population. Having a CT-based complete response at end of induction, as assessed by the IRC, was significantly prognostic for progression-free survival when comparing responders versus nonresponders (figure 2A); but not for overall survival (2•5-year overall survival for patients who had a complete response was 97•7% [95% CI 94•0-99•1] vs 93•5% [90•5-95•6] for those who did not; HR 0•5, 95% CI 0•3-1•2, p=0•124). According to IRC-assessed IHP 2007 response criteria, end-of-induction complete response status on PET was prognostic for both progression-free survival (figure 2B) and overall survival (2•5-year overall survival for patients with complete response 96•9% [95% CI 94•5-98•2] vs non-complete response 90•6% [84•6-94•3]; HR 0•4, 95% CI 0•2-0•9, p=0•011). The results for investigator-assessed progression-free survival according to PET status by IHP 2007 response criteria are in the appendix (p 4). When

  combined analysis of PET and minimal residual disease from GALLIUM 25 might provide additional prognostic value. Nevertheless, there are concerns that the lack of sensitivity of minimal residual disease markers, multicompartmental nature of follicular lymphoma, and complexity of this expensive and time-consuming detection technique might preclude the implementation of minimal residual disease detection as a prognostic tool beyond clinical trials.

Table 2 :Table 4 :

 24 Patients with IRC-assessed response at end of induction by imaging technique, response criteria, and treatment group. Table 3: IRC-assessed response at end of induction per treatment group. Cox multivariate and univariate analyses for progression-free survival andoverall survival in the landmark analysis populations.

Figure 1 :

 1 Figure 1: Study profile

Figure 2 :

 2 Figure 2: Landmark analysis of progression-free survival by IRC-assessed response

Figure 3 :

 3 Figure 3: Landmark analysis of overall survival by IRC-assessed metabolic response

Figure 4 :

 4 Figure 4: Landmark analysis of progression-free survival by IRC-assessed response

  after the end of the last cycle of obinutuzumab chemotherapy. 2%) patients had their response downgraded to partial metabolic response due to a positive bone marrow biopsy.IRC-assessed end-of-induction CT response and PET response by IHP 2007 andLugano 2014 response criteria for the PET population are shown in table 2. On CT assessment alone, the proportion of patients achieving an overall response in the PET

	Baseline disease and demographic characteristics are provided in table 1. Baseline characteristics for patients in the PET IHP 2007 and Lugano 2014 response populations were well balanced (appendix p 2). End-of-induction bone marrow biopsy results were available for 247 (55%) of 450 patients who had a complete metabolic response on standard Lugano 2014 response included in the response assessment, 517 (86•9%; 95% CI 83•9-89•5) of 595 patients had an overall response according to IHP 2007 response criteria and 486 (81•7%; 95% CI 78•3-assessment; of these, five (population was 539 (90•6%; 95% CI 88•0-92•8) of 595 patients (table 2). When PET was 84•7) of 595 according to Lugano 2014 response criteria (table

  p=0•0044). A higher percentage of patients who did not achieve a complete response or IHP 2007 and Lugano 2014), FLIPI was similar between patients who achieved complete response or complete metabolic response compared with those who did not (88 [23%] of 390 for complete response vs 25 [17%] of 145 for no complete response for FLIPI low; 153 [39%] vs 54 [37%] for FLIPI intermediate; and 149 [38%] vs 66 [46%] for FLIPI high; and 94 [21%] of 450 for complete metabolic response vs 12 [17%] of 69 for no complete metabolic response for FLIPI low; 178 [40%] vs 23 [33%] for FLIPI intermediate; and 178 [40%] vs 34 [49%] for FLIPI high).

	complete metabolic response had bulky disease (≥7 cm) at baseline (79 [55%] of 144 vs 168 [43%]
	of 390, p=0•015 for complete response; and 39 [57%] vs 198 [44%], p=0•039 for complete metabolic
	response), and extranodal involvement was more common (116 [80%] for non-complete
	response vs 256 [66%] for complete response; p=0•0013 for IHP 2007 response criteria). Using
	both criteria (

The starting point of the landmark analysis of progressionfree survival was the end-of-induction tumour assessment. Patients with progressive

Acknowledgments

GALLIUM is sponsored by F Hoffmann-La Roche. We thank the patients, investigators, and study nurses, and PET centres taking part in GALLIUM. The first draft was written by JT;

Data sharing

Qualified researchers can request access to individual patient level data through the clinical study data request platform. Further details on Roche's criteria for eligible studies and on Roche's Global Policy on the Sharing of Clinical Information and how to request access to related clinical study documents are available.

Further studies, combining PET with other prognostic tools, might help to identify patients at high risk of both relapse and early death to optimise risk-adapted follow-up. Although additional validation is required, PET might be a useful, early surrogate marker of progressionfree and overall survival in clinical trials, and provide the platform to guide response-adapted therapy in follicular lymphoma.

Contributors

JT, REM, WH, GRF-R, and AD were involved in the study design. JT, REM, WH, and GRF-R were involved in the study conduct. JT, DB, RM, REM, CO, WH, AR, and AD were involved in the recruitment or follow-up of patients. TN, GRF-R, and VP were involved in data collection. JZ, TN, DS, and GRF-R were involved in data analysis. JT, DS, DB, SFB, RM, TN, JZ, WH, GRF-R, MM, AR, and AD were involved in data interpretation. JT wrote the first draft of the report. All authors critically reviewed the manuscript for scientific content and approved the final version for submission.

Declaration of interests

JT reports no financial interests; she reports unremunerated participation in Roche, Celgene, Janssen, and Takeda advisory boards. SFB has received research funding from AstraZeneca, Hermes Medical Solutions, and Siemens, and has received fees for healthcare consultancy from Roche Pharmaceuticals. DB has participated in advisory boards for Roche, Janssen-Cilag, and Gilead Sciences, and has received travel grants from Roche and Gilead Sciences. MM has provided unremunerated consultancy for Roche Pharmaceuticals, and has received honoraria for lectures and preparation of educational materials from Roche China. CO has received honoraria from F Hoffmann-La Roche, Lundbeck, AbbVie, Merck, Janssen, Gilead, and AstraZeneca. VP has received honoraria from F Hoffmann-La Roche, and personal fees from Quintiles Eastern Holdings Gmb, Janssen-Cilag, Bristol-Myers Squibb, and F Hoffmann-La Roche. JZ and DS are employed by F Hoffmann-La Roche. GRF-R and TN are employed by and own stock in F Hoffmann-La Roche. WH has received consultancy fees, research funding, and honoraria from F Hoffmann-La Roche, Janssen, and Gilead. REM has received research funding, travel support, and honoraria for advisory boards and lectures from F Hoffmann-La Roche. AD has received research support from Roche, Celgene, Gilead, Takeda, GlaxoSmithKline, Bayer, Janssen, Karyopharma, Pfizer, Acerta, and MSD; has attended advisory boards for Roche, Celgene, Gilead, Takeda, CTI, Mundipharma, and Karyopharma;


M Pettes-Duler

X Roboam

B Sareni

Integrated design process and sensitivity analysis of a hybrid electric propulsion system for future aircraft

This paper is situated in the framework of future hybrid electric aircrafts which embedded weight minimization and maximization of power efficiency are the key challenges to address fuel reduction and environmental constraints. In the first part, the integrated design process aiming the overall power train optimization is described. The second part presents models specifically oriented towards the integrated design . Finally, a sensitivity analysis is carried out at the power train system level to study the influence of both electric components specific powers and efficiencies on the Maximum Take Off Weight (MTOW) and on the fuel burn of the hybrid propulsion aircraft.

Introduction

Nowadays, transport is the worldwide fastest growing sector [START_REF] Roboam | More Electricity in the Air: Toward Optimized Electrical Networks Embedded in More-Electrical Aircraft[END_REF] which significantly contributes to environmental degradation. Finding sustainable solutions is a key challenge to solve this issue especially for the aircraft sector which represents about 2% of the global CO2 emissions. The Clean Sky (H2020 EU) project assists with the aircraft manufacturers finding aircraft cleaning/noiseless solutions. Currently hybrid-electric or all electric aircrafts are not commercialized but several aircraft manufacturers explore the future of electric flight. Airbus has teamed up with Rolls Royce and Siemens to build a 100-passenger hybrid-electric technology flight demonstrator, E-Fan X, scheduled for 2020 [START_REF] Rolls | The E-FAN X programme[END_REF]. The same year, backed by Boeing and Jetblue technology ventures, Zunum Aero, a hybrid electric aircraft manufacturer startup, plans to fly a 12-passenger hybrid electric prototype in 2020 [START_REF] Aero | [END_REF]. The hybrid electric technology is taking off and the studies too. It exists several electrified propulsion architectures: Full electric, Turboelectric and Hybrid Electric. A complete state of the art has been made by the National Aeronautics and Space Administration (NASA) [START_REF] Ralph | Overview of NASA Electrified Aircraft Propulsion Research for Large Subsonic Transports[END_REF] where several electrified propulsion architectures (series hybrid/ parallel hybrid/ series-parallel partial hybrid /turbo-electric) have been studied with the pursued targets to think the aircraft of tomorrow. Many assessments have been done to estimate fuel saving quantity. In the same idea, the University of Michigan proposes different architectures [START_REF] Brelje | Electric, Hybrid, and Turboelectric Fixed-Wing Aircraft: A Review of Concepts, Models, and Design Approaches[END_REF] in this paper, a deep study is made on future electric components. The following step in the Technology Readiness Level (TRL) is the validation of concept through models. The NASA develops a mission analysis coupled with a regional aircraft sizing [START_REF] Antcliff | Mission Analysis and Aircraft Sizing of a Hybrid-Electric Regional Aircraft[END_REF], by means of very simple models to estimate the weight of a parallel hybrid-electric aircraft. In the same idea, a complete study has been done in Airbus with ICA and LAPLACE labs [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF] about hybrid electric propulsive architectures for a regional aircraft. In those works, the overall aircraft architecture has been studied taking into account both energy and aerodynamics benefits. Hybridization with electric auxiliary sources (batteries or fuel cells) may also offer the opportunity to redesign the Internal Combustion Engines by limiting mechanical power demand constraints in particular flight sequences thus allowing to optimize the engine weight [START_REF] Sgueglia | Exploration and Sizing of a Large Passenger Aircraft with Distributed Electric Ducted Fans[END_REF] and fuel consumption. The obtained results are the same for all of these hybrid architectures: hybrid electric powertrains are heavier than conventional thermal systems. But the global gain, due to aerodynamics, engine redesign and energy optimization are often positive in terms of fuel burn. These studies clearly emphasize the technological sensitivity: the lower the MTOW, the lower the fuel burn. The key challenge is then to minimize embedded weights by optimizing efficiencies and specific powers. This objective is the main target of the HASTECS (Hybrid Aircraft Academic reSearch on Thermal and Electrical Components and Systems) EU project that aims at coupling thermal and electrical studies for a regional aircraft. Only a series hybrid electric architecture has been studied in this project as it leads to huge power constraints on the electric power train, the thrust being fully provided by electric devices. From an input data set and given environment conditions (temperature, pressure, aircraft speed, etc) we use different "surrogate" models to simplify assessments of efficiencies and masses from each device to the whole powertrain. Unlike the previous references, a fixed aircraft structure is considered. Only the propulsive system is refined through a looped process linking weight variations and thrust consequences as described in section 2: this integrated design approach allows assessing energy efficiency and mass benefits. As in some examples described in section 3, the main issue of this study is to provide surrogate models in view of an integrated design allowing to efficiently progress (with moderate computation cost) towards the optimal trade-off of the whole hybrid electric powertrain. Finally, after setting up the integrated design process, a sensitivity analysis is carried out in the last section showing the effects of variations on both specific power and efficiency of the main electric devices at the system level.

Integrated design process

A series hybrid electric propulsion system (see Fig. 1) is composed of gas turbines as main power sources that drive electric generators with rectifiers supplying a uHVDC 1Electric Power Distribution Unit (EPDU). This latter is also powered by auxiliary sources composed of batteries or fuel cells. This uHVDC power distribution unit supplies inverter fed electric motors (here 4 motors) which drive propellers through gearbox. For each component of the hybrid electric propulsive device, a "system-oriented design model", also called "surrogate model", must be integrated into a global looped process estimating the MTOW at aircraft level and the fuel consumption from Turboshaft power demand. In this framework, "surrogate models" based on simplified analytic derivation, scaling, regression laws or response surfaces are necessary to address the integrated design process objectives with moderate computation cost.

FIG.1 : INTEGRATED DESIGN PROCESS

Both efficiency and mass are assessed from each component model at the end of each iteration of the looped process; masses are added in the whole powertrain to be included in the MTOW. After an iteration, based on the new (after redesign) MTOW (MTOWnew) and its ratio versus the weight reference value (MTOWref) at the initial point of the process, a new thrust must be derived:

𝑻𝒉𝒓𝒖𝒔𝒕 𝒏𝒆𝒘 = 𝑻𝒉𝒓𝒖𝒔𝒕 𝒓𝒆𝒇 × 𝑴𝑻𝑶𝑾 𝒏𝒆𝒘 𝑴𝑻𝑶𝑾 𝒓𝒆𝒇 (1)
Thus, by considering the evolution of "new" variables displayed in (1) at each iteration, an implicit looped process is achieved which is stopped when the MTOW error between two successive iterations is lower than 50 kg. The process is initialized with a full thermal reference aircraft with a MTOWref of 20 T. Then, adding the embedded weights corresponding with the electric devices (power electronics, electric motors, auxiliary source, cables), new MTOW and consequently new thrust values are derivated. Our looped simplified model has been validated with reference to a complete aerodynamic model described in [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF]. From AIRBUS side, input data have been given: -Environmental aircraft data: 𝐴𝑙𝑡𝑖𝑡𝑢𝑑𝑒(𝑡) -Mach speed along the mission profile: 𝑀𝐴𝐶𝐻(𝑡) Given these inputs, some examples of surrogate models are proposed to design the hybrid-electric power train of the studied aircraft. Readers will find more detailed models in [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF].

Taxi out

Taxi in

Takeoff

Climb

Cruise Descent

Time (pu) Thrust (N)

Environment model

An environment model is required to design different components of the power train (turboshaft, propeller) over the flight mission. Main environment variables are derived:

𝑃 𝑠𝑡𝑎𝑡𝑖𝑐 = 101325 × (1 - 𝐴𝑙𝑡𝑖𝑡𝑢𝑑𝑒 44331 ) 5.256 (2)
𝑇 𝑠𝑡𝑎𝑡𝑖𝑐 = 288.15 -0.0065 × 𝐴𝑙𝑡𝑖𝑡𝑢𝑑𝑒 + 𝐷𝐼𝑆𝐴 (3)

𝜌 𝑎𝑖𝑟 = 0.0034837 × 𝑃 𝑠𝑡𝑎𝑡𝑖𝑐 𝑇 𝑠𝑡𝑎𝑡𝑖𝑐 (4)
𝑃 𝑑𝑦𝑛𝑎𝑚𝑖𝑐 = 𝑃 𝑠𝑡𝑎𝑡𝑖𝑐 × (1 + 0.2 × 𝑀𝐴𝐶𝐻 2 ) 3.5 (5)

𝑇 𝑑𝑦𝑛𝑎𝑚𝑖𝑐 = 𝑇 𝑠𝑡𝑎𝑡𝑖𝑐 × (1 + 0.2 × 𝑀𝐴𝐶𝐻 2 ) (6)
𝑉 𝑠𝑜𝑢𝑛𝑑 = √401.8 × 𝑇 𝑠𝑡𝑎𝑡𝑖𝑐 [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF] Where 𝐴𝑙𝑡𝑖𝑡𝑢𝑑𝑒 based on the input flight mission is in meter, 𝐷𝐼𝑆𝐴 is the temperature difference from the International Standard Atmosphere (ISA). 𝜌 𝑎𝑖𝑟 is the air density in 𝑘𝑔/𝑚 3 . Finally, static and dynamic pressures (𝑃 𝑠𝑡𝑎𝑡𝑖𝑐 , 𝑃 𝑑𝑦𝑛𝑎𝑚𝑖𝑐 ) and temperatures (𝑇 𝑠𝑡𝑎𝑡𝑖𝑐 , 𝑇 𝑑𝑦𝑛𝑎𝑚𝑖𝑐 ) are respectively assessed in [Pa] and in [K]. These variables will be used in particular in turboshaft and propeller models.

Propeller model

A 6-bladed variable-pitch propeller is considered. The propeller geometry is sized by two equations. The same tip speed limit and the same maximum shaft power are considered as for the ATR 72 propeller used in [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF] . The propeller diameter can be sized from the maximum shaft power ( 𝑃 𝑚𝑎𝑥 𝑠ℎ𝑎𝑓𝑡 ) giving the maximum rotation speed (Nprop), and the propeller mass (𝑀 𝑝𝑟𝑜𝑝 ):

𝐷 𝑝𝑟𝑜𝑝 = 3.93 × √ 𝑃 𝑚𝑎𝑥 𝑠ℎ𝑎𝑓𝑡 2.4×10 6 (8)
𝑁 𝑝𝑟𝑜𝑝 = 1200 × 3.93 𝐷 𝑝𝑟𝑜𝑝 (9)
𝑀 𝑝𝑟𝑜𝑝 = 185 × ( 𝐷 𝑝𝑟𝑜𝑝 3.93 ) 2 (10)
Where 𝐷 𝑝𝑟𝑜𝑝 is the corresponding diameter. The model is based on the Disk Actuator Theory (16) with a saturation function at low speed which is implemented in (15). In (13), the maximum thrust 𝑇 𝑚𝑎𝑥 has been estimated. The use of the actuator disk theory during low speed phases tends to over predict the propeller thrust, that is why we have refined the thrust 𝑇 𝑣𝑖𝑟 in a saturation function (15) from the real thrust 𝑇 𝑟𝑒𝑎𝑙 . 𝑇 𝑟𝑒𝑎𝑙 comes from the input data. .

𝑘𝑃 = 1 𝜌 𝑎𝑖𝑟 0.1 ≤ 𝑘𝑃 ≤ 1.5 (11)

Gearbox model

For the gearbox, the linear regression model proposed by NASA in [START_REF] Antcliff | Mission Analysis and Aircraft Sizing of a Hybrid-Electric Regional Aircraft[END_REF] is considered for estimating the mass:

𝐺𝑏𝑜𝑥 = ( 𝑃 𝑝𝑟𝑜𝑝𝐻𝑃 𝑅𝑃𝑀 𝑝𝑟𝑜𝑝 ) 0.75 × 𝑅 𝑔𝑏𝑜𝑥 0.15 (17)
𝑀 𝐺𝑏𝑜𝑥 𝐿𝐵𝑆 = -37.43 + 116.33 × 𝐺𝑏𝑜𝑥 (18)

𝜂 𝐺𝑏𝑜𝑥 = 0.985 (19)
Where 𝑃 𝑝𝑟𝑜𝑝𝐻𝑃 is the maximum propeller shaft power in horsepower [HP], 𝑅𝑃𝑀 𝑜𝑢𝑡 the propeller rotation speed in [rpm] and 𝑅 𝑔𝑏𝑜𝑥 is the gearbox ratio. A linear function allows estimating the gearbox weight in [lbs] (18). A constant efficiency value is finally assessed in (19).

Turboshaft model

The Turboshaft model is based on response surfaces. We consider three inputs: the static power at sea level 𝑃 𝑆𝐿𝑆 , the ratio between total and static pressures at sea level 𝛿 [Pa] and the ratio between total and static temperatures at sea level 𝜃 [K] previously calculated in ( 5) and ( 6). From these inputs, a one column-vector is derived in (22) to assess the maximum mechanical turboshaft power 𝑃 𝑚𝑎𝑥 𝑠ℎ𝑎𝑓𝑡 𝐺𝑇 . 𝛼 1 and 𝛽 1 are two constant values of the linear regression. A convenient 𝑃 𝑆𝐿𝑆 value must be designed in order to supply conveniently the hybrid electric propulsion during the whole flight mission. In this model, the specific fuel consumption variation is taken into account: As displayed on Fig 3, the turboshaft consumption is minimum at 100% of the rating power [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF]. Contrarily, at low rating, the SFC evolution may be referred to a hyperbolic function (see Fig. 3). In that way, using secondary energy source in taxi and descent phases switching off the main thermal source could be interesting in a hybrid electric aircraft. An efficient, reliable and fast starting system is mandatory.

FIG.3: SPECIFIC FUEL CONSUMPTION EVOLUTION

VERSUS RATING POWER.

The turboshaft mass is difficult to estimate. For that purpose, a typical specific power of 9.86 kW/kg is assessed from experimental data set [START_REF] Thauvin | Exploring the design space for a hybrid-electric regional aircraft with multidisciplinary design optimisation methods[END_REF]. Finally, the fuel mass is obtained by the time integral of the mass flow rate (29):

𝑀 𝑓𝑢𝑒𝑙 = ∫ 𝐷 𝑚 𝑓𝑢𝑒𝑙 (𝑡)𝑑𝑡 (29)
𝑀 𝑡𝑢𝑟𝑏𝑜𝑠ℎ𝑎𝑓𝑡 = 𝑃 𝑆𝐿𝑆 × 𝑃 𝑆𝑃𝐸 (30)

Electric component models

For the electric components, technological models with corresponding design are currently achieved in the HASTECS project. However, in this paper mainly oriented towards system level sensitivity analysis, very simple models based on assessments with fixed efficiency and specific power/energy targets have been considered. In the HASTECS project, two targets have been challenged for 2025 and for 2035 as displayed in Table 1. In this latter table of assessments, future 20xx target has been added with more aggressive assumptions. In our case, specific powers of the electric motors, (respectively electric generators) and power electronics (rectifiers and inverters) include the cooling system. A liquid hydrogen storage with fuel cell stack are considered in this study with corresponding assesments in Table 1 [START_REF] Michel | Liquid Hydrogen Technologies for Mobil Use[END_REF]. Aggressive targets have been chosen, but certain targets are already achieved. In particular Siemens [START_REF]Electric propulsion components with high power densities for aviation[END_REF], with the electric motor SP260D at 5.2 kW/kg. The University of Illinois is designing and building a permanent magnet synchronous motor to exceed a specific power of 13 kW/kg and efficiency of 96 percent showing that these targets can be reached [START_REF] Yi | Multi-Physics Optimization for High-Frequency Air-Core Permanent-Magnet Motor of Aircraft application[END_REF]. Concerning the inverters, General Electric [START_REF] Zhang | NASA SiC Light-Weight Inverter for MW-Power (SLIM)-Phase I[END_REF] has reached a specific power by19kW/kg for its product.

𝑆𝑃 = Specific Power -𝑆𝐸 = Specific Energy
Other simple models have been developed to assess cable weights and losses, following the transferred power, the voltage level and the cable type (AC or DC). Based on this model set, the mass distribution of the hybrid power train is displayed in Fig. 4 with the particular assessments dealing with the "2035 Target".

FIG.4: HYBRID POWER TRAIN MASS SHARING. 4 Sensitivity analysis at system level

We consider a hybrid-electric aircraft composed of two same sized turboshafts which turn generators to supply the electric powertrain. The power distribution over the flight sequences is displayed on Fig. 5: in this management strategy, fuel cells are used during full electric taxi and descent phases which may correspond to a "light hybridization scenario". For the other phases, the power is here equally shared between turboshafts. The sensitivity analysis consists in varying both the efficiencies and specific powers of two device classes (power electronics and electric machines) of the hybrid electric conversion chain with regard to the 2025 and 2035 targets.

FIG.5: POWER DISTRIBUTION BETWEEN SOURCES.

In the first analysis (see Fig. It can be noticed that the impact of technological progress both in terms of specific powers and efficiency is significant on the fuel burn even if this impact is slightly lower for power electronics than for electromechanical converters. It can also be seen that both progress axis (efficiency and specific power) are really influent.

The following analysis deals with the sensitivity of same factors on the whole hybrid electric system by coupling all the elements of the system in the same figures. In the final figures, the two influence factors have been coupled (see Fig. 10 and Fig. 11). In this last sensitivity analysis, it is interesting to gather the two influent factors (specific powers and efficiencies) which characterize the technological and conceptual advance in terms of power integration and efficiency. With reference to the less aggressive assumptions (target 2025) and regarding the targets 2035 then 20XX assessments, the whole weight would be reduced by more than 12% (see Fig. 10) when the fuel burn is reduced by 17% (see Fig. 10). To conclude, electric components specific power is more sensitive to lower the MTOW. But the efficiency effect is not negligible: a trade-off between both specific powers and efficiencies has to be find.

Conclusions

A series hybrid-electric aircraft architecture performance is "strongly" linked with specific power and efficiency of each electric component. The whole embedded weight (MTOW) of a hybrid structure is a priori higher than for a full thermal chain. Two different progress axis exist to minimize the embedded weight: the specific power of each device as well as its efficiency. When adding supplementary masses of electric devices, there is a snowball effect with the MTOW which leads to enhance the aircraft thrust and consequently to enhance fuel consumption. Fortunately, energy gains offered by a higher efficiency of the electric chain, especially at low power operation (taxi and descent phases), compensate the weight increase. But this paper emphasizes why both specific powers and device efficiency have a huge impact on the MTOW and consequently the fuel burn. Future works in the HASTECS project consist in a more precise sensitivity analysis based on the technical models of power electronics and electromechanical converters. The aim of this prospect is to find the more sensitive input parameters which may be the decision variable of our future system design optimization. For that purpose, sizing models of electric machines and power electronics have to be refined but sufficiently simplified to be included in an integrated design process involving the whole power train.

  FIG.2 : COMPARISON OF AERODYNAMIC AND LOOPED MODELS

(

]

6 /Fig. 7 /FIG. 6 :FIG. 8 :FIG. 9 :

 67689 FIG. 6: IMPACT OF SPECIFIC POWER VARIATIONS OF ELECTRIC MOTOR/GENERATOR ON THE MTOW AND THE FUEL MASS FROM THE 2025 TARGET.

FIG. 10

 10 FIG.10: MTOW VARIATIONS VERSUS TECHNOLOGICAL IMPROVEMENT OF THE ELECTRIC CONVERSION CHAIN FROM THE 2025 TARGET

  Where 𝑘𝑃 is the input value of the linear regression of the model (14). 𝜌 𝑎𝑖𝑟 is the air density varying during the flight mission in 𝑘𝑔/𝑚3 . 𝑉 𝐴/𝐶 is the aircraft speed in 𝑚/𝑠 also defined by the mission profile. We have defined an advance ratio 𝑘 for the saturation function. 𝑓(𝑘𝑃) is the linear regression function used by the model where 𝛼 𝑝𝑟𝑜𝑝 , 𝛽 𝑝𝑟𝑜𝑝 and 𝛾 are constant values. After that, we can use the disk actuator theory formula with a constant value 𝑘 𝑒𝑓𝑓 = 0.9

			𝑓(𝑘𝑃) = 𝛼 𝑝𝑟𝑜𝑝 + 𝛽 𝑝𝑟𝑜𝑝 × log(𝑘𝑃) 𝛾	(14)
			𝑇 𝑣𝑖𝑟 = (	2.𝑘.𝑇 𝑚𝑎𝑥 𝜋	) × tan (	𝑇 𝑟𝑒𝑎𝑙 𝜋 2.𝑘.𝑇 𝑚𝑎𝑥	)	(15)
			𝑃 𝑠ℎ𝑎𝑓𝑡 = √(𝑉 𝐴/𝐶 . 𝑇 𝑣𝑖𝑟 ) 1 2𝑘 𝑒𝑓𝑓 2 + (𝑉 𝐴/𝐶 𝑇 𝑣𝑖𝑟 + 𝜌 𝑎𝑖𝑟 𝐴 𝑝𝑟𝑜𝑝 ) 2𝑇 𝑣𝑖𝑟 3	(16)
			and with the propeller disk area: 𝐴 𝑝𝑟𝑜𝑝 =	2 𝜋.𝐷 𝑝𝑟𝑜𝑝 4
	𝑘 = 1.6 +	60 𝑉 𝐴/𝐶 3.93×1200	(12)
	𝑇 𝑚𝑎𝑥 = 10 𝑓(𝑘𝑃) . 𝑃 𝑚𝑎𝑥 𝑠ℎ𝑎𝑓𝑡	(13)

Table 1 :

 1 Electric component assessments

2025 target 2035 target 20xx target Emotor/ Egenerator 𝑺𝑷 +cooling Efficiency

		5 kW/kg	10 kW/kg	15 kW/kg
		96%	98.5%	99%
	Power Electronics
	𝑺𝑷 +cooling	15 kW/kg	25 kW/kg	35 kW/kg
	Efficiency	98%	99.5%	99.8%
	Fuel Cell -Liquid H2
	𝑯 𝟐 + 𝐭𝐚𝐧𝐤 𝑺𝑬		3.3 kWh/kg
	Auxiliary 𝑺𝑷		1.3 kW/kg
	Stack 𝑺𝑷		4 kW/kg
	DC Bus
	Ultra 𝑯𝑽𝑫𝑪		2000V

uHVDC means "ultra-high voltage" DC" standards beyond HVDC bus (+/-270V), leading to bus voltages in the range of kVs.

Acknowledgements

This project has received funding from the [European Union Horizon 2020 (cleansky 2 JTI) research and innovation programme, 2014-2024] under grant agreement No 715483.