C Vicentini

Anne-Sophie S Vignion-Dewalle
email: anne-sophie.vignion@inserm.fr

E Thecua

F Lecomte

C Maire

P Deleporte

H Béhal

D Kerob

A Duhamel

S Mordon

L Mortier

Keywords:

Photodynamic therapy for actinic keratosis of the forehead and scalp: a randomized, controlled, phase II clinical study evaluating the noninferiority of a new protocol involving irradiation with a light-emitting, fabric-based device (the Flexitheralight protocol) compared with the conventional protocol involving irradiation with the Aktilite CL 128 lamp.

Introduction

Visible actinic keratoses (AK) are often associated with subclinical lesions on the surrounding skin, resulting in areas of field cancerization [START_REF] Ibrahim | Actinic keratoses: a comprehensive update[END_REF][START_REF] Szeimies | Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy[END_REF] . Photodynamic therapy (PDT) using 5aminolevulinic acid nanoemulsion (BF-200-ALA) (BF-200-ALA-PDT) or methyl aminolevulinate (MAL) (MAL-PDT) is an effective therapeutic option to treat AK and field cancerization [START_REF] Szeimies | Clinical, histopathological and immunohistochemical assessment of human skin field cancerization before and after photodynamic therapy[END_REF][START_REF] Braathen | Guidelines on the use of photodynamic therapy for nonmelanoma skin cancer: an international consensus. International Society for Photodynamic Therapy in Dermatology[END_REF][START_REF] Morton | Guidelines for topical photodynamic therapy: update[END_REF][START_REF] Morton | European Dermatology Forum Guidelines on topical photodynamic therapy[END_REF][START_REF] Wiegell | Update on photodynamic treatment for actinic keratosis[END_REF] . Topical application of BF-200-ALA or MAL induces selective accumulation of the photosensitizer protoporphyrin IX (PpIX) in AK; subsequent PpIX activation by specific wavelengths of light generates reactive oxygen species, which causes tissue injury and AK destruction [START_REF] Plaetzer | Photophysics and photochemistry of photodynamic therapy: fundamental aspects[END_REF] .

In Europe, activation with red light using the Aktilite CL 128 (Galderma SA, Lausanne, Switzerland) and a total light dose of 37 J/cm 2 after 3 hours of incubation with MAL is the conventional PDT protocol used to treat AK [START_REF] Morton | Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study[END_REF][START_REF] Pariser | Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study[END_REF][START_REF] Szeimies | Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study[END_REF] . Although effective [START_REF] Morton | Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study[END_REF][START_REF] Pariser | Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study[END_REF][START_REF] Szeimies | Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study[END_REF] , this protocol (hereafter referred to as C-PDT) is known to be painful, and concurrent use of cold air analgesia, hypnosis, and local anaesthesia with nerve blocks may be required to relieve discomfort and pain [START_REF] Pariser | Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study[END_REF][START_REF] Szeimies | Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study[END_REF] .

Recently, several protocols applying irradiation with daylight have been reported to be equally as effective as C-PDT. Because a maximum of 30 minutes was allowed for MAL incubation, allowing continuous activation of small amounts of PpIX, these protocols are better tolerated by patients than C-PDT [START_REF] Wiegell | Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study[END_REF][START_REF] Wiegell | A randomized, multicentre study of directed daylight exposure times of 1(1/2) vs. 2(1/2) h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp[END_REF][START_REF] Wiegell | Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: a double-blinded randomized clinical trial[END_REF][START_REF] Wiegell | Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study[END_REF][START_REF] Wiegell | Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology[END_REF][START_REF] Rubel | Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial[END_REF] . Nonetheless, using daylight as the irradiation source is not realistic for all weather conditions (e.g., different temperatures or rain, among others) 17 and is also not suitable for all patients or all anatomical sites. Furthermore, the dermatologist is unable to control the total light dose.

The Flexitheralight protocol, developed within the Flexitheralight project supported by the The aim of this study was to assess the efficacy and tolerability of FLEXI-PDT compared to C-PDT for treating patients with AK on the forehead and scalp. The primary hypothesis was that FLEXI-PDT was non-inferior to C-PDT in terms of lesion complete response rate at three months.

II. Patients and methods

A. Study design

This study was a monocentric, randomized, controlled, non-inferiority, phase II clinical study that compared two PDT protocols to treat AK.

This study was performed in accordance with the ethical principles of the Declaration of

B. Patients

Patients aged 18 years or older with 10 to 14 non-pigmented grade I or II AK lesions on the forehead and/or scalp were recruited from patients referred to the Department of Dermatology, Lille University Hospital. Patients with clinically diagnosed AK that were symmetrically distributed over the forehead and/or scalp were enrolled and treated from September 2014 to January 2017 and followed for six months. All of the patients gave written informed consent before entering the study, which is registered at ClinicalTrials.gov (Identifier: NCT03076918).

The exclusion criteria included pregnancy; immunosuppression; use of topical corticosteroids within the last 2 weeks; use of cryotherapy, curettage or PDT within the last 30 days; use of topical or systemic retinoids, urea, alpha-hydroxy acids, chemotherapy or immunotherapy within the last four weeks; use of topical ingenol mebutate, 5-fluoro-uracil, imiquimod or diclofenac within the last 3 months; contra-indication to PDT and patients included in a clinical trial within the last 30 days.

At the screening visit, each patient's demographic characteristics, medical history, current medications and Fitzpatrick skin type were recorded, and a physical examination including general appearance, regional lymph nodes and dermatologic examination of the skin was performed.

Follow-up visits were scheduled at 7 days, 3 months and 6 months.

C. The Flexitheralight protocol

FLEXI-PDT, which includes a 30-minute incubation with MAL cream under transparent occlusive dressing (Tegaderm, 3M, London Ontario, Canada), applies irradiation with a lightemitting, fabric-based device without removing the transparent occlusive dressing. As illustrated in Figure 1, this device consists of a power and control unit including three 5 W laser diodes, each connected to a flexible, light-emitting fabric sample of size 21.5 cm × 5 cm that is made of biocompatible optical fibres [START_REF] Cochrane | New design of textile light diffusers for photodynamic therapy[END_REF] . The fabric samples, which were sewn together (total area: 3 × 21.5 cm × 5 cm = 322.5 cm 2 ), sequentially emit 635 nm red light at a low fluence rate (12.3 mW/cm 2 ) for one minute, such that fractionated irradiation (1 minute of light, 2 minutes of darkness) is achieved. An irradiation time of two and a half hours delivers a total light dose of approximately 37 J/cm 2 anywhere in the treated area (12.3 mW/cm 2 × 9000 s × 1 minute of light / (1 minute of light + 2 minutes of darkness)). The device has been tested and classified into the exempt risk group in accordance with IEC 60601-2-57/2012.

FLEXI-PDT has two main features. First, the short incubation time should allow for continuous activation of small amounts of porphyrins during their formation and reduced patient-reported pain, similarly to protocols in which irradiation is applied using daylight. In addition, the fabrics are flexible and allow optimal adaptability to the treatment area, providing more homogeneous irradiation than that delivered by standard rigid light sources.

D. Treatment

The treatment regimen included one mandatory PDT session and a second identical session if at least one AK (among the included AK) remained at three months after the first PDT session. This second PDT session was performed within the three weeks following the 3month follow-up visit.

For each patient on the day of treatment, AK lesions were graded, photographed and divided into two areas, with both the same number of lesions and the same grades of lesions in each area. The protocol used for each area was assigned according to randomization.

The two areas were prepared by removing crusts and gently scraping the lesion surface.

Approximately 2 to 4 g of MAL cream (Metvixia, Galderma) was applied in a 1 mm thick layer to the lesions and the surrounding normal skin (5-10 mm margin) of both areas. The area randomized to receive FLEXI-PDT was covered with a transparent occlusive dressing (Tegaderm, 3M, London Ontario, Canada), whereas both a transparent occlusive dressing (Tegaderm, 3M, London Ontario, Canada) and a lightproof dressing (aluminium foil) were applied over the area randomized to receive C-PDT. The light-emitting, fabric-based device used for FLEXI-PDT was immediately applied to the corresponding assigned area. After 30 minutes, the device was switched on, and irradiation was performed. Two and a half hours later, the treatment was completed, and the treated area was protected with aluminium foil.

MAL was then removed from the area randomized to receive C-PDT with a saline solution.

Finally, the Aktilite CL 128 was placed between 8 and 10 cm from the area to be treated (illumination surface of the Aktilite CL 128: 144 cm 2 ) and was programmed to deliver 37 J/cm 2 over 10 minutes.

E. Randomization

The randomization schedule was generated by the statistician using the PROC PLAN procedure of SAS (SAS Institute Inc., Cary, North Carolina, USA) with a 1:1 allocation ratio and a block size of six. Allocation was concealed using sequentially numbered, opaque, sealed envelopes that were opened sequentially by the investigator at the beginning of the treatment.

F. Endpoints

The primary endpoint was the lesion complete response rate at three months. Lesion response (complete response vs. incomplete response) was clinically assessed by the investigator.

Lesion localization was performed using photographs taken on the day of treatment (before treatment).

The secondary endpoints were multiple and included evaluation of treatment tolerability at the end of irradiation, evaluation of lesion complete response rate at six months, evaluation of cosmetic outcome at three and six months, estimation of the number of patients with AK reduction higher than 75% at three and six months, and evaluation of patient satisfaction seven days after treatment. Adverse events and pain were used as criteria for treatment tolerability. Pain was assessed using a visual analogue scale (0: no pain, 10: worst pain). The cosmetic outcome was evaluated as "excellent", "good", "fair", or "poor" using a standardized scale. Patient satisfaction was assessed with a standard questionnaire.

G. Data analysis

The study was designed to have a statistical power of 80% with a one-sided alpha level of 0.025 to demonstrate non-inferiority in terms of lesion complete response rate at three months of FLEXI-PDT compared to C-PDT. A split-cluster design was adopted, and a design effect was assumed for the sample size calculation to account for both the correlation between lesions within the same patient (cluster) (intra-cluster correlation (ICC) of 0.011) and the correlation between lesions within the same area (period) (inter-period correlation (IPC) of 0.0022). Assuming a mean lesion number per patient per area of six (which, with the aboveset ICC and IPC, led to a design effect of 1.0528), a lesion complete response rate of 75% in both areas, and an absolute non-inferiority margin of -10%, the number of required lesions per area was 245. This corresponds, based on the above-assumed six lesions per patient per area, to 42 patients.

Continuous variables were expressed as the mean and standard deviation (SD), and categorical variables were expressed as the frequency and percentage. The normality of the distribution was assessed graphically and using the Shapiro-Wilk test.

The non-inferiority of FLEXI-PDT compared to C-PDT was assessed by estimating a twosided 95% confidence interval of the absolute difference in lesion complete response rates at three months. This estimation was performed using a generalized estimating equation (GEE) model with a binomial distribution and identity link function to account for repeated measures from individual patients. Treatment area was included as a covariate. If the lower limit of the 95% confidence interval was high than the pre-stated absolute margin of non-inferiority, FLEXI-PDT was declared non-inferior to C-PDT, and a two-sided superiority test was performed at an alpha level of 0.05.

The two-sided 95% confidence interval of the absolute difference in lesion complete response rates at six months between FLEXI-PDT and C-PDT was estimated using the GEE model as above. Depending on the lower limit of this confidence interval, declaration of non-inferiority at six months and a subsequent superiority test were performed.

The difference between FLEXI-PDT and C-PDT in pain levels reported at the end of each protocol was assessed using a linear mixed model with patients as random effects (the significance level was set at a two-sided alpha level of 0.05).

Finally, the difference between FLEXI-PDT and C-PDT regarding the rates of patients with at least 75% reduction in AK at three and six months was assessed using the GEE model to account for intra-patient correlation among areas (the significance level was set at a two-sided alpha level of 0.05).

All of the statistical analyses were performed using SAS software version 9.4 (SAS Institute Inc., Cary, North Carolina, USA).

III. Results

A. Population study

Twenty-seven patients were enrolled in the study. Two patients dropped out for personal reasons before treatment, resulting in a final study sample of 25 patients. These 25 patients with a total of 310 AK lesions underwent treatment and were examined three months after treatment. The ICC and IPC were estimated to be 0.08 and 0.036, respectively. Due to 116 remaining AK, a second treatment session was required for 20 patients who had exhibited a total of 252 AK at the first treatment session. This second treatment session was performed within the three weeks following the 3-month follow-up visit. Between three and six months following the first treatment session, one patient dropped out due to a serious adverse event not related to the treatment, and one patient did not return for the 6-month visit for personal reasons. Therefore, twenty-three patients with 286 AK lesions completed the study at 6

months. The study flow diagram is shown in Figure 2.

Patient and lesion characteristics are reported in Table 1 Grade I 67 (42.9) 66 (42.9)

Grade II 89 (57.1) 88 (57.1)

B. Efficacy

With 91 AK lesions exhibiting a complete response and 63 AK lesions showing an incomplete response, C-PDT achieved a lesion complete response rate of 59.1% at three months, which is lower than the 66.0% achieved with FLEXI-PDT (absolute difference, 6.9%; 95% confidence interval, -0.6% to 14.5%). Because the lower limit was above the prestated absolute margin of non-inferiority (-10%), the non-inferiority of FLEXI-PDT compared to C-PDT was supported (Figure 3). However, with a p-value of 0.07, FLEXI-PDT was not superior to C-PDT, in terms of efficacy at three months.

Six months following treatment, the lesion complete response rate achieved for the 23 patients who completed the study (286 AK lesions) was 84.0% with FLEXI-PDT vs. 76.8% with C-PDT (absolute difference, 7.2%; 95% CI -1.0% to 15.4%). The non-inferiority of FLEXI-PDT compared to C-PDT was therefore demonstrated, although the superiority test was not significant (p=0.09) (Figure 3).

The response rate at six months was approximately 1.3 times higher than that at three months for both FLEXI-PDT and C-PDT.

Regarding the rates of patients with at least 75% reduction in AK, there was no significant difference between the two protocols at three months (p=0.71) or six months (p=1.00).

C. Tolerability

Pain

As shown in Figure 4, the patient-reported pain level at the end of irradiation was significantly lower (almost non-existent) for FLEXI-PDT (mean ± SD: 0.4 ± 0.6 for the first treatment session and 0.2 ± 0.5 for the second) than for C-PDT (mean ± SD: 5.0 ± 2.6 for the first treatment session and 5.0 ± 2.2 for the second) (p<0.0001 for both treatment sessions).

Adverse events

Similar local side effects, such as erythema and oedema, were observed with both FLEXI-PDT and C-PDT. In dermatological PDT practice, these effects typically do not require special care.

One patient experienced scalp impetiginisation caused by Staphylococcus aureus in both areas 2 days after treatment. Neither fever nor adenopathy were detected. This grade I adverse event was treated with systemic antibiotic therapy.

One patient with multiple risk factors for retinal detachment and a history of retinal detachment experienced retinal detachment in one eye a few minutes after the beginning of FLEXI-PDT. This adverse event was reported by the patient only at the end of FLEXI-PDT during the completion of the questionnaire about satisfaction. The evolution was favourable with resolution of the detachment by laser therapy and partial recovery of visual acuity. No relation between this grade III adverse event and the treatment was found.

One patient with ischaemic heart disease, high blood pressure and diabetes had heart and kidney failure a few days after the three-month follow-up visit; therefore, neither the second treatment session nor the six-month follow-up visit were performed. No relation between this grade IV adverse event and the study was assumed.

Cosmetic outcome and patient satisfaction

For each patient evaluated, the cosmetic outcomes three or six months following treatment were identical for both protocols. Three months following treatment, the overall cosmetic outcome was good in almost two-thirds of patients (62.5%), fair in one-third of patients (33.3%) and excellent in one patient (4.2%). A higher rate of patients with an excellent cosmetic outcome (13.1%) was achieved at the 6-month follow-up visit, while the rates of patients with fair or good cosmetic outcomes were slightly lower (30.4% and 56.5%, respectively).

Including all protocols, 13/23 (56.5%) patients were very satisfied with the treatment, 9/23 (39.1%) patients were satisfied, and 1/23 (4.4%) patient was very dissatisfied. Two patients did not respond to the questionnaire.

Of the 24 patients who responded to the treatment choice question, 15 (62.5%) preferred FLEXI-PDT, three (12.5%) preferred C-PDT, and six patients (25%) expressed no preference.

IV. Discussion

In this study, we demonstrated that FLEXI-PDT was significantly non-inferior to C-PDT for treating AK of the forehead and scalp. FLEXI-PDT showed a lesion complete response rate at three months of 66.0% vs. 59.1% for C-PDT. Moreover, we found that FLEXI-PDT was significantly better tolerated than C-PDT, particularly in terms of patient-reported pain (mean patient-reported pain: 0.4 for FLEXI-PDT vs. 5.0 for C-PDT).

Based on studies that found no association between the complete response rate and irradiance [START_REF] Langmack | Topical photodynamic therapy at low fluence rates-theory and practice[END_REF][START_REF] Apalla | The impact of different fluence rates on pain and clinical outcome in patients with actinic keratoses treated with photodynamic therapy[END_REF] , FLEXI-PDT, with a light dose (37 J/cm 2 ) equal to C-PDT and an irradiance (12.3 mW/cm 2 ) more than five times lower [START_REF] Galderma | Tailored for PDT -Galderma[END_REF] , was expected to be non-inferior to C-PDT. The light dose delivery method might even boost FLEXI-PDT into superiority over C-PDT. Indeed, FLEXI-PDT combines two features that have been demonstrated to improve the efficacy of PDT to treat AK. On the one hand, there is fractionated irradiation, which allows the reoxygenation of tissues and photosensitizer relocalization during the dark periods and reperfusion injury with the release of free radicals causing tissue damage during light periods [START_REF] Curnow | Oxygen monitoring during 5-aminolaevulinic acid induced photodynamic therapy in normal rat colon. Comparison of continuous and fractionated light regimes[END_REF][START_REF] De Haas | Fractionated aminolevulinic acidphotodynamic therapy provides additional evidence for the use of PDT for non-melanoma skin cancer[END_REF][START_REF] Sotiriou | Single vs. fractionated photodynamic therapy for face and scalp actinic keratoses: a randomized, intraindividual comparison trial with 12-month follow-up[END_REF] . On the other hand, the flexible, light-emitting fabric exhibits optimal adaptability to the area to be treated, which results in more homogeneous irradiation than that delivered by standard rigid light sources such as the Aktilite CL 128 lamp used in C-PDT [START_REF] Vicentini | PDT of AK with the Aktilite CL128: irradiance distribution and impact of light dose on the treatment efficacy[END_REF] . Despite these two features, FLEXI-PDT unfortunately demonstrated no significant superiority. Nonetheless, p-values for superiority, which are slightly higher than 0.05, can be accepted as representing a tendency to superiority for FLEXI-PDT and indicate the need for additional study with more patients.

Furthermore, with a short MAL incubation of 30 minutes and a low irradiance of 12.3 mW/cm 2 , FLEXI-PDT allows for a balance between the development and photodegradation of PpIX (the PpIX molecules are photoactivated/photodegraded as quickly as they are formed), thus ensuring low PpIX accumulation. This low accumulation reduces patientreported pain and enables FLEXI-PDT to be nearly pain-free (mean patient-reported pain: 0.4) without the use of strategies to cope with pain, similar to protocols involving irradiation with daylight [START_REF] Wiegell | Daylight-mediated photodynamic therapy of moderate to thick actinic keratoses of the face and scalp: a randomized multicentre study[END_REF][START_REF] Wiegell | A randomized, multicentre study of directed daylight exposure times of 1(1/2) vs. 2(1/2) h in daylight-mediated photodynamic therapy with methyl aminolaevulinate in patients with multiple thin actinic keratoses of the face and scalp[END_REF][START_REF] Wiegell | Photodynamic therapy of actinic keratoses with 8% and 16% methyl aminolaevulinate and home-based daylight exposure: a double-blinded randomized clinical trial[END_REF][START_REF] Wiegell | Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study[END_REF][START_REF] Wiegell | Daylight photodynamic therapy for actinic keratosis: an international consensus: International Society for Photodynamic Therapy in Dermatology[END_REF][START_REF] Rubel | Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial[END_REF] . However, in contrast to those protocols, FLEXI-PDT can be conducted in all weather conditions, in any geographic location, and year-round (subject to sufficient temperature) and always delivers a light dose of 37 J/cm 2 . FLEXI-PDT could become the treatment of choice for AK, particularly for patients with large field cancerization, as the size of the treated area is the strongest pain predictor, and the most sensitive areas to treat include the face and the scalp 26 .

The lesion complete response rate at three months for C-PDT, which was 59.1% in this study, is lower than most rates reported in the literature, which usually range from 70% to 90% 8- 10,14,16,27 . This lower lesion complete response rate can be explained by the difference in AK grade across studies; in the present study, 57.1% of AK were grade II, whereas most previous studies [START_REF] Morton | Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study[END_REF][START_REF] Pariser | Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study[END_REF][START_REF] Wiegell | Continuous activation of PpIX by daylight is as effective as and less painful than conventional photodynamic therapy for actinic keratoses; a randomized, controlled, single-blinded study[END_REF][START_REF] Rubel | Daylight photodynamic therapy with methyl aminolevulinate cream as a convenient, similarly effective, nearly painless alternative to conventional photodynamic therapy in actinic keratosis treatment: a randomized controlled trial[END_REF] involved a large majority of grade I AK, which are known to exhibit better response to MAL-PDT than grade II AK [START_REF] Morton | Intraindividual, right-left comparison of topical methyl aminolaevulinate-photodynamic therapy and cryotherapy in subjects with actinic keratoses: a multicentre, randomized controlled study[END_REF][START_REF] Szeimies | Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study[END_REF][START_REF] Tarstedt | A randomized multicenter study to compare two treatment regimens of topical methyl aminolevulinate (Metvix)-PDT in actinic keratosis of the face and scalp[END_REF] . The use of multiple treatment sessions to increase treatment efficiency, as in previous studies [START_REF] Pariser | Topical methyl-aminolevulinate photodynamic therapy using red light-emitting diode light for treatment of multiple actinic keratoses: A randomized, double-blind, placebo-controlled study[END_REF][START_REF] Szeimies | Topical methyl aminolevulinate photodynamic therapy using red light-emitting diode light for multiple actinic keratoses: a randomized study[END_REF] , may also have contributed to this difference in the lesion complete response rate. Nevertheless, other studies (on the current use of MAL-PDT in France 29 or performed by Kessels et al. [START_REF] Kessels | Laser-mediated Photodynamic Therapy: An Alternative Treatment for Actinic Keratosis?[END_REF] ) have shown similar "low" lesion complete response rates for C-PDT.

Due to the initiation of the PHOS-ISTOS clinical study (ClinicalTrials.gov Identifier: NCT03076892) that aimed to assess the non-inferiority of the PHOS-ISTOS protocol compared to C-PDT, this study was stopped earlier than planned. Like FLEXI-PDT, the PHOS-ISTOS protocol is a protocol for PDT that applies irradiation with a light-emitting fabric-based device to treat AK. However, compared to FLEXI-PDT, the device is more compact, and the illumination parameters (irradiance: 1.3 mW/cm 2 ; light dose: 12 J/cm 2 ; irradiation time: 2 h 30) are different. Given the premature termination of the Flexitheralight study, only 25 patients were included instead of the planned 42. Although this reduction in sample size resulted in a reduction in the a priori statistical power of the study for the primary endpoint, our sample of 25 patients was sufficient to demonstrate the statistical non-inferiority and higher tolerability of FLEXI-PDT compared with C-PDT. Nevertheless, this reduction in statistical power may have led to upward-biased estimates of the treatment effect. In addition to avoiding the risk of biased estimates, the recruitment of more patients might have allowed us to demonstrate the above-discussed superiority of FLEXI-PDT to C-PDT.

The use of the light-emitting, fabric-based device has already been extended to PDT treatment for vulvar Paget's disease [START_REF] Vicentini | Treatment of a vulvar Paget's disease by photodynamic therapy with a new light emitting fabric based device[END_REF] . This extension was motivated by the low pain levels experienced by patients during FLEXI-PDT, and extension to other medical indications is currently under investigation.

V. Conclusion

This randomized controlled clinical study demonstrated that PDT using the Flexitheralight protocol is non-inferior to PDT using the conventional protocol in terms of efficacy at three months and is better tolerated. Furthermore, PDT using the Flexitheralight protocol can be performed in all weather conditions, in any geographic location, year-round and could therefore become the treatment of choice for AK.

VI.

  //www.flexitheralight.com/), uses a 30-minute MAL incubation followed by 2.5 h of irradiation with a light-emitting, fabric-based device. Due to the short incubation time, the Flexitheralight protocol (FLEXI-PDT) provides a nearly pain-free, year-round alternative to C-PDT. Moreover, the high flexibility of the light-emitting, fabric-based device ensures optimal adaptability to the treatment area, offering clear advantages over other protocols.

  Helsinki (2008) and the International Conference on Harmonisation -Good Clinical Practices (ICH-GCP) and in compliance with article L. 1121-4 of the French Public Health Code. The study design was reviewed and approved by the French National Agency for the Safety of Medicines and Health Products (ANSM) (authorization number: 2013-A01096-39) and the French Ethics Committee (CPP) (authorization number: CPP-03/051/2013).

Figure 1 :

 1 Figure 1: The three flexible, light-emitting optical fibre-based fabrics used for FLEXI-PDT sequentially emit 635 nm red light for 1 minute, resulting in fractionated irradiation (1 minute of light, 2 minutes of darkness).

Figure 2 :

 2 Figure 2: Study flow diagram (SCC: Squamous cell carcinoma)

Figure 3 :

 3 Figure 3: AK lesion complete response comparing FLEXI-PDT and C-PDT. The absolute differences in lesion complete response rates between FLEXI-PDT and C-PDT and the associated 95% confidence intervals (CI) were estimated from the GEE model, accounting for repeated measures from individual patients and including treatment area as a covariate. Error bars indicate the two-sided 95% CI. The blue dashed line indicates the absolute noninferiority margin, while the blue tinted region indicates the zone of inferiority.

Figure 4 :

 4 Figure 4: Box plot of pain levels. The red crosses correspond to the mean pain levels, and the central horizontal bars are the median pain levels. The lower and upper limits of the boxes are the first and third quartiles, respectively. Points above or below the upper and lower bounds of the whiskers can be considered outliers. The ends of the whiskers represent the minimum and maximum pain levels when excluding outliers.

This work was supported by the French National Research Agency (ANR) through the Flexitheralight project (Projet-ANR-12-EMMA-0018) (http://www.flexitheralight.com/). Metvixia cream (168 mg of MAL/g) was graciously supplied by Galderma R&D (France).

Conflicts of interest:

Claire Vicentini received travel grants and accommodation expenses to attend the 16 th


Luis Felipe

E Akin Sisbot

Rachid Alami

Geometric Tools for Perspective Taking for Human-Robot Interaction

Psychological studies on human interactions made surface the notion Perspective Taking. This notion, referring to reason on other persons' points of view, eases the communication between interacting individuals. For a robot interacting with people, we believe that Perspective Taking can play an important role that will allow the robot to understand, reason and act according to human's point of view thus allowing an efficient communication and cooperation.

In this paper, we propose a group of algorithms to evaluate and generate robot configurations that are not only collision free but also obeying HRI constraints by reasoning explicitly on human's perspective.

Introduction

One of the challenges of human-robot interaction (HRI), is the environment sharing and spatial placement between the robot and the human. This, added to the problem of understanding human intentions to improve the robot's cognitive capabilities in order to result a better interaction. For these purposes, robot has to adopt different human behaviors, like perspective taking.

The notion of perspective taking comes from psychological studies on human to human interactions. It refers essentially to the fact of reasoning from other persons point of view. It is also interpreted as taking its own perspective from a different place on the space by applying what is called a mental rotation to perceive the environment from different place. These sets of actions are used by humans in their everyday lifes, and are intended to ease comunication between individuals and to help to have shorter and faster interactions.

Perspective taking can be used by the robot to generate configurations to approach human or to compute a geometric way to place itself where it can perceive an object referred by a person. The introduction of perspective taking concepts on robot's spatial reasonning for placement is called here perspective placement.

In this paper, we introduce a group of algorithms that introduces perspective taking to the geometrical reasoning of the robot. In section 2, we present the foundations of perspective taking as well state of the art approaches using this notion. Section 3 introduces PerSpective Placement (PSP), a system that generates and evaluates robot configurations according to human's perspective. Section 4 and 5 illustrates simulation and real world results of this system applied in various scenarios. Finally, the section 6 concludes this paper and gives perspectives on perspective taking in robotics.

Related work

Although human-robot interaction is a very active research field, there is no extensive amount of research on perspective taking on robotics.

Teversky et al. [1] [2] show the effectiveness of changing perspectives between persons in face-to-face communication scenarios for spatial descriptions. They conclude that the perspective switching is more effective than trying to avoid it.

Akerman [START_REF] Ackerman | Perspective-Taking and Object Construction: Two keys to learning[END_REF], on the other hand, explains how a person can estimate his relative position in the world by 3D mental transformation of an object or of an entire place. As mental rotation and perspective taking are important for interacting with humans, they are often taken into account in 1) computer graphics for simulating human-like view [START_REF] Costella | A Beginner's Guide to the Human Field of View[END_REF][5], 2) in virtual reality for home or car design [START_REF] Gomes De Sá | Virtual Prototyping -The Integration of Design and Virtual Reality[END_REF] [7], 3) in human training [START_REF] Menchaca-Brandan | Influence of perspective-taking and mental rotation abilities in space teleoperation[END_REF] and 4) in interface design for human-computer interaction [START_REF] Hsu | Third-Person Interactive Control of Humanoid with Real-Time Motion Planning Algorithm[END_REF].

Mental rotation has also found its place in robotics, precisely in mobile robot simulators [START_REF] Faust | A Video Game-based Mobile Robot Simulation Environment[END_REF], where a virtual environment simulates sensor data for the robot. With this, researchers can test different robot programs without moving real robots. Next best view problems are also applications where mental rotation is calculated in order to obtain a position to construct 3D models of objects [START_REF] Bottino | What's NEXT? An interactive next best view approach[END_REF] [START_REF] Li | Automatic view planning with self-termination in 3D object reconstructions[END_REF] or to obtain an automatic surface acquisition [START_REF] Pito | A Solution to the Next Best View Problem for Automated Surface Acquisition[END_REF].

Perspective taking has begun to be used in HRI research field in the last years. Richarz et al. [START_REF] Richarz | There You Go! -Estimating Pointing Gestures In Monocular Images For Mobile Robot Instruction[END_REF] use the area in front of a human in order to obtain pointing places so that the robot can interact with him. Trafton et al. show in [START_REF] Gregory Trafton | Enabling effective human-robot interaction using perspective-taking in robots[END_REF] and [START_REF] Trafton | Perspective-taking with robots: experiments and models[END_REF] a robot system that uses geometrical reasoning in perspective taking to take decisions about human reasoning. They prove how human-human interaction helps if it is applied to human-robot interaction. [START_REF] Breazeal | Using perspective taking to learn from ambiguous demonstrations[END_REF] and [START_REF] Berlin | Perspective Taking: An Organizing Principle for Learning in Human-Robot Interaction[END_REF] describe in a 3D simulated environment using perspective taking to help a robot with the learning process, the authors establish some principles in perspective taking for HRI, and treat the problem on high level layer, but don't take into account robot motion to change its own perspective.

Nevertheless, to our knowledge mental rotation and perspective taking have not been used for a mobile robot who is in a close interaction with humans. In this article we present the importance of these characteristics in finding robot configurations to place itself.

PerSpective Placement (PSP) for HRI

As in every robot motion planning, the robot has to find a continous path between its actual configuration (starting point) and its final configuration (destination point). Perspective Placement (PSP) is concerned by this last part of motion planning.

We define perspective placement as a set of robot tasks to find, validate and evaluate robot configurations in a human shared environment, performing perspective taking and mental rotation in order to interact and ease communication with humans.

PSP for Humans

To interact with human, the robot has to find how to place itself in a configuration where it has direct contact with this person. This constraint helps to reduce search space to find such a point. This search can be subdivided in two phases: first, the robot has to find positions that belong to the human field of view represented as a semicircle area in front of human (with preference on the attentional field of view) and; second, it has to validate positions obtained for visual contact, preventing big visual obstructions from blocking robot perception.

The area in human attentional field of view, called here as "Interaction Area", is defined as the zone in front of the person by the angle and by the radius:

α view | 0 • ≤ α view ≤ 180 • Rad | Rad min ≤ Rad ≤ Rad max
α and Rad and are defined by the characteristics of the interaction (e.g. proximity needed for just visual interaction or handing an object), by robot sensor capabilities and by human preferences. Once defined this area, ilustrated in figure 1, a set of points around the person are generated and will be chosen in order to ensure these properties:

• Collision Free: Robot in this position must not be in collision neither with objects and persons nor with itself.

• Sensor Oriented: Selected sensors must be oriented towards the human in order to perceive it.

• Without Visual Obstructions: In sensor's acquisition, human has to be perceived depending on the interaction task.

• Human-Like Positioning: Based on user studies [START_REF] Huettenrauch | Investigating spatial relationships in human-robot interaction[END_REF] of robot-human spatial placement, robot has to find spatial formation with the person in a human acceptable way.

• Minimal Cost: Robot should find a position that minimizes the cost based on human-robot distance and on human's comfort [20] [21].

To determine what is perceived by a camera, we use 2D perspective projection of the 3D environment. This projection is obtained from the sensors's position when the robot is placed in desired configuration. The projection obtained is a matrix M atP where the value of the position (x, y) represents one point in the object's projection image in sensor's field of view. In the figure 2, 2D projection is illustrated.

We define "Projection rate" P r as the projection percentage of an element El (object, human or obstacle) on the environment represented in M atP . P r is obtained by: P r(El) = ΣM atP (x, y) | (x, y) El.

The projection rate of an element that is not projected P r hidden can be obtained with: P r hidden (El) = P r desired (El) -P r visible (El) where P r visible is the projection rate that considers visual obstructions (only visible projection). On the other hand, P r desired is the relative projection obtained without considering objects in the environment (as it should look without visual obstacles). In figure 3 we can observe the difference between desired and visible relative projections. Finally, to know if a point is cadidate for perspective placement by: W atch(Ob) ≥ μ where μ is a threshold that corresponds to a desired percentage.

In the other hand, costs for each point are, as we have introduced before, based partially on the direct distance from robot's actual position Cost distance , and the total cost is calculated as:

Cost total (x, y) = (Cost distance (x, y) * Gain distance )+ ((Cost f rontal (x, y) + Cost inarea (x, y)) * Gain f rontal )+ (Cost HAMP (x, y) * Gain HAMP )
Where Cost f rontal is the distance from the front of the human gaze orientation, to incite a face-to-face human like position. Cost inarea (x, y) is a fixed cost depending if the point is in the interaction area (cost is higher otherwise). Cost HAMP is the cost of the point calculated by the Human Aware Motion Planner (explained in detail on [START_REF] Sisbot | A mobile robot that performs human acceptable motion[END_REF] and [START_REF] Sisbot | A Human Aware mobile robot motion planner[END_REF]) based on human safety and comfort. Gain x is the weight given to this criterion. An example of calculated costs is shown in figure 4 for the scenario of figure 1. Maximal and minimal ranges of interaction area are predefined based on Hall's interpersonal distances mentioned in [START_REF] Huettenrauch | Investigating spatial relationships in human-robot interaction[END_REF] depending on desired interaction task.

PSP for Known Objects

Objects in the environment like tables, desks, sofas, chairs, etc. All considered as fixed obstacles and are called here as "known objects". The robot knows object's model and its position in the environment.

Methodology of perspective placement for a known object, is similar to PSP for humans. Here the object's perspective is not taken into account, so the robot can place itself all around object's position. Nevertheless, robot has to take into account its own perspective to look for the best placement configuration.

In this case "Interaction area" is called "Approach area" (obviously because there is no interaction with unanimated objects). Maximal an minimal ranges are defined based only on collision avoidance and robot sensor limits. For a given point, costs are calculated with:

Cost total (x, y) = (Cost distance (x, y) * Gain distance )+ (Cost HAMP (x, y) * Gain HAMP )
An example of costs function for a known object is illustrated in figure 5. Configuration search starts at the least expensive point that contains all the properties mentioned above.

PSP for Non-visible or Unknown Objects

Sometimes there are manipulable objects in the environment that are small. But they are not always at the same place and they can be hidden by another object. The object referenced by the human can be unperceivable to the robot (e.g. too far from robot sensors to create a model or know the exact position and orientation of the referenced object).

Here, our approach to this problem is to create a simple geometrical object, called "search sphere", that could be set on possible places like the one referenced by human or on surfaces of known objects (e.g. on the top of a table). Discovering the referred object can be interpreted as seeing the search sphere.

Due to the search sphere's shape and position, its approaching area and its costs functions are placed around the sphere as it is in for known objects. Maximal and minimal approaching ranges are defined by the specifications of the task.

Simulation Results

Our perspective taking system is implemented in C and integrated and tested within the Move3D [START_REF] Siméon | Move3D: a generic platform for motion planning[END_REF] software platform developed at LAAS-CNRS. Fig. 6 illustrates two similar situations where the robot has to interact with a person, in the first scenario (fig. 6-a) there is no obstacles between human and robot, and on the second one (fig. 6-b) we can see an obstacle between them but it doesn't cause a visual obstruction for the robot, the interaction zone is also further from human.

In the scenario illustrated in figure 7, a desk prevents the robot to see the human that is seated behind this visual obstruction. Robot finds a position where it can see the person whom it wants to interact.

Figure 8 gives examples of how PSP can find a configuration for known object (a furniture) in two different situations. In the first case with a person is blocking the obstacle and causing a visual obstruction, here the robot finds a position on the right side of the person, by avoiding it in order to perceive the table. Note that the robot computes a final configuration where it avoids not only collisions with human or obstacles but also with visual obstacles.

On the second situation an extra person is occluding the table from the position chosen on the first case, here the robot computes a configuration on the other side of table where none of the persons is present on the environment are visualy blocking this table.

Robot Implementation and results

The PSP system is implemented into OpenGenom [START_REF] Fleury | Genom: a tool for the specification and the implementation of operating modules in a distributed robot architecture IEEE[END_REF] with the help of other modules of supervision, task planning, human detection and tracking, robot self localization, path and motion planning, etc. that forms the same architecture as described in detail on [START_REF] Sisbot | Supervision and Motion Planning for a Mobile Manipulator Interacting with Humans Proc in[END_REF]. The whole system has been carried into our robot Jido equiped of three Pentium IV procesors, one Laptop with a Intel core-duo processor, two 2D SICK laser scaner (front and rear), a six DOF Mitsubishi PA-10 manipulator, 1 tilt and pan stereo camera, 1 color stereo cameras on the end axis of the manipulator, 8 sonar sensors, and three finger tactile hand.

In figure 9, a scenario is shown with a person interacting with the robot. The person indicates the robot to go to pick up an object on the table and bring it back to him ("bring me the yellow bottle"). The robot makes the respective plan with the sequence of different tasks. PSP module finds a valid configuration to execute each task that implies navigation motion of the robot.

The first configuration is placed to see the table where the bottle is located, maximum and mininimum distances are set according to arm capabilities for grasping the bottle. Second configuration is found to get close to human and give him the bottle.

Another example is ilustrated in 10, where an obstacle (a table) prevents the robot from several positions close to the human to bring him the bottle.

Conclusions and future work

In this work, we have shown how using perspective taking concepts added to motion planning techniques can be useful on human-robot interaction. Furthermore, we have presented different algorithms that take into account human and robot perspectives to determine different robot configurations, where the robot can perceive its objective (human or objects) without any collision and visual obstructions. This allows robot to plan its trajectory to a position where both, the human and the robot, can see each other and interact.

A posible extension of this approach is a fusion of a task planner with these geometical tools. This could increase the precision for obtaining viable tasks. Another extension of PSP, could be on the close human-robot interaction where the robot has to reason about manipulating objects, deciding positions on a shared space with human.

Also we plan to integrate these systems to obtain a general solver which will produce friendly and socially acceptable robot positions.

Figure 1 .

 1 Figure 1. The interaction area is marked as the band in front of the human.

Figure 2 .

 2 Figure 2. a) Robot positioned in the interaction area. b) Computed robot perception (2D projection)

Figure 3 .

 3 Figure 3. Relative projections, here the person is the objective and differs from other elements on the environment. a)Desired relative projection b) Visible relative projection

Figure 4 .

 4 Figure 4. Computed costs of the points. a) Points in all around the field of view area, those points out of the interaction area have the highest cost. b) Points on the interaction area, lower cost are due to robot proximity and that are closer to front.

Figure 5 .

 5 Figure 5. Costs of the points in modeling area around an object.

Figure 6 .Figure 7 .

 67 Figure 6. Simple case: Results of PSP for Humans. Robot have found a point near the human where it can see him

Figure 8 .

 8 Figure 8. Approaching to the table, a) Initial position, b) Final configuration looking at the table c), d)initial and final configuration with two persons hidding the table.

Figure 9 .Figure 10 .

 910 Figure 9. First PSP for known objects, approaching to the table, a) Initial position, b) Final configuration looking at the table. Second, PSP for humans, c)-d) Initial and final configuration looking at human

Acknowledgements

Special thanks to Assia and Juan Pablo for their comments and suggestions.


Luis F Marin-Urias

Amit Emrah Akin Sisbot

Kumar Pandey

Riichiro Tadakuma

Rachid Alami

Towards Shared Attention through Geometric Reasoning for Human Robot Interaction

Human Robot Interaction brings new challenges to the geometric reasoning and space sharing. The robot should not only reason on its own capacities but also consider the actual situation by looking from human's eyes, thus "putting itself to human's perspective".

In humans, the "visual perspective taking" ability begins to appear by 24 months of age and is used to determine if another person can see an object or not. In this paper, we present a geometric reasoning mechanism that employs psychological concepts of "perspective taking" and "mental rotation" in order to reason what the human sees, what the robot sees and where the robot should focus to share human's attention. This geometric reasoning mechanism is demonstrated with HRP-2 humanoid robot in a human-robot face-to-face interaction context.

I. INTRODUCTION

As the research on human-robot interaction approaches more and more towards robot interacting closely with people having knowledge, beliefs, attention, perspectives and capacities, the necessity of taking these notions into account in robot's design appeared. In this paper, we are focusing on geometric tools to model the attention of the human towards the goal of enabling the robot to share it.

In [START_REF] Kaplan | The challenges of joint attention The challenges of joint attention[END_REF], the notion of "joint attention" is defined as a bilateral process between at least two agents (human and/or robot), where both are aware about the intentions of each other. This process has to contain at least four prerequisites:

• Attention detection. To follow other agent's attentional behavior (i.e. Gaze following) • Attention manipulation. To influence the attentional behavior of the other agents. • Social coordination. Joint coordinated actions (turntaking, role-switching, etc.) • Intentional understanding. Agents must notice if they share the same intention to achieve the same goal. Attention sharing requires, among others, the notions of "perspective taking" and "mental rotation" taken into account robots reasoning mechanism. "Mental rotation" is the ability to acquire the representation of the environment from another point of view. On the other hand, "perspective taking" is the general notion of reasoning from another person's point of view to obtain a representation of that person's knowledge. In the context of this paper, we are interested in mental rotation and visual perspective taking where the robot should place itself to human's place to determine what he is actually seeing. Visual perspective taking is one of the elements that contribute to the general knowledge and actual attention of a person because of the fact that a thing that is seen becomes automatically known.

In literature, the research towards joint attention is mainly based on detecting human gaze and following it in an image to find out what the human is looking and focusing the robot towards that objective [START_REF] Huang | Development of the joint attention with a new face tracking method for multiple people , Advanced robotics and Its Social Impacts[END_REF], [START_REF] Nagai | How does an infant acquire the ability of joint attention?: A Constructive Approach[END_REF]. Visual occlusions are not taken into account and the reasoning done is generally on the 2D image of the robot. [START_REF] Scassellati | Imitation and Mechanisms of Joint Attention: A Developmental Structure for Building Social Skills on a Humanoid Robot[END_REF] describes that the imitation of some other "human social cues" has to be taken into account (added to tracking gaze system). It is mentioned that the recognition or execution of a gesture that can manipulate the attention (i.e. declarative and imperative pointing and "eye contact") of an attentional partner, helps to the development of better social behaviors. The implementation of what is called "mutual gaze" has shown an efficient task-based decomposition to achieve Joint attention.

Imai et al. presented a robot platform [START_REF] Imai | Physical relation and expression: joint attention for human-robot interaction, Industrial Electronics[END_REF] that performs vocal utterances added to "eye contact" with predefined pointing gestures that carries the attention of the human to an referenced object (performing joint attention). A basic 3D reasoning is employed to infer the position of the pointed object.

In [START_REF] Brooks | Robot's Play: Interactive Games with Sociable Machines[END_REF], Brooks et al. presented Leonardo showing also some characteristics of shared attention on the robot gestures to communicate with human. The robot looking at the same button, that human is making reference, included reasoning on human's pointing motion.

An important geometric tool for attention sharing is the mental rotation. This notion is often used in computer graphics and simulation where the screen allows the watcher to see a scene from different angles (e.g. to simulate humanlike view in order to obtain fast object drawing [START_REF] Zhang | Visibility Culling Using Hierarchical Occlusion Map[END_REF], [START_REF] Chhugani | vLOD : High-Fidelity Walkthrough of large Virtual environments[END_REF], or to increase the level reality of environment, home or car design [START_REF] Mueller | Procedural Modeling of Buildings[END_REF]).

Mental rotation is also used in robotics to simulate robot sensors [START_REF] Faust | Smart, A Video Gamebased Mobile Robot Simulation Environment[END_REF] and also in the interface design of games and human-computer interaction scenarios [START_REF] Hsu | Third-Person Interactive Control of Humanoid with Real-Time Motion Planning Algorithm[END_REF]. The most common use of mental rotation in HRI is the research on teleoperation where the operator needs to see the scene that the robot actually sees [13].

Perspective taking is also employed in HRI where the robot needs to put itself on human's place and share his state of mind. In [START_REF] Breazeal | Using Perspective Taking to Learn from Ambiguous Demonstrations[END_REF], Breazeal et al. presented a learning algorithm that takes into account information about teacher's visual perspective with a predefined perspective information. Berlin et al. used a 3D simulated dynamic environment for the same learning scheme where perspective taking entered to modify the belief system [START_REF] Berlin | Perspective Taking: An Organizing Principle for Learning in Human-Robot Interaction[END_REF].

Trafton et al. presented a robot [START_REF] Trafton | Enabling Effective Human-robot Interaction Using Perspective-taking in Robots[END_REF] that uses geometrical reasoning with perspective taking to take decisions about human reasoning. They proposed a polyscheme propositional system to take decisions in ambiguous scenarios. In a similar way, Johnson et al. [START_REF] Johnson | Demiris Perceptual Perspective Taking And Action Recognition[END_REF] used the perspective taking to make a more accurate action recognition in the interaction between two robots.

In this paper, we present a geometric reasoning system involving mental rotation and perspective taking capabilities that can be used for human-robot attention sharing. This system reasons entirely in 3D, modeling different visual capabilities for each agent and determining objects from different angles with visual obstruction taken into account. This will enable the robot capability to plan motions in order to attempt sensor-based configurations, where the robot can share or influence the human attention, as shown in previous work in [START_REF] Luis | Geometric Tools for Perspective Taking for Human-Robot Interaction Seventh Mexican International Conference on Artificial Intelligence 2008[END_REF], [START_REF] Sisbot | Spatial Reasoning for Human Robot Interaction[END_REF].

II. GEOMETRIC TOOLS

Attention sharing requires psychological notions of perspective taking and mental rotation taken into account in robots reasoning. As mentioned in previous section, perspective taking is the general notion of taking another person's point of view to acquire an accurate representation of that person's knowledge. In the context of this paper, we are interested in visual perspective taking where the robot should place itself to human's place to determine what he is actually seeing.

A. Mental Rotation

In order to find out what human is seeing, we attach a virtual camera into "human's eyes" in its model within Move3D [START_REF] Siméon | Move3D: a generic platform for motion planning[END_REF] simulation and planning environment. The attached camera will move as the configuration of the human model changes. To determine what is perceived by this camera, we use 2D perspective projection of the 3D environment. This projection is obtained from an image taken from the human's eyes point of view.

The obtained result is the matrix M atP where the value of the position (x, y) represents one point in the projection image in human's field of view. A 2D projection of the scenario shown on figure 1 is illustrated in the figure 2.

The 2D projection image, which is the result of this mental rotation process, represents the points of the environment that the human is actually seeing.

Even though the information on visible and invisible points is interesting, for an HRI scenario the most important information that can be extracted from this image is, which objects, humans, obstacles or robots are actually seen by the human. This image will be used as an input of perspective taking mechanism that reasons the visibility of each body in this image.

B. Visual Perspective Taking

We define "Projection rate" P r as the projection percentage of an element El (object, human, obstacle or robot) on the environment represented in M atP . P r is obtained by:

P r(El) = ΣM atP (x, y) | (x, y) El
The projection rate of an element that is not projected P r hidden can be obtained with: P r hidden (El) = P r desired (El) -P r visible (El)

where P r visible is the projection rate that considers visual obstructions (only visible projection). On the other hand, P r desired is the relative projection obtained without considering objects in the environment (as it should look without visual obstacles). Figure 3 illustrates the difference between desired and visible relative projections of the robot from human's point of view. As the perspective taking system reasons the visibility by taking into account everything in the 3D environment, including the human himself, human's hand causes a small visual occlusion on the laptop (figure 4). Finally, an element is considered visible to the human by: W atch(El) ≥ µ where µ is a threshold that corresponds to a desired percentage.

A snapshot of a scenario where a person is sitting on a table is illustrated in figure 5. In this example, the human is looking at the laptop. By using mental rotation and perspective taking systems, the robot determines that the object in human focus is the laptop. Although the human looks also in the direction of the bottle and the white box, these two objects are evaluated as invisible by the system because of the occlusion of the laptop.

C. Seen Objects

Some objects in the environment can be considered as fixed obstacles and can be excluded from the perspective taking. This functionality can allow the robot to react according to the context and human's activity. In the scenario illustrated by Figure 5, the table is considered as an obstacle and is not returned by perspective placement system. In the context of a person sitting next to a table, we can consider that the attention of the human will be mainly on the object on the table but not on the table itself.

The human is provided with a wide field of view. Nevertheless, when it is centering its attention to something the visual attention reduces its size to a particular cone form as we can see in [START_REF] Notger | The attentional field has a Mexican hat distribution[END_REF]. The objects outside the attentional field of view, also can be ignored from the perspective taking process.

On the final elimination step, we pass the list of objects to the perspective process and like that we can obtain the objects perceived from the human's perspective.

Although all the process of elimination of the non attentional objects (objects that are not of interest), we still could have many objects that can enter in the attentional field of view and that are not occluded by another object. Perspective taking of the human gaze is not enough to determine an attentional object, so that we have to consider temporal constraints of attention. Human has to spend little time on an object to become an attentional object.

Finally, in the case of ambiguous attentional objects, we take the first closest object to the line in the center of the visual attention cone. In other words the closest to human's line of perception.

For acquiring more reliable data, a process of data fusion with utterances and context should be applied to the process.

III. INTEGRATION AND RESULTS

A. Scenario

The experimental environment resembles a Face to Face interaction scenario of human and our Humanoid Robot HRP2. The table serves as common work platform and the objects on the table are a toolbox, a small box and a cup. Figure 6 shows the real scenario and figure 8 shows its 3D representation in the interface of our Move3D [START_REF] Siméon | Move3D: a generic platform for motion planning[END_REF] software platform, where the geometric tools are implemented.

Note that apart from using the static model of the environment, our system puts objects dynamically in this 3D model, which has been described in next section.

B. Implementation and Results

The entire system has been carried to our HRP2 robotic platform. HRP2 is a humanoid robot developed by Kawada Industries, Inc. It has 30 degrees of freedom. In LAAS-CNRS, it has the vision system composed of four cameras on its head. The robot's height is 1570 mm and its width is 613 mm. Its mass is 58kg, including batteries.

The system architecture is consisting of various taskspecific dedicated OpenGenom modules [START_REF] Fleury | Genom: a tool for the specification and the implementation of operating modules in a distributed robot architecture[END_REF]. The environment Move3D is managed by one of these modules, called GEO, in order to interface it with the other modules. A scheme of the system architecture is illustrated on the figure 9, showing all the data flow with the GEO module. The acquisition of the dynamic changes in the environment is mainly done by two modules: the vision based module ViMan and head markers detection based on motion capture system. ViMan uses stereo cameras of the robot and tags on the object to identify and calculate its position in the 3D space. The GEO module continuously obtains this 3D positions and orientations, and then updates the environment placing models of the objects on the table ( or elsewhere ) dynamically, at the moment of its detection.

As a temporal platform for obtaining a precise motion of the human head as also the gaze orientation, a Motion Capture system was installed in the experimental environment. It consists of 10 cameras at different positions which covers a volume in the environment.

The person whom the robot is intended to interact, is equipped with an special cap consisting of a set of markers.

Since the motion capture system can only localize and track human head position and orientation, the gaze direction of the human is simplified to his head direction. With a more precise "gaze detection", the overall system can be easily adapted to human eye motions.

The server of the motion capture system broadcasts the position of the markers, a dedicated client running communicates to the server and updates the position of the markers. Our GEO module acquires data from this client, interprets markers position and geometrically calculates the orientation of the human head in real time.

Once the perspective taking process is done and the attentional object has been defined, the robot turns its head to the center of gravity on this object.

Figure 10 shows the simplest face to face scenario. It illustrates the results on an image sequence from different videos, here the robot turns the head each time it detects that the human is changing of attentional object. The attentional object can be verified because it is on the center of the image of the robot's camera.

Figure 11 illustrates the results when two objects are in the same field of view but one of them is occluding the other. The attentional object is the one that the human can see, and not the hidden one1 .

IV. CONCLUSION AND FUTURE WORK

In this work we have presented a first step of the development of a set of useful geometric tools that helps to the development of a shared attention ability in human robot interaction.

We also have shown the importance of the implementation of algorithms based on perspective taking and mental rotation concepts to obtain visual attentional objects.

Furthermore, we have not only developed the geometric tools on a 3D simulation environments but also we have shown its implementation on a humanoid robotic platform, and obtaining promising results. Nevertheless, we are still working on the evolution and improvement of the system.

For this paper, we have activated two joints on the neck of the robot. This means that, at this step of the integration of the geometric tools, it only work on a static behavior in a face to face interaction, moving only the robot's head to look at the same object that the human is looking at.

The system is intended to perform more complex shared attention and interaction actions. In the very near future, this system will be able to plan sensor based configurations and motions using its arms, hand, and waist joints, based on Inverse kinematics and collision detection. All this, integrating it with other systems of human aware motion planning that also use perspective taking and mental rotation concepts [START_REF] Luis | Geometric Tools for Perspective Taking for Human-Robot Interaction Seventh Mexican International Conference on Artificial Intelligence 2008[END_REF].

In order to evaluate the overall system we also plan to conduct user studies with naive users using the simulation environment as well as the robot.

Also, we are currently working on process of influence of the human visual attention, reasoning human perspective and Fig. 10. Scenario 1: the robot looks to the object that the human is looking. In the images: The scenario (up), the GEO-Move3D interface showing the process and the attentional object marked with a green grid box around the object (down-left) and robot's camera (down-right) tracking the human gaze on objects that the robot is currently manipulating. All this to perform human understandable actions to achieve joint activities of interaction.

V. ACKNOWLEDGMENTS

The research leading to these results has received funding from the European Community's Information and Communication Technologies Seventh Framework Programme FP7/2007-2013 under grant agreement no 215805, the

Fig. 1 .

 1 Fig. 1. A scenario where the human and the robot are sitting face to face

Fig. 3 .

 3 Fig. 3. Relative projections: The robot is the target and differs from other elements on the environment. a)Desired relative projection b) Visible relative projection. The table and the objects are blocking the human's view.

Fig. 4 .

 4 Fig.4. Relative projections: The laptop on the table is the target and differs from other elements on the environment. As the perspective taking system reasons the visibility by taking into account everything in the 3D environment, including the human himself, human's hand causes a small visual occlusion on the laptop.

Fig. 5 .

 5 Fig. 5. An instance of the situation assessment. Object marked with a green wire box (the laptop) is evaluated as visible. The violet bottle and the white box are not visible to the human because of the occluding laptop.

Fig. 6 .

 6 Fig. 6. Face to face scenario. The table is the common work platform for the interaction objects.

Fig. 7 .

 7 Fig. 7. The scenario from robot's and human's eyes.

Fig. 8 .

 8 Fig. 8. The 3D representation of the same environment including the robot, the human and the objects.

Fig. 9 .

 9 Fig. 9. The system architecture in the robot. The GEO module receives markers positions from the MoCap Client and sets the human position and head orientation. From Viman, object positions are obtained and updated. Once the reasoning about human perspective is done, robot head configuration is passed to the controller modules.

Fig. 11 .

 11 Fig. 11. Scenario 2: the robot is capable of detecting and looking at the object of attention, avoiding visual occlusions between objects. The toolbox is occluding the small cup to the human.

The videos of the mentioned results are shown in http://www.laas.fr/∼lfmarin/Videos.html


Pamela C Nolz
email: pamela.nolz@ait.ac.at

Diego Cattaruzza

Nabil Absi

Dominique Feillet

Two-echelon distribution with city hub capacity management

Problem Description

In this paper, we present an innovative distribution scheme aiming at improving the environmental footprint of companies operating in a city logistics context. More specifically, we investigate the daily operations of a parcel delivery company settled in the urban area of Vienna. We propose a two-echelon distribution scheme where goods are not transported directly from their origin (a depot or a warehouse) to their final destination (end customers), but are initially moved into an intermediate platform (a city hub), from where their final distribution is performed. The city hub is located near the city center, close to the final destination of the goods, allowing for a more efficient and environmentally friendly last mile transport.

On the first echelon, trucks transport goods, i.e. parcels, from the depot outside the city to the city hub, where goods are transferred to tricycles, operating on the second echelon between the city hub and the final customers. Tricycles are able to access narrow streets, are not exposed to the problem of limited parking space and decrease the amount of emissions produced through delivery operations inside city centers. However, since not all parcels fit the cargo space of a tricycle, trucks are allowed to visit final customers if these customers require a quantity exceeding the capacity of a tricycle.

All parcels are present at the depot in the morning, when the trucks can pick-up a certain amount of goods and deliver them to the final customers and the city hub. Being located in the inner-city area, the storage capacity of the city hub is limited, which implies that not all goods can be transported from the depot to the city hub at once. Instead, the trucks are obliged to transfer parcels on the first echelon performing multiple trips, while respecting the capacity of the city hub and the final customer time windows. On the second echelon, tricycles can only start their delivery tours as soon as the goods have arrived to the city hub, thus freeing city hub capacity as parcels are picked-up on multiple trips.

We specify time windows (TWs) to indicate the earliest and latest time a final customer demands to receive an order (this trend has become very popular in restaurants or small stores, where the availability of goods at a specific time is crucial for their operation).

Nonetheless, TWs can also be used to regulate the access to certain areas at specific times due to public regulations.

Organizing the described distribution scheme is a challenging task, since the coordination of first-and second-echelon trips is necessary: all second-echelon trips depend on the delivery of goods on the first echelon, which is limited by the city hub capacity. We call the problem of optimizing vehicle routes in this distribution scheme the Capacitated Two-Echelon Vehicle Routing Problem with Time Windows (C2E-VRPTW).

The goal of the C2E-VRPTW is to properly determine a set of vehicle routes to satisfy customer demands at a minimum travel cost, while respecting capacity and time constraints.

Solution Method

To cope with the challenges encountered in this real-world problem, we propose an iterative three phase solution method aiming at efficiently eliminating infeasible solutions.

First phase: solving the second-echelon problem

The second-echelon problem corresponds to the final leg of distribution performed by (electric) tricycles. In our characterization, the tricycles cannot start their trips before the goods of the customers to be served by those trips arrive to the city hub. However, for this phase (at least for the first iteration) we assume that all the goods are permanently available in the city hub; meaning that the tricycles can start their trips without waiting for the goods to arrive. Hence, the problem is seen as a Multi Trip Vehicle Routing Problem with Time Windows (MTVRPTW). The first echelon of the problem is not yet considered.

To solve this subproblem, the population-based algorithm developed by Cattaruzza et al. [START_REF] Cattaruzza | The multi-trip vehicle routing problem with time windows and release dates[END_REF] for the MTVRPTW with release dates is used. The method proposed in Cattaruzza et al. [START_REF] Cattaruzza | The multi-trip vehicle routing problem with time windows and release dates[END_REF] is a population-based algorithm using the giant tour decomposition scheme introduced by Prins [START_REF] Prins | A simple and effective evolutionary algorithm for the vehicle routing problem[END_REF], coupled with local search operators.

Each solution indicates a set of trips plus the order and assignment of every trip to the tricycles, in such a way that the demand of every customer is satisfied during the imposed TW. The starting time, load, and sequence of nodes to be visited, is given by the solution for each one of the trips. Moreover, considering that this might not be the final arrangement of the second-echelon trips, load and time window violations are permitted but signalized in the solution.

Second phase: define the visits to the city hub

After having an initial solution for the second-echelon problem, the next step is to generate an input for the first echelon, based on the information obtained from the previous phase.

To accomplish this, a set of visits to the city hub is introduced. These visits are meant to indicate the services that the first-echelon vehicles will need to do to the city hub with the goods for the second-echelon customers, throughout one working day.

The input for this process is the starting time, load, and sequence of the second-echelon trips, together with the city hub capacity. A visit is defined for every second-echelon trip and the demand of the visit corresponds to the load of the related trip. A greedy algorithm is used to determine the visiting time windows for the city hub, respecting its limited capacity.

Third phase: solve the first-echelon problem

Taking advantage of the fact that the visits defined in the previous phase share the same characteristics as the first-echelon customers, a set of vertices that indifferently refers to the first-echelon customers given by the problem, and the visits defined during the second phase, is fixed.

Through this characterization, the first-echelon problem can further be reduced to an instance of the MTVRPTW, by fixing release dates to 0 for all the vertices. Thus, it is solved resembling the first phase of the method, using the algorithm proposed by Cattaruzza et al. [START_REF] Cattaruzza | The multi-trip vehicle routing problem with time windows and release dates[END_REF].

In this case, the input for the algorithm will consist in the set of vertices (visits plus first-echelon customers) to be served by trucks in the first echelon with their related demands, time windows, and release dates.

Iterative Process

From the input defined in the third phase, the algorithm will provide a first-echelon solution. Yet, it might be impossible for the trucks to perform the visits within the established TWs, meaning that the goods of the trip related to that infeasible visit will arrive after the stipulated starting time. With this in mind, a new starting time sT* given by the actual arrival of the goods to the city hub is introduced. This sT* implies a delay in the service of the second-echelon customers related to that trip. Thus, we also introduce an actual service time aT to refer to this new service time.

After delaying the second-echelon trips, the aT obtained for every customer, may (or may not) violate the TW of the customer. By saying this we imply that even if a trip is delayed, it might still serve some customers in their respective TW; or it can indeed violate their TW. Thus, we make a distinction between these 2 types of customers: customers with an aT that is still within their associated TW, and customers with a TW violation given by the delay of the trip. From this distinction we proceed to update release dates of the second-echelon customers in the first phase, giving way to the iterative process.

Results and Conclusion

For testing the performance of our algorithm we use two types of test instances. As a first set of data we use adapted Solomon instances for the VRPTW, while the second set of data is based on real-world information from a parcel delivery company operating in the city of Vienna.

We will present experiments on sensitivity analysis with respect to relevant parameters. First, we vary the capacity of the city hub ranging between half and twice the capacity of the first-echelon vehicles. Second, we investigate the effects of variations in the distance between the depot and the city hub. Results include the CPU time in seconds, the number of used vehicles, the number of first-and second-echelon routes and distance traveled, and the number of iterations of the method. These parameters act as key performance indicators for decision makers aiming at implementing an efficient two-echelon distribution system with limited storage capacity.

Acknowledgements

This work received funding from the Austrian Federal Ministry for Transport, Innovation and Technology (BMVIT) in the framework of the research programme "Stadt der Zukunft" and the Austrian Federal Ministry of Science, Research and Economy (BMWFW) under grant agreement no. 854921 (CIVIC), as well as from the European Union's Horizon 2020 research and innovation program, and from the Austrian Research Promotion Agency (FFG) under project no. 845100 (EMILIA).