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Topical methyl aminolaevulinate photodynamic therapy versus cryotherapy for superficial basal cell carcinoma: a 5 year randomized trial

European Journal of Dermatology. Volume 18, Number 5, 547-53, September-October 2008, Therapy

DOI : 10.1684/ejd.2008.0472

Summary

Author(s) : Nicole Basset-Seguin, Sally H Ibbotson, Lennart Emtestam, Mikael Tarstedt, Colin Morton, Marianne Maroti, Piergiacomo Calzavara-Pinton, Sandeep Varma, Rik Roelandts, Peter Wolf , Service de dermatologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France, Dept of Dermatology, University of Dundee, Ninewells Hospital, Dundee, UK, Dept of Dermatology, Karolinska University Hospital Huddinge, Stockholm, Sweden, Dept of Dermatology, Karlskoga Hospital, Karlskoga, Sweden, Dept of Dermatology, Stirling Royal Infirmary, Stirling, UK, Dept of Dermatology, Ryhov County Hospital, Jönköping, Sweden, Dept of Dermatology, Brescia University Hospital, Brescia, Italy, Dept of Dermatology, University Hospital of Wales, Cardiff, UK, Dept of Dermatology, Leuven University Hospital, Leuven, Belgium, Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria.

Summary : This multicentre, randomized study compared photodynamic therapy using topical methyl aminolaevulinate (MAL PDT), a non-invasive modality, with cryotherapy for treatment of superficial basal cell carcinoma. Sixty patients with 114 lesions were treated with MAL cream (160 mg/g) applied for 3 hours before illumination (570-670 nm, light dose 75 J/cm) (1 session), and 58 with 105 lesions received cryotherapy (2 freeze-thaw cycles). Patients with an incomplete response at 3 months received 2 further MAL PDT sessions (n \= 20) or repeat cryotherapy (n \= 16). 100 lesions treated with MAL PDT and 93 lesions treated with cryotherapy were in complete response at 3 months after the last treatment and evaluable for recurrence over 5 years. There was no difference in 5-year recurrence rates with either treatment (20% with cryotherapy vs. 22% with MAL PDT, p \= 0.86). However, more patients had an excellent cosmetic outcome with MAL PDT (60% vs. 16% with cryotherapy, p \= 0.00078). These results provide support for the use of MAL PDT as a non-invasive, selective treatment alternative for primary superficial basal cell carcinoma.

Keywords : methyl aminolaevulinate, photodynamic therapy, superficial basal cell carcinoma

Pictures

ARTICLE

Auteur(s) : Nicole Basset-Seguin¹, Sally H Ibbotson², Lennart Emtestam³, Mikael Tarstedt⁴, Colin Morton⁵, Marianne Maroti⁶, Piergiacomo Calzavara-Pinton⁷, Sandeep Varma⁸, Rik Roelandts⁹, Peter Wolf¹⁰

¹Service de dermatologie, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75010 Paris, France
²Dept of Dermatology, University of Dundee, Ninewells Hospital, Dundee, UK
³Dept of Dermatology, Karolinska University Hospital Huddinge, Stockholm, Sweden
⁴Dept of Dermatology, Karlskoga Hospital, Karlskoga, Sweden
⁵Dept of Dermatology, Stirling Royal Infirmary, Stirling, UK
⁶Dept of Dermatology, Ryhov County Hospital, Jönköping, Sweden
⁷Dept of Dermatology, Brescia University Hospital, Brescia, Italy
⁸Dept of Dermatology, University Hospital of Wales, Cardiff, UK
⁹Dept of Dermatology, Leuven University Hospital, Leuven, Belgium
¹⁰Research Unit for Photodermatology, Department of Dermatology, Medical University of Graz, Graz, Austria

accepté le 11 Avril 2008

Basal cell carcinoma (BCC) is the most common cancer in adults [1], affecting over 1 million people each year. BCC is associated with various clinical presentations, which are generally subdivided into three types: nodular, superficial, and morpheaform with nodular being the most common form. Small superficial BCC are considered to be low risk BCC [2, 3]. Superficial BCC differs from the other subtypes as it tends to appear at a younger age, usually occurs on the trunk, limbs and neck [4], and is often multiple.

Although a variety of surgical and nonsurgical treatments are available for BCC, surgery is often used for treatment of superficial BCC [2, 5-7]. Cryotherapy is used in patients for whom surgery is contraindicated or untenable. However, healing can be slow and may be accompanied by painful side effects [2]. In fact, all of the available treatments are associated to a varying extent with scarring, tissue defects, and changes in pigmentation, as well as potential complications such as prolonged healing time and increased risk of infection. Therefore, there continues to be an unmet need for effective, non-invasive therapies for BCC, particularly superficial BCC, which can often be treated with less aggressive procedures, as it is widely accepted as a low risk tumour [2].

Photodynamic therapy (PDT) is a non-invasive treatment option for superficial BCC [2, 8, 9]. The procedure involves preferential uptake of a photosensitizer by malignant cells, which are then selectively destroyed following photoactivation [10]. Clinical studies show that PDT using the photosensitizer methyl aminolaevulinate (MAL) is an effective, acceptable treatment for BCC [11-16]. The aim of this multicentre, randomized, parallel-group, prospective study was to compare the efficacy, safety, and cosmetic outcome of topical MAL PDT with cryotherapy for the treatment of primary superficial BCC.

Materials and methods

Patient selection

Between October 1999 and March 2000, 120 patients aged 18 years or older with previously untreated primary superficial BCC lesions suitable for cryotherapy were enrolled in the study by 13 centres in seven European countries. Diagnosis of primary superficial BCC was confirmed by histology using a 4 mm punch biopsy. Patients with up to 10 eligible lesions were considered for inclusion in the study. Lesions with a diameter of more than 6 mm but less than 15 mm on the face or scalp, of less than 20 mm on the extremities or neck and less than 30 mm on the trunk, which were not pigmented, morpheaform or infiltrating, were considered for treatment. To ensure homogeneity of the sample, we excluded patients with xeroderma pigmentosum, porphyria, Gorlin’s syndrome, history of arsenic exposure, allergy to MAL or other topical photosensitizers or excipients of the cream, who had participated in other investigational studies in the last 30 days and pregnant or breast-feeding women. Concomitant treatment with immunosuppressive medication was prohibited. The study was approved by the local ethics committee responsible for each centre and conducted in accordance with the Declaration of Helsinki of 1975, as amended in 1996 (West Somerset, South Africa). All patients gave written informed consent prior to entry into the study.

Assignment

Eligible patients were randomized by the investigator to treatment with PDT using MAL 160 mg/g cream (Metvix^®; Galderma International, Paris France; PhotoCure ASA, Oslo Norway) or double freeze-thaw cryotherapy within 4 weeks of the screening visit, using a computer-generated randomization scheme prepared by PAREXEL International GmbH, Berlin, Germany. Randomization was stratified by centre.

Procedures, participant flow and follow-up

In the MAL PDT group, the lesions were prepared by slight surface debridement using a curette or scalpel blade to facilitate access of the cream and light. Lesion preparation was always very superficial and insufficient to cause pain. A 1 mm layer of MAL cream was applied to each lesion and 5 mm of surrounding tissue, and then covered with an adhesive occlusive dressing for 3 hours. The dressings were then removed and the cream washed off with 0.9% saline solution before illumination with non-coherent red light (wavelength 570-670 nm, light dose 75 J/cm) from a standard light source (Curelight^®; PhotoCure ASA, Oslo Norway), constituting one MAL PDT treatment session. It should be noted that as the study was conducted prior to European regulatory approval of the treatment procedure for BCC (two MAL PDT treatment sessions 7 days apart), lesions were only treated once at baseline. Cryotherapy was performed using a hand-held liquid nitrogen spray and a double freeze-thaw cycle. After an initial ice field formation with a 3 mm rim of clinically healthy tissue, the ice field was maintained for up to 20 seconds. The procedure was repeated after a thaw of 2-3 times the freeze duration.

Lesion response was evaluated at 3 months by clinical inspection by the same investigator as either complete (i.e., complete disappearance of the lesion) or non-complete (i.e., non-complete disappearance of the lesion: demarcated erythema, infiltration, crust). Lesions with non-complete response were treated again with either two MAL PDT sessions 7 days apart or repeat double freeze-thaw cryotherapy and then evaluated 3 months later. Clinical evaluation of lesion response and recurrence was performed at 1, 2, 3, 4 and 5 years after the last treatment for all patients with lesions in complete response 3 months after the last treatment. Any clinically suspected recurrence was confirmed by histology and treated routinely at the discretion of the clinician.

Cosmetic outcome was assessed for all patients who had shown a complete response in all lesions at 3 months after last treatment by both the investigator and patient at 3 months and 1 and 2 years, and by the investigator at 3, 4 and 5 years. Outcome was rated using a 4-point scale: 1) excellent, no scarring, atrophy or induration and no or slight occurrence of redness or change in pigmentation compared with adjacent skin; 2) good, no scarring, atrophy, or induration, moderate redness or change in pigmentation compared with adjacent skin; 3) fair, slight to moderate occurrence of scarring, atrophy, or induration; and 4) poor, extensive occurrence of scarring, atrophy or induration.

A safety follow-up was performed via telephone 2 weeks after each treatment. Adverse events reported spontaneously by the patient or elicited following non-leading questioning (including local phototoxic reactions in the skin) were noted at each follow-up visit up to 3 months after the last treatment together with their severity, duration, and need for additional therapy. At further follow-up visits, adverse events leading to study withdrawal were recorded. The severity of the adverse event was rated as mild, moderate or severe. The clinician assessed the causal relationship of the event to the study treatment as related, uncertain, or not related.

Statistical analysis

The primary efficacy analysis was based on the per protocol (PP) population, which included all eligible patients who received treatment in accordance with the protocol procedures and for whom lesion response was assessed 3 months after the last treatment. Statistical analysis was performed independently by PAREXEL International GmbH, Berlin, Germany, using SAS software (SAS Institute Inc, Cary, NC). Based on the study protocol, the hypothesis tested was whether the treatments were non-inferior with respect to patient complete response, as defined by an upper limit for the 95% confidence interval (CI) for the treatment difference (cryotherapy – MAL PDT) less than 15%. From a clinical perspective, however, lesion response is more relevant than patient complete response.

Treatment differences in lesion complete response rates were analysed using Fisher’s exact test. Lesion complete response rates over time were analysed using a time-to-event approach to account for missing response assessments and for the possible dependency between lesions within the same patient. As the interval-censoring and the lesion clusters made the data unsuitable for standard procedures, the complementary log-log model of Guo and Lin (1994) [17] was used with baseline hazards of 0 to 3 months, 3 to 12 months, 12 to 24 months, 24 to 36 months, 36 to 48 months, and 48 to 60 months. Logistic regression using the complementary log-log link function was performed with standard software (SAS PROC LOGISTIC) and standard errors of the estimates were adjusted for dependencies in the data using SAS IML. Lesion recurrence rates were estimated as the proportion of recurrent lesions from those lesions in complete response at the 3 months follow up irrespective of later discontinuation. The proportions of patients with excellent versus good, fair or poor overall cosmetic outcome were compared between treatment groups using Fisher’s exact test.

Results

Patients

A total of 118 of 120 randomized patients were treated; 60 patients with MAL PDT and 58 patients with cryotherapy. Two patients randomized to treatment with MAL PDT were excluded from the study before treatment as diagnosis of BCC could not be verified by histology (figure 1). Three patients, two in the MAL PDT group and one in the cryotherapy group, were excluded from the PP population. In the MAL PDT group, one patient was excluded due to insufficient follow-up of the response assessment and one patient died from causes unrelated to study treatment and had no assessment of response. One patient in the cryotherapy group withdrew his consent. Therefore, data from 115 patients, 58 patients with 103 lesions treated with MAL PDT and 57 patients with 98 lesions treated with cryotherapy, were included in the PP analysis (figure 1). Only results for the PP population are presented as the population of primary interest in this non-inferiority trial. As only three patients were excluded from the PP population the results of the ITT population and the PP population were similar in all aspects.

The two treatment groups were well-matched with respect to demographic and disease characteristics. The majority of patients in each group had one or two lesions (80% [46/58] in the MAL PDT group and 82% [47/57] in the cryotherapy group); most lesions were less than 20 mm in diameter and were located on the trunk/neck or extremities (table 1).

In the MAL PDT group, 38 (66%) patients with 72 (70%) lesions received one MAL PDT treatment session. Twenty (34%) patients with 31 (30%) lesions who did not show complete response at 3 months received an additional 2 treatment sessions (i.e. 3 MAL PDT treatment sessions). Patients received a mean light dose of 77 J/cm (range 72 to 88 J/cm) and a mean light intensity of 150 mW/cm (range 66 to 290 mW/cm). The mean illumination time was 9 minutes (range 4 to 20 minutes). In the cryotherapy group, 41 (72%) patients with 67 (68%) lesions received one treatment, and treatment was repeated for 16 (28%) patients with 31 (32%) lesions who did not show complete response at 3 months. The mean total freezing time (i.e., including all freeze-thaw cycles administered to a patient) was 35 seconds (range 20 to 90 seconds), which was generally accordance with the procedure specified in the protocol.

Forty-two patients discontinued before the 5-year assessment, 28 due to treatment failure of all lesions (17 in the MAL PDT group and 11 in the cryotherapy group) and 14 patients (9 in the MAL PDT group and 5 in the cryotherapy group) for other reasons (figure 1). None of the adverse events leading to withdrawal were treatment-related.
Table 1 Baseline characteristics (per protocol population)

Characteristic	MAL PDT (n = 58)	Cryotherapy (n = 57)
Gender
Male; n (%)	39 (67)	30 (53)
Female; n (%)	19 (33)	27 (47)
Caucasian; n (%)	58 (100)	57 (100)
Mean age (range); years	62 (25 to 86)	64 (38 to 90)
Skin type (Fitzpatrick score); n (%)
I	3 (5)	3 (5)
II	33 (57)	36 (63)
III	19 (33)	17 (30)
IV	3 (5)	1 (2)
No. of lesions per patient; n (%)
1	38 (66)	39 (68)
2	8 (14)	8 (14)
3	7 (12)	5 (9)
> 3	5 (9)	5 (9)
Total no. of lesions	103	98
Location of lesions; n (%)
Face/scalp	6 (6)	4 (4)
Trunk/neck	74 (72)	74 (76)
Extremities	23 (22)	20 (20)
Longest lesion diameter; n (%)
5-10 mm	44 (43)	41 (42)
11-19 mm	43 (42)	41 (42)
≥ 20 mm	16 (16)	16 (16)

Lesion complete response rate

Overall lesion complete response rates in the PP population 3 months after last study treatment did not differ significantly, treatment difference (cryotherapy vs. MAL PDT) –2.2% (95%CI –7.6% to 3.2%), p = 0.49. Within each treatment group, the lesion complete response rate was similar irrespective of lesion size or whether one or repeat treatments were given (table 2). Lesion complete response rates over time for each treatment, estimated with the Guo-Lin complementary log-log model [18] were almost superimposable (figure 2). For the PP population, the estimated complete lesion response rate at 5 years was 75% (95%CI 64.3% to 83.3%) in the MAL PDT group versus 74% (95%CI 58.6% to 84.6%) in the cryotherapy group (p = 0.90).
Table 2 Lesion complete response 3 months after last study treatment. Per protocol population. Data are given as n/N (%) with 95% confidence interval

Stratification	MAL PDT	Cryotherapy
Overall response	100/103 (97.1%) [91.7% to 99.4%]	93/98 (94.9%) [88.5% to 98.3%]
One treatment	70/72 (97.2%) [90.3% to 99.7%]	65/67 (97.0%) [89.6% to 99.6%]
Repeated treatments¹	30/31 (96.8%) [83.3% to 99.9%]	28/31 (90.3%) [74.2% to 98.0%]
Response by lesion diameter
5-10 mm	43/44 (97.7%) [88.0% to 99.9%]	38/41 (92.7%) [80.1% to 98.5%]
11-19 mm	42/43 (97.7%) [87.7% to 99.9%]	39/41 (95.1%) [83.5% to 99.4%]
≥ 20 mm	15/16 (93.8%) [69.8% to 99.8%]	16/16 (100%) [79.4% to 100.0%]

¹Three treatments for MAL PDT and two treatments for cryotherapy.

Recurrence rates

Recurrence rates up to 5 years after last treatment are summarized for the PP population in table 3. With the exception of one recurrent lesion in the cryotherapy group reported at 5 years, all other recurrent lesions were reported within 3 years. The two groups did not differ significantly in the overall lesion recurrence rate at any time during follow-up. At 5 years, overall lesion recurrence rates were 20% with cryotherapy versus 22% with MAL PDT. The mean estimated treatment difference was –1.57 (95%CI -13.1% to 10.0%), p = 0.86.
Table 3 Lesion recurrence rates, per protocol population

	MAL PDT (%, n/N)	Cryotherapy (%, N/n)	Estimated mean treatment difference [95% CI] and p value
Lesions in complete response at 3 months, N	100	93
1 year
Overall recurrence	9 (9/100)	13 (12/93))	3.90% [– 4.9%,12.7%], p = 0.49
Missing	1 (1/100)	2 (2/93)
2 years
Overall recurrence	17 (17/100)	19 (18/93)	2.35% [–8.5%, 13.2%], p = 0.71
Missing	5 (5/100)	4 (4/93)
3 years
Overall recurrence	22 (22/100)	19 (18/93)	–2.65% [–14.1%, 8.8%], P = 0.72
Missing	9 (9/100)	8 (7/93)
4 years
Overall recurrence	22 (22/100)	19 (18/93)	–4.20% [–17.1%, 8.7%], p=0.59
Missing	15 (15/100)	11 (10/93)
5 years
Overall recurrence	22 (22/100)	20 (19/93)	–1.57% [–13.1%, 10.0%], p = 0.86
Missing	16 (16/100)	11 (10/93)

Cosmetic outcome

Cosmetic outcome at 3 months and up to 5 years was much better with MAL PDT than cryotherapy (figure 3A and B). PP analysis showed that the cosmetic outcome was significantly superior with MAL PDT at 3 months after the last treatment; 30% of patients (95% CI 18.3% to 44.3%) in the MAL PDT group had an excellent outcome compared with 4% (95% CI 0.5% to 14.0%) in the cryotherapy group (p = 0.0005). At 5 years, 60% of patients (95%CI 38.7% to 78.9%) in the MAL PDT group had an excellent outcome compared with 16% of patients (95%CI 6.2% to 32.0%) in the cryotherapy group (p = 0.00078) (figure 3A). Two examples of the excellent cosmetic outcome achieved with MAL PDT are shown in figure 4.

Safety and tolerability

Overall, 73% (44/60) of patients treated with MAL PDT and 79% (46/58) of patients treated with cryotherapy reported adverse events. As anticipated, most adverse events were local, most frequently local pain (37% of patients in the MAL PDT group and 33% in the cryotherapy group), crusting (35% and 47%) and erythema (30% and 21%), as well as blisters in the cryotherapy group (21%). All local adverse events were transient, resolving within a mean of 5 days with the exception of crusting, erythema, and itching reported with both treatments and suppuration in the cryotherapy group. None of the patients discontinued the study due to treatment-related adverse events. Of the treatment-related local adverse events in the MAL PDT group, 80% were reported as mild, 13% as moderate and 5% as severe (local pain, local burning and crusting), and for the cryotherapy group, the corresponding percentages were 73%, 25% and 1% (local pain).

Discussion

Recurrence is a problem in the treatment of BCC. Nearly two-thirds of all recurrent BCC lesions appear in the first 3 years after treatment, with 18% appearing between 5 and 10 years post-treatment [6, 18, 19]. For this reason a minimum follow-up period of 2 years, and preferably 5 years, is currently recommended for evaluation of any new strategy for treating BCC [2, 6, 18, 19]. However there is a paucity of prospective comparative long-term data for the many alternative treatments to surgery, particularly for superficial BCC.

The current study shows that MAL PDT was as effective as cryotherapy with respect to overall lesion complete response at 3 months. Initial non-responders can still benefit from an additional treatment (2 cycles 8 days apart). Accordingly overall 5-year lesion recurrence was comparable between the two treatment groups (i.e. cryotherapy and PDT). It is notable that, with the exception of one recurrent lesion in the cryotherapy group reported at 5 years, all other recurrences were reported before or at 3 years, indicating the similar long-term efficacy profile of each treatment modality. Recurrence rates for cryotherapy were consistent with those previously reported (13% at 12 months) [20].

Lesion recurrence rates in the current study contrast with those for nodular BCC reported by Rhodes et al. (2004) [13]. Even though nodular BCC is generally considered more clinically challenging than superficial BCC, recurrence rates 2 years after two sessions of MAL PDT were lower than those observed with superficial BCC in the current study (10% versus 17%) [13]. It is possible that lesions deemed clear (on clinical inspection) following a single treatment of MAL PDT may be more vulnerable to recurrence than those initially treated with two sessions. Recurrence rates in the current study may have been improved by using the approved BCC treatment protocol, which stipulates two treatments 7 days apart (a complete treatment cycle), with the option of a repeat treatment cycle at 3 months. Interestingly fewer recurrences were observed in the group of patients treated with repeated PDT cycles. At 5 years, there were 6 recurrences in patients who received three treatments compared with 16 recurrences in patients who received one treatment. Overall recurrence rates were similar in these two cohorts (26.1% and 26.2%) as fewer patients (23 vs. 61) received multiple treatments with MAL PDT.

Cosmesis is also a consideration in the treatment of superficial BCC. The current study showed that the cosmetic outcome (as assessed by the investigator) was superior with MAL PDT compared with cryotherapy. Other studies have shown that the cosmetic outcome with MAL PDT is superior to surgery in nodular BCC [13]. The better cosmetic outcome with MAL PDT in the current study [11, 12] is almost certainly due to the sparing of dermal damage due to selective uptake of the photosensitizer primarily by neoplastic cells within the epidermis [13, 14]. In contrast, cryotherapy results in epidermal and dermal tissue necrosis of lesional and surrounding normal skin, causing scarring and pigmentary changes [2, 21, 22]. Our study findings are consistent with previous reports on the good or excellent cosmetic outcome of MAL PDT for superficial BCC [12, 14, 23]. The cosmetic advantage associated with MAL PDT is of great interest for low risk superficial BCC [11], as lesions are often multiple, typically affecting skin sites predisposed to dystrophic scarring (such as the trunk). Moreover, repeat treatment is a viable option with PDT [2, 4, 24]. Finally, treatment with MAL PDT was well tolerated, with a profile of adverse events consistent with that previously reported [13-15].

We conclude that this 5-year prospective controlled study demonstrated that MAL PDT was as effective as double freeze-thaw cryotherapy for the treatment of superficial BCC with a similar recurrence rate, but with a significantly better cosmetic outcome. The study provides evidence to support the use of MAL PDT as an effective, non-invasive, selective treatment for superficial BCC with favourable cosmesis.

Acknowledgements

The authors would like to acknowledge the following investigators for their participation in this study: A. Finlay, University Hospital of Wales, Cardiff, UK; R. Mackie, Glasgow University Hospital, Glasgow, UK; I. Rosdahl, Linköping University Hospital, Linköping, Sweden; and O. Saksela, Helsinki University Hospital, Helsinki, Finland. Financial support: This study was supported by a financial grant by PhotoCure ASA, Oslo, Norway. Conflict of interest: Prof N Basset-Séguin has received financial reimbursement from PhotoCure for participation in studies and honoraria from Galderma for consultancy. Dr S Ibbotson has received financial reimbursement for involvement in other studies undertaken by PhotoCure and Galderma within the last 5 years. Dr M Tarstedt has received honoraria for lectures including travel costs from PhotoCure AS. Dr C Morton has been an investigator for studies sponsored by PhotoCure AS Oslo, Galderma Paris; Schering AG Berlin; and Phototherapeutics Ltd, Tamworth UK and has received honoraria from participating in sponsored symposia. Dr P Calzavara- Pinton has received honoraria for lectures and advisory boards as well as travel and research grants from Galderma Italy, Wyeth Italy, Shire Italy, Novartis Italy and Roche-Posay Italy. Dr S Varma has received honoraria for lectures and travel from Photocure, Galderma, Valeant and has received honoraria as a member of 3M Pharmaceuticals’ advisory board. P Wolf has received honoraria for lectures, research and travel grants from PhotoCure AC and honoraria for lectures from Galderma. Professor L Emtestam, Dr M Maroti and Dr R Roelandts state no conflict of interest relevant to the material in this manuscript.

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