Non-ablative Photographs of AKs were taken before each

Non-ablative fractional laser therapy for facial actinic keratosis: 6-month follow-up Introduction and aim: Many skin damages can be treated with laser. The aim of this study was to assess the therapeutic effect of a 1540-nm non-ablative fractional laser on the facialactinic keratosis (AKs).  Methods: The patients were included in the study according to the inclusion and exclusion criteria. They were under treatment with non-ablative fractional laser (1540 nm) 3- times at 4 weeks intervals in a non-contact mode. Photographs of AKs were taken before each session and 3 months after the last session and the improvement of damages were assessed by a dermatologist. It is pertinent to mention that the patients, themselves, were also involved in the assessment of improvement.Results: The results of present study showed that in comparison to the baseline, 3-sessionAK therapy with non-ablative fractional laser significantly not only improved the AKsseverity but also reduced the AK counts. In this respect, 3- months after the last treatment the number of AKs significantly attenuated. In addition, the severity of damages reduced by 79%. On the other hand, the patients consented to the therapeutic effect. Discussion: According to the obtained results and available studies, it seems that therapy with a 1540-nm non-ablative fractional laser is a safe and effective method for the treatment of light-induced damages and AKs and it can be considered as a new therapeutic option. However, more studies with more participants are needed to introduce this method as a definite therapeutic method. Keywords: skin, actinic keratosis, laser, non-ablative fractional laser  Introduction Actinic keratosis (AKs) is the second most common dermatological disorder diagnosed by dermatologists. Actinic keratosis is a small area of damaged skin that is causedby exposure to the sun. It is considered as a pre-cancerous skin lesion and can progress into invasive squamous cell carcinoma 1, 2. Damages are usually found on the face, scalp, dorsal surface of hand, chest and areas exposed to the sun.  The overall incidence of AKs on the North Pole is about 25%. Normally, people who are exposed to the sunlight or UV rays, aged people and patients with suppressed immune systems are more vulnerable to AK 3, 4.?Numerous therapeutic approaches are available for the treatment of AKs. Cryosurgery and curettage are known as invasive methods, which their effectiveness is determined 3 , 5. Among the causative factors of AKs, it is emphasized on the long-term exposure to the sunlight 6. In addition to available therapeutic methods, there is an increasing use of approaches in which local treatments are considered; like using 5-fluorouracil, imiquimod and photodynamic therapy. Also, using tazarotene, cox inhibitors, chemical peels and laser therapy are under investigation 6-8.Using laser for the treatment of AKs is a new therapeutic method. Recently, ablativeand non-ablative fractional lasers have been used for the treatment of AKs. The most common ablative lasers are CO2 (10,600 nm) and erbium: YAG (2940-nm) which are used for the complete resurfacing of damage area 9, 10. Furthermore, it has been established that using ablative laser reduces the risk of cancer in actinic skin 11. Although the ablative laser has a good therapeutic efficacy, it has side effects including edema, oozing, crusting, and burning discomfort during the first week of treatment, and long-term erythema which are not pleasant for most of the patients 12,13.To prevent the side effects of ablative laser, another approach namely non-ablative laser has been introduced. In this method, the light is absorbed into the dermis rather than epidermis. The absorbed light produces very tiny columns with 400 to 1000 nm in depth into the dermis. The live cells surrounding each column generate new cells that give rise to fastheal of wound and reduction of side effects 14.         While this approach is very effective in inducing dermal regeneration, it does not always provide an adequate response in the epidermis—where most of the photodamage isincurred and where most premalignant and malignant skin lesions arise. Therefore, the non-ablative approach, by definition, cannot provide an adequate solution for epidermalrejuvenation or resurfacing.         In addition to the wavelength, two additional factors contribute to the largely dermal absorption of the nonablative fractional lasers. In some devices, the laser is focused at a depth, which corresponds to the dermis. In addition, in some devices the epidermis is cooled by contact during treatment in order to prevent excessive heating and thereby to maintain the epidermal integrity, which defines non-ablative fractional laser treatments.Given these considerations, a classical non-ablative laser could be used, provided modifications in technique, to produce foci of epidermal damage, thereby rendering the samedevice a tool for both non-ablative and ablative laser procedures. Either a change in the position of the focus, such that the peak energy is delivered to the epidermis, or the removalof contact cooling, could potentially render a non-ablative fractional laser ablative. A non-obvious but very easy solution to both factors is to hold the handpiece a few millimetersabove the skin surface while delivering the laser pulse 15. At present, this treatment is becoming one of the best approaches to the treatment of AKs and can be considered as an applied therapeutic approach. The aim of this study was to examine the therapeutic and improving effect of 1540-nm non-ablative fractional laser on the treatment of AK. Methods In the current study, 10 patients with AKs were included. Their AKs were clinically diagnosed by a dermatologist or the AKs were approved by performing biopsy. Patients with the history of non-healing ulcer, keloid and scars were excluded from the study. The exclusion criteria included the experience of using ablative cures or chemical pills, other methods for the treatment of AKs like cryotherapy, curette or keratolitic 1 month before the study, pregnancy or lactation.   The patients were treated with a 1540-nm non-ablative fractional laser 3 times at 4 weeks intervals in a non-contact mode. Photographs were taken before each session and 3months after the last session and were assessed by a dermatologist.A dermatologist as follow scored the severity of damages: 0, 1, 2, 3 and 4 (0 = no damage and 4 = the most damage based on the thickness, coarseness and scaling). Follow-up visits, based on the appearance of lesions, were also made by the patients at the beginning of each session and 3- months after the last session of laser therapy (the third session). They scored the severity of lesions from 1 (the least lesions) to 4 (the most lesions). The experiments were carried out in accordance with the ethical guidelines of University of Tehran. All procedures were carried out with informed consent of the patients.  StatisticsThe obtained results were expressed as mean ± SD. Changes in the number and severity of lesions were expressed as percent reduction from the baseline. For two-paired comparisons and for more than two-paired comparisons, the Wilcoxon matched pairs test and Friedman’s test were used, respectively. The differences with p-values less than 0.05 were considered statistically significant. ResultsIn the present study, 10 patients (3 female and 7 male) were included. Patients, on average, were 60 years old (53-80). Patient’s skin type was 3 and 4. During the treatment and after that no serious side effects were reported. The count of lesions in different patients and in different time points after the beginning of treatment is shown in Table 1. As it can be seenin Table 1, at the end of study the lesions in 2 patients were completely disappeared, the number of AKs in some patients reduced and in some of them did not change.        Table 1: Actinic keratosis count at the beginning of study and at 1-, 2-, and 6-month follow-up visits.Patient            AK Nu; Baseline           AK Nu; at 1 mo        AK Nu; at 2 mo            AK Nu; at 6 mo  1                                 5                                     5                                 2                               22                                 1                                     1                                 1                               13                                 3                                     3                                 1                               34                                 1                                     1                                 1                               15                                 4                                     3                                 4                               16                                 2                                     2                                 2                               27                                 5                                     4                                 5                               58                                 5                                     5                                 1                               09                                 2                                     2                                 2                               210                               3                                     3                                 3                               0 The reduction in overall AKs counts and in the severity of AK lesions are shown in Table 2. At the beginning of study, the total number of AK lesions was 31 (in all patients). The mean level of severity was 3.12 ± 0.15. One month after the first session of laser therapy the number of AK lesions reduced and total number of lesions became 29. In addition, the mean reduction in AK severity was 2.09 ± 0.28. Two months after the beginning of laser therapy and before the beginning of the third session of treatment, 9 AK lesions were completely removed and the severity of lesions were significantly attenuated. In this respect, the mean reduction in AK severity was 0.87 ± 0.12. At the end of study (3 months after the third session or 6 months after the beginning of treatment), the number and severity of AK lesions were examined. Fourteen of 31 lesions were completely treated. The mean reduction in AK severity was 0.64 ± 0.1 (Table 2).    Table 2: The overall mean reduction in actinic keratosis count and the severity of actinic keratosis lesions at the beginning of study and at 1 ,  2 , and 6-month follow-up visits.3 monthsafter the 3rd treatment1 monthafter the 2nd treatment1 monthafter the 1st treatmentBaselineTreatment0.64 ± 0.10.87 ± 0.122.09 ± 0.283.12 ± 0.15Overall mean of AK severity%79%72%23 % of improvement17222931Overall AK number The severity of lesions were scored 0, 1, 2, 3 and 4 (0 = no damage and 4 = the most damage based on thethickness, coarseness and scaling).  Altogether, the results showed that 3-session laser therapy has significantly reduced the number and severity of lesions (p < 0.001). Compared with the baseline, the severity of AKs 1 month after the first treatment, 1 month after the second session of laser therapy and 3months after the third session of treatment reduced 23%, 72% and 79 % respectively (Table 2 and Figure 1). In addition, as it can be seen in Figure 1, the continuation of treatment gave rise to a reduction in the severity of lesions. In this regard, at the 3-months follow-up visit after the last treatment a marked reduction in severity of AK lesions was observed (p < 0.001). On the other hand, the results showed that there were not any significant differences between the severity of AKs before and 3 months after the last session of treatment (p = 0.092).   Figure 1. The effect of non-ablative fractional laser therapy on the improvement of actinic keratosis lesions. Treatment courses reduced the severity of lesions in comparison to the baseline.** P < 0.01 and *** P < 0.001 compared to the baseline.   In addition, at the beginning of study and 3 months after the last session, patients, themselves, scored the AK lesions based on appearance of the AKs. These resultsdemonstrated that the mean severity of AK lesions at the beginning of treatment was 3.5 ±0.52; while, 3 months after the last session of laser therapy the severity of AKs was 1.1 ± 0.1. This difference represents a significant reduction in the severity of AK lesions and consent of patients from treatment (p < 0.01) (Fig. 2).      Figure 2: Studying the effect of laser therapy on the improvement of actinic keratosis lesions based on patient's reports. According to the patient's reports, in comparison to the baseline, the severity of actinic keratosis lesions reduced significantly 3 months after the third treatment session.** P < 0.01 compared to the baseline.   Discussion The present study showed the efficacy and safety of non-ablative fractional laser therapy for the treatment of AK lesions. The results demonstrated that in comparison to the baseline, 3-session laser therapy with non-ablative fractional laser not only attenuates theseverity but also the count of AK lesions. In this respect, 3 months after the last session of laser therapy the number of lesions reduced remarkably and the severity of the AK lesions improved by 79 %. The patients expressed satisfaction at the treatment process and they were pleased with the level of improvement. Furthermore, no side effects were reported by the participants. This is while, in other therapeutic methods for instance cryotherapy which is the most common therapeutic approach for the treatment of AK, based on the dose of treatment, the improvement rate was 39-83% 14. However, it should bear in mind that our study was a preliminary study in which a few number of participants were included to assess the efficacy of 1540-nm non-ablative fractional laser on the treatment of AKs not to make a comparison with the result of cryotherapy studies. On the other hand, the goal of these two studies was different from each other. Cryotherapy is a kind of targeted treatment method; while treatment with a 1540-nm laser is considered as a field-based treatment method. It seems that the combination of these methods or combination of focal and field studies can be useful approaches to yield a better result in each session of treatment. In addition, it should be mention that this study was limited by a small number of participants and the lack of a group as control.  The result of our study could be affected by the experimental design that was non-blinded. In line with our study, in the study conducted by Lapidoth et al. (2013) 17 patients with AKs were subjected to the non-contact fractional 1540-nm erbium glass laser 15. In this study, 3 months after the beginning of study the level of improvement for the Aks was 4.3 ± 0.72 and for the skin appearance was 3.3 ± 0.54. The side effects after each treatment session included mild erythema, edema and erosions observed in 2 patients, Also, a mild peeling was reported. No scare, inflammation or changes in pigmentation were observed. The findings of present study revealed that non-contact fractional 1540-nm laser therapy can be used as an effective and safe approach for the treatment of light-induced skin damages and AKs 15.In another study, Demetriou (2011) used a non-ablative laser for the therapy of AKs. In this study 10 patients with long term experience of AKs were included and treated with 1session of mixed Q-switched KTP 532 nm and Nd: YAG 1064 nm laser therapy. During a period of 20 days, patients responded to the treatment very well. No pain was reported. In addition, the least amount of irritation, minimum recovery period and good cosmetic effects were observed 16.There are a number of studies that are in line with our study 17-20. Wanner et al. (2007) applied 3 session of 1550-nm laser therapy at 3 days intervals for the treatment of facial and non-facial lesions. They showed that during a period of nine months, at least 55 % of patients experienced 51 to 75 % improvement 18. Similar to our study, the wavelength applied in their study was 1540 nm; but it was used in a contact mode. In this method, the most of energy is transferred to the dermis. The rate of improvement in our study was better than their result; such that the mean reduction in AK lesions was 79%. As it has been previously mentioned, we used a non-contact approach. It seems that non-contact approach has better outcomes. Iyer et al. (2004) reported the overall improvement rate of 94% after treatment with either CO2 or ablative erbium: yttrium-aluminum-garnet laser 21. Hantash et al. (2006) 2 months after therapy with CO2, found a 92% attenuation in the count of AKs. There were no significant differences among CO2 laser ablation, trichloroacetic acid, and fluorouracil 22. Findings obtained from other studies showed that the improvement rate of AK damages in 72% of patients with severe AK lesions was 75-100% 23.Comparison of our findings with the results of other studies revealed that the fractional 1540-nm non-ablative laser is a safe and effective method for the treatment of light-induced damages and AKs. Also, it seems that it can be used as a new and alternative therapeutic method. However, more studies with more participants are needed to introduce this method as a definite therapeutic method.    References1. Feldman SR, Fleischer AB Jr. Progression of actinic keratosis to squamous cell carcinoma revisited: clinical and treatment implications. Cutis, 2011. 87(4): p. 201-7.2. Quatresooz P, Piérard-Franchimont C, Paquet P, Hubert P, Delvenne P, Piérard GE. Crossroads between actinic keratosis and squamous cell carcinoma, and novel pharmacological issues. Eur J Dermatol, 2008. 18(1): p. 6-10.3. Costa C, Scalvenzi M, Ayala F, Fabbrocini G, Monfrecola G. How to treat actinic keratosis? An update. J Dermatol Case Rep, 2015. 9(2): p. 29-35.4. Strunk T, Szeimies RM. Actinic keratoses. Pathogenesis, clinical aspect and modern therapeutic options. Hautarzt, 2014. 65(3): p. 241-52.5. Schwartz RA. The actinic keratosis. A perspective and update. Dermatol Surg, 1997. 23(11): p. 1009-19.6. Martin G, The impact of the current United States guidelines on the management of actinic keratosis: is it time for an update? J Clin Aesthet Dermatol, 2010. 3(11): p. 20-5.7. Martin GM. Impact of interval and combination therapies on the management of actinic keratosis: review and clinical considerations. J Dermatolog Treat, 2011. 22(5): p. 288-97.8. Lawrence N. New and emerging treatments for photoaging. Dermatol Clin, 2000. 18(1): p. 99-112.9. Trimas SJ, Ellis DA, Metz RD. The carbon dioxide laser. An alternative for the treatment of actinically damaged skin. Dermatol Surg, 1997. 23(10): p. 885-9.10. Fulton JE, Rahimi AD, Helton P, Dahlberg K, Kelly AG. Disappointing results following resurfacing of facial skin with CO2 lasers for prophylaxis of keratoses and cancers. Dermatol Surg, 1999. 25(9): p. 729-32.11. Halachmi S, Lapidoth M. Lasers in skin cancer prophylaxis. Expert Rev Anticancer Ther, 2008. 8(11): p. 1713-7.12. Trimas SJ, Ellis DA, Metz RD. The carbon dioxide laser: an alternative for the treatment of actinically damaged skin. Dermatol surg, 1997. 23(10): p. 885-9.13. Manstein D, Herron GS, Sink RK, Tanner H, Anderson RR. Fractional photothermolysis: a new concept for cutaneous remodeling using microscopic patterns of thermal injury. Lasers Surg Med, 2004. 34(5): p. 426-38.14. Thai KE, Fergin P, Freeman M, Vinciullo C, Francis D, Spelman L, Murrell D, Anderson C, Weightman W, Reid C, Watson A, Foley P. A prospective study of the use of cryosurgery for the treatment of actinic keratoses. Int J Dermatol, 2004. 43(9): p. 687-92.15. Lapidoth M, Adatto M, Halachmi S. Treatment of actinic keratoses and photodamage with non-contact fractional 1540-nm laser quasi-ablation: an ex vivo and clinical evaluation. Lasers Med Sci, 2013. 28(2): p. 537-42.16. Demetriou C. Reversing precancerous actinic damage by mixing wavelengths (1064 nm, 532 nm). J Cosmet Laser Ther, 2011. 13(3): p. 113-9.17. Geronemus RG. Fractional photothermolysis: current and future applications. Lasers Surg Med, 2006. 38(3): p. 169-76.18. Wanner M, Tanzi EL, Alster TS. Fractional photothermolysis: treatment of facial and nonfacial cutaneous photodamage with a 1,550-nm erbium-doped fiber laser. Dermatol Surg, 2007. 33(1): p. 23-8.19. Jih MH, Goldberg LH, Kimyai-Asadi A. Fractional photothermolysis for photoaging of hands. Dermatol Surg, 2008. .34(1): p. 73-8. 20. Gold MH, Heath AD, Biron JA. Clinical evaluation of the SmartSkin fractional laser for the treatment of photodamage and acne scars. J Drugs Dermatol, 2009. 8(11): p. s4-8.21. Iyer S, Friedli A, Bowes L, Kricorian G, Fitzpatrick RE. Full-face laserresurfacing:  therapy and prophylaxis for actinic keratoses and non-melanoma skin cancer. Lasers Surg Med, 2004. 34: p. 114-9. 22. Hantash BM, Stewart DB, Cooper ZA, Rehmus WE, Koch RJ, Swetter SM. Facial resurfacing for nonmelanoma skin cancer prophylaxis. Arch Dermatol, 2006. 142(8): p. 976-82.23. Ostertag JU, Quaedvlieg PJ, Neumann MH, Krekels GA. Recurrence rates and long-term follow-up after laser resurfacing as a treatment for widespread actinic keratoses on the face and scalp. Dermatol Surg, 2006. 32(2): p. 261-7.   3 

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