16th CONGRESS OF EHA_EUROPEAN HEMATOLOGY ASSOCIATION, June 9-12, 2011 SIDE EFFECTS OF HYDROXYUREA IN CLASSIC CHRONIC MYELOPROLIFERATIVE NEOPLASMS. A RETROSPECTIVE STUDY OF 3,411 PATIENTS E Antonioli 1, P Guglielmelli 2, L Pieri 2, MC Finazzi 3, E Rumi 4, V Martinelli 5, N Vianelli 6, ML Randi 7, I Bertozzi7 , V De Stefano 8, T Za 8,M Ruggeri 9, F Rodeghiero 9, E Elli 10, E Pogliani 10, R Ca
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Topical delivery of triamcinolone via skin pretreated with ablative radiofrequency: a new method in hypertrophic scar treatmentTopical delivery of triamcinolone via skin pretreated withablative radiofrequency: a new method in hypertrophic scartreatment Maria C. A. Issa, MD, PhD, Luiza E. B. P. Kassuga, MD, Natalia S. Chevrand, MD, andMarianna T. F. Pires, MD Federal University, Nitero´i, Rio de Janeiro, Background Epidermal permeability alterations induced by ablative fractional resurfacing and low-frequency ultrasound technology may offer drug delivery for the treatment of hypertrophic scars through transepidermal drug delivery (TED). This technology can improve treatment efficacy and minimize side effects.
Objective To evaluate clinical response and side effects of TED technology in hypertrophic scars in the body and on the face using ablative fractional radiofrequency (RF) associated with low-frequency acoustic pressure ultrasound (US).
Methods Four patients with hypertrophic scars were treated with triamcinolone using Conflicts of interest: Dr. Maria C A Issa is fractional ablative RF and US. The treatment procedure comprised three steps: (i) ablative fractional RF for skin perforation; (ii) topical application of triamcinolone acetonide 20 mg/ml on the perforated skin; and (iii) acoustic pressure wave US applied to enhance triamcinolone penetration into the skin.
Results Complete resolution was seen after one session in patients with scars on the nose and mandibular area. The scar on the neck showed complete resolution after four sessions. The scar on the knee showed a marked improvement after four sessions. Mild and homogeneous atrophy was observed in hypertrophic scars on the neck.
Conclusion Ablative fractional RF associated with acoustic pressure US is a new technology aiming to increase drug delivery into skin. This new method can improve the efficacy of steroids in hypertrophic scar treatment, minimizing the risks of localized atrophy and irregular appearance of the treated lesion.
We reported four cases of HS treated with TED. We used ablative fractional radiofrequency (RF) to open Hypertrophic scars (HS) are dysfunctions of the healing micro-channels in the epidermis before applying triamcin- process in response to different injuries. HS appear olone. Acoustic pressure US was applied over the steroid four weeks after a triggering event, limited to the original to push molecules into the dermis through the micro- wound, grow intensely for a few months, and then regress.1 Treatment remains a challenge for dermatolo-gists. Intralesional steroids are the first-line therapy, and triamcinolone is the one most used.2 Use of intralesionalsteroids is painful, and atrophy is a common side effect.
A prospective study was carried out to evaluate the clinical Innovative technologies, such as transepidermal drug efficacy and side effects of applying steroid in four cases of HS delivery (TED), provide an attractive alternative to using both fractional RF and acoustic pressure US technology.
conventional methods.3 Use of fractional YAG laser4–6 None of the patients have had any clinical intervention before.
and CO2 laser7–9 to create micro-channels in the Case 1 was a 23-year-old woman (Fitzpatrick phototype II) epidermis with the aim of increasing skin drug permeabil- with HS for six weeks, after having her nose pierced. Case 2 ity was recently reported. Similarly, there are studies was a 44-year-old woman (Fitzpatrick phototype III) with HS on reporting the use of low-frequency ultrasound (US) to the knee for four months after a car accident. Case 3 was a 22-year-old-man (Fitzpatrick phototype III) with HS on the neck ª 2013 The International Society of Dermatology International Journal of Dermatology 2013, 52, 367–370 Topical delivery of triamcinolone via skin pretreated with ablative radiofrequency Table 1 Patients demographics and biometric profile for three months after a tracheostomy. Case 4 was a 50-year- (triamcinolone) and skin surface to enhance delivery of the old-woman (Fitzpatrick phototype IV) with HS on the face triamcinolone. The mode of operation is based on mechanical (mandibular area) for two years after surgery to remove a (acoustic) pressure and torques by propagation of US wave via the sonotrode to the distal horn and the creation of a Before each session, the skin was cleaned with “hammering”-like effect (“push–pull”) in the thin layer between chlorhexidine. First, the fractional RF applicator, with a round the medication, treated skin, and operative surface of mushroom-shaped tip and 110 tiny stainless pins 200 lm in sonotrode. This layer should contain a delivered medication, length 9 thickness, was applied on to the skin using the which is chosen according to the disease to be treated. The following protocol: 45 watts 9 3 passes. Secondly, hammering effect by the sonotrode creates transport of the triamcinolone acetonide (20 mg/ml) was dropped (0.1 ml each delivered drugs/material to the area of preliminary RF lesion) on the perforated skin surface. Finally, the acoustic perforated skin and increasing penetration of the drug into the pressure wave US applicator was applied using the following settings: frequency of the sonotrode vibration rate = 50 Hz; US The combined treatment (RF + US) protocol was done every energy intensity = 80%, for 30–60 seconds each lesion (Fig. 1).
3–4 weeks until clinical improvement. The number of treatmentsranged from one (cases 1 and 4) to four (cases 2 and 3) Ablative fractional radiofrequency module The ablative fractional RF module is incorporated into a Patients were submitted to dermatologic exam every 21 days unipolar RF-based hand-piece. The hand-piece receives RF during treatment and after 30, 90, 180 days and one year after energy, which includes a stationary tip (12 mm in diameter). An the last session. They were advised not to use any other array of protrusions (tiny metal pins) arranged 1 mm apart is configured to cause multiple electrical discharges to be The degree of clinical improvement was evaluated according generated in response to the RF electrical power in a space to a quartile scale of improvement: no improvement; 1 = 1–25% between the protrusions and the skin. The ablative micro- minimal improvement; 2 = 26–50% moderate improvement; plasma RF energy stimulates micro-sparks between the skin 3 = 51–75% marked improvement; 4 = 76–100% excellent surface and RF protrusions, producing holes of 100–150 lm in improvement. Side effects such as erythema, edema, and depth (evaporation + thermal) and 80–120 lm in diameter atrophy as well as the pain during procedure were evaluated on a three-point scale: 0 = absent, 1 = mild, 2 = moderate,3 = severe.13 Digital photographs (Sony DSC-H9 – Super Steady Short 8.1 MP, Japan) were taken at baseline and at The acoustic pressure module is comprised of a transducer, each follow-up visit to document clinical response.
sonotrode, and distal (hollow) horn. It is applied perpendicular to the surface of the skin and in continuous contact with the skin surface in a circular (concentric-eccentric) in-motion movement of the sonotrode. The distal surface of the horn Complete resolution was seen after one session in patients creates vibrational cycles (“push–pull”) on the medication with scars on the nose and mandibular area. The scar on Figure 1 Procedural steps: (1) ablativefractional RF; (2) topical medication; (3)acoustic pressure US International Journal of Dermatology 2013, 52, 367–370 ª 2013 The International Society of Dermatology Topical delivery of triamcinolone via skin pretreated with ablative radiofrequency the neck (furcula area) presented marked involution afterthree sessions and complete involution after four sessions.
The scar on the knee presented a marked improvementafter four sessions (Figs. 2–5).
All patients reported a mild burning sensation during the procedure. They presented mild erythema and edemajust after the procedure, which persisted for 24–48 hours.
Fine scale could be observed 7–10 days after the proce-dure. In one patient (case 3), mild atrophy, homoge- Figure 5 Hypertrophic scar on the face (mandibular area) neously distributed in the lesion, could be observed before treatment and 1 year after one treatment ate. In a recent in-vivo rat model study,14 Evans blue (EB) was used as a marker together with fractional In the last years, ablative fractional lasers have been used ablative RF and acoustic pressure US modules for detect- with the aim of increasing drug delivery.7,8 Wang et al.6 ing transepidermal delivery. In this benchmark study, described the use of Erbium:YAG laser as a pretreatment frozen section biopsies (qualitative) and spectroscopy to accelerate the response of Bowen’s disease treated by (quantitative) measurements were analyzed in four differ- topical 5-fluorouracil and Haerdersdal et al.,8 in 2010, ent conditions on a rat’s skin: (i) topical EB; (ii) EB + US; EB + RF; (iv) EB + RF + US. Histopathological studies (hematoxylin and eosin frozen section) revealedsignificant EB penetration in the EB + RF + US condition,when compared with EB + US and EB + RF conditions.
Multiple studies have shown improvement of laser treated scars using both ablative and non-ablative modali-ties. However, scar treatment with bimodal energydelivery devices for the purpose of TED of medicationhas not been reported.15,16 To our knowledge, this is thefirst study using a combination of physical methods (i.e.
fractional ablative method and acoustic pressure US) for Figure 2 Hypertrophic scar on the nose before treatment and1 week after one treatment the treatment of scars. The ablative fractional methodused was RF, which created micro-channels on the skinsurface, and the acoustic pressure US was applied withthe aim of pushing triamcinolone through these channelsinto the skin. Despite initial reports of poor response andhigh recurrence rate of HS after laser treatment,15,16 ourstudy used fractional ablative RF and acoustic pressureUS to increase triamcinolone permeability, and we couldobserve marked to excellent results within a few sessionswith a long follow-up. In one case where mild atrophywas observed, it was probably caused by triamcinolone,as it is a very common side effect of steroids. In this case, Figure 3 Hypertrophic scar on the knee before and 3 months we should have stopped the treatment after the third ses- sion and waited for continuous regression of the lesion.
Figure 4 Hypertrophic scar on the neck(furcula area) before treatment, aftersession 3 and 2 months after fourtreatments ª 2013 The International Society of Dermatology International Journal of Dermatology 2013, 52, 367–370 Topical delivery of triamcinolone via skin pretreated with ablative radiofrequency The atrophic aspect of this lesion looked even worse than treated by topical 5-fluorouracil. Dermatol Surg 2004; it really was because the HS was located in the concave 7 Letada PR, Shumaker PR, Uebrlhoer NS. Demonstration of protoporphyrin IX (PpIX) localized to areas of palmar skininjected with 5 aminolevulinic acid (ALA) and pre-treated with a fractionated CO2 laser prior to topically appliedALA. Photodiagnosis Photodyn Ther 2010; 7: 120–122.
The use of a laser as a monotherapy modality for the 8 Haerdersdal M, Sakamoto FH, Farinelli WA, et al.
treatment of HS is reported as non-effective with a high Fractional CO2 laser-assisted drug delivery. Laser Surg recurrence rate of HS.15,16 In contrast, the use of a method such as ablative fractional RF with the aim of 9 Yoo KH, Kim BJ, Kim MN. Enhanced efficacy of increasing skin permeability is a new treatment option.
photodynamic therapy with methyl 5-aminolevulinic acid HS treatment with fractional RF and acoustic pressure US in recalcitrant periungual warts after ablative carbon allowed triamcinolone penetration with a marked to dioxide fractional laser: a pilot study. Dermatol Surg excellent response in a few sessions with few side effects.
10 Dudelzak J, Hussain M, Phelps RG. Evaluation of histological and electron microscopic changes after novel treatment using combined microdermabrasion andultrasound induced phonophoresis of human skin.
1 Wolfram D, Tzankov A, Plzl P, et al. Hypertrophic scars J Cosmet Laser Ther 2008; 10: 187–192.
and keloids – a review of their pathophysiology, risk 11 Yang JH, Kim DK, Yun MY, et al. Transdermal delivery factors, and therapeutic management. Dermatol Surg system of triamcinolone acetonide from a gel using phonophoresis. Arch Pharm Res 2006; 29: 412–417.
2 Al-Attar A, Mess S, Thomassen JM, et al. Keloid 12 Liu H, Li S, Pan W, et al. Investigation into the potential pathogenesis and treatment. Plast Reconstr Surg 2006; of low-frequency ultrasound facilitated topical delivery of cyclosporin A. Int J Pharm 2006; 326: 32–38.
3 Lee WR, Shen SC, Fang CL, et al. Topical delivery of 13 Walgrave SE, Ortiz AE, MacFalls MT, et al. Evaluation methotrexate via skin pretreated with physical of a novel fractional resurfacing device for treatment of enhancement techniques: low fluence Erbium:YAG laser acne scarring. Lasers Surg Med 2009; 41: 122–127.
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14 Orenstein A, Bem-Yosef T, Kostenich G, et al. Fractional 4 Shen SC, Lee WR, Fang YP. In vitro percutaneous ablative radiofrequency and acoustic wave technology for absorption and in vivo protoporphyrin IX accumulation trans-epidermal delivery: in-vivo rat model study. ASLMS in skin and tumors after topical 5-aminolevulinic acid Annual Meeting; 2012 April 18–22; Kissimee, FL; USA.
application with enhancement using an Erbium:YAG laser. J Pharm Sci 2006; 95: 929–938.
15 Norris JE. The effect of carbon dioxide laser surgery on 5 Fang JY, Shen SC, Lee WR. Enhancement of topical the recurrence of keloids. Plast Reconstr Surg 1991; 87: 5-aminolevulinic acid delivery by Erbium:YAG laser and microdermoabrasion: a comparison of iontophoresis and 16 Apfelberg DB, Maser MR, White DN, et al. Failure of electroporation. Br J Dermatol 2004; 151: 132–140.
carbon dioxide laser excision of keloids. Lasers Surg Med 6 Wang KF, Fang JY, Hu CH. Erbium:YAG laser pretreatment accelerates the response of Bowens disease International Journal of Dermatology 2013, 52, 367–370 ª 2013 The International Society of Dermatology
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