Anti-PD-1 immunotherapy with adjuvant ablative fractional laser displays increased tumour clearance of squamous cell carcinoma, a murine study.

PD-1 checkpoint inhibitors are used as systemic immunotherapy for locally advanced and metastatic cutaneous squamous cell carcinoma (SCC); however, improved treatment efficacy is urgently needed. In this study, we aimed to investigate the effect of combining systemic anti-PD-1 treatment with adjuvant ablative fractional laser (AFL) in a spontaneous SCC mouse model. Tumours induced by ultraviolet radiation in the strain C3.Cg-Hrhr /TifBomTac were divided into four groups: anti-PD-1-antibody+AFL (n = 33), AFL alone (n = 22) anti-PD-1-antibody alone (n = 31) and untreated controls (n = 46). AFL was given at Day 0 (100 mJ/mb, 5% density), while anti-PD-1-antibody (ip, 200 µg) at Days 0, 2, 4, 6 and 8. Response to treatment was evaluated by tumour growth, survival time and by dividing response to treatment into complete responders (clinically cleared tumours), partial responders (reduced tumour growth rate compared to untreated controls) and non-responders (no decrease in tumour growth rate compared to untreated controls). The strongest tumour response was observed following the combination of systemic anti-PD-1 treatment combined with laser exposure, resulting in the highest percentage of complete responders (24%) compared with untreated controls (0%, p < 0.01), AFL monotherapy (13%, p > 0.05) and anti-PD-1-antibody monotherapy (3%, p > 0.05). Moreover, all three treatment interventions demonstrated significantly reduced tumour growth rates compared with untreated controls (p < 0.01), and the mice had significantly longer survival times (p < 0.01). In conclusion, the combination treatment revealed an improved treatment effect that significantly enhanced the complete tumour clearance not observed with the monotherapies, indicating a possible additive effect of anti-PD-1 with adjuvant AFL in treatment of SCC.

Ablative fractional CO2 laser treatment promotes wound healing phenotype in skin macrophages.

OBJECTIVES: Ablative fractional laser (AFL) treatment is a well-established method for reducing signs of skin photoaging. However, the biological mechanisms underlying AFL-induced healing responses and skin rejuvenation remain largely unknown. It is known that macrophages play an important role in orchestrating healing, normalization, and remodeling processes in skin. Macrophage phenotypes are characterized by inflammatory markers, including arginase-1 (Arg1), major histocompatibility class II molecules (MHC II), and CD206. This study aims to explore AFL's effect on macrophage phenotype by evaluating changes in inflammatory markers and the potential concurrent accumulation of Arg1 in the skin. METHODS: Mice (n = 9) received a single AFL treatment on the left side of the back skin (100 mJ/microbeam, 5% density) while the right side of the back remained untreated as control. Treated and untreated skin from each mouse were collected Day 5 posttreatment for flow cytometry and histology analysis. Flow cytometry evaluated the immune infiltration of macrophages and the expression of macrophage inflammatory markers (Arg1, MHC II, and CD206). In addition, Arg1 presence in the skin was evaluated through antibody staining of histology samples and quantification was performed using QuPath image analysis software. RESULTS: Following AFL, the number of macrophages increased 11-fold (p = 0.0053). Phenotype analysis of AFL-treated skin revealed an increase in the percentage of macrophages positive for Arg1 (p < 0.0001) and a decrease in the percentage of macrophages positive for MHC II (p < 0.0001) compared to untreated skin. No significant differences were observed in percentage of CD206-positive macrophages (p = 0.8952). Visualization of AFL-treated skin demonstrated a distinct pattern of Arg1 accumulation that correlated with the microscopic treatment zones (MTZ). Quantification of the percentage of Arg1-positive area in epidermis and dermis showed a significant increase from 3.5% ± 1.2% to 5.2% ± 1.7 (p = 0.0232) and an increase from 2.2% ± 1.2% to 9.6% ± 3.3 (p < 0.0001) in whole skin samples. CONCLUSION: AFL treatment polarizes macrophages toward a wound healing phenotype and induces Arg1 accumulation in the MTZ. We propose that the polarized wound healing macrophages are a major source for the increased Arg1 levels observed in the skin following treatment.

Impact of skin hydration on patterns of microthermal injury produced by fractional CO2 laser.

OBJECTIVES: The impact of skin hydration on patterns of thermal injury produced by ablative fractional lasers (AFLs) is insufficiently examined under standardized conditions. Using skin with three different hydration levels, this study assessed the effect of hydration status on microchannel dimensions generated by a fractional CO2 laser. METHODS: A hydration model (hyperhydrated-, dehydrated- and control) was established in ex vivo porcine skin, validated by changes in surface conductance and sample mass. After, samples underwent AFL exposure using a CO2 laser (10,600 nm) at two examined pulse energies (10 and 30 mJ/mb, fixed 10% density, six repetitions per group). Histological assessment of distinct microchannels (n = 60) determined three standardized endpoints in H&E sections: (1) depth of microthermal treatment zones (MTZs), (2) depth of microscopic ablation zones (MAZs), and (3) coagulation zone (CZ) thickness. As a supplemental in vivo assessment, the same laser settings were applied to hyperhydrated- (7-h occlusion) and normohydrated forearm skin (no pretreatment) of a human volunteer. Blinded measurement of MAZ depth (n = 30) was performed using noninvasive optical coherence tomography (OCT). RESULTS: Modest differences in microchannel dimensions were shown between hyperhydrated, dehydrated and control skin at both high and low pulse energy. Compared to controls, hyperhydration led to median reductions in MTZ and MAZ depth ranging from 5% to 8% (control vs. hyperhydrated at 30 mJ/mb; 848 vs. 797 µm (p < 0.003) (MAZ); 928 vs. 856 µm (p < 0.003) (MTZ)), while 14%-16% reductions were shown in dehydrated skin (control vs. dehydrated at 30 mJ/mb; MAZ: 848 vs. 727 µm (p < 0.003); MTZ: 928 vs. 782 µm (p < 0.003)). The impact of skin hydration on CZ thickness was in contrast limited. Corresponding with ex vivo findings, hyperhydration was similarly associated with lower ablative depth in vivo skin. Thus, median MAZ depth in hydrated skin was 10% and 14% lower than in control areas at 10 and 30 mJ/mb pulse energy, respectively (10 mJ: 210 vs. 180 µm (p < 0.001); 30 mJ: 335 vs. 300 µm (p < 0.001)). CONCLUSION: Skin hydration status can exert a minimal impact on patterns of microthermal injury produced by fractional CO2 lasers, although the clinical implication in the context of laser therapy requires further study.

Histological analysis of laser-enabled tissue coring with a novel 2910 nm erbium-doped fluoride glass fiber laser.

OBJECTIVES: There remains an unmet need for a laser-enabled tissue coring device that can effectively improve face and neck skin laxity and rhytides. We investigate a novel 2910 nm erbium-doped fluoride glass fiber laser (2910 nm fiber laser) (UltraClear; Acclaro Medical) for laser-coring of submental tissue. METHODS: Five subjects, Glogau scale III-IV, were treated with a single pulse of the laser-coring mode of the 2910 nm fiber laser in the submentum. A 4 mm punch biopsy was immediately performed. Biopsy specimens were sectioned and stained with hematoxylin and eosin and placed on glass slides. All sections were reviewed, and sections containing the center of the transected core were analyzed for depth and diameter of the ablative microchannel and width of the surrounding zone of coagulation. RESULTS: A total of 15 intact micro-cores were analyzed. Histological analysis revealed an average ± standard deviation microchannel diameter of 242.5 ± 65.2 µm, an average ablative depth of 980 ± 318.8 µm, and an average zone of coagulation of 104 ± 32 µm. CONCLUSIONS: Laser-enabled tissue coring with a novel 2910 nm fiber laser can safely achieve a wider microchannel diameter with ablative depth extending to the mid and deep dermis, which has the potential for collagen contraction and tissue tightening. Laser-coring to this ablation diameter and depth and with the surrounding zone of coagulation was found to be safe without adverse effects of post-inflammatory erythema or scarring in our study.

Full-face and neck resurfacing with a novel ablative fractional 2910 nm erbium-doped fluoride glass fiber laser for advanced photoaging.

OBJECTIVES: Ablative fractional lasers have long been considered the gold standard for facial resurfacing for advanced photoaging. These lasers offer an improved safety profile compared to traditional ablative lasers but typically require more treatment sessions given their fractional approach. In this study, we evaluate a new novel 2910 nm erbium-doped fluoride glass fiber laser (2910 nm fiber laser) (UltraClear; Acclaro Medical) for full-face and neck resurfacing for the treatment of advanced photoaging. METHODS: Twenty-two healthy subjects aged 44-80 years presenting for advanced facial photoaging and rhytides were enrolled in the study. All subjects received three full-face and neck, multipass treatments utilizing the 2910 nm fiber laser spaced 6-8 weeks apart. Subjects were asked to rate the average level of pain during the treatment. At 90 days following subjects' third treatment subjects evaluated their improvement using a Global Aesthetic Improvement Scale (GAIS) and rated their satisfaction with the treatment. Evaluation of pretreatment and posttreatment photos was completed by two blinded physician reviewers. Reviewers were asked to identify the pretreatment and posttreatment photographs and to rate the degree of improvement utilizing a GAIS. RESULTS: Fifteen participants completed the study; six were exited from the study (withdrew or lost to follow-up). The average subject GAIS score for overall appearance was 3.8. The average subject satisfaction level at follow-up was 4.8. The average subject pain score was 4.9. One blinded physician reviewer correctly identified 100% of subjects' posttreatment photographs, while the second blinded reviewer correctly identified 93%. Blinded evaluation of digital photographs revealed an average GAIS score of 3.2. Posttreatment skin responses included pin-point hemorrhage, erythema, edema, and soft tissue crusting lasting 5-7 days. There were no instances of infection, scarring or hypopigmentation. There were two instances of temporary hyperpigmentation. CONCLUSIONS: Treatment with the novel 2910 nm fiber laser is safe and effective in treating advanced photoaging and rhytides. Three treatments produced moderate to marked improvement with high patient satisfaction and treatment was associated with less discomfort and downtime compared to conventional fractional ablative lasers.

Laser-assisted topical delivery of vismodegib reduces hedgehog gene expression in human basal cell carcinomas in vivo.

BACKGROUND: Systemically delivered hedgehog inhibitors including vismodegib and sonidegib are widely used to treat basal cell carcinomas (BCCs). Ablative fractional laser (AFL)-assisted topical delivery of vismodegib has been demonstrated in preclinical studies. The aim of this explorative clinical study was to evaluate intratumoral vismodegib concentrations and effect on hedgehog pathway gene expression following AFL-assisted topical vismodegib delivery to BCCs. METHODS: In an open-label clinical trial, 16 nodular BCCs (in n = 9 patients) received one application of CO2 -AFL (40 mJ/microbeam, 10% density) followed by topical vismodegib emulsion. After 3-4 days, vismodegib concentrations in tumor biopsies (n = 15) and plasma were analyzed and compared with samples from patients receiving oral treatment (n = 3). GLI1, GLI2, PTCH1, and PTCH2 expression was determined by quantitative polymerase chain reaction (n = 7) and GLI1 additionally by in situ hybridization (n = 3). RESULTS: Following AFL-assisted topical administration, vismodegib was detected in 14/15 BCCs and reached a median concentration of 6.2 µmol/L, which compared to concentrations in BCC tissue from patients receiving oral vismodegib (9.5 µmol/L, n = 3, p = 0.8588). Topical vismodegib reduced intratumoral GLI1 expression by 51%, GLI2 by 55%, PTCH1 and PTCH2 each by 73% (p ≤ 0.0304) regardless of vismodegib concentrations (p ≥ 0.3164). In situ hybridization demonstrated that GLI1 expression was restricted to tumor tissue and downregulated in response to vismodegib exposure. CONCLUSION: A single AFL-assisted topical application of vismodegib resulted in clinically relevant intratumoral drug concentrations and significant reductions in hedgehog pathway gene expressions.

Efficacy and Safety of Ablative Fractional Laser in Melasma: A Meta-analysis and Systematic Review.

Melasma is a common acquired skin pigmentation disorder. The treatment is urgent but challenging. Ablative fractional laser (AFL) can improve pigmentation, but the efficacy and potential side effects are still debatable. This study aimed to evaluate the efficacy and safety of ablative fractional lasers in the treatment of melasma. A comprehensive systematic search of literature published before June 20, 2023, was conducted on online databases, including PubMed, Embase, Cochrane Library, and Web of Science. The data obtained were analyzed using Review Manager 5.4 software. Fourteen randomized controlled trials, comprising 527 patients, were included. Compared to the drug alone, the combination of AFL and the drug showed improved therapeutic efficacy in the melasma area and severity index (MASI) (MD = 1.54, 95% CI [0.16, 2.92], P = 0.03) and physician global assessment (RR = 1.61, 95% CI [1.08, 2.41], P = 0.02). However, no statistically significant results were found in patient self-assessment (RR = 1.56, 95% CI [0.88, 2.76], P = 0.12). As an individual therapy, AFL is not superior to any other lasers in terms of MASI (MD = 2.66, 95% CI [-1.32, 6.64], P = 0.19) or melanin index (MD = -7.06, 95% CI [-45.09, 30.97], P = 0.72). Common adverse events included transient erythema, burning, edema, and superficial crusting. Only a few patients experienced reversible post-inflammatory hyperpigmentation, herpes labialis, and acne breakouts. These results support the application of AFL as a viable treatment option for melasma, particularly in refractory and severe cases. Rational parameterization or combination therapy may lead to significant clinical improvement with fewer complications.

Ablative fractional laser treatment reduces hedgehog pathway gene expression in murine basal cell carcinomas.

This study aimed to investigate the impact of ablative fractional laser (AFL) on hedgehog pathway gene expression in murine microscopic basal cell carcinomas (BCCs) and compare these results to the effect of topical treatment with vismodegib, an FDA-approved hedgehog inhibitor. In 25 mice, 1 cm2 skin test sites (n = 44) containing microscopic BCCs were exposed to one of three interventions: a single CO2 AFL treatment (1 pulse, 40 mJ/microbeam, wavelength 10.6 µm, 5% density, pulse rate 250 Hz, n = 12), eight topical vismodegib treatments (3.8 mg/mL, n = 8), or combination of AFL and vismodegib treatments (n = 9). Untreated controls were included for comparison (n = 15). After 4 days, skin samples were analyzed for hedgehog gene expression (Gli1, Gli2, and Ptch1) by qPCR and vismodegib concentrations by liquid chromatography mass spectrometry (data analyzed with two-tailed t-tests and linear regression). A single treatment with AFL monotherapy significantly reduced hedgehog gene expression compared to untreated controls (Gli1 72.4% reduction, p = 0.003; Gli2 55.2%, p = 0.010; Ptch1 70.9%, p < 0.001). Vismodegib treatment also reduced hedgehog gene expression (Gli1 91.6%; Gli2 83.3%; Ptch1 83.0%), significantly surpassing AFL monotherapy for two out of three genes (Gli1, p = 0.017; Gli2, p = 0.007; Ptch1, p = 0.15). AFL and vismodegib combination mirrored the effects of vismodegib monotherapy (Gli1, p = 0.424; Gli2, p = 0.289; Ptch1, p = 0.593), possibly due to comparable cutaneous vismodegib concentrations (mean ± SD, vismodegib monotherapy 850 ± 475 µmol/L; combination 1036 ± 824 µmol/L; p = 0.573). In conclusion, a single AFL treatment significantly reduced hedgehog gene expression in murine BCCs mimicking the effects of eight topical applications of vismodegib. Further studies are needed to assess whether AFL can be utilized for BCC treatment, either as monotherapy or in combination with other drugs.

The effect of combined red, blue, and near-infrared light-emitting diode (LED) photobiomodulation therapy on speed of wound healing after superficial ablative fractional resurfacing.

Objective of the study is to assess the effects of wound healing with a commercially available light emitting diode (LED) photo biomodulation (PBM) device that emits three wavelengths (465, 640 and 880nm) after ablative fractional laser (AFL) treatment to healthy skin on the bilateral inner biceps. We conducted a prospective intraindividual randomized controlled study with 25 volunteers. AFL treatment was performed on healthy skin of the bilateral inner biceps. Subjects applied the LED light device for 30 min to the assigned bicep 3 times a week over 4 weeks, beginning on day 0. Subjects were followed up on days 2, 4, 6, 9, 13, 20 and 27 for treatment with the PBM device, clinical digital photography of the test and control sites, and in-person subject assessment, with follow ups on days 34 and 55 for clinical photography and assessment. Three blinded evaluators were asked to determine which bicep healed faster between day 0 to day 13. Pain, discomfort, and itch were also assessed. The three blinded evaluators chose the treatment arm as the faster healed arm in greater than 50% of the images, although the results were not statistically significant. There was no statistically significant difference between test and control arms in terms of pain, discomfort and itch. In conclusion, PBM therapy has the potential to improve wound healing. In this study, a three wavelength PBM device resulted in some subjects achieving faster healing after AFL but the results were not statistically significant.

In vivo characterization of laser-assisted delivery of hyaluronic acid using multiphoton fluorescence lifetime imaging.

Laser-assisted drug delivery (LADD) is a treatment method to enhance the penetration of pharmaceuticals through the skin. The aim of the present study is to track hyaluronic acid (HA) and analyse its effect on human skin in vivo after ablative fractional laser (AFL) treatment. Healthy male and female subjects were recruited. Four areas were marked on their forearms of each volunteer, and each area was assigned to one of the following treatment options: AFL + HA, AFL only, HA only or untreated control. A carbon dioxide laser was used for the AFL treatment. Follow-up measurements were scheduled 30 min and 30 days after treatment using multiphoton tomography equipped with fluorescence lifetime imaging (MPT-FLIM). A total of 11 subjects completed the study. By detecting fluorescence lifetimes, the HA and the anaesthetic ointment were clearly distinguishable from surrounding tissue. After AFL treatment, HA could be visualized in all epidermal and upper dermal layers. In contrast, HA in intact skin was only detected in the superficial layers at distinctly lower levels. The applied HA gel seemed to have beneficial properties for the wound healing process after laser treatment. LADD has proven to be a fast and effective method to increase HA uptake into the skin, allowing for improved hydration and skin rejuvenation over time. Furthermore, LADD could be a beneficial treatment option in laser resurfacing. MPT-FLIM proved to be an appropriate diagnostic tool for drug delivery tracking and monitoring of treatment response for individualized therapy adjustment.

Repeated exposure to fractional CO2 laser delays squamous cell carcinoma formation and prevents clinical and subclinical photodamage visualized by line-field confocal optical coherence tomography and histology.

OBJECTIVES: Ablative fractional laser (AFL) is a well-established modality for treating ultraviolet radiation (UVR)-induced skin photodamage. We aimed to investigate the potential of AFL to delay squamous cell carcinoma (SCC) formation and prevent photodamage in a preclinical UVR-induced SCC model. MATERIALS AND METHODS: Hairless C3.Cg-Hrhr /TifBomTac mice (n = 50) were exposed to UVR three times weekly throughout the study. UV-exposed mice were randomized to two groups that received dorsal CO2 AFL (10 mJ/mb, 10% density) or no treatment. AFL was performed every other week for a total of 16 weeks (nine treatments in total). The primary outcome was time to tumor occurrence. In a subset of mice on Day 150, prevention of clinical photodamage was assessed by examination of skin tightness and dyspigmentation. Concomitantly, assessment of subclinical photoprevention based on normalization of keratinocyte dysplasia, dermo-fiber morphology (collagen and elastin fibers), and skin thickness, was performed using line-field confocal optical coherence tomography (LC-OCT) and histology. RESULTS: Repeated AFL treatments delayed SCC tumor development compared to UVR control mice by 12, 19, and 30 days for first, second, and third tumors, respectively (p ≤ 0.0017). Compared to UVR controls, AFL prevented photodamage both clinically and subclinically, based on LC-OCT and histology. In the epidermal layer, AFL imparted photopreventative effects including reduced dyspigmentation and keratinocyte dysplasia (1 vs. 2.5, p = 0.0079) and partial normalization of the epidermal thickness (p < 0.0001). In the dermis, AFL led to twofold greater skin tightness (p = 0.0079), improved dermo-fiber structure, and dermal thickness (p = 0.0011). CONCLUSION: In conclusion, repeated AFL treatments of UVR-exposed skin significantly delayed SCC tumor formation and prevented clinical and imaging-assessed subclinical signs of photodamage, indicating a potential for AFL in prevention strategies for SCC and photodamage in high-risk populations.

Striae gravidarum treatment: evaluating non-ablating fractional laser (NAFL) efficacy and safety.

BACKGROUND: Striae gravidarum (SG) is a common pregnancy-related dermatologic problem, for which finding an effective treatment remains a challenge. AIM: To evaluate the safety and efficacy of 1540 nm non-ablative fractional laser (Star lux 500) in the treatment of SG in Iranian women and peruse the relationship between clinical improvement rate and patient characteristics as well as clinical features of striae. METHOD: A prospective before-after study was conducted on 50 patients with SG who received three monthly sessions of 1540 nm non-ablative fractional laser and were followed for 2 months after the last treatment session. Clinical changes were measured using both provider-rated outcome through before/after pictures represented by final clinical score (from 0 to 5) and patient-reported outcome (patient global assessment or PGA). RESULTS: Over the course of the study both final clinical score and PGA increased significantly from week 4 to week 20 (P value: <0.001 and 0.048, respectively). Only modest adverse effects including erythema, edema and hyperpigmentation were noted. CONCLUSION: In conclusion, patients with SG of different type (rubra/alba) or maturity may somehow benefit from treatment with NAFL experiencing minimal transient side effects.Therefore, NAFL may be considered a safe and partially effective treatment option for stretch mark of patients with SG.

Evaluation of 30% supramolecular salicylic acid followed by 1565-nm non-ablative fractional laser on facial acne and subsequent enlarged pores.

The treatment of acne vulgaris and enlarged pore remains challenging. The 30% supramolecular salicylic acid (SSA) is a newly developed form of SA which affects pathogenic factors of acne. Non-ablative fractional laser (NAFL) promotes remodeling and decreases sebum excretion with minimal side effect. The current study was aimed to evaluate the sequential modality with 30% SSA followed by 1565-nm NAFL on facial acne and subsequent enlarged pores. A 20-week-duration prospective study was performed. Consecutive 4 sessions of 30% SSA treatment were conducted, at 2-week intervals. Two weeks after the last session of 30% SSA, 3 sessions of 1565-nm NAFL treatment were applied, at 4-week intervals. The noninvasive devices measured scores of red areas and pores, cuticle moisture, and sebum secretion. The main subjective evaluation was global acne grading system (GAGS). The side effects were recorded. Compared to baseline, the scores of red areas and pores, sebum secretion, and GAGS significantly decreased after series sessions of 30% SSA treatments (P < 0.05). The sequential application of 1565-nm NAFL maintained the good results (P < 0.05, comparing to baseline) and even further decreased the sebum secretion (P < 0.05, comparing to SSA). The cuticle moisture remained unchanged during whole period, and side effects including tingling sensation, pain, erythema, and edema were quickly reversible and acceptable. The significant improvements of acne and pores were produced by 30% SSA, and 1565-nm NAFL inhibited the sebum secretion and maintained the efficacies of 30% SSA. The sequential modality of 30% SSA followed by 1565-nm NAFL was an alternative choice for acne vulgaris companied with enlarged pores.

A systematic review of the comparison between needling (RF-needling, meso-needling, and micro-needling) and ablative fractional lasers (CO2, erbium YAG) in the treatment of atrophic and hypertrophic scars.

The aim of this study is to compare needling (RF-needling, meso-needling, micro-needling) and ablative fractional lasers (CO2, erbium-YAG) in the treatment of atrophic and hypertrophic scars in a systematic review. The database was searched, and 10 articles were selected that were relevant in terms of content, topic, and purpose and met the inclusion criteria. Of all the articles reviewed in this study, there were 2 randomized split-face trials (20%), 1 controlled nonrandomized trial (10%), 1 controlled randomized phase III clinical trial (10%), 1 prospective trial (10%), 1 prospective nonrandomized open-label trial (10%), and 1 randomized comparative trial (10%), with the type of study not reported in 3 articles. We used Endnote X8 to review the articles and extract data. After review, the studies were analyzed and categorized. No statistically significant difference was found between the two methods, laser and micro-needling, in the treatment of atrophic and hypertrophic scars in 60% of the articles studied, and both showed significant improvement (70% or more improvement to complete response). Significant improvement was noted in 20% of the studies reviewed for the laser and micro-needling treatment methods. The results of this study show that needling and ablative fractional lasers are tolerable and safe procedures with no significant difference in the treatment of skin scars in sixty percent of the studies.

Efficacy of Photodynamic Therapy for the Treatment of Bowen's Disease: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND: Photodynamic therapy is an established treatment option for Bowen's disease. Our meta-analysis was aimed at evaluating the efficacy and recurrence of photodynamic therapy or other topical treatments (5-fluorouracil, cryotherapy) and of photodynamic therapy alone or in combination with other therapies (ablative fractional CO2 laser or plum-blossom needle) for the treatment of Bowen's disease. METHODS: Trials that met our inclusion criteria were identified from PubMed, EMBASE, Web of Science, and Cochrane Library databases, and meta-analyses were conducted with RevMan V.5.4. The risk of bias was estimated with the Cochrane Collaboration's risk of bias tools. Complete response rate, recurrence, pain/visual analogue scale score, cosmetic outcome, and adverse events were considered as outcomes. RESULTS: Of the 2,439 records initially retrieved, 8 randomized controlled trials were included in this meta-analysis. According to our analyses, photodynamic therapy exhibited a significantly higher complete response rate (RR = 1.36, 95% CI [1.01, 1.84], I2 = 86%, p = 0.04), less recurrence (RR = 0.53, 95% CI [0.30, 0.95], I2 = 0%, p = 0.03), and better cosmetic outcome (RR = 1.34, 95% CI [1.15, 1.56], I2 = 0%, p = 0.0002) compared with other treatments. Moreover, there was a significant difference between the complete response rate of photodynamic therapy combined with ablative fractional CO2 laser and that of photodynamic therapy (RR = 1.85, 95% CI [1.38, 2.49], I2 = 0%, p < 0.0001). Photodynamic therapy combined with ablative fractional CO2 laser or plum-blossom needle also showed significantly less recurrence (RR = 0.21, 95% CI [0.09, 0.51], I2 = 0%, p = 0.0005) and a lower visual analogue scale score (RR = 0.51, 95% CI [0.06, 0.96], I2 = 0%, p = 0.03) than photodynamic therapy alone. However, there was no significant difference in the complete response rate between photodynamic therapy combined with ablative continuous CO2 laser and photodynamic therapy combined with ablative fractional CO2 laser (RR = 1.00, 95% CI [0.54, 1.86], I2 not applicable, p = 1.00). CONCLUSIONS: This meta-analysis shows that photodynamic therapy can be used in the treatment of Bowen's disease with better efficacy, less recurrence, and better cosmetic outcomes than cryotherapy and 5-FU. Some methods, including ablative fractional CO2 laser, can be applied in combination with photodynamic therapy to improve efficacy. However, which laser-assisted photodynamic therapy scheme has the most advantages in the treatment of Bowen's disease warrants further exploration.

HeaLED: Assessment of skin healing under light-emitting diode (LED) exposure-A randomized controlled study versus placebo.

BACKGROUND: Light-emitting diodes (LEDs) in the visible or near-infrared spectrum have been reported to promote wound healing. However, despite being frequently proposed in daily clinical practice, the efficacy of photobiomodulation treatment after a laser procedure relies on very limited clinical data. OBJECTIVE: To compare the relative efficacy of LED versus placebo treatment in decreasing erythema and transepidermal water loss (TEWL) after a fractional CO2 session. METHODS: We conducted an open prospective intraindividual randomized controlled study with 10 healthy volunteers. An ablative fractional laser was performed on the seven forearm areas. Three consecutive daily sessions of LED (590, 630, and 850 nm [two tested irradiances each] and placebo) were applied after randomization. Physical measures (colorimetry, TEWL), photography, and clinical evaluation were performed on Days 1, 2, 3, 7, and 21. The main criterion of evaluation was the variation of parameter a* (erythema) at 72 hours for each LED parameter compared to placebo treatment. RESULTS: No significant differences in the variation of the parameter a* or any of the other studied parameters were found for the different LEDs compared to the placebo area. CONCLUSION: Photobiomodulation failed to improve healing after laser ablation compared to placebo.

Management of oral leukoplakia by ablative fractional laser-assisted photodynamic therapy: A 3-year retrospective study of 48 patients.

OBJECTIVES: This study aimed to review the results of oral leucoplakia (OL) using ablative fractional laser-assisted photodynamic therapy (AFL-PDT) and to further evaluate the risk factors for recurrence and malignant transformation. MATERIALS AND METHODS: Forty-eight patients diagnosed with OL using histopathology were enrolled in this study. All patients received one session of AFL-PDT. Therapeutic efficacy was evaluated 1 month posttreatment. Follow-up was scheduled every 3 months in the first year and every 6 months thereafter. RESULTS: An overall positive response rate of 87.5% (42/48) was achieved, including 62.5% (30/48) complete responses and 25.0% (12/48) partial responses. During the 3-year follow-up period, the recurrence and malignant transformation rates were 37.5% (18/48) and 8.3% (4/48), respectively. Lesions on gingiva/palate seemed to be associated with recurrence (p < 0.001; odds ratio [OR]: 1.64, 95% confidence interval [CI]: 1.13-2.37). The severity of epithelial dysplasia (p = 0.02; OR: 2.93, 95% CI: 1.96-4.42) and recurrence (p = 0.016; OR: 3.14, 95% CI: 2.04-4.84) were associated with a predisposition to malignant transformation. CONCLUSIONS: AFL-PDT is an effective management of OL, but requires close follow-up. OL lesions on the gingiva/palate are predisposed to recurrence. OLs that recur with moderate/severe epithelial dysplasia have a higher risk of transforming into oral squamous cell carcinoma.

Treatment of periorbital wrinkles using thermo-mechanical fractional injury therapy versus fractional non-ablative 1565 nm laser: A comparative prospective, randomized, double-arm, controlled study.

BACKGROUND: Non-ablative fractional laser is an effective modality for the treatment of periorbital wrinkling, one of the earliest signs of skin aging. Thermo-mechanical fractional injury (TMFI) therapy (Tixel®, Novoxel®, Israel) is an innovative technology that is now being used for facial skin rejuvenation. Our study compares the clinical results, side effects, and downtime profile between TMFI treatment and non-ablative fractional 1565 nm laser (ResurFX®, Lumenis, Israel). METHODS: This was a prospective study of 68 patients (64 women, 4 men) with skin types I-VI in two medical centers (34 from Israel, 34 from the USA) that were randomized to receive either TMFI or NAFL treatment for periorbital wrinkling. Patients received 3-5 treatments, 3-5 weeks apart. Six months after the last treatment, the change in Fitzpatrick Wrinkling Classification System (FWCS) was calculated by three non-involved physicians and compared to pretreatment results. Side effects and downtime profiles were assessed in each group (including VAS pain assessment, time required to refrain from work and social activity, and time required for the resolution of redness, edema, and crusts.) RESULTS: A moderate improvement in periorbital wrinkling was demonstrated in both groups, with an average improvement of 1.6 ± 0.6 in FWCS in the TMFI group and an average improvement of 1.7 ± 0.8 in the NAFL group (p < 0.001). Postprocedural VAS score was 5.86 ± 2.3 in the NAFL group and 4.01 ± 2.6 in the Tixel® group. Approximately 80% of subjects returned to both work and social activities two days postprocedure. Crusts were reported by 52% of patients in the TMFI group, compared to 16% of patients in the NAFL group more than 48 hours postprocedure (p < 0.05). There were no statistically significant differences in the other parameters between the two groups. CONCLUSION: TMFI is an effective and safe modality for the treatment of periorbital wrinkling, with comparable results to the 1565 nm NAFL.

Topical delivery of PD-1 inhibitors with laser-assisted passive diffusion and active intradermal injection: Investigation of cutaneous pharmacokinetics and biodistribution patterns.

BACKGROUND AND OBJECTIVES: Current cancer immunotherapeutic treatment with PD-1 inhibitors is administered systemically. However, a local treatment strategy may be advantageous as it could provide targeted drug delivery as well as attenuate side effects seen with systemic treatments. For keratinocyte cancers, where surgical excision is not always applicable, an alternate local treatment approach would be beneficial. This study aims to examine cutaneous pharmacokinetics and biodistribution of the PD-1 inhibitor nivolumab, locally delivered either by ablative fractional laser (AFL)-assisted passive diffusion or active intradermal injection, in vivo. MATERIALS AND METHODS: In vivo pig skin was either exposed to CO2 AFL (80 mJ/mb by two stacked pulses of 40 mJ/mb) at 5% or 15% density followed by topical application of nivolumab (1 mg/ml, 100 µl/10 × 10 mm) or intradermally injected with nivolumab (1 mg/ml, 100 µl). Cutaneous nivolumab delivery was evaluated at different timepoints (0, 1, 2, 4 hours and 2 days) at two tissue depths (100-800 and 900-1600 µm) by ELISA. Visualization of cutaneous biodistribution was shown in vertical tissue sections using HiLyte FluorTM 488 SE labeled nivolumab for fluorescence microscopy whereas nivolumab was DOTA-tagged with Dysprosium before the laser ablation-inductively coupled plasma-mass spectrometry analysis (LA-ICP-MS). RESULTS: Our in vivo study revealed different pharmacokinetic and biodistribution patterns for the AFL- and injection techniques. A superficial horizontal band-like uptake of nivolumab was provided with AFL-assisted passive diffusion whereas a deep focal deposition was seen with active intradermal injection, compared with controls showing remnant deposition on the skin surface. AFL-assisted nivolumab uptake in upper dermis peaked after 4 hours (p < 0.01). The cutaneous concentration of nivolumab achieved by intradermal injection was markedly higher than with AFL, the highest deposition with intradermal injection was detected at time 0 hours in both upper and deep dermis (p < 0.01) and decreased throughout the study period, although the concentration remained higher compared with saline control injections at all time points (0 hours -2 d) (p < 0.01). CONCLUSION: Local cutaneous delivery of nivolumab with either AFL or intradermal injection revealed two different pharmacokinetic and biodistribution patterns. Passive AFL-assisted diffusion of nivolumab resulted in enhanced uptake after 4 hours, while intradermal actively injected nivolumab showed immediate enhanced cutaneous deposition with retention up to 2 days after injection. The two local delivery techniques show potential for development of individualized treatment strategies depending on the clinical tumor appearance.

Low-fluence and low-density CO2 laser: histological analysis of collagen fiber changes in skin and its clinical repercussions in photorejuvenation.

This study refers to clinical and histologic analysis of effects on photorejuvenation after one single treatment of fractional CO2 laser with low fluence and low density. To analyze histologically the quantitative variation of collagen fibers type I and III, elastic fibers, and epidermal thickness on D84, besides clinical evaluation of amount, length, thickness, and depth of periocular wrinkles during the same period. This is an open, prospective, interventional study. There were 40 healthy female with age between 35 and 65 years. Twenty-six participants were randomly selected for D0 and D84 biopsy. A single session of fractional CO2 laser was done in the hole face, using a 800-µm tip, 5% density, and 10 mJ fluence with a single pass. On D0, D42, and D84, a clinical comparative analysis of amount, length, depth, and thickness of periocular wrinkles has been done. On histological analysis, a comparative quantitative evaluation of collagen fibers type I and III, elastic fibers, and epidermal thickness has been done on D0 and D84. The results of this study denoted a significant clinical improvement of amount (- 32.17%; p < 0.0001), thickness (- 33%; p < 0.0001), lenght (- 35.84%; p < 0.0001), and depth of periocular wrinkles (- 32.46%; p < 0.0001). A significant increase in the amount of collagen fibers type III was observed on D84 (+ 60.67%; p = 0.0013). Collagen fibers type I and elastic fibers did not have the same result, with a nonsignificant increase (+ 8.31%; p = 0.3820) and a decrease (- 12.4%; p = 0.0585) respectively. Epidermal thickness has a tendency to significant variation (p = 0.05553). The results demonstrate that fractional CO2 laser with low fluence and low density is a safe and efficient option for photorejuvenation of the face.