Line-field confocal optical coherence tomography in dermato-oncology: A literature review towards harmonized histopathology-integrated terminology.

Non-invasive diagnostics like line-field confocal optical coherence tomography (LC-OCT) are being implemented in dermato-oncology. However, unification of terminology in LC-OCT is lacking. By reviewing the LC-OCT literature in the field of dermato-oncology, this study aimed to develop a unified terminological glossary integrated with traditional histopathology. A PRISMA-guided literature-search was conducted for English-language publications on LC-OCT of actinic keratosis (AK), keratinocyte carcinoma (KC), and malignant melanoma (MM). Study characteristics and terminology were compiled. To harmonize LC-OCT terminology and integrate with histopathology, synonymous terms for image features of AK, KC, and MM were merged by two authors, organized by skin layer and lesion-type. A subset of key LC-OCT image-markers with histopathological correlates that in combination were typical of AK, squamous cell carcinoma in situ (SCCis), invasive squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and MM in traditional histopathology, were selected from the glossary by an experienced dermatopathologist. Seventeen observational studies of AK (7 studies), KC (13 studies), MM (7 studies) utilizing LC-OCT were included, with 117 terms describing either AK, KC, or MM. These were merged to produce 45 merged-terms (61.5% reduction); 5 assigned to the stratum corneum (SC), 23 to the viable epidermis, 2 to dermo-epidermal junction (DEJ) and 15 to the dermis. For each lesion, mandatory key image-markers were a well-defined DEJ and presence of mild/moderate but not severe epidermal dysplasia for AK, severe epidermal dysplasia and well-defined DEJ for SCCis, interrupted DEJ and/or dermal broad infiltrative strands for invasive SCC, dermal lobules connected and/or unconnected to the epidermis for BCC, as well as single atypical melanocytes and/or nest of atypical melanocytes in the epidermis or dermis for MM. This review compiles evidence on LC-OCT in dermato-oncology, providing a harmonized histopathology-integrated terminology and key image-markers for each lesion. Further evaluation is required to determine the clinical value of these findings.

Early Results of a Screening Program for Skin Cancer in Liver Transplant Recipients: A Cohort Study.

(1) Background: Skin cancer is the most common cancer in transplant recipients. Timely and regular screening may reduce advanced disease. The study aimed to determine referral rates to screening, the incidence, and risk factors of skin cancer in a Danish liver transplant recipient cohort. (2) Methods: All first-time liver transplant recipients, >18 years old, attending outpatient care between January 2018 and December 2021 were included. The referral rates and incidence of skin cancer/preneoplastic lesions were calculated. Risk factors were assessed using Cox regression analyses. (3) Results: Of the 246 included recipients, 219 (89.0%) were referred to screening, and 102 skin cancer/preneoplastic lesions were diagnosed in 32 (15.6%) recipients. The IR of any skin cancer/preneoplastic lesion was 103.2 per 1000 person-years. BCC was the most frequent skin cancer followed by SCC, IR: 51.3 vs. 27.1 per 1000 person-years, respectively. No cases of MM were observed. The IR of actinic keratosis and Bowen's Disease were 48.1 vs. 13.2 per 1000 person-years, respectively. Time since transplantation was independently associated with skin cancer/preneoplastic lesions, HR (95%CI) 2.81 (1.64-4.80). (4) Conclusions: The study determined the incidence and risk factors of skin cancer/preneoplastic lesions in liver transplant recipients enrolled in a screening program, while demonstrating a high screening referral rate.

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.

Skin Cancer Development Is Strongly Associated with Actinic Keratosis in Solid Organ Transplant Recipients: A Danish Cohort Study.

BACKGROUND AND OBJECTIVES: Solid organ transplant recipients (SOTRs) are at increased risk of skin cancer and suffer from greater disease-specific morbidity and mortality. To risk stratify the expanding SOTR population for more targeted skin cancer screening, a detailed understanding of risk factors is needed. Using combined clinical and pathological data to capture prevalence of actinic keratosis (AK) and skin cancer, this study aimed to identify risk factors of skin cancer development in a Danish SOTR cohort. METHODS: The trial comprised a retrospective cohort study of patients attending organ transplant clinics at the dermatological departments of Bispebjerg and Gentofte Hospitals in Copenhagen, Denmark, between 2009 and 2021. In addition to pathology records, AK prevalence was determined by review of electronic medical records (EMRs) of SOTR visits which specifically included descriptions of clinical AK. Prevalence of skin cancer, here defined as basal cell carcinoma (BCC), squamous cell carcinoma (SCC) (invasive or in situ), or melanoma (invasive or in situ), was determined by EMR and pathology code review. Additional data extracted from EMRs included age, sex, Fitzpatrick skin type, transplantation date and type, and immunosuppressive therapy. The effect of risk factors on skin cancer was calculated by Cox proportional hazards regression. RESULTS: A total of 822 SOTRs were included with a mean follow-up duration of 10.8 years (SD 2.4 years). A skin dysplasia diagnosis was identified in 30% (n = 250) of the population, consisting of either AK (22%; n = 177), skin cancer (23%; n = 186) or both (14%; n = 113). An AK diagnosis predicted both SCC (odds ratio [OR]: 31.5 [95% CI: 9.8-100.6], p < 0.0001) and BCC development (OR: 2.3 [95% CI: 1.6-3.3], p < 0.0001), with AKs diagnosed an average 3.1 years before the first SCC (p < 0.0001). Correspondingly, while the risk of SCC in SOTRs without AK was 1.4% 25 years after transplantation, SOTRs with AKs had a 23% SCC risk only 10 years posttransplant. Other identified risk factors included Fitzpatrick skin type I (BCC: OR: 2.4 [95% CI: 1.2-5.0], p = 0.018; SCC: 3.2 [95% CI: 1.2-8.2], p = 0.016) and transplantation duration >15 years (BCC: OR: 1.8 [95% CI: 1.2-2.7], p = 0.007). No significant association between skin cancer development and sex or immunosuppressive regimen was shown. CONCLUSION: Keratinocyte carcinoma is strongly associated with an AK diagnosis in SOTRS and should prompt intensified skin cancer screening in affected individuals.

Local vasoregulative interventions impact drug concentrations in the skin after topical laser-assisted delivery.

INTRODUCTION: The ability of ablative fractional lasers (AFL) to enhance topical drug uptake is well established. After AFL delivery, however, drug clearance by local vasculature is poorly understood. Modifications in vascular clearance may enhance AFL-assisted drug concentrations and prolong drug dwell time in the skin. Aiming to assess the role and modifiability of vascular clearance after AFL-assisted delivery, this study examined the impact of vasoregulative interventions on AFL-assisted 5-fluorouracil (5-FU) concentrations in in vivo skin. METHODS: 5-FU uptake was assessed in intact and AFL-exposed skin in a live pig model. After fractional CO2 laser exposure (15 mJ/microbeam, 5% density), vasoregulative intervention using topical brimonidine cream, epinephrine solution, or pulsed dye laser (PDL) was performed in designated treatment areas, followed by a single 5% 5-FU cream application. At 0, 1, 4, 48, and 72 h, 5-FU concentrations were measured in 500 and 1500 µm skin layers by mass spectrometry (n = 6). A supplemental assessment of blood flow following AFL ± vasoregulation was performed using optical coherence tomography (OCT) in a human volunteer. RESULTS: Compared to intact skin, AFL facilitated a prompt peak in 5-FU delivery that remained elevated up to 4 hours (1500 µm: 1.5 vs. 31.8 ng/ml [1 hour, p = 0.002]; 5.3 vs. 14.5 ng/ml [4 hours, p = 0.039]). However, AFL's impact was transient, with 5-FU concentrations comparable to intact skin at later time points. Overall, vasoregulative intervention with brimonidine or PDL led to significantly higher peak 5-FU concentrations, prolonging the drug's dwell time in the skin versus AFL delivery alone. As such, brimonidine and PDL led to twofold higher 5-FU concentrations than AFL alone in both skin layers by 1 hour (e.g., 500 µm: 107 ng/ml [brimonidine]; 96.9 ng/ml [PDL], 46.6 ng/ml [AFL alone], p ≤ 0.024), and remained significantly elevated at 4 hours (p ≤ 0.024). A similar pattern was observed for epinephrine, although trends remained nonsignificant (p ≥ 0.09). Prolonged 5-FU delivery was provided by PDL, resulting in sustained drug deposition compared to AFL alone at both 48 and 72 hours in the superficial skin layer (p ≤ 0.024). Supporting drug delivery findings, OCT revealed that increases in local blood flow after AFL were mitigated in test areas also exposed to PDL, brimonidine, or epinephrine, with PDL providing the greatest, sustained reduction in flow over 48 hours. CONCLUSION: Vasoregulative intervention in conjunction with AFL-assisted delivery enhances and prolongs 5-FU deposition in in vivo skin.

Assessing Light and Energy-Based Therapy by Optical Coherence Tomography and Reflectance Confocal Microscopy: A Randomized Trial of Photoaged Skin.

BACKGROUND AND OBJECTIVES: Image-guided quantitative and semi-quantitative assessment of skin can potentially evaluate treatment efficacy. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) are ideal for this purpose. This study assessed clinically relevant statistical changes in RCM and OCT features in photoaged skin after light and energy-based therapy. METHODS: Novel statistical analyses were performed using OCT and RCM data collected during a previously published trial: a 12-week study of female décolleté skin randomized to four areas treated with thulium laser (L), photodynamic therapy (PDT), combined L-PDT, and control. Eight semi-quantitative RCM scores of photodamage and OCT measurements of skin roughness, blood flow, and epidermal thickness (ET) were evaluated and compared to dermoscopy and clinical skin scores. In statistical analysis, estimated treatment difference (ETD) was calculated. RESULTS: Twelve women with moderate to severe photodamage were included. RCM and OCT data demonstrated a trend towards rejuvenation of epidermis with increased ET, changes in skin surface, and improved honeycomb pattern in RCM. In angiographic OCT, non-significant changes towards more regular capillary meshes were shown, which matched a decline in appearance of gross telangiectasias in dermoscopy. Improved skin tone after laser and L-PDT was identified in RCM, showing less edged papillae in 36% and 45%, and lentigo number declined in 55% of patients after treatments in dermoscopy. Based on clinical scores, L-PDT provided the greatest clinical improvement, which corresponded to superior ETD outcomes in ET and edged papillae shown in OCT and RCM, respectively. CONCLUSION: Objective OCT and RCM assessment of skin rejuvenation was demonstrated in this study. Importantly, image-based improvements corresponded to favorable clinical skin scores and fewer photoaging characteristics in dermoscopy. Importantly, most changes did not reach statistical significance, prompting further studies and emphasizing the modest value of non-randomized, non-blinded anti-aging trials.

Efficacy and safety of laser-assisted combination chemotherapy: A follow-up study of treatment with 5-fluorouracil and cisplatin for basal cell carcinoma.

BACKGROUND AND OBJECTIVES: There is a growing need for effective topical treatments for basal cell carcinoma (BCC). By altering the skin barrier, ablative fractional lasers (AFLs) enhance cutaneous uptake of the synergistic chemotherapeutic agents, cisplatin, and 5-fluorouracil (5-FU). In our recently reported clinical trial, AFL-assisted delivery of cisplatin and 5-FU showed favorable short-term clearance rates of 95% with good cosmetic results at 3 months. This follow-up study assessed sustained tumor clearance, safety, and cosmesis in the same patient cohort, observed 6- and 12-months posttreatment. MATERIALS AND METHODS: This follow-up study assessed AFL-assisted cisplatin and 5-FU in low-risk BCC. Among the 18/19 patients who achieved clinical tumor clearance in our 3-months primary trial, all were included for a 6-months follow-up. At 12 months, 17/19 were included due to one 6-month residual. During follow-up visits, treated areas were evaluated for signs of recurrent tumour by clinical inspection and optical coherence tomography (OCT). Residual tumors were confirmed histologically. Cosmetic outcome was evaluated at both follow-up visits by patients and physicians. RESULTS: Overall, complete tumor clearance was 89% (17/19) and 79% (15/19) at 6 and 12 months, respectively. Clearance rate for superficial BCCs (sBCCs) 1 year after treatment was 100% (6/6) and lower for nodular BCC (nBCC) at 69% (9/13). Among recurrent tumors, 67% (2/3) had received only a single treatment and all were of the nodular subtype, situated in the head and neck area. All histologically confirmed BCC recurrences were identified by OCT. Cosmetic outcomes were similarly rated "good" or "excellent" by patients and evaluators (p = 0.289 and p = 0.250). Treatment-related local skin reactions were mild and tolerable, consisting of persisting erythema in two patients at the end of the study. Dyspigmentation was commonly observed at both follow-up visits, while the appearance of scarring resolved in the majority of patients between 6 months (56%; 10/18) and 12 months (76%; 13/17). CONCLUSION: AFL-assisted cisplatin + 5-FU in double sessions represents an acceptable and safe treatment strategy for low-risk sBCC, while clearance rates following single treatment or for nBCC seem inferior. This intensified topical strategy may be best suited to cases of multiple lesions or in instances where surgical excision or extended courses of at-home therapy is challenging.

Off-Label 9-Valent Human Papillomavirus Vaccination for Actinic Keratosis: A Case Series.

BACKGROUND: The suspected link between human papillomavirus (HPV) and the development of premalignant and malignant skin lesions remains inadequately examined in clinical settings. This case series describes HPV vaccination as an off-label adjuvant therapy for actinic keratosis (AK). METHODS: Twelve immunocompetent AK patients underwent HPV vaccination at a private dermatology clinic in Naestved, Denmark. Prior to vaccination, all patients demonstrated a high AK burden that required regular control visits. At 0, 2, and 6 months, the patients received an intramuscular injection of a commercially available 9-valent HPV vaccine. Concurrently, patients continued conventional AK therapies at 3-month intervals. Clinical response, consisting of reduction in AK number and general change in skin appearance, was assessed by a dermatologist over 12 months following first vaccination. RESULTS: All patients (mean age 76.2 years; 10 M and 2 F) completed the vaccine schedule. Overall, an average 85% reduction in total AK burden was recorded 12 months after beginning vaccination. Median AK burden thus fell from 56 (IQR: 44-80) to 13.5 (IQR: 1-18) lesions after 12 months. Lesion reduction was observable by the second inoculation at month 2 (34 AKs; IQR 22-80), continuing steadily until month 6 (15 AKs; IQR 5-30) and plateauing between 6 and 12 months. Clinically, HPV vaccination elicited fading of lesions' erythematous background after the first dose, often followed by sloughing of hyperkeratotic elements in subsequent weeks. Patients reported no adverse effects related to HPV vaccination. CONCLUSION: This case series introduces the possibility that 9-valent HPV vaccination in combination with conventional treatments may be used as a therapeutic strategy for AK.

Laser Immunotherapy: A Potential Treatment Modality for Keratinocyte Carcinoma.

The role of the immune system in cancer growth is well recognized and the development of immunotherapy represents a breakthrough in cancer treatment. Recently, the use of systemic immunotherapy was extended to keratinocyte carcinoma (KC), specifically locally advanced and metastasizing basal and squamous cell carcinoma. However, since most KC lesions are non-aggressive, systemic treatment with associated side effects is rarely justified. Conversely, topical immunotherapy with imiquimod remains restricted to premalignant and superficial lesions. Use of laser in the treatment of KC has evolved from physical tumor destruction and laser-assisted drug delivery to laser-mediated immune modulation. Evidence indicates that laser monotherapy can lead to immune cell infiltration, tumor reduction and resistance to tumor re-inoculation. Combining laser with immunotherapeutic agents, termed laser immunotherapy (LIT), may further potentiate immune activation and tumor response. Studies on LIT show not only direct anti-tumor effects but systemic adaptive immunity, illustrated by the prevention of tumor recurrence and regression in distant untreated tumors. These findings imply a therapeutic potential for both local and metastatic disease. This work provides rationales for immune-based treatment of KC and presents the current status of KC immunotherapy. Aiming to expand the field of KC immunotherapy, the review discusses the literature on immune activation following laser monotherapy and LIT.

Efficacy and Safety of Laser-Assisted Combination Chemotherapy: An Explorative Imaging-Guided Treatment With 5-Fluorouracil and Cisplatin for Basal Cell Carcinoma.

BACKGROUND AND OBJECTIVES: Rising incidences of basal cell carcinoma (BCC) have increased the need for effective topical therapies. By enhancing cutaneous uptake of the chemotherapeutic agents, cisplatin and 5-fluorouracil (5-FU), laser-assisted delivery may provide a new combination treatment for BCC. Accordingly, this study aimed to evaluate tumor response, safety, and drug biodistribution in tumors and blood after topical laser-assisted 5-FU + CIS treatment in BCC patients. STUDY DESIGN/MATERIALS AND METHODS: This open-label, proof-of-concept trial investigated laser-assisted combination cisplatin + 5-FU treatment in 20 patients with histologically verified, low-risk superficial or nodular BCCs on the face (<20 mm) or trunk/extremities (<50 mm). After tumor demarcation guided by optical coherence tomography (OCT), BCCs were exposed to ablative fractional CO2 laser followed by 60 minutes topical cisplatin solution and 7-day exposure to 5% 5-FU cream under occlusion. After 30 days, treatment was repeated if any tumor residual was identified. Tumor response at day 30 and month 3 was assessed clinically as well as by OCT, reflectance confocal microscopy, and ultrasound, supplemented by histological verification at 3 months. Local skin reactions (LSRs) and side effects were evaluated on days 1, 3-5, 14, 30, and month 3. Drug detection in tumors and blood was performed in a subset of patients 1- and 24 hours after treatment. RESULTS: Nineteen patients completed the trial, with 32% (6/19) receiving a single treatment and 68% (13/19) treated twice. At 3 months, clinical clearance was seen in 18/19 patients with a corresponding 94% (17/18) achieving histological clearance. Baseline tumor thickness and subtype did not influence treatment number or clearance rate (P ≥ 0.61). LSRs were well-tolerated and consisted of erythema, edema, and erosion, followed by crusting by day 14. Erythema declined gradually by month 3, with 94% of patients and 79% of physicians rating cosmesis as "good" or "excellent." Scarring or hyperpigmentation was noted in 50% and 56%, respectively, while pain and infection were not observed during the follow-up period. Although chemotherapy uptake was visualized extending to deep skin layers, no systemic exposure to cisplatin or 5-FU was detected in patient blood. CONCLUSION: Laser-assisted cisplatin + 5-FU shows potential as an effective and tolerable treatment option for low-risk BCC, particularly in instances where self-application is not possible or where in-office, non-surgical therapy is preferred. Lasers Surg. Med. © 2020 Wiley Periodicals LLC.

Fractional 1,927 nm Thulium Laser Plus Photodynamic Therapy Compared and Combined for Photodamaged Décolleté Skin: A Side-by-Side Randomized Controlled Trial.

BACKGROUND AND OBJECTIVES: Décolleté photodamage is a common condition typically treated with light and energy-based devices. This study investigated the efficacy and safety of a fractional 1,927 nm thulium laser (TL) alone and combined with photodynamic therapy (PDT). STUDY DESIGN/MATERIALS AND METHODS: In a 12-week follow-up study, participant décolletés were divided into four treatment areas and randomized to receive a single treatment with field-directed TL, PDT, combination TL-PDT, or lesion-directed curettage control. All actinic keratoses (AKs) underwent lesion-directed curettage before randomization. TL was delivered at 20 mJ/mb, 500 mJ/cm2 fluence, 5 W, and 8 (n = 6 pts.) or 16 (n = 6 pts.) passes. PDT was performed with 16% methyl aminolevulinate (MAL) creme incubated for 3 h, followed by red light-emitting diode light at 37 J/cm2 . Outcome measures included clinical assessment of overall photodamage and specific subcomponents, assisted by optical coherence tomography (OCT) imaging. RESULTS: Twelve women with moderate to severe photodamage on the décolleté and a cumulative total of 184 thin grade I AKs were included. Field-directed treatments TL and combination TL-PDT equally improved the overall photodamage, mottled pigmentation, and rhytides compared with lesion-directed control (P < 0.05). The skin texture improved by TL alone and was further improved by combining TL and PDT (P < 0.05). Median AK complete responses were similar for field-directed interventions TL-PDT (100%), TL (90%), PDT (82%), and lesion-directed curettage control (52%) (P = 0.464). Patients presented with mild local skin responses, slightly more pronounced when combining TL with PDT versus individual treatments (P < 0.05). No scarring or adverse events were observed. CONCLUSIONS: The 1,927 nm fractional thulium laser is an effective, tolerable, and safe field-directed treatment for décolleté photodamage. Provided alone, TL proved to be as effective as combined TL-PDT for overall photodamage, while a greater improvement in skin texture was achieved using TL and PDT in combination. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Fundamentals of fractional laser-assisted drug delivery: An in-depth guide to experimental methodology and data interpretation.

In the decade since their advent, ablative fractional lasers have emerged as powerful tools to enhance drug delivery to and through the skin. Effective and highly customizable, laser-assisted drug delivery (LADD) has led to improved therapeutic outcomes for several medical indications. However, for LADD to reach maturity as a standard treatment technique, a greater appreciation of its underlying science is needed. This work aims to provide an in-depth guide to the technology's fundamental principles, experimental methodology and unique aspects of LADD data interpretation. We show that drug's physicochemical properties including solubility, molecular weight and tissue binding behavior, are crucial determinants of how laser channel morphology influences topical delivery. Furthermore, we identify strengths and limitations of experimental models and drug detection techniques, interrogating the usefulness of in vitro data in predicting LADD in vivo. By compiling insights from over 75 studies, we ultimately devise an approach for intelligent application of LADD, supporting its implementation in the clinical setting.

Microneedle fractional radiofrequency-induced micropores evaluated by in vivo reflectance confocal microscopy, optical coherence tomography, and histology.

BACKGROUND: Microneedle fractional radiofrequency (MNRF) is a minimally invasive technique that delivers radiofrequency (RF) energy into the skin via microneedles. Reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) enable the characterization of device-tissue interactions in in vivo skin. The aim of this study is to describe MNRF-induced micropores using RCM and OCT imaging. MATERIALS AND METHODS: Five healthy participants were treated with a 7 × 7 array of 1500 µm microneedles on two adjacent areas of the right hip. One area received MNRF using high RF energy while the other underwent MNRF at low RF energy. Micropore morphology was evaluated qualitatively and quantitatively with RCM and OCT. To relate imaging with histology, one participant underwent punch biopsy in both areas. RESULTS: Reflectance confocal microscopy visualized shape, content, and thermal-induced coagulation zone (CZ) of MNRF micropores. At high RF energy, micropores showed concentric shape, contained hyperreflective granules, and coagulated tissue from epidermis to dermo-epidermal junction (diameter 63-85 µm). Micropores at low RF energy, presented with a stellate shape, no content and CZs that were visible only in epidermis (CZ thickness 9 µm, IQR 8-21 µm). Evaluating OCT, high RF energy showed deeper (150 µm), more easily identifiable micropores compared to low RF energy micropores (70 µm). Histology showed tissue coagulation to a depth of 1500 µm at high RF energy, while at low RF energy, disruption was only visible in epidermis. CONCLUSION: Microneedle fractional radiofrequency micropores show distinct characteristics in both RCM and OCT, depending on RF energy. These in vivo imaging modalities are complementary and allow combined, qualitative, and quantitative evaluation.

Laser-assisted delivery enhances topical uptake of the anticancer agent cisplatin.

Systemic chemotherapy with the anticancer agent cisplatin is approved for advanced non-melanoma skin cancer (NMSC), but topical treatment is limited by insufficient cutaneous penetration. We studied the impact of ablative fractional laser (AFL) exposure on topical cisplatin's pharmacokinetics and biodistribution in skin, using microscopic ablation zones reaching the mid- (MAZ-MD; 620 µm depth) and deep dermis (MAZ-DD; 912 µm depth) (λ = 10,600 nm, 196 MAZ/cm2). Assessed in an in vitro Franz cell model after 0.5-, 4-, 24 h topical exposure (n = 8), cisplatin delivery was greatly accelerated by AFL, shown by quantitative- and imaging-based inductively coupled plasma-mass spectrometry (ICP-MS). After 30 minutes, cisplatin concentrations were 91.5, 90.8 and 37.8 µg/cm3 in specific 100-, 500, and 1500 µm skin layers respectively, contrasting to 8.08, 3.12, 0.64 µg/cm3 in non-laser-exposed control skin (p < .001; control vs MAZ-MD). Supported by element bioimaging, the greatest relative increases occurred in the deep skin compartment and at later time points. After 24 h, cisplatin concentrations thus rose to 1829, 1732 and 773 µg/cm3, representing a 25-, 103- and 447-fold enhancement in the 100, 500, and 1500 µm deep skin layers versus corresponding controls (p < .001; MAZ-MD). A significant difference in cutaneous uptake using MAZ-MD and MAZ-DD was not shown at any time point, though deeper laser channels resulted in increased transdermal cisplatin permeation (p ≤ .015). In conclusion, AFL is a rapid, practical and existing skin treatment that may provide greatly enhanced uptake of topical cisplatin for treatment of superficial and deep skin cancer.

Laser-assisted delivery of synergistic combination chemotherapy in in vivo skin.

The effectiveness of topical drugs for treatment of non-melanoma skin cancer is greatly reduced by insufficient penetration to deep skin layers. Ablative fractional lasers (AFLs) are known to enhance topical drug uptake by generating narrow microchannels through the skin, but information on AFL-drug delivery in in vivo conditions is limited. In this study, we examined pharmacokinetics, biodistribution and toxicity of two synergistic chemotherapy agents, cisplatin and 5-fluorouracil (5-FU), following AFL-assisted delivery alone or in combination in in vivo porcine skin. Detected at 0-120 h using mass spectrometry techniques, we demonstrated that fractional CO2 laser pretreatment (196 microchannels/cm2, 852 µm ablation depth) leads to rapid drug uptake in 1500 µm deep skin layers, with a sixfold enhancement in peak cisplatin concentrations versus non-laser-treated controls (5 h, P = 0.005). Similarly, maximum 5-FU deposition was measured within an hour of AFL-delivery, and exceeded peak deposition in non-laser-exposed skin that had undergone topical drug exposure for 5 days. Overall, this accelerated and deeper cutaneous drug uptake resulted in significantly increased inflammatory and histopathological effects. Based on clinical scores and transepidermal water loss measurement, AFL intensified local toxic responses to drugs delivered alone and in combination, while systemic drug exposure remained undetectable. Quantitative histopathologic analyses correspondingly revealed significantly reduced epidermal proliferation and greater cellular apoptosis after AFL-drug delivery; particularly after combined cisplatin + 5-FU exposure. In sum, by overcoming the primary limitation of topical drug penetration and providing accelerated, enhanced and deeper delivery, AFL-assisted combination chemotherapy may represent a promising treatment strategy for non-melanoma skin cancer.

Early intervention with non-ablative fractional laser to improve cutaneous scarring-A randomized controlled trial on the impact of intervention time and fluence levels.

BACKGROUND AND OBJECTIVES: Laser treatment in the early phases of wound healing may reduce scar formation. However, little is known on when in the early wound healing phases laser exposure most optimally should be provided and at which fluence levels. This study investigates the clinical effect of non-ablative-fractional-laser (NAFL) performed at three early time points at a range of fluence levels versus untreated control scars. MATERIALS AND METHODS: A randomized, controlled, intra-individual trial with erbium-glass 1,540 nm NAFL versus no laser treatment on sixteen subjects receiving 10 standardized full-thickness punch-biopsy wounds. A single NAFL-exposure was applied to test-wounds 1 day before, immediately after, or 2 weeks after wounding. Three fluence levels provided deep and superficial energy depositions (range 30-70 mJ/microbeam). Primary outcome comprised the total-score of the observer part of Patient-Observer-Scar-Assessment-Scale (POSAS), performed by blinded on-site assessment at 3 months follow-up. Secondary outcomes were clinical evaluation on visual-analogue-scale (VAS), reflectance measurements, and histology. RESULTS: NAFL-treatment applied 1 day before, immediately after or 2 weeks after wounding had the potential to offer subtle but detectable improvement in clinical scar appearance compared to untreated controls. Thus, NAFL-exposure 1 day before wounding (POSAS-total: median of 15 vs. control-median of 16, P = 0.03, VAS: median 4.1 vs. control-median 5.5, P = 0.03, medium-fluence), as well as immediately-, and 2 weeks after wounding (POSAS-total: P ≤ 0.05, low-fluence) induced improvement compared to untreated controls. No significant differences in dyschromia were detected between NAFL-treated and control scars. Histology showed subtle changes towards more mature interwoven bundles of collagen in NAFL-treated scars as compared to controls. CONCLUSIONS: This study indicates that a single NAFL-treatment at low to medium fluence performed 1 day prior, or in the early phases of wound healing, may have the potential to optimize scar formation in full thickness wounds. Lasers Surg. Med. 50:28-36, 2018. © 2017 Wiley Periodicals, Inc.