Health Economic Consequences Associated With COVID-19-Related Delay in Melanoma Diagnosis in Europe.

Importance: The COVID-19 pandemic resulted in delayed access to medical care. Restrictions to health care specialists, staff shortages, and fear of SARS-CoV-2 infection led to interruptions in routine care, such as early melanoma detection; however, premature mortality and economic burden associated with this postponement have not been studied yet. Objective: To determine the premature mortality and economic costs associated with suspended melanoma screenings during COVID-19 pandemic lockdowns by estimating the total burden of delayed melanoma diagnoses for Europe. Design, Setting, and Participants: This multicenter economic evaluation used population-based data from patients aged at least 18 years with invasive primary cutaneous melanomas stages I to IV according to the American Joint Committee on Cancer (AJCC) seventh and eighth editions, including melanomas of unknown primary (T0). Data were collected from January 2017 to December 2021 in Switzerland and from January 2019 to December 2021 in Hungary. Data were used to develop an estimation of melanoma upstaging rates in AJCC stages, which was verified with peripandemic data. Years of life lost (YLL) were calculated and were, together with cost data, used for financial estimations. The total financial burden was assessed through direct and indirect treatment costs. Models were building using data from 50 072 patients aged 18 years and older with invasive primary cutaneous melanomas stages I to IV according to the AJCC seventh and eighth edition, including melanomas of unknown primary (T0) from 2 European tertiary centers. Data from European cancer registries included patient-based direct and indirect cost data, country-level economic indicators, melanoma incidence, and population rates per country. Data were analyzed from July 2021 to September 2022. Exposure: COVID-19 lockdown-related delay of melanoma detection and consecutive public health and economic burden. As lockdown restrictions varied by country, lockdown scenario was defined as elimination of routine medical examinations and severely restricted access to follow-up examinations for at least 4 weeks. Main Outcomes and Measures: Primary outcomes were the total burden of a delay in melanoma diagnosis during COVID-19 lockdown periods, measured using the direct (in US$) and indirect (calculated as YLL plus years lost due to disability [YLD] and disability-adjusted life-years [DALYs]) costs for Europe. Secondary outcomes included estimation of upstaging rate, estimated YLD, YLL, and DALY for each European country, absolute direct and indirect treatment costs per European country, proportion of the relative direct and indirect treatment costs for the countries, and European health expenditure. Results: There were an estimated 111 464 (range, 52 454-295 051) YLL due to pandemic-associated delay in melanoma diagnosis in Europe, and estimated total additional costs were $7.65 (range, $3.60 to $20.25) billion. Indirect treatment costs were the main cost driver, accounting for 94.5% of total costs. Estimates for YLD in Europe resulted in 15 360 years for the 17% upstaging model, ranging from 7228 years (8% upstaging model) to 40 660 years (45% upstaging model). Together, YLL and YLD constitute the overall disease burden, ranging from 59 682 DALYs (8% upstaging model) to 335 711 DALYs (45% upstaging model), with 126 824 DALYs for the real-world 17% scenario. Conclusions and Relevance: This economic analysis emphasizes the importance of continuing secondary skin cancer prevention measures during pandemics. Beyond the personal outcomes of a delayed melanoma diagnosis, the additional economic and public health consequences are underscored, emphasizing the need to include indirect economic costs in future decision-making processes. These estimates on DALYs and the associated financial losses complement previous studies highlighting the cost-effectiveness of screening for melanoma.

Novel 40 µm spot size 3050/3200 nm DFG laser versus CO2 laser for laser-assisted drug delivery.

BACKGROUND AND OBJECTIVES: The use of ablative fractional lasers to enhance the delivery of topical drugs through the skin is known as laser-assisted drug delivery. Here, we compare a novel 3050/3200 nm difference frequency generation (DFG) fiber laser (spot size: 40 µm) to a commercially used CO2 laser (spot size: 120 µm). The objective is to determine whether differences in spot size and coagulation zone (CZ) thickness influence drug uptake. MATERIALS AND METHODS: Fractional ablation was performed on ex-vivo human abdominal skin with the DFG (5 mJ) and CO2 (12 mJ) lasers to generate 680 µm deep lesions. To evaluate drug delivery, 30 kDa encapsulated fluorescent dye was topically applied to the skin and histologically analyzed at skin depths of 100, 140, 200, 400, and 600 µm. Additionally, transcutaneous permeation of encapsulated and 350 Da nonencapsulated dye was assessed using Franz Cells. RESULTS: The DFG laser generated smaller channels (diameter: 56.5 µm) with thinner CZs (thickness: 22.4 µm) than the CO2 laser (diameter: 75.9 µm, thickness: 66.8 µm). The DFG laser treated group exhibited significantly higher encapsulated dye total fluorescence intensities after 3 h compared to the CO2 laser treated group across all skin depths (p < 0.001). Permeation of nonencapsulated dye was also higher in the DFG laser treated group vs the CO2 laser treated group after 48 h (p < 0.0001), while encapsulated dye was not detected in any group. CONCLUSION: The DFG laser treated skin exhibited significantly higher total fluorescence uptake compared to the CO2 laser. Additionally, the smaller spot size and thinner CZ of the DFG laser could result in faster wound healing and reduced adverse effects while delivering similar or greater amount of topically applied drugs.

Possible Explanations for Rising Melanoma Rates Despite Increased Sunscreen Use over the Past Several Decades.

The incidence of cutaneous melanoma continues to rise despite the increased use of sunscreens within the last several decades. Some research even suggests that the use of sunscreen is associated with increased rates of melanoma. Given the aggressive, and often deadly, nature of cutaneous melanoma, the aim of this communication is to better elucidate the relationship between sunscreen use and melanoma development and if there are other preventative measures to be aware of. A search was performed to identify the studies that have investigated melanoma development in individuals who used sunscreen and those who did not. Study limitations and possible confounding variables were identified, which guided a subsequent search to determine what data were available to support that these limitations and confounding variables may explain the perplexing association between sunscreen use and melanoma development. Five hypotheses were generated, which were related to increased awareness and reporting, the relationship between sunscreen use and the duration of sun exposure, the importance of broad-spectrum protection, and the effect of sunscreen on reactive oxygen species formation. The main conclusion is that more recent studies that control for confounding variables are required to determine the true effect of adequate broad-spectrum sunscreen use today on the development of melanoma.

Novel assessment of lip redness and microcirculation using optical coherence tomography after dermal filler injection.

OBJECTIVES: Lip filler injections are one of the most popular procedures in esthetic dermatology. In this study, we used three-dimensional colorimetric photography to assess lip color and optical coherence tomography-angiography (OCT-A), a noninvasive alternative to histopathology, to evaluate microcirculation after hyaluronic acid (HA) injection. The pain of the injection procedure was also assessed. METHODS: An average of 0.85cc of the total volume of HA with lidocaine was injected into the upper and lower lip of eighteen young (<30yo) and nine postmenopausal healthy women. OCT-A, two-dimensional, and three-dimensional images were acquired immediately before (visit 1) and 15 days after injection (visit 2). Custom-made software was used to analyze the imaging data to detect vessel morphology and redness changes. The Wong-Baker FACES pain rating scale (0-10) was used to score the subject procedural pain. RESULTS: For young and old subjects, three-dimensional lip volume was greater than the injected volume. OCT-A images of the lips showed higher vessel density and thickness, reaching statistical significance in the younger cohort. The overall trend of increased redness assessed by three-dimensional colorimetric imaging and increased vascularity evaluated by OCT-A imaging were similar. However, the correlation was not statistically significant for standard two-dimensional digital photography. The average pain score after the first needle insertion and overall procedure were 2.9 and 3.5, respectively. CONCLUSIONS: The results suggest an increased microvasculature network observed in OCT-A images in young females. The increased blood vessel density and thickness observed by OCT-A after HA lip filler injection is associated with increased lip redness and volume as assessed by colorimetric three-dimensional photography; however, more research is needed to confirm these findings. This study presents OCT-A as a novel noninvasive tool to investigate changes in lip microvascularity after HA filler injection and indicates that HA filler procedures may affect lip vascularity.

Mouse model of selective cryolipolysis.

BACKGROUND: Cryolipolysis is a noninvasive method of destroying adipocytes using controlled cooling, thereby enabling localized and targeted fat reduction. Due to their greater vulnerability to cold injury, adipocytes are selectively targeted, while other cell types are spared. OBJECTIVES: This study aims to develop a mouse model of cryolipolysis to offer a reliable and convenient alternative to human models, providing a methodology to validate clinical hypotheses in-depth with relative ease, low cost, and efficiency. This further facilitates comprehensive studies of the molecular mechanisms involved in cryolipolysis. MATERIALS AND METHODS: Mice (C57BL/6J) were placed under general anesthesia and were treated using our custom, miniaturized cryolipolysis system. A thermoelectric cooling probe was applied to the inguinal (ING) area for either a cold exposure of -10°C, or for a room temperature exposure for 10 minutes. The thickness of the subcutaneous fat of the mice was quantified using an optical coherence tomography (OCT) imaging system before and after the treatment. Histological analyses were performed before and after cryolipolysis at multiple time points. RESULTS: OCT analysis showed that mice that underwent cold cryolipolysis treatment induced a significantly greater reduction of subcutaneous fat thickness 1 month after treatment than the control mice. The mice that received cold treatment had no skin injuries. The selective damage of adipocytes stimulated cold panniculitis that was characterized histologically by infiltration of immune cells 2 and 3 days after treatment. CONCLUSION: This study shows that cryolipolysis performed in mice yields reproducible and measurable subcutaneous fat reduction, consistent with previous studies conducted in humans and pigs. Future studies can utilize the model of selective cryolipolysis developed by our group to further elucidate the cellular and molecular mechanisms of fat cell loss and improve clinical outcomes in humans.

Assessment of a 3050/3200 nm fiber laser system for ablative fractional laser treatments in dermatology.

BACKGROUND AND OBJECTIVES: Mid-infrared (IR) ablative fractional laser treatments are highly efficacious for improving the appearance of a variety of dermatological conditions such as photo-aged skin. However, articulated arms are necessary to transmit the mid-IR light to the skin, which restricts practicality and clinical use. Here, we have assessed and characterized a novel fiber laser-pumped difference frequency generation (DFG) system that generates ablative fractional lesions and compared it to clinically and commercially available thulium fiber, Erbium:YAG (Er:YAG), and CO2 lasers. MATERIALS AND METHODS: An investigational 20 W, 3050/3200 nm fiber laser pumped DFG system with a focused spot size of 91 µm was used to generate microscopic ablation arrays in ex vivo human skin. Several pulse energies (10-70 mJ) and pulse durations (2-14 ms) were applied and lesion dimensions were assessed histologically using nitro-blue tetrazolium chloride stain. Ablation depths and coagulative thermal damage zones were analyzed across three additional laser systems. RESULTS: The investigational DFG system-generated deep (>2 mm depth) and narrow (<100 µm diameter) ablative lesions surrounded by thermal coagulative zones of at least 20 µm thickness compared to 13, 40, and 320 µm by the Er:YAG, CO2 , and Thulium laser, respectively. CONCLUSION: The DFG system is a small footprint device that offers a flexible fiber delivery system for ablative fractional laser treatments, thereby overcoming the requirement of an articulated arm in current commercially available ablative lasers. The depth and width of the ablated microcolumns and the extent of surrounding coagulation can be controlled; this concept can be used to design new treatment procedures for specific indications. Clinical improvements and safety are not the subject of this study and need to be explored with in vivo clinical studies.

First Assessment of a Carbon Monoxide Laser and a Thulium Fiber Laser for Fractional Ablation of Skin.

BACKGROUND AND OBJECTIVES: A recent generation of 5,500 nm wavelength carbon monoxide (CO) lasers could serve as a novel tool for applications in medicine and surgery. At this wavelength, the optical penetration depth is about three times higher than that of the 10,600 nm wavelength carbon dioxide (CO2 ) laser. As the amount of ablation and coagulation is strongly influenced by the wavelength, we anticipated that CO lasers would provide extended coagulation zones, which could be beneficial for several medical applications, such as tissue tightening effects after laser skin resurfacing. Until now, the 1,940 nm wavelength thulium fiber (Tm:fiber) laser is primarily known as a non-ablative laser with an optical penetration depth that is eight times higher than that of the CO2 laser. The advantage of lasers with shorter wavelengths is the ability to create smaller spot sizes, which has a determining influence on the ablation outcome. In this study, the ablation and coagulation characteristics of a novel CO laser and a high power Tm:fiber laser were investigated to evaluate their potential application for fractional ablation of the skin. STUDY DESIGN/MATERIALS AND METHODS: Laser-tissue exposures were performed using a novel CO laser, a modified, pulse-width-modulated CO2 laser, and a Tm:fiber laser. We used discarded ex vivo human skin obtained from abdominoplasty as tissue samples. Similar exposure parameters, such as spot size (108-120 µm), pulse duration (2 milliseconds), and pulse energy (~10-200 mJ) were adjusted for the different laser systems with comparable temporal pulse structures. Laser effects were quantified by histology. RESULTS: At radiant exposures 10-fold higher than the ablation threshold, the CO laser ablation depth was almost two times deeper than that of the CO2 laser. At 40-fold of the ablation threshold, the CO laser ablation was 47% deeper. The ablation craters produced by the CO laser exhibited about two times larger coagulation zones when compared with the CO2 laser. In contrast, the Tm:fiber laser exhibited superficial ablation craters with massive thermal damage. CONCLUSIONS: The tissue ablation using the Tm:fiber laser was very superficial in contrast to the CO laser and the CO2 laser. However, higher etch depths should be obtainable when the radiant exposure is increased by using higher pulse energies and/or smaller spot sizes. At radiant exposures normalized to the ablation threshold, the CO laser was capable of generating deeper ablation craters with extended coagulation zones compared with the CO2 laser, which is possibly desirable depending on the clinical goal. The effect of deep ablation combined with additional thermal damage on dermal remodeling needs to be further confirmed with in vivo studies. Lasers Surg. Med. © 2020 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc.

Assessment of skin lesions produced by focused, tunable, mid-infrared chalcogenide laser radiation.

BACKGROUND: Traditionally, fractional laser treatments are performed with focused laser sources operating at a fixed wavelength. Using a tunable laser in the mid-infrared wavelength range, wavelength-dependent absorption properties on the ablation process and thermal damage formation were assessed with the goal to obtain customizable tissue ablations to provide guidance in finding optimized laser exposure parameters for clinical applications. METHODS: Laser tissue experiments were carried out on full thickness ex vivo human abdominal skin using a mid-infrared tunable chromium-doped zinc selenide/sulfide chalcogenide laser. The laser has two independent channels: a continuous wave (CW) output channel which covers a spectrum ranging from 2.4 µm to 3.0 µm with up to 9.2 W output power, and a pulsed output channel which ranges from 2.35 µm to 2.95 µm. The maximum pulse energy of the pulsed channel goes up to 2.8 mJ at 100 Hz to 1,000 Hz repetition rate with wavelength-dependent pulse durations of 4-7 ns. RESULTS: Total ablation depth, ablation efficiency, and coagulation zone thickness were highly correlated to wavelength, pulse width, and pulse energy. Using the same total radiant exposure at 2.85 µm wavelength resulted in 10-times smaller coagulation zones and 5-times deeper ablation craters for one hundred 6 ns pulses compared to one 100 ms pulse. For a fixed pulse duration of 6 ns and a total radiant exposure of 2.25 kJ/cm2 the ablation depth increased with longer wavelengths. CONCLUSION: The tunable laser system provides a useful research tool to investigate specific laser parameters such as wavelength on lesion shape, ablation depth and thermal tissue damage. It also allows for customization of the characteristics of laser lesions and therefore facilitates the selection of suitable laser parameters for optimized fractional laser treatments. Lasers Surg. Med. 50:961-972, 2018.© 2018 Wiley Periodicals, Inc.

Rapid fibrin plug formation within cutaneous ablative fractional CO2 laser lesions.

BACKGROUND: Ablative fractional laser procedures have been shown to facilitate topical drug delivery into the skin. Past studies have mainly used ex vivo models to demonstrate enhanced drug delivery and in vivo studies have investigated laser created channels over a time course of days and weeks rather than within the first few minutes and hours after exposures. We have noticed rapid in vivo fibrin plug formation within ablative fractional laser lesions impairing passage through the laser created channels. MATERIAL AND METHODS: In vivo laser exposures were performed in a porcine model. A fractional CO2 laser (AcuPulse™ system, AcuScan 120™ handpiece, Lumenis, Inc., Yokneam, Israel) was programmed in quasi-continuous wave (QCW) mode, at 40W, 50 mJ per pulse, 5% coverage, nominal 120 µm spot size, 8 × 8 mm square pattern, 169 MTZs per scan. Six millimeters punch biopsies were procured at 0, 2, 5, 10, 15, 30, 60, 90 minutes after completion of each scan, then fixed in 10% formalin. 12 repeats were performed of each time point. Skin samples were processed for serial vertically cut paraffin sections (5 µm collected every 25 µm) then H&E and special immunohistochemistry staining for fibrin and platelet. Dimensions of Microscopic Treatment Zones (MTZs) and extent of fibrin plug were assessed and quantified histologically. Ex vivo laser exposures of the identical laser parameter were performed on porcine and human skin at different storage conditions. RESULTS: Histology procured at various predetermined time intervals after in vivo fractional CO2 laser exposures revealed a rapidly forming fibrin plug initiating at the bottom of the MTZ lesions. At longer time intervals, the fibrin plug was extending towards the superficial sections. Within the first 5 minutes, more than 25% length of the entire laser-ablated channel was filled with a fibrin plug. With increased time intervals, the cavity was progressively filled with a fibrin plug. At 90 minutes, more than 90% length of the entire laser-ablated channel was occluded. Ex vivo exposures failed to produce any significant fibrin plug formation. CONCLUSIONS: The current study has demonstrated rapid fibrin plug formation after ablative fractional laser procedures. It was shown that the passage through laser created pathways is critically time dependent for in vivo exposures. In contrast, ex vivo exposures do not exhibit such time dependent passage capacity. In particular, drug, substance, and cell delivery studies for ablative fractional laser treatments should take early fibrin plug formation into consideration and further investigate the impact on transdermal delivery.