Acne Treatment With Light Absorbing Gold Microparticles and Optical Pulses: An Open-Label European Multi-Centered Study in Moderate to Moderately Severe Acne Vulgaris Patients.

BACKGROUND AND OBJECTIVE: Recently, a novel acne treatment based on selective photothermolysis of pilosebaceous units with follicular delivery of inert gold microparticles as an exogenous chromophore and diode laser pulses has been developed. To evaluate the efficacy and safety of a single monotherapy treatment regimen with gold microparticles and diode laser exposure in patients with moderate and moderately severe acne. Further, to evaluate the added benefit of a second treatment regimen combined with pharmaceutical acne treatment in patients with inadequate initial response. MATERIALS AND METHODS: Patients with moderate and moderately severe facial acne were recruited in this open-label, pilot study. A single treatment regimen consisted of three weekly facial treatments with topically applied gold microparticles and diode laser pulses. Outcome measures were the proportion of patients with ≥40% improvement in number of acne lesions (weighted lesion count [WLC]) at 12 weeks (single treatment regimen, primary outcome measure), 24, and 36 weeks from baseline (two treatment regimens), safety, and patient satisfaction. RESULTS: A total of 28 patients were enrolled in the study (18 males, 10 females, 19 patients with moderate acne severity, 9 with moderately severe, mean age: 19.8 years). Twenty-five patients underwent analysis for outcome measures. After a single monotherapy treatment regimen, 76% patients (19/25) achieved ≥40% reduction in WLC (mean WLC reduction: 63%; SD: 13%). Of the patients undergoing two treatment regimens (n = 9 patients), 56% experienced a reduction in acne lesion burden (WLC) ≥40% at 24 weeks and 89% 36 weeks post-baseline. Mean pain score was 4.0 (SD: 1.3), and transient erythema and perifollicular edema were commonly noted after treatment. Most patients (81%) were either "satisfied" or "very satisfied" with the treatment. CONCLUSION: Acne therapy based on selective photothermolysis with gold microparticles shows promise and may be used in treatment of moderate to moderately severe acne. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

Skin reactions after photodynamic therapy are unaffected by 839 nm photobiomodulation therapy: A randomized, double-blind, placebo-controlled, clinical trial.

BACKGROUND AND OBJECTIVE: Photodynamic therapy (PDT) is associated with erythema and edema. Photobiomodulation (PBM) therapy may stimulate the skin recovery process. We investigated the potential of PBM to reduce PDT-induced skin reactions. STUDY DESIGN AND METHODS: Healthy volunteers (n = 20) were randomized to receive left- or right side PBM (near-infrared 839/595 nm) or placebo-PBM (595 nm) on their buttocks. Corresponding test areas were exposed to standardized PDT reactions, using ablative fractional laser-assisted PDT (AFXL-PDT) with methyl-aminolevulinate (MAL) incubated for 30, 90, and 180 minutes before red-light illumination. Each buttock received PBM and placebo-PBM for five consecutive days, starting one day before PDT interventions. Follow-up visits were performed 4 and 11 days after PDT. Outcome measure included blinded, observer-assessed skin reactions, substantiated by objectively measured erythema and pigment percentages and skin temperatures. RESULTS: PDT interventions induced a standardized range of erythema and edema in all subjects. Skin reactions were clinically unaffected by PBM throughout the active treatment period and at all subsequent follow-up visits (PBM vs. placebo-PBM, P = 1.000). Clinical results were supported by similar erythema intensities and skin temperatures in PBM and placebo-PBM treated skin: median erythema 28.1% versus 30.3% (AFXL-PDT with 30 minutes MAL-incubation), 36.1% versus 35.2% (90 minutes MAL-incubation) and 39.4% versus 40.9% (180 minutes MAL-incubation) (Day 4, P > 0.05). No differences in clinical hyperpigmentation or pigment percentages were observed between corresponding test areas in any subject on the final 11-day follow-up. CONCLUSION: Under the current study conditions, PDT-induced skin reactions were unaffected by PBM. Lasers Surg. Med. 49:810-818, 2017. © 2017 Wiley Periodicals, Inc.

Comparison of Physical Pretreatment Regimens to Enhance Protoporphyrin IX Uptake in Photodynamic Therapy: A Randomized Clinical Trial.

IMPORTANCE: Skin pretreatment is recommended for adequate penetration of topical photosensitizing agents and subsequent protoporphyrin IX (PPIX) accumulation in photodynamic therapy (PDT). OBJECTIVE: To compare the relative potential of different physical pretreatments to enhance PPIX fluorescence in normal skin. DESIGN, SETTING, AND PARTICIPANTS: This intraindividual, randomized clinical trial was performed from November 28 to December 20, 2014, at Bispebjerg Hospital, Copenhagen, Denmark, among 12 healthy volunteers 18 years or older. Analysis was based on intention to treat. All participants completed the study protocol. INTERVENTIONS: Participants were each exposed to standardized skin preparation with curettage, microdermabrasion with abrasive pads, microneedling with dermarollers, ablative fractional laser (AFXL), non-AFXL, and no pretreatment, followed by 3 hours of methyl aminolevulinate hydrochloride incubation and subsequent red light illumination. MAIN OUTCOMES AND MEASURES: The primary outcome measure was methyl aminolevulinate-induced PPIX fluorescence accumulation. Secondary outcome measures were PPIX photobleaching and clinical local skin reactions, supported by noninvasive reflectance measurements of percentage of skin redness, transepidermal water loss, and participant-assessed pain. RESULTS: Among the 12 healthy study participants (8 men; 4 women; mean [SD] age, 33 [15] years), histologic findings confirmed standardization of interventions with partial removal of the stratum corneum after curettage and microdermabrasion and similar vertical penetration depths for microneedling, AFXL, and non-AFXL (median, 125 µm). PPIX fluorescence reached highest intensities in skin pretreated with AFXL (median, 8661 arbitrary units [AU]) compared with microdermabrasion (median, 6731 AU), microneedling (median, 5609 AU), and curettage (median, 4765 AU) (P < .001), among which similar enhancement was shown. Comparatively lower fluorescence levels were demonstrated for skin pretreated with non-AFXL (median, 2898 AU), methyl aminolevulinate-treated controls (median, 2254 AU), and untreated controls (median, 239 AU) (P < .03). Increasing laser densities (2% vs 4% vs 6%) and the number of pretreatment passes (1, 2, and 3 passes) did not enhance PPIX fluorescence. Local skin reactions were most intensified in AFXL-pretreated skin and correlated with PPIX fluorescence and degree of PPIX photobleaching. CONCLUSIONS AND RELEVANCE: Under standardized conditions, PPIX accumulation was most enhanced after AFXL pretreatment, followed by microdermabrasion, microneedling, and curettage. Increasing the number of pretreatment passes and laser densities did not further augment PPIX accumulation. These results may indicate relatively enhanced PDT response by AFXL pretreatment in diseased skin. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02372370.

Fractional laser-assisted drug uptake: Impact of time-related topical application to achieve enhanced delivery.

BACKGROUND AND OBJECTIVE: Ablative fractional laser (AFXL) is acknowledged to increase uptake of topically applied agents in skin. AFXL channels gradually close over time, which may impair this capability. The time frame for applying a drug after AFXL exposure remains to be established. The aim of this study, was to investigate the importance of time-related topical application after AFXL exposure and to relate resultant uptake in skin with AFXL channel morphology and skin integrity. STUDY DESIGN/MATERIALS AND METHODS: Buttock skin of healthy volunteers (n = 11) was exposed to 10,600 nm fractional CO2 laser using 5% density, 120 µm beam diameter, 15 mJ pulse energy. Sodium fluorescein (NaF) a small, hydrophilic molecule (370 MW, log P = -1.52) was applied under standardized conditions at specific time points after laser exposure (0, 2, 5, 10, 30, 60, 90 minute, 6, 24, and 48 hours). Fluorescence photography collected fluorescence images up to 180 minute after NaF application. Optical coherence tomography (OCT) assessed AFXL channel dimensions and transepidermal water loss (TEWL) estimated loss of skin integrity. RESULTS: Fluorescence intensities (FI) were significantly elevated when NaF was applied up to 6 hours after laser exposure compared to non-laser-processed skin (median FI 1947 arbitrary units [interquartile range 1,246-3,560] versus 1,004 [350-1,538], P < 0.02). The highest FI occurred when NaF was applied within 30 minute after laser exposure and similar FI were reached for applications at 0, 2, 5, 10, and 30 minute after AFXL exposure (0 minute: 3,866 [3,526-4,575], 30 minute: 3,775 AU [3,070-4,484], P > 0.1). NaF application later than 30 minute after AFXL exposure resulted in gradually decreasing FI, becoming similar to intact skin when applied at 24-48 hours after AFXL exposure (P > 0.2). OCT images demonstrated that AFXL channels closed over time (100% [100-100%] open up to 30 minute, 75% [4-86%] at 6 hours and 3% [0-15%] at 24-48 hours after AFXL exposure). TEWL measurements proved loss of skin integrity up to 6 hours after AFXL exposure, while integrity was similar in laser-exposed and non-laser-exposed skin at 24-48 hours. CONCLUSIONS: The time frame to maintain enhanced drug delivery sustained for several hours after AFXL exposure, corresponding to channel morphology and loss of skin integrity. Lasers Surg. Med. 49:348-354, 2017. © 2016 Wiley Periodicals, Inc.

Repeated Treatments with Ingenol Mebutate Prevents Progression of UV-Induced Photodamage in Hairless Mice.

BACKGROUND AND AIM: Ingenol mebutate (IngMeb) is an effective treatment for actinic keratosis. In this study, we hypothesized that repeated treatments with IngMeb may prevent progression of UV-induced photodamage, and that concurrent application of a corticosteroid may reduce IngMeb-induced local skin responses (LSR). METHODS: Hairless mice (n = 60; 3 groups of 20 mice) were irradiated with solar simulated ultraviolet radiation (UVR) throughout the study. Five single treatments with IngMeb were given at 4-week intervals (Days 21, 49, 77, 105, and 133). Clobetasol propionate (CP) was applied once daily for 5 days prior to each IngMeb application, as well as 6 h and 1 day post treatment. One week after IngMeb treatment No. 1, 3, and 5 (Days 28, 84, and 140), biopsies from four mice in each group were collected for histological evaluation of UV-damage on a standardized UV-damage scale (0-12). LSR (0-24) were assessed once daily (Days 1-7) after each IngMeb treatment. RESULTS: IngMeb prevented progression of photodamage in terms of keratosis grade, epidermal hypertrophy, dysplasia, and dermal actinic damage with a lower composite UV-damage score on day 140 (UVR 10.25 vs. UVR+IngMeb 6.00, p = 0.002) compared to UVR alone. IngMeb induced LSR, including erythema, flaking, crusting, bleeding, vesiculation, and ulceration. Concurrent CP increased LSR (max LSR Tx 1-5: UVR+IngMeb+CP 3.6-5.5 vs. UVR+IngMeb 2.6-4.3) and provided better prevention of photodamage compared to IngMeb alone (Day 140: UVR+IngMeb 6.00 vs. UVR+IngMeb+CP 3.00 p < 0.001). CONCLUSION: Repeated field-directed treatments with IngMeb prevent progression of cutaneous photodamage in hairless mice, while CP cannot be used to alleviate IngMeb-induced LSR. The findings suggest that IngMeb may potentially serve as a prophylactic treatment for UV-induced tumors.

Repeated treatments with ingenol mebutate for prophylaxis of UV-induced squamous cell carcinoma in hairless mice.

BACKGROUND AND AIM: The incidence of squamous cell carcinomas (SCC) is increasing, and effective chemopreventative strategies are needed. We hypothesized that repeated treatments with ingenol mebutate (IngMeb) would postpone development of SCC in hairless mice, and that application of a corticosteroid would reduce IngMeb-induced local skin responses (LSRs) without affecting tumor postponement. METHODS: Hairless mice (n=150; 6 groups á 25 mice) were irradiated with solar simulated ultraviolet radiation (UVR) until SCC developed. During UV-irradiation and before tumor development, five single treatments (Tx) with IngMeb were given at four-week intervals (days 21, 49, 77, 105, 133). Clobetasol propionate (CP) was applied once daily for 5days prior to IngMeb, as well as 6h and 1day post treatment. Tumor formation was evaluated weekly for 52weeks. LSR (scale 0-24) were assessed at baseline, 1h, 6h, 1-, 2-, 3-, 4-, 5-, 6-, and 7days after each IngMeb treatment. RESULTS: IngMeb significantly delayed tumor development compared to UVR alone (UVR day 168 vs. UVR+IngMeb day 189; p=0.025). LSR included erythema, flaking, crusting, bleeding, vesiculation, and ulceration. The composite LSR-scores were of moderate intensity in non-UV irradiated skin (max LSR IngMeb Tx 1-5: 1.5-2.5) and more pronounced in photodamaged skin (max LSR Tx 5; IngMeb 1.5 vs. UVR+IngMeb 1.8; p<0.001). LSR intensity correlated with tumor development by means of greater composite LSR-score resulted in longer tumor-free survival (r(2)=0.257, p<0.001). Contrary to our hypothesis, concurrent CP increased LSR (max LSR Tx 1-5: UVR+CP+IngMeb 3.2-4.9 vs. UVR+IngMeb 1.3-2.2, p<0.001) and postponed tumor development compared to IngMeb alone (UVR+CP+IngMeb day 217 vs. UVR+IngMeb day 189, p<0.001). CONCLUSION: Repeated field-directed treatments with IngMeb delay development of UV-induced SCC in hairless mice, and increased IngMeb induced LSRs correlated with improved clinical outcomes. The findings highlight the potential of IngMeb as a prophylactic remedy for SCC in humans.

Skin tumor development after UV irradiation and photodynamic therapy is unaffected by short-term pretreatment with 5-fluorouracil, imiquimod and calcipotriol. An experimental hairless mouse study.

BACKGROUND: Photodynamic therapy (PDT) delays ultraviolet (UV) radiation-induced squamous cell carcinomas (SCCs) in hairless mice. Efficacy may be enhanced by combining PDT with antineoplastic or pro-differentiating agents. We investigated if pretreatment with 5-fluorouracil (5FU), imiquimod (IMIQ) or calcipotriol (CAL) before PDT further delays tumor onset. METHODS: Hairless mice (n=224) were exposed 3 times weekly to 3 standard erythema doses (SED) of UV radiation. Methyl-aminolevulinate (MAL)-PDT sessions were given on days 45 and 90 before SCC development. Three applications of topical 5FU, IMIQ or CAL were given before each PDT session. Fluorescence photography quantified protoporphyrin IX (PpIX) formation. RESULTS: PDT delayed UV-induced SCC development by 59 days (212 days UV-MAL-PDT vs. 153 days UV-control, P<0.001). Pretreatment with 5FU, IMIQ or CAL before PDT did not further delay SCC onset compared to PDT alone (207 days UV-5FU-MAL-PDT, 215 days UV-IMIQ-MAL-PDT, 206 days UV-CAL-MAL-PDT vs. 212 days UV-MAL-PDT, P=ns). PpIX fluorescence intensified by 5FU-pretreatment (median 21,392 au UV-5FU-MAL-PDT, P=0.011), decreased after IMIQ-pretreatment (12,452 au UV-IMIQ-MAL-PDT, P<0.001), and was unaffected by CAL-pretreatment (19,567 au UV-CAL-MAL-PDT, P=ns) compared to MAL alone (18,083 au UV-MAL-PDT). CONCLUSIONS: Short-term three-day pretreatment with 5FU, IMIQ and CAL before PDT does not further delay tumor onset in UV-exposed hairless mice.

[Patients with basal cell naevus syndrome should be offered an early multidisciplinary follow-up and treatment]. / Patienter med basalcellenævussyndrom bør tilbydes tidlig interdisciplinær opfølgning og behandling.

Basal cell naevus syndrome (Gorlin-Goltz syndrome) is a rare, autosomal dominantly inherited condition with a wide range of developmental and multiple organ-related anomalies. Cardinal features include multiple basal cell carcinomas, jaw cysts, palmoplantar pits and calcification of the falx cerebri. Other important clinical features are skeletal abnormalities and facial dysmorphism including macrocephaly. Germ-line mutations are found in PTCH1. Management of the syndrome requires a multidisciplinary approach, and in this article management guidelines are reviewed and discussed.

Incidence and survival in patients with cutaneous melanoma by morphology, anatomical site and TNM stage: a Danish Population-based Register Study 1989-2011.

INTRODUCTION: The incidence of melanoma of the skin has risen in Denmark in recent decades, the increase being steeper from 2004. It is unclear whether this represents a true rise in incidence or whether it is caused by an increased awareness of the condition. METHODS: To assess whether the increase was characterised by early-stage melanomas and a higher proportion of melanomas with superficial spreading morphology, we studied all skin melanoma patients registered in the Danish Cancer Register 1989-2011 (n=27,010) and followed up for death through 2013. Trends in age-standardised incidence by sex, subsite and morphology, relative survival, TNM stage distribution and stage-specific relative survival from 2004 were analysed. RESULTS: The incidence of melanoma more than doubled over 23 years. A steeper increase from 2004 was driven mainly by superficial spreading tumours, but the proportion of nodular melanomas in patients 50 years of age and over also increased significantly. The largest increase occurred for stage I tumours and for tumours on the trunk. From 1989-1993 to 2009-2011 the 5-year relative survival increased at 12% and 6% points for male and female patients, respectively. INTERPRETATION: Greater awareness, and thus lower stage at diagnosis (mediated by a large skin cancer prevention campaign from 2007), might explain part of the increase, but the increase in nodular melanoma also points to a genuine increase in the risk of melanoma.

Nocturnal continuous glucose monitoring: accuracy and reliability of hypoglycemia detection in patients with type 1 diabetes at high risk of severe hypoglycemia.

BACKGROUND: A reliable method to detect biochemical nocturnal hypoglycemia is highly needed, especially in patients with recurrent severe hypoglycemia. We evaluated reliability of nocturnal continuous glucose monitoring (CGM) in patients with type 1 diabetes at high risk of severe hypoglycemia. PATIENTS AND METHODS: Seventy-two type 1 diabetes patients with recurrent severe hypoglycemia (two or more events within the last year) participated for 4 nights in blinded CGM recordings (Guardian(®) REAL-Time CGMS and Sof-Sensor(®); Medtronic MiniMed, Northridge, CA). Blood was drawn hourly from 23:00 to 07:00 h for plasma glucose (PG) measurements (gold standard). RESULTS: Valid data were obtained in 217 nights. The sensitivity of CGM was 65% (95% confidence interval, 53-77%) below 4 mmol/L, 40% (24-56%) below 3 mmol/L, and 17% (0-47%) below 2.2 mmol/L. PG and CGM readings correlated in the total measurement range (Spearman's ρ=0.82; P<0.001). In the normo- and hyperglycemic ranges CGM underestimated PG by 1.1 mmol/L (0.9-1.2 mmol/L) (P<0.001); in contrast, in the hypoglycemic range (PG<4 mmol/L) CGM overestimated PG levels by 1.0 mmol/L (P<0.001). The mean absolute relative differences in the hypo- (≤3.9 mmol/L), normo- (4-9.9 mmol/L), and hyperglycemic (≥10 mmol/L) ranges were 45% (37-53%), 23% (22-25%), and 20% (19-21%), respectively. Continuous glucose error grid analysis indicated a clinical accuracy of 56%, 99%, and 93% in the hypo-, normo-, and hyperglycemic ranges, respectively. CONCLUSIONS: The accuracy in the hypoglycemic range of nocturnal CGM data using Sof-Sensor is suboptimal in type 1 diabetes patients at high risk of severe hypoglycemia. To ensure clinical useful sensitivity in detection of nocturnal hypoglycemic episodes, an alarm threshold should not be lower than 4 mmol/L.

The immunomodulatory effect of inhaled granulocyte-macrophage colony-stimulating factor in cystic fibrosis. A new treatment paradigm.

BACKGROUND: Patients with cystic fibrosis (CF) experience recurrent infections and develop chronically infected lungs, which initiates an altered immunological alveolar environment. End-stage pulmonary dysfunction is a result of a long sequence of complex events in CF, progressing to alveolar macrophage dysfunction via a T-helper 2 (T(H)2) dominated alveolar inflammation with CD20 T-cell activation, induced by the chronic infection and showing a poor prognosis. There is great potential for treatment in transforming the T(H)2 into the more favorable T-helper 1 (T(H)1) response. METHODS: Current literature in the PubMed database and other sources was reviewed in order to evaluate aspects of the innate alveolar host defense mechanisms and the potential impact on the immunoinflammatory response of inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients with CF. RESULTS: It seems that the cellular host defense, (ie, the alveolar macrophage and neutrocyte function) and the inhaled GM-CSF interact in such a way that the so-called tolerant alveolar environment dominated by the T(H)2 response may be transformed into an active T(H)1 state with a normal pulmonary host defense. The shift of the T(H)2 to the T(H)1 subset dominated by specific and unspecific antibodies may be achieved after the inhalation of GM-CSF. A clinical report has shown promising results with inhalation of GM-CSF in a chronically-infected CF patient treated with several antibacterial and antifungal agents. Inhaled GM-CSF transformed the tolerance toward the Gram-negative infection reflected by the so-called T(H)2 subset into the more acute T(H)1 response characterized by recruitment of the T-cells CD8 and CD16, a condition related to better-preserved lung function. This indicated a transformation from a state of passive bacterial tolerance toward the Gram-negative infecting and colonizing bacteria. This GM-CSF effect cannot be achieved by administering the drug via the IV route because the drug is water-soluble and too large to penetrate the alveolocapillary membrane. CONCLUSIONS: Inhalation of GM-CSF seems to be a novel way to positively modulate the alveolar environment toward an altered immunological state, reflected by a positive change in the pattern of surrogate markers, related to better preservation of pulmonary function and thus improved outcomes in CF patients. It is suggested that future studies examining standard endpoint variables such as number of infections and amount of antibiotics used should be supplemented by surrogate markers, to reveal any positive cellular and cytokine responses reflecting changes in the alveolar compartment after GM-CSF inhalation. The immunological alveolar environment should be monitored by a specific pattern of surrogate markers. Continued research is clearly indicated and the role of inhaled GM-CSF in modulating pulmonary host defense in CF patients should be investigated in a large study.

Acute radiation syndrome (ARS) - treatment of the reduced host defense.

BACKGROUND: The current radiation threat from the Fukushima power plant accident has prompted rethinking of the contingency plan for prophylaxis and treatment of the acute radiation syndrome (ARS). The well-documented effect of the growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte-macrophage colony-stimulating factor [GM-CSF]) in acute radiation injury has become standard treatment for ARS in the United States, based on the fact that growth factors increase number and functions of both macrophages and granulocytes. METHODS: Review of the current literature. RESULTS: The lungs have their own host defense system, based on alveolar macrophages. After radiation exposure to the lungs, resting macrophages can no longer be transformed, not even during systemic administration of growth factors because G-CSF/GM-CSF does not penetrate the alveoli. Under normal circumstances, locally-produced GM-CSF receptors transform resting macrophages into fully immunocompetent dendritic cells in the sealed-off pulmonary compartment. However, GM-CSF is not expressed in radiation injured tissue due to defervescence of the macrophages. In order to maintain the macrophage's important role in host defense after radiation exposure, it is hypothesized that it is necessary to administer the drug exogenously in order to uphold the barrier against exogenous and endogenous infections and possibly prevent the potentially lethal systemic infection, which is the main cause of death in ARS. RECOMMENDATION: Preemptive treatment should be initiated after suspected exposure of a radiation dose of at least <2 Gy by prompt dosing of 250-400 µg GM-CSF/m(2) or 5 µg/kg G-CSF administered systemically and concomitant inhalation of GM-CSF < 300 mcg per day for at least 14-21 days. CONCLUSION: The present United States standard for prevention and treatment of ARS standard intervention should consequently be modified into the combined systemic administration of growth factors and inhaled GM-CSF to ensure the sustained systemic and pulmonary host defense and thus prevent pulmonary dysfunction.