Phototesting in erythropoietic protoporphyria trials: A systematic review.

Severe skin pain when exposed to long wave ultraviolet radiation or visible light is the main symptom of erythropoietic protoporphyria (EPP). Treatment options for EPP are inadequate and new treatments are needed but hampered by the lack of valid efficacy outcomes. Phototesting with well-defined illumination of the skin can be performed reliably. We aimed to provide an overview of phototest procedures used to evaluate EPP treatments. Systematic searches of Embase, MEDLINE and the Cochrane Library were performed. Searches identified 11 studies using photosensitivity as efficacy outcome. The studies used eight different phototest protocols. Illuminations were performed with a filtered high-pressure mercury arc, or a xenon arc lamp equipped with monochromator or filters. Some used broadband, others narrowband illumination. In all protocols phototests were performed on the hands or the back. Endpoints were minimal dose required to induce either first symptom of discomfort, erythema, urticaria or intolerable pain. Other endpoints were change in erythema intensity or diameter of any type of flare after exposure compared to before. In conclusion, protocols displayed extensive variability in illumination set-up and evaluation of phototest reactions. Implementation of a standardized phototest method will allow more consistent and reliable outcome evaluation in future therapeutic research of protoporphyric photosensitivity.

RNA analysis of tape strips to rule out melanoma in lesions clinically assessed as cutaneous malignant melanoma: A diagnostic study.

BACKGROUND: Distinguishing cutaneous malignant melanoma (CMM) from nevi can be clinically challenging. Suspicious lesions are therefore excised, resulting in many benign lesions being removed surgically to find 1 CMM. It has been proposed to use tape strip derived ribonucleic acid (RNA) to distinguish CMM from nevi. OBJECTIVE: To develop this technique further and validate if RNA profiles can rule out CMM in clinically suspicious lesions with 100% sensitivity. METHODS: Before surgical excision, 200 lesions clinically assessed as CMM were tape stripped. Expression levels of 11 genes on the tapes were investigated by RNA measurement and used in a rule-out test. RESULTS: Histopathology showed that 73 CMMs and 127 non-CMMs were included. Our test correctly identified all CMMs (100% sensitivity) based on the expression levels of 2 oncogenes, PRAME and KIT, relative to a housekeeping gene. Patient age and sample storage time were also significant. Simultaneously, our test correctly excluded CMM in 32% of non-CMM lesions (32% specificity). LIMITATIONS: Our sample contained a very high proportion of CMMs, perhaps due to inclusion during COVID-19 shutdown. Validation in a separate trial must be performed. CONCLUSION: Our results demonstrate that the technique can reduce removal of benign lesions by one-third without overlooking any CMMs.

Detection of cutaneous malignant melanoma by tape stripping of pigmented skin lesions - A systematic review.

BACKGROUND: Cutaneous malignant melanoma (MM) is potentially aggressive, and numerous clinically suspicious pigmented skin lesions are excised, causing unnecessary mutilation for patients at high healthcare costs, but without histopathological evidence of MM. The high number of excisions may be lowered by using more accurate diagnostics. Tape stripping (TS) of clinically suspicious lesions is a non-invasive diagnostic test of MM that can potentially lower the number needed to biopsy/excise. MATERIALS AND METHODS: The aim is to determine the diagnostic accuracy of TS in detecting MM in clinically suspicious pigmented skin lesions. This systematic review following PRISMA guidelines searched PubMed, Web of Science, and Embase (September 2022) using melanoma combined with tape stripping, adhesive patch(es), pigmented lesion assay, or epidermal genetic information retrieval. RESULTS: Ten studies were included. Sensitivity ranged from 68.8% (95% confidence interval [CI] 51.5, 82.1) to 100% (95% CI 91.0, 100). Specificity ranged from 69.1% (95% CI 63.8, 74.0) to 100% (95% CI 78.5, 100). A pooled analysis of five studies testing the RNA markers LINC00518 and PRAME found a sensitivity of 86.9% (95% CI 81.7, 90.8) and a specificity of 82.4% (95% CI 80.8, 83.9). CONCLUSION: Overall quality of studies was low, and the reliability of sensitivity and specificity is questionable. However, TS may supplement well-established diagnostic methods as pooled analysis of five studies indicates a moderate sensitivity. Future studies are needed to obtain more reliable data as independent studies with no conflict of interest.

A Handful of Sunscreen for Whole-Body Application.

BACKGROUND: The rule of thumb "Fill up a handful of sunscreen and spread it all over your body" has been used in several sun safety campaigns. The intention was to increase the applied sunscreen to obtain a quantity of 2 mg/cm2 to all accessible skin. The present study is the first to investigate how this advice works in practice, evaluated by quantity of sunscreen applied and amount of covered skin. METHODS: Seventeen volunteers wearing swimwear were asked to "Fill up a handful and spread it all over your body." Before and after sunscreen application, the volunteers were photographed in black light. As sunscreen absorbs black light, the darkness of the skin increases with increasing amounts of applied sunscreen, making it possible to identify skin left without coverage. The sunscreen container was weighed before and after to quantify the amount of sunscreen applied. RESULTS: A median of 21% of the accessible skin was left completely without coverage. The 79% covered area was covered with a median of 1.12 mg/cm2, not the expected 2 mg/cm2. CONCLUSION: In practice, the advice "Fill up a handful of sunscreen and spread it all over your body" led to a better but still modest protection, compared to the intended effect.

Mortality Among Users of Anabolic Steroids.

This cohort study investigates mortality and cause of death among a large cohort of androgenic anabolic steroid users, compared with a control group, in Denmark from January 3, 2006, to March 1, 2018.

Photoprotection by sunscreen depends on time spent on application.

BACKGROUND: To be effective, sunscreens must be applied in a sufficient quantity and reapplication is recommended. No previous study has investigated whether time spent on sunscreen application is important for the achieved photoprotection. AIM: To determine whether time spent on sunscreen application is related to the amount of sunscreen used during a first and second application. METHODS: Thirty-one volunteers wearing swimwear applied sunscreen twice in a laboratory environment. Time spent and the amount of sunscreen used during each application was measured. Subjects' body surface area accessible for sunscreen application (BSA) was estimated from their height, weight and swimwear worn. The average applied quantity of sunscreen after each application was calculated. RESULTS: Subjects spent on average 4 minutes and 15 seconds on the first application and approximately 85% of that time on the second application. There was a linear relationship between time spent on application and amount of sunscreen used during both the first and the second application (P < .0001). Participants applied 2.21 grams of sunscreen per minute during both applications. After the first application, subjects had applied a mean quantity of sunscreen of 0.71 mg/cm2 on the BSA, and after the second application, a mean total quantity of 1.27 mg/cm2 had been applied. CONCLUSION: We found that participants applied a constant amount of sunscreen per minute during both a first and a second application. Measurement of time spent on application of sunscreen on different body sites may be useful in investigating the distribution of sunscreen in real-life settings.

Red tattoos, ultraviolet radiation and skin cancer in mice.

Ultraviolet radiation (UVR) induces skin cancer. The combination of UVR and red tattoos may be associated with increased risk of skin cancer due to potential carcinogens in tattoo inks. This combination has not been studied previously. Immunocompetent C3.Cg/TifBomTac hairless mice (n=99) were tattooed on their back with a popular red tattoo ink. This often used ink is banned for use on humans because of high content of the potential carcinogen 2-anisidine. Half of the mice were irradiated with three standard erythema doses UVR thrice weekly. Time to induction of first, second and third squamous cell carcinoma (SCC) was measured. All UV-irradiated mice developed SCCs. The time to the onset of the first and second tumor was identical in the red-tattooed group compared with the control group (182 vs 186 days and 196 vs 203 days, P=ns). Statistically, the third tumor appeared slightly faster in the red-tattooed group than in the controls (214 vs 224 days, P=.043). For the second and third tumor, the growth rate was faster in the red-tattooed group compared with the control (31 vs 49 days, P=.009 and 30 vs 38 days, P=.036). In conclusion, no spontaneous cancers were observed in skin tattooed with a red ink containing 2-anisidine. However, red tattoos exposed to UVR showed faster tumor onset regarding the third tumor, and faster growth rate of the second and third tumor indicating red ink acts as a cocarcinogen with UVR. The cocarcinogenic effect was weak and may not be clinically relevant.

Long-term Trend in Sunscreen Use among Beachgoers in Denmark.

This observational study examined the trend from the 1990s to 2016 of sunscreen use, sun protection factor (SPF) and quantity of sunscreen applied amongst beachgoers in Denmark. In 1997, 1998, 1999 and 2016, a total of 1,306 beachgoers were asked if they had used sunscreen on that day and, if so, which SPF. In 1992 and 2016 another 143 beachgoers had their sunscreen bottles weighed before and after application. The frequency of sunscreen use among women increased from 45% in 1997 to 78% in 2016, while the frequency of use among men increased from 39% to 49%. For both sexes the median SPF increased, on average, by one unit per year, from SPF 5 in 1997 to SPF 20 in 2016. The quantity of sunscreen applied increased from 0.48 mg/cm2 in 1992 to 0.57 mg/cm2 in 2016. Thus, the frequency of sunscreen use, the SPF, and the quantity of sunscreen applied have increased in the recent decades.

Alternatives to Outdoor Daylight Illumination for Photodynamic Therapy--Use of Greenhouses and Artificial Light Sources.

Daylight-mediated photodynamic therapy (daylight PDT) is a simple and pain free treatment of actinic keratoses. Weather conditions may not always allow daylight PDT outdoors. We compared the spectrum of five different lamp candidates for indoor "daylight PDT" and investigated their ability to photobleach protoporphyrin IX (PpIX). Furthermore, we measured the amount of PpIX activating daylight available in a glass greenhouse, which can be an alternative when it is uncomfortable for patients to be outdoors. The lamps investigated were: halogen lamps (overhead and slide projector), white light-emitting diode (LED) lamp, red LED panel and lamps used for conventional PDT. Four of the five light sources were able to photobleach PpIX completely. For halogen light and the red LED lamp, 5000 lux could photobleach PpIX whereas 12,000 lux were needed for the white LED lamp. Furthermore, the greenhouse was suitable for daylight PDT since the effect of solar light is lowered only by 25%. In conclusion, we found four of the five light sources and the greenhouse usable for indoor daylight PDT. The greenhouse is beneficial when the weather outside is rainy or windy. Only insignificant ultraviolet B radiation (UVB) radiation passes through the greenhouse glass, so sun protection is not needed.

Effects of iron supplements in individuals with erythropoietic protoporphyria.

BACKGROUND: Protoporphyrin IX (PPIX) is the final precursor of heme, forming heme when iron is inserted. Individuals with erythropoietic protoporphyrias (EPP) have accumulation of PPIX, causing photosensitivity and increased liver disease risk. Many also have iron deficiency and anemia. We investigated outcomes of oral iron supplements in individuals with EPP. METHODS: A systematic review identified literature on oral iron supplements in EPP patients. Subsequently, we administered iron supplements to EPP patients with iron deficiency. The primary outcome was impact on PPIX level. Secondary outcomes were adverse events and relative differences in hemoglobin and iron parameters. RESULTS: The systematic review found 13 case reports and one uncontrolled clinical trial with uncertain results. From our department 10 patients with EPP and iron deficiency took daily dosages of 330 mg of ferrous fumarate for two months. Five of our patients had anemia at baseline. After 2 months of supplementation seven patients had increased PPIX level compared to baseline, two had decrease, one remained unchanged. The administration of iron led to a rise in ferritin, and in four of the anemic patients also to an improvement in blood hemoglobin. A small transiently elevation in plasma alanine transaminase concentration was observed during supplementation. CONCLUSIONS: Overall, iron supplementation in EPP patients replenished iron stores and elevated erythrocyte PPIX and plasma alanine transaminase. For anemic patients, there was some degree of normalization of the hemoglobin level. If iron therapy is needed for EPP patients, monitoring of photosensitivity, PPIX, hemoglobin, and plasma liver enzymes is advisable.

Extensive androgen exposure and meningioma risk - A matched cohort study.

INTRODUCTION: Meningiomas frequently occur within the field of neuro-oncology, but it is unclear whether exogenous or imbalanced endogenous hormones are involved in the pathophysiology. A previous case-control study found an almost 20-fold increase in the risk of developing meningioma among users of androgenic anabolic steroids. We, therefore, investigated this hypothesis. METHODS: We compared the incidence rate of meningioma in a cohort of males sanctioned for the use of androgenic anabolic steroids with age- and sex-matched controls with an identical enrollment date. RESULTS: We followed 1189 males sanctioned for using androgenic anabolic steroids for a total of 13,305 person-years and found 0 cases of meningioma. The control cohort of 59,450 males was followed for a total of 654,938 person-years, and 16 were diagnosed with meningioma. Thus, the incidence rate ratio was 0 (95% CI: 0-12.8). CONCLUSION: We did not find any evidence supporting the hypothesis of an increased risk of meningioma development with the use of androgenic anabolic steroids. Due to the limited sample size, we cannot exclude androgenic anabolic steroids as a potential risk factor for meningioma development, despite the lack of apparent evidence in this study.

Reevaluating the role of interferon-beta in psoriasis pathogenesis: A registry-based self-controlled study.

Interferon-beta has been suggested as a trigger of psoriasis, yet a systematic investigation is lacking. This study aimed to assess the risk of developing psoriasis following interferon-beta treatment, utilizing a pharmaco-epidemiological approach to investigate the role of interferon-beta in psoriasis pathogenesis. We included all treatment-naïve patients with multiple sclerosis (MS) in Denmark who initiated interferon-beta treatment for MS from January 1996 to June 2023. These patients were compared to a control cohort of patients with MS treated with other disease-modifying drugs. We compared the incidence rates of psoriasis before and during the treatment. Data for this study were extracted from the Danish MS Registry and integrated with information from other national Danish health registries. Among 7174 patients treated with interferon-beta, the incidence rate of psoriasis post-treatment initiation was slightly higher (2.01 per 1000 person-years) compared to the rate prior to treatment (1.67 per 1000 person-years). This increase did not achieve statistical significance (P = 0.53), with an incidence rate ratio (IRR) of 1.20 (95% confidence interval [CI] 0.68-2.13). The control cohort showed an increase in psoriasis incidence post-treatment initiation (3.12 per 1000 person-years) compared to prior (1.11 per 1000 person-years), with an IRR of 2.80 (95% CI 1.36-4.77, P = 0.0038). This registry-based self-controlled study does not support the theory that interferon-beta acts as a trigger for psoriasis development.

Excessive androgen exposure and risk of malignancies: A cohort study.

BACKGROUND: A link between androgen use and the risk of cancers, especially prostate and breast cancer, has been suggested. The knowledge about a possible association is limited. OBJECTIVE: The study aimed to investigate cancer incidence rates, particularly those related to prostate and breast cancer, in male androgen users and compare them to a control group. METHODS: We included male androgen users identified through a nationwide anti-doping testing program in Danish fitness centers from 2006 to 2018. We paired each case with 50 male controls of the same age, selected randomly. The cohort was followed from baseline and until 2023. The outcome was the incidence of prostate cancer, breast cancer, or any cancer excluding non-melanoma skin cancer. RESULTS: The study included 1,189 androgen users and 59,450 controls, with a mean age of 27 years at enrolment. During the follow-up period with a mean length of 11 years, 13 androgen users, and 612 controls were diagnosed with cancer. This resulted in an incidence rate ratio of 1.05 (95% CI: 0.55-1.81). None of the androgen users were diagnosed with prostate or breast cancer. DISCUSSION AND CONCLUSION: Male androgen users did not face an increased short-term risk of cancer, neither overall nor related to prostate or breast cancer. Our study indicates that the absolute risk of malignancies in androgen users is comparable to that in the background population. However, we cannot exclude androgens as a cancer risk factor due to the limited sample size, relatively short follow-up period, and subject age.

Experimental and approved treatments for skin photosensitivity in individuals with erythropoietic protoporphyria or X-linked protoporphyria: A systematic review.

Erythropoietic protoporphyria (EPP) and X-linked protoporphyria (XLP) are characterized by skin photosensitivity caused by accumulation of protoporphyrin IX. We aimed to review the clinical evidence of efficacy and safety of skin photosensitivity treatments in individuals with EPP or XLP. We systematically searched MEDLINE, Embase, the Cochrane Library, and ClinicalTrials.gov. A total of 40 studies with data on 18 treatment modalities were included. Comprehensive treatment safety data were obtained from the European Medicines Agency and the United States Food and Drug Administration. The studies used different outcome measures to evaluate the sensitivity without a generally accepted method to assess treatment effect on skin photosensitivity. Of the included studies, 13 were controlled trials. Gathered, the trials showed moderate positive effect of inorganic sunscreen application and subcutaneous implant of afamelanotide and no effect of organic sunscreen application, or oral treatment with beta-carotene, cysteine, N-acetylcysteine, vitamin C, or warfarin. Studies without control groups suggested treatment effect of foundation cream, dihydroxyacetone/lawsone cream, narrow-band ultraviolet B phototherapy, erythrocyte transfusion, extracorporeal erythrocyte photodynamic therapy, or oral treatment with zinc sulphate, terfenadine, cimetidine, or canthaxanthin, but the real effect is uncertain. Assessment of treatment effect on photosensitivity in patients with EPP or XLP carries a high risk of bias since experienced photosensitivity varies with both weather conditions, exposure pattern, and pigmentation. Controlled trials of promising treatment options are important although challenging in this small patient population.

Protection against visible light by dihydroxyacetone in erythropoietic protoporphyria.

BACKGROUND: Patients with erythropoietic protoporphyria (EPP) are hypersensitive to long wave ultraviolet (UVA) radiation and visible light and they experience severe skin pain by light exposure. The patients have very limited treatment options. Sunless skin tanning with dihydroxyacetone (DHA) is now being investigated as a possible treatment modality of skin photosensitivity in EPP. METHODS: We simulated the theoretical light protection factor provided by DHA application. In addition, we present 19 cases with EPP who were treated at our department with DHA weekly during spring and summer from 2018 to 2021 inclusive. RESULTS: The protection factor against UVA and visible light was estimated to approximately two. Out of the 19 patients with EPP who were treated with DHA in 2018, 11 patients experienced a sustained good effect and continued to use the treatment on a weekly basis in the spring and summer of 2019, 2020, and 2021. CONCLUSION AND PERSPECTIVES: Both the theoretical estimates and the uncontrolled study suggest that sunless tanning with DHA reduces photosensitivity in patients with EPP. Our hypothesis is that skin treated with DHA can tolerate twice the daylight dose compared to untreated skin before onset of skin symptoms. To validate this conclusion, we plan a randomized clinical trial to determine the effect of DHA application to reduce photosensitivity in patients with EPP under controlled clinical conditions. The study protocol for this trial is presented in the paper.

Cimetidine for erythropoietic protoporphyria.

BACKGROUND: Erythropoietic protoporphyria (EPP) is caused by deficiency of the enzyme converting protoporphyrin IX (PpIX) into heme resulting in accumulation of PpIX; leading to photosensitivity and liver toxicity. Cimetidine might inhibit δ-aminolevulinic acid synthase influencing the heme biosynthesis. We present cases with EPP treated with cimetidine at our department, and a literature review. METHODS: Systematic searches were performed to identify literature describing EPP patients treated with cimetidine. On that ground we treated EPP patients with cimetidine through spring and summer in 2020 and 2021 at our department. Their erythrocyte PpIX level and standard blood and liver parameters were collected before and during 4 months of treatment. Using a questionnaire, patients were asked about change in photosensitivity, side effects, and whether they would like to resume treatment in the spring of 2022. RESULTS: Literature searches identified 9 patients treated with cimetidine. Four were outpatients reporting decreased photosensitivity. At our department 18 outpatients started treatment. Fifteen used oral cimetidine daily for 4 months or more providing a significant decrease in erythrocyte PpIX with a median of 20% (range: -18% to 53%) after 4 months. Eleven of the 15 patients reported a decrease in photosensitivity during treatment, 3 patients were unsure, and 1 patient experienced unchanged photosensitivity. Only mild side effects were reported. Fourteen patients requested to resume treatment in the spring of 2022. CONCLUSIONS: These cases suggest that cimetidine can lower erythrocyte PpIX in patients with EPP.

Bringing the gentle properties of daylight photodynamic therapy indoors: A systematic review of efficacy and safety.

Classic photodynamic therapy (PDT) is an effective, but painful, treatment of actinic keratosis (AK). Daylight PDT with simultaneous activation of protoporphyrin IX during its formation is almost painless and as effective. Recent studies suggest that this gentle simultaneous activation can be performed indoors by replacing daylight with a suitable light source. We aimed to systematically review efficacy and tolerability of indoor gentle PDT of AKs using various light sources. We systematically searched MEDLINE, Embase, and the Cochrane Library for clinical studies of treatment efficacy or adverse events. Indoor gentle PDT consists of application of methyl aminolevulinate or 5-aminolevulinic acid on the skin prior to long time illumination, starting no later than one hour after application. Fifteen studies met the selection criteria, enrolling 518 patients with more than 5,000 AKs undergoing indoor gentle PDT. The studies mainly included thin AKs comprised of 8 uncontrolled studies and 7 randomized controlled trials (RCT) of which 3 were designed as non-inferiority RCTs. Results from both controlled and uncontrolled trials indicated good treatment tolerability with very low pain scores like those of daylight PDT. Reduction of AK lesions 3 months after indoor gentle PDT in RCTs ranged from 52% to 79%, which is comparable to classic and daylight PDT. All 3 non-inferiority RCTs reported that indoor gentle PDT was non-inferior in terms of efficacy to classic PDT. The included studies used varying treatment protocols with different pretreatments, incubation time, light sources, and irradiation time. No standard protocol for indoor gentle PDT exists yet.