A pediatric case of squamous cell cancer in situ in the setting of sclerodermatous graft-versus-host disease and voriconazole treatment.

Sclerodermatous graft-versus-host disease is a subtype of cutaneous chronic graft-versus-host disease that is characterized by sclerosis of the skin and subcutaneous tissue, resulting in debilitating contractures, among other life-threatening complications. Children with sclerodermatous graft-versus-host disease are at high risk of developing nonmelanoma skin cancer because of several risk factors, including young age at transplantation, prolonged immunosuppression, and exposure to photosensitizing antimicrobial prophylaxis such as voriconazole. The immunosuppression required to treat sclerodermatous graft-versus-host disease makes effectively treating nonmelanoma skin cancer and sclerodermatous graft-versus-host disease in the same patient challenging. We describe a challenging case of a 6-year-old boy with a history of sclerodermatous graft-versus-host disease and voriconazole exposure presenting with squamous cell carcinoma in situ on the left temple and actinic keratoses on the scalp treated with topical chemotherapy agents.

Molecular genetic basis for fluoroquinolone-induced retinal degeneration in cats.

OBJECTIVES: Distribution of fluoroquinolones to the retina is normally restricted by ABCG2 at the blood-retinal barrier. As the cat develops a species-specific adverse reaction to photoreactive fluoroquinolones, our goal was to investigate ABCG2 as a candidate gene for fluoroquinolone-induced retinal degeneration and blindness in cats. METHODS: Feline ABCG2 was sequenced and the consensus amino acid sequence was compared with that of 10 other mammalian species. Expression of ABCG2 in feline retina was assessed by immunoblot. cDNA constructs for feline and human ABCG2 were constructed in a pcDNA3 expression vector and expressed in HEK-293 cells, and ABCG2 expression was analyzed by western blot and immunofluorescence. Mitoxantrone and BODIPY-prazosin efflux measured by flow cytometry and a phototoxicity assay were used to assess feline and human ABCG2 function. RESULTS: Four feline-specific (compared with 10 other mammalian species) amino acid changes in conserved regions of ABCG2 were identified. Expression of ABCG2 on plasma membranes was confirmed in feline retina and in cells transfected with human and feline ABCG2, although some intracellular expression of feline ABCG2 was detected by immunofluorescence. Function of feline ABCG2, compared with human ABCG2, was found to be deficient as determined by flow cytometric measurement of mitoxantrone and BODIPY-prazosin efflux and enrofloxacin-induced phototoxicity assays. CONCLUSION: Feline-specific amino acid changes in ABCG2 cause a functional defect of the transport protein in cats. This functional defect may be owing, in part, to defective cellular localization of feline ABCG2. Regardless, dysfunction of ABCG2 at the blood-retinal barrier likely results in accumulation of photoreactive fluoroquinolones in feline retina. Exposure of the retina to light would then generate reactive oxygen species that would cause the characteristic retinal degeneration and blindness documented in some cats receiving high doses of some fluoroquinolones. Pharmacological inhibition of ABCG2 in other species might result in retinal damage if fluoroquinolones are concurrently administered.

Risk of squamous cell carcinoma of the lip and cutaneous melanoma in older Australians using hydrochlorothiazide: A population-based case-control study.

Recent European and US studies reported increased risks of skin cancers associated with hydrochlorothiazide (HCTZ) treatment. Our study aimed to determine the risk of lip cancer and malignant melanoma among Australians prescribed HCTZ. We conducted a case-control study nested within a population of veterans residing in New South Wales in 2004-2015, using Australian Department of Veterans' Affairs data linked with cancer registrations, hospitalisation and prescription dispensings. Among DVA healthcare card holders 65 years and older, we identified incident cases of squamous cell carcinoma of the lip and of cutaneous melanoma, each matched with up to 20 controls through risk-set sampling. We estimated odds ratios (ORs) associating HCTZ use with each cancer using conditional logistic regression, adjusting for predefined confounders. For lip cancer (45 cases), ever-use of HCTZ yielded an OR of 2.6 (95% CI: 1.4-5.0) and high HCTZ use (≥25 000 mg) an OR of 4.7 (95% CI: 1.6-13.7). For cutaneous melanoma (659 cases), ever-use of HCTZ resulted in an OR of 1.2 (95% CI 1.0-1.5) and high HCTZ use in an OR of 1.2 (95% CI: 0.8-1.8). Our findings align with risk estimates from previous studies and provide further evidence that HCTZ's photosensitising properties may promote carcinogenesis in sun-exposed tissues.

Evaluation of the Effectiveness of Additional Risk Minimization Measures for Voriconazole in the EU: Findings and Lessons Learned from a Healthcare Professional Survey.

BACKGROUND: Voriconazole is an extended-spectrum antifungal agent approved for the treatment and prophylaxis of invasive aspergillosis and other serious fungal infections. In 2014, additional risk minimization measures (aRMM) consisting of a Healthcare Professional (HCP) Question and Answer (Q&A) Brochure, HCP Checklist, and Patient Alert Card were implemented on a rolling basis across the European Union (EU) to mitigate three key risks with voriconazole: phototoxicity, squamous cell carcinoma (SCC) of the skin, and hepatotoxicity. The risks of phototoxicity and hepatotoxicity have been documented in the Summary of Product Characteristics (SmPC) since voriconazole was first approved in the EU in 2002. However, the risk of SCC of the skin was a more recent addition to the SmPC (added in 2010). OBJECTIVES: We evaluated the effectiveness of the aRMM, as per EU Good Pharmacovigilance Practices Module XVI, via a survey of HCPs. METHODS: An online survey was conducted among specialty care HCPs in 10 EU countries who had received by mail aRMM tools 12 months previously. Survey questions evaluated HCPs' receipt and utilization of aRMM tools, and knowledge of the three risks. RESULTS: Of 27,396 HCPs invited to participate, 332 eligible respondents completed the survey (response rate: 447/26,735; 1.7%). In total, 19.6% of respondents recalled receiving the HCP Q&A Brochure, 22.6% the HCP Checklist, and 25.9% the Patient Alert Card. HCPs had a high level of knowledge of phototoxicity and hepatotoxicity; however, knowledge of SCC was lower. Knowledge of the three risks and self-reported risk minimization behavior was slightly improved in those who had read the HCP Q&A Brochure compared with those who had not. CONCLUSION: The effectiveness of the voriconazole aRMM cannot be meaningfully inferred from the results due to the low survey response rate. The assessment indirectly points to the SmPC or other resources being the main source of risk information for HCPs. Engaging HCPs before designing and implementing an aRMM program is crucial to ensure an effective and focused program. (EU PAS registration number: EUPAS12624).

Use of photosensitising diuretics and risk of skin cancer: a population-based case-control study.

Diuretics have photosensitising properties. However, little is known about how these diuretics affect the risk of skin cancers. In North Jutland County, Denmark, we investigated whether the use of photosensitising diuretics was associated with an increased risk for developing basal cell carcinoma (BCC), squamous cell carcinoma (SCC) and malignant melanoma (MM). From the cancer registry, we identified primary cases of BCC, SCC and MM during the period of 1989-2003. We selected four population controls for each case from the Danish Civil Registration System, matched on age and gender. Prescriptions for photosensitising diuretics before cancer diagnosis were ascertained in the county's Prescription Database. We used conditional logistic regression to compute incidence rate ratio (IRR), controlling for the chronic medical conditions and for the previous use of oral glucocorticoids. We found an increased risk of SCC (IRR of 1.79 (95% confidence interval (CI): 1.45-2.21)) and MM (IRR of 1.43 (95% CI: 1.09-1.88)) among users of combined amiloride and hydrochlorothiazide therapy. An increased risk of MM (IRR of 3.30 (95% CI: 1.34-8.10)) was found among users of indapamide. We found little associations with risk of BCC. Our findings provide evidence that the use of some photosensitising diuretics is associated with an increased risk for SCC and MM.

Low risk of postinflammatory hyperpigmentation in skin types 4 and 5 after treatment with fractional CO2 laser device.

BACKGROUND/OBJECTIVE: Hyperpigmentation occurs in more than 37% of dark-skinned subjects treated with a fully ablative CO2 laser device. This study assessed the risk of postinflammatory hyperpigmentation (PIH) in subjects with skin types 4 and 5 treated once with a specific protocol of treatment using a fractional CO2 laser. METHODS: Seven subjects with photodamaged skin received a single facial treatment using a fractional CO2 laser. Anesthesia was limited to a lidocaine and prilocaine cream for 1 hour before the single-pass treatment. Subjects were evaluated for improvement and PIH on alternate days for 14 days, and at 1 month, 3 months, and 6 months posttreatment. RESULTS: All subjects achieved improvement in their specific skin conditions and in skin texture. Postinflammatory hyperpigmentation was not observed in any subject. Four subjects experienced no pain during treatment, while 3 reported mild pain. Recovery was associated with minimal pain and itching. CONCLUSION: In dark-skinned subjects, fractional CO2 laser treatment and topical anesthesia subjectively improves common skin conditions without PIH.

Sparfloxacin-induced photo-onycholysis and photosensitivity characteristically sparing lepromatous skin lesions: an interesting observation.

Sparfloxacin is an antibiotic in the quinolone group of antibacterial agents, which often induce photosensitive skin reactions, more often phototoxic reactions than photoallergic ones, and sometimes associated photo-onycholysis. We present a case of phototoxic dermatitis with photo-onycholysis in a 38-year-old man probably induced by sparfloxacin, which was prescribed to him along with rifampicin and clofazimine because he was suffering from borderline lepromatous leprosy. He developed exaggerated sunburn-like eruptions mainly on sun-exposed sites along with painful onycholysis of the fingernails. Interestingly, the hypopigmented patches of leprosy were spared, which is a very rare phenomenon. Withdrawal of sparfloxacin along with administration of systemic steroids and other supportive measures helped heal the skin eruptions with hyperpigmentation, but the photo-onycholysis was slow to resolve.

Challenging cause of bullous eruption of the hands in the Arctic.

Phytophotodermatitis is caused by deposition of photosensitising compounds on the skin followed by ultraviolet exposure. We present an unusual case of a 29-year-old Australian male visiting Greenland who presented with severe itchy bullous eruption on his hands. The cause was a combination of exposure to lime fruit juice and prolonged sun exposure from the Arctic midnight sun.

Menthol reduces phototoxicity pain in a mouse model of photodynamic therapy.

Phototoxicity-induced pain is a major clinical problem triggered by light acting on photosensitising drugs or endogenous porphyrins, notably protoporphyrin IX (PpIX), an intermediary in heme biosynthesis. Protoporphyrin IX accumulates in individuals with erythropoietic protoporphyria and is elevated during photodynamic therapy subsequent to application of 5-aminolevulinic acid (ALA). Pain occurs during irradiation of PpIX and responds poorly to conventional analgesics. Our objective was to develop a model of PpIX phototoxicity pain and investigate the potential of menthol as an analgesic. Application of ALA to the tails of C57 black and SWISS white mice caused PpIX accumulation and nociception during irradiation (630 nm at 3.7 J/cm). Despite similar PpIX accumulation, C57 mice exhibited less pain behavior compared with SWISS mice because of light absorption by pigmentation. Irradiation of ALA-treated dorsal root ganglion neurons caused phototoxicity-evoked action potentials (APs) in both mouse strains. The antioxidant L-tryptophan increased the light dose required to elicit such APs. By contrast, the addition of keratinocytes to neuronal cultures decreased the threshold for APs, suggesting a requirement for proliferating cells. Inhibition of fatty acid amide hydrolase, selective antagonism of TRPV1 or the application of lidocaine or its quaternary derivative QX-314, reduced AP frequency, whereas antagonism of TRPA1 had no effect. These results suggest that products of singlet oxygen-mediated lipid peroxidation trigger nociceptor activation via TRPV1. Menthol inhibited phototoxicity-evoked APs and reduced pain behavior when applied topically to mice. These findings suggest that menthol might provide pain relief in patients experiencing PpIX-phototoxicity pain caused by photodynamic therapy or erythropoietic protoporphyria.

Phototoxicity, Pseudoporphyria, and Photo-onycholysis Due to Voriconazole in a Pediatric Patient With Leukemia and Invasive Aspergillosis.

Voriconazole is a triazole antifungal agent superior to amphotericin B in the treatment of invasive aspergillosis. It is generally well tolerated and has excellent oral bioavailability, providing significant benefit in the treatment of invasive fungal infections. There have been numerous reports of dermatologic reactions to this agent, including erythroderma, cheilitis, Stevens-Johnson syndrome, discoid lupus erythematosus, pseudoporphyria, squamous cell carcinoma, and photosensitivity reactions. Pseudoporphyria, a dermatologic condition mimicking porphyria cutanea tarda, has been described as an adverse effect of voriconazole use. Clinical findings include photosensitivity, vesicles, bullae, milia, and scarring in sun-exposed areas. Photo-onycholysis is a phenomenon of nail discoloration and onycholysis that has been described in the setting of a phototoxic drug reaction and pseudoporphyria. Implicated drugs have most commonly been tetracyclines, fluoroquinolones, and psoralens; others have been reported as well. We report a case of a pediatric patient with leukemia who developed symptoms consistent with pseudoporphyria and later photo-onycholysis while being treated with voriconazole. To our knowledge, this is the first reported case of pseudoporphyria due to voriconazole in a pediatric patient and the first reported case of photo-onycholysis as a consequence of voriconazole use.

Unusual complications after occupational exposure to giant hogweed (Heracleum mantegazzianum): a case report.

Exposure to giant hogweed brings about the risk of serious skin damage, usually in the form of phytophotodermatitis. Initially, skin changes are signaled by a burning sensation, followed by a vesiculobullous rash and long-term hyperpigmentation. Usually, skin disorders improve after the application of topical and oral corticosteroids. In extremely rare instances, full skin thickness burns or epidermal necrosis occur. The study presents a case of occupational exposure to hogweed, which resulted in extensive skin lesions leading to the disablement of a 27-year-old man. The principles of procedure to be followed when contact with giant hogweed is an occupational hazard are also outlined.

[Ocular phototoxicity and altitude among mountain guides]. / Phototoxicité oculaire et altitude chez des guides de haute montagne.

PURPOSE: This study aimed to evaluate ocular phototoxicity in mountaineer guides who experience overexposure to ultraviolet related to the altitude at which they work, as well as light reflection on snow. MATERIALS AND METHODS: Ninety-six guides and 90 controls living in plains, over 50 years old, underwent complete examinations. They responded to a questionnaire assessing altitude exposure and protective eyewear. We compared the two groups and performed a logistic regression within the guide group so as to identify risk and protective factors. RESULTS: Guides develop more ocular surface diseases. They exhibit more anterior cortical cataract (P<0.01) and cataract surgery (P=0.01). Only 61.5% of guides had a normal ocular fundus versus 81.1% in control group (P<0.01). They exhibit more drusen (27.2% vs. 15.6%, P<0.01). Among the guide group, exposure at an altitude above 3000 m is risk factor for anterior cortical cataract (OR=1.16, P<0.01). Wearing ski masks (OR=0.50, P=0.04) or photochromic lenses (OR=0.53, P=0.03) reduces this risk. Exposure to snow increases the risk of maculopathy (OR=1.9, P<0.01). Wearing a hat reduces this risk (OR=0.40, P=0.02) and the risk of cataract formation (OR=0.46, P=0.04). CONCLUSIONS: Guides develop more ocular surface diseases, anterior cortical lens opacities and drusen. These results underscore the potential deleterious role of ultraviolet radiation and the importance of light reflection on snow. The best ocular protection includes sunglasses and a hat with a visor or brim.

Full thickness burn caused by exposure to giant hogweed: delayed presentation, histological features and surgical management.

We report the case of a 10-year-old boy with a full thickness chemical burn on his right pretibial area due to phytophotodermatitis (PPD) following contact with giant hogweed (Heracleum mantegazzianum). Although cutaneous burns due to plants are a well-established cause of chemical burn, previous reports described partial thickness burns that healed with conservative measures. This patient presented to our unit two weeks after the initial injury with an established full thickness burn. Debridement and split thickness skin grafting was required. We presented the histological features of the debrided skin specimen and discussed potential factors leading to this unexpected full thickness injury.

Lesiones ampollosas tras contacto con plantas / Blistering lesions after contact with plants

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