Patricia Lowe

A phase II randomized controlled trial of nicotinamide for skin cancer chemoprevention in renal transplant recipients

DEAR EDITOR, Immunosuppressed organ transplant recipients have an 80-fold increased risk of squamous cell carcinoma (SCC) and a 16-fold increased risk of basal cell carcinoma (BCC); SCCs are more aggressive and more likely to metastasize in these patients. While mammalian target of rapamycin (mTOR) inhibitors may help reduce the incidence of SCC, the current mainstay of nonmelanoma skin cancer (NMSC) chemoprevention post-transplant is oral retinoids, which have side-effects, including liver and lipid abnormalities, mucocutaneous dryness and teratogenicity. Nicotinamide (vitamin B3) enhances repair of photodamaged DNA and prevents the inhibitory effects of ultraviolet radiation on the immune system without altering baseline immune reponses. In 386 immunocompetent participants at high risk of having skin cancer, nicotinamide 500 mg twice daily reduced new NMSCs by 23% (P = 0 02), with 20% fewer BCCs and 30% fewer SCCs compared with placebo. Actinic keratoses (AKs) were also significantly reduced by nicotinamide in the same phase III randomized controlled trial. However, it is unknown whether nicotinamide prevents NMSCs and is safe in immunosuppressed renal transplant recipients. Eligible adult immunosuppressed participants included those who had received a renal transplant ≥ 12 months ago, had stable renal function and a history of ≥ 2 NMSCs in the previous 12 months. Participants were ineligible if they commenced retinoids or mTOR inhibitors within 6 months, or used nicotinamide supplements or AK field treatments within the 4 weeks prior to enrolment. This double-blind study was conducted at the Royal Prince Alfred Hospital (Sydney, Australia; Australian New Zealand Clinical Trials Registry ACTRN12612000628842) after ethical approval was received. All participants provided written informed consent. Participants were enrolled (by A.C.C. and R.A.D.) and randomized 1:1 to receive either nicotinamide 500 mg twice daily or matched placebo (Insolar; Blackmores, Warriewood, Australia) by centralized randomization (permuted blocks; National Health and Medical Research Council Clinical Trials Centre) stratified by lifetime NMSC history (< 6 or ≥ 6 NMSCs), oral retinoid use and mTOR inhibitor use. Compliance was monitored by tablet counts at each visit (A.C.C). Skin cancer checks were performed at baseline and twice monthly up to 6 months by dermatologists blinded to treatment allocation (D.L.D., P.M.L.). AKs on the face, scalp, forearms and hands were counted at baseline and twice monthly up to 6 months by a dermatology Fellow blinded to allocation (A.C.C). All squamous lesions were reviewed by a single (blinded) histopathologist (C.A.M.) to ensure consistent reporting of SCC differentiation. Blood and urine samples were taken at baseline, 2 and 4 weeks, and 2, 4 and 6 months for full blood count, electrolytes, renal and liver function tests, drug levels and urine microalbumin/creatinine ratio. Blood pressure and weight were measured at baseline and twice monthly for 6 months. The primary end point was the number of new NMSCs (BCC + SCC, including invasive and in situ SCC) up to 6 months. Secondary end points included new BCCs, new SCCs, AK counts up to 6 months and safety. The planned sample size was 80 participants, in order to provide 80% power to detect a 50% reduction in the 6-month NMSC rate at the 5% level of significance, assuming that NMSC counts followed a Poisson distribution with a mean of 1 5 for the placebo group, allowing for ≤ 10% noncompliance. However, owing to slow recruitment because of an overestimation of the eligible participant population at our site, the study was stopped early; 22 participants were recruited over 1 5 years. Analyses were by intention to treat. As per the provision specified in the statistical analysis plan, a negative binomial model was used to analyse NMSC, SCC and BCC data, owing to overdispersion that rendered the Poisson model inappropriate. Models included an offset term to account for variation in follow-up duration. The 2-monthly postbaseline AK data were analysed using a mixed model for repeated measures, including treatment group, baseline value, time point and a time-by-treatment group interaction as covariates. From August 2012 to March 2014, 25 participants were assessed for eligibility and 22 were randomized [11 in each group; Figure S1 (see Supporting Information)]. The groups had similar baseline characteristics (Table 1). Follow-up was from August 2012 to August 2014. Median compliance was 93% and 98% for the placebo and nicotinamide groups, respectively. The 6-month NMSC rate was not significantly lower for the nicotinamide group [mean 2 7, 95% confidence interval (CI) 1 4–5 3; total 30 cancers] compared with placebo (mean 4 2, 95% CI 2 2–7 8; total 45 cancers); however, the numeric trend was dominated by one patient in the placebo group

A quantitative approach to histopathological dissection of elastin-related disorders using multiphoton microscopy

Multiphoton microscopy (MPM) is a novel imaging technology that has recently become applicable for diagnostic purposes. The use of (near) infrared light in MPM allows for deep tissue imaging. In addition, this modality exploits the autofluorescent nature of extracellular matrix fibres within the skin.

Lasers and laser-like devices: Part two: Clinical use of lasers in dermatology

Part two of this review series evaluates the use of lasers and laser‐like devices in dermatology based on published evidence and the collective experience of the senior authors. Dermatologists can laser‐treat a wide range of dermatoses, including vascular, pigmentary, textural, benign proliferative and premalignant conditions. Some of these conditions include vascular malformation, haemangioma, facial telangiectases, café‐au‐lait macules, naevi of Ota, lentigines, acne scarring, rhytides, rhinophyma and miscellaneous skin lesions. Photodynamic therapy with lasers and intense pulsed light is addressed, with particular reference to actinic keratosis and actinic cheilitis. A treatment algorithm for acne scarring based on scar morphology and severity is comprehensively outlined. Following from part one, the various devices are matched to the corresponding dermatological conditions with representative pictorial case vignettes illustrating likely clinical outcomes as well as limitations and potential complications of the various laser and light therapies.

Complicated lichenoid drug eruption.

We report a case of severe lichenoid drug eruption with multiple possible causative agents. A hepatitis C‐positive male presented with a short history of painful erosions of the vermilion, lichenoid lesions on the buccal mucosa and glans penis, and erosions and lichenification of the scrotum. In addition, he had a pruritic polymorphic eruption over the scalp, trunk and limbs, comprising psoriasiform and eczematous lesions. He had received combination therapy of pegylated interferon‐α‐2a and ribavirin, along with granulocyte colony‐stimulating factor for interferon‐induced leucopenia, and propranolol for portal hypertension. The former three agents were ceased 3 weeks prior to presentation, but he remained on propranolol at the initial dermatology consultation. The polymorphous clinical picture was consistent with lichenoid drug eruption, which was confirmed on histology. The papulosquamous eruption responded quickly to 2 weeks of oral prednisone 25 mg daily, which was tapered to 1 mg over 3 months and then ceased. The mucosal lesions were slow to improve and required the addition of tacrolimus 0.03% solution t.d.s. for complete resolution.

Ice anaesthesia in procedural dermatology.

This article presents findings from a survey of Australian dermatologists who were questioned about their preferred pain control methods when carrying out injectable procedures. We also present, what is to the best of our knowledge, the first proof‐of‐concept experiment exploring the relationship between ice‐to‐skin contact time and skin surface temperature, using both ice wrapped in latex and ice wrapped in aluminium foil. Of 79 dermatologists 32 responded to the survey (41% response rate): 31 (97%) injected botulinum toxin type A (BTA) for dynamic lines, 26 (81%) injected BTA for hyperhidrosis, and 24 (75%) injected skin fillers. Ice anaesthesia was the most common method of pain control (75%) followed by use of topical anaesthesia (50%) such as EMLA, compound agents and lignocaine 4%. Ice wrapped in latex or latex‐like material was the most common ice packaging used by those surveyed and the median ice‐to‐skin contact time was 10 s. The ice experiment results indicated that ice wrapped with aluminium foil was equivalent to ice wrapped in latex for short contact times (< 20 s), but more effective at reducing skin temperature with longer contact times (> 20 s). These findings will be of relevance to cosmetic and paediatric dermatologists or any area of procedural medicine where effective non‐injectable pain control is required.

Bullous pemphigoid-like reaction in a patient with metastatic melanoma receiving pembrolizumab and previously treated with ipilimumab.

1. Byrom L, Barksdale S, Weedon D et al. Unstable solar lentigo: a defined separate entity. Australas. J. Dermatol. 2016; 57 (3): 229–34. doi: 10.1111/ajd.12447. 2. Zagarella S. Reply to unstable solar lentigo is not a defined separate entity. Australas. J. Dermatol. 2016. 3. Weedon D. Skin Pathology, 3rd edn. Australia: Churchill Livingstone, 2009. 4. Goldstein AM, Tucker MA. Dysplastic nevi and melanoma. Cancer Epidemiol. Biomarkers Prev. 2013; 22: 528–32. 5. Ratushny V, Gober MD, Hick R et al. From keratinocyte to cancer: the pathogenesis and modeling of cutaneous squamous cell carcinoma. J. Clin. Invest. 2012; 122: 464–72. 6. Kanitakis J. Porokeratoses: an update of clinical, aetiopathogenic and therapeutic features. Eur. J. Dermatol. 2014; 24: 533–44.

Crazy in Love

Every February brings with it St Valentines Day, and while expressions of loveaboundduring thismonth, onanygivenday throughout theyear there are ample romantic descriptions to be found in dermatology. Drawing on classical mythology, the hypopigmented macules of syphilis are known as the necklace of Venus, and the vermillion border of the upper lip is referred to as Cupids bow. Infectiousmononucleosis is knownas “kissingdisease,” “kissing” lesionshavebeendescribed inZoonbalanitis andelectrical burns, and the ideal apposition ofwound edges has been described as that of a “social kiss.” Ecchymoses on the neck are known as “love bites,” and, somewhat less desirably, those with excess abdominal adiposity are said to have “love handles.” Part of the tradition of Valentines Day is the exchange of gifts, and plentyof inspirationcanbedrawn fromthedermatological realm.While the rose is perhaps themost popular gift, it is also a popular descriptor of cutaneous lesions, suchas “dewdropsona rosepetal” for thevesicles of varicella, roseola infantum, and the “rose spots” of Salmonella typhi infection. The rosette is a widely used dermatology descriptor; clinically as in linear IgA disease, dermoscopically as in keratinizing tumors and histologically as in cyclindromas. Chocolates are always a favorite, and chocolate agar is also the desiredmediumforgrowthofMycobacteriumchelonae. Champagne is liberally consumed on Valentine’s Day, and once the bottle is overturned, it resembles the legofapatientwithadvanced lipodermatosclerosis.Oysters and caviarmay feature on the romantic dinnermenu, conjuring images of rupioid psoriatic plaques and “caviar tongues” (sublingual varicosities). For dessert, strawberries, as in the “strawberry tongue” of Kawasaki disease, are often coupled with cream, the ubiquitous medium for delivery of topical medicaments. Followed by port of course, as in port-wine stains (best referred to as capillary malformations). The luckiest among us will receive jewelry, be it silver, as in the scale of psoriasis, or gold, as in lichen aureus or Staphylococcus aureus infection (with special mention of the Panton-Valentine leucocidin strain). Pearls for some, hopefully rarer types than the common “pearly” surface of nodular basal cell carcinomas, and diamonds for others, such as the rhomboid structures seen dermoscopically in lentigo maligna. While skin remains the loveof all dermatologists, theuniversal symbol of St Valentines Day is of course the heart, and a wide range of cutaneous abnormalities with heart-shaped morphologic characteristics have been reported. So this February, let us all remember that dermatology ismore than skin deep and that caring for patients with cutaneous disease remains at the heart of dermatology.

Laser skin resurfacing: A patient-centred classification based on downtime

Laser skin resurfacing is used to address cutaneous concerns including acne scarring, photoageing (particularly dyschromia and vascular changes), rhytides and skin laxity. In response to the increasing consumer demand for clear, concise and relevant information and in the interests of informed consent, we have devised a user-friendly patientcentred classification system for laser skin resurfacing. Existing skin resurfacing classifications do not adequately meet the above objectives. In this article, we categorise resurfacing lasers, review existing resurfacing classification systems and propose a patient-centred classification based on downtime (the period of time following resurfacing where patients may choose not to appear in public due to expected side-effects such as erythema, oedema and exudate).

Fractional filling with the microdepot technique as an alternative to bolus hyaluronic acid injections in facial volume restoration

For volume restoration of the face, hyaluronic acid is conventionally injected through long, large‐bore, 18‐gauge needles because of the higher viscosity subtypes required. These hyaluronic acids are either more highly cross‐linked or larger in particle size than the less‐viscous subtypes. The microdepot injection technique involves using the 31‐gauge BD insulin syringe (Becton‐Dickinson, North Ryde, NSW Australia) to deposit small amounts of filler (0.05–0.1 mL) throughout the area of volume loss. The procedure is extremely well tolerated, requiring only topical and ice anaesthesia. Using this method, volume restoration can be achieved naturally and progressively over a period of time. Fractional filling every 3–4 months is continued until the desired level of volume correction is attained. Patients undergoing fractional filling followed over a 12‐month period did not indicate any observable compromise in filler longevity, even when highly viscous hyaluronic acid fillers were injected through small‐bore, 31‐gauge insulin syringes.

Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management

Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD-1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti-CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed.