The spectrum of cutaneous adverse events during encorafenib and binimetinib treatment in B-rapidly accelerated fibrosarcoma-mutated advanced melanoma.

BACKGROUND: B-rapidly accelerated fibrosarcoma (BRAF) inhibitor encorafenib alone and in combination with MEK inhibitor binimetinib improves survival in BRAF-mutated melanoma patients. So far, the range of cutaneous adverse events has been characterized only for established BRAF inhibitors (vemurafenib, dabrafenib) and MEK inhibitors (trametinib, cobimetinib). OBJECTIVE: The aim of this study was to investigate cutaneous adverse events emerging in melanoma patients treated with encorafenib and binimetinib. METHODS: Patients treated with BRAF and MEK inhibitors in clinical trials at the University Hospital of Zurich were identified. Frequency and features of cutaneous adverse events as well as their management were assessed based on the prospectively collected clinical and histopathological data. The events emerging during encorafenib and/or binimetinib therapy were compared to other BRAF and MEK inhibitors at the institution and in the literature. RESULTS: The most frequent cutaneous adverse events observed in patients treated with encorafenib alone (n = 24) were palmoplantar hyperkeratosis (54%), palmoplantar erythrodysesthesia (58%) and alopecia (46%). Drug-induced papulopustular eruptions prevailed in patients with binimetinib monotherapy (n = 25). The most frequent cutaneous adverse events in patients treated with encorafenib/binimetinib (n = 49) were palmoplantar hyperkeratosis (10%). CONCLUSION: Compared to data published for established BRAFi, encorafenib monotherapy showed less hyperproliferative cutaneous adverse events. In contrast, palmoplantar hyperkeratosis and palmoplantar erythrodysesthesia seem to occur more often. The combination of encorafenib and binimetinib is well tolerated and induces few cutaneous adverse events.

Painful nipple hyperkeratosis secondary to vemurafenib.

Vemurafenib is a selected BRAF kinase inhibitor approved for treating metastatic or unresectable melanoma, which has numerous cutaneous side effects unfortunately, including three previously reported cases of asymptomatic areola and/or nipple hyperkeratosis. We present the first case of painful bilateral nipple hyperkeratosis secondary to vemurafenib in an 84-year-old woman. She was successfully treated with tretinoin 0.05% cream that allowed her to comfortably continue treatment. With increased awareness of this condition, we found a second case of asymptomatic nipple hyperkeratosis secondary to vemurafenib in our clinic. As this medication gains acceptance for treatment of metastatic melanoma, it is imperative that dermatologists are aware of this potentially uncomfortable side effect that can result in decreased compliance and impaired quality of life.

A patient case highlighting the myriad of cutaneous adverse effects of prolonged use of hydroxyurea.

BACKGROUND: Hydroxyurea is an antimetabolite primarily used to treat myeloproliferative disorders, and chronic treatment is associated with many cutaneous adverse effects ranging in severity from ichthyosis to aggressive nonmelanoma skin cancer. CASE PRESENTATION: We report a 67-year-oldman with a history of polycythemia vera who was referred for management of progressively worsening dorsal hand lesions. The patient presented withhyperpigmentation, ichthyosis, plantar keratoderma, dermatomyositis-like eruptions, two squamous cell carcinomas, and actinic keratoses. The adversereactions observed were acknowledged to be related to chronic hydroxyurea use. The patient underwent Mohs excision of the squamous cell carcinomas and thehydroxyurea was promptly discontinued; subsequent cutaneous improvement of the dermatomyositislike lesions ensued. Another clinically suspicious aggressive squamous cell carcinoma was suspected and the patient was referred to the plastic surgery department for complete excision because of the size of the lesion. The patient remains on periodic dermatology follow up. CONCLUSIONS: We report a case that exemplifies the cutaneous adverse effects of chronic hydroxyurea therapy. Although many cases improve after drug discontinuation, strict photoprotection and ongoing surveillance are indicated given the recently proposed premalignant potential of dermatomyositis-like eruptions and the aggressive nature of hydroxyurea-induced nonmelanoma skin cancer.

[Eruptive epidermoid cysts during topical imiquimod treatment]. / Éruption de kystes épidermiques après application d'imiquimod topique.

BACKGROUND: Imiquimod is a local immune-response modifier that works by stimulating innate and acquired immunity. It is frequently used to treat superficial basal cell carcinoma, the most common form of skin cancer. Marked local inflammatory reaction is common during treatment. We report a case of the rare condition, multiple eruptive milia, during topical imiquimod therapy. PATIENTS AND METHODS: A 67-year-old male patient presented infiltrating basal cell carcinoma above the left eyebrow. The patient underwent surgery and skin grafting. He presented superficial relapse at the periphery of the graft and was initially treated with Aldara®. Fifteen days after initiation, Aldara® was withdrawn due to a critical inflammatory reaction. A few weeks after complete healing, an erythematous annular plaque of milia, excluding the graft zone, appeared. This element was confirmed by histopathology. DISCUSSION: The most common local side effects reported with Aldara® are erythema, irritation and crusting. Reports of eruptive milia following Aldara® therapy are rare and they are never mentioned in the summary of product characteristics. Application of imiquimod in fact induces local inflammatory reaction due to stimulation of local cytokines, which can result in marked reaction in the infundibular epithelium of hair follicles and thus in the production of abnormal keratin that can cause pilosebaceous duct obstruction and thus the formation of epidermoid cysts. This pathological mechanism explains the absence of lesions on the skin graft of the inner arm. CONCLUSION: The occurrence of eruptive milia during treatment with Aldara® is rarely described. The timing of occurrence of these eruptive milia as well as the mechanism of action of the drug made such a reaction highly probable in our patient.

Cutaneous Adverse Events of New Anti-melanoma Therapies: Classification and Management.

Over the past decade, targeted therapies such as BRAF inhibitors, MEK inhibitors and immunotherapies such as anti-CTLA4 and anti-PD1 antibodies have emerged as novel treatments of advanced melanoma. Along with increased use of these therapies, a range of cutaneous adverse events have also emerged, varying from more serious and frequent cutaneous squamous cell carcinoma to mere cosmetic changes such as curly hair or rare severe toxic epidermal necrolysis. Early detection and management of these cutaneous adverse events will aid patients to receive accurate treatment, avoid unnecessary discontinuation of anti-tumour treatment and improve the patient's overall quality of life. This review will describe various cutaneous adverse events of anti-melanoma therapies and its management.

Acral keratoses and leucocytoclastic vasculitis occurring during treatment of essential thrombocythaemia with hydroxyurea.

Hydroxyurea is used in essential thrombocythaemia to lower thromboembolic risk. Cutaneous adverse effects from hydroxyurea are diverse. Small vessel vasculitis has been rarely reported, and the coexistence of several different morphologies has not been described. We report a case of acral keratoses, psoriasiform plaques and leucocytoclastic vasculitis (LCV) in a patient with essential thrombocythaemia. A 69-year-old woman developed a confusing array of skin lesions including keratotic papules, psoriasiform plaques and keratoderma 4 years after commencing hydroxyurea therapy. The initial diagnosis was hand and foot psoriasis, but lesions were resistant to therapy. With an increase in the dose of hydroxyurea, the lesions ulcerated. Skin biopsies taken from different sites indicated different diagnoses, including LCV. Discontinuation of hydroxyurea yielded rapid improvement. Although the most commonly reported cutaneous adverse effect from hydroxyurea is leg ulceration, this can be preceded or accompanied by less dramatic skin lesions. Unless recognized, delayed diagnosis and lesion progression can occur.

Vemurafenib-induced hyperkeratosis of the areola treated with topical adapelene.

We present a rare condition, hyperkeratosis of the areola, induced by vemurafenib. Only a few papers have described an association of BRAF inhibitors with hyperkeratosis of the areola and/or nipple. Vemurafenib is a selective BRAF inhibitor used in patients with unresectable or metastatic melanoma who are positive for the V600 mutation. This drug has been associated with numerous cutaneous side effects, both benign and malignant. We report a male patient with vemurafenib-induced hyperkeratosis of the areola managed successfully with a topical retinoid, and describe for the first time a treatment for this side effect.

Acitretin-induced spiny follicular hyperkeratosis.

Spiny follicular hyperkeratosis (SFH) is follicular flesh-colored hyperkeratotic spicules that are linked to different situations including drug reactions. Previously suspected drugs are BRAF inhibitors and cyclosporine. We described a 51-year-old psoriasis patient with SFH who had been using acitretin.

Vemurafenib-associated keratoses with genetic heterogeneity of RAS.

Vemurafenib is a recently approved targeted therapy for advanced melanoma harboring the B-Raf valine-to-glutamate mutation at residue 600 (V600E). In many patients, the use of vemurafenib leads to a rapid onset of cutaneous neoplasms, including squamous cell carcinomas, keratoacanthomas, and benign keratoses. Paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway by vemurafenib in the setting of RAS hyperactivation has been demonstrated in the laboratory and may account for the pathogenesis of some of these neoplasms. Activating RAS mutations have been discovered in vemurafenib-associated squamous cell carcinomas, but have not been reported in benign keratoses, which are a more common side effect that affects patient quality of life. Here, we report on the mutational analysis of RAS genes at known activating hotspots in verrucous keratoses from a stage IV melanoma patient undergoing vemurafenib therapy. The results lend genetic evidence to the current hypothesis for how some of these lesions develop and suggest potential strategies in the research on preventive and therapeutic measures.

Dermatologic adverse events to chemotherapeutic agents, Part 2: BRAF inhibitors, MEK inhibitors, and ipilimumab.

The advent of novel targeted chemotherapeutic agents and immunotherapies has dramatically changed the arena of cancer treatment in recent years. BRAF inhibitors, MEK inhibitors, and ipilimumab are among the newer chemotherapy drugs that are being used at an increasing rate. Dermatologic adverse events to these medications are common, and it is important for dermatologists and oncologists alike to learn to recognize and treat such side effects in order to maintain both patients' quality of life and their anticancer treatment. This review describes the cutaneous side effects seen with BRAF inhibitors (eg, maculopapular eruption, photosensitivity, squamoproliferative growths, melanocytic proliferations), MEK inhibitors (eg, papulopustular eruption), and ipilimumab (eg, maculopapular eruption, vitiligo), with a mention of vismodegib and anti-PD-1 agents.

[Analysis of associations of polymorphic loci of a tumor suppressor gene TP53 with malignant neoplasms in glass fiber manufacturing workers].

The purpose of the study was to determine the role of TP53 tumor suppressor gene polymorphisms in the occurrence of skin malignant neoplasms in glass fiber manufacturing workers. We carried out a comparative study of polymorphous loci Arg72Pro and dup16bp in TP53 gene in workers with skin cancer and hyperkeratosis (n = 68), occupied in continuous glass fiber manufacture, and in healthy workers (n = 52). The associations of both Pro and dup16 minor alleles of TP53 gene, and Arg/Pro-W/dup16 genotype combination with higher risks for skin oncologic diseases of occupational genesis have been revealed.

Cutaneous toxicities of RAF inhibitors.

The RAF inhibitors vemurafenib and dabrafenib are emerging as the standard of care for Val600 BRAF-mutant metastatic melanoma. These drugs have shown clinical benefit over the standard care (dacarbazine); however, they are associated with frequent cutaneous adverse events, which can be concerning to the patient and their physician. Herein, we review the range of cutaneous disorders that seem to be induced by RAF inhibitors, including cutaneous squamous-cell carcinoma, hyperkeratotic lesions, Grover's disease, keratosis pilaris-like reactions, and photosensitivity. These disorders often affect patients' quality of life; therefore, dermatological assessment and timely management is essential to ensure that patients continue to use RAF inhibitors.

Hematoporphyrin injection mediated photodynamic therapy for secondary squamous cell carcinoma of arsenical keratosis: A case report.

Hematoporphyrin injection (HpD) mediated photodynamic therapy (PDT) has demonstrated efficacy in treating various types of Bowen's disease, including basal-cell carcinoma, squamous cell carcinoma, extramammary Paget's disease, and actinic keratosis. We present a case of a male patient who developed squamous cell carcinoma as a result of repeated instances of arsenic-induced keratosis on both his hands and feet. Due to the involvement of the joint in both hands, the patient declined the conventional surgical resection treatment since it could potentially impact normal physiological function. Instead, the patient chose to undergo hemoporphyrin photodynamic therapy. After the treatment, the rash was entirely eliminated and there were no restrictions in the movement of the joint. Nevertheless, a local recurrence was detected throughout the two-year monitoring period. Arsenical keratosis carries a substantial likelihood of recurring. However, we believe that hemoporphyrin photodynamic therapy is effective in treating this condition.

Pyrogallol-associated dermal toxicity and carcinogenicity in F344/N rats and B6C3F1/N mice.

Pyrogallol (CAS No. 87-66-1), a benzenetriol used historically as a hair dye and currently in a number of industrial applications, was nominated to the National Toxicology Program (NTP) for testing based on the lack of toxicity and carcinogenicity data. Three-month and two-year toxicity studies to determine the toxicity and carcinogenicity of pyrogallol when applied to naïve skin (i.e. dermal administration) were conducted in both sexes of F344/N rats and B6C3F1/N mice. In the three-month studies, adult rodents were administered pyrogallol in 95% ethanol five days per week for 3 months at doses of up to 150 mg/kg body weight (rats) or 600 mg/kg (mice). Based on the subchronic studies, the doses for the two-year studies in rats and mice were 5, 20 and 75 mg/kg of pyrogallol. All mice and most rats survived until the end of the three-month study and body weights were comparable to controls. During the two-year study, survival of dosed rats and male mice was comparable to controls; however survival of 75 mg/kg female mice significantly decreased compared to controls. The incidences of microscopic non-neoplastic lesions at the site of application were significantly higher in all dosed groups of rats and mice and in both the 3-months and two-year studies. In the two-year study, hyperplasia, hyperkeratosis and inflammation tended to be more severe in mice than in rats, and in the mice they tended to be more severe in females than in males. The incidence of squamous cell carcinoma at the site of application (SOA) in 75 mg/kg female mice and SOA squamous cell papillomas in 75 mg/kg male mice were greater than controls. Pyrogallol was carcinogenic in female mice and may have caused tumors in male mice.

Cutaneous malignant and premalignant conditions caused by chronic arsenicosis from contaminated ground water consumption: a profile of patients from eastern India.

Natural arsenic pollution is a major global health problem. The two worst affected areas e Bangladesh and West Bengal, India. Arsenic is a well-documented human carcinogen that affects many organs including the skin. The authors sought to find out the clinical patterns of different malignant and premalignant conditions associated with chronic arsenicosis from drinking contaminated ground water in a group of patients from eastern India. This was a clinical observational study. Patients with chronic arsenicoses with suspected cutaneous malignancies for whom dermatology service was sought were enrolled in the study. A total of 24 patients (male to female ratio, 11:1; age range, 32-71 years; mean age, 52.2 years) were evaluated. Squamous cell carcinoma (SCC) was the commonest malignancies in our series, seen in 10 (41.7%) patients. This was followed by Bowen's disease (9 [37.5%]) and basal cell carcinoma (8 [33.3%]). Three patients (12.5%) had > 1 type of cutaneous malignancies. Multicentric lesions were seen in 3 cases. The most common site of involvement was the chest (8 [33.3%]). No statistically significant correlation was found between number of lesions and arsenic content in the hairs and nails of the patients.

[Adverse skin reactions induced by BRAF inhibitors: a systematic review]. / Effets indésirables cutanés des inhibiteurs de BRAF: revue systématique.

Recent developments and therapeutic use of selective BRAF inhibitors (e.g. dabrafenib and vemurafenib) have significantly improved overall survival and disease-free survival of patients with BRAF V600 mutation-positive metastatic melanoma. Despite their survival benefits, small-molecule inhibitors of BRAF are associated with significant and sometimes severe treatment-related dermatological toxicity. The most common adverse skin reactions include photosensitivity, induced malignant lesions of the skin such as keratoacanthomas, squamous cell carcinoma and new primary melanomas, as well as keratinocyte proliferation and differentiation dysfunctions that can manifest as skin papillomas, hand-foot skin reaction, keratosis pilaris-like rash, acantholytic dyskeratosis and cysts of the milia type. In this article, we describe the clinical and histological features of the cutaneous manifestations induced by vemurafenib and dabrafenib on the basis of our clinical experience and a literature review. The crucial role of dermatologists in patient management is also highlighted.

Intakes of several nutrients are associated with incidence of arsenic-related keratotic skin lesions in Bangladesh.

Risk of skin lesions due to chronic arsenic exposure can be further affected by nutrient intake. We prospectively evaluated the association of nutrient intake and gender with incident skin lesions using data from the Health Effects of Arsenic Longitudinal Study (HEALS) in Araihazar, Bangladesh. Discrete time hazard models were used to estimate these effects in stratified analyses based on skin lesion severity. Overall, we observed significant associations between low intakes of various nutrients (retinol, calcium, fiber, folate, iron, riboflavin, thiamin, and vitamins A, C, and E) and skin lesion incidence, particularly for keratotic skin lesions. Associations for vitamins C and E showed significant linear trends. Gender-specific analyses revealed an inverse association between the lowest quartile of nutrient intake and keratotic skin lesion incidence for retinol equivalents, calcium, folate, iron, and fiber among women. Interactions by gender were observed for retinol equivalents (P-interaction = 0.03), calcium (P-interaction = 0.04), vitamin A (P-interaction = 0.03), and riboflavin (P-interaction = 0.04) with the incidence of keratotic skin lesions. Understanding differential susceptibility to skin lesion incidence based on nutrient intake will help researchers develop targeted interventions to prevent health consequences of arsenic poisoning in Bangladesh and beyond.