Combined Systemic and Intratumoral Administration of Human Papillomavirus Vaccine to Treat Multiple Cutaneous Basaloid Squamous Cell Carcinomas.

Importance: Squamous cell carcinoma (SCC) is the second most common form of skin cancer, and its incidence is increasing. When surgical management is not an option, finding a safe and efficacious treatment is a challenge. Mounting evidence suggests that the human papillomavirus (HPV) is involved in the pathogenesis of some SCCs. Objective: To assess whether the 9-valent HPV vaccine could be an effective treatment strategy for cutaneous SCC. Design, Setting, and Participants: A woman in her 90s with multiple, inoperable cutaneous basaloid SCCs was successfully treated at a university-based outpatient dermatology clinic with a combination of systemic and intratumoral delivery of the 9-valent HPV vaccine from March 17, 2016, through February 27, 2017, and then followed up through May 21, 2018. Main Outcomes and Measures: Reduction in tumor size and number after a combination of systemic and intratumoral administration of the HPV vaccine. Results: All tumors resolved 11 months after the first intratumoral injection of the vaccine. The patient remained free of tumors at the end of follow-up. Conclusions and Relevance: This is the first report, to our knowledge, of complete regression of a cutaneous malignant tumor after combined systemic and direct intratumoral injection of the 9-valent HPV vaccine. This report suggests that the HPV vaccine may have therapeutic utility for SCCs in patients who are poor surgical candidates, have multiple lesions, or defer surgery.

Enlarging Bump on the Scrotum.

Extramammary Paget disease is a rare, slow-growing intraepithelial neoplasm of the skin or its underlying appendages. It more commonly affects the apocrine glands of the axilla, vulva, perianal region, scrotum, and/or penis. It often presents as a well-demarcated, thickened, erythematous, or gray-white scaly plaque with indolent growth that may become ulcerated, crusted, papillomatous, or eczematous over time. Pruritus, pain, and burning sensations are common symptoms; however, they are not appreciated by all patients. Many patients are erroneously treated for eczema for months to years before a proper diagnosis is reached. Patients presenting with chronic genital or perineal dermatitis or skin lesions that have been unresponsive to topical therapy should be biopsied for definitive diagnosis.

Ichthyosiform Pityriasis Rubra Pilaris-Like Eruption Secondary to Ponatinib Therapy: Case Report and Literature Review.

Tyrosine kinase inhibitors have revolutionized the chemotherapy arena as targeted therapies for a multitude of malignancies. They are more selective than conventional chemotherapy, and often elicit fewer systemic adverse events, however toxicities still exist. Cutaneous toxicities are common and their management presents a novel challenge to physicians and patients. Ponatinib is a third-generation tyrosine kinase inhibitor increasingly reported to cause cutaneous eruption. A 50-year-old woman with a history of chronic myelogenous leukemia presented with a 4-month history of worsening atrophic and ichthyosiform pink plaques involving the axillae, thighs and abdomen; red patches were also observed on the cheeks and forehead. She was started on the third-generation, ponatinib, 5 months earlier because of disease refractory to previous therapies including interferon, imatinib, dasatinib and bosutinib. A skin biopsy revealed perifollicular fibrosis, alternating orthokeratosis and parakeratosis, and a sparse perivascular lymphocytic infiltrate consistent with a pityriasis rubra pilaris-like reaction. Topical tretinoin 0.025% cream was initiated, resulting in resolution within 3 weeks without discontinuation of ponatinib. A review of previous reports identified significant similarities among the ponatinib-induced drug reactions. Here, we highlight not only that cutaneous eruptions occur on ponatinib therapy, but that the dermatologic manifestations are characteristic and unique, and benefit from retinoid therapy, without requiring interruption of vital chemotherapy.

Clinico-morphological features of BRAF inhibition-induced proliferative skin lesions in cancer patients.

BACKGROUND: The use of BRAF inhibitors may lead to the development of cutaneous toxicities such as rashes, photosensitivity, alopecia, palmoplantar erythrodysesthesia, and proliferative skin lesions, including keratoacanthomas (KAs) and cutaneous squamous cell carcinomas (cuSCCs). The latter are noteworthy for their potential to exhibit malignant features, and they may necessitate invasive treatment. Their prompt identification is of primary importance for directing supportive care efforts and maintaining dose intensity while minimizing the morbidity associated with supportive care interventions. Because such lesions are less familiar to oncologists, this study was designed to characterize their clinico-morphological features, which have not been hitherto described. METHODS: The clinical and dermoscopic characteristics and risk factors of new-onset proliferative skin lesions (benign verrucous lesions and KAs/cuSCCs) developing after the initiation of treatment with vemurafenib, dabrafenib, and XL281 were analyzed; the histopathological diagnoses were ascertained. RESULTS: The majority of the lesions were benign verrucous lesions (78%, n = 87), whereas KAs/cuSCCs represented 22% (n = 25). The median times to biopsy for the initial verrucous lesions and KAs/cuSCCs were 4.8 and 10.5 weeks, respectively. The clinico-morphological features significant for KAs/cuSCCs included a larger size (P < .001), a nodular appearance (P < .001), a central keratin plug (P < .001), a central ulceration or crust (P = .04), an adherent scale (P = .02), an erythematous halo (P = .03), and a scaly ring (collarette; P < .001) at the periphery. CONCLUSIONS: Our findings represent the first detailed description of the clinico-morphological characteristics that permit distinction between the benign and malignant skin lesions induced by BRAF inhibitors. They are valuable for the recognition of lesions that require intervention and/or a dermatology referral versus those that permit provisional monitoring.

Life-threatening dermatologic adverse events in oncology.

The incidences of life-threatening toxicities such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are inconsistently reported. The potential association of anticancer agents with SJS or TEN has not been systematically investigated. We searched the literature (Ovid: 1950 to June 2013 and PubMed: 1948 to June 2013) using terms for SJS/TEN and anticancer therapies. Primary case reports, case series, and clinical trials were included. In addition, MedWatch, the Food and Drug Administration Adverse Event Reporting System (FAERS), was searched (1968 to August 2012) for SJS/TEN reports associated with anticancer therapies. Proportional reporting ratios (PRR>2, N>3), empirical Bayes geometric mean (EBGM>2, N>3), and lower 95% confidence interval (EBGM0.05>2) were used as thresholds to constitute a signal of association between SJS/TEN and anticancer drugs. There were 46 SJS and 37 TEN cases associated with 18 and 22 anticancer drugs in the literature, respectively. Among cases in the FAERS, significant signals were associated with SJS for bendamustine and with TEN for bendamustine, busulfan, chlorambucil, fludarabine, lomustine, and procarbazine. Several drugs reported in the published literature to be associated with SJS/TEN were not found to have significant signals in FAERS. Proactive pharmacovigilance to detect and define safety signals serves to aid oncology practitioners in the recognition of possible, yet uncommon, serious, and/or life-threatening skin reactions.

Rash to the mTOR inhibitor everolimus: systematic review and meta-analysis.

BACKGROUND: Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved for treatment of renal cell carcinoma, subependymal giant cell astrocytoma, breast cancer, and progressive neuroendocrine tumors of pancreatic origin. Its use may be hindered because of adverse events, including rash. The reported incidence and risk of a rash to everolimus varies widely and has not been closely investigated. Therefore, we conducted a systematic review and meta-analysis of the literature to determine the incidence and risk of developing a rash. METHODS: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology from 1998 to December 2011 using the keyword "everolimus" to identify relevant clinical trials. Eligible studies included prospective phase II and III clinical trials of cancer patients on 10 mg of everolimus daily with available data on incidence of rash. The summary incidence and relative risk (RR) of rash were calculated using either the random-effects or fixed-effects model, depending on the heterogeneity of the constituent studies. RESULTS: A total of 2242 patients with various malignancies from 13 clinical trials were included in the analysis. The summary incidences of all-grade and high-grade rash in patients on everolimus were 28.6% [95% confidence interval (CI), 20.8-38.0] and 1.0% (95% CI, 0.6-1.8), respectively. Everolimus was associated with a statistically significant increased risk of all-grade rash (RR=3.853, 95% CI, 2.470-6.013, P=0.000), but the RR for high-grade rash (RR=2.997, 95% CI, 0.633-14.185) was not statistically significant, with a P value of 0.166. CONCLUSIONS: Everolimus is associated with a significant risk of developing a rash. Management of rash to everolimus is critical to prevent dose modifications and decreased quality of life, both of which can negatively affect overall clinical outcomes.

Pruritus in patients treated with targeted cancer therapies: systematic review and meta-analysis.

BACKGROUND: Pruritus has been anecdotally described in association with targeted cancer therapies. The risk of pruritus has not been systematically ascertained. OBJECTIVE: A systematic review and meta-analysis of the literature was conducted for axitinib, cetuximab, dasatinib, erlotinib, everolimus, gefitinib, imatinib, ipilimumab, lapatinib, nilotinib, panitumumab, pazopanib, rituximab, sorafenib, temsirolimus, tositumomab, vandetanib, and vemurafenib. METHODS: Databases from PubMed, Web of Science (January 1998 through July 2012), and American Society of Clinical Oncology abstracts (2004 through 2012) were searched. Incidence and relative risk of pruritus were calculated using random- or fixed-effects model. RESULTS: The incidences of all-grade and high-grade pruritus were 17.4% (95% confidence interval 16.0%-19.0%) and 1.4% (95% confidence interval 1.2%-1.6%), respectively. There was an increased risk of all-grade pruritus (relative risk 2.90 [95% confidence interval 1.76-4.77, P < .001]) and variation among different drugs (P < .001). LIMITATIONS: The reporting of pruritus may vary, resulting from concomitant medications, comorbidities, and underlying malignancies. We found a higher incidence of pruritus in patients with solid tumors, concordant with those targeted therapies with the highest pruritus incidences. CONCLUSION: There is a significant risk of developing pruritus in patients receiving targeted therapies. To prevent suboptimal dosing and decreased quality of life, patients should be counseled and treated against this untoward symptom.

Impact of dermatologic adverse events on quality of life in 283 cancer patients: a questionnaire study in a dermatology referral clinic.

BACKGROUND: Anticancer therapies cause a wide range of dermatologic adverse events (AE). Although the frequency and severity of these events have been described, their effects on health-related quality of life (QoL) remain poorly understood, and the ones having a greater impact have not been ascertained. OBJECTIVE: To assess QoL in patients on conventional versus targeted anti-cancer therapies using a dermatology-specific questionnaire. METHODS: Patients (n = 283) completed the Skindex-16, a QoL questionnaire measuring the effects on three domains: symptoms, emotions, and function. Patients were grouped into two categories according to the types of oncology treatments received: (1) targeted therapies and (2) non-targeted therapies. Correlations of Skindex-16 scores with type of anti-cancer therapy, number of AEs, and specific dermatologic AEs were investigated. RESULTS: Significant differences between patients treated with targeted versus non-targeted therapy with regards to total Skindex-16 (p = 0.02) and emotion subdomain (p = 0.02) scores were observed. Additionally, patients on targeted therapies experienced a significantly greater number of AEs (p < 0.001) compared with patients on non-targeted therapies. Patients who exhibited epidermal growth factor receptor (EGFR) inhibitor-induced rash had higher Skindex-16 scores (p = 0.009) and higher scores in the symptom (p < 0.001), emotion (p = 0.01), and function (p = 0.001) subdomains than patients without this AE. Similar results were observed for pruritus. All p values were two sided. CONCLUSIONS: Dermatologic AEs are associated with a diminished QoL. Targeted therapies are associated with a significantly increased number of AEs and worse total and emotion Skindex-16 scores in comparison with non-targeted therapies. EGFR inhibitor rash and pruritus produced the greatest negative impact.

Pruritus to anticancer agents targeting the EGFR, BRAF, and CTLA-4.

In the past decade, the expanded use of targeted anticancer drugs has significantly prolonged survival in patients treated for a variety of cancers. Despite their increased specificity, agents such as epidermal growth factor receptor inhibitors (EGFRIs), BRAF inhibitors, and targeted immunotherapies have commonly been associated with a number of dermatologic adverse events, often necessitating treatment modifications and negatively impacting patients' quality of life. Although toxicities such as rash and xerosis are frequently discussed, symptomatic pruritus, or itch, has emerged as an important, and frequently neglected, event. The present study reviews the incidence and clinical presentation of pruritus with the EFGRIs, and with two novel anti-melanoma drugs, vemurafenib and ipilimumab, with a focus on the putative underlying pathophysiology, and current management strategies.