Emily S. Yin

Nivolumab-associated vitiligo-like depigmentation in a patient with acute myeloid leukemia: A novel finding

Programmed cell death–1 receptor (PD-1) inhibitors enhance the antitumoral immune response via immune checkpoint inhibition. In a healthy immune system, the binding of ligands to PD-1 induces T-cell inactivation and prevents overactive immune responses. However, PD-1 ligands are also expressed by a variety of tumors, including melanomas, renal cell carcinomas, and brain tumors, in an effort to evade the host immune response. Although immune checkpoint inhibitors have revolutionized care for cancer patients, new cutaneous and systemic toxicities are still being discovered. Nivolumab is a humanized IgG4 anti–PD-1 monoclonal antibody that is currently approved by the US Food and Drug Administration for the treatment of melanoma, non–small cell lung cancer, renal cancer, and classical Hodgkin lymphoma.1 Several adverse effects of immune-targeting therapies are described and are referred to as immune-related adverse events (irAEs). Systemic irAEs include enterocolitis, pneumonitis, hepatitis, nephritis, hypophysitis, and autoimmune thyroid disease. In addition, dermatologic toxicity is the most common irAE of checkpoint inhibitors and ranges from pruritus and mild dermatoses to severe reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis.2 Vitiligo-like depigmentation is well described in melanoma patients receiving immunotherapy with PD-1 inhibitors and may be associated with favorable outcomes.3 Here we report a case of vitiligo-like depigmentation in a patient with acute myeloid leukemia (AML) receiving nivolumab as part of a phase II clinical trial. To our knowledge, this is the first reported case of vitiligo-like depigmentation associated with PD-1 inhibitor treatment in a patient with a nonmelanoma malignancy. Previous reports of PD-1 inhibitor–associated vitiligo-like depigmentation have been exclusively described in patients being treated for melanoma.

Topical Corticosteroid Phobia in Atopic Dermatitis: A Systematic Review

Importance Topical corticosteroid (TCS) phobia refers to the negative feelings and beliefs related to TCSs experienced by patients and patients’ caregivers. This phenomenon may be a major contributing factor in treatment failure in patients with atopic dermatitis, yet it has been sparsely described in the literature. Objective To systematically assess the nomenclature, prevalence, origins, and effect on treatment adherence of TCS phobia in atopic dermatitis. Evidence Review A literature search was conducted using specific eligibility criteria across electronic databases, including Ovid (MEDLINE, EMBASE), PubMed, and Web of Science, for articles published from January 1, 1946, to October 31, 2016. Included articles must have assessed TCS phobia in patients with atopic dermatitis or their caregivers. Quality ratings of studies were based on a modified version of the Oxford Centre for Evidence-Based Medicine quality rating scheme for individual studies. Findings Of the 490 articles identified by literature search, 16 met the eligibility criteria. All studies were cross-sectional. Topical corticosteroid phobia prevalence ranged from 21.0% (95% CI, 15.8%-26.2%) to 83.7% (95% CI, 81.9%-85.5%). There was significant variation in how phobia was defined, ranging from concern to irrational fear. Questionnaires used to assess for TCS phobia included 1 to 69 questions. In the 2 studies that compared nonadherence between a phobia group and a nonphobia group, patients in both phobia groups were found to have a significantly higher rate of nonadherence (49.4% vs 14.1% and 29.3% vs 9.8%). The sources from which patients were receiving information about corticosteroids included physicians, friends and relatives, broadcast media, print media, and the internet. Conclusions and Relevance Features of TCS phobia are commonly reported by patients across cultures and may be associated with a higher rate of nonadherence. Patients with TCS phobia and the sources from which patients are receiving information about corticosteroids may be targetable for intervention to increase adherence to treatment regimens. The nomenclature and assessment methods for TCS phobia used in studies, however, lack standardization, precluding quantitative comparison and extrapolation of data. Additional research, using standardized definitions and methods of assessment, is needed to better characterize this phenomenon and evaluate the efficacy of potential interventions.

Speed of Adoption of Immune Checkpoint Inhibitors of Programmed Cell Death 1 Protein and Comparison of Patient Ages in Clinical Practice vs Pivotal Clinical Trials

Importance The US Food and Drug Administration (FDA) is increasing its pace of approvals for novel cancer therapeutics, including for immune checkpoint inhibitors of programmed cell death 1 protein (anti–PD-1 agents). However, little is known about how quickly anti–PD-1 agents agents reach eligible patients in practice or whether such patients differ from those studied in clinical trials that lead to FDA approval (pivotal clinical trials). Objectives To assess the speed with which anti–PD-1 agents agents reached eligible patients in practice and to compare the ages of patients treated in clinical practice with the ages of those treated in pivotal clinical trials. Design, Setting, and Participants This retrospective cohort study, performed from January 1, 2011, through August 31, 2016, included patients from the Flatiron Health Network who were eligible for anti–PD-1 agents treatment of selected cancer types, which included melanoma, non–small cell lung cancer (NSCLC), and renal cell carcinoma (RCC). Main Outcomes and Measures Cumulative proportions of eligible patients receiving anti–PD-1 agents treatment and their age distributions. Results The study identified 3089 patients who were eligible for anti–PD-1 agents treatment (median age, 66 [interquartile range, 56-75] years for patients with melanoma, 66 [interquartile range, 58-72] years for patients with RCC, and 67 [interquartile range, 59-74] years for patients with NSCLC; 1742 male [56.4%] and 1347 [43.6%] female; 2066 [66.9%] white). Of these patients, 2123 (68.7%) received anti–PD-1 agents treatment, including 439 eligible patients with melanoma (79.1%), 1417 eligible patients with NSCLC (65.6%), and 267 eligible patients with RCC (71.2%). Within 4 months after FDA approval, greater than 60% of eligible patients in each cohort had received anti–PD-1 agents treatment. Overall, similar proportions of older and younger patients received anti–PD-1 agents treatment during the first 9 months after FDA approval. However, there were significant differences in age between clinical trial participants and patients receiving anti–PD-1 agents treatment in clinical practice, with more patients being older than 65 years in clinical practice (range, 327 of 1365 [60.6%] to 46 of 72 [63.9%]) than in pivotal clinical trials (range, 38 of 120 [31.7%] to 223 of 544 [41.0%]; all P < .001). Conclusions and Relevance Anti-PD-1 agents rapidly reached patients in clinical practice, and patients treated in clinical practice differed significantly from patients treated in pivotal clinical trials. Future actions are needed to ensure that rapid adoption occurs on the basis of representative trial evidence.

The skin as a window to the blood: Cutaneous manifestations of myeloid malignancies

Cutaneous manifestations of myeloid malignancies are common and have a broad range of presentations. These skin findings are classified as specific, due to direct infiltration by malignant hematopoietic cells, or non-specific. Early recognition and diagnosis can have significant clinical implications, as skin manifestations may be the first indication of underlying hematologic malignancy, can reflect the immune status and stage of disease, and cutaneous reactions may occur from conventional and targeted agents used to treat myeloid disease. In addition, infections with cutaneous involvement are common in immunocompromised patients with myeloid disease. Given the varying presentations, dermatologic findings associated with myeloid malignancies can pose diagnostic challenges for hematologists and dermatologists. In this clinical review intended for the practicing hematologist/oncologist, we discuss the presentation, diagnosis, treatment, and prognostic value of the most common cutaneous manifestations associated with myeloid malignancies using illustrative macro- and microscopic figures and with a special emphasis on practical considerations.

Transparency and Dermatologic Device Approval by the US Food and Drug Administration

Importance The US Food and Drug Administration approves Class III medical devices via the premarket approval pathway, often requiring clinical data on safety and efficacy. Manufacturers can submit incremental device changes via supplemental applications, which are not subjected to such vetting measures and can cause understudied changes that lead to drift from a device’s original design. Objectives To characterize the postapproval changes to Class III dermatologic devices and to evaluate inconsistencies in the use of the premarket approval pathway. Design, Setting, and Participants This study was a cross-sectional retrospective cohort analysis of a public US Food and Drug Administration database for premarket approval of devices. Included were dermatologic devices approved by the US Food and Drug Administration between January 1, 1980, and November 1, 2016, through the premarket pathway for device approval. Main Outcomes and Measures Original devices were identified, and their supplements were characterized chronologically, by review track, and by modification category. Results The 27 dermatologic devices studied consisted of 14 injectables, 11 photodynamic therapies, a dermal replacement matrix, and a diagnostic imaging instrument. Supplemental applications are increasingly used: the data-requiring panel-track pathway was the least common approach (2.8% [16 of 562 supplements]), while the 30-day track, which does not require clinical data, was most frequently used (42.5% [239 of 562 supplements]). Four devices (14.8%) underwent low-risk recalls (Class II or Class III), and 10 devices (37.0%) were voluntarily withdrawn. Conclusions and Relevance As manufacturers make increasing use of supplemental applications, minor device changes may occur without supporting clinical data, which could pose a safety risk to patients.

Biodegradable bioadhesive nanoparticle incorporation of broad-spectrum organic sunscreen agents

Abstract Conventional emulsion‐based sunscreen formulations are limited by postapplication epicutaneous penetration that increases the risk of allergic dermatitis, cellular damage, and filter photodegradation upon ultraviolet radiation (UVR) exposure. Encapsulation of the UVB filter padimate O within bioadhesive biodegradable nanoparticles (BNPs) composed of poly(d,l‐lactic acid)‐hyperbranched polyglycerol was previously shown to enhance UVR protection while preventing skin absorption. Herein, we assess the capacity of BNP co‐incorporation of avobenzone and octocrylene to provide broad‐spectrum UVR protection. The ratio of UV filters within nanoparticles (NPs) was optimized for filter–filter stabilization upon UV irradiation and maximum drug loading. In vitro water‐resistance test showed significant particle retention at 85% over 3 hr. In a pilot clinical study, protection against UVR‐induced erythema of BNPs was found to be comparable to the FDA standard P2. Thus, sunscreen formulations utilizing BNP incorporation of a combination of organic filters may offer key safety and performance advantages.

A 54-year-old woman with arthritis and discoloration of the hands, ears, and sclerae.

A 54-year-old woman presented with a 1-year history of blue discoloration on the web spaces of her hands and a 5-year history of black deposits on her sclerae. The patient’s past medical history was significant for debilitating arthritis for which she had undergone bilateral knee replacement surgeries, at which time her orthopedist discovered black-colored cartilage intraoperatively (Fig. 1). She also reported a history of fracturing her ribs and clavicle while swimming. She denied use of topical medications, family history of similar findings, or discolored urine. On physical examination, the bilateral interdigital web spaces had multiple blue–gray speckled macules (Fig. 2). There was dark gray scleral pigmentation (Fig. 3) and slate blue–gray discoloration of the conchal bowls. On histopathology, a punch biopsy of the right hand interdigital web space revealed solar elastosis with thickened collagen and yellow– brown discoloration of both dermal collagen fibers and elastotic fibers (Figs. 4 and 5). A von Kossa stain was negative for calcium. Relevant laboratory data included a urine organic acid screen with markedly elevated homogentisic acid (HGA) excretion (1832 mmol/mol creatinine, reference <11) by gas chromatography–mass spectrometry. X-ray imaging of her cervical spine revealed multilevel degenerative disc disease with intervertebral disc calcifications. Magnetic resonance imaging of the knees demonstrated complete loss of joint space with Figure 1 Black discolored cartilage was found intraoperatively during a previous bilateral knee replacement surgery