ABSTRACT
BACKGROUND: MEK inhibitors cause a wide spectrum of mucocutaneous toxicities which can delay or interrupt life-saving therapy. PURPOSE: To summarize the morphology, incidence, and clinical presentation of mucocutaneous toxicities from MEK inhibitors via a scoping review of the literature. METHODS: We conducted a scoping review of the published literature, including clinical trials, retrospective and prospective studies, reviews, and case reports and series. All included literature was analyzed by a panel of pediatric and adult oncodermatologists. RESULTS: Of 1626 initial citations, 227 articles met final inclusion criteria. Our review identified follicular reactions, ocular toxicities, xerosis, eczematous dermatitis, edema, and paronychia as the most common mucocutaneous side effects from MEK inhibitor therapy. Grade 1 and 2 reactions were the most prevalent and were typically managed while continuing treatment; however, grade 3 toxicities requiring dose reductions or treatment interruptions were also reported. CONCLUSION: Mucocutaneous toxicities to MEK inhibitor therapy are common and most often mild in severity. Early recognition and treatment can mitigate disruptions in oncologic therapy.
Subject(s)
Protein Kinase Inhibitors , Humans , Protein Kinase Inhibitors/adverse effects , Antineoplastic Agents/adverse effects , Neoplasms/drug therapy , Severity of Illness Index , Drug Eruptions/etiologyABSTRACT
With an increasing number of patients eligible for immune checkpoint inhibitors, the incidence of immune-related adverse events (irAEs) is on the rise. Dermatologic immune-related adverse events (D-irAEs) are the most common and earliest to manifest, often with important downstream consequences for the patient. Current guidelines lack clarity in terms of diagnostic criteria for D-irAEs. The goal of this project is to better define D-irAE for the purposes of identification, diagnosis, and future study of this important group of diseases.The objectives of this project were to develop consensus guidance for an approach to D-irAEs including disease definitions and severity grading. Knowing that consensus among oncologists, dermatologists, and irAE subspecialists would be critical for usability, we formed a Dermatologic irAE Disease Definition Panel. The panel was composed of 34 experts, including oncologists, dermatologists, a rheumatologist, and an allergist/immunologist from 22 institutions across the USA and internationally. A modified Delphi consensus process was used, with two rounds of anonymous ratings by panelists and two virtual meetings to discuss areas of controversy. Panelists rated content for usability, appropriateness, and accuracy on 9-point scales in electronic surveys and provided free text comments. A working group aggregated survey responses and incorporated them into revised definitions. Consensus was based on numeric ratings using the RAND/UCLA Appropriateness Method with prespecified definitions.Following revisions based on panelist feedback, all items received consensus in the second round of ratings. Consensus definitions were achieved for 10 core D-irAE diagnoses: ICI-vitiligo, ICI-lichen planus, ICI-psoriasis, ICI-exanthem, ICI-bullous pemphigoid, ICI-Grover's, ICI-eczematous, ICI-eruptive atypical squamous proliferation, ICI-pruritus without rash, and ICI-erosive mucocutaneous. A standard evaluation for D-irAE was also found to reach consensus, with disease-specific exceptions detailed when necessary. Each disorder's description includes further details on disease subtypes, symptoms, supportive exam findings, and three levels of diagnostic certainty (definite, probable, and possible).These consensus-driven disease definitions standardize D-irAE classification in a useable framework for multiple disciplines and will be the foundation for future work. Given consensus on their accuracy and usability from a representative panel group, we anticipate that they can be used broadly across clinical and research settings.
Subject(s)
Exanthema , Oncologists , Humans , Consensus , Immune Checkpoint Inhibitors/adverse effects , RadioimmunotherapyABSTRACT
Purpose: Trichodysplasia spinulosa (TS) is a rare, disfiguring skin condition which presents with widespread asymptomatic or pruritic, skin-colored papules with white protruding keratin spiculations in immunocompromised individuals. Due to its rarity, there is little data to guide treatment decisions. The purpose of this article is to report a case of TS that completely resolved after treatment with topical cidofovir.Materials and methods: A 19-year-old immunosuppressed female presented with widespread painful, itchy bumps on the nose and face. Upon examination, there were erythematous papules with hyperkeratinized spicules affecting the central face. Biopsy of the lesions was consistent with TS which was confirmed via PCR analysis. The tenderness of this patient's eruption was highly atypical for TS. Once daily topical application of compounded 1% cidofovir cream was prescribed.Results: The patient's symptoms resolved completely after 4 weeks of therapy with topical cidofovir 1% cream, without reduction of immunosuppression.Conclusions: Topical cidofovir 1% cream may be a valuable treatment for this rare disease.
Subject(s)
Polyomavirus Infections , Skin Diseases , Female , Humans , Young Adult , Cidofovir/therapeutic use , Immunocompromised Host , Polyomavirus Infections/diagnosis , Polyomavirus Infections/pathology , Polyomavirus Infections/therapy , Pruritus , Skin Diseases/pathologyABSTRACT
OBJECTIVES: Cutaneous diseases that disproportionately affect patients with darker pigmentation and their histologic features are historically understudied and undertreated. This review article aims to highlight the key clinical features, histopathology, and diagnostic pearls of several cutaneous diseases that commonly present in patients with darker pigmentation. METHODS: A literature search was conducted, and a list of cutaneous diseases that frequently affect patients with darker pigmentation was compiled. A group of experts expounded upon those that were most common or misdiagnosed according to scientific evidence and clinical practice. RESULTS: The diseases were divided into hypopigmented disorders, hyperpigmented disorders, scarring disorders, and alopecic disorders. Within each category, the etiology, clinical features, histopathology, and key histologic differential diagnoses are described and discussed. CONCLUSIONS: As many clinicians are taught that there are no effective treatment options or that these diseases are considered "cosmetic" in nature, patients often do not get a thorough medical workup or skin biopsy. This article aims to decrease the knowledge gap and serve as a resource for anyone involved in the care of patients with these cutaneous conditions.
Subject(s)
Skin Diseases , Skin Pigmentation , Humans , Skin Diseases/pathology , Skin Diseases/diagnosis , Pigmentation Disorders/pathology , Pigmentation Disorders/diagnosis , Diagnosis, Differential , Hyperpigmentation/pathology , Hyperpigmentation/diagnosisABSTRACT
PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS: We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS: Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). CONCLUSIONS: Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.
Subject(s)
Neurofibromatosis 1 , Protein Kinase Inhibitors , Adolescent , Adult , Child , Child, Preschool , Female , Humans , Male , Young Adult , Drug Eruptions/etiology , Follow-Up Studies , Neurofibroma, Plexiform/drug therapy , Neurofibroma, Plexiform/pathology , Neurofibromatosis 1/drug therapy , Prognosis , Protein Kinase Inhibitors/adverse effects , Retrospective StudiesABSTRACT
Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative. This strategic initiative aims to facilitate the seamless integration of key domains: (1) standardized clinical practice and innovative decision toolsets; (2) patient and provider education; and (3) a comprehensive clinical and translational research platform. The ultimate goal of this initiative is to develop and disseminate clinical best practices and biologic insights into irAEs to improve outcomes of patients with irAEs at MDACC and in the wider oncology community.
Subject(s)
Immune Checkpoint Inhibitors , Neoplasms , Humans , Neoplasms/drug therapy , Neoplasms/immunology , Neoplasms/therapy , Immune Checkpoint Inhibitors/adverse effects , Immune Checkpoint Inhibitors/therapeutic use , Drug-Related Side Effects and Adverse Reactions/therapy , Texas , Immunotherapy/methods , Immunotherapy/adverse effectsABSTRACT
BACKGROUND: Alternative bibliometrics or altmetrics, is a measure of an academic article's impact on social media outlets, which is quantified by the Altmetric Attention score (AAS). Given a lack of data for altmetric trends during the COVID-19 pandemic, we conducted a comprehensive, multivariable analysis of top dermatology manuscripts published during this time period. OBJECTIVE: We aim to assess (1) the relationship between traditional bibiliometrics and Altmetrics and (2) factors associated with high AAS. METHODS: All abstracted articles published in the top-5 (ranked by SCImago Journal Rankings) peer-reviewed dermatology journals published in 2021 were included in our study. We collected AAS as the dependent variable and categorical predictor variables included journal title, whether a conflict of interest existed, open access status, whether the article was related to COVID-19 or skin-of-color research, and the type of research (eg, clinical, basic science, review, etc). Numerical predictor variables consisted of the impact factor of journal, total citations, and number of authors. Multivariable linear or logistic regression models were used. RESULTS: The relationship between AAS and citation number was significant by multivariable analysis during the COVID-19 pandemic (P<.001). Numerous factors, including studies related to COVID-19, whether the article was open access, title of the journal, and journal impact factor were also independently related to higher AAS (P<.002). CONCLUSIONS: Our results validate the use of altmetrics as a complement to traditional bibliometrics, especially in times of widespread scientific interest. Despite existing in a complex realm of bibliometrics, there are also discernable patterns associated with higher AAS. This is especially relevant in the era of growing technologic importance and utility to assess the impact of scientific works within the general public.
ABSTRACT
For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.
Subject(s)
Melanoma , Skin Neoplasms , Humans , Melanoma/drug therapy , Melanoma/genetics , Melanoma/pathology , Skin Neoplasms/drug therapy , Skin Neoplasms/genetics , Skin Neoplasms/pathology , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins B-raf/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Protein Kinase Inhibitors/adverse effects , Mutation , Mitogen-Activated Protein Kinase KinasesABSTRACT
Although the management options for psoriasis have progressed with the use of systemic agents, there are few efficacious nonsteroidal topical therapies for patients with limited or lower grade disease. The effects of allopurinol (Allo) and glutathione (GSH) were examined in two different in vitro models for psoriasis. In the first model, human immortalized keratinocytes (HaCaT) were treated with M5 cocktail (IL-17A, IL-22, oncostatin M, IL-1α, and TNF-α) in four interventional groups (control, Allo, oxypurinol (Oxy), and methotrexate (MTX)). The number of live and dead cells was determined after treatment for 48 and 72 hrs. Allo decreased cell proliferation (total cells) without increasing cell death compared to both its xanthine oxidase inhibiting metabolite Oxy and a standard agent in clinical use, MTX. In the second model, a human psoriatic skin equivalent (PSE) culture system, cells were treated with vehicle control, Allo and GSH (as monotherapies and in combination), and vitamin D (VitD) for 2 and 6 days followed by histological analysis and altered gene expression. The combined exposure to Allo and GSH was equivalent to a standard antipsoriasis agent VitD in the inhibition of both proliferative and replicative markers. Histologic examination of the tissue at 6 days of exposure to VitD resulted in loss of the integrity of the squamous/epithelial continuity whereas tissue integrity was preserved with Allo and GSH exposure. The additional exposure of GSH to Allo reversed the increased thickness of the dermis layer caused by Allo exposure alone. Taken together, this data shows that topical Allo and GSH may have a synergistic effect with low toxicity and constitute a therapeutic advantage over current nonsteroidal therapies in the treatment of inflammatory skin conditions marked by increased cell proliferation such as psoriasis.
Subject(s)
Psoriasis , Humans , Psoriasis/metabolism , Skin/pathology , Keratinocytes/metabolism , Tumor Necrosis Factor-alpha/metabolism , Methotrexate/pharmacology , Methotrexate/therapeutic use , Cell ProliferationABSTRACT
Immune checkpoint inhibitors (ICIs) represent an emerging treatment option for a variety of cancer types. Through inhibition of programmed cell death protein 1 (PD-1), programmed cell death ligand 1 (PD-L1), and/or cytotoxic lymphocyte-associated antigen-4 (CTLA-4), ICIs activate the host's immune system causing a heightened anti-tumor response. However, off-target effects of ICIs can result in numerous different immune-related cutaneous adverse events (irCAEs). Beyond impacting quality of life, irCAEs can lead to dose limitations or discontinuation of anti-cancer therapies. Correct diagnosis is necessary for expedient and appropriate management. Skin biopsies are often performed to increase diagnostic accuracy and guide clinical management. An extensive literature review was performed using the PubMed database to identify the reported clinical and histopathologic features of irCAEs. This comprehensive review primarily details the histopathologic features of various irCAEs reported to date. Clinical presentation and immunopathogenesis are also discussed in relation to histopathology.
ABSTRACT
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy. Since the approval of ipilimumab in 2011, a total of nine ICIs have gained indications for various solid and hematologic malignancies. The expanding use of ICIs in oncology underscores the need for diagnosis and treatment expertise in immune related adverse events (irAE). Cutaneous toxicities are the earliest and most common irAE in this class of therapy. In addition to the more frequent reactions including vitiligo, lichenoid dermatitis, psoriasiform dermatitis, other less common skin toxicities including bullous dermatoses, neutrophilic dermatoses, and autoimmune dermato-rheumatologic diseases have been reported. Even though less than 3% of cutaneous irAEs (irCAEs) are classified as grade 3 or higher events, irCAEs can greatly impact quality of life. Appropriate management of irCAEs is critical to avoid unwarranted interruptions or discontinuation of lifesaving immunotherapy.
ABSTRACT
This study highlights the range of non-melanoma cancers where ICI-induced vitiligo can be present and challenges the exclusivity of this phenomenon to melanoma. We believe our manuscript will encourage awareness in our colleagues and stimulate interest in further studies to elucidate the mechanisms of ICI-induced vitiligo in both melanoma and non-melanoma cancers, and to understand whether this phenomenon holds the same positive prognostic value in both cancer groups. This is a retrospective cohort study from a single-institution's electronic medical record for cancer patients treated with ICIs who subsequently developed vitiligo. We identified 151 patients with ICI-induced vitiligo, 19 (12.6%) non-melanoma and 132 (77.4%) melanoma patients. Time to onset of vitiligo was nearly doubled in the non-melanoma cohort, however, this is confounded by possible delayed diagnosis or under reporting of this asymptomatic condition in patients who do not regularly receive skin exams. The majority of patients had a stable course of vitiligo with 91.4% receiving no treatment in this largely Caucasian cohort. Two patients with non-melanoma cancers and Fitzpatrick type IV or above skin received treatment with narrowband ultraviolet B light therapy and topical steroids with near-complete response. This study highlights the occurrence of ICI-induced vitiligo in a variety of non-melanoma cancers, where skin of color patients will be more prevalent and the need for treatment will potentially be more urgent. Further study is needed to elucidate the mechanism of ICI-induced vitiligo and determine if non-melanoma cancers have the same association between vitiligo and increased tumor response.
Subject(s)
Skin Neoplasms , Ultraviolet Therapy , Vitiligo , Humans , Vitiligo/chemically induced , Vitiligo/epidemiology , Vitiligo/therapy , Immune Checkpoint Inhibitors/adverse effects , Skin Neoplasms/therapy , Skin Neoplasms/drug therapy , Retrospective StudiesABSTRACT
PREVENTION RELEVANCE: Bexarotene is a rexinoid that has been shown to prevent mammary tumors in mouse models but oral dosing has toxicities. This phase I study evaluates topical bexarotene, as a potential chemoprevention agent, for safety and toxicity in high-risk women for breast cancer.
Subject(s)
Bexarotene , Neoplasms , Female , Bexarotene/administration & dosage , Bexarotene/adverse effects , Neoplasms/drug therapy , Humans , Administration, Topical , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effectsABSTRACT
As treatment with immune checkpoint inhibitors (CPIs) for cancer increases, so has the incidence of immune-related cutaneous adverse events (irCAEs). These toxicities can significantly impact quality of life and may be dose-limiting. Current guidelines for irCAEs offer only corticosteroids or CPI discontinuation. Evidence supports biologic immunomodulatory therapies when corticosteroids fail or need avoidance. A review of literature from 2010 to 2020 yielded 45 articles, resulting in 185 irCAEs, including bullous pemphigoid-like eruption (n = 55), psoriasis/psoriasiform dermatitis (n = 41), and maculopapular rash (n = 31). Treatments included immunomodulators, intravenous immunoglobulin, aprepitant, acitretin, tetracyclines, and biologic agents. Overall, 92.3% of patients saw improvement or resolution of their rash. Bullous pemphigoid-like eruptions were treated with a tetracycline +/- niacinamide (94.7% success [18/19]), omalizumab (100% success [7/7]), and rituximab (100% success [10/10]). Although prospective research is required, this review provides a comprehensive list of successful, non-corticosteroid treatment options for irCAEs to improve compliance with lifesaving cancer therapy.