The spectrum of cutaneous toxicities related to novel genitourinary cancer therapies.

CONTEXT: Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities. OBJECTIVE: To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors. EVIDENCE ACQUISITION: A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs). EVIDENCE SYNTHESIS: Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender. CONCLUSIONS: Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.

[Drug-related exanthema under immunotherapy and targeted oncological therapy]. / Arzneimittelexantheme unter Immun- und zielgerichteter onkologischer Therapie.

BACKGROUND: Oncological therapies can cause a variety of mucocutaneous adverse events. Exanthematous adverse events can be challenging in the context of the urgent need for cancer treatment due to their spread, sometimes rapid progression, and mucous membrane or organ involvement. MATERIALS AND METHODS: This article provides an overview of the most important exanthematic dermatoses as side effects of modern drug-based tumor therapies with diagnostic and therapeutic information for clinicians, taking into account the current literature and guidelines. RESULTS: Exanthematous adverse events of immune checkpoint inhibitors, EGFR antagonists, kinase inhibitors, bispecific T­cell engagers, and the CCR4 inhibitor mogamulizumab are reviewed in detail. CONCLUSIONS: Cutaneous side effects are common across all drug classes and cover a broad spectrum. While some adverse events are specific to one drug class, many exanthemas can occur with both oncological immunotherapies and various targeted therapies. A reliable diagnosis, dose adjustment or discontinuation of the offending agent in consultation with the treating oncologists and appropriate symptomatic therapy are important for correct management. In the case of severe, life-threatening drug reactions, however, permanent discontinuation of the drug is essential.

[Chinese expert consensus on diagnosis and treatment of immune checkpoint inhibitor-related skin adverse reactions (2024 edition)].

Immune checkpoint inhibitors (ICIs) have emerged as crucial therapeutic agents for various malignancies by activating the host immune system against tumor cells. However, many different types of skin adverse reactions may occur during its use, including eruption, pruritus, blistering, hypopigmentation, alopecia, and even severe cases, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). These cutaneous immune-related adverse events (cirAEs) had a high incidence, which seriously affected patients' quality of life and antitumor treatment decisions. Some severe cutaneous adverse reactions (SCARs) even endanger patients' lives. Therefore, the Chinese Society of Dermatology, the Chinese Dermatologist Association of the Chinese Medical Doctor Association, the Dermatology Division of the Chinese Geriatrics Society, and other relevant experts jointly discussed and formulated the 'Chinese Expert Consensus on the Diagnosis and Treatment of Immune Checkpoint Inhibitor-Related Cutaneous Adverse Reactions'. This consensus covers the name, epidemiology, pathogenesis, clinical features, classification and grading of cirAEs, principles of management and the re-initiation of ICIs. It aims to provide a more scientific and authoritative reference for the diagnosis and treatment of cirAEs in China in the future.

[Cutaneous adverse events to systemic anticancer therapies : Hand-foot syndrome and nail changes]. / Kutane Nebenwirkungen onkologischer Systemtherapien : Hand-Fuß-Syndrom und Nagelveränderungen.

BACKGROUND: Hand-foot syndrome (HFS) and nail changes are frequent adverse events of anticancer therapies. OBJECTIVES: To provide a review of current evidence in HFS and nail disorders associated with medical tumor treatment. MATERIALS AND METHODS: Basis is the current German S3 guideline "Supportive therapy in oncologic patients" and literature on this topic published since the guideline was finalized. RESULTS: Two variants of HFS are distinguished: a chemotherapy-associated and a kinase-inhibitor-associated variant. In the first form, painful erythema, blisters and ulceration can occur, also in other areas with a high number of sweat glands such as axillary and inguinal regions. Thus, the secretion of toxic substances through sweat glands is a proposed pathogenetic mechanism. For the second form, which results in callus-like painful thickening of the horny layer on areas of mechanic pressure, a vascular mechanism is proposed. For prophylaxis of HFS, avoidance of mechanical stress, regular cleaning of predisposed areas, and also urea- and diclofenac-containing ointments are recommended; in case of infusions (taxanes, doxorubicine), cooling of hands and feet during infusion is recommended. In case of manifest HFS, dose reduction or prolongation of intervals of the associated treatment are recommended. Nail changes often develop under therapy with chemotherapeutic agents but also under treatment with agents such as checkpoint inhibitors or under targeted therapy. Different components of the nail unit may be involved such as the nail matrix, nail bed, nail plate, hyponychium, lunula and proximal and lateral nail folds. CONCLUSION: This work gives insight into the pathophysiology of HFS and nail disorders that develop under systemic oncologic treatments and gives recommendations for prophylaxis and treatment.

Annular drug eruptions.

Cutaneous adverse drug reactions are undesirable cutaneous changes caused by medications. Drug eruptions can mimic a wide range of dermatoses that include exanthematous (morbilliform), urticarial, pustular, bullous, papulosquamous, or granulomatous lesions, and sometimes these eruptions may present with annular, polycyclic, or polymorphous configurations. The correct identification of a cutaneous drug eruption depends on a high index of suspicion, detailed medication exposure history, chronologic evaluation of the causal relationships between drug exposures and eruptions, and the exclusion of other infectious or idiopathic diseases. Most drug eruptions are annoying but self-limited, usually resolving after the withdrawal of the causative agents. Rarely, patients have severe cutaneous adverse reactions, such as Stevens-Johnson syndrome, toxic epidermal necrolysis, and drug reaction with eosinophilia and systemic symptoms (DRESS), which are potentially lethal adverse drug reactions that involve the skin and mucous membranes and may also damage internal organs. Prompt recognition of the alarming signs of severe cutaneous adverse reactions and providing adequate treatment may thus be life-saving. We present the main clinical presentations, histopathology, possible implicated medications, and treatment of cutaneous adverse drug reactions that can present in annular configurations.

Dermatologic Adverse Events in Oncologic Therapies.

During recent decades, the number of patients diagnosed with cancer has been increasing. Conventional treatments, which comprise chemotherapy, radiotherapy, surgery, and hormonal treatment, represent improvements in effectiveness and safety of administration and continue to be the standard model of treating malignancies. Advances in oncology have enabled the development of newer therapies such as immunotherapy and targeted therapy. However, numerous adverse events continue to emerge, including dermatologic adverse events, which significantly impact the course of treatment, treatment outcomes, and patient quality of life. Alopecia occurs most commonly, along with mucositis, xerosis, pruritus, hyperpigmentation, acral erythema, nail changes, and many others. The early detection, monitoring, and adequate treatment of these adverse events could prevent reduction, interruption, or permanent discontinuation of oncologic therapies. Herein we review various dermatologic adverse events that may occur due to the therapy applied, present their possible treatments, and emphasize the need to evaluate their impact on patient quality of life.

Lichenoid drug eruption on the lower lip caused by anti-PD-1 monoclonal antibody: a case report and literature review.

Anti-PD-1/PD-L1 monoclonal antibodies result in a unique spectrum of side effects, widely known as immune-related adverse events. Toripalimab is an anti-PD-1 monoclonal antibody used for the treatment of some cancers. Here we report the first case, to our knowledge, of oral lichenoid drug reaction triggered by toripalimab. A 78-year-old man who was diagnosed with systemic metastatic prostate cancer presented with ulcers on the lower lip after the fifth cycle of toripalimab. We diagnosed him with oral lichenoid drug reaction based on clinical manifestation, histopathological findings and the history of anti-PD-1 therapy. The patient responded well to oral corticosteroids combined with helium-neon laser therapy. The anti-PD-1 therapy was not restarted because of stable disease, and the eruptions did not recur.

Current Perspectives on Severe Drug Eruption.

Adverse drug reactions involving the skin are commonly known as drug eruptions. Severe drug eruption may cause severe cutaneous adverse drug reactions (SCARs), which are considered to be fatal and life-threatening, including Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS). Although cases are relatively rare, approximately 2% of hospitalized patients are affected by SCARs. There is an incidence of 2 to 7 cases/million per year of SJS/TEN and 1/1000 to 1/10,000 exposures to offending agents result in DRESS. However, the mortality rate of severe drug eruptions can reach up to 50%. SCARs represent a real medical emergency, and early identification and proper management are critical to survival. The common pathogenesis of severe drug eruptions includes genetic linkage with HLA- and non-HLA-genes, drug-specific T cell-mediated cytotoxicity, T cell receptor restriction, and cytotoxicity mechanisms. A multidisciplinary approach is required for acute management. Immediate withdrawal of potentially causative drugs and specific supportive treatment is of great importance. Immunoglobulins, systemic corticosteroids, and cyclosporine A are the most frequently used treatments for SCARs; additionally, new biologics and plasma exchange are reasonable strategies to reduce mortality. Although there are many treatment methods for severe drug eruption, controversies remain regarding the timing and dosage of drug eruption. Types, dosages, and indications of new biological agents, such as tumor necrosis factor antagonists, mepolizumab, and omalizumab, are still under exploration. This review summarizes the clinical characteristics, risk factors, pathogenesis, and treatment strategies of severe drug eruption to guide clinical management.

Dermatological manifestations associated with COVID-19: A comprehensive review of the current knowledge.

Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become a significant health problem globally. The virus has spread widely and become a global pandemic. The pathophysiology for SARS-CoV-2 has not been explained clearly. It has been associated with several multiorgan symptoms, among which its dermatological manifestations are of great interest. Primarily, there has been no report of skin features among COVID-19 patients. Nevertheless, recently there have been several reports regarding COVID-19 patients who presented with cutaneous manifestations. In the current review, we focus on the various cutaneous manifestations of COVID-19 infection.

Patterns of Cutaneous and Noncutaneous Immune-Related Adverse Events Among Patients With Advanced Cancer.

Importance: Cutaneous immune-related adverse events (cirAEs) are some of the earliest toxic reactions to emerge following immune-checkpoint inhibitor (ICI) initiation. As an early indicator of robust inflammatory response, cirAEs may be associated with patterns of immune-mediated toxic effects, but associations between these events and noncutaneous immune-related adverse events (irAEs) remain underexplored. Objectives: To characterize patterns of cirAEs and irAEs across care settings and examine associations between the features of first cirAE, overall irAE risk, and risk of specific irAE subtypes. Design, Setting, and Participants: A retrospective cohort study was conducted at a single academic medical center. The cohort included 358 patients with cancer who initiated anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 ICI therapy between January 1, 2016, and March 8, 2019, and developed 1 or more cirAEs, identified using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes and confirmed via manual medical record review. All relevant information documented before March 31, 2020, was included. Exposures: Anti-programmed death 1/ligand 1 and/or anticytotoxic-T-lymphocyte-4 therapy. Main Outcomes and Measures: Associations between specific cirAE morphologic classes and patterns of irAEs (occurrence, timeline, organ class, and specific toxic effects). Given the potential that shared underlying factors are associated with the risk of both noncutaneous and cutaneous toxic effects, the presence of observed positive associations between certain cirAE and irAE subtypes was hypothesized. Results: Of the 358 patients, 213 were men (59.5%); median age was 65 years (interquartile range, 55-73 years). Nearly half of the patients (177 [49.4%]) with cirAE also developed a noncutaneous irAE. Most patients (128 [72.3%]) experienced their first cirAE before developing any irAE. Several cirAE morphologic classes were found to be associated with overall, organ-based, and specific irAEs. More specifically, mucositis was found to be associated with overall irAE risk (odds ratio [OR], 5.28; 95% CI, 1.11-24.26; P = .04), gastrointestinal irAEs (OR, 5.70; 95% CI, 1.11-29.40; P = .04), and the specific diagnosis of gastroenterocolitis (OR, 6.80; 95% CI, 1.24-37.39; P = .03). In addition, psoriasis was associated with an increased risk of endocrine irAEs (OR, 4.54; 95% CI, 1.21-17.04; P = .03). Conclusions and Relevance: In this cohort study, these findings underscore the risk of multisystem toxic effects in patients experiencing cirAEs and highlight potential opportunities for dermatologists in the management of noncutaneous toxic effects.

A 62-year-old man with new-onset bullae.

Cutaneous blisters and/or bullae can occur in autoimmune disorders, infections, genetic diseases, and drug hypersensitivity. We present the case of a 62-year-old man with two autoimmune conditions who was admitted for antibiotic treatment of a lower extremity infection and suddenly developed a bullous rash. His physical examination was significant for tense, bullous lesions that involved his chin, palms, and inner thighs. Narrowing the differential diagnosis for patients with blistering skin lesions is imperative for timely and appropriate management.

Tolerance induction to deferasirox in a child with transfusion-dependent beta thalassemia.

Beta thalassemias are autosomal recessive hemoglobin disorders related to a defect in the beta-globin chain production. Most of the major forms of beta-thalassemia are transfusion dependent leading to iron overload. Today, three iron chelators are available in France. We report the case of a patient suffering from ß+ major transfusion-dependent thalassemia who presented with severe skin reactions to deferoxamine and deferasirox as well as with agranulocytosis after deferiprone administration. The patient benefited from successful tolerance induction to deferasirox. With the increasing number of children suffering from iron overload, we believe that our protocol can be useful to pediatric hematology teams confronted with multiple iron chelator reactions.

Implementing a Locally Made Low-Cost Intervention for Wound and Lymphedema Care in Western Kenya.

In Western Kenya, the burden of chronic wounds and lymphedema has a significant impact on functionality and quality of life. Major barriers to provision of care include availability, affordability, and accessibility of bandages. At the Academic Model Providing Access to Healthcare, dermatologists and pharmacists collaborated to develop a 2-component compression bandage modeled after the Unna boot, using locally available materials, that is distributed through a revolving fund pharmacy network. In partnership with nursing, use of these bandages at a national referral hospital and a few county facilities has increased, but increasing utilization to an expanded catchment area is needed.

Cutaneous Immune-Related Adverse Events (irAEs) to Immune Checkpoint Inhibitors: A Dermatology Perspective on Management [Formula: see text].

Immune checkpoint inhibitors have proven to be efficacious for a broad spectrum of solid organ malignancies. These monoclonal antibodies lead to cytotoxic T-cell activation and subsequent elimination of cancer cells. However, they can also lead to immune intolerance and immune-related adverse event (irAEs) that are new and specific to these therapies. Cutaneous irAEs are the most common, arising in up to 34% of patients on PD-1 inhibitors and 43% to 45% on CTLA-4 inhibitors. The most common skin manifestations include maculopapular eruption, pruritus, and vitiligo-like lesions. A grading system has been proposed, which guides management of cutaneous manifestations based on the percent body surface area (BSA) involved. Cutaneous irAEs may prompt clinicians to reduce drug doses, add systemic steroids to the regiment, and/or discontinue lifesaving immunotherapy. Thus, the goal is for early identification and concurrent management to minimize treatment interruptions. We emphasize here that the severity of the reaction should not be graded based on BSA involvement alone, but rather on the nature of the primary cutaneous pathology. For instance, maculopapular eruptions rarely affect <30% BSA and can often be managed conservatively with skin-directed therapies, while Stevens-Johnson syndrome (SJS) affecting even 5% BSA should be managed aggressively and the immunotherapy should be discontinued at once. There is limited literature available on the management of the cutaneous irAEs and most studies present anecdotal evidence. We review the management strategies and provide recommendations for psoriatic, immunobullous, maculopapular, lichenoid, acantholytic eruptions, vitiligo, alopecias, vasculitides, SJS/toxic epidermal necrolysis, and other related skin toxicities.

Cutaneous drug eruptions including serum sickness-like reaction, symmetrical drug-related intertriginous and flexural exanthema, and drug-induced lupus.

Cutaneous manifestations of drug reactions are common yet vary widely in their appearance and degree of internal organ involvement. Serum sickness--like reactions, symmetrical drug-related intertriginous and flexural exanthem, granulomatous drug eruption, pseudolymphoma, and drug-induced lupus are medication-induced conditions with dermatologic presentations. Many of the conditions discussed are relatively rare but nonetheless demand our attention and understanding. Some of the conditions presented may be more likely encountered in the hospital setting, as is the case with serum sickness-like reactions and drug-induced lupus, whereas others may present to outpatient clinic for diagnosis. Given the similarities in clinical history of patients presenting with these conditions, an understanding of the clinical presentation, pathophysiology, culprit medications, histologic appearance, and serologic characteristics is warranted to correctly diagnose and manage these uncommon adverse reactions. We also discuss how to differentiate some of these conditions from more serious mimickers, as in the case of pseudolymphoma drug reaction mimicking a true lymphoma and drug-induced lupus mimicking acute systemic lupus erythematosus.

Neutrophilic drug reactions.

Neutrophilic drug reactions are unique eruptions that can affect hospitalized patients and share a common pathophysiology with neutrophils as the key mediators of inflammation. They range in clinical presentation from papules and plaques to bullae and erosions to pustules. Although there is some overlap in presentation, each has distinguishing features that aid the clinician in differentiation from one another and from other drug hypersensitivity reactions. Much of the data on these reactions are from case reports and series or retrospective review studies. There are limited prospective observational studies dedicated to these adverse drug reactions. We review the more common and life-threatening neutrophilic drug reactions, their proposed mechanism of action, and their management.

Cutaneous immune-related adverse events to checkpoint inhibitors.

The development of immunotherapy has led to a paradigm shift in the treatment of both solid and hematologic malignancies. As immunomodulatory therapies are employed with increasing frequency, a greater number of immune-related adverse reactions are being reported, and the majority of these involve the skin. As a result, dermatologists are increasingly becoming involved in the management of these cutaneous adverse reactions-often providing critical recommendations regarding ongoing cancer treatment. Cutaneous immune-related adverse reactions can vary significantly from patient to patient, making early recognition and timely intervention imperative to mitigate associated morbidity and potential treatment interruption. Although there is considerable overlap in the cutaneous adverse events caused by these immune checkpoint inhibitors, specific eruptions are characteristically associated with particular checkpoint inhibitors. In addition, a patient's comorbidities or immune status can play a significant role in the presentation and management of such adverse reactions. This review characterizes and provides management guidelines for the various cutaneous toxicities associated with checkpoint inhibitor therapy, including CTLA-4 inhibitors, PD-1 inhibitors, and PD-L1 inhibitors. © 2020 Elsevier Inc. All rights reserved.

Adverse cutaneous reactions to chemotherapeutic drugs.

Drug reactions resulting from chemotherapy agents are common and frequently affect the skin. Although often benign, a select few of these cutaneous reactions may necessitate immediate changes to the antineoplastic regimens. Given the diversity of chemotherapeutic skin reactions and their complex implications on patient management, an organized conceptual schema is imperative for proper patient care. We evaluate a number of commonly seen chemotherapy-induced skin toxicities organized by pathogenic mechanism and drug class, providing a framework for the identification and categorization of adverse events to prevent unrecognition. Groupings of these reactions include direct cytotoxicity and/or drug accumulation, immunologic hypersensitivity, and aberrant molecular signaling.

Pediatric drug eruptions.

Drug eruptions in children are common but in general less studied than their adult counterparts. Aside from having significant impact on the child's health and quality of life, these reactions can limit what medications the patient can receive in the future. Familiarity with pediatric drug eruptions is important for accurate diagnosis and to prevent future recurrence or ineffective therapy. Our current understanding of how drug reactions differ mechanistically between children and adults is poor. There are multiple factors that could be contributing to the differing incidence, presentation, and treatment modalities offered to pediatric versus adult patients. For many of these cutaneous drug reactions, the treatment regime is not standardized, being based primarily on case reports. Although not comprehensive, this review highlights common pediatric drug eruption patterns and discuss diagnostic mimickers. Five cutaneous adverse drug reactions in the pediatric population are presented: morbilliform (exanthematous) eruptions, urticarial eruptions, serum sickness-like reactions, fixed drug eruptions, and DRESS syndrome. Clinical features, diagnostic workup, and management are discussed with an emphasis on the pediatric population.