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Antibody-drug conjugates (ADCs) are a new and emerging category of oncologic treatments that combine the target specificity of a monoclonal antibody with a cytotoxic payload. These drugs are associated with unique cutaneous toxicities that vary across agents. Currently, there are eleven ADCs with regulatory approval for solid and liquid tumors and over 80 ADCs currently in clinical development, it is critical for dermatologists to recognize and appropriately mitigate the cutaneous toxicities associated with these therapies. This clinical review will summarize the novel mechanisms and indications of approved ADCs, discuss dermatologic toxicities demonstrated in clinical trials and postmarketing studies, and impart recognition and management guidance when encountering these reactions to help maintain patients safely and comfortably on their medications. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous irAEs are some of the most reported adverse reactions to ICIs. This prospective monocentric study seeks to offer a comprehensive overview of the skin toxicity associated with these therapies in a single-center institution, with the aim of describing their incidence and our approach for management. Additionally, we aim to highlight the importance of dermatological assessment for affected patients, as it can have a major impact on both their quality of life and the decision to continue treatment. Background/Objectives: The landscape of advanced melanoma treatments has shifted dramatically in recent years. Target therapy and immunotherapy have changed the management of patients with both metastatic (stage IV according to AJCC 8th ed.) and nodal (stage IIB/C and III) disease. As the use of novel agents has increased, so have the cutaneous toxicities associated with these medications. While most skin reactions are low-grade and can be managed conservatively with topical therapies, high-grade or life-threatening drug reactions can arise during therapy, requiring prompt dermatologic recognition and treatment. Given the survival benefit attributed to these new agents, treating skin toxicity and maintaining a patient's quality of life is of paramount importance. Methods: We undertook a prospective, monocentric, and descriptive study in Bologna, Italy, including patients referred to the Oncologic Dermatology Unit of IRCCS AOU of Bologna who developed biopsy-proven cutaneous adverse events (AE) under treatment with immunotherapy for cutaneous melanoma with nodal (stage IIB/C, III) and metastatic (stage IV) disease from January 2016 to April 2024. Results: In 202 identified patients, 75 (37.5%) developed skin AEs. Ipilimumab was causal for 48.1% of skin AEs, followed by nivolumab (37%) and pembrolizumab (31.4%). Recorded types of skin AEs included erythematous rash, vitiligo, alopecia, lichenoid, maculopapular, acneiform, urticarial, psoriasiform, granulomatous, eczematous, and severe cutaneous AEs, such as Erythema multiforme/Stevens-Johnson syndrome and bullous autoimmune dermatoses. Most AEs were low-grade [CTCAE 1–2] (97%) and typically occurred after 10 weeks of treatment. Conclusions: This study comprehensively describes skin AEs occurring during systemic treatment with ICIs for cutaneous melanoma at a single center. [ABSTRACT FROM AUTHOR]

Antibody-drug conjugates (ADCs) are an emerging class of anticancer agents that combine targeting antibodies with potent cytotoxic agents. Their molecular configuration allows for increased therapeutic efficacy and reduced adverse-effect profiles compared to monoclonal antibodies or cytotoxic chemotherapy alone. ADCs cause off-target toxicities through several mechanisms, including premature deconjugation of the cytotoxic agent in the serum and the presence of the targeted antigen on normal tissues. Given cutaneous adverse events comprise 31.3% of all-grade adverse events in clinical trials involving ADCs, dermatologists are increasingly called upon to manage the cutaneous toxicities caused by these drugs. In this review, we summarize known cutaneous toxicities of the ADCs that have been approved for use by the US Food and Drug Administration to date. Dermatologists can play a key role in recognizing cutaneous reactions associated with ADCs, contributing to guidelines for their management, and aiding during clinical trials to generate detailed morphologic and histopathologic descriptions of cutaneous toxicities caused by ADCs. [ABSTRACT FROM AUTHOR]

Enfortumab vedotin (EV) is used to treat unresectable/metastatic urothelial carcinoma but often causes cutaneous toxicity (EVRCT) because of Nectin4 expression in the skin, which reduces patients’ quality of life and can lead to dose adjustments or discontinuation. We explored whether applying topical steroids prophylactically to intertriginous areas could prevent EVRCT. Five patients received clobetasol propionate on one side and Vaseline on the other. Three patients developed grade ≥2 EVRCT at Vaseline-treated sites, but no EVRCT at clobetasol-treated sites. The results suggest that prophylactic topical steroid application can reduce the incidence of EVRCT, which prompted early study termination and progression to the next trial phase. Patient summary: A drug called enfortumab vedotin (EV) used to treat advanced cancer of the urinary tract can cause severe skin reactions. We compared application of a steroid cream or Vaseline to the skin in five patients who were starting EV therapy. Three patients had an EV reaction on Vaseline-treated skin patches but not on steroid-treated skin patches. Because of these positive results, we are testing steroid cream at the start of EV treatment in a larger study.

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Introduction: Enfortumab vedotin (EV) combined with pembrolizumab (EV+P) is a promising first-line therapy for metastatic urothelial carcinoma. While it has shown significant efficacy, severe cutaneous adverse events such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. We present this case as another example of severe skin off-target toxicity associated with this treatment, emphasising the importance of recognising this potential complication. Case description: A 67-year-old male with metastatic urothelial carcinoma, chronic kidney failure and liver cirrhosis presented with fever, respiratory symptoms and a pruritic rash after two doses of EV+P. The rash rapidly worsened, leading to extensive skin desquamation affecting 20–30% of his body surface area. Skin biopsies confirmed SJS with early-stage TEN (SJS/TEN overlap). The patient was treated with high-dose intravenous steroids, empirical antibiotics for neutropenia and intensive topical care. Significant re-epithelialisation occurred by day 13, and the patient was discharged on day 15 with cessation of EV+P therapy. Conclusion: This case demonstrates the potential for severe cutaneous toxicity in patients receiving EV+P, especially those with complex comorbidities. Early recognition and prompt, aggressive management with systemic corticosteroids are essential for improving outcomes. The case highlights the need for vigilance in monitoring for such adverse events and reporting them to improve patient safety.

Cyclin-dependent kinase (CDK) 4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are widely used in combination with endocrine therapy for the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer. Despite their efficacy, these drugs are associated with a range of adverse events, including dermatologic toxicities. This case report presents a rare instance of lichenoid dermatitis in a 48-year-old woman following treatment with abemaciclib. The patient developed erythematous, edematous plaques and papules on her hands and forearms, which resolved after discontinuation of the drug and treatment with topical corticosteroids. This report highlights the need for awareness of cutaneous side effects associated with CDK4/6 inhibitors, particularly abemaciclib.

Dermatomyositis (DM) is a systemic autoimmune disorder characterized by proximal myopathy and dermatological findings. Approximately 15-30% of DM cases emerge as a paraneoplastic syndrome caused by a concomitant malignancy. Although more rare, in cancer patients DM has also been reported as a possible result of toxicity of some antineoplastic agents, such as taxanes and monoclonal antibodies. Herein, we report a 35-year-old woman with metastatic breast cancer who presented with skin lesions after initiation of paclitaxel and anti-HER2 agents. Clinical, laboratory, and histological findings were consistent with the diagnosis of DM.

An introduction is presented in which the editor discusses articles within the issue on topics including integration of data from in silico, in chemico and in vitro methods for skin sensitization Adverse Outcome Pathway, new approach methodologies for research on skin color changes in response to tobacco and air pollution, and association of drug exposure with T-cell mediated cutaneous hypersensitivity reactions.

Hand-foot syndrome (HFS) is a widely recognized dose-limiting cutaneous toxicity effect of fluoropyrimidine chemotherapy agents that impairs clinical benefits and treatment outcomes. Even though the cause and pathophysiology of HFS are relatively widely reported, how the toxicity of fluoropyrimidine translates into persistent inflammation has not been studied. Additionally, prevention and treatment strategies for HFS based on its mechanistic occurrence and development are scarce. In our study, we demonstrated that cGAS-STING signaling pathway-mediated cellular senescence played a critical role in the inflammatory reaction and provided a therapeutic solution for HFS. Mechanistically, DNA damage, as the primary cytotoxic cause, in keratinocytes induces cell cycle arrest, activates the cGAS-STING signaling pathway, and subsequently mediates cellular senescence, ultimately fueling a robust secondary inflammatory response that results in HFS. More importantly, the thymidine prodrug thymidine diacetate was proven to be effective in preventing HFS by compensating for thymidylate deficiency to facilitate the replication and repair of DNA and thus causing the escape from cellular senescence. These data highlight the importance of DNA damage-mediated cellular senescence in the etiology of HFS and provide a potential therapeutic anchor point for fluoropyrimidine-induced HFS.

Epidermal growth factor receptor inhibitors (EGFRIs) induced cutaneous toxicity is a common adverse event (AE), although it is not as severe as major cancers, we still need to pay enough attention to them. Therefore, it is necessary to evaluate the diversity of EGFRI class drugs. The objective of this study was to conduct a scientific and systematic investigation into the correlation between EGFRI and cutaneous toxicities. The data accessed from the FDA adverse event reporting system database (FAERS) encompass a time frame spanning from January 2013 to March 2023. By utilizing reporting odds ratios (RORs), information components (ICs), proportional reporting ratios (PRRs), and chi-squared (χ2), the relationship between drugs and adverse reactions was evaluated through disproportionality analysis. Within the FAERS database, a total of 29,559 skin adverse events were recorded. A robust indication of the correlation between EGFRI and elderly patients (≥65 years) was identified. Among EGFRIs, erlotinib accounted for the largest proportion of skin adverse events (39.72%). Rash, dry skin, and pruritus ranked top among all preferred terms, and signals such as rash, skin lesions, and acneiform dermatitis were detected in every single drug. Clinicians should guide patients customize the treatment plan for each patient.

Key Clinical Message: Erythema nodosum (EN) is a type of panniculitis occurring due to various conditions. It can be associated with certain malignancies or manifest as a side effect of drugs. This article presents a unique case of EN in a patient with chronic myeloid leukemia (CML‐blast phase) following dasatinib and chemotherapy. Timely recognition and appropriate management are crucial to alleviate symptoms and consider potential drug‐induced etiology. [ABSTRACT FROM AUTHOR]

Key Clinical Message Erythema nodosum (EN) is a type of panniculitis occurring due to various conditions. It can be associated with certain malignancies or manifest as a side effect of drugs. This article presents a unique case of EN in a patient with chronic myeloid leukemia (CML‐blast phase) following dasatinib and chemotherapy. Timely recognition and appropriate management are crucial to alleviate symptoms and consider potential drug‐induced etiology.

Background: Various biologic agents targeting specific molecules present new treatment options for various tumors. Acneiform eruption is a very common skin reaction to these agents. Although not life‐threatening, acneiform eruption can affect patients' emotional and social lives. In very exceptional cases, it can lead to cancer therapy interruption. Aims: The aim of this study was to review the incidence rate, clinical characteristics, pathogenesis, and current management of acneiform eruption induced by molecularly targeted agents. Methods: This review was carried out through PubMed, Embase, and Cochrane searching terms 'acneiform eruption', 'papulopustular eruption' or 'acne‐like rash' and 'skin toxicity', 'cutaneous toxicity', 'skin reactions', 'dermatological toxicities', 'target therapy,' or 'drug therapy'. Results: Of the 73 articles matched our search terms, 61 were original articles and 12 were case reports or case series. Acneiform eruption is most commonly observed in patients treated with epidermal growth factor receptor inhibitors and mitogen‐activated protein kinase inhibitors. Typical lesions consist of erythematous papules and pustules without comedones, accompanying with burning, pruritus, or xerosis. The pathogenesis involves inflammation and abnormalities of the follicular epithelium, where a disorder in EGFR signaling plays a key role. The treatment of acneiform eruption depends on the severity of the rash. Conclusions: Early recognition and effective management of this cutaneous adverse reaction can prevent unnecessary reduction and discontinuation of drug use and improve patient survival and quality of life. Close collaboration between oncologists and dermatologists is important to optimize therapy and improve patient survival. [ABSTRACT FROM AUTHOR]

Introduction Enfortumab vedotin is a novel drug for locally advanced or metastatic urothelial carcinoma, but it is associated with a high incidence of skin reactions (up to 47.0%). Case presentation A 71‐year‐old male was administered enfortumab vedotin for bladder cancer associated with lymph node metastases. Slight erythema of the upper limbs appeared on Day 5. Erythema gradually worsened. On Day 8, second administration was performed. On Day 12, based on the extents of blisters, erosion, and epidermolysis, a diagnosis of toxic epidermal necrolysis was made. The patient died of multiple organ failure on Day 18. Conclusion As serious cutaneous toxicity may appear early after the start of administration, it is important to consider the timing of the second administration of the initial course carefully. In cases of skin reaction, reduction or discontinuation should be considered.

Keratinocytic cancers (KCs), specifically cutaneous squamous cell and basal cell carcinomas, can respond to topical, intralesional, or systemic immunotherapies, but cutaneous adverse events (CAEs) may occur. Understanding these risks, early recognition of these CAEs, and effective treatment may enable patients to continue their anticancer immunotherapies without dose impact. Immune checkpoint inhibitor-related CAEs after KCs can have multiple clinical presentations, with specific observed types including psoriasis and bullous pemphigoid. Cutaneous toxicities can require biopsies to confirm the diagnosis, especially in patients who are not responsive to topical or oral steroids, since the selection of biologic drugs depends on accurate diagnosis. Different types of CAEs from immune checkpoint inhibitors have been associated with different oncologic outcomes in various primary cancer types, and this remains to be determined for KC patients. CAE characterization and management after immune checkpoint inhibitors in KC patients is a rapidly growing field that needs specific and prospective studies. [ABSTRACT FROM AUTHOR]

The new landscape of treatments for metastatic clear cell renal carcinoma (mRCC) is constantly expanding, but it is associated with the emergence of novel toxicities, adding to up to those observed in the tyrosine-kinase inhibitor (TKI) era. Indeed, the introduction of immune checkpoint inhibitors (ICIs) alone or in combination has been associated with the development of immunerelated adverse events (irAEs) involving multiple-organ systems which, even if rarely, had led to fatal outcomes. Moreover, due to the relatively recent addition of ICIs to the previously available treatments, the potential additive adverse effects of these combinations are still unknown. A prompt recognition and management of these toxicities currently represents a fundamental issue in oncology, since it correlates with the outcome of cancer patients. Even if clinical guidelines provide indications for the management of irAEs, no specific protocol to evaluate the individual risk of developing an adverse event during therapy is currently available. A multidisciplinary approach addressing appropriate interventions aimed at reducing the risk of any insidious, severe, and/or dose-limiting toxicity might represent the most efficacious strategy to timely prevent and manage severe irAEs, allowing indirectly to improve both patients' cancer-specific survival and quality of life. In this review, we reported a five-case series of toxicity events that occurred at our center during treatment for mRCC followed by the remarks of physicians from different specialties, pinpointing the relevant role of an integrated and extended multidisciplinary team in a modern model of mRCC patient management. [ABSTRACT FROM AUTHOR]

Introduction: Enfortumab vedotin (EV) combined with pembrolizumab (EV+P) is a promising first-line therapy for metastatic urothelial carcinoma. While it has shown significant efficacy, severe cutaneous adverse events such as Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. We present this case as another example of severe skin off-target toxicity associated with this treatment, emphasising the importance of recognising this potential complication., Case Description: A 67-year-old male with metastatic urothelial carcinoma, chronic kidney failure and liver cirrhosis presented with fever, respiratory symptoms and a pruritic rash after two doses of EV+P. The rash rapidly worsened, leading to extensive skin desquamation affecting 20-30% of his body surface area. Skin biopsies confirmed SJS with early-stage TEN (SJS/TEN overlap). The patient was treated with high-dose intravenous steroids, empirical antibiotics for neutropenia and intensive topical care. Significant re-epithelialisation occurred by day 13, and the patient was discharged on day 15 with cessation of EV+P therapy., Conclusion: This case demonstrates the potential for severe cutaneous toxicity in patients receiving EV+P, especially those with complex comorbidities. Early recognition and prompt, aggressive management with systemic corticosteroids are essential for improving outcomes. The case highlights the need for vigilance in monitoring for such adverse events and reporting them to improve patient safety., Learning Points: High clinical suspicion recognition of early signs of dermolysis is essential in managing severe cutaneous toxicity associated with enfortumab vedotin. A multidisciplinary approach the management of Stevens-Johnson syndrome/toxic epidermal necrolysis should involve a multidisciplinary team, especially in patients with complex comorbidities. Pharmacovigilance continuous monitoring and prompt reporting of adverse events to health authorities are vital for improving patient safety and therapeutic outcomes., Competing Interests: Conflicts of Interests: The Authors declare that there are no competing interests., (© EFIM 2024.)

Immunotherapy and target therapy have revolutionized treatment of stage III/IV melanoma. Both treatments show a favorable toxicity profile even if cutaneous adverse events (AEs) are frequent (30%–40% of cases). This is a retrospective single center cohort study that included patients with stage IV or inoperable stage III metastatic melanoma (AJCC 8th) who received BRAFi + MEKi therapy or immunotherapy with Checkpoint inhibitors. All cutaneous AEs were ascertained by a dermatologist based on clinical and histological findings. The primary outcome was to provide a detailed clinical dermatological classification of cutaneous adverse events and an evaluation of the incidence of skin toxicity in the two arms of therapy (immunotherapy and target therapy). A total of 286 patients with stages III–IV metastatic melanoma were included: 146 received immunotherapy and 140 target therapy. In the immunotherapy cohort, 63 (43.1%) cutaneous reactions were observed while 33 skin reactions (23.6%) were identified in patients treated with target therapy. All the skin toxicities observed were grade I, excepted four cases: an erythema multiforme‐like eruption, a grade III psoriasis and two grade III maculopapular rashes. Immunotherapy in older age resulted statistically related to skin toxicities (p = 0.011), meanly in metastatic setting (p = 0.011). Cumulative incidence of skin toxicities was 65.63% in immunotherapy cohort (p = 0.001). Also multivariate logistic regression shows a significant association between skin adverse events and immunotherapy (odds ratio [OR] = 0.50; 95% confidence interval [CI]: 0.29–0.85, p: 0.01) and between cutaneous AEs and metastatic setting (OR = 1.97; 95% CI: 1.04–3.74, p: 0.04). We have also shown that as the age of initiation of therapy increases the probability of developing skin toxicity grows. However, stratifying by type of therapies the effect of age persists only in immunotherapy (OD: 1.04; CI: 1.01–1.06; p: 0.04) while for target therapy age does not affect the onset of skin toxicity (OD 1.01; CI 0.98–1.04; p = 0.42). No differences were shown between patients on target therapy and immunotherapy regarding gender. Patients were also evaluated regarding concomitant therapies and seems that Levotyroxine may be involved in AEs during immunotherapy treatment. More studies are needed to deepen this aspect, also considering the medical history and diverse drug associations. Cutaneous adverse events are characterized by heterogeneous manifestations, are more often seen in patients on immunotherapy and dermatologists can play a crucial role in multidisciplinary care. [ABSTRACT FROM AUTHOR]

Introduction: Enfortumab vedotin (EV) has been demonstrated to have a significant response rate in early phase trials and is known for its tolerable side-effect profile. Emerging case reports have raised awareness of cutaneous toxicities, which may be a potentially fatal complication. Objective: To assess the potential relevance between EV and cutaneous toxicities reports through data mining of the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS). Methods: Data from January 1, 2019, to November 4, 2021, in the FAERS database were retrieved. Information component (IC) and reporting odds ratio (ROR) were used to evaluate the association between EV and cutaneous toxicities events. Results: EV was significantly associated with cutaneous toxicities in the database compared with both all other drugs (ROR 12.90 [10.62–15.66], IC 2.76 [2.52–3.01], middle signal) and platinum-based therapy (ROR 15.11 [12.43–18.37], IC 2.91 [2.66–3.15], middle signal) in the FAERS database. A significant association was detected between EV and all the cutaneous adverse effects (AEs) except erythema, palmar–plantar erythrodysesthesia syndrome, and dermatitis allergic. Both Stevens–Johnson syndrome and toxic epidermal necrolysis occurred 15 times as frequently for EV compared with all other drugs (ROR = 15.20; ROR = 15.52), while Stevens–Johnson syndrome occurred 18 times and toxic epidermal necrolysis occurred 7 times as frequently for EV compared with platinum-based therapy in the database (ROR = 18.74; ROR = 7.80). All groups that limited the gender and age showed a significant association between EV and cutaneous toxicities. Conclusions: A significant signal was detected between EV use and cutaneous toxicities. It is worth noting that Stevens–Johnson syndrome and toxic epidermal necrolysis were significantly associated with EV use. [ABSTRACT FROM AUTHOR]

Cutaneous reactions are among the most prevalent immune-related adverse events in patients treated with immunotherapy. Given that immunotherapies often act through blocking inhibitory signals on T cells, these treatments also have the potential to generate a host of immune toxicities. We report the case of a 73-year-old woman with a history of non-small cell lung cancer treated with nivolumab 10 months prior to presentation who developed painful nodules, bullae, and a scaly rash on her extremities. Four months after discontinuation of nivolumab, she noted an acute eruption of painful nodules on her extremities, followed by pink papules and tense bullae on her palms and soles. Biopsies were performed of three lesions in sites of varying morphologies. These findings were felt to be consistent with a nivolumab-induced lichenoid reaction. She was initially treated with intralesional steroid injections, topical steroid ointment, and liquid nitrogen cryotherapy with minimal improvement. As the lesions continued to progress, the patient was admitted to the hospital and started on intravenous methylprednisolone. She eventually transitioned to daily oral prednisone with a slow taper with good effect and no recurrence of lesions.

Anti-epidermal growth factor receptor (EGFR) therapy–associated cutaneous toxicity is a syndrome characterized by papulopustular rash, local inflammation, folliculitis, and microbial infection, resulting in a decrease in quality of life and dose interruption. However, no effective clinical intervention is available for this adverse effect. Here, we report the atrophy of dermal white adipose tissue (dWAT), a highly plastic adipose tissue with various skin-specific functions, correlates with rash occurrence and exacerbation in a murine model of EGFR inhibitor-induced rash. The reduction in dWAT is due to the inhibition of adipogenic differentiation by defects in peroxisome proliferator-activated receptor γ (PPARγ) signaling, and increased lipolysis by the induced expression of the lipolytic cytokine IL6. The activation of PPARγ by rosiglitazone maintains adipogenic differentiation and represses the transcription of IL6, eventually improving skin functions and ameliorating the severity of rash without altering the antitumor effects. Thus, activation of PPARγ represents a promising approach to ameliorate cutaneous toxicity in patients with cancer who receive anti-EGFR therapy.

IntroductionEnfortumab vedotin (EV) has been demonstrated to have a significant response rate in early phase trials and is known for its tolerable side-effect profile. Emerging case reports have raised awareness of cutaneous toxicities, which may be a potentially fatal complication.ObjectiveTo assess the potential relevance between EV and cutaneous toxicities reports through data mining of the U.S. Food and Drug Administration (FDA) adverse event reporting system (FAERS).MethodsData from January 1, 2019, to November 4, 2021, in the FAERS database were retrieved. Information component (IC) and reporting odds ratio (ROR) were used to evaluate the association between EV and cutaneous toxicities events.ResultsEV was significantly associated with cutaneous toxicities in the database compared with both all other drugs (ROR 12.90 [10.62–15.66], IC 2.76 [2.52–3.01], middle signal) and platinum-based therapy (ROR 15.11 [12.43–18.37], IC 2.91 [2.66–3.15], middle signal) in the FAERS database. A significant association was detected between EV and all the cutaneous adverse effects (AEs) except erythema, palmar–plantar erythrodysesthesia syndrome, and dermatitis allergic. Both Stevens–Johnson syndrome and toxic epidermal necrolysis occurred 15 times as frequently for EV compared with all other drugs (ROR = 15.20; ROR = 15.52), while Stevens–Johnson syndrome occurred 18 times and toxic epidermal necrolysis occurred 7 times as frequently for EV compared with platinum-based therapy in the database (ROR = 18.74; ROR = 7.80). All groups that limited the gender and age showed a significant association between EV and cutaneous toxicities.ConclusionsA significant signal was detected between EV use and cutaneous toxicities. It is worth noting that Stevens–Johnson syndrome and toxic epidermal necrolysis were significantly associated with EV use.

Competing Interests: None disclosed.

Competing Interests: None disclosed.

Competing Interests: None disclosed.

Competing Interests: Dr Shi reports conflicts with VisualDX (honoraria/consulting), unrelated to the scope of this work. Drs Russell-Goldman and Lai have no conflicts of interest to declare.

Background/aim: The clinical outcomes associated with cutaneous toxicity and changes in the renal function of patients receiving enfortumab vedotin (EV) for advanced urothelial carcinoma (UC) is unclear., Patients and Methods: We retrospectively analyzed the relationship between clinical outcomes and EV-related cutaneous toxicity, and the influence on the renal function in 58 patients with advanced UC who received EV after the failure of platinum-based chemotherapy and immune checkpoint inhibitors from December 2021 to July 2023., Results: There were no differences in the overall response and disease control rates between patients with any grade of EV-related cutaneous toxicity and without (p=0.605 and p>0.99, respectively) nor of grade ≥3 (p>0.99 and p=0.173, respectively). Progression-free survival was not significantly associated with EV-related cutaneous toxicity of any grade (5.4 vs. 5.6 months, p=0.557) nor of grade ≥3 (2.7 vs. 5.6 months, p=0.053). Overall survival was not significantly associated with EV-related cutaneous toxicity of any grade (11.8 vs. 8.9 months, p=0.389), nor of grade ≥3 (4.6 vs. 11.4 months, p=0.168). The incidence of EV-related cutaneous toxicity of any grade was significantly higher in patients with any grade of ICI-related cutaneous toxicity (88.9% vs. 36.7%, p=0.008). There was no significant difference in the serum creatinine levels after EV treatment (p=0.211). Divided into two groups according to their renal function, using a serum creatinine cut-off of 2 mg/dl, there were no significant changes after EV treatment in either group (p=0.187 and p=0.938)., Conclusion: EV-related cutaneous toxicity did not affect clinical outcomes, although it occurred in patients who experienced immune checkpoint inhibitor-related cutaneous toxicity. EV did not affect renal function., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tuberculosis (TB) is an infection that can affect any organ, affecting mainly the lungs. Isolated testicular TB is very rare. Six months of a multiple drug scheme is the mainstay of TB treatment. Adverse reaction to anti-TB chemotherapy is frequent and affects the course of the therapy, leading sometimes to discontinuation of drugs. Ethambutol optic nerve toxicity is frequent. However, severe cutaneous and anaphylactic reactions associated to ethambutol are very rare. We present the case of an immunocompetent patient presenting with isolated testicular TB that exhibited a severe cutaneous and anaphylactic reaction to ethambutol during the consolidation treatment phase. This led to exhaustive etiologic study and treatment modification.

Cancer remains a leading cause of morbidity and mortality among children. Targeted therapies may improve survivorship; however, unique side‐effect profiles have also emerged with these novel therapies. Changes in hair, skin, and nails—termed dermatologic adverse events (AEs)—are among the most common sequelae and may result in interruption or discontinuation of therapy. Though dermatologic AEs have been detailed in adults, these findings are not well described in the pediatric population. We reviewed the literature to characterize dermatologic AEs to anticancer targeted therapies available as of July 2020 and summarized the spectrum of clinical findings as well as treatment recommendations for children. Dermatologic AEs are among the most common AEs reported in pediatric patients receiving targeted therapy, but morphologic and histologic descriptions are often lacking in current publications. Pediatric dermatologists are uniquely poised to recognize specific morphology of dermatologic AEs and make recommendations for prevention and treatment that may improve quality of life and enable ongoing cancer therapy. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Immune-modulatory therapy, especially with immune-checkpoint inhibitors (ICIs), has reshaped cancer therapeutics. Immunotherapy is relatively a novel approach that can effectively delay the progression of aggressive tumors and inhibit tumor recurrence and metastasis in many different tumor types. In the past years, ICIs have shown a sustained response and promising long-term survival in patients with advanced hepatocellular carcinoma (HCC). Nevertheless, ICI therapy can unbalance the immune system and result in a wide range of immune-related adverse events (irAEs), which are generally manageable but occasionally lead to a fatal outcome. HCC generally develops in the context of liver cirrhosis which is typically caused by viral hepatitis and non-alcoholic steatohepatitis. These underlying diseases may cause symptoms that overlap with irAEs and lead to consequences such as late recognition, inadequate work-up, and inappropriate treatment. Owing to the growing use of immunotherapy in HCC, it is necessary for clinicians to strengthen their understanding of the frequency, clinical features, and management of irAEs. This review focuses on the common toxicities associated with ICI therapy in patients with HCC and summarizes therapeutic strategies that can be used to monitor and manage such toxicities. [ABSTRACT FROM AUTHOR]

We present the first detailed report of acneiform eruptions in patients on CTLA-4 inhibitor therapy. Acneiform eruptions commonly occur (up to 75-100%) as a cutaneous adverse event associated with EGFR inhibition; however, acneiform eruptions have not been highly reported as a cutaneous adverse event associated with CTLA-4 inhibitor therapy. We conducted a retrospective chart review of our institution's database to assess cutaneous adverse events associated with ipilimumab and tremelimumab, identifying 12 patients with acneiform eruptions (2 on tremelimumab and 10 on ipilimumab). The median time to onset of rash was 3 weeks after starting CTLA-4 inhibitor therapy, ranging from 0.7-45 weeks. Median time to cutaneous resolution was 6 weeks, ranging from 2 to 282 weeks. Treatment included oral and topical antibiotics, antihistamines, and oral or topical corticosteroids with four patients receiving no treatment. Acneiform eruptions are seen less commonly with CTLA-4 inhibitors than other cancer therapies, but awareness that it does occur is important for clinical practice. Better description is a necessary help to aid in early diagnosis and intervention. While EGFR inhibitor-associated acneiform eruptions are associated with clinical benefit, our sample size is too small to determine whether CTLA-4 inhibitor associated acneiform eruptions display the same correlation. [ABSTRACT FROM AUTHOR]

Pemetrexed, frequently used for the treatment of pulmonary adenocarcinoma, may cause cutaneous reactions that can be reduced with three oral doses of dexamethasone starting the day before treatment, and continuing after chemotherapy for a number of doses which varies according to the emetogenic potential of the protocol. Dexamethasone may induce side effects and no guideline suggests the conduct to favor when dexamethasone doses are omitted before treatment with pemetrexed. This study was performed to evaluate the efficacy of a simplified regimen of dexamethasone administered before a pemetrexed-based chemotherapy in preventing cutaneous toxicities. A prospective study was conducted with patients starting a pemetrexed-based treatment between February 2016 and August 2017 at the ambulatory oncology clinic of an academic hospital. Patients were divided into two groups, one receiving the usual oral premedication and the other receiving a 20-mg intravenous dose of dexamethasone prior to chemotherapy. Among the 70 patients included, 39 received the alternative regimen prior to a total of 114 chemotherapy cycles, while the other 31 patients received the usual premedication before a total of 154 cycles. The cutaneous toxicity incidence was of 10 events in the simplified treatment group compared to 9 events in the standard group (p = 0.35). These events occurred in nine patients within the experimental group and five patients within the control group (p = 0.56). A single intravenous dexamethasone regimen represents a valid alternative to the usual prophylaxis in preventing cutaneous reactions. [ABSTRACT FROM AUTHOR]

• Crizotinib induces apoptosis of human keratinocytes directly. • Crizotinib induces human keratinocytes apoptosis through caspase-dependent way. • The extrinsic pathway is responsible for crizotinib-induced apoptosis. • The apoptosis independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition. Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased cleaved-caspase-8, a signaling protein of extrinsic apoptosis pathway, in a concentration and time-dependent manner. Moreover, we found the targets of crizotinib were not involved in HaCaT cells apoptosis. Collectively, our findings first report keratinocytes apoptosis is the key cause of crizotinib-induced cutaneous toxicity. We also reveal crizotinib induce apoptosis through the extrinsic apoptosis pathway due to detected up-regulated cleaved-caspase-8. Meanwhile, the apoptosis is independent of mitochondrial dysfunction, DNA damage and related drug targets inhibition. [ABSTRACT FROM AUTHOR]

Competing Interests: None disclosed.

Epidermal growth factor receptor inhibitors (EGFRIs) induced cutaneous toxicity is a common adverse event (AE), although it is not as severe as major cancers, we still need to pay enough attention to them. Therefore, it is necessary to evaluate the diversity of EGFRI class drugs. The objective of this study was to conduct a scientific and systematic investigation into the correlation between EGFRI and cutaneous toxicities. The data accessed from the FDA adverse event reporting system database (FAERS) encompass a time frame spanning from January 2013 to March 2023. By utilizing reporting odds ratios (RORs), information components (ICs), proportional reporting ratios (PRRs), and chi-squared (χ 2 ), the relationship between drugs and adverse reactions was evaluated through disproportionality analysis. Within the FAERS database, a total of 29,559 skin adverse events were recorded. A robust indication of the correlation between EGFRI and elderly patients (≥65 years) was identified. Among EGFRIs, erlotinib accounted for the largest proportion of skin adverse events (39.72%). Rash, dry skin, and pruritus ranked top among all preferred terms, and signals such as rash, skin lesions, and acneiform dermatitis were detected in every single drug. Clinicians should guide patients customize the treatment plan for each patient., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Dan, Jiang, Jia, Qi, Zong and Li.)

Cutaneous reactions are among the most prevalent immune-related adverse events in patients treated with immunotherapy. Given that immunotherapies often act through blocking inhibitory signals on T cells, these treatments also have the potential to generate a host of immune toxicities. We report the case of a 73-year-old woman with a history of non-small cell lung cancer treated with nivolumab 10 months prior to presentation who developed painful nodules, bullae, and a scaly rash on her extremities. Four months after discontinuation of nivolumab, she noted an acute eruption of painful nodules on her extremities, followed by pink papules and tense bullae on her palms and soles. Biopsies were performed of three lesions in sites of varying morphologies. These findings were felt to be consistent with a nivolumab-induced lichenoid reaction. She was initially treated with intralesional steroid injections, topical steroid ointment, and liquid nitrogen cryotherapy with minimal improvement. As the lesions continued to progress, the patient was admitted to the hospital and started on intravenous methylprednisolone. She eventually transitioned to daily oral prednisone with a slow taper with good effect and no recurrence of lesions. [ABSTRACT FROM AUTHOR]

Checkpoint inhibition is the mainstay of treatment in metastatic melanoma. More recently combined cytotoxic T‐lymphocyte antigen‐4 and programmed‐death‐1 blockade has resulted in improved response rates and overall survival in treatment naïve patients compared to monotherapy albeit with increased rates of adverse events. Dermatologic toxicities are an emerging consequence of the use of checkpoint inhibitors and have reportedly been more prevalent with the use of combined therapy. However, grade 3 and 4 adverse event rates are still less than 5%. Here, we report a case of a 63‐year‐old Caucasian male with metastatic melanoma treated with first line combined ipilimumab and nivolumab who then developed a steroid refractory, biopsy confirmed pityriasis lichenoides‐like, drug related rash that resolved with cyclosporine. Time of onset was 24 days and presenting symptoms demonstrated a maculopapular rash presenting over the back and chest with pruritus. Unfortunately, the patient subsequently had multi‐organ failure with acute kidney injury requiring dialysis, hypotension requiring vasopressor support, hepatic dysfunction, and bilateral lung infiltrates resulting in a fatal outcome. This case report highlights the effective use of cyclosporine as an immunomodulatory agent in the management of severe dermatological toxicity due to combination immunotherapy. [ABSTRACT FROM AUTHOR]