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BACKGROUND: The somatic BRAFV600E mutation occurs in 38-64% of pediatric cases of Langerhans cell histiocytosis (LCH). Vemurafenib (VMF), a BRAF inhibitor, was approved for refractory BRAFV600E mutated LCH. In adults, VMF causes frequent cutaneous adverse events (CAE) including skin tumors (squamous cell carcinomas, melanomas), but little is known in children. The objective of this study was to evaluate the frequency, clinical spectrum, and severity of CAEs in children treated with VMF for LCH. In addition, a correlation between CAE occurrence and VMF dose, residual plasma levels (RPLs), and efficacy was searched for.
METHODS: Multicentric retrospective observational study including patients <18 years treated with VMF alone for refractory BRAFV600E mutated LCH in 13 countries between October 1, 2013 and December 31, 2018.
RESULTS: Fifty-seven patients: 56% female, median age 2.1 years (0.2-14.6), median treatment duration 4.1 months (1.4-29.7). Forty-one patients (72%) had at least one CAE: photosensitivity (40%), keratosis pilaris (32%), rash (26%), xerosis (21%), and neutrophilic panniculitis (16%). No skin tumor was observed. Five percent of CAEs were grade 3. None were grade 4 or led to permanent VMF discontinuation. Dose reduction was necessary for 12% of patients, temporary treatment discontinuation for 16%, none leading to loss of efficacy. VMF dose, median RPL, and efficacy were not correlated with CAE occurrence.
CONCLUSIONS: At doses used for pediatric LCH, CAEs are frequent but rarely severe and have little impact on the continuation of treatment when managed appropriately. Regular dermatological follow-up is essential to manage CAEs and screen for possible induced skin tumors.

Immunoglobulin E (IgE) blockade with omalizumab has demonstrated clinical benefit in pruritus-associated dermatoses (e.g. atopic dermatitis, bullous pemphigoid, urticaria). In oncology, pruritus-associated cutaneous adverse events (paCAEs) are frequent with immune checkpoint inhibitors (CPIs) and targeted anti-human epidermal growth factor receptor 2 (HER2) therapies. Thus, we sought to evaluate the efficacy and safety of IgE blockade with omalizumab in cancer patients with refractory paCAEs related to CPIs and anti-HER2 agents.
Patients included in this multicenter retrospective analysis received monthly subcutaneous injections of omalizumab for CPI or anti-HER2 therapy-related grade 2/3 pruritus that was refractory to topical corticosteroids plus at least one additional systemic intervention. To assess clinical response to omalizumab, we used the Common Terminology Criteria for Adverse Events version 5.0. The primary endpoint was defined as reduction in the severity of paCAEs to grade 1/0.
A total of 34 patients (50% female, median age 67.5 years) received omalizumab for cancer therapy-related paCAEs (71% CPIs; 29% anti-HER2). All had solid tumors (29% breast, 29% genitourinary, 15% lung, 26% other), and most (n = 18, 64%) presented with an urticarial phenotype. In total 28 of 34 (82%) patients responded to omalizumab. The proportion of patients receiving oral corticosteroids as supportive treatment for management of paCAEs decreased with IgE blockade, from 50% to 9% (P < 0.001). Ten of 32 (31%) patients had interruption of oncologic therapy due to skin toxicity; four of six (67%) were successfully rechallenged following omalizumab. There were no reports of anaphylaxis or hypersensitivity reactions related to omalizumab.
IgE blockade with omalizumab demonstrated clinical efficacy and was well tolerated in cancer patients with pruritus related to CPIs and anti-HER2 therapies.

OBJECTIVE: Although strategies to prevent premature sensor loss for flash glucose monitoring (FGM) systems may have substantial benefit, limited data are available. This study among youth with high-risk type 1 diabetes evaluated whether an additional adhesive patch over FGM sensors would reduce premature sensor loss frequency and not cause additional cutaneous adverse events (AEs).
METHODS: This is a six-month, open-label, randomized crossover trial. Participants were recruited at completion of prior \'Managing Diabetes in a Flash\' randomized controlled trial and allocated to three months of Freestyle Libre FGM sensors with either standard adhesive (control) or additional adhesive patches (RockaDex, New Zealand) (intervention), before crossing over to the opposite study arm. Participants self-reported patch use or non-use, premature sensor loss and cutaneous AEs fortnightly via an electronic questionnaire.
RESULTS: Thirty-four participants were enrolled: mean age (± SD) 17.0 (± 2.2) years; mean HbA1c (± SD) 89 (± 16) mmol/mol (10.3% ± 1.4%). The response rate of questionnaires was 77% (314/408). Premature sensor loss was reported in 18% (58/314) of questionnaires: 20% (32/162) from intervention and 17% (26/152) from control (p = 0.56). Thirty-eight percent (118/314) of questionnaires were non-compliant to protocol allocation. However, per-protocol analysis showed similar findings. No significant difference in AEs was reported between compliant adhesive patch use and non-use (6% [5/78] and 3% [3/118], respectively, p = 0.27).
CONCLUSIONS: The adhesive patch investigated in this study does not appear to prevent premature FGM sensor loss. However, the low risk of AEs and low cost of an adhesive patch suggest an individualized approach to their use may still be warranted. Further research is needed to explore alternative strategies to prevent sensor loss.

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Subcutaneous injection of azacitidine (AZA) is an important treatment option for myelodysplastic syndrome (MDS), which improves overall survival. In hematology, the incidence of AZA-induced cutaneous adverse events (AE) has been known to be relatively high, which has not been well recognized by dermatologists. Discontinuation of AZA can result in the deterioration of MDS disease activity. Therefore, on dermatological consultation, precise evaluation of AE severity and careful consideration is required for post-AE medication management. To enhance our understanding of AZA-induced cutaneous AE, we report four cases with two representative cutaneous AE subtypes and summarize the clinicopathological phenotypes and courses of the cases in the published work. Case 1, a 71-year-old man, developed neutrophilic dermatosis involving the dermis and subcutaneous tissue. The other three cases, a 75-year-old man, a 78-year-old woman and a 68-year-old man, presented injection-site erythema associated with flare-up reaction. Discontinuation of AZA was necessary for case 1 alone. The published work review delineated three major subtypes of AZA-induced cutaneous AE: systemic cutaneous reaction, neutrophilic dermatosis type and erythematous type injection-site reaction. Histologically, the first two subtypes are mostly characterized by neutrophil infiltration, while the third subtype presents lymphocytic cell infiltration. Neither AZA discontinuation nor intensive interventions were required for the erythematous type injection-site reaction, while AZA termination or systemic treatments, represented by corticosteroid administration, were preferentially conducted for the systemic cutaneous reaction or the neutrophilic dermatosis type injection-site reaction subgroup. These observations support the necessity of subtype-dependent treatment strategies for the management of AZA-induced cutaneous AE.

Sorafenib is a multikinase inhibitor that is used to treat hepatocellular carcinoma by inhibiting tumor cell growth and angiogenesis. Cutaneous adverse events of sorafenib are commonly reported, with alopecia and hand-foot skin reactions most frequently encountered. Acneiform eruptions represent rare adverse events that have only been reported at high doses of sorafenib. We present a patient who started low dose sorafenib for hepatocellular carcinoma and subsequently developed a fulminant facial acneiform eruption in the absence of other cutaneous adverse events. Treatment included topical clindamycin and tretinoin with some improvement. Facial acneiform eruption represents a rare consequence of sorafenib that has not previously been described at low doses. Additionally, acneiform papules in the absence of other cutaneous adverse events is unusual. The cutaneous mechanism is not well understood but may be related to indirect epidermal growth factor receptor inhibition or direct cytotoxic effects on eccrine glands. Topical treatment produces only minimal improvement in patients who continue sorafenib therapy. Discontinuation of the drug is usually unwarranted except in special circumstances.

BACKGROUND: Anti-programmed cell death-1 (PD-1) immunotherapy using antibodies such as nivolumab or pembrolizumab has shown promise for treating various types of cancer. In this study, we reviewed the frequency and spectrum of cutaneous adverse events (AEs) caused by PD-1 antibodies and their possible correlation with treatment response.
METHODS: We reviewed records of all patients from a single institution treated with either nivolumab or pembrolizumab from August 1, 2014 to April 1, 2017.
RESULTS: Of 211 patients included in the study, 134 (63.5%) were treated with nivolumab and 77 (36.5%) with pembrolizumab. Thirty-five patients (16.4%) developed cutaneous AEs. Cutaneous AEs were significantly associated with longer treatment cycles (P = 0.001). The prevalence of cutaneous AEs did not differ between nivolumab (17.2%) and pembrolizumab (15.6%). Patient age, gender, baseline Eastern Cooperative Oncology Group scale and underlying malignancy were not associated with development of cutaneous AEs. Median time until onset of cutaneous AEs was 50.0 days (range, 1-378 days). Anti-PD-1 therapy was tolerable in most of patients with grade 1 (65.2%) and grade 2 (23.9%) cutaneous AEs. Pruritus (32.6%) and eczema (21.7%) were the most commonly reported cutaneous AEs. In lung cancer patients, cutaneous AEs were not associated with better treatment outcomes after adjusting for the number of treatment cycles.
CONCLUSIONS: Both pembrolizumab and nivolumab exhibited tolerable cutaneous safety profiles in a variety of cancer patients undergoing anti-PD-1 therapy. Cutaneous AEs of anti-PD-1 therapy were not associated with antibody type, underlying malignancy, patient characteristics, or improved response.