Germline cancer susceptibility in individuals with melanoma.

BACKGROUND: Prior studies have estimated a small number of individuals with melanoma (2%-2.5%) have germline cancer predisposition, yet a recent twin study suggested melanoma has the highest hereditability among cancers. OBJECTIVE: To determine the incidence of hereditary melanoma and characterize the spectrum of cancer predisposition genes that may increase the risk of melanoma. METHODS: Four hundred individuals with melanoma and personal or family history of cancers underwent germline testing of >80 cancer predisposition genes. Comparative analysis of germline data was performed on 3 additional oncologic and dermatologic data sets. RESULTS: Germline pathogenic/likely pathogenic (P/LP) variants were identified in 15.3% (61) individuals with melanoma. Most variants (41, 67%) involved genes considered unrelated to melanoma (BLM, BRIP1, CHEK2, MLH1, MSH2, PMS2, RAD51C). A third (20, 33%) were in genes previously associated with familial melanoma (BAP1, BRCA2, CDKN2A, MITF, TP53). Nearly half (30, 46.9%) of P/LP variants were in homologous repair deficiency genes. Validation cohorts demonstrated P/LP rates of 10.6% from an unselected oncologic cohort, 15.8% from a selected commercial testing cohort, and 14.5% from a highly selected dermatologic study. LIMITATIONS: Cohorts with varying degrees of selection, some retrospective. CONCLUSION: Germline predisposition in individuals with melanoma is common, with clinically actionable findings diagnosed in 10.6% to 15.8%.

Quality of life in cemiplimab-treated patients with locally advanced basal cell carcinoma in a Phase II clinical trial.

Aim: To evaluate health-related quality of life (HRQoL) in cemiplimab-treated patients with locally advanced basal cell carcinoma (laBCC).Materials & methods: Eighty-four patients with laBCC received cemiplimab 350 mg every 3 weeks (up to 9 cycles). HRQoL was assessed using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (QLQ-C30) and Skindex-16 questionnaires at baseline and each cycle. Mixed-effects repeated-measures models evaluated change from baseline across cycles.Results: Clinically meaningful improvement or maintenance was reported by 62-90% of patients on QLQ-C30 scales and by approximately 80% on Skindex-16 scales at Cycle 2, with consistent results at Cycle 9 except fatigue.Conclusion: Most cemiplimab-treated patients with laBCC reported improvement or maintenance of HRQoL with low symptom burden except fatigue.Clinical Trial Registration: ClinicalTrials.gov identifier NCT03132636, registered 28 April 2017.

Locally advanced basal cell carcinoma (laBCC) is a type of skin cancer that has the potential to invade surrounding tissues including bone, cartilage, nerve and muscle. Cemiplimab-rwlc is approved in the US for patients with laBCC following a therapy called hedgehog inhibitor (HHI) treatment or for whom HHIs are not appropriate. In a Phase II clinical trial, intravenous (in the vein) cemiplimab 350 mg every 3 weeks for up to nine treatment cycles resulted in clinically meaningful antitumor activity in patients with laBCC who progressed on or were intolerant to HHIs.This analysis evaluated health-related quality of life, symptom burden, emotions and functional status in these patients using the European Organization for Research and Treatment of Cancer Quality of Life Core 30 (QLQ-C30) and Skindex-16 questionnaires. Baseline scores (scores at the start of the clinical trial) showed moderate to high levels of functioning and low symptom burden that, except for fatigue, were maintained or improved over the course of cemiplimab treatment. These results show that despite the presence of fatigue, health-related quality of life and functional status were maintained with cemiplimab across the study duration.

A Retrospective Study of Diameter and Breslow Thickness in Invasive Melanomas.

INTRODUCTION: A diameter larger than 6 mm is included in the criteria used in public health messages to detect a cutaneous melanoma. We aimed to investigate the independent association of Breslow thickness with the melanoma diameter. METHODS: A retrospective study was performed in patients with invasive melanomas of the nodular melanoma (NM) or superficial spreading melanoma (SSM) subtype. The quartiles of the diameter (lower, median, upper) were studied in non-parametric quantile regression model. RESULTS: In total, 537 cases of invasive melanomas were included and 60% had Breslow thickness ≤1.0 mm. There were 429 SSM (79.9%) and 108 NM (20.1%). Although NMs were significantly thicker (median Breslow thickness: 2.7 mm vs. 0.7 mm, respectively, p < 0.0001), they were not associated with larger diameter compared to SSMs (p = 0.71). After adjustment for age and sex, melanoma location and subtype, having Breslow thickness ≤1.0 mm was not significantly associated with the lower quartile, median and upper quartile of the diameter (p values: 0.063, 0.083, and 0.791, respectively). CONCLUSION: In our study including melanomas of the NM or SSM subtype, Breslow thickness was not associated with the diameter, adding evidence to support the limitations of using diameter larger than 6 mm for the detection of invasive melanomas and indicating the potential of smaller melanomas to be thicker tumors.

Actinic keratosis: Current challenges and unanswered questions.

Actinic keratoses (AK) are common skin lesions associated with chronic exposure to sun. They are believed to be precursors of malignancy as they potentially may progress to invasive squamous cell carcinomas. The goal of current therapies is to reduce the number of AK and to prevent future cancer development. This review aims at providing an overview of the hallmarks of AK and skin field cancerization. We discuss epidemiology trends, risk factors and the state of the art and evidence of the current treatments. We review key figures of AK prevalence from different countries with regard to skin cancer risk and the associated economic burden of AK. We discuss the mutational status in AK lesions and the difficulties encountered by clinicians in evaluating AK visible and invisible lesions, referring to the concept of field cancerization. Based on a systematic literature review, we further evaluate the available treatment options. The presence of subclinical skin alterations in the periphery of visible AK lesions has gained a particular attention as those non-visible lesions are known to contain the same genetic changes as those found in the AK lesions themselves, prompting the concept of 'field cancerization'. Therefore, AK treatment guidelines now recognize the importance of treating the field in patients with AK. A recent systematic literature review and network meta-analysis showed that 5-FU interventions were associated with the best efficacy and a satisfactory acceptability profile compared with other field-directed therapies used in the treatment of AK. Although AK are considered quite common, they lack an accurate descriptive definition and conclusive epidemiologic data. Limited public awareness is a barrier to early and effective treatment, including prevention strategies. While different treatment options are available, there is still a limited understanding of long-term outcomes of treatment as measured by recurrence of cancer prevention.

European consensus-based interdisciplinary guideline for diagnosis, treatment and prevention of actinic keratoses, epithelial UV-induced dysplasia and field cancerization on behalf of European Association of Dermato-Oncology, European Dermatology Forum, European Academy of Dermatology and Venereology and Union of Medical Specialists (Union Européenne des Médecins Spécialistes).

A collaboration of multidisciplinary experts from the European Association of Dermato-Oncology, the European Dermatology Forum, the European Academy of Dermatology and Venereology, and the European Union of Medical Specialists was formed to develop European recommendations on AK diagnosis and treatment, based on current literature and expert consensus. This guideline addresses the epidemiology, diagnostics, risk stratification and treatments in immunocompetent as well as immunosuppressed patients. Actinic keratoses (AK) are potential precursors of cutaneous squamous cell carcinoma (cSCC) and display typical histopathologic and immunohistochemical features of this malignancy in an early stage. They can develop into cSSC in situ and become invasive in a low percentage of cases. AK is the most frequent neoplasia in white populations, frequently occurring within a cancerous field induced by ultraviolet radiation. Since it cannot be predicted, which lesion will progress to cSCC and when treatment is usually recommended. The diagnosis of AK and field cancerization is made by clinical examination. Dermatoscopy, confocal microscopy, optical coherence tomography or line-field confocal-OCT can help in the differential diagnosis of AK and other skin neoplasms. A biopsy is indicated in clinically and/or dermatoscopically suspicious and/or treatment-refractory lesions. The choice of treatment depends on patients' and lesion characteristics. For single non-hyperkeratotic lesions, the treatment can be started upon patient's request with destructive treatments or topical treatments. For multiple lesions, field cancerization treatment is advised with topical treatments and photodynamic therapy. Preventive measures such as sun protection, self-examination and repeated field cancerization treatments of previously affected skin areas in high-risk patients are advised.

International Skin Imaging Collaboration-Designated Diagnoses (ISIC-DX): Consensus terminology for lesion diagnostic labeling.

BACKGROUND: A common terminology for diagnosis is critically important for clinical communication, education, research and artificial intelligence. Prevailing lexicons are limited in fully representing skin neoplasms. OBJECTIVES: To achieve expert consensus on diagnostic terms for skin neoplasms and their hierarchical mapping. METHODS: Diagnostic terms were extracted from textbooks, publications and extant diagnostic codes. Terms were hierarchically mapped to super-categories (e.g. 'benign') and cellular/tissue-differentiation categories (e.g. 'melanocytic'), and appended with pertinent-modifiers and synonyms. These terms were evaluated using a modified-Delphi consensus approach. Experts from the International-Skin-Imaging-Collaboration (ISIC) were surveyed on agreement with terms and their hierarchical mapping; they could suggest modifying, deleting or adding terms. Consensus threshold was >75% for the initial rounds and >50% for the final round. RESULTS: Eighteen experts completed all Delphi rounds. Of 379 terms, 356 (94%) reached consensus in round one. Eleven of 226 (5%) benign-category terms, 6/140 (4%) malignant-category terms and 6/13 (46%) indeterminate-category terms did not reach initial agreement. Following three rounds, final consensus consisted of 362 terms mapped to 3 super-categories and 41 cellular/tissue-differentiation categories. CONCLUSIONS: We have created, agreed upon, and made public a taxonomy for skin neoplasms and their hierarchical mapping. Further study will be needed to evaluate the utility and completeness of the lexicon.

Age affects drug survival rates of interleukin (IL)-17 and IL-23 inhibitors in patients with plaque psoriasis: Results from a retrospective, multicentric, multi-country, cohort study.

BACKGROUND: Scarce data related to the drug survival of biologic agents in psoriasis patients aged ≥65 years is available. OBJECTIVES: To evaluate the drug survival of interleukin (IL)-23 or the IL-17 inhibitors approved for the treatment of moderate-to-severe psoriasis in elderly patients (aged ≥65 years), compared with younger adult patients (aged <65 years), and to identify clinical predictors that can influence the drug survival. METHODS: This retrospective multicentric cohort study included adult patients with moderate-to-severe psoriasis, dissecting two-patient subcohorts based on age: elderly versus younger adults. Kaplan-Meier estimator and proportional hazard Cox regression models were used for drug survival analysis. RESULTS: We included 4178 patients and 4866 treatment courses; 934 were elderly (1072 treatment courses), and 3244 were younger patients (3794 treatment courses). Drug survival, considering all causes of interruption, was higher in patients aged <65 years than in elderly patients overall (log-rank p < 0.006). This difference was significant for treatment courses involving IL-23 inhibitors (p < 0.001) but not for those with IL-17 inhibitors (p = 0.2). According to both uni- and multi-variable models, elder age was associated with an increased risk of treatment discontinuation (univariable analysis: HR: 1.229, 95% CI 1.062-1.422; p < 0.006; multivariable analysis: HR: 1.199, 95% CI 1.010-1.422; p = 0.0377). Anti-IL-23 agents were associated with a reduced likelihood of treatment discontinuation after adjusting for other variables (HR: 0.520, 95% CI 0.368-0.735; p < 0.001). Being previously treated with IL-17 inhibitors increased the probability of discontinuation. CONCLUSION: Elderly patients with psoriasis have an increased risk of biologic treatment discontinuation compared with younger adult patients, particularly, if being treated with IL-23 inhibitors. However, in stratified analyses conducted in elderly patients, IL-23 inhibitors showed higher drug survival rates than IL-17 inhibitors.

Management of primary plantar hyperhidrosis with botulinum toxin type A: A retrospective case series of 129 patients.

BACKGROUND/OBJECTIVES: To date, scientific data on the efficacy of botulinum toxin type A (BoNT-A) for primary plantar hyperhidrosis (PPH) are mainly derived from case reports and small case series. Herein, we sought to assess the efficacy and safety of BoNT-A for PPH on a large series of patients. METHODS: Medical records of patients who were referred to the outpatient department for hyperhidrosis of a tertiary care hospital and received BoNT-A for PPH from March 2003 until December 2022 were reviewed. RESULTS: A total of 129 patients [12 males, 117 females; median age 32 years (range, 16-72)] were included in the study, after excluding 24 patients with insufficient documented follow-up data. Most patients [115 (89.1%)] received onabotulinumtoxin-A, nine (7.0%) abobotulinumtoxin-A and five (3.9%) both in subsequent sessions. The mean number of sessions was 2.02 [standard deviation (SD), 2.29] and the mean duration of response 6.16 months (SD, 4.01). The percentage of response, as evaluated by Minor's test, was 71.67%, 63.44%, 47.78% and 34.13% after 1, 3, 6 and 9 months, respectively. Most patients were satisfied (21.7%) or very satisfied (58.9%) with the treatment. No serious side effects were reported. CONCLUSIONS: The results of this retrospective study suggest that BoNT-A is an effective and safe treatment option for PPH.

A dermatologic assessment of 101 mpox (monkeypox) cases from 13 countries during the 2022 outbreak: Skin lesion morphology, clinical course, and scarring.

BACKGROUND: In the 2022 mpox (monkeypox) outbreak, 79,000 global cases have been reported. Yet, limited dermatologic data have been published regarding lesion morphology and progression. OBJECTIVE: The objective of this study was to characterize skin lesion morphology, symptomatology, and outcomes of mpox infection over time. METHODS: The American Academy of Dermatology/International League of Dermatological Societies Dermatology COVID-19, Mpox, and Emerging Infections Registry captured deidentified patient cases of mpox entered by health care professionals. RESULTS: From August 4 to November 13, 2022, 101 cases from 13 countries were entered, primarily by dermatologists (92%). Thirty-nine percent had fewer than 5 lesions. In 54% of cases, skin lesions were the first sign of infection. In the first 1-5 days of infection, papules (36%), vesicles (17%), and pustules (20%) predominated. By days 6-10, pustules (36%) were most common, followed by erosions/ulcers (27%) and crusts/scabs (24%). Crusts/scabs were the predominant morphology after day 11. Ten cases of morbilliform rash were reported. Scarring occurred in 13% of the cases. LIMITATIONS: Registry-reported data cannot address incidence. There is a potential reporting bias from the predilection to report cases with greater clinical severity. DISCUSSION: These findings highlight differences in skin findings compared to historical outbreaks, notably the presence of skin lesions prior to systemic symptoms and low overall lesion counts. Scarring emerged as a major possible sequela.

Adalimumab-Induced Paradoxical Psoriasis Treated with Biologics Targeting the IL-17/IL-23 Axis in Patients with Hidradenitis Suppurativa.

BACKGROUND: Paradoxical psoriasis (PP) has been mainly described in patients receiving tumor necrosis factor-α (TNFα) inhibitors for inflammatory bowel disease or psoriasis vulgaris, while such data in the context of hidradenitis suppurativa (HS) are scarce. The purpose of this study was to demonstrate the course of PP and the underlying HS upon switching from adalimumab to a biologic agent targeting the interleukin (IL)-17/IL-23 axis. METHODS: The electronic medical database of the outpatient department for HS of a tertiary hospital for skin diseases was searched to identify patients with moderate-to-severe HS under treatment with adalimumab, who developed PP and were switched to biological therapy with an IL-17 or IL-23 inhibitor between February 2016 and January 2022. Disease assessment scores were evaluated at baseline, at time of PP development, as well as six and 12 months thereafter. RESULTS: Among the 83 patients who received adalimumab for the treatment of HS between February 2016 and January 2022, 10 patients (12%) developed paradoxical psoriasiform skin reactions after a median time of seven (range, 2-48) months. There were four females (40%) and six males (60%) with a median age of 42.5 (range, 33-56) years. Five patients presented with plaque psoriasis and five with palmoplantar pustulosis, while four had intertriginous and three nail involvement. In most of the patients, HS responded well to adalimumab at onset of PP. Eight patients were changed to secukinumab, one to ustekinumab, and one to risankizumab. HS further improved in all but 2 patients, one receiving secukinumab and one receiving risankizumab. In addition, all patients achieved improvement of PP. CONCLUSION: Despite the small number of patients, this study provides support that patients with adalimumab-induced PP may benefit from biologics targeting the IL-17/IL-23 axis. Further studies are needed to establish the optimal therapeutic strategy of the anti-TNFα-induced PP in the context of HS.

Brodalumab in plaque psoriasis: Real-world data on effectiveness, safety and clinical predictive factors of initial response and drug survival over a period of 104 weeks.

BACKGROUND: Brodalumab, a fully human IgG2k antibody blocking the receptor of IL17, is characterized by a rapid onset of action with high skin clearance rates in clinical trials. Since setting PASI90/100 or absolute PASI ≤ 3 as treatment goals have become attainable, evaluating the effectiveness and safety profile of biologic agents, such as brodalumab, in a real-world setting is essential. OBJECTIVE: The aim of this study was to evaluate the effectiveness and safety profile of brodalumab over a period of 104 weeks in everyday practice. Clinical predictive factors of initial (week 12/16) response to treatment and long-term drug survival were also investigated. METHODS: In this monocentric, retrospective study, PASI90/100 and absolute PASI ≤ 1/3 were assessed in 91 patients with moderate-to-severe skin psoriasis under brodalumab at weeks 12/16, 24, 52 and 104 of treatment. At week 12/16, patients with an absolute PASI ≤ 3 were defined as 'initial responders' and ≤1 as 'super-responders'. Clinical parameters, such as age, gender, BMI, comorbidities and previous systemic treatment, were assessed in order to predict 'super-responders'. Drug survival and its prognostic factors were also evaluated. RESULTS: PASI90/100 has reached 81.1/66.0% in week 12/16. This response rate increased at week 104, where 87.1/80.7% had PASI90/100 and 84.9% had absolute PASI ≤ 1. The presence of >3 comorbidities, prior treatment with >2 systemic agents and obesity tended to be negative predictive factors of 'super-response'. Previous exposure to IL17 inhibitors had no impact on both PASI < 1 and PASI < 3 initial response. One- and two-year drug survival probability was 87.6% and 77.32%, respectively. 'Initial responders' and anti-IL17 drug-naïve patients had better drug survival. Drug discontinuation occurred in 24.2%, mostly due to secondary failure, and arthralgia was the most common adverse event that led to discontinuation. CONCLUSIONS: Our study confirms the high effectiveness and good safety profile of brodalumab in the real-world setting.

Clinical associations and classification of immune checkpoint inhibitor-induced cutaneous toxicities: a multicentre study from the European Academy of Dermatology and Venereology Task Force of Dermatology for Cancer Patients.

BACKGROUND: Cutaneous immune-related adverse events (irAEs) represent the most frequent toxicities induced by immune checkpoint inhibitors (ICIs). OBJECTIVES: To investigate clinical associations of cutaneous toxicities induced by different ICI therapies. METHODS: This was a multicentre retrospective international cohort study of patients with cancer who developed cutaneous irAEs under ICI therapy. Analysis was performed of the rates and basic characteristics of all cutaneous toxicities, and identification of any associations was performed using univariate and multivariate models. RESULTS: In total, 762 patients were included, who developed 993 cutaneous toxicities. Forty different types of skin toxicities were identified. Psoriasis (175 patients, 23·0%) and pruritus (171 patients, 22·4%) were the most common toxicities, followed by macular rash (161 patients, 21·1%) and eczematous-type reactions (150 patients, 19·7%). Multivariate analysis showed that among patients with macular rash, vitiligo or multiple toxicities, patients received ICIs more frequently for melanoma than for NSCLC. Moreover, anti-CTLA4 was less frequent than anti-programmed death 1 treatment in patients with macular rash [odds ratio (OR) 0·11, 95% confidence interval (CI) 0·01-0·76] and vitiligo (OR 0·07, 95% CI 0·006-0·78). A significant association was also seen in patients treated with a combination of ICI and chemotherapy vs. ICI monotherapy. They less frequently developed psoriasis (OR 0·08, 95% CI 0·02-0·31), lichenoid reactions (OR 0·15, 95% CI 0·03-0·77) and eczematous reactions (OR 0·24, 95% CI 0·07-0·78), all compared with pruritic rash. CONCLUSIONS: Our study showed that skin-oriented toxicities do not share a single pattern and are related to several factors, including the specific agent administered and the underlying malignancy treated. Follow-up plans should be individualized in order to minimize the risk for severe reactions that could compromise optimum therapeutic outcome. What is already known about this topic? Patients with cancer treated with different immune checkpoint inhibitors (ICIs) carry an increased risk of developing various types of skin toxicities. What are the clinical implications of this work? In this multicentre cohort study we showed that ICI-related skin toxicities do not share a single pattern and may depend on several factors, including the specific agent administered and the underlying malignancy. Among patients with macular rash, vitiligo or multiple skin toxicities, patients received ICIs more frequently for melanoma than for non-small cell lung cancer. The combination of ICI and chemotherapy compared with ICI monotherapy occurred to a lesser extent in patients with psoriatic rash lichenoid and eczematous reactions, compared with patients with pruritus. Clinical awareness and specialized dermatological consultation should be advocated.

The American Academy of Dermatology and International League of Dermatological Societies Monkeypox Registry: Expanding the COVID-19 registry to emerging infections.

The World Health Organization declared the global monkeypox outbreak a public health emergency of international concern in July 2022. In response, the American Academy of Dermatology and International League of Dermatological Societies expanded the existing COVID-19 Dermatology Registry to become the "AAD/ILDS Dermatology COVID-19, Monkeypox, and Emerging Infections Registry." The goal of the registry is to rapidly collate cases of monkeypox and other emerging infections and enable prompt dissemination of findings to front-line healthcare workers and other members of the medical community. The registry is now accepting reports of monkeypox cases and cutaneous reactions to monkeypox/smallpox vaccines. The success of this collaborative effort will depend on active case entry by the global dermatology community.

A Sensitivity Meta-Analysis of Disease-Specific Death in Localized Cutaneous Squamous Cell Carcinoma.

BACKGROUND: Patients with localized cutaneous squamous cell carcinoma (cSCC) have different risk for disease-specific death (DSD) from patients with metastatic cSCC. PATIENTS AND METHODS: We conducted a sensitivity meta-analysis to identify the risk factors associated with DSD, in patients with localized cSCC at initial diagnosis (without locoregional or distant metastasis). RESULTS: Nine studies, with 5,205 patients, were included. Median follow-up ranged from 18 to 81 months. The number of deaths due to cSCC ranged from 3 to 40. Patients with immunosuppression were almost 2 times more likely to die from cSCC compared to immunocompetent patients (risk ratio: 1.85, 95% CI: 1.32-2.61). There was a positive but nonsignificant overall association with DSD for depth beyond fat, tumor diameter, presence of perineural invasion, location, and thickness. These results should be interpreted with caution, as there was limited evidence-based data on DSD in localized cSCC, due to the small number of studies reporting DSD, the absence of reporting the margin status, the variability of selected risk factors across studies, and the variability of definition of risk factors. CONCLUSIONS: In our meta-analysis, in localized cSCC at initial diagnosis, patients with immunosuppression were at significantly higher risk to die from cSCC. Our findings further highlight the need for a standardized set of risk factors to be included in studies on prognosis of cSCC and for including margin status and DSD among the studied outcomes.

Antidiabetic Treatment in Patients at High Risk for a Subsequent Keratinocyte Carcinoma.

BACKGROUND: Metformin and sulfonylureas are the most commonly prescribed drugs used for the treatment of type II diabetes. Type II diabetes has been linked to the development of keratinocyte carcinoma (KC), consisting of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Previously we have demonstrated lower risk for a subsequent KC in metformin users. In this study, we aim to investigate the association between sulfonylureas use and the development of KC in patients with KC history. We performed a retrospective cohort study of the Veterans Affairs Keratinocyte Carcinoma Chemoprevention Trial, which was a randomized double-blind vehicle-control cream originally investigating the effect of 5-fluorouracil on KC development. 932 patients with a history of KC were enrolled (98% male, 99% white, median age of 70 years) and followed for a median duration of 2.8 years. 153 patients were on metformin and 94 on sulfonylureas. We performed a survival analysis with cox regression and controlled for body mass index and known predictors: number of prior BCCs and age (for BCC) and for number of prior SCCs (invasive and in situ), number of actinic keratoses at baseline (for SCC). Sulfonylurea-users com-pared to non-users had a HR of 0.67 (CI: 0.40–1.56; P=0.49) and 0.94 (CI: 0.63–1.40; P= 0.77), for SCC and BCC, respectively. Diabetic patients at high risk for KC might benefit from the use of metformin versus sulfonylureas. J Drugs Dermatol. 2022;21(5):502-505. doi:10.36849/JDD.6087.

Cemiplimab in locally advanced basal cell carcinoma after hedgehog inhibitor therapy: an open-label, multi-centre, single-arm, phase 2 trial.

BACKGROUND: Before February, 2021, there was no standard treatment regimen for locally advanced basal cell carcinoma after first-line hedgehog inhibitor (HHI) therapy. Cemiplimab, a PD-1 antibody, is approved for treatment of advanced cutaneous squamous cell carcinoma and has shown clinical activity as monotherapy in first-line non-small-cell lung cancer. Here, we present the primary analysis data of cemiplimab in patients with locally advanced basal cell carcinoma after HHI therapy. METHODS: We did an open-label, multicentre, single-arm, phase 2 trial across 38 outpatient clinics, primarily at academic medical centres, in Canada, Europe, and the USA. Eligible patients (aged ≥18 years and with an Eastern Cooperative Oncology Group performance status of 0 or 1) with a histologically confirmed diagnosis of metastatic basal cell carcinoma (group 1) or locally advanced basal cell carcinoma (group 2) who had progressed on or were intolerant to previous HHI therapy were enrolled. Patients were not candidates for further HHI therapy due to progression of disease on or intolerance to previous HHI therapy or having no better than stable disease after 9 months on HHI therapy. Patients received cemiplimab 350 mg intravenously every 3 weeks for up to 93 weeks or until progression or unacceptable toxicity. The primary endpoint was objective response by independent central review. Analyses were done as per the intention-to-treat principle. The safety analysis comprised all patients who received at least one dose of cemiplimab. The primary analysis is reported only for group 2; group 1 data have not reached maturity and will be reported when the timepoint, according to the statistical analysis plan, has been reached. This study is registered with ClinicalTrials.gov, NCT03132636, and is no longer recruiting new participants. FINDINGS: Between Nov 16, 2017, and Jan 7, 2019, 84 patients were enrolled and treated with cemiplimab. At data cutoff on Feb 17, 2020, median duration of follow-up was 15 months (IQR 8-18). An objective response per independent central review was observed in 26 (31%; 95% CI 21-42) of 84 patients, including two partial responses that emerged at tumour assessments before the data cutoff and were confirmed by tumour assessments done subsequent to the data cutoff. The best overall response was five (6%) patients with a complete response and 21 (25%) with a partial response. Grade 3-4 treatment-emergent adverse events occurred in 40 (48%) of 84 patients; the most common were hypertension (four [5%] of 84 patients) and colitis (four [5%]). Serious treatment-emergent adverse events occurred in 29 (35%) of 84 patients. There were no treatment-related deaths. INTERPRETATION: Cemiplimab exhibited clinically meaningful antitumour activity and an acceptable safety profile in patients with locally advanced basal cell carcinoma after HHI therapy. FUNDING: Regeneron Pharmaceuticals and Sanofi.

The systemic influence of chronic smoking on skin structure and mechanical function.

One of the major functions of human skin is to provide protection from the environment. Although we cannot entirely avoid, for example, sun exposure, it is likely that exposure to other environmental factors could affect cutaneous function. A number of studies have identified smoking as one such factor that leads to both facial wrinkle formation and a decline in skin function. In addition to the direct physical effects of tobacco smoke on skin, its inhalation has additional profound systemic effects for the smoker. The adverse effects on the respiratory and cardiovascular systems from smoking are well known. Central to the pathological changes associated with smoking is the elastic fibre, a key component of the extracellular matrices of lungs. In this study we examined the systemic effect of chronic smoking (>40 cigarettes/day; >5 years) on the histology of the cutaneous elastic fibre system, the nanostructure and mechanics of one of its key components, the fibrillin-rich microfibril, and the micromechanical stiffness of the dermis and epidermis. We show that photoprotected skin of chronic smokers exhibits significant remodelling of the elastic fibre network (both elastin and fibrillin-rich microfibrils) as compared to the skin of age- and sex-matched non-smokers. This remodelling is not associated with increased gelatinase activity (as identified by in situ zymography). Histological remodelling is accompanied by significant ultrastructural changes to extracted fibrillin-rich microfibrils. Finally, using scanning acoustic microscopy, we demonstrated that chronic smoking significantly increases the stiffness of both the dermis and the epidermis. Taken together, these data suggest an unappreciated systemic effect of chronic inhalation of tobacco smoke on the cutaneous elastic fibre network. Such changes may in part underlie the skin wrinkling and loss of skin elasticity associated with smoking. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Immune checkpoint-mediated psoriasis: A multicenter European study of 115 patients from the European Network for Cutaneous Adverse Event to Oncologic Drugs (ENCADO) group.

BACKGROUND: Immune checkpoint inhibitor (ICI)-mediated psoriasis poses significant diagnostic and therapeutic challenges. OBJECTIVE: To report data on ICI-mediated psoriasis, emerging from the largest cohort to date, to our knowledge, and to propose a step-by-step management algorithm. METHODS: The medical records of all patients with ICI-mediated psoriasis were retrospectively reviewed across 9 institutions. RESULTS: We included a cohort of 115 individuals. Grade 1, 2, and 3 disease severity was reported in 60 of 105 (57.1%, 10 missing data), 34 of 105 (32.4%), and 11 of 105 (10.5%), respectively. The ratio between exacerbation and de novo cases was 1:4.3. The most common systemic therapy was acitretin (23 patients, 20.1%), followed by systemic steroids (8 patients, 7%), apremilast (7 patients, 6.1%), methotrexate (5 patients, 4.3%) and biologics (4 patients, 3.6%). Overall, 29 of 112 patients (25.9%) interrupted and 20 of 111 (18%) permanently discontinued ICIs because of psoriasis. Body surface area of greater than 10% at baseline had a 3.6 increased risk for ICI treatment modification (odds ratio, 3.64; 95% confidence interval, 1.27-10.45; P = .03) and a 6.4 increased risk for permanent discontinuation (odds ratio, 6.41; 95% confidence interval, 2.40-17.11; P < .001). Guttate psoriasis and grade 2 or 3 disease were significant positive predictors for antitumor response of ICI, whereas pruritus was a negative predictor. LIMITATIONS: Retrospective design. CONCLUSION: Acitretin, apremilast, and methotrexate are safe and effective modalities for ICI-mediated psoriasis. In most cases, ICI can be completed unhindered. A therapeutic algorithm is proposed.

Combining common genetic variants and non-genetic risk factors to predict risk of cutaneous melanoma.

Melanoma heritability is among the highest for cancer and single nucleotide polymorphisms (SNPs) contribute to it. To date, only SNPs that reached statistical significance in genome-wide association studies or few candidate SNPs have been included in melanoma risk prediction models. We compared four approaches for building polygenic risk scores (PRS) using 12 874 melanoma cases and 23 203 controls from Melanoma Meta-Analysis Consortium as a training set, and newly genotyped 3102 cases and 2301 controls from the MelaNostrum consortium for validation. We estimated adjusted odds ratios (ORs) for melanoma risk using traditional melanoma risk factors and the PRS with the largest area under the receiver operator characteristics curve (AUC). We estimated absolute risks combining the PRS and other risk factors, with age- and sex-specific melanoma incidence and competing mortality rates from Italy as an example. The best PRS, including 204 SNPs (AUC = 64.4%; 95% confidence interval (CI) = 63-65.8%), developed using winner's curse estimate corrections, had a per-quintile OR = 1.35 (95% CI = 1.30-1.41), corresponding to a 3.33-fold increase comparing the 5th to the 1st PRS quintile. The AUC improvement by adding the PRS was up to 7%, depending on adjusted factors and country. The 20-year absolute risk estimates based on the PRS, nevus count and pigmentation characteristics for a 60-year-old Italian man ranged from 0.5 to 11.8% (relative risk  = 26.34), indicating good separation.

Prognosis and Management of BRAF V600E-Mutated Pregnancy-Associated Melanoma.

BACKGROUND: Approximately one third of women who develop melanoma at childbearing age are diagnosed during gestation or the postpartum period, facing pregnancy-associated melanoma (PAM). However, only some retrospective studies with heterogeneous data have analyzed the impact of pregnancy on melanoma development, and no evidence exists about the behavior and the management of BRAF-mutated disease. SUBJECTS, MATERIALS, AND METHODS: In order to better describe the evolution of BRAF V600E-mutated PAM, we present here all consecutive cases diagnosed in our site during the last 7 years, recording oncological, obstetrical, and perinatal parameters, as well as the therapeutic decisions for both melanoma and gestation. Based on our institutional experience, we weigh the current published evidence and discuss upcoming clinical considerations about the prognosis of PAM, the role of BRAF status, and the possible treatment options during pregnancy in localized or advanced/metastatic disease. Five women were diagnosed with newly metastatic or relapsed BRAF V600E-mutated PAM (four during gestation and one in the 1st year postpartum) between 2012 and 2019. All of them developed extensive metastatic disease with multiple organ involvement, and four developed brain metastases. All cases experienced melanoma progression in less than 6 months under targeted therapy and died soon independently of the followed sequence of treatments. All the neonates were delivered alive and healthy, but one developed melanoma earlier than the second year of life. RESULTS: Reviewing the literature to confirm our unfavorable outcomes, no specific data on BRAF-mutated PAM were retrieved and current evidence still supports that the prognosis of PAM should be guided by the established risk factors, whereas the management of advanced/metastatic PAM should be evaluated on a case-by-case basis. CONCLUSION: More data are required to ascertain whether BRAF-mutated profile adversely affects PAM outcome, although the clinicians should be aware to detect any potential melanoma lesion during pregnancy as soon as possible, treating it locally, regardless of its BRAF status. IMPLICATIONS FOR PRACTICE: The prognosis and management of pregnancy-associated melanoma whether BRAF-mutated or wild type, is currently guided by the same parameters as in the nonpregnant condition. In this special nontrial subpopulation, BRAF-mutated status seems to have a detrimental effect on disease outcome, independently of the following treatments. In early stage melanoma, wide local excision with or without sentinel lymph node dissection may be curative at any trimester of gestation, while in advanced/metastatic setting, therapeutic strategy including immune-checkpoint or BRAF/MEK inhibitors, is more challenging, regardless of BRAF status, and should be based on an individualized decision in each case at a multidisciplinary level.