Association of age with survival in older patients with cutaneous melanoma treated with immune checkpoint inhibitors.

INTRODUCTION: Several types of immune checkpoint inhibitors (ICIs) are approved to treat advanced melanoma, but their effectiveness has not been compared in older patients treated outside of a clinical trial. Moreover, evidence suggests that a patient's response to ICI therapy may vary by age and type of ICI. The purpose of this study was to compare survival by ICI type in older patients with melanoma and to investigate treatment effect modification by age. MATERIALS AND METHODS: Using the SEER-Medicare database, we identified patients with cutaneous melanoma (2012-2015) treated with an ICI (CTLA-4, PD-1, or combination CTLA-4 + PD-1 inhibitors). Cox proportional hazards regression was used to estimate hazard ratios (HRs) with 95% confidence intervals (CI) for ICI types. We used an interaction term and stratified models to test for treatment effect modification by age. RESULTS: Of the 1435 patients included in our analysis, 790 (55.1%) received CTLA-4 inhibitors, 512 (35.7%) received PD-1 inhibitors, and 133 (9.3%) were treated with combination ICIs. Median survival ranged from 13.4 months (95%CI: 10.7-16.3) for CTLA-4 inhibitors to 23.5 months (95%CI: 16.2-30.0) for combination ICIs. In multivariable models, the risk of death was lower with PD-1 inhibitors compared to CTLA-4 inhibitors (HR = 0.78, 95%CI: 0.68-0.89). An age*ICI type interaction term was significant (p < 0.001), and survival gains were greater the older age group (≥80) compared to the younger group (65-79). DISCUSSION: In a population-based setting, we identified important differences in survival by ICI type in older patients with melanoma treated with ICIs, with prolonged survival associated with PD-1 inhibitors compared to CTLA-4 inhibitors.

Clinical and pathologic correlation of cutaneous COVID-19 vaccine reactions including V-REPP: A registry-based study.

BACKGROUND: Cutaneous reactions after COVID-19 vaccination have been commonly reported; however, histopathologic features and clinical correlations have not been well characterized. METHODS: We evaluated for a history of skin biopsy all reports of reactions associated with COVID-19 vaccination identified in an international registry. When histopathology reports were available, we categorized them by reaction patterns. RESULTS: Of 803 vaccine reactions reported, 58 (7%) cases had biopsy reports available for review. The most common histopathologic reaction pattern was spongiotic dermatitis, which clinically ranged from robust papules with overlying crust, to pityriasis rosea-like eruptions, to pink papules with fine scale. We propose the acronym "V-REPP" (vaccine-related eruption of papules and plaques) for this spectrum. Other clinical patterns included bullous pemphigoid-like (n = 12), dermal hypersensitivity (n = 4), herpes zoster (n = 4), lichen planus-like (n = 4), pernio (n = 3), urticarial (n = 2), neutrophilic dermatosis (n = 2), leukocytoclastic vasculitis (n = 2), morbilliform (n = 2), delayed large local reactions (n = 2), erythromelalgia (n = 1), and other (n = 5). LIMITATIONS: Cases in which histopathology was available represented a minority of registry entries. Analysis of registry data cannot measure incidence. CONCLUSION: Clinical and histopathologic correlation allowed for categorization of cutaneous reactions to the COVID-19 vaccine. We propose defining a subset of vaccine-related eruption of papules and plaques, as well as 12 other patterns, following COVID-19 vaccination.

Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: A registry-based study of 414 cases.

BACKGROUND: Cutaneous reactions after messenger RNA (mRNA)-based COVID-19 vaccines have been reported but are not well characterized. OBJECTIVE: To evaluate the morphology and timing of cutaneous reactions after mRNA COVID-19 vaccines. METHODS: A provider-facing registry-based study collected cases of cutaneous manifestations after COVID-19 vaccination. RESULTS: From December 2020 to February 2021, we recorded 414 cutaneous reactions to mRNA COVID-19 vaccines from Moderna (83%) and Pfizer (17%). Delayed large local reactions were most common, followed by local injection site reactions, urticarial eruptions, and morbilliform eruptions. Forty-three percent of patients with first-dose reactions experienced second-dose recurrence. Additional less common reactions included pernio/chilblains, cosmetic filler reactions, zoster, herpes simplex flares, and pityriasis rosea-like reactions. LIMITATIONS: Registry analysis does not measure incidence. Morphologic misclassification is possible. CONCLUSIONS: We report a spectrum of cutaneous reactions after mRNA COVID-19 vaccines. We observed some dermatologic reactions to Moderna and Pfizer vaccines that mimicked SARS-CoV-2 infection itself, such as pernio/chilblains. Most patients with first-dose reactions did not have a second-dose reaction and serious adverse events did not develop in any of the patients in the registry after the first or second dose. Our data support that cutaneous reactions to COVID-19 vaccination are generally minor and self-limited, and should not discourage vaccination.

Sebaceous Carcinoma of the Eyelid: A Systematic Review and Meta-Analysis.

BACKGROUND: Sebaceous carcinoma (SC) of the eyelid is a rare, aggressive malignancy associated with high rates of recurrence, metastasis, and tumor-related mortality. OBJECTIVE: Provide a collective analysis of clinical presentations, management techniques, and outcomes, and compare outcomes of common treatment methods. METHODS AND MATERIALS: Observational studies reporting management and outcomes of SC of the eyelid were included. Patient and clinical data were extracted, and meta-analysis of proportions was performed. RESULTS: One thousand three hundred thirty-three subjects were included with a mean age of 65.2 years and 803 (60.2%) women. Of 647 initial diagnoses reported, 277 (42.8%) were correct, and the mean diagnostic delay was 14.7 months (range 8.5-34.8). The tumor location was reported in 1,246 subjects and involved the upper eyelid in 780 (62.6%), lower eyelid in 409 (32.8%), and 57 (4.8%) involved both. Overall rates of recurrence, metastasis, and tumor-related mortality were 15.9%, 12.1%, and 6.2%, respectively. There were no statistically significant differences in wide local excision (WLE) versus Mohs micrographic surgery (MMS) outcomes. CONCLUSION: Sebaceous carcinoma of the eyelid is more common in women, on the upper eyelid, and is frequently misdiagnosed initially. Rate of recurrence, metastasis, and tumor-related mortality were similar in subjects managed with WLE versus MMS.

A cohort study of personal and family history of skin cancer in relation to all-cause and cancer-specific mortality.

PURPOSE: Even though the fatality rate from skin cancers is low, evidence from a few cohort studies has raised the possibility that people with a personal history of skin cancer may have a higher all-cause mortality rate compared with those without a personal history of skin cancer. The purpose of the present study was to investigate the potential links between a personal history or family history of skin cancer and all-cause and cancer-specific mortality METHODS: A prospective cohort (n = 8,622) was assembled within the NHANES I follow-up study. Cox Proportional Hazard Regression analysis was used to estimate the hazard ratios (HR) and 95% confidence intervals (CI) for the association for personal and family history of skin cancer and all-cause and cancer-specific mortality. RESULTS: After adjustment for several potential confounding variables, a personal history of skin cancer was associated with decreased risk for all-cause mortality (HR 0.72, 95% CI 0.61-0.85), whereas the results for cancer-specific mortality were consistent with a null association (HR 0.97, 95% CI 0.74-1.27). A family history of skin cancer was not significantly associated with all-cause mortality (HR 0.97, 95% CI 0.76-1.24) or cancer-specific mortality (HR 0.69, 95% CI 0.38-1.24). CONCLUSION: The results of the present study do not support the hypothesis that a personal history or family history of skin cancer is associated with an increased risk of all-cause or cancer-specific mortality. The high prevalence of skin cancer adds to the public health significance of this question, providing a strong rationale for further research to resolve this question.

Immune checkpoint inhibitors retain effectiveness in older patients with cutaneous metastatic melanoma.

INTRODUCTION: Immune checkpoint inhibitors (ICIs) have dramatically changed the treatment landscape for advanced melanoma, but their use in older patients remains understudied. An age-related decline in immune function is of concern when treating older patients because host immune factors can influence clinical outcomes with immunotherapy. Therefore, we aimed to evaluate the effectiveness of ICIs in patients 65 years and older. METHODS: Using the SEER-Medicare data, we evaluated survival by first systemic treatment type in a retrospective cohort study of patients aged 65 years and older who were diagnosed with stage IV cutaneous melanoma between 2012 and 2015. Cox proportional hazards regression was used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals. RESULTS: A total of 541 patients were included in this study. Median survival differed significantly between groups (p < 0.0001) and was longest in patients treated with PD-1 inhibitors (34.0 months), followed by CTLA-4 inhibitors (16.8 months), targeted therapy (9.7 months), chemotherapy (7.1 months), and no systemic therapy (3.6 months). The ICI survival benefit persisted after adjusting for age, sex, comorbidities, M stage, the presence of brain metastases, and evaluation at an NCI-designated cancer center. Hazard ratios comparing ICIs to no systemic therapy were 0.35 (95% CI: 0.24-0.52) for PD-1 inhibitors and 0.48 (95% CI: 0.37-0.63) for CTLA-4 inhibitors. We did not observe a difference in ICI effectiveness by age group (65-74 vs ≥75). CONCLUSIONS: In a nationally representative cohort of patients with advanced melanoma, ICI therapy delivered in a real world setting significantly improved survival in patients aged 65 years and older.

The spectrum of COVID-19-associated dermatologic manifestations: An international registry of 716 patients from 31 countries.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has associated cutaneous manifestations. OBJECTIVE: To characterize the diversity of cutaneous manifestations of COVID-19 and facilitate understanding of the underlying pathophysiology. METHODS: Case series from an international registry from the American Academy of Dermatology and International League of Dermatological Societies. RESULTS: The registry collected 716 cases of new-onset dermatologic symptoms in patients with confirmed/suspected COVID-19. Of the 171 patients in the registry with laboratory-confirmed COVID-19, the most common morphologies were morbilliform (22%), pernio-like (18%), urticarial (16%), macular erythema (13%), vesicular (11%), papulosquamous (9.9%), and retiform purpura (6.4%). Pernio-like lesions were common in patients with mild disease, whereas retiform purpura presented exclusively in ill, hospitalized patients. LIMITATIONS: We cannot estimate incidence or prevalence. Confirmation bias is possible. CONCLUSIONS: This study highlights the array of cutaneous manifestations associated with COVID-19. Many morphologies were nonspecific, whereas others may provide insight into potential immune or inflammatory pathways in COVID-19 pathophysiology.

Pernio-like skin lesions associated with COVID-19: A case series of 318 patients from 8 countries.

BACKGROUND: Increasing evidence suggests pernio-like lesions are cutaneous manifestations of coronavirus infectious disease 2019 (COVID-19). OBJECTIVE: To describe clinical and pathologic findings of pernio-like lesions in patients with confirmed or suspected COVID-19. METHODS: An international dermatology registry was circulated to health care providers worldwide through the American Academy of Dermatology, International League of Dermatologic Societies, and other organizations. RESULTS: We documented 505 patients with dermatologic manifestations associated with COVID-19, including 318 (63%) with pernio-like lesions. Patients with pernio-like lesions were generally young and healthy, with relatively mild COVID-19. Of 318 patients with confirmed or suspected COVID-19 by providers, 23 (7%) were laboratory-confirmed COVID-19 positive, and 20 others (6%) were close contacts of patients with confirmed COVID-19. Given current testing criteria, many patients lacked COVID-19 testing access. For 55% of patients, pernio-like lesions were their only symptom. In patients with other COVID-19 symptoms, pernio-like lesions typically appeared after other symptoms. Pernio-like lesions lasted a median of 14 days (interquartile range, 10-21 days). LIMITATIONS: A case series cannot estimate population-level incidence or prevalence. In addition, there may be confirmation bias in reporting. We cannot exclude an epiphenomenon. CONCLUSIONS: Pernio-like skin changes of the feet and hands, without another explanation, may suggest COVID-19 infection and should prompt confirmatory testing.

Keratinocyte Carcinoma and Risk for Another Type of Cancer: Assessment of a Dose-response Relationship.

BACKGROUND/AIM: Keratinocyte carcinoma (KC) is a marker of increased risk of other cancer types. To assess if this association exhibits a dose-response relationship, a case-control study was carried out. PATIENTS AND METHODS: This was a clinic-based study of cases with KC plus another type of cancer matched by age, race (all Caucasian), sex and histologic type to controls with KC only (n=48 matched pairs). RESULTS: Compared with the KC only group, those with KC plus another cancer had a mean number of lesions that were 43%, 35%, and 41% greater for basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and total KC, respectively. The odds ratio (OR) of developing another type of cancer increased from 1.0 to 1.09 (95% confidence interval (CI)=0.23-5.13) to 2.12 (95%CI=0.50-9.08) according to whether the patient had zero, one, or ≥two BCC lesions; for SCC, the corresponding ORs were 1.0, 1.24 (95%CI=0.48-3.24), and 1.39 (95%CI=0.29-6.61). CONCLUSION: A dose-response relationship seems to exist between the number of skin lesions and the risk of another type of cancer, but the lack of statistical significance weakens this evidence.

A cohort study of personal and family history of skin cancer in relation to future risk of non-cutaneous malignancies.

PURPOSE: Skin cancer has repeatedly been observed to be a marker of increased risk for developing an internal malignancy. The purpose of our study was to further investigate this association while also characterizing the potential role of family history of skin cancer in relation to risk for non-cutaneous malignancies. METHODS: Our study used data from 8,408 participants from the NHANES I epidemiological follow-up study. Cox-proportional hazards models were used to estimate the risk for developing an internal cancer associated with a personal history and family history of skin cancer during follow-up. RESULTS: A personal history of skin cancer was associated with significantly increased risk of developing an internal cancer in adjusted models [hazard ratio (HR) 1.33, 95% confidence interval (CI) 1.09-1.61] but a family history of skin cancer was not associated with increased risk (HR 0.80, 95% CI 0.58-1.11). CONCLUSIONS: Consistent with prior reports, a personal history of skin cancer was associated with increase of developing internal malignancies, but this did not hold true for a family history of skin cancer. Further research is needed to understand why a personal history of skin cancer acts as a marker for increased risk for internal cancer.

Changes in Lipid Levels and Incidence of Cardiovascular Events Following Tofacitinib Treatment in Patients With Psoriatic Arthritis: A Pooled Analysis Across Phase III and Long-Term Extension Studies.

OBJECTIVE: The risk of cardiovascular disease (CVD) is higher in patients with psoriatic arthritis (PsA) compared to the general population. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Because tofacitinib increases circulating lipid levels in some patients, we evaluated CVD risk factors and major adverse cardiovascular events (MACE) in patients with active PsA receiving tofacitinib 5 or 10 mg twice daily plus conventional synthetic disease-modifying antirheumatic drugs. METHODS: Data were pooled from 2 phase III studies (Efficacy and Safety of Tofacitinib in Psoriatic Arthritis [OPAL Broaden] and Tofacitinib in Patients with Psoriatic Arthritis With Inadequate Response to TNF Inhibitors [OPAL Beyond]) and 1 ongoing long-term extension (Open-Label Extension Study of Tofacitinib in Psoriatic Arthritis [OPAL Balance], data cutoff January 2017; database not locked). Outcomes included fasting lipid levels, blood pressure, hypertension-related adverse events (AEs; including hypertension, high blood pressure, and increased blood pressure), and MACE. RESULTS: Overall, 783 tofacitinib-treated patients were included. Percentage increases from baseline in low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels ranged from 9% to 14% for tofacitinib 5 mg and 10 mg at 3 and 6 months; no meaningful changes in LDL-c:HDL-c or total cholesterol:HDL-c ratios were observed. Blood pressure remained stable for 24 months. Fifty-eight patients (7.4%) had hypertension-related AEs; none were fatal (incidence rate [IR] per 100 patient-years 4.81 [95% confidence interval (95% CI) 3.65-6.22]). Five patients (0.6%) had MACE (IR 0.24 [95% CI 0.05-0.70]); 2 were fatal. CONCLUSION: Serum lipid level increases at month 3 following tofacitinib treatment in PsA were consistent with observations in rheumatoid arthritis and psoriasis. The IR of hypertension-related AEs and MACE was low; long-term follow-up is ongoing.

Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease associated with increased cardiovascular (CV) risk and altered lipid metabolism. Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: The aim of the study was to investigate the effects of tofacitinib on traditional and nontraditional lipid parameters and CV risk markers in patients with psoriasis from a phase III study, OPT Pivotal 1. METHODS: Patients with psoriasis were randomized to tofacitinib 5 or 10 mg twice daily (BID) or placebo BID. Serum samples were collected at baseline, week 4, and week 16. Analyses included serum cholesterol levels, triglycerides, lipoproteins, lipid particles, lipid-related parameters/CV risk markers, and high-density lipoprotein (HDL) function analyses. RESULTS: At week 16, small concurrent increases in mean low-density lipoprotein cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels were observed with tofacitinib; total cholesterol/HDL-C ratio did not change. There was no significant change in the number of small dense LDL particles, which are considered to be more atherogenic than large particles, and oxidized LDL did not increase. Paraoxonase 1 activity, linked to HDL antioxidant capacity, increased, and HDL-associated serum amyloid A, which reduces the anti-atherogenic potential of HDL, decreased. HDL capacity to promote cholesterol efflux from macrophages did not change. Lecithin-cholesterol acyltransferase activity, which is associated with reverse cholesterol transport, increased. Markers of systemic inflammation, serum amyloid A and C-reactive protein, decreased with tofacitinib. CONCLUSION: While small increases in lipid levels are observed with tofacitinib treatment in patients with psoriasis, effects on selected lipid-related parameters and other circulating CV risk biomarkers are not suggestive of an increased CV risk [NCT01276639].