Integrated analysis of a phase 2 study of cemiplimab in advanced cutaneous squamous cell carcinoma: extended follow-up of outcomes and quality of life analysis.

BACKGROUND: To provide pooled longer term data from three groups of a phase 2 study of cemiplimab in patients with advanced cutaneous squamous cell carcinoma (CSCC), and to determine duration of response (DOR) and impact on quality of life (QoL). METHODS: Patients received cemiplimab 3 mg/kg every 2 weeks (group 1, metastatic CSCC [mCSCC], n=59; group 2, locally advanced CSCC, n=78) or cemiplimab 350 mg every 3 weeks (group 3, mCSCC, n=56). Primary endpoint was objective response rate (ORR) per independent central review (ICR). QoL was repeatedly measured at day 1 of each treatment cycle (groups 1 and 2: 8 weeks; group 3: 9 weeks). RESULTS: Median duration of follow-up was 15.7 months. Overall, ORR per ICR was 46.1% (95% CI: 38.9% to 53.4%). Complete response (CR) rates were 20.3%, 12.8%, and 16.1% for groups 1, 2, and 3, respectively. Median time to CR was 11.2 months. Among patients with partial response or CR, the estimated proportion of patients with ongoing response at 12 months from the first objective response was 87.8% (95% CI: 78.5% to 93.3%), with median DOR not reached. Kaplan-Meier estimated probability of overall survival (OS) was 73.3% (95% CI: 66.1% to 79.2%) at 24 months, with median OS not reached. Global Health Status (GHS)/QoL improvements were observed as early as cycle 2 and were significantly improved and durable until last assessment. Kaplan-Meier estimate of median time to first clinically meaningful improvement for pain was 2.1 (95% CI: 2.0 to 3.7) months and was significantly improved in responders versus non-responders (p<0.0001). CONCLUSIONS: This is the largest (n=193) clinical dataset for a programmed cell death-1 inhibitor against advanced CSCC, confirming the sustained substantial clinical activity of cemiplimab in these patients, including new findings of improved CR rates over time, increasing DOR, and durable pain control and GHS/QoL improvement. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT02760498), https://clinicaltrialsgov/ct2/show/NCT02760498.

Rejuvenation of gene expression pattern of aged human skin by broadband light treatment: a pilot study.

Studies in model organisms suggest that aged cells can be functionally rejuvenated, but whether this concept applies to human skin is unclear. Here we apply 3'-end sequencing for expression quantification ("3-seq") to discover the gene expression program associated with human photoaging and intrinsic skin aging (collectively termed "skin aging"), and the impact of broadband light (BBL) treatment. We find that skin aging was associated with a significantly altered expression level of 2,265 coding and noncoding RNAs, of which 1,293 became "rejuvenated" after BBL treatment; i.e., they became more similar to their expression level in youthful skin. Rejuvenated genes (RGs) included several known key regulators of organismal longevity and their proximal long noncoding RNAs. Skin aging is not associated with systematic changes in 3'-end mRNA processing. Hence, BBL treatment can restore gene expression pattern of photoaged and intrinsically aged human skin to resemble young skin. In addition, our data reveal, to our knowledge, a previously unreported set of targets that may lead to new insights into the human skin aging process.

Differential effects of dietary supplements on metabolomic profile of smokers versus non-smokers.

BACKGROUND: Cigarette smoking is well-known to associate with accelerated skin aging as well as cardiovascular disease and lung cancer, in large part due to oxidative stress. Because metabolites are downstream of genetic variation, as well as transcriptional changes and post-translational modifications of proteins, they are the most proximal reporters of disease states or reversal of disease states. METHODS: In this study, we explore the potential effects of commonly available oral supplements (containing antioxidants, vitamins and omega-3 fatty acids) on the metabolomes of smokers (n = 11) compared to non-smokers (n = 17). At baseline and after 12 weeks of supplementation, metabolomic analysis was performed on serum by liquid and gas chromatography with mass spectroscopy (LC-MS and GC-MS). Furthermore, clinical parameters of skin aging, including cutometry as assessed by three dermatologist raters blinded to subjects' age and smoking status, were measured. RESULTS: Long-chain fatty acids, including palmitate and oleate, decreased in smokers by 0.76-fold (P = 0.0045) and 0.72-fold (P = 0.0112), respectively. These changes were not observed in non-smokers. Furthermore, age and smoking status showed increased glow (P = 0.004) and a decrease in fine wrinkling (P = 0.038). Cutometry showed an increase in skin elasticity in smokers (P = 0.049) but not in non-smokers. Complexion analysis software (VISIA) revealed decreases in the number of ultraviolet spots (P = 0.031), and cutometry showed increased elasticity (P = 0.05) in smokers but not non-smokers. CONCLUSIONS: Additional future work may shed light on the specific mechanisms by which long-chain fatty acids can lead to increased glow, improved elasticity measures and decreased fine wrinkling in smokers' skin. Our study provides a novel, medicine-focused application of available metabolomic technology to identify changes in sera of human subjects with oxidative stress, and suggests that oral supplementation (in particular, commonly available antioxidants, vitamins and omega-3 fatty acids) affects these individuals in a way that is unique (compared to non-smokers) on a broad level.

Association of facial skin aging and vitamin D levels in middle-aged white women.

To investigate the relationship between UV-induced skin photodamage and 25(OH) vitamin D levels, we performed a cross-sectional study in 45 female subjects aged >40. Menopausal status, smoking status, skin cancer history, oral supplement use, and season of blood draw were recorded and serum 25(OH)D measured. A single-blinded, dermatologist evaluated standardized digital facial images for overall photodamage, erythema/telangiectasias, hyperpigmentation, number of lentigines, and wrinkling. Adjusting for age and season of blood collection, women with lower photodamage scores were associated with a 5-fold increased odds of being vitamin D insufficient (OR 5.0, 95% CI: 1.1, 23). Low scores for specific photodamage parameters including erythema/telangiectasias, hyperpigmentation, and wrinkling were also significantly associated with vitamin D insufficiency. Our results suggest an association between skin aging and 25(OH)D levels.

A two-year, double-blind, randomized placebo-controlled trial of oral green tea polyphenols on the long-term clinical and histologic appearance of photoaging skin.

BACKGROUND: Green tea polyphenols (GTPs) have significant antioxidant and antiinflammatory activities, and prior short-term studies suggest that these compounds may improve photoaging skin. OBJECTIVES: To evaluate the long-term effects of oral GTPs on the clinical and histologic characteristics of photoaging skin. MATERIALS AND METHODS: Double-blind, placebo-controlled trial of 56 women aged 25 to 75 randomized to 250 mg GTPs or placebo twice daily for 2 years. A blinded dermatologist scored the appearance of photodamaged facial skin at 0, 6, 12, and 24 months. A blinded dermatopathologist scored the histologic characteristics of sun-exposed arm skin at 0 and 24 months. RESULTS: Clinical assessment of facial skin revealed that the GTP group had significant improvement in overall solar damage at 6 months (p=.02) and significant improvement in erythema and telangiectasias at 12 months (p=.02). The placebo group did not have significant improvements in these parameters at 6 months or 12 months. There were no statistically significant differences in other photoaging parameters at 6, 12, or 24 months in the GTP or placebo groups. Histopathologic analysis of sunexposed arm skin showed no statistically significant difference in photoaging parameters in the GTP group or the placebo group at 24 months. CONCLUSIONS: Long-term supplementation with oral GTPs was not superior to placebo in improving clinical or histologic photoaging parameters after 24 months of use.

A case of argyria after colloidal silver ingestion.

BACKGROUND: Argyria is often considered an entity of the past, one which has largely disappeared with the cessation of silver usage in oral medications. However, with the practice of colloidal silver ingestion in current "alternative health" treatments, argyria should be considered in the differential diagnosis of blue-gray hyperpigmentation. METHODS: A single case report with clinicopathological correlation. RESULTS: Histological examination of skin biopsy specimen, which showed perieccrine brown-black granules, verified that colloidal silver rather than a prescribed medication was the source of the patient's dyspigmentation.