AtopyReg®, the Prospective Italian Patient Registry for Moderate-to-Severe Atopic Dermatitis in Adults: Baseline Demographics, Disease Characteristics, Comorbidities, and Treatment History.

BACKGROUND AND OBJECTIVE: AtopyReg® is a multicenter, prospective, observational, non-profit cohort study on moderate-to-severe atopic dermatitis in adults promoted in 2018 by the Italian Society of Dermatology and Venereology (SIDeMaST). We aimed to describe baseline demographics, disease characteristics, comorbidities, and therapeutic data of adult patients affected by moderate-to-severe atopic dermatitis. METHODS: Patients were selected based on the following inclusion criteria: age ≥ 18 years; Eczema Area and Severity Index score ≥ 16 or localization in visible or sensitive areas (face, neck, hands, or genitalia), or a Numeric Rating Scale itch score ≥ 7 or a Numeric Rating Scale sleep loss score ≥ 7, or a Dermatology Life Quality Index score ≥ 10. Demographic and clinical data at baseline were recorded and analyzed. RESULTS: A total of 1170 patients (male 51.1%; mean age: 44.7 years; range 18-90 years) were enrolled by 12 Italian Dermatology Units between January 2019 and November 2022. Skin lesions were eczematous in 83.2% of patients, the most involved site were the flexures (53.9%), face (50.9%), and neck (48.0%). Mean Eczema Area and Severity Index score was 22.3, mean Dermatology Life Quality Index value was 17.6, mean Patient Oriented Eczema Measure score was 13.1, and mean Numeric Rating Scale itch and sleep loss scores were 7.6 and 5.9, respectively. Previous systemic therapies were corticosteroids in 77.7% of patients, antihistamines in 50.3% of patients, and cyclosporine A in 42.6% of patients. CONCLUSIONS: This baseline data analysis deriving from AtopyReg® provides real-life evidence on patients with moderate-to-severe atopic dermatitis in Italy confirming the high burden of atopic dermatitis with a significant impact on patients' quality of life.

Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial.

PURPOSE: Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS: This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable ESR1 mutations. RESULTS: Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). ESR1 mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; P = .002) and patients with ESR1 mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; P = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION: Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with ESR1 mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer.

Ultrasound-guided injection of intralesional steroids in acute hidradenitis suppurativa lesions: A prospective study.

The management of hidradenitis suppurativa (HS) flares with intralesional steroids lacks strong scientific evidence but limited data suggest that it may be useful. The objective of this study is to assess the clinical and ultrasound responses of HS flares to ultrasound-guided injections of intralesional triamcinolone (40 mg/ml) with a dilution 1:4 versus 1:2 at 30-day (t1), 60-day (t2), and 90-day (t3) follow-up. We recruited patients with ≤3 acute lesions, unresponsive to topical therapy. At baseline we assessed lesions clinically and by ultra-high frequency ultrasound (48 or 70 MHz) and randomly performed an ultrasound-guided injection of triamcinolone. Assessments were repeated at t1, t2, and t3 follow-up, re-injecting the lesion in the case of no or partial response. We treated 49 lesions: 38.8% showed improvements at t1; 46.9% at t2; 6% at t3; and 8.3% showed no clinical and ultrasound improvements. Long-term follow-up data confirmed a statistically significant reduction in Visual Analogue Scale (VAS)-pain, Dermatology Life Quality Index (DLQI), and HS-Physician Global Assessment (HS-PGA), as well as edema and vascular signals. No adverse effects were reported. Our study suggests that ultrasound-injections with a 1:2 dilution are beneficial for HS flares that do not respond to topical treatment and should be included in the therapeutic algorithm.

Definition of treatment goals in terms of clinician-reported disease severity and patient-reported outcomes in moderate-to-severe adult atopic dermatitis: a systematic review.

BACKGROUND: Atopic dermatitis (AD) is a chronically relapsing skin disease. Although a definitive cure is not available, appropriate treatment can control the disease. The advent of biologic drugs has led to the need for a clear definition of the disease severity and treatment response. A standardized list of outcomes that defines clinician-reported disease severity and patients' reported severity are therefore essential. Solid criteria to define the response to treatment and treatment failure are lacking to date. OBJECTIVE: This systematic review defines treatment goals in terms of clinician-reported disease severity and patient-reported outcomes, referring to the published moderate-to-severe AD clinical trials. The application of these goals in daily clinical practice will ensure a better selection of available treatment options, thus increasing patient quality of care. MATERIALS AND METHODS: A systematic literature search was performed to identify the treatments goals of randomized controlled clinical trials (RCTs) on moderate-to-severe adult AD published between January 2000 and October 2020. RESULTS: In total, 14 studies met the eligibility criteria. The most widely used tools in terms of clinician-reported disease severity were the Scoring of Atopic Dermatitis (SCORAD) followed by the Eczema Area Severity Score (EASI) and Investigator Global Assessment (IGA). For disease severity scales as efficacy outcome in RCTs, the greatest standardization and reproducibility was for improvement of at least 50% in EASI score and IGA score reduction of ≥2 grades from baseline. The most widely used tools from the patients' perspective were the Dermatology Life Quality Index (DLQI), Numeric Rate Scale (NRS)-itch and Patient Oriented Eczema Measure Score (POEM). In terms of patients' reported efficacy outcomes in RCTs, a numerical DLQI, NRS-itch and POEM score improvement of at least 4 points from baseline was reported. CONCLUSIONS: This systematic review highlights the need for collaboration between experts in order to define and optimize treatment outcomes. Despite considerable progress in harmonizing outcome measures, promoted by the foundation of the Harmonizing Outcome Measures for Eczema (HOME) initiative in 2008, our results demonstrate that this endpoint is still an unmet need. Based on the literature data we propose a minimum treatment goal algorithm for use in daily clinical practice aimed at stimulating a discussion on how the care of AD patients could be further improved.

Tuscan Consensus on the diagnosis, treatment and follow up of adult atopic dermatitis.

Atopic dermatitis (AD) is an inflammatory disease with a chronic-relapsing course that is intensely itchy. A correct diagnosis of AD in adults and consequently appropriate clinical therapeutic management is a critical issue for extreme clinical expression heterogeneity and various grades of disease severity. In order to ensure high levels of care and standardization of clinical therapeutic management of Adult AD, the decision was taken to create an AD Tuscan Consensus Group (the Group), to work on and validate a consensus based regional clinical-therapeutic management model. The aims of the Group were to find agreement on the criteria for diagnosis, scoring of severity, multidisciplinary approach and treatment of adult atopic dermatitis and to create an easier way for patients to access specialized dermatology outpatient services and importantly to reduce waiting lists and costs related to the management of AD. The Tuscan Consensus Group adopted a simplified Delphi method, in three principal steps: 1) literature metanalysis and critical review of patient's clinical experience to identify the main areas considered questionable or uncertain; 2) discussion of those areas requiring consensus and statement definition through four different sub-committees (diagnosis, severity evaluation, scoring and comorbidities); 3) a consensus based simplified process with final approval of each statement by plenary vote with approval >80% of the participants. The Group here presents and discusses the consensus based recommendation statements on adult atopic dermatitis.

Itch in Chronic Wounds: Pathophysiology, Impact, and Management.

Background: The aims of this review are to analyze the current literature regarding the characteristics and pathophysiological mechanisms of itch in chronic wounds, to assess the impact on quality of life and delayed-healing, to focus on the best strategies of prevention and treatment, to highlight the importance of on-going research in order to fully understand the pathophysiology, and to improve the management of target therapies. Methods: A systematic literature review was performed using MEDLINE, PubMed, Embase, Scopus, ScienceDirect, and the Cochrane Library. We included a total of 11 articles written in English with relevant information on the pathophysiology of itch in chronic wounds and on management strategies. Results: Itch in chronic wounds was found to be correlated with xerosis, larger wound areas, necrotic tissue and amount of exudate, peripheral tissue edema, sclerosis, granulation tissue, contact dermatitis, and bacterial burden, as well as with lower quality of life. Conclusions: Although there are several aspecific pharmacological and non-pharmacological approaches, there appears to be no validated prevention or management strategy for itch in chronic wounds. Further studies are needed to clarify the association and pathophysiology of itch in chronic wounds, to evaluate the safety and efficacy of topical treatments on perilesional skin to reduce itch, to characterize multidimensional sensations of itch in chronic wounds, to identify specific cytokine and chemokine expressions that are correlated to a tailored-based approach, and to develop practical guidelines.

Dermoscopic and reflectance confocal microscopy features of two cases of vulvar basal cell carcinoma.

Basal cell carcinoma (BCC) is the most common malignant skin cancer. Its genital localization is rare, and the diagnosis in this site could be challenging. Here, we report two patients with vulvar BCC and describe their clinical, dermoscopic and in vivo and ex vivo reflectance confocal microscopic (RCM) features. Dermoscopy and RCM can be useful tools for helping the clinical diagnosis of vulvar BCC and for identifying the correct surgical margins.

Ranolazine in the treatment of atrial fibrillation: Results of the dose-ranging RAFFAELLO (Ranolazine in Atrial Fibrillation Following An ELectricaL CardiOversion) study.

BACKGROUND: Currently available antiarrhythmic agents for the treatment of atrial fibrillation (AF) have important limitations, leaving an unmet need for safe and effective therapy. Ranolazine is an approved antianginal agent with a favorable safety profile and electrophysiologic properties suggesting a potential role in the treatment of AF. OBJECTIVE: The purpose of this study was to assess the safety and efficacy of ranolazine in the prevention of AF recurrence after successful electrical cardioversion and to ascertain the most appropriate dose of this agent. METHODS: This prospective, multicenter, randomized, double-blind, placebo-control parallel group phase II dose-ranging trial randomized patients with persistent AF (7 days to 6 months) 2 hours after successful electrical cardioversion to placebo, or ranolazine 375 mg, 500 mg, or 750 mg bid. Patients were monitored daily by transtelephonic ECG. The primary end-point was the time to first AF recurrence. RESULTS: Of 241 patients randomized, 238 took at least 1 drug dose. Ranolazine proved to be safe and tolerable. No dose of the drug significantly prolonged time to AF recurrence. AF recurred in 56.4%, 56.9%, 41.7%, and 39.7% of patients in the placebo, ranolazine 375 mg, ranolazine 500 mg, and ranolazine 750 mg groups, respectively. The reduction in overall AF recurrence in the combined 500-mg and 750-mg groups was of borderline significance compared to the placebo group (P = .053) and significant compared to 375-mg group (P = .035). CONCLUSION: No dose of ranolazine significantly prolonged time to AF recurrence. However, the 500-mg and 750 mg-groups combined reduced AF recurrences, suggesting a possible role for this agent in the treatment of AF.

Coordinated and interactive expression of genes of lipid metabolism and inflammation in adipose tissue and liver during metabolic overload.

BACKGROUND: Chronic metabolic overload results in lipid accumulation and subsequent inflammation in white adipose tissue (WAT), often accompanied by non-alcoholic fatty liver disease (NAFLD). In response to metabolic overload, the expression of genes involved in lipid metabolism and inflammatory processes is adapted. However, it still remains unknown how these adaptations in gene expression in expanding WAT and liver are orchestrated and whether they are interrelated. METHODOLOGY/PRINCIPAL FINDINGS: ApoE*3Leiden mice were fed HFD or chow for different periods up to 12 weeks. Gene expression in WAT and liver over time was evaluated by micro-array analysis. WAT hypertrophy and inflammation were analyzed histologically. Bayesian hierarchical cluster analysis of dynamic WAT gene expression identified groups of genes ('clusters') with comparable expression patterns over time. HFD evoked an immediate response of five clusters of 'lipid metabolism' genes in WAT, which did not further change thereafter. At a later time point (>6 weeks), inflammatory clusters were induced. Promoter analysis of clustered genes resulted in specific key regulators which may orchestrate the metabolic and inflammatory responses in WAT. Some master regulators played a dual role in control of metabolism and inflammation. When WAT inflammation developed (>6 weeks), genes of lipid metabolism and inflammation were also affected in corresponding livers. These hepatic gene expression changes and the underlying transcriptional responses in particular, were remarkably similar to those detected in WAT. CONCLUSION: In WAT, metabolic overload induced an immediate, stable response on clusters of lipid metabolism genes and induced inflammatory genes later in time. Both processes may be controlled and interlinked by specific transcriptional regulators. When WAT inflammation began, the hepatic response to HFD resembled that in WAT. In all, WAT and liver respond to metabolic overload by adaptations in expression of gene clusters that control lipid metabolism and inflammatory processes in an orchestrated and interrelated manner.

Deregulation of ion channel and transporter encoding genes in pediatric gliomas.

Brain tumors, including the majority gliomas, are the leading cause of cancer-related death in children. World Health Organization has divided pediatric brain tumors into different grades and, based upon cDNA microarray data identifying gene expression profiles (GEPs), it has become evident in the last decade that the various grades involve different types of genetic alterations. However, it is not known whether ion channel and transporter genes, intimately involved in brain functioning, are associated with such GEPs. We determined the GEPs in an available cohort of 10 pediatric brain tumors initially by comparing the data obtained from four primary tumor samples and corresponding short-term cultures. The correspondence between the two types of samples was statistically significant. We then performed bioinformatic analyses on those samples (a total of nine) which corresponded to tumors of glial origin, either tissues or cell cultures, depending on the best "RNA integrity number." We used R software to evaluate the genes which were differentially expressed (DE) in gliomas compared with normal brain. Applying a p-value below 0.01 and fold change ≥4, led to identification of 2284 DE genes. Through a Functional Annotation Analysis (FAA) using the NIH-DAVID software, the DE genes turned out to be associated mainly with: immune/inflammatory response, cell proliferation and survival, cell adhesion and motility, neuronal phenotype, and ion transport. We have shown that GEPs of pediatric brain tumors can be studied using either primary tumor samples or short-term cultures with similar results. From FAA, we concluded that, among DE genes, pediatric gliomas show a strong deregulation of genes related to ion channels and transporters.

Kernel machine approach to testing the significance of multiple genetic markers for risk prediction.

There is growing evidence that genomic and proteomic research holds great potential for changing irrevocably the practice of medicine. The ability to identify important genomic and biological markers for risk assessment can have a great impact in public health from disease prevention, to detection, to treatment selection. However, the potentially large number of markers and the complexity in the relationship between the markers and the outcome of interest impose a grand challenge in developing accurate risk prediction models. The standard approach to identifying important markers often assesses the marginal effects of individual markers on a phenotype of interest. When multiple markers relate to the phenotype simultaneously via a complex structure, such a type of marginal analysis may not be effective. To overcome such difficulties, we employ a kernel machine Cox regression framework and propose an efficient score test to assess the overall effect of a set of markers, such as genes within a pathway or a network, on survival outcomes. The proposed test has the advantage of capturing the potentially nonlinear effects without explicitly specifying a particular nonlinear functional form. To approximate the null distribution of the score statistic, we propose a simple resampling procedure that can be easily implemented in practice. Numerical studies suggest that the test performs well with respect to both empirical size and power even when the number of variables in a gene set is not small compared to the sample size.

Cross-sectional and longitudinal evaluation of bone mass in children and young adults with juvenile idiopathic arthritis: the role of bone mass determinants in a large cohort of patients.

OBJECTIVE: To assess the prevalence of reduced spine bone mineral apparent density (BMAD), and to identify the main predictors of reduced spine BMAD in a cross-sectional and longitudinal evaluation of the same large cohort of patients with juvenile idiopathic arthritis (JIA). There are few prospective data on bone mass evaluation in a large number of patients with JIA, and with enthesitis-related arthritis onset. METHODS: Two hundred nineteen patients with JIA (median age 8.7 yrs, range 6.1-13.1 yrs; 104 oligoarticular JIA, 61 polyarticular, 20 systemic, and 34 enthesitis-related arthritis onset) were retrospectively evaluated. A dual-energy x-ray absorptiometry (DEXA) scan at the lumbar spine was performed in all subjects. Of these, 89 consecutive patients were followed up randomly and longitudinally with a second and a third DEXA evaluation. The data obtained were compared with 80 age-matched and sex-matched healthy subjects. RESULTS: At the first DEXA, patients with JIA showed a reduced spine BMAD standard deviation score (SDS) in comparison to controls (p < 0.001). These results were confirmed when the subjects were divided into JIA subtypes (p < 0.005) with the exception of enthesitis-related arthritis onset. Spine BMAD SDS significantly correlated with JIA onset type (p < 0.01), age at JIA onset (p < 0.005), and flares (p = 0.008). The longitudinal evaluation showed that spine BMAD SDS did not significantly improve at the followup in comparison to controls, in all subsets with JIA except for systemic onset (p < 0.05). Spine BMAD correlated with sex (p < 0.01), systemic corticosteroid exposure (p < 0.01), the number of intraarticular corticosteroid injections (p < 0.01), the interval from last steroid injection (p < 0.05), erythrocyte sedimentation rate (p < 0.005), and C-reactive protein levels (p < 0.005). CONCLUSION: Patients with JIA have a low bone mass and, after a first increase due to therapy, do not reach a healthy condition over time despite our current more effective drugs. These patients have a high risk of osteoporosis in early adulthood. To reduce the risk and improve the bone mass, close monitoring of bone mineral density, better control of disease activity, physical activity, and intake of calcium and vitamin D are recommended. In patients with osteoporosis, therapeutic approaches including bisphosphonates should be considered.

Dietary extra-virgin olive oil rich in phenolic antioxidants and the aging process: long-term effects in the rat.

The aim of the present work was to verify whether extra-virgin olive oil, a food naturally containing phenolic antioxidants, has the potential to protect from the pro-aging effects of a high-calorie diet. Male rats were fed from age 12 months to senescence a high-calorie diet containing either corn oil (CO), or extra-virgin olive oil with high (H-EVOO) or low (L-EVOO) amounts of phenols. The prolonged high fat intake led to obesity, liver lipid degeneration and insulin resistance, which were not counteracted by high phenol intake. No difference in overall survival was found at the end of the experiment in the animals treated with H-EVOO compared to the other groups. However, we did detect a protective effect of olive oil on some age-related pathologies and on blood pressure, of which the former was associated with the antioxidant content. Concomitantly, a decrease in DNA oxidative damage in blood cells and plasma TBARS and an increase in liver superoxide dismutase were detected following H-EVOO consumption. Thus, although olive oil phenols cannot reverse the detrimental effects of a prolonged intake of high amounts of fat, improving the quality of olive oil in terms of antioxidant content can be beneficial.