Survival of Patients with Metastatic Melanoma Treated with Ipilimumab after PD-1 Inhibitors: A Single-Center Real-World Study.

BACKGROUND: When monotherapy with PD-1 inhibitors in metastatic melanoma fails, there are currently no standard second-line choices. In case of the unavailability of clinical trials, ipilimumab represents a possible alternative treatment. METHODS: We collected data of 44 patients who received ipilimumab after the failure of PD-1 inhibitors from July 2017 to May 2023 at our Institute. Overall survival (OS), progression-free survival (PFS), and post-progression survival (PPS) based on BRAF or NRAS mutation status, sex, and the presence of brain metastases were estimated using the Kaplan-Meier method. Cox regression was used to evaluate independence in multivariate analysis. The objective response rate (ORR) was estimated based on RECIST 1.1. RESULTS: Among the 44 patients enrolled in this study, 28 BRAF-wildtype, 9 BRAF-mutated, and 7 NRAS-mutated patients were identified. OS analysis showed a significant difference between wildtype and BRAF- or NRAS-mutated patients: 23.2 months vs 5.3 and 4.59, respectively, p = 0.017. The presence of brain metastases and BRAF or NRAS mutation were independent factors for mortality in multivariate analysis. CONCLUSIONS: In case of failure to enroll patients in innovative clinical trials, second-line ipilimumab still represents an effective therapy in patients with metastatic wildtype melanoma and in the absence of brain metastases.

COVID-19 Vaccine: A Potential Risk Factor for Accelerating the Onset of Bullous Pemphigoid.

Bullous pemphigoid (BP) is the most common autoimmune bullous disease, whose main autoantigens are hemidesmosomal components BP180 and BP230. Although recent studies found no association between COVID-19 vaccines and BP, since mass vaccinations started, more than 90 vaccine-associated BP cases have been reported. To find an agreement among real-life clinical observations and recent epidemiologic data, we further investigated this topic. A total of 64 patients with BP onset in 2021 were demographically, clinically, and serologically characterized: 14 (21.9%) vaccine-associated patients (VA) developed BP within 5 weeks from the first/second vaccine dose. VA and vaccine-non-associated (VNA) patients had similar demographics and clinical and immunological characteristics. Noteworthy, the monthly distribution of BP onset during mass vaccinations paralleled vaccine administration to the elderly in the same catchment area. Additionally, in 2021, BP onsets in April-May and June-July significantly increased (p = 0.004) and declined (p = 0.027), respectively, compared to the three years before vaccination campaigns (2018-2020). Interestingly, VA and VNA patients showed statistically significant differences in the use of inhalers and diuretics. Our findings suggest that the COVID-19 vaccine may constitute an accelerating factor that, together with other triggering factors, could act in genetically predisposed individuals with possible sub-clinical autoreactivity against BP antigens, slightly accelerating BP onset.

Assessing a measure for Quality of Life in patients with severe Alopecia Areata: a multicentric Italian study.

Objective: The prevalence of anxiety and depression in patients diagnosed with Alopecia Areata (AA) is very high and this significant burden of psychological symptoms threatens the Health-Related Quality of Life (HRQoL) of affected patients. Indeed, AA often does not produce significant physical symptoms, but it nonetheless disrupts many areas of mental health. Clinical assessment of disease severity may not reliably predict patient's HRQoL, nor may it predict the patient's perception of illness. For this reason, considerable effort has been made to apply and develop measures that consider patient's perception and assess the HRQoL of individuals affected by AA. The aim of this multicentric study was to provide the Italian version of the Skindex-16AA and to evaluate its psychometric properties in a clinical sample of consecutive patients with moderate-to-severe AA. Methods: This is a longitudinal, multicenter, observational study. Patients returned for follow-up visits at 4-, 12-, and 24-weeks. The analyses of the current work aimed to confirm the factorial structure of the Skindex-16AA. In the case of non-fit, an alternative structure for the model was proposed, using an Exploratory Graph Analysis and the Bayesian approach. Results: The sample was composed of 106 patients with AA. Alopecia Universalis was the most frequently diagnosed type of alopecia at all time points. The analyses on the Skindex-16AA revealed that a two-factor structure with eight items fit the data best (Bayesian Posterior Predictive Checking using 95% Confidence Interval for the Difference Between the Observed and the Replicated Chi-Square values = -6.246/56.395, Posterior Predictive P-value = 0.06), and reported satisfactory psychometric properties (i.e., internal consistency and convergent validity). Conclusion: The Skindex-8AA demonstrated optimal psychometric properties (i.e., convergent and construct validity, and test-retest reliability) measured in a sample of patients with AA, that may suggest that it is an appropriate tool to measure the HRQoL in AA patients. However, further studies are needed in order to confirm and tested other psychometric features of this tool.

Quality of life measurement in assessing treatment effectiveness in urticaria: European experts position statement.

In this study, the European Academy of Dermatology and Venereology (EADV) Task Forces on Quality of Life and Patient-Oriented Outcomes and Urticaria and Angioedema has examined the Health-Related Quality of Life (HRQoL) measurement in the treatment of urticaria. The Dermatology Life Quality Index was the most frequently used HRQoL instrument in clinical trials on urticaria. Many reports of clinical trials of urticaria gave no exact numeric results related to HRQoL changes, making clear conclusions and comparisons with other studies impossible. The interpretation of HRQoL impairment data is more difficult when assessed by instruments without severity stratification systems. The minimal clinically significant difference (MCID) is a more clinically oriented and relevant parameter than depending on statistically significant changes in HRQoL scores. Therefore, using HRQoL instruments with established MCID data in clinical trials and clinical practice is preferred.

"Quality of Life in Epidermolysis Bullosa" and "Epidermolysis Bullosa Burden of Disease": Italian translation, cultural adaptation, and pilot testing of two disease-specific questionnaires.

BACKGROUND: Inherited epidermolysis bullosa (EB) is a clinically and genetically heterogeneous group of skin fragility disorders characterized by blister formation following minor trauma. Four major types are distinguished based on the level of cleavage within the skin. Most EB forms present severely disabling cutaneous and systemic signs and symptoms. Management relies on daily time-consuming and distressing topical medications, and symptomatic treatment of systemic findings. Disease manifestations, symptoms, and daily care strongly affect patient and caregiver quality of life (QoL). To date, there are two validated EB-specific questionnaires, the "Quality of Life in Epidermolysis Bullosa" (QOLEB) and the "Epidermolysis Bullosa Burden of Disease" (EB-BoD) for the evaluation of patient and family disease burden, respectively. The aim of our study was to develop an Italian translation of the two questionnaires and to pilot-test them. METHODS: The guidelines for translation and cross-cultural adaptation of health-related QoL measures were followed. Initially, two separate translations were generated for each questionnaire, and subsequently reconciled by an expert committee. This was followed by a back-translation process. The original texts and all translations underwent revision by the expert committee, resulting in definitive versions. The final versions were then tested in a pilot study involving cognitive debriefing in a group of 17 families, representative of all EB major types. RESULTS: The translation and reconciliation process led to minor changes to obtain semantic/idiomatic/cultural equivalence of the Italian versions with the original ones and to reconcile the questions with the answer options. The cognitive debriefing process showed a good understanding and did not require text modifications. CONCLUSIONS: The Italian versions of the QOLEB and EB-BoD provide valuable tools in everyday clinical practice of reference centers, and they allow the participation in multicenter international real-life observational studies as well as in controlled clinical trials. They enable the identification of disease-specific psychological and socioeconomic challenges for EB patients and their families, guiding targeted interventions to ensure appropriate and timely care.

Proposal of a new dermoscopic criterion for pigmented basal cell carcinoma: a multicentre retrospective study.

Dermoscopy is widely used for the diagnosis of skin cancer and it increases the accuracy of basal cell carcinoma (BCC) detection. BCC dermoscopic criteria have been updated and divided into vascular, pigment-related, and non-vascular/non-pigment-related. Our multicenter retrospective study tested a new dermoscopic pigment-related characteristic to detect pigmented BCC (pBCC) [brown homogeneous blotches (BHB)]. Cases of pBCC were collected from the databases of IDI-IRCCS of Rome and from three Italian private dermatology centers. BHB are confined patches of brown uniform pigmentation without dermoscopic features (net, fat fingers, etc.) or other internal dermoscopic structures, except for occasional vascular ones like arborizing vessels or globules/dots. Melanocytic and non-melanocytic controls were used. We reviewed photos of 270 pigmented lesions (female 145; 51.8%), including 90 histopathologically verified pBCC and 180 control cases (90 melanocytic and 90 non-melanocytic). BHB were found in 61 cases of 90 pBCC patients. The results showed a 67.8 sensitivity, 93.3 specificity, 83.6 positive and 85.3 negative predictive values, posLR 10.2, negLR 0.3, odds ratio 29.4, p<0.001. Our multicentre retrospective analysis suggested the BHB may be a novel dermoscopic pBCC diagnosis criterion.

Cross-Sectional Study on Autosomal Recessive Congenital Ichthyoses: Association of Genotype with Disease Severity, Phenotypic, and Ultrastructural Features in 74 Italian Patients.

BACKGROUND: Autosomal recessive congenital ichthyoses (ARCIs) are a clinically heterogeneous group of keratinization disorders characterized by generalized skin scaling due to mutations in at least 12 genes. The aim of our study was to assess disease severity, phenotypic, and ultrastructural features and to evaluate their association with genetic findings in ARCI patients. METHODS: Clinical signs and symptoms, and disease severity were scored in a single-center series of patients with a genetic diagnosis of ARCI. Skin ultrastructural findings were reviewed. RESULTS: Seventy-four consecutive patients (mean age 11.0 years, range 0.1-48.8) affected with lamellar ichthyosis (50/74, 67.5%), congenital ichthyosiform erythroderma (18/74, 24.3%), harlequin ichthyosis (two/74, 2.7%), and other minor ARCI subtypes (four/74, 5.4%) were enrolled. Mutated genes were as follows: TGM1 in 18/74 (24.3%) patients, ALOX12B in 18/74 (24.3%), CYP4F22 in 12/74 (16.2%), ABCA12 in nine/74 (12.2%), ALOXE3 in seven/74 (9.5%), NIPAL4 in seven/74 (9.5%), and CERS3, PNPLA1, and SDR9C7 in 1 patient each (1.4%). Twenty-five previously undescribed mutations in the different ARCI causative genes, as well as two microduplications in TGM1, and two microdeletions in CYP4F22 and NIPAL4 were identified. The mean ichthyosis severity score in TGM1- and ABCA12-mutated patients was significantly higher than in all other mutated genes, while the lowest score was observed in CYP4F22-mutated patients. Alopecia, ectropion, and eclabium were significantly associated with TGM1 and ABCA12 mutations, and large, thick, and brownish scales with TGM1 mutations. Among specific phenotypic features, psoriasis-like lesions as well as a trunk reticulate scale pattern and striated keratoderma were present in NIPAL4-mutated patients. Ultrastructural data available for 56 patients showed a 100% specificity of cholesterol clefts for TGM1-mutated cases and revealed abnormal lamellar bodies in SDR9C7 and CERS3 patients. CONCLUSION: Our study expands the phenotypic and genetic characterization of ARCI by the description of statistically significant associations between disease severity, specific clinical signs, and different mutated genes. Finally, we highlighted the presence of psoriasis-like lesions in NIPAL4-ARCI patients as a novel phenotypic feature with diagnostic and possible therapeutic implications.

Clinical Features and Response to Treatment in Elderly Subjects Affected by Hidradenitis Suppurativa: A Cohort Study.

Hidradenitis suppurativa (HS) is a chronic-relapsing inflammatory skin disease. It usually appears in the second and third decades, but a smaller proportion of patients develop late-onset HS. Geriatric HS, defined as the persistence or the development of HS after the age of 65 years, has been poorly explored. This study aimed to investigate the clinical features, treatment management and response to therapies of HS elderly subjects (≥65 years old). We designed a multicentric observational study, gathering data from seven Italian university hospitals. Demographic and clinical data of HS patients aged over 65 years were collected at baseline, week 12 and week 24. Overall, 57 elderly subjects suffering from HS were enrolled. At baseline, disease severity was predominantly moderate-to-severe, with 45.6% of patients classified as Hurley III. The gluteal phenotype was the most frequently observed; it also appeared to affect patients' quality of life more than other phenotypes. Gluteal involvement was detected in about half (49.1%) of cases and associated with severe stages of the disease. In terms of therapeutic response, Hurley III patients showed the persistency of higher values of mean IHS4, DLQI, itch- and pain-NRS scores compared to Hurley I/II. In conclusion, disease severity in this subpopulation appears high and treatment is often challenging.

Item-specific patterns of the Skindex-17 in individuals with different levels of Hidradenitis Suppurativa severity: a network analysis study.

Background: Recent studies are stressing the idea that the level of Hidradenitis Suppurativa (HS) severity does not always correspond to the same illness load. In fact, it was found that there was no significant association between Skindex-17 and clinical severity of HS, and that some items of the Skindex-17 might be more related to HS severity than others. Objective: The aim of the current study was to explore the associations between different levels of clinical severity of HS (mild, moderate, severe) and the Skindex-17 single-item responses in a large sample of adults patients. Methods: A cross-sectional study with a sample include 547 consecutive HS patients, approaching for the first time the specific dermatologic evaluation. Eligible criteria included age ≥ 18 years, HS diagnosis formulated contextually by the same expert clinician, and providing informed consent. All participants completed the Skindex-17 and were evaluated for the disease clinical severity with the International Hidradenitis Suppurativa Severity Score System. A Network Analysis was conducted, which represents a powerful methodological approach in clinical research. It allows to study specific patterns and the structure of complex system in order to better understand how the elements of the system interact with each-other. Three different Network Analyses were conducted for each group of HS clinical severity by including the items of the Skindex-17 as the nodes of each network. Results: Among 547 patients, 40% (219) were female and mean age was of 32.70 (±11.41). Different patterns among items of the Skindex-17 for the three clinical severity groups emerged, meaning that in each group different items are more crucial than others. The psychosocial subscale of the Skindex-17 is the most relevant when assessing the Quality of Life of individuals with different levels of HS severity, however, with the progression of the disease, individuals place attention also on two different aspects of the symptoms subscale of the Skindex-17, irritation and pain, which in turn perfectly reflect the severity of HS, from a clinical perspective. Conclusion: These results provide new insights on the association between levels of HS severity and related Quality of Life, measured with the Skindex-17.

Emotions at diagnosis in patients with bullous diseases.

BACKGROUND: Diagnosis of a severe condition may have a strong emotional impact on patients. Specific emotions experienced when receiving the diagnosis of a bullous disease have not been investigated. METHODS: Adult patients diagnosed with a bullous condition were recruited through the Italian Association of patients with pemphigus and pemphigoid (ANPPI). Information was collected online on sociodemographic and clinical data. We asked which emotions the patient experienced at the time of the diagnosis, i.e., isolation, anger, confusion, sadness, despair, disregard, fear, avoidance, and challenge. Also, the patients reported to whom they talked as soon as they had the diagnosis. RESULTS: Data were collected on 105 patients, most of whom were affected by pemphigus vulgaris. The emotion most frequently experienced at diagnosis was confusion (47.6% of patients). More than 30% of patients reported sadness and fear, 12.5% anger, and 10.5% despair. A significantly higher percentage of women than men experienced isolation and despair. Despair was more frequent in patients who were older at diagnosis. Patients with children experienced more sadness and despair, and less avoidance and challenge, while those who had a relative with a bullous disease reported less fear, and more challenge. CONCLUSIONS: Clinicians should be aware of the emotions of the patient when communicating the diagnosis of severe conditions, such as bullous diseases. Active listening and empathy are necessary to provide patients with correct information on the disease, so that they are not overwhelmed with negative emotions.

Incidence of keratinocyte carcinomas in Italy: an exercise in indirect estimation based on melanoma data.

BACKGROUND: The occurrence of keratinocyte carcinomas (KC) worldwide appears to be increasing, however, information on the actual incidence of these tumours is often incomplete. OBJECTIVES: The aim of this study was to provide information on the KC/melanoma ratio in order to indirectly estimate the occurrence of KC. MATERIALS & METHODS: Data were collected according to a snowball sampling procedure between Italian dermatologists. Colleagues working on melanoma and non-melanoma units were excluded. These ratios were applied to estimates derived from histopathological records, namely melanoma incidence estimates available from the Italian National Cancer Registry Network. The final estimates for KC incidence were thus obtained using the formula: KC incidence (per 100,000) = melanoma incidence (per 100,000) * (KC/melanoma ratio). RESULTS: Our results revealed a BCC/melanoma ratio of 4.4 and SCC/melanoma ratio of 1.7; values that are approximately 4 to 5 times smaller than those self-reported by dermatologists. Interestingly, this large discrepancy was not observed for the BCC/SCC ratio, which was 2.5 in the north, 2.7 in the centre, and 3.2 in the south of Italy, with an overall value of 2.8. Based on the histopathological data, this ratio was 2.6. CONCLUSION: In Italy, the actual occurrence of BCC and SCC seems to be vastly underestimated based on histopathological data, compared to data reported by dermatologists.

Systemic Photoprotection in Melanoma and Non-Melanoma Skin Cancer.

Non-melanoma skin cancers (NMSCs), which include basal cell carcinoma (BCC), squamous cell carcinoma (SCC), and actinic keratosis (AK), are the most common cancer diseases in the Caucasian race. If diagnosed late and improperly treated, BCC and SCC can become locally advanced and metastasize. Malignant melanoma (MM) is less frequent but more lethal than NMSC. Given the individual and social burdens of skin cancers, performing an adequate prevention is needed. Ultraviolet (UV) ray exposure is one of the main risk factors for skin cancer. Thus, the first-choice prevention strategy is represented by photoprotection that can be both topical and systemic. The latter consists of the oral administration of molecules which protect human skin against the damaging effects of UV rays, acting through antioxidant, anti-inflammatory, or immunomodulator mechanisms. Although several compounds are commonly used for photoprotection, only a few molecules have demonstrated their effectiveness in clinical trials and have been included in international guidelines for NMSC prevention (i.e., nicotinamide and retinoids). Moreover, none of them have been demonstrated as able to prevent MM. Clinical and preclinical data regarding the most common compounds used for systemic photoprotection are reported in this review, with a focus on the main mechanisms involved in their photoprotective properties.

Maculopapular sarcoidosis: the importance of skin signs.

Sarcoidosis is a multisystem disease that affects the skin in 20 to 30% of cases. Skin findings are often the initial presenting signs, and cutaneous sarcoidosis may appear with a wide variety of lesions; it is often considered an imitator of many other skin diseases. Clinical appearance and specific dermoscopic criteria, confirmed by a typical pathology, may guide to the correct diagnosis. We report the case of a man affected by maculo-papular sarcoidosis on the back, in which the detection of cutaneous lesions was the initial step to determine the systemic nature of the disease.

Early inflammatory biomarkers and melanoma survival.

BACKGROUND: Few studies have investigated the role of inflammatory markers in predicting cutaneous melanoma survival. The aim of the study was to identify, if any, early inflammatory markers in the prognosis of all stages of primary cutaneous melanoma. METHODS: We conducted a 10-year cohort study among 2,141 melanoma patients from the same geographic area (Lazio) with primary cutaneous melanoma diagnosed between January 2005 and December 2013. In situ cutaneous melanoma was excluded from the analysis (N = 288), leaving 1,853 cases of invasive cutaneous melanoma. The following hematological markers were obtained from clinical records: white blood cells count (WBC), count and percentages of neutrophils, basophils, monocytes, lymphocytes, and large unstained cells (LUC). Survival probability was estimated by Kaplan-Meier methods, and prognostic factors were evaluated by multivariate analysis (Cox proportional hazards model). RESULTS: In the multivariate analysis, high levels of NLR (>2.1 vs. ≤2.1, HR: 1.61; 95% CI: 1.14-2.29, P = 0.007) and high levels of d-NLR (>1.5 vs. ≤1.5, HR: 1.65; 95% CI: 1.16-2.35, P = 0.005) were independently associated with an increased risk of 10-year melanoma mortality. However, when we stratified by Breslow thickness and clinical stage, we observed that NLR and d-NLR were good markers of prognosis only for patients with Breslow thickness of 2.0 mm and more (NLR, HR: 1.62; 95% CI: 1.04-2.50; d-NLR, HR: 1.69; 95% CI: 1.09-2.62) or clinical stage II-IV (NLR, HR: 1.55; 95% CI: 1.01-2.37; d-NLR, HR: 1.72; 95% CI: 1.11-2.66), independent of other prognostic factors. CONCLUSION: We suggest that a combination of NLR and Breslow thickness may be a useful, cheap, and readily available prognostic marker for cutaneous melanoma survival.