A retrospective observational study on cutaneous adverse events induced by immune checkpoint inhibitors.

BACKGROUND: Cutaneous adverse events (CAEs) related to oncological therapies are a common scenario in daily clinical practice. METHODS: This is a retrospective observational study collecting the data regarding CAEs of patients treated with immune checkpoints inhibitors (ICIs) in four different Italian centers. RESULTS: Of 323 patients included, 305 were evaluable for this analysis; 182 patients (59.7%) had metastatic cutaneous melanoma (CM), 99 (32.5%) non-small cell lung cancer (NSCLC) and 24 (7.8%) renal cell carcinoma (RCC). The most frequent CAEs that we found, considering all the 305 patients, were pruriginous maculopapular rash (10.2% of the patients), vitiligo-like areas (7.2% of the patients), psoriasiform rash (6.2% of the patients), asymptomatic maculopapular rash (4.6% of the patients), and lichenoid rash (4.3% of the patients). Vitiligo-like areas occurred more frequently in patients with CM, while a lichenoid rash was more frequently observed in patients with RCC. Treatment interruption was related to drug-induced CAEs in 15.4% of melanoma patients and 0.0% of lung and kidney patients. Patients developing a cutaneous adverse event had better overall response rate and higher progression free survival and overall survival than the patients without CAEs. CONCLUSIONS: Our study brings new information on the characteristics of CAEs related to ICIs treatment in three different types of cancers, CM, NSCLC and RCC.

Analysis of predictive factors influencing dupilumab continuation rate in adult patients with atopic dermatitis: results from an Italian multicenter study.

OBJECTIVES: The purpose of this study was to analyze the drug survival rate of dupilumab up to 2 years in a large real-world cohort of adult patients affected by moderate/severe atopic dermatitis (AD), and to investigate the clinical, demographic and predictive factors influencing the patients' treatment persistence. MATERIAL AND METHODS: This study included adult patients affected by moderate-to-severe AD treated with dupilumab for at least 16 weeks who visited 7 dermatologic outpatient clinics in Lazio, Italy, from January 2019 until August 2021. RESULTS: A total of 659 adult patients (345 male [52.3%], mean age: 42.8 years) with an average treatment duration of 23.3 months were enrolled in the study. Overall, 88.6% and 76.1% of patients were still on treatment after 12 and 24 months, respectively. The drug survival rate for discontinuation due to AEs and dupilumab ineffectiveness was 95.0% at 12 months and 90.0% at 24 months. The main reasons for drug discontinuation included inefficacy (29.6%), failed compliance (17.4%), persistent efficacy (20.4%) and adverse events (7.8%). Adult AD onset (≥18 years) and EASI score severity measured at the last follow-up visit were the only factors significantly associated with lower drug survival. CONCLUSION: This study revealed an increased cumulative probability of dupilumab survival at 2 years, reflected by a sustained effectiveness and a favorable safety profile of the drug.

Effectiveness of risankizumab in the treatment of palmoplantar psoriasis: a 52-week Italian real-life experience.

Background: Data on the treatment of palmoplantar psoriasis (PP) are scarce, representing a therapeutic challenge. This study aims to assess the efficacy and safety of risankizumab in a population of patients with psoriasis with a palmoplantar involvement, over a 52-week treatment period. Methods: We performed a retrospective analysis in a cohort of patients with PP, with or without involvement of other skin sites. Palmoplantar Psoriasis Area and Severity Index (ppPASI) was assessed at baseline and after 4, 16, 28 and 52 weeks, to evaluate the PP severity. Results: Sixteen patients were enrolled. The rates of ppPASI90 responses constantly increased during the period of observation and were 18.7%, 62.2%, 75.0% and 81.2% at weeks 4, 16, 28 and 52, respectively. Only two patients suspended treatment because of ineffectiveness at week 16. Conclusion: Our data from a series of 16 patients reveal that risankizumab could represent an effective and safe therapeutic choice in patients with PP.

Long-Term Sequential Digital Dermoscopy of Low-Risk Patients May Not Improve Early Diagnosis of Melanoma Compared to Periodical Handheld Dermoscopy.

Sequential digital dermoscopy (SDD) enables the diagnosis of a subgroup of slow-growing melanomas that lack suspicious features at baseline examination but exhibit detectable change on follow-up. The combined use of total-body photography and SDD is recommended in high-risk subjects by current guidelines. To establish the usefulness of SDD for low-risk individuals, we conducted a retrospective study using electronic medical records of low-risk patients with a histopathological diagnosis of cutaneous melanoma between 1 January 2016 and 31 December 2019, who had been referred and monitored for long-term follow-up of clinically suspicious melanocytic nevi. We sought to compare the distribution of "early" cutaneous melanoma, defined as melanoma in situ and pT1a melanoma, between SDD and periodical handheld dermoscopy in low-risk patients. A total of 621 melanomas were diagnosed in a four-year timespan; 471 melanomas were diagnosed by handheld dermoscopy and 150 by digital dermoscopy. Breslow tumor thickness was significantly higher for melanomas diagnosed by handheld compared to digital dermoscopy (0.56 ± 1.53 vs. 0.26 ± 0.84, p = 0.030, with a significantly different distribution of pT stages between the two dermoscopic techniques. However, no significant difference was found with respect to the distribution of pT stages, mean Breslow tumor thickness, ulceration, and prevalence of associated melanocytic nevus in tumors diagnosed on periodical handheld dermoscopy compared to SDD. Our results confirm that periodical dermoscopic examination enables the diagnosis of cutaneous melanoma at an earlier stage compared to first-time examination as this was associated in our patients with better prognostic features. However, in our long-term monitoring of low-risk subjects, Breslow tumor thickness and pT stage distribution did not differ between handheld periodical dermoscopy and SDD.

Risankizumab for the treatment of moderate-to-severe psoriasis: A multicenter, retrospective, 1 year real-life study.

Several new biologic agents targeting IL23/Th17 axis, such as risankizumab, have been developed for the treatment of psoriasis. The aim of the present study was to analyze the efficacy and safety of risankizumab in patients with moderate-to-severe psoriasis over a 52-week period. A multicentric retrospective study was conducted in patients who initiated risankizumab between July 2019 and December 2020. Psoriasis Area and Severity Index-PASI was measured at baseline and after 4, 16, 28 and 52 weeks. Clinical responses were evaluated by PASI75, PASI90 and PASI100 at the same timepoints. Potential safety issues and adverse events (AEs) were collected. Univariable and multivariable logistic regressions were performed for variables predicting clinical response. One hundred and twelve patients with psoriasis were included. PASI90 response was achieved by 17.86% of patients at week 4, 72.22% at week 16, 91.0% at week 28 and 95.24% at week 52 (as observed analysis). No associations between the considered variables and the efficacy endpoints were retrieved, influence of variables such as Body Mass Index (BMI), baseline PASI or previous biologics were not shown. No serious safety issues or discontinuations related to adverse events were reported. Risankizumab showed high efficacy and a favorable safety profile, regardless of patient- and disease-related factors.

Predictive factors of lack of response to adalimumab among bio-naive patients suffering from moderate-to severe psoriasis: analysis of a multicenter data collection in Italy.

INTRODUCTION: Efficacy of anti-TNF-a agents seems inferior to IL-17 and IL-23 inhibitors. Nevertheless, after biosimilars approval, anti TNF-a agents are recommended as first-line for psoriatic patients, for economic reasons. METHODS: Predictive factors of response or non-response to adalimumab in bionaive patients who started adalimumab (originator or biosimilar) over 12 years in 9 dermatologic centers in Italy. Effectiveness was assessed with Psoriasis Area and Severity Index (PASI75 and PASI90) at weeks 12, 24 and 48. Multiple logistic regressions were used for variables predicting clinical response; Kaplan-Meier survival curves and Cox regression for drug survival. RESULTS: The drug survival analysis showed reduced hazard ratio of overall discontinuation with male gender and scalp localization. In contrast, baseline PASI and genital psoriasis were significantly associated with increased risk of overall discontinuation. Predictive factors of non-response seemed elevated in patients with baseline PASI, older age groups, previously treated patients with phototherapy, females or patients with palmo-plantar while scalp psoriasis, previous cyclosporine and acitretin appeared as a positive predictive factor. CONCLUSIONS: This real-life analysis might be useful for clinicians in case of bio-naive patients with moderate-to-severe psoriasis and various comorbidities.

Personalized and targeted mutational analysis of multiple second primary melanomas under kinase inhibitors.

BACKGROUND: Second primary melanomas (SPMs) are new developed primary melanomas occurring in a subset of patients affected by BRAF-mutated metastatic melanoma during treatment with BRAF-inhibitors. A drug-induced paradoxical activation of mitogen-activated protein kinase (MAPK) signaling pathway in BRAF-wild type/RAS-mutated cells have been proposed as a possible molecular mechanism but data on the mutational status of SPMs are lacking. In order to better understand genetic alterations affecting the biological mechanism of SPMs, we performed a personalized and targeted next-generation sequencing analysis of a patient affected by metastatic melanoma who developed multiple SPMs during treatment with encorafenib (LGX818). METHODS: Using a cancer panel of 50 genes for solid tumors enriched with a custom panel of 10 genes specifically involved in melanoma pathogenesis, we analyzed the primary melanoma, two SPMs, one benign compound nevus and the normal DNA extracted from blood lymphocytes of the patient. RESULTS: We identified HRAS Q61 somatic mutation in one SPM developed in a pre-existing nevus. In the primary melanoma, besides the BRAF mutation, we identified the clinically actionable IDH1 R132C somatic mutation. Both SPMs were BRAF wild type. The patient harbors the recently recognized pathogenetic germline variant KDR Q472. We observed that mutations detected in tumor samples involving genes related to melanoma pathogenesis (TP53, PIK3CA, FGFR3, ATF1, KIT, HRAS and MAP2K2) were present in heterozygosis in the germline status of the patient. CONCLUSIONS: Our results support the paradoxical mechanism of MAPK pathway for SPMs under BRAF inhibitors. Moreover, they suggest that targeted mutational assessment based on matching somatic and germline analysis represent a promising approach to detect the neoplastic landscape of the tumor and to identify most accurate treatment in metastatic melanoma patient.

Expression of estrogen receptors in Spitz and Reed nevi.

BACKGROUND: Estrogens play a key role in the skin. They are associated with an increased production of melanin, proliferation of melanocytes, increased skin thickness and increased cutaneous vascularization. Spitz and Reed nevi are acquired melanocytic lesions that generally develop during childhood or adolescence, a period of changes in sex hormones background. Our study project aimed at investigating, through immunohistochemical analysis, the expression levels of ERß receptors and their expression patterns (cytoplasmic or nuclear) in Spitz and Reed nevi. METHODS: In our study, we collected a total of 86 melanocytic lesions of patients: of these, 16 were common nevi, 23 were Spitz nevi, 18 were Reed nevi and 29 were melanomas. Expression curves for estrogen receptors were constructed using the Kaplan-Meier method and compared using a log-rank test. Statistical analysis was performed using MedCalc® (MedCalc Software, Ostend, Belgium). Immunohistochemical analysis on all histological sections of nevi and melanomas was performed to evaluate the expression levels of of ERß and their expression patterns (cytoplasmic or nuclear). The agreement between the operators was calculated using Fleiss κ values. RESULTS: The correlation between immunoreactivity for the ß-estrogen receptor and the sex of patients with Spitz and Reed nevi showed that immunoreactivity was higher in male patients. The correlation between ß-estrogen receptor immunoreactivity and patient age for Spitz and Reed nevi showed no statistically significant correlation. Correlation between immunoreactivity for the ß-estrogen receptor and histotype: Spitz and Reed nevi showed a high intensity, while in common nevi and in melanomas the immunoreactive was low. The correlation between receptor immunoreactivity for ß estrogens and Breslow thickness in melanomas indicated that Breslow thickness of non-immunoreactive melanomas for ERß was much higher than those showing high immunoreactivity for this receptor. CONCLUSIONS: Spitz and Reed nevi express a higher immunoreactivity for estrogens than common nevi and melanomas, especially those with a high Breslow thickness; and immunoreactivity is higher in younger age groups.

Basal cell carcinoma thickness evaluated by high-frequency ultrasounds and correlation with dermoscopic features.

BACKGROUND: Basal cell carcinoma (BCC) is the most common skin cancer, and it can be easily treated by surgery or by various other physical modalities and topical chemotherapy. For metastatic, locally advanced BCC and for cancers that cannot be removed by surgery, systemic drugs known as hedgehog pathway blocker are used. High-frequency ultrasound (HFUS) is a non- invasive technique used in diagnosis of some skin cancers. It has proven potentially useful for BCC management. In this study we used high frequency ultrasounds to evaluate BCCs' thickness and the correlation with dermoscopic features. METHODS: We examined 86 basal cell carcinomas with dermoscopy and with high-frequency ultrasound. The main patterns identified by ultrasound were linear, ellipsoid and non-specific or undefined. Patients were divided by sex and age. The BCCs were grouped by anatomic location. Finally, we recorded specific dermoscopic features of BCCs noting their presence/absence in lesions overall and in each of four quadrants. Then the lesions were excised, and histological examination was made with definition of tumor thickness (in mm). RESULTS: In our study, two main echographic patterns were described: linear, associated with superficial BCC, and ellipsoid, found primarily in nodular variants. However, a small percentage of lesions have otherwise non-specific patterns. We observed a significant correlation between echographic tumor thickness and histotype. We observed high concordance between histological tumor thickness and ultrasounds. Also, dermoscopic criteria as large branching and blue ovoid nests were significantly associated with heightened histologic and echographic assessments of tumor thickness. CONCLUSIONS: Our study confirmed the utility of ultrasound in the diagnosis of BCCs and for the first time we have correlated ultrasounds' patterns with dermoscopy and tumor thickness.

Phenotypical Markers, Molecular Mutations, and Immune Microenvironment as Targets for New Treatments in Patients with Mycosis Fungoides and/or Sézary Syndrome.

Primary cutaneous lymphomas encompass a wide spectrum of rare lymphoproliferative disorders originating in the skin, among which, mycosis fungoides (MF) is the most common subtype. The treatment of this disease is based on skin-directed therapies eventually in association with biologic response modifiers in the early phases, whereas in patients with the advanced stages, several therapeutic strategies can be used including mono and/or polychemotherapy and bone marrow transplantation. In recent years, the identification of specific markers (phenotypical, immunological, and molecular) has led to the development of several studies (including two randomized phase III trials). The results of these studies are modifying our therapeutic strategy toward a personalized treatment approach in which the clinical characteristics of the patients and tumor-node-metastasis-blood stage are considered together with the expression of specific markers (i.e., a CD30-positive expression for the use of brentuximab vedotin). This review will provide a comprehensive scenario of the main phenotypical, molecular, and immunological markers related to MF pathogenesis and disease evolution, which could represent the target for the development of innovative effective treatments in this disease.

Correction to: The Role of Skin Thickness in the Choice of a Rhinoplasty Technique for Thin-Skinned Patients: Analysis of Long-Term Results and Patient Satisfaction.

The authors of this article wish to make the following clarification: The FACE-Q is a trademarked patient reported outcome instrument. The "Satisfaction with Nose" scale described and reproduced in this article is similarly trademarked; the copyright is retained by the Q-Portfolio. If readers would like to use the FACE-Q in research or clinical practice, they are directed to www.qportfolio.org to obtain a license permission from the copyright holders. Reproduction of the FACE-Q in publications without prior permission is not permitted.

The Role of Skin Thickness in the Choice of a Rhinoplasty Technique for Thin-Skinned Patients: Analysis of Long-Term Results and Patient Satisfaction.

INTRODUCTION: This randomized controlled study aimed to analyse the long-term results of thin-skinned patients who underwent rhinoplasty. MATERIALS AND METHODS: All the included study patients had the following characteristics: underwent primary rhinoplasty for functional and/or cosmetic problems, were thin-skinned, had been followed for almost 2 years, underwent both standard pre- and post-operative photography, had a good understanding of the Italian language, and had signed a consent form for inclusion in the study. The patients were randomly divided into 4 groups as follows: group 1, camouflage of the dorsum by diced cartilage; group 2, camouflage of the dorsum with lipofilling; group 3, camouflage of the dorsum by a temporal fascia graft; and group 4 (control group), without camouflage of the dorsum. Patients answered the Italian version of the FACE-Q rhinoplasty module. The Obagi skin pinch test was used to measure nasal skin thickness. We compared pre- and post-operative patient satisfaction with the appearance of their nose between the 4 patient groups by the Chi-squared test for unpaired data. Two plastic surgeons reviewed all the post-operative photographs of the study patients and rated the photographs on a scale of 1 to 5. RESULTS: A total of 101 patients who underwent primary rhinoplasty between January 2016 and March 2018 in our department of plastic surgery and satisfied the inclusion criteria were enrolled in this study. The mean patient age was 38.5 years. The mean follow-up time was 2.5 years. The differences between the preoperative and post-operative FACE-Q values for group 1 were significant (P < 0.01), whereas the differences between the preoperative and post-operative FACE-Q values for the other groups were not significant. The results for group 1 patients remained stable over the long-term follow-up compared with the results for other groups (P < 0.01). Groups 2 and 4 underwent more secondary procedures than groups 1 and 3 (P < 0.01). The 2 reviewers determined that patient groups 1 and 3 obtained more satisfactory outcomes than groups 1 and 4 (P < 0.01). CONCLUSIONS: This was the first randomized study to demonstrate that diced cartilage grafts used for thin-skinned patients was the best approach for obtaining a satisfactory long-term outcome and durable natural appearance. LEVEL OF EVIDENCE I: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Upper eyelid Merkel cell carcinoma treated with neoadjuvant chemotherapy and surgical excision.

Merkel cell carcinoma is a rare cutaneous carcinoma, featured by an aggressive clinical course and a mortality rate of 28% at 2 years. A 71-year-old female was affected by a 4.1-cm-wide locally advanced Merkel cell carcinoma of the upper eyelid, previously misdiagnosed as chalazion, with involvement of the extraocular muscles. Although the tumor showed a macroscopic spontaneous regression in size after the incisional biopsy, the mass was treated with neoadjuvant chemotherapy and surgical excision. Good functional and aesthetic result with preservation of the eyeball and absence of tumor recurrence were achieved at 3-year follow-up. In our experience, the combination of the inflammatory cascade due to the incisional biopsy and neoadjuvant chemotherapy led to the regression of a locally advanced large Merkel cell carcinoma of the eyelid.

Definition of "Gender Angle" in Caucasian Population.

INTRODUCTION: The goal of this study report is to define the "gender angle," a new angle which represents the masculine or feminine nasal shape, for performing a gender-oriented rhinoplasty. The use of the "gender angle" in Caucasian patients will help the plastic surgeon in the search for a suitable nose for the patient's face and above all for the search for maximum patient satisfaction. MATERIALS AND METHODS: The study population was obtained from Caucasian patients who had undergone rhinoplasty between January 1986 and September 2016 at our department. Patients answered the Italian version of the FACE-Q outcome instrument on post-rhinoplasty satisfaction with their nose. Anthropometric measurements were taken retrospectively by AutoCAD for MAC on a photograph of the profile view taken postoperatively at the last follow-up. RESULTS: A total of 1774 (706 male and 1068 female) patients satisfied the inclusion criteria and were finally enrolled in this study. We identified a gender-specific angle ranging from 168° to 182° for the male nose and from 160° to 178° for the female nose. We subdivided all study patients into 3 ranges of angles as follows: male nose, range 1 = 168°-172°, range 2 = 173°-177°, range 3 = 178°-182°; female nose, range 1 = 160°-166°, range 2 = 167°-171°, range 3 = 172°-178°. All study patients completed the FACE-Q rhinoplasty postoperative module. Analysis was performed of the FACE-Q results and the angle obtained for each nose. The most satisfactory angle range for male patients was range 3 (P = 0.01) and for the female patients was range 2 (P = 0.01). CONCLUSIONS: The "gender angle" might be a parameter that effectively provides the optimal cosmetic result for male and female patients who undergo rhinoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors - www.springer.com/00266 .

Beyond appearance: An unusual manifestation of isolated oral secondary syphilis.

Syphilis is a sexually acquired chronic infection caused by Treponema pallidum and is characterized by a variety of clinical manifestations. The secondary stage of the disease results from the hematogenous and lymphatic dissemination of treponemes after a few weeks or months, and it is characterized by recurrent activity of the disease, with muco-cutaneous as well as systemic manifestations. Mucosal lesions range from small, superficial ulcers that resemble painless aphthae to large gray plaques, and they are generally associated with systemic manifestations of the disease. The exclusive asymptomatic oral localization not associated with general manifestations is uncommon but may actually be unrecognized and under-reported. We report a case of isolated oral manifestation as the unique presentation of secondary syphilis.