Treatment of psoriasis with different classes of biologics reduces the likelihood of peripheral and axial psoriatic arthritis development.

OBJECTIVE: To assess the potential role of biological treatment for psoriasis (PsO) in reducing the likelihood of psoriatic arthritis (PsA), through a detailed analysis that considered the different historical phases in the PsA management, the different biologics classes, and the different patterns of articular involvement. METHODS: A monocentric cohort of 1023 PsO patients underwent a rheumatologic assessment in which clinical and therapeutic data were recorded. Chi-squared test and multivariate logistic regression analysis (adjusted for the main PsA risk factors) were performed to compare the likelihood of PsA development in different treatment groups. RESULTS: The PsA prevalence in PsO patients treated at least once with biologics was significantly lower than in patients never treated with biologics (8.9% vs 26.1%, p< 0.001). In multivariate analysis, a significantly (p< 0.01) lower likelihood of PsA development in biologic-treated patients was confirmed in the whole cohort (adjOR 0.228), as well as in the subgroups of patients with PsO onset after 2005 (adjOR 0.264) and after 2014 (adjOR 0.179). Separately analysing the different biologics classes, both the TNF (adjOR 0.206), IL-17 (adjOR 0.051) and IL-23 or 12/23 (adjOR 0.167) inhibitors were significantly (p< 0.01) associated with a lower likelihood of PsA development. Finally, patients treated with biologics had a significantly (p< 0.04) lower prevalence of both pure peripheral PsA (adjOR 0.182) and peripheral PsA with axial involvement (adjOR 0.115). CONCLUSIONS: This study provides meaningful and concordant evidence supporting the significant role of different classes of biologics in reducing the likelihood of peripheral and axial PsA development.

Short-, mid- and long-term efficacy of dupilumab in moderate to severe atopic dermatitis: a real life multicenter Italian study on 2576 patients.

BACKGROUND: The efficacy and safety of dupilumab in atopic dermatitis (AD) have been defined in clinical trials but limited real-world evidence on long term treatment outcomes are currently available to inform clinical decisions. OBJECTIVES: to describe long-term effectiveness and safety of dupilumab up to 48 months in patients with moderate-to-severe AD. METHODS: a multicenter, retrospective, dynamic cohort study was conducted to assess long term effectiveness and safety of dupilumab in patients with moderate to severe AD in a real-world setting. Predictors of minimal disease activity (MDA) optimal treatment target criteria (defined as the simultaneous achievement of EASI90, itch NRS score ≤1, sleep NRS score ≤1 and DLQI ≤1) were investigated. RESULTS: 2576 patients were enrolled from June 2018 to July 2022. MDA optimal treatment target criteria were achieved by 506 (21.91%), 769 (40.63%), 628 (50.36%), 330 (55.37%) and 58 (54.72%) of those that reached 4, 12, 24, 36 and 48 months of follow-up, respectively. Logistic regression revealed a negative effect on MDA achievement for conjunctivitis and food allergy at all timepoints. Adverse events (AE) were mild and were observed in 373 (15.78%), 166 (7.02%), 83 (6.43%), 27 (4.50%) and 5 (4.55%) of those that reached 4, 12, 24, 36 and 48 months of follow-up. Conjunctivitis was the most frequently reported AE during the available follow-up. AE led to treatment discontinuation in <1% of patients during the evaluated time periods. CONCLUSION: High long-term effectiveness and safety of dupilumab were confirmed in this dynamic cohort of patients with moderate to severe AD, regardless of clinical phenotype and course at baseline. Further research will be needed to investigate the effect of Th2 comorbidities and disease duration on the response to dupilumab and other newer therapeutics for AD.

Association between maternal dupilumab exposure and pregnancy outcomes in patients with moderate-to-severe atopic dermatitis: A nationwide retrospective cohort study.

BACKGROUND: There is limited epidemiological evidence on outcomes associated with dupilumab exposure during pregnancy; monitoring pregnancy outcomes in large populations is required. OBJECTIVE: To investigate the potential association between exposure to dupilumab in pregnant women with atopic dermatitis and any adverse pregnancy, neonatal, congenital and post-partum outcomes. METHODS: We performed a multicentre retrospective cohort study across 19 Italian tertiary referral hospital. Childbearing women were eligible if aged 18-49 years and carried out the pregnancy between 1 October 2018 and 1 September 2022. RESULTS: We retrospectively screened records of 5062 patients receiving dupilumab regardless of age and gender, identifying 951 female atopic dermatitis patients of childbearing age, 29 of whom had been exposed to the drug during pregnancy (3%). The median duration of dupilumab treatment prior to conception was 22.5 weeks (range: 3-118). The median time of exposure to the drug during pregnancy was 6 weeks (range: 2-24). All the documented pregnancies were unplanned, and the drug was discontinued in all cases once pregnancy status was reported. The comparison of the study cohort and the control group found no significant drug-associated risk for adverse pregnancy, congenital, neonatal or post-partum outcomes. The absence of a statistically significant effect of exposure on the event was confirmed by bivariate analysis and multivariate analysis adjusted for other confounding factors. CONCLUSIONS: This cohort of pregnant patients exposed to dupilumab adds to the existing evidence concerning the safety of biologic agents in pregnancy. No safety issues were identified regarding the primary outcome assessed. In clinical practice, these data provide reassurance in case of dupilumab exposure during the first trimester. However, the continuous use of dupilumab throughout pregnancy warrants further research.

Exercise in Older Adults to Prevent Depressive Symptoms at the Time of Covid-19: Results of a Randomized Controlled Trial with Follow-Up.

Background: This study aimed to verify, through a randomized controlled trial, whether a medium-intensity mixing/aerobic/anaerobic exercise (accessible to older adults even with mild chronic diseases) can effectively counteract depressive episodes. A characteristic of the trial was that the follow-up coincided (unscheduled) with the lockdown due to Covid-19. Methods: Participants (N=120) were randomized into an intervention group, performing physical exercise, and a control group. Participants, aged 65 years and older, belonged to both genders, living at home, and cleared a medical examination, were evaluated with a screening tool to detect depressive episodes, the PHQ9, at pre-treatment, end of the trial (12-week), and follow-up (48-week). Results: A decrease in the frequency of depressive episodes after the trial (T1) was found in both groups; however, a statistically significant difference was observed only in the control group (p=0.0039). From T1 to follow-up (conducted during the lockdown), the frequency of depressive episodes increased in the control group, reaching a frequency equal to the time of study entry (p=0.788). In the experimental group, the frequency of depressive episodes did not change at the end of the trial but reached a statistically significant difference compared to the start of the study (p = 0.004) and was higher than the control group (p=0.028). Conclusion: Moderate-intensity physical exercise can be conducted safely, benefitting older adults even suffering from mild chronic disorders. Physical exercise seems to guarantee a long-term preventive effect towards depressive symptoms, especially in serious stressful situations such as the lockdown due to the Covid-19 pandemic.

The surgical treatment of non-metastatic melanoma in a Clinical National Melanoma Registry Study Group (CNMR): a retrospective cohort quality improvement study to reduce the morbidity rates.

BACKGROUND: Reproducible, high-quality surgery is a key point in the management of cancer patients. Quality indicators for surgical treatment of melanoma has been presented with benchmarks but data on morbidity are still limited. This study presents the quality indicators on morbidity after surgical treatment for non-metastatic skin melanoma in an Italian registry. METHODS: Data were extracted from the Central National Melanoma Registry (CNMR) promoted by the Italian Melanoma Intergroup (IMI). All surgical procedures (WE, SNLB or LFND) for non-metastatic skin melanoma between January 2011 and February 2017 were evaluated for inclusion in the study. Only centers with adequate completeness of information (> 80%) were included in the study. Short-term complications (wound infection, dehiscence, skin graft failure and seroma) were investigated. RESULTS: Wound infection rate was 1.1% (0.4 to 2.7%) in WE, 1.3% (0.7 to 2.5%) in SLNB and 4.1% (2.1 to 8.0%) in LFND. Wound dehiscence rate was 2.0% (0.8 to 5.1%) in WE, 0.9% (0.2 to 3.0%) in SLNB and 2.8% (0.9 to 8.6%) in LFND. Seroma rate was 4.2% (1.5 to 11.1%) in SLNB and 15.1% (4.6 to 39.9%) in LFND. Unreliable information was found on skin graft failure. CONCLUSIONS: Our findings contribute to available literature in setting up the recommended standards for melanoma centers, thus improving the quality of surgery offered to patients. A consensus on the core issues around surgical morbidity is needed to provide practical guidance on morbidity prevention and management.

A previously undescribed variant of cutaneous clear-cell squamous cell carcinoma with psammomatous calcification and intratumoral giant cell granulomas.

Cutaneous clear-cell squamous cell carcinoma (ccSCC) is a rare variant of SCC composed of clear cells that lack cytoplasmic glycogen or evidence of tricholemmal keratinization. We report a previously undescribed variant of ccSCC with psammomatous calcification and intratumoral giant cell granulomas. The differential diagnosis with trichilemmal carcinoma is outlined according to the criteria of the fourth edition of World Health Organization (WHO) classification. Our findings outline that psammomatous calcification may occur inside the keratinous pearls of the neoplastic lobules triggering an intratumoral giant cell granulomatous reaction. The prognostic significance of this histopathological presentation is unknown but the potential for formation of psammoma bodies in cSCC should be considered to avoid diagnostic pitfalls.

Pilomatrix carcinoma: a rare cutaneous adnexal tumor.

Pilomatrix carcinoma is a rare tumor that is generally not diagnosed clinically. An 80-year-old man presented with a 5-month history of rapidly growing nodule of the submandibular area. Histological examination revealed a pilomatrix carcinoma, an aggressive malignancy with metastatic potential.

Clear-cell variant of superficial cutaneous leiomyosarcoma associated with RB1 mutation: Clinical, dermoscopic, and histopathological characteristics.

Leiomyosarcoma is a relatively rare soft tissue tumor whose clear-cell variant has only been reported in leiomyosarcomas of the uterus. We report here for the first time a primary cutaneous clear-cell leiomyosarcoma in the trunk skin of a 49-year-old man, characterized by a very indolent clinical and dermoscopic presentation, mimicking a dermatofibroma. Genetic analysis of the otherwise healthy patient revealed a germline mutation in the retinoblastoma 1 gene (RB1); the same mutation was found in his son, who had previously developed retinoblastoma. Moreover, the mother of the patient had died of uterine leiomyosarcoma with clear-cell changes. Mutations in the RB1 gene occur commonly in human neoplasms. In this patient, we were able to link his clear-cell variant of cutaneous leiomyosarcoma with the loss of retinoblastoma protein expression, as revealed by immunohistochemical staining analysis.

Efficacy of Imiquimod 3.75% for the treatment of extensive Bowen's disease of the face in an elderly patient.

Bowen's disease is a cutaneous squamous cell carcinoma (SCC) in situ with a potential risk of progression to invasive SCC. Despite the high number of approved treatments, elderly patients with extensive lesions of critical sites may represent a therapeutical challenge, especially in cases of treatment failure or recalcitrant disease. Here, we report the successfully use of topical Imiquimod 3.75% to treat an extensive Bowen's disease of the cheek in an elderly.

Atypical fibroxanthoma/pleomorphic dermal sarcoma of the scalp with aberrant expression of HMB-45: a pitfall in dermatopathology.

Atypical fibroxanthoma (AFX) has been considered as the non-infiltrating precursor lesion of pleomorphic dermal sarcoma (PDS), which shows an aggressive clinical behavior, because of its extensive invasion of the deeper skin layers. Although these two tumors may represent two stages of the same disease, it can be difficult to differentiate between them, because of their similar clinical and histological features 1. Furthermore, they must be distinguished from a spindled variant of squamous carcinoma, melanoma and leiomyosarcoma 2. AFX/PDS still remains a diagnosis of exclusion, that needs to combine immunohistochemical markers for a definitive diagnosis. Usually AFX/PDS shows positivity for CD10, CD99, CD68, vimentin and lysozyme, while S100, HMB45, MART-1, cytokeratins, CD34, CD31, desmin and h-caldesmon are absent.We report a case of 89-year-old male, with a history of squamous cell carcinoma removed from the right ear, presented to our department with a recently growing, ulcerated and bleeding 2 cm nodule on the scalp. After surgery the tumor recurred with infiltration to the cranial theca. The final histological diagnosis was "pleomorphic dermal sarcoma" (PDS), which showed an unexpected positivity for HMB45. We present, to the best of our knowledge, the first case of AFX/PDS with an aberrant diffuse expression of HMB45 and an aggressive biological behavior, that leads us to a difficult exclusion diagnosis.

Tyrosinase and nestin immunohistochemical expression in melanocytic nevi as a histopathologic pattern to trace melanocyte differentiation and nevogenesis.

While histological analysis represents a powerful tool for the classification of melanocytic lesions as benign or malignant, a clear-cut distinction between a nevus and a melanoma is sometimes a challenging step of the diagnostic process. The immunohistochemical detection of tyrosinase, cardinal melanogenic enzyme during melanocytic maturation, has often been helpful in formulating a differential diagnosis due to the peculiar staining pattern in nevocytes compared with melanoma cells. Tyrosinase distribution in nevi appears to overlap with the cytoarchitectural changes observable within these lesions, that result in epidermal or superficial dermal nevocytes being larger and strongly expressing melanocytic differentiation antigens, such as tyrosinase, compared with deeper dermal nevus cells. Our study aimed to evaluate the immunohistochemical expression pattern of tyrosinase in different histological types of acquired dysplastic melanocytic nevi, including junctional, compound, and intradermal nevi. Moreover, to estimate whether in nevocytes the expression of tyrosinase was associated with their differentiation state, we investigated the expression of two recognized markers of pluripotency, CD34 and nestin. In all examined nevi, our analysis revealed a remarkable immunoreactivity for tyrosinase in junctional and superficial dermal nevocytes and a decreasing gradient of staining in dermal nevocytes, up to become negative in deeper dermis. Meanwhile, junctional and dermal nevocytes were lacking in CD34 protein. Furthermore, nestin immunostaining showed an opposite distribution compared with tyrosinase, leading us to look into the tyrosinase/nestin expression pattern in melanocytic nevus as a tool to better understand the final stages of differentiation of melanocyte precursors toward their ultimate anatomical site into the epidermis.

Role of epithelial-mesenchymal transition involved molecules in the progression of cutaneous melanoma.

Epithelial-mesenchymal transition (EMT) has been suggested to have a driving role in the acquisition of a metastatic potential by melanoma cells. Important hallmarks of EMT include both E-cadherin downregulation and increased expression of N-cadherin. This switch in distinct classes of adhesion molecules leads melanoma cells to lose contact with adjacent keratinocytes and interact instead with stromal fibroblasts and endothelial cells, thus promoting dermal and vascular melanoma invasion. Consequently, tumor cells migrate to distant host tissues and establish metastases. A key regulator in the induction of EMT in melanoma is the Notch1 signaling pathway that, when activated, is prompt to upregulate N-cadherin expression. By means of this strategy, melanoma cells gain enhanced survival, proliferation and invasion properties, driving the tumor toward a more aggressive phenotype. On the basis of these statements, the present study aimed to investigate the possible association between N-cadherin and Notch1 presence in primary cutaneous melanomas and lymph node metastases. Our results from immunohistochemical analysis confirmed a positive correlation between N-cadherin and Notch1 presence in the same tumor samples. Moreover, this study highlighted that a concomitant high expression of N-cadherin and Notch1, both in primary lesions and in lymph node metastases, predicts an adverse clinical outcome in melanoma patients. Therefore, N-cadherin and Notch1 co-presence can be monitored as a predictive factor in early- and advanced-stage melanomas and open additional therapeutic targets for the restraint of melanoma metastasis.

Skin manifestations of POEMS and AESOP syndrome in the same patient revealing plasma cell dyscrasia.

POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin signs) and AESOP (adenopathy and extensive skin patch overlying a plasmacytoma) syndromes are rare paraneoplastic conditions due to an underlying plasma cell dyscrasia. We report a 70-year-old patient with the rare coexistence of POEMS and AESOP syndromes and in whom skin signs, that differ both clinically and histologically, were the clues to the diagnosis of a plasma cell disorder. Vascular endothelial growth factor-A overexpression seems to be the common pathogenetic link of the different clinicopathological presentations of the skin lesions.

Enhanced contact endoscopy for the assessment of the neoangiogenetic changes in precancerous and cancerous lesions of the oral cavity and oropharynx.

Dysplasia and squamous cell carcinoma of the upper aerodigestive tract show significant neoangiogenesis appearing as subepithelial and epithelial microvascular irregularities that can be detected by Image-Enhanced Endoscopy such as Narrow Band Imaging and Storz Professional Image Enhancement System. In the present study, the most advanced endoscopic enhancement systems were coupled with Contact Endoscopy (Enhanced Contact Endoscopy). This original method improved the identification and the understanding of the neoangiogenetic changes of the chorion in 42 patients with leukoplakia, erythroplakia, and leuko-erythroplakia of the oral cavity and oropharynx. The physiologic and pathologic mucosa was described in five obvious vascular patterns observed at Enhanced Contact Endoscopy ranging from normal to squamous cell carcinoma, passing through inflammation, hyperplasia, and dysplasia. Each vascular pattern was then compared to histology, showing that the microvascular architectural changes seen with Enhanced Contact Endoscopy are almost constant. Sensitivity, specificity, positive predictive value, and negative predictive value in the differentiation between healthy mucosa and inflammation versus pathologic hyperplasia, dysplasia, and carcinoma were, respectively, 96.6, 93.3, 98.2, 87.5, and 95.9 %. Sensitivity and specificity were 100 % in differentiation between non-malignant lesions versus squamous cell carcinoma. Our preliminary experience shows that accuracy of Image-Enhanced Endoscopy in the diagnosis of precancerous lesions and squamous cell carcinoma of the oral cavity and oropharynx can be increased if associated to Contact Endoscopy.