Efficacy and Safety of Dupilumab in the Treatment of Hand Eczema: A Retrospective Study.

Background: Hand eczema (HE) is a prevalent chronic condition that exerts a substantial and enduring adverse effect on quality of life (QoL) and imposes an economic burden on society. Managing HE poses challenges due to the limited effectiveness and potential adverse effects associated with many currently available topical and systemic treatments. Methods: This article examines twenty-one patients affected by HE treated with dupilumab, a fully human monoclonal antibody targeting interleukin IL-4 and IL-13 signaling. This involves a retrospective descriptive statistical analysis. Results: At week 6, HECSI-75 was achieved by 12 patients (57.9%). The proportion of patients meeting the HECSI-75 criteria steadily increased over the observation weeks, reaching 90% at week 16 and 100% at week 104. Furthermore, HECSI-90 and HECSI-100 were achieved by 75% and 60% of patients at week 16 and by 100% and 85% of patients at week 68, respectively. All patients who reached week 104 maintained complete disease remission according to HECSI 100. Conclusions: In all patients, dupilumab was shown to be an effective drug in achieving disease clearance, as indicated by all the parameters considered at each evaluation point (Week 6, Week 16, Week 32, Week 52, Week 68, Week 84, and Week 104), in comparison to the initial baseline.

Dupilumab for Treatment of Prurigo Nodularis: Real-Life Effectiveness for up to 84 Weeks.

(1) Background: Prurigo nodularis (PN) is a persistent and inflammatory dermatological condition characterized by chronic itching and the formation of hardened nodules, significantly impacting the affected individuals' quality of life and psychological well-being. The management of PN poses challenges due to the limited efficacy and undesirable side effects associated with current interventions. (2) Methods: This article examines sixteen patients affected by PN treated with dupilumab, a fully human monoclonal antibody targeting interleukin IL-4 and IL-13 signaling. This involves a retrospective descriptive statistical analysis. (3) Results and (4) Conclusions: In all patients, dupilumab proves to be an effective drug in achieving disease clearance, as indicated by all the parameters considered as assessed by both physicians and patients at each evaluation point (Week 6, Week 16, Week 32, Week 52, Week 68, and Week 84), in comparison to the initial baseline.

Epidemiological and clinical analysis of exposure-related factors in non-melanoma skin cancer: A retrospective cohort study.

BACKGROUND: The incidence of non-melanoma skin cancers (NMSCs) increased over last decades, probably due to environmental concerns or to the increase of frail patients with age related comorbidities. Currently, the relationship of increasing global skin cancer rates with increased ultraviolet radiations (UVRs) resulting from stratospheric ozone depletion, global warming, and air pollution from fossil-fuel combustion. AIMS: We conducted a retrospective epidemiological study including 546 NMSC patients managed at the Dermatology Unit of the Tor Vergata Hospital to highlight different trends of sun exposure or different comorbidities. METHODS: Descriptive and inferential statistical analyses were performed to evidence differences between continous variable and Spearman rank test for dicotomical variables. Charlson Comorbidity Index was calculated to obtain the 10-years survival rate in order to identify the mean comorbidity burden of our patients. RESULTS: Considering patients with comorbidities (73.81%), actinic keratoses (AKs) was the most frequent lesion. In patients with a history of previous melanoma, basal cell carcinoma (BCC) was predominant (ANOVA test, p < 0.05) with a statistically significant correlation (rho = 0.453; p < 0.01). Squamous cell carcinoma (SCC) showed a higher rate in arterial hypertension patients, followed by the chronic heart failure and hematologic neoplasms (60%, 29.7% and 32.1%, respectively) groups. Men were more affected than women, representing 61.54% of patients. Chronic sun exposure is directly correlated with SCC rho = 0.561; p < 0.01), whereas BCC correlated with a history of sunburns (rho = 0.312; p < 0.05). CONCLUSIONS: History of photo-exposition had an important role on NMSC development especially for work or recreational reasons. Sex, age, and presence of comorbidities influenced different NMSC types. BCC was more frequent in younger patients, associated with melanoma and sunburns. The presence of SCC is associated with older patients and the hypertension group. AKs were diagnosed predominantly in oldest men, with a chronic sun-exposure history, and hematologic neoplasms group.

The Diagnosis and Management of Cutaneous Metastases from Melanoma.

Melanoma is one of the deadliest skin tumors, accounting for almost 90% of skin cancer mortality. Although immune therapy and targeted therapy have dramatically changed the prognosis of metastatic melanoma, many patients experience disease progression despite the currently available new treatments. Skin metastases from melanoma represent a relatively common event as first sign of advanced disease or a sign of recurrence. Skin metastases are usually asymptomatic, although in advanced stages, they can present with ulceration, bleeding, and superinfection; furthermore, they can cause symptoms related to compression on nearby tissues. Treatments vary from simple surgery resections to topical or intralesional local injections, or a combination of these techniques with the most recent systemic immune or target therapies. New research and studies should focus on the pathogenesis and molecular mechanisms of the cutaneous metastases of melanoma in order to shed light on the mechanisms underlying the different behavior and prognoses of different patients.

Epithelial-to-Mesenchymal Transition Gene Signature in Circulating Melanoma Cells: Biological and Clinical Relevance.

The most promising method for monitoring patients with minimal morbidity is the detection of circulating melanoma cells (CMCs). We have shown that CD45-CD146+ABCB5+ CMCs identify a rare primitive stem/mesenchymal CMCs population associated with disease progression. The epithelial-to-mesenchymal transition (EMT) confers cancer cells a hybrid epithelial/mesenchymal phenotype promoting metastatization. Thus, we investigated the potential clinical value of the EMT gene signature of these primitive CMCs. A reliable quantitative real-time polymerase chain reaction (qRT-PCR) protocol was settled up using tumor cell lines RNA dilutions. Afterwards, immune-magnetically isolated CMCs from advanced melanoma patients, at onset and at the first checkpoint (following immune or targeted therapy), were tested for the level of EMT hallmarks and EMT transcription factor genes. Despite the small cohort of patients, we obtained promising results. Indeed, we observed a deep gene rewiring of the EMT investigated genes: in particular we found that the EMT gene signature of isolated CMCs correlated with patients' clinical outcomes. In conclusion, We established a reliable qRT-PCR protocol with high sensitivity and specificity to characterize the gene expression of isolated CMCs. To our knowledge, this is the first evidence demonstrating the impact of immune or targeted therapies on EMT hallmark gene expressions in CMCs from advanced melanoma patients.

Role of Neutrophil-to-Lymphocyte Ratio (NLR) in Patients with Mycosis Fungoides.

BACKGROUND: The neutrophil/lymphocyte ratio (NLR) at baseline has been demonstrated to correlate with higher stages of disease and to be a prognostic factor in numerous cancers. However, its function as a prognostic factor for mycosis fungoides (MF) has not been yet clarified. OBJECTIVE: Our work aimed to assess the association of the NLR with different stages of MF and to outline whether higher values of this marker are related to a more aggressive MF. METHODS: We retrospectively calculated the NLRs in 302 MF patients at the moment of diagnosis. The NLR was obtained using the complete blood count values. RESULTS: The median NLR among patients with early stage disease (low-grade IA-IB-IIA) was 1.88, while the median NLR for patients with high-grade MF (IIB-IIIA-IIIB) was 2.64. Statistical analysis showed positive associations of advanced MF stages with NLRs higher than 2.3. CONCLUSIONS: Our analysis demonstrates that the NLR represents a cheap and easily available parameter functioning as a marker for advanced MF. This might guide physicians in recognizing patients with advanced stages of disease requiring a strict follow-up or an early treatment.

Advanced Cutaneous Squamous Cell Carcinoma: Italian Multicentric Retrospective Analysis of Patient Profiles and Therapeutic Approaches.

BACKGROUND: Advanced cutaneous squamous cell carcinoma (aCSCC) represents an area of unmet clinical need, with no standardized treatments until the recent approval of immune checkpoint inhibitors (ICIs). OBJECTIVES: The aim of the study was to describe clinical characteristics and therapeutic strategies of a real-life Italian cohort of aCSCC patients managed at the beginning of cemiplimab approval as compassionate use in Italy. METHODS: A multicenter retrospective study was performed by 10 Italian centers in the period January 1, 2018-May 31, 2020. Patients aged ≥18 years and diagnosed with aCSCC (locally aCSCC and metastatic CSCC) were eligible for the study. Analysis of patients' characteristics and treatment strategies was performed. RESULTS: 239 patients were initially recruited in the study: 19 patients were excluded due to incomplete data collection, yielding a final cohort of 220 patients, of which 191 and 220 were included for patients' clinical characteristics and therapeutic intervention analysis, respectively. Median age at the time of diagnosis was 81 years (range: 72-86); nodal metastases were detected in 64/220 (29%) patients, and distant metastatic spread was reported in 33/220 (15%) patients. Most of our patients referred chronic occupational and/or recreational sun exposure, experienced ≥1 sunburn during their lifetime, never wore hats or used photoprotective filters, and presented with signs of cumulative sun damage (solar lentigines and/or actinic keratosis). Majority of our cohort received at least one intervention directed to the primary tumor (n = 212, 96.3%); surgery and radiotherapy were the most common therapeutic choices. Immunotherapy was administered to a small number of patients as compassionate use, especially in the metastatic setting. CONCLUSIONS: Our study outlines the complex and heterogeneous clinical and therapeutic landscape of aCSCC patients at the beginning of ICI era, highlighting the need of a standardized care for this fragile and high-need patient population.

Topical Treatment of Actinic Keratosis and Metalloproteinase Expression: A Clinico-Pathological Retrospective Study.

Actinic keratosis is an intraepithelial proliferation of atypical keratinocytes that could progress into invasive squamous cell carcinoma. Most evidence suggests an important role of the dermal matrix metalloproteinases in the progression of atypical skin epithelial lesions. We evaluated the clinical efficacy of three different therapeutic modalities (a medical device containing 0.8% piroxicam cream and 50+ sunscreen, photodynamic therapy, and ingenol mebutate gel) to treat suspicious actinic keratoses, which were biopsied for histopathological examination and then analyzed for the expression of matrix metalloproteinases by immunohistochemistry. Clinical, dermoscopic, and reflectance confocal microscopy evaluations revealed a gradual decrease in all standard scores validated for actinic keratosis assessment at the end of the treatments. From a histopathological point of view, we documented the substantial restoration of normal skin architecture, while the immunohistochemical evaluation of matrix metalloproteinases showed a reduction in expression in the treated skin lesions compared to the baseline. As actinic keratoses are considered the precursors of squamous cell carcinoma, their treatment is crucial to prevent the development of a more aggressive disease. Our study monitored the evolution of actinic keratoses subjected to three different topical therapies, with the value of correlating clinical and histopathological findings. Moreover, as the matrix metalloproteinases are largely recognized factors involved in the pathogenesis and evolution of actinic keratosis to squamous cell carcinoma, the demonstration by immunohistochemistry of a reduction in their expression after the treatments adds new valuable concern to the field.

Aggressive Primary Cutaneous Anaplastic T-Cell Lymphoma Successfully Treated with Autologous Stem Cell Transplant and Brentuximab Vedotin Consolidation: Case Report and Review of the Literature.

Primary cutaneous CD30+ lymphoproliferative disorders include primary cutaneous anaplastic large cell lymphoma (pcALCL) and lymphomatoid papulosis. The prognosis of the disease is usually excellent but, in a minority of cases, it presents with extracutaneous involvement and aggressive behavior. The case we present-relapsed after surgical excision, immunosuppressive therapy, and conventional chemotherapy-is the first one treated with Autologous Stem Cell transplant followed by Brentuximab Vedotin consolidation, a scheme already used for high risk Hodgkin Lymphoma.

Early clinical response to 5-fluorouracil 0.5% and salicylic acid 10% topical solution in the treatment of actinic keratoses of the head: an observational study.

BACKGROUND: Actinic keratosis is one of the most common dermatological disorders. A new topical solution, constituted by 0.5% 5-fluorouracil and 10% salicylic acid (Actikerall, Almirall) has been introduced in the treatment pipeline of hyperkeratotic actinic keratoses of the head and neck. PATIENTS AND METHODS: We analyzed in an observational prospective clinical study the short-term treatment effectiveness of 5-fluorouracil and salicylic acid on face and scalp actinic keratoses of grade 1 and 2 of 40 patients. Efficacy assessment was performed by clinical dermatological examination, collecting color photographs, calculating AKASI score, and by means of dermoscopy for each target lesion at every visit. RESULTS: AKASI score decreased from an initial score of 3.3 to a final score of 0.9. At week 4, we were able to record a complete clearance of 50% of the treated lesions and a partial clearance of 28%. At the end of 12 weeks, 84% of the total lesions showed complete clearance, while 8% had partial clearance. CONCLUSIONS: 5-fluorouracil and salicylic acid topical solution is effective in the treatment of mild to moderate actinic keratoses. In the future, further studies are needed to evaluate the chance of adjusting drug dosage according to patients' and actinic keratoses features.

Continuous low-dose gemcitabine in primary cutaneous T cell lymphoma: A retrospective study.

The aim of our retrospective study was to evaluate the efficacy of a continuous therapy with a lower dosage of gemcitabine compared to those usually administered in patients with cutaneous T cell lymphomas (CTCL). Twenty-two patients received different dosages of gemcitabine. Dosage and schedule of the drug were chosen on the basis of clinical features. Gemcitabine was given at 1000 mg every 15 days in 13 patients (four mycosis fungoides [MF], nine Sezary syndrome [SS]); at 1000 mg at days +1, +8, +15 in six cases (three MF, three SS). All patients had been previously treated: four patients had received both skin directed and systemic treatments. Eighteen patients had received photopheresis, IFN, chemotherapy and immunotherapy. The objective response rate (CR + PR) among all patients was 54.5% (12 of 22 patients) with a CR of 4.5% (one of 22 patients) and a PR of 50% (11 of 22 patients). Patients with SS had an ORR of 61.5% (eight of 13 patients) with one CR (7%) and seven PR (53.8%); patients with MF showed an ORR of 55.6% (five of nine patients) but no patients experienced CR (0%). The schedule with the highest efficacy and the lowest toxicity profile was 1000 mg every 15 days. Median progression free survival and overall survival in all patients were 17 and 45 months respectively. Gemcitabine was generally well tolerated. We have demonstrated that a much lower dose of gemcitabine (1000 mg once every 15 days) in patients with advanced-stage and refractory CTCL can lead to a durable response, with tolerable and manageable adverse effects.

Expression of immune checkpoint molecules programmed death protein 1, programmed death-ligand 1 and inducible T-cell co-stimulator in mycosis fungoides and Sézary syndrome: association with disease stage and clinical outcome.

BACKGROUND: The relationship between immune checkpoint status and disease outcome is a major focus of research in cutaneous T-cell lymphoma (CTCL), a disfiguring neoplastic dermatological disorder. Mycosis fungoides (MF) and Sézary syndrome (SS) are the two most common types of CTCL. OBJECTIVES: The aim was to evaluate the immune checkpoint markers programmed death protein 1 (PD1), inducible T-cell co-stimulator (ICOS) and programmed death-ligand 1 (PD-L1) in skin biopsies from patients with CTCL relative to disease stage and overall survival. METHODS: This consecutive case series enrolled 47 patients: 57% had stage IA-IIA disease and 43% had stage IIB-IVA2 disease (including seven with SS). RESULTS: PD1, PD-L1 and ICOS expression was seen in all biopsies. Notably, PD-L1 was predominantly expressed on histiocytes/macrophages, but focal expression on CTCL cells was seen. High expression of either ICOS or PD-L1 was associated with advanced-stage disease (P = 0·007 for both) and with the appearance of large-cell transformation (LCT), a histopathological feature associated with a poor prognosis (ICOS: P = 0·02; PD-L1: P = 0·002). PD1 expression was not significantly associated with disease stage (P = 0·12) or LCT (P = 0·49), but expression was high in SS biopsies. A high combined checkpoint marker score (PD1, PD-L1 and ICOS) was associated with advanced-stage disease (P = 0·001), LCT (P = 0·021) and lower overall survival (P = 0·014). CONCLUSIONS: These findings demonstrate the existence of a complex immunoregulatory microenvironment in CTCL and support the development of immunotherapies targeting ICOS and PD-L1 in advanced disease.

Baseline neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width (RDW) correlate with advanced stages in cutaneous squamous cell carcinoma.

BACKGROUND: The neutrophil/lymphocyte ratio (NLR) and red blood cell distribution width (RDW) at diagnosis have been shown to correlate with advanced disease and to be prognostic factors in many tumors. However, their role as a prognostic factor for cutaneous squamous cell carcinoma (cSCC) has not yet been studied. OBJECTIVE: Therefore, the aim of our study was to evaluate the correlation of NLR and RDW with stages of disease in patients with cSCC in order to define whether or not higher values of these two markers correlate with a more aggressive disease. METHODS: We retrospectively analyzed the NLR and RDW in a total of 51 newly diagnosed cSCC patients. NLR and RDW were calculated using data obtained from the complete blood count (CBC). RESULTS: Median NLR among patients with the non-advanced disease (in situ and stage I) was 2.2, whereas median NLR for patients with advanced disease was 4.87. Median RDW among patients with early stage disease was 13.7%, while median RDW in patients with advanced disease was 15.81%. Statistical analysis showed positive associations of advanced cSCC stages with NLR or RDW higher than 3.07 or 14.5%, respectively. CONCLUSIONS: Therefore, our analysis demonstrated how both NLR and RDW represent cheap and easily available factors that could be used as markers for advanced cSCC. They could help to identify patients with advanced stages disease that requires a strict follow-up.

MCAM/MUC18/CD146 as a Multifaceted Warning Marker of Melanoma Progression in Liquid Biopsy.

Human malignant melanoma shows a high rate of mortality after metastasization, and its incidence is continuously rising worldwide. Several studies have suggested that MCAM/MUC18/CD146 plays an important role in the progression of this malignant disease. MCAM/MUC18/CD146 is a typical single-spanning transmembrane glycoprotein, existing as two membrane isoforms, long and short, and an additional soluble form, sCD146. We previously documented that molecular MCAM/MUC18/CD146 expression is strongly associated with disease progression. Recently, we showed that MCAM/MUC18/CD146 and ABCB5 can serve as melanoma-specific-targets in the selection of highly primitive circulating melanoma cells, and constitute putative proteins associated with disease spreading progression. Here, we analyzed CD146 molecular expression at onset or at disease recurrence in an enlarged melanoma case series. For some patients, we also performed the time courses of molecular monitoring. Moreover, we explored the role of soluble CD146 in different cohorts of melanoma patients at onset or disease progression, rather than in clinical remission, undergoing immune therapy or free from any clinical treatment. We showed that MCAM/MUC18/CD146 can be considered as: (1) a membrane antigen suitable for identification and enrichment in melanoma liquid biopsy; (2) a highly effective molecular "warning" marker for minimal residual disease monitoring; and (3) a soluble protein index of inflammation and putative response to therapeutic treatments.

Identification of a Distinct miRNA Regulatory Network in the Tumor Microenvironment of Transformed Mycosis Fungoides.

Large cell transformation of mycosis fungoides (LCT-MF) occurs in 20-50% of advanced MF and is generally associated with poor response and dismal prognosis. Although different mechanisms have been proposed to explain the pathogenesis, little is known about the role of microRNAs (miRs) in transcriptional regulation of LCT-MF. Here, we investigated the miR and mRNA expression profile in lesional skin samples of patients with LCT-MF and non-LCT MF using RNA-seq analysis. We found miR-146a and miR-21 to be significantly upregulated, and miR-708 the most significantly downregulated miR in LCT-MF. Integration of miR and mRNA expression profiles revealed the miR-regulated networks in LCT-MF. Ingenuity pathway analysis (IPA) demonstrated the involvement of genes for ICOS-ICOSL, PD1-PDL1, NF-κB, E2F transcription, and molecular mechanisms of cancer signaling pathways. Quantitative real time (qRT)-PCR results of target genes were consistent with the RNA-seq data. We further identified the immunosuppressive tumor microenvironment (TME) in LCT-MF. Moreover, our data indicated that miR-146a, -21 and -708 are associated with the immunosuppressive TME in LCT-MF. Collectively, our results suggest that the key LCT-MF associated miRs and their regulated networks may provide insights into its pathogenesis and identify promising targets for novel therapeutic strategies.

Patidegib in Dermatology: A Current Review.

BACKGROUND: Basal cell carcinoma is one of the most common types of non-melanoma skin cancers, which can be locally destructive despite low-rate metastasis. Surgery is the treatment of choice, but it lacks of efficacy on advanced cases. Hedgehog pathway inhibitors are a class of drugs providing a new therapeutic option for patients affected by advanced disease. Besides systemic therapy, such as vismodegib and sonidegib, also topical inhibitors have been developed. Patidegib is able to decrease tumor burden, reducing the adverse effects induced by systemic targeted therapies. METHODS: We performed comprehensive research to summarize the use of patidegib in advanced and recurrent aggressive basal cell carcinomas. Only English language human studies were included in the search. RESULTS: Seven trials reported the application of patidegib. Both topical and systemic patidegib demonstrated safety, tolerability, and efficacy in naïve patients with stage II and III basal cell carcinomas, while stage IV disease and not-naïve patients did not show any benefit. CONCLUSION: Unlike systemic Hedgehog pathway inhibitors, patidegib 2% gel is not associated with systemic adverse effects and allows a better patient management. Considering the multidisciplinary management of neoplasia, in the era of precision medicine, it is mandatory to confide in pharmacogenomics to obtain personalized combined or sequential therapies.