Neuroimmunomodulatory Effect of NO on Chronic Wound Healing After Photodynamic Therapy.

Neuroimmunomodulation is the capacity of the nervous system to regulate immune processes. The existence of neurotransmitter receptors in immune cells enables this phenomenon to take place. Neuronal mediators possess the capacity to direct and control several occurrences during the wound healing process. Nitric oxide (NO) functions as a neuromodulator, playing a crucial role in the regulation of vascular tone and blood pressure with antimicrobial properties. Photodynamic therapy has been shown to augment the function of immune cells involved in the healing process of venous leg ulcers. Nitric oxide can be secreted into the extracellular environment by these cells. In lesions treated with PDT, the synthesis of iNOs (the enzyme that releases NO) increased, as demonstrated by the experimental results. Therefore the significance of PDT in enhancing the clinical condition of the lesion is thus highlighted.

Immunotherapy in cutaneous melanoma and biologics in psoriatic disease: similarities and differences from a clinical multidisciplinary perspective.

INTRODUCTION: Immunomodulating therapies harness the power of the immune system to combat disease. In advanced melanoma, immune checkpoint inhibitors have significantly improved survival outcomes by activating the immune system to recognize and eliminate cancer cells. In psoriasis, interleukin inhibitors effectively suppress inflammation and improve disease symptoms. AREAS COVERED: We provide a meta-opinion-based consensus paper on the analogies and differences in treatment mechanisms, duration, frequency between immunotherapy for advanced melanoma and biologics for psoriasis. Combining the current scientific evidence with expert insights, we provide valuable guidance for future research and decision-making processes. EXPERT OPINION: The development of immunological treatments in melanoma and psoriasis has revolutionized dermatology, but the quest for tailored therapies that maximize efficacy continues. Managing cutaneous exacerbations during melanoma immunotherapy in psoriatic patients remains challenging. Similarly, treating oncologic psoriasis patients resistant to traditional therapies requires individualized approaches. Research is needed to identify response predictors in both conditions and address the sustainability of healthcare systems due to the high cost of biologics. Drug delay studies for psoriasis and longer follow-up evaluations after immunotherapy discontinuation in melanoma are essential for optimizing treatment outcomes and resource allocation.

Identifying and addressing unmet clinical needs in primary cutaneous B-cell lymphoma: A consensus-based paper from an ad-hoc international panel.

Primary cutaneous B-cell lymphomas (PCBCLs) are lymphoproliferative disorders that appear on the skin without evidence of extracutaneous manifestations at the time of diagnosis. There is a lack of evidence-based guidelines for their clinical management due to the availability of very few large scale studies and controlled clinical trials. Here we present and discuss a series of major unmet clinical needs (UCNs) in the management of PCBCLs by a panel of 16 experts involved in research and clinical practice of PCBCL. The Panel produced recommendations on the appropriateness of the clinical decisions concerning the identified clinical needs and proposed research for improving the knowledge needed to solve them. Recommendations and proposals were achieved by multiple-step formalized procedures to reach a consensus after a comprehensive analysis of the scientific literature. Recommendations and proposals lay in the domain of classification uncertainties of PCBCL, optimization of diagnosis, optimization of prognosis, optimization of staging and critical issues on therapeutic strategies with particular focus on new treatments. These recommendations are intended for use not only by experts but above all by dermatologists and hematologists with limited experience in the field of PCBCLs as well as general practitioners.

Burden of Disease in the Real-Life Setting of Patients with Atopic Dermatitis: Italian Data From the MEASURE-AD Study.

INTRODUCTION: Atopic dermatitis (AD) is a chronic inflammatory skin disease that negatively impacts the quality of life and work productivity of patients. OBJECTIVES: We sought to evaluate the real-world burden of AD patients in Italy. METHODS: This sub-analysis of the MEASURE-AD multicountry study conducted between December 2019-2020 included patients diagnosed with moderate-to-severe AD eligible for or receiving systemic therapy in the previous 6 months. During a single visit, physician and patient-reported questionnaires were used. RESULTS: A total of 118 adult patients were enrolled and 57.6% (N = 68) of patients had moderate-to-severe AD at the time of enrolment according to the Eczema Area and Severity Index. Sleep disorders interfered with daily function in the previous week in 58.5% (N = 69) of patients, pruritus was severe in 50% (N = 59) and 42.4% (N = 50) reported a flare lasting >7 days in the previous 6 months. According to the Dermatology Quality of Life Index, 37.3% (N = 44) of patients reported a severe impact of AD and approximately 10% had clinical depression/anxiety. Current drug therapy was considered inadequate in controlling AD in 26.3% (N=31) of patients. Work activity impairment was 38.6±31.7% and monthly AD-related expenses were 148.6±134.6 Euros per patient. CONCLUSIONS: This real-life study documents a high burden of disease in patients with moderate-severe AD in Italy.

A Retrospective Chart Review of Treatment Patterns and Overall Survival among a Cohort of Patients with Relapsed/Refractory Mycosis Fungoides in France, Germany, Italy, Spain and the United Kingdom.

(1) Background: Most patients with mycosis fungoides (MF), a form of cutaneous T-cell lymphoma (CTCL), develop relapsed/refractory (R/R) disease following front-line systemic therapy. This report describes treatment patterns and outcomes from the subpopulation with R/R MF. (2) Methods: This observational, retrospective, cohort study analyzed patient records (1984-2016) from 27 clinical sites in Europe. Outcomes included treatments received, response to first-, second- and third-line treatment, overall survival (OS) and progression-free survival (PFS). (3) Results: Of 104 patients with MF, 100 received second-line and 61 received third-line therapy. The median (range) times from the start of first-line therapy to the first R/R MF and from the first to the second R/R MF were 11.2 (0.3-166.5) and 13.5 (0.0-174.6) months, respectively. Second-and third-line treatment options varied and comprised systemic therapies (85% and 79% of patients, respectively), radiotherapy (32% and 34%, respectively) and topical therapies (48% and 36%, respectively). The median (95% confidence interval [CI]) OS from the diagnosis of the first R/R MF was 11.5 (6.5-not reached [NR]) years and was higher with non-chemotherapy (NR) versus chemotherapy (6.5 years); the estimated median PFS (95% CI) from the time of the first R/R MF was 1.3 (1.0-2.1) years. (4) Conclusions: High rates of R/R disease were observed after second- and third-line treatments in this real-world cohort, with longer median OS in patients receiving non-chemotherapy treatment versus chemotherapy. Following the standard management of MF and using recently approved targeted therapies can help improve patient outcomes in advanced-stage MF.

EORTC consensus recommendations for the treatment of mycosis fungoides/Sézary syndrome - Update 2023.

On behalf of the EORTC Cutaneous Lymphoma Tumours Group (EORTC-CLTG) and following up on earlier versions published in 2006 and 2017 this document provides an updated standard for the treatment of mycosis fungoides and Sézary syndrome (MF/SS). It considers recent relevant publications and treatment options introduced into clinical practice after 2017. Consensus was established among the authors through a series of consecutive consultations in writing and a round of discussion. Treatment options are assigned to each disease stage and, whenever possible and clinically useful, separated into first- and second line options annotated with levels of evidence. Major changes to the previous version include the incorporation of chlormethine, brentuximab vedotin, and mogamulizumab, recommendations on the use of pegylated interferon α (after withdrawal of recombinant unpegylated interferons), and the addition of paragraphs on supportive therapy and on the care of older patients. Still, skin-directed therapies are the most appropriate option for early-stage MF and most patients have a normal life expectancy but may suffer morbidity and impaired quality of life. In advanced disease treatment options have expanded recently. Most patients receive multiple consecutive therapies with treatments often having a relatively short duration of response. For those patients prognosis is still poor and only for a highly selected subset long term remission can be achieved with allogeneic stem cell transplantation. Understanding of the disease, its epidemiology and clinical course, and its most appropriate management are gradually advancing, and there is well-founded hope that this will lead to further improvements in the care of patients with MF/SS.

Epidemiology of cutaneous T-cell lymphomas: state of the art and a focus on the Italian Marche region.

Among primary cutaneous T-cell lymphomas (CTCL), mycosis fungoides (MF) is the most frequent and, along with Sézary syndrome (SS), the best-studied subtype. Most available studies on epidemiology of MF and SS are based on small cohorts or different inclusion criteria. Moreover, although this has become a hot topic, most studies show limitations, such as selection bias and lack of clinical information or follow-up data. Therefore, no reliable conclusions can be drawn. This paper reviews the current data underpinning our understanding of the epidemiology of MF and SS, and presents some original findings based on data retrieved from the cutaneous lymphoma registry of the Italian Marche region. The Marche Regional Cutaneous Lymphoma Registry is a multidisciplinary team founded 27 years ago to share the management of these rare disorders. All patients with a clinical and histologically confirmed diagnosis of primary cutaneous lymphoma are centralized in Ancona (Italy) at the Haematology Clinic, Polytechnic University of Marche, for clinical evaluation, staging, treatment, and follow-up. This paper emphasizes the need for a national registry of pCLs in Italy, as no detailed epidemiological information is available in the country except for the Marche Regional Cutaneous Lymphoma Registry. A national registry would allow for more comprehensive data collection from all over Italy and could provide more accurate information on incidence and epidemiology. This would be beneficial for understanding the pathogenesis and diagnostic procedures of these diseases and could improve patient outcomes. Therefore, we advise the creation of a national registry of pCLs in Italy.

Pso-Reg: a web registry for psoriasis in real life.

BACKGROUND: Psoriasis (PsO) is a common immune mediated inflammatory disease, affecting about 60 million people worldwide. Although current therapies have dramatically changed the therapeutic approach to the disease, the heterogeneity of responses often results in an essential unmet clinical need. This study describes the design and development of the Psoriasis Registry (Pso-Reg), an Italian electronic-based-registry, aimed to collect real life data of patients with psoriasis. METHODS: Pso-Reg is a multicenter, retrospective and observational cohort study based on the Research Electronic Data Capture (REDcap) tool. Five Italian medical centres were part of the network and all patients affected by PsO were included in the study. Socio-demographic, clinical characteristics, laboratory findings and therapies were collected, and descriptive analysis was carried out. RESULTS: Among the 768 patients analyzed, 446 were men (58.1%), with a mean age of 55.5 years. The first more frequent comorbidity was psoriatic arthritis (26.8%), followed by hypertension (25.3%), diabetes (10%) and dyslipidemia (11.7%). Of the entire cohort, 240 patients (38.2%) had a positive family history for PsO. Vulgar type was the most common phenotype (85.5%), with a major involvement of the scalp (13.8%). The mean PASI (Psoriasis Area Severity Index) score at the baseline was 7.5 (7.8). At the enrolment, 107 patients were treated with topic treatments (13.9%), 5 with phototherapy (0.7%), 92 with cDMARDs (conventional disease-modifying anti-rheumatic drugs) (12.0%) and 471 with biologic therapies (61.3%). CONCLUSIONS: Real-life data from Pso-Reg could contribute providing the rationale for an individual-based strategy and a more tailored approach for the management of psoriasis.

BRAFV600 variant allele frequency predicts outcome in metastatic melanoma patients treated with BRAF and MEK inhibitors.

BACKGROUND: The prognostic impact of variant allele frequency (VAF) on clinical outcome in BRAFV600 mutated metastatic melanoma patients (MMPs) receiving BRAF (BRAFi) and MEK inhibitors (MEKi) is unclear. MATERIALS AND METHODS: A cohort of MMPs receiving first line BRAFi and MEKi was identified by inspecting dedicated databases of three Italian Melanoma Intergroup centres. VAF was determined by next generation sequencing in pre-treatment baseline tissue samples. Correlation between VAF and BRAF copy number variation was analysed in an ancillary study by using a training and a validation cohort of melanoma tissue samples and cell lines. RESULTS: Overall, 107 MMPs were included in the study. The VAF cut-off determined by ROC curve was 41.3%. At multivariate analysis, progression-free survival (PFS) was significantly shorter in patients with M1c/M1d [HR 2.25 (95% CI 1.41-3.6, p < 0.01)], in those with VAF >41.3% [HR 1.62 (95% CI 1.04-2.54, p < 0.05)] and in those with ECOG PS ≥1 [HR 1.82 (95% CI 1.15-2.88, p < 0.05)]. Overall survival (OS) was significantly shorter in patients with M1c/M1d [HR 2.01 (95% CI 1.25-3.25, p < 0.01)]. Furthermore, OS was shorter in patients with VAF >41.3% [HR 1.46 (95% CI 0.93-2.29, p = 0.06)] and in patients with ECOG PS ≥1 [HR 1.52 (95% CI 0.94-2.87, p = 0.14)]. BRAF gene amplification was found in 11% and 7% of samples in the training and validation cohort, respectively. CONCLUSIONS: High VAF is an independent poor prognostic factor in MMP receiving BRAFi and MEKi. High VAF and BRAF amplification coexist in 7%-11% of patients.

Effectiveness and tolerability of chlormethine gel for the management of mycosis fungoides: a multicenter real-life evaluation.

Background: Topical chlormethine (CL) is recommended as a first-line treatment for early-stage mycosis fungoides (MF) and in 2017, the European Medicines Agency approved the CL gel formulation to treat adult patients. More recently, to increase patient compliance and adherence, clinicians have developed flexible protocols that allow the concomitant use of CL gel with topical corticosteroids in daily practice regimens. Therefore, sharing real-life data on CL gel use and side effects management may help improve the use of this agent. Objectives: To expand knowledge about the actual use of CL gel in patients with MF, the present study assessed the improvement of MF skin lesions after CL gel treatment and provided information on the management of cutaneous adverse events (AEs) in a real-life setting. Methods: This was an Italian retrospective study conducted among six dermatology referral centers. Patients ≥18 years affected by MF and in treatment with CL gel (160 µ/g), alone or in combination according to routine clinical practice, between December 2019 and December 2021 were considered. The study's primary aim was to evaluate the effectiveness of CL gel in terms of overall response rate (ORR) after 3 months of treatment. Results: A total of 79 patients (61% male) with different stages of MF (84% early stage) were included. CL gel was prescribed mainly in association with topical corticosteroids (66% of patients). ORR after 3 months of treatment was 42%, with no differences between early- and advanced-stage MF. Response rates improved over time up to 97% after 18 months of treatment. Overall, 66 AEs were reported in 67% of patients; most were hyperpigmentation (45%) and irritant contact dermatitis (37%). Six AEs led to treatment discontinuation, and five out of six (83%) patients who reported these events resumed treatment after interruption. No AEs were classified as severe. Conclusions: Our observations support the use of CL gel in patients with early- and advanced-stage MF, making it a valuable treatment option.

Comparison Between First Line Target Therapy and Immunotherapy in Different Prognostic Categories of BRAF Mutant Metastatic Melanoma Patients: An Italian Melanoma Intergroup Study.

Background: BRAF and MEK inhibitors target therapies (TT) and AntiPD1 immunotherapies (IT) are available first-line treatments for BRAF v600 mutant metastatic melanoma patients. ECOG PS (E), baseline LDH (L), and baseline number of metastatic sites (N) are well-known clinical prognostic markers that identify different prognostic categories of patients. Direct comparison between first-line TT and IT in different prognostic categories could help in first line treatment decision. Methods: This is a retrospective analysis conducted in 14 Italian centers on about 454 metastatic melanoma patients, divided in 3 groups: group A-patients with E = 0, L within normal range, and N less than 3; group B-patients not included in group A or C; group C-patients with E > 0, L over the normal range, and N more than 3. For each prognostic group, we compared TT and IT in terms of progression free survival (PFS), overall survival (OS), and disease control rate (DCR). Results: In group A, results in 140 TT and 36 IT-treated patients were, respectively, median PFS 35.5 vs 11.6 months (HR (95% CI) 1.949 (1.180-3.217) p value 0.009); median OS not reached vs 55 months (HR (95% CI) 1.195 (0.602-2.373) p value 0.610); DCR 99% vs 75% p value <0.001). In group B, results in 196 TT and 38 IT-treated patients were, respectively, median PFS 11.5 vs 5 months (HR 1.535 (1.036-2.275) p value 0.033); median OS 19 vs 20 months (HR 0.886 (0.546-1.437) p value 0.623); DCR 85% vs 47% p value <0.001). In group C, results in 41 TT and 3 IT-treated patients were, respectively, median PFS 6.4 vs 1.8 months (HR 4.860 (1.399-16) p value 0.013); median OS 9 vs 5 months (HR 3.443 (0.991-11.9) p value 0.052); DCR 66% vs 33% p value 0.612). Conclusions: In good prognosis, group A-TT showed statistically significant better PFS than IT, also in a long-term period, suggesting that TT can be a good first line option for this patient category. It is only in group B that we observed a crossing of the survival curves after the 3rd year of observation in favor of IT. Few patients were enrolled in group C, so few conclusions can be made on it.