Primary cutaneous lymphoma: recommendations for clinical trial design and staging update from the ISCL, USCLC, and EORTC.

The number of patients with primary cutaneous lymphoma (PCL) relative to other non-Hodgkin lymphomas (NHLs) is small and the number of subtypes large. Although clinical trial guidelines have been published for mycosis fungoides/Sézary syndrome, the most common type of PCL, none exist for the other PCLs. In addition, staging of the PCLs has been evolving based on new data on potential prognostic factors, diagnosis, and assessment methods of both skin and extracutaneous disease and a desire to align the latter with the Lugano guidelines for all NHLs. The International Society for Cutaneous Lymphomas (ISCL), the United States Cutaneous LymphomaConsortium (USCLC), and the Cutaneous Lymphoma Task Force of the European Organization for the Research and Treatment of Cancer (EORTC) now propose updated staging and guidelines for the study design, assessment, endpoints, and response criteria in clinical trials for all the PCLs in alignment with that of the Lugano guidelines. These recommendations provide standardized methodology that should facilitate planning and regulatory approval of new treatments for these lymphomas worldwide, encourage cooperative investigator-initiated trials, and help to assess the comparative efficacy of therapeutic agents tested across sites and studies.

Real-world study on the use of pegylated interferon alpha-2a for treatment of mycosis fungoides/Sézary syndrome using Time to Next Treatment as a measure of clinical benefit: An EORTC CLTG study.

INTRODUCTION: Mycosis fungoides (MF) and Sézary syndrome (SS) are chronic malignant diseases that typically necessitate diverse strategies to achieve remission. Systemic interferon alpha (IFN-α, subtypes 2a and 2b) has been used for MF/SS since 1984, however its production was recently stopped and so the recombinant pegylated (PEG) form of IFN α-2a remains as single IFN alternative treatment, even though not approved for MF/SS. OBJECTIVE: To assess effectiveness and safety of PEG IFN α-2a in monotherapy and in combination with other treatments using time to next treatment (TTNT) as a measure of clinical therapeutic benefit in real world setting. METHODS: We conducted an international and multicenter retrospective study of patients with MF and SS at any stage, treated with PEG IFN α-2a, from July 2012 to February 2022. Patients were included across 11 centers in 10 countries. Primary endpoints were to determine TTNT of PEG IFN α-2a and the adverse events (AE) in MF/SS. RESULTS: In total 105 patients were included, mean age was 61 (22-86 years); 42 (40%) with disease stage IA-IIA, 63 (60%) with stage IIB-IVB. PEG IFN α-2a was combined with other therapies in 67 (64%) patients, usually with extracorporeal photopheresis (36%) and bexarotene (22%). Fifty-seven percent of stage I-IIA patients achieved ORR, whereas 51% of stage IIB-IVB. Combination therapy showed a TTNT of 10.4 months, while 7 months in monotherapy (p=0.0099). Overall, TTNT was 9.2 months, ORR was 53% (56/105), CR and PR were 13% and 40%, respectively.AE were described in 69% (72) of the patients. Flu-like symptoms (27%), lymphopenia (23%) and elevated liver function (10%) were the most frequently reported. Grade 3-4 adverse events were reported in 23 (21%) patients, which were mostly related to myelosuppression. LIMITATIONS: retrospective data analysis and unrestricted number of combination therapies. CONCLUSIONS: PEG IFN α-2a for MF/SS showed ORR of 53%, TTNT of 9.2 months, superiority of combination regimens in comparison to monotherapy and doses of 180 mcg/weekly related to higher ORR.

Real-world data on the effectiveness of brodalumab in patients with moderate-to severe plaque psoriasis in the Greek clinical setting (the BrIDGE study).

BACKGROUND: Despite that brodalumab's efficacy and safety have been assessed in randomized clinical trials, real-life data remain scarce. BrIDGE was an observational, prospective, single-cohort, multicentre study that recruited patients with moderate-to severe plaque psoriasis in Greece. OBJECTIVES: The primary objective was to assess the proportion of patients who achieved Psoriasis Area and Severity Index (PASI)100 after 24 weeks. Other endpoints included: the maintenance of PASI90/100 through to 104 weeks, the short-term response [PASI75/90/100 and static Physician's Global Assessment (sPGA) 0/1] to brodalumab at 12-16 weeks and time to complete clearance. Moreover, we explored the change in quality of life [Dermatology Life Quality Index (DLQI) 0/1] and adherence to brodalumab. METHODS: Two hundred patients who were initiating treatment with or switching to brodalumab, were recruited. Analyses were conducted using the as observed data and three imputation approaches were also applied for the missing data (last observation carried forward, 'worst case' and 'best case' scenario). Continuous variables were reported using summary statistics, whereas categorical variables were reported in frequency tables. RESULTS: Based on the 'as observed data', 42.0% of patients achieved PASI100 at Week 24 after 25.9 ± 3.5 weeks and 65% of patients attained PASI100 at Week 104. In total, 70.2%, 47.5% and 32.0% achieved PASI75/90/100, respectively, whereas 72.6% of patients achieved sPGA 0/1, at Weeks 12-16. With respect to sPGA status 82.8%, 89.2% and 92.5% of patients achieved sPGA 0/1 at Weeks 24, 52 and 104, respectively. The time to achieve PASI100 at Weeks 12-16 was 13.7 ± 1.3, 52.1 ± 3.4 weeks at Week 52 and 105.5 ± 4.8 weeks at Week 104. Mean DLQI and Psoriasis Symptom Inventory (PSI) scores decreased by 11.4 ± 7.0 and 15.4 ± 6.5 points from baseline to Week 104, respectively. Adherence to treatment was equal to 98.9%. CONCLUSIONS: Brodalumab confers rapid and durable responses, as well as improvements in the quality of life of moderate-to-severe psoriasis patients.

The Effect of a Ketogenic Diet versus Mediterranean Diet on Clinical and Biochemical Markers of Inflammation in Patients with Obesity and Psoriatic Arthritis: A Randomized Crossover Trial.

The effect of different diet patterns on psoriasis (PSO) and psoriatic arthritis (PSA) is unknown. Τhe aim of our study was to evaluate the effectiveness of a Mediterranean diet (MD) and Ketogenic diet (KD), in patients with PSO and PSA. Twenty-six patients were randomly assigned to start either with MD or KD for a period of 8 weeks. After a 6-week washout interval, the two groups were crossed over to the other type of diet for 8 weeks. At the end of this study, MD and KD resulted in significant reduction in weight (p = 0.002, p < 0.001, respectively), in BMI (p = 0.006, p < 0.001, respectively), in waist circumference (WC) (p = 0.001, p < 0.001, respectively), in total fat mass (p = 0.007, p < 0.001, respectively), and in visceral fat (p = 0.01, p < 0.001, respectively), in comparison with baseline. After KD, patients displayed a significant reduction in the Psoriasis Area and Severity Index (PASI) (p = 0.04), Disease Activity Index of Psoriatic Arthritis (DAPSA) (p = 0.004), interleukin (IL)-6 (p = 0.047), IL-17 (p = 0.042), and IL-23 (p = 0.037), whereas no significant differences were observed in these markers after MD (p > 0.05), compared to baseline. The 22-week MD-KD diet program in patients with PSO and PSA led to beneficial results in markers of inflammation and disease activity, which were mainly attributed to KD.

Psoriatic Insomnia: A Subjective and Objective Sleep Evaluation.

Psoriasis may affect patients' sleep. In order to examine this relationship, this study evaluated non-anxious and non-depressive patients with moderate to severe psoriasis before and after 6 months of systemic treatment. A prospective case-control study with 46 consecutive patients (mean age 51.1 ± 12.8 years, 18 women) and 24 age-, sex- and body mass index-matched controls (mean age 46.5 ± 15.4 years, 12 women) was conducted to assess sleep using both sleep questionnaires and actigraphy. Of psoriatic patients, 91.3% were poor sleepers, and 65.2% of the psoriatic patients presented insomnia symptoms, compared with 54.2% and 33.3% of the control group (p < 0.001, p = 0.02, respectively). Actigraphy showed that Total Sleep Time was shorter in patients, while 82.6% of the psoriatic patients had poor Sleep Efficiency, compared with controls (p = 0.004, p = 0.03, respectively). Patients' quality of life was associated with sleep disturbance (p < 0.001), and pruritus was negatively correlated with sleep duration (p < 0.001). After 6 months of treatment, patients' sleep pattern, according to actigraphy, had not changed significantly; however, they had insomnia for no longer than the control group (p = 0.65), whereas the above-mentioned correlations were non-significant after treatment. Psoriatic insomnia was improved after 6 months of systemic treatment. Actigraphy may be used as an objective tool to evaluate sleep in these patients.

Sub-population analysis of patients with plaque psoriasis treated with calcipotriol/betamethasone aerosol foam; effectiveness and patient satisfaction, according to baseline disease severity and prior psoriasis treatment experience, in a Greek population.

Fixed combination calcipotriol/betamethasone (Cal/BD) aerosol foam has been shown to be effective in psoriasis treatment in clinical trials, but real-world evidence is currently sparse. The real-world CELSUS study in Greece found that Cal/BD aerosol foam treatment was effective and associated with satisfaction in psoriasis patients. Patients from the CELSUS study (N = 400) were stratified by baseline disease severity according to physician's global assessment (PGA) score (mild vs. moderate vs. severe) and by previous psoriasis treatment (naïve vs. treatment-experienced). Proportions of patients achieving treatment success (clear/almost clear [PGA 0/1]) after 4 weeks' treatment with Cal/BD aerosol foam were reported for each subgroup. Psoriasis area and severity index (PASI) and patient-reported itch, itch-related sleep loss, scaling, dry skin, and erythema numerical rating scores were reported by subgroup. At baseline, 216 (54%) patients were systemic-or-topical psoriasis treatment-naïve and 184 (46%) were treatment experienced. By disease severity, there were 135 versus 89 patients with mild, 69 versus 83 with moderate and 12 versus 12 with severe disease in the treatment-naïve versus treatment-experienced groups, respectively. In the treatment-naïve group, treatment success was achieved by 72.6%, 56.5%, and 66.7% of patients with mild, moderate, and severe disease, respectively, while the proportions in the treatment-experienced group were 60.7%, 42.2%, and 25%, respectively. Reduction from baseline in psoriasis symptoms was observed in all patient groups. The greatest reductions were observed in treatment-naïve patients with severe disease. Clinically relevant benefits were observed with Cal/BD aerosol foam in psoriasis patients, regardless of prior treatment-experience and disease severity at baseline.

Real world experience of brodalumab treatment in patients with moderate-to-severe plaque psoriasis in the Greek population: Results from an interim analysis of the BrIDGE study.

Brodalumab's clinical efficacy and favorable safety profile have been demonstrated during controlled clinical trials, but real-world data remain scarce. BrIDGE, an ongoing 104 week, observational, prospective, multicenter study conducted in Greece, enrolled moderate-to-severe plaque psoriasis patients, with body surface area (BSA) > 10 or psoriasis area severity index score (PASI) > 10 and dermatology life quality index (DLQI) > 10, based on European consensus, initiating brodalumab treatment as per routine clinical practice. This interim analysis includes evaluations 12-16 weeks following treatment initiation. Key efficacy endpoints included proportion of patients achieving static Physician's Global Assessment (sPGA) score of "clear/almost clear" (0/1) and a reduction ≥75%, 90%, 100% from baseline in PASI (PASI75, PASI90, and PASI100) at weeks 12-16. Other endpoints included time to achieve PASI100, changes in self-reported DLQI and psoriasis symptom inventory (PSI) at weeks 12-16. From 200 patients (mean age 51.4 years, 70% male, mean disease duration 13.8 years) enrolled, 72.8% achieved sPGA of 0/1, whereas 70.2%, 47.5%, and 32.0% achieved corresponding PASI75, PASI90, and PASI100 responses following 12-16 weeks of brodalumab treatment, according to the "as-observed" analysis. The mean time to achieve PASI100 was 13.7 ± 1.2 weeks for the 32% who achieved PASI100. Concurrent decreases in mean DLQI and PSI were observed. Furthermore, 90% adherence to brodalumab was noted and nine adverse events were reported. Brodalumab confers substantial clinical improvements short-term as reflected by high levels of skin clearance in moderate-to-severe plaque psoriasis patients within 12-16 weeks of treatment under everyday clinical conditions, followed by improvements in symptoms and quality of life and a favorable safety profile.

Chlormethine Gel is Efficient and Safe in Mycosis Fungoides Skin Lesions.

Chlormethine is a bifunctional cytotoxic alkylating agent that binds to DNA, resulting in cell death (apoptosis). Chlormethine (also known as mechlorethamine) gel (CL gel) was approved in the European Union in 2017 and was first used in 2019. The aim of the study is to examine evidence regarding the efficacy and safety of chlormethine gel in everyday clinical experience from a cutaneous lymphoma centre. Twenty-three patients with stage IA-IIB mycosis fungoides received chlormethine gel between September 2020 and May 2021. All patients started by applying the gel daily and were monitored every month. At 1, 3, 6 and 9 months, 0%, 43.47%, 56.52% and 65.22% of patients, respectively, achieved an overall response. Five out of 23 patients (21.73%) achieved near complete response at a mean time of 6 months. Chlormethine gel was given as monotherapy in 12 patients (52.17%), and in addition to systemic treatments (methotrexate and peginterferon alpha-2a) in 11 patients (47.82%). Adverse events (AE) were recorded in 43.47% of patients, but only 3 discontinued treatment, due to dermatitis. Scale down of the treatment to application 3-times per week led to better patient compliance. This study shows that chlormethine gel is effective and safe in patients with mycosis fungoides with different types of skin lesions.

Predominant Role of mTOR Signaling in Skin Diseases with Therapeutic Potential.

The serine/threonine kinase mechanistic target of rapamycin (mTOR) plays a pivotal role in the regulation of cell proliferation, survival, and motility in response to availability of energy and nutrients as well as mitogens. The mTOR signaling axis regulates important biological processes, including cellular growth, metabolism, and survival in many tissues. In the skin, dysregulation of PI3K/AKT/mTOR pathway may lead to severe pathological conditions characterized by uncontrolled proliferation and inflammation, including skin hyperproliferative as well as malignant diseases. Herein, we provide an update on the current knowledge regarding the pathogenic implication of the mTOR pathway in skin diseases with inflammatory features (such as psoriasis, atopic dermatitis, pemphigus, and acne) and malignant characteristics (such as cutaneous T cell lymphoma and melanoma) while we critically discuss current and future perspectives for therapeutic targeting of mTOR axis in clinical practice.

The association of bullous pemphigoid with dipeptidyl-peptidase 4 inhibitors: a ten-year prospective observational study.

BACKGROUND: Bullous pemphigoid is the most common bullous chronic autoimmune skin disease. Recent studies have suggested dipeptidyl-peptidase 4 inhibitors as possible predisposing agents of bullous pemphigoid. The objective of our study was to prospectively estimate the association between gliptins and the development of bullous pemphigoid. METHODS: We conducted a prospective study which included all patients diagnosed with biopsy-proven bullous pemphigoid in the Dermatology Department of our hospital between April 1, 2009 and December 31,2019. The diagnosis of bullous pemphigoid was based on specific clinical, histological and immunological features. RESULTS: Overall 113 consecutive patients (age 75 ± 13 years, 62 females) with the diagnosis of bullous pemphigoid were enrolled. Seventy-six patients (67.3%) suffered from type 2 Diabetes and 52 (46%) were treated with dipeptidyl-peptidase 4 inhibitors. The most frequent prescribed gliptin was vildagliptin, being administered to 45 cases (39.8% of total patients enrolled, 86.5% of the patients treated with gliptins). Gliptins were withdrawn immediately after the diagnosis of bullous pemphigoid, which together with steroid administration led to remission of the rash. CONCLUSIONS: This study revealed that treatment with dipeptidyl-peptidase 4 inhibitors, especially vildagliptin, is significantly associated with an increased risk of bullous pemphigoid development.

Comorbidities burden and previous exposure to biological agents may predict drug survival of apremilast for psoriasis in a real-world setting.

Apremilast is the first small molecule approved for the treatment of moderate to severe psoriasis and psoriatic arthritis in adult patients. To evaluate survival, efficacy and safety of apremilast in patients with moderate to severe psoriasis and investigate possible associations between apremilast survival and clinical parameters in a real-world setting. In this retrospective study, a total of 71 patients who started on apremilast treatment between March 2017 and December 2019 were identified and included in the study: 40 (56.3%) males and 31 (43.7%) females, with a mean age of 55.6 ± 13.8 years and a mean Body Mass Index of 28.4 ± 6.9 kg/m2 . At the end of the study 49.3% of patients remained on apremilast with mean treatment duration 67.2 ± 41.1 weeks (range 4-132). Overall, mean drug survival duration was 78.51 weeks (95% CI: 65.8-91.2 weeks). Mean drug survival was shorter when comorbidities burden was higher (P = .012) and with previous exposure of biological agents (P = .001). Previous exposure to biological agents (HR:3.86, 95% CI: 1.35-11.04, P = .012) and comorbidities burden (HR: 2.27, 95% CI: 1.25-4.12, P = .007) were independent predictors of drug discontinuation adjusting for important clinical parameters. In this real-world setting, apremilast presented better survival rates when introduced early on the onset of moderate psoriasis, especially in biologic naïve patients with less comorbidities. More prospective and larger studies are required to determine clinical parameters affecting drug survival.

How does the joint dermatology-rheumatology clinic benefit both patients and dermatologists?

Psoriasis (Pso) and psoriatic arthritis (PsA) are chronic and debilitating diseases which often develop in the same patient and are linked to a wide range of comorbid conditions. Dermatologists and rheumatologists need to cooperate in combined clinics, especially when they deal with severe, recalcitrant disease, and multiple comorbidities. The clinical and research benefits of this collaboration have been previously described to contribute to a better and more sustainable health care system. To apply a more holistic approach of patients with Pso and PsA, we established the first dual care clinic in Greece, for Pso and PsA patients, based at Attikon General University Hospital. Hereby, we describe the infrastructure and operation of a combined Pso and PsA clinic (PPAC), in the national health care system of Greece, and its impact on the management of Pso and PsA. The PPAC is a single-day joint clinic, held once a week, which consists of three dermatologists and three rheumatologists. We present the results of 185 newly diagnosed patients between December 2018 and January 2019. Mean age of onset of Pso was 34 ± 16 years old and 47 ± 12 years old for PsA. Most patients suffered from severe plaque Pso (144/185, 78%) and asymmetric oligoarticular arthritis (59/185, 32%), for which they were receiving treatment with biologic agents (105/185, 57%). Many required monitoring for hypertension (74/185, 40%), dyslipidemia (69/185, 37%), diabetes (17/185, 9%), and depression (20/185, 11%). Patients reported high levels of care satisfaction (visual analogue scale: 86 ± 11.5), using the PPAC facility, compared to different referrals between specialties. This is the first joint dermatology-rheumatology clinic in Greece, providing comprehensive care in patients with Pso and PsA. Our results support the concept of combined clinics delivering better integrated care for such patients.

Low dose total skin electron beam therapy for the management of T cell cutaneous lymphomas.

Mycosis fungoides (MF) represent the most common type of primary cutaneous lymphomas. Total skin electron beam (TSEB) therapy to a total skin administered dose of 36 Gy represents a very effective treatment regimen and its role in the management of MF is well established. Unfortunately, the issue in MF is that despite the proved effectiveness of radiation therapy, disease regress, and the main goal of TSEB treatment seems to be the prolongation of the overall response duration time. Taking into consideration the high radio-sensitivity of the disease, lower radiation doses have been tested with acceptable and comparable results. We prospectively analyzed low dose TSEB in 14 patients treated at ATTIKON University Hospital from 2011 to 2017. After a median duration of follow up time of 39 months we found that low dose TSEB is an effective treatment option, since therapeutic results are more than acceptable, with minimal toxicity. The fact that it can be repeated safely in the natural course of a "regressive" disease makes it more attractive than the standard full dose scheme of 36 Gy.

The Course of Mycosis Fungoides under Cytokine Pathway Blockers: A Multicentre Analysis of Real-life Clinical Data.

Literature regarding the effect of biologics on the course of mycosis fungoides (MF) is scarce. This multicentre study analysed retrospective data on 19 patients with MF, who were treated with biologics; 12 for inflammatory conditions coexisting with MF, and 7 for MF misdiagnosed as an inflammatory skin disease. Eight patients were treated with anti-tumour necrosis factor-α-monotherapy; 6 had early-stage MF, in 3 patients MF preceded and in 3 MF was diagnosed after initiation of biologics, with no stage-progression or with stable disease, respectively (median treatment time concurrent with MF 57 months). Two patients had advanced stage MF: IIB, treated for 15 months with no stage-progression, and IVA1, treated for 8 months, died of disease 10 months later. The other 11/19 patients received anti-interleukin-17A and/or anti-interleukin-12/23 or anti-interleukin-23 (with/without anti-tumour necrosis factor-α/anti-interleukin-4/13), with stage-progression in 8 patients after a median of 8 months' treatment. Although, in general, biologics should be avoided in patients with MF, these results indicate that anti-tumour necrosis factor-α-monotherapy might not aggravate the disease course in early-stage patients. Interleukin-17A, interleukin-12/23 and interleukin-23 pathway-blockers may prompt progression of MF.

Echocardiography in Autoimmune Rheumatic Diseases for Diagnosis and Prognosis of Cardiovascular Complications.

Autoimmune rheumatic diseases are systemic diseases frequently affecting the heart and vessels. The main cardiovascular complications are pericarditis, myocarditis, valvular disease, obstructive coronary artery disease and coronary microcirculatory dysfunction, cardiac failure and pulmonary hypertension. Echocardiography, including transthoracic two and three-dimensional echocardiography, Doppler imaging, myocardial deformation and transesophageal echo, is an established and widely available imaging technique for the identification of cardiovascular manifestations that are crucial for prognosis in rheumatic diseases. Echocardiography is also important for monitoring the impact of drug treatment on cardiac function, coronary microcirculatory function, valvular function and pulmonary artery pressures. In this article we summarize established and evolving knowledge on the role of echocardiography for diagnosis and prognosis of cardiovascular abnormalities in rheumatic diseases.

Real world data from the use of secukinumab in the treatment of moderate-to-severe psoriasis, including scalp and palmoplantar psoriasis: A 104-week clinical study.

Several clinical studies demonstrated the safety and efficacy of the interleukin-17 inhibitor secukinumab in the systemic treatment of moderate-to-severe psoriasis, as well as psoriatic arthritis (PsA) in adults, whereas real-world data is limited. A single-center clinical study was performed to evaluate in real-world practice the efficacy of secukinumab up to Week 104 of treatment in moderate-to-severe chronic plaque psoriasis, including scalp and palmoplantar involvement, according to Physician Global Assessment (PGA), PASI75/90/100 and scalp, and palmoplantar PGA. Drug survival, the safety profile of secukinumab, and patient's quality of life were also assessed during a 2-year observation period. Out of 83 patients included, 56.3% were biologic-naïve, and 94% had scalp, 25.3% palmoplantar, and 43.9% joint involvement. At Week 16, PASI75/PASI90/PASI100 were observed in 83.8/70.0/46.3%, respectively. Scalp and palmoplantar PGA were rapidly improved, with 98.7 and 95.5%, respectively, reaching clear/almost clear skin at Week 16. After 104 weeks, drug survival was 74.5%. A significant improvement of the quality of life was observed. Biologic-naïve patients without coexisting PsA benefited the most. Real-world data demonstrated secukinumab efficacious in chronic plaque psoriasis, including specific locations such as scalp and palmoplantar psoriasis with a safety profile similar to that in clinical trials.

Health-related Quality of Life in Cutaneous Lymphomas: Past, Present and Future.

Previous studies have reported that primary cutaneous lymphomas profoundly influence patients' health-related quality of life (HRQoL). However, assessment of this psycho-social concept is not common in routine patient care unless required within clinical trials. The aim of this review is to provide a comprehensive overview of HRQoL measures and outcomes in cutaneous lym-phomas in order to inform clinicians. Advanced-stage cutaneous lymphomas were found to be associated with worse HRQoL than early-stage disease. Specifically, progression of the disease, age, sex, psychosocial issues, educational level and therapy were related to the extent of impairment of HRQoL. Treatment response was linked to improved HRQoL, but notably ameliorated HRQoL scores were also reported despite objective disease response. However, the variety of instruments applied to measure HRQoL in cutaneous lymphomas makes it difficult to compare data directly. In conclusion, speciality-specific HRQoL instruments were superior to generic ones, which probably failed to recognize small, but relevant, changes, demonstrating the need for a disease-specific tool.

Gene-Specific Intron Retention Serves as Molecular Signature that Distinguishes Melanoma from Non-Melanoma Cancer Cells in Greek Patients.

BACKGROUND: Skin cancer represents the most common human malignancy, and it includes BCC, SCC, and melanoma. Since melanoma is one of the most aggressive types of cancer, we have herein attempted to develop a gene-specific intron retention signature that can distinguish BCC and SCC from melanoma biopsy tumors. METHODS: Intron retention events were examined through RT-sqPCR protocols, using total RNA preparations derived from BCC, SCC, and melanoma Greek biopsy specimens. Intron-hosted miRNA species and their target transcripts were predicted via the miRbase and miRDB bioinformatics platforms, respectively. Ιntronic ORFs were recognized through the ORF Finder application. Generation and visualization of protein interactomes were achieved by the IntAct and Cytoscape softwares, while tertiary protein structures were produced by using the I-TASSER online server. RESULTS: c-MYC and Sestrin-1 genes proved to undergo intron retention specifically in melanoma. Interaction maps of proteins encoded by genes being potentially targeted by retained intron-accommodated miRNAs were generated and SRPX2 was additionally delivered to our melanoma-specific signature. Novel ORFs were identified in MCT4 and Sestrin-1 introns, with potentially critical roles in melanoma development. CONCLUSIONS: The property of c-MYC, Sestrin-1, and SRPX2 genes to retain specific introns could be clinically used to molecularly differentiate non-melanoma from melanoma tumors.