Pulsed Radiofrequency Electromagnetic Fields as Modulators of Inflammation and Wound Healing in Primary Dermal Fibroblasts of Ulcers.

Venous leg ulcers are one of the most common nonhealing conditions and represent an important clinical problem. The application of pulsed radiofrequency electromagnetic fields (PRF-EMFs), already applied for pain, inflammation, and new tissue formation, can represent a promising approach for venous leg ulcer amelioration. This study aims to evaluate the effect of PRF-EMF exposure on the inflammatory, antioxidant, cell proliferation, and wound healing characteristics of human primary dermal fibroblasts collected from venous leg ulcer patients. The cells' proliferative and migratory abilities were evaluated by means of a BrdU assay and scratch assay, respectively. The inflammatory response was investigated through TNFα, TGFß, COX2, IL6, and IL1ß gene expression analysis and PGE2 and IL1ß production, while the antioxidant activity was tested by measuring GSH, GSSG, tGSH, and GR levels. This study emphasizes the ability of PRF-EMFs to modulate the TGFß, COX2, IL6, IL1ß, and TNFα gene expression in exposed ulcers. Moreover, it confirms the improvement of the proliferative index and wound healing ability presented by PRF-EMFs. In conclusion, exposure to PRF-EMFs can represent a strategy to help tissue repair, regulating mediators involved in the wound healing process.

Hedgehog Inhibitors Beyond Clinical Complete Response in Basal Cell Carcinoma: Should I Stop or Should I Go?

INTRODUCTION: In advanced basal cell carcinoma (BCC), the issue of whether Hedgehog inhibitors (HHIs) should be stopped or not after clinical complete response (cCR) achievement remains an unmet clinical need. MATERIALS AND METHODS: We conducted a retrospective, multicenter study across 7 Italian dermato-oncology units including patients with BCC who continued vismodegib after cCR between 2012 and 2019. We assessed the relationship between the duration of vismodegib intake (days to cCR [DTCR], days to stop after cCR [DTS], total treatment days [TTD]), and disease-free survival (DFS). Reasons to stop vismodegib were (R1) toxicity and (R2) disease recurrence. The relationship between DTCR, DTS, TTD, and DFS in the whole population and in R1 subgroup was assessed by Pearson's correlation coefficient (P < .05) and Bayesian statistics (BF10). RESULTS: Sixty-eight BCC patients with a median (m) age of 75.5 years (39-100) were included. Most patients were male (N = 43, 63%), without Gorlin syndrome (N = 56, 82%) and with head and neck area as primary site (N = 51, 75%). After cCR, out of 68 patients, 90% (N = 61/68) discontinued vismodegib: 82% (N = 50/61) due to toxicity (R1), and 18% (N = 11/61) due to recurrence (R2). Conversely, 10% (N = 7/68) continued vismodegib until last follow-up. In the whole population (N = 68), cCR was achieved with a mDTCR of 180.50 days. DFS showed a significant correlation with DTS (P < .01, BF10 = 39.2) and TTD (P < .01, BF10 = 35566), while it was not correlated to DTCR (BF10 < 0.1). The analysis of R1 subgroup (N = 50) confirmed these results. DFS correlated with DTS in all recurrent patients (N = 38, r = 0.44, P < .01) and in the recurrent patients who stopped vismodegib for toxicity (N = 26, r = 0.665, P < .01). DFS was longer when vismodegib was maintained for >2 months after cCR (mDFS > 2 months, N = 54 vs. ≤ 2 months, N = 14: 470 vs. 175 d, P < .01). CONCLUSIONS: Our retrospective results suggest that HHIs should be continued after cCR to improve DFS in BCC.

Defining the Profile of Patients with Primary Merkel Cell Carcinoma in Central Italy: A Retrospective Analysis.

Merkel cell carcinoma (MCC) is a rare neuroendocrine skin cancer that usually occurs in elderly people on sun-exposed areas, with a predisposition to local recurrence. Evidence suggests a growing incidence over the past decade; however, robust epidemiologic data are still lacking. We describe the MCC population in clinical practice in a retrospective analysis of demographic, clinical, and tumor characteristics from medical records of primary MCC patients, between 2015 and 2020, at six dermatology clinics in Central Italy. Ninety-four patients were included (57.4% male; mean age 78.2 ± 10.1 years, range 47-99 years). The estimated incidence rate of MCC was 0.93 per 100,000 inhabitants/year. Lower limbs were the most frequently affected site (31.5%), and 54% of patients for whom information was available were immunosuppressed. Lymph node involvement was reported in 42.5% of patients, and distant metastases in almost 20%. Most patients underwent surgery for tumor excision and were mainly referred to specialized dermatology clinics by dermatologists (47.9%) and general surgeons (28.7%). Apart from the relatively balanced prevalence of MCC in men and women, the predominant location on lower limbs, and the higher incidence rate compared with previous reports in Italy, this population is, overall, similar to the populations described in other observational studies. MCC management requires the involvement of several specialties. Increased awareness of MCC and standardization of its management are urgently needed.

Sequential treatments of Hailey-Hailey disease with photodynamic therapy, botulinum toxin type A and dapsone: A case report.

Hailey-Hailey disease is a rare autosomal dominant chronic recalcitrant blistering genodermatosis involving the intertriginous areas. Therapeutic options are various, depending on the type and size of the lesion, and include topical and systemic corticosteroids, topical and systemic retinoids, and DMARDs, but the only true curative approach is represented by the destruction of the affected areas through different techniques like carbon dioxide laser, photodynamic therapy, electron beam radiotherapy, botulinum toxin type A. We report a case of Hailey-Hailey disease successfully treated with a consequential regimen of PDT, botulinum toxin type A and dapsone.

Paradoxical Effect on Epidermal Barrier of Anti-TNF-alpha Treatment for Psoriasis.

Background: Epidermal barrier defects have been described in psoriatic lesions. Transepidermal water loss (TEWL) is the measure of steady-state water vapor flux crossing the skin to the external environment, and it has been used extensively to characterize skin barrier function. We evaluated how biological treatments impact TEWL in with psocratic patients. Methods: TEWL measurements were collected from psoriatic lesions and from adjacent unaffected skin areas before introducing a biological anti-tumor necrosis factor (TNF) alpha treatment and after six months of therapy. Results: Our data show that the skin barrier function is restored after biologic therapy. Analysis of healthy skin values, indicated significant increases in TEWL. Conclusion: A restoration of TEWL on psoriatic lesions was coupled with an alteration of this parameter in nonlesional skin of all patients, underscoring the general homeostatic effect of an anti-TNF on the integrity of skin barrier. These results suggest the need of an emollient therapy in patients with psoriasis undergoing systemic biological treatment.

Effects of Growth Hormone (GH) Supplementation on Dermatoscopic Evolution of Pigmentary Lesions in Children with Growth Hormone Deficiency (GHD).

Recent reports have confirmed higher levels of growth hormone (GH) receptor (GHR) transcripts in malignant melanomas (MM), yet the role of GH in the pathogenesis of MM remains controversial. Although melanocytes appear to be hormonally responsive, the effects of GH on MM cells are less clear. A direct correlation between GH administration and the development of melanoma seems possible. Our study aimed to assess whether GH supplementation in children with growth hormone deficiency (GHD) could induce changes in the melanocytic lesions both from a dimensional and dermoscopic point of view. The study population consisted of 14 patients sorted into two groups. The experimental group consisted of seven GHD pediatric patients who underwent dermatological examination with epiluminescence through the use of digital video recording of all melanocytic lesions before and after 12 months of GH supplementation, whilst the control group consisted of seven healthy pediatric patients matched for age, sex and phototype. All patients were evaluated according to auxological and dermatological features. A total of 225 melanocytic lesions were examined in the experimental group and 236 in the control group. Our study shows a significant increase in the mean size values of the lesions in the study group but not in the control group. Increases in the dermoscopic ABCD Score and in BMI correlated to an increase in the size of the melanocytic lesions and the dermoscopic parameters. The increase in SDS Height correlated with ABCD Score changes and with dermoscopic score structures. No differences were found compared to the control group. Dimensional/structural modifications in melanocytic lesions of patients treated with GH were closely related to weight and statural growth and can be considered a normal physiological process induced by GH supplementation.

Identifying candidates for immunotherapy with cemiplimab to treat advanced cutaneous squamous cell carcinoma: an expert opinion.

Cutaneous squamous cell carcinoma (CSCC) is the second most common skin malignancy in white-skinned populations. Only a minority of patients (<5%) develop advanced disease, but this is often difficult to treat and characterised by a poor prognosis. Cemiplimab, a fully human IgG4 monoclonal antibody against programmed cell death-1 receptor, is indicated for advanced (i.e. locally advanced or metastatic) CSCC. Although the definition of metastatic CSCC is clear, there is currently no agreed definition of locally advanced CSCC. In recent guidelines, locally advanced CSCC was described as non-metastatic CSCC that is unlikely to be cured with surgery, radiotherapy or combination treatment. A multi-disciplinary advisory group of Italian CSCC experts was convened to develop criteria to assist in identifying appropriate candidates for cemiplimab therapy in advanced CSCC, based on the literature and clinical experience. In locally advanced CSCC, absolute, or mandatory, criteria for the use of cemiplimab are deep invasion, multiple lesions without defined margins, inadequate surgical excision margins and multiple recurrences, whereas relative criteria include large lesions, in critical or functionally significant areas and that are surgically complex. In addition, physicians should consider patient willingness/preferences (an absolute criterion), and their age and health status/comorbidities (relative criteria). It is hoped that these proposed absolute and relative criteria will help guide rational identification of patients who will receive maximum benefit from immunotherapy, while more clinical data accumulate.

Melanoma Management during the COVID-19 Pandemic Emergency: A Literature Review and Single-Center Experience.

BACKGROUND: The current COVID-19 pandemic has influenced the modus operandi of all fields of medicine, significantly impacting patients with oncological diseases and multiple comorbidities. Thus, in recent months, the establishment of melanoma management during the emergency has become a major area of interest. In addition to original articles, case reports and specific guidelines for the period have been developed. PURPOSE: This article aims to evaluate whether melanoma management has been changed by the outbreak of COVID-19, and if so, what the consequences are. We summarized the main issues concerning the screening of suspicious lesions, the diagnosis of primary melanoma, and the management of early-stage and advanced melanomas during the pandemic. Additionally, we report on the experience of our dermatological clinic in northern Italy. METHODS: We performed a literature review evaluating articles on melanomas and COVID-19 published in the last two years on PubMed, as well as considering publications by major healthcare organizations. Concerning oncological practice in our center, we collected data on surgical and therapeutic procedures in patients with a melanoma performed during the first months of the pandemic. CONCLUSIONS: During the emergency period, the evaluation of suspicious skin lesions was ensured as much as possible. However, the reduced level of access to medical care led to a documented delay in the diagnosis of new melanomas. When detected, the management of early-stage and advanced melanomas was fully guaranteed, whereas the follow-up visits of disease-free patients have been postponed or replaced with a teleconsultation when possible.

The Effect of the COVID-19 Lockdown on Melanoma Diagnosis in Italy.

The coronavirus disease 2019 (COVID-19) pandemic has led to lockdowns for much of the world. In Italy, all health procedures not directly related to COVID-19 were reduced or suspended, thus limiting patient access to hospitals. Any delay in cancer treatment presents the additional risk of tumors progressing from being curable to incurable. Specifically, melanoma survival rate strictly depends on tumor thickness, which, in turn, is a function of time. To estimate the impact on melanoma progression caused by the reduction in dermatologic services during the COVID-19 lockdown, a retrospective observational cohort study was conducted. This study was designed to compare the clinical and histologic characteristics of the primary melanomas removed in the first 2 months after the end of the lockdown (May-July 2020) in 12 Italian centers characterized by different COVID-19 case frequencies. The control group was represented by the melanomas removed during the same period in the previous 3 years. Overall, 1,124 melanomas were considered: 237 as part of the study group and 887 from the control group (average, 295), with a 20% reduction. Breslow thickness, as well as high-risk histotypes and melanomas with vertical growth, increased for all melanomas. Ulcerated and high mitotic index melanomas increased, particularly in northern Italy. In Italy, the lockdown led to a significant worsening of melanoma severity, causing a staging jump, with a consequent worsening of outcomes.

Nested graft for chronic ulcer in scar tissue after heroin extravasation in a drug addict.

INTRODUCTION: Nested graft is a surgical technique that allows to manage difficult-to-treat medical conditions such as chronic cutaneous ulcers, thanks to the high efficacy it has in reverting the fibroblasts senescence. Because of its peculiar regenerative property, nested graft is a surgical technique suitable also for the treatment of cutaneous ulcers developing on fibrotic scar tissue. CASE REPORT: We reported the case of a 45-year-old man, drug-addict, with a large ulcer on the back of the right forearm in the context of scar fibrotic tissue. This lesion resulted from a previous heroin extravasation treated with a dermo-epidermal skin graft, that was accidentally scratched away by mechanical trauma. After several therapeutic failures with topical medications, we decided to treat the ulcer performing a skin graft using the nested graft technique. No adverse events were reported by the patient during or after the surgery. At the clinical evaluation performed three years later the wound was completely healed. CONCLUSIONS: Nested graft represents a safe and easy-to-use technique that can be successfully used to treat ulcers on scar tissue, ensuring the achievement and the long-term maintenance of optimal resistance and aesthetic results.

Characterization of Basosquamous Cell Carcinoma: A Distinct Type of Keratinizing Tumour.

Basosquamous carcinoma is a rare clinical entity, which comprises 1.7-2.7% of all skin carcinomas. It is described as a basal cell carcinoma with features of squamous differentiation. To date, studies of the epidemiology of basosquamous carcinoma have been few and small in size. We report here the most extensive series of basosquamous carcinomas published to date, highlighting the differences between basosquamous carcinoma and other keratinizing tumours. Patients undergoing surgical excision for keratinizing tumours were enrolled in this study. Age, sex and tumour characteristics were recorded. A total of 1,519 squamous cell carcinomas, 288 basosquamous carcinomas and 4,235 basal cell carcinomas were collected. Basosquamous features were compared with those of basal cell and squamous cell carcinomas. For basosquamous carcinomas, 70.5% were located on the head and neck, particularly on the nose, forehead and cheeks, and represented almost 10% of the keratinizing tumours on the ears. Significant differences were found between basosquamous carcinoma and basal cell or squamous cell carcinomas. Basosquamous carcinoma should be considered a distinct type of keratinizing tumour with different anatomical, sex and age distributions.

Intralesional Methotrexate for the Treatment of Advanced Keratinocytic Tumors: A Multi-Center Retrospective Study.

INTRODUCTION: Keratinocyte tumors (KT) are frequently observed. Surgery is the treatment gold standard. In some cases, a surgical approach might not be the best option. Radiotherapy (RT) and systemic treatments can frequently cause side effects or be contraindicated. Intralesional methotrexate (MTX) can be a conservative yet effective alternative. We decided to evaluate the effectiveness and safety of intralesional chemotherapy with MTX for the treatment of squamous cell carcinoma (SCC), keratoacanthoma (KA), and basal cell carcinoma (BCC). METHODS: All patients had a histologically confirmed diagnosis of BCC, SCC, or KA and no indication to surgery or RT. MTX was injected subcutaneously proceeding from the periphery of the lesion toward the center. Different protocols in terms of dose, frequency, and length of treatment were used to compare them. Treatment efficacy was evaluated in terms of tumor size reduction. Patients were divided into three groups: responders (improvement of more than 50%), partial responders (< 50%), and non-responders (no improvement or worsening). All data were analyzed using the chi-squared test (χ2). RESULTS: Thirty-five patients were included. Twenty-one patients suffered from SCC, 12 from KA, and 2 from BCC. KA showed a higher response rate than SCC and BCC. For AK, 92% of patients had a complete resolution; 8% were partial responders. For SCC, 47.6% of cases were responders and 14.3% partial responders, while 38% non-responders. All BCCs showed no improvement. A treatment protocol of weekly injections, performed for 4 to 6 weeks, was the most efficient. Doses of 25 mg/ml per session seemed to be most effective. About one third of our patients developed side effects with mild anemia being the most frequent. CONCLUSIONS: For selected cases, intralesional MTX can be a safe and effective option for the treatment of KT, especially in case of KA and, to a lesser extent, SCC.

Speed rate (SR) as a new dynamic index of melanoma behavior.

Melanomas are skin tumors that show a variety of biological behavior. Some develop very fast and some other grow extremely slow, with metastasis appearing, eventually, many years after the diagnosis. The number of mitoses in primary melanoma has been related to a more aggressive tumor and may have a potential as predictive factor for cutaneous melanoma survival. However, tumor mitotic rate is a static measure and in multivariate analysis on tumor survival, it has scored less than other tumor characteristics. We tried to evolve tumor mitotic rate from a static parameter to a time-dependent one. Similar to the already described growth rate (GR), we propose the speed rate (SR). SR is defined as the ratio of tumor mitotic rate to time to melanoma development. A prospective series of 345 patients with melanoma was investigated for the role of SR as predictive factor for sentinel lymph node (SLN) positivity and tumor progression. We calculated the best threshold for SR and GR to predict the risk of recurrence. Melanoma clinical and histological characteristics as well as GR were correlated in a multivariated analysis with SR. SR values >0.2 mitoses/month were associated with negative prognostic factors such as ulceration (82.8%), SLN positivity (80%), progression (82.8%), and death (85.7%). The association of GR > 0.3 mm/months and SR > 0.2 mitoses/month had a significant predictive value in terms of SLN positivity, progression, and recurrence-free survival. We propose SR as a new "dynamic" predictor of histological SLN positivity and melanoma recurrence risk. We think that he association with this new feature with GR may be helpful in improving the accuracy of predicted clinical outcome of patient especially with thin melanomas.