The dynamics of circulating tumour DNA (ctDNA) during treatment reflects tumour response in advanced melanoma patients.

Despite the introduction of targeted (BRAFi/MEKi) and immune checkpoint inhibitors (ICIs) has significantly reduced the recurrence rate and improved the overall survival (OS) of patients with Stage III and IV melanoma, only a percentage will benefit of durable disease control. The aim of this study was to examine whether the levels of circulating tumour DNA (ctDNA) in plasma of advanced melanoma patients undergoing BRAFi/MEKi or ICIs vary according to the patients' survival outcomes (i.e. progression-free survival (PFS) and OS) and disease progression. Plasma samples of Stage III-IV melanoma patients were collected at baseline (treatment initiation) and thereafter every 3 months. Circulating BRAFV600E/K and NRASQ61R/K mutations were analysed through droplet digital PCR (ddPCR, Bio-Rad) in a total of 177 plasma samples from 48 melanoma patients (19 Stage III, 29 Stage IV). Baseline ctDNA concentration was significantly associated with OS (HR = 1.003, 95% CI = 1.000-1.006, p = 0.043) and PFS (HR = 1.004, 95% CI = 1.000-1.007, p = 0.029) independent of clinical-prognostic confounders. For each unit increase in the ∆ctDNA (concentration difference between the last follow-up and baseline) there was a 24% increased risk of disease progression, irrespective of treatment type and stage at diagnosis (OR = 1.24, 95% CI = 1.03-1.49, p = 0.020, AUC = 0.93). Patients with reduction of ctDNA level from baseline to the last follow-up had longer OS (HR = 0.14; 95% CI = 0.05-0.44, p = 0.001) and PFS (HR = 0.08; 95% CI = 0.03-0.27, p < 0.0001) compared to patients with increased ctDNA, including adjustment for confounding factors. Our findings suggest that variation of ctDNA over time during melanoma treatment reflects the clinical outcome and tumour response to therapy and might be helpful in clinical monitoring.

Photodynamic therapy with 5-aminolevulinate patch for the treatment of superficial basal cell carcinomas.

5-Aminolevulinate (ALA) patches with red light (630-nm light source and a total light dose of 37 J/cm2 ) is an effective treatment indicated by food and drug administration (FDA) and european medicines agency (EMA) only for grade I to II actinic keratosis located on the scalp and face. Currently, there are no efficacy data on their use in the treatment of other types of epithelial neoplasms. We analyzed the efficacy of ALA patches in seven superficial basal cell carcinomas (sBCCs) that occurred in four patients. All lesions were treated with topical ALA patches. A complete response of all sBCCs was achieved at week 24 after treatment. Our study suggests that ALA patches for sBCCs have good efficacy rates and excellent safety profile.

Clinical and Ultrasonographic Profile of Adalimumab-treated Hidradenitis Suppurativa Patients: A Real-life Monocentric Experience.

Ultrasonography has proven useful for diagnosis and treatment monitoring in patients with hidradenitis suppurativa. The aim of this study was to assess the clinical response to adalimumab using ultrasound findings. This prospective study collected data on demographic features, disease severity, and hidradenitis suppurativa findings from patients with hidradenitis suppurativa treated with adalimumab. Generalized estimating equations investigated relationships between disease severity measures and clinical/demographic variables. The study included a total of 41 patients with hidradenitis suppurativa who were treated with adalimumab for a mean period of 50.8 ± 32.2 weeks; range 6-108 weeks). Clinical improvement was observed during adalimumab therapy, with a progressively greater number of patients achieving HiSCR50 response (36.4% at week 52). Disease duration was identified as the most relevant clinical variable affecting disease severity and treatment response. Treatment response was also influenced by treatment duration, with a 4% greater likelihood of achieving HiSCR50 response at each time-point. At the ultrasound examination, subcutaneous involvement of hidradenitis suppurativa lesions was identified as a predictive negative factor for clinical response to adalimumab (HiSCR50 achievement).

Electromechanical delays during a fatiguing exercise and recovery in patients with myotonic dystrophy type 1.

PURPOSE: The partitioning of the electromechanical delay by an electromyographic (EMG), mechanomyographic (MMG) and force combined approach can provide further insight into the electrochemical and mechanical processes involved with skeletal muscle contraction and relaxation. The aim of the study was to monitor by this combined approach the changes in delays' electrochemical and mechanical components throughout a fatiguing task and during recovery in patients with myotonic dystrophy type 1 (DM1), who present at the skeletal muscle level fibres rearrangement, muscle weakness and myotonia, especially in the distal muscles. METHODS: After assessing maximum voluntary contraction (MVC), 14 male patients with DM1 and 14 healthy controls (HC) performed a fatiguing exercise at 50% MVC until exhaustion. EMG, MMG, and force signals were recorded from tibialis anterior and vastus lateralis muscles. The electromechanical delay during contraction (DelayTOT) and relaxation (R-DelayTOT) components, EMG and MMG root mean square (RMS) and mean frequency (MF) were calculated off-line. RESULTS: The fatiguing exercise duration was similar in both groups. In patients with DM1, delays components were significantly longer compared to HC, especially in the distal muscle during relaxation. Delays components recovered quickly from the fatiguing exercise in HC than in patients with DM1 in both muscles. CONCLUSIONS: The alterations in delays observed in DM1 during the fatiguing exercise may indicate that also the lengthening of the electrochemical and mechanical processes during contraction and relaxation could play a role in explaining exercise intolerance in this pathology.

Giant neglected squamous cell carcinoma of the skin.

Nonmelanoma skin cancers (NMSCs) are the most common type of skin tumor, representing about one-third of all malignancies diagnosed worldwide each year. Cutaneous squamous cell carcinoma (cSCC) is the second most common form of NMSCs and the risk of cSCC invasiveness should be assessed on the basis of tumor size, anatomical location, and histological subtype. Although most cSCCs are early diagnosed and successfully treated, in a small percentage of patients with giant cSCC (maximum diameter >5 cm), metastases may occur; treatment options are limited and not really effective. We report the case of a giant metastatic cSCC that had been neglected for more than 20 years. Radiotherapy or surgery were not feasible and polichemotherapy (cisplatin, 5-fluorouracil and paclitaxel) was not effective. Therefore, the patient was treated with palliative electrochemotherapy (ECT) achieving a partial reduction of cutaneous metastasis and pain relief but unfortunately the patient died 3 months after the second ECT treatment.

Efficacy and safety of a combined pharmacological and surgical approach in patients affected by hidradenitis suppurativa: data from a retrospective real-world clinical study.

BACKGROUND: Hidradenitis suppurativa (HS) is a debilitating chronic skin disease; its therapeutic approach often requires combined medical and surgical treatment. METHODS: The aim of this study was to assess the efficacy and safety of the surgical approach combined with different pharmacological treatments, evaluating the proportion of patients achieving the hidradenitis suppurativa clinical response (HiSCR), along with the incidence of postoperative complications, and local recurrence. A retrospective study of HS patients (Hurley I-III) presenting at least one skin lesion requiring surgery was performed. Demographic and clinical data were collected (kind and anatomical location of lesion excised, type of surgical procedure). Further data included: Hurley stage and IHS4 at baseline and week 16, HiSCR at week 16 after surgery, ongoing therapy at the time of surgery (topical, systemic antibiotic, biologics), postoperative complications and local recurrence at week 16. RESULTS: Forty-two patients with female predominance (66.7%, 28/42), with a mean age of 30.3 (SD±10.5) years, were enrolled. At week 16, 53% of patients achieved HiSCR, with baseline Hurley III inversely related to HiSCR achievement (P<0.05). No increased incidence of postoperative complications was detected. Three cases of local recurrence were reported at week 16. CONCLUSIONS: The results support the efficacy and safety of the combined therapy in the management of HS; no increased risk of complications emerged among patients concomitantly treated with biologics, compared to those on conventional systemic therapy or exclusively treated with surgery.

Dermoscopy of melanocytic lesions in patients affected by oculocutaneous albinism: a case series.

BACKGROUND: Although the majority of skin cancers in albino patients consists of squamous and basal cell carcinomas, malignant melanomas have also been described, albeit less frequently. OBJECTIVE: The aim of our study was to evaluate melanocytic lesions in albino patients to look for any recurrent dermoscopic pattern. METHODS: We enrolled 12 consecutive albino patients presenting to our department and examined each patient for the presence of melanocytic nevi with the unaided eye and then with dermoscopy. Melanocytic lesions with suspicious clinical or dermoscopic features were excised and histopathologically evaluated. RESULTS: Analysis of the recorded images permitted us to find two main dermoscopic patterns in this group of patients. The first one was represented by a homogeneous light-brown yellowish pattern associated with comma-like and dotted vessels; the second one consisted of a classical brown reticular pattern frequently associated with central depigmentation and with comma-like vessels. Moreover, based on some atypical dermoscopic features, in 2 patients we excised 3 melanomas in situ (in the same patient) and a thick melanoma (3.2 mm). CONCLUSIONS: Dermoscopy may represent a useful tool for the evaluation of melanocytic lesions in albino patients, permitting an early diagnosis of melanoma.

Erythema nodosum induced by kerion celsi of the scalp in a child: a case report and mini-review of literature.

A 9-year-old girl, presented with a 4-week history of an inflammatory suppurative plaque, 8 cm in diameter, localised in the occipital area of the scalp. Mycological direct examination showed ectoendothrix invasion of the hair and Trichophyton mentagrophytes was isolated. Oral therapy with griseofulvin 25 mg kg(-1) day(-1) was prescribed, but after 2 weeks of treatment appeared multiple erythematous subcutaneous nodules localised in the legs. Erythema nodosum (EN) was confirmed by histological examination of a nodule and then we combined therapy with 1 mg Kg(-1) day(-1) of prednisone. At the remission of the panniculitis, which occurred in about 10 days, the steroid therapy was suspended, while the orally administered griseofulvin continued for 6 weeks until full recovery. EN is the most frequent clinical form of acute nodular panniculitis and it is considered an epiphenomenon relative to various infectious and non-infectious stimuli. The association of EN with dermatophytosis of the scalp is infrequent, with only 15 cases reported in the Literature.

The preclinical discovery and development of deucravacitinib for the treatment of psoriasis.

INTRODUCTION: Psoriasis is a chronic inflammatory skin disease that most commonly presents as plaque psoriasis. The understanding of the pivotal pathogenetic role of the IL-23/IL-17 axis has dramatically changed the therapeutic approach to the disease. The identification of intracellular signaling pathways mediating IL-23 activity provided the rationale for targeting TYK2. AREAS COVERED: This review assesses the underlying rationale that led to development of deucravacitinib, a novel oral TYK2 inhibitor, as a therapeutic option for the treatment of moderate-to-severe psoriasis, primarily focusing on pre-clinical and early phase clinical studies. EXPERT OPINION: Innovative therapies used in patients with moderate-to-severe psoriasis include biologic agents and small molecules, which are associated with less adverse events than traditional systemic agents. Deucravacitinib, which selectively targets TYK2, has demonstrated to be effective in treating psoriasis, preserving a more favorable safety profile compared to other JAK inhibitors approved for the treatment of other immune diseases that block the ATP-binding site. Because of its oral administration, deucravacitinib represents an intriguing option in the therapeutic armamentarium of psoriasis, though the evaluation of long-term efficacy and safety is necessary to establish its place-in-therapy.

Pharmacodynamics of Janus kinase inhibitors for the treatment of atopic dermatitis.

INTRODUCTION: Atopic dermatitis (AD) is the most common inflammatory skin disorder. Despite the high disease burden, the therapeutic options are limited and their efficacy in controlling AD might be partially satisfactory. AREAS COVERED: Most of the key mediators in AD pathogenesis act through the JAK/STAT signaling pathway, which represents a valid therapeutic target. The first generation of JAK inhibitors, namely tofacitinib and ruxolitinib, inhibit multiple JAKs, whereas newer JAK inhibitors show more selective inhibitory effects for specific JAKs. The aim of this review was to discuss the role of the JAK/STAT pathway in AD and its inhibition, with a special focus on pharmacodynamic properties. EXPERT OPINION: JAK inhibitors have different selectivity for various JAK molecules, which influences their pharmacodynamics, efficacy, and safety profile. Since many key cytokines in AD signal through JAK1, the selective JAK1 inhibition may be effective, avoiding the concomitant inhibition of JAK2- and JAK3-dependent pathways could be associated with additional safety issues. Therefore, selective JAK1 inhibitors may represent promising therapeutic agents for AD, as they might prevent off-target effects of JAK inhibitors, especially related to the hematologic profile.

Delirium in hospitalized patients with COVID-19 pneumonia: a prospective, cross-sectional, cohort study.

Delirium is an acute confusional state characterized by altered level of consciousness and attention. Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), can manifest itself with this neuropsychiatric disorder. The endpoints of our study were: the frequency of delirium in subjects with COVID-19 pneumonia; the risk factors that predispose to this condition; and the impact of delirium on mortality. Subjects were consecutively enrolled in a Geriatric Unit from January 5th to March 5th, 2021. Inclusion criteria were: diagnosis of SARS-CoV-2 infection, a radiologically documented pneumonia, and the ability of providing informed consent. Exclusion criteria were: absence of radiological evidence of pneumonia, sepsis, and the need of intensive care unit treatment. All subjects were evaluated by means of Richmond Agitation Sedation Scale (RASS) and Confusion Assessment Method-Intensive Care Unit (CAM-ICU) at least twice per day. In the study cohort (n = 71), twenty patients (28.2%) had delirium. Delirium was present on admission in 11.3%, and occurred during hospitalization in 19.0%. Compared to patients without delirium, patients who developed this neuropsychiatric disorder had a higher mortality rate (35% vs 5.9%) and an increased average hospital length of stay (21 days vs 17 days). In the multivariate analysis delirium was associated with frailty (OR = 2.81; CI = 1.4-5.8) and helmet ventilation (OR = 141.05; CI = 4.3-4663.9). Delirium was an independent predictor of mortality. Nearly a third of subjects (28.2%) had delirium during hospitalization for COVID-19. This finding supports the notion that delirium is a common complication of SARS-CoV2 infection. Since delirium is associated with longer hospital stay, and it is an independent marker of increased mortality, clinicians should assess and prevent it.

Molecular alterations in basal cell carcinoma subtypes.

A number of genes have been implicated in the pathogenesis of BCC in addition to the Hedgehog pathway, which is known to drive the initiation of this tumour. We performed in-depth analysis of 13 BCC-related genes (CSMD1, CSMD2, DPH3 promoter, PTCH1, SMO, GLI1, NOTCH1, NOTCH2, TP53, ITIH2, DPP10, STEAP4, TERT promoter) in 57 BCC lesions (26 superficial and 31 nodular) from 55 patients and their corresponding blood samples. PTCH1 and TP53 mutations were found in 71.9% and 45.6% of BCCs, respectively. A high mutation rate was also detected in CSMD1 (63.2%), NOTCH1 (43.8%) and DPP10 (35.1%), and frequent non-coding mutations were identified in TERT (57.9%) and DPH3 promoter (49.1%). CSMD1 mutations significantly co-occurred with TP53 changes (p = 0.002). A significant association was observed between the superficial type of BCC and PTCH1 (p = 0.018) and NOTCH1 (p = 0.020) mutations. In addition, PTCH1 mutations were significantly associated with intermittent sun exposure (p = 0.046) and the occurrence of single lesions (p = 0.021), while NOTCH1 mutations were more frequent in BCCs located on the trunk compared to the head/neck and extremities (p = 0.001). In conclusion, we provide further insights into the molecular alterations underlying the tumorigenic mechanism of superficial and nodular BCCs with a view towards novel rationale-based therapeutic strategies.

Safety considerations when using non-ergot dopamine agonists to treat Parkinson's disease.

INTRODUCTION: Nonergot dopamine agonists (NEDA) represent an excellent treatment option for Parkinson's disease (PD) patients, in both early and advanced stages of the disease. The post-marketing phase of NEDA has highlighted, though, the occurrence of important long-term adverse events. AREAS COVERED: This review reports recent updates on NEDA adverse events, analyzing neurobiological bases and risk factors of these complications. A literature search has been performed using Medline and reviewing the bibliographies of selected articles. EXPERT OPINION: NEDA represents a very important option in the treatment of PD. Criticisms on their use can be overcome through a better knowledge of these molecules and of the risk factors for adverse events which allow specialists to prevent the occurrence of undesired complications and consent a tailor-based approach. Abbreviations: PD: Parkinson's disease, DA: dopamine agonists, NEDA: non-ergot dopamine agonists, ICD: impulse control disorders, DAWS: dopamine agonist withdrawal syndrome, CYP: Cytochrome P, PK: pharmacokinetic, AUC: area under the curve, HRT: hormone replacement therapy, AV: atrioventricular, HF: heart failure, OH: orthostatic hypotension, RBD: REM behavior disorders, PDP: Parkinson's disease psychosis, DRT: dopamine replacement therapy, DDS: dopamine dysregulation syndrome, MMSE: Mini-Mental state examination, EDS: excessive daytime somnolence.

Rare Disease: Cardiac Risk Assessment With MRI in Patients With Myotonic Dystrophy Type 1.

Introduction: To evaluate myocardial strain and extracellular volume in myotonic dystrophy type 1 (DM1) patients as potential imaging biomarkers of subclinical cardiac pathology. Materials and methods: We retrospectively analyzed 9 DM1 patients without apparent cardiac disease who had undergone cardiac magnetic resonance at our center. Patients were age- and sex-matched with healthy controls. The Mann-Whitney U test was used to compare cardiac strain between the two groups. The t-test was used to compare the extracellular volume obtained in DM1 patients with that in healthy subject. Spearman's ρ was used for studying the associations among imaging parameters. Results: Global cardiac strain (median -19.1%; IQR -20.5%, -16.5%) in DM1 patients was lower (p = 0.011) than that in controls (median-21.7%; IQR-22.7%,-21.3%). Global extracellular volume in DM1 patients (median 32.3%; IQR 29.3%,36.8%) was significantly (p = 0.008) higher than that reported in literature in healthy subjects (median 25.6%; IQR 19.9%,31.9%). Global cardiac strain showed a strong, positive correlation with septal strain (ρ = 0.767, p = 0.016) and with both global (ρ = 0.733 p = 0.025) and septal extracellular volume (ρ = 0.767, p = 0.016). Discussion: The increase in cardiac extracellular volume and decrease in strain are signs of early cardiac pathology in DM1. Physicians dealing with DM1 may take into consideration cardiac magnetic resonance as a screening tool to identify early cardiac involvement in this condition.

New JAK inhibitors for the treatment of psoriasis and psoriatic arthritis.

Psoriasis is a common inflammatory skin disease that can be associated with various pathological conditions among which arthritis is a frequent comorbidity. Based on the current pathogenetic model, development of psoriasis is mainly driven by the IL-23/IL-17A axis. Though the therapeutic armamentarium is expanding in the latest years, new therapies are needed because of the lack or loss of response or intolerance/contraindication to the currently approved drugs. The most recently developed drugs for the treatment of psoriasis and psoriatic arthritis specifically target cytokines, cytokine receptors, and intracellular signaling transducers that are involved in the pathogenesis of psoriasis. Janus kinase (JAK) pathway transduces signals of multiple cytokines, such as TNF-α, IL-23, IL-12, IFN, IL-6, IL-17, that have resulted crucial in the induction and maintenance of psoriasis inflammation. Thereby, JAK-1, JAK-3, TYK-2 belonging to the JAK family, have been identified as valid therapeutic targets in the treatment of psoriasis. Nowadays, different JAK inhibitors have been investigated in clinical trials showing promising results in terms of efficacy and safety. In this review, we systematically collected publications and data related to JAK inhibitors used in psoriasis and psoriatic arthritis providing the state-of-the-art on this new class of molecules in the treatment of these diseases.

Lentigo maligna: diagnosis and treatment.

Lentigo maligna (LM) is an in situ subtype of melanoma, clinically presenting as a pigmented, asymmetric macule that originates mostly on the head and neck and spreads slowly. The diagnosis may be challenging both for clinicians and pathologists. Dermatoscopy and reflectance confocal microscopy represent a useful tool in the differentiation of LM from other pigmented lesions, such as pigmented actinic keratosis, solar lentigines, seborrheic keratosis and lichen planus-like keratosis. Moreover, those non-invasive diagnostic technique may be crucial in the selection of optimal biopsy sites in equivocal lesions, in pre-surgical mapping and in evaluating and monitoring response to non-surgical treatments. Histologic examination remains the gold standard for the diagnosis of LM, showing a lentiginous proliferation of basal atypical melanocytes on a severe sun-damaged skin. The management of LM is constantly evolving. Treatments include surgery (the first choice, when available), radiotherapy and imiquimod cream (in patients not candidates to surgery). Many other possible treatments for LM have been tested, but they are not yet supported by strong evidences. We collected current guidelines and PubMed available reviews, studies and case-reports in order to make an overview on diagnosis and treatment of LM.

The Safety of Radiotherapy in the Treatment of Primary Cutaneous B-Cell Lymphoma: A Multidisciplinary Systematic Review.

Primary cutaneous B-cell lymphomas (PCBCL) are rare types of extranodal non-Hodgkin's lymphoma. The choice of treatment usually depends on the variant of PCBCL, number, size, and location of the lesions, involved body surface area as well as patient's age and health condition. The efficacy of radiotherapy (RT) in the treatment of PCBCL has been widely reported conversely, data about the acute and late skin toxicity, patient's treatment satisfaction and quality of life are scarce. A systematic search using PubMed, Scopus, and Cochrane library was performed to identify full original articles analyzing the safety of RT in patients with PCBCL with the primary outcome to assess the acute and late skin toxicity. Secondary outcomes were complete remission, disease free survival, and overall survival. The literature search resulted in 276 articles including eight studies assessing the safety of RT for the treatment of PCBCL. Most patients (median 73%, range 11.9-99.9%) were recorded as having acute skin toxicity of grade 1-2, while acute grade 3-4 toxicity occurred in a median of 8% (range 4-23%) of patients. A median of 20% (range 4-54%) of patients had late skin toxicity of grade 1-2. No late grade 3-4 toxicity was reported. Only one study evaluated patient's satisfaction showing that the 97% of patients were satisfied with radiation therapy. This systematic review confirms the safety of RT in the treatment of PCBCL. Patients with a PCBCL should be managed in highly specialized centers in the context of a multidisciplinary team including dermatologist, hematologist, pathologist, and radiation oncologist.

Sodium Channel Myotonia Due to Novel Mutations in Domain I of Nav1.4.

Sodium channel myotonia is a form of muscle channelopathy due to mutations that affect the Nav1.4 channel. We describe seven families with a series of symptoms ranging from asymptomatic to clearly myotonic signs that have in common two novel mutations, p.Ile215Thr and p.Gly241Val, in the first domain of the Nav1.4 channel. The families described have been clinically and genetically evaluated. p.Ile215Thr and p.Gly241Val lie, respectively, on extracellular and intracellular loops of the first domain of the Nav1.4 channel. We assessed that the p.Ile215Thr mutation can be related to a founder effect in people from Southern Italy. Electrophysiological evaluation of the channel function showed that the voltage dependence of the activation for both the mutant channels was significantly shifted toward hyperpolarized potentials (Ile215Thr: -28.6 ± 1.5 mV and Gly241Val: -30.2 ± 1.3 mV vs. WT: -18.5 ± 1.3 mV). The slow inactivation was also significantly affected, whereas fast inactivation showed a different behavior in the two mutants. We characterized two novel mutations of the SCN4A gene expanding the knowledge about genetics of mild forms of myotonia, and we present, to our knowledge, the first homozygous patient with sodium channel myotonia.