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Introduction Rapamycin (Rapa) is an immunosuppressive macrolide that inhibits the mechanistic target of rapamycin (mTOR) activity. Thanks to its anti-proliferative effects towards different cell types, including keratinocytes and T cells, Rapa shows promise in the treatment of skin diseases characterized by cell hyperproliferation. However, Rapa skin penetration is limited due to its lipophilic nature (log P = 4.3) and high molecular weight (MW = 914 g/mol). In previous studies, new microenvironment-sensitive core multishell (CMS) nanocarriers capable of sensing the redox state of inflamed skin were developed as more efficient and selective vehicles for macrolide delivery to inflamed skin. Methods In this study, we tested such redox-sensitive CMS nanocarriers using an inflammatory skin model based on human skin explants co-cultured with Jurkat T cells. Serine protease (SP) was applied on skin surface to induce skin barrier impairment and oxidative stress, whereas phytohaemagglutinin (PHA), IL-17A, and IL-22 were used to activate Jurkat cells. Activation markers, such as CD45 and CD69, phosphorylated ribosomal protein S6 (pRP-S6), and IL-2 release were monitored in activated T cells, whereas pro-inflammatory cytokines were measured in skin extracts and culture medium. Results We found that alteration of skin barrier proteins corneodesmosin (CDSN), occludin (Occl), and zonula occludens-1 (ZO-1) as well as oxidation-induced decrease of free thiol groups occurred upon SP-treatment. All Rapa formulations exerted inhibitory effects on T cells after penetration across ex vivo skin. No effects on skin inflammatory markers were detected. The superiority of the oxidative-sensitive CMS nanocarriers over the other formulations was observed with regard to drug delivery as well as downregulation of IL-2 release. Conclusion Overall, our results demonstrate that nanocarriers addressing features of diseased skin are promising approaches to improve the topical delivery of macrolide drugs., Graphical Abstract

An association of vitamin D receptor (VDR) polymorphisms and vitiligo has been suggested. However, previous studies have reported contradictory results while including limited data among Caucasians. The aim of this single-center study was to evaluate the effect of three common VDR gene polymorphisms (FokI, TaqI and BsmI) on suscep-tibility and clinical aspects of vitiligo in a Southeastern European Caucasian population. A total of 110 unrelated vitiligo cases and 509 general population controls were enrolled from October 2018 to November 2019. Genomic DNA was extracted from whole blood after de-identification and anonymization of the samples and genotyped for the selected VDR polymorphisms by the qPCR (melting curve analysis). Subgroup analysis by clinical features among subsets of patients indicated that, compared to subjects with the FokI TT genotype or T allele, carriers of the FokI CC genotype or C allele exhibited significantly decreased risk of developing vitiligo before the age of 30 [TT vs. CC: odds ratio (OR)=0.286, 95% confidence interval (CI): 0.083-0.984, P=0.041; T vs. C: OR=0.545, 95% CI: 0.313-0.948, P=0.031]. Intra-patient analysis also revealed that, compared to T allele, the presence of TaqI C allele was adversely associated with the incidence of concurrent leukotrichia (T vs. C: OR=1.874, 95% CI: 1.018-3.451, P=0.042). Comparisons between the case and control groups showed no evidence to support an association between susceptibility to vitiligo and the VDR BsmI, TaqI, and FokI polymorphisms in this cohort. Thus, the studied VDR polymorphisms might indirectly impact the clinical course and treatment decision-making despite their lack of association with vitiligo per se. Further research with larger sample sizes, especially across Caucasian individuals, should be performed to confirm these findings.

Background Few studies have investigated the long-term outcomes of secukinumab in real-life psoriasis treatment where diverse patient profiles require a personalized approach. Objectives To determine long-term performance of secukinumab in moderate-to-severe plaque psoriasis, and identify potential clinical factors predictive of sustained optimal response under real-world conditions. Methods In this 78-week, single-centre, retrospective study, effectiveness, safety and drug survival of secukinumab were evaluated. Effectiveness data are reported as observed. Co-primary endpoints were absolute Psoriasis Area and Severity Index (PASI) ≤3 at week 4, 16, 52, 78, and clinical predictors of PASI ≤3 and PASI100 responses at week 52 and 78. Results A total of 85 patients (75.3% male; mean age 48.6 years) were included. Absolute PASI ≤3 was achieved in 73% and 83% of patients at week 52 and 78, respectively. PASI 75/90/100 responses at week 52 (71.6%, 50.8%, and 40.3%, respectively) were sustained at week 78 (73.6%, 64.2%, and 45.3%, respectively). Median absolute PASI remained low at week 52/78 (0.9/0.6, respectively), while mean absolute PGA also sustained low (0-1) values after 16-78 weeks. Investigator's Global Assessment 0/1 response rate was maintained by week 52/78 (72/83%, respectively). The drug survival rate of secukinumab at week 78 was 79.1%. Treatment was discontinued in 17.9% of patients after an average of 41.7 weeks, mainly due to loss of effectiveness (10.4%). A total of 27% experienced adverse events, without critical safety concerns. Based on multivariate analysis, advanced body mass index (BMI) and presence of ≥3 comorbidities decreased the chance of achieving PASI ≤3 at week 78 [OR (95% CI) 0.78 (0.64-0.97); P = 0.024, and OR (95% CI) 0.045 (0.002-0.83); P = 0.037, respectively]. Conclusions Secukinumab showed consistently high effectiveness in this real-life cohort, with an acceptable safety profile. Over time, persistence of PASI ≤3 response appears to be lower in patients with high BMI or multiple comorbidities.

We are living an ongoing global COVID-19 pandemic which is associated with a considerable number of fatal cases worldwide1 . Vaccines are the promising solution to minimise the problem amongst cancer patients, however there are limitations to be considered such as the efficacy of COVID vaccines for immunocompromised individuals and possible interactions between the vaccine and cancer 3,4,5.

Palmar hyperhidrosis is a potentially disabling condition for which management remains a therapeutic challenge. Given the significant impact on quality of life, various treatment options are available, ranging from topical agents and medical devices to systemic therapies and surgical interventions. Nonsurgical approaches, i.e. topical antiperspirants, botulinum toxin injections, iontophoresis, and systemic agents, are all supported by the current literature. Patients with mild-to-moderate disease can often benefit from topical therapies only. As disease severity progresses, systemic oral medication, such as anticholinergic drugs, usually becomes necessary. Last-line surgical approaches (sympathetic denervation) should be reserved for severe refractory cases. Recently, therapeutic strategies have been evolving with several new agents emerging as promising alternatives in clinical trials. In practice, however, each modality comes with its own benefits and risks. An individual therapeutic ladder is generally recommended, taking into account disease severity, benefit-to-risk profile, treatment cost, patient preference, and clinician expertise. This review will provide an update on current and emerging concepts of management for excessive hand sweating to help clinicians optimize therapeutic decision-making.

As the coronavirus disease 2019 (COVID-19) continues to spread worldwide, it has become evident that the morbidity and mortality rates clearly vary across nations. Although several factors may account for this disparity, striking differences within and between populations indicate that ethnicity might impact COVID-19 clinical outcomes, reflecting the 'color of disease'. Therefore, the role of key biological variables that could interplay with viral spreading and severity indices has attracted increasing attention, particularly among non-Caucasian populations. Although the links between vitamin D status and the incidence and severity of COVID-19 remain elusive, several lines of emerging evidence suggest that vitamin D signaling, targeting several immune-mediated pathways, may offer potential benefits at different stages of SARS-CoV-2 infection. Given that the vitamin D status is modulated by several intrinsic and extrinsic factors, including skin type (pigmentation), melanin polymers may also play a role in variable COVID-19 outcomes among diverse population settings. Moreover, apart from the well-known limiting effects of melanin on the endogenous production of vitamin D, the potential crosstalk between the pigmentary and immune system may also require special attention concerning the current pandemic. The present review article aimed to shed light on a range of mostly overlooked host factors, such as vitamin D status and melanin pigments, that may influence the course and outcome of COVID-19.

Simple Summary There is currently no consensus on a widely accepted algorithm for imaging Merkel cell carcinoma (MCC) patients. Baseline, tomographic imaging is not generally recommended in early-stage disease, but its value in locally advanced and/or distant metastatic MCC has been well established. In this context, the hybrid imaging modality positron emission tomography/computed tomography (PET/CT) is increasingly applied in the workup of metastatic or unresectable MCC, providing essential information for staging, restaging, and treatment monitoring of the disease. Although the role of PET/CT in the management of loco-regional MCC is still limited and less well-defined, current evidence suggests its important contribution also in cases of localized MCC. Herein, we provide a structured literature review summarizing the most important studies on the role of PET or PET/CT with different radiopharmaceuticals in the clinical care of MCC. Abstract Merkel cell carcinoma (MCC) is a rare neuroendocrine skin malignancy usually arising as a nonspecific nodule on sun-exposed areas of the head and neck. Given the poor prognosis of this aggressive tumor, assessment of disease burden in pre- and post-treatment care may ensure an optimal management with significant implications for patient surveillance and prognosis. Although imaging has established its role in locally advanced or distant metastatic MCC, a standard imaging algorithm is yet to be determined and respective recommendations are mainly based on melanoma. Positron emission tomography/computed tomography (PET/CT) is increasingly evolving as a valuable imaging tool in metastatic or unresectable MCC, mostly utilizing the glucose analogue 18F-fluorodeoxyglucose (18F-FDG) as a radiotracer. Despite being inferior in detecting the disease in its early stages compared to the “gold standard” of sentinel lymph node biopsy, recent evidence suggests an important role for 18F-FDG PET/CT in the routine workup of localized MCC. Moreover, 68Ga-labeled somatostatin analogues have been employed as PET tracers in the field of MCC with promising, yet comparable to 18F-FDG, results. This article provides a structured literature review of the most important studies investigating the role of PET or PET/CT in the clinical practice of MCC.

Onychotillomania, or nail-picking disorder, is an uncommon and misdiagnosed behavioral pattern focused on the nail apparatus. It is demarcated by the compulsive or irresistible urge in patients to constantly injure their own nails, with the fingers or tools, inflicting noticeable or even irreversible self-destruction of the nail unit. Despite its rarity, this self-injurious coercion often poses a diagnostic and therapeutic challenge. Not only do many patients deny nail manipulation, but also the disorder has long been recognized to present itself with a wide range of clinical features, which hampers early and indisputable diagnosis. Furthermore, onychotillomania constitutes a persistent and hardly manageable problem, mostly because of its psychocutaneous nature as well as its high propensity to coexist with underlying neuropsychiatric illnesses or other behavioral disorders. However, the medical literature concerning obsessive nail picking still remains relatively scarce. Herein, we present an extraordinary, yet very intriguing case of a Caucasian patient with onychotillomania and onychophagia coexistence masquerading a weird inflammation-like lesion.

A woman in her 60s presented with a four month history of nail discoloration (chromonychia). On examination, diffuse erythema with a purpuric hue was noted on the nail bed of all fingernails (nail bed haemorrhage), as well as loss of adhesion of the nail to the nail bed (onycholysis) (fig 1). There were no clinical signs on the toenails. The palms and soles presented a fine desquamation that extended all the way to the dorsal surface and the tips. Diffuse alopecia was evident on the scalp. The patient had no other symptoms or signs involving the skin or any other system. Fig 1 Diffuse purpuric erythema on all fingernails of a 60 year old woman Six months earlier she had undergone surgery for advanced breast cancer and was started on docetaxel at a dose of 75 mg/m …

Introduction: We are living an ongoing global COVID-19 pandemic associated with a considerable number of fatal cases worldwide. Cancer patients seem to exhibit exacerbated conditions and higher mortality rates. Vaccines are a promising solution to minimize the problem amongst cancer patients but there are limitations to be considered. Case summary: Herein, we present two cutaneous T-cell lymphoma (CTCL) cases which were in long-term remission and experienced a flare after immunization with a viral vector COVID-19 vaccine (Vaxzevria, Oxford/AstraZeneca). The first case was a 60-year-old male with early-stage (T1a) folliculotropic mycosis fungoides (MF) clinically presented as alopecia areata-like lesions. The patient was in clinical remission during the last two years, maintaining a T1aN0M0 stage with only a single, stable alopecic patch on the scalp. Four weeks after the first COVID-19 vaccine dose, a minor lichenoid induration was observed in the periphery of the lesion, while a week after the second dose, small nodules surrounding the lesion were also noted. Histology confirmed the diagnosis of CD30+ Large cell transformation (LCT) of tumor-stage MF. The second case was a 73-year-old female with early-stage MF (T1a/IA) and Lymphomatoid papulosis (LyP). Clinically, she presented with pruritic erythematous patches and nodules on the trunk and upper legs. The patient was successfully treated with psoralen plus ultraviolet A (PUVA) phototherapy remaining in clinical remission for six years. After vaccination, she developed multiple erythematous papules and nodules on the trunk and limbs. A flare of LyP was confirmed from the pathology, which correlated to her clinical picture. Discussion: These cases raise the question of whether and via which pathways the vaccine might induce disease exacerbation of both MF and LyP. According to the literature, the education of T (CD4+ and CD8+) and B cells against SARS-CoV-2 spike protein appears to be the main strategy for COVID-19 vaccine production. Both cancers and viral infections can provide a chronic and persistent antigenic load, leading to up-regulated programmed cell death protein 1 (PD1) expression and ultimately T cell exhaustion. CD30 is known to be expressed in a small subset of activated T and B cells, as well as a variety of lymphoid neoplasms. Initial studies showed that CD30 expression on lymphocytes could be induced via in vitro antigenic stimulation by mitogens or viruses. CD30 expression also appears to be higher on CD4+ and CD8+ T cells producing a Th2-type cytokine profile. In our cases, the viral vector-based vaccines used do not contain a live virus but specific parts of the coronavirus attached to adenovirus, which can also stimulate an anti-viral immune response. Conclusion: The reported cases suggest that disease flare-ups may be associated with overproduction and exhaustion of CD4+/CD8+ T cells expressing CD30 after stimulation by the adenovirus. Expression of CD30, which can be a marker for disease progression, was high in biopsy samples of our patients.

Spontaneous bleeding of this lesion, located on the medial side of the thigh, led to consultation. Dermatoscopy made it possible to observe the presence of white circles and scales, associated with a polymorphous vascular pattern including dotted and irregular linear vessels; these are criteria for the diagnosis of squamous cell carcinoma.

Background Retinoids have long been used in the treatment of cutaneous T-cell lymphomas. However, data on acitretin use for mycosis fungoides (MF) are very limited. Objectives To evaluate treatment outcomes of acitretin in patients with MF attending three academic referral centres in different regions of Greece. Methods Data on effectiveness, safety and drug survival of acitretin as monotherapy or as adjuvant regimen were collected in a multicentre, register-based, retrospective study. Results Overall, 128 patients (64.8% male; mean age at MF diagnosis 59.7 years) were included. Folliculotropic MF was present in 24 (18.8%) cases. Most patients (n = 118; 92.2%) had early-stage disease (≤IIA) at acitretin initiation. In all, 28 (21.9%) patients received acitretin monotherapy, while 100 (78.1%) subjects on acitretin concomitantly received phototherapy (n = 65; 50.8%) or topical steroids (n = 27; 21.1%). Acitretin was given as a first-line agent in 73 (57%) cases. A 77.3% overall response rate was noted: 44.5% and 32.8% for complete and partial responses, respectively. Acitretin was more effective as first-line than as a subsequent agent (P = 0.008). A trend towards better response was observed in the combination arm compared to patients receiving acitretin alone (P = 0.056). Median time to best response was 6.9 months (IQR 4.4-9.4); median duration of response was 23.7 months (IQR 11.9-35.4). Overall, the mean length of all treatment patterns was 569 days (SD 718.8). Therapy was discontinued in 5 (3.9%) cases due to drug intolerance. Adverse effects were recorded in 62 (48.4%) cases with dyslipidaemia (n = 31; 24.2%), xerosis (n = 24; 18.6%) and hair loss (n = 10; 7.8%) being the most commonly recorded. Conclusions Acitretin, either alone or as adjuvant, showed a stable long-term effectiveness in this cohort, especially when used in the first-line setting. This RAR-selective agonist may serve as an attractive option for treatment of MF and should be further evaluated.

The role of tumor infiltrating immune cells in cancer development and progression is a new, promising field in oncological research. An increasing number of novel anti-cancer agents are focussing on the tumor microenvironment. Various studies have reported on B-cell infiltrates in mycosis fungoides (MF), but despite the substantial volume of interesting findings, solid evidence regarding their specific role in cancer is still vague. We present a case of tumor stage MF responding to rituximab. We support the hypothesis that lymphoma-infltrating B-cells have a significant impact on cutaneous lymphoma course and seem to be both an important and effective therapeutic target. The reduction of B-cell population led to disease's overall remission, probably by restoring patient's immunologic tumor control.

BACKGROUND Mycosis fungoides (MF) accounts for the majority of cutaneous lymphomas. Apart from the predominant Alibert-Bazin type, several clinicopathological variants of diverse prevalence and biological behavior have been described. Data on clinical and epidemiological aspects of MF clinical subtypes are still weak. AIM To outline the clinical and epidemiological profile of the different MF types in a large volume of Greek patients. METHODS Retrospective analysis of 688 MF cases treated in our lymphoma clinic. Epidemiological, clinical, pathological, and immunohistochemical data were retrieved. RESULTS Six-hundred and thirty-six patients (416 males, 220 females) were included. The mean age at diagnosis was 60.2 years; the mean duration of disease prior to diagnosis was 63.2 months. Early-stage MF (I-IIA) involved 475 cases (74.7%). The prevalent type was classical MF (68.5%), followed by folliculotropic (17%), poikilodermic (5.5%), and psoriasiform (4.7%) MF. Atypical MF lesions as the sole manifestation of folliculotropic mycosis fungoides (FMF) - alopecia areata-like lesions (n = 10), keratosis pilaris-like lesions (n = 9) or acneiform rash (n = 4) - were also observed. Both poikilodermic and folliculotropic subtypes mainly involved younger patients. A significant diagnostic latency concerning poikilodermic and psoriasiform MF cases was recorded. Only 23 (3.3%) cases were of juvenile onset, with classical and poikilodermic MF equally affecting this age group, closely followed by FMF. CONCLUSIONS Our study presents the whole clinical-epidemiological spectrum of MF in a large Greek cohort. The high prevalence of atypical MF manifestations characterized by early onset and indolent clinical course stood out among our FMF sample.

pared to normal-weight people with CVD (HR 2.33, 95%CI 1.25, 4.36, P=0.007). From the individual components of MetS, impaired fasting glucose (HR 1.5, 95% 1.23-1.92), hypertension (HR 1.1, 95% 1.03-1.47), dyslipidemia (HR 0.48, 95% 0.39-0.58) and central-obesity (HR 1.33, 95% 1.17-1.64) were all associated with increased CVD risk. Physical inactivity, smoking insulin-resistance, and low-grade inflammation were independently associated with CVD incidence. Conclusions: In contrast to normal-weight insulin-resistant people, MHO individuals show decreased CVD-risk in a 6-year follow-up study.