Valerio De Vita

Resveratrol-containing gel for the treatment of acne vulgaris: a single-blind, vehicle-controlled, pilot study.

AbstractBackground: Acne vulgaris is a complex, chronic, and common skin disorder of pilosebaceous units. The major pathogenic factors involved are ductal hyperkeratinization, obstruction of sebaceous follicles resulting from abnormal keratinization of the infundibular epithelium, stimulation of sebaceous gland secretion by androgens, and microbial colonization of pilosebaceous units by Propionibacterium acnes, which promotes perifollicular inflammation. Aim: The aim of the study was to investigate the therapeutic effects of resveratrol, a natural phytoalexin produced by some spermatophytes, such as grapes and other plants, on acneic skin. Methods: Resveratrol was incorporated in a carboxymethylcellulose-based gel. The chemical stability of resveratrol after storage at 4°C for 30 days was investigated by high-performance liquid chromatography (HPLC). The resveratrol-containing hydrogel was administered to 20 patients affected by acne vulgaris enrolled in this single-blind study. The resveratrol-containing formulation was applied daily as a solo treatment on the right side of the face for 60 days, while the hydrogel vehicle was applied to the left side of the face as a control. To objectively evaluate the results, a digital photographic database was used to collect images. The number and type of lesions were recorded for each patient, to compare the Global Acne Grading System (GAGS) score before treatment with that obtained at the end of the study. Moreover, with the innovative technique of follicular biopsy, areas of acneic skin were prepared for histopathology. The average area occupied by microcomedones at baseline was compared with that at the end of treatment. Results: HPLC analysis demonstrated that resveratrol, upon incorporation into the gel, did not convert to its cis-isomer when stored at 4°C for 30 days. All patients were satisfied with the active treatment and none experienced adverse effects. Clinical evaluation showed a 53.75% mean reduction in the GAGS score on the resveratrol-treated sides of the face compared with 6.10% on the vehicle-treated sides of the face. These data were supported by histologic analysis, which showed a 66.7% mean reduction in the average area of microcomedones on the resveratrol-treated sides of the face. The comparison with the vehicle-treated side of the face (9.7% reduction) showed a clinically relevant and statistically significant decrease of lesions in areas treated with resveratrol-containing hydrogel. Conclusion: This pilot study showed positive results for resveratrol gel in acne, and should be considered a valid starting point for further testing of the effectiveness of this molecule in different concentrations and formulations and in a larger group of patients.

Mechanistic target of rapamycin (mTOR) expression is increased in acne patients' skin.

Abbreviations: mTOR, Mechanistic target of rapamycin; mTORC, mTOR signalling complex; BCAA, branched-chain essential amino acid; 4E-BP1, the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1; SREBP-1, sterol response element-binding protein-1; S6K1, ribosomal protein S6 kinase 1; FOXO1, forkhead box protein O1; HOMAIR, homoeostatic model assessment of insulin resistance; GAGS, global acne grading system; HS, healthy skin; LS, lesional skin; NLS, non-lesional skin; RT-PCR, real-time polymerase chain reaction; IHC, immunohistochemistry; IF, immunofluorescence; ELISA, enzyme-linked immunosorbent assay; P-S6K1, phospho-S6-ribosomal protein.

Epidemiology of skin cancer: role of some environmental factors.

The incidence rate of melanoma and non-melanoma skin cancer entities is dramatically increasing worldwide. Exposure to UVB radiation is known to induce basal and squamous cell skin cancer in a dose-dependent way and the depletion of stratospheric ozone has implications for increases in biologically damaging solar UVB radiation reaching the earth’s surface. In humans, arsenic is known to cause cancer of the skin, as well as cancer of the lung, bladder, liver, and kidney. Exposure to high levels of arsenic in drinking water has been recognized in some regions of the world. SCC and BCC (squamous and basal cell carcinoma) have been reported to be associated with ingestion of arsenic alone or in combination with other risk factors. The impact of changes in ambient temperature will influence people’s behavior and the time they spend outdoors. Higher temperatures accompanying climate change may lead, among many other effects, to increasing incidence of skin cancer.

Automatic Diagnosis of Melanoma Based on the 7-Point Checklist

An image based system implementing a well-known diagnostic method is disclosed for the automatic detection of melanomas as support to clinicians. The software procedure is able to recognize automatically the skin lesion within the digital image, measure morphological and chromatic parameters, carry out a suitable classification for detecting the dermoscopic structures provided by the 7-Point Checklist. Advanced techniques are introduced at different stages of the image processing pipeline, including the border detection, the extraction of low-level features and scoring of high order features.

Activated mTORC1 signaling: The common driving force of type 2 diabetes and hidradenitis suppurativa

To the Editor: The results of the recent meta-analysis by Bui et al have confirmed that hidradenitis suppurativa (HS) is significantly associatedwith an increased prevalence of type 2 diabetes mellitus (T2DM). According to the authors, this association could be due to the fact thatHSpatients tend tobemoreobese. In this regard, we think that altered mechanistic target of rapamycin complex 1 (mTORC1) signaling might contribute and explain the connection between HS and T2DM. mTOR is the core constituent of the phosphatidylinositol 3-kinaseerelated kinase protein family that forms at least 2 multiprotein complexes known as mTORC1 and mTORC2. mTORC1 is the major regulator of survival, growth, proliferation, and motility in response to mitogens, energy, and nutrient levels. Because of its central role in cellular functions, mTORC1 dysregulation is involved in a large number of diseases. Upregulation of mTORC1 has also been observed in common inflammatory dermatoses, such as psoriasis and HS. Interestingly, mTORC1 plays a key role in diabetes mellitus pathogenesis. Overactivated mTORC1 causes insulin resistance. First, mTORC1 activates S6 kinase, which in turn causes phosphorylation and degradation of insulin receptor substrate 1/2. This impairs insulin signaling. Second, mTORC1 causes insulin resistance by affecting growth factor receptorebound protein 10. Thus, hyperactivation of mTORC1 causes insulin resistancebyat least 2mechanisms.Glucose activates mTORC1, thus causing expansion and hypertrophy of beta cells and increasing insulin secretion. Initially, this hyperfunction of beta cells compensates for insulin resistance, preventing hyperglycemia. However, it is hyperfunction that eventually causes beta-cell failure and manifests as diabetes. In fact, chronic hyperstimulation of mTORC1 renders beta cells resistant to insulin-like growth factor 1 and insulin, fostering cell death. Furthermore, the mTORC1 pathway is of pivotal importance for metabolic regulation and functioning of innate and adaptive immune cells, as clearly verified by the immune-suppressive function of mTORC1 inhibitors such as rapamycin. Notably, the differentiation of T helper 17 (TH17) cells is controlled and promoted by mTORC1. Substantial infiltration of TH17 cells into lesional skin and increased IL-17 serum levels have been found in HS patients. Evidence shows that interleukin (IL)-17 also plays a key role in insulin resistance and diabetes mellitus. Obesity is one of themain known causes of the development of T2DM. In obese patients,

Salicylic acid for the treatment of melasma: new acquisitions for monitoring the clinical improvement

The Melasma Area and Severity Index (MASI) and the Melasma Severity Score (MSS) are calculated on the basis of only a subjective clinical assessment. This raises the need to have an objective score, uniform in the evaluation by different clinicians. The purpose of this study was to establish if the images by Canfield Reveal Imager can be correlated to MASI score to better evaluate the clinical efficacy of salicylic acid 33% peeling in the treatment of melasma respect to the clinical observation.

Sunbathing and sunlamp exposure: awareness and risk among Italian teenagers.

To the Editor, Adolescence represents a critical period of life during which ultraviolet (UV) radiation can increase skin cancer risk. ‘Tanorexia’ is a new term used to describe an intense desire to be tanned, that multiple studies have tried to classify as a dysmorphic disorder, deriving from an obsessive and distressing desire to be suntanned (1).According to Molly M.Warthan et al. (2), we consider tanorexia as the repetitive behavior of an individual with regard to UV exposure.We have analyzed attitudes to indoor tanning among young people aged from 16 to 19, selected from a high school in Naples (Italy) to identify the risk of this disorder among Italian adolescents.

Altered mTORC1 signalling may contribute to macrophage dysregulation in hidradenitis suppurativa

complexes known as mTORC1 and mTORC2 [5]. mTORC1 is the major regulator of survival, growth, proliferation and motility, in response to mitogens, energy and nutrient levels [6]. Due to its central role in cellular functions, mTORC1 dysregulation is involved in a number of inflammatory or neoplastic conditions [7]. Upregulation of mTORC1 has also been observed in common inflammatory dermatoses, such as psoriasis, acne vulgaris and HS [8–10]. The mTORC1 pathway is of pivotal importance for metabolic regulation and functioning of innate and adaptive immune cells as clearly verified by the immune-suppressive function of mTORC1 inhibitors such as rapamycin [11]. In particular, mTORC1 signalling has been found to play a crucial role in the control of macrophage metabolism and activation [12]. In fact, macrophage activation is associated with metabolic shifts and metabolic reprogramming that enable bioenergetic and biosynthetic support as well as regulatory control of macrophage activities [13, 14]. In response to different stimuli, macrophages can differentiate into either a pro-inflammatory subtype (M1, classically activated macrophages) or acquire an anti-inflammatory phenotype (M2, alternatively activated macrophages). The metabolism of M1 macrophages is characterized by enhanced glycolysis, flux through the pentose phosphate pathway (PPP), fatty acid synthesis, and a truncated tricarboxylic acid cycle, leading to accumulation of succinate and citrate. The metabolic profile of M2 macrophages is defined by oxidative phosphorylation, fatty acid oxidation, a decreased glycolysis, and PPP [15]. Interestingly, the mTOR signalling enhances aerobic glycolysis [16]. In addition, mTORC1 promotes the synthesis of lipids and proteins in growing and proliferating cells. Lipid synthesis requires citrate production as well as activation of Srebp1, the transcriptional regulator of lipogenesis. Srebp1 is activated by mTORC1 in macrophages. Expansion of the ER and Golgi compartments, which has been linked I have read with interest the paper by Shah and colleagues [1]. The authors have underlined that macrophages play a critical role in the pathogenesis of hidradenitis suppurativa (HS). Dysregulation of macrophage activity is a big culprit in causing chronic tissue inflammation and damage. More specifically, dysregulated activation and proliferation of macrophages contribute to elevated macrophage secretion of pro-inflammatory cytokines and matrix metalloproteases (MMPs), which activate other inflammatory effectors and directly lead to tissue injury. In particular, macrophages are the most numerous inflammatory cells found in HS infiltrate and release numerous pro-inflammatory cytokines such as interleukin (IL)-23 [2], IL-1b [3] and tumour necrosis factor (TNF)-alpha [3, 4], which work to further enhance the inflammation. As a result, macrophages may modify the pericellular environment by influencing other inflammatory cells and may act as key players in the pathogenesis of the disease. This evidence helps to understand why HS patients often have concurrent inflammatory conditions which are also characterized by macrophage dysfunction such as Crohn’s disease and spondyloarthropathy. The authors have also tried to identify molecular players and lifestyle factors which may contribute to macrophage dysregulation in HS. In this regard, I think that altered mechanistic target of rapamycin complex 1 (mTORC1) signalling may contribute to macrophage dysregulation in HS. mTOR belongs to the phosphatidylinositol 3-kinase-related kinase protein family and forms at least two multiprotein Inflammation Research

Letter to the Editor referring to Hessam et al. - Squamous cell carcinoma arising in hidradenitis suppurativa: subclinical lymphedema may have favored the tumor onset

We read with great interest the case report recently published in the Journal der Deutschen Dermatologischen Gesellschaft by Hessam et al. [ 1 ] , which describes a 63-year-old woman with a 25-year history of inguinal, gluteal, and perianal hidradentis suppurativa (HS), who developed a squamous cell carcinoma (SCC), extending from the left gluteal and perianal region to the posterior upper thigh. Hessam et al., while underlining that the literature reports several cases of perineal/buttock HS patients developing SCC, speculate on the pathogenic mechanisms leading to the development of SCC in HS affected areas. HPV infection has been supposed to have a role in the causation of SCC in patients with anogenital HS [ 2, 3 ] . However, Hessam et al. were unable to detect HPV DNA (genotypes 6, 11, 16, 18, and 33) using PCR, which demonstrates that HPV infection has a limited role in the process that leads to the development of SCC in HS affected areas. Then, the authors suppose that longstanding infl ammation is the most signifi cant factor with respect to the development of SCC. According to this hypothesis, the infi ltration of immune cells and the release of pro-infl ammatory cytokines, such as TNF-alpha, would give rise to an infl ammatory microenvironment facilitating tumor initiation, promotion, and progression. However, the authors underline that, in contrast with this thesis, TNF-alpha also has an anticancer activity and anti-TNF drugs may increase the risk of developing a SCC. In our opinion, subclinical lymphedema is the key factor to explain the oncogenic potential of HS. In fact, anogenital lymphedema due to chronic, recurrent episodes of infl ammation and scarring occurring in patients with HS and causing the blockade/destruction of lymph drainage routes, has long been noted to be a common sequela of HS [ 4–6 ] . We think that a subclinical condition of lymphedema occurs in all patients with HS in the perineal or buttock areas. In fact, in most cases lymphedema is not being diagnosed until tissue swelling is clinically visible, but, according to the International Society of Lymphology, a “stage 0 lymphedema” does exist [ 7, 8 ] . At the beginning, only physiologic changes (increased protein content) with no measurable fl uid accumulation occur in the body region which is a candidate for lymphedema. Fluid accumulation supervenes later, and only then the clinician makes the diagnosis of lymphedema. In advanced stages, fi brotic changes and lipid deposition due to stasis of protein-rich extracellular fl uid appear, resulting in an overt and diffi cult to manage condition. Interestingly, a recent study has focused on the role of subclinical lymphedema in the origin of both benign and malignant neoplasia [ 9 ] . We believe that the outbreak of SCC in long-standing HS may well be explained by the locoregional immune default depending on the hindered traffi c of immunocompetent cells in the lymphedematous area. In other words, long-standing HS is a typical example of an immunocompromised district. The immunocompromised cutaneous district is a novel concept, delineated by Ruocco et al. [ 10 ] , that applies to an area of diseased or injured skin where local immune control has been altered, thereby permitting the development of a dysimmune reaction, infection, or tumor confi ned to the diseased or injured site [ 11, 12 ] . Lymphedema is a well-recognized cause of cutaneous immunodestabilization. Whether the origin is congenital or acquired from infection, radiation, trauma, or surgery, chronic lymph stasis impairs local immune surveillance by disrupting the regular traffi cking of the immunocompetent cells in the lymphedematous district. When the local mechanisms of immune surveillance begin to fail, the lymphedematous region becomes an immunologically vulnerable area, predisposed to malignancy.Post-mastectomy Stewart-Treves angiosarcoma is a prototypical example of this condition [ 13 ] . We thank the authors for giving us the opportunity to discuss such an intriguing topic.

Hidradenitis suppurativa after radiotherapy for uterine adenocarcinoma: A typical example of an isoradiotopic response

To the Editor: We read with great interest the case report by Haber et al in the May 2017 issue of JAAD Case Reports which described a 57-year-old woman who developed radiation-induced hidradenitis suppurativa (HS) after radiotherapy (RT) for uterine adenocarcinoma. In this patient, HS appeared 1 year after the last cycle of RT and, interestingly, the lesions were strikingly contained within the distinct margins of the radiation treatment, clearly indicating induction by ionizing radiation. The onset of primary skin cancers on previously irradiated areas has been considered the sole long-term cutaneous side effect of RT for a long time. Actually, an irradiated area is prone to the development not only of tumors, but also of opportunistic infections and immune-mediated skin disorders, representing a typical example of an immunocompromised cutaneous district (ICD). The ICD is a novel concept, delineated by Ruocco et al, that applies to an area of diseased or injured skin where local immune control has been altered, thereby permitting the development of a dysimmune reaction, infection, or tumor confined to the diseased or injured site. In the ICD, the locoregional immune dysregulation is caused by an obstacle to the normal trafficking of immunocompetent cells through lymphatic channels or an interference with the signals that the neuropeptides and neurotransmitters, released by peripheral nerves, send to membrane receptors of immunocompetent cells. In the radiation dermatitis, the lymph network is deeply disrupted with abnormal dilation of some vessels and obstruction of others, which results in an obvious obstacle to the trafficking of immune cells. Moreover, peripheral nerve fibers are compressed by dermal fibrosis. Therefore, the dysregulation of the immune control occurring in irradiated areas may well be explained by the impaired lymph flow on one hand and the fibrotic constriction or reduction of peptidergic nerve fibers on the other hand. Both