Microbiome Modulation in Acne Patients and Clinical Correlations.

BACKGROUND: The imbalance of skin microbiota in acne can induce changes leading to induction or to aggravation of chronic inflammatory lesions; complex mechanisms are involved. Cutibacterium acnes (C. acnes) ribotypes RT4 and RT5 express more biofilm and are associated with inflammatory acne lesions. C. acnes RT6 is a non-acne ribotype, beneficial for the skin. OBJECTIVES: In an open clinical trial, acne adults were included and assessed clinically at baseline and at month 2 using the Investigator Global Assessment of Acne (IGA) score. A topical emulsion was applied twice daily for 2 months (M2) in each included patient. In the same series of acne patients, skin swab samples were collected from acne patients at baseline and M2 from lesional and non-lesional skin; skin swabs were collected for the metagenomic long-read analysis of microbiota. MATERIALS AND METHODS: Acne patients with a gravity score IGA of >1<3 were included in this pilot study. An emulsion of O/W formulated with vegetal extract of Umbelliferae associated with a polysaccharide at 1% was applied twice daily for 2 months. At baseline and M2 clinical assessments were made; skin swab samples were also taken for microbiota analysis from lesional and non-lesional skin in each included patient. Extractions of genomic DNA (gDNA) from swab samples from baseline and from M2 were made, followed by full-length (V1-V9) amplification of the 16S rDNA and sequencing of amplicon libraries for strain-level bacterial community profiling. RESULTS: In a series of 32 adult acne patients, the mean initial IGA scale was 3.1; at M2 the IGA scale was 1.5 (p < 0.001). The mean decrease in acne lesions was by 63%. Microbiome metagenomic long-read analysis in these series was mainly dominated by C. acnes followed by Staphylococcus epidermidis (S. epidermidis). The density of C. acnes ribotypes RT6 (non-acne strain) was increased at M2 compared to baseline and the density of ribotypes C. acnes RT1 to RT5 was decreased at M2, compared to baseline (p < 0.0001). S. epidermidis ribotypes (1 to 36) were non significantly increased at M2, compared to baseline (p < 0.1). CONCLUSIONS: In a series of 32 acne patients that applied an emulsion based on vegetal extract of Umbelliferae and a polysaccharide at 1% twice daily, a significant clinical improvement in IGA scale for acne lesions was seen at M2, compared to baseline (p < 0.0001). The clinical improvement was correlated with an improvement in skin microbiome at M2 compared to baseline, indicated by the increase in the relative abundance of non-acne strain of C. acnes ribotype 6 and of the decrease in the relative abundance of acne strains ribotypes C. acnes RT1 to RT5.

DRESS and Stevens-Johnson Syndrome Overlap Secondary to Allopurinol in a 50-Year-Old Man-A Diagnostic and Treatment Challenge: Case Report.

Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a drug reaction commonly related to eosinophilia, from uncertain epidemiology, and without consensus for diagnosis and treatment globally. It presents a great challenge in its management and is characterized by fever, lymphadenopathy, skin rash, and multisystemic involvement. An aggressive and difficult-to-manage clinical case is presented in a 50-year-old man with chronic kidney disease due to diabetes mellitus type 2 and systemic arterial hypertension, who developed an unusual variant similar to DRESS and Stevens-Johnson syndrome (SJS) overlap secondary to allopurinol, with skin manifestations without eosinophilia, but fulfilling clinical and laboratory criteria for DRESS and SJS syndrome.

Role of Silver Nitrate Spray for Skin Wound Care in Patients with Toxic Epidermal Necrolysis: Our Experience in 4 Patients.

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are examples of severe cutaneous adverse reactions to drugs (SCARs) with several international recommendations for global medical management, ranging from pharmacological systemic therapy to skin wound care. There is no defined best management of the skin wounds in SJS/TEN. The care of wounds is essential to initiate re-epithelialization. Our objective is to improve the cicatrization process, avoiding scarring due to deepening of the wounds, as well as prevent infections, achieve pain control, and avoid loss of serum proteins, fluids, and electrolytes. In this retrospective case series, we highlight the value of systemic therapy and the use of silver nitrate for wound management in four patients with TEN.

Psoriasis Management Challenges Regarding Difficult-to-Treat Areas: Therapeutic Decision and Effectiveness.

Psoriasis is not optimally controlled in spite of newly developed treatments, possibly due to the difficulty of objectively quantifying the disease's severity, considering the limitations of the clinical scores used in clinical practice. A major challenge addresses difficult-to-treat areas, especially in the absence of significant body surface involvement. It is controversial whether the severity evaluation of patients with several affected areas (having at least one difficult-to-treat area) should be done differently from current methods. Scores used for special areas (PSSI, NAPSI and ESIF) allow an accurate assessment of disease severity in difficult-to-treat areas, but the issue of whether to integrate these scores into PASI, BSA or DLQI remains. The review's purpose resides in providing an overview of the main current issues in determining psoriasis severity in patients with psoriasis in difficult-to-treat areas and suggesting possible solutions for the optimal integration of the area assessment in current scores: severity can be either established according to the highest calculated score (PASI or PSSI or NAPSI or ESIF) or by adding a correction factor in the calculation of PASI for special areas.

Identification of a prognostic signature in colorectal cancer using combinatorial algorithm-driven analysis.

Colorectal carcinoma is one of the most common types of malignancy and a leading cause of cancer-related death. Although clinicopathological parameters provide invaluable prognostic information, the accuracy of prognosis can be improved by using molecular biomarker signatures. Using a large dataset of immunohistochemistry-based biomarkers (n = 66), this study has developed an effective methodology for identifying optimal biomarker combinations as a prognostic tool. Biomarkers were screened and assigned to related subsets before being analysed using an iterative algorithm customised for evaluating combinatorial interactions between biomarkers based on their combined statistical power. A signature consisting of six biomarkers was identified as the best combination in terms of prognostic power. The combination of biomarkers (STAT1, UCP1, p-cofilin, LIMK2, FOXP3, and ICOS) was significantly associated with overall survival when computed as a linear variable (χ2  = 53.183, p < 0.001) and as a cluster variable (χ2  = 67.625, p < 0.001). This signature was also significantly independent of age, extramural vascular invasion, tumour stage, and lymph node metastasis (Wald = 32.898, p < 0.001). Assessment of the results in an external cohort showed that the signature was significantly associated with prognosis (χ2  = 14.217, p = 0.007). This study developed and optimised an innovative discovery approach which could be adapted for the discovery of biomarkers and molecular interactions in a range of biological and clinical studies. Furthermore, this study identified a protein signature that can be utilised as an independent prognostic method and for potential therapeutic interventions.

COVID-19 skin lesions are rarely positive at RT-PCR test: the macrophage activation with vascular impact and SARS-CoV-2-induced cytokine storm.

BACKGROUND: Several skin manifestations have been reported since the start of the COVID-19 pandemic: chilblains-like, livedoid lesions, urticaria-like, pseudo-Kawasaki disease, and others. Histopathologic images of these lesions most often show aspects of endothelitis, images similar to autoimmune vasculitis. Cutaneous lesions are often negative at RT-PCR for SARS-CoV-2 virus. METHOD AND RESULTS: We reviewed recent articles on the mechanisms of COVID-19 and we synthesized main pathways of inflammatory cascade. After the penetration into the cells of the respiratory epithelium, SARS-CoV-2 virus initiates a "cytokine storm" well described in previous publications: the expression of interferon type I (IFN-I) is one of the key elements of the antiviral response in COVID-19 patients, IFN-I expression seems to play an important role in the induction of interleukin 6 (IL-6), chemotactic factors such as Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and the consequent activation of monocyte-macrophage system followed by the expression of TNF-alpha, and finally by the induction of coagulation factors by both extrinsic and intrinsic pathways. CONCLUSIONS: The simplified synthesis of the main pathophysiological mechanisms of COVID-19 could help us to understand at least partially the importance of macrophage activation and its vascular involvement in many skin lesions that remain often negative at in situ tests for SARS-CoV-2.

Topical non-occlusive polymers in hand-foot syndrome.

BACKGROUND: Many cytotoxic and biological drugs are cause of severe dermatological side effects, such as hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR). Oncologic patients with HFS or HFSR presents relevant symptoms that interferes with daily activities and with adherence to anticancer treatment. The HFRS control and treatment are important goals to enhance the quality of life of oncologic patients. The aim of this study was to assess the efficacy and tolerability of a b.i.d. (bis in die) topical administration of an anhydric ointment based on topical non-occlusive polymers (TNOP) in patients with HFS on current anticancer drug regiments. METHODS: A prospective, open, multicenter clinical study was conducted in oncologic patients with HFS attended two hospital-based Italian dermatological unit. A global-non-instrumental evaluation, based on different standardized tools (i.e., Sum Score System Index [SRRC] Score, Dermatology Life Qualiy Index [DLQI] and global efficacy) was conducted using measurements at baseline, at 4 and 8 weeks. Non-parametric test for two correlate samples, was used to assess changes in means of the different scores. The protocol was approved by ethical committee of both dermatology service pariticipating to the study. RESULTS: Twenty-one oncologic patients were enrolled. Thirteen (61.9%) of participants were female. The median age was 63 years (range: 37-73). Seventeen (80.9%) patients presenting a HFS associated to capecitabine, and four patients (19.1%) associated to docetaxel. At the enrollment, 33.3% (7/21) of patients showed at level of the hands a HFS of grade 2 and 9.5% (2/21) of grade 3. At level of the feet, 28.6% (6/21) showed a HFS of grade 2, and 17.4% (4/21) of grade 3. The SRRC scores were significantly decreased after 8 weeks of treatment compared to baseline, for both sites. In particular, SRRC score decreased from 4.38 to 1.67 (Z=-3.60, P=0.00) and from 4.48 to 1.43 (Z=-3.87, P=0.00) for hands and feet, respectively. A consistent significant improvement in the perceived QoL of patients was also observed. From baseline to visit 3, the total mean score of DLQI decreased from 10.62 to 4.57 (Δ=-57%, Z=-4.020, P=0.000). CONCLUSIONS: In a sample of oncologic patients with HFS, the b.i.d. administration of TNOP for eight weeks, induced a progressive and significant decrease of the SRRC Score and a relevant improvement in the perceived quality of life.

Bacillus cereus strain isolated from Demodex folliculorum in patients with topical steroid-induced rosaceiform facial dermatitis.

The aim of the study was to identify Bacillus species from the Demodex folliculorum of patients with topical steroidinduced facial rosaceiform dermatitis. Of the 75 patients examined, 20% had clinical spinulosis, while 18.66% had dermoscopic features of Demodex: follicular plugs and tails. Of the 17.33% positive patients identified upon microscopy for Demodex, samples for bacterial culture were plated on trypticase soy Colombia agar. Identification was performed by microorganisms grown method mass spectrometry. We identified a strain of Bacillus cereus.

Bacillus cereus strain isolated from Demodex folliculorum in patients with topical steroid-induced rosaceiform facial dermatitis

Abstract: The aim of the study was to identify Bacillus species from the Demodex folliculorum of patients with topical steroidinduced facial rosaceiform dermatitis. Of the 75 patients examined, 20% had clinical spinulosis, while 18.66% had dermoscopic features of Demodex: follicular plugs and tails. Of the 17.33% positive patients identified upon microscopy for Demodex, samples for bacterial culture were plated on trypticase soy Colombia agar. Identification was performed by microorganisms grown method mass spectrometry. We identified a strain of Bacillus cereus.

Hypereosinophilic syndrome and proliferative diseases.

Therapy principles of the last decade and recent advances in the research of polynuclear eosinophil have led to a new approach in the hypereosinophilic syndrome (HES), with important consequences on the development of new and effective therapies. HES is defined by persistent and marked eosinophilia and eosinophil-related organ damage in the absence of any evident cause of hypereosinophilia. Two variants of HES have been characterized, with different prognosis and possible associations with malignant diseases such as myeloid leukemia or T-cell lymphomas. The lymphocytic variant of HES (L-HES) is characterized by the presence of T cell clones, IL-5 expression and possible progression to T-cell lymphoma. Besides steroid therapy, the anti-IL-5 monoclonal antibody mepolizumab is considered as a target therapy for L-HES. The myeloproliferative variant of HES (M-HES) is associated with an increased risk of myeloid leukemia and good response to anti-tyrosine-kinase therapy. The imatinib target is a kinase resulting from an 800-kb deletion on chromosome 4. The fusion gene Fip1-like 1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) has been validated as a marker of response to anti-tyrosine-kinase therapy. Early identification of HES variants is crucial for the rapid introduction of early and appropriately adjusted therapy.

Could anti IL12/23 therapy replace anti-TNF biologics?

Biologic therapies improved dramatically the outcome of psoriatic arthritis and moderate to severe chronic plaque psoriasis. Anti-TNF agents were developed approximately one decade ago by rheumatologists and today represent one of the most effective classes of drugs in severe psoriasis resistant to 2 out of 3 "classic" systemic therapies (methotrexate, cyclosporine, and PUVA). Recent studies on psoriasis pathogenesis were focused on early steps of the inflammatory cascade, i.e. activation of T cells with a recently described phenotype Th17 and consequent expression of interleukins (IL) 12 and 23. IL12 and IL23 have a common p40 subunit that is a target of a new therapeutic class, fully human monoclonal antibodies anti IL12/23: ustekinumab and ABT-874. Randomized, placebo-controlled clinical trials in patients with moderate to severe chronic plaque psoriasis using ustekinumab and ABT-874 showed PASI 75 achievements at week 12 in 80% and 93% of patients, respectively. Larger studies are ongoing in order to assess the safety profile of this new therapy. As anti-TNF drugs represent an important and effective treatment of psoriatic arthritis and moderate to severe plaque psoriasis, comparative studies are needed to assess the advantages, the safety and the place of anti-IL12/23 in the era of biologic therapy.

Sun protection and sunscreen labeling--an update.

Sun exposure is today well recognized as having an adverse effect on human skin. Part of sun radiation, ultraviolet radiation A (UVA) and B (UVB), can modify skin structures and induce short-term skin changes (sunburn, tanning, hyperkeratinization, brown spots) and long-term skin damages (accelerated skin aging and skin cancers). Protection against both UVA and UVB is very important, therefore sun protection by clothes, avoiding sun exposure and correct use of sunscreens are important means to reduce short- and long-term solar radiation effects. The recommendation of appropriate sunscreen by doctors and cosmetic professionals (the function of skin type and sun radiation intensity) is today easier due to the recently implemented European uniform labeling system of sunscreens and detailed information for consumers.

Deficient contact hypersensitivity reaction in CD4-/- mice is because of impaired hapten-specific CD8+ T cell functions.

Mice deficient in the CD4 molecule (CD4-/-) are widely used to evaluate the requirement for CD4+ T cell help in viral, tumoral, and transplantation immunity. Previous studies, showing that CD4-/- mice develop impaired contact hypersensitivity (CHS) responses, have suggested that CD4+ T cells are required for the optimal induction of this skin inflammatory reaction. other studies have, however, demonstrated that CHS was mediated by CD8+ T cells, without the need for CD4+ T cell help. Here, we show that CD4-/- mice develop a normal delayed-type hypersensitivity response to protein antigen, which is mediated by major histocompatibility molecules class II-restricted CD4-CD8- T cells, but a decreased CHS response to 2,4-dinitro-fluorobenezene. Analysis of the hapten-specific T cell pool demonstrates that priming of CD8+ T cells occurred normally in CD4-/- mice, as assessed by specific proliferative responses and interferon-gamma (IFN-gamma) production of purified CD8+ T cells. Furthermore, CD8+ T cells were able to adoptively transfer a normal CHS reaction. In contrast, total lymph node cells from CD4-/- mice showed decreased IFN-gamma production and diminished specific cytotoxic T lymphocytes (CTL) activity, which could be reversed by in vitro restimulation with hapten-pulsed class II-deficient antigen-presenting cells. These data confirm that class I-restricted CD8+ T cells can fully develop in effectors of CHS in the absence of CD4+ T cell help and suggest that the impaired CHS in CD4-/- mice is because of the presence of a class II-restricted T cell subset, which controls CHS by inhibiting hapten-specific CTL responses.

In situ eosinophil activation in 26 primary cutaneous T-cell lymphomas with blood eosinophilia.

Blood and tissue eosinophils can be associated with Hodgkin and non-Hodgkin lymphomas in that they have prognostic value. Tissue eosinophils in T-cell lymphoma patients with blood eosinophilia have not been systematically assessed. The objective of this research was to study the presence, density, and activation of tissue eosinophils in patients with primary cutaneous T-cell lymphomas (CTCLs) with blood eosinophilia and a possible relationship between features of the disease and prognosis. With skin biopsy specimens from 26 CTCL patients with blood eosinophilia, tissue eosinophils were studied with electron microscopy, extracellular eosinophil peroxidase deposits, and interleukin-5 expression. Tissue eosinophils, found in 22 of 26 cases, were constantly activated. Both density and activation of tissue eosinophils were significantly related to disease progression. The state of activation of tissue eosinophils in CTCL might reflect inflammatory flare-ups associated with aggressive lymphomas. Further studies are needed to confirm the value of eosinophil density as a simple and reliable marker of CTCL progression.

Prognostic value of blood eosinophilia in primary cutaneous T-cell lymphomas.

OBJECTIVE: To investigate the prognostic value of initial characteristics including blood eosinophilia in patients with primary cutaneous T-cell lymphoma. DESIGN: A retrospective inception cohort, patients included from date of diagnosis (1982-1998). SETTING: Two dermatology departments of a university hospital. Patients A total of 104 patients with cutaneous T-cell lymphoma, including patients with mycosis fungoides (n = 69), Sézary syndrome (n = 13), and nonepidermotropic cutaneous lymphoma (n = 22). The following variables were recorded: age, sex, diagnosis according to the European Organization for Research and Treatment of Cancer (EORTC) classification, type of skin involvement at the time of diagnosis, initial eosinophil absolute count, lactate dehydrogenase value, date of disease progression, and cause and date of death or date of last contact. MAIN OUTCOME MEASURES: Time from diagnosis to disease progression and to disease-specific death. RESULTS: The median follow-up was 43 months (range, 7-197 months). Estimated rates of disease progression and disease-specific death for 3 years were 19.5% (95% confidence interval [CI],11.3%-27.6%) and 9.9% (95% CI, 2.8%-13.6%), respectively. Univariable analysis of initial variables possibly influencing disease progression revealed significant prognostic value for diagnosis according to EORTC classification (hazard ratio [HR], 2.77; 95% CI, 1.04-7.41; P =.04), type of skin involvement (HR, 2.70; 95% CI, 1.00-7.25; P =.04), raised blood eosinophil absolute count (HR, 7.33; 95% CI, 2.84-18.91; P<.001), and raised serum level of lactate dehydrogenase (HR, 3.72; 95% CI, 1.58-8.78; P =.001). Concerning disease-specific death, significant prognostic indicators were diagnosis according to the EORTC classification (HR, 6.62; 95% CI, 1.68-26.12; P =.007) and a raised blood eosinophil absolute count (HR, 10.57; 95% CI, 2.28-49.0; P<.001). In multivariable analysis, only blood eosinophilia was associated with disease progression and disease-specific death. CONCLUSION: These results strongly suggest that blood eosinophilia at baseline is a prognostic factor in patients with primary cutaneous T-cell lymphoma.

Psychological stress exerts an adjuvant effect on skin dendritic cell functions in vivo.

Psychological stress affects the pathophysiology of infectious, inflammatory, and autoimmune diseases. However, the mechanisms by which stress could modulate immune responses in vivo are poorly understood. In this study, we report that application of a psychological stress before immunization exerts an adjuvant effect on dendritic cell (DC), resulting in increased primary and memory Ag-specific T cell immune responses. Acute stress dramatically enhanced the skin delayed-type hypersensitivity reaction to haptens, which is mediated by CD8(+) CTLs. This effect was due to increased migration of skin DCs, resulting in augmented CD8(+) T cell priming in draining lymph nodes and enhanced recruitment of CD8(+) T cell effectors in the skin upon challenge. This adjuvant effect of stress was mediated by norepinephrine (NE), but not corticosteroids, as demonstrated by normalization of the skin delayed-type hypersensitivity reaction and DC migratory properties following selective depletion of NE. These results suggest that release of NE by sympathetic nerve termini during a psychological stress exerts an adjuvant effect on DC by promoting enhanced migration to lymph nodes, resulting in increased Ag-specific T cell responses. Our findings may open new ways in the treatment of inflammatory diseases, e.g., psoriasis, allergic contact dermatitis, and atopic dermatitis.