Fascinating Molecular and Immune Escape Mechanisms in the Treatment of STIs (Syphilis, Gonorrhea, Chlamydia, and Herpes Simplex).

The incidence of syphilis, gonorrhea, chlamydia, and herpes simplex has increased over the last decade, despite the numerous prevention strategies. Worldwide scientists report a surge in drug-resistant infections, particularly in immunocompromised patients. Antigenic variations in syphilis enable long-term infection, but benzathine penicillin G maintains its efficiency, whereas macrolides should be recommended with caution. Mupirocin and zoliflodacin were recently introduced as therapies against ceftriaxone-resistant gonococcus, which poses a larger global threat. The gastrointestinal and prostatic potential reservoirs of Chlamydia trachomatis may represent the key towards complete eradication. Similar to syphilis, macrolides resistance has to be considered in genital chlamydiosis. Acyclovir-resistant HSV may respond to the novel helicase-primase inhibitors and topical imiquimod, particularly in HIV-positive patients. Novel drugs can overcome these challenges while nanocarriers enhance their potency, particularly in mucosal areas. This review summarizes the most recent and valuable discoveries regarding the immunopathogenic mechanisms of these sexually transmitted infections and discusses the challenges and opportunities of the novel molecules and nanomaterials.

Treatment of Plaque-Type Psoriasis With Oral CF101: Data from a Phase II/III Multicenter, Randomized, Controlled Trial.

BACKGROUND: CF101, an adenosine A3 receptor agonist, is an orally bioavailable small molecule drug presenting an anti-psoriatic effect demonstrated in a Phase 2 clinical trial in psoriasis patients.
OBJECTIVE: To evaluate the safety and efficacy of CF101 treatment in a Phase 2/3 study in patients with moderate to severe plaque-type psoriasis.
METHODS: This multicenter, double-blind, 2-segment, placebo-controlled study randomized subjects with moderate to severe plaque psoriasis to CF101 1 or 2 mg, or placebo twice daily. At either week 12 (Segment 1) or 16 (Segment 2), the placebo group crossed over to CF101 BID through week 32 in an open-label fashion. At week 12, following an interim analysis, the CF101 1mg group was discontinued due to futility. The primary endpoint was proportion of patients achieving ≥75% improvement in Psoriasis Area Severity Index (PASI 75). Efficacy testing was performed using the Cochran-Mantel Haenszel test, the primary analysis of PASI 75 was performed at the 0.035 significance level.
RESULTS: CF101 had an excellent safety profile at all tested dosages with a profile similar to the placebo group. The most common adverse events were infections and gastrointestinal events, and there was no cumulative intolerance over the 32-week dosing period. The study did not meet the primary endpoint of PASI 75 at week 12 (2 mg: 8.5% vs. placebo: 6.9%, P=0.621). However, at week 32, PASI mean percent improvement with CF101 2 mg was 57% (P<0.001) compared to baseline, with linear improvement in PASI 50 (63.5%), 75 (35.5%), 90 (24.7%), and 100 (10.6%).
CONCLUSIONS: Oral CF101 was found to be safe and very well tolerated, demonstrating evidence of efficacy in patients with moderate to severe plaque psoriasis through 32 weeks of treatment.

J Drugs Dermatol. 2016;15(8):931-938.

The Cutaneous Telocytes.

Telocytes (TCs) are interstitial cells found in stroma of many organs, including the skin dermis. Ultrastructurally, normal skin TCs recapitulates all the previously documented features in interstitum of other organs. Their (ultra)structural hallmark is the presence of particular shaped cellular prolongations (termed telopodes), along other features as cellular organelles representation and their distribution within cell body and its prolongations. Transmission electron microscopy (TEM) or high magnification light microscopy indicated that the particular shape of telopodes alternate characteristically thin segments (termed podomeres) and dilated segments (called podoms). A new and powerful technique, focused ion beam scanning electron microscopy (FIB-SEM), indicated that, ultrastructurally, telopodes could be either irregular ribbon-like structures, or uneven tubular-like structures. TEM images shown that podoms consists mitochondria, elements of endoplasmic reticulum and caveolae. Immunohisochemical studies on skin TCs revealed their positive expression for CD34 and PDGFRα, but for vimentin and c-kit, also. In normal dermis, TCs are involved in junctions, either homocellular (TCs-TCs), or heterocellular (TCs - other type of cells). The junctional attribute of TCs underlies their ability of forming a 3D network within dermis. Beyond the physical interactions, the connections between TCs and other cells could be also chemical, by paracrine secretion via shed vesicles as ultrastructural studies demonstrated. In normal dermis, TCs were found distributed in particular spatial relationships with other interstitial structures and/or cells: vascular structures, nerves, skin adnexa, stem cells and immune reactive cells.To date, the study of TCs was approached into two pathologic conditions: systemic sclerosis and psoriasis. In both diseases, the normal ultrastructure of TCs and also their distribution were shown to be altered. Moreover, the pattern of TCs ultrastructural changes differs in systemic sclerosis (cytoplasmic vacuolization, swollen mitochondria, lipofuscin bodies) from those appeared in psoriasis, characterized by important dystrophic changes (telopodes fragmentation, cytoplasmic disintegration, apoptotic nuclei, nuclear extrusions). Furthermore, in psoriasis, the lesional remission is (ultra)structurally displaying a recovery of dermal TCs at values similar to normal.Considering TCs ultrastructural features, their connections and spatiality in normal dermis and also their pathologic changes, TCs are credited with roles in skin homeostasis and/or pathogeny of dermatological disorders. In our opinion, further researches should be focused on identifying a specific marker for TCs and also on comprehending the pattern of their response in different dermatoses.

Telocyte dynamics in psoriasis.

The presence of telocytes (TCs) as distinct interstitial cells was previously documented in human dermis. TCs are interstitial cells completely different than dermal fibroblasts. TCs are interconnected in normal dermis in a 3D network and may be involved in skin homeostasis, remodelling, regeneration and repair. The number, distribution and ultrastructure of TCs were recently shown to be affected in systemic scleroderma. Psoriasis is a common inflammatory skin condition (estimated to affect about 0.1-11.8% of population), a keratinization disorder on a genetic background. In psoriasis, the dermis contribution to pathogenesis is frequently eclipsed by remarkable epidermal phenomena. Because of the particular distribution of TCs around blood vessels, we have investigated TCs in the dermis of patients with psoriasis vulgaris using immunohistochemistry (IHC), immunofluorescence (IF), and transmission electron microscopy (TEM). IHC and IF revealed that CD34/PDGFRα-positive TCs are present in human papillary dermis. More TCs were present in the dermis of uninvolved skin and treated skin than in psoriatic dermis. In uninvolved skin, TEM revealed TCs with typical ultrastructural features being involved in a 3D interstitial network in close vicinity to blood vessels in contact with immunoreactive cells in normal and treated skin. In contrast, the number of TCs was significantly decreased in psoriatic plaque. The remaining TCs demonstrated multiple degenerative features: apoptosis, membrane disintegration, cytoplasm fragmentation and nuclear extrusion. We also found changes in the phenotype of vascular smooth muscle cells in small blood vessels that lost the protective envelope formed by TCs. Therefore, impaired TCs could be a 'missed' trigger for the characteristic vascular pathology in psoriasis. Our data explain the mechanism of Auspitz's sign, the most pathognomonic clinical sign of psoriasis vulgaris. This study offers new insights on the cellularity of psoriatic lesions and we suggest that TCs should be considered new cellular targets in forthcoming therapies.

FIB-SEM tomography of human skin telocytes and their extracellular vesicles.

We have shown in 2012 the existence of telocytes (TCs) in human dermis. TCs were described by transmission electron microscopy (TEM) as interstitial cells located in non-epithelial spaces (stroma) of many organs (see www.telocytes.com). TCs have very long prolongations (tens to hundreds micrometers) named Telopodes (Tps). These Tps have a special conformation with dilated portions named podoms (containing mitochondria, endoplasmic reticulum and caveolae) and very thin segments (below resolving power of light microscopy), called podomers. To show the real 3D architecture of TC network, we used the most advanced available electron microscope technology: focused ion beam scanning electron microscopy (FIB-SEM) tomography. Generally, 3D reconstruction of dermal TCs by FIB-SEM tomography revealed the existence of Tps with various conformations: (i) long, flattened irregular veils (ribbon-like segments) with knobs, corresponding to podoms, and (ii) tubular structures (podomers) with uneven calibre because of irregular dilations (knobs) - the podoms. FIB-SEM tomography also showed numerous extracellular vesicles (diameter 438.6 ± 149.1 nm, n = 30) released by a human dermal TC. Our data might be useful for understanding the role(s) of TCs in intercellular signalling and communication, as well as for comprehension of pathologies like scleroderma, multiple sclerosis, psoriasis, etc.

Basal cell carcinoma-a clinical indicator of immunosuppression.

Background: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are skin-derived carcinomas. The literature strongly connects SCC with acquired immunosuppression. Current data regarding BCC's association with immunosuppressive comorbidities are vague. The primary objective of this study was to establish the correlations between BCC and immunosuppressive comorbidities of patients. Materials and methods: We conducted a retrospective cohort study on 275 patients with a histopathological proven diagnosis of BCC from October 2019 to October 2023. Demographic data, BCC characteristics, and patients' comorbidities were analyzed. Comorbidities were classified as non-immunosuppressant and immunosuppressant (primary and secondary immunodeficiencies). Results: We recorded 292 BCCs from 275 patients (142 females, 133 males), with equally distributed skin phototypes. 66.44% of the BCCs were detected in patients with various comorbidities (p < 0.001), of which 81.44% had immunosuppressive comorbidities (p < 0.001). All the immunosuppressive comorbidities were secondary and included diabetes mellitus (47.55%), history of solid or hematogenous cancer in the last 5 years (26.57%), chronic kidney disease (8.39%), chronic infections (9.09%), and antirheumatic immunosuppressive therapies (8.39%) (p < 0.001). BCC patients with immunosuppressive comorbidities did not develop larger BCCs (p = 0.2577) or more aggressive subtypes (p = 0.4269) and BCC did not arise earlier in their life (p < 0.001). BCC on the nasal pyramid was frequent in cancer history patients (p = 0.008). The ulcerated form of BCC is more confined to patients with chronic kidney disease (p = 0.006). Multiple BCCs are more frequent in patients with secondary immunodeficiencies (p = 0.027). Conclusion: BCC represents a clinical indicator of secondary immunodeficiency. Further research should establish if cancer screening campaigns may be beneficial in BCC patients.

Paraneoplastic Pemphigus Mimicking Pemphigus Vulgaris Associated With Castleman Disease.

Paraneoplastic pemphigus (PNP) is a rare bullous disease with a polymorphic presentation. Diagnosis can be difficult because it can mimic other bullous diseases, while the underlying neoplasm may be completely asymptomatic. We present the case of a 19-year-old female with a four-year history of exclusively oral bullous lesions, mimicking pemphigus vulgaris, before the diagnosis of a retroperitoneal Castleman disease. While PNP is a severe and sometimes deadly condition, our patient had a mild and long evolution on minimal treatment, with complete resolution after tumor excision. Practitioners should be aware of PNP in young patients presenting with bullous disease and should conduct prompt systemic investigations in refractory or long-evolving cases, even when PNP diagnostic criteria are not fully met.

A Disguising Fast-Growing Metachronous Melanoma and COVID-19.

An unusual case of a 52-year-old female with two metachronous melanomas is presented. An atypical fast-growing nodular melanoma appeared 18 months after the complete excision of an in situ melanoma and one month afterward a SARS-CoV-2 infection. Intra-nodal melanocytic proliferations were identified during lymph node assessment, raising important diagnostic and prognostic concerns. No melanoma susceptibility genes were found. This case report raises the question about the COVID-19 immunosuppression effect on the tumor microenvironment and the oncogenic potential of SARS-CoV-2. It also highlights the importance of clinical follow-up in melanoma patients, which was significantly delayed during the COVID-19 pandemic.

Platelet-Rich Plasma (PRP) in Dermatology: Cellular and Molecular Mechanisms of Action.

Platelet-rich plasma (PRP) therapy has gained attention in the scientific field due to its potential regenerative effects and great benefit-risk ratio. This review extensively explores the most studied mechanisms of this therapy according to the etiopathogenesis of skin diseases: cellular proliferation, matrix formation, regulation of inflammation, angiogenesis, collagen synthesis, and the remodeling of new tissue. Moreover, it draws on newly reported and lesser-known effects of PRP: its anti-apoptotic effects, immunological suppression, decrease in melanin synthesis, anti-microbial effects, overexpression of miR-155, antioxidant effects, and their involved pathways. This work aims to provide a complete update for understanding PRP's benefits and clinical relevance in wound healing, alopecia, pigmentary disorders, scars, rejuvenation, lichen sclerosus, and other inflammatory dermatoses, based on the current evidence. Furthermore, recent reports with novel indications for PRP therapy are highlighted, and new potential pathways correlated with the pathogenesis of skin diseases are explored.

Telocytes in human skin--are they involved in skin regeneration?

Telocytes (TCs), a particular interstitial cell type, have been recently described in a wide variety of mammalian organs (www.telocytes.com). The TCs are identified morphologically by a small cell body and extremely long (tens to hundreds of µm), thin prolongations (less than 100 nm in diameter, below the resolving power of light microscopy) called telopodes. Here, we demonstrated with electron microscopy and immunofluorescence that TCs were present in human dermis. In particular, TCs were found in the reticular dermis, around blood vessels, in the perifollicular sheath, outside the glassy membrane and surrounding sebaceous glands, arrector pili muscles and both the secretory and excretory portions of eccrine sweat glands. Immunofluorescence screening and laser scanning confocal microscopy showed two subpopulations of dermal TCs; one expressed c-kit/CD117 and the other was positive for CD34. Both subpopulations were also positive for vimentin. The TCs were connected to each other by homocellular junctions, and they formed an interstitial 3D network. We also found TCs adjoined to stem cells in the bulge region of hair follicles. Moreover, TCs established atypical heterocellular junctions with stem cells (clusters of undifferentiated cells). Given the frequency of allergic skin pathologies, we would like to emphasize the finding that close, planar junctions were frequently observed between TCs and mast cells. In conclusion, based on TC distribution and intercellular connections, our results suggested that TCs might be involved in skin homeostasis, skin remodelling, skin regeneration and skin repair.

Apoptosis in seborrheic keratoses: an open door to a new dermoscopic score.

The aetiology of seborrheic keratoses (SK), the most common benign epithelial tumours, and any relationship with malignancy are not yet known. As a protective anti-cancer mechanism, apoptosis reflects cellular loss as a reaction to proliferative activity. The objective of this study was to quantify apoptosis in different SK types (acanthotic, hyperkeratotic, reticulated, irritated and clonal) and correlate the dermoscopic picture with apoptosis rate. After a qualitative and quantitative analysis of dermoscopic images, we defined a new quantitative dermoscopic score (C3V2F, crypts, millia cysts, colours, hairpin vessels, irregular vessels, fissures) from 0 to 22, which enabled us to establish cut-offs correlating with apoptosis rates. All five SK forms were associated with lower apoptosis rates compared with normal skin. A C3V2F score >10 and greater number of crypts and colours reflected a higher apoptosis rate, which implies a benign character of evolution. In contrast, the presence of irregular vessels on more than 50% of the lesion surface implied a lower rate of apoptosis and probably associated with a risk of malignant transformation. On the basis of dermoscopic information, we used multiple regression to establish a model for estimating the rate of apoptosis with a 0.7 prediction interval (approximately 1S.D.). The new C3V2F score could be valuable for the clinical evaluation of possible SK prognosis and decisions regarding excision.

Hypocomplementemic Urticarial Vasculitis Associated With Hashimoto's Thyroiditis and Hepatitis B Virus Infection: A Case Report.

Urticarial vasculitis (UV) is an uncommon condition characterized by recurrent episodes of urticarial lesions and angioedema and the pathological features of leukocytoclastic vasculitis. UV divides into two subgroups based on the level of serum complement. Usually, patients with hypocomplementemia experience internal organ involvement and an unfavorable prognosis. We report the case of a 33-year-old woman with a history of hepatitis B infection and autoimmune thyroiditis who developed hypocomplementemic urticarial vasculitis with recurrent angioedema and arthralgia. Complete remission was achieved using dapsone in monotherapy. We suggest dapsone as a potential treatment of choice for hypocomplementemic urticarial vasculitis. This clinical case emphasizes the need for urticarial vasculitis treatment guidelines.

A Conservative Combined Laser Cryoimmunotherapy Treatment vs. Surgical Excision for Basal Cell Carcinoma.

Surgical excision is the standard treatment for basal cell carcinoma (BCC), but it can be challenging in elderly patients and patients with comorbidities. The non-surgical guidelines procedures are usually regarded as monotherapy options. This quasi-experimental, non-randomized, comparative effectiveness study aims to evaluate the efficacy of a combined, conservative, non-surgical BCC treatment, and compare it to standard surgical excision. Patients with primary, non-ulcerated, histopathologically confirmed BCCs were divided into a conservative treatment (129 patients) and a standard surgery subgroup (50 patients). The conservative treatment consisted of ablative CO2 laser, cryosurgery, topical occlusive 5-fluorouracil, and imiquimod. The follow-up examinations were performed 3 months after remission, then every 3 to 6 months, and were extended with telephone follow-ups. Cosmetic-self assessment was recorded during a telephone follow-up. Subjects from the conservative subgroup presented a clearance rate of 99.11%, and a recurrence rate of 0.98%. No recurrences were recorded in the surgical group, nor during the telephone follow-up. There were no differences regarding adverse events (p > 0.05). A superior self-assessment cosmetic outcome was obtained using the conservative method (p < 0.001). This conservative treatment is suitable for elders and patients with comorbidities, is not inferior to surgery in terms of clearance, relapses, or local adverse events, and displays superior cosmetic outcomes.

Soluble Factors and Receptors Involved in Skin Innate Immunity-What Do We Know So Far?

The pattern recognition receptors, complement system, inflammasomes, antimicrobial peptides, and cytokines are innate immunity soluble factors. They sense, either directly or indirectly, the potential threats and produce inflammation and cellular death. High interest in their modulation has emerged lately, acknowledging they are involved in many cutaneous inflammatory, infectious, and neoplastic disorders. We extensively reviewed the implication of soluble factors in skin innate immunity. Furthermore, we showed which molecules target these factors, how these molecules work, and how they have been used in dermatological practice. Cytokine inhibitors have paved the way to a new era in treating moderate to severe psoriasis and atopic dermatitis.

Histopathological diagnosis of cutaneous vascular sarcomas.

Cutaneous sarcomas represent a heterogeneous group of mesenchymal lesions. This study investigates the histopathological and immunohistochemical features in different cases of angiosarcoma and Kaposi's sarcoma (cutaneous vascular sarcomas), which are representative for medical practice. The clinical-histopathological-immunohistochemical correlations render possible the differential diagnosis and a proper treatment can be applied to obtain a favorable prognosis.

Statistical correlations between peripheral blood lymphocyte subpopulations and tumor inflammatory infiltrate in stage I of skin melanoma.

The article presents statistical correlations of immune cell parameters investigated in patients diagnosed with skin melanoma stage I. Recent data indicate a suppressed immune response, probably sustained by immune-regulating molecules expressed or shed from the tumor. These molecules block an efficient immune response and thus the tumor develops. All the molecules that are part of the tumor escape mechanisms can be targets for immune-mediated anti-tumor agents. We try to find the significance of some immunohistochemical markers (UCHL1, CD4, CD8) in tumoral inflammatory infiltrate and to establish the statistical correlations between molecular markers and tumor grade and stage. The studied parameters were: CD3+, CD4+, CD8+, CD56+16+ and CD19+. The statistical results were performed with SPSS v. 15.0. We demonstrate that a CD4+ on-going immune response is elicited in the investigated patients. We found a possible compensatory mechanism between T-lymphocytes and NK-cells and also between the antibodies generating cells and the natural cytotoxic cells. We are confident that these statistical correlations between clinical, immunological and immunohistochemical data can be useful in the disease management and personalized immune-therapy.

Dermatoscopy of an invasive melanoma on the upper lip shows possible association with Laugier-Hunziker syndrome.

We report mucosal melanoma of the upper lip in a patient affected by the Laugier-Hunziker disease. Using dermatoscopy, two distinct parts were identified in the same mucosal area: nodular (malignant) and macular (benign). A complete surgical excision was performed and the patient has been free of disease for 16 months.

Biological therapies in psoriasis - revisited.

Psoriasis is a chronic, immune mediated disorder affecting approximately 2% of the population. Even in our days, patients with psoriasis are confronted with stigmatization and social rejection. As a result, their quality of life is significantly impaired. Biological therapies have revolutionized the treatment of moderate to severe psoriasis. The aim of this paper is to look over the most important biological therapies available for the management of plaque-type psoriasis.

Cutaneous metastases carcinoma. Case report and pathological considerations.

Diagnostic of cutaneous metastases is relatively rare; this is important because sometimes may be the first manifestation of an undiscovered internal malignancy. Usually dissemination may take place through the lymphatics or the blood stream. The case of a patient, female, which has on the inferior 1/3 part of the abdominal wall skin a multinodular tumor mass, which evolves from about three months ago and accompanying by lymphoedema of the legs, is presented.

Apoptosis in cutaneous melanomas.

Cutaneous melanomas has become one of the most discussed and studied tumor because its particular immunologic development but also its increasing rate worldwide in the last decades. Even thought many patients are diagnosed at an early stage, the death rate continues to rise due to the increasing incidence of more advanced lesions. The aim of this study is to detect apoptosis in 30 cases of cutaneous melanomas using the in situ end-labeling technique (TUNEL) who quantify apoptotic cell death at single cell level and tissues.