Expert Agreement on the Presence and Spatial Localization of Melanocytic Features in Dermoscopy.

Dermoscopy aids in melanoma detection; however, agreement on dermoscopic features, including those of high clinical relevance, remains poor. In this study, we attempted to evaluate agreement among experts on exemplar images not only for the presence of melanocytic-specific features but also for spatial localization. This was a cross-sectional, multicenter, observational study. Dermoscopy images exhibiting at least 1 of 31 melanocytic-specific features were submitted by 25 world experts as exemplars. Using a web-based platform that allows for image markup of specific contrast-defined regions (superpixels), 20 expert readers annotated 248 dermoscopic images in collections of 62 images. Each collection was reviewed by five independent readers. A total of 4,507 feature observations were performed. Good-to-excellent agreement was found for 14 of 31 features (45.2%), with eight achieving excellent agreement (Gwet's AC >0.75) and seven of them being melanoma-specific features. These features were peppering/granularity (0.91), shiny white streaks (0.89), typical pigment network (0.83), blotch irregular (0.82), negative network (0.81), irregular globules (0.78), dotted vessels (0.77), and blue-whitish veil (0.76). By utilizing an exemplar dataset, a good-to-excellent agreement was found for 14 features that have previously been shown useful in discriminating nevi from melanoma. All images are public (www.isic-archive.com) and can be used for education, scientific communication, and machine learning experiments.

Melanoma in children: A systematic review and individual patient meta-analysis.

The current evidence on paediatric melanoma is heterogeneous, especially regarding the prognosis of different histological subtypes. We sought to systematically review the evidence on paediatric melanoma, highlighting the major sources of heterogeneity and focusing on available data on single patients. A systematic search was performed from 1948 to 25 January 2021. Only studies reporting at least one case of cutaneous melanoma in patients aged ≤18 years were included. Unknown primary and uncertain malignant melanomas were excluded. Three couples of authors independently performed title/abstract screening and two different authors reviewed all the relevant full texts. The selected articles were manually cross-checked for overlapping data for qualitative synthesis. Subsequently data on single patients were extracted to perform a patient-level meta-analysis. PROSPERO registration number: CRD42021233248. The main outcomes were melanoma-specific survival (MSS) and progression-free survival (PFS) outcomes. Separate analyses were done of cases with complete information on histologic subtype, focusing on superficial spreading (SSM), nodular (NM) and spitzoid melanomas, as well as of those classified as de-novo (DNM) and acquired or congenital nevus-associated melanomas (NAM). The qualitative synthesis covered 266 studies; however, data on single patients were available from 213 studies including 1002 patients. Among histologic subtypes, NM had a lower MSS than both SSM and spitzoid melanoma, and a lower PFS than SSM. Spitzoid melanoma had a significantly higher progression risk than SSM and trended toward lower mortality. Focusing on nevus-associated status, DNM demonstrated better MSS after progression than congenital NAM, and no differences were highlighted in PFS. Our findings describe the existence of different biological patterns in paediatric melanoma. Specifically, spitzoid melanomas demonstrated intermediate behaviour between SSM and NM and showed a high risk of nodal progression but low mortality. This raises the question of whether spitzoid lesions are being over-diagnosed as melanoma in childhood.

Indications for Digital Monitoring of Patients With Multiple Nevi: Recommendations from the International Dermoscopy Society.

Introduction: In patients with multiple nevi, sequential imaging using total body skin photography (TBSP) coupled with digital dermoscopy (DD) documentation reduces unnecessary excisions and improves the early detection of melanoma. Correct patient selection is essential for optimizing the efficacy of this diagnostic approach. Objectives: The purpose of the study was to identify, via expert consensus, the best indications for TBSP and DD follow-up. Methods: This study was performed on behalf of the International Dermoscopy Society (IDS). We attained consensus by using an e-Delphi methodology. The panel of participants included international experts in dermoscopy. In each Delphi round, experts were asked to select from a list of indications for TBSP and DD. Results: Expert consensus was attained after 3 rounds of Delphi. Participants considered a total nevus count of 60 or more nevi or the presence of a CDKN2A mutation sufficient to refer the patient for digital monitoring. Patients with more than 40 nevi were only considered an indication in case of personal history of melanoma or red hair and/or a MC1R mutation or history of organ transplantation. Conclusions: Our recommendations support clinicians in choosing appropriate follow-up regimens for patients with multiple nevi and in applying the time-consuming procedure of sequential imaging more efficiently. Further studies and real-life data are needed to confirm the usefulness of this list of indications in clinical practice.

Development of Two-Layer Hybrid Scaffolds Based on Oxidized Polyvinyl Alcohol and Bioactivated Chitosan Sponges for Tissue Engineering Purposes.

Oxidized polyvinyl alcohol (OxPVA) is a new polymer for the fabrication of nerve conduits (NCs). Looking for OxPVA device optimization and coupling it with a natural sheath may boost bioactivity. Thus, OxPVA/chitosan sponges (ChS) as hybrid scaffolds were investigated to predict in the vivo behaviour of two-layered NCs. To encourage interaction with cells, ChS were functionalized with the self-assembling-peptide (SAP) EAK, without/with the laminin-derived sequences -IKVAV/-YIGSR. Thus, ChS and the hybrid scaffolds were characterized for mechanical properties, ultrastructure (Scanning Electron Microscopy, SEM), bioactivity, and biocompatibility. Regarding mechanical analysis, the peptide-free ChS showed the highest values of compressive modulus and maximum stress. However, among +EAK groups, ChS+EAK showed a significantly higher maximum stress than that found for ChS+EAK-IKVAV and ChS+EAK-YIGSR. Considering ultrastructure, microporous interconnections were tighter in both the OxPVA/ChS and +EAK groups than in the others; all the scaffolds induced SH-SY5Y cells' adhesion/proliferation, with significant differences from day 7 and a higher total cell number for OxPVA/ChS+EAK scaffolds, in accordance with SEM. The scaffolds elicited only a slight inflammation after 14 days of subcutaneous implantation in Balb/c mice, proving biocompatibility. ChS porosity, EAK 3D features and neuro-friendly attitude (shared with IKVAV/YIGSR motifs) may confer to OxPVA certain bioactivity, laying the basis for future appealing NCs.

Dermatoscopy of nodular/plaque-type primary cutaneous T- and B-cell lymphomas: A retrospective comparative study with pseudolymphomas and tumoral/inflammatory mimickers by the International Dermoscopy Society.

BACKGROUND: Limited data on dermatoscopy of nodular/plaque-type T-/B-cell primary cutaneous lymphomas (PCLs) is available. OBJECTIVE: To describe dermatoscopic features of nodular/plaque-type PCLs, comparing them with those of clinical mimickers (pseudolymphomas, tumors, and inflammatory lesions) and investigating possible differences according to histologic subtypes. METHODS: Participants were invited to join this retrospective, multicenter case-control study by submitting histologically/immunohistochemically confirmed instances of nodular/plaque-type PCLs and controls. Standardized assessments of the dermatoscopic images and comparative analyses were performed. RESULTS: A total of 261 lesions were included (121 PCLs and 140 controls). Orange structureless areas were the strongest PCL dermatoscopic predictor on multivariate analysis compared with tumors and noninfiltrative inflammatory dermatoses. On the other hand, a positive association was found between PCLs and either unfocused linear vessels with branches or focal white structureless areas compared with infiltrative inflammatory dermatoses, whereas white lines were predictive of PCLs over pseudolymphomas. Differences in the vascular pattern were also seen between B- and T-cell PCLs and among B-cell PCL subtypes. LIMITATIONS: Retrospective design and the lack of a dermatoscopic-pathologic correlation analysis. CONCLUSION: Nodular/plaque-type PCLs display dermatoscopic clues, which may partially vary according to histologic subtype and whose diagnostic relevance depends on the considered clinical differential diagnoses.

Poikiloderma With Neutropenia and Mastocytosis: A Case Report and a Review of Dermatological Signs.

Poikiloderma with neutropenia (PN) is a very rare genetic disorder mainly characterized by poikiloderma and congenital neutropenia, which explains the recurrence of respiratory infections and risk of developing bronchiectasis. Patients are also prone to develop hematological and skin cancers. Here, we present the case of a patient, the only child of apparently unrelated Serbian parents, affected by PN resulting from the homozygous mutation NM_024598.3:c.243G>A (p.Trp81Ter) of USB1; early onset of poikiloderma (1 year of age) was associated with cutaneous mastocytosis. We also provide a review of the literature on this uncommon condition with a focus on dermatological findings.

Cutaneous Findings in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a complex autosomal dominant disorder associated with germline mutations in the NF1 tumor suppressor gene. NF1 belongs to a class of congenital anomaly syndromes called RASopathies, a group of rare genetic conditions caused by mutations in the Ras/mitogen-activated protein kinase pathway. Generally, NF1 patients present with dermatologic manifestations. In this review the main features of café-au-lait macules, freckling, neurofibromas, juvenile xanthogranuloma, nevus anemicus and other cutaneous findings will be discussed.

Impact of Magnetic Stimulation on Periodontal Ligament Stem Cells.

The aim of this study was to evaluate the effect of a time-dependent magnetic field on the biological performance of periodontal ligament stem cells (PDLSCs). A Western blot analysis and Alamar Blue assay were performed to investigate the proliferative capacity of magnetically stimulated PDLSCs (PDLSCs MAG) through the study of the MAPK cascade (p-ERK1/2). The observation of ALP levels allowed the evaluation of the effect of the magnetic field on osteogenic differentiation. Metabolomics data, such as oxygen consumption rate (OCR), extracellular acidification rate (ECAR) and ATP production provided an overview of the PDLSCs MAG metabolic state. Moreover, the mitochondrial state was investigated through confocal laser scanning microscopy. Results showed a good viability for PDLSCs MAG. Magnetic stimulation can activate the ERK phosphorylation more than the FGF factor alone by promoting a better cell proliferation. Osteogenic differentiation was more effectively induced by magnetic stimulation. The metabolic panel indicated significant changes in the mitochondrial cellular respiration of PDLSCs MAG. The results suggested that periodontal ligament stem cells (PDLSCs) can respond to biophysical stimuli such as a time-dependent magnetic field, which is able to induce changes in cell proliferation and differentiation. Moreover, the magnetic stimulation also produced an effect on the cell metabolic profile. Therefore, the current study demonstrated that a time-dependent magnetic stimulation may improve the regenerative properties of PDLSCs.

Breast Cancer Cell Cultures on Electrospun Poly(ε-Caprolactone) as a Potential Tool for Preclinical Studies on Anticancer Treatments.

During anticancer drug development, most compounds selected by in vitro screening are ineffective in in vivo studies and clinical trials due to the unreliability of two-dimensional (2D) in vitro cultures that are unable to mimic the cancer microenvironment. Herein, HCC1954 cell cultures on electrospun polycaprolactone (PCL) were characterized by morphological analysis, cell viability assays, histochemical staining, immunofluorescence, and RT-PCR. Our data showed that electrospun PCL allows the in vitro formation of cultures characterized by mucopolysaccharide production and increased cancer stem cell population. Moreover, PCL-based cultures were less sensitive to doxorubicin and electroporation/bleomycin than those grown on polystyrene plates. Collectively, our data indicate that PCL-based cultures may be promising tools for preclinical studies.

NMR Structure of the FIV gp36 C-Terminal Heptad Repeat and Membrane-Proximal External Region.

Feline immunodeficiency virus (FIV), a lentivirus causing an immunodeficiency syndrome in cats, represents a relevant model of pre-screening therapies for human immunodeficiency virus (HIV). The envelope glycoproteins gp36 in FIV and gp41 in HIV mediate the fusion of the virus with the host cell membrane. They have a common structural framework in the C-terminal region that includes a Trp-rich membrane-proximal external region (MPER) and a C-terminal heptad repeat (CHR). MPER is essential for the correct positioning of gp36 on the lipid membrane, whereas CHR is essential for the stabilization of the low-energy six-helical bundle (6HB) that is necessary for the fusion of the virus envelope with the cell membrane. Conformational data for gp36 are missing, and several aspects of the MPER structure of different lentiviruses are still debated. In the present work, we report the structural investigation of a gp36 construct that includes the MPER and part of the CHR domain (737-786gp36 CHR-MPER). Using 2D and 3D homo and heteronuclear NMR spectra on 15N and 13C double-labelled samples, we solved the NMR structure in micelles composed of dodecyl phosphocholine (DPC) and sodium dodecyl sulfate (SDS) 90/10 M: M. The structure of 737-786gp36 CHR-MPER is characterized by a helix-turn-helix motif, with a regular α-helix and a moderately flexible 310 helix, characterizing the CHR and the MPER domains, respectively. The two helices are linked by a flexible loop regulating their orientation at a ~43° angle. We investigated the positioning of 737-786gp36 CHR-MPER on the lipid membrane using spin label-enhanced NMR and ESR spectroscopies. On a different scale, using confocal microscopy imaging, we studied the effect of 737-786gp36 CHR-MPER on 1,2-dioleoyl-sn-glycero-3-phosphocholine/1,2-dioleoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DOPC/DOPG) multilamellar vesicles (MLVs). This effect results in membrane budding and tubulation that is reminiscent of a membrane-plasticizing role that is typical of MPER domains during the event in which the virus envelope merges with the host cell membrane.

Pattern of response of unresectable and metastatic cutaneous squamous cell carcinoma to programmed death-1 inhibitors: A review of the literature.

Cutaneous squamous cell carcinoma (cSCC) is the second most frequent nonmelanoma skin cancer (NMSC). The majority of in situ cSCC [cSCC (Tis)] can be cured surgically, while local advanced and metastatic ones require other treatments, but there are no therapies approved by U.S. Food and Drug Administration (FDA). Available treatments for these stages included radiotherapy, chemotherapy as cisplatin, but responses to these treatments are usually of short duration. Programmed death-1 (PD-1) inhibitors (pembrolizumab, nivolumab, and cemiplimab) are an innovative immunologic treatment that now has been shown to be useful for the treatment of advanced cSCC. Nowadays, data about the response rate with the use of PD-1 inhibitors in cSCC are still few and, especially, the duration of the response after the start of treatment is short. Moreover, the number of cases is too small to express the beneficial effects of these treatments, although most data reported in the literature show quite good response rates. This review focused on some of the studies and associated results through an interesting research on search engines of all the cases about these systemic drugs, analyzing effects and side effects, and the research has been conducted considering published cases since March 2016 to October 2019.

EAK Hydrogels Cross-Linked by Disulfide Bonds: Cys Number and Position Are Matched to Performances.

Hydrogels produced by self-assembling peptides are intrinsically biocompatible and thus appropriate for many biomedical purposes. Their application field may be even made wider by reducing the softness and improving the hydrogel mechanical properties through cross-linking treatments. To this aim, modifications of EAK16-II sequence by including Cys residues in its sequence were here investigated in order to obtain hydrogels cross-linkable through a disulfide bridge. Two sequences, namely, C-EAK and C-EAK-C, that contain Cys residues at the N-terminus or at both ends were characterized. Fiber-forming abilities and biological and dynamic mechanical properties were explored before and after the oxidative treatment. In particular, the oxidized version of C-EAK presents a good cell viability and sustains osteoblast proliferation. Furthermore, molecular dynamics (MD) simulations on monomeric and assembled forms of the peptides were performed. MD simulations explained how a specific Cys functionalization was better than the other one. In particular, the results suggested that EAK16-II functionalization with a single Cys residue, instead of two, together with biocompatible cross-linking may be considered an intriguing strategy to obtain a support with better dynamic mechanical properties and biological performances.