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Background: Line‐field confocal optical coherence tomography (LC‐OCT) is an emerging diagnostic tool with imaging depth reaching ~400 μm and a novel three‐dimensional (3D) cube providing cellular resolution. As far as we are aware, there are only a limited number of papers that have reported diagnostic criteria for melanocytic lesions using this technique, and none of them have been multicentric. Objectives: Our aim was to establish the diagnostic criteria for melanocytic lesions using LC‐OCT and identify the most significant architectural and cytologic features associated with malignancy. Methods: A retrospective evaluation of 80 consecutive melanocytic lesions from a prospective multicentric data set spanning three European centres was conducted. We excluded facial, acral and mucosal lesions from the study. Dermoscopic and LC‐OCT images were evaluated by a consensus of four observers. Multivariate logistic regression with backward elimination was employed. Results: The main melanoma diagnostic criteria include detecting >10 pagetoid cells in 3D acquisition, irregular 3D epidermal architecture, disrupted dermoepidermal junction (DEJ) and clefting. Significant risk factors were irregular 3D epidermal architecture, >10 pagetoid cells, dendritic cells at DEJ without underlying inflammation. Novel malignancy criteria in vertical view were DEJ disruption and clefting around atypical melanocyte nests. Exclusive melanoma features were epidermal nests, epidermal consumption, dense dermal nests with atypia. Protective features in the absence of any malignancy indicators were DEJ ring pattern, cobblestone, elongated rete ridges (vertical), well‐defined DEJ and wave pattern (vertical). Conclusions: A series of diagnostic criteria for the identification of melanocytic lesions with LC‐OCT have been established. Validation of these criteria in clinical practice through future studies is essential to further establish their utility. [ABSTRACT FROM AUTHOR]

Background: Early melanoma detection is the main factor affecting prognosis and survival. For that reason, non‐invasive technologies have been developed to provide a more accurate diagnosis. Recently, line‐field confocal optical coherence tomography (LC‐OCT) was developed to provide an in vivo, imaging device, with deep penetration and cellular resolution in three dimensions. Combining the advantages of conventional OCT and reflectance confocal microscopy, this tool seems to be particularly suitable for melanocytic lesions. Objectives: The objective of this study was to identify and describe the correlation between specific dermoscopic criteria and LC‐OCT features in three dimensions associated with melanocytic lesions. Methods: Dermoscopic and LC‐OCT images of 126 melanocytic lesions were acquired in three different centres. The following dermoscopic criteria have been considered: reticular pattern, dots and globules, structureless areas, blue‐whitish veil, regression structures, negative network, homogeneous pattern, streaks and blotches. Results: 69 (55%) benign and 57 (45%) malignant lesions were analysed. A regular reticular pattern was found associated in the 75% of the cases with the presence of elongated rete ridges with pigmented cells along the basal layer, while atypical reticular pattern showed an irregular organization of rete ridges with melanocytic hyperplasia, broadened and fused ridges and elongated nests. Both typical and atypical dots and globules were found associated with melanocytic nests in the dermis or at the dermoepidermal junction (DEJ), as well as with keratin cysts/pseudocysts. Grey globules corresponded to the presence of melanin‐containing dermal inflammatory cells (melanophages) within the papillae. Structureless brown/black areas correlated with alterations of the DEJ. We observed the same DEJ alterations, but with the presence of dermal melanophages, in 36% of the cases of blue/white/grey structureless areas. A description of each LC‐OCT/dermoscopy correlation was made. Conclusions: LC‐OCT permitted for the first time to perform an in vivo, 3D correlation between dermoscopic criteria and pathological‐like features of melanocytic lesions. [ABSTRACT FROM AUTHOR]

This article discusses the use of line-field confocal optical coherence tomography (LC-OCT) as a new tool for assessing cutaneous mycosis fungoides (MF), the most common variant of cutaneous T-cell lymphoma. The early diagnosis of MF is challenging and often results in a therapeutic delay. LC-OCT allows for the visualization of various features of MF, such as epidermal architectural disarray, atypical lymphocytes, and dermal changes. The study demonstrates that LC-OCT has a high correlation with histology and can provide valuable information for the diagnosis and follow-up of MF. [Extracted from the article]

Background Objective Method Results Conclusion There is currently no staging system for cutaneous squamous cell carcinoma (cSCC) that is adapted to decision‐making and universally used. Experts have unconscious ability to simplify the heterogeneity of clinical situations into a few relevant groups to drive their therapeutic decisions. Therefore, we have used unsupervised clustering of real cases by experts to generate an operational classification of cSCCs, an approach that was successful for basal cell carcinomas.To generate a consensual and operational classification of cSCCs.Unsupervised independent clustering of 248 cases of cSCCs considered difficult‐to‐treat. Eighteen international experts from different specialties classified these cases into what they considered homogeneous clusters useful for management, each with freedom regarding clustering criteria. Convergences and divergences between clustering were analysed using a similarity matrix, the K‐mean approach and the average silhouette method. Mathematical modelling was used to look for the best consensual clustering. The operability of the derived classification was validated on 23 new practitioners.Despite the high heterogeneity of the clinical cases, a mathematical consensus was observed. It was best represented by a partition into five clusters, which appeared a posteriori to describe different clinical scenarios. Applicability of this classification was shown by a good concordance (94%) in the allocation of cases between the new practitioners and the 18 experts. An additional group of easy‐to‐treat cSCC was included, resulting in a six‐group final classification: easy‐to‐treat/complex to treat due to tumour and/or patient characteristics/multiple/locally advanced/regional disease/visceral metastases.Given the methodology based on the convergence of unguided intuitive clustering of cases by experts, this new classification is relevant for clinical practice. It does not compete with staging systems, but they may complement each other, whether the objective is to select the best therapeutic approach in tumour boards or to design homogeneous groups for trials. [ABSTRACT FROM AUTHOR]

Background and Objectives: Central sensitization (CS) is believed to play a role in many chronic pain conditions. Direct non-invasive recording from single nociceptive neurons is not feasible in humans, complicating CS establishment. This review discusses how secondary hyperalgesia (SHA), considered a manifestation of CS, affects physiological measures in healthy individuals and if these measures could indicate CS. It addresses controversies about heat sensitivity changes, the role of tactile afferents in mechanical hypersensitivity and detecting SHA through electrical stimuli. Additionally, it reviews the potential of neurophysiological measures to indicate CS presence., Databases and Data Treatment: Four databases, PubMed, ScienceDirect, Scopus and Cochrane Library, were searched using terms linked to 'hyperalgesia'. The search was limited to research articles in English conducted in humans until 2023., Results: Evidence for heat hyperalgesia in the SHA area is sparse and seems to depend on the experimental method used. Minimal or no involvement of tactile afferents in SHA was found. At the spinal level, the threshold of the nociceptive withdrawal reflex (RIII) is consistently reduced during experimentally induced SHA. The RIII area and the spinal somatosensory potential (N13-SEP) amplitude are modulated only with long-lasting nociceptive input. At the brain level, pinprick-evoked potentials within the SHA area are increased., Conclusions: Mechanical pinprick hyperalgesia is the most reliable behavioural readout for SHA, while the RIII threshold is the most sensitive neurophysiological readout. Due to scarce data on reliability, sensitivity and specificity, none of the revised neurophysiological methods is currently suitable for CS identification at the individual level., Significance: Gathering evidence for CS in humans is a crucial research focus, especially with the increasing interest in concepts such as 'central sensitization-like pain' or 'nociplastic pain'. This review clarifies which readouts, among the different behavioural and neurophysiological proxies tested in experimental settings, can be used to infer the presence of CS in humans., (© 2024 The Author(s). European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation ‐ EFIC ®.)

Extramammary Paget disease (EMPD) is an uncommon adenocarcinoma of apocrine gland-rich areas, presenting significant diagnostic challenges due to its nonspecific clinical appearance and frequent misidentification as benign, inflammatory skin conditions. Traditional diagnostic methods such as biopsy are invasive and uncomfortable, often required repeatedly due to high recurrence rates. Dermoscopy and non-invasive imaging techniques have been used but provide limited diagnostic accuracy due to their constraints in depth penetration and resolution. Recent advancements in imaging technologies, such as line-field confocal optical coherence tomography (LC-OCT), show promise in enhancing diagnostic precision while minimizing invasive procedures. LC-OCT merges high-resolution imaging with deep penetration capabilities, capturing detailed horizontal and vertical skin images akin to histopathology. This study evaluated the diagnostic performance of LC-OCT in detecting EMPD and its recurrence in 17 clinically suspicious anogenital regions, belonging to six patients. Data were collected prospectively at the patient's bedside by an LC-OCT expert with poor training for EMPD, and, then, reviewed retrospectively by an independent LC-OCT expert with adequate training for EMPD and no concerns about time. The prospective examination yielded 64.7% accuracy (11 true results out of 17 total cases), 71.4% sensitivity (10 true positives out of 14 actual positives), and 33.3% specificity (1 true negative out of 3 actual negatives). The retrospective analysis achieved 94.1% accuracy (16 true results out of 17 total cases), 100% sensitivity (14 true positives out of 14 actual positives), and 66.7% specificity (2 true positives out of 3 actual positives), with the only false positive case being a difficult-to-diagnose concomitant presentation of a lichen sclerosus et atrophicus. Despite the need for specialized training, our results suggest that LC-OCT represents a valuable tool for accurately identifying EMPD and improving its management by reducing unnecessary biopsies. Further studies are needed to standardize its clinical application.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases 1,2 . The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder 3 . Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV 4 . Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit 5,6 . In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation 7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8 + T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: The autoimmune lymphoproliferative syndrome (ALPS) is a noninfectious and nonmalignant lymphoproliferative disease frequently associated with autoimmune cytopenia resulting from defective FAS signaling. We previously described germline monoallelic FAS (TNFRSF6) haploinsufficient mutations associated with somatic events, such as loss of heterozygosity on the second allele of FAS, as a cause of ALPS-FAS. These somatic events were identified by sequencing FAS in DNA from double-negative (DN) T cells, the pathognomonic T-cell subset in ALPS, in which the somatic events accumulated., Objective: We sought to identify whether a somatic event affecting the FAS-associated death domain (FADD) gene could be related to the disease onset in 4 unrelated patients with ALPS carrying a germline monoallelic mutation of the FADD protein inherited from a healthy parent., Methods: We sequenced FADD and performed array-based comparative genomic hybridization using DNA from sorted CD4 + or DN T cells., Results: We found homozygous FADD mutations in the DN T cells from all 4 patients, which resulted from uniparental disomy. FADD deficiency caused by germline heterozygous FADD mutations associated with a somatic loss of heterozygosity was a phenocopy of ALPS-FAS without the more complex symptoms reported in patients with germline biallelic FADD mutations., Conclusions: The association of germline and somatic events affecting the FADD gene is a new genetic cause of ALPS., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)