A slow-cycling LGR5 tumour population mediates basal cell carcinoma relapse after therapy.

Basal cell carcinoma (BCC) is the most frequent cancer in humans and results from constitutive activation of the Hedgehog pathway1. Several Smoothened inhibitors are used to treat Hedgehog-mediated malignancies, including BCC and medulloblastoma2. Vismodegib, a Smoothened inhibitor, leads to BCC shrinkage in the majority of patients with BCC3, but the mechanism by which it mediates BCC regression is unknown. Here we used two genetically engineered mouse models of BCC4 to investigate the mechanisms by which inhibition of Smoothened mediates tumour regression. We found that vismodegib mediates BCC regression by inhibiting a hair follicle-like fate and promoting the differentiation of tumour cells. However, a small population of tumour cells persists and is responsible for tumour relapse following treatment discontinuation, mimicking the situation found in humans5. In both mouse and human BCC, this persisting, slow-cycling tumour population expresses LGR5 and is characterized by active Wnt signalling. Combining Lgr5 lineage ablation or inhibition of Wnt signalling with vismodegib treatment leads to eradication of BCC. Our results show that vismodegib induces tumour regression by promoting tumour differentiation, and demonstrates that the synergy between Wnt and Smoothened inhibitors is a clinically relevant strategy for overcoming tumour relapse in BCC.

Belgian Patients of the European Registry for Hidradenitis Suppurativa (ERHS-Be): Data, Scores, and Phenotypes since 2015.

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease, characterized by painful and recurrent lesions in apocrine gland-bearing skin areas. It is a heterogeneous disease, which makes assessment and data collection difficult. Questionnaires with detailed items, such as the Belgian European Registry for Hidradenitis Suppurativa (ERHS-Be), are useful to study HS and its associated comorbidities. The aim of this registry was to uncover new factors associated with HS and understand HS patients' clinical profiles and efficacy of treatments. MATERIAL AND METHODS: The ERHS-Be registry is based on questionnaires, with sections for sociodemographic data, medical and HS history, clinical examination, and treatment plan. It allows identification of different clinical phenotypes and automatic calculation of severity scores. RESULTS: At present, 606 patients are included in the ERHS-Be (67% women, 33% men). The mean age at the first visit is 38.5 years. Tobacco use is present in 72.6% of patients. A family history of HS is noted in 42% of patients. Comorbidities are documented in this cohort: depression is present in 43.8% of patients, arthritis in 27.8%, obesity in 31.5%, hypertension in 10.6%, diabetes mellitus in 6.4%, and dyslipidemia in 12.4%. Moreover, 7.7% of patients suffer from IBD and 27.4% have a pilonidal sinus. History of severe acne is found in 32.1% of patients and psoriasis in 9.3%. Thirteen percent of women in our cohort suffer from polycystic ovarian syndrome. Severity of disease is quantified in 533 patients: for instance, Hurley I, II, and III scores proportions are, respectively, 32.3%, 52.7%, and 15%, while the mean IHS4 score is 5.2. This registry also enables determination of relative phenotype proportions in our cohort, according to different classifications. CONCLUSION: The ERHS-Be questionnaires allow systematic and larger data collection, including detailed comorbidities, phenotypes, and severity of disease. Analysis of this large database will contribute to a better understanding and management of HS, at a time where new therapeutic options are becoming available.

Dermoscopy of atypical pigmented lesions of the face: Variation according to facial areas.

Atypical pigmented facial lesions (aPFLs)-including lentigo maligna (LM) and lentigo maligna melanoma (LMM), solar lentigo (SL), pigmented actinic keratosis (PAK), atypical nevi (AN), seborrheic keratosis (SK) and lichen planus-like keratosis (LPLK)-can exhibit clinical and dermoscopic overlapping features. We aimed to investigate if and how 14 dermoscopic features suggestive for the aforementioned aPFLs vary according to six facial sites among 1197 aPFLs cases (excised to rule out malignancy) along with lesion and patients' metadata. According to distribution and association analysis, aPFLs on the forehead of a male patient aged > 69 years displaying the obliterated follicular openings pattern, appear to be more at risk of malignancy. Of converse, aPFLs of the orbital/cheek/nose area with evident and regular follicular openings with diameter < 10 mm in a female aged below 68 are probably benign. The obliterated follicular openings, keratin plugs, evident and regular follicular openings and target-like pattern features differed significantly among six facial areas in all aPFLs cases. Lesion of the nose may show both features suggestive of malignancy and benignity (e.g. many SL and PAK may display target-like pattern and some LM/LMM cases display keratin plugs and evident and follicular openings), making these features less specific.

Treatment of Acne with Isotretinoin Should Be Avoided in Patients with Hidradenitis Suppurativa "Conglobata Phenotype".

BACKGROUND: Acne conglobata (AC) and nodulocystic acne have long been confused clinically, despite the presentation and the response to treatment being different. AC and hidradenitis suppurativa (HS) resemble each other; a subtype of HS called "conglobata phenotype" has recently been reported in a large Dutch cohort. Acne vulgaris and HS are often associated. Isotretinoin is typically ineffective in treating HS and may even aggravate it, but it is often indispensable in treating acne vulgaris. OBJECTIVE: The aim of the study was to assess whether isotretinoin may be used safely in adults with both HS and acne vulgaris and when it might be contraindicated. MATERIALS AND METHODS: Belgian HS patients from the European Registry for Hidradenitis Suppurativa Registry (ERHS) reporting a history of severe acne of the face and/or the back, and who have ever used isotretinoin for their acne, were all selected. Patients whose acne worsened on isotretinoin were compared to patients whose acne did not worsen (improvement or no change). RESULTS: Among the 82 selected patients, 10 (12.2%) report that their acne was aggravated while taking isotretinoin, while 72 (87.8%) report that their acne was not aggravated on isotretinoin. Of the 10 HS patients whose acne worsened with isotretinoin, 9 (90%) were men (p = 0.04) and 8 (80%) were HS "conglobata phenotype" (p < 0.001). In contrast, 47 (65.3%) of the 72 patients whose acne did not worsen on isotretinoin belonged to the HS "regular phenotype" (p = 0.01). On multivariate analysis, the item most strongly associated with poor response to isotretinoin was the HS "conglobata phenotype," followed by body mass index (BMI) (worse response to isotretinoin if BMI >25 kg/m2). Additionally, of 26 patients who received isotretinoin while their HS had already started, only 6 (23.1%) reported isotretinoin effectiveness on their HS. CONCLUSION: Subject to confirmation by larger studies, our study suggests that isotretinoin should be avoided in the treatment of acne in HS patients with the HS "conglobata phenotype," as it may worsen the acne, likewise being male or having a BMI above 25 seems to increase this risk of a bad therapeutic outcome. Patients with an HS "regular phenotype" appear to be at a reduced risk of isotretinoin treatment worsening their acne.

Role of ultra-high-frequency ultrasound in the diagnosis and management of basal cell carcinoma: pilot study based on 117 cases.

BACKGROUND: Ultrasound imaging has recently benefited from the introduction of a new 70 MHz transducer able to provide high-resolution images, i.e. ultra-high-frequency ultrasound (UHFUS). AIM: To study the morphological features of basal cell carcinomas (BCCs) and measure BCC thickness by means of UHFUS examination. METHODS: In this retrospective multicentric study, 171 consecutive patients underwent UHFUS examination between November 2018 and May 2019 for suspected BCC. Diagnosis was confirmed by histopathology. A series of morphological parameters including echogenicity, structure, borders, shape composition (presence of intralesional structures) were investigated along with objective measurements such as thickness (maximum distance between the surface of the epidermis and the deepest part of the tumour) and width. RESULTS: In total, 117 BCCs from 93 patients were examined, including superficial (n = 13; 11.1%), nodular (n = 64; 54.7%), infiltrative (n = 18; 15.4%), mixed subtypes (n = 20; 17.1%) and other subtypes (n = 2; 1.7%). The most frequently observed UHFUS parameters included: hypoechoic signal (n = 80; 68.4%, P < 0.001), homogeneous structure (n = 76, 65.0%, P = 0.01), well-defined borders (n = 77, 65.8%, P < 0.001) and elongated shape (n = 71, 60.7%, P < 0.001). An excellent correlation was found between the BCC thickness measured by UHFUS and the value estimated by histology (interclass correlation ≥ 0.80). CONCLUSION: UHFUS is a new rapid and easy noninvasive skin imaging technique able to provide data on the dimensions and morphology of BCCs in real time and at the bedside. These characteristics mean UHFUS has a number of possible applications, ranging from presurgical mapping to the detection of disease recurrence and treatment monitoring.

Comparison of reflectance confocal microscopy and line-field optical coherence tomography for the identification of keratinocyte skin tumours.

BACKGROUND: Reflectance confocal microscopy (RCM) and line-field confocal optical coherence tomography (LC-OCT) are non-invasive imaging devices that can help in the clinical diagnosis of actinic keratosis (AK) and cutaneous squamous cell carcinoma (SCC). No studies are available on the comparison between these two technologies for the identification of the different features of keratinocyte skin tumours. OBJECTIVES: To compare RCM and LC-OCT findings in AK and SCC. METHODS: A retrospective multicenter study was conducted. Tumours were imaged with RCM and LC-OCT devices before surgery, and the diagnosis was confirmed by histological examinations. LC-OCT and RCM criteria for AK/SCC were identified, and their presence/absence was evaluated in all study lesions. Gwet AC1 concordance index was calculated to compare RCM and LC-OCT. RESULTS: We included 52 patients with 33 AKs and 19 SCCs. Irregular epidermis was visible in most tumours and with a good degree of agreement between RCM and LC-OCT (Gwet's AC1 0.74). Parakeratosis, dyskeratotic keratinocytes and both linear dilated and glomerular vessels were better visible at LC-OCT than RCM (p < 0.001). Erosion/ulceration was identified with both methods in more than half of the cases with a good degree of agreement (Gwet AC1 0.62). CONCLUSIONS: Our results suggest that both LC-OCT and hand-held RCM can help clinicians in the identification of AK and SCC, providing an in vivo and non-invasive identification of an irregular epidermis. LC-OCT proved to be more effective in identifying parakeratosis, dyskeratotic keratinocytes and vessels in this series.

A risk-scoring model for the differential diagnosis of lentigo maligna and other atypical pigmented facial lesions of the face: The facial iDScore.

BACKGROUND: Due to progressive ageing of the population, the incidence of facial lentigo maligna (LM) of the face is increasing. Many benign simulators of LM and LMM, known as atypical pigmented facial lesions (aPFLs-pigmented actinic keratosis, solar lentigo, seborrheic keratosis, seborrheic-lichenoid keratosis, atypical nevus) may be found on photodamaged skin. This generates many diagnostic issues and increases the number of biopsies, with a subsequent impact on aesthetic outcome and health insurance costs. OBJECTIVES: Our aim was to develop a risk-scoring classifier-based algorithm to estimate the probability of an aPFL being malignant. A second aim was to compare its diagnostic accuracy with that of dermoscopists so as to define the advantages of using the model in patient management. MATERIALS AND METHODS: A total of 154 dermatologists analysed 1111 aPFLs and their management in a teledermatology setting: They performed pattern analysis, gave an intuitive clinical diagnosis and proposed lesion management options (follow-up/reflectance confocal microscopy/biopsy). Each case was composed of a dermoscopic and/or clinical picture plus metadata (histology, age, sex, location, diameter). The risk-scoring classifier was developed and tested on this dataset and then validated on 86 additional aPFLs. RESULTS: The facial Integrated Dermoscopic Score (iDScore) model consisted of seven dermoscopic variables and three objective parameters (diameter ≥ 8 mm, age ≥ 70 years, male sex); the score ranged from 0 to 16. In the testing set, the facial iDScore-aided diagnosis was more accurate (AUC = 0.79 [IC 95% 0.757-0.843]) than the intuitive diagnosis proposed by dermatologists (average of 43.5%). In the management study, the score model reduced the number of benign lesions sent for biopsies by 41.5% and increased the number of LM/LMM cases sent for reflectance confocal microscopy or biopsy instead of follow-up by 66%. CONCLUSIONS: The facial iDScore can be proposed as a feasible tool for managing patients with aPFLs.

Development and Implementation of a Web-Based International Registry Dedicated to Atypical Pigmented Skin Lesions of the Face: Teledermatologic Investigation on Epidemiology and Risk Factors.

Background: Atypical pigmented facial lesions (aPFLs) often display clinical and dermoscopic equivocal and/or overlapping features, thus causing a challenging and delayed diagnosis and/or inappropriate excisions. No specific registry dedicated to aPFL paired with clinical data is available to date. Methods: The dataset is hosted on a specifically designed web platform. Each complete case was composed of the following data: (1) one dermoscopic picture; (2) one clinical picture; (3) two lesion data, that is, maximum diameter and facial location (e.g., orbital area/forehead/nose/cheek/chin/mouth); (4) patient's demographics: family history of melanoma, history of sunburns in childhood, phototype, pheomelanine, eyes/hair color, multiple nevi/dysplastic nevi on the body; and (5) acquisition device (videodermatoscope/camera-based/smartphone-based system). Results: A total of 11 dermatologic centers contributed to a final teledermoscopy database of 1,197 aPFL with a distribution of 353 lentigo maligna (LM), 146 lentigo maligna melanoma (LMM), 231 pigmented actinic keratoses, 266 solar lentigo, 125 atypical nevi, 48 seborrheic keratosis, and 28 seborrheic-lichenoid keratoses. The cheek site was involved in half of aPFL cases (50%). Compared with those with the other aPFL cases, patients with LM/LMM were predominantly men, older (69.32 ± 12.9 years on average vs. 62.69 ± 14.51), exhibited larger lesions (11.88 ± 7.74 mm average maximum diameter vs. 9.33 ± 6.46 mm), and reported a positive history of sunburn in childhood. Conclusions: The iDScore facial dataset currently represents a precious source of data suitable for the design of diagnostic support tools based on risk scoring classifiers to help dermatologists in recognizing LM/LMM among challenging aPFL in clinical practice.

Morphological evaluation of melanocytic lesions with three-dimensional line-field confocal optical coherence tomography: correlation with histopathology and reflectance confocal microscopy. A pilot study.

BACKGROUND: Line-field confocal optical coherence tomography (LC-OCT) is a new in vivo emerging technique that provides cellular resolution, allows deep imaging (400 µm) and produces real-time images in both the horizontal and vertical plane and in three dimensions. No previous description of different subtypes of melanocytic lesions and their correlation with histopathology and reflectance confocal microscopy has been reported. AIM: To describe the features of melanocytic lesions by LC-OCT and their correlation with histopathology and reflectance confocal microscopy (RCM) findings. METHODS: Selected melanocytic benign lesions and melanomas were imaged in vivo with RCM and LC-OCT at the Fundación Hospital Clinic (Barcelona, Spain). A minimum area of 4 × 4 mm (block image) at four depths (stratum granulosum, suprabasal, layer dermoepidermal junction and upper dermis) were acquired with RCM and a minimum of three cubes with LC-OCT. Horizontal, vertical sections and three-dimensional (3D) cubes of LC-OCT were matched with RCM (Vivablock two-dimensional composite mosaic) and histopathology, with ~5 µm lateral resolution accuracy (the same cell nuclei were measured in X, Y and Z) and evaluated by three observers experienced in using RCM and histopathology. RESULTS: In total, 12 melanocytic tumours (2 in situ melanomas, 2 invasive melanomas, 4 atypical naevi, 2 intradermal naevi, 1 compound naevus and 1 junctional naevus) were included. High correlation with 5 µm accuracy between RCM and LC-OCT was observed for each tumour. The 3D images of melanocytic lesions were obtained with cellular resolution and correlated with both RCM and histopathology, allowing an understanding of the architecture and precise correlation at the cellular level with RCM. Similarities between LC-OCT and RCM for the described diagnostic features and architecture (nests of melanocytic cells, ringed and meshwork pattern, and cellular details of tumour cells as dendritic and pagetoid cells) were confirmed. The main advantage of diagnosis by RCM fixed probe was the ability to produce larger scans of the lesion using mosaicing compared with an LC-OCT handheld probe. CONCLUSION: LC-OCT allows the architectural and cellular description of different types of melanocytic lesions. LC-OCT showed high correlation with histopathology (vertical sections) and RCM (horizontal sections) in melanocytic lesions. Diagnostic criteria for RCM were similar to those for LC-OCT.

Proposed Definitions of Typical Lesions in Hidradenitis Suppurativa.

BACKGROUND: Although not rare, hidradenitis suppurativa (HS) is often under-recognized by physicians. The diagnosis of HS is clinical via the recognition of lesions typical of the disease, but universally accepted definitions of these latter are currently lacking, which means that certain severity scores employed for HS classification/management are used differently by different physicians. Our aim was to develop a set of descriptive definitions and associated images of HS lesions, in order to enable doctors to better recognize and evaluate the disease. METHODS: MEDLINE-available literature and dermatological textbooks on HS morphology were retrieved (January 1996 to February 2016). A preliminary set of definitions of HS typical lesions was created, including 10 terms. Each term was associated with a pathophysiological classification and an image. This preliminary set was shown during the 5th Conference of the European HS Foundation (EHSF). The physicians attending the event were invited to vote on each term and make comments via a voting sheet. RESULTS: A total of 81 physicians answered the questionnaire. Their agreement/disagreement rates and comments were used to obtain a revised set of definitions and images. Pathophysiological classifications were dropped. CONCLUSION: A user-friendly set of definitions/images of HS typical lesions was proposed and will need to be validated by further studies. This set could ultimately serve as a tool to better recognize, score, and assess treatment efficacy.

Melanoma Epidemiology and Sun Exposure.

The worldwide incidence of melanoma has increased rapidly over the last 50 years. Melanoma is the most common cancer found in the young adult population, and its incidence is very high among geriatric populations. The incidence of melanoma varies by sex, and this factor is also associated with differences in the anatomical site melanoma. Adolescent and young adult women have a higher incidence than men. This may be, in part, due to the greater use of sunbeds, as well as intentional sun exposure among girls and, in general, risky behaviours in seeking to suntan, due to socially-determined aesthetic needs. Indeed, the World Health Organization declared that there is sufficient evidence to classify exposure to ultraviolet radiation (sunbed use and sun exposure) as carcinogenic to humans. Although pigmentation characteristics, such as skin colour, hair and eye colour, freckles and number of common and atypical naevi, do influence susceptibility to melanoma, recommendations regarding prevention should be directed to the entire population and should include avoiding sunbed, covering sun-exposed skin, wearing a hat and sunglasses. Sunscreen use should not be used to prolong intentional sun exposure. Primary prevention should be focused mainly on young adult women, while secondary prevention should be focused mainly on elderly men. In fact, after the age of 40 years, incidence rates reverse, and the incidence of melanoma among men is greater than among women. This is probably due to the fact that men are less likely than women to examine their own skin or present to a dermatologist for skin examination.

New Perspectives in Food Allergy.

The improvement of the knowledge of the pathophysiological mechanisms underlying the tolerance and sensitization to food antigens has recently led to a radical change in the clinical approach to food allergies. Epidemiological studies show a global increase in the prevalence of food allergy all over the world and manifestations of food allergy appear increasingly frequent also in elderly subjects. Environmental and nutritional changes have partly changed the epidemiology of allergic reactions to foods and new food allergic syndromes have emerged in recent years. The deepening of the study of the intestinal microbiota has highlighted important mechanisms of immunological adaptation of the mucosal immune system to food antigens, leading to a revolution in the concept of immunological tolerance. As a consequence, new prevention models and innovative therapeutic strategies aimed at a personalized approach to the patient affected by food allergy are emerging. This review focuses on these new perspectives and their practical implications in the management of food allergy, providing an updated view of this complex pathology.

IL-33/IL-31 Axis in Osteoporosis.

The study of the immunoskeletal interface has led to the discovery of numerous cytokines involved in the regulation of bone remodeling, providing valuable information on the pathogenesis of osteoporosis. The role of inflammatory cytokines of the Th1 and Th17 profile in osteoporosis is well known. Here we focus on two newly discovered Th2 cytokines, IL-31 and IL-33, whose implications in osteoporosis are recently emerging. Clinical and experimental observations suggest an important role of the IL-33/IL-31 axis in osteoporosis. IL-33 induces IL-31 secretion by Th2 cells and inhibits RANKL-dependent osteoclastogenesis, thus counteracting bone loss. IL-31 influences Th1/Th17 osteoclastogenetic inflammation and limits Th2 osteoprotective processes, thus favoring osteoporosis. Better knowledge of the role of IL-31 and IL-33 and their receptor complexes in osteoporosis could provide an interesting perspective for the development of new and more effective therapies, possibly with less side effects.

Does Allergy Break Bones? Osteoporosis and Its Connection to Allergy.

: Osteoporosis and allergic diseases are important causes of morbidity, and traditionally their coexistence has been attributed to causality, to independent processes, and they were considered unrelated. However, the increasing knowledge in the field of osteoimmunology and an increasing number of epidemiological and biological studies have provided support to a correlation between bone and allergy that share pathways, cells, cytokines and mediators. If the link between allergic pathology and bone alterations appears more subtle, there are conditions such as mastocytosis and hypereosinophilic or hyper-IgE syndromes characterized by the proliferation of cells or hyper-production of molecules that play a key role in allergies, in which this link is at least clinically more evident, and the diseases are accompanied by frank skeletal involvement, offering multiple speculation cues. The pathophysiological connection of allergy and osteoporosis is currently an intriguing area of research. The aim of this review is to summarize and bring together the current knowledge and pursue an opportunity to stimulate further investigation.

Sex and Gender Aspects for Patient Stratification in Allergy Prevention and Treatment.

Allergies are rapidly worsening in recent decades, representing the most common immunological diseases. The mechanism of disorders such as asthma, rhinocongiuntivitis, urticaria, atopic dermatitis, food and drug allergies, and anaphylaxis still remain unclear and consequently treatments is mostly still symptomatic and aspecific while developments of new therapies are limited. A growing amount of data in the literature shows us how the prevalence of allergic diseases is different in both sexes and its changes over the course of life. Genes, hormones, environmental and immunological factors affect sex disparities associated with the development and control of allergic diseases, while they more rarely are considered and reported regarding their differences related to social, psychological, cultural, economic, and employment aspects. This review describes the available knowledge on the role of sex and gender in allergies in an attempt to improve the indispensable gender perspective whose potential is still underestimated while it represents a significant turning point in research and the clinic. It will offer insights to stimulate exploration of the many aspects still unknown in this relationship that could ameliorate the preventive, diagnostic, and therapeutic strategies in allergic diseases.

Sunbeds and melanoma risk: time to close the debate.

PURPOSE OF REVIEW: In spite of the established scientific evidence on the association of sunbed use with melanoma risk, some have recently expressed scepticism about the carcinogenicity of indoor tanning. This may have raised confusion among both physicians and patients. The purpose of this review is to make the point about the real impact of sunbed use on melanoma risk in light of the most recently published evidence. RECENT FINDINGS: Seven themes were covered: recent studies on age at first sunbed exposure and melanoma risk; sunbed use and melanoma at different body sites; sunbed use and development of additional primary melanomas; new studies on proportion of melanomas attributable to sunbed use; sunbed use and melanoma risk factors; economic burden of sunbed use; and recent debate over whether indoor tanning contributes to melanoma. SUMMARY: We were able to apply all epidemiological criteria for causality to the relationship between sunbed use and melanoma. Together with the new evidence on the strength, dose response, and temporality of the association of sunbeds with melanoma, this will hopefully close the debate over whether indoor tanning contributes to melanoma.