Using Artificial Intelligence as a Melanoma Screening Tool in Self-Referred Patients.

INTRODUCTION: Early detection of melanoma requires timely access to medical care. In this study, we examined the feasibility of using artificial intelligence (AI) to flag possible melanomas in self-referred patients concerned that a skin lesion might be cancerous. METHODS: Patients were recruited for the study through advertisements in 2 hospitals in Halifax, Nova Scotia, Canada. Lesions of concern were initially examined by a trained medical student and if the study criteria were met, the lesions were then scanned using the FotoFinder System®. The images were analyzed using their proprietary computer software. Macroscopic and dermoscopic images were evaluated by 3 experienced dermatologists and a senior dermatology resident, all blinded to the AI results. Suspicious lesions identified by the AI or any of the 3 dermatologists were then excised. RESULTS: Seventeen confirmed malignancies were found, including 10 melanomas. Six melanomas were not flagged by the AI. These lesions showed ambiguous atypical melanocytic proliferations, and all were diagnostically challenging to the dermatologists and to the dermatopathologists. Eight malignancies were seen in patients with a family history of melanoma. The AI's ability to diagnose malignancy is not inferior to the dermatologists examining dermoscopic images. CONCLUSION: AI, used in this study, may serve as a practical skin cancer screening aid. While it does have technical and diagnostic limitations, its inclusion in a melanoma screening program, directed at those with a concern about a particular lesion would be valuable in providing timely access to the diagnosis of skin cancer.

An Examination of Melanoma Detection and Characteristics at a Nova Scotia Tertiary Care Centre, From 2015-2019.

BACKGROUND: Melanoma is one of the most common cancers in Canada,1 with the highest incidence in Nova Scotia (NS). OBJECTIVES: To describe the demographics, lesion characteristics, and diagnostic accuracy of suspected melanomas excised at the largest center in NS. METHODS: The dermatopathology database was interrogated for cases of possible melanoma from 2015 through 2019. Age, gender, site of lesion, pathologic diagnosis, Breslow depth, and equivocal pathology were assessed. RESULTS: 984 lesions had a clinical diagnosis of possible melanoma, identifying 301 melanomas. Of these, 142 (47%) were melanoma in situ (MIS) which in females occurred mostly on the extremities, while in males the head predominated. For invasive melanoma (IM), the extremities remained predominant for women, while the back was most common in men. Lower extremity lesions were more likely to be invasive and female patients were more likely to present with them at a younger age compared to males. The pathology was challenging for 23.94% of MIS, and 16.18% of IM. A mean of 3.1 lesions were excised for every melanoma identified. CONCLUSIONS: Early diagnosis of melanoma is challenging clinically and pathologically. Our melanoma detection rate was 31%, with an increasing trend in the proportion of MIS, and decreasing trend in the proportion of IM over the years. Almost 50% of melanomas were detected in early stages, supporting positive outcomes. Melanomas were more common on extremities in females and the back in males. Melanomas on the lower limbs were more likely to be invasive regardless of gender.

The use of noninvasive imaging techniques in the diagnosis of melanoma: a prospective diagnostic accuracy study.

BACKGROUND: Early detection of melanoma is crucial to improving the detection of thin curable melanomas. Noninvasive, computer-assisted methods have been developed to use at the bedside to aid in diagnoses but have not been compared directly in a clinical setting. OBJECTIVE: We conducted a prospective diagnostic accuracy study comparing a dermatologist's clinical examination at the bedside, teledermatology, and noninvasive imaging techniques (FotoFinder, MelaFind, and Verisante Aura). METHODS: A total of 184 patients were recruited prospectively from an outpatient dermatology clinic, with lesions imaged, assessed, and excised. Skin specimens were assessed by 2 blinded pathologists, providing the gold standard comparison. RESULTS: Fifty-nine lesions from 56 patients had a histopathologic diagnosis of melanoma, whereas 150 lesions from 128 patients were diagnosed as benign. Sensitivities and specificities were, respectively, MelaFind (82.5%, 52.4%), Verisante Aura (21.4%, 86.2%), and FotoFinder Moleanalyzer Pro (88.1%, 78.8%). The sensitivity and specificity of the teledermoscopist (84.5% and 82.6%, respectively) and local dermatologist (96.6% and 32.2%, respectively) were also compared. LIMITATIONS: There are inherent limitations in using pathology as the gold standard to compare sensitivities and specificities. CONCLUSION: This study demonstrates that the highest sensitivity and specificity of the instruments were established with the FotoFinder Moleanalyzer Pro, which could be a valuable tool to assist with, but not replace, clinical decision making.

Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families.

Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.

AAGAB Mutations in 18 Canadian Families With Punctate Palmoplantar Keratoderma and a Possible Link to Cancer.

BACKGROUND: Punctate palmoplantar keratoderma type 1 (PPPK1) presents in late childhood to adulthood with multiple small discrete hyperkeratotic papules on palms and soles. PPPK1 is an autosomal dominant skin disease caused by AAGAB mutations. It has been suggested that PPPK1 may be associated with an increased predisposition to systemic malignancies. OBJECTIVES: To evaluate the presence of AAGAB mutations in Canadian families with PPPK1 and the possible increased predisposition to systemic malignancies. METHODS: Eighteen unrelated Canadian families with PPPK1 were recruited for this study. Genomic DNA was extracted from saliva and PCR amplification was performed for all AAGAB exons and exon/intron junctions. PCR products were sequenced and analyzed for mutations. A family history of malignancy was obtained from the index case and, when possible, from other family members. RESULTS: We have identified 5 heterozygous AAGAB loss of function mutations in 11 families. The mutation c.370 C>T, p.Arg124* was the most prevalent and was identified in 6 families. A splice site mutation, c.451+3delAAGT, was identified in 2 families. The other mutations c.473delG, p.Gly158Glufs*0; c.550-551insAAT, p.Gly183*; and c.505-506 dupAA, p.Asn169Lysfs*6 were each identified in 1 family. Different cancers were reported in 11 families (Table 1 and Supplemental Figure S1). CONCLUSIONS: AAGAB mutations were found in 11 of 18 families with PPPK1. In some families there appears to be an association with cancer.

Filaggrin gene loss-of-function mutations constitute a factor in patients with multiple contact allergies.

BACKGROUND: Polysensitivity is defined as three or more positive patch test reactions. The role of filaggrin gene (FLG) loss-of-function mutations in patients with polysensitivity has not been studied when barrier bypass and possible preceding barrier damage have been excluded. OBJECTIVES: To determine whether FLG loss of function mutations play a role in patients with multiple contact sensitivities when barrier bypass is excluded. METHODS: One hundred and sixty-nine patients with three or more, non-cross-reacting, positive patch test reactions were prospectively enrolled in this study. Exclusion criteria were a history of hand dermatitis, nickel and metal implants, and stasis dermatitis. Subjects were patch tested with the North American extended patch test series, and with other relevant haptens. DNA was obtained and sequenced for the following FLG loss-of-function mutations: R501X, 2282del4, R2447X, and S3247X. RESULTS: One hundred and sixty-five patients were genotyped for the four FLG mutations. There was a significant association between R501X mutation and polysensitivity. For the other three tested mutations, there were no significant associations with polysensitivity. When all mutations were combined, there was a significant association between loss-of-function FLG mutations and polysensitivity in patients with a history of atopic dermatitis. CONCLUSION: When skin barrier bypass is excluded, there is a significant association between polysensitivity and FLG loss-of-function mutations.

Disseminated Eczema Following Radiotherapy: A Case Report.

BACKGROUND: Radiotherapy-induced acute skin reactions are common and an expected effect of radiotherapy. Eczematous eruptions, however, are rarely reported, with disseminated eczema in particular being infrequently seen and likely underrecognized. OBJECTIVE: We present a unique case of disseminated vesicular eczema following radiotherapy for ductal carcinoma in situ. CONCLUSIONS: The development of a localized vesicular eruption with subsequent dissemination can occur following radiotherapy. The mechanism of autosensitization is poorly understood but likely involves a cell-mediated immune response. Recognition is important to prevent excessive and inappropriate investigation and treatment.

Dyshidrotic Bullous Pemphigoid: Case Report and Review of Literature.

BACKGROUND: Dyshidrotic pemphigoid (DP) is a rare variant of bullous pemphigoid (BP) that affects the hands and feet and may resemble an acute vesicular eczema. While it can remain confined to hands and feet, spread that involves the entire body is described. BP and DP are associated with autoantibodies directed against hemidesmosomal proteins BP180 (collagen XVII) and BP230 (dystonin), which are transmembrane and intracellular proteins in the basement membrane zone, respectively. CASE SUMMARY: We present a case of DP in a 78-year-old woman who was diagnosed based on histopathologic and immunofluorescence findings and subsequently successfully treated. CONCLUSION: DP is an unusual form of localized BP. While the pathogenesis is still unclear, it may involve differential expression of BP antigens in the cutaneous basement membrane of the hands and feet. The clinical presentation is a diagnostic challenge, and skin biopsies with immunofluorescence studies are required for diagnosis.

Recurrent and Fixed Neutrophilic Dermatosis Associated With Dasatinib.

BACKGROUND: Dasatinib is a tyrosine kinase inhibitor indicated for the treatment of chronic myeloid leukemia (CML). Skin rashes are common, occurring in about a quarter of patients treated, and are generally mild. The commonest rash is a keratosis pilaris-like eruption. A neutrophilic dermatosis has rarely been reported. OBJECTIVE: We report a patient whose CML was successfully treated with dasatinib and who several years later developed episodes of a neutrophilic dermatosis recurring at the same sites. CONCLUSION: This report extends the clinical spectrum of neutrophilic dermatoses to include dasatinib-induced recurrent and fixed erythematous plaques.

Chronic Spontaneous Urticaria: A Questionnaire Survey.

BACKGROUND: Chronic spontaneous urticaria (CSU) is urticaria persisting for more than 6 weeks with no identifiable provoking cause and associated with significant disability. OBJECTIVES: The aim of this study was to survey patients with CSU with a view to establishing prognosis, efficacy of treatments, suspected causality, and effects on lifestyle. METHODS: One hundred seventy-four patients with CSU were seen between 2003 and 2013. A questionnaire was sent to all, and 101 participated. RESULTS: The ratio of female to male participants was 4:1. The mean age of onset was 36 years. The average duration of symptoms was 8.8 years, with a range of 0.33 to 55 years. Seven percent of participants had autoimmune thyroiditis, and another 17% had various other autoimmune diseases. Common symptoms were pruritus, disturbed sleep, and anxiety. Slightly more than 70% had missed work or school. Most were frustrated at the lack of efficacy of treatments. CONCLUSIONS: CSU is frequently associated with a history of autoimmune diseases. It may persist for decades and causes significant disruption to lifestyle.

Comprehensive analysis of the gene encoding filaggrin uncovers prevalent and rare mutations in ichthyosis vulgaris and atopic eczema.

We recently reported two common filaggrin (FLG) null mutations that cause ichthyosis vulgaris and predispose to eczema and secondary allergic diseases. We show here that these common European mutations are ancestral variants carried on conserved haplotypes. To facilitate comprehensive analysis of other populations, we report a strategy for full sequencing of this large, highly repetitive gene, and we describe 15 variants, including seven that are prevalent. All the variants are either nonsense or frameshift mutations that, in representative cases, resulted in loss of filaggrin production in the epidermis. In an Irish case-control study, the five most common European mutations showed a strong association with moderate-to-severe childhood eczema (chi2 test: P = 2.12 x 10(-51); Fisher's exact test: heterozygote odds ratio (OR) = 7.44 (95% confidence interval (c.i.) = 4.9-11.3), and homozygote OR = 151 (95% c.i. = 20-1,136)). We found three additional rare null mutations in this case series, suggesting that the genetic architecture of filaggrin-related atopic dermatitis consists of both prevalent and rare risk alleles.

Extracorporeal photopheresis for the treatment of Crohn's disease.

Small, open-label studies show promising results for ECP in the treatment of steroid-dependent and medically-refractory Crohn's disease. However, proper randomized, sham-controlled trials have not yet been performed. Based on the proposed mechanism of action of ECP, induction of a tolerogenic T cell response, ECP should be assessed in patients with early inflammatory disease rather than those who have progressed to fibrotic or stricturing disease. Randomized, sham-controlled trials need to be performed before ECP can be incorporated into standard clinical practice for the treatment of Crohn's disease.

Loss-of-function variants in the filaggrin gene are a significant risk factor for peanut allergy.

BACKGROUND: IgE-mediated peanut allergy is a complex trait with strong heritability, but its genetic basis is currently unknown. Loss-of-function mutations within the filaggrin gene are associated with atopic dermatitis and other atopic diseases; therefore, filaggrin is a candidate gene in the etiology of peanut allergy. OBJECTIVE: To investigate the association between filaggrin loss-of-function mutations and peanut allergy. METHODS: Case-control study of 71 English, Dutch, and Irish oral food challenge-positive patients with peanut allergy and 1000 non peanut-sensitized English population controls. Replication was tested in 390 white Canadian patients with peanut allergy (defined by food challenge, or clinical history and skin prick test wheal to peanut ≥ 8 mm and/or peanut-specific IgE ≥ 15 kUL(-1)) and 891 white Canadian population controls. The most prevalent filaggrin loss-of-function mutations were assayed in each population: R501X and 2282del4 in the Europeans, and R501X, 2282del4, R2447X, and S3247X in the Canadians. The Fisher exact test and logistic regression were used to test for association; covariate analysis controlled for coexistent atopic dermatitis. RESULTS: Filaggrin loss-of-function mutations showed a strong and significant association with peanut allergy in the food challenge-positive patients (P = 3.0 × 10(-6); odds ratio, 5.3; 95% CI, 2.8-10.2), and this association was replicated in the Canadian study (P = 5.4 × 10(-5); odds ratio, 1.9; 95% CI, 1.4-2.6). The association of filaggrin mutations with peanut allergy remains significant (P = .0008) after controlling for coexistent atopic dermatitis. CONCLUSION: Filaggrin mutations represent a significant risk factor for IgE-mediated peanut allergy, indicating a role for epithelial barrier dysfunction in the pathogenesis of this disease.

Acute onset of blisters in an infant with acrodermatitis enteropathica: A case report.

We represent a pediatric case of the congenital disorder caused by zinc malabsorption, acrodermatitis enteropathica, presenting with acute onsetof blisters. Although blisters can be seen in this condition, it is not always a key feature and can therefore be overlooked when considering a differential diagnosis of acute blistering in infancy. We therefore review the common and less common features of this cutaneous eruption as well as provide an extensive differential diagnosis for acute blistering in infancy. We also emphasize the importance of lifelong treatment with zinc supplementation in these children.

Two SMARCAD1 Variants Causing Basan Syndrome in a Canadian and a Dutch Family.

Basan syndrome is an autosomal dominant genodermatosis characterized by congenital adermatoglyphia, transient congenital facial milia, neonatal acral bullae, and absent or reduced sweating. Basan syndrome is rare and has been reported in only 10 kindreds worldwide. It is caused by variants in the skin-specific isoform of SMARCAD1, which starts with an alternative exon 1. All reported variants, except for one large deletion, are point mutations within the donor splice site of the alternative exon 1. In this paper, we report two families with Basan syndrome and describe two SMARCAD1 variants. In one family, we have identified a complex structural variant (a deletion and a nontandem inverted duplication) using whole-genome optical mapping and whole-genome sequencing. Although this variant results in the removal of the first nine exons of SMARCAD1 and exon 1 of the skin-specific isoform, it manifested in the typical Basan phenotype. This suggests that unlike the skin-specific isoform, a single copy of full-length SMARCAD1 is sufficient for its respective function. In the second family, whole-exome sequencing revealed a deletion of 12 base pairs spanning the exon‒intron junction of the alternative exon 1 of the skin-specific SMARCAD1 isoform. In conclusion, we report two additional families with Basan syndrome and describe two SMARCAD1 pathogenic variants.

Therapeutic siRNAs for dominant genetic skin disorders including pachyonychia congenita.

The field of science and medicine has experienced a flood of data and technology associated with the human genome project. Over 10,000 human diseases have been genetically defined, but little progress has been made with respect to the clinical application of this knowledge. A notable exception to this exists for pachyonychia congenita (PC), a rare, dominant-negative keratin disorder. The establishment of a non-profit organization, PC Project, has led to an unprecedented coalescence of patients, scientists, and physicians with a unified vision of developing novel therapeutics for PC. Utilizing the technological by-products of the human genome project, such as RNA interference (RNAi) and quantitative RT-PCR (qRT-PCR), physicians and scientists have collaborated to create a candidate siRNA therapeutic that selectively inhibits a mutant allele of KRT6A, the most commonly affected PC keratin. In vitro investigation of this siRNA demonstrates potent inhibition of the mutant allele and reversal of the cellular aggregation phenotype. In parallel, an allele-specific quantitative real-time RT-PCR assay has been developed and validated on patient callus samples in preparation for clinical trials. If clinical efficacy is ultimately demonstrated, this "first-in-skin" siRNA may herald a paradigm shift in the treatment of dominant-negative genetic disorders.