3D Whole-body skin imaging for automated melanoma detection.

BACKGROUND: Existing artificial intelligence for melanoma detection has relied on analysing images of lesions of clinical interest, which may lead to missed melanomas. Tools analysing the entire skin surface are lacking. OBJECTIVES: To determine if melanoma can be distinguished from other skin lesions using data from automated analysis of 3D-images. METHODS: Single-centre, retrospective, observational convenience sample of patients diagnosed with melanoma at a tertiary care cancer hospital. Eligible participants were those with a whole-body 3D-image captured within 90 days prior to the diagnostic skin biopsy. 3D-images were obtained as standard of care using VECTRA WB360 Whole Body 3-dimensional Imaging System (Canfield Scientific). Automated data from image processing (i.e. lesion size, colour, border) for all eligible participants were exported from VECTRA DermaGraphix research software for analysis. The main outcome was the area under the receiver operating characteristic curve (AUC). RESULTS: A total of 35 patients contributed 23,538 automatically identified skin lesions >2 mm in largest diameter (102-3021 lesions per participant). All were White patients and 23 (66%) were males. The median (range) age was 64 years (26-89). There were 49 lesions of melanoma and 22,489 lesions that were not melanoma. The AUC for the prediction model was 0.94 (95% CI: 0.92-0.96). Considering all lesions in a patient-level analysis, 14 (28%) melanoma lesions had the highest predicted score or were in the 99th percentile among all lesions for an individual patient. CONCLUSIONS: In this proof-of-concept pilot study, we demonstrated that automated analysis of whole-body 3D-images using simple image processing techniques can discriminate melanoma from other skin lesions with high accuracy. Further studies with larger, higher quality, and more representative 3D-imaging datasets would be needed to improve and validate these results.

The long-term evolution of melanocytic nevi among high-risk adults.

BACKGROUND: There is little understanding regarding the long-term natural history of melanocytic nevi among adults. OBJECTIVE: The objective of the study was to describe the long-term natural history of individual nevi located on the torso of high-risk patients. METHODS: All patients attending Memorial Sloan Kettering Cancer Center (MSKCC) who underwent two total body photography (TBP) sessions 15+ years apart were included ('retrospective' group). To account for a potential selection bias, we also included consecutive patients who had TBP 15+ years ago and consented to undergo follow-up TBP ('prospective' group). We compared baseline and follow-up torso images on the TBPs and evaluated the number of total, new and disappearing nevi; number of seborrheic keratoses and actinic keratoses; each nevus' diameter at both time points; each nevus' colour change; the presence of clinical atypia; and when dermoscopy was available, the dermoscopic features at each time point. RESULTS: One hundred six patients were included in the study. Although the average age of the patients was 40 at baseline TBP, most patients developed new nevi between imaging sessions (median 16.4 years) with an average of 2.6 (SD = 4.8) nevi per participant. The average number of disappearing nevi was 0.3 (SD = 0.6). In addition, 62/106 (58%) patients had an absolute increase, and 9/106 (8%) patients had an absolute decrease in their total nevus count. Roughly half (49%: 1416/2890) of the nevi that could be evaluated at both time points increased in diameter by at least 25%. Only 6% (159/2890) of nevi shrunk in diameter by at least 25%. Patients with a history of melanoma had a higher rate of disappearing nevi, and their nevi were more likely to grow. Most nevi demonstrated no significant dermoscopic changes. CONCLUSIONS: High-risk patients acquire new nevi throughout life with very few nevi disappearing over time. Contrary to prior reports, most nevi in adults increase in diameter, while few nevi shrink.

Skin cancer risk among testicular germ-cell cancer survivors: a systematic review and meta-analysis.

Testicular germ-cell tumours (TGCT) are the most common cancer among young adult men. Previous studies suggested TGCT survivors have an increased risk for skin cancer. The goal of this study was to systematically review the literature and evidence regarding skin cancer risk among TGCT survivors compared with the general population. PubMed, EMBASE, Web of Science, Cochrane Databases and reference lists were included in the search. A systematic review of all comparative studies with more than 10 TGCT survivors reporting on skin cancer incidence was performed. A meta-analysis of the Standardized Incidence Rate (SIR) was calculated by pooling study-specific log-transformed estimates using the random-effects model. Risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. Nineteen studies that reported on 147 935 TGCT survivors were included. Pooled SIR for skin cancer and for melanoma incidence among TGCT survivors were 1.93 (95% CI 1.62-2.29, P < 0.0001) and 1.81 (95% CI 1.57-2.08, P < 0.0001), respectively. In conclusion, compared to the general population, TGCT survivors have an increased risk for developing skin cancer and melanoma. Additional long-term studies that include TGCT survivors, additional risk factors and all subtypes of skin cancer are required.

Context-dependent neural responses to minor notes in frontal and temporal regions distinguish musicians from nonmusicians.

Musical training is required for individuals to correctly label musical modes using the terms "major" and "minor," whereas no training is required to label these modes as "happy" or "sad." Despite the high accuracy of nonmusicians in happy/sad labeling, previous research suggests that these individuals may exhibit differences in the neural response to the critical note-the note (the third of the relevant key) that defines a melody as major or minor. The current study replicates the presence of a late positive component (LPC) to the minor melody in musicians only. Importantly, we also extend this finding to examine additional neural correlates of critical notes in a melody. Although there was no evidence of an LPC response to a second occurrence of the critical note in either group, there was a strong early right anterior negativity response in the inferior frontal gyrus in musicians in response to the first critical note in the minor mode. This response was sufficient to classify participants based on their musical training group. Furthermore, there were no differences in prefrontal asymmetry in the alpha or beta bands during the critical notes. These findings support the hypothesis that musical training may enhance the neural response to the information content of critical note in a minor scale but not the neural response to the emotional content of a melody.

Human surface anatomy terminology for dermatology: a Delphi consensus from the International Skin Imaging Collaboration.

BACKGROUND: There is no internationally vetted set of anatomic terms to describe human surface anatomy. OBJECTIVE: To establish expert consensus on a standardized set of terms that describe clinically relevant human surface anatomy. METHODS: We conducted a Delphi consensus on surface anatomy terminology between July 2017 and July 2019. The initial survey included 385 anatomic terms, organized in seven levels of hierarchy. If agreement exceeded the 75% established threshold, the term was considered 'accepted' and included in the final list. Terms added by the participants were passed on to the next round of consensus. Terms with <75% agreement were included in subsequent surveys along with alternative terms proposed by participants until agreement was reached on all terms. RESULTS: The Delphi included 21 participants. We found consensus (≥75% agreement) on 361/385 (93.8%) terms and eliminated one term in the first round. Of 49 new terms suggested by participants, 45 were added via consensus. To adjust for a recently published International Classification of Diseases-Surface Topography list of terms, a third survey including 111 discrepant terms was sent to participants. Finally, a total of 513 terms reached agreement via the Delphi method. CONCLUSIONS: We have established a set of 513 clinically relevant terms for denoting human surface anatomy, towards the use of standardized terminology in dermatologic documentation.

Accuracy of tele-consultation on management decisions of lesions suspect for melanoma using reflectance confocal microscopy as a stand-alone diagnostic tool.

BACKGROUND: Diagnostic accuracy of reflectance confocal microscopy (RCM) as a stand-alone diagnostic tool for suspect skin lesions has not been extensively studied. OBJECTIVE: Primary aim was to measure experts' accuracy in RCM-based management decisions. Secondary aim was to identify melanoma-specific RCM features. METHODS: The study enrolled patients ≥18 years that underwent biopsy of skin lesions clinically suspected to be melanoma. One hundred lesions imaged by RCM were randomly selected from 439 lesions prospectively collected at four pigmented lesion clinics. The study data set included 23 melanomas, three basal cell and two squamous cell carcinomas, 11 indeterminate melanocytic lesions and 61 benign lesions including 50 nevi. Three expert RCM evaluators were blinded to clinical or dermoscopic images, and to the final histopathological diagnosis. Evaluators independently issued a binary RCM-based management decision, 'biopsy' vs. 'observation'; these decisions were scored against histopathological diagnosis, with 'biopsy' as the correct management decision for malignant and indeterminate lesions. A subset analysis of 23 melanomas and 50 nevi with unequivocal histopathological diagnosis was performed to identify melanoma-specific RCM features. RESULTS: Sensitivity, specificity and diagnostic accuracy were 74%, 67% and 70% for reader 1, 46%, 84% and 69% for reader 2, and 72%, 46% and 56% for reader 3, respectively. The overall kappa for management decisions was 0.34. Readers had unanimous agreement on management for 50 of the 100 lesions. Non-specific architecture, non-visible papillae, streaming of nuclei, coarse collagen fibres and abnormal vasculature showed a significant association with melanoma in the evaluation of at least two readers. CONCLUSIONS: Reflectance confocal microscopy tele-consultation of especially challenging lesions, based on image review without benefit of clinical or dermoscopy images, may be associated with limited diagnostic accuracy and interobserver agreement. Architectural and stromal criteria may emerge as potentially useful and reproducible criteria for melanoma diagnosis.

Cross-sectional analysis of the dermoscopic patterns and structures of melanocytic naevi on the back and legs of adolescents.

BACKGROUND: Junctional (flat) naevi predominate on the extremities, whereas dermal (raised) naevi are found primarily on the head, neck and trunk. Few studies have investigated the anatomical site prevalence of melanocytic naevi categorized using dermoscopy. OBJECTIVES: To identify the prevalence of dermoscopic patterns and structures of naevi from the back and legs of adolescents. METHODS: Dermoscopic images of acquired melanocytic naevi were obtained from the back and legs of students from a population-based cohort in Framingham, Massachusetts. Naevi were classified into reticular, globular, homogeneous or complex dermoscopic patterns. Multinomial logistic regression modelling assessed the associations between dermoscopic pattern and anatomical location. RESULTS: In total 509 participants (mean age 14 years) contributed 2320 back naevi and 637 leg naevi. Compared with homogeneous naevi, globular and complex naevi were more commonly observed on the back than the legs [odds ratio (OR) 29·39, 95% confidence interval (CI) 9·53-90·65, P < 0·001 and OR 6·8, 95% CI 2·7-17·14, P < 0·001, respectively], whereas reticular lesions were less likely to be observed on the back than on the legs (OR 0·67, 95% CI 0·54-0·84, P = 0·001). Naevi containing any globules were more prevalent on the back than on the legs (25% vs. 3·6%, P < 0·001). Naevi containing any network were more prevalent on the legs than on the back (56% vs. 40·6%, P < 0·001). CONCLUSIONS: These findings add to a robust body of literature suggesting that dermoscopically defined globular and reticular naevi represent biologically distinct naevus subsets that differ in histopathological growth pattern, age- and anatomical-site-related prevalence, molecular phenotype and aetiological pathways.

Genetic factors associated with naevus count and dermoscopic patterns: preliminary results from the Study of Nevi in Children (SONIC).

BACKGROUND: Melanocytic naevi are an important risk factor for melanoma. Naevi with distinct dermoscopic patterns can differ in size, distribution and host pigmentation characteristics. OBJECTIVES: We examined MC1R and 85 other candidate loci in a cohort of children to test the hypothesis that the development and dermoscopic type of naevi are modulated by genetic variants. METHODS: Buccal DNAs were obtained from a cohort of 353 fifth graders (mean age 10·4 years). Polymorphisms were chosen based on a known or anticipated role in naevi and melanoma. Associations between single-nucleotide polymorphisms (SNPs) and baseline naevus count were determined by multivariate regression adjusting for sex, race/ethnicity and sun sensitivity. Dermoscopic images were available for 853 naevi from 290 children. Associations between SNPs and dermoscopic patterns were determined by polytomous regression. RESULTS: Four SNPs were significantly associated with increasing (IRF4) or decreasing (PARP1, CDK6 and PLA2G6) naevus count in multivariate shrinkage analyses with all SNPs included in the model; IRF4 rs12203952 showed the strongest association with log naevus count (relative risk 1·56, P < 0·001). Using homogeneous naevi as the reference, IRF4 rs12203952 and four other SNPs in TERT, CDKN1B, MTAP and PARP1 were associated with either globular or reticular dermoscopic patterns (P < 0·05). CONCLUSIONS: Our results provide evidence that subsets of naevi defined by dermoscopic patterns differ in their associations with germline genotypes and support the hypothesis that dermoscopically defined subsets of naevi are biologically distinct. These results require confirmation in larger cohorts. If confirmed, these findings will improve the current knowledge of naevogenesis and assist in the identification of individuals with high-risk phenotypes.

Melanocytic naevi with globular and reticular dermoscopic patterns display distinct BRAF V600E expression profiles and histopathological patterns.

BACKGROUND: BRAF (v-raf murine sarcoma viral oncogene homologue B) V600E mutations have been detected with high frequency in melanocytic naevi. Few studies have stratified analyses by naevus dermoscopic pattern. OBJECTIVES: To determine the frequency of BRAF V600E expression and histopathological pattern in acquired melanocytic naevi distinguished by a globular vs. reticular dermoscopic pattern. METHODS: We retrospectively identified histologically proven melanocytic naevi with banal reticular or globular dermoscopic patterns and evaluated BRAF V600E expression using immunohistochemistry. RESULTS: BRAF V600E expression was detected in 11 of 12 globular naevi vs. four of 13 reticular naevi (91·7% vs. 30·1%, P = 0·004). A predominantly dermal growth pattern (P < 0·001) and the presence of large junctional nests (P = 0·017) were each associated with a globular dermoscopic pattern. The presence of either a predominantly dermal growth pattern or large junctional nests was found in 13 of 15 naevi positive for BRAF V600E and in two of 10 naevi negative for BRAF V600E (86·7% vs. 20%, P = 0·002). CONCLUSIONS: The frequency of BRAF V600E mutations differs in naevi distinguished by unique dermoscopic structures and microanatomical growth patterns. Globular naevi, which most often histologically correspond to a predominantly dermal growth pattern and/or the presence of large junctional nests, are significantly more likely to express BRAF V600E than reticular naevi. These preliminary results require validation, but may directly inform future studies of naevogenesis and melanoma genesis.

Clinical and dermoscopic characteristics of new naevi in adults: results from a cohort study.

BACKGROUND: Naevogenesis is a process known to occur throughout life. To date, investigators have made conclusions about new naevi in adults based on results of cross-sectional studies. OBJECTIVES: To determine the incidence of new naevus development in adults and to describe the dermoscopic morphology of new naevi. METHODS: A cohort of 182 patients seen at the outpatient dermatology clinic at Memorial Sloan-Kettering Cancer Center between 2000 and 2009 was evaluated with baseline total body photographs. The patients were aged 17 years or older and had presented for routine follow-up surveillance examination at least 3 months after baseline total body photographs. The number of new naevi and the dermoscopic morphology of these naevi were recorded. RESULTS: Of the 182 patients evaluated, 50 (27%) developed at least one new naevus during follow-up. The incidence of new naevi was 202 per 1000 person-years of follow-up. The most common types of naevi were reticular (47·1%), followed by the homogeneous (22·1%) and complex (reticuloglobular) patterns (15·4%). CONCLUSIONS: Our results provide support for the theory that there are two distinct pathways of naevogenesis, a dynamic process occurring throughout life. This study demonstrates that the predominant dermoscopic morphology of newly acquired naevi in adults is reticular.

One-year follow-up of dermoscopy education on the ability of medical students to detect skin cancer.

BACKGROUND: Learning skin cancer detection skills is important, yet many medical schools lack a standardized skin cancer examination (SCE) curriculum. OBJECTIVE: To determine medical students' skills in discriminating benign from malignant skin lesions on a 10-item image-based test one year after receiving a SCE intervention. METHODS: Cohort 1 received SCE teaching only. Cohort 2 received SCE teaching with dermoscopy tutorial, and a dermatoscope. The same test was given to assess students post-intervention and one year later. RESULTS: 43% (n = 145) and 38% (n = 143) of cohorts 1 and 2, respectively, participated one year later. Both cohorts improved or maintained their scores to correctly classify all lesions from post-intervention to one-year follow-up. After one year, cohort 2 maintained higher scores for successful identification of both benign and malignant lesions as compared to cohort 1. CONCLUSION: Medical students receiving a SCE intervention can improve their diagnostic skills after one year, especially with the aid of dermoscopy.

A randomized double-blind placebo-controlled study of the long-term efficacy and safety of diethylpropion in the treatment of obese subjects.

OBJECTIVE: To evaluate the efficacy of diethylpropion on a long-term basis, with emphasis in cardiovascular and psychiatric safety aspects. DESIGN: Randomized, double-blind, placebo-controlled trial. MEASUREMENTS: Following a 2-week screening period, 69 obese healthy adults received a hypocaloric diet and were randomized to diethylpropion 50 mg BID (n=37) or placebo (n=32) for 6 months. After this period, all participants received diethylpropion in an open-label extension for an additional 6 months. The primary outcome was percentage change in body weight. Electrocardiogram (ECG), echocardiography and clinical chemistry were performed at baseline and every 6 months. Psychiatric evaluation and application of Hamilton rating scales for depression and anxiety were also performed by experienced psychiatrists at baseline and every 3 months. RESULTS: After 6 months, the diethylpropion group lost an average of 9.8% (s.d. 6.9%) of initial body weight vs 3.2% (3.7%) in the placebo group (P<0.0001). From baseline to month 12, the mean weight loss produced by diethylpropion was 10.6% (8.3%). Participants in the placebo group who were switched to diethylpropion after 6 months lost an average of 7.0% (7.7%) of initial body weight. The difference between groups at month 12 was not significant (P=0.07). No differences in blood pressure, pulse rate, ECG and psychiatric evaluation were observed. Dry mouth and insomnia were the most frequent adverse events. CONCLUSION: Diethylpropion plus diet produced sustained and clinically significant weight loss over 1 year. It seems to be safe in relation to cardiovascular and psychiatric aspects in a well-selected population.

Tissue and cellular distribution of the extended family of protein kinase C isoenzymes.

Polyclonal isoenzyme-specific antisera were developed against four calcium-independent protein kinase C (PKC) isoenzymes (delta, epsilon, epsilon', and zeta) as well as the calcium-dependent isoforms (alpha, beta I, beta II, and gamma). These antisera showed high specificities, high titers, and high binding affinities (3-370 nM) for the peptide antigens to which they were raised. Each antiserum detected a species of the predicted molecular weight by Western blot that could be blocked with the immunizing peptide. PKC was sequentially purified from rat brain, and the calcium-dependent forms were finally resolved by hydroxyapatite chromatography. Peak I reacted exclusively with antisera to PKC gamma, peak II with PKC beta I and -beta II, and peak III with PKC alpha. These same fractions, however, were devoid of immunoreactivity for the calcium-independent isoenzymes. The PKC isoenzymes demonstrated a distinctive tissue distribution when evaluated by Western blot and immunocytochemistry. PCK delta was present in brain, heart, spleen, lung, liver, ovary, pancreas, and adrenal tissues. PKC epsilon was present in brain, kidney, and pancreas, whereas PKC epsilon' was present predominantly in brain. PKC zeta was present in most tissues, particularly the lung, brain, and liver. Both PKC delta and PKC zeta showed some heterogeneity of size among the different tissues. PKC alpha was present in all organs and tissues examined. PKC beta I and -beta II were present in greatest amount in brain and spleen. Although the brain contained the most PKC gamma immunoreactivity, some immunostaining was also seen in adrenal tissue. These studies provide the first evidence of selective organ and tissue distributions of the calcium-independent PKC isoenzymes.

Dermoscopic patterns and subclinical melanocytic nests in normal-appearing skin.

BACKGROUND: Dermoscopic patterns of normal-appearing skin have received little scrutiny. We have recently completed an analysis of dermoscopic patterns of naevi in children. OBJECTIVES: To describe dermoscopic patterns in the normal-appearing skin surrounding naevi and to explore histological features of patterned background skin. METHODS: Dermoscopic images of back naevi were obtained from a population-based sample of fifth grade students. The dermoscopic pattern of the background skin around the naevi was analysed. We examined histopathological features of background skin patterns in a convenience sample of seven specimens from six adult patients. RESULTS: We observed a dermoscopic pattern in the background of normal-appearing skin in 41% of 1192 dermoscopic images from the backs of the 443 children. The background skin pattern was less frequent in individuals with a fair skin (P < 0.001). A globular pattern was observed in 201 images (17%) and a reticular pattern was seen in 287 images (24%), of which 112 images also showed globules. Inter-rater reliability between the two observers for a random sample of 100 images was excellent (kappa = 0.77). In four specimens with a globular background pattern, microscopic melanocytic nests were observed in the normal-appearing skin. No subclinical naevus nests were observed in three reticular pattern specimens. CONCLUSIONS: Dermoscopically recognized patterns are commonly present in clinically normal skin of children. Microscopic melanocytic nests may be observed in normal-appearing skin with a globular skin pattern.

A whole-genome assembly of Drosophila.

We report on the quality of a whole-genome assembly of Drosophila melanogaster and the nature of the computer algorithms that accomplished it. Three independent external data sources essentially agree with and support the assembly's sequence and ordering of contigs across the euchromatic portion of the genome. In addition, there are isolated contigs that we believe represent nonrepetitive pockets within the heterochromatin of the centromeres. Comparison with a previously sequenced 2.9- megabase region indicates that sequencing accuracy within nonrepetitive segments is greater than 99. 99% without manual curation. As such, this initial reconstruction of the Drosophila sequence should be of substantial value to the scientific community.

The sequence of the human genome.

A 2.91-billion base pair (bp) consensus sequence of the euchromatic portion of the human genome was generated by the whole-genome shotgun sequencing method. The 14.8-billion bp DNA sequence was generated over 9 months from 27,271,853 high-quality sequence reads (5.11-fold coverage of the genome) from both ends of plasmid clones made from the DNA of five individuals. Two assembly strategies-a whole-genome assembly and a regional chromosome assembly-were used, each combining sequence data from Celera and the publicly funded genome effort. The public data were shredded into 550-bp segments to create a 2.9-fold coverage of those genome regions that had been sequenced, without including biases inherent in the cloning and assembly procedure used by the publicly funded group. This brought the effective coverage in the assemblies to eightfold, reducing the number and size of gaps in the final assembly over what would be obtained with 5.11-fold coverage. The two assembly strategies yielded very similar results that largely agree with independent mapping data. The assemblies effectively cover the euchromatic regions of the human chromosomes. More than 90% of the genome is in scaffold assemblies of 100,000 bp or more, and 25% of the genome is in scaffolds of 10 million bp or larger. Analysis of the genome sequence revealed 26,588 protein-encoding transcripts for which there was strong corroborating evidence and an additional approximately 12,000 computationally derived genes with mouse matches or other weak supporting evidence. Although gene-dense clusters are obvious, almost half the genes are dispersed in low G+C sequence separated by large tracts of apparently noncoding sequence. Only 1.1% of the genome is spanned by exons, whereas 24% is in introns, with 75% of the genome being intergenic DNA. Duplications of segmental blocks, ranging in size up to chromosomal lengths, are abundant throughout the genome and reveal a complex evolutionary history. Comparative genomic analysis indicates vertebrate expansions of genes associated with neuronal function, with tissue-specific developmental regulation, and with the hemostasis and immune systems. DNA sequence comparisons between the consensus sequence and publicly funded genome data provided locations of 2.1 million single-nucleotide polymorphisms (SNPs). A random pair of human haploid genomes differed at a rate of 1 bp per 1250 on average, but there was marked heterogeneity in the level of polymorphism across the genome. Less than 1% of all SNPs resulted in variation in proteins, but the task of determining which SNPs have functional consequences remains an open challenge.