Gender differences in pediatric and adolescent melanoma: A retrospective analysis of 4645 cases.

BACKGROUND: There is paucity of data on how gender impacts melanoma prognosis in pediatric and adolescent patients. OBJECTIVES: This study explores gender differences in presentation and survival among pediatric and adolescent patients with melanoma. METHODS: The National Cancer Database 2004-2018 was queried for cases of primary invasive cutaneous melanoma in pediatric and adolescent patients (birth to 21 years) for a retrospective cohort study. RESULTS: Of the 4645 cases, 63.4% were female. Median Breslow depth was 1.05 mm for males (interquartile range 0.50-2.31) and 0.80 mm for females (interquartile range 0.40-1.67; P < .001). Trunk was the most common primary site for females (34.3%) and males (32.9%). More females than males were diagnosed with stage I disease (67.8% vs 53.6%). Males had higher rates of regional lymph node positivity (27.9% vs 18.1%; P < .001) and ulceration (17.1% vs 11.4%; P < .001). Five-year overall survival was 95.9% for females and 92.0% for males (P < .001). After adjusting for confounders, male gender independently increased mortality risk (reference: females; adjusted hazard ratio 1.57; 95% confidence interval 1.32-1.86). LIMITATIONS: Retrospective study. CONCLUSION: Males exhibited more aggressive pathologic features including greater Breslow thickness and higher ulceration and lymph node positivity rates. Male gender independently increased mortality risk.

International Skin Imaging Collaboration-Designated Diagnoses (ISIC-DX): Consensus terminology for lesion diagnostic labeling.

BACKGROUND: A common terminology for diagnosis is critically important for clinical communication, education, research and artificial intelligence. Prevailing lexicons are limited in fully representing skin neoplasms. OBJECTIVES: To achieve expert consensus on diagnostic terms for skin neoplasms and their hierarchical mapping. METHODS: Diagnostic terms were extracted from textbooks, publications and extant diagnostic codes. Terms were hierarchically mapped to super-categories (e.g. 'benign') and cellular/tissue-differentiation categories (e.g. 'melanocytic'), and appended with pertinent-modifiers and synonyms. These terms were evaluated using a modified-Delphi consensus approach. Experts from the International-Skin-Imaging-Collaboration (ISIC) were surveyed on agreement with terms and their hierarchical mapping; they could suggest modifying, deleting or adding terms. Consensus threshold was >75% for the initial rounds and >50% for the final round. RESULTS: Eighteen experts completed all Delphi rounds. Of 379 terms, 356 (94%) reached consensus in round one. Eleven of 226 (5%) benign-category terms, 6/140 (4%) malignant-category terms and 6/13 (46%) indeterminate-category terms did not reach initial agreement. Following three rounds, final consensus consisted of 362 terms mapped to 3 super-categories and 41 cellular/tissue-differentiation categories. CONCLUSIONS: We have created, agreed upon, and made public a taxonomy for skin neoplasms and their hierarchical mapping. Further study will be needed to evaluate the utility and completeness of the lexicon.

Review: PD-L1 as an emerging target in the treatment and prevention of keratinocytic skin cancer.

Recent advances in the understanding and targeting of immune checkpoints have led to great progress in immune therapies against many forms of cancer. While many types of immune checkpoints are currently targeted in the clinic, this review will focus on recent research implicating the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) axis as an emerging focus for the treatment of keratinocytic tumors. PD-L1 is of particular interest in nonmelanoma skin cancer (NMSC), as it is not only upregulated in these tumors but is stimulated by environmental ultraviolet exposure. This response may also make PD-L1 an excellent target for photochemoprevention using topically applied small molecule inhibitors. Here, we summarize recent investigations on PD-L1 expression and clinically relevant immune checkpoint inhibitor treatment in cutaneous squamous cell carcinoma, basal cell carcinoma, and head and neck squamous cell carcinoma, as well as small molecule agents targeting PD-L1 that may be useful for clinical development aiming at treatment or prevention of NMSC.

Handheld cross-polarised microscope for imaging individual pigmented cells in human skin in vivo.

We present the development of a simple, handheld cross-polarised microscope (CPM) and demonstration of imaging individual pigmented cells in human skin in vivo. In the CPM device, the cross-polarised detection approach is used to reduce the specular reflection from the skin surface and preferentially detect multiply-scattered light. The multiply-scattered light works as back illumination from within the tissue towards the skin surface, and superficial pigment such as intraepidermal melanin absorbs some spectral bands of the multiply-scattered light and cast coloured shadows. Since the light that interacted with the superficial pigment only needs to travel a short distance before it exits the skin surface, microscopic details of the pigment can be preserved. The CPM device uses a water-immersion objective lens with a high numerical aperture to image the microscopic details with minimal spherical aberrations and a small depth of focus. Preliminary results from a pilot study of imaging skin lesions in vivo showed that the CPM device could reveal three-dimensional distribution of pigmented cells and intracellular distribution of pigment. Co-registered CPM and reflectance confocal microscopy images showed good correspondence between dark, brown cells in CPM images and bright, melanin-containing cells in reflectance confocal microscopy images.

Comprehensive Physicochemical Characterization, In Vitro Membrane Permeation, and In Vitro Human Skin Cell Culture of a Novel TOPK Inhibitor, HI-TOPK-032.

Nonmelanoma skin cancers (NMSC) are the most common skin cancers, and about 5.4 million people are diagnosed each year in the United States. A newly developed T-lymphokine-activated killer cell-originated protein kinase (TOPK) inhibitor, HI-TOPK-032, is effective in suppressing colon cancer cell growth, inducing the apoptosis of colon cancer cells and ultraviolet (UV) light-induced squamous cell carcinoma (SCC). This study aimed to investigate the physicochemical properties, permeation behavior, and cytotoxicity potential of HI-TOPK-032 prior to the development of a suitable topical formulation for targeted skin drug delivery. Techniques such as scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) spectroscopy, differential scanning calorimetry (DSC), hot-stage microscopy (HSM), X-ray powder diffraction (XRPD), Karl Fisher (KF) coulometric titration, Raman spectrometry, confocal Raman microscopy (CRM), attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR), and Fourier transform infrared microscopy were used to characterize HI-TOPK-032. The dose effect of HI-TOPK-032 on in vitro cell viability was evaluated using a 2D cell culture of the human skin keratinocyte cell line (HaCaT) and primary normal human epidermal keratinocytes (NHEKs). Transepithelial electrical resistance (TEER) at the air-liquid interface as a function of dose and time was measured on the HaCAT human skin cell line. The membrane permeation behavior of HI-TOPK-032 was tested using the Strat-M® synthetic biomimetic membrane with an in vitro Franz cell diffusion system. The physicochemical evaluation results confirmed the amorphous nature of the drug and the homogeneity of the sample with all characteristic chemical peaks. The in vitro cell viability assay results confirmed 100% cell viability up to 10 µM of HI-TOPK-032. Further, a rapid, specific, precise, and validated reverse phase-high performance liquid chromatography (RP-HPLC) method for the quantitative estimation of HI-TOPK-032 was developed. This is the first systematic and comprehensive characterization of HI-TOPK-032 and a report of these findings.

Innovative Rocuronium Bromide Topical Formulation for Targeted Skin Drug Delivery: Design, Comprehensive Characterization, In Vitro 2D/3D Human Cell Culture and Permeation.

Cutaneous squamous cell carcinoma (cSCC) is the second-most common type of non-melanoma skin cancer and is linked to long-term exposure to ultraviolet (UV) radiation from the sun. Rocuronium bromide (RocBr) is an FDA-approved drug that targets p53-related protein kinase (PRPK) that inhibits the development of UV-induced cSCC. This study aimed to investigate the physicochemical properties and in vitro behavior of RocBr. Techniques such as thermal analysis, electron microscopy, spectroscopy and in vitro assays were used to characterize RocBr. A topical oil/water emulsion lotion formulation of RocBr was successfully developed and evaluated. The in vitro permeation behavior of RocBr from its lotion formulation was quantified with Strat-M® synthetic biomimetic membrane and EpiDerm™ 3D human skin tissue. Significant membrane retention of RocBr drug was evident and more retention was obtained with the lotion formulation compared with the solution. This is the first systematic and comprehensive study to report these findings.

Clinically Significant Risk Thresholds in the Management of Primary Cutaneous Melanoma: A Survey of Melanoma Experts.

BACKGROUND: Risk-based thresholds to guide management are undefined in the treatment of primary cutaneous melanoma but are essential to advance the field from traditional stage-based treatment to more individualized care. METHODS: To estimate treatment risk thresholds, hypothetical clinical melanoma scenarios were developed and a stratified random sample was distributed to expert melanoma clinicians via an anonymous web-based survey. Scenarios provided a defined 5-year risk of recurrence and asked for recommendations regarding clinical follow-up, imaging, and adjuvant therapy. Marginal probability of response across the spectrum of 5-year recurrence risk was estimated. The risk at which 50% of respondents recommended a treatment was defined as the risk threshold. RESULTS: The overall response rate was 56% (89/159). Three separate multivariable models were constructed to estimate the recommendations for clinical follow-up more than twice/year, for surveillance cross-sectional imaging at least once/year, and for adjuvant therapy. A 36% 5-year risk of recurrence was identified as the threshold for recommending clinical follow-up more than twice/year. The thresholds for recommending cross-sectional imaging and adjuvant therapy were 30 and 59%, respectively. Thresholds varied with the age of the hypothetical patient: at younger ages they were constant but increased rapidly at ages 60 years and above. CONCLUSIONS: To our knowledge, these data provide the first estimates of clinically significant treatment thresholds for patients with cutaneous melanoma based on risk of recurrence. Future refinement and adoption of thresholds would permit assessment of the clinical utility of novel prognostic tools and represents an early step toward individualizing treatment recommendations.

Development of a Checklist Tool to Assess the Quality of Skin Lesion Images Acquired by Consumers Using Sequential Mobile Teledermoscopy.

BACKGROUND: Mobile teledermoscopy is an emerging technology that involves imaging and digitally sending dermoscopic images of skin lesions to a clinician for assessment. High-quality, consistent images are required for accurate telediagnoses when monitoring lesions over time. To date there are no tools to assess the quality of sequential images taken by consumers using mobile teledermoscopy. The purpose of this study was to develop a tool to assess the quality of images acquired by consumers. METHODS: Participants imaged skin lesions that they felt were concerning at baseline, 1-, and 2-months. A checklist to assess the quality of consumer sequential imaging of skin lesions was developed based on the International Skin Imaging Collaboration guidelines. A scale was implemented to grade the quality of the images: 0 (low) to 18 (very high). Intra- and inter-reliability of the checklist was assessed using Bland-Altman analysis. Using this checklist, the consistency with which 85 sets of images were scored by 2 evaluators were compared using Kappa statistics. Items with a low Kappa value <0.4 were removed. RESULTS: After reliability testing, 5 of the items were removed due to low Kappa values (<0.4) and the final checklist included 13 items surveying: lesion selection; image orientation; lighting; field of view; focus and depth of view. Participants had a mean age of 41 years (range 19-73), and 67% were female. Most participants (84%, n = 71/85) were able to select and image the correct lesion over time for both the dermoscopic and overview images. Younger participants (<40 years old) scored significantly higher (8.1 ± 2.1) on the imaging checklist compared to older participants (7.1 ± 2.4; p = 0.037). Participants had most difficulty with consistent image orientation. CONCLUSIONS: This checklist could be used as a triage tool to filter images acquired by consumers prior to telediagnosis evaluation, which would improve the efficiency and accuracy of teledermatology and teledermoscopy processes. It may also be used to provide feedback to the consumers to improve image acquisition over time.

Digital skin imaging applications, part I: Assessment of image acquisition technique features.

BACKGROUND: The rapid adoption of digital skin imaging applications has increased the utilization of smartphone-acquired images in dermatology. While this has enormous potential for scaling the assessment of concerning skin lesions, the insufficient quality of many consumer/patient-taken images can undermine clinical accuracy and potentially harm patients due to lack of diagnostic interpretability. We aim to characterize the current state of digital skin imaging applications and comprehensively assess how image acquisition features address image quality. MATERIALS AND METHODS: Publicly discoverable mobile, web, and desktop-based skin imaging applications, identified through keyword searches in mobile app stores, Google Search queries, previous teledermatology studies, and expert recommendations were independently assessed by three reviewers. Applications were categorized by primary audience (consumer-facing, nonhospital-based practice, or enterprise/health system), function (education, store-and-forward teledermatology, live-interactive teledermatology, electronic medical record adjunct/clinical imaging storage, or clinical triage), in-app connection to a healthcare provider (yes or no), and user type (patient, provider, or both). RESULTS: Just over half (57%) of 191 included skin imaging applications had at least one of 14 image acquisition technique features. Those that were consumer-facing, intended for educational use, and designed for both patient and physician users had significantly greater feature richness (p < 0.05). The most common feature was the inclusion of text-based imaging tips, followed by the requirement to submit multiple images and body area matching. CONCLUSION: Very few skin imaging applications included more than one image acquisition technique feature. Feature richness varied significantly by audience, function, and user categories. Users of digital dermatology tools should consider which applications have standardized features that improve image quality.

Digital skin imaging applications, part II: a comprehensive survey of post-acquisition image utilization features and technology standards.

BACKGROUND: Despite the increasing ubiquity and accessibility of teledermatology applications, few studies have comprehensively surveyed their features and technical standards. Importantly, features implemented after the point of capture are often intended to augment image utilization, while technical standards affect interoperability with existing healthcare systems. We aim to comprehensively survey image utilization features and technical characteristics found within publicly discoverable digital skin imaging applications. MATERIALS AND METHODS: Applications were identified and categorized as described in Part I. Included applications were then further assessed by three independent reviewers for post-imaging content, tools, and functionality. Publicly available information was used to determine the presence or absence of relevant technology standards and/or data characteristics. RESULTS: A total of 20 post-image acquisition features were identified across three general categories: (1) metadata attachment, (2) functional tools (i.e., those that utilized images or in-app content to perform a user-directed function), and (3) image processing. Over 80% of all applications implemented metadata features, with nearly half having metadata features only. Individual feature occurred and feature richness varied significantly by primary audience (p < 0.0001) and function (p < 0.0001). On average, each application included under three features. Less than half of all applications requested consent for user-uploaded photos and fewer than 10% provided clear data use and privacy policies. CONCLUSION: Post-imaging functionality in skin imaging applications varies significantly by primary audience and intended function, though nearly all applications implemented metadata labeling. Technical standards are often not implemented or reported consistently. Gaps in the provision of clear consent, data privacy, and data use policies should be urgently addressed.

Intralesional Bleomycin Combined With Cryotherapy in the Treatment of Recalcitrant Verruca Vulgaris.

Verruca vulgaris is a common cutaneous manifestation of Human Papillomavirus (HPV) infection that presents as hyperkeratotic, cauliflower-like papules with central black petechiae. These lesions may be resistant to conventional therapies, posing a therapeutic challenge and prolong significant morbidity for the patient. This case report demonstrates an immediate and robust response of recalcitrant warts to intralesional bleomycin injection paired with cryotherapy. J Drugs Dermatol. 2022;21(2):195-196. doi:10.36849/JDD.6424.

Deep Learning-Based Denoising in High-Speed Portable Reflectance Confocal Microscopy.

BACKGROUND AND OBJECTIVE: Portable confocal microscopy (PCM) is a low-cost reflectance confocal microscopy technique that can visualize cellular details of human skin in vivo. When PCM images are acquired with a short exposure time to reduce motion blur and enable real-time 3D imaging, the signal-to-noise ratio (SNR) is decreased significantly, which poses challenges in reliably analyzing cellular features. In this paper, we evaluated deep learning (DL)-based approach for reducing noise in PCM images acquired with a short exposure time. STUDY DESIGN/MATERIALS AND METHODS: Content-aware image restoration (CARE) network was trained with pairs of low-SNR input and high-SNR ground truth PCM images obtained from 309 distinctive regions of interest (ROIs). Low-SNR input images were acquired from human skin in vivo at the imaging speed of 180 frames/second. The high-SNR ground truth images were generated by registering 30 low-SNR input images obtained from the same ROI and summing them. The CARE network was trained using the Google Colaboratory Pro platform. The denoising performance of the trained CARE network was quantitatively and qualitatively evaluated by using image pairs from 45 unseen ROIs. RESULTS: CARE denoising improved the image quality significantly, increasing similarity with the ground truth image by 1.9 times, reducing noise by 2.35 times, and increasing SNR by 7.4 dB. Banding noise, prominent in input images, was significantly reduced in CARE denoised images. CARE denoising provided quantitatively and qualitatively better noise reduction than non-DL filtering methods. Qualitative image assessment by three confocal readers showed that CARE denoised images exhibited negligible noise more often than input images and non-DL filtered images. CONCLUSIONS: Results showed the potential of using a DL-based method for denoising PCM images obtained at a high imaging speed. The DL-based denoising method needs to be further trained and tested for PCM images obtained from disease-suspicious skin lesions.

Speckle-free, near-infrared portable confocal microscope.

We have developed a portable confocal microscope (PCM) that uses an inexpensive near-infrared LED as the light source. Use of the spatially incoherent light source significantly reduced the speckle contrast. The PCM device was manufactured at the material cost of approximately $5000 and weighed only 1 kg. Lateral and axial resolutions were measured as 1.6 and 6.0 µm, respectively. Preliminary in vivo skin imaging experiment results showed that the PCM device could visualize characteristic cellular features of human skin extending from the stratum corneum to the superficial dermis. Dynamic imaging of blood flow in vivo was also demonstrated. The capability to visualize cellular features up to the superficial dermis is expected to facilitate evaluation and clinical adoption of this low-cost diagnostic imaging tool.

Chemoprevention agents for melanoma: A path forward into phase 3 clinical trials.

Recent progress in the treatment of advanced melanoma has led to unprecedented improvements in overall survival and, as these new melanoma treatments have been developed and deployed in the clinic, much has been learned about the natural history of the disease. Now is the time to apply that knowledge toward the design and clinical evaluation of new chemoprevention agents. Melanoma chemoprevention has the potential to reduce dramatically both the morbidity and the high costs associated with treating patients who have metastatic disease. In this work, scientific and clinical melanoma experts from the national Melanoma Prevention Working Group, composed of National Cancer Trials Network investigators, discuss research aimed at discovering and developing (or repurposing) drugs and natural products for the prevention of melanoma and propose an updated pipeline for translating the most promising agents into the clinic. The mechanism of action, preclinical data, epidemiological evidence, and results from available clinical trials are discussed for each class of compounds. Selected keratinocyte carcinoma chemoprevention studies also are considered, and a rationale for their inclusion is presented. These data are summarized in a table that lists the type and level of evidence available for each class of agents. Also included in the discussion is an assessment of additional research necessary and the likelihood that a given compound may be a suitable candidate for a phase 3 clinical trial within the next 5 years.

Guidelines of care for the management of primary cutaneous melanoma.

The incidence of primary cutaneous melanoma continues to increase each year. Melanoma accounts for the majority of skin cancer-related deaths, but treatment is usually curative following early detection of disease. In this American Academy of Dermatology clinical practice guideline, updated treatment recommendations are provided for patients with primary cutaneous melanoma (American Joint Committee on Cancer stages 0-IIC and pathologic stage III by virtue of a positive sentinel lymph node biopsy). Biopsy techniques for a lesion that is clinically suggestive of melanoma are reviewed, as are recommendations for the histopathologic interpretation of cutaneous melanoma. The use of laboratory, molecular, and imaging tests is examined in the initial work-up of patients with newly diagnosed melanoma and for follow-up of asymptomatic patients. With regard to treatment of primary cutaneous melanoma, recommendations for surgical margins and the concepts of staged excision (including Mohs micrographic surgery) and nonsurgical treatments for melanoma in situ, lentigo maligna type (including topical imiquimod and radiation therapy), are updated. The role of sentinel lymph node biopsy as a staging technique for cutaneous melanoma is described, with recommendations for its use in clinical practice. Finally, current data regarding pregnancy and melanoma, genetic testing for familial melanoma, and management of dermatologic toxicities related to novel targeted agents and immunotherapies for patients with advanced disease are summarized.

Transforming Dermatologic Imaging for the Digital Era: Metadata and Standards.

Imaging is increasingly being used in dermatology for documentation, diagnosis, and management of cutaneous disease. The lack of standards for dermatologic imaging is an impediment to clinical uptake. Standardization can occur in image acquisition, terminology, interoperability, and metadata. This paper presents the International Skin Imaging Collaboration position on standardization of metadata for dermatologic imaging. Metadata is essential to ensure that dermatologic images are properly managed and interpreted. There are two standards-based approaches to recording and storing metadata in dermatologic imaging. The first uses standard consumer image file formats, and the second is the file format and metadata model developed for the Digital Imaging and Communication in Medicine (DICOM) standard. DICOM would appear to provide an advantage over using consumer image file formats for metadata as it includes all the patient, study, and technical metadata necessary to use images clinically. Whereas, consumer image file formats only include technical metadata and need to be used in conjunction with another actor-for example, an electronic medical record-to supply the patient and study metadata. The use of DICOM may have some ancillary benefits in dermatologic imaging including leveraging DICOM network and workflow services, interoperability of images and metadata, leveraging existing enterprise imaging infrastructure, greater patient safety, and better compliance to legislative requirements for image retention.

Standardization of terminology in dermoscopy/dermatoscopy: Results of the third consensus conference of the International Society of Dermoscopy.

BACKGROUND: Evolving dermoscopic terminology motivated us to initiate a new consensus. OBJECTIVE: We sought to establish a dictionary of standardized terms. METHODS: We reviewed the medical literature, conducted a survey, and convened a discussion among experts. RESULTS: Two competitive terminologies exist, a more metaphoric terminology that includes numerous terms and a descriptive terminology based on 5 basic terms. In a survey among members of the International Society of Dermoscopy (IDS) 23.5% (n = 201) participants preferentially use descriptive terminology, 20.1% (n = 172) use metaphoric terminology, and 484 (56.5%) use both. More participants who had been initially trained by metaphoric terminology prefer using descriptive terminology than vice versa (9.7% vs 2.6%, P < .001). Most new terms that were published since the last consensus conference in 2003 were unknown to the majority of the participants. There was uniform consensus that both terminologies are suitable, that metaphoric terms need definitions, that synonyms should be avoided, and that the creation of new metaphoric terms should be discouraged. The expert panel proposed a dictionary of standardized terms taking account of metaphoric and descriptive terms. LIMITATIONS: A consensus seeks a workable compromise but does not guarantee its implementation. CONCLUSION: The new consensus provides a revised framework of standardized terms to enhance the consistent use of dermoscopic terminology.

Teledermoscopy in High-risk Melanoma Patients: A Comparative Study of Face-to-face and Teledermatology Visits.

Teledermoscopy is considered a reliable tool for the evaluation of pigmented skin lesions. We compared the management decision in face-to-face visits vs. teledermatology in a high-risk melanoma cohort using total-body photography, macroscopic and dermoscopic images of single lesions. Patients were assessed both face-to face and by 4 remote teledermatologists. Lesions identified as suspicious for skin cancer by face-to-face evaluation underwent surgical excision. The teledermatologists recommended "self-monitoring", "short-term monitoring", or "excision". A 4-year monitoring was completed in a cohort of participating subjects. The general agreement, calculated by prevalence and bias-adjusted κ (PABAK), showed almost perfect agreement (PABAK 0.9-0.982). A total of 23 lesions were excised; all teledermatologists identified the 9 melanomas. The greatest discrepancy was detected in "short-term monitoring". During 4-year monitoring one melanoma was excised that had been considered benign. In conclusion, melanoma identification by experts in pigmented lesions appears to be equivalent between face-to-face and teledermatological consultation.