Revealing the pathogenesis of keloids based on the status: Active vs inactive.

Recently, the pathomechanisms of keloids have been extensively researched using transcriptomic analysis, but most studies did not consider the activity of keloids. We aimed to profile the transcriptomics of keloids according to their clinical activity and location within the keloid lesion, compared with normal and mature scars. Tissue samples were collected (keloid based on its activity (active and inactive), mature scar from keloid patients and normal scar (NS) from non-keloid patients). To reduce possible bias, all keloids assessed in this study had no treatment history and their location was limited to the upper chest or back. Multiomics assessment was performed by using single-cell RNA sequencing and multiplex immunofluorescence. Increased mesenchymal fibroblasts (FBs) was the main feature in keloid patients. Noticeably, the proportion of pro-inflammatory FBs was significantly increased in active keloids compared to inactive ones. To explore the nature of proinflammatory FBs, trajectory analysis was conducted and CCN family associated with mechanical stretch exhibited higher expression in active keloids. For vascular endothelial cells (VECs), the proportion of tip and immature cells increased in keloids compared to NS, especially at the periphery of active keloids. Also, keloid VECs highly expressed genes with characteristics of mesenchymal activation compared to NS, especially those from the active keloid center. Multiomics analysis demonstrated the distinct expression profile of active keloids. Clinically, these findings may provide the future appropriate directions for development of treatment modalities of keloids. Prevention of keloids could be possible by the suppression of mesenchymal activation between FBs and VECs and modulation of proinflammatory FBs may be the key to the control of active keloids.

Revisiting roles of mast cells and neural cells in keloid: exploring their connection to disease activity.

Background: Mast cells (MCs) and neural cells (NCs) are important in a keloid microenvironment. They might contribute to fibrosis and pain sensation within the keloid. However, their involvement in pathological excessive scarring has not been adequately explored. Objectives: To elucidate roles of MCs and NCs in keloid pathogenesis and their correlation with disease activity. Methods: Keloid samples from chest and back regions were analyzed. Single-cell RNA sequencing (scRNA-seq) was conducted for six active keloids (AK) samples, four inactive keloids (IK) samples, and three mature scar (MS) samples from patients with keloids. Results: The scRNA-seq analysis demonstrated notable enrichment of MCs, lymphocytes, and macrophages in AKs, which exhibited continuous growth at the excision site when compared to IK and MS samples (P = 0.042). Expression levels of marker genes associated with activated and degranulated MCs, including FCER1G, BTK, and GATA2, were specifically elevated in keloid lesions. Notably, MCs within AK lesions exhibited elevated expression of genes such as NTRK1, S1PR1, and S1PR2 associated with neuropeptide receptors. Neural progenitor cell and non-myelinating Schwann cell (nmSC) genes were highly expressed in keloids, whereas myelinating Schwann cell (mSC) genes were specific to MS samples. Conclusions: scRNA-seq analyses of AK, IK, and MS samples unveiled substantial microenvironmental heterogeneity. Such heterogeneity might be linked to disease activity. These findings suggest the potential contribution of MCs and NCs to keloid pathogenesis. Histopathological and molecular features observed in AK and IK samples provide valuable insights into the mechanisms underlying pain and pruritus in keloid lesions.

Assessment of hair loss and skin changes during treatment in Asian breast cancer patients: A prospective cohort study.

With the increasing number of young breast cancer (BC) patients worldwide, concerns about hair loss and skin change persist among BC survivors. This study aimed to evaluate the hair loss and skin changes in Asian BC patients and to compare them according to the treatment regimens. This study enrolled 322 patients scheduled to undergo BC surgery. Hair loss and skin changes were assessed at the following two time points: one day before surgery and 6 months after surgery. Patients who had received systemic anticancer treatment before surgery were assigned to the neoadjuvant treatment group, while patients who were scheduled to receive systemic anticancer treatment were assigned to the adjuvant treatment group. In the adjuvant treatment group, patients with taxane-based chemotherapy had significantly higher odds of increased hair loss, a higher melanin index, and an increased volume of wrinkles (p < 0.0001, p = 0.0110, and p = 0.0371, respectively). In the neoadjuvant treatment group, hair loss was reversed in most patients at 6 months after surgery. Clinicians should inform BC patients about the potential for hair loss and skin changes and provide supportive care to mitigate the effects on the patients' quality of life.

Pleomorphic dermal sarcoma presenting in a child with Li-Fraumeni syndrome: A case report and review of the literature.

Pleomorphic dermal sarcoma (PDS) is an uncommon malignant soft-tissue tumor that occurs mostly in elderly patients, with only 5% of cases occurring in children. However, pediatric patients with Li-Fraumeni syndrome (LFS) can develop several types of cancer, particularly sarcomas. Here, we describe a young LFS patient who presented with early-onset PDS and review the literature.

Clinical characteristics and survival analysis of cutaneous metastases in a single tertiary centre in Korea.

BACKGROUND: Cutaneous metastasis (CM) refers to the spread of malignancy to the skin. CM is perceived as an advanced stage. It might be the first sign of a primary cancer or an indicator of recurrence. OBJECTIVES: To identify primary cancers associated with CMs and perform a survival analysis according to advanced stage of cutaneous metastasis at a single tertiary centre in Korea. METHODS: A total of 219 patients from Samsung Medical Center from January 2009 to April 2020 were retrospectively analysed to identify cases with biopsy-proven CMs. According to advanced stage of metastasis, patients were divided into three stages, CM only (CMO), CM with lymph node metastasis (CM/LM) and CM with distant metastasis (CM/DM), to analyse clinical characteristics and survival rate. RESULTS: The most common CM from primary cancer was breast cancer, followed by lung cancer, stomach cancer, colorectal cancer and others. When all primary cancers were included, the median survival period was 4.82 years for the CMO stage, 2.15 years for the CM/LM stage and 0.80 years for the CM/DM stage, with a tendency to deteriorate with advancing stage. At 1- and 3-year after occurrence of CM, the CM/DM stage showed a significantly poorer survival rate than the other two stages. CONCLUSIONS: This study showed a median survival period of 22 months for CM patients overall. Breast cancer has greater accessibility to the skin than other cancers. Therefore, breast cancer can metastasize to the skin without involving lymph nodes or other sites.

A Case of Cowden Syndrome Presenting with Diverse Cutaneous Manifestations.

Cowden syndrome is caused by mutations in the phosphatase and tensin homolog (PTEN) gene and is part of the PTEN hamartoma tumor syndrome. Skin lesions including trichilemmomas, acral keratosis, mucocunateous neuromas and oral paillomas are the most prevalent feature found in patients with Cowden syndrome. It also possesses an increased risk of developing malignancies including breast, thyroid, endometrial, and colorectal cancers. Due to the increased risk of cancer, early diagnosis and regular surveillance are important for Cowden syndrome patients. Herein, we report a case of Cowden syndrome with diverse cutaneous manifestations and thyroid cancer.

Molecular characterization of onychomatricoma: Spatial profiling reveals the role of onychofibroblasts in its pathogenesis.

Onychomatricoma (OM) is a rare nail unit tumour with a characteristic presentation of finger-like projections arising from the nail matrix. Due to the lack of transcriptome information, the mechanisms underlying its development are largely unknown. To characterize molecular features involved in the disease pathogenesis, we used digital spatial profiling (DSP) in 2 cases of OM and normal control nail units. Based on the histological evaluation, we selectively profiled 69 regions of interest covering epithelial and stromal compartments of each tissue section. Dermoscopic and histopathologic findings were reviewed in 6 cases. Single-cell RNA sequencing of nail units and DSP were combined to define cell type contributions of OM. We identified 173 genes upregulated in stromal compartments of OM compared to onychodermis, specialized nail mesenchyme. Gene ontology analysis of the upregulated genes suggested the role of Wnt pathway activation in OM pathogenesis. We also found PLA2G2A, a known modulator of Wnt signalling, is strongly and specifically expressed in the OM stroma. The potential role of Wnt pathway was further supported by strong nuclear localization of ß-catenin in OM. Compared to the nail matrix epithelium, only a few genes were increased in OM epithelium. Deconvolution of nail unit cell types showed that onychofibroblasts are the dominant cell type in OM stroma. Altogether, integrated spatial and single-cell multi-omics concluded that OM is a tumour that derives a significant proportion of its origin from onychofibroblasts and is associated with upregulation of Wnt signals, which play a key role in the disease pathogenesis.

Impact of Pediatric Alopecia Areata on Quality of Life of Patients and Their Family Members: A Nationwide Multicenter Questionnaire Study.

BACKGROUND: Pediatric alopecia areata (AA) can affect the quality of life (QoL) of patients and their family members. Research on the QoL and burden on family members in pediatric AA is limited. OBJECTIVE: This nationwide multicenter questionnaire study described the QoL and burden of the family members of patients with pediatric AA. METHODS: This nationwide multicenter questionnaire study enrolled AA patients between the ages of 5 and 18 years from March 1, 2017 to February 28, 2018. Enrolled patients and their parents completed the modified Children's Dermatology Life Quality Index (CDLQI) and the modified Dermatitis Family Impact (mDFI). The disease severity was measured using the Severity of Alopecia Tool (SALT) survey scores. RESULTS: A total of 268 patients with AA from 22 hospitals participated in this study. Our study found that the efficacy and satisfaction of previous treatments of AA decreased as the severity of the disease increased. The use of home-based therapies and traditional medicines increased with the increasing severity of the disease, but the efficacy felt by patients was limited. CDLQI and mDFI scores were higher in patients with extensive AA than those with mild to moderate AA. The economic and time burden of the family members also increased as the severity of the disease increased. CONCLUSION: The severity of the AA is indirectly proportional to the QoL of patients and their family members and directly proportional to the burden. Physicians need to understand these characteristics of pediatric AA and provide appropriate intervention to patients and their family members.

Comparative Spatial Transcriptomic and Single-Cell Analyses of Human Nail Units and Hair Follicles Show Transcriptional Similarities between the Onychodermis and Follicular Dermal Papilla.

The nail unit and hair follicle are both hard keratin-producing organs that share various biological features. In this study, we used digital spatial profiling and single-cell RNA sequencing to define a spatially resolved expression profile of the human nail unit and hair follicle. Our approach showed the presence of a nail-specific mesenchymal population called onychofibroblasts within the onychodermis. Onychodermis and follicular dermal papilla both expressed Wnt and bone morphogenetic protein signaling molecules. In addition, nail matrix epithelium and hair matrix showed very similar expressions profile, including the expression of hard keratins and HOXC13, a transcriptional regulator of the hair shaft. Integration of single-cell RNA sequencing and digital spatial profiling data through computational deconvolution methods estimated epithelial and mesenchymal cell abundance in the nail- and hair-specific regions of interest and revealed close transcriptional similarity between these major skin appendages. To analyze the function of bone morphogenetic proteins in nail differentiation, we treated cultured human nail matrix keratinocytes with BMP5, which are highly expressed by onychofibroblasts. We observed increased expressions of hard keratin and its regulator genes such as HOXC13. Collectively, our data suggest that onychodermis is the counterpart of dermal papilla and that BMP5 in onychofibroblasts plays a key role in the differentiation of nail matrix keratinocytes.

Incidence and Prevalence of Skin Cancers in South Korea from 2008 to 2016: A Nation-Wide Population Based Study.

Background: In South Korea, there have been few nationwide epidemiologic studies about premalignant actinic keratosis (AK), squamous cell carcinoma in situ (Bowen's disease), nonmelanoma skin cancer (NMSC), malignant melanoma of the skin (MM), Kaposi's sarcoma (KS), connective and soft tissue cancers, or mycosis fungoides (MF). Objective: Using a nationwide population-based study, we attempted to measure the incidence and the prevalence of the above-mentioned tumors in South Korea. Methods: The database we used included all claims in the Korean National Health Insurance program and the Korean Medical Aid program from 2008 to 2016. The International Classification of Diseases, 10th revision (ICD-10) was used to record diagnoses in this database. This data included AK, Bowen's disease, NMSC, MM, KS, connective and soft tissue cancers, and MF. Results: The age-standardized incidence and prevalence rate of AK, Bowen's disease, NMSC, MM, KS, connective and soft tissue cancers, as well as MF increased during the periods we investigated. The incidence and prevalence rate of AK and NMSC have increased two- to three-fold. In the case of Bowen's disease, MM, KS, connective and soft tissue cancers, or MF, we observed no significant tendency in age-standardized incidence or prevalence. Conclusion: We confirmed that the age-standardized incidence and prevalence rates of NMSC and AK tended to increase. These results might contribute to developing preventive and therapeutic strategies for skin cancers and may become a source for further studies.

Integrated Analysis of Single-Cell and Spatial Transcriptomics in Keloids: Highlights on Fibrovascular Interactions in Keloid Pathogenesis.

Studies on the etiopathogenesis of keloids mostly have focused on fibroblasts and their dysfunction. In this study, two cutting-edge technologies, single-cell RNA sequencing and spatial transcriptomics, were applied to uncover the underlying pathophysiology of keloids. Keloid tissue samples and normal skin control data were analyzed as well as those of patient-matched keloid and normal mature scar. Single-cell RNA sequencing revealed cellular heterogenicity such as fibroblasts, endothelial cells (ECs), and myofibroblasts within the keloids. Spatial transcriptomics results showed that disease-associated fibroblasts were enriched in the deeper keloid areas, mostly located around the spots with endothelial transcripts. Mesenchymal activation was observed in keloid ECs, characterized by dysregulation of TGF-ß/SMAD signaling. Colocalization of mesenchymal and vascular markers through multiplex immunofluorescence suggested mesenchymal activation of keloid ECs. Cell‒cell interaction analysis identified a significant network between keloid fibroblasts and ECs, and this cellular crosstalk was supported by colocalization analysis of spatial transcriptomics. This study depicted the cellular landscape of keloids at a single-cell resolution as well as the integration of single-cell and valuable spatial data of keloids using spatial transcriptomics and multiplex immunofluorescence technologies. Our findings suggested a potential role of fibrovascular communication and mesenchymal activation of ECs that might be involved in the keloid pathogenesis.

Hutchinson Sign: Biopsy May Assist in Diagnosis of Subungual Melanoma in Situ.

BACKGROUND: Early and accurate diagnosis of subungual melanoma (SUM) through histopathologic examination is critical, but lack of clinical suspicion leads to delays in diagnosis. Hutchinson sign (HS) can be one of the important clinical indicators for diagnosing SUM. OBJECTIVE: To evaluate the diagnostic value of small biopsies of HS for detecting SUM in situ. METHODS: We retrospectively evaluated 12 patients who were diagnosed as SUM in situ and underwent punch biopsy at HS areas. Clinical features, dermoscopic findings, and histopathologic findings in HS regions were analyzed. RESULTS: In most cases, HS was seen in hyponychium (11/12, 91.7%) with 1 case found in proximal nail fold, and 1 case in both the hyponychium and proximal nail fold. Dermoscopic features of HS showed irregular diffuse pigmentation (12/12, 100%) and parallel ridge pattern (7/12, 58.3%). Histopathologically, all cases showed irregularly scattered atypical melanocytes with hyperchromatic nuclei. Two cases showed subtle changes in melanocytes with little nuclear atypia, but additional section specimen showed more definitive findings of SUM in situ. CONCLUSION: We present a supplementary biopsy technique for diagnosing SUM. Biopsy of HS may help in the diagnosis of SUM.