Augmented interpretation of HER2, ER, and PR in breast cancer by artificial intelligence analyzer: enhancing interobserver agreement through a reader study of 201 cases.

BACKGROUND: Accurate classification of breast cancer molecular subtypes is crucial in determining treatment strategies and predicting clinical outcomes. This classification largely depends on the assessment of human epidermal growth factor receptor 2 (HER2), estrogen receptor (ER), and progesterone receptor (PR) status. However, variability in interpretation among pathologists pose challenges to the accuracy of this classification. This study evaluates the role of artificial intelligence (AI) in enhancing the consistency of these evaluations. METHODS: AI-powered HER2 and ER/PR analyzers, consisting of cell and tissue models, were developed using 1,259 HER2, 744 ER, and 466 PR-stained immunohistochemistry (IHC) whole-slide images of breast cancer. External validation cohort comprising HER2, ER, and PR IHCs of 201 breast cancer cases were analyzed with these AI-powered analyzers. Three board-certified pathologists independently assessed these cases without AI annotation. Then, cases with differing interpretations between pathologists and the AI analyzer were revisited with AI assistance, focusing on evaluating the influence of AI assistance on the concordance among pathologists during the revised evaluation compared to the initial assessment. RESULTS: Reevaluation was required in 61 (30.3%), 42 (20.9%), and 80 (39.8%) of HER2, in 15 (7.5%), 17 (8.5%), and 11 (5.5%) of ER, and in 26 (12.9%), 24 (11.9%), and 28 (13.9%) of PR evaluations by the pathologists, respectively. Compared to initial interpretations, the assistance of AI led to a notable increase in the agreement among three pathologists on the status of HER2 (from 49.3 to 74.1%, p < 0.001), ER (from 93.0 to 96.5%, p = 0.096), and PR (from 84.6 to 91.5%, p = 0.006). This improvement was especially evident in cases of HER2 2+ and 1+, where the concordance significantly increased from 46.2 to 68.4% and from 26.5 to 70.7%, respectively. Consequently, a refinement in the classification of breast cancer molecular subtypes (from 58.2 to 78.6%, p < 0.001) was achieved with AI assistance. CONCLUSIONS: This study underscores the significant role of AI analyzers in improving pathologists' concordance in the classification of breast cancer molecular subtypes.

An artificial intelligence-powered PD-L1 combined positive score (CPS) analyser in urothelial carcinoma alleviating interobserver and intersite variability.

AIMS: Immune checkpoint inhibitors targeting programmed death-ligand 1 (PD-L1) have shown promising clinical outcomes in urothelial carcinoma (UC). The combined positive score (CPS) quantifies PD-L1 22C3 expression in UC, but it can vary between pathologists due to the consideration of both immune and tumour cell positivity. METHODS AND RESULTS: An artificial intelligence (AI)-powered PD-L1 CPS analyser was developed using 1,275,907 cells and 6175.42 mm2 of tissue annotated by pathologists, extracted from 400 PD-L1 22C3-stained whole slide images of UC. We validated the AI model on 543 UC PD-L1 22C3 cases collected from three institutions. There were 446 cases (82.1%) where the CPS results (CPS ≥10 or <10) were in complete agreement between three pathologists, and 486 cases (89.5%) where the AI-powered CPS results matched the consensus of two or more pathologists. In the pathologist's assessment of the CPS, statistically significant differences were noted depending on the source hospital (P = 0.003). Three pathologists reevaluated discrepancy cases with AI-powered CPS results. After using the AI as a guide and revising, the complete agreement increased to 93.9%. The AI model contributed to improving the concordance between pathologists across various factors including hospital, specimen type, pathologic T stage, histologic subtypes, and dominant PD-L1-positive cell type. In the revised results, the evaluation discordance among slides from different hospitals was mitigated. CONCLUSION: This study suggests that AI models can help pathologists to reduce discrepancies between pathologists in quantifying immunohistochemistry including PD-L1 22C3 CPS, especially when evaluating data from different institutions, such as in a telepathology setting.

Discontinuation risk from adverse events: immunotherapy alone vs. combined with chemotherapy: a systematic review and network meta-analysis.

BACKGROUND: While immunotherapy combined with chemotherapy (Chemo-IO) is generally recognized for providing superior outcomes compared to monotherapy (mono-IO), it is associated with a higher incidence of treatment-related adverse events (TRAEs), which may lead to treatment discontinuation. In this study, we compared the rates of treatment discontinuation between mono-IO and Chemo-IO as first-line treatments for various solid tumors. METHODS: We systematically reviewed clinical trials from databases (PubMed, Embase, Cochrane Library, and an additional source) published from January 1, 2018, to July 10, 2023. We included phase III randomized controlled trials (RCTs) that utilized immunotherapy agents in at least one arm as first-line treatments for a variety of solid tumors. Data extraction followed the Preferred Reporting Items for Systematic Reviews (PRISMA) extension statement for network meta-analysis. A random effects model was used for the network meta-analysis, with the risk of bias assessed using the Cochrane risk-of-bias tool II. The primary outcomes encompassed treatment discontinuation rates due to TRAEs among patients who underwent immunotherapy, either alone or combined with chemotherapy, for various solid tumors. Pooled relative risks (RRs) with 95% confidence intervals (CIs) were calculated to compare between treatment groups. RESULTS: From 29 RCTs, a total of 21,677 patients and 5 types of treatment were analyzed. Compared to mono-IO, Chemo-IO showed a significantly higher rate of discontinuation due to TRAEs (RR 2.68, 95% CI 1.98-3.63). Subgroup analysis for non-small cell lung cancer (NSCLC) patients also exhibited a greater risk of discontinuation due to TRAEs with Chemo-IO compared to mono-IO (RR 2.93, 95% CI 1.67-5.14). Additional analyses evaluating discontinuation rates due to either treatment emergent adverse events (TEAEs) or AEs regardless of causality (any AEs) consistently revealed an elevated risk associated with Chemo-IO. CONCLUSIONS: Chemo-IO was associated with an elevated risk of treatment discontinuation not only due to TRAEs but also any AEs or TEAEs. Given that the treatment duration can impact clinical outcomes, a subset of patients might benefit more from mono-IO than combination therapy. Further research is imperative to identify and characterize this subset.

Clinical and Histological Effects of Topical Epidermal Growth Factor on Acne and Acne Scars.

BACKGROUND: The inflammatory lesions of acne leave scars which greatly affect patients' quality of life. Treatment options targeting both acne and acne scars are still lacking. OBJECTIVES: To evaluate the clinical efficacy of epidermal growth factor ointment (EGFO) on acne and acne scars. METHODS: The study design was 12-week, prospective, split-face, single-blinded. The 36 patients with mild to moderate acne vulgaris applied EGFO on one side of the face and the vehicle ointment on the other side twice daily. The patients were assessed every 4 weeks by acne lesion and scar counts, investigator's global assessment for acne (IGA) and scar (SGA), and the ECCA scar grading scale. Biopsies were performed before and after treatment. RESULTS: Acne and acne scars were significantly improved on EGFO-treated sides, while control sides were not. Acne lesion and scar counts were significantly reduced after 4 weeks, while IGA, SGA, and ECCA grade significantly decreased after 8 weeks. Immunohistochemistry showed decreased expression of keratin 16, NF-κB p65, IL-1α, and IL-8, and increased expression of TGF-ß1, elastin, and collagen type 1, 3 after treatment. CONCLUSIONS: EGFO can be a treatment option targeting acne and acne scars.

Risk of Skin Cancer and Actinic Keratosis in Patients with Rosacea: A Nationwide Population-based Cohort Study.

The association between rosacea and skin cancer remains inconclusive, with conflicting reports. The aim of this nationwide population-based cohort study was to determine the risk of skin cancer in patients with rosacea. A rosacea cohort (n = 11,420) was formulated and evaluated from 2010 to 2019. The incidence rate ratios of actinic keratosis, cutaneous melanoma, keratinocyte carcinoma and gastric, colorectal, and liver cancer were analysed in comparison with a matched control group, and multivariable stratified Cox proportional hazards model analysis was performed. The risk of actinic keratosis and keratinocyte carcinoma was increased in the rosacea group compared with the control group, with adjusted hazard ratios of 6.05 (95% confidence interval 3.63-10.09) and 2.66 (1.53-4.61), respectively. The risk of cutaneous melanoma and gastric, colorectal and liver cancer was not increased, with adjusted hazard ratios of 1.69 (0.25-11.37), 0.81 (0.59-1.10), 0.91 (0.69-1.18) and 1.32 (0.89-1.95), respectively. These results reveal an increased risk of actinic keratosis and keratinocyte carcinoma in patients with rosacea.

Granulomatous Rosacea in Korean Patients: Diagnosis Based on Combining Clinical and Histological Findings.

BACKGROUND: Granulomatous rosacea (GR) is a rare inflammatory skin disease, which is considered a variant of rosacea, apart from other types of rosacea. OBJECTIVE: This study aimed to summarize the characteristics of Korean patients diagnosed with GR by combining clinical and histological findings. METHODS: Fifteen cases, both clinically and histologically consistent with GR, were selected and were subsequently analyzed to describe clinical and histological characteristics. RESULTS: A total of 20 patients showed granulomatous infiltration in skin biopsies, but only 15 of them were clinically consistent with GR. Five patients who showed granulomatous inflammation were clinically consistent with erythematotelangiectatic or papulopustular rosacea. Among 15 patients, 13 (86.7%) were female and 2 (13.3%) were male. The most frequently involved area was the cheek, and none of the patients showed extrafacial lesions. There seems to be a possibility that treatment duration may be associated with the treatment response. CONCLUSIONS: This study confirms clinical characteristics of GR based on the diagnosis combining both clinical and histological findings.

Intradermal Microdroplet Injection of Diluted Incobotulinumtoxin-A for Sebum Control, Face Lifting, and Pore Size Improvement.

BACKGROUND: Intradermal injections of botulinum toxin have been reported to improve sebum secretion, facial skin laxity, and facial pores. However, the effects of Incobotulinumtoxin-A for these indications have not been reported. OBJECTIVE: To evaluate the efficacy of Incobotulinumtoxin-A for the improvement of sebum secretion, face laxity, and facial pores. MATERIALS AND METHODS: This single-center retrospective study included patients treated with Incobotulinumtoxin-A to improve facial skin laxity, sebum secretion, and facial pores. The microdroplet injection protocol included injection points on the lateral face, anterior medial cheek, mandibular line, depressor anguli oris points, mid-glabella area, and chin. Outcomes were measured using a Sebumeter and three-dimensional scanner and were evaluated by facial laxity ratings and the Global Aesthetic Improvement Scale. RESULTS: Twenty patients were included in the analysis. Sebum secretion, mandibular length, facial pores, and facial laxity ratings were improved at 1 week and results were sustained through 12 weeks. All outcomes showed maximum improvement after 4 weeks. Evaluation using the Global Aesthetic Improvement Scale showed that all subjects reported at least a score of 2 (improved) after 4 weeks. CONCLUSION: This study showed that intradermal injection with Incobotulinumtoxin-A could be effective for face lifting, reduced sebum production, and improved facial pores. J Drugs Dermatol. 2021;20(1):49-54. doi:10.36849/JDD.5616.

Histone Deacetylase 1 Reduces Lipogenesis by Suppressing SREBP1 Transcription in Human Sebocyte Cell Line SZ95.

Proper regulation of sebum production is important for maintaining skin homeostasis in humans. However, little is known about the role of epigenetic regulation in sebocyte lipogenesis. We investigated histone acetylation changes and their role in key lipogenic gene regulation during sebocyte lipogenesis using the human sebaceous gland cell line SZ95. Sebocyte lipogenesis is associated with a significant increase in histone acetylation. Treatment with anacardic acid (AA), a p300 histone acetyltransferase inhibitor, significantly decreased the lipid droplet number and the expression of key lipogenic genes, including sterol regulatory-binding protein 1 (SREBP1), fatty acid synthase (FAS), and acetyl-CoA carboxylase (ACC). In contrast, treatment with trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, increased the expression of these genes. Global HDAC enzyme activity was decreased, and HDAC1 and HDAC2 expression was downregulated during sebaceous lipogenesis. Interestingly, HDAC1 knockdown increased lipogenesis through SREBP1 induction, whereas HDAC1 overexpression decreased lipogenesis and significantly suppressed SREBP1 promoter activity. HDAC1 and SREBP1 levels were inversely correlated in human skin sebaceous glands as demonstrated in immunofluorescence images. In conclusion, HDAC1 plays a critical role in reducing SREBP1 transcription, leading to decreased sebaceous lipogenesis. Therefore, HDAC1 activation could be an effective therapeutic strategy for skin diseases related to excessive sebum production.

Association of frequent intake of fast foods, energy drinks, or convenience food with atopic dermatitis in adolescents.

PURPOSE: Specific food consumption, besides food allergy, may aggravate atopic dermatitis (AD). However, previous reports on the association between AD and food intake in adolescents are scarce. The aim of this study was to determine the relationship between AD and specific food consumption frequency in adolescents. METHODS: A cross-sectional analysis using data from the Korea Youth Risk Behavior Web-based Survey 2017 was performed. The frequency of food consumption in the recent-diagnosed AD group (AD diagnosed within 12 months) compared to those in the previous-diagnosed AD (AD diagnosed more than 12 months ago) or control group were investigated. RESULTS: A total of 53,373 participants were eligible for this study. The weighted prevalence of the recent-diagnosed AD and the previous-diagnosed AD was 7.39% and 18.00%, respectively. When compared with subjects with the previous-diagnosed AD, those with the recent-diagnosed AD were significantly more likely to frequently consume fast foods (odds ratio OR 1.405; 95% CI 1.150-1.717), energy drinks (OR 1.457; 95% CI 1.175-1.807), or convenience food (OR 1.304; 95% CI 1.138-1.495). Patients of the recent-diagnosed AD were significantly more likely to frequently consume fast foods (OR 1.374; 95% CI 1.155-1.634) than the control group. The differences in the frequency of specific food consumption among groups were more pronounced in high school students than in middle school students. CONCLUSIONS: Frequent intake of fast foods, energy drinks, and convenience food was related to the recent-diagnosed AD in adolescents. Prospective cohort and interventional studies are needed to identify causal relationships.

Functional surgery versus amputation for in situ or minimally invasive nail melanoma: A meta-analysis.

BACKGROUND: Evidence on whether functional surgery is not inferior to amputation for the treatment of in situ or minimally invasive (Breslow thickness ≤0.5 mm) nail melanoma is limited. OBJECTIVE: To investigate the difference in local recurrence between the 2 interventions for in situ or minimally invasive nail melanoma using available published studies. METHODS: We performed systematic search on PubMed, Embase, Cochrane Library, trial registers, and grey literature databases from inception to June 28, 2018. We included observational studies with at least 5 patients with in situ or minimally invasive nail melanoma. Main outcome was local recurrence. RESULTS: The odds ratio synthesized from 5 studies including 109 patients (88 functional operations and 21 amputations) was 1.57 (95% confidence interval, 0.31-8.00). LIMITATIONS: Small sample size and possible interstudy heterogeneity. CONCLUSIONS: Our meta-analysis revealed no difference in local recurrence between the 2 interventions. Considering the functional deficit after amputation, conservative surgery should be the treatment of choice for in situ or minimally invasive nail melanoma.

Mucosal involvement is a risk factor for poor clinical outcomes and relapse in patients with pemphigus treated with rituximab.

Many studies have reported the outcome of rituximab use in pemphigus but studies regarding the clinical risk factors for poor clinical outcomes or relapse are lacking. To clarify the risk factors for poor clinical outcomes or relapse in patients with pemphigus treated with rituximab, a retrospective chart analysis was performed on patients with pemphigus who were treated with rituximab in the dermatology clinic of Seoul National University Hospital. Forty patients with pemphigus were treated with rituximab, of which 39 (97.5%) experienced remission and 19 (48.7%) experienced relapse. Patients with mucosal lesions demonstrated poor clinical outcomes. The risk for relapse was 4.626 (confidence interval: 1.126-19.001, p = .034) times higher in patients with mucosal lesions than in those without lesions. In patients with pemphigus treated with rituximab, the presence of mucosal lesions resulted in poor clinical outcomes and frequent recurrence.

Pruritus in Patients Under Targeted Anticancer Therapy: A Multidimensional Analysis Using the 5-D Itch Scale.

Pruritus is a very common symptom in patients, undergoing targeted anticancer therapy. However, the characteristics of pruritus, according to the targeted anticancer agents, are still unclear. The objective of this study was to determine the characteristics of pruritus, induced by targeted anticancer agents, using a questionnaire-based survey. The survey was administered to cancer patients currently receiving anticancer agents. Medical records were also reviewed. A total of 374 cancer patients completed the survey, of which 108 were treated with the targeted therapy. A total of 205 patients had pruritus, of which 66 were under the targeted therapy. Epidermal growth factor receptor inhibitor (EGFRI) users showed the highest prevalence rate of itching and numeric rating scale score for itching. The 5-D itch score was also highest among users of EGFRIs. In conclusion, patients receiving EGFRIs suffer from severe pruritus frequently. They not only experienced long lasting and intense itching, causing sleep discomfort, but also developed itching at specific body sites.

Increased expression of three types of transient receptor potential channels (TRPA1, TRPV4 and TRPV3) in burn scars with post-burn pruritus.

Post-burn pruritus is a common distressing consequence of burn wounds. Empirical treatment often fails to have a satisfactory outcome on post-burn pruritus, as the mechanism of post-burn pruritus has not been fully elucidated. The aim of this study was to evaluate the manifestation of transient receptor potential (TRP) channels in post-burn pruritus. Fifty-one burn patients with (n=33) or without (n=18) pruritus were investigated, including skin biopsies. Not unexpectedly, the scarred body area was larger in the former group. In immunohistochemistry, TPRV3 was significantly elevated in the epidermis of burn scars with pruritus. Furthermore, real time- PCR showed that mRNA of TRPA1 and TRPV4 was increased in itching burn scars. Staining for substance P and CGRP did not differ between the 2 grouped, but the former neuropeptide was increased in burn scars. These results may help determine a specific therapeutic approach for post-burn pruritus.