Tumor-associated macrophages (TAM) exert essential functions during the immune response to cancer. However, investigations of TAM within a native human tumor microenvironment (TME) have been impeded by a lack of appropriate model systems. Here, patient-derived organoids (PDO) from air-liquid interface (ALI)-grown tumor fragments, containing a human TME that encompassed stroma and immune subsets, robustly preserved TAM that were maintained by endogenous CSF-1 and appropriately responded to polarization signals. Antibody blockade of the CD47 regulatory checkpoint in organoids stimulated phagocytosis and remodeled TAM cytokine secretion profiles that were confirmed in anti-CD47 phase I trial patients. Amongst PDO histologies screened, anti-CD47 tumor killing was notable in clear cell renal cell carcinoma (ccRCC) which was associated with increased TAM infiltration. PDO contained diverse previously described TAM subsets; however, anti-CD47 reprogrammed organoid TAM toward an immunosuppressive SPP1+ phenotype, highlighting a negative feedback mechanism. Our findings uncover a resistance circuit engaged by macrophage checkpoint blockade and position ALI PDO as a robust translational platform for dissecting human macrophage biology and informing precision immunotherapy.

According to the United States Census Bureau, the population aged ≥ 65 years is projected to increase, and the percentage of office visits from older adults to specialist physicians, such as dermatologists, will also increase. Despite older adults comprising an estimated 40

Older adults represent a growing proportion of dermatology patients, yet their care is complicated by multimorbidity, cognitive vulnerability, polypharmacy, functional decline, and competing health priorities. The Geriatric 5Ms framework (Mind, Mobility, Medications, Multi-Complexity, and Matters Most) offers a structured, patient-centered approach to address these challenges. This review applies the 5Ms to the management of common dermatoses in older adults, highlighting cognitive–regimen mismatch and preservation of autonomy (Mind), fall-risk and physical limitations affecting treatment feasibility (Mobility), polypharmacy and prescribing cascades (Medications), multimorbidity and caregiver context (Multi-Complexity), and alignment of care with patient goals (Matters Most). Integrating the 5Ms into dermatologic practice can enhance safety, preserve function, and align treatment with individual priorities.

BACKGROUND:Acanthosis nigricans (AN) is a highly visible cutaneous condition that has been associated with cardiometabolic factors, drugs, or malignancy in various populations. AN can be challenging to treat. Transmasculine patients are a special population, but their AN prevalence, and whether AN associates with demographic factors, co-morbidities and gender affirming care (GAC) treatment types have not been well-studied. Our study explores whether GAC treatment type is associated with AN while controlling for confounders in a large group of transmasculine patients at an academic center. METHODS:Following Institutional Review Board approval, the Stanford Research Repository (01/01/2016-21/09/2023) was searched to identify transmasculine patients for individual chart review. The primary outcome was AN and its association with demographic factors, co-morbidities, and gender-affirming care (GAC) treatment type by multivariate logistic regression (presented as Odds Ratio (OR) and 95% Confidence Interval (CI)). RESULTS:Out of 945 transmasculine patients, AN prevalence was 4.55%, an elevated rate compared to the overall database prevalence of 0.3% for the same period. Prevalence of AN in transmasculine patients never exposed to GAC was 4.02% (7/174). Median age was 20.1 years (interquartile range (IQR) 17.2-25.4). On multivariate logistic regression, AN was associated with obesity (OR 9.31, 95% CI 4.40-20.33), metabolic syndrome (OR 4.04, 95% CI 1.09-15.23), prediabetes (OR 3.17, 95% CI 1.10-8.54), hypertension (OR 2.74, 95% CI 0.96-7.18), and Hispanic ethnicity (OR 2.46, 95% CI 1.12-5.25). GAC type (including exogenous testosterone usage) was not associated with AN, despite >99% power to detect a 10% difference in AN prevalence. CONCLUSIONS:Because AN is enriched in transmasculine patients, and precedes co-morbidities in a majority of cases, dermatologists and other physicians should consider examination of common areas for AN in in transmasculine patients, as screening and diagnosis of co-morbidities could lead to improved health outcomes.

ABSTRACT Background Age‐associated skin frailty affects hundreds of millions of adults globally. However, a validated and reliable scale to visually quantitate skin frailty is lacking, posing a barrier to clinical care and research. Objectives To develop a validated and reliable visual scale for skin frailty and assess its association with demographic and clinical factors. Methods Stanford Human Subjects Panel approval and informed consent were obtained prior to all procedures. Skin frailty parameters were identified on a literature review and assessed by two expert board‐certified dermatologists to generate content validity indices (CVIs). Skin frailty parameters on 219 digital photographs of the upper extremity in outpatient adult volunteers (age 18–89 years) were assessed, with reliability calculated by Kendall's coefficient or Gwet's AC2. A Skin Frailty Score (SFS) was developed using parameters with excellent, good, or moderate reliability. SFS was interrogated for the association with demographic/clinical factors. To improve SFS usability, factor analysis was performed to reduce the number of parameters, while retaining reliability and clinical relevance. Results Nine parameters demonstrated CVI > 0.80. Strong intra‐rater reliability was observed for these 9 parameters (Kendall's coefficient or Gwet's AC2 > 0.80). Strong inter‐rater reliability was observed for 8/9 parameters (Kendall's coefficient and Gwet's AC2 > 0.80); one showed good inter‐rater reliability (Kendall's coefficient = 0.67). This 9‐parameter SFS demonstrated good intra‐rater reliability (intra‐class correlation coefficient = 0.85) and moderate inter‐rater reliability (intra‐class correlation coefficient = 0.69). By multivariate analysis, higher SFS was associated with age, female sex, and non‐melanoma skin cancer (all p < 0.01). To improve SFS usability, factor analysis enabled parameter reduction to 6, while maintaining moderate inter‐rater and good intra‐rater reliability (intra‐class correlation coefficient = 0.62 and 0.77, respectively) and clinical relevance. Conclusions SFS is a novel, validated, and reliable visual scoring scale of skin frailty of the upper extremity that could be incorporated into clinical and research settings.

The number of people with nonmelanoma skin cancers (NMSCs) and chronic haematopoietic disorders (CHDs) is increasing worldwide. Using three databases, we found that acitretin was associated with a decreased incidence of NMSCs (particularly cutaneous squamous cell carcinoma/squamous cell carcinoma in situ) in patients with CHDs. Prospective studies are needed to define dosing and side-effects.

Immune checkpoint inhibitors such as anti-Programmed Death-1 antibodies (aPD-1) can be effective in treating advanced cancers. However, many patients do not respond, and the mechanisms underlying these differences remain incompletely understood. In this study, we profile a cohort of patients with locally advanced or metastatic basal cell carcinoma undergoing aPD-1 therapy using single-cell RNA sequencing, high-definition spatial transcriptomics in tumors and draining lymph nodes, and spatial immunoreceptor profiling, with long-term clinical follow-up. We find that successful responses to PD-1 inhibition are characterized by an induction of B cell receptor (BCR) clonal diversity after treatment initiation. These induced BCR clones spatially colocalize with T cell clones, facilitate their activation, and traffic alongside them between tumor and draining lymph nodes to enhance tumor clearance. Furthermore, we validated aPD-1-induced BCR diversity as a predictor of clinical response in a larger cohort of glioblastoma, melanoma, and head and neck squamous cell carcinoma patients, suggesting that this is a generalizable predictor of treatment response across many types of cancers. We find that pretreatment tumors harbor a characteristic gene expression signature that portends a higher probability of inducing BCR clonal diversity after aPD-1 therapy, and we develop a machine learning model that predicts PD-1-induced BCR clonal diversity from baseline tumor RNA sequencing. These findings underscore a dynamic role of B cell diversity during immunotherapy, highlighting its importance as a prognostic marker and a potential target for intervention in non-responders.

This qualitative study examines whether patient-reported outcomes measures for acne incorporate LGBTQ+-inclusive language.

Smoothened inhibitors (SMOi), also known as hedgehog inhibitors (HHI), are targeted therapies that have transformed the locally advanced BCC and metastatic BCC treatment landscape. Landmark studies ERIVANCE and BOLT facilitated FDA approval of vismodegib in 2012 and sonidegib in 2015, respectively, and provided valuable insights into SMOi efficacy, dosing, pharmacokinetics, and adverse effects (AE). However, study differences have caused wide variability in treatment utilization. Nuanced clinical interpretation is critical. A 35-item RedCAP survey was released in Spring 2024 via email to the Skin Cancer Outcomes Consortium. Twenty-nine clinicians who treat advanced BCC responded. The majority of respondents (58.3%) indicated that they believed that vismodegib and sonidegib are similar therapeutic options for laBCC and mBCC. Similarly, 45.8% believed both SMOi to have similar tolerability, followed by 29.9% who believed sonidegib to be somewhat more tolerable than vismodegib. When asked, “All things considered, which drug do you believe is superior for treating locally advanced BCC?” 41.7% responded that they believed them to be similar, 25% said ‘I don’t know’, 20.8% chose sonidegib, and only 12.4% chose vismodegib. However, reported prescribing habits paradoxically favored vismodegib, with 54.5% of clinicians primarily prescribing vismodegib, 36.4% preferring sonidegib, and only 9.1% endorsing prescribing both equally. These findings highlight the lack of uniformity, as well as familiarity, with the therapeutic options of SMOi for advanced BCC. Updating SMOi clinical guidelines and the creation of management strategies, including considerations for AE, dosing options, and drug switching, are needed to improve and standardize patient care.

Metastatic cutaneous squamous cell carcinomas (CSCCs) in patients with dysregulated immune systems, such as those with chronic lymphocytic leukemia (CLL), are a challenging yet growing group of patients, especially when they are not responsive to checkpoint immunotherapies. Talimogene laherparepvec (TVEC) is an oncolytic herpes virus approved by the US Food and Drug Administration in 2015 for melanoma recurrent after initial surgery and delivers human granulocyte-macrophage colony-stimulating factor leading to antitumor immune response.

AbstractBackgroundA phase 2 cemiplimab study (NCT03132636) demonstrated a 24.1% objective response rate in patients diagnosed with metastatic basal cell carcinoma (mBCC) who were not candidates for continued hedgehog inhibitor (HHI) therapy due to intolerance to previous HHI therapy, disease progression while receiving HHI therapy, or having not better than stable disease on HHI therapy after 9 months. Here, health‐related quality of life (QoL) for this patient population is reported.MethodsAdult patients with mBCC were treated with intravenous cemiplimab at a dose of 350 mg every 3 weeks for 5 treatment cycles of 9 weeks/cycle then 4 treatment cycles of 12 weeks/cycle. Patients completed the European Organisation for Research and Treatment of Cancer Quality of Life‐Core 30 (QLQ‐C30) and Skindex‐16 questionnaires at baseline and Day 1 of each cycle. Across Cycles 2 to 9, the overall change from baseline was analyzed using a mixed model with repeated measures. Responder analyses determined clinically meaningful improvement or deterioration (changes ≥10 points) or maintenance across all scales.ResultsPatients reported low symptom burden and moderate‐to‐high functioning at baseline. Maintenance for QLQ‐C30 global health status (GHS)/QoL and across all functioning and symptom scales was indicated by overall mean changes from baseline. Clinically meaningful improvement or maintenance was reported at Cycle 2 for GHS/QoL (77%), functioning scales (77% to 86%), and symptom scales (70% to 93%), with similar proportions of improvement or maintenance at Cycles 6 and 9, excluding fatigue. On the Skindex‐16, clinically meaningful improvement or maintenance was reported across the emotional, symptom, and functional subscales, in 76%–88% of patients at Cycle 2, which were generally maintained at Cycles 6 and 9. Overall mean changes from baseline showed maintenance across these subscales.ConclusionsThe majority of patients treated with cemiplimab reported improvement or maintenance in GHS/QoL and functioning while maintaining a low symptom burden.

Background• Patients with metastatic basal cell carcinoma (mBCC) who are not candidates for surgery or radiation therapy are generally treated with hedgehog signaling pathway inhibitors (HHIs). 1 -However, intolerance and resistance to HHIs are common. 1• Cemiplimab-rwlc is approved in the United States for patients with mBCC and locally advanced BCC (laBCC) following HHI treatment or for whom HHIs are not appropriate. 2• In a Phase 2 clinical trial (NCT03132636), cemiplimab demonstrated an objective response rate of 24.1% (95% CI: 13.5-37.6%) in patients with mBCC who progressed on or were intolerant to HHIs. 3• Efficacy and health-related quality of life (HRQoL) data for patients with laBCC were previously reported. 4 Objective• To evaluate HRQoL in patients with mBCC who were treated with cemiplimab in the phase 2 clinical trial (NCT03132636). Methods• In this phase 2, non-randomized, multicenter, pivotal trial of cemiplimab, adults (≥18 years old) with mBCC and Eastern Cooperative Oncology Group performance status ≤1 (N=54) received cemiplimab 350 mg intravenous every 3 weeks for up to 9 treatment cycles.-mBCC was based on histologic confirmation of distant BCC metastases to lung, liver, bone, or lymph node, and included patients with both nodal and distant metastatic disease.• At baseline and Day 1 of each treatment cycle, patients were administered the European Organisation forResearch and Treatment of Cancer Quality of Life-Core 30 (EORTC QLQ-C30) 6 and Skindex-16 7 questionnaires (Table 1).-Follow-up assessment was conducted 28-42 days after the last study treatment administration if a patient discontinued early.• Analyses were conducted on the full analysis set, which consisted of all enrolled patients who were deemed eligible for the study.• Mixed-model repeated-measures (MMRM) analyses were used to estimate overall least-squares (LS) mean change from baseline and 95% CI across Cycles 2-9 on all scales for patients with baseline and ≥1 post-baseline value. Conclusions• Results of this pivotal clinical trial of cemiplimab showed that, in addition to providing clinically meaningful antitumour activity and durable responses in patients with mBCC, 3 patient-reported HRQoL was maintained during the study.-From baseline to Cycle 9, most patients treated with cemiplimab reported:• Maintenance or improvement in QLQ-C30 GHS/QoL and functioning while maintaining a low symptom burden.• Maintenance across all 3 subscales on the Skindex-16.