Sex-dependent effects in the aged melanoma tumor microenvironment influence invasion and resistance to targeted therapy.

There is documented sex disparity in cutaneous melanoma incidence and mortality, increasing disproportionately with age and in the male sex. However, the underlying mechanisms remain unclear. While biological sex differences and inherent immune response variability have been assessed in tumor cells, the role of the tumor-surrounding microenvironment, contextually in aging, has been overlooked. Here, we show that skin fibroblasts undergo age-mediated, sex-dependent changes in their proliferation, senescence, ROS levels, and stress response. We find that aged male fibroblasts selectively drive an invasive, therapy-resistant phenotype in melanoma cells and promote metastasis in aged male mice by increasing AXL expression. Intrinsic aging in male fibroblasts mediated by EZH2 decline increases BMP2 secretion, which in turn drives the slower-cycling, highly invasive, and therapy-resistant melanoma cell phenotype, characteristic of the aged male TME. Inhibition of BMP2 activity blocks the emergence of invasive phenotypes and sensitizes melanoma cells to BRAF/MEK inhibition.

NCCN Guidelines® Insights: Merkel Cell Carcinoma, Version 1.2024.

The NCCN Guidelines for Merkel Cell Carcinoma (MCC) provide recommendations for diagnostic workup, clinical stage, and treatment options for patients. The panel meets annually to discuss updates to the guidelines based on comments from expert review from panel members, institutional review, as well as submissions from within NCCN and external organizations. These NCCN Guidelines Insights focus on the introduction of a new page for locally advanced disease in the setting of clinical node negative status, entitled "Clinical N0 Disease, Locally Advanced MCC." This new algorithm page addresses locally advanced disease, and the panel clarifies the meaning behind the term "nonsurgical" by further defining locally advanced disease. In addition, the guideline includes the management of in-transit disease and updates to the systemic therapy options.

Factors associated with residual tumor at time of Mohs micrographic surgery for basal cell and squamous cell carcinomas.

BACKGROUND: Residual tumor is not always clinically apparent following biopsy of cutaneous carcinomas, which may prompt patients to question the need for definitive treatment. OBJECTIVE: We investigated the percentage of cases in which residual tumor was histologically present at the time of Mohs micrographic surgery (MMS) for basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) and investigated factors associated with residual tumor. METHODS: We examined 483 MMS cases performed for biopsy-proven BCC (n = 287) and SCC (n = 196) between October 2022 and April 2023. Single-stage MMS specimens were step-sectioned en face to exhaust the block. Univariate and multivariable logistic regression models were created. RESULTS: Residual tumor was identified in 83.3% of BCC and 66.8% of SCC at the time of MMS (P = .01). In patients clinically appearing tumor-free following biopsy, residual histologic tumor was identified in 68.2% of BCC and 41.5% of SCC. Residual tumor was significantly more likely in men (P = .04), high-risk sites (P = .002), smaller biopsy sizes (P = .0003), and larger preoperative sizes (P < .0001). LIMITATIONS: Single center, retrospective cohort. CONCLUSION: The majority of patients with BCC and SCC have residual histologic tumor at the time of MMS, oftentimes even when tumor is not clinically apparent. Multiple factors impact the presence/absence of residual tumor.

Predictor Variables Associated With Dermatology Referral Completion and the Impact on Surgical Treatment: A Retrospective Cohort Study.

BACKGROUND: Delays or failure to complete a dermatologic referral may affect health care outcomes. Factors associated with these delays remain understudied. OBJECTIVE: This study investigated socioeconomic and demographic factors associated with delays or failure to complete dermatology referrals and potential impact on surgical outcomes. METHODS: A retrospective chart review was performed for 400 patients internally referred to an academic dermatology center from 19 primary-care clinics from July 2018 to June 2019. Only patients referred after an in-person primary-care visit in which the provider documented a specific concerning lesion were included. Multivariate analyses were performed to explore variables associated with delays or failure to complete dermatology referrals. RESULTS: Patients were more likely to complete their referral if they had a personal history (adjusted odds ratio [aOR] = 7.843, 95% CI 1.383-14.304) or family history (aOR = 11.307, 95% CI 2.344-20.27) of skin cancer. Patients were more likely to delay referral completion past 30 days if they were ages 18 to 34 (aOR = 6.665, 95% CI 1.285-12.044) and less likely to delay referral past 30 days if they had a previous history of skin cancer (aOR = 0.531, 95% CI 0.181-0.882). LIMITATIONS: Single institution, retrospective study, limited surgical patients. CONCLUSION: Understanding factors associated with delays in dermatology referral completion can help identify at-risk patient populations.

Modelling cutaneous squamous cell carcinoma for laboratory research.

Cutaneous squamous cell carcinoma (cSCC) leads to significant morbidity for patients with progression and metastases. However, the molecular underpinnings of these tumors are still poorly understood. Dissecting human cSCC pathogenesis amplifies the exigence for preclinical models that mimic invasion and nodal spread. This review discusses the currently available models, including two- and three-dimensional tissue cultures, syngeneic and transgenic mice, and cell line-derived and patient-derived xenografts. We further highlight studies that have utilized the different models, considering how they recapitulate specific hallmarks of cSCC. Finally, we discuss the advantages, limitations and future research directions.

Basal Cell Skin Cancer, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology.

Basal cell carcinoma (BCC) is the most common form of skin cancer in the United States. Due to the high frequency, BCC occurrences are not typically recorded, and annual rates of incidence can only be estimated. Current estimated rates are 2 million Americans affected annually, and this continues to rise. Exposure to radiation, from either sunlight or previous medical therapy, is a key player in BCC development. BCC is not as aggressive as other skin cancers because it is less likely to metastasize. However, surgery and radiation are prevalent treatment options, therefore disfigurement and limitation of function are significant considerations. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) outline an updated risk stratification and treatment options available for BCC.

Predictors of patient satisfaction with Mohs micrographic surgery at time of surgery and 3 months postsurgery: A prospective cohort study.

BACKGROUND: Despite the importance of patient satisfaction in ensuring high-quality care, studies investigating patient satisfaction in Mohs micrographic surgery (MMS) are limited. OBJECTIVE: We investigated the factors associated with patient satisfaction in MMS for nonmelanoma skin cancer and how patient satisfaction changes in the postoperative period. METHODS: In this prospective cohort study including 100 patients, patient satisfaction surveys were administered at the time of surgery and at 3 months postsurgery. Sociodemographic characteristics, medical history, and surgical parameters were collected by chart review. Univariate linear and logistic regression models were created to examine these relationships. RESULTS: Decreased satisfaction was observed in patients requiring 3 or more MMS stages both at the time of surgery (P = .047) and at 3 months post-surgery (P = .0244). Patients with morning procedures ending after 1:00 pm had decreased satisfaction at the time of surgery (P = .019). A decrease in patient satisfaction between the time of surgery and 3 months postsurgery was observed in patients with surgical sites on the extremities (P = .036), larger preoperative lesion sizes (P = .012), and larger defect sizes (P = .033). LIMITATIONS: Single-institution data, self-selection bias, and recall bias. CONCLUSION: Patient satisfaction with MMS is impacted by numerous factors and remains dynamic over time.

Patient Anxiety Related to Patient-Perceived Delays in Surgical Treatment of Skin Cancer.

BACKGROUND: Patients undergoing dermatologic surgery report higher anxiety levels than those undergoing nonsurgical treatments. However, little is known about the association between patient-perceived delays in skin cancer surgery and patient-reported anxiety. OBJECTIVE: To examine the relationship between patient-perceived delays in surgery and patient-reported anxiety. METHODS MATERIALS: Patients undergoing wide local excision or Mohs micrographic surgery were recruited to complete a survey to assess perception of surgical delay and anxiety related to skin cancer surgery using the validated Psychosocial Screen for Cancer-Revised. Demographic and surgical characteristics were collected through chart review. Chi-square and Student t -tests were used to compare demographic and surgical information between patients who did and did not perceive a surgical delay. Differences in anxiety and depression scores for patients who did and did not report a delay were assessed using univariate and multivariate regressions. RESULTS: Twenty-seven percent ( N = 33) of patients perceived a surgical delay. Perception of surgical delay was associated with increased time between biopsy and surgery ( p = .0001) and increased self-reported anxiety scores after controlling for various demographic and surgical factors ( p = .038). CONCLUSION: Patient-perceived delays in dermatologic surgery are associated with increased time to surgery and patient-reported anxiety.

Interventions After First Post-Transplant Cutaneous Squamous Cell Carcinoma: A Proposed Decision Framework.

Cutaneous squamous cell carcinoma (CSCC) is a major cause of morbidity and mortality after organ transplant. Many patients subsequently develop multiple CSCC following a first CSCC, and the risk of metastasis and death is significantly increased compared to the general population. Post-transplant CSCC represents a disease at the interface of dermatology and transplant medicine. Both systemic chemoprevention and modulation of immunosuppression are frequently employed in patients with multiple CSCC, yet there is little consensus on their use after first CSCC to reduce risk of subsequent tumors. While relatively few controlled trials have been undertaken, extrapolation of observational data suggests the most effective interventions may be at the time of first CSCC. We review the need for intervention after a first post-transplant CSCC and evidence for use of various approaches as secondary prevention, before discussing barriers preventing engagement with this approach and finally highlight areas for future research. Close collaboration between specialties to ensure prompt deployment of these interventions after a first CSCC may improve patient outcomes.

Validation of a 40-gene expression profile test to predict metastatic risk in localized high-risk cutaneous squamous cell carcinoma.

BACKGROUND: Current staging systems for cutaneous squamous cell carcinoma (cSCC) have limited positive predictive value for identifying patients who will experience metastasis. OBJECTIVE: To develop and validate a gene expression profile (GEP) test for predicting risk for metastasis in localized, high-risk cSCC with the goal of improving risk-directed patient management. METHODS: Archival formalin-fixed paraffin-embedded primary cSCC tissue and clinicopathologic data (n = 586) were collected from 23 independent centers in a prospectively designed study. A GEP signature was developed using a discovery cohort (n = 202) and validated in a separate, nonoverlapping, independent cohort (n = 324). RESULTS: A prognostic 40-GEP test was developed and validated, stratifying patients with high-risk cSCC into classes based on metastasis risk: class 1 (low risk), class 2A (high risk), and class 2B (highest risk). For the validation cohort, 3-year metastasis-free survival rates were 91.4%, 80.6%, and 44.0%, respectively. A positive predictive value of 60% was achieved for the highest-risk group (class 2B), an improvement over staging systems, and negative predictive value, sensitivity, and specificity were comparable to staging systems. LIMITATIONS: Potential understaging of cases could affect metastasis rate accuracy. CONCLUSION: The 40-GEP test is an independent predictor of metastatic risk that can complement current staging systems for patients with high-risk cSCC.

Initial skin cancer screening for solid organ transplant recipients in the United States: Delphi method development of expert consensus guidelines.

Skin cancer is the most common malignancy affecting solid organ transplant recipients (SOTR), and SOTR experience increased skin cancer-associated morbidity and mortality. There are no formal multidisciplinary guidelines for skin cancer screening after transplant, and current practices are widely variable. We conducted three rounds of Delphi method surveys with a panel of 84 U.S. dermatologists and transplant physicians to establish skin cancer screening recommendations for SOTR. The transplant team should risk stratify SOTR for screening, and dermatologists should perform skin cancer screening by full-body skin examination. SOTR with a history of skin cancer should continue regular follow-up with dermatology for skin cancer surveillance. High-risk transplant patients include thoracic organ recipients, SOTR age 50 and above, and male SOTR. High-risk Caucasian patients should be screened within 2 years after transplant, all Caucasian, Asian, Hispanic, and high-risk African American patients should be screened within 5 years after transplant. No consensus was reached regarding screening for low-risk African American SOTR. We propose a standardized approach to skin cancer screening in SOTR based on multidisciplinary expert consensus. These guidelines prioritize and emphasize the need for screening for SOTR at greatest risk for skin cancer.

Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.

Human polyomavirus-7-associated rash and pruritus (PVARP) is a chronic superficial viral skin infection, which primarily impacts immunocompromised individuals. We report on a case of PVARP in a lung transplant recipient. Our patient developed symptoms 13 years after being on his immunosuppressive regimen, with an insidious course of progressive gray lichenification with marked islands of sparing and quality of life-altering pruritus. Treatment for PVARP is not established; however, topical cidofovir combined with immunomodulation may offer sustained therapeutic benefit.

Eruptive Melanocytic Acral Nevi in the Setting of 6-mercaptopurine Therapy.

Eruptive melanocytic nevi (EMN) are a rare clinical finding characterized by sudden-onset nevi that often present in a grouped distribution. They have been associated with chemotherapy, immunosuppression, bullous diseases, and medications including multikinase and BRAF inhibitors. It is important for dermatologists to be able to identify patients with sudden development of new melanocytic nevi secondary to particular medications. Herein, we describe a case of eruptive melanocytic acral nevi secondary to 6-mercaptopurine therapy.

J Drugs Dermatol. 2017;16(5):516-518.

Rapamycin nanoparticles target defective autophagy in muscular dystrophy to enhance both strength and cardiac function.

Duchenne muscular dystrophy in boys progresses rapidly to severe impairment of muscle function and death in the second or third decade of life. Current supportive therapy with corticosteroids results in a modest increase in strength as a consequence of a general reduction in inflammation, albeit with potential untoward long-term side effects and ultimate failure of the agent to maintain strength. Here, we demonstrate that alternative approaches that rescue defective autophagy in mdx mice, a model of Duchenne muscular dystrophy, with the use of rapamycin-loaded nanoparticles induce a reproducible increase in both skeletal muscle strength and cardiac contractile performance that is not achievable with conventional oral rapamycin, even in pharmacological doses. This increase in physical performance occurs in both young and adult mice, and, surprisingly, even in aged wild-type mice, which sets the stage for consideration of systemic therapies to facilitate improved cell function by autophagic disposal of toxic byproducts of cell death and regeneration.

Genomic and transcriptomic analysis of cutaneous squamous cell carcinoma arising in immunocompetent and immunosuppressed patients.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is the most common skin malignancy arising in immunocompromised patients such as solid organ transplant recipients. In addition to an abundance in number, the morbidity and mortality of these tumors in this patient population exceeds that of immune competent individuals. Here, we used whole exome and bulk RNA sequencing to analyze mutation profiles between tumors arising in immunocompetent and immunosuppressed patients. METHODS: DNA and RNA extracted from twenty formalin-fixed, paraffin embedded tumors and adjacent skin was sequenced. Bioinformatic analysis revealed tumor mutational burden, mutational signatures, microsatellite instability, and aberrant signaling pathways. RESULTS: Similar median tumor mutational burden was found in both the tumors from the immunocompetent and the immunosuppressed cohorts. Mutation signature analysis revealed UVR signatures and evidence of azathioprine exposure. 50% of tumors from the immunosuppressed patients have mutations consistent with microsatellite instability, yet mismatch repair protein expression was preserved in the samples analyzed. Additionally, frequently mutated genes in this cohort belong to the extracellular matrix receptor interaction and calcium signaling pathways, suggesting these may be targets for future treatments of this disease. CONCLUSIONS: This study utilizes whole exome and bulk RNA sequencing to identify difference between cSCC arising in immunosuppressed and immunocompetent patients using the patient's photo exposed, but histologically normal appearing skin as the "germline" comparison. We demonstrate an enrichment in microsatellite instability in the tumors from immunosuppressed patients and differences in oxidative phosphorylation and epithelial-mesenchymal transition which may be targets for therapeutic intervention based on identification of mutations.

No Increased Risk of Major Adverse Cardiovascular Events following Nicotinamide Exposure.

IMPORTANCE: Nicotinamide metabolites have recently been implicated in increased risk of major cardiovascular events (MACE). Supportive data about clinical risk of MACE for nicotinamide users is lacking. OBJECTIVE: To determine whether nicotinamide use results in an increase of MACE. DESIGN SETTING PARTICIPANTS: Retrospective cohort study of two patient cohorts, Vanderbilt University Medical Center (VUMC) and Military Veteran Program (MVP). The risk of MACE in patients exposed to nicotinamide was compared to the risk of MACE in unexposed patients. In the VUMC cohort, 1228 patients were exposed to nicotinamide based on keyword entry for "nicotinamide" or "niacinamide" and hand-review of charts, while 253 were unexposed but had documented recommendation for use. In the MVP cohort, there were 1594 with exposure to nicotinamide propensity score matched to 2694 without exposure. EXPOSURES: The primary exposure for the VUMC cohort was a confirmed exposure to nicotinamide in chart review. The primary exposure for the MVP cohort was medication entry for "nicotinamide" or "niacinamide". MAIN OUTCOMES AND MEASURES: The primary outcome was development of MACE based on a validated phenotype. RESULTS: Between both cohorts, 6039 patients were included, of whom 5125 were male with a mean age of 63.2 years. Neither cohort had significant differences in mean age, sex, race and ethnicity between the nicotinamide exposed and unexposed groups. In the VUMC cohort, there was no significant association between nicotinamide exposure and the primary outcome of MACE (HR 0.76, 95% CI 0.46 - 1.25, p = 0.28). MACE prior to nicotinamide exposure was strongly associated with subsequent MACE (HR 9.01, 95% CI 5.90 - 13.70, p < 0.001). In the MVP cohort, we adjusted for MACE risk factors as potential confounding variables and saw no significant association between nicotinamide exposure and MACE (HR 1.00 95% CI 0.75 - 1.32), while history of prior MACE remained strongly associated with subsequent MACE (HR 9.50, 95% CI 6.38 - 14.1). CONCLUSIONS AND RELEVANCE: In this retrospective cohort study of 6039 adults from two different patient populations, we found no increased risk of MACE in patients with nicotinamide exposure.