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.

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.

Standardizing Retrospective Observational Research in Cutaneous Squamous Cell Carcinoma: Expert Panel Guidelines from ITSCC.

Importance: Cutaneous squamous cell carcinoma (CSCC) is the second most common malignant disease in the US. Although it typically carries a good prognosis, a subset of CSCCs are highly aggressive, carrying regional and distant metastatic potential. Due to its high incidence, this aggressive subset is responsible for considerable mortality, with an overall annual mortality estimated to equal or even surpass melanoma. Despite this morbidity, CSCC is excluded from national cancer registries, making it difficult to study its epidemiology and outcomes. Therefore, the bulk of the CSCC literature is composed of single-center and multi-institutional retrospective cohort analyses. Given variations in reporting measures and analyses in these studies, interpretability between studies and the ability to pool results are limited. Objective: To define standardized reporting measures for retrospective CSCC studies. Findings: An expert panel was convened to determine standardized guidelines for recording and analyzing retrospective CSCC data. A total of 13 dermatologists and dermatologic surgeons with more than 5 years of posttraining experience and considerable experience with performing CSCC outcomes research were recruited to the panel. Consensus recommendations were achieved for CSCC retrospective study reporting measures, definitions, and analyses. Conclusions and Relevance: The recommendations in this report present the potential to standardize future CSCC retrospective studies. With such standardization, future work may have greater interstudy interpretability and allow for pooled analyses.

Nivolumab + Tacrolimus + Prednisone ± Ipilimumab for Kidney Transplant Recipients With Advanced Cutaneous Cancers.

PURPOSE: Cancer-related mortality rates among kidney transplant recipients (KTR) are high, but these patients have largely been excluded from trials of immune checkpoint inhibitors because of immunosuppression and risk of treatment-related allograft loss (TRAL). We conducted a prospective clinical trial testing nivolumab (NIVO) + tacrolimus (TACRO) + prednisone (PRED) ± ipilimumab (IPI) in KTR with advanced cutaneous cancers. METHODS: Adult KTR with advanced melanoma or basal, cutaneous squamous, or Merkel cell carcinomas were eligible. Immunosuppression was standardized to TACRO (serum trough 2-5 ng/mL) + PRED 5 mg once daily. Patients then received NIVO 480 mg IV once every 4 weeks. The primary composite end point was partial or complete (tumor) response (CR) or stable disease per RECIST v1.1 without allograft loss at 16W. Patients with progressive disease (PD) could receive IPI 1 mg/kg IV + NIVO 3 mg/kg once every 3 weeks × 4 followed by NIVO. Donor-derived cell-free DNA (dd-cfDNA) levels were measured approximately once every 2 weeks as a potential predictor of allograft rejection. RESULTS: Among eight evaluable patients, none met the trial's primary end point. All eight patients experienced PD on NIVO + TACRO + PRED; TRAL occurred in one patient. Six patients then received IPI + NIVO + TACRO + PRED. Best overall responses: two CR (one with TRAL) and four PD (one with TRAL). In total, 7 of 8 pre-NIVO tumor biopsies contained a paucity of infiltrating immune cells. In total, 2 of 5 on-NIVO biopsies demonstrated moderate immune infiltrates; both patients later experienced a CR to IPI + NIVO. In 2 of 3 patients with TRAL, dd-cfDNA elevations occurred 10 and 15 days before increases in serum creatinine. CONCLUSION: In most KTR with advanced skin cancer, TACRO + PRED provides insufficient allograft protection and compromises immune-mediated tumor regression after administration of NIVO ± IPI. Elevated dd-cfDNA levels can signal treatment-related allograft rejection earlier than rises in serum creatinine.

The apical sorting signal for human GLUT9b resides in the N-terminus.

The two splice variants of human glucose transporter 9 (hGLUT9) are targeted to different polarized membranes. hGLUT9a traffics to the basolateral membrane, whereas hGLUT9b traffics to the apical region. This study examines the sorting mechanism of these variants, which differ only in their N-terminal domain. Mutating a di-leucine motif unique to GLUT9a did not affect targeting. Chimeric proteins were made using GLUT1, a basolaterally targeted transporter, and GLUT3, an apically targeted protein whose signal lies in the C-terminus. Overexpression of the chimeric proteins in polarized cells demonstrates that the N-terminus of hGLUT9b contains a signal capable of redirecting GLUT1 to the apical membrane. The N-terminus of hGLUT9a, however, does not contain a basolateral signal sufficient enough to redirect GLUT3. Portions of the GLUT9a N-terminus were substituted with corresponding portions of the GLUT9b N-terminus to determine the motif responsible for apical targeting. The first 16 amino acids were not found to be a sufficient apical signal. The last ten amino acids of the N-termini differ only in amino-acid class at one location. In the B-form, leucine, a hydrophobic residue, is substituted for lysine, a basic residue, found in the A-form. However, mutation of the leucine in hGLUT9b to a lysine resulted in retention of the apical signal. We therefore believe the apical signal exists as an interplay between the final ten amino acids of the N-terminus and another motif within the protein such as the intracellular loop or other motifs within the N-terminus.

Risk factors for the development of acne in healthcare workers during the COVID-19 pandemic.

The COVID-19 pandemic has led to many healthcare workers having prolonged contact with tight-fitting masks, leading to maskne. "Maskne" is defined as acne secondary to mask use. There are limited studies on maskne during the COVID-19 pandemic. The objective of this study is to identify risk factors for the development of maskne amongst healthcare workers. A cross-sectional survey was completed by 227 medical students, resident physicians, and nursing students at Johns Hopkins Medicine, with 68.7% of participants reporting development of maskne. Surgical masks and respirators were the most prevalent mask types worn at work. The most common prevention methods were the use of mild cleansers and moisturizers. Chi-squared analysis was used for data analysis. The results of this study indicate that gender (p = 0.003) and duration of mask use (p = 0.048) are significant risk factors for maskne development. These factors are non-modifiable, but may be used for more targeted education for prevention.