Multiplexed Imaging Mass Cytometry Analysis Characterizes the Vascular Niche in Pancreatic Cancer.

Oncogenesis and progression of pancreatic ductal adenocarcinoma (PDAC) is driven by complex interactions between the neoplastic component and the tumor microenvironment (TME), which includes immune, stromal, and parenchymal cells. In particular, most PDACs are characterized by a hypovascular and hypoxic environment that alters tumor cell behavior and limits the efficacy of chemotherapy and immunotherapy. Characterization of the spatial features of the vascular niche could advance our understanding of inter- and intra-tumoral heterogeneity in PDAC. Here, we investigated the vascular microenvironment of PDAC by applying imaging mass cytometry using a 26-antibody panel on 35 regions of interest (ROIs) across 9 patients, capturing over 140,000 single cells. The approach distinguished major cell types, including multiple populations of lymphoid and myeloid cells, endocrine cells, ductal cells, stromal cells, and endothelial cells. Evaluation of cellular neighborhoods identified 10 distinct spatial domains, including multiple immune and tumor-enriched environments as well as the vascular niche. Focused analysis revealed differential interactions between immune populations and the vasculature and identified distinct spatial domains wherein tumor cell proliferation occurs. Importantly, the vascular niche was closely associated with a population of CD44-expressing macrophages enriched for a pro-angiogenic gene signature. Together, this study provides insights into the spatial heterogeneity of PDAC and suggests a role for CD44-expressing macrophages in shaping the vascular niche.

Plasticity-induced repression of Irf6 underlies acquired resistance to cancer immunotherapy in pancreatic ductal adenocarcinoma.

Acquired resistance to immunotherapy remains a critical yet incompletely understood biological mechanism. Here, using a mouse model of pancreatic ductal adenocarcinoma (PDAC) to study tumor relapse following immunotherapy-induced responses, we find that resistance is reproducibly associated with an epithelial-to-mesenchymal transition (EMT), with EMT-transcription factors ZEB1 and SNAIL functioning as master genetic and epigenetic regulators of this effect. Acquired resistance in this model is not due to immunosuppression in the tumor immune microenvironment, disruptions in the antigen presentation machinery, or altered expression of immune checkpoints. Rather, resistance is due to a tumor cell-intrinsic defect in T-cell killing. Molecularly, EMT leads to the epigenetic and transcriptional silencing of interferon regulatory factor 6 (Irf6), rendering tumor cells less sensitive to the pro-apoptotic effects of TNF-α. These findings indicate that acquired resistance to immunotherapy may be mediated by programs distinct from those governing primary resistance, including plasticity programs that render tumor cells impervious to T-cell killing.

Performance measurement part I: Foundational knowledge for measure development.

As medicine is moving toward performance and outcome-based payment and is transitioning away from productivity-based systems, value is now being appraised in healthcare through "performance measures." Over the past few decades, assessment of clinical performance in health care has been essential in ensuring safe and cost-effective patient care. The Centers for Medicare & Medicaid Services is further driving this change with measurable, outcomes-based national payer incentive payment systems. With the continually evolving requirements in health care reform focused on value-based care, there is a growing concern that clinicians, particularly dermatologists, may not understand the scientific rationale of health care quality measurement. As such, in order to help dermatologists understand the health care measurement science landscape to empower them to engage in the performance measure development and implementation process, the first article in this 2-part continuing medical education series reviews the value equation, historic and evolving policy issues, and the American Academy of Dermatology's approach to performance measurement development to provide the required foundational knowledge for performance measure developers.

Performance measurement part II: A guide to developing dermatology performance measures.

Throughout the 21st century, national and local governments, private health sectors, health insurance companies, healthcare professionals, labor unions, and consumers have been striving to develop an effective approach to evaluate, report, and improve the quality of healthcare. As medicine improves and health systems grow to meet patient needs, the performance measurement system of care effectiveness must also evolve. Continual efforts should be undertaken to effectively measure quality of care to create a more informed public, improve health outcomes, and reduce healthcare costs. As such, recent policy reform has necessitated that performance systems be implemented in healthcare, with the "performance measure" being the foundation of the system in which all of healthcare must be actively engaged in to ensure optimal care for patients. The development of performance measures can be highly complex, particularly when creating specialty-specific performance measures. To help dermatologists understand the process of creating dermatology-specific performance measures to engage in creating or implementing performance measures at the local or national levels, this article in the two-part continuing medical education series reviews the types, components, and process of developing, reviewing, and implementing performance measures.

Coffee, Citrus, and Alcohol: A Review of What We Drink and How it May Affect our Risk for Skin Cancer.

Climate change and environmental health are closely linked with agriculture and food supply. The environment influences accessibility, quality, and variety of foods and drinks that are available for consumption, which in turn influences population health. A growing area of research is the role of dietary intake of nutrients and how they may influence risk for skin cancer. In recent years, our group has studied dietary nutrients, particularly those found in commonly consumed beverages, such as those containing caffeine, citrus products, and alcohol, in large prospective cohorts to evaluate how their intake may influence risk for skin cancer. Our data suggest that intake of citrus juices, when consumed around once per day or more, or around 5 to 6 times per week, may be associated with increased risk for both keratinocyte carcinomas (KC) and malignant melanoma (MM). With regards to alcohol consumption, we have found that intake of white wine may be associated with increased risk for both KC and MM, while beer and red wine have not shown such associations. Lastly, our work suggests caffeinated beverages, including coffee, tea, and cola, may be associated with decreased risk for basal cell carcinoma (BCC) and MM. While the associations between food intake and skin cancer development are complex, and remain to be further analyzed in future studies, we hope that our summary may help guide individuals to small changes they may make towards potentially reducing their risk for certain skin cancers.

Understanding melanoma in situ: Lentigo maligna surgical treatment terminology and guideline adherence, a targeted review.

BACKGROUND: Malignant melanoma in-situ, lentigo maligna (MMIS-LM) can be successfully treated with several different surgical techniques; however, the literature is inconsistent in defining them. OBJECTIVE: To comprehensively define and describe the national guideline recommended surgical techniques used to treat MMIS-LM to help clarify and standardize this terminology to ensure compliance with the guidelines. METHODS: A targeted literature review was performed from 1990 to 2022 focusing on articles that discussed the national guideline recommended surgical techniques of wide local excision, Mohs micrographic surgery (MMS), modified Mohs surgery, and staged excision/Slow-Mohs for MMIS-LM, as well as the related methods of tissue processing. National Comprehensive Cancer Network and American Academy of Dermatology guidelines were reviewed to identify how the techniques need to be employed to be compliant with guideline recommendations. RESULTS: We describe the various surgical and tissue processing techniques and discuss advantages and disadvantages of each. LIMITATIONS: This paper was styled as a narrative review defining and clarifying terminology and technique and does not investigate these topics more broadly. CONCLUSION: Understanding the methodology and terminology for these surgical procedures and tissue processing methods is critical so that both general dermatologists and surgeons can employ these techniques effectively for optimal patient care.

How to make effective HPV vaccine recommendations starting at age 9.

This article provides best and promising practices for recommending HPV vaccination at age 9 as a way to ensure high uptake. An effective method for recommending HPV vaccination is the Announcement Approach, which consists of 3 evidence-based steps. The first step, Announce, involves noting that the child is 9 years old, saying they are due for a vaccine that prevents 6 HPV cancers, and saying you'll vaccinate today. This adapted version of the Announce step simplifies the bundled approach used at ages 11-12 that emphasizes the prevention of meningitis and whooping cough in addition to HPV cancers. For hesitant parents, the second step, Connect and Counsel, involves finding common ground with the parent and communicating the value of starting HPV vaccination at the first opportunity. Finally, for parents who decline, the third step is to Try Again at a later visit. Using the Announcement Approach at age 9 stands to increase HPV vaccine uptake, save time, and lead to high family and provider satisfaction.

When Surgery Won't Cut It: Successful Management of Eruptive Squamous Atypia With Combination Medical Therapy.

The termeruptive squamous atypia(ESA) is used to describe squamous proliferations that do not present with high-grade histologic features and for which surgical management may exacerbate the condition. Non-surgical management of ESA with radiation, local or systemic chemotherapy, retinoids, or immunotherapy have been reported with variable success. In contrast, combination treatment with retinoids, immunomodulatory or chemotherapeutic agents may result in a more durable response. We report a case of recalcitrant ESA of the lower extremities where complete clinical remission was induced with triple combination medical management with intralesional 5-fluorouracil, field treatment with topical 5-fluorouracil and imiquimod, and oral acitretin. Our case adds to the literature supporting combination medical therapy for challenging cases of ESA.

Getting Human Papillomavirus Vaccination Back on Track: A National Survey.

PURPOSE: Adolescent human papillomavirus (HPV) vaccine uptake in the United States dropped during the COVID-19 pandemic due to a decrease in well visits. This study sought to identify opportunities for primary care professionals (PCPs) to get adolescent vaccination back on track. METHODS: In early 2021, we recruited 1,047 PCPs (71% physicians) who provided adolescent vaccines in the United States from an existing panel. Participants completed an online survey about changes in adolescent HPV vaccine uptake and actions taken to promote vaccination during the pandemic, as well as intentions to engage in activities to increase adolescent vaccination in the next 3 months. RESULTS: A substantial proportion of PCPs (43%) reported that HPV vaccine uptake decreased in the first year of the pandemic; few (7%) PCPs reported an increase in uptake. PCPs reporting increased uptake were more likely to have used nurse-only vaccination visits, held drop-in and drive-through vaccination clinics, and used telehealth visits to recommend vaccination (all p < .05). Nearly two-thirds (62%) of all PCPs planned to promote adolescent vaccine uptake in the next 3 months. Planning was more common among PCPs who believed HPV vaccine uptake at their clinics increased during the pandemic, who saw more than 10 adolescent patients per week, who had ever reviewed their clinic's vaccination rates, and were nurses (all p < .05). DISCUSSION: Many PCPs saw HPV vaccination drop during the pandemic. Several interventions could help clinics get HPV vaccination back on track, including increasing the availability of nurse-only vaccination visits and vaccination-only clinics.

Framing of national HPV vaccine recommendations and willingness to recommend at ages 9-10.

Proactive HPV vaccination at age 9 better prevents infection and improves vaccine series completion. Because national organizations recommend starting the vaccine at different ages, we sought to understand the impact of these recommendation frames. In 2022, we surveyed 2,527 US clinical staff (45% physicians) who provide HPV vaccine for children. We randomized respondents to one of three frames based on HPV vaccine recommendations of national organizations or a no-recommendation control, and assessed willingness to recommend HPV vaccine for children ages 9-10. Respondents also reported perceived benefits of HPV vaccination at ages 9 or 12. Recommending HPV vaccination "at ages 11-12" led to lower willingness to vaccinate at ages 9-10 than control (37% vs. 54%, p < .05). Recommending vaccination "at ages 9-12" led to similar willingness as control. However, "starting at age 9" led to higher willingness than control (63% vs. 54%, p < .05). Results were similar across respondents' training, specialty, or years in practice, or their clinic's rurality or healthcare system membership. More common benefits of recommending at age 9 than 12 were avoiding the topic of sex (24% vs. 10%, OR = 2.78, 95%CI: 2.23, 3.48) and completing the vaccine series before age 13 (56% vs. 47%, OR = 1.44, 95%CI: 1.23, 1.68). Less common benefits for age 9 were having parents ready to talk about HPV vaccine and agreeing to vaccination (both p < .05). An effective way to encourage proactive HPV vaccination is to say that it starts at age 9. Aligning national recommendations to start at age 9 can promote timely vaccination.

Efficacy of a Small-Molecule Inhibitor of KrasG12D in Immunocompetent Models of Pancreatic Cancer.

Mutations in the KRAS oncogene are found in more than 90% of patients with pancreatic ductal adenocarcinoma (PDAC), with Gly-to-Asp mutations (KRASG12D) being the most common. Here, we tested the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in implantable and autochthonous PDAC models with an intact immune system. In vitro studies validated the specificity and potency of MRTX1133. In vivo, MRTX1133 prompted deep tumor regressions in all models tested, including complete or near-complete remissions after 14 days. Concomitant with tumor cell apoptosis and proliferative arrest, drug treatment led to marked shifts in the tumor microenvironment (TME), including changes in fibroblasts, matrix, and macrophages. T cells were necessary for MRTX1133's full antitumor effect, and T-cell depletion accelerated tumor regrowth after therapy. These results validate the specificity, potency, and efficacy of MRTX1133 in immunocompetent KRASG12D-mutant PDAC models, providing a rationale for clinical testing and a platform for further investigation of combination therapies. SIGNIFICANCE: Pharmacologic inhibition of KRASG12D in pancreatic cancer models with an intact immune system stimulates specific, potent, and durable tumor regressions. In the absence of overt toxicity, these results suggest that this and similar inhibitors should be tested as potential, high-impact novel therapies for patients with PDAC. See related commentary by Redding and Grabocka, p. 260. This article is highlighted in the In This Issue feature, p. 247.

Stratifying clinical complexity of dermatology outpatient visits: Validation of a pilot instrument.

The United States population is aging and increasing in comorbidities, and patient care is accordingly growing increasingly complex. Complexity impacts patterns of resource consumption, adverse event and medical error rates, health-related quality of life, physician burnout, and more. Tools capturing complexity can be of benefit in the modern value-based reimbursement landscape and have been well studied in specialties other than dermatology. In this report, we describe the validation of a tool specific to outpatient dermatologic care that captures the complexity of clinical visit medical decision making. We performed a cross-sectional retrospective study to determine the inter-rater reliability and face validity of the tool. By objectively grading a clinical encounter based on clinical complexity, there is increased awareness of opportunities to improve clinical care, and the allocation of health care costs and resources within the dermatologic community can be better assessed.

A Narrative Review of Nicotinamide Adenine Dinucleotide (NAD)+ Intermediates Nicotinamide Riboside and Nicotinamide Mononucleotide for Keratinocyte Carcinoma Risk Reduction.

Oral nicotinamide (NAM) supplementation has been shown to decrease the incidence of keratinocyte carcinoma (KC) in high-risk skin cancer patients. NAM is a nicotinamide adenine dinucleotide (NAD+) intermediate and thus directly leads to increased NAD+. This increase in NAD+ is believed to be responsible for NAM’s impact on keratinocyte carcinoma risk. NAD+ has protective cellular effects and is a necessary cofactor for DNA repair, helping to prevent potentially oncogenic mutations. Nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN) are NAD+ intermediates like NAM; however, their protective roles on cellular DNA and effects on cancer have been under-explored. Research into cellular metabolism and aging suggests that NR and NMN can lead to greater increases in NAD+ vs NAM. NR and NMN are safe and well-tolerated and are consequently currently undergoing investigation as agents able to protect against age-associated disease caused by NAD+ depletion. We hypothesize that oral supplementation with NR or NMN may lead to greater reductions in KC than NAM. J Drugs Dermatol. 2022;21(10): 1129-1132. doi:10.36849/JDD.6870.

Pembrolizumab-induced Toxic Epidermal Necrolysis in a Patient with Metastatic Esophageal Adenocarcinoma.

Adverse cutaneous reactions associated with the immune checkpoint inhibitor (ICI) pembrolizumab are well documented, yet life-threatening reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) are infrequent.1,2 We present a case of pembrolizumab-induced TEN in a patient with metastatic esophageal adenocarcinoma who was successfully treated with cyclosporine and systemic corticosteroids.

Educational video promotes durable knowledge about actinic keratoses in patients with field cancerization: a pseudorandomized, single-blind, controlled pilot study.

BACKGROUND: Diffuse actinic keratoses (AKs) have multiple treatment options. Patient understanding of treatment options may enhance patient autonomy, satisfaction, treatment adherence, and clinical outcomes. Delivering effective and consistent verbal counseling on AK treatment can be challenging. OBJECTIVE: We investigated the effect on patient knowledge of implementing, prior to standard counseling, a novel video decision aid explaining diffuse AK treatment options. METHODS & MATERIALS: Participants were recruited from an academic Mohs surgery clinic and randomized to receive the video decision aid plus standard verbal counseling (video) or standard verbal counseling alone (control). Both groups completed baseline, immediate post-intervention, and 1-2 week delayed durable knowledge assessments. Secondary endpoints included participant satisfaction and verbal counseling duration. RESULTS: Thirty-one eligible patients (16 control, 15 video) participated. No baseline differences existed between the groups. The video group had significantly higher mean durable knowledge scores than the controls (video 10.00 ± 1.48, control 8.36 ± 1.69, p = .018). Patients were highly satisfied with the video. Verbal counseling duration did not significantly differ between groups. CONCLUSION: A video decision aid for treatment of diffuse AKs improved durable patient knowledge.